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Clinical NLP Lab 21

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: primary pancreatic lymphoma ( ppl ) is extremely rare , comprising 2.2 % of non - hodgkin 's lymphomas ( nhls ) and 4.9 % of all pancreatic malignancies . clinical manifestations and imaging findings of ppl are similar to adenocarcinoma , but ppl must be distinguished from it because unlike pancreatic adenocarcinoma , ppl is potentially treatable . hepatitis c virus ( hcv ) infection has been associated with the development of b cell nhl ( including diffuse large b cell lymphoma , marginal zone lymphoma and extranodal marginal zone b cell lymphoma of mucosa - associated lymphoid tissue ) . an association of hepatitis c and hepatic and splenic marginal zone lymphoma has been reported , however its association with pancreatic lymphomas is unknown . the patient was a 49 - year - old man admitted to the hospital with the complaint of epigastric abdominal pain , icterus , significant weight loss , fever and sweating since 1.5 months prior to admission . blood pressure was 120/80 mm hg , pulse rate was 88 bpm and temperature was 37.9 c . hemoglobin level was 14 g / dl with a leukocyte count of 5,400 / mm ( neutrophils 57 % , lymphocytes 35 % ) and a platelet count of 245,000 / mm . aspartate aminotransferase was 85 u / l , alanine aminotransferase 105 u / l , total bilirubin 12 mg / dl , direct bilirubin 8 mg / dl , alkaline phosphatase 735 u / l , serum lactate dehydrogenase ( ldh ) 725 iu / l and serum carbohydrate antigen 19 - 9 ( ca19 - 9 ) 25 u / ml . hcv genotype was 1a and viral load was 20,199,805 iu / ml . abdominal ultrasound showed a hypoechoic mass adjacent to the head of the pancreas and the common bile duct was dilated with a diameter of 12 mm . computed tomography ( ct ) of the abdomen showed a hypodense mass located in the head of the pancreas ( fig . endoscopic ultrasound ( eus ) showed a 33 cm mass in the head of the pancreas with portal invasion , and fine needle aspiration ( fna ) was performed ( fig . endoscopic retrograde cholangiopancreatography was performed and showed dilated common and hepatic bile ducts , thus a metallic biliary stent was placed . microscopic pathologic examination was done on cell block specimen and reported a malignant undifferentiated tumor ( fig .3 a ) ; immunohistochemistry of the specimen revealed positive leukocyte common antigen in tumor cells ( fig .3 b ) , diffuse and strong membrane staining for the b cell marker protein cd20 ( fig .3 c ) , scattered cd3 in nontumoral lymphocytes and negative cytokeratin in tumoral cells ( fig . ppl is extremely rare , comprising 2.2 % of nhls and 4.9 % of all pancreatic malignancies . ppl can be confounded with pancreatic adenocarcinoma . in a study by mishra et al . based on the surveillance , epidemiology , and end results database , 523 cases of ppl were identified . presenting symptoms are nonspecific , including abdominal pain , weight loss , jaundice , nausea and vomiting . this 49 - year - old man presented with abdominal pain , weight loss , jaundice , fever and sweating . systemic b symptoms are uncommon in pancreatic lymphoma , but this patient had b symptoms . the combination of a bulky localized tumor in the pancreatic head without significant dilatation of the main pancreatic duct strengthens a diagnosis of pancreatic lymphoma over adenocarcinoma . the presence of calcification or necrosis is a reliable finding for ruling out nhl . eus - guided fine needle biopsy of tumors can also be performed and provide a histological diagnosis of ppl in some cases . eus - guided fna ( eus - fna ) of pancreatic masses is as accurate as ct / ultrasound - guided sampling and surgical biopsies , and immunocytochemistry examination of the specimen can improve the accuracy of eus - fna cytology . in this case , microscopic examination of eus - fna of the pancreas mass did not provide a definite diagnosis , but immunohistochemistry was compatible with b cell nhl . ca19 - 9 is usually normal and sometimes slightly elevated . ldh is a useful marker for the diagnosis of ppl and also an important prognostic factor . ppl should be suspected in a patient with pancreatic mass and elevated ldh and b2 microglobulin serum markers . in this case serumthis case met the criteria for the definition of ppl as used by dawson et al . . these criteria include : ( 1 ) neither superficial lymphadenopathy nor enlargement of mediastinal lymph nodes on chest radiography ; ( 2 ) a normal leukocyte count in peripheral blood ; ( 3 ) main mass in the pancreas with lymph node involvement confined to the peripancreatic region ; ( 4 ) no hepatic or splenic involvement . stomach mucosa - associated lymphoid tissue lymphoma is known to be caused by helicobacter pylori ; no such association with ppl is known to date . familial pancreatic lymphoma has also been reported to be associated with pancreatic lymphoma . a causative role of hcv in b cell lymphoproliferative disorders has been suggested by several reports . in a study by mizorogi et al . , among 123 patients with b cell lymphoproliferative disorders , 38 patients with non - b cell lymphoproliferative disorders and 516 patients with miscellaneous diseases , the prevalence of hcv infection was higher in patients with b cell nhl than in those with non - b cell nhl and the control group . despite these strong associations , an association of hcv infection with pancreatic lymphoma has only been shown by few reports . takagi et al . in japan reported a case of pancreas lymphoma with chronic hepatitis c. visco et al. in italy analyzed 156 previously untreated consecutive hcv - positive patients with diffuse large b cell lymphoma observed from 1994 to 2004 . the spleen was the most frequently involved extranodal site , followed by liver and stomach . lymphoproliferation induced by hcv may occur due to binding of the virion to receptors on the surface of b lymphocytes , which might lower their threshold for antigen response or induce dna mutations . in patients with hcv infection and splenic marginal zone nhl , moreover , hcv infection can directly drive lymphoproliferation . in a large study by giordano et al . among military veterans infected with hcvhcv infection was associated with an increased risk of cryoglobulinemia , supporting the hypothesis that chronic hcv infection serves as an immunological stimulus for progression to hematological malignancy . our patient had a high hcv viral load and he did not have other risk factors for lymphoma , therefore hcv infection may have played a role in the pathogenesis of lymphoma . because of the patient 's high viral load and probability of hepatitis exacerbation after chemotherapy initiation , we started peg - interferon plus ribavirin and he was initially referred to radiotherapy and then chemotherapy was started .\noutput:\n" }, { "from": "agent", "value": "we report a rare case of pancreas tumor ( lymphoma ) in a patient with a history of chronic hepatitis c virus ( hcv ) infection without treatment , with a high viral load ( 20,199,805 iu / ml ) . he presented with abdominal pain , jaundice , weight loss and sweating . computed tomography showed a hypodense mass located in the head of the pancreas , and immunohistochemistry of a specimen obtained by endoscopic ultrasound - guided fine needle aspiration revealed non - hodgkin 's lymphoma of the pancreas , b cell type . an association of hcv infection with pancreatic lymphoma has only been reported rarely in the literature and its clinical significance is uncertain ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: autosomal dominant facioscapulohumeral muscular dystrophy ( fshd , omim 158900 ) is referred as one of the most prevalent hereditary neuromuscular disorders . the disease is foremost characterized by progressive and asymmetric weakness of muscles in the facial and shoulder - girdle , later involving pelvic and proximal lower limb . the clinical spectrum is widely variable , ranging from asymptomatic gene carriers to patients with wheelchair dependency . no biochemical , histological , or instrumental markers are available to independently confirm a specific fshd diagnosis except genetic testing . in most patients ( 95 % ) , the molecular defect is linked to a reduced ecori fragment ( 38 kb ) with contraction of the 3.3 kb d4z4 repeat on the subtelomere of chromosome 4q35 , which has been considered as a key diagnostic signature with the p13e - 11 probe . the copies of 4q35 - located d4z4 repeat in the normal individuals range from 11 to 150 , whereas fshd patients carry 10 repeats . our previous study emphasized that d4z4 repeat length analysis alone was not sufficient for the genetic diagnostics , especially when used as an exclusion criterion . the chromosome 10q26 region displays a highly homologous ecori fragment including d4z4 repeats , and ought to be distinguished by double enzymes ecori , ecori / blni ( avrii ) digestion . a pair of additional 4q subtelomeric variations ( 4qa / 4qb ) locates immediately distal to d4z4 repeat , and fshd is uniquely associated with the 4qa variant . consequently , integral molecular diagnosis is based on the analysis of reduced d4z4 repeats on the permissive 4qa chromosome by southern blotting of genomic dna after digestion with a specific set of restriction enzymes . although the identity of the specific gene ( s ) responsible for fshd is still elusive , the deletion of d4z4 repeats leading to the chromatin relaxation and the epigenetic overexpression of dux4 retrogene ( mim * 606009 ) ( encoding the double - homeobox 4 ) from the distal telomeric d4z4 repeat is proposed as the pathogenic mechanism . it is prevalently accepted that there is a reverse correlation between d4z4 repeats number and clinical severity . however , the wide inter - and intra - familial variability of clinical expression appears to be more pronounced than expected . andseveral observations including novel large - scale genotype - phenotype analyses and increasing atypical patients have emerged to complicate this relationship . because the genetic diagnosis for fshd is laborious and time - consuming , there were only a few reports about the genetically confirmed patients in china . in the present study , we performed the completely genetic testing for a large cohort of fshd patients according to the guideline of the international consortium . the potential relationship of genotype - phenotype has been examined to assess the impact of the molecular defect on phenotypic manifestations . in all , our investigation offered the available data for the molecular analysis and clinical spectrum of chinese fshd patients . this study concerned 178 affected individuals ( 86 females , 92 males ; mean age at investigation , 30.311.7 years ; range , 561 years ) and 137 unaffected members belonging to 136 unrelated families , in which at least one subject with a contracted 4qa allele . of these families , 70 had multiple affected individuals , and 66 had only one affected individual . each patient was given a thorough clinical examination at least twice during the last decade , and the medical history included family history , gender , symptoms of disease onset , age onset , disease duration was well obtained . informed consent was obtained from each patient or legal guardian of those under 18 years of age , and the protocol was approved by the local ethics committee for medical research . in the present study , muscle strength was objectively evaluated by manual muscle testing ( mmt ) according to the standard procedure . a modified medical research council scale score and a 10 - grade fshd clinical severity scalewere adopted to evaluate the phenotypic spectrum , ranking from mildly affected ( facial involvement only ) at 0.5 to severe weakness ( wheelchair - dependent ) at 5 . these data documented decline in strength relied mainly on neurological examination , which is more objective than the criteria like onset age and extend to include the available affected members of each family . given variation of onset age , we adopted the age - corrected clinical severity score ( css ) to assess the relationship of ecori fragment and clinical phenotype . five affected relatives younger than , 173 patients were classified into six distinct severity groups ( i vi ) according to the css ( i : 01 ; ii : 1.5 ; iii : 22.5 ; iv : 3 ; v : 3.5 ; vi : 45 ) . high molecular weight dna was extracted from peripheral lymphocytes derived from freshly collected blood using the standard protocols . five micrograms of dna were digested with ecori , ecori / blni , or hindiii ( takara , japan ) , and separated by pulsed - field gel electrophoresis on a 1.2 % agarose gel ( sangon , china ) in 0.5 tbe for 39 h. nytran + membranes ( ge healthcare , usa ) for allele sizing were hybridized with probe p13e - 11 , and those for allele typing were hybridized with probe 4qa and 4qb as previously described . data were analyzed by a statistical package ( the spss program pasw statistics 17.0 , spss inc , chicago , usa ) . linear regression analyses were employed to examine the relationship between the age - corrected css and fragment size . the chi - square test was adopted to compare the proportions of patients among different groups . two sample t - test and one - way analysis of variance were used to compare the continuous variables among groups for normally distributed values ( age , ecori fragment size ) . this study concerned 178 affected individuals ( 86 females , 92 males ; mean age at investigation , 30.311.7 years ; range , 561 years ) and 137 unaffected members belonging to 136 unrelated families , in which at least one subject with a contracted 4qa allele . of these families , 70 had multiple affected individuals , and 66 had only one affected individual . each patient was given a thorough clinical examination at least twice during the last decade , and the medical history included family history , gender , symptoms of disease onset , age onset , disease duration was well obtained . informed consent was obtained from each patient or legal guardian of those under 18 years of age , and the protocol was approved by the local ethics committee for medical research . in the present study , muscle strength was objectively evaluated by manual muscle testing ( mmt ) according to the standard procedure . a modified medical research council scale score and a 10 - grade fshd clinical severity scalewere adopted to evaluate the phenotypic spectrum , ranking from mildly affected ( facial involvement only ) at 0.5 to severe weakness ( wheelchair - dependent ) at 5 . these data documented decline in strength relied mainly on neurological examination , which is more objective than the criteria like onset age and extend to include the available affected members of each family . given variation of onset age , we adopted the age - corrected clinical severity score ( css ) to assess the relationship of ecori fragment and clinical phenotype . five affected relatives younger than 10 years were a lack of mmt to evaluate the css . for statistical analysis , 173 patients were classified into six distinct severity groups ( i vi ) according to the css ( i : 01 ; ii : 1.5 ; iii : 22.5 ; iv : 3 ; v : 3.5 ; vi : 45 ) . high molecular weight dna was extracted from peripheral lymphocytes derived from freshly collected blood using the standard protocols . five micrograms of dna were digested with ecori , ecori / blni , or hindiii ( takara , japan ) , and separated by pulsed - field gel electrophoresis on a 1.2 % agarose gel ( sangon , china ) in 0.5 tbe for 39 h. nytran + membranes ( ge healthcare , usa ) for allele sizing were hybridized with probe p13e - 11 , and those for allele typing were hybridized with probe 4qa and 4qb as previously described . data were analyzed by a statistical package ( the spss program pasw statistics 17.0 , spss inc , chicago , usa ) . linear regression analyses were employed to examine the relationship between the age - corrected css and fragment size . the chi - square test was adopted to compare the proportions of patients among different groups . two sample t - test and one - way analysis of variance were used to compare the continuous variables among groups for normally distributed values ( age , ecori fragment size ) . molecular analysis revealed that 178 individuals from total 136 families carried 4q35 reduced ecori fragments in the range from 10 kb to 35 kb ( 19 d4z4 repeats ) with p13e - 11 probe . importantly , all the polymorphic d4z4 repeat contractions possessed the 4qa allele with two allelic variant genotypes on chromosome 4q35 , including 4qa / 4qa homozygote and 4qa / 4qb heterozygote . among them , 151 patients carried standard configuration distribution without translocation or mosaicism and the remaining 27 patients displayed a nonstandard configuration of the chromosome 4q35 . the mean onset age in this cohort was 18.49.0 years , with a wide range from childhood to adulthood . as to analysis of clinical manifestation [ table 1 ] , 59.1 % ( 91/154 ) of the patients displayed asymmetrical weakness at the first time of neurological examination . the disturbances related symptoms to facial and scapulo - humeral weakness are quite typical onset pattern to the fshd diagnostic criteria , which were reported to be the presenting symptoms by 137 of the 154 patients ( 89.0 % ) . when facial weakness was considered separately from scapulo - humeral invasion , the onset of facial weakness was predominant in 12 patients at the mean age of 12.55.4 years . by contrast , 125 patients began with scapulo - humeral weakness were at the mean age of 18.95.4 years . there was significant difference for age of onset between facial weakness and scapula - humeral weakness ( t = 3.258 , p 0.05 ) . onset with atypical proximal weakness in lower limbs was collected in 11 patients , including 7 unilateral , and 4 bilateral cases . meanwhile , associated signs of facial or scapulo - humeral region were also demonstrated at the first neurological examination in these patients with atypical onset . the significant higher proportion of female than male was observed in atypical onset pattern ( = 5.41 , p 0.05 ) . facioscapulohumeral muscular dystrophy clinical data of typical and nontypical onset ( 91/154 asymmetrical weakness ) * * five affected children younger than 10 years were considered as preclinical cases and excluded ; ecori fragment size and the onset of age was given as means sd . about 51.4 % ( 70/136 ) of the probands were familial cases and their 42 relatives were detected to carry the consistently same ecori fragments . in the total affected relatives ,19 were asymptomatic ( or minimally affected ) carriers with ecori fragments ranging from 13 kb to 30 kb ( mean size 19.64.3 kb ) . all asymptomatic carriers were more than 20 years old ( mean age 36.410.5 years ) , which were not considered in the preclinical condition . among the 66 isolated cases , 35 ( 23 males and 12 females ) were de novo since both parents were available to confirm their normal ecori fragments . the remaining 31 patients were uncertain because it was unable to get molecular analysis from either of their parents . size distribution of the short ecori fragments from136 probands showed statistically significant difference between the sporadic and familial cases ( = 5.69 , p 0.05 , figure 1 ) .67.1 % ( 47/70 ) of the familial cases carried 4q35 ecori fragment ranging from16 kb to 24 kb , whereas a lower proportion ( 42.9 % , 15/35 ) of sporadic patients was detected with the same range . size distribution of the p13e - 11 ecori short fragments in 136 unrelated facioscapulohumeral muscular dystrophy probands . correlation in total symptomatic patients it showed the significantly reverse correlation between the ecori fragment size and age - corrected css ( f = 12.803 , p 0.01 , figure 2a ) . when male and female were observed respectively , only significant correlation for males ( f = 9.257 , p 0.01 ) . there was no correlation between the age of onset and the ecori fragment size in both genders ( p 0.05 ) . correlation between the size of short ecori fragment and age - corrected clinical severity score . ( a ) the diagram refers to the correlation in 154 symptomatic patients ( r = 0.279 , p 0.005 ) ; ( b ) the diagram refers to the correlation only in 35 sporadic patients ( r = 0.512 , p 0.005 ) . sporadic and familial cases there was significant correlation between the ecori fragment size and age - corrected css in 35 sporadic cases ( f = 11.711 , p 0.01 , figure 2b ) . compared to the correlation in total , the coefficient r raised to 0.512 . however , the correlation in the familial cases and clinically affected relatives showed closely matched the coefficient of total ( f = 5.297 , r = 0.241 , p 0.05 ) . in groupi , the proportion of females was significantly higher than that of males among asymptomatic carriers ( 16 females , 3 males ; = 10.86 , p 0.01 ) [ table 2 ] . if the symptomatic carriers were considered as nonpenetrants , the penetrance for fshd - associated allele was estimated to 89.0 % ( 154/173 ) . there was significantly lower penetrance in females ( 68/84 , 81.0 % ) than that in males ( 86/89 , 96.6 % ) . the classification of clinical severity score , mean age and ecori fragment in 173 facioscapulohumeral muscular dystrophy patients * groups according to clinical severity score . i : asymptomatic individuals ; ii : 1.5 ; iii : 22.5 ; iv : 3 ; v : 3.5 ; vi : 45 ; age : the age on examination . herein , we classified severely affected patients into group vi ( cs45 ) , in which the proportion of females showed higher than males ( = 4.93 , p 0.05 ) . all male patients in this group presented severe phenotype with very small ecori fragment ranging from 10 kb to 15 kb . however , a large heterozygosity of ecori fragment ranging from 14 kb to 27 kb was observed in severe female patients . only one early wheelchair - dependent male was evaluated as cs5 in our study , who presented marked lumbar lordosis and joint contracture with the smallest fragment size of 10 kb ( only one d4z4 repeat left , figure 3 ) . on the other hand , the proportion of males was significantly different from females in sum group ii to group v ( = 17.37 , p 0.01 ) . however , there was no significant difference between males and females in each group separately ( ii v , p 0.05 ) . ( a ) dna was digested with ecori ( e ) and ecori / blni ( b ) , separated by pulsed - field gel electrophoresis and hybridized with probe p13e - 11 . two 4q - type alleles of 10 kb ( arrow ) and 50 kb ; two 10q - type alleles of 42 kb and 156 kb ; ( b ) the same dna was digested with hind iii ( h ) and hybridized with probes 4qa and 4qb .4 q - type allele of 10 kb ( arrow ) was identified as 4qa variant and 50 kb - allele was 4qb variant . if the difference of age at examination was not considered , no significant correlation of css with short fragment size was observed in all symptomatic patients . in order to distinctly investigate the correlation between d4z4 repeats and clinical severity , our patients were classified into three groups ( a , b , c ) according to different d4z4 repeats [ figure 4 ] . although the median css of these three groups showed no different ( h = 3.020 , p 0.05 ) , the relative proportion of patients with clinical severity classification was quite different . as mentioned above , only one patient with the smallest ecori fragment of cs 5 belonged to group a. the patients of group a showed larger variation of cs ranging from 0.5 to 5 . compared to cs3 .55 in group a ( 32.7 % + 2.0 % ) , the proportion of patients with cs3 .5 - 4.5 was remarkably decreased in group b ( 22.5 % ) and group c ( 13.6 % ) . however , there was no significant correlation between group a and group ( b + c ) with cs 3.54.5 ( = 3.54 , p 0.05 ) . conversely , 45.5 % of the patients in group c presented mild involvement of facial and scapulohumeral regions compared with 29.0 % of the patients in groups ( a + b ) , although it was showed no significant difference between group c and groups ( a + b ) with cs0 .51.5 ( = 2.17 , p 0.05 ) . among 16 patients with severe phenotype ( cs4 - 5 ) ( 16/173 , 9.24 % ) , 9 patients ( 9/49 , 18.4 % ) in group a compared with 6 ( 6/102 , 5.89 % ) in group b and 1 ( 1/22 , 4.54 % ) in group c. these data indicated that significant difference between group a and groups ( b + c ) for developing severe phenotype ( = 5.34 , p 0.05 ) . molecular analysis revealed that 178 individuals from total 136 families carried 4q35 reduced ecori fragments in the range from 10 kb to 35 kb ( 19 d4z4 repeats ) with p13e - 11 probe . importantly , all the polymorphic d4z4 repeat contractions possessed the 4qa allele with two allelic variant genotypes on chromosome 4q35 , including 4qa / 4qa homozygote and 4qa / 4qb heterozygote . among them , 151 patients carried standard configuration distribution without translocation or mosaicism and the remaining 27 patients displayed a nonstandard configuration of the chromosome 4q35 . the mean onset age in this cohort was 18.49.0 years , with a wide range from childhood to adulthood . as to analysis of clinical manifestation [ table 1 ] , 59.1 % ( 91/154 ) of the patients displayed asymmetrical weakness at the first time of neurological examination . the disturbances related symptoms to facial and scapulo - humeral weakness are quite typical onset pattern to the fshd diagnostic criteria , which were reported to be the presenting symptoms by 137 of the 154 patients ( 89.0 % ) . when facial weakness was considered separately from scapulo - humeral invasion , the onset of facial weakness was predominant in 12 patients at the mean age of 12.55.4 years . by contrast , 125 patients began with scapulo - humeral weakness were at the mean age of 18.95.4 years . there was significant difference for age of onset between facial weakness and scapula - humeral weakness ( t = 3.258 , p 0.05 ) . onset with atypical proximal weakness in lower limbs was collected in 11 patients , including 7 unilateral , and 4 bilateral cases . meanwhile , associated signs of facial or scapulo - humeral region were also demonstrated at the first neurological examination in these patients with atypical onset . the significant higher proportion of female than male was observed in atypical onset pattern ( = 5.41 , p 0.05 ) . facioscapulohumeral muscular dystrophy clinical data of typical and nontypical onset ( 91/154 asymmetrical weakness ) * * five affected children younger than 10 years were considered as preclinical cases and excluded ; ecori fragment size and the onset of age was given as means sd . about 51.4 % ( 70/136 ) of the probands were familial cases and their 42 relatives were detected to carry the consistently same ecori fragments . in the total affected relatives ,19 were asymptomatic ( or minimally affected ) carriers with ecori fragments ranging from 13 kb to 30 kb ( mean size 19.64.3 kb ) . all asymptomatic carriers were more than 20 years old ( mean age 36.410.5 years ) , which were not considered in the preclinical condition . among the 66 isolated cases , 35 ( 23 males and 12 females ) were de novo since both parents were available to confirm their normal ecori fragments . the remaining 31 patients were uncertain because it was unable to get molecular analysis from either of their parents . size distribution of the short ecori fragments from136 probands showed statistically significant difference between the sporadic and familial cases ( = 5.69 , p 0.05 , figure 1 ) .67.1 % ( 47/70 ) of the familial cases carried 4q35 ecori fragment ranging from16 kb to 24 kb , whereas a lower proportion ( 42.9 % , 15/35 ) of sporadic patients was detected with the same range . size distribution of the p13e - 11 ecori short fragments in 136 unrelated facioscapulohumeral muscular dystrophy probands . correlation in total symptomatic patients it showed the significantly reverse correlation between the ecori fragment size and age - corrected css ( f = 12.803 , p 0.01 , figure 2a ) . when male and female were observed respectively , only significant correlation for males ( f = 9.257 , p 0.01 ) . there was no correlation between the age of onset and the ecori fragment size in both genders ( p 0.05 ) . correlation between the size of short ecori fragment and age - corrected clinical severity score . ( a ) the diagram refers to the correlation in 154 symptomatic patients ( r = 0.279 , p 0.005 ) ; ( b ) the diagram refers to the correlation only in 35 sporadic patients ( r = 0.512 , p 0.005 ) . sporadic and familial cases there was significant correlation between the ecori fragment size and age - corrected css in 35 sporadic cases ( f = 11.711 , p 0.01 , figure 2b ) . compared to the correlation in total , the coefficient r raised to 0.512 . however , the correlation in the familial cases and clinically affected relatives showed closely matched the coefficient of total ( f = 5.297 , r = 0.241 , p 0.05 ) . in group i , the proportion of females was significantly higher than that of males among asymptomatic carriers ( 16 females , 3 males ; = 10.86 , p 0.01 ) [ table 2 ] . if the symptomatic carriers were considered as nonpenetrants , the penetrance for fshd - associated allele was estimated to 89.0 % ( 154/173 ) . there was significantly lower penetrance in females ( 68/84 , 81.0 % ) than that in males ( 86/89 , 96.6 % ) . the classification of clinical severity score , mean age and ecori fragment in 173 facioscapulohumeral muscular dystrophy patients * groups according to clinical severity score . i : asymptomatic individuals ; ii : 1.5 ; iii : 22.5 ; iv : 3 ; v : 3.5 ; vi : 45 ; age : the age on examination . herein , we classified severely affected patients into group vi ( cs45 ) , in which the proportion of females showed higher than males ( = 4.93 , p 0.05 ) . all male patients in this group presented severe phenotype with very small ecori fragment ranging from 10 kb to 15 kb . however , a large heterozygosity of ecori fragment ranging from 14 kb to 27 kb was observed in severe female patients . only one early wheelchair - dependent male was evaluated as cs5 in our study , who presented marked lumbar lordosis and joint contracture with the smallest fragment size of 10 kb ( only one d4z4 repeat left , figure 3 ) . on the other hand , the proportion of males was significantly different from females in sum group ii to group v ( = 17.37 , p 0.01 ) . however , there was no significant difference between males and females in each group separately ( ii v , p 0.05 ) . ( a ) dna was digested with ecori ( e ) and ecori / blni ( b ) , separated by pulsed - field gel electrophoresis and hybridized with probe p13e - 11 . two 4q - type alleles of 10 kb ( arrow ) and 50 kb ; two 10q - type alleles of 42 kb and 156 kb ; ( b ) the same dna was digested with hind iii ( h ) and hybridized with probes 4qa and 4qb .4 q - type allele of 10 kb ( arrow ) was identified as 4qa variant and 50 kb - allele was 4qb variant . if the difference of age at examination was not considered , no significant correlation of css with short fragment size was observed in all symptomatic patients . in order to distinctly investigate the correlation between d4z4 repeats and clinical severity , our patients were classified into three groups ( a , b , c ) according to different d4z4 repeats [ figure 4 ] . although the median css of these three groups showed no different ( h = 3.020 , p 0.05 ) , the relative proportion of patients with clinical severity classification was quite different . as mentioned above , only one patient with the smallest ecori fragment of cs 5 belonged to group a. the patients of group a showed larger variation of cs ranging from 0.5 to 5 . compared to cs3 .55 in group a ( 32.7 % + 2.0 % ) , the proportion of patients with cs3 .5 - 4.5 was remarkably decreased in group b ( 22.5 % ) and group c ( 13.6 % ) . however , there was no significant correlation between group a and group ( b + c ) with cs 3.54.5 ( = 3.54 , p 0.05 ) . conversely , 45.5 % of the patients in group c presented mild involvement of facial and scapulohumeral regions compared with 29.0 % of the patients in groups ( a + b ) , although it was showed no significant difference between group c and groups ( a + b ) with cs0 .51.5 ( = 2.17 , p 0.05 ) . among 16 patients with severe phenotype ( cs4 - 5 ) ( 16/173 , 9.24 % ) , 9 patients ( 9/49 , 18.4 % ) in group a compared with 6 ( 6/102 , 5.89 % ) in group b and 1 ( 1/22 , 4.54 % ) in group c. these data indicated that significant difference between group a and groups ( b + c ) for developing severe phenotype ( = 5.34 , p 0.05 ) . the contraction of d4z4 repeat in 4q35 is responsible for fshd , so the 4q - derived ecori fragment is considered as one major factor for determining clinical phenotype , including age of onset , clinical course , and age at loss of ambulation . our study represents new insights into genotype - phenotype correlations in chinese fshd , and supports that other epigenetic factors appear to involve in phenotypic regulation . in agreement with the clinical description of fshd , the characteristic presentation at onset associated with facial or scapulohumeral weaknessthe major clinical problem with typical onset was characterized by difficulty in arm abduction , often with asymmetry . facial weakness was one common associated sign on the neurological examination , while only a few of our patients were aware of facial involvement as initial presentation at early age . although the obvious appearance of facial weakness is helpful for fshd diagnosis , the facial - sparing phenotype at late - onset was often associated with very small 4q35 deletion , which alerts the clinician for the disease heterogeneity . as a clinically heterogeneous myopathy , the atypical patterns of fshd were usually characterized by the focal presentation and have been reported on the increasing basis . foot drop , which was observed in 2.6 % ( 4/154 ) of our series , has been known as an uncommon feature of disease onset when carefully investigated . although all showed the associated sign of facial or scapulohumeral region , these atypical cases were often delayed diagnosis by the highly focal presentation . it is worth noting that the distinct foot drop as initial manifestation ought to be distinguishing from other mimic neuromuscular disorder , such as distal myopathy with rimmed vacuoles . another atypical presentation characterized by proximal lower limb weakness was found in 7.1 % of our patients , in greatly accordance with the report in italy . the clinical course in these cases seemed to different from the common occurrence , which involvement of lower limbs is expected to occur in the later stage . in our patients with atypical onset , the 4q35 ecori fragment size was similar to that one found in majority with typical onset . therefore , the genetic and epigenetic factors contributing to these disease manifestations need further investigation . because other unclassified myopathies similar to atypical forms of fshd may carry nonpathogenic short ecori fragment on 4q35 , analysis of the d4z4 repeat length alone easily leads to misdiagnosis , and its distinguishing requires to determinate 4qa / 4qb variant . the remarkable intra - and inter - familial clinical heterogeneity is one well - known characteristic of fshd . in our survey , the most severe patient was detected with the smallest 10 kb fragment ( one d4z4 repeat ) , and obviously clinical variability was noticed in patients carrying contracted fragments above 13 kb , for there is no significant correlation of mutation spectrum associated with phenotypic manifestation . however , we indicated a roughly inversed correlation between the ecori fragment size and age - corrected css . this result supports that the various age at examination could influence the genotype - phenotype correlation and deteriorating synergistic factors could affect the disease progression . further analysis revealed that inverse correlation was only significantly observed in male , inconsistent with a similar survey . on the other hand , females ( 16/19 ) predominantly occupied in our asymptomatic carriers and half of them ( 8/16 ) were probands mother . in addition , both asymptomatic gene carriers and patients with severe phenotype ( cs4 - 5 ) were predominately occupied by females , which showed large variation of ecori fragment incompatible with clinical phenotype . hence , the clinicians should catch more attention to perform genetic test in the proband 's female relatives . now , increasing evidences support that the ( epi ) genetic or unknown modifying genes / factors contribute to phenotypic heterogeneity in fshd , especial in females . accordingly , it is difficult to provide accurate clinical prognosis and genetic counseling for the asymptomatic gene carriers or late - onset patients . the intra - familial variability is another genetic influential factor in analysis of genotype - phenotype correlation . the correlation between the ecori fragment size and age - corrected css in our sporadic cases displayed much stronger supporting that intra - familial variability is higher than inter - familial one . the familial patients with ecori fragment ranging from 16 kb to 24 kb presented significantly higher proportion , indicating that this length size of ecori fragment is more stably co - segregated . we speculated those familial patients with very small ecori fragment often cause severe phenotype and affect fertility . in contrast to the variable proportion of asymptomatic carriers in other studies ( 3.550 % ) , our results revealed that high incidence ( 14/42 , 45.2 % ) of asymptomatic ( or minimally affected ) gene carriers in some pedigrees with at least one symptom - free individual . inconsistent to asymptomatic carrier with relatively large fragment size from 21 kb to 27 kb in previous study , we detected more various fragment size from 13 kb to 30 kb in nonpenetrant carriers . therefore , it is difficult to offer genetic counseling for the families , especially female cases , upon determining whether their offsprings with segregated short ecori fragment is in preclinical phase or asymptomatic carrier . on the whole , we only observed rough correlation between the short ecori fragment and age - corrected cs , implying that genetic testing of short ecori fragment is insufficient for predicting clinical progression . high proportions of family members carrying the same short fragment were asymptomatic or minimally affected , which alerts the clinicians to offer molecular detection for the probands relatives in genetic counseling .\noutput:\n" }, { "from": "agent", "value": "background : facioscapulohumeral muscular dystrophy ( fshd ) , a common autosomal dominant muscular disorder , is caused by contraction of the d4z4 repeats on 4q35 . the complicated genotype - phenotype correlation among different ethnic population remains a controversial subject . we aimed to refine this correlation in order to provide new information for genetic counseling.methods : here , a cohort of 136 chinese families including 178 affected individuals and 137 unaffected members were investigated . genetic analyses were performed using the p13e - 11 , 4qa and 4qb probes after pulsed field gel electrophoresis separation and southern blotting . a 10 - grade fshd clinical severity scale was adopted for clinical assessment . the genotype - phenotype correlation was established by linear regression analyses.results : we observed a roughly inversed correlation between the short ecori fragment size and age - corrected clinical severity score in 154 symptomatic patients ( p < 0.05 ) . compared to male patients , a significant higher proportion of females in both asymptomatic carriers and severe patients showed larger variation in the size of short ecori fragment . a high incidence ( 19/42 , 45.2 % ) of asymptomatic ( or minimally affected ) carriers was found in familial members.conclusions : although the number of d4z4 repeats is known as one of the critical influences on genotype - phenotype correlation , a majority of phenotypic spectrum was still incompatible with their heterozygous contraction of the d4z4 repeat , especial in female cases . our results suggest that there are multi - factors synergistically modulating the phenotypic expression ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the most important factor in implant longevity as a factor for clinically successful implant treatment is the formation of a direct interface between the implant and the bone , without intervening soft tissue , a process called osseointegration . osseointegrated dental implants represent an advance in modern odontology , which has become a great option for the rehabilitation of missing single teeth in partially or totally edentulous patients . despite the very high success rates , complications associated with implant treatmentearly loading failure may affect 2 % to 6 % of implants , and as many as 15 % of restorations fail as a result of this problem . excess load on a final restoration after successful implant integration can result in failure of the implant itself . therefore , it is important to clarify the risk factors for failure of implant prostheses in order to further improve the good success rate . the consequences of overload of dental implants can be divided into two groups : biological and biomechanical complications . biological complications can be divided into early failures and late failures . in case of early failures , late biological failures are characterized by pathological bone loss after full osseointegration was obtained at an earlier stage . is needed for a proper understanding of these mechanisms . in case of biomechanical complications , one or more components of an implant systemfail , for example , fracture of an implant itself , loosening or fracture of connecting screws or abutment screws , loosening or excessive wear of mesostructural components in overdentures , and excessive wear or fracture of suprastructural porcelain or acrylic teeth . bruxism is a movement disorder of the masticatory system that is expressed , among others , by tooth grinding and clenching , during sleep as well as during wakefulness . especially , sleep bruxism is a repetitive sleep movement disorder characterized by rhythmic masticatory muscle activity ( rmma ) at a frequency of approximately 1 hz and by occasional tooth grinding . it is reported that during light sleep , most episodes of sleep bruxism ( sb ) are observed in relation to brief cardiac and brain reactivations termed micro - arousals . rmma is secondary to a sequence of events in relation to sleep microarousals : as a result of the increase in autonomic sympathetic activity , the heart and brain are activated in the minutes and seconds , respectively , before the onset of activity in the suprahyoid muscles and finally , rmma occurs in the jaw - closing masseter and temporalis muscles . since sb is controlled by the central nervous system , it may be difficult to prevent the occurrence of bruxism events . recognized a causal relation between bruxism and fracture of the suprastructure , but they could not show the relation between bruxism and failure of the implant itself . on the other hand , engel et al . suggested that bruxism never affected the marginal bone loss of the dental implantfrom these studies , it is difficult to conclude that bruxism is a risk factor for dental implants . since most of the clinical research in dental implants excluded subjects with bruxism , there are only few research data on the influence of bruxism on dental implant outcome , and there is still no scientific evidence for a causal relation between bruxism and implant failure . in this paper , the relation between occlusion and overload of dental implants is described , and the available evidence for a possible cause - and - effect relationship between bruxism and implant failure is discussed . further , the possibility of clinical management of implant prostheses using an alteration of occlusal materials in the suprastructure and night guards in patients with bruxism is being presented . taylor et al . suggested that since mastication is a side - to - side action that does not lend itself to axial loading of teeth or implants in the jaws , the damaging effects of bruxism are created through lateral friction between the occlusal surfaces of maxilla and mandible . the attachment of natural teeth through periodontal ligaments and osseointegrated implants with a rigid bone contact in the jaw presents a significantly different environment , and this needs consideration . a natural tooth can be intruded about 50 m by a light force ( 20 n ) compared to only 2 m for an osseointegrated implant . in an animal study , miyata et al . investigatedthe relationship between occlusal overload and peri - implant tissue and suggested that peri - implant bone resorption occurred under occlusal overload . on the other hand , heitz - mayfield et al . demonstrated that a period of 8 months of excessive occlusal load on titanium implants did not result in loss of osseointegration or marginal bone loss when compared with nonloaded implants in animal study . however , much of oral and masticatory function seems to be similar in natural and implant - supported dentitions . the periodontal ligament is lost after tooth extraction , but most of its functional role as related to occlusion and mastication seems to be taken over by other mechanisms , such as , muscle spindles , mechanoreceptors in the temporomandibular joints . sincesuccessful long - term results of implant prostheses have been reported repeatedly , it may be concluded that the variety of methods related to occlusal morphology used in fixed prosthodontics on natural teeth are equally acceptable for rehabilitation on dental implants . the simple principles described for conventional prosthodontics may therefore be followed also for implant prostheses . a literature review concluded that the occlusal scheme for an implant prosthesis should be designed to decrease cuspal interferences , centralize forces along the long axis , and minimize lateral forces ; that is , it should be like that of a similar prosthesis on a natural dentition . since the occlusal perception level is higher for implant prostheses than for natural teeth , complaints of implant patients should be carefully considered when checking their occlusion . it is established that the lack of periodontal receptors leads to impaired fine motor control of the mandible in implant patients . however , early studies concluded that the functional clinical capacity of patients with implant prostheses was almost equal to or approaching that of dentate subjects . a study showing that the tactile sensibility of single - tooth implants opposing natural teeth was similar to that of pairs of opposing natural teeth led to the conclusion that the implants can be integrated in the stomatognathic control circuit . in 1996 , lavigne et al . proposed sleep bruxism research diagnostic criteria ( sb - rdc ) for polysomnographic recording , as follows : ( 1 ) a history of frequent tooth grinding occurring at least 3 nights per week for the preceding 6 months , as confirmed by a sleep partner ; ( 2 ) clinical presence of tooth wear ; ( 3 ) masseter muscle hypertrophy ; ( 4 ) report of jaw muscle fatigue or tenderness in the morning . bruxism is frequently considered an aetiological factor for temporomandibular disorders ( tmds ) , tooth wear ( e.g. , attrition ) , loss of periodontal support , and failure of dental restorations , although conflicting evidence for many of these purported aetiological relationships can be found in the literature . bruxism has also been suggested to cause excessive ( occlusal ) load of dental implants and their suprastructures , ultimately resulting in bone loss around the implants or even in implant failure . therefore , bruxism is often considered a cause of concern or even a contraindication for implant treatment . in addition , many researchers use bruxism as an exclusion criterion for the selection of their participants in clinical studies concerning treatment modalities with dental implants . bruxism , other oral parafunctions , fractures of natural teeth resulting from occlusal forces , and lateral occlusal contacts on the implant prostheses were listed as important risk factors for dental implants and their suprastructures . in a study of 379 patients who had used implant prostheses for many years , occlusal wear had no statistically significant impact on vertical peri - implant bone loss . it was presupposed that occlusal wear was closely related to bruxism , and thus bruxism did not seem to be a risk factor for the examined variables . it must be emphasized , of course , that bruxism is not the only cause of tooth wear and in fact is not a major factor . a review of literature on dental implants in patients with bruxing habits concluded that , so far , studies on bruxism and implant failure do not yield consistent results . however , a careful approach was recommended , although it was admitted that these recommendations were experience based , not evidence based . as many clinicians still have the impression that there is some relevance in these risk factors , it may be prudent to exercise caution , perform careful clinical control , and acknowledge the need for occlusal adjustments of the suprastructure in all implant patients . when alarm signals are found , for example , repeated loosening or fracture of abutment screws and fracture of veneering material , a careful analysis of potential reasons for these signals should follow with the aim to modify the situation and reduce excessive risks . in the past decades , for implant prostheses , it was strongly recommended to use a shock - absorbing material , such as , acrylic resin on top of the superstructure , in order to protect the implant - bone interface . based on biomechanical analyses , acrylic resin denture teeth were therefore predominantly used during the initial years of dental implant use . however , biomechanical calculations do not always stand the test in the clinic . in a clinical study on five subjects using fixed prostheses with either acrylic resin or porcelain occlusal surfaces , no differences related to tooth material could be detected in the load rates . in a study covering 6 years , the use of porcelain instead of composite resin as occlusal material had no influence on the marginal bone height around the implants . these findings can be interpreted as a support for the use of porcelain as occlusal material because no serious biological consequences of the hard material were reported . furthermore , the most common complications of implant prostheses have been related to fractures of the acrylic resin of the prostheses . wear of acrylic occlusal surfaces increased substantially with time , according to a 15 - year followup of fixed implant - supported prostheses in the edentulous maxilla . in current clinical practice , porcelain has become the primary occlusal material for single - tooth and partial fixed implant prostheses ( figure 1 ) . it is generally agreed that ceramic occlusal surfaces provide superior esthetics and wear resistance . regarding full - arch fixed prostheses on implants , metal ceramic prostheses are sometimes presented in clinical reports , but in many centers acrylic resin teeth continue to be the material of choice . in removable types of implant prostheses , for example , overdentures , although there is no evidence regarding the preferred restorative materials in implant prosthesis for patients with bruxism , some clinicians prefer metal restorations and not porcelain to protect the implant prostheses in patients with bruxism , especially for second molar teeth in the maxilla ( figure 2 ) . however , in a clinical trial on fractured dental zirconia implants , gahlert et al . reported that the patient with the fracture of the 4 mm diameter zirconia implant was adversely affected by strong bruxism . recently , some investigators demonstrated zirconia as a new dental implant material . the development of new dental implant material might change the relationship between fractured dental implants and bruxism . a night guard fabricated for the maxillary teeth can be a useful tool to evaluate the influence of the occlusion scheme and its relationship to nocturnal bruxism . occlusal schemes and designs of fixed and removable implant prostheses must satisfy the requirements for an innocuous vertical loading of dental implants . parafunctional habits ( clenching or grinding ) can transmit forces to the supporting bone that may result in destructive lateral stresses and overloading . a hard stabilization splint for nightly use ( night guard ) contributes to optimally distributing and vertically redirecting forces that go with nocturnal teeth grinding and clenching . a night guard that promotes even occlusal contacts around the arch in centric - related occlusion can be helpful to prevent fractures of implant prostheses . this device may be fabricated with 0.5 - to 1 - mm colored acrylic resin on the occlusal surface . if the patient wears this device for 1 month , the consequences or intensity of the bruxism habit may be directly observed . as examples , when partial implant prosthesis is present in the maxilla , the night guard is hollowed out at the implant sites so no occlusal force is transmitted to the implant prostheses . when the partial restoration is in the mandible , the occluding surface of the guard is relieved over the implant prostheses so no occlusal force is transmitted to the implants . a soft material may also be placed around the crowns for stress relief and to decrease the impact force on the crowns ( figure 3 ) . in this field , future clinical trials on possible new materials should be planned to investigate the protection of implant prostheses from bruxism . on the other hand , some investigators proposed a pharmacological approach for bruxism patients with implant prostheses , especially in cases where oral implants failed as a probable consequence of severe , polysomnographically confirmed sleep bruxism . as the patient had the wish to be reimplanted after this failure , the operators decided to try diminishing the frequency of bruxism and duration first . the selected management strategies , the administration of low doses of the dopamine d1 / d2 receptor agonist pergolide finally resulted in a substantial and lasting reduction in the bruxism outcome measures under study . only little research has focused upon the clinical approach to protect implant prostheses from bruxism . the presented results do not reflect a high level of scientific evidence and may need modification when new research results or new dental implant materials appear . it is a fact that clinicians feel that the overload caused by bruxism may result in failure of implant supported prostheses . following the recent developments with the introduction of immediate or early loading , the clinical management of bruxism will become an important subject for implant prostheses . the lack of well - designed clinical trials regarding the consequence of bruxism on implant prostheses poses a serious problem . at present , expert opinion and cautionary approaches are still considered the best available sources for suggesting good practice indicators . there is an urgent need for those actively engaged in clinical research centers and university research institutes to provide evidence on whether the subjective feeling of clinicians regarding the approach of bruxism in implant patients is correct or not .\noutput:\n" }, { "from": "agent", "value": "there is general agreement that excessive stress to the bone - implant interface may result in implant overload and failure . early failure of the implant due to excessive loading occurs shortly after uncovering the implant . excess load on a final restoration after successful implant integration can result in physical failure of the implant structure . many clinicians believe that overload of dental implants is a risk factor for vertical peri - implant bone loss and / or may be detrimental for the suprastructure in implant prostheses . it has been documented that occlusal parafunction , such as , bruxism ( tooth grinding and clenching ) affects the outcome of implant prostheses , but there is no evidence for a causal relation between the failures and overload of dental implants . in spite of this lack of evidence , often metal restorations are preferred instead of porcelain for patients in whom bruxism is presumed on the basis of tooth wear . the purpose of this paper is to discuss the importance of the occlusal scheme used in implant restorations for implant longevity and to suggest a clinical approach and occlusal materials for implant prostheses in order to prevent complications related to bruxism ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the anatomic spectrum of diaphragmatic hernias is highly variable extending from sliding hiatus hernia , which is the commonest and predominantly asymptomatic type , to paraoesophageal hernia in which the stomach with other organs , such as the colon , spleen , and small bowel herniate into the chest . the tendency is for paraoesophageal herniae to enlarge with time . because of this , elective surgical repair is recommended for patients who are symptomatic , as surgery becomes more difficult with increasing size of the hernia and age of the patient . in addition , emergency repair of paraoesophageal hernia is associated with a high mortality rate .1 the two most frequent causes of pancreatitis are gallstones and alcohol , which combined account for over 80 % of cases . once gallstones or alcohol misuse have been excluded , the search for other aetiological factors begins ( see table 1 ) .2 any condition that obstructs the pancreatic ducts can result in acute pancreatitis . a systematic search of the literature identified four other reported instances of acute pancreatitis secondary to incarcerated paraoesophageal hernia .36 a 61 - year - old female presented as an emergency with severe pain associated with vomiting and dyspnoea . the symptoms were progressive in the six weeks prior to presentation with the patient being otherwise fit and well . the only past medical history included a hiatus hernia seen on oesophago - gastroduodenoscopy ( ogd ) a number of years ago . there were no gallstones seen on previous ultrasound scan nor was there a history of alcohol consumption . the only regular medication that the patient was taking was omeprazole 40 mg , the dose of which she had recently increased from once to twice daily . there was no family history of pancreatitis nor was there any history of recent systemic upset apart from the above . on examination she was tender in the epigastrium and had reduced air entry on the left . blood tests revealed a hyperamylasemia of 408 somogyi units , a leukocytosis of 15,000 white blood cells / l , and hypoxia with a po2 of 8.63 kpa on room air . chest radiograph showed considerable eventration of left hemidiaphragm with shift of heart and mediastinum to right ( fig . this patient had nasogastric tube decompression of the stomach and supportive management for a putative diagnosis of acute pancreatitis . subsequent computed tomogram ( ct ) scan of chest and abdomen confirmed a paraoesophageal hernia ( diaphragmatic neck 6.5 cm ) with stomach , large bowel , and small bowel with mesenteric vessels within the left hemithorax . the neck and body of pancreas were positioned above the diaphragmatic defect and were not inflamed . there was inflammation and prominent ductal dilatation in the proximal body and tail of pancreas , which lay below the diaphragmatic defect . there was decreased enhancement of pancreatic tail , however , no definite necrosis was seen ( fig . complimentary magnetic resonance cholangiopancreatography ( mrcp ) revealed a pancreatic pseudocyst as well as confirming pancreatitis of tail with dilated duct . the driving pathological mechanism being obstruction of the distal pancreatic duct secondary to the mechanical displacement of the pancreatic head and body to the thorax as part of the type iv paraoesophageal hernia . no structural abnormalities of the pancreas , such as , pancreas divisum were seen , nor was there any other obstructing ductal lesion . on resolution of her acute pancreatitisthe patient was seen at the hepatobiliary clinic with a view to both repair of the hernia and potential distal pancreatectomy . at laparotomystomach , colon , spleen , pancreas , and small bowel were reduced and on inspection the pancreas appeared essentially normal , confirmed by intra - operative ultrasound . the diaphragmatic defect was repaired with a teflon reinforced suture technique with a posterior wrap fundoplication . the patient made steady progress post - operatively and the recovery continued and she was eventually discharged after two weeks . from a practical perspective diaphragmatic hernias are described as sliding or paraoesophageal . however , traditionally hiatal hernias are classified into four types by the position of the gastro - oesophageal junction relative to the diaphragm . the gastro - oesophageal junction ( goj ) ascends above the impression made by the diaphragmatic crura , the oesophagus and stomach ascending together with the goj . ii there is a separate orifice containing protruded fundus of stomach adjacent to a normally located goj . type iii is a combination of types i and ii hernias with cranially displaced goj and stomach through the hiatus .1 type iv is characterized by displacement of the stomach with other organs into the chest and was the type encountered in this case . the most frequent herniated organs are the colon , small intestine , omentum , or spleen . complications such as volvulus , occlusion , ischaemia , or even perforation can occur .78 standard preoperative investigations include ct scan chest / abdomen , upper gastrointestinal contrast study , and upper gastrointestinal endoscopy .9,10 previously published cases of pancreatic herniation through the diaphragm37 ,11,12 include four cases associated with pancreatitis ,36 two of which were in cases of congenital diaphragmatic herniae .4,6 the causal elements of acute pancreatitis in such a herniation have been postulated as repetitive trauma associated with pancreatic movement across the hernia , ischemic compromise of the vascular pedicle , or intermittent folding of the main pancreatic duct .46 it is easy to envisage the sharp folding of the pancreatic body depicted in our patient with acute pancreatitis , resulting from folding and occlusion of the main pancreatic duct . herniation of the pancreas through the diaphragm without complicating pancreatitis is described .7,11,12 the case presented here offers an evaluation of the inflamed pancreas with magnetic resonance imaging , including mrcp . computed tomography and magnetic resonance imaging both offer evaluation of the pancreatic parenchyma and adjacent soft tissues ; however , magnetic resonance imaging allows multiplanar imaging , and mrcp offers a unique non - invasive opportunity to investigate the pancreatic and biliary ducts in these rare patients . similarly , ambulatory ph testing does not alter the planned operation .9,10 the approaches available for repair of paraoesophageal hernia include transthoracic , transabdominal , and laparoscopic . the components to a successful repair include complete tension free reduction of hernia contents into the subdiaphragmatic position , excision of hernia sac , closure of hiatal defect , and an antireflux procedure .10 roof top incision gives excellent access for repair of large hiatus hernia with associated pancreatitis where pancreatectomy is also being considered . owing to the progressive nature of paraoesophageal herniae early repair is recommended in symptomatic patients . symptoms of obstruction or worsening reflux in someone with a history of hiatus hernia should raise the possibility of paraoesophageal hernia .\noutput:\n" }, { "from": "agent", "value": "this is a rare case report of acute pancreatitis secondary to a massive incarcerated paraoesophageal hernia . the pathogenesis resulted from obstruction of the distal pancreatic duct after displacement of the pancreatic head and body into the thorax as part of a type iv paraoesophageal hernia . although this condition is rare , the patient made steady progress following laparotomy and open repair of hernia . she made a good recovery after prompt therapy , therefore , this report can be a guide to the diagnosis and treatment of similar conditions ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: perinuclear granules in germ cells of drosophila have been named nuage ( which means cloud in french ) . the main marker and essential component of nuage in both sexes is rna - helicase vasa . proteomic content of ovarian nuage granules includes : proteins of the piwi subfamily , aubergine and argonaute 3 ; rna - helicases , vasa , spindle e and belle ; tudor domain - containing proteins , tudor , spindle e , krimper , tejas ; proteins known as components of somatic p - bodies taking part in mrna degradation , dcp1 , me31b and pacman ; and other proteins , such as putative nuclease squash and high mobility box group protein maelstrom . nuage is thought to be involved in the selection and translational control of mrnas transported from the nucleus . recent studies revealed the association of nuage with the pirna biogenesis and pirna - dependent silencing of transposons . proteins of the piwi subfamily , piwi , aubergine ( aub ) and argonaute 3 ( ago3 ) , form complexes with pirnas . these complexes recognize mrnas complementary to guide pirnas and perform rna slicing , causing target degradation . two main models of pirna processing have been suggested based on deep - sequencing analysis of ovarian pirnas . in germinal cells of the ovaries , pirnas complementary to transposon transcripts undergo amplification via the ping - pong cycle . sense transposon transcripts are targeted by the aub - containing antisense silencing complexes , which cause transcript cleavage . these sense pirnas are subsequently loaded into the ago3 - containing sense silencing complexes , which presumably recognize long antisense transcripts and generate 5 - ends of antisense pirnas , which are involved in the next round of the cycle . the amplification cycle produces pairs of sense and antisense pirnas which have a ten nucleotide overlap of complementary sequence in their 5 - ends . nuage in nurse cells of the drosophila ovaries is considered to be a site for both the pirna maturation and the pirna - guided silencing . the third member of piwi subfamily , nuclear protein piwi , is expressed in both germline and somatic cells of the ovaries . in somatic cells in the absence of germline - specific aub and ago3 piwi - associated pirnas are produced by another mechanism , presumably via direct cleavage of long transcripts ( primary processing ) . however , piwi is essential for transposon silencing in the germline , and , according to recent data , is involved in co - transcriptional repression of telomeric retrotransposons . the first case of natural pirna - mediated silencing of endogenous genes was discovered in the drosophila testes . however , the majority of papers published since then is devoted to the pirna silencing in the ovaries , where powerful transposon activity is easily detectable in pirna pathway mutant flies . transcripts of the x - linked endogenous tandemly repeated stellate genes , but not of transposons , are shown to be the main targets of the pirna silencing in the testes of d. melanogaster . stellate gene expression is strongly repressed by the pirna machinery in wild type males . in case of a deletion of the homologous y - linked crystal or suppressor of stellate ( su ( ste ) ) locus , abnormally high - level stellate expression occurs in primary spermatocytes and leads to the accumulation of protein crystals , disturbances in meiotic chromosome condensation and segregation and essentially reduced fertility . abundant anti - sense transcription of the crystal locus is responsible for the production of antisense su ( ste ) pirnas complementary to stellate transcripts . nuage proteins , such as aub , ago3 , spindle e , armitage , tejas , krimper , maelstrom , vasa and squash are found to be necessary for the pirnas - mediated stellate silencing . mutations in these genes result in the loss of su ( ste ) pirnas and stellate derepression . it should be noted that the proteins , which deficiencies lead to stellate derepression , are largely concentrated to nuage . piwi , the founder of piwi clade , is known to be expressed mainly in somatic cells of the testis germinal proliferative center . large - scale sequencing of testis aub - associated short rnas revealed that 70 % of these pirnas were su ( ste ) - derived , predominately in antisense orientation . about 90 % of su ( ste ) pirnas were presented by a pirna of a single type , called su ( ste ) - 4 , or its variants . this observation strongly favors the assumption that su ( ste ) pirnas are non randomly produced from precursor anti - sense su ( ste ) transcripts , but rather from a limited number of hotspots . however , among ago3 - associated pirnas only 6 % belongs to su ( ste ) pirnas abundantly represented by su ( ste ) - 4 too . only a trace amount of sense su ( ste ) pirnas was found in aub and ago3 complexes . also , a few complementary pairs of su ( ste ) pirnas overlapping by 5 - ends ( bearing signatures of the ping - pong cycle ) were found . thus , the bulk of testis pirnas is generated by primary processing rather than the ping - pong mechanism . in spite of ago3 expression level being significantly lower in the testes than that of aub , the biogenesis of su ( ste ) pirnas and stellate silencingonly 54 % of pirnas from the ago3 - derived library and 7 % from the aub - derived one belong to transposon sequences . a significant part of transposon - associated pirnas demonstrated ping - pong signatures and generated ping - pong pairs similarly to the situation in the ovarieshowever , contrary to their effects in the ovaries , aub and ago3 deficiencies only slightly affect transposon expression in the testes . apparently , mobilization of transposons in the testes is essentially under the control of an alternative mechanism . in our recent paper we found at least two types of perinuclear nuage granules in germinal cells of the testes : a lot of small particles of about 0.6 m that were concentrated around the nuclei , and significantly larger structures of about 2.4 m , usually one per cell . the volume of larger granules is found to be more than 50 times that of the smaller ones . large granules are enriched by the known nuage proteins : vasa , aub , ago3 , tudor , spindle e , belle , squash , cutoff and also ago1 , the principal component of the microrna pathway . since most of the identified components are known as participants of the pirna pathway , the new structure was named the ping - body ( pirna nuage giant body ) . vasa and aub are shown to be completely colocalized at the periphery of the ping - bodies , whereas ago3 is located in the central lobe . the ping - bodies appear in primary spermatocytes during active transcription period and are lost before meiotic divisions ( fig . 1 ) . mutational analysis demonstrated a strong association of ping - bodies formation with the stellate silencing . symmetrical arginine methylation of piwi clade proteins provided by arginine methyltransferase capsuleen ( dart5 ) is found to be essential for ping - body formation . capsuleen mutations leading to aub delocalization to random cytoplasmic foci induce strong stellate derepression and loss of su ( ste ) pirnas . since ago1 is found to be a ping - body component , the functions of the large granules in the microrna - mediated mrna silencing can also be expected . in addition to that we detected dcp1 , a decapping enzyme and marker of somatic p - bodies , as a ping - body constituent ( kibanov , unpublished data ) . scheme of spermatogenesis in mouse and drosophila . left : germ granules in mouse gonocytes ( imc or pi - bodies , pip - bodies ) , spermatogonia , early sprematocytes ( imc ) , late spermatocytes ( imc , cb precursors ) and haploid round spermatids ( cb ) are depicted . adapted from ref . cb formation coincides with periods of active transcription ( arrows ) and emerging of abundant pachytene pirnas . in elongating spermatidsthere are a lot of small nuage granules , that appear early in germline stem cells , and significantly larger structures , the ping - bodies . whereas no ping - body - like large nuage structures are observed in the ovaries , a question concerning their role in the testes is raised . taking into account that the conventional nuage granules in the ovarian nurse cells appear to be enough for functioning of the ping - pong pirna silencing mechanism , the ping - bodies seem to be dispensable for the amplification cycle . we know that stellate transcription occurs in primary spermatocytes and temporarily coincides with the ping - body formation . the analysis of su ( ste ) pirnas derived from the testis libraries favors their generation by primary processing rather than by the ping - pong cycle . the arranged internal structure of the ping - body and a high concentration of pirna pathway components seem to contribute to effective kinetics of the stellate silencing process . abundant transcription of antisense su ( ste ) starts in spermatogonial cells , earlier than that of stellate genes . it is tempting to speculate that su ( ste ) pirnas are produced before the start of stellate transcription by a variant of primary processing . however , details of stellate repression by the pirna pathway and su ( ste ) pirna biogenesis remain obscure to date . the mammalian cb is another large granular organelle involved in posttranscriptional mrna processing in the testes . although it appears in late pachytene spermatocytes and finally forms in round spermatids as a single structure per cell ( fig . 1 ) , its persistence , similar to the ping - body , coincides with the strong wave of transcription . the cb contains mvh , the mammalian homolog of drosophila vasa protein ; miwi and mili , piwi clade proteins ; tudor domain - containing proteins ; dicer , the nuclease necessary for the micrornas processing . micrornas and microrna pathway proteins were found in the cbs suggesting their role in microrna - mediated expression regulation . biochemical isolation of mouse cbs reveals a high concentration of pirnas , named late or pachytene pirnas , which do not demonstrate ping - pong signatures unlike pre - pachytene pirnas that are expressed earlier in gonocytes . pachytene pirnas originate mainly from large non - repeated clusters located in non - annotated genome regions , but not from transposon - related sequences . targets of pachytene pirnas are largely unknown . although the exact roles of the cb and pachytene pirnas in mouse spermatogenesis remain to be determined , we suggest that the ping - body and cb have shared attributes and can be functionally related structures . the recent studies of the pirna pathway using drosophila testes provide important insights into the biological role of the germ granules . similar characteristics and protein content of the cb and ping - body allow using drosophila as the model organism for further investigation of molecular principles of the germ granules organization and functioning .\noutput:\n" }, { "from": "agent", "value": "ribonucleoprotein - containing granules in the cytoplasm of germinal cells are known to be a common attribute of eukaryotic organisms . germ granules appear to ensure the posttranscriptional regulation of germline mrnas . recent studies specify the participation of the germ granules in genome integrity maintenance by mechanisms involving short pirnas . piwi clade proteins and associated pirnas are considered as key participants of the germline - specific pirna pathway . proteins of the piwi clade , aub and ago3 , concentrated in the germline - specific perinuclear granules called nuage , are involved in silencing of retrotransposons and other selfish repetitive elements in the drosophila genome . in drosophila testes , two types of perinuclear nuage granules are found : a large amount of small particles around the nuclei and significantly larger structures , the ping - bodies . in this mini - review , we analyze the recent published data about structure and functions of drosophila male germ granules , and especially their involvement in the pirna silencing pathway ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: polycystic ovary syndrome ( pcos ) is a common disorder with a prevalence of 6 - 7 % of women of reproductive age . the clinical picture commonly includes obesity , hirsutism , oligomenorrhoea , and subfertility . around 3075 % of pcos womenare obese , and many pcos women show evidence of insulin resistance and hyperandrogenism . in 2003 , the european society for human reproduction and embryology ( eshre ) and the american society for reproductive medicine ( asrm ) cosponsored the rotterdam polycystic ovary syndrome consensus workshop that revised and broadened the national institute of health ( nih ) 1990 diagnostic criteria . while chronic anovulation with biochemical and / or clinical hyperandrogensim is essential for making the diagnosis under the nih 1990 , classic pcos , the revised rotterdam criteria ( box 1 ) included women with hyperandrogenism but regular menses and those with menstrual disturbance without overt androgen excess , nonclassic pcos . the revised rotterdam criteria , although commonly , used are still controversial and reflect the heterogeneous presentation of the syndrome and the advances in understanding its uncertain aetiology . the exact role that obesity plays in the development of pcos remains to be determined . the theories that have been put forward to explain the metabolic abnormalities associated with obesity may also be applicable to explain the role of obesity in the development of pcos . the adipokine theory suggests that the adipose tissue is an endocrine organ that secretes several hormones ( adipokines ) . several studies have shown adiponectin to be lower in pcos women when compared to weight - matched controls . while some studies suggest a strong correlation between adiponectin and androgen levels in pcos , others did not show similar association . leptin is not produced exclusively by adipocytes but its circulating levels are strongly correlated to adipose mass and are higher in obese people . in most studies , leptin levels in pcos were similar to those of controls of similar body weight . whether leptin levels in pcos are associated with androgen levels remains controversial . hyperleptinaemia has been associated with insulin resistance and is inversely related to fertility in pcos women . resistin is another adipokine and its relationship to pcos remains debatable . increased levels of resistin have been linked to the development of insulin resistance and may play a role in the development of cardiovascular disease . however , while some studies suggest increased levels in pcos , others showed pcos women to have similar levels when compared to weight - matched controls . on the other hand , the adipose tissue expandability theory proposes that at a set point of positive energy imbalance , which is determined on an individual basis by genetics and environmental factors , the subcutaneous adipose tissue fails to expand to store more fat subcutaneously . this results in a state of lipotoxicity and fat starts to deposit in other tissues like the liver , muscles , and pancreas . one of the difficulties that face any theory trying to explain the origin of pcos is that it is not one entity . women with pcos are not all obese or insulin resistant , and the presence of hyperandrogenism and oligo / amenorrhoea is not necessary for making the diagnosis . many cardiovascular ( cv ) risk factors are increased in pcos even after adjusting for weight . for example , women with pcos have impaired glucose tolerance , dyslipidaemia , endothelial and platelets dysfunction , lower adiponectin , and higher homocysteine levels . despite the lack of long - term cv outcome data , it has been suggested that pcos women have a sevenfold increase in relative risk for myocardial infarction , higher prevalence of cerebrovascular disease , and worsening cv event - free survival . central obesity is often associated with pcos and carries increased risk for developing cardiovascular disease and type 2 diabetes . over the past 2 decades , the rate of obesity has raised threefold . whether there is an increase in the prevalence of pcos to parallel the increase in obesity is still controversial . even modest weight loss of less than 10 % of initial body weight has been shown to increase the frequency of ovulation , improve conception , and reduce testosterone , free androgen index , hyperlipidaemia , hyperglycaemia , and insulin resistance in women with pcos . . 4457 % of pcos women had improvement in either menstrual cycle or ovulation after lifestyle changes and subsequent weight loss . one of the main challenges of lifestyle changes is the low participants ' compliance rate over time . therefore , pharmaceutical intervention is an additional essential therapeutic tool to lifestyle changes in many patients . although sibutramine and rimonabant have been shown to be effective in inducing weight loss in pcos women , they have both been withdrawn from the uk . rimonabant increased the risk of psychiatric disorders and sibutramine has been associated with hypertension and cardiovascular disease . orlistat is a lipase inhibitor that reduces fat absorption in the gut by approximately 30 % . in a meta - analysis , it is estimated that orlistat treatment led to an average placebo - subtracted weight loss of 2.7 kg at 1 year . in a 4 - yearrandomised controlled trial of 3305 obese , nondiabetic patients , orlistat treatment was associated with a 3.6 - kg weight loss compared with 1.4 kg for placebo at 4 years . in women with pcos , a 4.69 % weight reduction was reported with orlistat therapy with an associated improvement in total testosterone levels . in a 12 - week randomised open labelled study , orlistat reduced insulin resistance by around 20 % and variability of insulin resistance by 40 % in obese pcos women . in a 6 - month clinical trial , therapeutic intervention with orlistat anda low - calorie diet resulted in a beneficial effect in pcos in reducing advanced glycation end - products ( age ) levels and testosterone concentrations independently of bmi changes . the use of orlistat is limited by its gastrointestinal side effects . approximately , 1530 % of those taking orlistat experience oily stool , faecal urgency , or oily spotting , and 7 % report faecal incontinence , particularly at the initiation of treatment . despite its relatively high rate of side effectsextrahepatic sites of action include the skeletal muscles , adipose tissue , endothelium , and the ovary . metformin is commonly used in women with pcos and is reported to improve insulin resistance , sex hormone binding globulin ( shbg ) , hyperandrogenaemia , and ovulation . metformin 's effect on weight management remains controversial . in a small ( n = 56 ) randomized , double - blinded , placebo controlled cross - over study , 6 - month treatment with metformin resulted in mean weight reduction of 2.3 kg ( p .009 ) . however , in a systematic review and meta - analysis , metformin was found to have no effect on body weight and body mass index ( bmi ) in women with pcos . metformin may be more effective in subgroups of pcos women and at higher doses . nonobese women with pcos responded better to metformin than obese women with regards to insulin sensitivity , free testosterone , and androstendione concentrations . metformin was also found to cause a dose - related weight loss in obese women with pcos , ( 1.5 and 3.6 kg weight loss in 1500 - and 2550 - mg / day metformin treated groups , resp . ) . metformin when given to obese pcos women after rimonabant , an endocannabinoid blocker , maintained the weight reduction and decrease in waist circumference achieved by rimonabant and augmented the initial improvements in testosterone levels and insulin resistance . it is possible that the insulin sensitisation action of metformin was complementary to the weight loss caused by rimonabant . most frequent side effects of metformin are gastrointestinal symptoms including nausea , anorexia , vomiting , abdominal discomfort , and diarrhoea and occur in up to 20 % of patients . in 35 % patients , therapy may have to be discontinued because of these adverse effects . slow release forms of metformin are available and are believed to be better tolerated . despite the lack of strong evidence , the use of metformin in obese pcos women is likely to be beneficial especially when taken at higher doses . ingested nutrients , especially fats and carbohydrates , stimulate glucagon - like peptide - 1 ( glp - 1 ) secretion from l cells in the distal small intestine . glp - 1 accentuates glucose - dependent insulin release , inhibits glucagon secretion , increases pancreatic cell growth , suppresses appetite and energy intake , and delays gastric emptying . glucagon - like peptide - 1 receptor ( glp - 1r ) is expressed by the gut , pancreas , brainstem , hypothalamus , and vagal - afferent nerves . a 24 - week randomised controlled trial in women with pcos , a combination treatment with exenatide ( glp1 mimetic ) and metformin was found to be superior to exenatide or metformin monotherapy in reducing weight ( mean weight loss of 60.5 kg ) and improving menstrual cycles , ovulation rate , free androgen index , and insulin sensitivity . in another 20 - weekrandomised open labelled study involving obese people without pcos , comparing liraglutide ( glp1 analogue ) to orlistat , it was shown that liraglutide treatment is well tolerated and induced significant dose - related weight loss ( mean weight loss 4.87.2 kg ) compared to placebo or orlistat . all the patients were obese and had a 500 kcal per day energy deficit diet and increased their physical activity throughout the study . in a head - to - head comparison study in people with type 2 diabetes , 1.8 mg liraglutide daily and 10 g exenatide twice daily produced similar weight loss ( 3.2 kg with liraglutide versus 2.9 kg with exenatide ) . most commonly reported side effects are nausea and vomiting , but the main safety concern remains a possible increased risk of pancreatitis attributable to drugs that act through the glp - 1 pathway . although , not yet licensed for obesity management , glp - 1r agonists offer a potential obesity treatment for women with pcos . in subjects with morbid obesity , bariatric surgeryfew studies have shown bariatric surgery to be associated with significant improvement in weight , hirsutism , insulin resistance , and fertility in women with pcos . many pcos women are obese , and weight reduction is an essential part in their management . in the management of obese women with pcos , lifestyle modification is the first step although low long - term compliance rate may reduce benefit . although not currently licensed , newer pharmacotherapeutic agents like incretin mimetics hold promise in managing obese women with pcos .\noutput:\n" }, { "from": "agent", "value": "polycystic ovary syndrome ( pcos ) is a common disorder affecting women of reproductive age and it is associated with increased cardiovascular risk . obesity plays an important role in the pathogenesis of pcos , and the majority of patients with pcos are obese . over the last 20 years , the prevalence of obesity has dramatically increased , with probable associated increase in pcos . weight reduction plays an integral part in the management of women with pcos . in this paper , current available weight reduction therapies in the management of pcos are discussed ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: atherosclerosis starts with increased circulating cholesterol levels and involves several events leading to chronic vascular inflammation . the initiation and progression of atherosclerosis largely depend on the function of macrophage foam cells , which focally accumulate within the artery wall and release various cytokines and chemokines to induce inflammation . the formation of foam cells primarily results from uncontrolled uptake of modified low - density lipoprotein ( ldl ) by macrophages , which leads to excess lipoprotein - derived lipid accumulation inside cells and induction of proinflammatory mediators . cellular lipid levels of foam cells are dynamically regulated by macrophage scavenger receptors ( srs ) and cholesterol efflux transporters . the internalization of oxidized ldl ( oxldl ) by macrophages is controlled by several types of srs , including sr - a and cd36 . conversely , cholesterol efflux is mediated by sr - bi and atp - binding cassette ( abc ) transporters such as abca1 and abcg1 . growing evidence indicates that preventing the formation of foam cells can impede the progression of atherosclerosis , but much remains to be explored . the transient receptor potential ( trp ) vanilloid type 1 ( trpv1 ) , a ligand - gated nonselective cationic channel , is mainly expressed in primary nociceptive sensory neurons . neuronal trpv1 is activated by heat , protons , endogenous lipid molecules and oxidative stimuli and exogenous agonists such as evodiamine ( an active ingredient of the evodia fruit ) and capsaicin ( an active ingredient of hot pepper ) . activation of trpv1 permits calcium ( ca ) entry , which results in an elevated level of intracellular ca and serves as a ca signal to elicit responses in neurons . trpv1 expresses in certain types of nonneuronal cells such as epithelial and endothelial cells and regulates several of their pathophysiological functions . emerging evidence suggests that trpv1 may be an important sensor and regulator of cardiovascular homeostasis and a protector against certain cardiovascular diseases such as hypertension , endothelial dysfunction , and stroke . recently , we reported that deletion of trpv1 worsened atherosclerotic lesions in apolipoprotein e - deficient mice ( apoe , a model of atherosclerosis - prone mice ) , so trpv1 may have a role in atherogenesis . however , the expression of trpv1 in macrophages is still unclear and its functional significance in macrophage foam cells remains largely unknown . in this study , we aimed to address the role of trpv1 in the pathophysiological functions of macrophage foam cells . we first examined trpv1 expression in macrophages and its distribution in mouse atherosclerotic lesions , then , investigated the therapeutic effects of 2 trpv1 agonists , evodiamine , and capsaicin , on the deregulation of lipid metabolism and inflammation in macrophages . finally , we explored the molecular mechanisms underlying the protection conferred by trpv1 agonists in macrophages . evodiamine , human ldl , capsaicin , capsazepine , apolipoprotein ai ( apoai ) , high - density lipoprotein ( hdl ) , egta , oil - red o , and mouse antibody for - tubulin were from sigma - aldrich ( st . louis , mo , usa ) . rabbit antibodies for abcg1 , cd36 , histone h1 , goat antibody for sr - a , control small interfering rna ( sirna ) , and lxr sirna were from santa cruz biotechnology ( santa cruz , ca , usa ) . mouse antibody for abca1 , - actin , and rabbit antibodies for sr - bi , lxr , and f4 / 80 were from abcam ( cambridge , ma , usa ) . macrophage colony - stimulating factor ( mcsf ) , tumor necrosis factor ( tnf ) , and elisa kits were from r & d systems ( minneapolis , mn , usa ) . dil - labeled oxldl was from biomedical technologies ( stoughton , ma , usa ) . nbd - cholesterol and t0901317 were from cayman chemical ( ann arbor , mi , usa ) . the fluo - 8 ca assay kit was from abd bioquest ( sunnyvale , ca , usa ) . cholesterol and triglyceride assay kits were from randox ( crumlin , co. antrim , uk ) . the investigation conformed to the guide for the care and use of laboratory animals by the us national institutes of health ( nih publication no .85 - 23 , revised 1996 ) , and all animal experiments were approved by the animal care and utilization committee of national yang - ming university . wild - type ( wt ) c57bl / 6 mice were purchased from the national laboratory animal center , national science council ( taipei ) bone - marrow - derived macrophages ( bmdms ) were prepared as described . briefly , wt mice were killed by co2 exposure , and mononuclear cells from femurs were harvested by percoll ( 1.073 g / cm ) density gradient centrifugation . the cells were seeded in minimum essential medium ( mem ) supplemented with 50 ng / ml mcsf , 10 % fetal bovine serum ( fbs ) , and penicillin ( 100 u / ml ) / streptomycin ( 100 g / ml ) at 37c for 5 d. mouse macrophage - like j774.a1 cells ( bioresource collection and research center ; hsinchu , taiwan ) were cultured in rpmi 1640 medium supplemented with 10 % fbs , penicillin ( 100 u / ml ) , and streptomycin ( 100 g / ml ) . ldl was exposed to cuso4 ( 5 mol / l ) for 24 h at 37c and cu , then , removed by extensive dialysis . the extent of modification was determined by measuring thiobarbituric acid - reactive substances ( tbars ) . oxldl containing approximately 3060 nmol of tbars defined as malondialdehyde equivalents per milligram ldl protein was used for experiments . bmdms were rinsed with pbs , then , lysed in immunoprecipitation lysis buffer ( 50 mmol / l tris ph 7.5 , 5 mmol / l edta , 300 mmol / l nacl , 1 % triton x-100 , 1 mmol / l phenylmethylsulfonyl fluoride , 10 g / ml leupeptin , and 10 g / ml aprotinin ) . aliquots ( 50 g ) of cell lysates were separated on 8 % sds - page . after transfer to membranes , samples were immunoblotted with primary antibodies , then , horseradish peroxidase - conjugated secondary antibodies . bands were revealed by use of an enzyme - linked chemiluminescence detection kit ( perkin elmer , waltham , ma , usa ) , and density was quantified by use of imagequant 5.2 ( healthcare bio - sciences , philadelphia , pa , usa ) . ca assay was performed according to the manufacturer 's protocol ( abd bioquest , sunnyvale , ca , usa ) . briefly , bmdms were seeded in 24 - well plates and grown for 24 h. cells were then washed and fluo - 8 ne dye - loading solution was added for 1 hr at room temperature . fluorescence was measured by fluorometry ( molecular devices , sunnyvale , ca , usa ) with 490 nm excitation and 525 nm emission . cells were fixed with 4 % paraformaldehyde and then stained with 0.5 % oil - red o. hematoxylin was used for counterstaining . dil - oxldl , labeled with green fluorescence , has been used to measure oxldl binding to srs of macrophages . briefly , bmdms were treated with concentrations of evodiamine or capsaicin for 24 h , then , incubated with dil - labeled oxldl ( 10 g / ml ) for an additional 4 h at 4c . after a washing with phosphate - buffered saline ( pbs ) , cell lysates were analyzed by fluorometry ( molecular devices , sunnyvale , ca , usa ) at 540 nm excitation and 590 nm emission . bmdms were treated with concentrations of evodiamine or capsaicin for 12 h , then , underwent equilibration with nbd - cholesterol ( 1 g / ml ) for an additional 6 h. nbd - cholesterol - labeled cells were washed with pbs and incubated in mem for 6 h with apoai ( 10 g / ml ) or hdl ( 50 g / ml ) . fluorescence - labeled cholesterol released from cells into the medium was measured by use of a multilabel counter ( perkinelmer , waltham , ma , usa ) at 485 nm excitation and 535 nm emission . cholesterol efflux was expressed as percentage fluorescence in the medium relative to total fluorescence ( cells and medium ) . bmdms were lysed in 10 mm hepes ph 7.9 , 10 mm kcl , 1.5 mm mgcl2 , 0.5 % nonidet p - 40 , 1 g / ml leupeptin , 10 g / ml aprotinin , and 1 mm phenylmethylsulfonyl fluoride . nuclei were pelleted at 5000 g for 5 min at 4c , and the resulting supernatant was used as the cytosolic fraction . nuclei were resuspended in lysis buffer , sheared for 15 sec by microprobe sonication , and incubated on ice for 5 min . after centrifugation at 12000 g for 5 min at 4c , supernatant was collected as the nuclear extract . bmdms were cultured in mem with or without pretreatment with evodiamine ( 0.5 m ) or capsaicin ( 10 m ) for 6 h and fixed by formaldehyde for 15 min at room temperature . after cells were lysed and sonicated , chromatin solution was diluted and cells were incubated overnight with rabbit anti - lxr ab or rabbit igg at 4c . immunocomplexes were precipitated with salmon sperm dna / protein a agarose and collected by centrifugation . after cells were washed , chromatin dna was eluted , purified , and subjected to pcr analysis . the mouse abca1 gene promoter containing lxr binding element was amplified by pcr with the following primer sequences : 5 - cca cgt gct ttc tgc tga gt - 3 and 5 - tgc cgc gac tag ttc ctt tt - 3 . pcr products were resolved on a 2 % agarose gel and visualized by ethidium bromide staining . cells were transfected with the plasmids phabca1 ( -928 ) - luc , a reporter plasmid for the human abca1 promoter with lxr responsive element ( lxre , 3 - aaactggc tatcattgga gacgcg - 5 ) or phabca1 - dr4 m - luc , a reporter plasmid with a mutation in the lxre ( 3 - aaacacac tatcattgat gacgcg - 5 ) , by use of turbofect . after transfection for 24 h , cells were treated with evodiamine ( 500 nm ) , capsaicin ( 10 m ) , or t0901317 ( 10 m ) , an lxr agonist , for another 24 h. cells were then lysed for luc and renilla activity assays . macrophages were transfected with control or lxr sirna with use of turbofect for 24 h and then treated with evodiamine or capsaicin for another 24 h before further experiments . the levels of proinflammatory cytokines , including monocyte chemoattractant protein - 1 ( mcp - 1 ) , interleukin - 6 ( il - 6 ) , and macrophage inflammatory protein - 2 ( mip - 2 ) , in culture medium were measured by use of elisa kits . mann - whitney test was used to compare 2 independent groups . the kruskal - wallis test followed by bonferroni post - hoc analysisto study the possible role of trpv1 in atherogenesis , we first investigated the expression of trpv1 in atherosclerotic lesions . the protein level of trpv1 was markedly higher in apoe than wild - type mouse aortas ( figure 1 ( a ) ) . in addition to the expression of trpv1 in aortic ecs , immunohistochemical staining for trpv1 demonstrated positive signals confined mainly to areas of macrophages in atherosclerotic lesions of apoe mice ( figure 1 ( b ) ) . because neuronal trpv1 can be activated by several oxidative stimuli and lipids , we next examined the effect of oxldl on the expression of trpv1 in macrophages . treating bmdms with 50 g / ml oxldl for up to 24 h time - dependently increased the expression of trpv1 ( figure 1 ( c ) ) as early as 3 h after treatment or up to 24 h. thus , trpv1 may play an important role in the development of atherosclerosis . we next investigate the stimulatory effect of oxldl on the channel activity of trpv1 in bmdms . in response to oxldl , the intracellular level of ca ( [ ca ] i ) in bmdms , as reflected by intensity of ca - sensitive fluo - 8 fluorescence , rapidly peaked at 30 sec , slightly decreased at 1 min , and gradually increased to peak again at 4 h ( figure 2 ( a ) ) . importantly , the oxldl - induced increase in [ ca ] i level at 30 sec and 4 h poststimulation were prevented by pretreatment with capsazepine ( a trpv1 antagonist ) ( figures 2 ( b ) and 2 ( c ) ) . we then checked the specificity of capsazepine and found that exposure of bmdms to evodiamine or capsaicin ( trpv1 agonists ) also increased [ ca ] i level at 30 sec , which was abolished by capsazepine pretreatment ( figure 2 ( d ) ) . we then determined the functional significance of trpv1 in foam - cell formation in bmdms . pretreatment with evodiamine or capsaicin decreased oxldl - induced lipid accumulation , as revealed by oil - red o staining ( figure 3 ( a ) ) and cellular levels of cholesterol and triglycerides ( figures 3 ( b ) and 3 ( c ) ) . in contrast , capsazepine treatment augmented oxldl - induced lipid accumulation ( figures 3 ( a ) 3 ( c ) ) . thus , activation of trpv1 by agonists may protect against foam - cell formation . pretreating bmdms with the trpv1 agonists evodiamine ( 0.5 m ) or capsaicin ( 10 m ) did not alter the cholesterol binding but dose - dependently increased the apoai - or hdl - dependent cholesterol efflux ( figures 4 ( a ) 4 ( c ) ) . sr - a , cd36 , sr - bi , abca1 , and abcg1 have crucial roles in cholesterol homeostasis during foam - cell formation . we therefore delineated the mechanisms of trpv1 agonists in attenuating lipid accumulation by examining the alteration in expression of these receptors and transporters . macrophages treated with evodiamine or capsaicin showed increased protein levels of abca1 and abcg1 , with no change in protein levels of sr - a , cd36 , and sr - bi ( figures 5 ( a ) and 5 ( b ) ) . therefore , trpv1 activation suppressing intracellular lipid accumulation is likely due to an increase in reverse - cholesterol - transporter - ( rct - ) dependent cholesterol efflux but not inhibition of sr - mediated oxldl uptake in macrophages . to address whether the lxr is involved in trpv1 - agonist - induced expression of abca1 and abcg1 , we examined the nuclear protein level of lxr in evodiamine - or capsaicin - treated macrophages . evodiamine , capsaicin , or t0901317 ( lxr agonist ) treatment increased the nuclear level of lxr ( figure 6 ( a ) ) and enhanced binding of lxr to lxre in the abca1 promoter ( figure 6 ( b ) ) . furthermore , to explore the transcriptional regulation of lxr in evodiamine - treated macrophages , we performed lxr activation assays by transfecting with phabca1 ( -928 ) - luc or phabca1 - dr4 m - luc ( reporter plasmid with a mutation in lxre ) , followed by evodiamine or capsaicin treatment . as compared with the control group , treatment with evodiamine , capsaicin , or t0901317 as a positive controlin contrast to phabca1 - luc , phabca1 - dr4 m - luc showed blunted induction with evodiamine , capsaicin , or t0901317 treatment ( figure 6 ( c ) ) . in addition , transfection with lxr sirna decreased the protein expression of lxr and abolished the mrna expression of abca1 and abcg1 induced by evodiamine or capsaicin ( figures 7 ( a ) and 7 ( b ) ) . moreover , sirna inhibition of lxr activation abrogated the beneficial effect of evodiamine or capsaicin on apoai - or hdl - dependent cholesterol efflux ( figure 7 ( c ) ) . these results indicate the essential role of lxr activation in evodiamine - or capsaicin - regulated gene expression of abca1 and abcg1 , which may contribute to the suppressive effect of the agonists in the transformation of macrophage foam cells . we next examined the effect of trpv1 agonists on the tnf -- induced inflammatory response in macrophages . tnf -- increased production of mcp - 1 , il - 6 , and mip - 2 in bmdms was significantly attenuated by pretreatment with the 2 trpv1 agonists ; moreover , pretreatment with capsazepine exacerbated the tnf -- induced production of mcp - 1 and il - 6 but not mip - 2 ( figure 8 ( a ) ) . additionally , evodiamine or capsaicin suppressing the tnf -- induced increase in mcp - 1 , il - 6 , and mip - 2 production was reversed by sirna inhibition of lxr activation ( figure 8 ( b ) ) . these results suggest that lxr activation is required for the anti - inflammatory action of trpv1 agonists in macrophages . here we characterized a new effect of trpv1 activation and its underlying molecular mechanism in suppressing oxldl - or tnf -- induced deregulation of lipid metabolism and inflammation in macrophages . we first validated trpv1 expression in atherosclerotic aortas and in particular regions of macrophage - foam cells . the accumulation of macrophage - derived foam cells in the intima and subsequent release of inflammatory cytokines from these cells are 2 critical steps in the initiation and progression of atherosclerosis . this cellular localization implies the possible role of trpv1 in regulating the pathophysiological functions of such cells . we thus used an in vitro model to study the role of trpv1 in macrophage - foam cells . incubation with evodiamine or capsaicin , trpv1 agonists , alleviated the oxldl - induced lipid accumulation and tnf -- induced inflammation in bmdms , so the function of trpv1 is linked to the lipid metabolism and inflammatory response of macrophage - foam cells . interestingly , the protective effects of trpv1 agonists may be due to the activation of lxr . our in vitro data suggest that trpv1 has a novel effect in maintaining lipid homeostasis and the inflammatory response in macrophages . we then investigated the molecular mechanisms underlying the beneficial function of trpv1 activation in macrophages by use of this experimental cell culture model . treatment with oxldl , the most important modulator in the development of atherosclerosis , increased trpv1 channel activity in bmdms , as evidenced by a trpv1 - mediated increase in [ ca ] i level to a profile similar to that evoked by trpv1 agonists . in addition , oxldl - induced foam - cell formation , as evidenced by increased cellular levels of cholesterol and triglycerides , was suppressed by trpv1 agonists but exacerbated by a trpv1 antagonist . removal of extracellular ca by egta aggravated the oxldl - induced lipid accumulation and abrogated the protective effect of trpv1 agonist in bmdms ( data not shown ) , which agrees with previous studies that the increase in [ ca ] i level induced by oxldl may play a key role in the formation of macrophage - foam cells . therefore , activation of trpv1 / ca signaling may inhibit the formation of foam cells in vitro . sr - dependent oxldl uptake and rct - mediated cholesterol efflux are 2 key regulatory mechanisms in the intracellular lipid homeostasis of macrophage - foam cells . several lines of evidence indicate that reduced expression of srs or elevated function of rcts in macrophages leads to reduced deposition of cholesterol in macrophages . interestingly , trpv1 agonist treatment did not alter the binding of dil - oxldl to srs or the protein expression of sr - a , cd36 , and sr - bi in bmdms but promoted cholesterol efflux . moreover , trpv1 agonist treatment upregulated both abca1 and abcg1 , 2 major types of abc transporters responsible for cholesterol efflux from macrophage - foam cells to apoai and hdl , respectively . the critical role of abca1 and abcg1 in maintaining cholesterol homeostasis in macrophages has been well defined . loss or impaired function of abca1 or abcg1 in human or experimental rodents leads to hyperlipidemia , excessive cholesterol accumulation in peripheral tissues , and an overwhelming inflammatory response . thus , our in vitro results strongly support that the trpv1 - mediated suppression of foam - cell formation was solely due to an increase in rct - dependent cholesterol efflux , which is consistent with the previous studies that cytokine - or flavonoid - induced upregulation of abca1 or abcg1 contributes to alleviated lipid accumulation in foam cells . the detailed mechanism by which activation of trpv1 leads to upregulation of abc transporters is not clear . however , an increase in [ ca ] i level evoked by other interventions may regulate the expression of abc transporters in macrophages . additionally , we showed that the trpv1 agonist - induced upregulation of abca1 and abcg1 was accompanied by an increase in nuclear levels of lxr and its dna binding ability . this notion is further supported by findings that trpv1 - agonist - induced increase in promoter activity was abrogated by transfection with the lxre mutant ( phabca1 - dr4 m - luc ) . inhibition of lxr activation by sirna diminished the trpv1 - agonist - mediated upregulation of abca1 and abcg1 . thus , lxr - mediated transcriptional regulation may be required for induction of abca1 and abcg1 expression by trpv1 agonists . although we found a unique pathway for trpv1 activity , the detailed molecular mechanisms of trpv1 agonists affecting cholesterol efflux merit further investigation . in functional analysis to inhibit lxr activation , the suppressive effect of trpv1 agonists on intracellular lipid accumulation was abolished . lxr may be required for the trpv1 activation - induced gene expression of abca1 and abcg1 , which may contribute to suppressing the transformation of macrophage foam cells in vitro . in addition to the lxr - mediated transcriptional regulation , increasing evidence suggests that abca1 is also regulated by the posttranscriptional modification . for example , calmodulin is known to prevent protein degradation of abca1 by interacting with calmodulin - binding motif ( 1244 to 1257 amino acids within abca1 protein ) , which is located near the pest sequence ( 1283 to 1306 amino acids ) and thus prevents the binding of calpain to abca1 , leading to the inhibition of abca1 degradation . however , whether the posttranscriptional regulation is engaged in the trpv1 agonist - mediated upregulation of abca1 remain the further investigations . emerging evidence suggests that in addition to its action on cholesterol metabolism , abca1 also functions as a critical modulator in regulating the inflammatory response . patients with tangier disease and abca1 mutation or mice with functional ablation of abca1 show an irregular inflammatory response . moreover , growing evidence demonstrates that the expression and activity of abca1 is impaired during inflammation in vivo . treatment with pro - inflammatory cytokines or lipopolysaccharide ( lps ) decreases the expression of abca1 and its related function in various types of cells . more importantly , viral or bacterial infection decreases the expression of lxr and that of its target genes , including abca1 . in addition , activation of lxr by its ligands inhibits the lps - induced production of pro - inflammatory mediators including tnf - , mcp - 1 , il - 6 , and mip - 2 in macrophages . we found that tnf -- induced production of mcp - 1 and il - 6 was inhibited by treatment with trpv1 agonists but augmented by the trpv1 antagonist . sirna knockdown of lxr expression abolished the anti - inflammatory effect of trpv1 agonists on tnf -- treated bmdms . activation of trpv1 by its agonists also suppressed the inflammatory response of macrophages in vitro , which both may explain the protective role of trpv1 in reducing atherosclerotic lesions in vivo . conceivably , the anti - inflammatory property of lxr may play a pivotal role in the crosstalk between reverse cholesterol transport and immunity . trpv1 is originally found expressed in primary nociceptive sensory neurons and plays an important role in detecting irritative , inflammatory , and oxidative substances by somatic and visceral afferents . however , increasing evidence suggests that trpv1 is expressed in several types of non - neuronal cells , including macrophages , endothelial cells ( ecs ) , and preadipocytes and vitally regulates their functions . recently , convergent sets of evidence support a physiological role for trpv1 as a crucial integrator in the functions of the cardiovascular system and in cardiovascular diseases . for example , trpv1 activation by capsaicin increased the activity of endothelial no synthase ( enos ) , promoted vasorelaxation , and thereby reduced blood pressure in experimental hypertensive rats . additionally , we previously reported that trpv1 activation by evodiamine or capsaicin triggered ca - dependent pi3 k / akt / camkii / ampk signaling , thus leading to enos activation in ecs . as well , inactivation of trpv1 accelerates the development of metabolic disorders such as hypertension , atherosclerosis , obesity , and fatty liver , whereas trpv1 agonist activation protects against these metabolic diseases . our previous study demonstrated that chronic treatment of apoe mice with the trpv1 agonist evodiamine alleviated hyperlipidemia , systemic inflammation , hepatic macrovesicular steatosis , and atherosclerosis . moreover , our recent data demonstrated that chronic treatment with evodiamine upregulated the hepatic levels of ldlr , abcg5 , abcg8 , and cyp7a1 in apoe mice , which may promote bile acid synthesis and fecal excretion . interestingly , activation of lxr potentiated cholesterol excretion by increasing the transcriptional regulation of ldlr , abcg5 , abcg8 , and cyp7a1 in liver . this notion is substantiated by our findings that activation of trpv1 by evodiamine increased [ ca ] i level , which activated the lxr signaling pathway and led to the upregulation of abca1 and abcg1 , ultimately reducing the lipid accumulation of macrophage - foam cells . altogether , although the target cells for evodiamine have not yet been identified , our studies strongly suggest that collaboration of multiple physiological pathways in different types of cells may be required for the beneficial effects of trpv1 agonists in treating metabolic disorders . in conclusion , we demonstrate a novel protective function of trpv1 in macrophages , whereby activation by trpv1 agonists could suppress the oxldl - induced deregulation of lipid metabolism and inflammation in vitro by an increase in lxr activation , thus leading to the promotion of cholesterol efflux and attenuation of the inflammatory response . our findings may help in developing novel pharmacological targets for treating atherosclerosis - related cardiovascular diseases .\noutput:\n" }, { "from": "agent", "value": "the transient receptor potential vanilloid type 1 ( trpv1 ) is crucial in the pathogenesis of atherosclerosis ; yet its role and underlying mechanism in the formation of macrophage foam cells remain unclear . here , we show increased trpv1 expression in the area of foamy macrophages in atherosclerotic aortas of apolipoprotein e - deficient mice . exposure of mouse bone - marrow - derived macrophages to oxidized low - density lipoprotein ( oxldl ) upregulated the expression of trpv1 . in addition , oxldl activated trpv1 and elicited calcium ( ca2 + ) influx , which were abrogated by the pharmacological trpv1 antagonist capsazepine . furthermore , oxldl - induced lipid accumulation in macrophages was ameliorated by trpv1 agonists but exacerbated by trpv1 antagonist . treatment with trpv1 agonists did not affect the internalization of oxldl but promoted cholesterol efflux by upregulating the efflux atp - binding cassette ( abc ) transporters abca1 and abcg1 . moreover , the upregulation of abc transporters was mainly through liver x receptor - ( lxr - ) dependent regulation of transcription . moreover , the tnf -- induced inflammatory response was alleviated by trpv1 agonists but aggravated by the trpv1 antagonist and lxr sirna in macrophages . our data suggest that lxr plays a pivotal role in trpv1 - activation - conferred protection against oxldl - induced lipid accumulation and tnf -- induced inflammation in macrophages ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the smile design theory can be broken down into four parts : facial esthetics , gingival esthetics , microesthetics and macroesthetics . gingival esthetics involves health of the gingiva , shape of the interdental papilla and the presence or absence of black triangles . microesthetic features involve the anatomy of the anterior teeth , incisal translucency , characterization and lobe development . golden proportion is based on the theory that a relationship exists between the beauty in nature and mathematics . it states that the width of maxillary lateral incisor , when viewed from front , should be in golden proportion to the width of maxillary central incisor . thus , the width of maxillary lateral incisor should be 62 % the width of maxillary central incisor and the width of maxillary canine should be 62 % the width of resulting lateral incisor . golden percentage proportion given by snow states that the width of maxillary central incisor should be 25 % the intercanine distance , when measured from distal of canine on one side to the distal of canine on the contralateral side in the frontal view . width of maxillary lateral incisors and canines should be 15 and 10 % , respectively , of the intercanine distance [ figure 1 ] . golden proportion : calculating the width of maxillary anterior teeth using the golden proportion preston in 1993 studied the existence of golden proportion in natural dentition and found that only 17 % of the maxillary lateral incisors width was in golden proportion with the width of maxillary central incisors and none of the canines width were in golden proportion to the width of maxillary lateral incisor . he proposed preston 's proportion , that is , the width of maxillary lateral incisor should be 66 % the width of central incisors and the width of maxillary canines should be 55 % the width of maxillary central incisors in the frontal view [ figure 2 ] . preston 's proportion : calculating the width of maxillary anterior teeth using preston 's proportion ward in 2000 proposed recurring esthetic dental ( red ) proportion based on the different heights of the maxillary anterior teeth , which had not been considered in any of the proportions mentioned above . tooth height and desired recurring esthetic dental proportion golden proportion is one of the red proportions forfifteen male subjects and 15 female subjects in each age group of 1823 years , 2429 years and 3035 years were selected for this study ( total 90 ) . restorations in anterior teeth malalignment of anterior teeth congenital or acquired facial and dental defects history of orthodontic treatment photographs of the subjects were taken from the frontal view with nikon d200 camera , 135 mm lens with a tripod , at a distance of 1 m , and by the same and single investigator throughout the study . the width and height of maxillary central incisors , lateral incisors and canines were measured using the scale tool provided in the software [ figure 3 ] . ( a ) subject with well - aligned dentition , measuring the ( b ) height and ( c ) width of maxillary central incisors using the adobe photoshop cs4 extended software magnification was calculated by finding out the ratio between the actual height of central incisors measured on the subject 's cast and height of the central incisors measured using the photograph . once the magnification was calculated , the actual height of the central incisors was found out . depending on the maximum and minimum values for the height of central incisors , central incisors were divided into three categories small , medium and tall . then , the following ratios were computed : 1 ) ra1 ( ratio of the width of maxillary lateral incisors to central incisors ) , 2 ) ra2 ( ratio of the width of maxillary canines to lateral incisors ) , 3 ) ra3 ( ratio of the height of maxillary lateral incisors to central incisors ) , and 4 ) ra4 ( ratio of the height of canines to lateral incisors ) [ figure 3 ] . restorations in anterior teeth malalignment of anterior teeth congenital or acquired facial and dental defects history of orthodontic treatment photographs of the subjects were taken from the frontal view with nikon d200 camera , 135 mm lens with a tripod , at a distance of 1 m , and by the same and single investigator throughout the study . the width and height of maxillary central incisors , lateral incisors and canines were measured using the scale tool provided in the software [ figure 3 ] . ( a ) subject with well - aligned dentition , measuring the ( b ) height and ( c ) width of maxillary central incisors using the adobe photoshop cs4 extended software magnification was calculated by finding out the ratio between the actual height of central incisors measured on the subject 's cast and height of the central incisors measured using the photograph . once the magnification was calculated , the actual height of the central incisors was found out . depending on the maximum and minimum values for the height of central incisors , central incisors were divided into three categories small , medium and tall . then , the following ratios were computed : 1 ) ra1 ( ratio of the width of maxillary lateral incisors to central incisors ) , 2 ) ra2 ( ratio of the width of maxillary canines to lateral incisors ) , 3 ) ra3 ( ratio of the height of maxillary lateral incisors to central incisors ) , and 4 ) ra4 ( ratio of the height of canines to lateral incisors ) [ figure 3 ] . we can see from table 2 that the mean ra1 ( lateral incisor to central incisor width ratio ) for small category teeth was 73 % ( proposed ratio 80 % ) , for medium teeth was 72 % ( proposed 76 % ) and for tall teeth was 71 % ( proposed 62 % ) . similarly , the mean ra2 ( canine to lateral incisor width ratio ) for teeth of all the three categories was found to be different as compared to that proposed by ward in red proportion . comparison of mean values of ratio of the various tooth also , the mean ra1 ( lateral incisor to central incisor width ratio ) for small category teeth was not similar to ra2 ( canine to lateral incisor width ratio ) and similar results were obtained for medium - and tall - sized teeth . the average lateral to central incisor height ratio was found to be 84 % in tall - sized teeth and 84 % for small - and medium - sized teeth . golden proportion was given by levin based on the principle that there exists a relationship between the beauty in nature and mathematics and the same principle was applied in designing the width of maxillary anterior teeth . preston in 1993 studied the existence of golden proportion in natural dentition with pleasant smiles and found that golden proportion was hardly seen in the natural dentition and proposes his own preston 's proportion . stephen rosenstiel and ward in 2000 in their web - based study were the first to consider the importance of length of teeth in determining the width of maxillary anterior teeth . in case of tall central incisors , lesser width of lateral incisors and caninesis desired for an esthetic smile so that the width proportion is less , while in case ofsmall - sized central incisor teeth , greater width of lateral incisors and canines is desired so that the width proportion is more . golden proportion of 62 % is one of the red proportions for tall - sized teeth . the study was conducted to evaluate the existence of red proportion proposed by rosenstiel and ward in a small section of indian population with pleasant smiles . the teeth were divided into three categories , and it was found that in none of the three categories the maxillary lateral incisor to central incisor width ratio was similar to that proposed , and the maxillary lateral incisor to central incisor width ratio was also not similar to maxillary canine and lateral incisor width ratio , the two ratios were not seen recurring . the reason for such a finding could be that the proportions proposed by ward and rosenstiel in 2000 were basically computer and software based and no efforts were made to check if these proportions really exist in the natural dentition . the results obtained were similar to that obtained in the study done by shreenivasan in 2008 . the study was conducted on 56 subjects and red proportion was not seen in the natural dentition . it was also concluded that the width of maxillary anterior teeth follows more closely the golden percentage proportion given by snow in 1999 . none of the proportions mentioned in the literature describe about the relative height of lateral incisors and canines to be used along with the widths during the smile designing . in this study , relative heights of lateral incisors and canines were also determined to estimate the height of lateral incisor and canine in cases of esthetic reconstruction . the term medium has been used for the second category of central incisors instead of normal as proposed by ward , as thetall - sized teeth may be normal for subjects with long faces . as a general rule , while designing smile , neither of the proportions can be taken as a sole criterion to determine the width of maxillary anterior teeth . heights of the lateral incisors and canines can be roughly determined ( not mentioned in any proportions ) using results obtained from this study . again , these need to be modified according to age , sex , personality and profession as the width of maxillary anterior teeth . major limitation of this study was the small sample size and further studies need to be undertaken with a large sample size . second limitation is the lack of definitive sizes according to which the central incisors were divided into three categories that is small , medium and tall , which is not mentioned in the original article proposed by ward . in this study , the central incisors were divided accordingly based on the highest and lowest values for the height ( central incisors ) obtained . within the limitations of the study , red proportion was not seen in the natural dentition . medium - sized teeth was found to be 88 % and for tall - sized teeth was found to be 84 % . medium - sized teeth was found to be 106 % and for tall - sized teeth was found to be 105 % .\noutput:\n" }, { "from": "agent", "value": "background : different proportions are described in the literature for smile designing , such as golden proportion , golden percentage , preston 's proportion , and recently , recurring esthetic dental ( red ) proportion.aims and objectives : to evaluate the existence of red proportion in natural dentition . to determine the relative height of maxillary lateral incisor and canine occurring in natural dentition so that it can be used in any of the above proportions.materials and methods : fifteen male subjects and 15 female subjects in each of the different age groups of 1823 years , 2429 years and 3035 years were selected for this study ( total 90 ) . photographs of the subjects were taken using nikon d200 camera with 135 mm lens and analyzed using adobe photoshop cs4 extended software . the height and width of maxillary central incisors , lateral incisors and canines were found out using the measuring tool provided in the software.results : average width ratio and height ratio of maxillary lateral incisor to central incisor and maxillary canine to lateral incisor were calculated to check the existence of red proportion in natural dentition . average lateral incisor to central incisor height ratio for small - and medium - sized teeth was found to be 88 % and for tall - sized teeth was found to be 84 % . average canine to lateral incisor height ratio for small - and medium - sized teeth was found to be 106 % and for tall - sized teeth was found to be 105 % . conclusions : within the limitations of the study , red proportion was not seen in natural dentition ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: low - carbon technologies such as electric vehicles , fuel cells and photovoltaic power generation are expected to be the leading contenders for establishing a low - carbon society . these technologies utilize the specific physical properties of a handful of metals in core components such as motors and batteries . the countries where some of these metals are mined are located eccentrically around the world and the metals are sometimes used for diplomatic leverage , leading to considerable concern about supply risks and the metals often being referred to as critical metals . mining of the metal ores also causes serious environmental damage around extraction sites and final disposal of the metal - containing products is likewise often accompanied by environmental and health impacts . on the policy side , the european commission and the u.s . department of energy , for example , have published reports concluding that certain metals , including rare earths , are critical to the emerging clean energy economy . as these reports imply , there is serious concern that the spread of green technologies by countries endeavoring to limit their greenhouse gas emissions will inevitably increase demand for the metals in question , leading to a tightening of supply . as we strive to reduce global carbon emissions , it is therefore essential to limit the current growth of metals consumption while still meeting rising demand for them . in other words , in those countries and regions involved in any way with the global flow of the metals in questionit is necessary to use these metals more efficiently , that is , less wastefully , to reduce unnecessary mining . as summarized in reck and graedel , several material flow analyses have identified the life cycles of up to 15 types of critical metals , including rare earth elements , and estimated global stocks , going on to recommend establishment of a closed - loop material system in the global economy that recognizes technological and social limitations . however , these studies have not yet led to an analysis of how individual countries in the global economy are involved in such flows of critical metals and given little attention to the responsibilities and roles to be adopted by those countries other than recommending recycling based on so - called urban mining to reduce unnecessary consumption of the metals embodied in the flows . against this background , the objective of this study is to estimate and characterize the global flows of three critical metals necessary for low - carbon technologies : neodymium ( nd ) ( used , for example , in motor magnets ) , cobalt ( co ) ( e.g. , battery electrodes ) and platinum ( pt ) ( e.g. , fuel cell electrolytes ) . the study also aims to develop a simple indicator to identify trade commodities meriting international priority with respect to improving the performance of production technologies and social systems governing use of these critical metals . using this indicator , we furthermore discuss logical and strategic identification of the responsibilities and roles of the countries involved in the global flows . a material flow analysis ( mfa ) was conducted on neodymium , cobalt , and platinum , which are among the critical metals most widely used in low - carbon technologies . for considerations of space , we suffice here with a brief description of mfa methodology , with detailed descriptions of methodology and data being provided in the supporting information ( si ) . to create a complete global mfa system boundary , this study considered 231 countries and regions as listed in table s1 in the si . from the commodities traded internationally , all commodities k considered to contain the metals to be estimated ( nd , co , and pt ) were then selected . to this end , the harmonized system ( hs - ) codes ( double - digit or six - digit ) , that is , international standard trade category codes , were used . this led to selection of 153 commodities containing nd , 160 commodities containing co ( including copper ore ) and 151 commodities containing pt . we then examined the volumes of each of the selected commodities k traded between country i and country j , vij ( k ) . the trade volumes of the commodities k were organized based on free on board ( fob ) price ( 1000 us dollar / year ) or weight ( t / year ) taking 2005 as the target year using the base pour lanalyze du commerce international ( baci ) or international trade database at the product level , which is an improvement of the un comtrade database . however , some of the hs - codes , even in the six - digit category , integrate multiple commodities , including instances where , among the many commodities , only one contains the metal ( s ) in question . hence , in this study , the trade volumes of each commodity obtained from baci were assigned a cutoff value ri ( k ) between 0 and 1 , which was multiplied by the trade volume to increase the accuracy of the estimated trade volume of the commodity containing the critical metal ( s ) of interest . the percentage metal content ci ( k ) ( t / 1000 us dollar or t / t ) of each selected commodity was then determined . next , the initial estimates of metals tij ( k ) moving between countries in commodity trade were calculated by multiplying the international trade volume of each commodity , the assigned cutoff value and the percentage metal content : tij ( k ) = vij ( k ) ri ( k ) ci ( k ) . finally , a calibration was made to the above initial estimates to satisfy the material balance of the metal within each country by resolving the quadratic problem ( as explained in the si ) . the estimated tij ( k ) indicates the amount of metal contained in commodity k that is produced in country i and moved to country j , where it is consumed or processed further and possibly exported to another country . to obtain a comprehensive overview of the structure of the flows with a view to exploring wasteful consumption , we partitioned the flows by examining the technological characteristics of the import and export country . such an analysis provides a ready way to identify hotspots of metal consumption where this is major room for improvement . conceptually , it is desirable that these characteristics are assessed using a quantitative indicator such as the material - use efficiency of the metal in producing or using commodity k in each country . as an mfa indicator , material - use efficiency is defined as the amount of raw material effectively utilized divided by the total amount consumed and gives an indication of the degree to which byproducts are recycled and waste generation is suppressed . here , the assumption is made that all countries can be approximately characterized as having either a high or low material - use efficiency , so that global flows of the metals can be classified into one of three material - use efficiency classes , as described below . in the first class of material - use efficiency , it is assumed that country i exporting commodity k has high - level production technologies and material - use efficiencies , and is capable of nonwasteful use of the metal in its products . at the same time , country j importing commodity k also has high - level production technologies and is capable of nonwastefully using commodity k containing the metal . in addition , even when country j consumes commodity k , it has a high technological level for recovering resources from spent products , such as mobile phones . this is in addition to it being a country that can establish and implement advanced social systems for recovering critical metals , making it a country with a high overall material - use efficiency . in the above cases , critical metals moved by country i to country jare produced based on a high material - use efficiency and subsequently consumed with a high material - use efficiency . this results in the highest material - use efficiency between two countries for the amount of metal tij ( k ) moved , so it can be classified as a flow that boosts nonwasteful use of critical metals . in this paper , such a flowis referred to as a green flow . in the second class , either the exporting country i or the importing country j does not have a high technological level or advanced social systems . if exporting country i currently has a low technological level , the amount of metal tij ( k ) moved in commodity k has a low material - use efficiency . even if commodity k is subsequently used more extensively with a high material - use efficiency in the importing country j with a high technological level , the material - use efficiency between the two countries for the amount of metal tij ( k ) moved is considered to be only moderate . in such a case , the flow can be considered to be inferior to the first class ( i.e. , green flows ) , where both countries have high technological and social levels . in this paper , such a flowis referred to as a yellow flow ( moderately efficient use ) . the same applies in the reverse situation . if exporting country i has a high technological level , commodity k is produced with a high material - use efficiency . if commodity k is used in importing country j with a low technological level , then the efficiency is poor , or the spent products can not be collected or resources recycled , making the material - use efficiency low . as a result , the material - use efficiency between the two countries for the amount of metal tij ( k ) moved is inferior to when both countries have high technological and social levels , that is , a green flow . however , determining when to characterize material - use efficiency as being superior or inferior to the previous case ( yellow flow ) in which the importing country has a low technological level and the exporting country has a high technological level is not straightforward . in this study , such a flow is therefore also classified as a yellow flow . in the final class , both the exporting country i and the importing country j have low levels of production technologies and social systems . the material - use efficiency between the two countries for the amount of metal tij ( k ) moved is lowest of all . this leads to an increase in the amount of mining . in this paper , this flow is classified as being the least efficient for the amount moved and is classified as a red flow ( inefficient use ) . partitioning the global flowstij ( k ) of metals based on the polarized characteristics of countries i , j with respect to commodity k as set out above is an extremely simple method . despite its simplicity , though , the strength of this approach is its usefulness in reviewing the structure of an extremely large number of complex global flows . moreover , this simple method is readily applicable to other environmental and social issues . partitioning the flows in terms of the degree of impact on biodiversity associated with metal use in each country , for instance , would yield a general picture of the hotspots of flows related to threatened species . alternatively , flow partition based on the trade risk of each country would permit identification of the bottlenecks of critical metal flows . additionally , because of the classification s focus on countries , this approach can be readily used to design a framework of international cooperation and partnership to resolve the environmental and social issues associated with international trade in metals . the first relates to the need for data on all the countries involved in the flows . in some cases it is necessary to use proxy values or indicators that provide only an indirect indication of the country s characteristics of interest . the second relates to the need to assign a representative single value to each country because of the assignment of polarized characteristics . this means that even if there are a few companies with a high technological level in a country , if the most of companies have a low technological level , the overall level of the country is defined as low . due attention therefore needs to be given to the limitations implied in in classifying flows by means of such proxy data or single values . classifying the metal flows into three types is equivalent to dividing a network into two subsets , assuming that the countries and regions i , j are nodes and that the flows are edges . this division has the same aim as the methodology of network partitioning employed in network theory to elucidate the network structure , a method that has recently been applied to the structural analysis of carbon footprints . by adopting the methodology of network partitioning and developing it further in more in - depth studies , it is anticipated that the structural characteristics of international resource flows can be comprehensively elucidated , thus laying the groundwork for proposals for international policies on resource use efficiency . in order to categorize critical metals use in producing or using commodity k by countries into those with high - level production technologies and social systems ( h countries ) andthose with low - level production technologies and social systems ( l countries ) , countries need to be distinguished according to the technologies and recycling systems they have implemented . unfortunately , conducting dedicated national surveys to examine these issues in any detail would be very costly in terms of time and labor , while at the same time technologies for using and recycling critical metals are constantly evolving . furthermore , there are currently no data or statistics available that quantitatively assess technological information relating to critical metals . we therefore attempted to classify countries based on their potential for technological improvement using available statistics on the general technological level of each country . to this endwe used the global competitiveness report published by the world economic forum as a source of surrogate data on the technological and social levels of individual countries . specifically , from among the more than 100 indicators evaluated by the report for 144 major countries , we focused on the following seven indicators relating to science and technology : availability of latest technologies , firm - level technology absorption , capacity for innovation , quality of scientific research institutions , company spending on r & d , university - industry collaboration in r & d and governmental procurement of advanced tech products . we then took countries scoring above average on all seven indicators to be countries having high - level production technologies and social systems ( h countries ) , with the remaining countries being classified as having low - level production technologies and social systems ( l countries ) . although these h and l countries should in principle be defined in relation to a specific commodity k , this study applied the same h and l classification of countries to all commodities . in alphabetical order , the following 29 nations emerged as h countries : australia , austria , belgium , brazil , canada , denmark , estonia , finland , france , germany , hong kong , iceland , israel , japan , south korea , luxembourg , malaysia , netherlands , new zealand , norway , portugal , puerto rico , qatar , saudi arabia , singapore , switzerland , taiwan , united kingdom , and united states . as outlined above , we here propose a simple indicator to prioritize myriad commodities in international trade in order to improve the efficiency of critical metal use . the indicator characterizes trade commodities as green - , yellow - , and red - flow commodities according to the extent to which the three color flows ( green , yellow , and red ) are involved in the flow of commodities containing critical metals . to this end , first the amounts of critical metals tij ( k ) contained in commodity k were classified as green , yellow , and / or red flows , using eqs 13 , below . when green flows are largest , commodity k is classified as a green - flow commodity , when yellow flows are largest as a yellow - flow commodity , and when red flows are largest as a red - flow commodity . when two values were the same , the next lowest color classification was used as a conservative estimate , and when all three values were the same the commodity was labeled a red - flow commodity . introducing h for the aggregate of country i and country j both having high - level production technologies and social systems , andl for the aggregate of country i and country j both having low - level production technologies and social systems , this gives123 when greenflow yellowflow , and greenflow redflow , commodity k is defined as a green - flow commodity . when yellowflow greenflow and yellowflow redflow , commodity k is defined as a yellow - flow commodity . when redflow greenflow and redflow yellowflow , commodity k is defined as a red - flow commodity . the results show that , in 2005 , 12540 t ( 1 t = 10 kg ) of nd ore was mined and 18565 t of nd was moved on global markets . metals move between countries and regions at various points in the course of their lifecycle : after mining , during conversion from ore to bare metal , following production of semiprocessed goods , components and products , and for disposal of scrap and waste material . the amount of metal is counted each time it moves , resulting in a volume moved that is greater than the volume mined . thus , the gross quantity of nd feeding into product supply chains around the world is about 1.5 times larger than the quantity mined . the implication is that the greater the amount of metal moved relative to the amount mined , the greater the international fragmentation of labor involved in the metal s fabrication and processing . aggregating the 153 types of traded commodities containing nd into the four categories of ore , materials , products , and scrap and waste reveals that the contribution of the latter three categories to global nd flows is 15586 t for materials , 2968 t for products , and 11 t for scrap and waste , with no flow as ore . specifically , at the commodity level ( hs - code ) , hs - 280530 ( rare - earth metals , scandium , and yttrium ) accounts for 6294 t , followed by 2693 t for hs - 850511 ( permanent magnets and magnetized articles of metal ) and 2219 t for hs - 284960 ( rare - earth metal compounds ) . when all commodities containing nd are included , the major exporting countries are not necessarily nd - mining countries . the top three exporters of nd are china ( 9874 t ) , japan ( 1494 t ) , and germany ( 765 t ) . the four commodity types exported from china consist of 8662 t as materials , representing 88 % of the total exported , and 1214 t ( 12 % ) as products . from japan and germany , in contrast , 615 t ( 41 % ) and 460 t ( 60 % ) are exported as materials and 879 t ( 59 % ) and 296 t ( 39 % ) as products , respectively . the top three importers of nd , on the other hand , are japan ( 4218 t ) , the u.s . japanese nd imports consist of 4128 t as materials , which account for 98 % of the total nd imported . for the u.s . andgermany , the share of nd imported as products is smaller than in the case of japan , with materials accounting for 2298 t ( 85 % ) and 868 t ( 88 % ) , respectively , and products for 396 t ( 15 % ) and 119 t ( 12 % ) . in 2005 , 1072 kt ( 1kt = 10 kg ) of co was mined , with 154 kt of co being moved on international markets : 38.3 kt as ore ( excluding copper ore not currently used as a source of co ) , 93.1 kt as materials , 2.16 kt as products and 0.81 kt as scrap and waste . among the 160 different commodities containing co , the top three global flows were 64.5 kt of hs - 810510 ( cobalt mattes and other intermediate products of cobalt metallurgy ; unwrought cobalt ; waste and scrap ; powders ) , 21.7 kt of hs - 260500 ( cobalt ores and concentrates ) and 20.1 kt of hs - 850780 ( electric accumulators ) . the top three exporting countries of co - containing commodities are the democratic republic of the congo ( 22 kt ) , china ( 13 kt ) and japan ( 10 kt ) . for congo , the flows consist mainly of exports of commodities categorized as ore , accounting for 74 % of its co exports . in the case of china and japan , in contrast , 59.0 % and 75.9 % of the commodity export flows are products . the top three importers of co , on the other hand , are japan ( 22.9 kt ) , china ( 18.7 kt ) , and the united states ( 14.5 kt ) . japan and the united states receive co mainly as a material , accounting for 60.4 % and 79.4 % of their total co imports , while china imports 52.6 % of its co as ore . in 2005 , 259 t of pt was mined from the ground . global pt flows were estimated at 402 t , comprising 6.2 t as ore , 384 t as material , 3.2 t as products and 8.9 t as scrap and waste . flows of hs - 711011 ( unwrought or in powder form platinum content ) comprise 321 t and hs - 711019 ( other platinum content ) 48 t. these amounts are followed by a 8.7 t flow of hs - 711290 ( waste and scrap of precious metal or of metal clad ) . for pt , the top three exporting countries are south africa ( 135 t ) , the uk ( 41 t ) and germany ( 39 t ) . these flows consist primarily of pt exported as material : 99.9 % for south africa , 98.3 % for uk , and 96.3 % for germany . ( 72 t ) , germany ( 55 t ) , and japan ( 54 t ) , with the main flows of pt to these counties taking the form of material , viz . figure 1a shows the 50 largest nd flows among the global flows estimated ; the top three routes are dominated by exports from china , viz . from china to japan ( 4053 t ) , the usa ( 1731 t ) and hong kong ( 425 t ) . these are followed by austria to unspecified regions ( the region category in baci ) , at 384 t , and china to germany , at 369 t. figure 2a summarizes the flows of nd among countries in eight regions of the world ( north america , latin america , western europe , africa , middle east , central - eastern europe and russia , asia and oceania ) . the flows are colored to represent the type of commodity ( ore , materials , products , and waste and scrap ) . immediately , the flow of materials within asia stands out . while flows of materials from asia to western europe and north america are comparatively large , it is the flows of nd - containing products from asia to foreign countries that dominate global flows . the 50 largest global flows of critical metals through international trade in 2005 ( a : neodymium , b : cobalt , c : platinum ) ; for the top 10 flows , the countries and volumes of critical metal involved ( tonne for neodymium and platinum , kt ( 10 tonne ) for cobalt ) are indicated in red letters . ( a ) global flows of neodymium among eight regions by four types of trade commodity ( ore , materials , products and w & s ( waste and scrap ) ) in 2005 ; each legend indicates the volume of neodymium in tonnes , the commodity type and the regions driving the flow ( as : asia , af : africa , c : central - eastern europe and russia , l : latin america , m : middle east , n : north america , o : oceania , w : western europe ) . ( b ) global flows of cobalt among eight regions by the trade commodity type in 2005 ; each legend indicates the volume of cobalt in kt larger than 200 kt . ( c ) global flows of platinum among eight regions by trade commodity type in 2005 ; each legend indicates the volume of platinum in tonne larger than 0.2 tonne . figure 1b , in turn , shows the 50 largest flows of co ( excluding co in copper ore ) between countries . the top five flows are from congo to china ( 7.7 kt ) , followed by congo to zimbabwe ( 6.5 kt ) , congo to finland ( 4.9 kt ) , finland to japan ( 4.3 kt ) and indonesia to japan ( 3.8 kt ) . figure 2b , characterizing co flows among eight regions of the world , shows that co moves as ore from africa , where it is mined , to asia and western europe , where it is processed to materials . it is then exported to broader regions , with the largest flow comprising material within western europe , followed by the flow from western europe to asia . with respect to product flows , those within asia and from asia to other regions are comparatively large , indicating that the flows in the international supply chain of co generally proceed from africa to western europe and then to asia . in the case of pt , illustrated in figure 1c , the flow from south africa to japan ( 35 t ) emerges as the largest , followed by the flows from south africa to the united states ( 33 t ) , south africa to switzerland ( 24 t ) , india to the united arab emirates ( 23 t ) and the uk to the united states ( 17 t ) . figure 2c shows the regional characteristics and flows of pt among eight regions of the world . the flow of pt as material consists primarily of the movement from africa , where it is mined , to asia , western europe and north america . pt moves as material within western europe , then flows from western europe to asia and north america . the shares of green , yellow , and red flows in total global flows of nd are 1.2 % , 98 % , and 1.2 % , respectively . in the case of co , the respective figures are 53 % , 28 % , and 19 % , whereas for pt they are 15 % , 84 % , and 0.87 % . by way of example , figure 3 shows the trading volumes of nd contained in the commodity hs - 852520 ( transmission apparatus for radiotelephony incorporating reception apparatus ) in 2005 . on the x - axis , importing l - countries are countries 1201 and h - countries are 202231 . for descriptive purposes , in each category the countries are ranked according to their gdp . on the y - axis , exporting countries are arranged in the same order , while the z - axis indicates the quantity of nd contained in the commodity in question . the area enclosed by countries 1201 on the x - and y - axes indicates red flows ( low to low ) , which comprise 11 % of the overall flow . the area enclosed by countries 202231 on the x - and y - axes represents the green flow ( high to high ) and comprises 36 % of the overall flow , while the remainder of the area represents the yellow flow ( high to low , low to high ) , which is the largest of all at 53 % . global flows of neodymium contained in transmission apparatus for radiotelephony incorporating reception apparatus ( hs - 852520 ) ; an example of the trade commodity characterization ( red , yellow , and green - flow commodities ) based on the relative shares of red , yellow , and green flows of the commodity in question . high , low refer to the technological level of the country ( see text ) . when we similarly categorized 153 types of internationally traded commodities containing nd , 19 were found to be green - flow commodities , 96 were yellow - flow commodities and the remainder 38 were red - flow commodities . si table s2 reports the categories of trade commodities containing nd , whereas table 1a shows those commodities with the three largest red , yellow , and green flows ( table 1b for co , table 1c for pt ) . among the red - flow commodities , those with the largest flows and deserving greatest attention are hs - 845019 ( washing machines of a dry linen capacity not exceeding 10 kg ) ( 15.0 t ) , hs - 850780 ( other electric accumulators ) ( 14.8 t ) and hs - 841869 ( refrigerating and freezing equipment except refrigerators , freezers , cabinets , display counters , showcases , and similar furniture ) ( 13.4 t ) . the yellow - flow commodities with the three largest flows are hs - 280530 ( rare - earth metals , scandium , and yttrium , whether or not intermixed or interalloyed ) ( 6294 t ) , hs - 850511 ( permanent magnets and articles intended to become permanent magnets of metal ) ( 2694 t ) and hs - 284690 ( compounds , inorganic or organic , of rare - earth metals , of yttrium or of scandium or of mixtures of these metals ( excl . cerium ) ) ( 2219 t ) . we also categorized 159 types of internationally traded commodities containing co ( excluding copper ore ) , of these , 22 are green - flow commodities , 49 are yellow - flow commodities and the remaining 88 are red - flow commodities . for the 151 types of commodities containing pt , 14 emerge as green - flow commodities , 58 as yellow - flow commodities , and the remaining 79 as red - flow commodities . the full lists of commodities containing co and pt are provided in si tables s3 and s4 . one of the ways in which nonwasteful use of critical metals can be enhanced is by countries improving their efficiency of material use . to improve such efficiency worldwide , countries with advanced production technologies and social systems to support themshould strategically spread these technologies and systems to countries that are technologically less advanced . the red , yellow , and green flow categories employed in the present study can be used to prioritize those production technologies and systems that are most in need of being disseminated . many of the commodities categorized as red - flow commodities have supply chains that pass through l - countries as exports or imports . consequently , improving technologies for producing and using red - flow commodities should be afforded very high priority . there are only a limited number of h - countries that produce or use red - flow commodities , and these countries need to play an international role in disseminating efficient production technologies to l - countries exporting such commodities . similarly , since few h - countries import red - flow commodities , they could provide the appropriate technologies for improving the material - use efficiencies of critical metals to l - countries importing such commodities . the next priority should be yellow - flow commodities whose supply chains pass through l - countries , either as exports or imports . among yellow - flow commodities , first there is the case where the exporting country is an h - country ( i.e. , h to l ) . since there are relatively few h - countries importing yellow - flow commodities , these h - countries need to assist the many l - countries importing yellow - flow commodities in order to improve the material - use efficiency of the latter countries . conversely , among yellow - flow commodities , in cases where the importing country is an h - country ( l to h ) , it is desirable for h - countries that export yellow - flow commodities to play a role in transferring their production technologies to the many l - countries exporting such commodities . these differences in the types of yellow - flow commodities ( h to l or l to h ) are shown in si tables s2s4 . finally , there are green - flow commodities that are traded between h - countries . for these commodities , it is essential for h - countries to constantly try to improve their own production and usage technologies . additionally , to reduce actual demand for critical metals , these h - countries need to invest in recycling technologies for green - flow commodities and to focus on social frameworks for reusing these commodities . based on the technical level of each country derived from the indicators of the global competitiveness report ( see section 2.2.3 ) , a specific analysis was undertaken to ascertain what specific contribution by which country would be important for upgrading red - flow commodities to yellow and green - flow commodities . si table s2 shows the top three h - countries with the largest imports and exports of red - flow commodities containing nd ( see si table s3 for co and si table s4 for pt ) . it would be desirable for h - countries importing red - flow commodities to transfer their own technologies to l - countries , that is , induce the latter to adopt technologies contributing to more efficient resource use . for instance , the key importing h - countries of hs - 845019 ( washing machines of a dry linen capacity not exceeding 10 kg ) listed in table 1 are malaysia , norway , and france . the top three h - countries importing hs - 850780 ( electric accumulators ) are finland , austria , and malaysia , whereas the top three importers of hs - 841869 ( refrigerating and freezing equipment except refrigerators , freezers , cabinets , display counters , showcases , and similar furniture ) are germany , austria , and france . on the other hand , the key exporting h - countries of hs - 845019 ( washing machines of a dry linen capacity not exceeding 10 kg ) are denmark , hong kong , and france . the top three h - countries exporting hs - 850780 ( electric accumulators ) are estonia , germany , and switzerland , whereas the top three exporters of hs - 841869 ( refrigerating and freezing equipment except refrigerators , freezers , cabinets , display counters , showcases , and similar furniture ) are switzerland , germany , and estonia . the dissemination and transfer of production technologies for the red - flow commodities associated with these countries will , once again , increase the sustainability of resource use . similarly , si table s2 indicates the h - countries with the highest imports and exports of yellow - flow commodities ( l to h and h to l , respectively ) . considering the yellow - flow commodities in table 1 , hs - 280530 ( rare - earth metals , scandium , and yttrium ) are type l to h , and in this case contributions can be made by the top three exporters among h countries : austria , japan , and malaysia . hs - 850511 ( permanent magnets and articles intended to become permanent magnets of metal ) and hs - 284690 ( compounds of rare - earth metals / yttrium / scandium / mix of these metals excl . cerium ) are also of type l to h. among h - countries , japan , germany , and the u.s . are the top three exporters of hs - 850511 and austria , france , and estonia of hs - 284690 . since such commodities contain the most nd , encouraging the h - countries to take the initiative to supply technologies to boost material - use efficiencies for nd will benefit the entire world as well as l - countries . in this way , h - countries can indirectly facilitate the procurement of nd from international flows of nd . that is , by considering the strategic supply of technologies , it is possible to create synergistic benefits at the national and global level . by making h - countriesunderstand the role expected of them , it may be possible to enhance the speed and likelihood of sustainable resource - use practices being adopted in the future . to achieve the aim of more sustainable resource use , there is also a need for policies that strongly encourage such technologies as well as associated r & d . at the same time , though , considerable caution needs to be applied with respect to the technological levels assumed in this study , as these were determined solely on the basis of information about the general scientific and technological status of individual countries . in order to rigorously and accurately characterize the commodities involved , the critical - metal production and processing technologies actually used in each country will need to be assessed , and policy decisions made on the basis of observed strengths and weaknesses . as with the global competitiveness report employed in the present study , it is desirable to implement the necessary research through international cooperation . as a starter , it would suffice to conduct a questionnaire survey on the critical - metal production and processing technologies used by the world s major industries , encompassing the entire life cycle of the metal from mining through to recycling and disposal . finally , innovation and dissemination of new energy technologies and low - carbon technologies involving growing consumption of critical metals are both necessary conditions for supporting a world population of over 9 billion people while at the same time limiting greenhouse gas emissions . to achieve these aims , as has here been illustrated with the example of certain h - countries with respect to red - flow and yellow - flow nd - containing commodities , it is essential for such countries to objectively consider their own positions and responsibilities in the international circulation of precious resources and to fulfill the roles required of them . in addition , it may be necessary to formulate international rules relating to trade , financial assistance , and technical assistance that will facilitate fulfilment of these roles and responsibilities .\noutput:\n" }, { "from": "agent", "value": "this study , encompassing 231 countries and regions , quantifies the global transfer of three critical metals ( neodymium , cobalt , and platinum ) considered vital for low - carbon technologies by means of material flow analysis ( mfa ) , using trade data ( baci ) and the metal contents of trade commodities , resolving the optimization problem to ensure the material balance of the metals within each country and region . the study shows that in 2005 international trade led to global flows of 18.6 kt of neodymium , 154 kt of cobalt , and 402 t of platinum and identifies the main commodities and top 50 bilateral trade links embodying these metals . to explore the issue of consumption efficiency , the flows were characterized according to the technological level of each country or region and divided into three types : green ( efficient use ) , yellow ( moderately efficient use ) , and red ( inefficient use ) . on this basis , the shares of green , yellow , and red flows in the aggregate global flow of nd were found to be 1.2 % , 98 % , and 1.2 % , respectively . for co , the respective figures are 53 % , 28 % , and 19 % , and for pt 15 % , 84 % , and 0.87 % . furthermore , a simple indicator focusing on the composition of the three colored flows for each commodity was developed to identify trade commodities that should be prioritized for urgent technical improvement to reduce wasteful use of the metals . based on the indicator , we discuss logical , strategic identification of the responsibilities and roles of the countries involved in the global flows ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: lactate is certainly not a pyromaniac : it is not toxic and possesses no harmful effect per se . it is probably a trustworthy sentinel because it sensitively indicates that fire is potentially in the house and numerous works have already shown a good relationship between lactate level and outcome . above all , it is an indispensable soldier that actively acts as a major intermediate involved in the vast cellular and organ energy interplay , allowing the body to cope with a wide range of metabolic disorders ( for example , exercise , hypoxia , ischemia , severe sepsis , shock ) . based on their broad experience in the management of the profound metabolic derangements observed in critical illnesses , associated with some experimental data , valenza et al . propose , in a review - hypothesis paper in this issue of critical care , to regard lactate increase in the intensive care unit as a marker of a metabolic adaptation requiring a therapeutic aid ( \" possibly indicating that ' there is still room ' to boost fast intervention \" ) rather than a sign of irreversible end - stage energy failure . in this context , these authors propose to take the decrease in blood lactate following a therapeutic challenge as a major indicator of the efficacy of such treatment . this proposal seems absolutely correct and very close to what has been already proposed regarding oxygen consumption ( vo2 ) , but with a simple bedside parameter of metabolic integration . indeed , whatever the cause of derangement and the metabolic environment , any rise in blood lactate indicates an attempt by the body to adapt to an unusual energetic situation , which may affect redox state , phosphate potential or ph . moreover , as indicated by the authors , lactate production requires a complete glycolytic pathway , that is , an intact cell with sufficient glucose supply or glycogen storage . therefore , in ischemic tissues , which do n't have a sustained supply of blood glucose , a substantial amount of lactate can be released as long as glucose is present in the interstitial fluid or in the cells ( glycogen ) . thus , it should be noted that a decrease in lactate might imply ' a correction ' of the initial disorder but also an exhaustion of the precursor ( glucose ) or a destruction of tissues . in fact , as for any metabolite , lactate concentration depends on the ratio between production and consumption . because these two parameters are not routinely assessed at the bedside , however , the pathophysiological view is mostly based on lactate concentration only , which may represent a sometimes hazardous shortcut . lactate metabolism is intimately linked to the three major potentials of living systems , all strictly related to energy metabolism : redox potential ( ( nadh , h + ) / nad + ) ; phosphate potential ( atp / ( adp pi ) ) ; and hydrogen potential or ph ( 6.1 + log ( hco3 - / 0.03 paco2 ) ) . the first indicates a potential deficit in oxidation ( oxygen or oxidative capacity ) , the second shortage in energy and the third , which is closely linked to these parameters , could be viewed as a metabolic tool allowing the exact matching between them . atp turnover is controlled by ph [ 5 - 10 ] : acidosis decreases atp turnover and oxygen demand , representing an adapted or deleterious event depending on how deep , how long and how reversible . although there is no doubt about the fact that a change in lactate metabolism is linked to energy imbalance , the complete picture of the mechanisms involved in lactate regulation , which represents just a piece of a very complex puzzle , triggering or inducing an adaptive response is not completely clear as yet . however , anaerobic atp supply from a glycolytic anaerobic source is limited in terms of its sustained rate of atp production , except for a very acute and short muscle contraction . as a matter of fact , 300 ml / minute oxygen consumption ( vo2 = 13.4 mmol o2 ) represents an atp turnover of approximately 80 mmol / minute , which costs about 1.6 mmol / minute ( 0.3 g ) of glucose when oxidized and 40 mmol / minute ( 7.2 g ) when metabolized anaerobically . hence , the entirety of liver glycogen would be consumed in about 15 minutes as there is no glucose release from glycogen in muscle cells because of the lack of glucose - 6 phosphatase . with the exception of initial muscle contraction , increased anaerobic glycolytic atp production is adaptive for a fall in mitochondrial ( aerobic ) atp supply only when associated with a decrease in atp consumption , imposing a new hierarchical setting on the different atp consuming pathways . in other words , lactate - associated ( anaerobic ) atp production is an appropriate response to ischemia , anoxia or any kind of energy crisis only when the body can simultaneously save energy . the consequences of these changes in cell priorities represent a major aspect of understanding metabolic derangement in acute organ failure . acidosis is linked to energy metabolism and lactate homeostasis is related to both ph and energy status . when metabolic or respiratory acidosis is the initial event , it depresses energy expenditure and lactate might rise , but only modestly . in contrast , when the primary defect concerns energy homeostasis , ph decrease is adaptive : lowering energy expenditure allows matching a decrease in oxidative atp synthesis capacity and the rise in lactate concentration and turnover is part of this adaptation . it should also be considered that rises in lactate also occur frequently in the absence of acidosis , or even simultaneously with alkalosis . indeed , several causes of hyperlactatemia encountered in intensive care unit patients appear to be independent of any defect in cellular energy status . in these situations , the significance and prognostic value of such hyperlactatemia are very different from those associated with acidosis . in conclusion , the significance of hyperlactatemia depends on the concomitant acid - base status because of a common link with energy metabolism . when acidosis is the primary cause of the metabolic abnormalities , cellular energy deficit is a consequence , lactate rise is modest and correction of ph improves the metabolic disorder . when the cellular energy defect is the primum movens , hyperlactatemia and acidosis are its consequences and ph correction without simultaneous improvement of the energy defect impairs the adaptive response to energy failure , as represented by acidosis . when lactate increases in the absence of acidosis , it probably indicates a lack of a relationship with energy deficit .\noutput:\n" }, { "from": "agent", "value": "lactate , indispensable substrate of mammalian intermediary metabolism , allows shuttling of carbons and reducing power between cells and organs at a high turnover rate . lactate is , therefore , not deleterious , although an increase in its concentration is often a sensitive sign of alteration in energy homeostasis , a rise in it being frequently related to poor prognosis . such an increase , however , actually signifies an attempt by the body to cope with a new energy status . hyperlactatemia , therefore , most often represents an adaptive response to an acute energy disorder . investigation of lactate metabolism at the bedside is limited to the determination of its concentration . lactate metabolism and acid - base homeostasis are both closely linked to cellular energy metabolism , acidosis being potentially a cause or a consequence of cellular energy deficit ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: thus , vitamin d levels , or serum 25 - hydroxyvitamin d ( 25 ( oh ) d ) , fluctuate seasonally .25 ( oh ) d levels are low during the winter in northern latitudes because of decreased amounts of sunlight . a conventional diet usually does not provide adequate amounts of vitamin d. vitamin d insufficiency results in a number of skeletal and extraskeletal complications . it has been associated with decreased muscle strength , breast cancer , colon cancer , cardiovascular disease , and autoimmune disorders such as type 1 diabetes , rheumatoid arthritis and systemic lupus erythematosus . based on vitamin d 's role in the basic innate immune defense mechanisms , levels of 25 ( oh ) d , below 17.8 ng / ml are associated with a 26 % increased risk of all - cause mortality in the general population even after adjusting for known cvd risk factors , socioeconomic status , and other characteristics . in vitro and in vivo studiesshow a role for vitamin d as an important component of the innate immune system . expression of vitamin d receptor occurs in different cells of the myeloid and lymphoid lineage . the active form of vitamin d , 1,25 - dihydroxyvitamin d ( 1,25 ( oh ) 2d ) , increases the production of endogenous antibiotics called antimicrobial peptides ( amp ) in human monocytes , neutrophils , and epithelial cells . amps such as defensin and cathelicidin have a broad range of actions against microorganisms , including bacteria , fungi , and viruses . liu et al . showed that stimulation of toll - like receptors ( tlr ) 2/1 engages a vitamin d - dependent intracellular circuit that results in the expression of cathelicidin , enhancing the microbicidal capability of the monocyte . remarkably , the authors also observed that sera from african - american individuals , who are known to have substantially lower serum 25 ( oh ) d levels than whites , were inefficient in inducing genetic expression of cathelicidin . when the sera was supplemented with 25 ( oh ) dthis suggests that vitamin d insufficiency during the winter may increase susceptibility to infections , particularly viral respiratory infections . it is estimated that 72 % of adults experience at least one uri per year and those adults experience an average of 2.5 uris per year . every year 5 % to 20 % of the u.s . vitamin d may also play a role in reducing the severity of uri symptoms by regulating specific cytokines that participate in the host inflammatory response . vitamin d 's role in fighting influenza may be dependent on suppression of pro - inflammatory cytokines interferon gamma , tnf - , and il - 12 in the macrophage .1,25 ( oh ) 2d has been shown to inhibit mononuclear and t lymphocyte cell proliferation by decreasing the production of il - 1 , il - 2 , il - 6 , interferon ( ifn - ) , and tnf - . a randomized controlled trial by schleithoff et al. showed that 50 g / day ( 2000 iu / day ) of vitamin d3 reduced the inflammatory milieu in chf patients .1,25 ( oh ) 2d may play a protective role against inflammatory bowel disease as was shown in a mouse model of colitis . tissue - specific alterations in the expression of cytokines il - 1 , il - 10 , and il - 17 were demonstrated in cyp27b1 knockout mice . when reviewing the adverse events from our prior study of vitamin d3 supplementation in postmenopausal african american women , we noticed a significant difference in the reported incidence of uri symptoms between the active vitamin d group and the placebo group . this finding led us to conclude that higher doses of vitamin d supplementation may protect against viral uri 's . current recommendations for vitamin d intake are based on amounts required to sustain optimal skeletal health . schleithoff 's study and our prior study suggest that optimal function of the innate immune system might require higher doses of vitamin d. in this study , we administered 50 g / day ( 2000 iu ) of vitamin d3 which is the tolerable upper intake level ( ul ) for vitamin d for children and adults set by the food and nutrition board of the institute of medicine . believe that higher intakes of vitamin d are necessary and that these higher intakes are safe . the role of vitamin d in the body 's ability to fight influenza and uri 's may be dependent on regulation of specific cytokines that participate in the host inflammatory response . the aim of this study was to test the hypothesis that vitamin d can influence intracellular signaling to regulate the production of cytokines . the levels of 10 different cytokines produced by t cells ( th1 , th2 , regulatory t cells , nk cells ) and macrophages were measured in the serum of participants at baseline and the final visit . study participants were recruited from the long island , new york community ( latitude , 40.7 degrees n ) between december 2006 and march 2007 ( figure 1 flowchart ) . volunteers were recruited from local newspaper advertisements , mailing of brochures to community residents , and flyers posted at winthrop university hospital medical offices . patients were eligible for the study if they met the following criteria : ambulatory adult age 1880 and stable medical condition with no change in medications for 6 months prior to study entry . exclusion criteria included morbid obesity ( body mass index 35 kg / m ) ; current tobacco use ; history of hypercalcemia , nephrolithiasis or sarcoidosis ; pregnancy ; recent hospitalization ; current liver or kidney disorders , malignancy and malabsorption ; and use of immunosuppressants or medications that interfere with vitamin d metabolism such as phenytoin and carbamazepine . all participants provided written informed consent and the trial was approved by the institutional review board of winthrop university hospital . this study was a 3 - month prospective , randomized , double - blind , placebo - controlled trial of vitamin d3 supplementation in ambulatory adults . recruitment began from december 2006 to march 2007 and the study was completed in june 2007 . the participants were randomly assigned using a computer - generated randomization sequence to receive either 50 g / d of vitamin d3 or matching placebo . each subject was sequentially assigned a number upon study entry and the investigators dispensed the corresponding sequentially numbered container of study medication to the subject . all participants and investigators were blinded throughout the study except for the research pharmacist and the statistician . neither the statistician nor the research pharmacist had any contact with study participants . eligible subjects underwent a baseline medical history , height and weight measurements , and blood tests .25 ( oh ) d and the levels of 10 different cytokines ( il - 2 , 4 , 5 , 6 , 8 , 10 , 13 , gm - csf , ifn - , tnf - ) were measured in the serum of participants at baseline and the final visit . serum samples were analyzed by ray biotech quantibody human th1 / th2 array 1 kit using glass - chip - based multiplexed sandwich elisa system . serum 25 ( oh ) d was measured by a radio - receptor assay from diasiorin , inc ( stillwater , mn ) . our laboratory participates in the international vitamin d external quality assessment program ( http://www.deqas.org/ ) . vitamin d3 content was analyzed in an independent laboratory ( vitamin d , skin , and bone research laboratory , department of medicine , boston university school of medicine , boston , ma ) . the signed rank test was used to assess the median percent change of each cytokine level within the active vitamin d or placebo group during the 12 - week period . the rank - sum test was used to compare median percent change between the active vitamin d and placebo groups . an estimate of the difference of the two medians ( active vitamin d - placebo ) and the corresponding 95 % confidence interval was calculated using the software confidence interval analysis ( cia ) , version 2.0.0 . we also pooled both groups together and calculated percent changes in 25 ( oh ) d over 12 weeks . spearman correlations were then calculated between these percent changes in 25 ( oh ) d and percent changes of each cytokine level . since analysis was done for 10 cytokines , we used the bonferroni adjustment and results were considered significant at the p = .05 / 10 = .005 level of significance . for all calculations ( except for confidence interval analysis ) , we utilized sas 9.2 for windows , sas institute inc . , cary , n.c . the baseline characteristics and laboratory values of the study population are summarized in table 1 . t - tests comparing active to placebo patients at baseline did not reveal any differences between the groups . the baseline 25 ( oh ) d levels ranged from 16 to 156 nmol / l with a mean level of 63.728.723 % of the active patients exceeded 75 nmol / l . adherence ( defined as the ratio of the number of pills consumed to the number of days in the study ) ranged from 59 % to 100 % . there were no statistically significant differences between the two groups with respect to median percent differences for each cytokine . the only exception was for il - 10 , where the percent change for the active vitamin d group was 70.4 % versus only 49.6 % for placebo ( p = .02 ) . however , the bonferroni adjustment would need to be removed in order to obtain significance at p .05 . in the active vitamin d group , we found a significant median percent decline in levels of gm - csf ( 62.9 % , p .0001 ) , ifn - ( 38.9 % , p .0001 ) , il - 4 ( 50.8 % , p = .001 ) , il - 8 ( 48.4 % , p there were significant declines ( but slightly smaller compared to the active vitamin d group ) for gm - csf ( 53.2 % , p = .0007 ) and ifn - ( 34.4 % , p = .0011 ) . for each cytokine , there was no significant difference in the rate of decline between the two groups .25 ( oh ) d levels increased in the active vitamin d group from a mean of 64.325.4 nmol / l to 88.523.273 % of the active vitamin d group patients exceeded 75 nmol / l . spearman correlation analysis showed no significant correlations for any of the 10 cytokines : the strongest correlations were r = 0.096 ( p = .30 ) for il - 8 and r = 0.079 ( p = .39 ) for il - 5 . we provide in table 3 , for each cytokine , the difference of the median percent change ( active vitamin d - placebo ) and the corresponding 95 % confidence interval . we note that for nine of the ten cytokines , the estimated difference of medians between the two groups was within 10 % , which would likely represent a clinically insignificant difference . the only exception was for cytokine il - 10 , where the group difference was statistically significant ( p = .02 before the bonferroni adjustment as previously mentioned ) . we also considered a subanalysis consisting of placebo group who are vitamin d insufficient ( 75nmol / l ) both at the start and the end of the study versus . active vitamin d group who were insufficient at the start and became sufficient at the end of the study . these modified placebo and active vitamin d groups consisted of 33 and 30 patients , respectively . when we repeat the analysis done in table 2 , the rank sum p - values ( comparing active vitamin d with placebo ) are all nonsignificant , with p .30 for all 10 parameters . a total of 72 adverse events were reported in the study over 3 months , 38 in the active vitamin d group and 34 in the placebo group , p = .99 . there were 3 serious adverse events , one in the active vitamin d group and two in the placebo group . none of the serious adverse events were considered to be related to the study medication . the present study did not show an effect of vitamin d3 supplementation on the circulating levels of certain cytokines . we predicted that the levels of il - 2 , 6 , ifn - , tnf - , and gm - csf will decrease under the influence of vitamin d , while the levels of il - 4 , 5 , 10 , and 13 were expected to rise . we did not find that cytokine levels or changes in cytokine levels were responsive to vitamin d supplementation or related to serum 25 ( oh ) d levels . however , there is accumulating evidence that vitamin d does significantly alter the immune system . in gene chip experiments , the active form of vitamin d has been shown to downregulate gene expression of t - helper 1 cells , at the same time up regulating gene expression of t - helper 2 cells . decreased production of inf - gamma and il - 12 by t - helper 1 cells , and induction of regulatory t cells influenced by 1,25 ( oh ) 2d regulates immune responses to infections .1,25 ( oh ) 2d has been shown to induce the expression of il - 10 by cd40 / il -4-activated b - cells by binding of the vdr to the promoter of il - 10 . the role of 1,25 ( oh ) 2d in innate and adaptive immunity has also been demonstrated in vivo . following in vivo stimulation of murine dendritic cells by lipopolysaccharide ( bacterial - derived endotoxin ) , they were found to produce 1 - alpha - hydroxylase , resulting in production of active form of vitamin d . hansdottir et al . proposed a mechanism by which vitamin d plays a role in host defense by demonstrating the conversion of inactive vitamin d ( 25 ( oh ) d ) to active 1,25 ( oh ) 2d by enzyme 1alpha - hydroxylase in respiratory epithelial cells . impaired production of 1,25 ( oh ) 2d due to low - circulating 25 ( oh ) d levels results in inhibition of vdr - dependent innate immune response .1,25 ( oh ) 2d inhibits the production of il - 12 , ifn - and promotes production of il - 4 following endotoxin stimulation in rats . human b - cells experiments demonstrated the ability of 1,25 ( oh ) 2d to induce the expression of chemokine ( c - c motif ) receptor 10 ( ccr10 ) , which plays an important role in the mucosal immune system . in patients with severe congenital neutropenia ,1,25 ( oh ) 2d induced the expression of the human cathelicidin antimicrobial peptide 18 precursor protein in myeloid precursors . the process of activation of vitamin d in human tracheobronchial cells causes upregulation of cathelicidin antimicrobial peptide gene and the tlr coreceptor cd14 , contributing to innate immunity in the lungs . data on vitamin d regulating serum cytokines in placebo - controlled clinical trials is very limited . in a 6 - month double - blind , placebo - controlled , randomized trial in vitamin d - insufficient patients with ms , 25 g ( 1000 iu ) vitamin d significantly increased serum levels of tgf - beta 1 , while having no effect on tnf - , ifn - , and il - 13 . another randomized , placebo - controlled clinical trial in 123 chf patients demonstrated that 50 g ( 2000 iu ) of vitamin d , administered for 9 months , increased median serum levels of anti - inflammatory il - 10 by 43 % , and suppressed the levels of proinflammatory tnf - . the median baseline 25 ( oh ) d levels in that trial were significantly lower compared to our study : 35.87 nmol / l in vitamin d group and 38.09 nmol / l in the placebo group . seasonal differences in cytokine levels were observed by stewart et al . among healthy controls , who noted lower winter levels of il - 4 , il - 10 and tnf - , and a winter excess of ifn - . these findings further support the hypothesis that seasonal differences in vitamin d influence the levels of cytokines and may help explain our finding of declining serum cytokines levels during winter months in the active vitamin d , as well as the control group . the strengths of this study include the high compliance rate of medication intake ( 94 % ) and low - dropout rate . the mean 25 ( oh ) d level of the subjects at baseline ( 63.728.7 nmol / l ) was in accord with the mean 25 ( oh ) d level in nhanes iii ( 64.8 our laboratory participates in the international vitamin d external quality assessment program which ensures the analytical reliability of 25 ( oh ) d assays .50 g / day may not be enough to stimulate innate immunity , and / or the length of the study may not have been sufficient to observe an effect . another reason why we may not have observed a benefit is that the mean 25 ( oh ) d level at the beginning of the study was not that low but it was not different from the average level seen in nhanes iii . vitamin d repletion in subjects who were deficient at baseline may have resulted in meaningful changes in cytokine levels however , our study was not designed to address this question .73 % of patients in the vitamin d group achieved 25 ( oh ) d levels greater than 75 nmol / l but the difference between baseline and end - of - study levels may not be enough to confer a benefit . although there is an increasing amount of evidence from animal experiments and human case - control studies that demonstrate the role of vitamin d in host defense , additional randomized clinical trials are needed .\noutput:\n" }, { "from": "agent", "value": "background . the role of vitamin d in the body 's ability to fight influenza and uri 's may be dependent on regulation of specific cytokines that participate in the host inflammatory response . the aim of this study was to test the hypothesis that vitamin d can influence intracellular signaling to regulate the production of cytokines . subjects and methods . this study was a 3 - month prospective placebo - controlled trial of vitamin d3 supplementation in ambulatory adults [ li - ng et al . , 2009 ] . 162 volunteers were randomized to receive either 50 g / d ( 2000 iu ) of vitamin d3 or matching placebo . 25 ( oh ) d and the levels of 10 different cytokines ( il - 2 , 4 , 5 , 6 , 8 , 10 , 13 , gm - csf , ifn - , tnf - ) were measured in the serum of participants at baseline and the final visit . there were 6 drop - outs from the active vitamin d group and 8 from the placebo group . results . in the active vitamin d group , we found a significant median percent decline in levels of gm - csf ( 62.9 % , p < .0001 ) , ifn - ( 38.9 % , p < .0001 ) , il - 4 ( 50.8 % , p = .001 ) , il - 8 ( 48.4 % , p < .0001 ) , and il - 10 ( 70.4 % , p < .0001 ) . in the placebo group , there were significant declines for gm - csf ( 53.2 % , p = .0007 ) and ifn - ( 34.4 % , p = .0011 ) . for each cytokine , there was no significant difference in the rate of decline between the two groups . 25 ( oh ) d levels increased in the active vitamin d group from a mean of 64.3 25.4 nmol / l to 88.5 23.2 nmol / l . conclusions . the present study did not show that vitamin d3 supplementation changed circulating cytokine levels among healthy adults ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: epidemiologic researches in the united states reveal that one out of four deaths is due to cancer ( 1 , 2 ) . breast cancer ( bc ) is the most common type of cancer among women worldwide , which accounts for approximately one - fifth of all deaths in women aged 40 to 50 years ( 2 , 3 ) . the most common and fatal cancer in women is bc while the most common cancer in men is lung cancer ( 1 ) . over one million new cases of bc are diagnosed each year and more than 600000 of them would lead to death . it is a worldwide - growing public health problem , specially in developing countries so that its incidence has increased to 5 % per year ( 5 ) . the proportion of death because of bc in developing countries is higher than developed countries . although just half of the cases of bc occur in developing countries , two - thirds of deaths due to bc occur in these countries ( 6 ) . regardless of their age , all of the women are at risk for bc ; however , aging increases its risk . bc prevalence in the world is increasing and it has had a concerning incremental trend in iran ( 7 ) , where its incidence was estimated at 20 per 105 women , and one of every ten women would develop bc during her life ( 8 , 9 ) . since all cases of bc are not registered in iran , we can not comment on its prevalence , incidence , and fatality . nonetheless , bc rate in iran is estimated at 20 new cases in 100000 female ( 10 ) . moreover , although bc is not preventable , we can increase patient s survival by more than 90 % through early diagnosis ( 11 ) . there are different ways for early diagnosis of bc including breast self - examination ( bse ) , physical exam by a physician , and mammography ; however , unfortunately , it is not diagnosed in early stages of the disease in many patients when they are mostly curable . in developed countries , most of women use screening tests and it has caused a reduction in bc mortality rates . nevertheless , the condition is not the same in developing countries ( 12 ) . in many countries , mammography is the best screening test for diagnosis of bc at early stages ( 13 ) . in iran , with regard to growing rate of bc and referring of patients in advanced stages of the disease , it is necessary to improve patient s attitude towards bc by performing behavior remodeling programs ( 14 ) among which bse is available and inexpensive and women show tendency to perform it ( 15 ) . by means of monthly correct bse , women become familiar with their breast s characteristics and can distinguish abnormal changes in future and in case of any unnatural changes , it would be diagnosed at early stages . if all of the women examine their breasts monthly and refer to the physician for further physical exam and mammography on time , it would be possible to prevent bc s progression to high stages of the disease in 95 % of cases ( 16 ) . the sooner the cancer is diagnosed , the lower the needed radiotherapy would be and hence , the higher the patient s quality of life would be . the reasons that prevent women from performing regular bse include disorientation about exam importance , fear and anxiety , and unawareness of correct way of performing exam ( 17 - 19 ) . studies showed that women with higher information about bse would perform it correctly and regularly ( 16 ) . a study on awareness and attitude of female employees of education ministry toward bc in shahrekord city in 2008 showed that the attitude was very good in 15.53 % , good in 17 % , and poor in 10.95 % ( 20 ) . in a similar study in kashan city in 2001 ,42 % had poor attitude and 5.5 % had negative and apathetic attitude toward bse ( 21 ) . bc is the most common cancer and the most common cause of death from cancer in women ( 1 ) . a study about women s awareness of mammography , bse , and other diagnostic methods in at - risk women has not been done in dezful city yet . our study aimed to evaluate the awareness of and attitude toward bse , which is one of the most simple diagnostic methods , among women in dezful city , iran , in 2013 health policymakers would use the results to design training programs on bse and provide information on correct performance of the examination . this descriptive cross - sectional study included 1020 women over 15 years of age and was performed in 2013 . simple random cluster of accessible women was used to recruit participants . sampling communities included women referred to medical centers ( rural and urban ) , students of dezful university of medicine , students of dezful islamic azad university , students of jundishapour engineering university , students of rural and urban high schools in dezful city and homemakers in five dezful city municipal districts . sample size was calculated by the following formula : n = [ ( z + z ) / ( 1 - 0 ) ] educated females were evaluated through questionnaire and illiterates through face - to - face interview . questionnaire included five sections : first section was the form of giving consent ; second section included sample s demographic characteristics ; third section included sample s awareness of bc , which according to standard protocols , consisted of prevalence , risk factors , sign and symptoms , bse , clinical breast exam , and mammography ( 22 ) ; fourth section included women awareness of and attitude toward bse questionnaire ; fifth section included assessment of bc risk factors in samples . the responses to 20 questions of questionnaires were calculated as follows : correct , 1 ; false , -1 ; and \" i do nt know \" , 0 . then the sum of them was classified to four levels , which was adjusted by likert scale ( good , 11 - 20 ; moderate , 1 - 10 ; and bad , 0 to -10 ) . validity questionnaire was validated using content validity method by five internal medicine specialists , endocrinologist , and immunologist in dezful university of medical sciences . reliability of this questionnaire was obtained by test - retest in which by a pilot study on 60 persons cronbach s alpha of 0.86 was obtained . chicago , il , usa ) using mean , absolute , and relative frequencies . in order to assess parameter s association , we used independent - samples t test and chi square test . the ethics committee of dezful university of medical sciences approved the study protocol ( code of ethical approval , durs104 ) . in this study , sampling strategy and inability to generalized finding to target population was one of the basic limitation . study about women s awareness of mammography , bse , and other diagnostic ways has not been done in dezful yet . in this study , we had 1020 participants with mean age of 37.11.3 years ( range , 15 - 79 ) . in this study , 195 women ( 19.1 % ) were single and the rest were married . the education level was under high school diploma in 385 women ( 37.7 % ) , high school diploma in 295 ( 28.9 % ) , and academic education in 340 ( 33.3 % ) . among the participants , 630 women ( 61.8 % ) were housekeeper , 170 ( 16.7 % ) were employed , and 220 ( 21.6 % ) were students . the history of bc in family members ( mother , aunt , and grandmother ) was reported by 7.8 % of women and 10.8 % of women had history of bc in distant relatives ( table 2 ) . most of participants ( 72 % ) believed that breast physical exam and mammography are efficient medical diagnostic ways . although 685 women ( 67.2 % ) knew that monthly bse was necessary , only 426 ( 41.8 % ) knew its proper time . the results of this study showed that the mean score of women 's knowledge 51.247.12 ( median , 53.17 ; interquartile range [ iqr ] , 17.43 ) . participants knowledge about bc and its screening tests was good in 206 women ( 20.2 % ) , moderate in 783 ( 76.8 % ) , and poor in 31 ( 3 % ) . the positive therapeutic effects of early diagnosis were acknowledged by 715 women ( 70.1 % ) . although 525 women ( 51.5 % ) performed bse , only 400 ( 39.2 % ) knew how to do it correctly . the results of this study showed that the mean score of women 's attitude was 74.1211.83 ( median , 67.71 ; iqr , 25.03 ) . overall , 83.3 % of participants believed that bse would have positive effects in early diagnosis of bc , 82.4 % believed that bse was not unpleasant , 47.1 % believed that bse was an appropriate way of bc diagnosis , and 72.5 % believed that it is necessary to train all of the women on performing bse correctly . only 37 % of participants were trained on examining their breasts themselves and among training sources , healthcare staff were the most important sources ( 38.2 % ) . among the reasons of not doing bse , the most important ones were consecutively not knowing how to do it and not having breast problems . although 51.5 % of women performed bse , only 33.3 % of women over 40 years of age performed it and 31.8 % of them knew how to do it correctly ( p 0.001 ) . table 5 shows participant s bse proportions in different age ranges and shows whether they were trained how to do it . chi - square test showed statistically significant association between participant s awareness of and attitude toward bse . it showed that the higher the level of awareness was , the more positive the attitude would be ( p 0.001 ) . it means that those who had a more positive attitude did the exam more frequently ( p 0.001 ) . there was statistically significant association between participant s awareness with age ( odds ratio [ or ] = 1.58 ; p 0.001 ) , marital status ( or = 1.3 ; p = 0.021 ) , education ( or = 2.2 ; p = 0.001 ) , a positive family history ( or = 3.45 , p 0.001 ) . there was a statistically significant correlation between participant s attitude with age ( or = 2.70 ; p 0.001 ) , marital status ( or = 1.6 ; p = 0.040 ) , education level ( or = 1.9 ; p = 0.001 ) , previous training history ( or = 3.4 ; p 0.001 ) , and positive family history ( or = 2.4 ; p 0.001 ) . there was an statistically significant relation between doing bse with age ( or = 2.4 , p 0.001 ) , marital status ( or = 2.01 , p 0.001 ) , education ( or = 1.5 , p = 0.015 ) , previous training ( or = 1.08 , p 0.001 ) , positive family history ( or = 2.6 , p 0.001 ) and participant s attitude to do the test ( or = 1.12 , p = 0.004 ) , but it does not have significant relation with test unpleasantness ( p = 0.682 ) . there was a statistically significant correlation between education level and knowing to do the test ( p = 0.009 ) . in addition , those who were trained on performing the test , did it more frequently ( p 0.001 ) . doing the test properly had a direct correlation with level of education ( p 0.001 ) . our study evaluated the degree of awareness and attitude of women about bc and bse in dezful city for the first time . we tried to study the association of women s attitude toward bse with parameters such as age , marital status , education , occupation , and family history ( bc grade 1 , 2 ) . the results of this study approved results of other studies on the positive effects of elevating women s awareness of and attitude toward bc on their participation in screening programs . the responses to the questionnaire about bc and its preventive routes in women in dezful city showed that only 20.2 % of participants had a good level of knowledge and the rest had moderate to poor knowledge of this issue . a survey by jokar and ghiasi in 1997 about women 's awareness of and attitude toward bc in ilam province showed that most of them ( 57.3 % ) had poor awareness and only 11.9 % had good awareness ( 22 ) . moreoverits screening tests showed that 42 % of kashan city s women did not know about bc screening tests and only 22 % were informed ( 23 ) . in a study by jokar andghiasi the women 's awareness of and attitude toward bc was good in 28.5 % , moderate in 67.3 % , and poor in 4.2 % . the women s awareness of positive effects of early diagnosis of bc was 89 % but this proportion was reduced to 70.1 % in dezful city 's women in our study . nevertheless , our research shows that dezful city women s information has not increased with the same anticipated rate . according to our results ,51.5 % of dezful city 's women performed bse , 82.4 % of them had a positive attitude toward the test , and 83.3 % believed that the test has a positive effect in early diagnosis of bc . in a study by jokar and ghiasi in 1998 , 64 % of women had positive attitude toward breast screening tests and 35 % of them did the bse ( 22 ) . a study by abedzadeh et al . showed that 94.5 % of women had a positive attitude toward bse , 42.7 % of them perform it , and 19.7 % were referred to healthcare staff to do it for them ( 23 ) . a study by banaiyan et al . on women 's awareness of and attitude toward bc screening tests in brijen city in 2004 , showed that only 16.7 % of women had a positive attitude towards screening tests , 67.7 % had moderate attitude , and 15.6 % had negative attitude . women s attitude toward bse was only positive in 23 % and only 47.1 % performed the exam ( 24 ) . a study by vietri et al . in the united states in 1997 showed that 58 % of women performed bse ( 25 ) , which was higher than the rate by dezful women . this result showed that women s culture has an important role in this difference and more efforts are needed to inform women and make bse important for them in developing countries . this issue showed us that to design training programs , we should consider two important points : providing appropriate bse training programs to diagnose it earlier ; and explaining its benefits to women . parameters such as age , education , marital status , and family history would affect the knowledge level of participants . women over 20 years of age with higher education and positive family history of bc had better information about bc preventing programs ( p 0.001 ) . these results were in parallel with many researches performed until now ( 23 , 24 ) . with regard to the higher level of education in iranian women than women in central asia , middle east , caucasus , africa , and south america , it seems that designation and performing training interventional health programs on cancers , especially bc , would improve establishment of bc screening tests in iranian women in comparison with above countries . in other words , interventional health training programs increase women s awareness of and attitude toward cancers , specially bc , and their screening and early diagnostic tests . in women with higher education level , there is a higher awareness of this issue . studied healthcare staff with high level of education and appropriate knowledge about bc and its screening tests . the results showed that their tendency toward participating in bc screening tests was higher than was in general population ( 26 ) . according to this survey , most of these women prefer bse in comparison with other screening tests . a survey by levshin et al . on 1500 cases of bc showed that 81 % of them had noticed its symptoms themselves first ( 27 ) . in conclusion , if women learn bc s sign and symptoms and perform bse monthly , it would be possible to diagnose bc in early stages , which would provide a better diagnosis . with regard to high prevalence of bc in iran and considering the positive awareness of dezful city 's women about bse , which was shown in our study , and paying attention to the fact that our target population lacked information about bc , we need interventional health training programs and regular screening tests in iran . we suggest the following ways in order to reduce mortality rate of bc : regular interventional health training programs performance to elevate awareness and attitude of women over 15 years toward cancers , especially bc . establishment of nongovernmental organizations ( ngo ) and support them to inform the people . establishing cancer clinics in each city . active screening tests and clinical breast exam and mammography by physicians in rural and urban health centers for women over 40 years . health policymakers of dezful city can establish bse training programs to elevate women 's awareness of and attitude toward early diagnosis of bc and bse .\noutput:\n" }, { "from": "agent", "value": "background : over one million new cases of breast cancer ( bc ) are diagnosed each year with a mortality rate of more than 600 thousand women per year . breast self - examination ( bse ) is a patient - centered , inexpensive , and noninvasive diagnostic test . we focused on the role of screening in bc in early diagnosis.objectives : the purpose of this study was to evaluate awareness and attitude of women toward bse in dezful city , iran , in 2013 . patients and methods : this descriptive cross - sectional study included 1020 women over 15 years of age in dezful city , in 2013 . simple random clustering was used to enroll accessible women . we have applied the available pieces of software for statistical analysis.results : the mean age of recruited women was 37.1 1.3 and 23.6 % of participants had a history of bc in themselves or in their relatives ( mother , sister , aunt , and grandmother ) . in addition , 70.1 % of participants benefited from early diagnosis of bc , 83.3 % of participants considered bse necessary and useful for early diagnosis of bc , and 51 % of them performed bse . there was a statistically significant correlation between being married and doing bse ( p = 0.034 ) and between womens level of education and awareness to perform bse ( p = 0.009 ) . conclusions : with regard to high prevalence of bc in iran , this study showed a positive attitude of women in dezful city toward bse . health policymakers in dezful city can establish training programs to increase women s awareness of bse and to instruct them to perform it properly ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: inflammatory bowel disease ( ibd ) includes 2 main conditions : ulcerative colitis ( uc ) and crohn disease . uc is a chronic inflammatory disorder characterized by inflammation of the mucosal layer of the colon . its pathogenesis is not fully understood , but studies have shown that an unknown agent activates immune cells . food antigens have been suspected to elicit an immunologic response in the development of uc . potential dietary risk factors include sensitivity to dairy , wheat , refined sugar , fiber and a typical western diet . several diets have been effective without conclusive scientific testing . the specific carbohydrate diet ( scd ) the scd is based on the theory that gut microbiome dysbiosis is associated with ibd . thus , by making dietary changes , the intestinal flora can potentially be altered , resulting in improvement . the diet incorporates a dual action of not only elimination of factors presumably contributing to the dysbiosis , but including restoration of the disrupted gut microbiome . most disaccharides , polysaccharides and starches are avoided as they are more complex , less easily digested and considered to aggravate intestinal inflammation . fermented yogurt is a vital component of the scd , promoting the replenishment of presumed healthy intestinal flora . we report the successful remission of disease activity in a single adult patient with known ibd with the scd . this case report , to the best of our knowledge , is the first documented instance in the literature in an adult with uc . a 73 - year - old female of asian origin with a long - standing history of uc presented with the most severe and persistent flare of her disease . she had received the initial diagnosis of uc in 1997 when she developed abdominal pain and rectal bleeding with loose mucous stools and underwent a diagnostic colonoscopy with a gastroenterologist . she responded to mesalamine ( asacol ) given for a period of 6 weeks , which was later discontinued by the patient . for the next 12 years , she was relatively stable with standard american diet recommendations and did not exclude wheat and dairy or focused on the inclusion of particular fermented foods . the patient incorporated powdered ayurvedic and homeopathic oral treatment , which included some spices like nutmeg but did not contain any fresh or fermented products . in the winter of 2009 , she experienced intermittent burning and shooting pain predominately in the left lower quadrant of the abdomen . pain in the right lower quadrant was present often concomitantly , and on occasion , was present in the absence of the left - sided pain . episodes of rectal bleeding and mucoid loose stools progressed over the duration of the next year . no fever or skin rashes were present at any time . decreased appetite and overall weight loss of 7 pounds occurred within the 12 months . she was admitted at assorted facilities and underwent consultations with various gastroenterologists and other specialists , with increasing fatigue and finally , an inability to continue working . the differential diagnosis included diverticulitis and tuberculosis among others , all of which were excluded . multiple , episodic and varied therapies including corticosteroids and mesalamine were prescribed , with limited efficacy and poor tolerance . in december of 2010 , her weight was 128 pounds , and she appeared pale , fatigued and chronically ill . she had not been able to function as a physician and was in constant abdominal pain with unremitting bloody diarrhea . hemoglobin of 10.5 g / dl and mild hypokalemia of 3.2 meq / l was seen with no elevation of the liver enzymes and normal renal function .1 ) with sigmoid colonic diverticula but no evidence of diverticulitis or neoplastic changes . mild to moderate ibd consistent with chronic uc was noted with patchy areas through the cecum , ascending , transverse , descending , and sigmoid and rectum , and some difficulty entering the ileocecal valve . biopsies were obtained throughout the colon and confirmed uc . since the patient had persistent and progressive symptoms , with worsening clinical parameters , given the failure of previous conventional therapy , the scd was recommended and initiated using elaine gottschall 's book as the guide . she proceeded to completely exclude wheat , soy , barley , corn and limited rice . following this highly restricted diet , within a period of 36 months , the patient started noticing improvement with decreased frequency as well as firmer consistency of the stools , blood in the stools was absent and abdominal pain resolved . within 6 months , she was able to return to her normal activities and career as a physician . she continued with strict adherence to the diet due to the remarkable recovery , with dissipation of all of her symptoms over the next 18 months . subsequent colonoscopy done 2 years after starting the diet was conducted in december 2012 , and findings on endoscopy showed a remarkable absence of any inflammation ( fig . biopsies obtained simultaneously confirmed the complete remission of uc with no inflammatory activity present . since this time , she has noted that accidental consumption of wheat , peppers and other nonapproved scd foods caused acute flare - ups , and the prompt elimination of these foods resulted in improvement of symptoms within a few days . she has not required hospitalization or additional therapy for uc since the institution of the diet and continues to be essentially in remission from the ibd . uc is known to have a bimodal peak in the age groups of 1530 and 6080 years . in both children and adults , while gluten - free diets have been used for ibd in adults , the scd has been found to be successful in a small retrospective study of 7 children . our case demonstrated unprecedented healing of recalcitrant and remitting uc , following institution of the scd , in an adult . this case study demonstrates the easy tolerability and lack of significant side effects of the scd . confirmation of healing with endoscopy and microscopy validates the clinical improvement experienced by this patient . the diet requirements were relatively simple to incorporate though highly restrictive and are similar to those undertaken with celiac disease but included a prominent component of fermented dairy . a major strength of this case study is the ease of translation into clinical practice by busy clinicians , without the need for additional resources . one of the limitations of this case study was the absence of definitive serological testing for celiac disease prior to the institution of the diet to determine occult gluten sensitivity . a further limitation of the dietary intervention are the restricted choices available outside of the home and the difficulty with absolute long - term adherence . however , similar to patients with celiac disease , the food choices for patients on restricted diets has been steadily increasing in the united states , with gluten - free options having had a 63 % percnt ; increase in sales from 2012 to 2014 . we anticipate that with greater promulgation of elimination diets , it will be more conducive to adhere outside of the home environment . we would recommend that physicians and dieticians who are involved with gastrointestinal diseases look into alternative therapies , not only for patients with celiac disease but potentially also for those with ibd and uc . our suggestion is that future studies incorporate genetic markers and serological testing prior to making the changes . the scd has been used anecdotally for uc ; however , the evidence of its effectiveness has not been conclusive . we report complete healing of uc in a patient who had failed conventional therapies within a 2 - year period . the use of the scd for uc in patients who are able to make sustainable dietary changes should be considered more often .\noutput:\n" }, { "from": "agent", "value": "a 73 - year - old female of asian origin was diagnosed with ulcerative colitis ( uc ) after initial gastrointestinal symptoms of abdominal pain and bloody diarrhea . she had a relatively benign course over the subsequent 12 years . in 2009 , she had increased left - sided abdominal pain , bloody diarrhea and progressive weight loss , due to a severe exacerbation . in spite of a variety of standard treatments , her condition continued to decline with a significant impact on normal life and functioning . in december of 2010 , repeat colonoscopy and microscopy confirmed pancolitis , without diverticulitis . the specific carbohydrate diet ( scd ) was initiated due to failure of conventional therapies . following this highly restricted diet , within a period of 36 months , improvement was noted , and within a year , no abdominal pain or diarrhea were present , and she returned to her baseline functioning and career . two years later , repeat colonoscopy showed resolution of the pancolitis , confirmed with microscopic evaluation . successful use of the scd in children with uc has been documented . we describe previously unreported , highly beneficial results with both symptomatic and clinical improvement and complete remission of uc in an adult female with the scd ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: several studies have been conducted in order to evaluate its biocompatibility and metal ion release . titanium dioxide exists in three different crystal lattices , anatase , rutile , and brookite . normally , a stochastic distribution of two titanium oxides ( rutile and anatase ) is present on the surface of the titanium , and this is responsible for the properties of the material . anatase has been shown in in vitro studies to be able to absorb more oh and po4 ( 3 ) than rutile , in body fluids , which favors depositing a bone - like apatite formation . the anatase coating releases , under ultraviolet ( uv ) irradiation , free radicals such as oh , o2 , ho2 , and h2o2 . this potent oxidizing power characteristically results in the lysis of bacteria and other organic substances . several reports have been published on the bactericidal properties of tio2 against organisms such as escherichia coli . this bactericidal action could be due to the elimination of the protection of the cell wall of the bacteria , and then to an increase in the cell permeability determining a loss of intracellular contents , leading to the death of the cells . the aim of this controlled clinical trial was to evaluate the bone response to implants made of titanium alloy or coated with a new combination of anatase and bactercline product . the present report represents the follow - up up to 1 year after loading of a previous article . any patients with partial edentulism having a residual bone height greater than 11 mm and a thickness of at least of 5 mm to allow placement at least of two implants , who was 18 or older and able to sign an informed consent form , was eligible for inclusion in this trial . patients were not included in the study if any of the following exclusion criteria was present : ( 1 ) general contraindication to implant surgery ; ( 2 ) subjected to irradiation , chemotherapy , or immunosuppressive therapy over the past 5 years ; ( 3 ) poor oral hygiene and motivation ; ( 4 ) uncontrolled diabetes ; ( 5 ) pregnant and lactating ; ( 6 ) substance abusers ; ( 7 ) smoking more than 15 cigarettes per day ; ( 8 ) psychiatric problem or unrealistic expectation ; ( 9 ) acute infection in the area intended for implant placement ; ( 10 ) positive to human immunodeficiency virus ( hiv ) and hepatitis b and c ; ( 11 ) affected by autoimmune diseases such as arthritis rheumatoid , systemic lupus erythematosus , sclerodermia , sjgren syndrome , and dermatomyositis / polymyositis ; ( 12 ) treated or under treatment with intra - venous amino - bisphosphonates ; ( 13 ) subjected previously to reconstructive procedures of the jaws ; and ( 14 ) under chronic treatment with steroid and non - steroidal anti - inflammatory drugs . this study was approved by the ethical committee of university of chieti - pescara , chieti , italy . in the period between july 2009 and june 2010 , 26 patients ( 10 females and 16 males ; median age 5111 years , min .72 years ) were operated and 62 implants were inserted . before surgery and in the follow - up period , in addition , the following parameters were considered : absence of persisting pain or dysesthesia , absence of peri - implant infection with suppuration , absence of mobility , and absence of persisting peri - implant bone resorption around implants . not only lost implant but also a bone resorption greater than 1.5 mm during the first year of loading and an additional 0.2 mm for the subsequent year were evaluated . additional information is available in international patent application ( 1 ) wo 2007 / 122651functional nanomaterials with antibacterial and antiviral activity .01.11.2007 b22f 1/02 pct / it2006 / 000280 and ( 2 ) wo 2008 / 020460nanomaterial coatings for osteointegrated biomedical prostheses . bactercline is a new disinfecting formulation , which has passed the examination of the italian national institute of health , rome , italy , and is now classified as presidio medico chirurgico n. 19258 . the product was applied on the implant surfaces by dip coating after deposition of an anatase layer prepared according to the procedure , which follows . sixty - two implants ( dental tech , misinto , italy ) were inserted . among themthere were two different surfaces : 25 with an acid - etched and sandblasted surface ( control ) and 37 with an acid - etched and sandblasted surface coated with an anatase ( bactercline solution , test ) . each patient received at least one test and one control implant placed close each other in the same surgical procedure . the choice of implant diameter and length was left to the surgeon according to the anatomical limitations . implants were placed with the neck flush with the surrounding bone and were submerged for a healing period of 4 months . four months later the implants were exposed , abutments were placed , and screw - retained , implant - supported acrylic resin temporary fixed crowns were delivered . definitive metal ceramic screw - retained prostheses or those cemented with provisional cement were inserted after an additional 4 months . patients were enrolled in an oral hygiene program with recall visits every 3 months for the entire duration of the study . intra - oral radiographs were made with the paralleling technique at implant placement and 1 year after loading [ figures 1 and 2 ] . in the case where the bone levels around the studied implants were hidden or difficult to read , a second radiograph was made . intra - oral rx showing implant with abutments the 12 - month post - loading control all surgical intervention was performed by two experienced operators , whereas prosthesis was fabricated by different dentists . this study tested the null hypothesis that there were no differences between test and control implants against the alternative hypothesis of a difference . the outcome measures were : prosthesis failures : planned prosthesis that could not be placed due to implant failure and loss of the prosthesis secondary to implant failure.implant failure : implant mobility and removal of stable implant dictated by progressive marginal bone loss or infection.peri - implant marginal bone evaluated on intra - oral radiographs taken with paralleling technique . briefly , peri - apical x - rays were taken at implant placement and 1 year after loading . peri - implant marginal bone levels were measured by using a software calibrated for each single image using the known implant length . mesial and distal bone crestal level adjacent to each implant were measured to the nearest 0.1 mm . reference points for the linear measurements were the most coronal margin of the implant collar point of the bone - to - implant contact and implant tip . prosthesis failures : planned prosthesis that could not be placed due to implant failure and loss of the prosthesis secondary to implant failure . implant failure : implant mobility and removal of stable implant dictated by progressive marginal bone loss or infection . peri - implant marginal bone evaluated on intra - oral radiographs taken with paralleling technique . briefly , peri - apical x - rays were taken at implant placement and 1 year after loading . peri - implant marginal bone levels were measured by using a software calibrated for each single image using the known implant length . mesial and distal bone crestal level adjacent to each implant were measured to the nearest 0.1 mm . reference points for the linear measurements were the most coronal margin of the implant collar point of the bone - to - implant contact and implant tip . in the period between july 2009 and june 2010 , 26 patients ( 10 females and 16 males ; median age 5111 years , min . before surgery and in the follow - up period , radiographic examinations were done with the use of an intra - oral and orthopantomograph . in addition , the following parameters were considered : absence of persisting pain or dysesthesia , absence of peri - implant infection with suppuration , absence of mobility , and absence of persisting peri - implant bone resorption around implants . not only lost implant but also a bone resorption greater than 1.5 mm during the first year of loading and an additional 0.2 mm for the subsequent year were evaluated . additional information is available in international patent application ( 1 ) wo 2007 / 122651functional nanomaterials with antibacterial and antiviral activity .01.11.2007 b22f 1/02 pct / it2006 / 000280 and ( 2 ) wo 2008 / 020460nanomaterial coatings for osteointegrated biomedical prostheses . bactercline is a new disinfecting formulation , which has passed the examination of the italian national institute of health , rome , italy , and is now classified as presidio medico chirurgico n. 19258 . the product was applied on the implant surfaces by dip coating after deposition of an anatase layer prepared according to the procedure , which follows . sixty - two implants ( dental tech , misinto , italy ) were inserted . among themthere were two different surfaces : 25 with an acid - etched and sandblasted surface ( control ) and 37 with an acid - etched and sandblasted surface coated with an anatase ( bactercline solution , test ) . each patient received at least one test and one control implant placed close each other in the same surgical procedure . the choice of implant diameter and length was left to the surgeon according to the anatomical limitations . implants were placed with the neck flush with the surrounding bone and were submerged for a healing period of 4 months . four months later the implants were exposed , abutments were placed , and screw - retained , implant - supported acrylic resin temporary fixed crowns were delivered . definitive metal ceramic screw - retained prostheses or those cemented with provisional cement were inserted after an additional 4 months . patients were enrolled in an oral hygiene program with recall visits every 3 months for the entire duration of the study . intra - oral radiographs were made with the paralleling technique at implant placement and 1 year after loading [ figures 1 and 2 ] . in the case where the bone levels around the studied implants were hidden or difficult to read , a second radiograph was made . intra - oral rx showing implant with abutments the 12 - month post - loading control all surgical intervention was performed by two experienced operators , whereas prosthesis was fabricated by different dentists . this study tested the null hypothesis that there were no differences between test and control implants against the alternative hypothesis of a difference . the outcome measures were : prosthesis failures : planned prosthesis that could not be placed due to implant failure and loss of the prosthesis secondary to implant failure.implant failure : implant mobility and removal of stable implant dictated by progressive marginal bone loss or infection.peri - implant marginal bone evaluated on intra - oral radiographs taken with paralleling technique . a detailed description of the technique has been reported previously . briefly , peri - apical x - rays were taken at implant placement and 1 year after loading . peri - implant marginal bone levels were measured by using a software calibrated for each single image using the known implant length . mesial and distal bone crestal level adjacent to each implant were measured to the nearest 0.1 mm . reference points for the linear measurements were the most coronal margin of the implant collar point of the bone - to - implant contact and implant tip . prosthesis failures : planned prosthesis that could not be placed due to implant failure and loss of the prosthesis secondary to implant failure . implant failure : implant mobility and removal of stable implant dictated by progressive marginal bone loss or infection . peri - implant marginal bone evaluated on intra - oral radiographs taken with paralleling technique . briefly , peri - apical x - rays were taken at implant placement and 1 year after loading . peri - implant marginal bone levels were measured by using a software calibrated for each single image using the known implant length . mesial and distal bone crestal level adjacent to each implant were measured to the nearest 0.1 mm . reference points for the linear measurements were the most coronal margin of the implant collar point of the bone - to - implant contact and implant tip . twenty - six patients were considered eligible and were consecutively enrolled into the clinical trial . all patients were treated according the allocated interventions ; no drop - out , exclusion , or deviation from the protocol occurred up to 1 year after loading , and the data of all patients were evaluated in the statistical analysis . patients were recruited and treated with implant insertion in the period between july and june 2010 , whereas all provisional restoration ( i.e. , loading ) was delivered with december 2010 . the mean patient age at the time of surgical procedure was 5111 years ( range 27 - 72 ) and there were 10 females and 16 males . in total 62 implants were inserted . length was 10 , 11.5 , and 13 mm in 25 , 12 , and 25 cases , respectively . thirty - four and 28 implants were placed in the mandible and maxilla , respectively . average bone resorption around implant was 0.3 mm ( both for standard and bactercline - coated implants ) , and no statistical difference was detected [ tables 1 and 2 ] . cross - tabulation showing bone resorption around implants using a cut - off equal to 1.5 mm , which is the international standard cross - tabulation showing bone resorption around implants using a cut - off equal to 0.3 mm , which was the mean bone resorptionmacro - design is the shape of the prosthesis : includes the cylindrical or root form of dental implants . mini - design is the dimension of the threads or the shape of the neck of the dental fixture . micro - design is the shape of implant surface , as exemplified by the grooves and holes resulting from surface treatments such as machination , acid - etching , and sand - blasting . these treatments determine the roughness of the surface and the holes have a cellular dimension . nano - design is determined by the molecular composition of the surfaces , such as those composed of hydroxypatite , zirconium , and titanium . usually , mechanical proprieties are related to macro - and mini - design , whereas biological proprieties are related to micro - and nano - design . mechanical proprieties are responsible for primary implant stability , whereas biological proprieties are relevant in the osseo - integration process . when exposed to air or liquids , titanium produces a layer of oxide that reduces its reactivity , and this oxide layer interacts with the tissues . the anatase form of tio2 is one of the most common crystalline forms of tio2 , and is normally produced by oxidation of titanium via thermal oxidation or anodization . recently , in a study in our laboratory , it has been demonstrated that coating of healing screws with a derivate of anatase ( i.e. , bactercline ) produced a lower quantity of bacteria on the surface of these screws . there could be some concern on the use of this bactercline coating on dental implants due to a possible interference with the osteoblastic activity . a preliminary report demonstrated that no adverse effect on osseo - integration was present , and no statistically significant differences between test and control implants was detected after a mean follow - up of 7 months . as shown in the work by lauritano and co - workers , bacteria can determinate bone re - absorption around dental implant caused by peri - implantitis . use of this coating at the implant body could have positive effects in cases of peri - implant crestal bone resorption during peri - implantitis , when a coating that could help in decreasing the bacterial charge could be helpful in the treatment of peri - implant infection . here , additional strength is given to previous results since results remain stable over a longer observation period .\noutput:\n" }, { "from": "agent", "value": "background : titanium dioxide exists in three different crystal lattices , anatase , rutile , and brookite . anatase coating releases , under ultraviolet ( uv ) irradiation , free radicals such as oh , o2 - , ho2 - , and h2o2 . this potent oxidizing power characteristically results in the lysis of bacteria and other organic substances . the purpose of this study was to evaluate the bone response to implants made of titanium alloy or coated with a new combination of anatase and bactercline product.materials and methods : in the period between july 2009 and june 2010 , 26 patients ( 10 females and 16 males ; median age 51 11 years , min . 27 years , max . 72 years ) were operated and 62 implants were inserted . lost fixtures and peri - implant bone resorption were considered as predictors of clinical outcomes . pearson 2 - test was used . prosthesis and implant failures , any complications after loading , and peri - implant marginal bone - level changes were assessed by a masked assessor . all patients were followed up to 1 year after loading.results : no implant was lost . average bone resorption around implant was 0.33 mm ( both for 25 standard and 37 bactercline - coated implants ) , and thus no statistical difference was detected.conclusion : these results shown that no adverse effects on osseo - integration were present ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: candida albicans is a serious human health concern , especially for the growing population of immunocompromised patients ( 1,2 ) . c.albicans is a common fungal organism that can live as a commensal in its mammalian host , and it does so in a large fraction of the human population ( 3 ) . it can also enter a pathogenic state , causing painful mucosal infections ( e.g. oral thrush and vaginitis ) or deadly systemic disease ( 4,5 ) . the candida genome database ( cgd , ) grew out of the candida research community 's need for a centralized resource for genomic sequence and gene annotation , and for improved access to the wealth of published experimental data about candida molecular biology . cgd is based on the framework of the saccharomyces genome database ( sgd , available at ) ( 6 ) . in the past 2 years cgd has grown in many respects , with greatly expanded curation of the experimental literature ( see table 1 ) . results of large - scale studies have been incorporated into or linked from cgd in several ways : the gene ontology terms assigned by the candida annotation working group have been added to cgd go annotations ( 7 ) ; an archive of publicly available large - scale datasets has been created ; and gene - specific locus pages in cgd have been linked to experimentally determined transcription modules ( 8 ) . additional community resources have also been added , including a candida labs directory and a listing of candida - related postdoctoral positions and other job opportunities . total go annotations figure includes the similarity - based predictions generated by the annotation working group , whereas the total literature - based go annotations figure excludes this set . this update highlights the sequence resources added to cgd over the past 2 years , a period in which there have been significant advances in the assembly , annotation and availability of the c.albicans genome sequence . a large - scale community - based revision of the c.albicans genome assembly was completed and has been recently released to the public ( 7,9 ) . during this time , cgd has incorporated extensive dna and protein sequence information from multiple versions of the c.albicans genome assembly , including assembly 20 , along with tools for accessing and comparing the sequences . the latest c.albicans genome assembly , assembly 20 , is a collaborative effort of groups at the biotechnology research institute of the national research council of canada , the university of minnesota , and chiba university of japan ( 9 ) . assembly 20 follows assembly 19 , which was released by the stanford genome technology center in 2004 ( 10 ) , and improves upon it in a number of ways . most notably , assembly 20 is a chromosome - level assembly ; the 266 assembly 19 contigs that span the haploid complement of the genome have been mapped onto the eight c.albicans chromosomes and joined into nearly contiguous sequence . numerous corrections to the sequence and to the predicted boundaries of orfs have also been made as part of this effort ( 9 ) . however , assembly 20 does not yet fully replace assembly 19 . assembly 19 is a diploid assembly , which for many regions of the genome includes two contigs , corresponding to polymorphic allelic regions that show significant sequence differences . in contrast , assembly 20 is a haploid assembly , and in generation of assembly 20 , updates to assembly 19 have been made in only one allele of each pair . it should also be noted that assembly 20 does not represent a haploid set of chromosomes from the sequenced strain per se , but instead is a mosaic of the two haplotypes . thus , it is important that access to assembly 19 sequences be maintained even though assembly 20 is considered to be a more complete assembly . in addition , earlier assemblies of the genomic sequence and their associated gene nomenclatures are in widespread use in the research community and in the scientific literature . cgd continues to provide easy access to all versions of the genome sequence ( including the outdated ones ) while minimizing confusion , despite the necessarily complex nature of the situation . in cgd , the primary sequence for each gene is the sequence that is specified in assembly 20 . where the sequence and annotation of individual genes has changed , it is essential for the research community to have access to the different versions , not only to be able to understand exactly what has changed , but also to facilitate a critical evaluation of the sequence and to facilitate the continuing refinement process . to this endthe assembly 20 and 19 sequences of each gene ( and of both alleles , if available ) are readily available from each gene 's locus page , and the genomic context on the chromosome ( from assembly 20 ) or the contig ( s ) ( from assembly 19 ) can be explored using the gbrowse genome browser ( 11 ) . sequences from all of the assemblies , including the archived assemblies 4 and 6 , are available for query by blast and for bulk download , as described in more detail below . frequently , users need to retrieve sequence information for a single gene , or for a small number of genes . the most direct route to this sequence information is through the locus page . cgd is gene - centric in nature ; the website is organized around locus pages that provide access to all available information about each gene , including the literature - derived information about the function , role and localization of the gene product , the phenotypes caused by mutation of the gene , the experimental literature that describes the gene , and , of course , its sequence . to make it possible for users to easily access sequence and other information about any given gene , cgd collects all of the names by which each gene has been called , and makes all of these gene name synonyms , orabc1 have been manually collected by cgd curators from the published literature ( 12 ) . numerically based names ( e.g. contig4 - 3061_0012 , orf6 .8002 and orf19 .5007 ) were assigned to the predicted protein - coding genes during the annotation of assemblies 4 , 6 and 19 , respectively ( 7,10 ) . at cgd , sequence comparisons were used to determine the mapping between the orfs from assemblies 4 and 6 and the corresponding genes in assembly 19 , and the appropriate aliases were added to each locus page . the orfs in assembly 20 share the names of format orf19 . # that were assigned during production of assembly 19 . ipf . # ( e.g. ipf22272 .1 and ipf1819 .1 ) and ca # ( e.g. ca5255 ) were assigned by candidadb ( 13 ) . additionally , names of format caj7 . # have been assigned to orfs on chromosome 7 ( 14 ) . cases in which confusion exists regarding the assignment of a give gene name are documented in cgd nomenclature notes , which appear prominently on the locus page so that users are alerted to the situation . in the future , it may be desirable to adopt a chromosomal position - based systematic gene nomenclature , similar to the one used in the saccharomyces cerevisiae community . if the candida research community decides to develop such a system , cgd will facilitate the process and will adopt the new nomenclature as the primary systematic gene identifiers . the cgd sequence retrieval tool is accessible via the get sequence link , located on the left - hand sidebar on the home page , under search options . the tool retrieves sequences specified by gene name , alias , systematic orf name or allele name . it also allows the user to define how much of the upstream and downstream flanking sequences to retrieve , to select only the coding sequence ( without introns ) , or to translate the sequence to protein . the tool is also able to retrieve an entire chromosome , contig , or a particular region of a chromosome or contig identified by starting and ending coordinates . several types of sequence may also be retrieved from individual cgd locus pages using options on thethe options include the genomic dna ( with introns ) , the coding sequence ( with introns removed ) , the genomic dna with 1 kb upstream and downstream flanking regions , and the predicted protein sequence ( orf translation ) . the sequences in assembly 20 and assembly 19 are available from this menu . in cases where the two diploid alleles are known to differ in sequence in assembly 19 , both of these sequences are available . the selected sequence is displayed in a browser window in fasta format , and may be copied and pasted into another application . the downloadable files are indexed on the cgd downloads page ( ) . the raw sequences of c.albicans chromosomes from assembly 20 are available , as well as an archive of contigs from previous assemblies ( assemblies 4 , 5 , 6 and 19 ) from the stanford genome technology center ( 10 ) . for assemblies 19 and 20 , files with processed sequencesare also available : dna sequences of all coding regions , with or without introns , and with and without 1 kb flanking regions . the protein sequences derived from orf translation are available for the assemblies 20 , 19 and 6 . the dna sequence of the mitochondrial genome is also available for download ( 10 ) , as are the sequences of the trna genes predicted at cgd using the trnascan - se algorithm ( 15 ) . cgd also makes c.albicans sequence information and gene annotation available via the gbrowse genome browser , which is a sequence visualization and analysis tool developed as part of the generic model organism database project ( 11 ) . the tool displays a user - selected fragment of the genome ( contig , chromosome , orf , etc . ) in the form of an interactive map that can be zoomed in and out , or scrolled along the selected region . the sequence of the region within the browser 's window can be saved to a file at any time . tracks . the user may elect to display ( or hide ) tracks containing orfs , trna genes , restriction enzyme sites , six - frame translation , and dna sequence ( at high resolution ) or g - c content ( at low resolution ) . at this time , users may choose to browse either the assembly 20 chromosomes or the assembly 19 contigs . the assembly 20 view includes a track containing the assembly 19 contigs , to facilitate comparison between the two assemblies ( figure 1 ) . in the future , historical tracks containing the contigs and orfs from assemblies 6 and 4 will be added to the browser . upon selecting these tracks , users will have a graphical view of the changes between the genome assemblies ; for example , it will be clear where contigs have been assembled with each other , or where orfs have been added , merged , or deleted from one version of the genome assembly to the next . the view may be scrolled along the assembly 20 chromosome , or zoomed in on a particular region . selectable tracks of data include orfs , contig 19s , centromeric regions , and sequence gap regions . all the features displayed in the genome browser are hyperlinked to their respective locus pages , so that all the other pieces of information ( experimental literature , mutant phenotypes , gene ontology assignments ) are just a mouse click away . on each locus page , gbrowse - generated thumbnails show schematic diagrams of the chromosomal surroundings and serve as a link to the full - featured genome browser , so that switching back and forth between the locus page and gbrowse windows is rapid and straightforward . for sequence analysis , cgd provides a blast tool accessible via a link shown in the banner at the top of almost every page on the cgd website ( ) . the tool allows comparison of any query sequence to one of several c.albicans sequence datasets . the full suite of blast programs is available [ blastn , blastp , blastx , tblastx and tblastn ( 16 ) ] . the sequence databases that can be searched include the complete sequence of assembly 20 chromosomes , assembly 19 supercontigs , assembly 6 contigs or assembly 4 contigs ; the coding sequences of orfs from assemblies 20 or 19 with or without introns ; the translation products of orfs from assemblies 20 , 19 or 6 ; the predicted trna genes from assembly 19 , or the mitochondrial genome sequence . sgd currently provides a fungal blast tool [ ; ( 17 ) ] that is updated regularly with all fungal sequences available in genbank ; it allows users to blast against all fungal sequences or against any desired combination of species . rather than re - creating this tool , cgd links to it from the cgd blast search page , such that users may readily input any sequence for comparison to myriad fungal species . since s.cerevisiae proteins have in general been more widely and deeply characterized than those of c.albicans , it is useful for cgd users to be able to access quickly any published information about the putative s.cerevisiae ortholog of a c.albicans protein . therefore , for each c.albicans protein with a predicted s.cerevisiae ortholog , we have added a prominent link to the locus summary page of the ortholog in the sgd ( ) . we have also added a search feature whereby the name of an s.cerevisiae gene may be used to search for the c.albicans ortholog in cgd . orthologs were mapped using the inparanoid software ( version 1.35 ) developed at the karolinska institutet ( 18 ) . the haploid complement of c.albicans proteins from cgd was compared to s.cerevisiae proteins from sgd , using the wormpep 145 set of c.elegans proteins from the sanger institute as an outgroup . using relatively stringent cutoffs ( blosum80 matrix and an inparanoid score of 100 % ) , 3594 ortholog mappings met these criteria when the analysis was performed in 2005 using assembly 19 of the c.albicans genome sequence . the analysis will be repeated using assembly 20 , and also periodically in the future when the sequence is updated significantly . the latest c.albicans genome assembly , assembly 20 , is a collaborative effort of groups at the biotechnology research institute of the national research council of canada , the university of minnesota , and chiba university of japan ( 9 ) . assembly 20 follows assembly 19 , which was released by the stanford genome technology center in 2004 ( 10 ) , and improves upon it in a number of ways . most notably , assembly 20 is a chromosome - level assembly ; the 266 assembly 19 contigs that span the haploid complement of the genome have been mapped onto the eight c.albicans chromosomes and joined into nearly contiguous sequence . numerous corrections to the sequence and to the predicted boundaries of orfs have also been made as part of this effort ( 9 ) . assembly 19 is a diploid assembly , which for many regions of the genome includes two contigs , corresponding to polymorphic allelic regions that show significant sequence differences . in contrast , assembly 20 is a haploid assembly , and in generation of assembly 20 , updates to assembly 19 have been made in only one allele of each pair . it should also be noted that assembly 20 does not represent a haploid set of chromosomes from the sequenced strain per se , but instead is a mosaic of the two haplotypes . thus , it is important that access to assembly 19 sequences be maintained even though assembly 20 is considered to be a more complete assembly . in addition , earlier assemblies of the genomic sequence and their associated gene nomenclatures are in widespread use in the research community and in the scientific literature . cgd continues to provide easy access to all versions of the genome sequence ( including the outdated ones ) while minimizing confusion , despite the necessarily complex nature of the situation . in cgd , the primary sequence for each gene is the sequence that is specified in assembly 20 . where the sequence and annotation of individual genes has changed , it is essential for the research community to have access to the different versions , not only to be able to understand exactly what has changed , but also to facilitate a critical evaluation of the sequence and to facilitate the continuing refinement process . to this endthe assembly 20 and 19 sequences of each gene ( and of both alleles , if available ) are readily available from each gene 's locus page , and the genomic context on the chromosome ( from assembly 20 ) or the contig ( s ) ( from assembly 19 ) can be explored using the gbrowse genome browser ( 11 ) . sequences from all of the assemblies , including the archived assemblies 4 and 6 , are available for query by blast and for bulk download , as described in more detail below . frequently , users need to retrieve sequence information for a single gene , or for a small number of genes . the most direct route to this sequence information is through the locus page . cgd is gene - centric in nature ; the website is organized around locus pages that provide access to all available information about each gene , including the literature - derived information about the function , role and localization of the gene product , the phenotypes caused by mutation of the gene , the experimental literature that describes the gene , and , of course , its sequence . to make it possible for users to easily access sequence and other information about any given gene , cgd collects all of the names by which each gene has been called , and makes all of these gene name synonyms , orabc1 have been manually collected by cgd curators from the published literature ( 12 ) . numerically based names ( e.g. contig4 - 3061_0012 , orf6 .8002 and orf19 .5007 ) were assigned to the predicted protein - coding genes during the annotation of assemblies 4 , 6 and 19 , respectively ( 7,10 ) . at cgd , sequence comparisons were used to determine the mapping between the orfs from assemblies 4 and 6 and the corresponding genes in assembly 19 , and the appropriate aliases were added to each locus page . the orfs in assembly 20 share the names of format orf19 . # that were assigned during production of assembly 19 . ipf . # ( e.g. ipf22272 .1 and ipf1819 .1 ) and ca # ( e.g. ca5255 ) were assigned by candidadb ( 13 ) . additionally , names of format caj7 . # have been assigned to orfs on chromosome 7 ( 14 ) . cases in which confusion exists regarding the assignment of a give gene name are documented in cgd nomenclature notes , which appear prominently on the locus page so that users are alerted to the situation . in the future , it may be desirable to adopt a chromosomal position - based systematic gene nomenclature , similar to the one used in the saccharomyces cerevisiae community . if the candida research community decides to develop such a system , cgd will facilitate the process and will adopt the new nomenclature as the primary systematic gene identifiers . the cgd sequence retrieval tool is accessible via the get sequence link , located on the left - hand sidebar on the home page , under search options . the tool retrieves sequences specified by gene name , alias , systematic orf name or allele name . it also allows the user to define how much of the upstream and downstream flanking sequences to retrieve , to select only the coding sequence ( without introns ) , or to translate the sequence to protein . the tool is also able to retrieve an entire chromosome , contig , or a particular region of a chromosome or contig identified by starting and ending coordinates . several types of sequence may also be retrieved from individual cgd locus pages using options on thethe options include the genomic dna ( with introns ) , the coding sequence ( with introns removed ) , the genomic dna with 1 kb upstream and downstream flanking regions , and the predicted protein sequence ( orf translation ) . the sequences in assembly 20 and assembly 19 are available from this menu . in caseswhere the two diploid alleles are known to differ in sequence in assembly 19 , both of these sequences are available . the selected sequence is displayed in a browser window in fasta format , and may be copied and pasted into another application . the downloadable files are indexed on the cgd downloads page ( ) . the raw sequences of c.albicans chromosomes from assembly 20 are available , as well as an archive of contigs from previous assemblies ( assemblies 4 , 5 , 6 and 19 ) from the stanford genome technology center ( 10 ) . for assemblies 19 and 20 , files with processed sequencesare also available : dna sequences of all coding regions , with or without introns , and with and without 1 kb flanking regions . the protein sequences derived from orf translation are available for the assemblies 20 , 19 and 6 . the dna sequence of the mitochondrial genome is also available for download ( 10 ) , as are the sequences of the trna genes predicted at cgd using the trnascan - se algorithm ( 15 ) . cgd also makes c.albicans sequence information and gene annotation available via the gbrowse genome browser , which is a sequence visualization and analysis tool developed as part of the generic model organism database project ( 11 ) . the tool displays a user - selected fragment of the genome ( contig , chromosome , orf , etc . ) in the form of an interactive map that can be zoomed in and out , or scrolled along the selected region . the sequence of the region within the browser 's window can be saved to a file at any time . tracks . the user may elect to display ( or hide ) tracks containing orfs , trna genes , restriction enzyme sites , six - frame translation , and dna sequence ( at high resolution ) or g - c content ( at low resolution ) . at this time , users may choose to browse either the assembly 20 chromosomes or the assembly 19 contigs . the assembly 20 view includes a track containing the assembly 19 contigs , to facilitate comparison between the two assemblies ( figure 1 ) . in the future , historical tracks containing the contigs and orfs from assemblies 6 and 4 will be added to the browser . upon selecting these tracks , users will have a graphical view of the changes between the genome assemblies ; for example , it will be clear where contigs have been assembled with each other , or where orfs have been added , merged , or deleted from one version of the genome assembly to the next . the view may be scrolled along the assembly 20 chromosome , or zoomed in on a particular region . selectable tracks of data include orfs , contig 19s , centromeric regions , and sequence gap regions . all the features displayed in the genome browser are hyperlinked to their respective locus pages , so that all the other pieces of information ( experimental literature , mutant phenotypes , gene ontology assignments ) are just a mouse click away . on each locus page , gbrowse - generated thumbnails show schematic diagrams of the chromosomal surroundings and serve as a link to the full - featured genome browser , so that switching back and forth between the locus page and gbrowse windows is rapid and straightforward . for sequence analysis , cgd provides a blast tool accessible via a link shown in the banner at the top of almost every page on the cgd website ( ) . the tool allows comparison of any query sequence to one of several c.albicans sequence datasets . the full suite of blast programs is available [ blastn , blastp , blastx , tblastx and tblastn ( 16 ) ] . the sequence databases that can be searched include the complete sequence of assembly 20 chromosomes , assembly 19 supercontigs , assembly 6 contigs or assembly 4 contigs ; the coding sequences of orfs from assemblies 20 or 19 with or without introns ; the translation products of orfs from assemblies 20 , 19 or 6 ; the predicted trna genes from assembly 19 , or the mitochondrial genome sequence . sgd currently provides a fungal blast tool [ ; ( 17 ) ] that is updated regularly with all fungal sequences available in genbank ; it allows users to blast against all fungal sequences or against any desired combination of species . rather than re - creating this tool , cgd links to it from the cgd blast search page , such that users may readily input any sequence for comparison to myriad fungal species . since s.cerevisiae proteins have in general been more widely and deeply characterized than those of c.albicans , it is useful for cgd users to be able to access quickly any published information about the putative s.cerevisiae ortholog of a c.albicans protein . therefore , for each c.albicans protein with a predicted s.cerevisiae ortholog , we have added a prominent link to the locus summary page of the ortholog in the sgd ( ) . we have also added a search feature whereby the name of an s.cerevisiae gene may be used to search for the c.albicans ortholog in cgd . orthologs were mapped using the inparanoid software ( version 1.35 ) developed at the karolinska institutet ( 18 ) . the haploid complement of c.albicans proteins from cgd was compared to s.cerevisiae proteins from sgd , using the wormpep 145 set of c.elegans proteins from the sanger institute as an outgroup . using relatively stringent cutoffs ( blosum80 matrix and an inparanoid score of 100 % ) , 3594 ortholog mappings met these criteria when the analysis was performed in 2005 using assembly 19 of the c.albicans genome sequence . the analysis will be repeated using assembly 20 , and also periodically in the future when the sequence is updated significantly . annotated genome sequences are now available for multiple fungal species related to c.albicans [ , ( 19 ) ; ; ] . to facilitate cgd users ' access to these data , which are stored at diverse locations , we will collect dna and protein sequences and make the files available for download . in the near future , we will implement two tools that allow comparison of closely related genomes with regard to conservation of gene order and of orthologous sequences . the synteny viewer , which is already in use at sgd ( 20 ) , is an interactive display of aligned chromosomal segments from different species , with genes color - coded by degree of similarity and hyperlinked to sequence or additional information . this tool will be used to display regions of synteny , or conserved gene order , between c.albicans and the other candida species . the fungal alignment viewer , also used by sgd ( 20 ) , facilitates comparison among orthologous genes as well as their 5 and 3 flanking sequences by generating custom color - coded clustalw alignments between nucleotide or protein sequences . the degree of similarity between a pathogen drug target and host molecules is an important consideration in predicting drug toxicity and side effects . in the future , cgd will implement a new blast tool containing sequences from pathogenic and non - pathogenic fungi plus sequences from mammalian hosts , so that users may evaluate conservation between possible drug targets and any host homologs . with the summer 2006 release of assembly 20 , the cgd team has now taken on the responsibility of maintaining the official copy of the c.albicans genome sequence , and the task of incorporating corrections and updates as the sequence data are refined . the most significant challenge remaining in refinement of the c.albicans sequence will be the completion of an updated diploid assembly . the adjustment of the boundaries of allelic orfs and , eventually , accurate representation of haplotype information ( as far as haplotype data are available ) are challenging tasks for the future . as the genomic sequence assembly continues to evolve , cgd looks forward to providing the candida research community with the latest dna and protein sequence , and with the tools necessary to navigate and analyze this wealth of information . annotated genome sequences are now available for multiple fungal species related to c.albicans [ , ( 19 ) ; ; ] . to facilitate cgd users ' access to these data , which are stored at diverse locations , we will collect dna and protein sequences and make the files available for download . in the near future , we will implement two tools that allow comparison of closely related genomes with regard to conservation of gene order and of orthologous sequences . the synteny viewer , which is already in use at sgd ( 20 ) , is an interactive display of aligned chromosomal segments from different species , with genes color - coded by degree of similarity and hyperlinked to sequence or additional information . this tool will be used to display regions of synteny , or conserved gene order , between c.albicans and the other candida species . the fungal alignment viewer , also used by sgd ( 20 ) , facilitates comparison among orthologous genes as well as their 5 and 3 flanking sequences by generating custom color - coded clustalw alignments between nucleotide or protein sequences . the degree of similarity between a pathogen drug target and host molecules is an important consideration in predicting drug toxicity and side effects . in the future , cgd will implement a new blast tool containing sequences from pathogenic and non - pathogenic fungi plus sequences from mammalian hosts , so that users may evaluate conservation between possible drug targets and any host homologs . with the summer 2006 release of assembly 20 , the cgd team has now taken on the responsibility of maintaining the official copy of the c.albicans genome sequence , and the task of incorporating corrections and updates as the sequence data are refined . the most significant challenge remaining in refinement of the c.albicans sequence will be the completion of an updated diploid assembly . the adjustment of the boundaries of allelic orfs and , eventually , accurate representation of haplotype information ( as far as haplotype data are available ) are challenging tasks for the future . as the genomic sequence assembly continues to evolve , cgd looks forward to providing the candida research community with the latest dna and protein sequence , and with the tools necessary to navigate and analyze this wealth of information .\noutput:\n" }, { "from": "agent", "value": "the candida genome database ( cgd , ) contains a curated collection of genomic information and community resources for researchers who are interested in the molecular biology of the opportunistic pathogen candida albicans . with the recent release of a new assembly of the c.albicans genome , assembly 20 , c.albicans genomics has entered a new era . although the c.albicans genome assembly continues to undergo refinement , multiple assemblies and gene nomenclatures will remain in widespread use by the research community . cgd has now taken on the responsibility of maintaining the most up - to - date version of the genome sequence by providing the data from this new assembly alongside the data from the previous assemblies , as well as any future corrections and refinements . in this database update , we describe the sequence information available for c.albicans , the sequence information contained in cgd , and the tools for sequence retrieval , analysis and comparison that cgd provides . cgd is freely accessible at and cgd curators may be contacted by email at [email protected] ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: diabetic retinopathy ( dr ) is the leading cause of visual loss in working - aged people and the most common microvascular complication in diabetic patients , despite the recent improvement in the management of dr via glycemic control and photocoagulation . pericyte loss is one of the earliest and most characteristic changes in dr . however , the mechanisms by which hyperglycemia leads to pericyte loss remain largely unknown . in recent years , sumoylation has emerged as an important mechanism in the regulation of multiple cellular signaling pathways . sumoylation is catalyzed by the activation ( e1 ) , conjugation ( e2 ) , and ligation ( e3 ) of enzymes . it can be reversed by a family of sentrin / sumo - specific proteases ( senps ) . among these family members , senp1 is able to deconjugate either sumo1 or sumo2 / 3 modified proteins . senp1 has been reported to play an important role in the control of dna damage responses and cellular apoptosis . dbc1 ( deleted in breast cancer ) was initially identified as a putative tumor suppressor . dbc1 modification by small ubiquitin - like modifier 2/3 ( sumo2 / 3 ) is crucial for cellular apoptosis under genotoxic stress . however , it remains unknown whether high glucose is involved in the regulation of dbc1 sumoylation . in the present study , we demonstrated that high glucose induces the sumoylation of dbc1 via the inhibition of senp1 expression in bovine retinal pericytes ( brpcs ) . knockdown of senp1 promoted hyperglycemia - induced brpc apoptosis , whereas the overexpression of senp1 inhibited it . these results indicate that modification of dbc1 by senp1 contributes to brpc apoptosis in response to high glucose . all chemicals were reagent - grade quality and were purchased from sigma chemicals ( st . the cells were cultured in dulbecco 's modified eagle 's medium ( dmem , gibco , usa ) supplemented with 10 % fetal bovine serum ( fbs , gibco , usa ) , at 37c , with 5 % co2 . the cells were identified using the anti- isoform of smooth - muscle actin ( sigma - aldrich corporation , st . cells cultured for more than three passages were used in further high glucose treatment and transfection . for high glucose treatment , the cells were exposed to either high glucose ( 30 mmol / l ; hg ) or normal glucose ( 5 mmol / l ; ng ) for 1248 h. the ha - senp1 plasmid ( ha - senp1 ) was created via pcr cloning into the hindiii and xbal i sites of the pcdna3.0 - ha vector . the primers of senp1 were 5 - atggatgatattgctgataggatg - 3 and 5 - tcacaagagttttcggtggagg - 3 . the pcdna3 .0 vector ( pcdna ) was used as a control empty plasmid . the flag - dbc1 plasmid ( flag - dbc1 ) was created by pcr cloning into the hindiii and kpn i sites of the pcdna3.0 - flag vector . the primers for dbc1 were 5 - atgtcccagtttaagcgccagc - 3 and 5 - tcagttgctaggtgccggctc - 3 . the ablation of senp1 was performed via the transfection of the brpc with sirna - senp1 ( si - senp1 ) as follows : 5 - ggctcaatgacgagatcattt - 3 . the ablation of dbc1 was performed by transfection of the brpc with sirna - dbc1 ( si - dbc1 ) , 5 - aaacggagc - cuacugaacauu - 3 . the nonspecific sirna was used as a control ( si - nc ) . the pcdna3.0 - flag - dbc1 mutant ( k591r ) construct was designed to mutate ( flag - dbc1 k591r ) ; the construct was prepared through site - directed mutagenesis based on the wild - type construct by using a quikchange mutagenesis kit ( agilent , usa ) . the primers used for the one - site mutation ( k591r ) were 5 - ccaaggaggaagaagccatcagagaggaggtgg - 3 and 5 - ccacctcctctctgatggcttcctccttgg - 3 . cells were transfected by lipofectamine 2000 ( invitrogen , usa ) following the protocol provided by the manufacturer . eight - week - old male sprague - dawley rats weighing ~ 200 g each ( shanghai laboratory animal center , chinese academy of sciences ) were randomly selected for intraperitoneal administration of either 65 mg / kg streptozotocin ( stz ) or citrate buffer alone . rats were categorized as diabetic when their blood glucose exceeded 16.7 mmol / l at 48 h after stz administration . after 8 weeks , the eyes were resected from deeply anesthetized animals and prepared for western blot analysis . fifty micrograms of protein obtained from each sample ( brpcs ) was subjected to sodium dodecyl sulfate - polyacrylamide gel electrophoresis ( sds - page ) in a bio - rad miniature slab gel apparatus and electrophoretically transferred onto a nitrocellulose membrane . the membrane was blocked in a 5 % nonfat dried - milk solution and incubated overnight with rabbit anti - senp1 ( ab108981 , 1 : 1000 , abcam , usa ) , rabbit anti - parp ( # 9542 , 1 : 1000 , cell signaling technology , usa ) , rabbit anti - bcl - 2 ( # 2870 , 1 : 1000 , cell signaling technology , usa ) , mouse anti - ha ( ab18181 , 1 : 1000 , abcam , usa ) , or flag antibody ( f1804 , 1 : 1000 , sigma , usa ) . blots were stained with mouse anti- - actin ( a5441 , 1 : 1000 , sigma , usa ) ( as an internal control ) to confirm equivalent total - protein loading . total rna was extracted from brecs and rat retinal tissue using trizol reagent ( invitrogen life technologies , gaithersburg , md ) and stored at 80c . the dynamo flash sybr green qpcr kit ( finnzymes oy , espoo , finland ) was used according to the manufacturer 's instructions . the primer sequences ( sense / antisense ) used were as follows : senp1 ( brecs ) , 5 - catgccattttccaccgtgtt - 3 / 5 - aaggcatgtggaggaagagtg - 3 ; senp1 ( rat ) , 5 - agtgaaacgctggacaaa - 3 / 5 - cctgggctttggtttgga - 3 ; - actin , 5 - gcaccgcaaatgcttcta - 3 / 5 - ggtctttacggatgtcaacg - 3 . the specificity of the amplification product was determined by a melting curve analysis . standard curves were generated for the expression of each gene by preparing serial dilutions with known quantities of each cdna template . relative quantification of the signals was performed by normalizing the signals of different genes with the - actin signal . cell lysates were incubated with an appropriate antibody overnight at 4c , followed by incubation with protein a / protein g - coated agarose beads ( millipore , massachusetts , usa ) for another 4 h at 4c . after samples were washed four times with ice - cold ip buffer and supernatants were removed by centrifugation at 2,000 g for 1 min , proteins were coprecipitated . the proteins were then separated from the beads using an immunoprecipitation loading buffer for 15 min at 95c . the supernatants were collected and subjected to sds - page followed by immunoblot analysis using antibodies against rh , sumo2 / 3 , dbc1 , ha , flag , and senp1 . apoptosis was assessed by using the annexin v / propidium iodide ( pi ) kit , according to the manufacturer 's instructions ( bender med systems , usa ) . brpcs ( 510 ) were washed twice with pbs and suspended in 90 l 1x binding buffer . a total of 4.0 l of annexin v fitc were added to the cell suspension , vortexed , and incubated for 10 min in the dark . thenfinally , 60 l of 1x binding buffer was added , and samples were evaluated using flow cytometry . the intensities of relative proteins were measured using imagej software ( national institutes of health ) . statistical analyses were performed using the standard two - tailed student 's t - test , assuming unequal variances . prism 4.0 software system ( graphpad , san diego , ca , usa ) and the statistical software program spss version 17.0 for windows ( spss , chicago , il , usa ) were used for these analyses . pericytes may be identified by morphological criteria and also through analysis of antigen expression detected by immunofluorescence with specific antibodies . as the previous study demonstrated , the brpcs showed to be characterized by highly irregular peripheries and phase - dense filaments at five days after isolation ( figure 1 ( a ) ) . at 10 days after isolation , the brpcs showed a non - contact - inhibited and overlapping pattern of growth at confluence ( figure 1 ( b ) ) . immunohistochemical staining showed positive staining for anti- isoforms of smooth - muscle actin ( figure 1 ( c ) ) and negative staining for von willebrand factor ( figure 1 ( d ) ) . as shown in figure 2 ( a ) , treatment with high glucose resulted in a decrease of senp1 expression ; the levels of mrna and protein were lower in the hg groups than in the ng group in brpcs . of note , we found that the effects of high glucose on senp1 expression were time dependent . we also examined the levels of senp1 mrna and protein in the retinas of control rats ( norm ) and rats that maintained hyperglycemia for eight weeks ( diab ) . we found that hyperglycemia caused a significant decrease in the mrna and protein of senp1 ( figure 2 ( b ) ) . in an attempt to determine the effects of senp1 on the apoptosis of brpcs under high glucose conditions , we overexpressed senp1 in brpcs . in these experiments , cells were transfected with pcdna ( control vector ) or the ha - senp1 and exposed to normal or high glucose for 48 h. pericyte apoptosis was assessed via annexin v / pi flow cytometric analysis . the apoptosis of brpc incubated under high glucose conditions was significantly greater than under normal glucose conditions , and this hyperglycemia - induced increase in cell apoptosis was attenuated by senp1 overexpression ( figure 3 ( a ) ) . , cells were transfected with si - nc or the si - senp1 and exposed to normal or high glucose for 48 h. knockdown of senp1 led to an increase in the apoptotic cells in the presence of high glucose , but not in its absence ( figure 3 ( b ) ) . we also investigated whether senp1 affected apoptosis - associated gene expression , such as cleaved poly - adp ribose polymerase ( cleaved parp ) and bcl - 2 . the levels of the two proteins in the senp1 overexpression ( figure 3 ( c ) ) or knockdown ( figure 3 ( d ) ) cells exposed to normal or high glucose , respectively , were determined by western blotting . the expression trends of the two proteins were found to be consistent with the flow cytometric results . these data suggest that senp1 plays an antagonistic role in pericyte apoptosis under high glucose conditions . because dbc1 sumoylation has been implicated in senp1 - mediated apoptosis , we examined whether high glucose induced dbc1 sumoylation . as expected , we found that dbc1 was modified by sumo3 ( figure 4 ( a ) ) . since sumoylation has been implicated in dna damage response , we examined whether hyperglycemia stress induces dbc1 sumoylation . we found that treatment of brpc with high glucose led to an increase in sumo3 modification of endogenous dbc1 ( figure 4 ( b ) ) . to determine whether senp1 was the desumoylating enzyme of dbc1 , we immunopurified dbc1 - associated proteins ( anti - dbc1 ) . western blotting with an anti - senp1 antibody revealed the association of senp1 with dbc1 , and this interaction was markedly reduced by high glucose treatment ( figure 5 ( a ) ) . to determine whether senp1 is indeed capable of desumoylating dbc1 , senp1 overexpression caused a marked reduction in dbc1 sumoylation which was induced by high glucose ( figure 5 ( b ) ) . to determine whether dbc1 sumoylation was responsible for senp1 - mediated apoptosis under high glucose conditions , two plasmids that expressed either the wild - type ( flag - dbc1 - wt ) or the dbc1 mutant ( flag - dbc1 - k591r ) were constructed . since lys591 had been reported as the main sumo acceptor site , the lys residues were substituted by arg . these plasmids were used for transfecting brpcs in which endogenous dbc1 expression was knocked down using sirnas and the cells were exposed to normal or high glucose for 48 h. the knockdown effect of the dbc1 sirna in brpcs was assessed using western blot analysis ( figure 6 ( b ) ) . consistently , flag - dbc1 - wt , but not the flag - dbc1 - k591r , increased the apoptosis of brpc under high glucose ( figure 6 ( c ) ) . the expression trend of the cleaved parp and bcl - 2 was found to be consistent with the flow cytometric results ( figure 6 ( d ) ) . these results indicated that dbc1 sumoylation is a crucial step in senp1 - mediated apoptosis under high glucose conditions . sumoylation is a highly transient posttranslational protein modification that affects the cell cycle , proliferation , apoptosis , and differentiation . senps , which remove sumo intact from their substrates , are the central players in the regulation of protein / sumoylation balances . in the current study , we provided evidence that dbc1 sumoylation increased as a result of the hyperglycemia - induced inhibition of senp1 expression in brpcs . overexpression of senp1 conferred resistance to the apoptosis of brpcs induced by high glucose via desumoylating dbc1 . to our knowledge , our study is the first to report that high glucose inhibits senp1 expression in brpcs . sumoylation / desumoylation is a highly dynamic process that regulates various physiological processes , including cell growth , differentiation , senescence , oxidative stress , and apoptosis . previously , the senp1 - mediated protein sumoylation has been demonstrated to play a key role in pancreatic immune responses , - cell damage , and , consequently , diabetes progression . senp1 has been shown to be a molecular mechanism for the pathogenesis of diabetes , and it may help to develop a novel therapeutic strategy for the treatment of diabetes . however , the role of senp1 in the pathogenesis of diabetic vascular complications is an important question that has never been answered . we sought to investigate the roles and detailed mechanisms by which senp1 regulates the apoptosis of brpc under high glucose conditions . importantly , senp1 sirna significantly aggravated the apoptosis of brpcs induced by hyperglycemia stress , whereas the overexpression of senp1 inhibited cellular apoptosis . the mechanisms by which senp1 suppresses apoptosis reactions under high glucose conditions are poorly understood . the discovery of dbc1 as a modulator of sirt1 , hdac3 , and several nuclear receptors raises the possibility that dbc1 may be a master regulator of the interconnection between metabolism and epigenetics . the study of this multifunctional protein is likely to provide novel understanding and potential new therapeutic options for multiple human diseases and conditions such as obesity , metabolic syndrome , atherosclerosis , inflammation , aging , and cancer . dbc1 sumoylation could cause a dramatic increase in dbc1 - sirt1 interactions , which could lead to the release of p53 from sirt1 for transcriptional activation . this study demonstrated that the treatment of brpcs with high glucose led to an increase in sumo - modification of endogenous dbc1 . we also found that senp1 overexpression could inhibit the dbc1 sumoylation induced by high glucose , and dbc1 wt ( though not the k591r mutant ) increased the apoptosis of brpcs . together , these results suggest that there may be causal relationships between the reduced levels of cellular apoptosis mediated by senp1 and the sumoylation levels of dbc1 . in conclusion , our results provide molecular insight into the regulation of the apoptosis induced by high glucose in brpcs . we also demonstrated the crucial role of senp1 in the control of apoptosis , through a dbc1 sumoylation - dependent pathway . our data suggest that senp1 could be a potential therapeutic target to prevent pericytes loss in dr .\noutput:\n" }, { "from": "agent", "value": "pericyte loss is an early characteristic change in diabetic retinopathy , but its precise molecular mechanisms have not been elucidated . this study investigated the role of senp1 in pericyte loss in diabetic retinopathy . we demonstrated that a high concentration of glucose inhibited the expression of the sentrin / sumo - specific protease 1 ( senp1 ) , which resulted in an increase in dbc1 sumoylation in bovine retinal pericytes ( brpcs ) . furthermore , senp1 overexpression attenuated hyperemia - induced apoptosis of bprcs , and senp1 knockdown aggravated this effect . we also provide evidence that dbc1 sumoylation / desumoylation is involved in the senp1 - regulated apoptosis of brpcs under high glucose conditions . understanding the role of senp1 in the pathogenesis of high glucose induced pericyte loss could help elucidate important targets for future pharmacological interventions ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: postmenopausal osteoporosis ( op ) is a major women s health problem that increases morbidity , mortality , and cost of healthcare . a revised perspective of the pathogenesis in this disease from estrogen - centric tooxidative stress has highlighted the need to identify reliable markers for reflecting oxidative stress status in this disease . loss of estrogens decreases defense against oxidative stress in bone , and this accounts for the increased bone resorption and decreased bone formation associated with the acute loss of these hormones , which is the main pathological characteristic of postmenopausal op . the involvement of oxidative stress in the development of postmenopausal op has recently been well documented . accurate measurement of ros to reflect the level of oxidative stress in vivo is difficult due to the bewildering variety , low quantity , high reactivity , and the extremely short half - life of ros generated during each cell cycle . therefore , measurement of some peroxidation end - products is used to evaluate the oxidative stress status in vivo . malondialdehyde ( mda ) , an end - product of lipid peroxidation , is extensively used as an oxidative stress parameter . however , the role of mda in postmenopausal op is still highly debatable . advanced oxidation protein products ( aopps ) were first detected in the plasma of chronic uremic patients , and are considered to be a novel marker of oxidative stress because it is stable and easy to detect . aopps result mainly from the action of ros ( chlorinated compounds ) in proteins , leading to the formation of dityrosine residues and protein crosslinking . our previous studies demonstrated that the serum levels of aopps were negatively correlated with age - related change in bone mineral density ( bmd ) in rats and could accelerate bone deterioration in aged rats . furthermore , we also confirmed that aopps could inhibit proliferation and differentiation of rat osteoblasts . hence , we wondered whether the level of aopps is elevated in postmenopausal osteoporotic women and if aopps might be used as a novel marker to predict the severity of this disease . to clarify this question we measured levels of plasma aopps as an indicator of oxidatively modified proteins and also tested plasma mda as a marker of lipid peroxidation . the relationships between the above oxidative stress makers and bmd or bone turnover markers were also analyzed . sixty postmenopausal women meeting op diagnostic criteria of the world health organization ( who ) and 60 postmenopausal women without op were recruited in this study . we excluded patients with secondary op , diseases known to be associated with increased oxidative stress ( dementia , cardio - and cerebrovascular disease , diabetes , renal or hepatic insufficiency , and inflammatory diseases ) , use of antioxidant vitamins in the 6 months before enrollment , or malnutrition . we also excluded subjects who had received medications potentially involving bone mineral metabolism within the last 6 months ( including corticosteroids , heparin , and anticonvulsants ) or who had previous or current use of active bone agents such as selective estrogen receptor modulators or estrogen replacement therapy , strontium ranelate , teriparatide or pth , calcitonin , and denosumab . fasting venous serum specimens were collected and blood tests were performed by the clinical laboratories in nanfang hospital . this study was performed in one of the largest hospital in china where the lab standards are nationalized . for laboratory investigations , following 12 h of fasting , blood samples of all subjects were collected in the morning in tubes containing sodium citrate as anticoagulant and then separated immediately by centrifugation at 3000 rpm for 10 min at + 4c . assays were carried out on duplicate samples using a microplate reader . to minimize the impact of lipid interferences , samples were centrifuged at 10000 g for 1 h at + 4c before determination . plasma aopps concentration was measured according to the spectrophotometric method and expressed in equivalents of chloramine t . plasma mda concentration was measured in terms of thiobarbituric acid reactive substances , spectrophotometrically by the previous protocol using mda assay kit ( nanjing jiancheng bioengineering institute , china ) . the concentrations of 2 specific markers of bone turnover , balp and tracp 5b , were quantified using elisa kits ( cusabio , china ) . measurement of bmd by dual - energy x - ray absorptiometry at the spine , hip , and / or forearm is the gold standard for establishing the diagnosis of osteoporosis . in the present study , bmd was measured at the lumbar spine region ( l2l4 ) by dual - energy x - ray absorptiometry ( xr246 norland usa ) . the diagnosis of osteoporosis is defined as a t score of 2.5 or less , indicating a bmd that is at least 2.5 sd less than the mean of young adults . fasting venous serum specimens were collected and blood tests were performed by the clinical laboratories in nanfang hospital . this study was performed in one of the largest hospital in china where the lab standards are nationalized . for laboratory investigations , following 12 h of fasting , blood samples of all subjects were collected in the morning in tubes containing sodium citrate as anticoagulant and then separated immediately by centrifugation at 3000 rpm for 10 min at + 4c . assays were carried out on duplicate samples using a microplate reader . to minimize the impact of lipid interferences , samples were centrifuged at 10000 g for 1 h at + 4c before determination . plasma aopps concentration was measured according to the spectrophotometric method and expressed in equivalents of chloramine t . plasma mda concentration was measured in terms of thiobarbituric acid reactive substances , spectrophotometrically by the previous protocol using mda assay kit ( nanjing jiancheng bioengineering institute , china ) . the concentrations of 2 specific markers of bone turnover , balp and tracp 5b , were quantified using elisa kits ( cusabio , china ) . measurement of bmd by dual - energy x - ray absorptiometry at the spine , hip , and / or forearm is the gold standard for establishing the diagnosis of osteoporosis . in the present study , bmd was measured at the lumbar spine region ( l2l4 ) by dual - energy x - ray absorptiometry ( xr246 norland usa ) . the diagnosis of osteoporosis is defined as a t score of 2.5 or less , indicating a bmd that is at least 2.5 sd less than the mean of young adults . basically , there was no statistically significant difference in age or years since menopause between the 2 groups . as shown in table 1 , plasma aopps ( p 0.001 ) , balp ( p 0.001 ) and tracp 5b ( p 0.001 ) levels were higher in the postmenopausal osteoporotic women than those in the control group , but there was no statistically significant difference in mda ( p = 0.124 ) between the 2 groups . as shown in table 2 , plasma aopps levels were negatively correlated with lumbar bmd ( r = 0.470 , p 0.001 ) and positively correlated with bone turnover markers balp ( r = 0.325 , p 0.001 ) and tracp 5b ( r = 0.317 , p 0.001 ) in all subjects . these findings were also confirmed by the statistical data from the postmenopausal osteoporotic women ( table 2 ) . however , plasma mda levels were not correlated with lumbar bmd or bone turnover markers in all subjects nor in the postmenopausal osteoporotic women ( table 2 ) . oxidative modified molecules were used as reliable parameters for monitoring oxidative stress status in vivo . in the present study , we measured plasma aopps and mda levels to evaluate the level of oxidative stress , and found that aopps levels was increased in postmenopausal osteoporotic women compared with controls . aopps levels were negatively correlated with lumbar bmd and positively correlated with bone turnover markers , while mda levels were not correlated with lumbar bmd or bone turnover markers . morphologic studies and measurements of certain biochemical markers have indicated that bone remodeling is accelerated at the menopause , as both markers of resorption and formation are increased . balp , which promotes bone mineralization , is considered primarily a sign of increased activity of osteoblasts and secondarily as a corrective reaction as a result of increased bone resorption . levels of this serum bone turnover marker are valuable in assessing systemic bone turnover in postmenopausal op . osteoclasts contain the tracp5b as bone - specific enzyme , the serum concentration of which generally reflects the extent of bone resorption . in this study , we found that the plasma balp and tacp 5b concentrations were higher in postmenopausal osteoporotic women compared with controls . many laboratory methods are available in the literature that are of help in establishing the presence of oxidative stress in vivo , but none of them proved to be unequivocally superior to the others . one of the most damaging effects of oxidative stress is lipid peroxidation , the end - product of which is mda , which is one of the most frequently used indicators of lipid peroxidation . mda is known as a potential biomarker of oxidative stress and possesses the ability to promote osteoclastogenesis . there have been some debates about using mda as a marker for op in postmenopausal women in the last decade . it has been reported that total femoral bmd measurements significantly correlated with mda levels in a limited sample of postmenopausal osteoporotic women . however , the results of the present study suggest that mda levels were not correlated with lumbar bmd or bone turnover markers . therefore , the use of mda levels may not assist estimation of the severity of postmenopausal op , which is highly consistent with results of published studies with larger sample sizes . prior to lipid and other cellular components , proteins are the primary target of ros . oxidative damage to proteins is reflected by increased levels of aopps , which therefore serve as a novel biomarker of oxidative stress . in addition to chronic uremia , levels of aopps are also elevated in patients with different oxidative stress - related diseases , such as diabetes , coronary artery disease , and chronic inflammatory bowel diseases . the published literature has provided convincing evidence that aopps are a reliable oxidative stress biomarker . in the present study , we also found that aopps seemed to be a more relevant marker to reflect the severity of postmenopausal op than mda after we investigated the relationship between aopps and bmd or bone turnover markers . apart from being regarded as an oxidative stress maker , aopps have also been shown to be a novel molecular basis of oxidative stress , participating in many biological events by inducing the production of intracellular ros . postmenopausal op is thought to be a type of high - turnover osteoporosis and is characterized by excessive bone resorption and inadequate bone formation , which is regulated by the coupling of osteoblasts and osteoclasts . ros can affect the genesis and lifespan of osteoblasts and osteoclasts . in precursors of osteoclasts , rankl - induced activation of rankmore recently , an in vitro study has revealed that os results in increased content of aopps in cultured mouse mc3t3 - e1 osteoblast - like cells . in addition , aopps can inhibit proliferation and differentiation of rat osteoblast ( rob ) cells through the ros - dependent nf - b pathway . taken together , these results show that aopps may be a reliable indicator in estimation of the severity of postmenopausal op as well as an important factor in the pathogenesis of this diseasefurther studies investigating relationship between aopps , antioxidants levels , and femoral bmd should be performed . our results show that the postmenopausal osteoporotic women have higher plasma levels of aopps compared with a normal age - matched reference population . plasma aopps concentrations are related to bone loss and bone turnover markers in postmenopausal women . therefore , plasma levels of aopps might be used as a novel marker of oxidative stress to predict the severity of postmenopausal op .\noutput:\n" }, { "from": "agent", "value": "backgroundadvanced oxidation protein products ( aopps ) are acknowledged as a novel marker of oxidation - mediated protein damage . this study aimed to investigate the plasma levels of aopps in postmenopausal osteoporotic women , and to determine the relationship between aopps accumulation and lumbar bone mineral destiny ( bmd ) or bone turnover markers.material / methodslumbar bmd was measured by dual - energy x - ray absorptiometry . plasma aopps levels as a marker of protein oxidation damage and malondialdehyde ( mda ) levels as a marker of lipid peroxidation were measured by spectrophotometry . the concentrations of 2 specific markers of bone turnover , bone - specific alkaline phosphatase ( balp ) and tartrate - resistant acid phosphatase5b , ( tracp 5b ) were quantified using elisa kits.resultswe recruited 60 postmenopausal women meeting osteoporosis ( op ) diagnostic criteria of world health organization ( who ) and 60 postmenopausal women without op . plasma levels of aopps ( p < 0.001 ) , balp ( p < 0.001 ) and tracp 5b ( p < 0.001 ) were statistically significantly increased in the postmenopausal osteoporotic women compared with controls , but there was no statistically significant difference in mda ( p = 0.124 ) between the 2 groups . plasma aopps levels were negatively correlated with lumbar bmd and positively correlated with bone turnover markers both in postmenopausal osteoporotic women and in all subjects . however , plasma mda levels were not correlated with lumbar bmd or bone turnover markers.conclusionsin postmenopausal osteoporotic women elevated aopps is associated with reduced bmd and increased bone turnover markers . because aopps is stable and easy to detect it may be used as a simple plasma marker to predict the severity of postmenopausal op ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: hepatoid adenocarcinoma ( hac ) is a type of extrahepatic carcinoma , which has a similar morphology to hepatocellular carcinoma ( hcc ) .1 the first hac case was described by bourrelille et al . in 1970.2 it occurs in many different organs such as the lung , pancreas , ovary , and gastric tissue .3 elevated alpha - fetoprotein ( afp ) level is a characteristic finding of hac .4 in patients at a high risk for hcc , such as patients with cirrhosis , chronic hepatitis b virus ( hbv ) or hepatitis c virus ( hcv ) infection , elevated serum afp level is usually indicative of hcc . if hac occurs in patients at a high risk for hcc , correct diagnosis of hac can be a challenging issue to clinicians . recently , hac cases with liver metastasis mimicking hcc have been reported in many countries .1,5,6 however , a case of a metachronous hcc and hac is very rare . herewe report an unusual case of hac of the stomach which was diagnosed in a patient who had hcc . he was receiving antiviral treatment with oral antiviral agents ( lamivudine and adefovir dipivoxil ) from 2003 to 2008 due to hbv reactivation with elevated liver enzyme , positive for hbeag and hbv dna of 199.1 pg / ml . after the administration of antiviral agents , liver enzyme was normalized and hbeag seroconversion occurred . in december 2001 , ten years prior to this evaluation , an arterial enhancing lesion approximately 3 cm in size with delayed washout at the segment 6/7 area of the liver ( fig .1 a , b ) , along with elevated serum afp level ( 7,463 ng / ml ) , was found . the patient was diagnosed with hcc and treated with a right lobectomy , which revealed edmondson grade ii hcc ( fig . six months after the liver resection , a 1.5 cm sized enhancing nodule with delayed washout was found in the caudate lobe . in august and october 2002 , two times of transarterial chemoembolization were performed at the lesion and follow - up computed tomography ( ct ) showed complete lipiodol uptake at the lesion . serum afp had returned to normal level ( 4.8 ng / ml ) and since then , he had been regularly followed up for nine years without evidence of tumor recurrence . in july 2010 , elevation of serum afp level was noticed ( from 6.5 ng / ml to 625.4 ng / ml during a period of six months ) . a white blood cell count was 3,990 / mm , a hemoglobin level was 14.6 g / dl , a platelet count was 73,000 / mm , a serum protein level was 7.7 g / dl , a serum albumin level was 3.8 g / dl , a serum bilirubin level was 1.5 mg / dl , a serum aspartate aminotrasferase level and a serum alanine aminotransferase level were 56iu / l , a serum creatinine level was 0.84 mg / dl , and a prothrombin time ( % ) was 81 % . other tumor markers were within normal range ( serum proteins induced by vitamin k absence or antagonist - ii ( pivka - ii ) : 23 mau / ml , carcinoembryonic antigen ( cea ) : 1.8 ng / ml and carbohydrate antigen 19 - 9 ( ca 19 - 9 ) : 9.2 iu / ml ) . liver ct revealed a 2.5 cm low - attenuated nodular lesion around the common hepatic artery , suggesting metastatic lymphadenopathy without intrahepatic lesion . positive emission tomography ( pet ) - ct found a hypermetabolic lymph node ( p - suv = 4.1 ) at the common hepatic artery area , but no other fluorodeoxyglucose ( fdg ) uptake that suggested the presence of a malignant tumor was found . based on elevated afp level and prior history of hcc , metastatic lymphadenopathy from hcc was the differential diagnosis . radiation therapy for regional lymph node was planned , and he underwent upper endoscopy for screening purposes before receiving radiation therapy . incidentally , a 4.0 cm ulcerative lesion at the lesser curvature side of the antrum was found during an upper endoscopy ( fig . microscopic examination revealed hac with lymph node metastasis as immunohistochemical ( ihc ) study showed that tumor cells were positive for afp and polyclonal cea ( fig . after the operation , serum afp level decreased , and he received titanium silicate ( ts ) - 1 for adjuvant chemotherapy . however , 6 months after the gastrectomy , multiple small hepatic nodules were found in the liver during adjuvant chemotherapy ( fig .3 a ) . a liver biopsy was taken and hac was diagnosed as ihc positive for afp and ck19 , focally positive for cea , whereas negative for ck7 and ck20 ( fig . he was then switched to palliative chemotherapy with carpecitabine and cisplatin ( xp regimen ) . after 4 months ( four cycles ) of chemotherapy , he was put under the second - line palliative chemotherapy with fluorouracil , leucovorin and irinotecan ( folfiri regimen ) . a case of hac which developed nine years after the treatment of hcc in one patient is extremely rare . morinaga et al6 described a case in which the patient was hcv seropositive , had high serum afp level and was confirmed to have liver masses . autopsy revealed the coexistence of primary hcc and hac of the stomach with multiple liver metastases . lauffer et al7 reported a case of a patient with hcc as well as hac of the stomach without liver metastasis . to our knowledge , only two cases described above have reported concurrent hcc and hac , and this is the first case of metachronous hcc and hac in a patient . afp is a tumor marker variably secreted by hcc and is widely used in clinical practice as a diagnostic tool . serial measurement of serum afp level is used for hcc surveillance in high risk individuals , and it is also used in post - hcc treatment assessment .8 changes in serum afp level help to assess treatment response , and also help to identify recurrence of hcc . however , afp is not hcc specific . elevation in the serum afp level can be found in cases of pregnancy , benign liver disease associated with liver regeneration such as hepatitis and cirrhosis , tumors of gonadal origin ( both germ cell and non - germ cell ) and variety of gastrointestinal malignancies as well as in hac .9 hac is an afp - producing malignant tumor that may be found in several organs . the stomach is the most common site affected .3 ishikura et al10 proposed the term ' hepatoid adenocarcinoma of the stomach ' as an afp - secreting gastric carcinoma with features of hepatic differentiation in 1985 . the reported incidences of afp - producing gastric adenocarcinoma have been from 1.3 % - 15 % of all gastric cancers .11 the pathogenesis of hac is not fully understood but several features have revealed . this tumor shows a high angioinvasiveness and this feature shared with epithelial neoplasm such as hcc and renal cell carcinoma .4 one hypothesis might be that hepatoid cells are more proximal to the totipotent cells , such as fetal cells , from an ontogenetic standpoint , that liver specific genes normally in the repressed state may be activated during the process of carcinogenesis , expressing cells with a hepatic phenotype .12 these assumptions need to be proven and more studies about pathogenesis and biology of this tumor are required . clinically , this neoplasm is characterized by a predilection for older age , aggressive clinical course , and poor prognosis because of its extensive hematogenous metastasis to the liver and early metastasis to regional lymph nodes .4,11,13,14 inagawa et al8 reviewed 85 cases of hepatoid adenocarcinoma of stomach that have been reported . early - stage cancer was seen in only 11 patients ; the had the were advanced stage . most of the reported patients preoperatively diagnosed with metastases to the liver or lymph nodes . furthermore , most of them died within 2 years of the surgery , despite systemic chemotherapy having been administered in several patients . one possibility of poor prognosis is afp has a suppressive effect on lymphocyte transformation .15 alpha - 1 antitrypsin and antichymotripsin , produced by hac , have immunosuppressive and protease - inhibitory properties that enhance invasiveness .16 diagnosis of hac depends on recognition of the histological feature . the histological finding reveals glandular adenocarcinoma with hepatoid foci and ihc study affords more special support .14,17 terracciano et al8 reported differences in reaction patterns of hac by ihc and molecular study of eight cases . all hacs showed positive in afp and seven out of eight cases were positive for polyclonal cea . on the other hand , in 121 hcc cases , positivity for afp and polyclonal cea was 8.2 % and 67.7 % , respectively . ihc positivity of ck19 and ck20 was 8.2 % and 1.6 % in hcc , 94 % and 47 % in hac , respectively . ck7 , which is highly positive for combined hepatocellular - biliary carcinoma , showed negative in all eight cases . in short , positivity of virtually all hacs for afp and canalicular staining for polyclonal cea underline its hepatoid nature . on the other hand , positivity for ck19 and ck20 and negativity for hepatocyte paraffin 1 ( heppar1 ) and ck7 were distinctive features of hac . most hac cases show elevation in the afp level , thus afp elevation in patients may indicate hac as in the case presented in our study . the elevation of serum afp level should be interpreted in context of the clinical situation . there can be various reasons for afp elevation , and this case demonstrates the importance of differential diagnosis in interpreting elevated afp level . on the first observation , the afp elevation was due to hcc while the second observed afp elevation was due to hac of the stomach . since this patient was among high risk patients for hcc ( chronic hbv infected patients who had prior treatment for hcc ) , elevation in serum afp levels were indicative for hcc recurrence . notably , this patient had no intrahepatic lesion , and a single lymphadenopathy was found . he received upper endoscopy because screening endoscopy was a routine procedure for patients planned to undergo radiation therapy in our center , and incidentally , the detected gastric lesion was later confirmed as hac . this case demonstrated that hac should be included in a differential diagnosis for patients with elevated afp level . since the stomach is the most frequently affected site for hac and regional lymph node metastasis frequently occurs , evaluation with upper endoscopy is recommendable to screen for hac of the stomach in patients with elevated afp , lymphadenopathy , but no intrahepatic lesion . in summary , the elevation of afp was due to hcc on initial observation , but was due to hac for the second spike in afp . hac was diagnosed incidentally , as elevation of afp was considered as an indicative of hcc . a differential diagnosis of hac should be considered even for a patients at a high risk for hcc in cases of serum afp elevation .\noutput:\n" }, { "from": "agent", "value": "hepatoid adenocarcinoma ( hac ) is a rare type of extrahepatic carcinoma whose morphology is similar to that of hepatocellular carcinoma ( hcc ) . metachronous hcc and hac in the same patient is extremely rare . the case of a 68 - year - old man with chronic hepatitis b infection who had both hcc and hac of the stomach is reported herein . nine years previously this patient had been diagnosed with hcc and received a right lobectomy . hcc that recurred at the caudate lobe at 6 months after the operation was successfully treated with transarterial chemoembolization . the patient was followed up regularly thereafter without evidence of tumor recurrence for 9 years . in july 2010 his serum alpha - fetoprotein ( afp ) level elevated from 6.5 ng / ml to 625.4 ng / ml , and he developed a probable single metastatic lymph node around the hepatic artery without intrahepatic lesions . subsequent evaluation with upper endoscopy revealed a 4 - cm ulcerative lesion on the antrum of the stomach . subtotal gastrectomy was performed with lymph - node dissection . histologic examination revealed a special type of extrahepatic afp - producing adenocarcinoma - hac with lymph - node metastasis - which indicates that hac can be a cause of elevated afp even in patients with hcc . hac should be considered if a patient with stable hcc exhibits unusual elevation of afp ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the skeletal muscle is the most abundant tissue in the human body comprising 4050 % of body mass . skeletal muscle protein undergoes rapid turnover , which is regulated by the balance between the rates of protein synthesis and degradation . physical activity ( exercise training ) and anabolic hormones and drugs ( sports doping ) increase muscle protein contenthowever , sarcopenia and muscle disuse ( due to unloading , microgravity , or inactivity ) and diseases decrease muscle protein content . the rate of protein synthesis is at least in part mediated by 2 - adrenergic receptors ( 2 - ars ) in skeletal muscles in both anabolic and catabolic conditions . ars belong to the guanine nucleotide - binding g - protein - coupled receptor ( gpcr ) family . the 2 subtype is the most abundant , while ~ 710 % of ars are the 1 subtype . furthermore , 2 - ar is more dense in slow - twitch muscles than in fast - twitch muscles . however , the magnitude of anabolic responses to 2 - adrenergic agonists is greater in fast - twitch muscles than in slow - twitch muscles . the family of - ars was originally believed to signal predominantly via coupling with a stimulatory guanine nucleotide - binding protein , gs ; however , recent studies revealed that both 2 - and 3 - ars in skeletal muscle are also capable of coupling to an inhibitory guanine nucleotide - binding protein , gi .2 - ar activates the gs / adenylyl cyclase ( ac ) / cyclic adenosine monophosphate ( camp ) / camp - dependent protein kinase a ( pka ) signaling pathway . the signaling pathway is at least in part responsible for the anabolic response of skeletal muscle to 2 - ar stimulation . further , in addition to the well - documented inhibition of ac activity , 2 - ar coupling to gi activates gs - independent pathways .2 - ar has 7 transmembrane helices forming 3 extracellular loops , including an nh2 terminus and 3 intracellular loops that include a cooh terminus . phosphorylation of these sites triggers the agonist - promoted desensitization , internalization , and degradation of the receptor . the adaptive responses of 2 - ar expression to anabolic and catabolic conditions in skeletal muscles are shown in figure 1 . understanding the correlation between changes in muscle mass and 2 - ar expression in several anabolic or catabolic conditions present scientific evidence to eradicate sports doping and identify novel approaches for attenuating muscle atrophy concomitant with disuse and various diseases . this paper will discuss the effects of ( 1 ) pharmacological 2 - ar stimulation ( sports doping ) , ( 2 ) muscle hypertrophy ( exercise training ) , and ( 3 ) muscle atrophy ( catabolic conditions and hormones ) on 2 - ar expression in skeletal muscles . a 2 - adrenergic agonist , clenbuterol [ 1 - ( 4 - amino -3,5-dichlorobenzyl ) - 2 - ( tert - butylamino ) ethanol ] , is used as a nonsteroidal anabolic drug for sports doping . according to the recent world anti - doping agency ( wada ) documents , clenbuterol was the seventh most commonly used anabolic agent in 2009 ( 67 cases ; 2.0 % of all anabolic agents used ) . numerous studies have shown that the administration of 2 - adrenergic agonists induces muscle hypertrophy in many species . experiments using mice lacking 1 - ar , 2 - ar , or both demonstrate that 2 - adrenergic agonist - induced functions such as muscle hypertrophy are mediated by 2 - ar .2 - adrenergic agonists promote muscle growth by increasing the rate of protein synthesis and / or decreasing protein degradation . furthermore , 2 - adrenergic agonists induce slow - to - fast [ myosin heavy chain ( mhc ) i / mhciia mhciid / x mhciib ] transformation of muscle fibers . the 2 - ar signaling pathway involves the agonist - dependent activation of gs , which in turn activates ac , resulting in increased camp production . cyclic amp - activated pka initiates the transcription of many target genes via the phosphorylation of camp - response - element - ( cre - ) binding protein ( creb ) or adaptor proteins such as creb - binding protein ( cbp ) and p300 , subsequently promoting protein synthesis . while 2 - ar - mediated signaling was traditionally believed to involve selective coupling to gs , recent studies revealed that 2 - ar exhibits dual coupling to both gs and gi in skeletal muscles . in addition to gs , gi - linked g subunits play an active role in various cell signaling processes such as the phosphoinositol 3 kinase ( pi3 k ) / protein kinase b ( akt ) / mammalian target of rapamycin ( mtor ) / p70s6 k and pi3 k / akt / forkhead box - o ( foxo ) pathways . these signaling pathways play important roles in 2 - adrenergic agonist - induced hypertrophy in skeletal muscles . in addition to promoting protein synthesis , the hypertrophic response of skeletal muscles following 2 - adrenergic agonist administration is associated with decreased protein degradation .2 - adrenergic agonists attenuate protein degradation predominantly via ca - dependent proteolysis and the atp / ubiquitin - dependent pathway . however , there is little knowledge regarding the preventive effects of 2 - adrenergic agonists on the proteolysis system compared with the protein synthesis system . the hypertrophic responses to 2 - adrenergic agonists are observed much frequently in fast - twitch muscle than in slow - twitch muscle . our group previously demonstrated that clenbuterol administration ( 1.0 mgkgday ) to rats for 10 days increases the mass of fast - twitch ( extensor digitorum longus : edl ) muscle without altering in slow - twitch ( soleus ) muscle ; other groups also observed the same tendency . however , the mechanisms of the fiber - type - dependent effects of 2 - adrenergic agonists on muscle hypertrophy remain unclear . and kawasaki et al . identified that 2 - ar activation increases the expression of the orphan nuclear receptor , nor - 1 ( nr4a3 ) , a negative regulatory factor of myostatin ( a member of the transforming growth factor - superfamily and a potent negative regulator of muscle mass ) , in fast - twitch muscles without altering that in slow - twitch muscles . demonstrate the possibility that 2 - adrenergic agonist - induced fiber - type - dependent hypertrophy is in part due to the extracellular signal - regulated kinase ( erk ) / mitogen activated protein kinase ( mapk ) pathway . moreover , the pharmacological inhibition of the pi3 k / akt / mtor signaling pathway revealed that the attenuation of the anabolic response to clenbuterol is greater in fast - twitch muscles than in slow - twitch muscles . in addition to the protein synthesis system , yimlamai et al . found that clenbuterol inhibits ubiquitination more strongly in fast - twitch muscles than in slow - twitch muscles . thus , 2 - ar - mediated signaling pathways tend to promote muscle hypertrophy to a greater extent in fast - twitch muscle than in slow - twitch muscle . as shown in table 1 , some reports focus on the responses of 2 - ar expression to 2 - ar stimulation in skeletal muscles . this is because 2 - ar functions such as muscle hypertrophy are maintained via receptor density , including synthesis and downregulation as well as receptor sensitivity , which includes receptor sensitization , desensitization , phosphorylation , and internalization . demonstrate that fast - twitch fibers mainly express nonphosphorylated 2 - ar , whereas slow - twitch fibers predominantly express phosphorylated 2 - ar . furthermore , treating muscle fibers with 2 - adrenergic agonists ( e.g. , clenbuterol , formoterol , and salbutamol ) increases the phosphorylation of 2 - ar in slow - twitch fibers but not in fast - twitch fibers . on the other hand , the receptor phosphorylation occurs via the actions of protein kinases ( such as pka ) and / or gpcr kinase ( grk ) . rat skeletal muscles contain predominantly grk2 and grk5 ; grk protein is expressed more in fast - twitch muscles than in slow - twitch muscles . these expression levels in each type of muscle fiber are not altered by 2 - adrenergic agonist administration . thus , there is a negative correlation between the level of phosphorylated 2 - ar and receptor kinase . therefore , further investigation is needed to reveal the detailed mechanism of 2 - ar phosphorylation . following 2 - ar phosphorylation , the receptor is internalized into the cytosol . the internalized 2 - ar is then degraded or dephosphorylated and subsequently recycled to the membrane . prolonged administration of 2 - adrenergic agonists leads to the downregulation of 2 - ar density in skeletal muscles . these posttranslational regulations are advantageous for maintaining the rate of muscle protein synthesis and / or degradation .2 - ar synthesis , including transcription and subsequent translation , is required to restore transmembrane receptor density . the process of 2 - ar synthesis can be separated into 2 pathways : ( 1 ) the positive autoregulation of 2 - ar gene transcription via receptor - mediated elevation of camp concentration followed by the phosphorylation and activation of creb and ( 2 ) the transactivation of the 2 - ar gene via interaction between hormones and the nuclear receptor complex and response elements on the 2 - ar promoter region . in particular , the transcription of the 2 - ar gene and the subsequent mrna expression via camp - mediated cre activation increased in response to short - term 2 - adrenergic agonist exposure . moreover , treatment with glucocorticoids or thyroid hormone transactivates the 2 - ar gene both in vitro and in vivo . our previous reports demonstrate that clenbuterol administration ( 1.0 mgkgday ) for 10 days to rats decreases 2 - ar mrna expression in the fast - twitch edl muscle without altering that in the slow - twitch soleus muscle . furthermore , the mrna expression of glucocorticoid receptors ( grs ) was also decreased with clenbuterol treatment in the edl muscle but not in the soleus muscle . glucocorticoids and the gr complex activate the transcription of the 2 - ar gene via interaction with glucocorticoid response elements ( gres ) , consensus cis - acting dna sequences ( i.e. , aga aca nnn tgt tct ) on its promoter regions , thus upregulating 2 - ar expression . these findings corroborate our results that there is a positive correlation between the expression levels of 2 - ar and gr in skeletal muscles . also report that administrating the - adrenergic agonist , fenoterol ( 1.4 mgkgday , i.p . ) , for 5 days decreases 2 - ar mrna expression in the edl and soleus muscles . thus , in contrast to the transactivation of the 2 - ar gene and increase in the mrna level in response to short - term agonist exposure , chronic 2 - adrenergic stimulation inhibits 2 - ar synthesis in skeletal muscles . in addition to post - translational and transcriptional regulation , several groups focus on the posttranscriptional regulation of 2 - ar mrna .2 - ar mrna contains an au - rich element ( are ) within the 3 - untranslated region ( 3 - utr ) that can be recognized by several mrna - binding proteins , including hu antigen r ( hur ) , au - rich element binding / degradation factor1 ( auf1 ) , and heterogeneous nuclear ribonucleoprotein a1 ( hnrnp a1 ) . these factors play a role in the regulation of 2 - ar mrna stability . our study demonstrates that clenbuterol - induced stimulation of 2 - ar decreases the mrna expressions of these factors in the edl but not in the soleus muscle , suggesting that the posttranscriptional process of 2 - ar synthesis requires the stability of its mrna to be regulated . strength - resistance training increases muscle mass , fiber cross - sectional area , protein and rna contents , and the capacity to generate force . in contrast to strength training , endurance training is characterized by increased mitochondrial mass , increased oxidative enzymes , decreased glycolytic enzymes , increased slow contractile and regulatory proteins , and decreased fast fiber area . these findings suggest that the functional roles of 2 - ar in skeletal muscles differ with the type of exercise training . investigated the changes in the weight of the edl muscle induced by clenbuterol administration , strength training , and a combination of both . they found that the effects of strength training and clenbuterol on muscle hypertrophy were not additive in fast - twitch muscles . their report also demonstrates that the strength - training - induced enhancement of lactate dehydrogenase - specific activity is completely inhibited by clenbuterol administration , while the clenbuterol - induced decrease in monocarboxylate transporter1 mrna expression is completely offset by strength training . thus , there are no synergetic effects of a combination of strength training and 2 - ar stimulation on muscle mass . furthermore , strength training counteracts molecular modifications such as glycolytic control induced by chronic clenbuterol administration in fast - twitch muscles to some extent . however , our evidence regarding the synergistic effects of strength training and 2 - ar stimulation is insufficient because the experimental models of strength - trained animals are not fully established . in contrast to strength training , 2 - ar stimulation affects endurance - training - induced modulations such as contractile activity , muscle fiber - type shift , metabolic enzyme activity , and insulin resistance . . demonstrated that low - intensity endurance training prevents clenbuterol - induced slow - to - fast ( type i fiber type ii fiber ) fiber - type transformation in the edl and soleus muscles , and thereby offsets the clenbuterol - induced decrease in ca sensitivity in fast - twitch fibers . these results suggest that endurance - training - heightened muscle aerobic capacity is attenuated by 2 - ar stimulation - induced muscle fiber - type transformations . furthermore , pharmacological - ar blockage diminishes the endurance - training - induced increase in citrate synthase activity in the fast - twitch plantaris muscle . moreover , clenbuterol administration prevents the endurance - training - induced improvement in insulin - stimulated glucose uptake and attenuates the increase in citrate synthase activity in the skeletal muscles of obese zucker rats . these findings demonstrate that the endurance - training - induced increase in aerobic metabolism in skeletal muscles requires moderate but not excessive stimulation of 2 - ar . recently , miura et al . demonstrated that an increase in peroxisome proliferator - activated receptor - coactivator - 1 ( pgc - 1 ) mrna in response to exercise is mediated by 2 - ar activation . furthermore , the ca - signaling and p38 mapk pathways , which is downstream of 2 - ar , are activated in skeletal muscles in response to exercise , which regulates pgc - 1 expression . since pgc - 1 promotes mitochondrial biogenesis , the exercise - induced activation of 2 - ar may in part enhance aerobic capacity by increasing pgc - 1 expression . thus , 2 - ar stimulation is essential for enhancing the effects of exercise training on muscle functions such as fiber - type shift as well as oxidative and anaerobic metabolism . as mentioned above , therefore , changes in the expression and sensitivity of 2 - ar should be important for the metabolic , anabolic , and catabolic adaptations of skeletal muscles during exercise training . nevertheless , there is little information on the response of 2 - ar expression to exercise training in skeletal muscles . however , many studies demonstrate the effects of exercise training on 2 - ar expression in several tissues and cell types such as myocardia , adipocytes , and macrophages . demonstrated that exercise training induces changes in the distribution of 1 - , 2 - , and 3 - ar densities in the rat left ventricle . in adipocytes , the exercise - induced trafficking of 2 - ar into the cell membrane from the cytosol is coupled with adipocytes ' function to increase intracellular camp production . kizaki et al . also found a reduction in the expression of 2 - ar mrna in macrophages and highlight the significance of 2 - ar in the exercise training - induced improvement of macrophages ' innate immune function . thus , changes in 2 - ar expression play a role in physiological adaptations to exercise training in several tissues . a few studies also report the effects of exercise training on - ar in skeletal muscles ( table 1 ) . demonstrate that - ar density and gs content in the fast - twitch gastrocnemius muscle are significantly lower in endurance - exercised rats than in controls . they also reveal that exercise reduces receptor - and nonreceptor - mediated ( i.e. , pharmacological stimulation of ac by forskolin ) ac activity in musclesreport that endurance training increases - ar density in slow - twitch muscles that are primarily recruited during endurance training , whereas - ar density is not altered in fast - twitch muscles . their report also demonstrates that receptor - mediated ac activity in slow - twitch muscles is increased by endurance training , and nonreceptor - mediated ac activity is increased by training in both fast - and slow - twitch muscles . in contrast to chronic endurance training , the effects of acute exercise on - ar density and ac activity in each type of muscle were not observed . therefore , endurance - exercise - training - induced changes in 2 - ar expression and signaling in slow - twitch muscle contributes to the adaptation of metabolic and anabolic capacities during exercise . muscle wasting and weakness are common in physiological and pathological conditions , including aging , cancer cachexia , sepsis , other forms of catabolic stress , denervation , disuse ( e.g. , unloading , inactivity , and microgravity ) , burns , human immunodeficiency virus - ( hiv ) - acquired immunodeficiency syndrome ( aids ) , chronic kidney or heart failure , chronic obstructive pulmonary disease ( copd ) , and muscular dystrophies . formany of these conditions , the anabolic properties of 2 - adrenergic agonists provide therapeutic potential for attenuating or reversing muscle wasting , muscle fiber atrophy , and muscle weakness . these 2 - adrenergic agonists also have important clinical significance for enhancing muscle repair and restoring muscle function after muscle atrophy . in particular , muscle disuse , which is mainly reflected by increased myofibrillar protein breakdown , causes a progressive decrease in muscle strength associated with a decreased cross - sectional area of muscle fibers . therefore , preventing disuse - induced muscle atrophy is a problem requiring urgent attention and highlights 2 - ar as a target of pharmacological stimulation . since 2000 , many groups have focused on the preventive effects of 2 - adrenergic agonist on disuse - induced muscle atrophy . demonstrate that clenbuterol attenuates the hindlimb unweighting - induced atrophy and reduces ubiquitin conjugates only in fast - twitch plantaris and tibialis anterior muscles but not in the slow - twitch soleus muscle ; this suggests that clenbuterol alleviates hindlimb unweighting - induced atrophy , particularly , in fast - twitch muscles at least in part through a muscle - specific inhibition of the ubiquitin - proteasome pathwayreport that clenbuterol treatment accelerates hindlimb unweighting - induced slow - to - fast ( mhci / mhciia mhciid / x mhciib ) transformation in the soleus muscle.2 - adrenergic agonist also reverses muscle wasting and weakness in several conditions such as aging , muscular dystrophy , denervation , cancer cachexia , and myotoxic injury . prolonged muscle disuse and / or unloading increases the secretion of glucocorticoids , which promotes the catabolism of muscle proteins via the ubiquitin - proteasome pathway . therefore , several studies focus on the counteractive effects of 2 - ar stimulation on glucocorticoid - induced muscle atrophy . report that clenbuterol almost prevents the decrease in the weight of gastrocnemius / plantaris muscle bundles induced by dexamethasone , a synthetic glucocorticoid . demonstrate that concurrent treatment of clenbuterol with dexamethasone minimizes mhc - transformation - induced by clenbuterol ( slow - to - fast ) or dexamethasone ( fast - to - slow ) alone . thus , 2 - ar stimulation plays an inhibitory role in muscle atrophy and weakness induced by catabolic diseases , mechanical unloading , catabolic hormones , and pharmacological agents . although the effectiveness of 2 - ar stimulation on muscle atrophy is well documented , catabolic condition - induced changes in the expression of 2 - ar in skeletal muscles are not fully understood . understanding the responses of 2 - ar expression to muscle atrophy is required to establish treatments for muscle atrophy . table 1 shows the catabolic - condition - induced changes in 2 - ar expression in skeletal muscles . our group investigated whether catabolic hormones or agents alter 2 - ar expression in skeletal muscles . dexamethasone administration ( 1.0 mgkgday ) to rats for 10 days decreases the expression of 2 - ar mrna in the soleus muscle without altering that in the edl muscle , although the expression of 2 - ar protein in the edl and soleus muscles is not altered . these phenomena are specifically observed in skeletal muscles ; meanwhile , glucocorticoids and the gr complex activate the transcription of 2 - ar gene in the human hepatoma cell line ( hepg2 ) , subsequently leading to the upregulation of 2 - ar levels in ddt1 mf - 2 smooth muscle cells and lung tissue . furthermore , dexamethasone decreases the expression of gr mrna in the soleus muscle . dexamethasone also decreases and increases the expression of creb mrna , a transcription factor of the 2 - ar gene , in the soleus and edl muscles , respectively . these findings suggest that the dexamethasone - induced decrease in the expression of 2 - ar mrna in the slow - twitch soleus muscle is associated with transcriptional regulations . the effects of physiological and pathological catabolic - condition - induced muscle atrophy on 2 - ar expression have also been studied ( table 1 ) . our recent investigation demonstrates that casted immobilization ( knee and foot arthrodesis ) for 10 days markedly induced atrophy in the soleus muscle , whereas it decreased the expression of 2 - ar mrna . these results suggest that casted immobilization decreases the expression of 2 - ar mrna in slow - twitch muscles via the downregulation of gr levels and subsequent glucocorticoid signals . on the other hand , ryall et al . demonstrate that aging - induced muscle wasting is observed in the edl and soleus muscles , although there are no age - associated changes in 2 - ar density in these muscles . furthermore , in the regeneration process from muscle injury induced by bupivacaine injection , 2 - ar density and mrna expression as well as gs content are decreased in the soleus but increased in the edl muscle . thus , the effects of catabolic conditions such as disuse , aging , and injury on 2 - ar expression are different from and / or dependent on the conditions , especially in fast - twitch muscles , whereas decreasing tendencies are observed in slow - twitch muscles . both pharmacological and mechanical studies indicate that the preventive effects of 2 - ar stimulation on muscle atrophy and weakness are limited by decreased 2 - ar synthesis and subsequently decreased density . in order to use 2 - adrenergic agonists as a therapeutic agent for muscle wasting , further studies are necessary to obtain detailed evidence regarding the responses of 2 - ar expression and function to muscle atrophy . in this paper , we discussed adaptive responses of 2 - ar expression in skeletal muscles to 2 - adrenergic agonist treatment , exercise training , muscle disuse , and glucocorticoid treatment . skeletal muscle partly requires 2 - ar activation for hypertrophy , regeneration , and atrophy prevention ; however , its functions and responsiveness must be adaptively regulated by the receptor itself via downregulation , synthesis , and desensitization . new insight in the form of scientific evidence is needed to eradicate sports doping and to identify new therapeutic targets for attenuating muscle atrophy induced by physiological and pathological conditions .\noutput:\n" }, { "from": "agent", "value": "we discuss the functional roles of 2 - adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of 2 - adrenergic receptor expression to anabolic and catabolic conditions . 2 - adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and / or attenuating protein degradation . these effects are prevented by the downregulation of the receptor . endurance training improves oxidative performance partly by increasing 2 - adrenergic receptor density in exercise - recruited slow - twitch muscles . however , excessive stimulation of 2 - adrenergic receptors negates their beneficial effects . although the preventive effects of 2 - adrenergic receptor stimulation on atrophy induced by muscle disuse and catabolic hormones or drugs are observed , these catabolic conditions decrease 2 - adrenergic receptor expression in slow - twitch muscles . these findings present evidence against the use of 2 - adrenergic agonists in therapy for muscle wasting and weakness . thus , 2 - adrenergic receptors in the skeletal muscles play an important physiological role in the regulation of protein and energy balance ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: we report here on a case of wound infection due to shewanella algae in the navel area of a patient . a 24 - year - old man was admitted to the mehr outpatient clinic in bushehr , southern iran , in december 2010 with an infection in his navel area . a preliminary diagnosis suggested that the patient had a pilonidal cyst and / or un - shut suture from his neonatal period which had caused the infection in that area . interviewing the patient revealed that a purulent discharge had developed after he had been swimming in the persian gulf , 3 months earlier . the patient was prescribed a combination of cloxacillin ( 500 mg / 6 h for a week ) , cefixime ( 400 mg / 12 h for 5 days ) and ciprofloxacin ( 500 mg / 12 h for a week ) . the affected area was also cleaned with 70 % alcohol daily but the purulent discharge did not stop . a swab culture was taken from the lesion s exudate and submitted to the pathology laboratory . results indicated the pure growth of an organism forming light - brown mucoid colonies on 5 % sheep blood agar . the organism was subsequently identified as a member of the s. putrefaciens group with the api 20e system ( biomerieux , inc . , further tests , including hydrogen sulfide production on tsi slants , growth on media containing 6.5 % nacl and reduction of nitrite 1 , identified the organism as s. algae although the bacterium did not produce - haemolysis on sheep blood agar as shown by others 2,3 . pcr amplification of the 16s rrna was performed using the universal primer pair fd1 and rp24 , and sequencing of the pcr product showed 99 % similarity to s. algae . the bacterium was susceptible to ceftazidime ( 30 g ) , ciprofloxacin ( 5 g ) , nalidixic acid ( 30 g ) , nitrophorantion ( 300 g ) , amikacin ( 30 g ) , ceftriaxone ( 30 g ) , cefotaxime ( 30 g ) , gentamicin ( 10 g ) , co - trimoxazole ( trimethoprim 1.25 g / sulfamethoxazole 23.75 g ) but was resistant to amoxicillin ( 30 g ) , vancomycin ( 30 g ) , doxycyclin ( 30 g ) , cephalexin ( 30 g ) , ampicillin ( 10 g ) , tetracycline ( 30 g ) , cephalothin ( 30 g ) and ceftizoxime ( 30 g ) . more than 50 species of shewanella have been described but with the exception of the recent case report of s. xiamensis causing a peripancreatic infection 5 , all other reported illnesses involving the genus shewanella have been linked to either s. putrefaciens and s. algae infection with the latter being more common in clinical cases 1,5,6 . these bacteria are found in marine environments and in countries with warm climates or during especially warm summers in other countries 1 with the most common portal of entry being injured skin 6,7 . the most common clinical syndrome reported in the literature is infection of the skin and soft tissues 810 . it often occurs in elderly patients with chronic ulcers of the lower extremities , but soft - tissue infections in healthy subjects have also been described 10 . meningitis 1,16 , and abscesses 17,18 . severe disease with bacteremia has been described in patients with predisposing factors such as immunodeficiency 6,19 , malignancy 8 , hepatobiliary disease 6,8 and renal failure 13 . only two cases of arthritis and two cases of osteomyelitis and one case of spondylodiscitis have been reported so far 13,20 . here , we report a wound infection caused by s. algae in a healthy young man without any underlying diseases . the source of organism that caused the cutaneous navel lesion was likely to be the marine environment and the bacterium was isolated in pure culture from the purulent discharge . to the best of our knowledge , this is first case of wound infection clearly caused by s. algae to be reported in iran . in this region , there has been only one more case of wound infection reported in turkey but the agent was shown to be s. putrefaciens 21 . commercial automated identification systems can not distinguish s. algae from s. putrefaciens and , therefore , it is possible that some of the isolates reported as s. putrefaciens might in fact have belonged to the species s. algae 1,2 . in thisregard we recommend that molecular techniques such as 16s rrna gene sequence analysis be used to confirm identification of this bacterium , as has also been emphasized by others 20 .\noutput:\n" }, { "from": "agent", "value": "shewanella algae was isolated from the purulent discharge in the navel area of a young male with a history of swimming in the persian gulf . a routine laboratory diagnosis procedure , followed by 16s rrna gene sequence analyses , was used to avoid misidentification with other species of shewanella . the bacterium was suscetible to ceftazidime , ciprofloxacin , nalidixic acid , nitrophorantion , amikacin , ceftriaxone , cefotaxime , gentamicin and co - trimoxazole but was resistant to amoxicillin , vancomycin , doxycycline , cephalexin , ampicillin , tetracycline , cephalothin and ceftizoxime . the patient successfully recovered after treatment with antibiotics ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: patients with mixed type evans syndrome are very rarely seen and it is difficult to manage them . although mixed type evans syndrome may initially respond well to steroids , it usually runs a chronic course with intermittent exacerbations ( 1 , 2 ) . rituximab , a chimaeric monoclonal antibody against cd20 that depletes b cells in the circulation and in lymphoid tissues , has shown efficacy for the treatment of cd20 - positive lymphoproliferative disorders . the pathogenetic mechanism of autoimmune cytopenias is complex and b cells play a crucial role in the pathogenesis of these disorders so that this agent rituximab has also been used with good success for patients with autoimmune disease , including immune thrombocytopenic purpura , autoimmune hemolytic anemia and the other types of immune disease ( 3 - 6 ) . we report here on a patient with the mixed type evans syndrome who had a prompt response to rituximab . in july 2004 , a 46 - yr - old korean woman was diagnosed with mixed type evans syndrome following her hospital admission because of the symptomatic anemia , jaundice and thrombocytopenia . the laboratory tests showed : hemoglobin , 4.1 g / dl ; reticulocytes , 12.6 % ; wbc , 3,030 / l ; platelets , 89,000 / l ; and elevated levels of indirect bilirubin ( 2.53 mg / dl ) and lactic dehydrogenase ( ldh ; 1,499 iu / l ) . her initial direct antiglobulin test was positive for complement ( c3d ) and igg . in addition , the patient 's serum contained a cold hemagglutinin that had high thermal amplitude . the serologies for hiv , ebv , cmv , hepatitis b and c viruses , and mycoplasma pneumoniae were all negative . rheumatoid factor , antinuclear antibodies , anti - double stranded dna antibodies and lupus anticoagulant were undetectable . the hemoglobin level and platelet count rose to 11.7 g / dl and 356,000 / l , respectively . fifteen weeks later ( december 2004 ) , the prednisone was tapered to a maintenance dose of 10 mg daily . she relapsed with hemolytic anemia ( 5.9 g / dl ) and thrombocytopenia ( 9,000 / l ) . despite retreatment of high dose steroidrituximab was started at the dose of 375 mg / m once a week for a total of 4 doses , and this was well - tolerated and it induced a normalization of hemoglobin , bilirubin and ldh , as well as inducing a significant platelet count increase . the hemoglobin increased to 13.2 g / dl on day 56 and the platelet count increased to 30,000 / l by day 12 after the first rituximab infusion . she subsequently entered a durable remission with her hemoglobin level in the range of 13.2 - 14.7 g / dl and her platelet count in the range of 32,000 - 42,000 / l ; she has maintained this remission now for 6 months ( fig . additional treatment modalities , including splenectomy , intravenous immunoglobulin , vincristine or azathioprine , are used for the steroid - resistant or relapsing cases . however , these treatment options are often unsuccessful and they may be associated with serious side effects ( 1 , 2 ) . rituximab was approved for the treatment of b - cell lymphomas , and this drug has emerged as a promising treatment for idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia ( aiha ) , including evans syndrome and mixed aiha . the mechanism of cellular killing is thought to be secondary to the antibody - dependent cellular toxicity and complement activation . suppression of autoreactive b cells may explain the sustained response attained when using rituximab for the treatment of lymphomas and autoimmune diseases ( 3 ) . in the three previous reports on rituximab treatment for the mixed type aiha , including one case of mixed type evans syndrome , all the patients had successful resolution of their hemolytic anemia ( 4 - 6 ) . our patient responded promptly and had a sustained response , and any rituximab related side effects were not observed . in conclusion , a decision to initiate rituximab early in the course of mixed aiha with / without immune thrombocytopenia is a reasonable treatment option if the syndrome is refractory to steroid treatment .\noutput:\n" }, { "from": "agent", "value": "mixed type evans syndrome is a very rare hematologic disease . although mixed type evans syndrome may initially respond well to steroids , this disease usually runs a chronic course with intermittent exacerbations . we describe here a 46 - yr - old female with the steroid - refractory , mixed type evans syndrome , and she had a prompt response to rituximab . she was diagnosed as having the mixed type evans syndrome with the clinical features of symptomatic anemia , jaundice and thrombocytopenia . prednisone therapy was commenced and her hemoglobin and platelet level returned to the normal . however , after 15 weeks , she relapsed with hemolytic anemia and thrombocytopenia . we started rituximab at the dose of 375 mg / m2 once weekly for a total of 4 doses , which was well - tolerated and this induced the normalization of hemoglobin , bilirubin and lactic dehydrogenase , and there was also a significant increase of the platelet count ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: annular erythemas can be arcuate , circinate , polycyclic or serpiginous , which may spread centrifugally or remain fixed . various causes of annular erythema during the first few days or weeks of life have been presented in table 1 . these vary from benign conditions like annular erythema of infancy to neonatal lupus erythematosus ( nle ) , with serious systemic involvement . occurrence of erythema annulare centrifugum , acute urticaria and tinea corporis ( tc ) are only incidental during the initial days of life . erythema chronicum migrans , although mentioned as one of the differential diagnoses of annular erythema of infancy , has not been reported at a very early age . a 7 - day - old , pre - term , female neonate under observation at the intensive care unit was referred for evaluation of the skin lesions that appeared on the 5 post - partum day and thereafter progressed rapidly . the infant 's mother was a 23 - year - old healthy primigravida , with uneventful course of pregnancy until 34 weeks , when there was premature rupture of membrane with evidence of fetal distress necessitating emergency lower segment caesarean section . a cutaneous examination showed multiple brightly erythematous , annular lesions distributed over the neck , back , arms and dorsa of the hands , sparing the face [ figure 1 ] . erythematous annular lesions on the back of the neonate a provisional diagnosis of nle was considered in this case and the infant was investigated accordingly . complete hemogram and urinalysis of both the infant and the mother were within normal limits . antinuclear antibody and antibodies against ss - a / ro and ss - b / la were not detectable in the mother or the child . a skin biopsy was performed from one of the skin lesions on the back of the infant . the h & e stained skin biopsy specimen showed hyperkeratotic and acanthotic epidermis with the presence of tubular structures in the stratum corneum suggestive of fungal hyphae . a periodic acid schiff stain confirmed the presence of fungal hyphae in the stratum corneum [ figure 2 ] . histopathological section of the skin showing fungal hyphae ( periodic acid schiff stain , 100 ) the diagnosis was revised as tinea corporis and the infant was advised topical application of terbinafine hydrochloride cream ( 1 % ) once daily . the source of the infection was searched and the child 's grandmother , who used to handle the child bare - handed while assisting breast - feeding , was found to have onychomycosis of a few finger nails . with topical antifungal treatment , the infant 's skin lesions improved significantly in 2 weeks and there was complete clearance in 4 weeks . clinically , annular erythemas of infancy can be distinguished by mode of onset , evolution , distribution and morphology of skin lesions , associated features and family history [ table 1 ] . scraping and potassium hydroxide ( koh ) preparation from scale detects fungal hyphae in cases with tc . presence of thrombocytopenia and positivity for markers of collagen vascular disorders ( antinuclear antibody , anti - ro / anti - la antibody ) on screening of mother and child are suggestive of nle . according to some authors , an anti - ro / anti - la antibody test should be performed in all cases of annular skin lesions in infancy to avoid missing a diagnosis of nle . cardiac screening with electrocardiogram for conduction defectshistopathological examination of the skin biopsy sample taken from the edge of the annular lesion is helpful in the diagnosis of the condition . dermatophyte infection in the first few days of life is not commonly encountered and hence not suspected in this case . however , this infection has been documented in neonates as early as on the 2 day of life . different clinical variants of this infection occur among neonates , e.g. tc , tinea capitis , tinea faciei and onychomycosis . in the published english literature , most frequent reports in the neonatal period are of tinea capitis . the inflammatory variant of tinea capitis , kerion , has also been reported in neonates . dermatophytes known to cause neonatal infections are m. canis ( commonest ) , t. tonsurans , t. rubrum , t. mentagrophytes , m. gypseum and t. violaceum . there is a report of two species of fungi causing tinea capitis in an infant . transmission of these fungi from infected handlers , as in our case , is the usual mode of acquiring infection by the newborn . pet animals with active infection may be an important source of infection , transmitting zoophilic dermatophytes . animals may also represent a healthy carrier state of m. gypseum , a geophilic fungus . when the source of infection is not identifiable , fomites or household environment may be considered . pre - mature , low - birth weight neonates may have a rapidly progressive infection due to inadequate barrier function of the skin , as in the index case . systemic antifungal drugs like itraconazole ( 35 mg / kg / day x 46 weeks ) may be used for tinea capitis . pulse therapy with oral itraconazole solution has been used in older infants with tinea capitis . annular erythema of infancy poses a diagnostic challenge for dermatologists . in the process of working up this case , an important lesson is learnt ; scrape a scaly lesion , irrespective of its presentation and the age of the infant\noutput:\n" }, { "from": "agent", "value": "a 7 - day - old premature female infant presented with rapidly progressive , erythematous , annular skin lesions from the 5th day of life . she was diagnosed provisionally as a case of neonatal lupus erythematosus and was investigated accordingly . histopathological examination of the skin biopsy specimen revealed presence of hyphae of dermatophytes in the stratum corneum , and the diagnosis was changed to tinea corporis . differential diagnosis of the annular erythema of infancy has been discussed and the importance of scraping a scaly lesion for koh preparation in the diagnostic work - up of such a patient has been highlighted ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: we report a case of a healthy 22 - year - old man who underwent an arthroscopic right acl reconstruction with hamstring grafts in january 2010 , 6 months after his initial injury . the graft was fixed with an endobutton ( smith & nephew , andover , ma , usa ) for the femoral side , and a biosure bioabsorbable screw ( smith & nephew ) and metal staples ( smith & nephew ) for the tibial side . after an initial uneventful postoperative recovery , he presented 7 weeks after surgery with right knee swelling associated with fever and chills . on examinationthe range of motion of the right knee was 5 to 100 and was limited by pain . the c - reactive protein , erythrocyte sedimentation rate , and total white cell count were 139 , 71 , and 7.3 , respectively . the right knee aspiration performed revealed turbid fluid , and bacterial cultures yielded no bacterial growth . he was offered , but refused , arthroscopic debridement of the right knee , and was given oral antibiotics with instructions to follow - up at the outpatient clinic . there was no resolution of his wound discharge , and the patient subsequently consented to an arthroscopic washout of his right knee , synovectomy , and debridement of the right tibial wound 3 months after his initial acl reconstruction . intraoperatively , there was florid synovitis but the acl graft was noted to be intact and healthy . there was no frank pus noted from the right tibial wound and the wound was debrided . the knee fluid was incubated at 35 , 5 % carbon dioxide levels on blood agar for five days . the mycobacterium detection dna accuprobe identification was positive and the organism was confirmed to be m. abscessus . susceptibility testing using a broth microdilution method confirmed that the organism was sensitive to amikacin , clarithromycin , and linezolid . postoperatively , the patient was given 2 weeks of intravenous ( iv ) amikacin and concurrently started on one week of iv cefoxitin and clarithromycin . there was a gradual decline in the laboratory markers of infection ( creactive protein and erythrocyte sedimentation rate ) . postoperatively , the wound showed progressive healing , with no further discharge noted during subsequent outpatient consultations . he was lost to follow - up 6 months after the arthroscopic washout and 9 months after his initial acl reconstruction . two years later , he presented to our outpatient clinic with right knee pain associated with discharge from the knee wound for the past six months . there was a chronic sinus located over the anteromedial aspect of the right knee with seropurulent discharge , giving the appearance of a chronic granuloma . there was otherwise no collections seen and the acl graft appeared intact ( figs . 1 and 2 ) . the patient subsequently underwent arthroscopic washout and removal of the screws and staples of the right tibia . intraoperatively , he was noted to have a chronic sinus tract over the staples and tibial tunnel site . he received 14 days of iv amikacin , iv cefoxitin , and oral clarithromycin for the duration of his hospitalization . he was discharged on postoperative day 17 with 6 weeks of oral clarithromycin and 2 weeks of oral cloxacillin . the patient was successfully contacted for a clinical review 14 months after the second arthroscopic washout and implant removal from his right knee . he reported no further symptoms of infection in his right knee since the second arthroscopic washout and had regained full premorbid function of his right knee . on examination , the wounds had since healed , the knee was not warm , effused , or tender and there was full range of motion of the right knee . after its separation from the m. chelonae group in 1992 , m. abscessus was recognized as the culprit pathogen for many human infections , including skin and soft tissue infections , surgical site infections , respiratory infections , and disseminated infections in immunocompromised individuals . infections caused by m. abscessus are notoriously difficult to treat because the bacteria is intrinsically resistant to most conventional anti - tuberculous drugs . reasons for this resistance include the slow growth of the bacteria , the presence of a waxy impermeable cell wall , which serves as both a physical ( by size exclusion ) and a chemical ( hydrophobic ) barrier , various drug export systems , and genetic polymorphism of targeted genes .4 ) m. abscessus possesses the ability to form smooth biofilms . hence , retention of the implants can possibly lead to a failure to achieve a microbiological cure and re - infection , especially since m. abscessus is notoriously resistant to most antibiotic regimes . there are published case reports of m. abscessus bacteremia associated with infected indwelling vascular catheters . a case series by chang et al. 5 ) involving 12 patients with rgm bacteremia demonstrated that the rate of relapsing bacteremia was significantly higher in patients with delayed catheter removal compared to patients with timely catheter removal . in our case report , the patient 's implants were initially left in situ , as it was deemed too premature to remove the implants because the graft had not yet integrated . however , leaving the implants in place may result in the persistence of infection , as shown in the vascular catheter case series . thus , the first learning point is the need for full removal of implants in m. abscessus infections for source control in persistent , recurrent infections . the literature demonstrates a lack of consensus for the treatment of septic arthritis following acl reconstruction . generally , the treatment involves either arthroscopic or open debridement with or without acl graft retention followed by antibiotic treatment . mcallister et al. 6 ) reported an average of 2.75 procedures ( range , 2 to 4 procedures ) required after the diagnosis to eradicate the infection and restore knee motion . the scar formation resulting from repeated invasive procedures to the involved knee joint can lead to capsular contraction , thus significantly limiting joint motion and affecting the patient 's functional outcome . a recent case report describing a m. wolinskyi infection post - total knee arthroplasty emphasizes the lack of a standardized treatment protocol in infections caused by rgm . in the case report , the authors described the successful eradication of the infection after prolonged targeted antibiotic therapy and surgical debridement without removal of the prosthesis .7 ) this suggests that the decision as to retain or remove the implant should be taken on a case - by - case basis . there is limited literature on the incidence and management of culture - negative septic arthritis following acl reconstruction . however , there are publications delineating the incidence of culture - negative prosthetic joint infections . berbari et al. 8 ) described 60 cases ( 7 % ) of culture - negative prosthetic joint infections out of 897 patients with prosthetic joint infections over a 9 - year period . these 60 patients were noted to have a sinus tract or purulence communicating with the prosthesis and / or features of acute inflammation on histology . the possible reasons for culture - negative infections are prior antimicrobial therapy , infection with fastidious organisms or unusual organisms such as fungi or mycobacterium , and biofilm formation . our patient had a similar presentation and his initial cultures did not yield any bacterial growth . hence , the second important learning point is that in patients presenting with chronic discharging sinuses over the previous surgical site with negative cultures , infection with rgms such as m. abscessus should be considered . there have been case reports of coinfections as well as secondary infections of prosthetic joints . the implicated organisms include listeria monocytogenes with s. aureus9 ) and candida albicans with methicillin - resistant s. aureus .10 ) hence , a third learning point is the need to consider the possibility of a coinfection or superinfection whenever there is an atypical organism involved , such as m. abscessus . the presence of a secondary or coinfection in post - acl reconstruction septic arthritis is clinically relevant , as it significantly affects the choice of antimicrobial therapy . it should also be considered in cases of infection which do not respond to the antimicrobial regime tailored to the initially identified organism . in our case , the chronicity of the discharge and low grade nature of the infection suggested an atypical infection . however , the presence of a purulent component to the discharge suggested an element of coinfection with a staphyloccal species . in our patient , the biosure bioabsorbable screw used was made of poly - l - lactic acid and hydroxyapatite . polylactic acid implants are thought to be less likely to cause local inflammatory and foreign body reactions as compared to similar implants manufactured using polyglycolic acid , due to the long degradation time of polylactic acid .3 ) despite this , abscess cavities in conjunction with the l tunnel have been reported , with negative gram stains and cultures .3 ) during the second debridement of our patient , the screw in the tibial tunnel was noted to be loose and fragmented , suggesting that the local inflammatory response from osteolysis associated with the use of a polylactic implant may provide a suitable environment for infection to occur . our case report has demonstrated that atypical organisms , such as m. abscessus , should be considered whenever bacterial cultures are negative in chronic lowgrade infections . the case also suggests that removal of orthopedic implants may be necessary for the complete eradication of this pathogen .\noutput:\n" }, { "from": "agent", "value": "infections following anterior cruciate ligament reconstruction are rare , with no previous reports citing mycobacterium abscessus as the culprit pathogen . a 22 - year - old man presented twice over three years with a painful discharging sinus over his right tibia tunnel site necessitating repeated arthroscopy and washout , months of antibiotic therapy , and ultimately culminating in the removal of the implants . in both instances , m. abscessus was present in the wound cultures , along with a coinfection of staphyloccocus aureus during the second presentation . though rare , m. abscessus is an important pathogen to consider in postoperative wounds presenting with chronic discharging sinuses , even in healthy non - immunocompromised patients . this case illustrates how the organism can cause an indolent infection , and how the removal of implants can be necessary to prevent the persistence of infection . coinfection with a second organism is not uncommon and necessitates a timely change in treatment regime as well ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: during surgical procedures precautionary measures are always taken to avoid or minimize complications . despite thesethese may arise as a result of the type of suture used , due to its physical and natural properties , as well as breach in the sterile procedure . furthermore , iatrogenic operative complications do occur when surgical materials like gauze , sponges , or surgical instruments are forgotten intraoperation leading to various complications , such as failure of the wound to heal , sinus formation , fistulations , and abscesses . the aim of this article is to report two cases of failure of thyroidectomy wounds to heal , one as a result ofgauzoma ( gossypiboma ) , and the other , a combination of gossypiboma and suture abscess , leading to a stitch sinus . a 53 - year - old civil servant was presented with a discharging wound that had failed to heal two - and - a - half months post thyroidectomy for a simple colloid goiter . the wound started discharging thick creamy pus postoperatively on the fifth day and this warranted wound exploration five weeks after the initial operation , in the same hospital . despite surgical exploration and other therapeutic measures , the wound still failed to heal , and as the discharge persisted for another six weeks she was referred to our facility . the essential findings on physical examination , at presentation in our hospital , revealed a middle - age woman , who was acutely ill - looking , febrile ( temperature 38.5 c ) , anicteric , and not dehydrated . there was a thyroidectomy scar with a fistula formation in the 2 cm mid - portion , discharging pus . the surrounding skin was inflamed and indurated with some degree of swelling in the lower flap of the wound . an impression was formed of stitch sinus with residual abscess , keeping in view retained surgical object post thyroidectomy . a repeat microscopy , culture , and sensitivity of the discharge in our hospital yielded atypical coliforms , sensitive to levofloxacin and augmentin . she was placed on two antimicrobial agents and she improved significantly within one week of admission . she subsequently had wound re - exploration , with the finding at operation revealing a strip of gauze ( gauzoma ) well tucked ( encapsulated ) into the lower flap , with some strands extruding into the subcutaneous layer [ figure 1 ] . extraction of the gauze in case 1 a 33 - year - old civil servant developed a wound infection on the fourth day post thyroidectomy performed in a private hospital for a simple multinodular goiter . culture of the discharge from the wound yielded heavy growth of staphylococcus aureus , which was sensitive to chloramphenicol and erythromycin . the wound , however , failed to heal , and there was recurrent discharge 10 weeks after surgery , despite antimicrobial treatment . a repeat microscopy , culture , and sensitivity yielded pseudomonas aeruginosa , which was sensitive to floxacillin and gentamycin . there was some degree of success as the wound started healing with exuberant granulation tissue , although the discharge persisted for another eight weeks until a stitch sinus eventually developed . she was found to be clinically stable , with a discharging sinus over the surgical scar . a deep - seated abscess , with some free chromic catgut sutures were encountered extruding from encapsulated surgical gauze left on the right side [ figure 2 ] . she did well postoperatively and was discharged after 10 days of admission , without any residual problem . she has been followed up in the clinic for six months and has remained stable since . a 53 - year - old civil servant was presented with a discharging wound that had failed to heal two - and - a - half months post thyroidectomy for a simple colloid goiter . the wound started discharging thick creamy pus postoperatively on the fifth day and this warranted wound exploration five weeks after the initial operation , in the same hospital . despite surgical exploration and other therapeutic measures , the wound still failed to heal , and as the discharge persisted for another six weeks she was referred to our facility . the essential findings on physical examination , at presentation in our hospital , revealed a middle - age woman , who was acutely ill - looking , febrile ( temperature 38.5 c ) , anicteric , and not dehydrated . there was a thyroidectomy scar with a fistula formation in the 2 cm mid - portion , discharging pus . the surrounding skin was inflamed and indurated with some degree of swelling in the lower flap of the wound . an impression was formed of stitch sinus with residual abscess , keeping in view retained surgical object post thyroidectomy . a repeat microscopy , culture , and sensitivity of the discharge in our hospital yielded atypical coliforms , sensitive to levofloxacin and augmentin . she was placed on two antimicrobial agents and she improved significantly within one week of admission . she subsequently had wound re - exploration , with the finding at operation revealing a strip of gauze ( gauzoma ) well tucked ( encapsulated ) into the lower flap , with some strands extruding into the subcutaneous layer [ figure 1 ] . a 33 - year - old civil servant developed a wound infection on the fourth day post thyroidectomy performed in a private hospital for a simple multinodular goiter . culture of the discharge from the wound yielded heavy growth of staphylococcus aureus , which was sensitive to chloramphenicol and erythromycin . the wound , however , failed to heal , and there was recurrent discharge 10 weeks after surgery , despite antimicrobial treatment . a repeat microscopy , culture , and sensitivity yielded pseudomonas aeruginosa , which was sensitive to floxacillin and gentamycin . there was some degree of success as the wound started healing with exuberant granulation tissue , although the discharge persisted for another eight weeks until a stitch sinus eventually developed . she was found to be clinically stable , with a discharging sinus over the surgical scar . a deep - seated abscess , with some free chromic catgut sutures were encountered extruding from encapsulated surgical gauze left on the right side [ figure 2 ] . she did well postoperatively and was discharged after 10 days of admission , without any residual problem . she has been followed up in the clinic for six months and has remained stable since . thyroidectomy is considered a clean operation , but when the wound fails to heal in the expected period of time , especially with purulent discharge or abscess formation , pyogenic infection is often primarily implicated . however , when the wound still fails to heal , retained surgical material or infected suture material ( due to poor surgical technique or nature of suturing material used ) are often ignored because of the medicolegal implication . for the same reason , these are not often published . although , gauze and sponges are usually used to achieve hemostasis , as well as in dissection , during surgery , they are still forgotten intraoperation , despite measures taken to avoid this . this also applies to other surgical materials and equipments like gelfoam , surgicel , artery forceps , and so on . there are quite a few causes for operative loss of gauze , sponges , and surgical instruments . notable among these are serious emergency procedures that might not allow initial sponge count , severe hemorrhagic procedures , time consuming operations , and no sponge counting while closing . others include , the nature of surgical materials like cotton pads that might break into pieces , lack of tags on the sponges , towels and gauze , inaccessible operation sites , poor surgical techniques , change of theater personnel , as well as lack of good rapport and understanding among the operating team ( assistant nurses , anesthetists , surgeons ) . the course of events , when they occur , are extrusion , elicitation of an exudative reaction leading to abscess , cellulitis , septic syndrome , or remaining inert with encapsulation and formation of a lot of adhesions . in our patients , severe cellulitis with abscess formation and copious pus discharge were elicited , as previously documented . an attempt at extrusion into the outside also occurred , as some of the chromic catgut used was seen projecting into the wound surface and some strands of the cotton gauze ( gauzoma ) were detected in the subcutaneous layer of the wound of the first patient . the radiological features of gossypiboma , textilioma , as well as others , are well known , including the use of ultrasonography and magnetic resonance imaging ( mri ) . the first patient started discharging pus on the fifth day , while the second started discharging pus on the fourth day post the operation ( both were accompanied with classical clinical features of acute pyogenic infection ) . we believed that the explorations that were done from the referring hospitals were just laying open the skin down to the platysma level , as the wounds continued to discharge despite the explorations.these eventually yielded the forgotten gauze in the first patient , [ figure 1 ] . in the second patient the chromic catgut used was trying to extrude , while a gauze was found on the right side , fully encapsulated [ figure 2 ] . suture materials are known to cause adverse effect on tissues and increase susceptibility to infection . the types of suture material used and the surgical technique also play some role in wound infection . this is further encouraged by the presence of devascularized tissue and hematoma dead space from tissue damage . the severity of infection elicited , depends on the physical and chemical configuration of the sutures . bacteria are known to adsorb into the strands of multifilament sutures such as silk and catgut ( especially plain catgut ) , hence , these should be taken into consideration when planning surgical procedures . in conclusion , gossypiboma should be given a high index of suspicion in the presence of a persistently discharging wound post operation , post - thyroidectomy wound inclusive . the routine gauze and instrument count prior to and after surgical procedure can not be over - emphasized .\noutput:\n" }, { "from": "agent", "value": "this case series presents two females , 53 and 33 years old , with thyroidectomy wounds that failed to heal , 16 and 18 weeks , respectively , following the operation . the wounds were explored with removal of gauze and catgut suture . the patients made remarkable improvement and the wounds healed satisfactorily within seven days . surgical materials forgotten intraoperatively , wrong use of and / or infected surgical materials should be considered when surgical wounds fail to heal ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the superior cervical ganglion ( scg ) is the center of sympathetic innervation of all head and neck organs . it provides sympathetic input to numerous key organs and structures such as the salivary glands , pineal gland , thyroid , carotid body , choroid plexus , brain and cranial muscle vasculature , eyes , and lacrimal gland , thus playing a vital role in a number of neuroendocrine , visceral , or vision - related processes ( cardinali et al . studies showed that scg is involved in circadian rhythm regulation ( lingappa and zigmond 2013 ) , thyroid function modulation ( young et al . 2005 ) , tear production ( ding et al .2003 ; tangkrisanavinont 1984 ) , skin vasoconstriction ( gibbins et al . 1998 ) , and cerebral arterial supply regulation ( arbab et al . 1986 ; cassaglia et al .1983 ) , a complex neurochemical phenotype of its preganglionic neurons and fibers has yet to be completed . in animal models studied so far , sympathetic preganglionic neurons ( spn ) supplying the scgwere found in cervico - thoracic neuromeres , which were confined to the following nuclei : ( 1 ) nucleus intermediolateralis pars principalis ( imlpp ) , ( 2 ) nucleus intermediolateralis pars funicularis ( imlpf ) , ( 3 ) nucleus intercalatus spinalis ( ic ) , and ( 4 ) nucleus intercalatus spinalis pars paraependymalis ( icpe ) ( dalsgaard and elfvin 1979 ; petras and faden 1978 ; yau et al .1991 ) ; however , until now there is no data clarifying the origins of porcine scg innervation . studies conducted in laboratory animals show that the chemical phenotype of these neurons is very diverse and complex , underscoring the importance of the ganglion in autonomic regulation . acetylcholine ( ach ) is the main spn neurotransmitter ; however , studies show that its actions upon scg activity are largely supported by nitric oxide ( no ) present in preganglionic neurons alongside ach ( okamura et al . it has been shown that no modulates cyclic gmp synthesis in cholinergic neurons , affecting ach release from these neurons and thus regulating overall ach activity ( prast et al . furthermore , data obtained from human and small animal laboratory species reveal that aside from ach and no , a number of other neuromodulatory substances such as serotonin ( jensen et al . 1995 ) , leu - enkephalin ( klimaschewski et al . 1995 ) , pituitary adenylate cyclase - activating polypeptide ( pacap ) ( beaudet et al . 1998 ) , neuropeptide ( npy ) , calcitonin gene - related peptide ( cgrp ) ( yamamoto et al .1989 ) , substance p ( sp ) ( klimaschewski et al . 1995 ; llewellyn - smith et al .1996 ) , and vasoactive intestinal peptide ( vip ) ( sasek et al . 1991 ) are present in the scg - innervating preganglionic neurons , likely contributing to the scg neuroendocrine function . here in the present study , we investigated the distribution and neurochemical coding of scg supplying neurons in the pig , an animal model physiologically and anatomically similar to humans . in our previous study , we showed a complete 2d reconstruction of porcine scg and provided neurochemical characteristics of scg neurons supplying the porcine parotid gland ( wojtkiewicz et al . in this project , we have advanced in our research , paving the way to the source of scg innervation and providing a detailed overview of scg preganglionic neuron distribution and their complex neurochemical phenotype . six 8 - week - old female pigs of the large white polish breed , weighing ca . the animals were housed in accordance with the principles of laboratory animal care ( nih publication no .86 - 23 , revised 1985 ) and approved by the ethical commission of veterinary medicine faculty at the university of warmia and mazury , olsztyn , poland ( resolution no . the animals were preanesthetized with propionyl promazine ( 0.4 mg / kg b / w , i.m . ) and deeply anesthetized with sodium barbital ( 25 mg / kg b / w ; i.v . ) . the left scg , exposed via midline neck incision , was injected with retrograde tracer , fast blue ( fb , ems , grivory , deutschland , gmbh , postfach ) at multiple sites along the scg . injections were given with a hamilton microsyringe at a total volume of 20 l 5 % dye solution ( 1 l dye solution per injection ) . after a 3 - week survival time , animals were re - anesthetized and sacrificed by an overdose of pentobarbital . following sacrifice , animals were perfused transcardially with heparinized physiological saline in 0.1 phosphate buffer ( pb , ph 7.4 ) and fixative solution containing 4 % paraformaldehyde 0.1 m pb ( ph 7.4 ) . immediately after perfusion , spinal cord c5th8 segments were exposed by laminectomy and dissected . the segments were immersed in the same fixative for 20 min and stored in 18 % phosphate - buffered sucrose solution for further processing . the spinal cord segments were sectioned transversally ( n = 3 ) and longitudinally ( n = 3 ) on the cryostat at 10 m in thickness , mounted on glass slides , and stored at 70 c . briefly , 10 - m - thick cryostat sections were air - dried at rt for 45 min and rinsed ( 315 min ) with phosphate - buffered saline ( pbs , ph 7.4 ) . afterwards , the samples were incubated with a blocking mixture containing 1 % triton x-100 ( sigma - aldrich , usa ) , 0.1 % bovine serum albumin ( sigma - aldrich , usa ) , 0.05 % thimerosal ( sigma - aldrich , usa ) , 0.01 % nan3 , and 10 % of normal goat serum ( mp biomedicals , usa ) in 0.01 m phosphate - buffered saline for 1 h at rt , rinsed in pbs ( 315 min ) , and incubated overnight with the following primary antibodies : mouse anti - nitric oxide synthase ( nos ) , co - stained with an array of rabbit antisera against dynorphin a ( dyn a ) , leu - 5 enkephalin ( lenk ) , neuropeptide y ( npy ) , - neoendorphin ( neo ) , calbindin d - 28 k ( cb - d28k ) , calretinin ( crt ) , galanin ( gal ) , vasoactive intestinal peptide ( vip ) , peptide histidine - isoleucine ( phi - 27 ) , vesicular acetylcholine transporter ( vacht ) , substance p ( sp ) , calcitonin gene - related peptide ( cgrp ) , pituitary adenylate cyclase - activating peptide - 27 ( pacap - 27 ) , somatostatin ( som ) , choline acetyltransferase ( chat ) , serotonin ( 5 - ht ) , cholecystokinin ( cck ) , cocaine - and amphetamine - regulated transcript ( cart ) , and gaba ( for dilutions and secondary antibodies , see table 1 ) . sections were then incubated with a mixture of appropriate fluorescein isothiocyanate ( fitc ) - conjugated secondary antisera and biotinylated goat anti - rabbit antibodies ( 1 h ) . after staining , the sections were mounted with carbonate - buffered glycerol ( ph 8.6 ) and cover slipped . the specificity of primary antisera was tested as follows : sections were incubated with antibody , preabsorbed with synthetic antigen ( 10 g of antigen / ml diluted antiserum ) ; the primary antibody was omitted from the incubation ; or normal rabbit or mouse serum was substituted for the primary antibody.table 1detailed list of primary and secondary antibodies used in the studyantiserareagentcodehost speciesdilutionsupplierprimary antibodies chatab5052rabbit1 : 10,000 chemicon int . inc , us ; www.biomol.com som8330 - 0154rabbit1 : 10,000 biogenesis inc , www.biogenesis.co.uk vip11428rabbit1 : 10,000 mp biomedicals ; www.mpbio.com galrin7153rabbit1 : 10,000 bachem ag ; www.bachem.comcb - d28kcb - 38rabbit1 : 10,000 swant , s ; www.swant.com crt7699 / 4rabbit1 : 20,000 swant , s ; www.swant.com nosn2280mouse1 : 2,000 sigma ; http://www.sigmaaldrich.com lenkea 1149rabbit1 : 10,000 bioreagents inc , uk ; www.bioreagents.com dynas - 4019rabbit1 : 10,000 bachem ag ; www.bachem.com neos - 3149rabbit1 : 10,000 bachem ag ; www.bachem.com vachth - v006rabbit1 : 10,000 phoenix , ; www.phoenixpeptide.com pacapihc 8922rabbit1 : 20,000 bachem ag ; www.bachem.com phis - 3130rabbit1 : 10,000 bachem ag ; www.bachem.com cgrp11189rabbit1 : 10,000 mp biomedicals ; www.mpbio.com sp8450 - 0505rabbit1 : 10,000 biogenesis inc , www.biogenesis.co.uk 5hts5545rabbit1 : 5,000 sigma , us ; www.sigma - aldrich.comsecondary antibodiesdonkey anti - mouse igg ( h + l ) conjugated with fitc1 : 800715 - 095 - 151 ; jackson ir lab , us ; www.jacksonimmuno.com cy3 - conjugated f ( ab ) 2 donkey anti - rabbit igg ( h + l ) -1:9,000711 - 166 - 152 , jackson ir lab , us ; www.jacksonimmuno.com detailed list of primary and secondary antibodies used in the study sections were examined under an olympus bx51 fluorescence microscope equipped with a barrier filter for fb . microphotographs were acquired with a ccd camera connected to a pc equipped with analysis image analysis software ( ver .3.2 ; soft imaging system gmbh , mnster , germany ) . to determine the relative number of fb - positive cells , neurons were counted in every 16th section at 20 objective . data was pooled from animals and analyzed with graphpad prism 5 software ( graphpad software , la jolla , ca , usa ) . nerve fiber distribution was assessed under 40 objective by subjective observation ( two independent researchers ) as previously described ( gonkowski et al .2013 ) and depending on the density of labeling , described as not found or very few , small , moderate , and large number of nerve fibers . following fb injections of left scg , fb - positive neurons were found on the ipsilateral side of the spinal cord . a total of 13,013 neurons , combined from longitudinal and transverse sections , were counted . the sympathetic preganglionic neurons ( spn ) projecting to the porcine scg were found in c8 to th6 neuromeres , with the vast majority of them located in th1th3 segments ( 944.4 % ) , ranging from 27.63.0 % ( th1 ) to 34.54.0 % ( th2 ) and 31.66.3 % ( th3 ) , respectively . fb neurons were localized predominantly in imlpp ( 85.92.4 % ; 4,313 cells ) and imlpf ( 9.01.5 % ; 451 cells ) and about 5 % of the cells were seen in icpe ( 0.50.2 % ; 23 cells ) . chat - , nos - , vacht - , crt - , cb - d28k - , som - , pacap - , and cck - immunoreactive fb neurons constituted approximately 88 , 72 , 7 , 3.5 , 3 , 3 , 1 , and 0.6 % of all fb neurons in the whole region , respectively . the largest population of fb + / nos + neurons was positive for chat ( 62.84.9 % ) , followed by a much smaller number of vacht ( 5.32.7 % ) - positive neurons . a few of the fb - positive nitrergic neurons also contained cb - 28 k ( 2.20.4 ) , som ( 2.00.7 % ) , and pacap ( 1.00.5 % ) and a very limited number of fb + / nos + neurons were positive to cck ( 0.60.4 % ) and crt ( 0.60.4 % ) ( table 2 ; figs 1 and 2 ) . none of the fb - positive perikarya was immunopositive to lenk , sp , phi , npy , vip , gal , cgrp , 5ht , and - neo . retrogradely labelled spn were surrounded by a very dense network of opioidergic ( lenk - , dyn a - , or - neo - ir ) , gaba - , pacap - , cart - , or vacht - ir nerve terminals , a moderately dense network of sp - , som - , calb - , crt - , or th - ir nerve fibers , and a scarce network of cck - , vip - , phi - , npy - , 5ht - , gal - , or cgrp - ir axons ( figs . 1 and 2 ) . table 2percentages of retrogradely labelled cells in sympathetic preganglionic neurons ( spn ; in neuromers th1th3 ) projecting to the porcine scgsubstancefb / nos / p fb / nos / p fb / nos / p fb / nos / p chat62.84.910.81.216.23.210.61.4vacht5.32.765.95.32.11.126.15.7cb - 28 k2 .20.464.34.50.80.532.64.9 som2 .00.767.51.30.80.229.71.5 pacap1 .00.566.03.90.20.232.73.4 cck0 .60.467.13.5032.43.6 crt0 .60.265.15.72.91.231.35.3 p substance ( chat , vacht , pacap . . ) . all pictures are composites of merged images taken separately from the red , green , and / or blue fluorescent channels . a double - labelled nos + / pacap + neurons in the th3 neuromere , a compilation of three photos . b , c three different populations of nos / chat - positive neurons in th3 neuromere ; fb / nos neurons positive for chat ( two double arrows ) , fb + / nos + negative for chat ( three long arrows ) , and double - labeled fb / chat negative for nos ( two small arrows ) . d , e single fb + neurons scattered between a small population of fb / nos / vacht + ( triple staining , two double arrows ) and fb + / vacht + neurons ( small arrow ) . f a population of double fb / nos / pacap ( two single arrows ) and fb / nos / pacap + ( small arrow ) neurons observed in th3 neuromere . g , j the fb / nos / cb - 28 k ( one double arrow ) and fb / nos / cb - 28 k ( single arrow ) neurons observed in th3 neuromere ( merged image ) . enlarged images of the triple - stained neuron , split channels : h bluek the fb / nos / crt ( single arrows ) and l fb / noscrt ( small arrow ) neurons observed in th3 neuromere . scale bar image 1120 m ; images 2 , 4 , 6 , 11 , and 12100 m ; images 3 and 550 m ; image 725 m ; images 8 , 9 , and 1020 mfig . 2 aj representative images of scg - projecting fb + / nos + neurons ( spn ) and surrounding fibers observed in th3 neuromere . all images are composites of merged images taken separately from the red , green , and blue fluorescent channels . retrogradely labelled spn were surrounded by a lenk - , b dyn a - , c - neo - ir , d 5ht - , e cgrp - , f sp - , g npy - , h phi - , i som - , j gal - ir axons ; scale bar 50 m percentages of retrogradely labelled cells in sympathetic preganglionic neurons ( spn ; in neuromers th1th3 ) projecting to the porcine scg p substance ( chat , vacht , pacap . . ) . data expressed as mean standard deviation ( sd ) representative images of scg - projecting neurons located in the spinal cord iml column . all pictures are composites of merged images taken separately from the red , green , and / or blue fluorescent channels . a double - labelled nos + / pacap + neurons in the th3 neuromere , a compilation of three photos . b , c three different populations of nos / chat - positive neurons in th3 neuromere ; fb / nos neurons positive for chat ( two double arrows ) , fb + / nos + negative for chat ( three long arrows ) , and double - labeled fb / chat negative for nos ( two small arrows ) . d , e single fb + neurons scattered between a small population of fb / nos / vacht + ( triple staining , two double arrows ) and fb + / vacht + neurons ( small arrow ) . f a population of double fb / nos / pacap ( two single arrows ) and fb / nos / pacap + ( small arrow ) neurons observed in th3 neuromere . g , j the fb / nos / cb - 28 k ( one double arrow ) and fb / nos / cb - 28 k ( single arrow ) neurons observed in th3 neuromere ( merged image ) . k the fb / nos / crt ( single arrows ) and l fb / noscrt ( small arrow ) neurons observed in th3 neuromere . scale bar image 1120 m ; images 2 , 4 , 6 , 11 , and 12100 m ; images 3 and 550 m ; image 725 m ; images 8 , 9 , and 1020 m aj representative images of scg - projecting fb + / nos + neurons ( spn ) and surrounding fibers observed in th3 neuromere . all images are composites of merged images taken separately from the red , green , and blue fluorescent channels . retrogradely labelled spn were surrounded by a lenk - , b dyn a - , c - neo - ir , d 5ht - , e cgrp - , f sp - , g npy - , h phi - , i som - , j gal - ir axons ; scale bar 50 mour results show that the majority of all neurons supplying scg is localized between first through third spinal cord thoracic segments ( th13 ) and originates predominantly from nucleus intermediolateralis pars principalis and pars funicularis with only a small percentage found elsewhere , that is , in nucleus intercalatus spinalis pars paraependymali . these results are consistent with data obtained from other species ( dalsgaard and elfvin 1979 ; petras and faden 1978 ; yau et al .1991 ) and provide further evidence establishing the predominant importance of intermediolateral nuclei in scg innervation . the observation bears clinical relevance as intermediolateral column injury apparently disrupts scg function , subsequently resulting in various vascular , respiratory , and cardiac dysfunctions ( grigorean et al . it has been shown that sympathetic iml morphological abnormalities in th13 segments observed in patients with familiar dysautonomia lead to scg shrinkage and activity suppression , resulting in numerous autonomic dysfunctions such as difficulties in swallowing , paresthesia , frequent vomiting , labile hypertension , propensity to lung infections , and corneal problems ( pearson and pytel 1978 ) ; these findings further support the notion of central role of scg in the autonomic coordination of major vital organs . further , our study revealed that the neurochemical composition of neurons supplying scg is complex , underscoring the importance of this ganglion as a neuroendocrine center . first , we found that the majority of scg preganglionic neurons is positive to both chat and nos , showing a much higher level of colocalization than previously observed ( blottner and baumgarten 1992 ; calka et al . chat , an acetylcholine marker , previously reported in the intermediolateral ( iml ) nuclei of several species ( caka et al . 2008 ; ichikawa and shimizu 1998 ; markham and vaughn 1990 ) is an important player in numerous neuromodulatory functions ( oda 1999 ) . it has been found that disturbance in neuronal chat levels contributes to the mechanisms underlying development of certain neurodegenerative diseases such as alzheimer s or huntington s disorder , schizophrenia , or amyotrophic lateral sclerosis ( oda 1999 ) . nos , an indicator of nitric oxide presence in the neuron , was shown in the iml nuclei of a number of small and large laboratory animals as well as in humans ( calka et al . it has been shown that nos is involved in the regulation of several metabolic pathways such as soluble guanylyl cyclase or adp - ribosyltransferase activation ( blottner and baumgarten 1992 ) and , most importantly , modulates acetylcholine neurotransmission in central nervous system neurons affecting their activity ( prast and philippu 2001 ) . to date , only a few studies have indicated that in the iml column , nos and chat co - exist in the same neurons ( burnett et al . it is plausible to assume that both nos and chat play a vital role in the scg preganglionic neurons , complementing each other s functions and synergistically modulating neuronal activity of autonomic nervous system cells . interestingly , vacht , an acetylcholine transporter and another marker of cholinergic neurons , has been found in only 7 % of all scg supplying neurons . this discrepancy between chat and vacht distribution in cholinergic neurons might be explained by the differential genetic expression and diverse functional patterns of these two molecules at the molecular level ( weihe and eiden 2000 ) . chat and vacht share the same genetic locus ( eiden 1998 ) ; however , it has been established that their expression levels might substantially differ and , depending on neuronal region and developmental stage , do not always correlate ( schutz et al .2001 ) , as observed in our study . furthermore , aside from chat , nos , and vacht , here for the first time we show the presence of a number of other neurochemicals such as crt , cb - d28k , som , pacap , and cck in iml neurons innervating the scg , indicating that these neurons largely contribute to and play an important role in maintaining the role of the scg as a neuroendocrine center . crt has been identified in iml preganglionic sympathetic neurons of the rat ( murphy et al .2003 ; ren and ruda 1994 ) , mouse ( ninomiya et al . 1993 ) , cat ( edwards et al . 1996 ) , and lizard ( gecko ) ( morona et al . it belongs to the family of calcium - binding proteins and is involved in a wide array of processes from intracellular calcium signaling through molecular protein targeting to long - time potentiation modification ( schwaller 2014 ) . it is also thought to be involved in neuroprotection , neuronal development , and homeostasis ( barinka and druga 2010 ; schwaller 2014 ) . in the sympathetic nervous system , crt is presumed to function as a regulator of sympathetic ganglion activity and as a potential contributor to age - related changes of target organ functions ( corns et al . cb , another member of the calcium - binding protein family , has been reported in the sympathetic preganglionic neurons of the rat s iml column ( grkovic and anderson 1997 ) . in the sympathetic nervous system , cb has been speculated to contribute to the secretory functions of salivary glands and fatty brown tissues ( grkovic and anderson 1997 ) , play a role in the development of the enteric nervous system ( hagl et al .2013 ) , and contribute to the pathogenesis of proliferative enteropathy ( wojtkiewicz et al . recent studies indicate that cb may also play a role in excitatory activity of gaba and glutamate neurons projecting to iml sympathetic preganglionic neurons ( llewellyn - smith et al . cck , first described as an intestinal hormone ( chandra and liddle 2007 ) , reported previously in rat , human , and guinea pig sympathetic neurons of iml nuclei ( chiba and masuko 1987 ; chung et al .1989 ; schroder 1983 ) , has been shown to participate in a number of gastrointestinal processes , affecting the activity of numerous digestive system organs , i.e. , stomach , gall bladder , pancreas , and intestines ( chandra and liddle 2007 ) . studies have shown that changes in cck expression or a reduction in a number of cck receptors contributes to various gastrointestinal and metabolic diseases such as diabetes mellitus , gall stone disease and irritable bowel syndrome ( chandra and liddle 2007 ) . som , observed previously in the iml column of the guinea pig spinal cord ( chiba and masuko 1989 ) , has been shown to modulate inflammatory response between neuronal and mast cells in the intestine ( van op den bosch et al .2009 ) and likely acts alongside cck in digestion and food intake ( schmidt et al . it has been demonstrated that in the sympathetic nervous system som affects vasodepressor response ( rioux et al .1981 ) and gastrin secretion ( olesen et al . 1984 ) and that it plays a role in insulin release ( lechin et al . 2013 ) . it might be speculated that in the scg , som plays a regulatory role , affecting the function of scg target organs . finally , pacap , previously found in scg neurons of the iml column in the rat ( beaudet et al .1998 ; klimaschewski et al . 1996 ) , is critically important in an array of autonomic nervous system - regulated activities , from metabolic and cardiovascular regulation through hormone secretion , stress response to appetite suppression , and food intake regulation ( merriam et al . 2013 ; roy et al . it has been shown that in the sympathetic nervous system , pacap contributes to the neuronal development of the sympathetic neuroblast ( lu , et al . , 1998 ) and modulates sympathetic neuron function via ip3 , cyclic amp / pka , and mapk / erk regulatory pathways ( girard et al . 2004 ; may et al . furthermore , pacap contributes to npy and catecholamine expression in scg neurons by regulating the mrna levels of these neurotransmitters , thus affecting the function of this ganglion overall ( braas and may 1999 ; may and braas 1995 ) . in addition to numerous neurochemicals present in scg - projecting neurons , we found a dense network of neurochemically complex fibers surrounding the neurons and containing a plethora of neuropeptides such as lenk , dyn a , - neo , gaba , pacap , cart , vacht , sp , som , calb , crt , th , cck , vip , phi , npy , 5ht , gal , or cgrp that likely modulate the activity of scg preganglionic neurons , thus regulating overall scg function . in conclusion , this is the first evidence of such a neurochemical complexity of iml preganglionic sympathetic neurons supplying mammalian scg . it might be speculated that such complexity is indispensable to scg activity and , as such , likely contributes to the central role of scg in numerous crucial physiological and metabolic functions . the findings of our studies underscore the importance of scg in the autonomic nervous system and lay the foundation for future translational and clinical studies .\noutput:\n" }, { "from": "agent", "value": "the superior cervical ganglion ( scg ) is a center of sympathetic innervation of all head and neck organs . scg sympathetic preganglionic neurons ( spn ) were found in the nucleus intermediolateralis pars principalis ( imlpp ) , the nucleus intermediolateralis pars funicularis ( imlpf ) , the nucleus intercalatus spinalis ( ic ) , and the nucleus intercalatus spinalis pars paraependymalis ( icpe ) . despite its importance , little is known of scg innervation and chemical coding in the laboratory pig , a model that is physiologically and anatomically representative of humans . here in our study , we established the distribution and chemical coding of fast blue ( fb ) retrogradely labelled spn innervating porcine scg . after unilateral injection of fb retrograde tracer into the left scg , labeled neurons were found solely on the ipsilateral side with approximately 98 % located in th1th3 segments and predominantly distributed in the imlpp and imlpf . neurochemical analysis revealed that approximately 80 % of spn were positive both to choline acetyltransferase ( chat ) and nitric oxide synthase ( nos ) and were surrounded by a plethora of opioidergic and peptiergic nerve terminals . the results of our study provide a detailed description of the porcine preganglionic neuroarchitecture of neurons controlling the scg , setting the stage for further studies concerning spn plasticity under experimental / pathological conditions ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: palm oil production is the second largest edible oil output and accounts for approximately 23 % fof the world 's fat and oil supply , which is approximately 2.810 tons . palm oil is now not only being used as edible oil , but also in the production of biodiesel as a renewable energy source . in 2009 , thailand consumed 24,872 ktoe of alternative energy sources , and biodiesel accounted for 3.2 % , the demand for which is continually increasing . biodiesel is set as one of the renewable energy sources in thailand 's strategic plan , which recently used 1.6210 l / day . the target for biodiesel production by the year 2021 is planned to produce 5.9710 l / day . therefore , the palm oil industry in thailand is expanding rapidly for production of edible oil , biodiesel , and other applications . the expansion of crude palm oil production will generate additional wastewater at an increasing rate . environmental impacts from wastewater of palm oil production known as palm oil mill effluent ( pome ) are a matter of great concern . pome is one of the most significant pollutants associated with its voluminous production . for every ton of palm oil production , 2.53.0 tons of pomeit has been classified as a high - strength wastewater due to its high biochemical oxygen demand ( bod ) and chemical oxygen demand ( cod ) , consisting of high organic pollutant concentrations in suspended solids ( ss ) and lipid or oil and grease ( o & g ) . fresh pome is an acidic ( ph 3.54.5 ) , brownish , viscous , and voluminous colloidal suspension being 95 - 96 % water , 1044 g / l of bod , 16100 g / l of cod , 545 g / l of ss , 115 g / l of o & g , andbiological treatment of pome is the most frequently used treatment method . since it contains high concentrations of organic matter , adoption of anaerobic digestion ( ad ) in the first stage of the processad is a multistep degradation of the organic compounds into biogas , methane , and carbon dioxide , by the action of a microbial consortium . the metabolic reactions that occur during the anaerobic digestion of the substrates involve four important reactions : hydrolysis , acidogenesis , acetogenesis , and methanogenesis . in general of ad , methanogenesis is the rate - limiting step . as such , conventional anaerobic digesters require long hydraulic retention time and large volume reactors to ensure the complete treatment of the influent . nonetheless , high - rate anaerobic bioreactors have been proposed to reduce reactor volume , shorten retention time , and capture methane gas for utilization . the anaerobic hybrid reactor ( ahr ) , like the upflow anaerobic sludge bed - fixed film reactor , was found to be high performing in cod removal efficiency and methane production . this hybrid system can overcome the existing deficiencies of the original upflow anaerobic sludge blanket ( uasb ) reactors by shortening the biogranule formation time . upflow ahrs can work well for the high - suspended solid pollutants like cassava starch wastewater , slaughterhouse waste , and pome . therefore , this study applied ahr , a combination of two zones in the reactor , namely , the sludge zone ( part of the microbial granules ) and the packed zone ( part of the biofilm on the packing material ) for the anaerobic treatment of pome . the major components in biological anaerobic digestion , microorganisms , play an important role as the main function in controlling reactor performance and stability . the performance and stability of an anaerobic digester is directly related to the quantity and quality of the microbial community present in the digester . furthermore , the operational and environmental parameters of the process obviously affect the microbial behavior resulting in wastewater treatment and biogas production performances . sss containing palm fiber and o & g are the main organic pollutants in pome . in this study , we looked specifically at the concentrations of these organic pollutants in the organic digestion of ahr . this work focused on the effect of the organic pollutant concentrations on the process performance and stability , that is , the microbial communities and the microbial performance in the sludge and packed zones of the ahr . the work will lead to an understanding of the operational efficiency of the ahr system , depending on the structure of the microbial communities present in the system and the environmental conditions needed to control the system . the raw pome characteristics were determined according to the procedures of the standard methods of wastewater analysis . its characteristics were in the range of total chemical oxygen demand ( tcod ) 5763 g / l , soluble chemical oxygen demand ( scod ) 4044l with ph 4.54.8 . to study the influence of ss combining with o & g concentrations , influent pome was prepared by varying the ss and o & g concentrations into three conditions , c1 , c2 , and c3 . these three operating conditions of the pome were fed into the reactor as shown in table 1 . a schematic diagram of the anaerobic hybrid sludge bed - fixed film reactor ( ahr ) used in this study is shown in figure 1 . the ahr was made up of an acrylic column with a working volume of 5.0 l. the bottom half of the reactor was occupied by the sludge zone and the upper half was occupied by the packed zone . this packed zone was fitted with nylon fibers having a specific surface area 150 m / m for microbial attachment as biofilm formation . seven sampling ports were distributed at several heights in the sludge and packed zones in the ahr . the influent was fed upflow from the bottom to the upper part of the ahr , and the treated wastewater was discharged through an effluent port . the ahr was initially fed with 5.0 l of diluted pome and inoculated with startup seed , which was collected from the ad of the pome treatment at a final concentration of 5.0 g vss / l . for acclimatization of the startup seed to a new environment , 1 l of diluted pome influent was fed semicontinuously once a day with a hydraulic retention time ( hrt ) of 5 days for 20 days . upon reactor startup operation , three experiments were set up by increasing the organic pollutant concentrations to c1 , c2 , and c3 ( table 1 ) . the reactor was operated in each condition until the process performance reached a steady state and was kept continually running for more than 3 cycles of hrt . the process performance of the sludge and packed zones , as well as the overall ahr , was routinely monitored through measurement of the tcod , scod , alkalinity ( alk ) , total volatile acid ( tva ) , o & g , ss , and the ph of the effluent pome . the tcod , scod , ss , alk , and tva analyses were carried out according to the procedures of the standard methods of wastewater analysis . the remaining parameters were measured three times a week throughout the steady - state period to ensure that representative data were obtained . biogas composition was determined using gas chromatography . at the end of each operating condition of c1 , c2 , and c3 , suspended sludge samples from the sludge zone and the attached biofilm samples from the supporting media in the packed zone were collected . dna sequencing was carried out to determine the microbial community ; 16s rdna quantitative real - time pcr was used for the microbial quantity ; microbial activity of nonmethanogens ( eubacteria : eub ) and methanogens ( archaea : arc ) was used for the microbial qualities . to study the microbial communities , samples were collected aseptically from the reactor and immediately stored in a freezer for community analysis and prepared with a centrifugation method prior to dna extraction . dna extraction and amplification and denaturing gradient gel electrophoresis ( dgge ) were performed as previously described . sequences were initially compared to known 16s rrna gene sequences in the genbank database using the blastn to locate nearly exact matches in the genbank database . copy numbers of 16s rdna of eub and arc were quantified by relative quantification real - time pcr ( qpcr ) . a kapa sybr fast qpcr kit was used for real - time reactions ( kapa , brazil ) . the two - step amplification protocol was as follows : initial denaturation for 10 min at 95c , followed by 40 cycles of 30 sec at 95c and combined annealing and elongation for 30 sec at 60c . standard curves were generated using 16s rdna of eubacteria and methanobacteria as standard eub and arc stains , respectively . amplicons of eub and arc were cloned to plasmid vector ( pgem - t easy vector , promega ) and inserted in chemically competent cells ( e. coli dh5 ) . plasmids dna were serially diluted in the range of 1010 copies rdna / l and used as templates for qpcr with primers and amplification protocol as defined . determination of microbial activity was carried out in triplicate using 120 ml vials with 50 ml of working volume . the inoculum - substrate ratio in the final volume was 30 : 70 v / v . glucose and acetate were used as the substrates for activity analysis of the eub and arc , respectively . determination of microbial activity was performed using the method of nopharatana et al . . in this study , the standard errors were all within 5 % of the mean value . a test of significant difference based on the paired t - statistic was performed using the minitab software ( minitab inc . the difference was regarded as nonsignificant if the paired t - statistic showed probability , p 0.05 and significant if p 0.05 . the ahr was operated for 144 days consecutively by increasing the organic pollutant ( ss and o & g ) concentrations under the three conditions , c1 , c2 , and c3 ( table 1 ) . the operating dates for the c1 , c2 , and c3 conditions were 40 , 51 , and 53 days , respectively . once each operating condition reached a steady state of process performance , the reactor was run for a further 20 to 25 days ( 3 cycles of hrt ) to ensure that representative data from the steady - state period were obtained and could yield shown values in mean and standard deviation from ten to fifteen determinations . figure 2 shows the overall process performance during the steady state of the anaerobic bioreactor under c1 , c2 , and c3 conditions . production of biogas was obtained at 210060 , 330035 , and 640075 ml / day for c1 , c2 , and c3 , respectively . the methane yield coefficient is defined as the ratio of methane produced in this experiment to the cod utilized . the paired t - test analysis of the methane yielded ( p 0.05 ) , indicating that c1 , c2 , and c3 produced methane yield at significantly different rates . the methane yield increased corresponding to the increase of the ss and o & g concentration . under c1 and c2 , methane yields of 0.130.01 and 0.200.01 l ch4 / g codremoved , a low methane yield was obtained , which was similar to the result found by chaiprasert et al . andpoh and chong , likely due to the organic carbon ( cod ) being consumed by microorganisms to build more cells during the initial startup period . under the c3 operation , this value was close to the theoretical methane yield of 0.35 l ch4 / g codremoved . considering a theoretical methane yield , the whole of the organic matter is transformed into methane , accounting for virtually negligible biomass growth and cell maintenance . the ahr in this study showed the high effectiveness of the this reactor in converting the pome into methane at mesophilic temperatures with an organic loading rate ( olr ) of 8.2 g cod / l day consisting of 10.2 g ss / l and 1.9 g o & g / l with 5 days of hrt . the process performance in terms of the efficiency of tcod and scod removal was higher than 70 % . the scod was easily biodegradable and almost completely removed while the tcod removal efficiency was between 7080 % . insoluble cod in the form of ss and o & g was slightly harder to biodegrade , and its removal was lower than 70 % ( figure 2 ) . this suspended organic matter is cell walls , short fibers , hemicelluloses , and nitrogenous compounds of proteins , which are less biodegradable and require a longer retention time for satisfactory digestion . in addition , the o & g or lipid content was one of the least biodegradable organic materials . the increase of o & g concentration from the c1 to the c3 operation showed a decrease in o & g removal . an inhibitory ad process by lipids was found in the other studies and indicated as an impeding step of hydrolysis . the overall conversion rate was limited either by degradation of long - chain fatty acids ( lcfas ) or by the physical processes of dissolution and mass transfer of these acids . however , the removal efficiency of o & g in this study was in the range of 50 to 60 % . o & g was generally hydrolyzed by bacterial enzymes under anaerobic conditions at an optimum ph value to a neutral value . the slightly high o & g removal obtained in this study might arise from the suitable ph and stability of process with the ratio of tva / alk 0.4 . the values of ph and ratio of tva / alk were 6.90.4 and 0.350.02 , respectively . at this point , the environmental condition in the ad process can control the system to neutralize the ph with a high buffer capacity and less acidification risk leading to the high process stability . each zone of the ahr , the sludge and packed zones , was monitored and considered for its process performance and stability , as shown in figures 3 and 4 , respectively . removal of the tcod , ss , and o & g in the sludge zone ( figure 3 ( a ) ) varied with an increase of the organic pollutant concentration . with a low organic pollutant concentration under the c1 condition , organic removal of tcod , ss , andwhen the reactor was operated under the c2 and c3 conditions , increasing the organic pollutants , the removal decreased to 50 % . high concentrations of ss and o & g in the pome influent caused a reduction in their removal because of the complex structure and less biodegradable compounds . remaining undigested matter , which settled and accumulated in the sludge zone , was observed . under the c2 and c3 operating conditions , the tva concentration indicated that hydrolysis and acidogenesis had occurred in this sludge zone . the increase in the tva concentration led to an increase in the ratio of tva / alk to 0.660.05 , anda high tva concentration in the sludge zone affected o & g removal because an inappropriate ph level inhibited the activity of the extracellular lipase enzyme . high organic pollutant removal was achieved ( 60 % ) , possibly due to the lower molecular weight or shorter chain compounds in the tcod , ss , and o & g obtained from the sludge zone , where they were more easily digested by anaerobic microorganisms . in the packed zone , the tva concentration was lower than 80010 mg ch3cooh / l , leading to the ph and the ratio of tva / alk increasing to 6.90.27.40.2 and 0.200.010.500.02 , respectively ( figure 4 ( b ) ) . microbial consortiums were attached and grew on supporting media as biofilm in the packed zone , and they biodegraded organic acids to methane . moreover , this study further increased the organic loading rate ( olr ) from 8.2 ( c3 ) to 9.6 g cod / l day consisting of 11.3 it was found that the process performance , that is , the organic pollutants removal and biogas production , was decreased , and the process stability tended to be unstable ( data not shown ) . this ahr with 50 % of suspended growth and 50 % of attached growth by volume can load high proportions of organic matter to 8.2 g cod / l day containing high ss ( 10.2 the capacity of organic loading fed to a high - rate anaerobic hybrid reactor for pome in this study was close to that in the study of najafpour et al . . pcr - dgge targeting the 16s rrna genes of eub and arc was performed to investigate the microbial communities in the sludge and packed zones of the ahr at the operating conditions c1 , c2 , and c3 . the dgge profiles of the eub ( lane s , a - f ) and the arc ( lane g - m ) communities from all the samples in the startup seed and both the sludge and packed zones are illustrated in figures 5 ( a ) and 5 ( b ) , respectively . from figures 5 ( a ) , and 5 ( b ) , the eub band patterns were more complicated than those of the arc due to the relatively higher diversity of domain eub in most microbial complexes of hydrolytic , acidogenic , and acetogenic bacteria . the partial 16s rrna gene fragments from the selected bands in the dgge profiles , twenty - two eub and fifteen arc bands , were sequenced , and affiliations were determined by comparison with the genbank ( tables 2 and 3 ) . in the startup seed , fourteen dgge bands of the eub communities ( s1 - 14 ) and five bands of arc communities ( g1 - 5 ) as shown in figures 5 ( a ) , and 5 ( b ) , respectively , were observed . ( s1 , s3 , s5 - 6 , and s8 - 9 ) and uncultured - proteobacterium ( s10 ) , acidogenic bacteria uncultured bacteroidetes bacterium ( s7 , s11 - 13 ) , and acetogenic bacteria ( s14 ) , and uncultured actinobacterium ( s4 ) , as shown in table 2 . ( g1 - 2 ) and methanomicrobiaceae ( g4 ) , which were classified as hydrogenotrophic methanogens . the other two bands were closely related to the uncultured methanococcoides sp . ( g5 ) and uncultured methanosaeta sp . the initial c1 condition was operated with the startup seed in the ahr for 40 days . the eub communities in the packed zone ( lane a ) and in the sludge zone ( lane b ) were analyzed and are shown in figure 5 ( a ) and table 2 . similar in the dgge profiles of the eub between the startup seed and c1 , we found in s1 - a1 - b1 ( pseudomonas sp . m130 ) , s5 - a4 - b4 and s8 - a7 - b7 ( pseudomonas sp . ) , s7 - a6 - b6 , s11 - a9 - b8 , s12 - a10 - b9 , and s13 - a11 - b10 ( uncultured bacteroidetes bacterium ) , s2 - a2 - b2 ( clostridiales bacterium ) , and s14 - a12 - b11 ( acetobacter sp . ) . the band intensity of a3 , b3 , and a8 increased during the operation period under c1 ( figure 5 ( a ) ) . a3 , b3 , and a8 were closely related to uncultured actinobacterium , pseudomonas entomophila str . the major eub communities of hydrolytic , acidogenic , and acetogenic bacteria in the startup seed also existed during the initial reactor startup with slightly increased organic pollutant concentration ( c1 condition ) which confers community stability during the beginning stage of anaerobic waste treatment . the dgge band profiles showed some changes in the eub community structure during the operations of the c2 and c3 conditions with the increase of the organic pollutant concentration . the eub communities in the packed and sludge zones under operating conditions c2 and c3 are shown in c - d and e - f , respectively , ( figure 5 ( a ) ) . three hydrolytic bacteria of unculture firmicutes bacterium ( c5 , d5 ) , uncultured - proteobacteria ( c9 , e8 - 9 , f7 - 8 ) , and uncultured delta proteobacterium ( e10 ) were first detected in the dgge band intensity under these conditions . some of the initially predominant eub bands , b3 - c3 - d3 , and a8 - d9 , under c1 and c2 conditions became practically undetectable in the dgge profile after increasing the organic pollutants to the c3 condition . the sharp intensity bands of e3 - f3 and e8 - f7 were detected after increasing the organic pollutant to the c3 condition . these were related to bacteriodes and uncultured clostridiaceae bacterium in the groups of hydrolytic and acetogenic bacteria , respectively . the dgge bands of e4 - f4 ( uncultured clostridiaceae bacterium ) in the operating condition of c3 were also detected . m130 ( a1 - f1 ) , uncultured bacteroidetes bacterium ( a11 - b10 - c11 - d11 - e12 - f11 ) , and clostridiales bacterium ( a2 - f2 ) were observed throughout the operating conditions of c1 to c3 ( figure 5 ( a ) and table 2 ) . it has an ability to produce extracellular lipase enzymes that hydrolyze triglycerides to fatty acids and glycerol , and is generally found in lipid - contaminated wastewater . with an increase of the organic pollutant of o & g concentration at 1.9 moreover , with the increase of organic loading from c1 to c3 , the ss concentration also increased , and - proteobacteria was found to be dominant at the high ss concentration of 10.2 g / l ( c3 condition ) . this is a common representative of the microbial communities in anaerobic processes of solid substrates . uncultured bacteroidetes bacterium , as an acidogenic bacterium , was only one species found under all operation conditions ( c1c3 ) in this study , and it is one of the major microbial components of acidogenesis in ad , as shown in other studies . in acidogenesis , simple organic compounds are transformed into fermentation endoproducts such as lactate , propionate , acetate , and ethanol including h2 and co2 . this acidogenic bacterium can exist in low and high tva concentrations , as found in this study at the range of 5001500 mgthe detected acetogenic bacteria were members of firmicutes , mostly represented by clostridiales bacterium and acetobacter sp . the exception was uncultured clostridiaceae bacterium , which was only found under the c3 condition . however , firmicutes and actinobacteria are known to produce cellulases , lipases , proteases , and other extracellular enzymes , suggesting they are also involved in hydrolysis through acetogenesis . the dgge band profiles and sequenced bands of arc during the c1c3 operations are shown in figure 5 ( b ) and table 3 , respectively . at the beginning of the reactor operation ( c1 ) , uncultured methanosaeta sp . ( g1 - h4 - i4 and g2 - h5 - i5 ) , and methanomicrobiaceae ( g4 - h7 - i7 ) in the startup seed were also detected in both the sludge and packed zones , with the exception of uncultured methanococcoides sp . an increase of arc diversity was observed as the first detected bands of i2 and h1 - 3 . these were represented by methanocaldococcus vulcanius m7 for acetoclastic methanogens and uncultured methanomicrobiales , methanospirillum hungatei and methanobacterium sp . for hydrogenotrophic methanogens . during the increase of organic pollutants from the c1 to the c2 and c3 operations , uncultured methanosaeta sp . ( h4 - i4 - j4 - k6 - l7 - m4 and h5 - i5 - j5 - k7 - l8 - m5 ) , methanomicrobiaceae ( h7 - i7 - j7 - k9 - l10 - m7 ) and uncultured methanomicrobiales ( h1 - i1 - j1 - k1 - l1 - m1 ) were found in both the sludge and packed zones . the low intensity of the dgge bands i8 - j9 - k11 - l12 - m8 belonged to uncultured methanococcoides sp . ; methanosaeta sp . is one of the acetoclastic methanogens presented in the startup seed and all operating conditions . is commonly found in stable anaerobic digestion systems and often represents the major arc in methanogenic communities . more diversity of hydrogenotrophic methanogens was detected with an increase in the organic pollutant concentration ( table 3 ) . not only methanobacterium sp . and methanomicrobiaceae , but also other hydrogenotrophic methanogens such as methanobacteriaceae ( k5 ) , methanoculleus sp . ( l6 ) were also found among the sludge and the packed zones of the ahr . two types of methanogenic arc , acetoclastic and hydrogenotrophic methanogens were found under all the operating conditions for this study . methanogenic acetate degradation was converted to methane by acetoclastic methanogens ( uncultured methahnosaeta sp . ) , whereas hydrogen and co2 were carried out by hydrogenotrophic methanogens ( methanobacterium sp , methanomicrobiaceae , and uncultured methanomicrobiales ) . during the methanogenic mineralization process , oxidation of reduced compounds ( alcohols and short - chain fatty acids ) by acidogenic bacteria and / or acetogenic bacteria is thermodynamically unfavorable . the oxidation of these reduced compounds can proceed only if hydrogen partial pressure is kept low by coupling with hydrogen consuming methanogenesis . thus , interspecies hydrogen transfer between syntrophic fatty acid - oxidizing bacteria ( uncultured bacteroidetes bacterium , clostridiales bacterium , and acetobacter sp . ) and the hydrogenotrophic methanogens appeared for the oxidation of these substrates . acetate is one of the most important intermediates for the methane production step in the anaerobic mineralization of organic substrates . hattori reported that methanogenic acetate degradation is carried out by either an acetoclastic reaction or an anaerobic acetate - oxidizing reaction ( syntrophic acetate oxidation and hydrogenotrophic methanogenesis ) . methanosaeta sp . has a high affinity for acetate , and the growth of this arc is affected by the concentration of acetate . in addition , high concentrations of ammonia and volatile fatty acids are considered important factors for acetate metabolism . acetoclastic methanogens are also known to be more sensitive to these compounds than hydrogenotrophic methanogens . some studies found syntrophic acetate - oxidizing bacteria in the class of clostridia within the phylum firmicutes ( acetate - oxidizing bacteria strain aor and clostridium ultunense ) and hydrogenotrophic methanogens ( methanobacterium and methanoculleus sp . ) for methane production under these stresses . we seemed to observe a similar result in the operation of c3 for high concentration of ss and o & g influent . there was the first detection of uncultured clostridiaceae bacterium within the phylum of firmicutes in both the sludge zone ( f4 ) and the packed zone ( e4 ) ( figure 5 ( a ) and table 2 ) and hydrogenotrophic methnanogens ( methanobacterium paluster , l5 , methanobacterium sp . , l6 , and methanoculleus sp . , quantitative changes in the 16s rrna gene concentration were determined by real - time pcr , and microbial quality was studied by microbial activity determination in the sludge and packed zones under the three operating conditions . the microbial populations and activity of eub and arc are described in table 4 . among the operating conditions of c1 , c2 , and c3 , there was an evident variation in the eub and arc populations and activity in the sludge and packed zones of ahr . the level of concentration of organic pollutants had an effect on the microbial populations and activity as well as on the structure of the microbial communities in each zone . this result will impact the environmental condition ( tva / alk and ph ) and the process performance . microbial populations in the startup seed , the 16s rrna gene concentrations of the eub and arc were 1.210 and 8.210 copies rdna / g vss , while their activity were 1.00 g cod / g vss a day and 0.12 g cod - ch4 / g vss a day , respectively . at the beginning of the reactor operation ( c1 ) , the overall microbial populations increased , resulting mostly from organic carbon being utilized for microbial cell development . the paired t - test analysis of the eub and arc activity ( p 0.05 ) indicated that under each of the conditions c1 , c2 , and c3 there was significantly different microbial activity in the reactor operation . the activity of the eub and arc in the sludge zone were close to those in the startup seed , while those in the packed zone were different . eub activity decreased and arc activity slightly increased compared to that in the startup seed . when the organic pollutant concentration was increased to the c2 and c3 conditions , the population and activity of the eub and arc in the sludge and packed zones were investigated for the development of these characteristics and compared to those under the c1 conditions . in the sludge zone , the eub population and activity were significantly increased from 3.510 to 6.410 copies rdna / g vss , and 1.08 to 1.65 g cod / g vss , respectively , while the arc population and activity were slightly increased from 1.110 to 7.510 copies rdna / g vss and 0.10 to 0.14 g cod - ch4 / g vss a day . in addition , when comparing the packed and the sludge zones , the eub population had decreased slightly , and the eub activity was lower , whereas the arc population and activity were higher , from 10 to 10 copies rdna / g vss and 0.1 to 0.3 g cod - ch4 / g vss a day . the sludge zone is the bottom part of the ahr , where there is the first contact with the influent pome . in this zone , most of the organic carbon was hydrolyzed to a simpler molecule and then converted to volatile fatty acids by hydrolytic , acidogenic and acetogenic bacteria . this resulted in the high tva concentration and tva / alk ratio ( figure 4 ( a ) ) . contrary to the arc characteristics , a higher population and activity were found in the microbial biofilm of the packed zone ( table 4 ) . the packed zone was located in the top part of the ahr , where the remaining organic compounds were continuously converted to short chains of volatile fatty acids . this was reflected in the low activity of eub , while the dominant arc characteristics were evident in this packed zone . the arc activity in the packed zone under operating conditions c1 to c3 was increased from 0.18 to 0.34 g cod - ch4 / g vss a day . this might relate to the uncomfortable environment for these arc in the sludge zone due to the high tva concentration , lower ph , and high tva / alk ; whereas , the dominant arc biofilm can resist more than that in suspended cells and was able to utilize the tva for its growth and methane production in the packed zone . this kept the process stable , with ph 6.90.4 and tva / alk 0.350.05 . an increased arc population andactivity reflected the low tva concentration ( 80010 mg ch3cooh ) with a ph in the neutral range and a lower tva / alk ratio ( 0.5 ) in the packed zone . the action of the sludge and packed zones , which work as hydrolysis or fermentative and methanogenesis zones , respectively , were mostly responsible for a properly enhanced reactor performance and maintained the process stability of the ahr . for pome , anaerobic digestion could be achieved completely within one reactor of an anaerobic hybrid reactor . the process performance and stability , as well as the microbial characteristics , varied according to the organic pollutant concentrations . the organic pollutants were studied at olr of 6.28.2 g cod / l day consisting of 5.210.2 g ss / l and 0.91.9 g o & g / l. the ahr utilized in the study can handle the olr to 8.2 g cod / l day containing 10.2 g ss / l and 1.9 g o & g / l with high performance and stability . process stability in terms of the tva / alk ratio and ph was in the range of 0.20.5 and 6.57.0 , respectively . the increase of organic pollutant concentration affected the eub and arc communities , populations , and activity in the sludge and packed zones , which was reflected in the organic removal of tcod , ss , and o & g . throughout the graduated c1 to c3 operating conditions , high organic hydrolysis / fermentation took place in the sludge zone of the ahr , and the dominant eubacteria were represented by pseudomonas sp . , uncultured bacteroidetes bacterium , and clostridiales bacterium . the dominant archaeal bacteria found under all the operating conditions related to acetoclastic methanogens as uncultured methanosaeta sp . and hydrogenotrophic methanogens as methanobacterium sp . , methanomicrobiaceae , and uncultured methanomicrobiales . higher levels of archaeal population and activity were found in the packed zone within the microbial biofilm . from the results of the microbial characteristics , this implied that the sludge and packed zones in the ahr acted overall as acidification and methanation zones , respectively .\noutput:\n" }, { "from": "agent", "value": "the anaerobic hybrid reactor consisting of sludge and packed zones was operated with organic pollutant loading rates from 6.2 to 8.2 g cod / l day , composed mainly of suspended solids ( ss ) and oil and grease ( o & g ) concentrations between 5.2 to 10.2 and 0.9 to 1.9 g / l , respectively . the overall process performance in terms of chemical oxygen demands ( cod ) , ss , and o & g removals was 73 , 63 , and 56 % , respectively . when the organic pollutant concentrations were increased , the resultant methane potentials were higher , and the methane yield increased to 0.30 l ch4 / g codremoved . it was observed these effects on the microbial population and activity in the sludge and packed zones . the eubacterial population and activity in the sludge zone increased to 6.4 109 copies rdna / g vss and 1.65 g cod / g vss day , respectively , whereas those in the packed zone were lower . the predominant hydrolytic and fermentative bacteria were pseudomonas , clostridium , and bacteroidetes . in addition , the archaeal population and activity in the packed zone were increased from to 9.1 107 copies rdna / g vss and 0.34 g cod - ch4 / g vss day , respectively , whereas those in the sludge zone were not much changed . the most represented species of methanogens were the acetoclastic methanosaeta , the hydrogenotrophic methanobacterium sp . , and the hydrogenotrophic methanomicrobiaceae ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: cardiac hypertrophy was induced by many kinds of physiological and pathophysiological stimuli , including exercise , pressure or volume overload , endocrine disorders , and valvular heart diseases . although it has been viewed as a temporary compensatory mechanism for hearts to diminish wall stress , cardiac hypertrophy is associated with increased risks of developing decompensatory heart failure . hearts consume more energy than any other organs to maintain excitation - contraction coupling . as a result , common heart diseases , either myocardial ischemia or myocardial infarction , were characterized by energy metabolism dysregulation . it has been demonstrated that fatty acid utilization was decreased significantly , resulting in energy insufficiency that exacerbated the progression of heart diseases . the reduction in fatty oxidation led to the abnormal accumulation of intracellular lipid , which could be lipotoxic to hearts . mitochondria provide atp to hearts for preserving contractile and relaxation functions through conversion of metabolism substrates to usable energy . thus , it is of great importance for hearts to maintain structure integrity and functional performance of mitochondria , as well as the efficiency in utilization of fatty acid . inducements of cardiac hypertrophy are of great complexities . the retention of salt and water , as well as excessive peripheral vasoconstriction , was to blame for the disease progression . andprior to overtly symptomatic decompensatory cardiac hypertrophy , sympathetic nervous system ( sns ) activation was induced to increase the cardiac output at the onset of heart disease ; however , the persistent stimulation of neurohormonal factors contributes to the mechanical dysfunction of hearts ultimately . it had been demonstrated that overexpression of biologically active neurohormonal molecules contributed to the progression of decompensated cardiac hypertrophy independently of the hemodynamic status , by virtue of the direct toxic effects of these neurohormonal molecules exert on hearts . in addition to its direct cardiac effect , isoproterenol was proved to have a cardiac trophic effect via stimulation of the renin angiotensin system ( ras ) . rapamycin is a clinically used immunosuppressor in preventing transplant rejection and restenosis in coronary arteries following balloon angioplasty . recently , rapa was demonstrated to ameliorate cardiac remodeling and improve the left ventricular function after myocardial infarction . besides , it has been reported that rapa regressed left ventricular hypertrophy in renal transplant recipients regardless of blood pressure changes , suggesting nonhemodynamic - effect mechanisms of rapamycin on left ventricular mass . thus , it is worthy of investigation that whether the treatment of rapa was capable of regressing cardiac hypertrophy induced by persistent stimulation of sympathetic nervous system . andthe underlying mechanisms of rapa in protecting against cardiac hypertrophy induced by isoproterenol remain to be elucidated . based on these considerations mentioned above , we established the rat model of cardiac hypertrophy induced by isoproterenol , and then rapa was administrated to evaluate the cardiac function and mitochondrial functional performance . in this study , rapa was observed to attenuate isoproterenol - induced cardiac hypertrophy and maintain energy homeostasis in adult rats . increased levels of proinflammatory cytokineswere detected in cardiomyocytes in response to isoproterenol , which could be substantially attenuated by rapa . moreover , these protective effects of rapa might be attributed to the inactivation of nf - b . the present data revealed that the role of rapa in protecting hearts from isoproterenol - induced cardiac hypertrophy and maintaining energy homeostasis was dependent on nf - b pathway . male sprague - dawley rats weighing 225 g to 250 g were purchased from animal breeding center of sun yat - sen university . isoproterenol ( 5.5 mg / kg , merck ) dissolved in saline was injected subcutaneously for consecutive ten days . control animals underwent the same procedure , except that saline vehicle was injected subcutaneously instead of isoproterenol . after the infusion of isoproterenol , rats surviving were assigned to the following groups randomly : a vehicle - treated group ( vehicle , n = 6 ) , a rapamycin - treated group ( 1.2 mg / kg , selleck ; n = 6 ) the doses we administrated here were comparable with those used in mice studies when normalized by body surface area . the experiments were approved by the ethics committees of sun yat - sen university of medical science . rats were anesthetized with 2 % isoflurane allowing spontaneous breathing . the vevo 2100 scanner equipped with a 16 mhz probe ( visual sonics , toronto , canada ) was used to perform echocardiography analysis . after a good - quality two - dimensional image was obtained , m - mode images of left ventricles were recorded . left ventricular anterior and posterior wall thickness ( lvaw and lvpw ) , fractional shortening ( lvfs ) , and ejection fraction ( lvef ) were measured and analyzed . once all rats were sacrificed , the hearts were washed with pbs and dried to weigh and fixed within 4 % paraform overnight . paraffin - embedded sections ( 7 m ) were stained with hematoxylin and eosin . the mean myocyte diameter was calculated by randomly measuring 100 cardiomyocytes in 10 randomly chosen fields according to method and criteria reported . cardiac tissues were cut into 1 mm cubes immediately after sacrifice and fixed in 2.5 % glutaraldehyde and then postfixed in 1 % osmium tetroxide . images were taken at 120 kv with jem1400 electron microscopy equipped with a high - performance ccd camera . hearts were freshly excised , and the apex of left ventricle ( 200 mg ) was obtained from hearts in three experimental groups . then fresh mitochondria were isolated using mitochondria extraction and isolation kit ( genmed scientifics ) according to the manufacturer 's instruction . clark - type oxygen electrode ( strathkelvin , scotland ) was used to determine the rate of mitochondrial respiration ( 25c ) . following the addition of 1 mm adenosine diphosphate ( adp ) , the state iii respiration was recorded . after the complete phosphorylation of the added adp , the state iv respiration was recorded as well . the respiration control rate ( rcr ) , which reflects the function of mitochondria , was represented by the ratio of rate of state iii respiration to the rate of state iv respiration . the rates of oxygen consumption were expressed as nmol o2 / min / mg . according to the manufacturer 's instruction , myocardial rna was extracted from snap - frozen tissues with trizol reagent ( invitrogen ) . the sybr - green quantitative pcr kit ( takara ) was used to determine the mrna expression levels of each target gene by icycler iq system ( bio - rad ) . gapdh and - actin served as an endogenous control . using an atp bioluminescent assay kit ( sigma ) , experiments were done in triplicate for each group . using a commercial available nuclear and cytoplasm extraction kit ( active motif ) , nuclear proteins were isolated from left ventricles of rats or primary neonatal rat ventricular cardiomyocytes . the homogenate proteins were separated on sds - page and then transferred to pvdf membrane ( millipore ) . the membranes were incubated with primary polyclonal antibodies against p65 ( cell signal technology ) , ib - ( cell signal technology ) , histone - h3 ( sigma ) , p - mtor ( cell signal technology ) , mtor ( cell signal technology ) , ppar ( sigma ) , pgc - 1 ( calbiochem ) , gapdh ( sigma ) , and - tubulin ( sigma ) overnight at 4c . after washing in tbs - t buffer , the second antibodies ( promega ) were conjugated at room temperature , and then protein bands were visualized using enhanced super - signal west pico substrates ( pierce ) . primary culture of neonatal rat ventricular cardiomyocytes was prepared using 1 - to 3 - day - old sprague - dawley rats as methods we reported .48 hours later , the serum - containing culture medium was replaced with dmem containing 0.1 % fbs . after incubation for 24 hours , the cells were further treated with isoproterenol ( 1 mol / l ) , or in combination with rapamycin ( 100the small interference rna ( sirna ) sequences against rat nf - b p65 subunit were synthesized by genepharma . nf - b p65 antisense sequences were 5 - ucuaugggaacuugaaaggtt - 3 ; the scrambled sequence was used as a negative control ( nc ) . small interference rna ( 100nmol / l ) was transiently transfected into cardiomyocytes by adding it to lipofectamine 2000 ( invitrogen ) according to the manufacturer 's instructions . the knockdown of p65 protein expression was confirmed by western blot analysis . an elisa kit ( dakewe ) was used to determine the concentrations of il - 1 , il - 2 , and tnf - in the culture medium according to the manufacturer 's instructions . to determine the cell surface area , cells were fixed with 4 % paraform and then permeabilized within 0.5 % tritonx - 100 , after which cells were incubated with tritc - labeled phalloidin ( sigma ) for 30 min at room temperature as methods reported . tmre ( 10 nmol / l ) , a mitochondrial potential - indicating fluorophore ( invitrogen , molecular probes ) , was added to cells for 30 min , after which cells were visualized under confocal laser scanning microscopy ( lsm710 , zeiss ) . data were expressed as mean sd . all results were obtained from three independent experiments . statistical significance of difference among experimental groups was assessed with one - way analysis of variance ( anova ) followed by the bonferroni post hoc test . the level of p 0.05 was considered to be statistically significant in all cases . we first determined whether the treatment of rapa after consecutive isoproterenol - infusion for ten days reverses indices of myocardial hypertrophy . the ratios of heart weight to body weight ( hw / bw ) and left ventricular weight to body weight ( lvw / bw ) were significantly upregulated in isoproterenol - infusion model group compared with those in control group ( p 0.01 versus control ) . as shown in figure 1 ( a ) , rats treated with rapa reduced the isoproterenol - induced increase in the ratios of both hw / bw and lvw / bw significantly ( hw / bw : 2.460.35 versus 3.150.39 ; p 0.01 versus model ; lvw / bw : 1.660.28 versus 2.400.55 ; p 0.01 versus model ) . histological analysis revealed that hearts under isoproterenol stimulation demonstrated direct evidence of increased mean myocyte diameters , which was reversed in the rapa - treated hearts ( figures 1 ( b ) and 1 ( c ) ) . consistently , echocardiographic analysis showed that rapa reduced the isoproterenol - induced increases in the thicknesses of left ventricular anterior and posterior walls during systole ( lvaws , lvpws ) ( lvaws : 2.520.21 versus 3.220.20 ; p 0.001 versus model ; lvpws : 2.800.27 versus 3.220.16 ; p 0.05 versus model ) . on the other hand , the cardiac function , which was represented by lvef and lvfs , was not changed ( p = ns versus model ) ( figure 1 ( d ) ) . additionally , real - time pcr analysis was performed to quantify the expression of hypertrophic marker genes including anf , bnp , and - mhc ( figure 1 ( e ) ) . as expected , levels of anf , bnp , and - mhc mrna were increased about 2-fold in model group ( p 0.05 versus control ) . in contrast , rapa treatment significantly decreased the expression of these marker genes , comparing with the model group ( p 0.05 versus model ) . tem analyses were used to examine the ultrastructures of mitochondria . as seen from figure 2 ( a ) , disorganized cristae and vacuoles of mitochondria were observed in the hypertrophied hearts ; in contrast , the structure of mitochondria was well organized and the cristae stayed intact and evident in rapa - treated hearts . in the hypertrophied hearts treated with rapa , state iii respiration rates were significantly increased compared with those in hypertrophied hearts ( p 0.01 versus model ) . this meant the dysfunction of mitochondria in the hypertrophied hearts could be attenuated by rapa treatment ( figure 2 ( b ) ) . consistently , the production of atp was significantly decreased in the hypertrophied hearts infused with isoproterenol , which was substantially reversed by rapa treatment ( 67.7410.04 versus 49.7811.09 , p 0.05 versus model ) ( figure 2 ( d ) ) , suggesting that the efficiency of energy supply was maintained by rapa . in order to investigate the role of rapa in regulating fatty acid metabolism genes in hypertrophied heartsas shown in figure 2 ( e ) , the treatment of rapa prevented the declines in representative metabolic target genes associated with fatty acid metabolism , including carnitine palmitoyl transferase - 1 and -2 ( cpt - 1 and cpt - 2 ) , and medium - and long - chain acyl - coa dehydrogenase ( mcad and lcad ) ( p 0.05 versus model ) . upon activation by hypertrophic stimuli , p65 , the subunit of nf - b , rapidly enters the nucleus , which resulted in elevated expression of hypertrophic genes . we next examined the effects of rapa treatment on the nuclear translocation of p65 and the degradation of ib - in adult rats . the persistent stimulation of isoproterenol significantly promoted the translocation of p65 from cytoplasm to the nucleus , which were prevented by rapa treatment ( p 0.05 versus model ) ( figures 2 ( f ) and 2 ( g ) ) . consistently , as shown in figures 2 ( h ) and 2 ( i ) , the degradation of ib - was detected to increase in response to isoproterenol stimulation ( p 0.05 versus control ) , and this effect can be reversed by rapa ( p 0.05 versus model ) . p65 was knocked down in neonatal rat cardiomyocytes using sirna , and tnf - , a cytokine known to activate nf - b signal pathway , was used to further clarify the role of nf - b in the protective effects of rapa in cardiomyocytes . it has been shown that the protein expression of p65 in cultured cardiomyocytes was increased by tnf - in a concentration - dependent manner by western blot analysis ( see supplementary figure 1 ( a ) in supplementary material available online at http://dx.doi.org/10.1155/2014/868753 ) , and p65 depletion was proved to decrease the protein expression of p65 ( supplementary figure 1 ( c ) ) in cardiomyocytes . to investigate whether the activation of the nf - b pathway is implicated in proinflammatory gene expressions and cytokines releases induced by isoproterenol , the extracellular production of cytokines was measured by elisa . as shown in figures 3 ( a ) , 3 ( b ) , and 3 ( c ) , releases of il - 1 , il - 2 , and tnf - were significantly induced by isoproterenol ( p 0.01 versus control ) . in contrast , the administration of rapa to cardiomyocytes attenuated the increases in releases of proinflammatory cytokines ( p 0.05 versus model ) , and this effect could be abrogated by tnf - ( 20 ng / ml ) . then real - time pcr analysis was performed to quantify the expression of representative cytokine genes . the stimulation of isoproterenol led to increases in mrna levels of il - 1 , il - 2 , and tnf - ( p 0.05 versus control ) , which could be reversed by rapa ( figure 3 ( d ) ) . furthermore , it was revealed that this downregulation of proinflammatory cytokines by rapa was reversed by tnf - ( 20 ng / ml ) , whereas the anti - inflammatory effect of rapa was preserved when nf - b / p65 was depleted in cardiomyocytes . in order to explore whether the activation of the nf - b pathway is implicated in the underlying mechanism of the inhibitory effects of rapa on cardiac hypertrophy , immunofluorescence analyses and real - time pcr analyses were performed in primary cultured neonatal cardiomyocytes . as shown in figures 4 ( a ) and 4 ( b ) , the surface area of cardiomyocytes , as well as mrna levels of hypertrophied maker genes , was increased significantly in response to isoproterenol stimulation for 24 hours ( p 0.05 versus control ) . in contrast , the administration of rapa to cardiomyocytes attenuated the increases in hypertrophy biomarkers ( p 0.05 versus model ) , and this protective effect could be abrogated by tnf - ( 20 ng / ml ) . in contrast , this antihypertrophic effect of rapa was maintained after p65 depletion in cardiomyocytes . these results suggested the involvement of nf - b inactivation in the protective effect of rapa against cardiac hypertrophy induced by isoproterenol . to investigate the role of nf - b pathway in preserving mitochondrial function in cardiomyocytes , tmre , a sensitive fluorescent probe that reflects the level of membrane potential , were used to assess the capacity of mitochondria to produce atp . as seen from figure 4 ( c ) , a significant loss of membrane potential was shown in cardiomyocytes treated with isoproterenol ( p 0.001 versus control ) , which could be abolished partially by rapa ( p 0.01 versus model ) . consistent with tmre staining , the atp production in cardiomyocytes was decreased notably in response to isoproterenol stimulation , compared with vehicle control ( p 0.01 versus control ) . andthis reduction in conversion of metabolic substrates into usable energy can be substantially attenuated by rapa ( p 0.05 versus model ) ( figure 4 ( d ) ) . moreover , it was observed that the effect of rapa on preserving mitochondrial function and atp production in hypertrophied cardiomyocytes was abrogated by tnf - ( 20 ng / ml ) . in contrast , the protective role of rapa in maintaining energy homeostasis was preserved after p65 depletion in cardiomyocytes . in order to explore the mechanisms underlying the protective role of rapa in maintaining energy homeostasis , the activation of mtor , which serves as a sensor of the energy state , was determined by western blot analysis . it was observed that the administration of isoproterenol to cardiomyocytes for 24 hours decreased the phosphorylation of mtor at the site of serine 2448 ( p 0.01 versus control ) , which could be substantially attenuated by rapa ( figures 5 ( a ) and 5 ( b ) ) . furthermore , the mrna and protein expression of its downstream transcriptional factor ppar and coactivator pgc - 1 were determined . as shown in figures 5 ( c ) , 5 ( d ) , and 5 ( e ) , the downregulation of ppar and pgc - 1 in both mrna and protein levels could be inhibited by rapa ( p 0.05 versus model ) , and these effects of rapa were abrogated by tnf - ( 20 ng / ml ) . besides , the mrna levels of medium - and long - chain acyl - coa dehydrogenase ( mcad and lcad ) and carnitine palmitoyl transferase - 1 and -2 ( cpt - 1 and cpt - 2 ) were notably decreased by isoproterenol , which could be partially reversed by rapa ( p 0.01 versus model ) ; however , the effect of rapa on upregulating these genes associated with fatty acid metabolism was abrogated by the pretreatment of tnf - ( 20 ng / ml ) ( figures 5 ( f ) and 5 ( g ) ) . collectively , these results suggested the involvement of nf - b inactivation in the role of rapa in upregulating genes associated with fatty acid metabolism in cardiomyocytes treated with isoproterenol . in this study , it was demonstrated that the regression of cardiac hypertrophy by rapa in adult rat was associated with attenuation of the increases in myocyte cell size and hw / bw , without loss of left ventricular function . activated nf - b pathway was detected in the hypertrophied hearts , which was substantially reversed by rapa . moreover , rapa protected cardiomyocytes from the mitochondrial dysfunction and abnormal energy utilization , which could be attributed to the inactivation of nf - b . conversely , activation of nf - b pathway resulted in the catastrophic loss of atp production in cultured cardiomyocytes and abrogated the protective role of rapa in regressing cardiac hypertrophy . our results revealed the mechanisms underlying the protective role of rapa against cardiac hypertrophy induced by isoproterenol , suggesting that blocking proinflammatory response by rapa might contribute to the maintenance of energy homeostasis during the progression of cardiac hypertrophy . long - lived postmitotic cells , including neurons and cardiomyocytes , are most vulnerable to mitochondrial dysfunction . in order to evaluate the effect of rapa on the functional performance of mitochondria in hypertrophied hearts , rcr , which reflects the mitochondrial function , decreased significantly in the hypertrophied hearts induced by isoproterenol ( figure 2 ( c ) ) , and these functional changes were associated with evidences of structural abnormalities in mitochondria ( figure 2 ( a ) ) . and consistently , these injuries on structure and functional performance of mitochondria caused by persistent stimulation of isoproterenol could be substantially attenuated by rapa . nf - b had been demonstrated to be involved in pathogeneses of inflammatory disorders and viewed as a link between cardiomyopathy and the dysregulation of energy metabolism . in this study , we observed that the administration of rapa to the hypertrophied hearts could reverse the activation of nf - b induced by isoproterenol ( figure 2 ( f ) ) . rapa was demonstrated to inhibit mtor activity through a mechanism involving interaction with fkbp12 . and prior to our study , this inhibition of mtor was proved to suppress the activity of i - b kinase ( an essential activator of nf - b ) through a mechanism that might involve dissociation of raptor from mtor . in keeping with these observations , we found that the degradation of ib - induced by isoproterenol was substantially attenuated by rapa administration ( figure 2 ( h ) ) , thereby maintaining nf - b in an inactive state . herein , we found that the administration of isoproterenol to cardiomyocytes led to an aberrant production of varieties of proinflammatory cytokines ( figures 3 ( a ) , 3 ( b ) , and 3 ( c ) ) , which was in line with the activation of nf - b pathway induced by isoproterenol . the nuclear translocated nf - b was demonstrated to regulate the expression of various genes which encode proinflammatory cytokines including tnf - . meanwhile , the downregulation of cytokine releases by rapa was impaired under tnf - treatment , indicating that the role of rapa in restraining the inflammatory responses in cardiomyocytes under persistent stimulation of isoproterenol was nf - b - dependent . in the present study , the stimulation of isoproterenol promoted inflammatory responses in hypertrophied cardiomyocytes and rapa could partially restrain the downregulation of ppar induced by isoproterenol ( figure 5 ( a ) ) . one potential explanation to this effect of rapa in upregulating ppar may be its activity in inactivation of mtor , just as we found in the decrease in the ratio of phosphor - mtor to total mtor ( figure 5 ( b ) ) . recently , it has been reported that pharmacological or genetic inhibition of mtorc1 was able to promote the translocation of transcription factor eb ( tfeb ) to the nucleus and increase its transcription activity . more importantly , it was demonstrated that tfeb controls cellular lipid metabolism trough a mechanism of upregulation of pgc - 1 and ppar , which were proved to play prominent roles in controlling genes mediating process from fatty acid uptake to oxidation , including medium - chain acyl - coa dehydrogenase ( mcad ) and carnitine palmitoyl transferase ( cpt ) . herein , the present results revealed that the administration of isoproterenol to hearts weakened the expression of cpt - 1 and cpt - 2 , which were proved to be crucial in mediating the rate - limiting reaction of fatty acid transport , and this effect could be partially abrogated by rapa ( figure 2 ( e ) ) . moreover , clusters of genes associated with fatty acid metabolism downregulated by isoproterenol in hypertrophied cardiomyocytes were activated by rapa , which could be abrogated by tnf - . in contrast , the role of rapa in upregulating these genes was maintained by inactivation of nf - b in cardiomyocytes ( figures 5 ( f ) and 5 ( g ) ) . our observations reconciled with those findings concerning that tnf - impaired fatty acid oxidation in the heart through activation of nf - b , which underlies cardiac dysfunction and heart failure in metabolic diseases . it has been reported that the activation of s6 kinase was critical for the development of cardiac hypertrophy in response to pressure overload . and rapa was able to attenuate this induction of cardiac hypertrophy , which could be attributed to the inhibition of s6 kinase . similarly , previous in vitro studies had reported that rapa was able to attenuate angiotensin - ii - induced cardiac hypertrophy through inactivation of s6 kinase . these results indicated that the role of rapa in regressing of cardiac hypertrophy induced by pressure - overload or angiotensin - ii was associated with inactivation of s6 kinase , which plays an important role in increases in overall protein synthesis in cardiomyocytes . in the present study , we established the model of cardiac hypertrophy induced by consecutive infusion of isoproterenol to mimic the sympathetic stimulation . herein , proinflammatory response was associated with energy metabolism alterations in the model of cardiac hypertrophy induced by isoproterenol . rapa was demonstrated to ameliorate energy homeostasis in cardiomyocytes via inactivation of nf - b , thereby attenuating established cardiac hypertrophy after isoproterenol stimulation . these findings suggested that blocking proinflammatory response by rapa might contribute to the maintenance of energy homeostasis and provided rational basis for development of novel strategies to prevent cardiac hypertrophy after sympathetic stimulation . in this study , although the thickness of lvaw increased markedly in the rat model of cardiac hypertrophy induced by isoproterenol , the left ventricular function ( represented by lvef and lvfs ) was maintained . one potential explanation to this paradox might be the compensatory ability of the heart , and it would develop heart failure after the infusion of isoproterenol for longer time . and our findings were consistent with the reported data that there was no significant decrease in cardiac function of the hypertrophic heart . herein , we observed that during the compensated state of cardiac hypertrophy induced by isoproterenol , rapa was able to attenuate cardiac remodeling and maintained energy homeostasis without loss of cardiac function in adult rat . this present study reconciled with the earlier findingsthat autophagy activated by rapa reduced endotoxin - induced inflammatory responses in epithelial cells , maintaining intestinal homeostasis ultimately . interestingly , it has been reported that the administration of rapa was less effective in regressing decompensated cardiac hypertrophy in mice than compensated cardiac hypertrophy ( 40 % and 70 % regression , resp . ) . therefore , further studies are required to investigate mechanisms underlying the difference of rapa in treating cardiac hypertrophy under different states . in summary , these present in vivo and in vitro studies demonstrated the protective role of rapa in isoproterenol - induced cardiac hypertrophy , which was dependent on nf - b pathway . these findings may provide clues to the pathophysiology of proinflammatory response associated with energy metabolism alterations during the progression of cardiac hypertrophy and shed new light on the underlying mechanism of rapa in protecting hearts from cardiac hypertrophy under the persistent stimulation of neurohormonal factors .\noutput:\n" }, { "from": "agent", "value": "rapamycin , also known as sirolimus , is an immunosuppressant drug used to prevent rejection organ ( especially kidney ) transplantation . however , little is known about the role of rapa in cardiac hypertrophy induced by isoproterenol and its underlying mechanism . in this study , rapa was administrated intraperitoneally for one week after the rat model of cardiac hypertrophy induced by isoproterenol established . rapa was demonstrated to attenuate isoproterenol - induced cardiac hypertrophy , maintain the structure integrity and functional performance of mitochondria , and upregulate genes related to fatty acid metabolism in hypertrophied hearts . to further study the implication of nf - b in the protective role of rapa , cardiomyocytes were pretreated with tnf - or transfected with sirna against nf - b / p65 subunit . it was revealed that the upregulation of extracellular circulating proinflammatory cytokines induced by isoproterenol was able to be reversed by rapa , which was dependent on nf - b pathway . furthermore , the regression of cardiac hypertrophy and maintaining energy homeostasis by rapa in cardiomyocytes may be attributed to the inactivation of nf - b . our results shed new light on mechanisms underlying the protective role of rapa against cardiac hypertrophy induced by isoproterenol , suggesting that blocking proinflammatory response by rapa might contribute to the maintenance of energy homeostasis during the progression of cardiac hypertrophy ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: promoting nutritional health equity among at risk older populations in nursing homes is of importance . effective interventions that reduce the risk of undernutrition can help to ensure that people stay healthier in old age . findings from a couple of studies indicate inequity between the nutritional care provided to patients in hospitals and elderly people in nursing homes . two surveys conducted in 2007 indicate that patients in hospitals and at risk of undernutrition are more likely to get oral supplements ( 4354 % ) than elderly persons at risk of undernutrition in nursing homes ( 1419 % ) . it is plausible that appropriate nutritional care for older people in nursing homes requires educational interventions . this study is a part of a larger project that has shown , in a before during after controlled trial , that by implementing action oriented study circles ( aosc ) for the staff in nursing homes , knowledge translation ( kt ) regarding eating and nutrition was achieved in terms of instrumental outcomes ( had a positive impact both on provider behaviour and on patient outcomes ) . the means by which this was achieved is believed to be inconsistent and complex , and what occurred can be described as a black box phenomenon . it is presumed that evidence , context , and facilitation influenced the kt in the previous studies , but this remains to be explored . this study puts action - oriented study circles ( aosc ) , a pedagogical method for work based collaborative learning , and kt into a theoretical context . it also looks into the black box of kt and reveals some of its content . knowledge translationit is a challenge to achieve improvements in nutritional care in an environment that is complex and evolving , and there is a tendency to measure the success of projects only in terms of instrumental outcomes of kt ( better system performance ( care ) and measurable change in patient outcomes ( health ) ) . however , besides instrumental outcomes , also conceptual outcomes are of interest when it comes to improving nutritional care . it is suggested that research translation should be used as an intermediate outcome , while patient outcomes and provider behaviour are endpoint outcomes . it is a challenge to achieve improvements in nutritional care in an environment that is complex and evolving , and there is a tendency to measure the success of projects only in terms of instrumental outcomes of kt ( better system performance ( care ) and measurable change in patient outcomes ( health ) ) . however , besides instrumental outcomes , also conceptual outcomes are of interest when it comes to improving nutritional care . it is suggested that research translation should be used as an intermediate outcome , while patient outcomes and provider behaviour are endpoint outcomes . kt can be defined as the exchange , synthesis , and ethically - sound application of knowledge within a complex system of interactions among researchers and users to accelerate the capture of the benefits of research through improved health , more effective services and products , and a strengthened health care systemthe purpose of kt is to decrease the gap between what is known from research and knowledge synthesis , and the implementation of this knowledge by key stakeholders , in order to improve care delivery , efficiencies of the health care system and health outcomes . for instance , more research is needed that focuses on developing theory - based kt interventions and on testing their effectiveness . the organisational influence and the parihs frameworkin this study , the success of the implementation of change is believed to be linked to the nursing home organisation . thus , in order to succeed , the type of organisation and decentralised decision making , in relation to the teams , are regarded as important . a framework for successful implementation that incorporates organisational factors ( such as facilitation and context ) is the parihs framework ( promoting action on research implementation in health sciences ) , developed since 1998 . the framework can be used to theory - based kt , and to better understand the black box of implementation . according to kitson and colleagues , ais a function ( f ) of the interrelations between three key elements evidence ( e ) , context ( c ) , and facilitation ( f ) : si = f ( e , c , and f ) . the dimension evidence includes research , clinical experience , patient experience , and routine data . thus , it is important to not only consider evidence within the evidence - based medicine framework . instead , in the parihs framework , also other sources of knowledge are considered , including research evidence , clinical experience , professional craft knowledge , patient preferences and experiences , and local information . conceptualise , in relation to kt , that knowledge can be empirically derived ( research based ) but also encompass other forms of knowing , such as experiential knowledge . both local and external knowledge creation or researchfor instance , local research can be carried out in order to determine the magnitude of the problem and the care gap . the context in a care setting is made up of several factors , factors that are interdependent . among others such as leadership , culture ( prevailing beliefs , values of relationships , teamwork , power , and reward systems ) , feedback processes ( information sharing ) , and organisational slack ( human resources , space , time ) are part of the context . the subelement purpose ( in the facilitation dimension ) can be technical or holistic . facilitation refers to the process of enabling ( making easier ) the implementation of evidence into practice and facilitation is achieved by an individual carrying out a specific role ( a facilitator ) , which aims to help othersthe facilitator has an appointed role , internal or external to the organisation , in which the change is being implemented . facilitators are said to have a key role in helping teams and individuals understand what and how they need to change practice . the role of facilitator is more about helping and enabling than persuading or telling . in the two previously mentioned studies , the intervention with study circles was theory based in the parihs framework.the success of the implementation of change is believed to be linked to the professionals ' needs and motivation and to the fact that people change their behaviour on the basis of experienced problems in practice . thus , in order to achieve improved nutritional care , a pedagogical method is needed to increase professional competence , to better serve the care recipients , to meet external expectations ( including pressure from colleagues ) , and to inspire to change by learning through social interaction . action - oriented study circles might have these qualities . in this study , the success of the implementation of change is believed to be linked to the nursing home organisation . thus , in order to succeed , the type of organisation and decentralised decision making , in relation to the teams , are regarded as important . a framework for successful implementation that incorporates organisational factors ( such as facilitation and context ) is the parihs framework ( promoting action on research implementation in health sciences ) , developed since 1998 . the framework can be used to theory - based kt , and to better understand the black box of implementation . according to kitson and colleagues , asuccessful implementation ( si ) of new ideas ( evidence , guidelines , etc . ) is a function ( f ) of the interrelations between three key elements evidence ( e ) , context ( c ) , and facilitation ( f ) : si = f ( e , c , and f ) . the dimension evidence includes research , clinical experience , patient experience , and routine data . thus , it is important to not only consider evidence within the evidence - based medicine framework . instead , in the parihs framework , also other sources of knowledge are considered , including research evidence , clinical experience , professional craft knowledge , patient preferences and experiences , and local information . conceptualise , in relation to kt , that knowledge can be empirically derived ( research based ) but also encompass other forms of knowing , such as experiential knowledge . both local and external knowledge creation or research can be integrated in the knowledge to action process . for instance , local research can be carried out in order to determine the magnitude of the problem and the care gap . the context in a care setting is made up of several factors , factors that are interdependent . among others such as leadership , culture ( prevailing beliefs , values of relationships , teamwork , power , and reward systems ) , feedback processes ( information sharing ) , and organisational slack ( human resources , space , time ) the subelement purpose ( in the facilitation dimension ) can be technical or holistic . facilitation refers to the process of enabling ( making easier ) the implementation of evidence into practice and facilitation is achieved by an individual carrying out a specific role ( a facilitator ) , which aims to help othersthe facilitator has an appointed role , internal or external to the organisation , in which the change is being implemented . facilitators are said to have a key role in helping teams and individuals understand what and how they need to change practice . the role of facilitator is more about helping and enabling than persuading or telling . in the two previously mentioned studies , the intervention with study circles was theory based in the parihs framework . the success of the implementation of change is believed to be linked to the professionals ' needs and motivation and to the fact that people change their behaviour on the basis of experienced problems in practice . thus , in order to achieve improved nutritional care , a pedagogical method is needed to increase professional competence , to better serve the care recipients , to meet external expectations ( including pressure from colleagues ) , and to inspire to change by learning through social interaction . action - oriented study circles might have these qualities . action oriented study circles by adding action oriented to study circles , i want to emphasise that it is not only studies that are expected but alsoaction - oriented study circles ( aosc ) is a pedagogical method that might increase the likelihood of achieving kt , as it emphasises work - based learning in the local social context . often , different theoretical perspectives must be considered in order to develop a good kt , and using aosc makes it possible to integrate pedagogical , social , and organisational theoretical perspectives . furthermore , the study circle methodology can be linked to the parihs framework in that the facilitation aspect is very much connected to enabling self directive learning and cooperative learning approaches . facilitative learning approaches that are student centred and problem based emphasise critical reflection and focus on experimental learning , and by achieving local consensus they have the potential to enhance changes in practice culture , as well as evidence - based improvements . it started in the temperance movement , and its instigator was oscar with the beardit has since then been the core method used by the workers ' educational association ( abf ) in sweden . the idea of the study circle can be connected to vygotsky 's ideas about cultural mediation and internalisation , namely , that by interacting in a group , individuals come to share the knowledge of a culture . in this wayalso piaget 's thoughts on cooperative relations are applicable to the ideas behind study circles . in cooperative relations , power is evenly distributed between participants so that a symmetrical relationship emerges . in cooperative relations , authentic forms of intellectual exchange become possible ; each partner has the freedom to project his or her own thoughts , consider the positions of others , and defend his or her own point of view . according to piaget , the knowledge that emerges is open , flexible , and regulated by the logic of argument rather than determined by an external authority . study circles also have similarities with problem - based learning ( pbl ) , and pedagogical research has shown that learning is enhanced when the student is active . the fundamental concepts of the study circle are voluntary , informal , and participant - centred learning in which flexibility of format and structure is important . if pedagogical models are divided into the persuasion model , the information model and the discussion model , the study circle belongs to the discussion model . the discussion model means that the participants engage in conversations , identify and analyse problems , and take actions . in addition , the study circle places great emphasis on the broader environmental and social context in which individuals work and where the interventions for change are expected to occur . by using a discussion model for learning , one assumes that knowledge acquisition is a collaborative process and that individual understanding is rooted in social interaction . because of its simple , flexible structure , and its capacity to address contextual factors , the study circle could serve as a model for educational interventions in care and service . the overall aim of study circles is to identify key problems and to learn how to master them . several positive experiences have been described by participants in study circle activities arranged within the popular education framework in sweden ( folkbildning ) , such as personal development , increased self - esteem , changed ways of thinking , increased courage , learning how to study , increased social and cultural competence , and improved cooperation and solidarity . study circles are becoming increasingly popular in sweden in care and service . the swedish institute for health sciences ( vrdalinstitutet ) , for instance , has several manuals for study circles for different areas such as dementia , ethics , culture , eating and nutrition , palliative care , pain , stroke , and elderly health . however , study circle interventions in care and service have been explored only in a few studies , and some of these have focused on nutrition in nursing homes and instrumental outcomes of kt . it was shown that study circle interventions with focus on nutrition in nursing homes can improve the care ( more residents with risk of undernutrition get the right treatment ) and the care recipients ' outcome ( decreased number of residents with undernutrition ) in a short - and long - term perspective . wallin states that if we want to understand what strategies are working in changing practice to be more evidence - based , then we must test these strategies ( page 579 ) . thus , research has shown that study circle interventions improve instrumental outcomes , and now we need to show what impact they have on staff knowledge and attitudes , that is , conceptual outcomes . furthermore , wallin highlights that there is a need for examining the parihs framework through intervention studies . thus , when exploring the process of kt with focus on nutrition using the aosc methodology , it should be done in relation to a theoretical framework.this study reports on the use of aosc as an intervention to promote the conceptual use of new knowledge concerning eating and nutrition in nursing homes in sweden , using the promoting action on research implementation in health sciences ( parihs ) framework as the explanatory theoretical model . by addingi want to emphasise that it is not only studies that are expected but alsoaction - oriented study circles ( aosc ) is a pedagogical method that might increase the likelihood of achieving kt , as it emphasises work - based learning in the local social context . often , different theoretical perspectives must be considered in order to develop a good kt , and using aosc makes it possible to integrate pedagogical , social , and organisational theoretical perspectives . furthermore , the study circle methodology can be linked to the parihs framework in that the facilitation aspect is very much connected to enabling self directive learning and cooperative learning approaches . facilitative learning approaches that are student centred and problem based emphasise critical reflection and focus on experimental learning , and by achieving local consensus they have the potential to enhance changes in practice culture , as well as evidence - based improvements . it started in the temperance movement , and its instigator was oscar with the beardit has since then been the core method used by the workers ' educational association ( abf ) in sweden . the idea of the study circle can be connected to vygotsky 's ideas about cultural mediation and internalisation , namely , that by interacting in a group , individuals come to share the knowledge of a culture . in this wayalso piaget 's thoughts on cooperative relations are applicable to the ideas behind study circles . in cooperative relations , power is evenly distributed between participants so that a symmetrical relationship emerges . in cooperative relations , authentic forms of intellectual exchangebecome possible ; each partner has the freedom to project his or her own thoughts , consider the positions of others , and defend his or her own point of view . according to piaget , the knowledge that emerges is open , flexible , and regulated by the logic of argument rather than determined by an external authority . study circles also have similarities with problem - based learning ( pbl ) , and pedagogical research has shown that learning is enhanced when the student is active . the fundamental concepts of the study circle are voluntary , informal , and participant - centred learning in which flexibility of format and structure is important . if pedagogical models are divided into the persuasion model , the information model and the discussion model , the study circle belongs to the discussion model . the discussion model means that the participants engage in conversations , identify and analyse problems , and take actions . in addition , the study circle places great emphasis on the broader environmental and social context in which individuals work and where the interventions for change are expected to occur . by using a discussion model for learning , one assumes that knowledge acquisition is a collaborative process and that individual understanding is rooted in social interaction . because of its simple , flexible structure , and its capacity to address contextual factors , the study circle could serve as a model for educational interventions in care and service . the overall aim of study circles is to identify key problems and to learn how to master them . several positive experiences have been described by participants in study circle activities arranged within the popular education framework in sweden ( folkbildning ) , such as personal development , increased self - esteem , changed ways of thinking , increased courage , learning how to study , increased social and cultural competence , and improved cooperation and solidarity . the swedish institute for health sciences ( vrdalinstitutet ) , for instance , has several manuals for study circles for different areas such as dementia , ethics , culture , eating and nutrition , palliative care , pain , stroke , and elderly health . however , study circle interventions in care and service have been explored only in a few studies , and some of these have focused on nutrition in nursing homes and instrumental outcomes of kt . it was shown that study circle interventions with focus on nutrition in nursing homes can improve the care ( more residents with risk of undernutrition get the right treatment ) and the care recipients ' outcome ( decreased number of residents with undernutrition ) in a short - and long - term perspective . wallin states that if we want to understand what strategies are working in changing practice to be more evidence - based , then we must test these strategies ( page 579 ) . thus , research has shown that study circle interventions improve instrumental outcomes , and now we need to show what impact they have on staff knowledge and attitudes , that is , conceptual outcomes . furthermore , wallin highlights that there is a need for examining the parihs framework through intervention studies . thus , when exploring the process of kt with focus on nutrition using the aosc methodology , it should be done in relation to a theoretical framework . this study reports on the use of aosc as an intervention to promote the conceptual use of new knowledge concerning eating and nutrition in nursing homes in sweden , using the promoting action on research implementation in health sciences ( parihs ) framework as the explanatory theoretical model . aimthe aims were to explore nursing home staffs ' views of participating in action - oriented study circles focused on eating and nutrition , to compare participants with non - participants , and to describe goals set by study circle participants . the aims were to explore nursing home staffs ' views of participating in action - oriented study circles focused on eating and nutrition , to compare participants with non - participants , and to describe goals set by study circle participants . in this study , both quantitative methods ( structured questionnaires , comparisons between groups and over time ) and qualitative methods ( knowledge - to - action goals and focus group interviews ) were used . the quantitative data focused on the content of the aosc , the participants and non - participants self - evaluation of their knowledge about eating and nutrition , and on how they thought the management acted upon ideas regarding food and mealtimes . the qualitative methods were used to explore nursing home staffs ' views of participating in aosc and to capture the knowledge - to - action goals set by the study circle participants . the project as a whole is built up by one all - embracing knowledge - to - action process as well as by smaller action processes within each study circle . the knowledge - to - action process described in this study is based on graham et al . . first of all , the problems with nutrition were identified by a large survey of nutritional status and nutritional care in 2005 , capturing the care gap . following this , a study circle manual , with reference to relevant literature , was developed . thus , based on the manual , as well as on the findings from the survey in 2005 , the identified knowledge was adapted to the local context by the participants in aosc . in addition , each study circle had the possibility to further adapt the knowledge to their particular setting . barriers to using the knowledge were continuously assessed by regular evaluations and through dialogues with the front - line staff . within each study circle , interventions were selected , tailored , and implemented to promote the use of knowledge ( i.e. , implement the change ) . the instrumental use of knowledge was monitored in 2007 , by repeating the survey of nutritional status and nutritional care , and comparing findings with baseline data from 2005 . the conceptual use of knowledge was monitored every six months ( during the two years in which the study circles were going on ) . to evaluate whether sustained instrumental knowledge use was achieved , a final survey ( with the same methodology as in 2005 and 2007 ) was conducted in 2009 . the focus of this study was the conceptual use of knowledge . in order to evaluate the process of change andthe important ingredients in that process , both qualitative and quantitative methods were used , that is , focus group interviews and questionnaires . wallin states that qualitative research is particularly helpful in uncovering why something happens and in identifying the active ingredients of an intervention . natural experiments , in the study of kt , as it makes it possible to capture real world initiatives that otherwise are not feasible to investigate or would be too costly . the study involved 24 nursing homes ( with one to nine units in each nursing home ) and three home care areas . the number of participants from each nursing home or home care area was in median 24 ( range 674 participants ) . this study describes the results from three to some extent overlapping samples : participants ( n = 592 ) in all study circles ( 71 study circles , about 8 participants / aosc ) continuously evaluated their experiences ( structured questionnaires ) ( during spring 2006 till autumn 2008 ) ( table 1 ) . the target group for the study circles was front - line staff working in the nursing homes ( long - term care facilities ) as well as staff working in the kitchens ( table 2 ) . aosc participants ( n = 74 ) and aosc non - participants ( n = 115 ) , staff working in nursing homes attending an education day ( spring 2007 ) with focus on eating and nutrition . thus , the non - participants were those that no yet had been involved in aosc but were attending the education day.at the end of the project period ( december 2008 ) , a focus group interview was carried out with project leaders ( n = 2 ) , study circle leaders ( n = 5 ) , both leader and participant ( n = 1 ) , and participants ( n = 4 ) ( in total n = 12 ) . the managers contacted the previous aosc participants and asked if they would like to participate in the focus group . participants ( n = 592 ) in all study circles ( 71 study circles , about 8 participants / aosc ) continuously evaluated their experiences ( structured questionnaires ) ( during spring 2006 till autumn 2008 ) ( table 1 ) . the target group for the study circles was front - line staff working in the nursing homes ( long - term care facilities ) as well as staff working in the kitchens ( table 2 ) . aosc participants ( n = 74 ) and aosc non - participants ( n = 115 ) , staff working in nursing homes attending an education day ( spring 2007 ) with focus on eating and nutrition . thus , the non - participants were those that no yet had been involved in aosc but were attending the education day . at the end of the project period ( december 2008 ) , a focus group interview was carried out with project leaders ( n = 2 ) , study circle leaders ( n = 5 ) , both leader and participant ( n = 1 ) , and participants ( n = 4 ) ( in total n = 12 ) . the managers contacted the previous aosc participants and asked if they would like to participate in the focus group . inspired by kitson and colleagues ' ideas about the three key elements ( evidence , context and facilitation ) for a successful implementation of evidence and knowledge into practice , the aosc intervention is here described . a manual for the study circles was developed by elisabet rothenberg and the author of this paper ( aw ) . six themes were discussed : ( 1 ) the importance of food for the care recipient , ( 2 ) difficulties with eating , ( 3 ) routines , tools and responsibility , ( 4 ) food as medicine , ( 5 ) food hygiene and ( 6 ) when the mealtime becomes a question of life and death . in the manual , references were made to chapters in two books from the national food administration , as well as to scientifically based texts online written by researchers in the field . besides this , the staff also had access to results from the survey of nutritional status and care done in 2005 . the pedagogical method included the identification of specific nutritionally related problems that the participants decided to discuss and a brainstorming session about ways to solve the problem in their own context , at their own unit . a structured plan of action was developed in order to achieve the necessary changes , bridging the gap between knowledge and care . the participants were encouraged to use the power of the group to achieve the changes . external facilitation was provided by the project leaders for the study circle intervention and the management . the project leaders coordinated the circles and evaluated them regularly ( every six months ) . the project leaders were not involved in the study circles but could be invited to the groups for discussions . internal facilitation was provided by the study circle leaders , who acted as facilitators for the participants . the role of the study circle leader was to administer the circles , facilitate discussions , and ensure that the participants focused on the issues . the study circle leader did not need to be an expert in the focused field . as strombeck ( page 10 ) states , the function of the leader is to help promote a positive environment in which participants are encouraged to analyze , discuss and critically examine what they have read . the study circle leaders were provided training in their forthcoming role . before the first six months of study circlesthe leaders were given half a day of training , and after the six - month evaluation , it was decided that the new leaders should be given a full day of training . in addition , it was decided after six months that the management should work towards recruiting homogenous groups ( persons from the same nursing home and ward ) instead of having the groups be heterogeneous ( persons from different nursing homes and wards ) , and that instead of having six meetings that last for one and a half - hour each , there should be three meetings that last for three hours each . thus , most ( about 65 ) of the aosc had three meetings that lasted for three hours each . based on the study circle manual and related references , the individuals made decisions about the value , usefulness , and appropriateness of the particular knowledge to their settings and circumstances . the topic area , the particular knowledge to implement , was agreed upon ( local consensus ) in each study circle and arose from the awareness that there was a need to improve the older persons ' experiences from mealtimes and outcomes relating to nutrition . each of the study circle teams was required to define the problem , work on how to create a potential for change , and then hopefully improve the older persons ' experiences and outcomes . . what knowledge to implement could vary from circle to circle , and it was not at all stressed that they should focus on screening for undernutrition and on what measures to take for those who were at risk for undernutrition , that is , the outcomes measured in the previously mentioned two studies of which this study is a part . structured questionnaires after each study circle , focusing on content , level of difficulty , and knowledge were used ( sample a ) . the participants retrospectively rated their knowledge , thus , they rated their knowledge before the intervention and after in the same questionnaire . besides this , qualitative data regarding goals for quality improvements set within each study circle ( n = 71 ) were collected . in addition , a questionnaire was given to participants attending an education day ( sample b ) . they filled in the questionnaire before the education began . both staff that previously had been aosc participants ( n = 74 ) and staff that no yet had been involved in aosc ( n = 115 ) answered the questionnaire that focused on knowledge development and perception of management engagement . within the focus group ( sample c ) , each participant gave written consent to participate and agreed to have the interview tape - recorded . the interview was transcribed verbatim and analysed using conventional and directed content analysis . parametric and non - parametric statistics were used depending on the level of data and based on unpaired comparisons between two groups . the following tests were applied : t - test , chi - square test , wilcoxon signed ranks test , and mann whitney u test . conventional ( latent and manifest ) and directed content analysis was chosen as the method of analysis for the focus group interviews in order to clarify deeper or latent meanings in the text . both manifest and latent content analysis include an interpretation of the text material , although both vary with regard to interpretation depth and abstraction level . the text was read several times in order to gain an overall understanding . on the basis of the first readings , distinguished patterns emerged from the texts . these first thoughts and reflections on the text contents were recorded in the margins and were used continuously during the remaining stages of the analysis . step - by - step , the material was analysed with the aim of the study in mind . meaning units were then identified , that is , assertions from the contents of the text . meaning units with similar content were organised into different areas ( categories ) with the study aim in focus . the meaning units were condensed ( the sentences were shortened while preserving the core ) . subcategories were created for sorting out the analysed material . at the last stage , the subcategories were linked together into two main categories that in turn were linked to a core category . afterwards , the concepts from the parihs framework were deduced to the qualitative findings ( directed content analysis ) . categories at different levels were ordered in relation to evidence , context , facilitation and successful implementation . both verbal and written information were given and respondents were guaranteed confidentiality ( no personal identification numbers or names were collected ) . within the focus group , each participant gave written consent to participate and agreed to have the interview tape recorded . as the study was part of an overall quality development project , no formal approval by an ethical committee was required , according to the swedish act concerning the ethical review of research involving humans . during three years ( 20062008 ) , 592 persons from 24 nursing homes participated in the study circles , according to the filled - in and returned questionnaires . there were 71 study circles in total with an average of eight persons per circle ( table 1 ) .566 women ( 96 % ) and 26 men ( 4 % ) participated , with a mean age of 45 years ( min 20 , max 66 , q1q33951 years ) . the most common profession participating in study circles was auxiliary nurses or nursing assistants ( 80 % ) . most participants had been working in their current line of work for more than 20 years ( table 2 ) . the most common combination of staff in each circle was one person working in the kitchen , who usually also was the circle leader , and seven auxiliary nurses or nursing assistants . the staff members attending each study circle usually came from the same unit , except during the first six months of study circles ( six study circles ) . of those attending the study circles , 98 % regarded the content as interesting / very interesting , 94 % thought that it was relevant / very relevant and 92 % considered that the difficulty level was easy / neither difficult or easy ( table 2 ) . when participants retrospectively rated their knowledge about food and nutrition before and after having participated in the study circle , there was a significant improvement . before the study circle , 72 % stated that they had sufficient or great knowledge and afterwards 96 % stated the same thing ( table 3 ) . the action orientation of the study circles included the identification of specific nutritionally related problems that the participants decided to discuss and brainstorm in order to find ways to solve the problem in their own context , at their own unit . a structured plan of action was developed by the participants in order to achieve the necessary changes . thus , each study circle worked with setting goals to work towards within each group 's workplace . these goals could be grouped into environment , food , hygiene , routines , shortening overnight fast , the ability to choose , and cooperation ( table 4 ) . in total 189 structured questionnaires were returned during the education day and it is unclear how many did not answer them . there were no differences in age , gender , or in number of years in current workplace between aosc participants and non - participants . however , there was a significant difference in professions , with more cook / kitchen helpers and less registered nurses among the aosc participants ( table 5 ) . more among those who had participated than among those who had not participated in the study circles agreed totally / partly that the management was engaged in and took care of ideas regarding food and mealtimes ( 80 % and 66 % , p - value = 0.009 ) . in addition , more of those who had participated in study circles than among those who had not felt that they had great or sufficient knowledge about the field ( 69 % versus 63 % , p - value = 0.044 ) ( table 5 ) . the analysis of the focus group interview with project leaders ( n = 2 , one man and one woman ) , circle leaders ( n = 5 , all women of whom two worked in kitchen ) , and participants ( n = 4 , all women ) in the study circles resulted in one core category : nutritional knowledge translation expressed as going from feeding to serving . this core category captures an awareness that includes both the meaning of the mealtime environment , being together , and staff that is service minded , lays the table and presents the food in an appealing way . it also captures the two categories that it was built up from ( table 5 ) . socioculturally mediated knowledge spread.facilitation of knowledge spread and sustainability socioculturally mediated knowledge spread . facilitation of knowledge spread and sustainability the main impression from this category was that the socio - culturally mediated knowledge spread contributed to a shared vision among the staff . this category was built up from three subcategories ( table 6 ) . together and from the same place we are stronger.getting together broadens one 's perspective and improves the work atmosphere.through discussions , the gap between knowledge and practice can be bridged . together and from the same place we are stronger . the participants expressed both that one person achieves less change than many and that one study circle achieves less change than many . one swallow does not make a summer can here be used as a metaphor ( developed by the researcher ) to illustrate that one single person who attends a training was described as having difficulties in achieving changes in the workplace . staff members say that attending a training day as the only representative from their workplace made it difficult to gain interest and understanding for what they had learned and what they wanted to change . it became clear that the staff experienced the study circle as the superior method , since it meant that several persons from the same setting came together and discussed and set goals that were adapted to their own workplace , their own context . in addition , many participants expressed a preference for homogenous groups rather than heterogeneous groups . study circles with participants from different workplaces made it difficult for participants to mutually agree on the same goals , and more difficult to communicate the goals to their own workplace . rings on the water can be used as a metaphor to say that the more study circles that had taken place at the same workplace , the greater was the possibility of achieving positive changes . to summarise , together and from the same place we are stronger . broadening one 's perspective signifies that the participants in the study circles experienced a greater understanding for each other and each other 's work tasks , saw new dimensions of their work , and communicated more with each other . the understanding between the staff improved , especially between those working in the ward and those working in the kitchen . the work atmosphere improved . the participants felt that the gap between knowledge and practice could be bridged through the discussions in the study circles . the ward culture and personal engagement were thought to have improved as a consequence of the knowledge - focused discussions between colleagues . the staff felt that they had gained a deeper knowledge about food and mealtimes , knowledge that was based on evidence and the groups ' experiences , and not only on the individuals ' own experiences . they also said that they had changed their attitudes regarding the food , from being negative to being more positive . the food and mealtime was regarded more and more important . in addition , they described how incorrect routines or a negative ward culture could be improved through relearning . facilitation of knowledge spread and sustainability was built up from three subcategories ( table 6 ) : action - oriented goalsfacilitation by anchoring and feedbackfacilitation of sustainability action - oriented goals facilitation by anchoring and feedback facilitation of sustainability it was seen as valuable to set and evaluate goals within the study circles . at wards where there had been many study circlesparticipants also described different ways of making the staff more aware of the goals , for instance , to write down all goals in a document that was framed and hung in a place where everyone could see it . staff members also talked about how they informed new staff and substitutes about the goals . many improvements were also described as being an effect of the set goals , improvements that for instance meant a calmer and more homelike mealtime environment , and better measuring and followup of weight , and so forth . a lot of information and persuasion were required in order to make the management understand the importance of the study circles . when management got feedback of the results from each six - month evaluation , their motivation to support and back up the intervention increased . facilitation of sustainability in order to maintain and achieve new improvements in practice was mainly focused on the time after finishing the project . it was clear from the focus group interviews that both the study circle participants and the leaders wanted to maintain and further develop the improvements that were initiated or achieved from the study circles . suggestions were put forward regarding how the work could be continued , for instance , by discussing food and mealtimes at workplace meetings and to continue with study circles for those who had still not participated in any ( table 6 ) . the deductive / directed content analysis , using the parihs framework , of the findings from the conventional / inductive analysis showed that the category socio - culturally mediated knowledge spread related to the components context and evidence , while the categoryfacilitation of knowledge spread and sustainability was related to the two categories facilitation and evidence . study circles focusing on eating and nutrition were found to have a positive effect on learning and the workplace context ( conceptual use of knowledge ) . in an earlier study , the study circle intervention was shown to also have positive effects on nutritional care and on care recipients ' nutritional status ( instrumental knowledge use ) . the study circle intervention seems to give quality improvements leading to professional development ( learning ) , better system performance ( care ) , and better patient outcomes ( health ) , by integrating evidence , context , and facilitation in the efforts to achieve kt . different methods were used to evaluate the effects of study circles . in some cases , the findings from using one methodfor instance , through the focus group interview some results found through the quantitative continuous evaluations were confirmed . it could be seen as a shortcoming that the results are based on the staff 's self - reflections , for instance , when it comes to reflecting on one 's own knowledge development retrospectively . anyhow , this result was indirectly confirmed when comparing the results of those who had participated in the intervention and those who had not , and it was confirmed by the focus group interviews . another example of what could be studied more directly is the improvements related to the working place context , for instance better working routines and work atmosphere . however , staff members are a part of and create the working place context , and their views are important to capture . in addition , some actual improvements in the provided care were described in the previous studies . even so , it seems worthwhile to conduct more studies directly focusing on the actual interaction between team members and between staff and care recipients during an intervention with study circles . in the efforts to achieve a successful implementation , it is of utmost importance to consider the context and the power of teamwork . this was evident in several ways in the results , not the least in the categorythus , the systematic implementation of study circles creates a favourable context , including workplace climate , that also leads to a more positive view among management and staff of what the circles can achieve for individuals , for the team , and for the care recipients . improving teamwork is not easily achieved by traditional methods , and single interventions have limited impact in kt . in this study , using multifaceted interventions , it was found that skills were developed within the study circles , by the teams , and that this in time could develop the overall capacity of the organisation , allowing further improvements . in a study by zeitz et al . , it was found that the complexity behind the so - called simple care ( providing warm drinks , appetizing food , energy enriched food , and oral supplements ) relied on the active management and broader transformation of the system . in order to achieve improvements in such pragmatic issues as giving care recipients good nutrition , organisational aspects had to be tackled , such as teamwork , communication processes , and organisational and individual values and beliefs . when using aosc as an intervention method , it is important to have homogenous groups and to understand that more study circles in the same workplace can possibly lead to better transformation of the system . aosc seems to be an optimal pedagogical method that gives priority to the context in order to achieve kt . these conceptual outcomes of kt are most likely generalizable also to other care settings implementing aosc with focus on nutrition and eating . the focus on eating and nutrition , and the fact that the staff came together in the study circles , contributed to competence development and led to positive outcomes . overall , participants experienced a high degree of satisfaction through participating in the study circles . this could be attributed to the format of the study circle , which provided the opportunity for participants to engage in sustained and meaningful discussions about eating and nutrition . it might , however , come as a surprise that the work atmosphere improved through an intervention focusing on improving nutritional care . there could be at least two reasons for this : first of all that the staff came together from the same workplace , and secondly that the focus was on eating and nutrition . in another study , food seemed to be a medium through which other themes were discussed , for example respect , teamwork , communication and redesigning systems of care delivery . thus , the successful conceptual outcome could be due to both the aosc and the actual focus within these , that is , an integration of context and evidence . this might in turn strengthen the fact that the directed content analysis connected both the parihs concept context and evidence to the category socio - culturally mediated knowledge spread . also , gougoulakis states in a thesis that learning in study circles is socio - culturally conditioned knowledge is created and grows in the meeting and communication with others in study circles . in this perspective , knowledge is not something that is only registered . instead , it is developed in collaboration , relates to the participants ' context , and a propitious learning atmosphere that comes about when participants have an exchange without competition . by attending study circlesfor instance , when staff retrospectively self - rated their knowledge , before and after attending the study circles , a significant improvement was indicated . in addition , the participants in the sc considered their knowledge more sufficient than what non - participants rated . thus , in study circles a socio - culturally mediated knowledge spread , including collaborative learning , takes place that can form the basis for kt and quite likely a successful implementation of evidence . in order to be successful in the kt , staffthe intervention needed to be anchored in the management and the management received feedback that in turn made them more eager to support the intervention . anchoring and feedback ( every six months ) was provided by the project leaders . participants experienced that the management was engaged in and took care of ideas regarding food and mealtimes to a greater extent than what the non - participants experienced . in addition , the need for facilitation was evident in the category facilitation of knowledge spread and sustainability . a full - day training in the study circle leader role was effective in helping them to get the group to focus on the tasks for the circle , which in turn most likely enhanced learning in the group . there were no experts involved in the study circles , which might have contributed to the high degree of satisfaction , as the power was evenly distributed between participants and symmetric relationships emerged , corresponding to piaget 's ideas about cooperative relations . this contributed to better communication between staff at the unit and staff working in the kitchen . from a project leader perspective , there needed to be a balance between structuring the process of study circles and enabling teams to maintain ownership and control . it might be that if the study circles had a more explicit focus on nutritional screening and management of residents with nutritional risk , the instrumental outcomes would have been even better than found in previous studies . however , this could be at the cost of conceptual outcomes , that is , understanding , knowledge , and attitudes . correspondingly , not only improvements in knowledge but also in the perception of how work was carried out , in the view of care recipients , working atmosphere and cooperation were described . the study circle participants and leaders wanted to continue the work , and felt that the work had only just begun similarly to what was found in a study by wiechula et al . . also it most likely did continue to some extent , as some positive instrumental outcomes ( provision of energy enriched food and / or oral supplements ) were seen also one year after the project ended . thus , facilitation from different levels in the organisation , together with regular evaluations and feedback from project leaders , is likely to contribute to a learning organisation , and it needs to continue also after the project has been completed . in the concept a learning organisationthe two parihs concepts facilitation and evidence get connected , as it is also evident in the category facilitation of knowledge spread and sustainability found in this study . by making the study circlesaction oriented , several positive effects are achieved . besides the findings in this paper , also a few earlier studies have shown positive effects , both in the care provided and for the care recipients . the parihs framework can be used to understand the interactions and complexities involved in kt activity . the positive changes achieved can possibly be attributed to the fact that complex interventions were developed in the study circles that fit the local contexts . melding and implementing evidence involves negotiation and shared understanding . in addition , the need to consider the context in order to achieve quality improvements as emphasised by kitson and colleagues is supported by the findings from this study . kt in nursing homes is a complex and challenging activity . through action - oriented study circles , priority is given to the staff 's experiences , feelings , values and beliefs , and teamwork when striving towards quality improvements . knowledge to action is achieved through socio - culturally mediated knowledge spread , including collaborative learning , and through facilitation of knowledge spread and sustainability in a learning organisation . the study circle seems to be an outstanding pedagogical method for getting staff in care and service from the same unit , in the same context , to focus on a specific knowledge area . by making study circlesaction oriented , several positive effects can be achieved for the staff 's learning , team collaboration , care provision , and most importantly , for the care recipients ' health . the findings from this study have implications for other care settings implementing aosc with focus on eating and nutrition .\noutput:\n" }, { "from": "agent", "value": "background . action - oriented study circles ( aosc ) have been found to improve nutrition in 24 nursing homes in sweden . little , however , is known about the conceptual use of knowledge ( changes in staffs ' knowledge and behaviours ) . methods . qualitative and quantitative methods , structured questionnaires for evaluating participants ' ( working in nursing homes ) experiences from study circles ( n = 592 , 71 aosc ) and for comparisons between aosc participants ( n = 74 ) and nonparticipants ( n = 115 ) . finally , a focus group interview was conducted with aosc participants ( in total n = 12 ) . statistical , conventional , and directed content analyses were used . results . participants experienced a statistically significant increase in their knowledge about eating and nutrition , when retrospectively comparing before participating and after , as well as in comparison to non - participants , and they felt that the management was engaged in and took care of ideas regarding food and mealtimes to a significantly greater extent than non - participants . the use of aosc was successful judging from how staff members had changed their attitudes and behaviours toward feeding residents . conclusions . aosc facilitates professional development , better system performance , and , as shown in previous studies , better patient outcome . based on a collaborative learning perspective , aosc manages to integrate evidence , context , and facilitation in the efforts to achieve knowledge translation in a learning organisation . this study has implications also for other care settings implementing aosc ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: given the complexity of natural organic matter ( nom ) in environmental matrices , it is has been difficult , over years , to determine its characteristic behaviour in water systems . studies in the last decade , however , have shown that nom is made up of fractions that include biopolymers , humic substances , building blocks , low molecular weight neutrals , and low molecular weight acids . this information is of particular importance because of specific chemical moieties or nom fractions have been shown to have different interactions with other components in water , for example . the low molecular weight acids are of particular interest because they influence water chemistry ( ph , ionic strength , and divalent cations ) , dipole - dipole interactions hydrogen bonding , and complexation reactions . undoubtedly , these considerations would make the extraction of these acids challenging . in order to choose the most appropriate extraction method that will be desirably recover most aliphatic and aromatic carboxylic acids from water , this research provided essential preliminary assessment on selected solid phase extraction methods . clearly , the determination of carboxylic acids in water calls for an effective primary extractive stage before chromatographic analysis . some of the extraction approaches reported in literature include precipitation , conventional electro - dialysis , the liquid - liquid extraction and solid phase extraction ( spe ) . despite all the advantages of the above mentioned methodsfor example , the liquid - liquid separation techniques use solvents whose distribution coefficient are low . a number of spe sorbents that extract carboxylic acids in water are commercially available the liquid chromatography with organic carbon detection ( lc - ocd ) , in this study , provided information on the changes in hydrophobicity / aromaticity of nom after the spe separation . this would in turn confirm the removal of the carboxylic acids from water . in this present work , we aimed to assess the extraction efficiencies of silica , c - 18 and strata x resins for recovery of aromatic and aliphatic acids in raw water used for cooling purposes in typical power generating stations in south africa . in addition , the aromatic / hydrophobic characteristics of the water before and after spe extraction were compared . clearly , the determination of carboxylic acids in water calls for an effective primary extractive stage before chromatographic analysis . some of the extraction approaches reported in literature include precipitation , conventional electrodialysis , the liquid - liquid extraction , and solid phase extraction ( spe ) . despite all the advantages of the above - mentioned methods , they still suffer from shortcomings . for example , the liquid - liquid separation techniques use solvents whose distribution coefficients are low . a number of spe sorbents that extract carboxylic acids in water are commercially available . few studies , however , report on extraction of carboxylic acids followed by chromatographic determinations . the liquid chromatography with organic carbon detection ( lc - ocd ) , in this study , provided information on the changes in hydrophobicity / aromaticity of nom after the spe separation . this study sought to assess the extraction efficiencies of silica , c - 18 , and strata x resins for recovery of aromatic and aliphatic acids in raw water used for cooling purposes at eskom , south africa . in addition , the aromatic / hydrophobic characteristics of the water before and after spe extraction were compared . this is part of a larger study that seeks to characterize nom in cooling water , a step forward in building up databases of significant nom fractions ( including carboxylic acids ) , which govern chemical reactions that control scale formation in pipes . eventually , an effective modelling strategy could be developed to monitor these reactions in water , at different physicochemical conditions with the view of scale minimization . the latter was used to assess the hydrophobicity / hydrophilicity levels of nom as a function of these carboxylic acids in industrial cooling water . in the present study , silica based c - 18 , silica , and strata x resins were employed in the extraction of aliphatic and aromatic carboxylic acids prior to their gc gc - tofms determination and lc - ocd assessment . some of these ( acetone , methylene chloride , tetrahydrofuran , and methanol ) were obtained from merck ( darmstadt , germany ) , while others ( n - hexane and n - propanol ) were obtained from sigma aldrich ( germany ) . the strata x and c - 18 spe resins were obtained from phenomenex ( torrance , ca 90501 - 1430 , usa ) . the synthesis of these spe sorbents is reported in literature . three critical steps were followed in each extraction : ( a ) conditioning of the sorbent ; ( b ) sample loading and isolation of the analytes ; and ( c ) the elution step . the cartridges were conditioned with 5 ml methanol and then followed by 5 ml of deionised water . approximately 1.5 - litre raw water samples were separately loaded onto the spe columns at a rate of 10 ml / min using the vacuum manifold apparatus . the analytes were eluted from strata x spe by 5 ml acetone , followed by 5 ml of methylene chloride , and from the silica based cartridges using a mixture of tetrahydrofuran ( thf ) and methanol in a 1 : 1 , v / v ratio . the eluted samples were dried in a controlled lamina flow apparatus at 25c , reconstituted using pure methylene chloride ( gc - grade ) , and thereafter injected into the gc for determination . the determination of carboxylic acids from water after spe extracted was performed using gc gc gas chromatograph ( pegasus 4d , leco corporation , south africa ) with a time of flight mass spectrometer ( tofms ) . the gc technique employed the rxi 5sil - ms primary column ( 40 m long with internal diameter ( i d ) of 0.25 mm and 0.25 m film thickness ) and the rxi 17sil - ms secondary dimension column ( 4 m long with an i d of 0.25 mm and the film thickness of 0.25 m ) . nitrogen gas , compressed air , and liquid nitrogen were used for quad - jet thermal modulator operation . the injector temperature for sampleswas set at 280c , at a volume of 1 l on a splitless mode . helium was used as the carrier gas at a flow rate of 1.0 ml / min and a head pressure of 90 kpa . the transfer line temperature was set at 300c and the ion source temperature at 240c . electron impact ionization energy was set at 70 ev with offset of 300 v totaling to the detector voltage of 1,600 v. the first - dimension column temperature was started at 55c and held for 4.5 min , then increased to 280c at a ramping rate of 10c / min , and held for 4.5 min , whereas the secondary column temperature started at 75c held for 4.5 min , then ramped to 310c at a ramping rate of 10c / min , and held for 4.5 min . the data was processed by identifying aliphatic and aromatic carboxylic acids with their respective unique compound masses ( q masses ) on spectral databases and first - and second - dimension retention times . the ms analysis was carried out at mass range of 40500 amu and acquisition rate was 100 spectra / sec . raw water samples filtered through spe cartridges were analysed using lc - ocd ( doc - labor , karlsruhe , germany ) . the raw water samples were obtained from the vaal river which feeds lethabo power station with cooling water . the lc - ocd technique , developed to identify fractions natural organic matter in water , gives quantitative information and qualitative results regarding molecular size distribution of organic matter in water . water samples were injected into a column filled with a chromatographic gel material where large molecules were eluted first followed by the smaller compounds . to achieve quantification of organic carbon , organic nitrogen , and specific uv absorbance at -254 , their responses in the samples at different retention times were measured with an organic carbon detector , organic nitrogen detector , and uv detector , respectively . table 1 shows fractions of the natural organic matter components based on their retention times and peak areas . after inline filtration through 0.45 m , the lc - ocd analysis was carried out following the procedure described by huber et al . , 2011 . results obtained from samples extracted by silica , c - 18 , and strata x cartridges and determined by first - and second - dimension chromatographic separation are presented in this section . the unique masses ( q masses ) , retention times , library hit similarities , and peak areas for selected carboxylic acids ( especially aromatic acids ) are shown in table 2 . the chromatograms of the total carboxylic acids and aromatic carboxylic acids are provided separately in the same figures ( figures 1 , 2 , and 3 ) . using deconvolution chromatof software and the structured unique masses ( q masses ) spectra in gc gc - tofms , the coeluting carboxylic acids were also identified . hitherto , a comparison , in terms of aliphatic and aromatic carboxylic acid extraction efficiency , was evaluated and results are discussed in this section . the hydrophilic or hydrophobic changes occurring in water after removal of carboxylic acids are shown in table 3 and figure 4 . as shown in table 2 , raw water using for cooling at eskom chiefly contains straight - chain and branched carboxylic acids ( all referred to as aliphatic carboxylic acids ) . the results showed a total of 42 carboxylic acids extracted by silica spe from the vaal river water . of these , there are aliphatic carboxylic acids ( 90.48 % ) while aromatic acids were 9.52 % of the total ( table 2 and figure 1 ) . these aromatic acids included 1,2 - benzenedicarboxylic acid , bis ( 2 - methyl ) propyl ester ; benzoic acid , 3,5 - bis ( 1,1 dimethylethyl ) -4-hydroxy - ethyl ester ; phthalic acid , di ( 2 - propylpentyl ) ester , and 7 - phenylheptanoic acid . comparatively , the number of aromatic carboxylic acids recovered by the silica spe cartridge was lower than those recovered by c - 18 ( 25 % ) and strata x ( 28 % ) cartridges . a possible explanation for the relatively large number of carboxylic acids in this river could be degradation and aggregation . related studies have reported short and medium chain carboxylic acids due to anaerobic fermentation of organic matter . clearly , microbial activity and changing physicochemical parameters ( such as ph , ionic strength , and temperature ) influence the distribution of nom fractions . the result of this influence explains the fact that higher molecular weight and aromatic compounds in water degrade and aggregate forming smaller intermediates , which include carboxylic acids of varying molecular weights . they include eicosanoic acid ( 1st t r = 728 ; 2nd t r = 2.800 ) ; hexanedioic acid , bis ( 2 - ethylhexyl ) ester ( 1st t r = 728 ; 2nd t r = 2.950 ) , eicosanoic acid , 2,3 - bis ( acetyloxy ) propyl ester ( 1st t r = 840 ; 2nd t r = 2.650 ) , 9,12,15 - octadecatrienoic acid , 2 - ( acetyloxy ) - 1 - [ ( acetyloxy ) methyl ] ethyl ester , ( 1st t r = 840 ; 2nd t r = 2.800 ) ; octanedioic acid ( 1st t r = 1048 ; 2nd t r = 2.800 ) , decanoic acid , 2 - propenyl ester ( 1st t r = 1048 ; 2nd t r = 3.070 ) . some other carboxylic acids were eluted at different times in the primary dimension but at the same time in the secondary dimension . these included benzoic acid , 3,5 - bis ( 1,1 - dimethylethyl ) -4-hydroxy - ethyl ester ( 1st t r = 676 ; 2nd t r = 2.800 ) ; octanedioic acid ( 1st t r = 1048 ; 2nd t r = 2.800 ) and 1,2 - benzenedicarboxylic acid , bis ( 2 - methyl ) propyl ester ( 1st t r = 688 ; 2nd t r = 2.810 ) . the total carboxylic acids extracted by the c - 18 resin were 20 , 15 of which were aliphatic and 5 aromatic ( table 2 and figure 2 ) . the aromatic acids included 1,2 - benzenedicarboxylic acid , bis ( 2 - methylpropyl ) ester ( 1st t r = 688 ; 2nd t r = 2.820 ) ; benzenepropanoic acid , 3,5 - bis ( 1,1 - dimethylethyl ) -4-hydroxy - , methyl ester ( 1st t r = 1080 ; 2nd t r = 2.660 ) ; phthalic acid , di ( oct -3-yl ) ester ( 1st t r = 1136 ; 2nd t r = 2.570 ) ; 1,2 - benzenedicarboxylic acid , butyl 2 - ethylhexyl ester ( 1st t r = 1152 ; 2nd t r = 2.590 ) ; phthalic acid , butyl undecyl ester ( 1st t r = 1188 ; 2nd t r = 2.520 ) . of these aromatic acids , only 1,2 - benzenedicarboxylic acid , bis ( 2 - methylpropyl ) esteraliphatic carboxylic acids were less retained on c - 18 ( 75 % ) compared to silica spe ( 90.48 % ) . this is because c - 18 consists of a silica surface functionalized with hydrophobic groups , which favour retention of the carboxylic acids in the reversed - phase . additional studies have reported the application of the c - 18 solid - phase in extraction of organic acids using the reverse phase and henceforth higher retention of those with higher hydrophobicities . the retention efficiency of c - 18 was 25 % for the aromatic carboxylic acids ( relatively more hydrophobic ) compared to silica 's 9.52 % . the remaining 75 % of the carboxylic acids extracted using c - 18 were mainly medium and long chain aliphatic acids . except for cis -13-octadecenoic acid ( 1st t r = 712 ; 2nd t r = 2.670 ) and 9,12 - octadecadienoic acid ( 1st t r = 716 ; 2nd 20 t r = 2.750 ) that had similar retention times , the time of flight rapid separation and mass spectral signatures did not show other closely eluting or coeluting compounds . this strata x polymeric resin has the capacity to adsorb both polar and nonpolar compounds with more capacity for the former . it consists of copolymers that have aromatic rings in their structures which allow for electron - donor interaction between the sorbent and the bonds in the analyte . therefore , this sorbent overcomes many limitations of bonded silicas because their hydrophobic surface contains a relatively large number of active aromatic sites that allow these - interactions with aromatic carboxylic compounds . more aromatic carboxylic acids were retained in the strata x than the two other sorbents ( table 2 and figure 3 ) . except for m - hydroxymandelic acid , tris ( trimethylsilyl ) , all the other aromatic acids extracted by strata x had 70 % gc - library hit similarity . the retention efficiency of aromatic acids for strata x 28 % is higher than the one obtained using c - 18 ( 25 % ) and silica ( 9.52 % ) . table 2 shows a total of 25 carboxylic acids extracted by strata x with 18 aliphatic carboxylic acids and 7 aromatic carboxylic acids . the strata x extracted 72 % aliphatic acids of the total carboxylic acids and 28 % aromatic acids . these were cis -10-heptadecenoic acid ( 1st t r = 984 ; 2nd t r = 2.520 ) and e-9-tetradecenoic acid ( 1st t r = 984 ; 2nd t r = 2.540 ) ( figure 3 ) . first , the lc - ocd analyses were performed to identify the major fractions of nom in raw water . second , results showed that the concentration of nom fractions decreased after filtration through the three spe methods , that is , silica , c - 18 , and strata x ( table 2 ) . the decrease was more pronounced in c - 18 filtered water and followed the order c - 18 silica strata x. the relative degrees of aromaticity against molecularities of nom in the four water samples are presented in the humic substances diagram ( hs diagram ) . from the results , the hydrophobicity degree of the samples depended onfigure 4 , which is the humic substances diagram ( hs diagram ) , shows the relationship between molecularity and aromaticity of organic compounds in the water samples . the concentrations of the hydrophobic component followed the order strata x c - 18 silica raw water and the hydrophilic fraction followed the order raw water silica strata x c - 18 . from figure 4 , more aromatic compounds were extracted by c - 18 ( h on the hs diagram ) followed by strata x ( f on the hs diagram ) . howeverthe molecular weights of nom components remaining in the water were higher in water extracted by strata x. this agrees with data obtained using 2 - dimensional gc . hydrophobicity of samples was also assessed using the specific uv absorbance at the wavelength of 254 ( suva ) . the various suva values and the composition of the samples are tabulated in table 3 . natural organic matter in water is reported to possess a hydrophobic characteristic , when the measured suva values are 4 . accordingly , the aromaticity of the water samples followed the order f g h and the molecularity values followed the order g f h . effective characterization of raw water samples was achieved by spe prior to gc gc - tofms determination . the use of strata - x cartridge resulted in the best recovery of aromatic carboxylic acids from raw water . this was relatively higher recovery and could be attributed to the fact that strata x is a polymeric resin with aromatic rings in its hydrophobic structure . the total number of carboxylic acids extracted by silica spe was 42 , with aromatic acids comprising 9.52 % of the total and the rest being aromatic . accurate determination of the various carboxylic acids was achieved by the first - and second - dimension gas chromatography . the lc - ocd results confirmed that the aromaticity degrees and molecular weights nom changed after extraction of carboxylic acids . largely , the hydrophobicity degree of the samples depended on the type and number of carboxylic acids that were removed by the spe cartridges .\noutput:\n" }, { "from": "agent", "value": "the extraction and determination of aliphatic and aromatic carboxylic acids as well as their influence on the aromaticity and molecularity relationship of natural organic matter ( nom ) in water are reported in this study . three solid phase extraction ( spe ) sorbents were used and their extraction efficiencies evaluated after chromatographic determinations ( using gas chromatography with a time of flight mass spectrometer ( gc gc - tofms ) and liquid chromatography with organic carbon detector ( lc - ocd ) ) . more than 42 carboxylic acids were identified in raw water from the vaal river , which feeds the lethabo power generation station , south africa , with cooling water . the aromatic carboxylic acid efficiency ( 28 % ) was achieved by using strata x spe while the highest aliphatic carboxylic acid efficiency ( 92.08 % ) was achieved by silica spe . the hydrophobic nature of nom in water depends on the nature of organic compounds in water , whether aromatic or aliphatic . the lc - ocd was used to assess the hydrophobicity levels of nom as a function of these carboxylic acids in cooling water . the lc - ocd results showed that the aromatic nature of nom in spe filtered water followed the order silica > strata x > c - 18 . from the results , the hydrophobicity degree of the samples depended on the type and number of carboxylic acids that were removed by the spe cartridges ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: up to 29 % of the 40000 new diagnoses of colorectal cancer each year in the uk present with obstructive symptoms . self - expanding metal stents ( semss ) are being used with increasing success for the palliation of metastatic colorectal cancer and as a bridge to surgery for obstructing tumours despite the absence of high level evidence for their safety and efficacy . with the advent of the colorectal stenting trial ( crest trial ) , a multicentred rct , this case series investigated the first three years of a single surgeon endoscopist stenting experience analysing the change in practice over time and the learning curve . data was collected prospectively on 40 patients presenting with acute or subacute large bowel obstruction that subsequently underwent the insertion of an sems . firstly , patients with disseminated malignancy from a lesion in the left colon who were experiencing obstructing symptoms were considered . the decision to attempt insertion of smesstenting was indicated in this cohort if the patient was at high risk for emergency surgery or had disseminated disease . consecutive eligible patients were selected over a three - year period ( 20062008 ) . the procedures were performed by a single surgeon endoscopist and a consultant radiographer in one centre . technical success was defined as successful placement of the sems across the obstructing lesion with good passage of contrast post stenting . in thisseries , technical success equated to clinical success and all patients who achieved a technical success had symptomatic relief . three patients were excluded at the time of the procedure as stenting was thought inappropriate ( stenting was not attempted ) . one patient had a pre - existing perforation demonstrated with contrast and preceded with operative intervention . endoscopy and radiological studies failed to detect an obstructing malignant lesion in the other two patients , and stenting was not performed . this paper analysed the resulting 37 - patient case series . to aid with analysis and to show a change in practice over time , the series was divided chronologically in half ( 1st 18 patient were stented in 2006 and 2nd 19 patients stented in 2007 and 2008 ) . the site of the lesions stented were 6 descending colon , 9 sigmoid colon , 12 rectosigmoid , 8 rectum , 1 extrinsic compression , and 1 at the splenic flexure . thirty seven patients underwent stent placement ( 22 male , 15 female ) with an average age of 74 ( 5595 ) . after discussion in the mdt all these patient were subsequently managed palliatively ( nonoperatively ) . all of these patients were later managed with palliation for disseminated disease . over 80 % of the patients in this seriesthe site of lesion and stenting varied : 6 descending colon , 9 sigmoid colon , 12 rectosigmoid , 8 rectum , 1 extrinsic compression , and 1 at the splenic flexure . complications included 4 failures ( 11 % ) , 4 tumour overgrowths ( 11 % ) , and 1 stent migration ( 3 % ) . three of the tumour overgrowth cases were restented at day 22 , 130 , and 146 after the original procedure . one patient had a late tumour overgrowth which was managed with a defunctioning loop ileostomy . there was 1 early perforation and 1 late ( 2 weeks ) perforation in 2 of the patients that were restented . figure 2 demonstrates the difference between the patients in the first and second half of the case series .67 % in the first 18 patients and 37 % in the subsequent 19 patients were electively stented for this indication . in the second half of the series , more sems are deployed acutely as a bridge to surgery or to palliate emergency large bowel obstruction . of the first 18 patientsonly 11 % of patients were stented following emergency presentation with acute large bowel obstruction , in comparison to 26 % in the subsequent 19 patients . the first 11 stents performed had an 82 % technical success rate and required an average of 1.7 stents per procedure . the subsequent 10 stents performed had a 90 % technical success rate and required average of 1.1 stents per procedure . this is shown in table 1 demonstrating how technical success increased and number of stents decreased with experience . colorectal cancer commonly presents with large bowel obstruction , often at an advanced stage with only 50 % of patients being suitable candidates for curative surgery . emergency surgery in these patients has a high mortality and morbidity when compared to elective surgery . over time , several techniques such as balloon dilatation and laser ablation have been attempted with the aim of decompressing the bowel . the use of stents in colorectal obstruction was first reported in the early 1990s and subsequently has been used to avoid surgery in patients with metastatic disease and as a bridge to surgery in those with localised disease . a study of 8000 patients found that emergency surgery has a mortality of 19.3 % compared to 5.6 % for elective surgery . elective surgery also reduces morbidity , with higher rates of primary anastomosis and lower rates of severe complications . martinez - santos et al . found that patients undergoing emergency surgery for acute malignant large bowel obstruction had a primary anastomosis rate of 41 % compared with 87 % in patients operated on following insertion of an sems , thus saving a significant amount of stoma - related morbidity . in the long term , only 60 % of patients with a colostomy proceed to stoma reversal . in patients having curative surgery following a bridge to surgery sems , up to 95 % go onto havingthere are also health economic advantages with reduced hospital stay and length of time in critical care beds . importantly , stenting can buy time for staging , treatment planning , neoadjuvant therapies and patient optimisation . in this case series 18 patients presented with acute bowel obstruction and underwent emergency stenting . of these patients , 11 ( 61 % ) were found to have disseminated disease at staging and hence avoided unnecessary major surgery . the majority of the published literature is limited by having a small sample size and being nonrandomised ; consequently there is a large range in quoted complication rates . a review by watt et al. found median complication rates of stent migration 11 % , perforation 4.5 % , and tumour overgrowth 12 % . clinical success is usually quoted at a rate of 85100 % with mortality between 0 and 2 % . this study had a primary perforation rate of 0 % in line with the literature , but we had an overall mortality of 2/37 ( 5 % ) when restented patients were taken into account . successful treatment of acute left - sided colorectal obstruction depends on a number of operator and patient factors . a cochrane review in 2002 concluded that the limited number of randomised control trials into the management of obstructing left - sided colorectal carcinoma together with methodological weaknesses does not allow reliable assessment of the best treatment strategy . the only prospective multicentred rct to date , the stent - in 1 study , was stopped early following a high rate of stent - related complications . in the proposed followup stent - in 2 study , it is suggested that sems should be placed by an experienced gastroenterologist . they defined an experienced gastroenterologist as one who has placed 20 enteral stents of which at least 10 were colonic , without giving evidence why these figures have been suggested . this study found that there was a definite learning curve for the insertion of sems , the first 11 stents having only an 82 % success rate , the next 10 having a 90 % success rate , and the subsequent sems having a 94 % success rate . in this case series , it was also noted that the number of sems required to relieve an obstruction decreased with experience . initially an average of 1.7 stents were used per successful procedure whereas towards the end of the series strictures were consistently requiring only one stent . this increased stent usage early in the series reflected inexperience and technical difficulty rather than length of stricture . this evidence suggests that operators should have a minimal experience of 20 colonic sems to be eligible for inclusion in future rcts . not being a randomised study , there is inevitable bias in the selection of patient and treatment options . as the study progressed , more stents were performed on an emergency basis ( 33 % of the first 18 patients and 63 % of the second 19 patients ) in a patient demographic who were likely to be more unwell . more stents were also performed as a bridge to surgery in the second half of the study ( 26 % compared with 11 % ) . this change in practice is likely to reflect an increase in operator confidence in their technical ability and knowledge of when stenting is and is not appropriate . the fact that the clinical success rates increased along this learning curve despite more technically difficult patients suggests that there may also be a significant learning curve in patient selection . the 2 mortalities in this series were patients who died following the restenting of a multilevel obstruction . both these patients required 2 - 3 stents to relieve the obstruction caused by a long stricture , which in retrospect was a mistake . if a reobstruction can not be solved with a single stent , practice has changed and a further stent would not be attempted . in conclusionthis case series suggests that initially there is a steep learning curve for the use of sems in the management of malignant colorectal bowel obstruction of about 11 cases . we suggest that at least twenty cases are required for an operator to be considered experienced .\noutput:\n" }, { "from": "agent", "value": "aim . self - expanding metal stents ( semss ) are increasingly used for the palliation of metastatic colorectal cancer and as a bridge to surgery for obstructing tumours . this case series analyses the learning curve and changes in practice of colorectal stenting over a three year period . methods . a study of 40 patients who underwent placement of sems for the management of colorectal cancer . patients spanned the learning curve of a single surgeon endoscopist . results . technical success rates increased from 82 % initially , using an average of 1.7 stents per procedure , to a 94 % success rate where all patients were stented using a single stent . there has been a change in practice from elective palliative stenting toward emergency preoperative stenting . conclusion . there is a steep learning curve for the use of sems in the management of malignant colorectal bowel obstruction . we suggest that at least 20 cases are required for an operator to be considered experienced ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: isotope ratios are excellent tracers of atmospheric source and loss processes over planetary timescales . in the case of martian oxygen and carbon , atmospheric evolution models must account for the exchange between atmospheric and surface / subsurface reservoirs [ jakosky , 1991 ; webster et al . , the potential for exchange of nitrogen between the atmosphere and surface of mars is not currently understood , but such exchange would be very important to the study of martian habitability that is the focus of the mars science laboratory ( msl ) mission [ grotzinger et al . , 2012 ] . very weak absorption lines are produced by the dipole forbidden vibrational - rotational transitions of ground state n2 , so the spectroscopic techniques used to measure isotope ratios in other molecules can not be applied to molecular nitrogen . of the 10 science instruments of the msl payload [ grotzinger et al . ,2012 ] , sample analysis at mars 's ( sam 's ) mass spectrometer provides the best capability to measure the nitrogen isotopic ratio [ mahaffy et al . , 2012 ] . independent measurements ofn / n were conducted by mass spectrometers on viking lander 2 [ owen et al . , 1977 ; owen , 1992 ] and the two viking lander aeroshells [ nier and mcelroy , 1977 ] . the surface and descent measurements foundn / n of 17015 and 16817 , respectively . sam is a highly capable and configurable instrument suite for analyzing gases either directly sampled from the atmosphere or evolved from solid samples [ mahaffy et al . , sam / quadrupole mass spectrometer ( qms ) determines isotopic ratios based on ratios of detector counting rates . in direct atmospheric experiments , co ions ( from co2 ) interfere at m / z 28 and 29 ( where the parent ions are detected ) . but there is no co contribution at m / z 14 , so we can deriven / n from direct atmospheric experiments using the m / z 14/14 .5 count ratio . in enrichment experiments , chemical scrubbers remove co2 , h2o , and other species with chemical affinity to the scrubber material . the enrichment process allows determination of the isotopic ratio using m / z 28/29 and 14/29 count ratios . we further boost signal level ( compared to the normal dynamic mode ) using a semistatic mode , where the pumping rate out of the qms is reduced . figure 1 shows a mass spectrum from an enrichment experiment in dynamic mode , spanning the relevant m / z range for nitrogen analysis . sample spectrum is an average of data from enrichment cycle 9 ( see figure 2 ) . nitrogen ions are present at m / z 14 , 14.5 , 28 , and 29 . the singly ionized n2 parent ion appears in the mars data at m / z 28 ( fornn ) and at m / z 29 ( fornn ) . a third parent ion , nn , is so rare as to produce only a small signal below the background level ( difference between red and blue curves ) . for a comparison of the m / z 1415 range in the direct atmospheric experiment , , the nitrogen isotopic ratio was determined using galileo probe mass spectrometer measurements of , to avoid interferences at m / z 17 and 18 from water [ owen et al . we use a similar approach in the msl / sam analysis , although there is an additional complication because the count ratio of m / z 14/14 .5 includes contributions from two nitrogen daughter ions , n and . to extract the nitrogen isotopic ratio , we first measure a splitting fraction ( derived from sam / qms preflight calibration data ) that gives the relative contributions from these two daughter ions : where the count rates at a mass / charge ratio of m / z x are represented as mx , andn / n is independently measured in the calibration gas . we find = 0.4040.033 based on five experiments [ wong et al . , 2013 ] . then / n isotopic ratio is then derived from the splitting fraction and the flight m / z 14/14 .5 count ratio ( see supporting information ) : additional count ratios can be used to measure nitrogen isotopes in the enrichment experiments . measurement of then / n ratio directly from the parent ions is difficult because the signal level is very high at m / z 28 over most of the enrichment experiment ; in fact , figure 2 shows that the m / z 28 signal is near saturation in the first enrichment cycle ( labeled 1a and 1b ) . the m / z 28 counting rate decreases in enrichment cycles 24 due to saturation , with 0 counts / s in the subsequent cycles . the isotope ratio can also be derived from m / z 14/29 data , but different voltage frequencies used above and below m / z 20 [ mahaffy et al . , background measurements ( shaded ) are used to characterize the background signal that must be subtracted from the data before calculating count ratios . detector corrections have been applied to the data ( see supporting information ) . in each of 10 enrichment cycles , an atmospheric sample was introduced , and co2 and h2o were removed by chemical scrubbers [ mahaffy et al . , the enriched sample from one cycle was then combined with a new injection of mars atmosphere and scrubbed to produce the next sample . signal at m / z 28 decreases in enrichment cycle 2 and later due to detector saturation at high source pressures . table 1 lists nitrogen isotopic results from sam up through msl sol 360 ( planetary data system release 4 ) . uncertainties include all sources of error ( see supporting information ) . specifically , we include uncertainties from detector corrections , background subtraction , statistical noise , and splitting fractions . sam background corrections are significant , so the limiting s / bg level is listed as a measure of the confidence in each measurement . where known , s / bg levels from other instruments are also given for comparison . mars nitrogen isotopic ratios measured in atmospheric n2 msl landing occurred on sol 0 at 15:03 local mean solar time or utc 2012 - 08 - 0605:17 . n ( ) = 1000 ( r / rair1 ) , where r = n / n in the sample , and rair = 0.003676 [ coplen et al . , 2002 ] . signal to background level ( s / bg ) is limiting because it refers to the count rate with the poorest s / bg ( e.g. , m / z 14 in the case of the m / z 14/14 .5 ratio ) . symbol means that the s / bg level changes over the course of the experiment , and the best s / bg ratio over the full experiment range is reported . testbed experiment is listed to confirm sam accuracy with a gas sample of known isotopic composition ( n = 0 , n / n = 272 ) . viking lander mass spectrometer publications do not describe count ratios used for isotopic determination or s / bg levels in the data . the most reliable msl / sam measurement ofn / n comes from m / z 14/14 .5 in the semistatic enrichment experiment , where a s / bg ratio of 388 was achieved . results at low s / bg have much more scatter than results at s / bg 50 ( see supporting information ) , suggesting that imperfect background corrections dominate the uncertainty in the direct atmospheric measurements . the largest single source of uncertainty in the isotopic ratio is the uncertainty in ( equation ( 1 ) and figure s1 ) . the range ofn / n ratios derived from msl / sam data falls completely within the error bars of viking measurements . nonterrestrial nitrogen isotopic ratios in martian meteorite samples have been interpreted as tracers of atmospheric gas , trapped within the meteorites at their time of ejection from mars [ bogard and johnson , 1983 ] . figure 3 compares laboratory analyses of gases evolved from meteorite samples to in situ measurements of the mars atmosphere by viking and msl . selected step - heating gas releases in the terrestrial laboratory experiments can be used to define mixing lines between the compositional measurements . the choice of steps for analysis ( black symbols and references in figure caption ) was intended to eliminate contributions from terrestrial air or organic contamination . for comparison , we also show meteorite data ( red symbols ) and linear fits based on the total gas released in each experiment . these total gas release data are free from uncertainties introduced by subjective interpretation of stepped heating data . the mixing line slope is not significantly affected by uncertainties in cosmic ray exposure ages [ nyquist et al . , 2001 ; schwenzer et al . , 2007 ] pseudo - three - isotope plots at two different magnifications ( comparingn , n , andar ) showing mars meteorite and atmosphere measurements and linear fits . the meteorite data suggest mixing between at least two components : martian atmosphere and terrestrial atmosphere . meteorite data are from becker and pepin [ 1984 , eeta 79001a samples c1 and c2 ] , wiens et al . [ 1986 , sample c3 ] , marti et al . [ 1995 , zagami ] , chennaoui aoudjehane et al . viking ar / n ratio is from oyama and berdahl , and viking n is from nier and mcelroy . msl values are from sam / qms measurements , with n described in this work , and ar / n is from mahaffy et al . . linear fits included uncertainties in both ar / n and n , following the method of york et al . , assuming uncorrelated errors . there is a clear disagreement between the ar / n measurement by msl / sam of 0.510.01 [ mahaffy et al . ,2013 ] and by multiple viking instruments of 0.350.08 [ oyama and berdahl , 1977 ] . all of the meteorite mixing lines are consistent with viking composition and inconsistent with msl . three possible explanations for the disagreements can be considered : that the msl composition is wrong , that the viking composition is wrong , or that the martian atmospheric composition is variable . internal and peer reviews of the msl / sam data argue against the first possibility at this time [ mahaffy et al . , 2013 ] . similarly , the viking composition seems highly robust , with good agreement among multiple instruments . the msln / n ratio falls easily within the error bars of the viking measurements by both lander and aeroshell mass spectrometer experiments . this ratio was repeatedly measured by both the viking lander mass spectrometer [ owen et al . , 1977 ] and the gas exchange experiment [ oyama and berdahl , 1977 ] . unfortunately , viking flight data are no longer available , so we can not repeat the same validation we applied to the msl data . therefore , the possibility that viking ar / n measurements were erroneous can only be speculation . there is currently no satisfactory mechanism that could explain a variable ar / n ratio in the martian atmosphere . adsorbed co2 and h2o in the regolith make up a large volatile reservoir that exchanges over time with the atmosphere and polar caps [ e.g. , fanale et al . are not thought to participate in this cycle , although these gases do adsorb onto martian soil [ ballou et al . , 1978 ] . a previously unknown surface - atmosphere exchange mechanism would need to involve very large column density changes : a release of up to 1 kg m ar or sequestration of up to 0.7 kg mn2 , prior to 2012 . column density changes might be thermally driven by global warming of 0.65 k since viking [ fenton et al . , 2007 ] , or related to a reduction of polar cap mass [ malin et al . ,2001 ] , but msl measurements from early spring to late summer on mars do not support any variation in ar / n [ atreya et al . , 2013 ; trainer et al . heavy nitrogen in the atmosphere of mars is enriched relative to both the protosolar isotopic ratio and the ratio in the terrestrial and venusian atmospheres ( table 2 ) , as well as to the primordial mars atmosphere as suggested by the meteorite alh84001 with n = 42 [ marti and mathew , 2000 ] . the enrichment ofn is due to preferential escape ofn from the martian atmosphere [ e.g. , mcelroy et al . , 1976 ; fox and dalgarno , 1983 ; fox and ha , 1997 ; chassefire and leblanc , 2004 ] . some models of sputtering and photochemical escape of nitrogen to space suggest that exchange with surface / interior reservoirs is needed to buffer the nitrogen against excessive fractionation due to escape [ jakosky et al .1994 ] , leading to a loss of 90 % of atmospheric nitrogen over time [ jakosky and phillips , 2001 ] . the detailed history and mechanisms of exchange between atmosphere and surface / interior are poorly understood for nitrogen , compared to similar processes that fractionate atmospheric carbon and oxygen [ webster et al . ,2013 ] , via exchange between polar ices , carbonates , and regolith adsorption [ jakosky , 1991 ; fanale et al . , 1992 ] . solar system nitrogen isotopic ratios sam may provide insight into these processes by investigating nitrogen - containing compounds in solid samples . reduced and oxidized compounds have tentatively been identified in evolved gases , includingn , no , hcn , cn , and ch3cn [ stern et al . , 2013 ; navarro - gonzlez et al . , 2013 ] . the origin of the detected nitrogen could include terrestrial sources within the sam instrument or the curiosity sample chain , exogenous nitrogen delivered by meteorites , or indigenous martian inorganic and organic matter . exchange between solid and atmospheric reservoirs could occur as organic surface nitrogen is photolytically or radiolytically decomposed to n2 or oxidized to inorganic nitrogen in the form of nitrates , which are also converted to n2 by the current impact flux [ manning et al .\noutput:\n" }, { "from": "agent", "value": "[ 1 ] the sample analysis at mars ( sam ) instrument suite on the mars science laboratory ( msl ) measured a mars atmospheric14n / 15n ratio of 173 11 on sol 341 of the mission , agreeing with viking 's measurement of 168 17 . the msl / sam value was based on quadrupole mass spectrometer measurements of an enriched atmospheric sample , with co2 and h2o removed . doubly ionized nitrogen data at m / z 14 and 14.5 had the highest signal / background ratio , with results confirmed by m / z 28 and 29 data . gases in snc meteorite glasses have been interpreted as mixtures containing a martian atmospheric component , based partly on distinctive14n / 15n and40ar / 14n ratios . recent msl / sam measurements of the40ar / 14n ratio ( 0.51 0.01 ) are incompatible with the viking ratio ( 0.35 0.08 ) . the meteorite mixing line is more consistent with the atmospheric composition measured by viking than by msl ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: these tumors may cause hyperthyroidism through inappropriate secretion of tsh , which can also lead to perioperative thyroid storm . thus , thyroid hormone ( th ) levels need to be preoperatively controlled for these patients . the first - line therapy for tshoma is neurosurgery , yet surgical cure rates vary reportedly around only 5060 % . tshomas are often invasive and fibrous which hamper complete removal ; somatostatin ( sst ) analogs are therefore primarily used in palliative care or for patients who were not cured by surgery . the role of somatostatin receptors ( sstrs ) as therapeutic targets in pituitary adenomassst analogs are reportedly effective in hormonal control of tshomas and growth hormones ( gh ) - secreting adenomas . sstr have five subtypes ( sstr15 ) mostly sstr2 and sstr5 those are widely expressed in both normal and neoplastic human pituitary cells . understanding of the highly variable expression of sstr subtypes in pituitary adenomas has risen sharply in recent years . interactions between ligands and receptors serve as the molecular basis of drug - targeting therapy . therefore , the expression profile of sstr subtypes in pituitary adenomas would be helpful to know . octreotide ( oct ) , a clinically available sstr2 - preferring analog , normalizes hormone levels for approximately 90 % of tshoma patients , yet its preoperative use is rarely reported . in our center , patients with tshoma are started on short - term preoperative sst analog to restore euthyroidism before transsphenoidal surgery as a definitive therapy . to probe into the underlying mechanisms of oct in tshoma treatment , we assessed the outcomes of short - term preoperative oct treatment for patients with tshoma and investigated sstr2 and sstr5 expression by immunohistochemistry ( ihc ) in tumor specimens , as well as their subcellular characteristics at electron microscopy , aiming at providing evidence for tshoma medical therapy . we included eight patients ( six men and two women ) who were diagnosed with tshoma in the department of endocrinology , beijing tiantan hospital , between july 2012 and july 2015 , based on their combinations of typical signs and symptoms of hyperthyroidism and / or intracranial compression ( e.g. , visual loss , headache , nasal obstruction , and hypopituitarism ) ; unsuppressed tsh levels with elevated th levels ; evidence of a pituitary tumor by imaging ; and confirmation by pathological diagnosis . all participants gave written informed consent and the study was approved by the institutional ethical review board of beijing tiantan hospital ( no . sanger sequencing was used to search for point mutations and deletions in the thyroid hormone receptor ( tr ) gene , but no definite pathogenic mutations were found . medical records of all the patients were thoroughly reviewed in terms of their sexes , ages at diagnosis , pathological diagnoses , tumor sizes , and dates of their last follow - ups . oct used in this investigation was obtained from novartis pharmaceuticals corporation ( east hanover , nj , usa ) . each patient received an initial dose of 100 g , injected subcutaneously at 8:00 a.m. if the patient showed no obvious side effects ( such as nausea , vomiting , stomach ache , and diarrhea ) , dosages were increased to 100 g 2 or 3 times / day . serum tsh , free triiodothyronine ( ft3 ) , free thyroxin ( ft4 ) , total triiodothyronine ( tt3 ) , and total thyroxin ( tt4 ) concentrations were measured by chemiluminescent enzyme assays using commercially available kits . the following formula was used to determine tsh suppression rate : tsh suppression rate ( % ) = ( before treatment after treatment ) / before treatment 100 % . serial 4 - m - thick sections were cut from formalin - fixed and paraffin - embedded pituitary adenoma tissues and used for histological diagnosis and ihc staining for sstr2 and sstr5 . for adenoma classification , specimens were subjected to routine ihc staining with monoclonal antibodies against tsh , adrenocorticotropic hormone , growth hormone , luteinizing hormone , follicle - stimulating hormone , and prolactin . fixed in formalin , the slides were prepared in unstained 3 - m sections and 48 dot cores ( diameter : 2.0 mm ) matrix chip template . ihc staining was performed using a leica bond - iii , automatic ihc and ish stainer ( leica biosystems , nussloch , germany ) , which was a fully automated , continuous - access ihc slide - staining system . the primary sstr2 antibody was ab13120 ( 1:100 ) , and the primary sstr5 antibody was ab13121 ( 1:100 ; abcam , cambridge , uk ) . sections were assessed independently by two experienced pathologists who were blinded to both clinical and pathological data . scoring of each section was determined by consensus , by the immunoreactive score ( irs ) method , which entailed multiplying staining intensity ( 0 = no staining , 1 = weak staining , 2 = moderate staining , and 3 = strong staining ) by percentage of positively stained cells ( 0 = 0 % , 1 = 133 % , 2 = 3466 % , and 3 = 66 % ) , for irs scores ranging from 0 ( no staining ) to 9 ( maximum staining ) , irs scores of 04 were considered low expression and 59 were high expression . specimens from all the eight patients were examined by an electron microscope . for electron microscopy ,1 - mm - thick sections were double fixed by 2.5 % glutaraldehyde ( by volume ) and 2 % formaldehyde solution for 2 h at 4c , and then washed three times with phosphate - buffered saline ( pbs ) . samples were then fixed in 1 % osmium tetroxide , washed with pbs , dehydrated in an ethanol gradient , and embedded , using fresh embed - 812 , in labeled embedding molds and polymerized . section blocks were conformed and cut into 60 - nm sections , stained in uranyl acetate and lead citrate , and their specific ultrastructure features were observed under a hitachi h - 7650 ( 120 kv ) transmission electron microscope . as controls , we randomly selected eight sets of electron microscopy data from patients who received surgical treatment instead of oct therapy . sas 9.4 ( sas institute , inc , north carolina , usa ) was used to analyze the data , and the statistical description of variables was shown as median ( interquartile range ) . signed rank sum test was used to compare the efficacy of short - term preoperative oct treatment . wilcoxon rank - sum test was used to investigate tsh suppression rate and sstr5 expression . we included eight patients ( six men and two women ) who were diagnosed with tshoma in the department of endocrinology , beijing tiantan hospital , between july 2012 and july 2015 , based on their combinations of typical signs and symptoms of hyperthyroidism and / or intracranial compression ( e.g. , visual loss , headache , nasal obstruction , and hypopituitarism ) ; unsuppressed tsh levels with elevated th levels ; evidence of a pituitary tumor by imaging ; and confirmation by pathological diagnosis . all participants gave written informed consent and the study was approved by the institutional ethical review board of beijing tiantan hospital ( no . sanger sequencing was used to search for point mutations and deletions in the thyroid hormone receptor ( tr ) gene , but no definite pathogenic mutations were found . medical records of all the patients were thoroughly reviewed in terms of their sexes , ages at diagnosis , pathological diagnoses , tumor sizes , and dates of their last follow - ups . oct used in this investigation was obtained from novartis pharmaceuticals corporation ( east hanover , nj , usa ) . each patient received an initial dose of 100 g , injected subcutaneously at 8:00 a.m. if the patient showed no obvious side effects ( such as nausea , vomiting , stomach ache , and diarrhea ) , dosages were increased to 100 g 2 or 3 times / day . serum tsh , free triiodothyronine ( ft3 ) , free thyroxin ( ft4 ) , total triiodothyronine ( tt3 ) , and total thyroxin ( tt4 ) concentrations were measured by chemiluminescent enzyme assays using commercially available kits . the following formula was used to determine tsh suppression rate : tsh suppression rate ( % ) = ( before treatment after treatment ) / before treatment 100 % . serial 4 - m - thick sections were cut from formalin - fixed and paraffin - embedded pituitary adenoma tissues and used for histological diagnosis and ihc staining for sstr2 and sstr5 . for adenoma classification , specimens were subjected to routine ihc staining with monoclonal antibodies against tsh , adrenocorticotropic hormone , growth hormone , luteinizing hormone , follicle - stimulating hormone , and prolactin . fixed in formalin , the slides were prepared in unstained 3 - m sections and 48 dot cores ( diameter : 2.0 mm ) matrix chip template . ihc staining was performed using a leica bond - iii , automatic ihc and ish stainer ( leica biosystems , nussloch , germany ) , which was a fully automated , continuous - access ihc slide - staining system . the primary sstr2 antibody was ab13120 ( 1:100 ) , and the primary sstr5 antibody was ab13121 ( 1:100 ; abcam , cambridge , uk ) . sections were assessed independently by two experienced pathologists who were blinded to both clinical and pathological data . scoring of each section was determined by consensus , by the immunoreactive score ( irs ) method , which entailed multiplying staining intensity ( 0 = no staining , 1 = weak staining , 2 = moderate staining , and 3 = strong staining ) by percentage of positively stained cells ( 0 = 0 % , 1 = 133 % , 2 = 3466 % , and 3 = 66 % ) , for irs scores ranging from 0 ( no staining ) to 9 ( maximum staining ) , irs scores of 04 were considered low expression andspecimens from all the eight patients were examined by an electron microscope . for electron microscopy ,1 - mm - thick sections were double fixed by 2.5 % glutaraldehyde ( by volume ) and 2 % formaldehyde solution for 2 h at 4c , and then washed three times with phosphate - buffered saline ( pbs ) . samples were then fixed in 1 % osmium tetroxide , washed with pbs , dehydrated in an ethanol gradient , and embedded , using fresh embed - 812 , in labeled embedding molds and polymerized . section blocks were conformed and cut into 60 - nm sections , stained in uranyl acetate and lead citrate , and their specific ultrastructure features were observed under a hitachi h - 7650 ( 120 kv ) transmission electron microscope . as controls , we randomly selected eight sets of electron microscopy data from patients who received surgical treatment instead of oct therapy . , north carolina , usa ) was used to analyze the data , and the statistical description of variables was shown as median ( interquartile range ) . signed rank sum test was used to compare the efficacy of short - term preoperative oct treatment . wilcoxon rank - sum test was used to investigate tsh suppression rate and sstr5 expression . the study included eight patients ( 6 men and 2 women ) with tshoma whose average age was 39.8 years ( range : 2552 years ) . their average duration of symptoms was 2.6 years ( range : 2 months7 years ) . magnetic resonance imaging showed one patient with microadenoma and seven with macroadenoma [ table 1 ] . all the eight patients had unsuppressed tsh levels with elevated th levels ; neuroimaging revealed pituitary lesions . clinical characteristics of eight patients with tshomas sstr : somatostatin receptor ; irs : immunoreactive score ; tsh : thyroid - stimulating hormone ; ft3 : free triiodothyronine ; ft4 : free thyroxin ; gd : graves disease ; ht : hashimoto s thyroiditis ; tshoma : thyrotropin - secreting pituitary adenoma . all the patients showed various thyrotoxicosis symptoms with goiters , including palpitations , excessive sweating , fatigue , and weight loss ; five also exhibited symptoms of intracranial compression , including paroxysmal headache and blurry vision . patient 3 had been misdiagnosed with graves disease and treated with antithyroid drugs ( thiamazole ) irregularly for 2 years . patient 4 had been misdiagnosed with hashimoto 's thyroiditis for 3.5 years , but had received no treatment before his tshoma diagnosis . patient 8 presented with high levels of tsh receptor antibodies and antithyroid peroxidase antibodies associated with hyperthyroxinemia and unexpectedly normal tsh values . short - term preoperative oct administration was highly effective in normalizing excessive hormone concentrations , with tolerable side effects . after oct treatments for a median of 7.9 days ( range : 316 days ) and with a total median dose of 1.8 mg ( range : 0.94.2 mg ) , all patients presented significant decreased tsh and th levels ( ft3 [ nmol / l ] : 8.33 [ 7.02 , 12.29 ] to 4.67 [ 3.52 , 5.37 ] [ p = 0.000 ] ; ft4 [ pmol / l ] : 25.36 [ 21.34 , 28.99 ] to 16.66 [ 14.88 , 21.49 ] [ p = 0.016 ] ; and tsh [ u / ml ] : 5.80 [ 4.37 , 6.78 ] to 0.57 [ 0.19 , 1.24 ] [ p = 0.008 ] ) [ table 2 ] . reference ranges are tsh : 0.354.94 u / ml ; ft3 : 2.635.7 nmol / l ; and ft4 : 9.0019.04 pmol / l . comparison of thyroid function before and after short - term octreotide treatment ( n = 8 ) data were shown as median ( interquartile range ) . tt3 : total triiodothyronine ; tt4 : total thyroxin ; ft3 : free triiodothyronine ; ft4 : free thyroxin ; tsh : thyroid - stimulating hormone . safety of treatment with sst analogs was proven ; no patients discontinued treatment due to unbearable side effects although patient 4 suffered diarrhea for 2 days , for which his oct dose was reduced to 100 g one time / day for 11 days . patients histology examinations showed positive staining for tsh , thus confirming the diagnoses of tshoma [ figure 1 ] . the ihc staining for sstr2 and sstr5 was positive in the cytoplasm , and notably , greater for sstr2 than sstr5 in tshoma . all patients showed high sstr2 immunoreactivity ( irs 9 ) , yet with heterogeneous and less intense staining for sstr5 ( sstr5 irs : 5/8 high and 3/8 low ) . due to small sample size , we saw no significant relationships between the tsh suppression rate and patients age , sex , tumor size , or treatment dosage ; however , tsh suppression rate and sstr5 expression were significantly related [ p = 0.036 , table 3 ] . relationship between thyroid - stimulating hormone suppression rate and sstr5 expression ( n = 8 ) * low expression : 04 ; high expression : 59 . tsh suppression rate ( % ) = ( before treatment after treatment ) / before treatment 100 % . analyzed with two independent sample wilcoxon rank sum test , patients with low sstr5 expression presented a significantly higher tsh suppression rate ( p = 0.036 ) . ultrastructurally , well - differentiated adenomatous thyrotrophs resemble normal ones , whereas poorly differentiated adenomas were composed of elongated angular cells with irregular nuclei , poorly developed rough endoplasmic reticulum , long cytoplasmic processes , and sparse small secretory granules ( 50200 nm ) that mostly line up along the cell membrane [ figure 2 ] . compared with the normal specimens , those from patients treated with oct showed changes ( to varying degrees ) in such tumor subcellular structure as mitochondrial swelling , dilatation of endoplasmic reticulum , vacuole formation , membrane dissolution and fracture , blurring of nucleus and organelle , cell disintegration , and thickened vascular basal lamina . characteristic apoptotic morphological changes were seen in tshoma cells after treatment with oct under transmission microscope . various types of damages were found at organelles and subcellular level , and decreased secretion activity in oct - treated tumor cells , which contribute to tumor shrinkage due to long - term actions of oct . ( b ) arrow points to untreated adenoma cells mostly round ; exteriors are dotted evenly with black tsh secretion granules along the cell membranes . ( c ) arrow points to actively growing pituitary adenoma cell with an irregular shape , mild dysplasia , and deep staining ; its nucleus is larger than those seen in normal cells . ( d ) arrow points to mitochondria with varying degrees of swelling , transparent mitochondrial matrix , missing granules , disorderly arrangement , and fractured cristae . ( e ) electron microscope shows cell membrane missing and fractured , as well as local defect and blurred structure of cell organelles and nuclei . g ) arrow points to elongated rough endoplasmic reticulum , which may lead to vacuole denaturalization if extended significantly . tshoma : thyrotropin - secreting pituitary adenoma ; oct : octreotide ; tsh : thyrotropin . the study included eight patients ( 6 men and 2 women ) with tshoma whose average age was 39.8 years ( range : 2552 years ) . their average duration of symptoms was 2.6 years ( range : 2 months7 years ) . magnetic resonance imaging showed one patient with microadenoma and seven with macroadenoma [ table 1 ] . all the eight patients had unsuppressed tsh levels with elevated th levels ; neuroimaging revealed pituitary lesions . clinical characteristics of eight patients with tshomas sstr : somatostatin receptor ; irs : immunoreactive score ; tsh : thyroid - stimulating hormone ; ft3 : free triiodothyronine ; ft4 : free thyroxin ; gd : graves disease ; ht : hashimoto s thyroiditis ; tshoma : thyrotropin - secreting pituitary adenoma . all the patients showed various thyrotoxicosis symptoms with goiters , including palpitations , excessive sweating , fatigue , and weight loss ; five also exhibited symptoms of intracranial compression , including paroxysmal headache and blurry vision . patient 3 had been misdiagnosed with graves disease and treated with antithyroid drugs ( thiamazole ) irregularly for 2 years . patient 4 had been misdiagnosed with hashimoto 's thyroiditis for 3.5 years , but had received no treatment before his tshoma diagnosis . patient 8 presented with high levels of tsh receptor antibodies and antithyroid peroxidase antibodies associated with hyperthyroxinemia and unexpectedly normal tsh values . short - term preoperative oct administration was highly effective in normalizing excessive hormone concentrations , with tolerable side effects . after oct treatments for a median of 7.9 days ( range : 316 days ) and with a total median dose of 1.8 mg ( range : 0.94.2 mg ) , all patients presented significant decreased tsh and th levels ( ft3 [ nmol / l ] : 8.33 [ 7.02 , 12.29 ] to 4.67 [ 3.52 , 5.37 ] [ p = 0.000 ] ; ft4 [ pmol / l ] : 25.36 [ 21.34 , 28.99 ] to 16.66 [ 14.88 , 21.49 ] [ p = 0.016 ] ; and tsh [ u / ml ] : 5.80 [ 4.37 , 6.78 ] to 0.57 [ 0.19 , 1.24 ] [ p = 0.008 ] ) [ table 2 ] . reference ranges are tsh : 0.354.94 u / ml ; ft3 : 2.635.7 nmol / l ; and ft4 : 9.0019.04 pmol / l . comparison of thyroid function before and after short - term octreotide treatment ( n = 8 ) data were shown as median ( interquartile range ) . tt3 : total triiodothyronine ; tt4 : total thyroxin ; ft3 : free triiodothyronine ; ft4 : free thyroxin ; tsh : thyroid - stimulating hormone . safety of treatment with sst analogs was proven ; no patients discontinued treatment due to unbearable side effects although patient 4 suffered diarrhea for 2 days , for which his oct dose was reduced to 100 g one time / day for 11 days . patients histology examinations showed positive staining for tsh , thus confirming the diagnoses of tshoma [ figure 1 ] . the ihc staining for sstr2 and sstr5 was positive in the cytoplasm , and notably , greater for sstr2 than sstr5 in tshoma . all patients showed high sstr2 immunoreactivity ( irs 9 ) , yet with heterogeneous and less intense staining for sstr5 ( sstr5 irs : 5/8 high and 3/8 low ) . due to small sample size , we saw no significant relationships between the tsh suppression rate and patients age , sex , tumor size , or treatment dosage ; however , tsh suppression rate and sstr5 expression were significantly related [ p = 0.036 , table 3 ] . relationship between thyroid - stimulating hormone suppression rate and sstr5 expression ( n = 8 ) * low expression : 04 ; high expression : 59 . tsh suppression rate ( % ) = ( before treatment after treatment ) / before treatment 100 % . analyzed with two independent sample wilcoxon rank sum test , patients with low sstr5 expression presented a significantly higher tsh suppression rate ( p = 0.036 ) . ultrastructurally , well - differentiated adenomatous thyrotrophs resemble normal ones , whereas poorly differentiated adenomas were composed of elongated angular cells with irregular nuclei , poorly developed rough endoplasmic reticulum , long cytoplasmic processes , and sparse small secretory granules ( 50200 nm ) that mostly line up along the cell membrane [ figure 2 ] . compared with the normal specimens , those from patients treated with oct showed changes ( to varying degrees ) in such tumor subcellular structure as mitochondrial swelling , dilatation of endoplasmic reticulum , vacuole formation , membrane dissolution and fracture , blurring of nucleus and organelle , cell disintegration , and thickened vascular basal lamina . characteristic apoptotic morphological changes were seen in tshoma cells after treatment with oct under transmission microscope . various types of damages were found at organelles and subcellular level , and decreased secretion activity in oct - treated tumor cells , which contribute to tumor shrinkage due to long - term actions of oct . ( b ) arrow points to untreated adenoma cells mostly round ; exteriors are dotted evenly with black tsh secretion granules along the cell membranes . ( c ) arrow points to actively growing pituitary adenoma cell with an irregular shape , mild dysplasia , and deep staining ; its nucleus is larger than those seen in normal cells . ( d ) arrow points to mitochondria with varying degrees of swelling , transparent mitochondrial matrix , missing granules , disorderly arrangement , and fractured cristae . ( e ) electron microscope shows cell membrane missing and fractured , as well as local defect and blurred structure of cell organelles and nuclei . ( g ) arrow points to elongated rough endoplasmic reticulum , which may lead to vacuole denaturalization if extended significantly . tshoma : thyrotropin - secreting pituitary adenoma ; oct : octreotide ; tsh : thyrotropin . tshoma is a rare lesion of the endocrine system , which favors no particular age group and neither sex . tshoma and primary hyperthyroidism share some symptoms of thyrotoxicosis and diffuse enlargement of the thyroid gland . tsh secretion is autonomous and refractory to negative feedback by ths ( inappropriate tsh secretion ) . tsh itself can hyperstimulate the thyroid gland and lead to hypersecretion of t4 and t3 . the differential diagnosis of inappropriate tsh secretion includes nonthyroidal illness , medications , assay interference due to heterophilic antibodies , th resistance , and tshoma . the syndrome of pituitary resistance to thyroid hormone ( prth ) is characterized by tissue hyposensitivity to elevated levels of ft3 and ft4 in association with unsuppressed serum tsh ( signs and symptoms are subjective ) . differentiating between these forms of prth and tshomas may be difficult . as mutations in the tr geneare responsible for prth , we excluded prth by sanger sequencing . normal or elevated tsh levels with elevated ft3 and ft4 concentrations in these hyperthyroid patients provided a clue to tshoma , and the confirmed diagnoses were based on ihc results . approximately , 30 % of the patients with tshoma are misdiagnosed with primary hyperthyroidism and might undergo such thyroid ablative treatment as antithyroid medication , thyroidectomy , or radioactive iodine thyroid ablation before their pituitary lesion is found . in our study , another was misdiagnosed with graves disease and treated with antithyroid drugs that worsened his thyroid functions . most patients present with mild signs of thyrotoxicosis and possible neurological features , due to pituitary mass ; they often have thyroid nodule disease . tshomas may be associated with thyroid diseases , and in diagnosing tshoma , the possibility of thyroid disease should be investigated and followed up . nmol / l ( normal range [ nr ] : 1.182.23 nmol / l ) , total thyroxine of 54.22 nmol / l ( nr : 57.92154.44 nmol / l ) , and tsh of 0.263 mu / ml ( nr : 0.474.64 mu / ml ) . central hypothyroidism was diagnosed , and postoperative hypothyroidism replacement therapy with levothyroxine 50 g once daily was begun postoperatively . tshomas are often diagnosed as macroadenomas and as plurihormonal ; they are clinically heterogeneous and difficult to treat . medically , sst analogs can control hormone hypersecretion for 90 % of patients ; long - time therapy should cause significant tumor shrinkage for about 45 % of patients . reportedly , tshomas that express sstrs support the use of oct for tsh - dependent hyperthyroidism . characteristic sstr expression patterns in pituitary adenomas are species - , tissue - , and subtype - specific . an sstr5 mutation in tumor tissue was reported in one acromegalic patient who was resistant to sst analog treatment , which implies a role for sstr5 in predicting response . sstr5 expression on the top of sstr2 reportedly may account for long - term suppression of hormone hypersecretion and tumor growth . additional studies with a larger number of cases are necessary to establish the exact role of sstr5 in oct therapy for tshoma . in general , sstr2 was expressed at higher levels than sstr5 in tshomas . use of sstr2 - and sstr5 - preferring oct and lanreotide may be a useful treatment for tshoma . all patients were significantly improved by oct treatment in our study , implying that oct can both help restore euthyroidism preoperatively and decrease the risk of perioperative thyroid storm , for better surgical outcomes . the oct test before surgery can also predict whether oct therapy would be effective if surgery alone is not curative . current studies on the effects of bromocriptine have shown shrunken cytoplasm and greater karyoplasmic ratios . changes confirmed with ultrastructural analyses included nuclear chromatin aggregation and margination , marked reduction of rough endoplasmic reticulum and golgi complexes , vascular degenerations , and necrosis and autolysis of tumor cells with dark cells and / or naked nuclear cells . electron microscopy used to elucidate the mechanism of oct in treating tshomas showed that specimens from patients who received short - term oct treatment presented ultrastructural changes at the organelle and subcellular levels that were not seen in tshomas patients who did not receive oct treatment . our main finding was that short - term preoperative oct use achieved the desired clinical outcome and biochemical euthyroidism . all these facts indicate that oct acts directly on tumor cell sstrs , causing damage to tumor cells and organelles to varying degrees , which is consistent with the existing studies . the first - generation sst analogs may serve as a medical alternative to surgical treatment , especially for patients in whom surgery is contraindicated or who present with invasive macroadenomas that render complete surgical resection difficult . the most obvious limitations of this study were the small size of our cohort , its single - institution design , and the patients rather short follow - up . optimally , a larger series with long - term follow - up is needed to determine outcomes and remission rates for oct - treated tshomas . safety and ethical concerns require that surgery should be performed only on the premise of hyperthyroidism control . after studies in the same patients and case - control study may be biased , and can also mask cause - and - effect relationships or , alternatively , suggest correlations where none exist . finally , apoptosis and necrosis measured by electron microscopy reflect only qualitative instead of quantitative analysis levels . resolving these limitationsis the objective of our ongoing studies . in conclusion , oct works on pituitary adenoma cells by binding to sstr2 and sstr5 . its short - term use as part of preoperative preparation for patients with tshomas can effectively control central hyperthyroidism , increase surgical safety , and present favorable long - term effects on proliferation , apoptosis , and tumor growth . we suggest that patients with tshoma can be managed with a combination of oct therapy and subsequent surgery , and recommend immunohistochemical staining to detect sstr subtypes in all surgical specimens . this study was supported by grants from the special research fund for public welfare industry heath ( no .201402008 ) , and the national high technology research and development program of china ( 863 program ; no . this study was supported by grants from the special research fund for public welfare industry heath ( no .201402008 ) , and the national high technology research and development program of china ( 863 program ; no .\noutput:\n" }, { "from": "agent", "value": "background : thyrotropin - secreting pituitary adenomas ( tshomas ) are a rare cause of hyperthyroidism . somatostatin ( sst ) analogs work by interacting with somatostatin receptors ( sstrs ) . this study aimed to evaluate short - term preoperative octreotide ( oct ) use in tshoma patients and to investigate sstr2 and sstr5 expression and observe structural changes in tumor tissue.methods : we reviewed records and samples from eight tshoma patients treated between july 2012 and july 2015 . we tested immunohistochemically for sstr2 / 5 expression and examined tshoma cells for morphological changes . signed rank sum test was used to compare the efficacy of short - term preoperative oct treatment.results : oct treatment ( median time : 7.9 days , range : 316 days ; median total dose : 1.8 mg , range : 0.94.2 mg ) led to significant decrease in all patients thyroid hormone levels ( ft3 [ nmol / l ] : 8.33 [ 7.02 , 12.29 ] to 4.67 [ 3.52 , 5.37 ] [ p = 0.008 ] ; ft4 [ pmol / l ] : 25.36 [ 21.34 , 28.99 ] to 16.66 [ 14.88 , 21.49 ] [ p = 0.016 ] ; and tsh [ u / ml ] : 5.80 [ 4.37 , 6.78 ] to 0.57 [ 0.19 , 1.24 ] [ p = 0.008 ] ) . all the eight tumor specimens expressed high sstr2 protein levels ; 5/8 expressed high sstr5 , but 3/8 that expressed low sstr5 presented a significantly higher tsh suppression rate ( p = 0.036 ) . electron microscopy showed subcellular level impairments , including clumped nuclear chromatin and reduced cytoplasmic volume . golgi complexes were observed in the oct - treated tshoma specimens.conclusions : oct can control hormone levels and damage the ultrastructure of tumor cells and organelles . short - term response to oct may be related to sstr5 expression . preoperative sst analog treatment for tshoma could be considered as a combination therapy ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: human milk has been considered as a package of essential nutrients ( vitamins , minerals , essential amino acids and fatty acids ) and is commonly known as the best kind of nutrition for neonates and infants for the first six months of life . studies documenting the protective effect of breast milk against various infectious diseases in infants are presented , including respiratory infections , diarrhea , otitis media , and infections in premature infants . in addition to numerous clinically significance of breastfeeding , it seems human milk has bioactive components that protect newborns from a hyperoxic challenge due to transition of life to an environment far richer in oxygen than intrauterine environment . oxygen is potentially toxic , because of the production of reactive oxygen species ( ros ) . since these components have the ability to interact with and alter essential cell molecules , they are extremely cytotoxic . antioxidant defense mechanisms of the body may prevent the production of ros or neutralize them . when the production of ros exceeds the capacity of the body s antioxidant defenses to detoxify them , a condition known as oxidative stress occurs . it is well believed that oxidative stress is involved in the pathogenesis of numerous neonatal diseases such as bronchopulmonary displasia , retinopathy of prematurity and necrotizing enterocolitis . human milk has a number of enzymatic and non enzymatic antioxidant constituents , like superoxide dismutase , glutathione peroxidase , catalase , vitamin e , vitamin c , - carotene , which may protect newborns against ros at the early stage of life . however , for the best benefits and functions , milk will always be recognized as a synergistic mixture of multiple interacting factors . in the other hand , the antioxidant status of breast milk seems to be affected by the maternal antioxidant status , which in turn , could influence the antioxidant status of the breast - fed infants . although data on the content of individual antioxidants in milk are available , there is a necessity in using methods for investigating the total antioxidant activity of milk . to measure all the antioxidant activity present in biological fluids , these assays are useful in getting a global picture of related antioxidant activities in body fluids and how they change in different conditions . the aim of this study is to evaluate the total antioxidant and free radical scavenging activity levels in human milk during the first six month period of lactation and its correlation with maternal plasma total antioxidant capacity . this evaluation was done by using the ferric reducing / antioxidant power ( frap ) assay and 1,1 - diphenyl -2-picrylhydrazyl ( dpph ) radical method as simple and reliable experiments adopted for this investigation . this study was approved by the ethics committees of the birjand university of medical sciences . a total of 115 healthy women ( 26.95.3 year old ) with normal pregnancy and delivery were included in this prospective consecutive study . exclusion criteria included gestation 37 weeks , birth weight 2.5 kg , multiple pregnancy , major illness requiring intensive care admission , and major congenital anomaly . we tried to take sample milk at 5 different times but due to missing some mothers at some points , our final samples were consist of 115 samples of colostrum at the first 21 days of postpartum , 97 samples of transitional milk at 73 days postpartum and 293 samples of mature milks in three times ( 102 at 303 days , 100 at 907 days and 91 at 18010 days postpartum ) , among them we had just 68 cases with 5 complete samples . the samples were taken by manual expression of each breast into 10 ml sterile containers between 9.0011.30 at morning and then aliquoted into 2 ml screw - top cryovials . blood samples were drawn by venipuncture ( 5 ml ) into heparinized tubes but due to some limitations we just took blood samples at 907 days postpartum for one time . the samples were immediately centrifuged to obtain plasma , which was then aliquoted into 2 ml cryovials and stored at 70c until analysis . the frap assay , developed by benzie and strain as a direct method for measuring the total antioxidant power of biological fluids , was adopted in this study . at low ph , reduction of a ferric 2,4,6 - tripyridyl - s - triazine [ fe ( iii ) - tptz ] complex to the ferrous 2,4,6 - tripyridyl - s - triazine [ fe ( ii ) - tptz ] complex , which has an intense blue color , can be monitored by measuring the change in absorption at 593 nm . the working frap reagent was prepared by mixing 10 volumes of 300 mmol / l acetate buffer , ph 3.6 , with 1 volume of 10 mmol / l tptz in 40 mmol / l hcl and 1 volume of 20 mmol / l fecl3 . a proper amount of sample ( 20 l of breast milk or 50 l of plasma ) was mixed with 1.5 ml of freshly prepared frap reagent and incubated at 25c for 10 min then reading was taken at 593 nm . to omit milk turbidity in experiments , 20 l of breast milk and adequate volume of acetate buffer , aqueous solutions of feso47h2o ( 1001000 m ) were used for the calibration and the results were expressed as frap value ( m fe ( ii ) ) of the samples . the free radical scavenging activity of milk samples were measured by the dpph method proposed by brand - williams , cuvelier , and berset with a slight modification . briefly , 100 l of each sample was added to 2 ml of dpph in ethanol solution ( 100 mm ) in a test tube . after incubation at 37c for 30 min , 1 ml of chloroform was added and centrifuged at 3000 g for 5 min . an ethanolic solution of dpph ( 100 mm ) was used as control and the percentage of dpph radical scavenging activity was calculated according to the following equation : scavenging activity ( % ) = [ ( absorbance of the controla paired - samples t test was used for comparison of means at different times with the colostrum samples and also statistical comparisons between all groups were made by analysis of variance ( anova ) with repeated measures . the frap assay , developed by benzie and strain as a direct method for measuring the total antioxidant power of biological fluids , was adopted in this study . at low ph , reduction of a ferric 2,4,6 - tripyridyl - s - triazine [ fe ( iii ) - tptz ] complex to the ferrous 2,4,6 - tripyridyl - s - triazine [ fe ( ii ) - tptz ] complex , which has an intense blue color , can be monitored by measuring the change in absorption at 593 nm . the working frap reagent was prepared by mixing 10 volumes of 300 mmol / l acetate buffer , ph 3.6 , with 1 volume of 10 mmol / l tptz in 40 mmol / l hcl and 1 volume of 20 mmol / l fecl3 . a proper amount of sample ( 20 l of breast milk or 50 l of plasma ) was mixed with 1.5 ml of freshly prepared frap reagent and incubated at 25c for 10 min then reading was taken at 593 nm . to omit milk turbidity in experiments , 20 l of breast milk and adequate volume of acetate buffer , aqueous solutions of feso47h2o ( 1001000 m ) were used for the calibration and the results were expressed as frap value ( m fe ( ii ) ) of the samples . the free radical scavenging activity of milk samples were measured by the dpph method proposed by brand - williams , cuvelier , and berset with a slight modification . briefly , 100 l of each sample was added to 2 ml of dpph in ethanol solution ( 100 mm ) in a test tube . after incubation at 37c for 30 min , 1 ml of chloroform was added and centrifuged at 3000 g for 5 min . an ethanolic solution of dpph ( 100 mm ) was used as control and the percentage of dpph radical scavenging activity was calculated according to the following equation : scavenging activity ( % ) = [ ( absorbance of the controla paired - samples t test was used for comparison of means at different times with the colostrum samples and also statistical comparisons between all groups were made by analysis of variance ( anova ) with repeated measures . the total antioxidant capacity and radical scavenging activity of breast milk in different times of lactation was presented in table 1 . according to the paired - samples t test , there was a significant higher level of total antioxidant capacity measured by frap assay in colostrum in comparison to transitional and mature milks . mol / l after six months of study . in the dpph test for radical scavenging activity , the colostrums were more potent ( 5020 % ) to reduce the stable radical dpph in comparison with transitional and mature milks . also statistical comparison were made by analysis of variance with repeated measures in cases with complete sampling ( n = 68 ) . these balanced data showed significant differences between the means of values at different times ( p = 0.015 ) . there was a significant correlation between the results of frap and dpph methods for total antioxidant capacity and radical scavenging activity of the samples of breast milk ( r = 0.562 , p 0.001 ) ( fig . 1 ) . the mean of maternal plasma antioxidant capacity was 842.0123.5 mol / l ranged from 565.2 to 1193.4 mol / l . this level was closely near to the mean of breast milk antioxidant capacity at 907 days that was 862.7457.7 mol / l and ranged from 121.5 to 3816 mol / l and there was a significant correlation between the maternal plasma and breast milk antioxidant capacity ( r = 0.267 , p 0.05 ) ( fig . 2 ) . in our research , the most significant result is that colostrums in comparison to transitional and mature milks has more total antioxidant activity decreasing during the course of lactation . there are only few reports that measured tac and free radical scavenging activity of breast milk . recently , the same pattern for total antioxidant capacity was reported by quiles et al . . they showed that the total antioxidant capacity of milk registered significantly higher values for colostrums compared with mature and transitional milk . these authors used 2,2 - azinobis ( 3 - ethylbenzothiazoline -6-sulfonic acid ) radical cation ( abts + ) assay for total antioxidant capacity of breast milk . they used biological antioxidant potential ( bap ) test for measuring of tac which is principally very similar to frap assay . also , fidanza et al . reported a high , but not significant antioxidant capacity in colostrumsthe reason for this difference is probably due to the type of the methods used for total antioxidant capacity of milk and the number of samples . they used orac ( oxygen radical absorbent capacity ) assay with 30 samples whereas we used frap assay with 115 samples . in the frap method the ability of the sample to reduce the ferric ion is used as a criterion on antioxidant capacity . ascorbic acid , - tochopherol , uric acid , bilirubin and phenolic compounds were found to have ferric - reducing activity , but this method was suggested to be unsuitable for proteins , glutathione and lipoic acid . dpph is a stable commercial available free radical using as a popular marker for screening of free radical scavenging activity of compounds or biological samples . this method measures hydrogen atom or electron - donating activity and the scavenging activity related to the structure of the active substances . since the activities of antioxidant may vary in different biological systems , it is necessary to employ several methods to measure total antioxidant capacity based on different principles . in our results , it is shown that there is a positive correlation between the results of the frap and dpph assays . so these simple , speedy and inexpensive methods may be considered as practical indicators of total antioxidant activity of biological samples and useful in all the studies concerning the evaluation of oxidative stress . high antioxidant capacity in colostrums can be effective in preventing newborns from exposure to an environment rich in oxygen after birth , 4 to 5 times as much as interauterine environment . there is some evidence that susceptible newborns , especially preterm ones , are potentially vulnerable to oxidative stress due to the inefficiency of their antioxidant defense system or increase in free radical production . in this situation damage to main molecules , lipids , proteins , carbohydrates and nucleic acids may increase . in this way , oxygen therapy in newborns with respiratory problems which can induce and intensify oxidative stress should be considered more cautiously . also it has been recently demonstrated that phototherapy for jaundiced neonates is related to increased oxidative stress and should be used with care . hence newborn feeding with the breast milk especially colostrums can be useful to neutralize free radicals and improve antioxidant system . it has been shown that 8 - oh deoxyguanosine levels as a sensitive marker for oxidative stress is lower in infants fed with breast milk compared with those fed with formula . in another reportan increase was also found in the frequencies of sister chromatid exchange of infants not breast - fed compared to those who were breast - fed . in addition according to epidemiologic studies , a reverse correlation between breast feeding and some diseases such as diabetes mellitus , cancer and cardiovascular diseases was found . in this studytotal antioxidant capacity of the breast milk showed a significant decrease during the course of lactation which can be a natural result of decline in antioxidant storage of the mothers . mothers with low values need more attention with regard to their nutrient intake , especially natural antioxidants during lactation . moreover , a significant correlation was observed between maternal plasma antioxidant capacity and their breast mature milk at 3rd month , which this situation may be observed in colostrum and transitional milk . this is in accordance with the result of vanderjagt et al . and can be used as a predictor of breast milk antioxidant capacity . despite closeness between the mean values of maternal plasma and breast milk antioxidant capacity , the variation among breast milk values is remarkable . on the other hand , since the uric acid concentration is lower in breast milk in comparison with plasma , equal and higher levels of breast milk antioxidant capacity indicate that milk is concentrated for some antioxidants . these data suggest that using colostrum , with high antioxidant capacity and radical scavenging activity during the first days of life is vital ; moreover , reduction in total antioxidant capacity during the course of lactation and its relation to maternal antioxidant status needs more attention about nutritional status of mothers . more investigations prefer to evaluate the in vivo efficacy of breast milks with different levels of total antioxidant capacity .\noutput:\n" }, { "from": "agent", "value": "human milk from healthy women contains numerous nutrients such as antioxidants which are necessary for newborns . the aim of this study was to evaluate the changes of total antioxidant capacity ( tac ) and free radical scavenging activity in human milk during the first six month period of lactation and also its relationship to maternal plasma . a total of 505 milk samples ( colostrum , transitional and mature milks ) collected from 115 healthy women with full term newborns . blood plasma was obtained from 58 women at 3 months postpartum . the tac of samples were measured by ferric reducing / antioxidant power assay and free radical scavenging activity were evaluated using 1,1 - diphenyl -2-picrylhydrazyl ( dpph ) radicals . tac was obviously higher in colostrums than transitional and mature milks . similar results were observed for dpph radical scavenging activity of the samples . there was a high significant correlation between the results of these two methods . the relationship between the antioxidant content of human milk and maternal plasma was also significant . these data suggest that using colostrum , with high antioxidant potential during the first days of life is vital ; moreover , reduction in total tac during the course of lactation may needs more attention about nutritional status ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: neurogenic pulmonary edema ( npe ) is a fatal complication of severe insults to the central nervous system .1,2 it is proposed that neurogenic pulmonary edema is a functional disturbance provoked by adverse stimuli from outside the lungs and that in the rat , the pulmonary afferent fiber is essential to the production of this edema .3 autonomic nervous dysfunction , possibly sympathetic nerve over - excitation or vagus nerve dysfunction by vagotomy or by lesion of vagal nuclei in the medulla , has been show to induce npe .2 studies involving npe by intracisternal injection of fibrinogen and thrombin have indicated that bilateral vagotomy or the treatment with atropine increased the severity of the edema .4 vagotomy increases the amount of edema for a given degree of pulmonary hypertension .5 vagotomy - induced pulmonary edema has been discussed as neurogenic pulmonary edema . the lungs of vagotomized rats showed alveolar edema .6 blood volume and hematocrit reading became considerably reduced during the development of acute pulmonary edema caused by bilateral cervical vagotomy , depending on whether pulmonary hemorrhage occurs as a complication of the edema and congestion .7 since 1966 , it has been proposed that bilateral interruption of afferent impulses of the tenth cranial nerve is the factor that initiates vagotomy - induced lung edema .8 a subsequent observation concluded that vagal capsaicin - sensitive nerves wielded an inhibitory effect on the development of fibrin injection into the cisterna magna - induced pulmonary edema .9 it was proposed that an unknown neurotransmitter released from capsaicin - sensitive nerves may participate in increasing the lung vascular permeability caused by sympathetic nerve stimulation and that norepinephrine may also play a role in the regulation of permeability through alpha - and beta - adrenoceptors .10 it has been recognized that the main site of nitric oxide ( no ) production in the circulatory system is in the lungs .11 no is produced by a group of enzymes known as nitric oxide synthases ( nos ) . three isoforms of nos have been identified , including two constitutive forms : neuronal ( nnos ) and endothelial ( enos ) , and an inducible form ( inos ) . no is a potent vasodilator in bronchial circulation and may play an important role in regulating airway blood flowexcess amounts of no may cause hypotension associated with sepsis , and decreased no levels within the lungs may contribute to the pathologic states associated with pulmonary hypertension . no may also play a critical role in ventilation - perfusion coupling in the lung . this theory is supported by the fact that endogenous no levels in the lung change rapidly in direct proportion to inspired oxygen .12 no has been related to pulmonary edema of various etiologies . pulmonary exhaled no was lower in mountaineers prone to high - altitude pulmonary edema than in those resistant to this condition .13,14 reduced exhaled no may be as a result of altered pulmonary no synthesis and / or transport and clearance , in line with the hypothesis that , in these subjects , a defect in pulmonary epithelial no synthesis may contribute to exaggerated hypoxic pulmonary vasoconstriction and , in turn , to pulmonary edema .13 it was also observed that susceptible subjects have decreased nitrate - nitrite concentrations in bronchoalveolar fluid at high altitude , while resistant subjects have increased concentrations , further supporting a critical role for endogenous no production in maintaining lower pulmonary vascular resistance .15 l - arginine , a no synthase substrate , and n - nitro - l - arginine ( l - nna ) , a no synthase inhibitor , prevented and aggravated , respectively , the increase in pulmonary vascular permeability induced by radiologic contrast medium at high doses , in rats .16 pretreatment with nos inhibitors , such as n - nitro - l - arginine methyl ester ( l - name ) , aminoguanidine and dexamethasone , significantly reduced endotoxin - induced pulmonary edema . overproduction of no was considered detrimental to the lung and exerted toxic effects on the pulmonary endothelial layer .11 however , the involvement of no in npe has not yet been evaluated . the main objective of this study was to evaluate the involvement of peripheric no and its enzymatic production in rats with vagotomy - induced pulmonary edema , by assessing the participation of the cnos and inos pathways in this mechanism . to this end , some animals were pretreated with l - name , a cnos inhibitor , and others with aminoguanidine , a relatively specific inos inhibitor . experimental protocols were performed in accordance with the guide for the care and use of laboratory animals and the ethical principles for animal experimentation , established by the brazilian committee for animal experimentation ( cobea ) , and in accordance with the animal experimentation ethics committee of the state university of londrina ( ceea / uel ) . adult male wistar rats ( n = 167 ) , weighing 250320 g , were distributed into 14 groups : c control animals ( n = 14 ) ; v vagotomized animals ( n = 14 ) ; cl 0.3 ( n = 11 ) ; cl 3.0 ( n = 11 ) ; cl 39 ( n = 11 ) control animals pretreated with 0.3 mg / kg , 3.0 mg / kg or 39.0 mg / kg l - name , respectively ; vl 0.3 ( n = 14 ) ; vl 3.0 ( n = 9 ) ; vl 39 ( n = 8 ) vagotomized animals pretreated with 0.3 mg / kg , 3.0 mg / kg or 39.0 mg / kg l - name , respectively ; ca 5 ( n = 11 ) ; ca 10 ( n = 11 ) ; ca 20 ( n = 11 ) control animals pretreated with 5.0 mg / kg , 10.0 mg / kg or 20.0 mg / kg aminoguanidine , respectively ; va 5 ( n = 14 ) ; va 10 ( n = 14 ) ; va 20 ( n = 14 ) vagotomized animals pretreated with 5.0 mg / kg , 10.0 mg / kg or 20.0 mg / kg aminoguanidine , respectively . pretreatment consisted of an intravenous injection of l - name or aminoguanidine 10 minutes before surgery . the drugs utilized in this study were : n ( g ) - nitro - l - arginine methyl ester , l - name ( rbi ) and aminoguanidine ( sigma co. , st louis , mo , usa ) . in controls and vagotomized rats , the vagus nerve was identified and separated from the common carotid artery . in vagotomized animals , those that died during this period were noted , along with their time of death . survivors were sacrificed , under ether anesthesia by severing the inferior vena cava and draining the blood . after the animals ' death , the trachea was cannulated in order to observe tracheal fluid and to classify the severity of pulmonary edema . by way of thoracic incision , lungs were removed and weighed to evaluate pulmonary weight gain and edema index . the severity of pulmonary edema was graded by a method proposed by hamdy et al . , with modifications .17 the edema was graded from 0 to 2 , according to the presence of fluid in the trachea , with 0 for none and 2 for severe . when edema fluid spontaneously appeared in the tracheal tube after opening the chest , the edema was classified as grade 2 . if fluid appeared in the tracheal tube only when the lungs were gently pressed , the edema was grade 1 . when edema fluid did not appear at all , even under gentle pressure , the grade was 0 . as previously proposed , edema was evaluated from the ratio of pulmonary weight : body weight ( 100xpw / bw ) ; this ratio is still in use as the edema index .18 differences between means and the se were examined for significance by anova , followed by tukes multiple comparison test . survival time was examined by student 's t - test , comparing each pair of control to vagotomized animals , vagotomized to vagotomized pretreated with drugs and the pairs of control and vagotomized animals pretreated with drugs . experimental protocols were performed in accordance with the guide for the care and use of laboratory animals and the ethical principles for animal experimentation , established by the brazilian committee for animal experimentation ( cobea ) , and in accordance with the animal experimentation ethics committee of the state university of londrina ( ceea / uel ) . adult male wistar rats ( n = 167 ) , weighing 250320 g , were distributed into 14 groups : c control animals ( n = 14 ) ; v vagotomized animals ( n = 14 ) ; cl 0.3 ( n = 11 ) ; cl 3.0 ( n = 11 ) ; cl 39 ( n = 11 ) control animals pretreated with 0.3 mg / kg , 3.0 mg / kg or 39.0 mg / kg l - name , respectively ; vl 0.3 ( n = 14 ) ; vl 3.0 ( n = 9 ) ; vl 39 ( n = 8 ) vagotomized animals pretreated with 0.3 mg / kg , 3.0 mg / kg or 39.0 mg / kg l - name , respectively ; ca 5 ( n = 11 ) ; ca 10 ( n = 11 ) ; ca 20 ( n = 11 ) control animals pretreated with 5.0 mg / kg , 10.0 mg / kg or 20.0 mg / kg aminoguanidine , respectively ; va 5 ( n = 14 ) ; va 10 ( n = 14 ) ; va 20 ( n = 14 ) vagotomized animals pretreated with 5.0 mg / kg , 10.0 mg / kg or 20.0 mg / kg aminoguanidine , respectively . pretreatment consisted of an intravenous injection of l - name or aminoguanidine 10 minutes before surgery . the drugs utilized in this study were : n ( g ) - nitro - l - arginine methyl ester , l - name ( rbi ) and aminoguanidine ( sigma co. , st louis , mo , usa ) . in controls and vagotomized rats , the vagus nerve was exposed through a midline incision in the neck . the vagus nerve was identified and separated from the common carotid artery . in vagotomized animals , all animals were observed for 120 minutes . those that died during this period were noted , along with their time of death . survivors were sacrificed , under ether anesthesia by severing the inferior vena cava and draining the blood . after the animals ' death , the trachea was cannulated in order to observe tracheal fluid and to classify the severity of pulmonary edema . by way of thoracic incision , lungs were removed and weighed to evaluate pulmonary weight gain and edema index . the severity of pulmonary edema was graded by a method proposed by hamdy et al . , with modifications .17 the edemawas graded from 0 to 2 , according to the presence of fluid in the trachea , with 0 for none and 2 for severe . when edema fluid spontaneously appeared in the tracheal tube after opening the chest , the edema was classified as grade 2 . if fluid appeared in the tracheal tube only when the lungs were gently pressed , the edema was grade 1 . when edema fluid did not appear at all , even under gentle pressure , the grade was 0 . as previously proposed , edema was evaluated from the ratio of pulmonary weight : body weight ( 100xpw / bw ) ; this ratio is still in use as the edema index .18 differences between means and the se were examined for significance by anova , followed by tukes multiple comparison test . survival time was examined by student 's t - test , comparing each pair of control to vagotomized animals , vagotomized to vagotomized pretreated with drugs and the pairs of control and vagotomized animals pretreated with drugs . our data showed that vagotomy promoted the development of pulmonary edema , as , in the vagotomized rats , the pulmonary weight ( g ) ( 2.600.31 ) and edema index ( 0.940.10 ) were higher than the pulmonary weight ( g ) ( 1.500.06 ) and edema index ( 0.540.01 ) of the control animals ( figures 1 and 2 ) . among vagotomized rats ( n = 14 ) , four animals died during the experimental period ( figure 3 ) and five animals developed grade 2 edema ( tables 1 and 2 ) . the effects observed in vagotomized animals pretreated with l - name varied according to the dose ( figure 1 ) . the highest dose , 39 mg / kg , reduced the edema index ( 0.580.02 ) and no animal in the group vl39 suffered edema grade 2 ( table 1 ) . on the other hand , at the lowest dose , 0.3 mg / kg , the pulmonary weight ( g ) ( 2.970.28 ) and edema index ( 1.000.10 ) remained high and , out of the 14 animals in the group vl0 .3 , 6 had edema grade 2 ( table 1 ) . the dose of 3.0 mg / kg promoted intermediate effects between the other two doses ( figure 1 ) . treatment with 39 mg / kg also prolonged the survival of the animals while , in the group pretreated with 0.3 mg / kg l - name , eight rats died during the observation period ( figure 3a ) . the results observed in control animals treated with l - name or with aminoguanidine were similar to those in the control animals without treatment . all three doses of aminoguanidine treatment reduced the pulmonary weight , the edema index and the edema grade in vagotomized rats ( figure 2 and table 2 ) . the objective of the present study was to assess the involvement of no pathways in the development of pulmonary edema . it was observed that the largest dose of l - name inhibited the development of pulmonary edema induced by vagotomy in the group vl39 and prolonged the survival of those animals , while the smallest dose did not promote the same effects . on the other hand , treatment with aminoguanidine , regardless of the dose administered , inhibited the development of the edema . our data suggest that no production from inos is involved in the pulmonary edema induced by vagotomy and , on the contrary , no derived by cnos seems to have protective effects against this type of edema . in rats , the vagus nerve and the sympathetic trunk are anatomically adjacent . hence , in the vagotomy performed in the present study , the sympathetic branch could be damaged , too . in early studies of pulmonary edema following vagotomyit was shown that when the midcervical vagosympathetic trunk in guinea pigs was severed , bilateral interruption of afferent impulses of the tenth cranial nerve was the factor that initiated lung edema .8 this edema was developed in artificially ventilated guinea pig ,19 and tracheotomy had no demonstrable effect in vagotomized rats submitted to moderate pulmonary congestion .7 the observation that edema induced by fibrinogen and thrombin was increased by bilateral vagotomy , or by treatment with atropine , indicates that efferent cholinergic fibers in the vagus nerve may play a role in lowering the severity of pulmonary edema .4 in a subsequent experiment involving the use of capsaicin , it was observed that afferent vagal impulses could exert an inhibitory effect on the development of fibrin - induced npe .9 moreover , it was observed that pretreatment with atropine attenuated pulmonary edema in spinal cord - injured rats .20 a hypothesis was introduced that early administration of high atropine doses can prevent npe development on the basis of the attenuation of heart rate decrease , which was recognized as an important factor of neurogenic pulmonary edema formation .21 in rats , bilateral vagotomy increased the incidence of npe .17 the rats that suffered vagotomy in our study developed a higher pulmonary edema index than the controls . among vagotomized rats , similar results were observed in rats treated with a dose of 0.3 mg / kg of l - name , which had a high edema index . although these results represent development of edema , not all animals showed a degree of edema . in our opinion , this is because of the fact that the rats were observed for a period of only 120 minutes and not until death , when more animals would possibly have developed edema . the establishment of an observation period followed by sacrifice of those who survived could also justify the degree of variance observed in the results presented . the incidence of pulmonary edema in rats promoted by intracisternal injection of fibrinogen and thrombin associated with vagotomy was related to the high ( 25 mg / kg or 50 mg / kg ) doses of pentobarbital anesthesia .4 it was later observed that neurogenic pulmonary edema in rats was more pronounced in pentobarbital - anesthetized ( 60 mg / kg ) rats compared with xylazine - ketamine anesthesia22 and that it developed in rats anesthetized with 1.5 % isoflurane , but not in those anesthetized with 3 % isoflurane ,20 illustrating that anesthetic drugs used in experimental neurogenic pulmonary edema may be an important factor in the genesis of edema . in the present studynpe has been also associated with pulmonary vascular permeability .17 concerning the mechanism of involvement of no in the maintenance of liquid balance in isolated rabbit lung , it was found that inhibition of no production with l - name caused a significant increase in the rate of weight gain , while the addition of lodoxamide or 8 br - cgmp attenuated this increase .23 these findings suggest a role for endogenous no in the relaxation of endothelial cells and also in helping to prevent pulmonary edema by stabilizing mast cells . thus , no production mediated by inos has been considered to exert a toxic effect on the pulmonary endothelial layer once l - name ( 10 mg / kg ) , aminoguanidine ( 15 mg / kg ) or dexamethasone ( 3 mg / kg ) all attenuated endotoxin - induced pulmonary edema .11 as inos has been implicated in the pathophysiology of congestive heart failure , it was hypothesized that inos deficiency would reduce the severity of congestive heart failure in mice . however , it was found that deficiency of inos did not significantly affect severe congestive heart failure in mice after myocardial infarction .24 according to the proposed involvement of no produced by inos mediation on pulmonary edema , it was suggested that morphine had a prophylactic effect on - naphthylthiourea - induced lung damage through inhibition of inos expression .18 the results observed in the present study demonstrate that the inhibition of no production through inos promoted an attenuation of vagotomy - induced pulmonary edema . thus , it is likely that , in this experimental model , no produced by inos is involved in the development of pulmonary edema . our group observed a similar result where pulmonary edema induced by endotoxemia was attenuated by aminoguanidine and worsened by l - name in control and exercise - trained animals .25 l - name increases weight gain in isolated perfused rabbit lung . the authors suggested that no had a protective role in the maintenance of normal pulmonary vascular permeability .23 moreover , it was observed that up - regulation of enos is a protective mechanism against inflammatory pulmonary damage following ischemia reperfusion .26 also , the role of no in the development of npe in spinal cord - injured rats was considered protective considering that acute treatment with l - name ( 30 mg / kg ) just before the injury enhanced npe severity .20 however , no data in the literature has studied the involvement of both pathways of no production in neurogenic pulmonary edema . l - name was considered an inhibitor of cnos , however , it may also inhibit inos at a dose of 10 mg / kg .11,27 the treatment of vagotomized rats with 39 mg / kg of l - name promoted a reduction in pulmonary edema , that was statistically different when compared with the group treated with 0.3 mg / kg of l - name , and the treatment with aminoguanidine ( at any dose ) reduced the incidence of pulmonary edema in vagotomized rats , as well as in the animals treated with the highest dose of l - name . our hypothesis is that the non - selective blockade of cnos by administering the highest dose of l - name could also inhibit the inos pathway . thus , cnos appears to participate in the mechanism of pulmonary edema induced by vagotomy , as a protective mechanism . on the other hand\noutput:\n" }, { "from": "agent", "value": "objective : the objective of this study was to evaluate the involvement of peripheral nitric oxide ( no ) in vagotomy - induced pulmonary edema by verifying whether the nitric oxide synthases ( nos ) , constitutive ( cnos ) and inducible ( inos ) , participate in this mechanism.introduction : it has been proposed that vagotomy induces neurogenic pulmonary edema or intensifies the edema of other etiologies.methods : control and vagotomized rats were pretreated with 0.3 mg / kg , 3.0 mg / kg or 39.0 mg / kg of l - name , or with 5.0 mg / kg , 10.0 mg / kg or 20.0 mg / kg of aminoguanidine . all animals were observed for 120 minutes . after the animals ' death , the trachea was catheterized in order to observe tracheal fluid and to classify the severity of pulmonary edema . the lungs were removed and weighed to evaluate pulmonary weight gain and edema index.results : vagotomy promoted pulmonary edema as edema was significantly higher than in the control . this effect was modified by treatment with l - name . the highest dose , 39.0 mg / kg , reduced the edema and prolonged the survival of the animals , while at the lowest dose , 0.3 mg / kg , the edema and reduced survival rates were maintained . aminoguanidine , regardless of the dose inhibited the development of the edema . its effect was similar to that observed when the highest dose of l - name was administered . it may be that the non - selective blockade of cnos by the highest dose of l - name also inhibited the inos pathway.conclusion : our data suggest that inos could be directly involved in pulmonary edema induced by vagotomy and cnos appears to participate as a protector mechanism ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: angioplasty with stenting is a well - established alternative to carotid endarterectomy ( cea ) for carotid artery stenosis . the advent of proximal occlusion devices and distal filter embolic protection devices ( epd ) have reduced the risk of embolic stroke . however , an improperly placed stent may prevent retraction of the epd within the capture sheath . few cases have been reported , and no clear guidelines exist on management . we report a case of retained stenting hardware left in situ , leading to subsequent complications requiring surgical intervention . a 57 - year - old male in beijing , china underwent carotid artery stenting via transfemoral approach for severe ( 90 % ) asymptomatic right internal carotid artery ( ica ) stenosis ( fig . a neurosurgical team at an outside facility performed the procedure using a 5 - mm spiderfx distal filter epd and ev3 protg 830 mm rx stent ( covidien ; plymouth , mn , usa ) . during deployment , this stent ( referred to as stent 1 ) inadvertently migrated cephalad and became lodged onto the epd . despite multiple attempts , the epd was unable to be retrieved with the capture sheath . the physicians placed another ev3740 mm protg rx stent in the right ica to compress the epd and guidewire against the arterial wall . we refer to this as stent 2 , which was placed at the c1c2 vertebral level , superior to stent 1 ( fig . the patient was discharged on aspirin and clopidogrel , with the retained guidewire sutured in place at the groin . at time of discharge , the ica stenosis had not been resolved . figure 1 : ( a ) digital subtraction angiography of patient prior to angioplasty with 90 % stenosis of the ica . ( c ) reconstructed ct image in anterior view showing the 3 guidewire fragments ( fragments a , b , c ) and the 2 carotid stents ( stent 1 and stent 2 ) in the right ica . ( d ) reconstructed ct image in the right lateral view of guidewire fragments and stents . ( a ) digital subtraction angiography of patient prior to angioplasty with 90 % stenosis of the ica . ( b ) fractured guidewire when patient presented to our facility . ( c ) reconstructed ct image in anterior view showing the 3 guidewire fragments ( fragments a , b , c ) and the 2 carotid stents ( stent 1 and stent 2 ) in the right ica . ( d ) reconstructed ct image in the right lateral view of guidewire fragments and stents . one month after discharge , the patient began experiencing substernal chest pain radiating to the neck with right suborbital pain . he was referred to our cardiovascular surgical team at the anzhen stroke center for further management . upon presentation , we found moderate ( 55 % ) stenosis in the right common carotid artery ( cca ) and severe ( 90 % ) stenosis in the ica inferior to stent 1 . the most superior of the three guidewire fragments ( fragment a ) , still attached to the epd , was compressed by stent 2 and extended into the cca ( fig . was adhered to the right cca wall by local fibrin deposits . the inferior fragment ( fragment c ) extended from the right femoral artery to the thoracic aorta , where it punctured the proximal aortic arch wall ( fig . thrombus had also formed along the entire 1 - meter length of fragment c. figure 2 : ( a ) the inferior aspect of fragment c extended down to the femoral artery . ( a ) the inferior aspect of fragment c extended down to the femoral artery . ( b ) the superior aspect of fragment c penetrated the thoracic aorta . given the risks of dislodging emboli during surgery , we initially considered employing two additional stents one to manage the stenosis and another to compress and stabilize fragment b. however , this would not resolve the fragmented guidewire . with the patient , we agreed upon cea and surgical removal . due to the extremely superior cervical location of the epd , it was not likely to be amenable to surgical retrieval . a second surgery was scheduled for a later time to remove fragment c. we performed cea at the right ica , after which stent 1 was cut open longitudinally and excised . since stent 2 was located more superiorly ( c1c2 vertebral level ) and had accrued significant thrombotic material since the initial stenting procedure , we were unable to safely remove it . fragment a was connected to the edp and compressed against the arterial wall by stent 2 . we cut fragment a near the stent and removed the freed portion of this fragment . intraoperative ultrasound confirmed the location of fragment b in the right cca ( t1 vertebral level ) . we extended the cca incision inferiorly to visualize the length of fragment b , which was then removed intact using an artery clamp . ( b ) ct image showing patent vasculature at 30 months post - operation . ( a ) guidewire fragments and stent 1 after removal from the patient . the endarterectomy incision was repaired with polytetrafluoroethylene carotid patch , and intact vasculature was confirmed via fluoroscopy . after a 1 - week recovery in the intensive care unit , the patient returned to the operating room for removal of fragment c , which was piercing the aortic arch . via median thoracotomya 6 - fr sheath was used to entrap thrombotic material as the guidewire was removed from femoral artery without incidence . carotid vasculature remained patent with sufficient flow , and stent 2 was still in place 30 months post - operatively ( fig .3 b ) . while the patient will require close follow - up , no complications have been reported to date , over 3 years after surgery . although rare , the risk of hardware entrapment should be considered during stenting procedures . when the epd is irretrievable , it is not suitable to leave it in situ . potential complications are imminent , ranging from vasospasm , thrombosis and embolism , guidewire fracture and vessel injury including carotid artery dissection . rigorous quality assurance practices are still lacking in many low - and middle - income countries , and despite china 's upper - middle income status , training and practice quality varies within the country , even in large urban settings . given the patient 's lack of comorbidities , a primary cea should have been performed to treat his stenosis . although successful interventional management has been reported , physicians must not hesitate to consider surgery if such methods prove futile . a robust referral system must be available for timely transfers of patient care within and between hospitals . there is growing impetus for such enhanced monitoring and quality measurement systems as china undergoes major healthcare reform . bolstering regulations on reporting and establishing best practices guidelines may prevent such adverse complications in the future .\noutput:\n" }, { "from": "agent", "value": "entrapment and fracture of carotid angioplasty and stenting hardware is a rare complication of percutaneous stenting procedures . we describe a case of a retained distal filter embolic protection device and guidewire in a 57 - year - old male in beijing , china . after unsuccessful attempts at removal via interventional methods , a second stent was deployed to secure the original hardware in situ , and the patient was discharged . he later experienced guidewire fragmentation in the carotid artery and aortic arch , with subsequent thrombus formation . we report partial removal of the guidewire and stent via carotid artery cutdown and open thoracotomy without complication . when efforts to retrieve stenting hardware are unsuccessful , it is never a suitable choice to leave them within the artery . we advocate for early surgical management of retained materials after unsuccessful carotid artery stenting . furthermore , improved quality monitoring and assurance programs are needed to prevent such complications in the future ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: decompressive craniectomy , which is performed worldwide for the treatment of severe traumatic brain injury ( tbi ) , is a surgical procedure in which part of the skull is removed to allow the brain to swell without being squeezed .1 although there is still controversy about the efficacy of the procedure in improving patient outcome , it is still widely used as a last resort in those patients with uncontrollable intracranial pressure ( icp ) . several retrospective and prospective studies have suggested the efficacy of decompressive craniectomy in decreasing icp and improving prognosis in patients with refractory intracranial hypertension after tbi .2 - 8 presently , the european brain injury consortium and brain trauma foundation guidelines for severe tbis refers to decompressive craniectomy as a second - tier therapy for refractory intracranial hypertension that does not respond to conventional therapeutic measures .9 , 10 to further determine the risks and benefits of this procedure and to define the role of decompressive craniectomy in the management of patients with severe tbi , several prospective randomized trials are underway . as early as 1901 , kocher was the first surgeon to promote surgical decompression in post - traumatic brain swelling .11 there are currently various decompressive craniectomy methods and technical improvements that have progressed the treatment of tbi . in this article , the technical changes in decompressive craniectomy in the treatment of severe tbi are reviewed . different methods of decompressive craniectomy have been developed for , or applied to , decompression of the brain at risk for the sequelae of traumatically elevated icp . these include subtemporal decompression ,12 - 14 circular decompression ,15 fronto - or temporoparietal decompressive craniectomy ,8 , 16 large fronto - temporoparietal decompressive craniectomy , hemisphere craniectomy , and bifrontal decompressive craniectomy .7 - 10 , 17 circular decompression was introduced decades ago . however , for patients who develop refractory intracranial hypertension , it is unable to take effect , because of the limited space .15 the procedure of subtemporal craniectomy , which was introduced by cushing ,11 involves removing the part of the skull beneath the temporal muscle by opening the dura . this was an important surgical method for the treatment of severe tbi with refractory intracranial hypertension for a time , and was shown to produce good results by some investigators .12 - 14 although it is still used in many centers , similar to circular decompression , the area of the skull removed is small and the room that it can provide for the expansion of the brain is restricted ; furthermore , this procedure may lead to temporal lobe herniation and necrosis .18 a study performed by alexander et al. demonstrated that the calculated additional space provided by subtemporal decompression ranged from 26 to 33 cm .12 generally , this space is inadequate when a patient develops diffuse cerebral swelling . by removing part of the skull , decompressive craniectomy seeks to prevent herniation and to reconstruct cerebral blood perfusion to improve patient outcome . the decompressive effect depends primarily on the size of the part of the skull removed . a small craniectomy may be helpful for preventing herniation ; however , considering its limited effect on refractory intracranial hypertension , the aim of reconstructing cerebral blood perfusion is almost impossible . at present , the more widely used methods are large unilateral fronto - temporoparietal craniectomy / hemisphere craniectomy for lesions or swelling confined to one cerebral hemisphere , and bifrontal craniectomy from the floor of the anterior cranial fossa to the coronal suture to the pterion for diffuse swelling . munch et al . found that large fronto - temporoparietal craniectomy could provide as much as 92.6 cm additional space ( median , 73.6 cm ) .14 large decompressive craniectomies , including fronto - temporoparietal / hemisphere craniectomy and bifrontal craniectomy , seemed to lead to better outcomes in patients with severe tbi compared with other varieties of surgical decompression in previous literature .7 , 8 , 18 the most direct proof was provided by jiang et al : a prospective , randomized , multi - center trial suggested that large fronto - temporoparietal decompressive craniectomy ( standard trauma craniectomy ) significantly improved the outcome in severe tbi patients with refractory intracranial hypertension , compared with routine temporoparietal craniectomy , and had a better effect in terms of decreasing icp .8 consequently , large decompressive craniectomy has been recommended by most authors , and prospective studies that are underway to further determine the role of surgical decompression in the management of tbi have adopted it as a standard procedure . decompressive craniectomy is sometimes combined with a simultaneous lobectomy .19 , 20 in our opinion , this should be performed with caution because excessive excavation of brain tissue may lead to poor results , though the icp could be reduced rapidly .19 normally , decompressive craniectomy is performed together with dura opening , and it was believed that this could maximize brain expansion after removal of part of the skull . however , opening the dura with no protection for the underlying brain tissue may increase the risk of several secondary surgical complications , such as brain herniation through the craniectomy defect ,21 , 22 epilepsy ,23 , 24 intracranial infection ,4 and cerebrospinal fluid ( csf ) leakage through the scalp incision16 or contralateral intracranial lesion .25 currently , decompressive craniectomy combined with augmentative duraplasty is widely performed and is recommended by most authors .11 , 26 the temporary removal of a piece of skull followed by loose closure of the dura and skin layers presumably allows for expansion of the edematous brain into a durotomy bag under the loosely closed scalp without restriction by the hard skull ; the dura would also protect the underlying brain tissue with prevention from over - cephalocele . yang et al . found that the patients who underwent decompressive craniectomy combined with initially augmentative duraplasty had better outcomes and lower incidences of secondary surgical complications ( such as hydrocephalus , subdural effusion , and epilepsy ) compared with those who only underwent surgical decompression , leaving the dura open .16 at present , large decompressive craniectomy combined with enlargement of the dura by duraplasty is used by most research groups and seems to have the most favorable results . several prospective studies have agreed that the procedure of decompressive craniectomy with simultaneous augmentative duraplasty would also be able to control refractory intracranial hypertension and play a beneficial role in patients with severe tbi . coplin et al . performed a prospective trial on the feasibility of craniectomy with duraplasty versustraditional craniotomy as a control group in patients who developed brain swelling , and found that despite more severe head trauma , the patients in the study group had similar outcomes to the control group .27 ruf et al. performed decompressive craniectomy and simultaneous dural augmentation with duraplasty in six children whose elevated icps could not be controlled with maximally intensified conservative therapies . subsequently , the icp normalized , with improved outcomes after the procedure .4 figaji et al . reported prospective studies on 12 patients who had undergone decompressive craniectomy with augmentative duraplasty . in this case series , the mean icp reduction was 53.3 % and clinical improvement as well as reversion of radiographic data was attained in most patients ( 11/12 ) ; all 11 survivors had good outcomes ( gos 4 or 5 ) .28 additionally , several other pathological indices improved after this combined procedure , including cerebral blood perfusion and cerebral oxygen supply .29 , 30 these results showed that large decompressive craniectomy combined with augmentative duraplasty has favorable decompressive effects in the treatment of traumatic refractory intracranial hypertension compared with surgical decompression with dura opening . however , no well - planned study has compared the two methods , and in many centers , decompressive craniectomy with complete dura opening is still performed routinely . technical improvements have been made to this surgical procedure . as mentioned above , whether it is combined with augmentative duraplasty or dura opening , decompressive craniectomy is recommended to be performed as a large craniectomy for severe tbi , including large fronto - temporoparietal / hemisphere craniectomy and bifrontal craniectomy .5 , 8 , 10 , 17 in decompressive craniectomy , preserving the inferior temporal lobe venous return requires that the craniectomy comes down to the floor of the middle cranial fossa , at the root of the zygoma ; this ensures adequate lateral decompression of the temporal lobe , allowing it to fall out of its usual calvarial boundaries . moreover , the following discussion about technical improvements is based on the procedure of large decompressive craniectomy . two main methods are used for dural augmentation with duraplasty : the dura is enlarged with the patient 's own tissue , such as temporal fascia , temporal muscle , or galea aponeurotica ,16 , 18 , 31 or this is performed with artificial or xenogeneic tissue , such as artificial dura substitute or bovine pericardium .27 , 28 in our institute , dural augmentation was performed with temporal fascia or artificial meninges . the method using temporal fascia is similar to the one introduced by yu et al. 32 they separated the temporal deep fascia from the temporal muscle to the zygomatic arch , and then cut the fascia from the base backwards along the zygoma but left the fascia base 1 - 2 cm long for the blood supply . finally , they turned the temporal fascia beneath the temporal muscle and sutured it to the dura . generally , temporal deep fascia is large enough for the enlargement of dura in during decompressive craniectomy , and forms a pedicle of temporal fascia that maintains the blood supply . brain herniation via the craniectomy defect may lead to compression of vessels and result in ischemic necrosis of the portion of the herniated brain . coskay et al . introduced an interesting method called the vascular tunnel to avoid this complication .33 following removal of part of the skull , they performed dural incisions in a stellate fashion . in this step , it is important that entrance points of major vessels are close to the midpoint between the angles of the dural opening . the most significant step involves constructing small supporting pillars on the bilateral sides of the vessels as they pass the edge of the dural window ( the pillars were made of hemostastic sponge wrapped by absorbable thread ) , and then the superficial vessels supporting the portion of brain run in the artificial vascular tunnel between the brain tissue and dura . , they performed this new technique with decompressive craniectomy in 21 patients , and the vascular tunnel method seemed to improve patient outcome compared with a control group consisting of 20 patients who underwent ordinary large decompressive craniectomy .34 another method , lattice duraplasty , was also introduced by mitchell et al. 35 to avoid herniation of the brain through the cranial defect . after conventional craniotomy , they made a series of dural incisions , each 2 cm long and with 1 - cm intervals . the process was repeated in parallel rows of incisions so that each incision in one row was adjacent to an intact dural bridge in the rows on either side . the same course was then performed , but in a direction vertical to the initial incision . this method was believed to be able to increase the tractility of the dura and to allow it to stretch and expand . they performed decompressive craniectomy combined with this technical improvement in six patients , and found that icp was reduced , by 20 - 30 mmhg . after decompressive craniectomy , patients are typically without a cranial flap for several months before cranioplasty , which places them at theoretical risk of injury to the unprotected brain . moreover , with the skin flap concavity , the hydrodynamic disturbance of csf circulation and the decrease in cortical perfusion after decompressive craniectomy may also hinder patient recovery .36 - 37 a method called the tucci flap was suggested by claudia et al . to resolve this problem .39 after craniotomy , removal of the intracranial lesion , and duraplasty , the bone flap was replaced and one side of the flap was attached to the cranium by plates . the plates act as a hinge that allows the unattached portion of the bone flap to float out with bone swelling . a similar technique was introduced by kathryn et al . , but was called an in situ hinge craniectomy .40 their series consisted of 16 patients , and icp was controlled to normal levels in all patients with this method , sometimes combined with csf drainage , and no severe surgical complication occurred . obviously , except for the prevention of potential injury after surgical decompression as mentioned above , this variation of the traditional decompressive craniectomy eliminates the need for a second major cranioplasty , or at least facilitates the process of cranioplasty . in consecutive procedures , most of the patients could undergo cranioplasty under local anesthesia . however , the replaced bone flap would account for a certain amount of space , and the efficacy of decompression would thus be weakened . introduced a method to prevent peridural fibrosis after decompressive craniectomy .41 for the survivors of decompressive craniectomy , development of multiple adhesions among the dura , temporal muscle , and galea would be a problem during subsequent cranioplasty , and would also be a potentially deleterious factor for patient recovery . to prevent adhesions , the authors placed a dural substitute between the dural anasynthesis flap and galea aponeurotica after augmentative duraplasty with temporal muscle . they performed this method in 23 patients who underwent decompressive craniectomy . compared with a control group consisting of 29 patients who underwent ordinary large decompressive craniectomy , they found that cranioplasty in the patients in their study group was easier , lacked severe secondary complications , required a shorter cranioplasty operating time , and resulted in less intraoperative blood loss . to increase the space of decompressive craniectomy , zhang et al . suggested a method of surgical decompression combined with removal of part of the temporal muscle .42 they resected the temporal muscle above the inferior edge of the bone window formed by the craniectomy . on average , additional space , as large as 26.5 cm , was obtained . in their retrospective series , the patients who underwent surgical decompression combined with removal of part of the temporal muscle seemed to have a lower mortality than those who underwent ordinary large decompressive craniectomy . the effect of bifrontal decompressive craniectomy with preservation or removal of the bone above the superior sagittal sinus is still undetermined ,3 , 17 , 43 , 44 though it seems that the procedure combined with removal of this bone is being accepted by more institutes . to increase the decompressive effect , simultaneous division of the falx at the floor of the anterior cranial fossa has also been recommended by some authors .3 moreover , except for the technical considerations of this operation , timely decompressive craniectomy before the development of irreversible changes in the injured brain would be equally important for patient outcome .4 , 45 - 48 with the exception of icp and clinical signs , ptio2 monitoring may be another important tool when a timely craniectomy is indicated .49 , 50several types of decompressive craniectomy have been performed for the management of traumatic refractory intracranial hypertension , and the variations in results between studies may be explained by the different methods of surgical decompression . presently , unilateral fronto - temporoparietal craniectomy / hemisphere craniectomy for lesions or swelling confined to one cerebral hemisphere , and bifrontal craniectomy for diffuse swelling , are recommended for the management of traumatic refractory intracranial hypertension . different technical improvements in decompressive craniectomy , based on large decompression , have been introduced to increase the decompressive effect , avoid surgical complications , and facilitate subsequent operations and management . although all of these methods are tentative and experiential , and in most reports the involved patient populations are small , these experiences are valuable . at present , in the absence of definite proof of the efficacy of decompressive craniectomy in the treatment of tbi , such as from multicenter , prospective , randomized , controlled trials , these technical improvements to increase the decompressive effect or avoid potential surgical complications should be considered .\noutput:\n" }, { "from": "agent", "value": "refractory intracranial hypertension is a leading cause of poor neurological outcomes in patients with severe traumatic brain injury . decompressive craniectomy has been used in the management of refractory intracranial hypertension for about a century , and is presently one of the most important methods for its control . however , there is still a lack of conclusive evidence for its efficacy in terms of patient outcome . in this article , we focus on the technical aspects of decompressive craniectomy and review different methods for this procedure . moreover , we review technical improvements in large decompressive craniectomy , which is currently recommended by most authors and is aimed at increasing the decompressive effect , avoiding surgical complications , and facilitating subsequent management . at present , in the absence of prospective randomized controlled trials to prove the role of decompressive craniectomy in the treatment of traumatic brain injury , these technical improvements are valuable ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: gingival cyst of adult is an uncommon , small , non inflammatory , developmental cyst of gingiva arising from the rests of dental lamina . the relative incidence of a gingival cyst of adult in a large case series of cysts has been reported to be less than 0.5 % . they usually occur on the facial gingiva as a single small flesh colored swelling , sometimes with a bluish hue due to the cystic fluid , in the canine and premolar area of the mandible and less frequently in the maxilla . rarely , it may occur in multiples , either unilaterally or bilaterally or on the lingual surface of the alveolar process . they are commonly seen in the canine and premolar regions of the mandible , and are sometimes confused with lateral periodontal cysts . gingival cyst lesions in adults may appear bluish due to fluid and cause pressure resorption of the labial bone . although the gingival cyst is typically a solitary unicystic lesion , reports of multilocular ( botryoid ) variants and of lesions either presenting in a bilateral distribution or occurring together with the intrabony lateral periodontal cyst have been described . the incidence of gingival cysts of adults show a racial predilection , with asians revealing a much lower prevalence of the lesion than caucasians ; however , there is no gender difference in the incidence of the disease . a 16 - year - old male patient presented to the central out - patient department ( opd ) , department of dental surgery , armed forces medical college , pune with a chief complaint of a swelling in the gum on the left side of the upper jaw from the past five to six months in nov 2009 . he could not recall any recent trauma , pain , or discharge from the swelling or an increase in size of the lesion . his medical history was non - significant , and he was not on any medication at that time . prior to this visit , the patient had not received dental care for more than 10 years . during intraoral examination , it was located on the attached gingiva in relation to the upper left canine and first premolar extending superiorly up to the mucogingival junction [ figure 1 ] . the nodule was non tender , soft , and cystic in consistency , fluctuant and non compressible . probing of the adjacent teeth yielded pocket depths of 2 - 3 mm with all sites exhibiting bleeding on probing , without any communication between the sulci of the adjacent teeth and the lesion . based on the clinical and radiographic findings , the provisional diagnosis of cystic lesion of the gingiva was made . the differential diagnosis included a lateral periodontal cyst , peripheral fibroma , parulis , and odontogenic keratocyst . lateral periodontal cyst was ruled out because there was no radiographical finding suggesting of osseous involvement , peripheral fibroma was ruled since the lesion was soft and cystic consistency , parulis was ruled out since the lesion was not associated with periodontal pocket or pus discharge on probing and odontogenic keratocyst was ruled out since the lesion was not associated with pain or localized expansion of bone , and radiographically there was no osseous involvement . clinical presentation of the lesion iopa radiograph 23,24 showing no radiographic involvement the periodontal treatment plan included scaling , root planing , re - evaluation , and excisional biopsy of the lesion . two weeks after scaling and root planing , a re - evaluation and excisional biopsy were performed in dec 2009 . an incision was placed on the mucosa overlying the lesion [ figure 3 ] and the lesion was separated from the adjacent tissues through blunt dissection and the lesion was removed [ figure 4 ] . the surgical specimen measuring 66 mm was placed in 10 % neutral buffered formalin . after the lesion was removed and the area irrigated with sterile saline , it was apparent that a well defined , 2 - 3 mm deep , saucer - like defect was present in the alveolar process in relation to 23 and 24 [ figure 5 ] . hydroxyapatite bone substitute hydrated with sterile saline was placed in the defect [ figure 6 ] , the edges of the soft tissue were undermined and approximated to facilitate primary closure and was secured with a 3 - 0 black silk suture . gentle pressure was applied with wet gauze to achieve hemostasis and the wound was covered with a periodontal dressing . the patient was given postoperative instructions and was dismissed with prescription for an analgesic ( tab ibuprofen - 400 mg tds every four to six hours as needed for pain ) , antibiotic ( capamoxicillin - 500 mg tds for three days ) and antimicrobial rinse ( 0.2 % chlorhexidine gluconate twice a day for one week ) . bone defect after excision hydroxyapatite bone substitute filled in the defect the biopsy specimen microscopically consisted of a fibrovascular connective tissue associated with a cystic lining of stratified squamous epithelium . histopathological slide showing a thin stratified squamous epithelium lining the lumen at one week postoperative visit , the patient reported minimal discomfort . the patient is on regular follow - up with a satisfactory healing at six months post - surgery [ figure 9 ] . the present report documented a case of gingival cyst of adult treated with excisional biopsy followed by a regenerative approach to correct the associated bony defect . the outward appearance of gingival cyst of adult is typically an oval - to - round , firm , elevated swelling located on the attached gingiva . mostly are 5 mm in diameter , but lesions 5 cm were also seen . the lesions often demonstrate little or no color change in the overlying mucosa , but some appear bluish due to the cystic fluid . eighty percent are found in the mandible , with the most common site being the canine premolar area . the gingival cyst of adult is believed to be of odontogenic derivation , specifically from the remnants of ectodermic tissue . the gingival cyst of adult is not related to any inflammatory lesion , and the associated teeth tested are vital . the radiograph does not accurately depict the topography of this soft tissue - originating cyst , as the cyst may involve the alveolar bone surface and can often compromise the buccal or lingual plate with a shallow saucer - like defect . gingival cyst of adult is routinely treated with excisional biopsy and has a rare chance of recurrence . the differential diagnosis of gingival cyst of adult includes several lesions presenting as gingival swellings such as a lateral periodontal cyst and peripheral fibroma . the lesion that may be more difficult to differentiate is the lateral periodontal cyst , especially in the presence of both radiographic and gingival involvement . this is because both lateral periodontal cyst and gingival cyst of adult are non - inflammatory cystic lesions , typically present in the mandibular canine - premolar area , and share histopathological characteristics . in the present case , the combined anatomic characteristics of the soft tissue presentation and the osseous destruction suggest that the lesion was gingival cyst of adult . the gingival cyst of adult is a unique pathologic lesion of the oral cavity , typically localized in the mandibular canine and premolar region , appearing in adults in their fourth to fifth decades of life . exposure of the tooth root is an extremely rare feature of the gingival cyst of adult ; in such cases , as in the present report , a combined regenerative treatment approach may be used to achieve resolution of the lesion - associated osseous defect and the excisional biopsy - associated soft tissue defect .\noutput:\n" }, { "from": "agent", "value": "gingival cyst of adult is an uncommon cyst of gingival soft tissue occurring in either the free or attached gingiva . this odontogenic epithelial cyst is most frequently seen near mandibular canine and premolar region , believed to represent the soft tissue counter part of the lateral periodontal cyst . this article presents a case of gingival cyst treated with exicisional biopsy followed by histopathological confirmation and an emphasis on the clinical aspects of this lesion ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: during the last two decades , contact lenses ( cls ) have gained widespread acceptance . the age of cl users is on average 31 years and about two - thirds of users are female .1 the function and optical performance of the corneal tissue after cl wear is currently receiving much attention . the structural integrity of the first optical surface of the cornea as well as normal corneal microstructure and metabolism are fundamental for the optical quality of the cornea .2 the measurement of corneal high - order wavefront aberration ( wa ) and corneal light backscattering ensures objective evaluation of the optical performance of corneal tissue .3 in subjects wearing cls , corneal wavefront sensing and scheimpflug imaging have been shown to be valuable for assessing the effect of lubricant ophthalmic solution on the optical quality of the cornea .48 increased corneal high - order wa has been mainly related to surface irregularities and / or tear film instability .913 increased corneal light backscatter has been related to the localized corneal epithelial and stromal response to cls ,14,15 and specifically to moderate corneal swelling associated with prolonged wearing of cls .16 hydrogel materials still represent 25 % of the global cl market .1 prolonged wearing of these types of cl has been associated with moderate corneal swelling due to their relatively low oxygen transmissibility ( dk ) ; specifically , etafilcon a materials have been associated with a greater risk of corneal swelling than other hydrogel cls ( eg , nelfilcon a , lotrafilcon a ) .1719 in the laboratory , use of hyperosmolar ophthalmic solutions has been shown to be effective in mini - mizing corneal swelling without altering corneal epithelial cells .20,21 the purpose of this pilot study was to evaluate the effect of topical administration of a 10 % mannitol - enriched 0.05 % sodium hyaluronate ophthalmic solution on corneal thickness and corneal optical properties in subjects wearing etafilcon a cls during one month of follow - up . the study followed the tenets of the declaration of helsinki and was approved by the local ethics committee ( azienda sanitaria locale roma a , rome , italy ) . the inclusion criteria were age 18 years , a manifest spherical equivalent refraction from + 4.0 to 8.0 d , 10/20 or better best corrected visual acuity ( bcva ) , and wearing of etafilcon a cls for more than 6 months and for more than 6 hours daily . the exclusion criteria were previous eye surgery , concomitant ocular pathology , schirmer 110 mm , tear film break - up time 5 seconds , daily topical administration of lubricant solutions or drug therapies , and chronic systemic disease . eligible subjects underwent a complete ocular examination , including scheimpflug imaging by pentacam hr ( oculus gmbh , wetzlar , germany ) and corneal topography / aberrometry by opd scan ii ( nidek co ltd , tokyo , japan ) both at baseline and at one month after recruitment . examinations were performed in the afternoon ( 2 pm to 6 pm ) , 90 minutes after discontinuing use of cls in all cases . schirmer test 1 and break - up time tests were performed to evaluate production and stability of tear film . slit - lamp biomicroscopy was performed to monitor for any cl - related complications according to the efron grading scale .22 subjects were evaluated by two expert corneal specialists ( ml and ss ) to minimize intersubject variance in grading of complications . subjects recruited into the study group received topical administration of a 10 % mannitol - enriched 0.05 % sodium hyaluronate ophthalmic solution ( terso , dmg italia srl , italy ; 1,000200 mosmol / ml ) . they were required to administer one drop daily in the morning before wearing their cls . pentacam hr and opd scan ii measurements were repeated three times for each eye , and the best test image was chosen for analysis . each eye was photographed using the 3d - scan 25 pictures program of the pentacam hr . two of the scheimpflug images , with a superior and temporal camera position , were exported as 8 bit.bmp format files ( 0256 intensity gray levels ) and processed using the imagej image - analysis program ( http://imagej.nih.gov/ij , nih , usa ) both at baseline and after one month of follow - up . for each eye , the baseline and one - month images acquired along the same corneal meridian were registered using a cross - correlation algorithm in order to determine their relative position displacements . the baseline image was used as a reference frame and a template of image features was selected on the reference frame in order to improve the algorithm precision . using a bicubic interpolation for translation , alignment with subpixel precision at the x and y directionsthis procedure permitted precise measurement of corneal light backscattering at exactly the same points before and after treatment . corneal light backscattering was then measured using the line tool of imagej at 50 points along a line perpendicular to the corneal optical center from scheimpflug images . the light backscattering pretreatment data were used for the baseline values and were compared with data obtained at one month . average and peak light - scattering values were assessed for each line ( figure 1 ) . the optical quality of the corneal surface was evaluated by calculating the root - mean - square error of higher - order aberrations ( hoa ) over a simulated 6 mm pupil ( ie , scotopic pupil condition ) .23,24 the corneal high - order wa was computed with respect to the line of sight , ie , the center of the entrance pupil .25 we considered corneal total hoa up to sixth order spherical aberration , coma , and trefoil . eligible subjects were consecutively allocated to the study group or control group according to a 1:2 scheme . the statistical test was calculated ( using gpower version 3.1.2 ) having 82 % power to determine differences of 10 arbitrary units ( au ; sd 15 % from the mean ) in the corneal light backscatter and of 0.04 m ( standard deviation [ sd ] 20 % from the mean ) in the corneal high - order wa between the study and control group ( total cases 45 ) . analysis of corneal backscattering data and corneal hoa were performed by two authors ( mp and dsl ) masked to the eye group . statistical package for the social sciences version 17 software ( spss inc , chicago , il , usa ) was used for all statistical testing . two sets of bcva and topography measurements taken at 10 - minute intervals from each other did not show any difference , so only the first measurement was used for the statistical analysis . high correlations were found between the corneal wa data and backscatter profiles for the right and left eyes at baseline . one - way analysis of variance was used to compare the baseline data with the one - month data in each group . statistical comparison of topographic , aberration , and cct values between groups was performed using multivariate analysis of variance . the pearson coefficient was used to estimate the correlation between changes in corneal light backscatter and cct . subjects recruited into the study group received topical administration of a 10 % mannitol - enriched 0.05 % sodium hyaluronate ophthalmic solution ( terso , dmg italia srl , italy ; 1,000200 mosmol / ml ) . they were required to administer one drop daily in the morning before wearing their cls . pentacam hr and opd scan ii measurements were repeated three times for each eye , and the best test image was chosen for analysis . each eye was photographed using the 3d - scan 25 pictures program of the pentacam hr . two of the scheimpflug images , with a superior and temporal camera position , were exported as 8 bit.bmp format files ( 0256 intensity gray levels ) and processed using the imagej image - analysis program ( http://imagej.nih.gov/ij , nih , usa ) both at baseline and after one month of follow - up . for each eye , the baseline and one - month images acquired along the same corneal meridian were registered using a cross - correlation algorithm in order to determine their relative position displacements . the baseline image was used as a reference frame and a template of image features was selected on the reference frame in order to improve the algorithm precision . using a bicubic interpolation for translation , alignment with subpixel precision at the x and y directionsthis procedure permitted precise measurement of corneal light backscattering at exactly the same points before and after treatment . corneal light backscattering was then measured using the line tool of imagej at 50 points along a line perpendicular to the corneal optical center from scheimpflug images . the light backscattering pretreatment data were used for the baseline values and were compared with data obtained at one month . average and peak light - scattering values were assessed for each line ( figure 1 ) . the optical quality of the corneal surface was evaluated by calculating the root - mean - square error of higher - order aberrations ( hoa ) over a simulated 6 mm pupil ( ie , scotopic pupil condition ) .23,24 the corneal high - order wa was computed with respect to the line of sight , ie , the center of the entrance pupil .25 we considered corneal total hoa up to sixth order spherical aberration , coma , and trefoil . eligible subjects were consecutively allocated to the study group or control group according to a 1:2 scheme . the statistical test was calculated ( using gpower version 3.1.2 ) having 82 % power to determine differences of 10 arbitrary units ( au ; sd 15 % from the mean ) in the corneal light backscatter and of 0.04 m ( standard deviation [ sd ] 20 % from the mean ) in the corneal high - order wa between the study and control group ( total cases 45 ) . analysis of corneal backscattering data and corneal hoa were performed by two authors ( mp and dsl ) masked to the eye group . statistical package for the social sciences version 17 software ( spss inc , chicago , il , usa ) was used for all statistical testing . two sets of bcva and topography measurements taken at 10 - minute intervals from each other did not show any difference , so only the first measurement was used for the statistical analysis . high correlations were found between the corneal wa data and backscatter profiles for the right and left eyes at baseline . one - way analysis of variance was used to compare the baseline data with the one - month data in each group . statistical comparison of topographic , aberration , and cct values between groups was performed using multivariate analysis of variance . the pearson coefficient was used to estimate the correlation between changes in corneal light backscatter and cct . forty - five subjects , comprising 30 females and 15 males , were recruited into the study . both schirmer 1 and break - up time tests were within normal limits in all subjects . there were no serious biomicroscopic signs of complications of cl wear ( efron grading scale 1 ) in any case . all subjects were wearing hydrogel ionic cls composed of etafilcon a ( hema / ma ) , with a water content of 58 % , a center thickness of 0.084 mm , and an oxygen transmissibility dk / t = 3310 cm / sec ( 1 - day acuvue moist , johnson & johnson vision care , inc . , there were no statistically significant differences ( p 0.05 , analysis of variance ) between the refractive errors and corneal parameters in the study group and the control group at baseline . subjects did not complain of any intolerance to daily administration of the hypertonic lubricant solution . no side effects were recorded in this series . at baseline , bcva was better than 20/25 in all subjects and was stable during one month of follow - up . the changes in corneal light backscattering did not differ between corresponding horizontal and vertical measurement points during follow - up ; therefore , the mean of the corresponding points was used in all cases . the changes of corneal light backscattering values were significantly different ( p 0.05 ) between the study group and the control group during follow - up . at one month , we found a decrease in the peak and average intensity of corneal light backscattering with respect to baseline in the study group ( figure 2 ) . the average peak intensity decreased from 93.8311.45 au at baseline to 75.5013.3 au at one month ( 19.3 % , ranging between 6.3 % and 36.0 % across subjects ; p 0.05 ) . the average light backscattering decreased from 30.765.90 au to 23.642.48 au during follow - up ( 23.2 % , ranging between 15.1 % and 38.1 % across subjects ; p 0.05 ) . this decrease was significantly correlated with corneal thinning ( r = 0.81 ; p = 0.04 ) , as shown in figure 3 . at one month , no significant change in corneal light backscatter was found in the control group ( peak 909.77 au and mean 28.172.12 au ) compared with baseline ( peak 889.48 au and mean 27.852.25 au ) . table 2 summarizes the average baseline and one - month corneal high - order wa data and cct values in both study groups . the changes in corneal total hoa ( p = 0.04 ) , spherical aberration ( p = 0.05 ) , trefoil ( p = 0.04 ) , and coma ( p = 0.03 ) were significantly different between the study group and the control group during follow - up . corneal total hoa and spherical aberration decreased on average by 9 % with respect to baseline , and coma and trefoil decreased on average by 15 % in the study group ( p 0.05 ; figure 4 ) . corneal total hoa and spherical aberration increased ( 9 % ; p 0.05 ) in the control group , while coma and trefoil values were essentially stable during follow - up ( changes 4 % ; p 0.05 ) .1.1 % ; p = 0.04 ) but was stable in the control group ( 0 m , p 0.05 ) during follow - up . figure 5 shows the corneal maps in a representative case from the study group at baseline and after one month of follow - up . forty - five subjects wearing hydrogel etafilcon a cls were recruited for this pilot study . of these subjects ,15 were allocated to the study group and administered a 10 % mannitol - enriched 0.05 % sodium hyaluronate ophthalmic solution once daily 20 minutes before wearing their cls , with the remaining 30 subjects being followed as a control group . the study design had enough statistical power ( 80 % ) to demonstrate the efficacy of daily administration of a hypertonic ophthalmic lubricant solution on corneal optical properties in subjects wearing etafilcon a cls . baseline and one - month follow - up examinations were done 90 minutes after removal of the cls . this procedure was based on previous work16 showing that both cct and the profile of corneal backscattered light are higher than expected immediately after cl removal , then decrease during the subsequent hour . this procedure allowed us to remove an important bias from our study , in that we were able to quantify the actual corneal properties reliably in each case . in addition , measurements were taken in the afternoon because this is the time of the day when the eye is most physiologically stable .26 indeed , corneal measurements were acquired twice with a 10 - minute interval in between , and the measurements did not show any differences , thus confirming the results reported by koh et al. 4 variation in corneal surface smoothness and anterior transparency can affect corneal light backscatter , which can be estimated by different approaches , such as optical coherence tomography , scheimpflug photography , and psychophysical methods ( glare testing , adaptive optics visual simulator with diffuser , direct compensation method ) .16,2729 we found a significant decrease in both peak and average corneal light back - scattering by scheimpflug imaging in the study group . the decrease in corneal light backscatter was highly correlated with corneal deswelling . no changes in corneal light backscatter or cct were found in the control group during follow - up , thus confirming the valuable effect of the hypertonic topical treatment on corneal hydration in patients wearing etafilcon a cls . this type of cl was previously associated with increased corneal swelling ( on average by 5.5 % ) after 8 hours of closed - eye wear ( overnight ) with respect to silicone hydrogel lenses ( on average1 .5 % swelling ) .30,31 lambert and klyce32 found increased light - scattering in the epithelium during corneal swelling induced by oxygen deprivation . farris et al14 and korb and exford33 reported that this phenomenon was due to a localized epithelial response to cl wear , resulting in a focal increase of backscattered light . in our study , the corneal backscattered light in the epithelium ( measured as peak intensity in this study ) could be related to the distortion of the surface microstructure ,34 and the backscattered light in the stroma ( measured as average intensity ) could be related to local hydration .15,35 one month after topical administration of 10 % mannitol - enriched 0.05 % sodium hyaluronate solution , corneal high - order wa tended to decrease in the study group . the corneal total hoa tended to increase in the control group during follow - up , thus confirming the potential benefit of the hypertonic hyaluronate - enriched lubricant solution in minimizing irregularities of the first optical surface of the cornea . indeed , the differences between groups were statistically significant at one month of follow - up . it has been already used for testing the effect on image quality of cl wearing as well as the benefit of lubricant ophthalmic solutions .37,36 several factors can affect the smoothness of the corneal surface following wearing of cls , and include tear film instability and corneal swelling .6,15,37 the improved optical quality of the cornea in subjects administering daily hypertonic hyaluronate - enriched lubricant solution could be ascribed to both corneal deswelling and decreased microir - regularities on the corneal first surface as a result of tear film stabilization .10,11,15,38,39 no correlation was found between bcva and decreased corneal scattering ( r = 0.08 ; p = 0.87 ) or decreased total hoa ( r = 0.06 ; p = 0.89 ) during follow - up . there was no intentional sex sampling bias in our study population ; however , 30 of the 45 subjects in this study were female . nevertheless , this did not impact our results since the groups were age - matched , and had matched manifest spherical equivalent refraction values and daily cl wearing time . additionally , in the range of age of subjects in this study , sex has not been associated with corneal aberrations and has been shown to have little or no impact on tear volume or its protein content .5,40,41 all subjects recruited into the present study had normal tear volume and film stability . the results of this pilot study show that daily administration of a hypertonic ophthalmic solution was effective in minimizing corneal swelling due to wearing of low dk etafilcon a cls , while improving the optical properties of the corneal surface . none of the subjects recruited into the present study complained of side effects during follow - up . in this study , we demonstrated recovery of corneal light backscattering and improvement in corneal optical quality associated with decreased cct in subjects wearing hydrogel etafilcon cls and applying one drop of hypertonic ophthalmic lubricant solution daily . we did not record any intolerance or side effects during one month of follow - up . a longer study is needed to assess the safety and efficacy of this approach and to determine whether this treatment may lead to improved visual performance ( eg , contrast sensitivity ) during wearing of low dk cls .6\noutput:\n" }, { "from": "agent", "value": "backgroundthe purpose of this study was to evaluate the effect of daily administration of mannitol - enriched sodium hyaluronate ophthalmic solution on the corneal optical properties of subjects wearing low dk hydrogel ( etafilcon a ) contact lenses ( cls ) . methodsforty - five subjects wearing etafilcon a cls daily for more than 6 months were recruited into this pilot study . fifteen of the subjects administered a 10 % mannitol - enriched 0.05 % sodium hyaluronate solution ( study group ) once daily and 30 subjects did not administer any ophthalmic solution ( control group ) . the subjects were examined at baseline and one month after recruitment . changes in central corneal thickness ( cct ) and corneal light backscatter were evaluated by scheimpflug imaging ( pentacam hr ) . changes in corneal total high - order aberration , corneal spherical aberration , coma , and trefoil were evaluated using the opd scan ii.resultsat one month , corneal light backscatter decreased significantly in the study group ( 18.30 arbitrary units ; p < 0.05 ) and this was highly correlated with a decrease in cct ( r = 0.81 ; p = 0.04 ) . the decrease in corneal total high - order aberration , spherical aberration , and coma was significantly higher in the study group than in the control group ( p < 0.05 ) . no changes in corneal light backscatter or cct were found in the control group during follow - up.conclusiononce - daily administration of a mannitol - enriched lubricant ophthalmic solution was effective for improving the corneal optical quality and reducing corneal swelling in subjects wearing low dk hydrogel ( etafilcon a ) cls during one month follow - up ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: bacterial vaginosis is a common yet poorly understood condition affecting women of childbearing age in both industrialized and developing countries . bacterial vaginosis is characterized simultaneously by an abnormal loss of the normal doderlen flora accompanied by an unexplained overgrowth of anaerobic bacteria that were previously minor in the vagina , . in pregnant women , this vaginal dysbiosis is the consequence of certain complications such as miscarriage , preterm birth or chorioamnionitis . bacterial vaginosis is mostly treated with antibiotics , mainly metronidazole and clindamycin , but treatment frequently fails ; the relapse rate is estimated at 50 % at 6 months , . in order to describe the vaginal flora as fully as possible and to better understand the condition in order to provide better treatment , we studied the vaginal microbiota from healthy women and patients with bacterial vaginosis using the culturomics concept . this is based on the multiplication of culture conditions ( atmosphere , media , and temperature ) and a rapid bacterial identification using matrix - assisted desorption ionization , it was only in 1992 that the name of this family was validated by reichenbach . some species are found in soil and the marine environment , while others are pathogens found in fish and the human urogenital tract . hence , in order to describe a new bacterium , our laboratory introduced taxonogenomics , a new approach that complements classic features with the proteomic information obtained by maldi - tof ms and the description of the annotated whole genome , . in the following section , we describe the vaginella massiliensis strain marseille p2517 ( = dsm 102346 = csur p2517 ) , a new genus isolated from a vaginal swab taken from a healthy 22 - year - old french woman without bacterial vaginosis . as previously described , a vaginal sample was taken from a healthy 22 - year - old french woman without bacterial vaginosis at la timone hospital in marseille ( france ) in january 2016 using a sigma transwab ( medical wire , corsham , united kingdom ) . the study was authorized by the local ifr48 ethics committee ( marseille , france ) under agreement number 09 - 022 . the vaginal sample was first preincubated in a blood culture bottle ( bd diagnostics , le pont - de - claix , france ) supplemented with 4 ml rumen and filtered at 0.2 m using a pore filter ( thermo fisher scientific , villebon - sur - yvette , france ) and 3 ml sheep 's blood ( biomrieux , marcy letoile , france ) . after 7 days of preincubation , 50 l of the supernatant was inoculated on chocolat polyvitex ( pvx ) agar ( bd diagnostics ) . after 2 days of incubation at 37c in aerobic conditions , purified colonies were deposited in duplicate on a msp 96 maldi - tof ms target plate ( bruker daltonics , leipzig , germany ) , and , as previously described , 1.5 l of matrix solution was added to each spot . identification was carried out using a microflex spectrometer ( bruker ) , which compares the protein spectra found to those in the bruker database ( constantly updated with spectra of new species discovered in our laboratory ) . in contrast , if no spectra match the database , and for unidentified bacteria with a clear spectrum , 16s rrna gene sequencing is performed . as stackebrandt andebers suggested , if the 16s rrna sequence similarity value is lower than 95 % or 98.7 % , the strain is defined as a new genus or species , respectively . a custom python script was used to automatically retrieve all species from the same order of the new genus and to download 16s sequences from national center for biotechnology information ( ncbi ) by parsing ncbi eutils results and the ncbi taxonomy page . this only retains sequences from type strains . in the event of multiple sequences for one type strain , it selects the sequence obtaining the best identity rate from the blastn alignment with our sequence . the script then separates 16s sequences into two groups : one containing the sequences of strains from the same family ( group a ) and one containing the others ( group b ) . finally , it only retains the 15 closest strains from group a and the closest one from group b. if it is impossible to retrieve 15 sequences from group a , the script selects more sequences from group b to achieve at least nine strains from both groups . the ideal growth was tested by cultivating the strain marseille p2517 on colombia agar with 5 % sheep 's blood incubated at different temperatures ( 25 , 28 , 37 , 45 and 56c ) and different atmospheres ( anaerobic , microaerophilic and aerobic ) . the anaerobic and microaerophilic atmospheres were generated using , respectively , genbag anaer and genbag microaer systems ( biomrieux ) . salinity and ph conditions were also tested at different concentrations of nacl ( 0 , 5 , 15 and 45 % ) and different ph ( 5 , 6 , 6.5 , 7 and 8.5 ) . sporulation , motility , gram stain , catalase and oxidase tests were performed using standard test procedures ( https://www.gov.uk/government/collections/standards-for-microbiology-investigations-smi#test-procedures ) . in order to observe cell morphology , samples were fixed with 2.5 % glutaraldehyde in 0.1 m cacodylate buffer for at least an hour at 4c . one drop of cell suspension was deposited for approximately 5 minutes on glow - discharged formvar carbon film on 400 mesh nickel grids ( fcf400 - ni , ems ) . the grids were dried on blotting paper , and cells were negatively stained for 10 seconds with 1 % ammonium molybdate solution in filtered water at room temperature . electron micrographs were acquired using a tecnai g cryo ( fei company , limeil - brevannes , france ) transmission electron microscope operated at 200 kev . biochemical characteristics were studied using api zym , api 20ne and api 50ch strips ( biomrieux ) according to the manufacturer s instructions . a cellular fatty acid methyl ester ( fame ) two samples were prepared with approximately 90 mg of bacterial biomass per tube collected from several culture plates . gc / ms analyses were carried out using a clarus 500 gas chromatograph equipped with a sq8s ms detector ( perkin elmer , courtaboeuf , france ) . fame extracts ( 2 ml ) were volatilized at 250c ( split 20 ml / min ) in a focus liner with wool and separated on an elite - 5ms column ( 30 m , 0.25 mm i.d . , 0.25 mm film thickness ) using a linear temperature gradient ( 70290c at 6c / min ) , enabling the detection of c4 to c24 fatty acid methyl esters . full scan monitoring was performed from 45 to 500 m / z . all data were collected and processed using turbomass 6.1 ( perkin elmer ) . fames were identified through a spectral database search using ms search 2.0 operated with the standard reference database 1a ( national institute of standards and technology ( nist ) , gaithersburg , md , usa ) and the fames mass spectral database ( wiley , chichester , uk ) . retention time correlations with estimated nonpolar retention indices from the nist database were obtained using a 37 - component fame mix ( supelco ; sigma - aldrich , saint - quentin fallavier , france ) ; fame identifications were confirmed using this index . the antibiotic susceptibility of strain marseille p2517 was tested using the disk diffusion method ( sirscan discs , perols , france ) . strain marseille p2517 was grown in aerobic conditions at 37c using columbia agar enriched with 5 % sheep 's blood ( biomrieux ) after 48 hours on four petri dishes . bacteria were resuspended in 500 l of tris - edta ( te ) buffer ; 150 l of this suspension was diluted in 350 l 10 te buffer , 25 l proteinase k and 50 l sodium dodecyl sulfate for lysis treatment . dna was purified using phenol / chloroform / isoamylalcohol successively for extraction , followed by ethanol precipitation at 20c for at least 2 hours each . genomic dna ( gdna ) of strain marseille p2517 was sequenced on the miseq technology ( illumina , san diego , ca , usa ) using the mate - pair strategy . the gdna was barcoded in order to be mixed with 11 other projects with the nextera mate pair sample prep kit ( illumina ) . gdna was quantified using a qubit assay with the high sensitivity kit ( life technologies , carlsbad , ca , usa ) to 153 ng / l . the mate - pair library was prepared with 1.5 g of gdna using the nextera mate pair illumina guide . the gdna sample was simultaneously fragmented and tagged with a mate - pair junction adapter . the fragmentation pattern was validated on an agilent 2100 bioanalyzer ( agilent technologies , santa clara , ca , usa ) with a dna 7500 labchip . the dna fragments ranged in size from 1.5 to 11 kb with an optimal size of 7.455 kb . no size selection was performed , and 410.7 ng of tagmented fragments were circularized . the circularized dna was mechanically sheared to small fragments with an optimal size of 1115 bp on the covaris device s2 in t6 tubes ( covaris , woburn , ma , usa ) . the library profile was visualized on a high sensitivity bioanalyzer labchip ( agilent technologies ) , and the final concentration library was measured at 12.49 after a denaturation step and dilution at 15 pm , the pool of libraries was loaded onto the reagent cartridge and then onto the instrument along with the flow cell . automated cluster generation and sequencing run were performed in a single 39 - hour run at a 2251 bp read length . a total of 9.2 gb of information was obtained from a 1042k / mm cluster density with a cluster passing quality control filters of 91.6 % ( 18the 1241784 paired reads were trimmed , then assembled in nine scaffolds . open reading frames ( orfs ) were predicted using prodigal software with default parameters . predicted orfs spanning a sequencing gap region ( containing n ) were excluded . we predicted the bacterial proteome sequences using blastp ( e value 1e - 03 , coverage 0.7 and identity percentage 30 ) against the clusters of orthologous groups ( cogs ) database . a search against the nr database was performed if no hit was found using blastp with an e value of 1e - 03 coverage of 0.7 and an identity percentage of 30 . the hmmscan analysis tools were used for searching pfam conserved domains ( pfam - a and pfam - b domains ) on each protein . we used rnammer and the trnascanse tool to find ribosomal rnas genes and trna genes respectively . for visualization and for data management of genomic features , we used artemis and dna plotter respectively . for the mean level of nucleotide sequence similarity analysis at the genome level , we used magi homemade software . it calculated the average genomic identity of orthologous gene sequences ( agios ) among compared genomes . the proteinortho software was incorporated into the magi homemade software for detecting orthologous proteins in pairwise genomic comparisons . the corresponding genes were then retrieved , and the mean percentage of nucleotide sequence identity among orthologous orfs was determined using the needleman - wunsch global alignment algorithm . genomes from the genus weeksella , empedobacter and elizabethkingia were used for the calculation of agios values . the genome of strain marseille p2517 ( european molecular biology laboratory ( embl ) / european bioinformatics institute ( ebi ) accession number flmr00000000 ) was compared to those of weeksella virosa dsm 16922 ( nc_015144.1 ) , empedobacter brevis atcc 43319 ( nz_arnt00000000.1 ) , empedobacter falsenii strain 282 ( nz_jsyq00000000.1 ) , elizabethkingia anophelis strain b2d ( jncg00000000 .1 ) , and elizabethkingia meningoseptica atcc 13253 ( bard00000000 .1 ) ; all these genomes were reannotated with prodigal . the multiagent software system dagobah was used to perform the annotation and comparison process , including figenix libraries , which provide pipeline analysis . genome - to - genome distance calculator ( ggdc ) analysis was performed using the ggdc web server , as previously reported . strain marseille p2517 was first cultivated in january 2016 after 7 days of preincubation in a blood culture bottle supplemented with sheep s blood and rumen under aerobic conditions and then inoculated on pvx agar incubated for 2 days at 37c in aerobic conditions . scores of 1.35 and 1.5 were obtained with the maldi - tof ms identification , suggesting that this isolate was not in the database and consequently was not a known species . the 16s rrna sequence ( accession no . lt223570 ) of our strain showed 93.03 % nucleotide sequence similarity with weeksella virosa , the phylogenetically closest species with a validly published name ( fig . 1 ) . because this 16s rrna nucleotide sequence similarity was lower than 95 % , the threshold recommended by stackebrandt and ebers for delineating a new genus , strain marseille p2517 was classified as a new genus , vaginella , with vaginella massiliensis as the type species ( table 1 ) .2 ) was then incremented in our database and compared to other known species of the family flavobacteriaceae .3 . cultivated on blood agar for 2 days at 37c under aerobic conditions , colonies of strain marseille p2517are yellow , opaque , circular and smooth with a diameter of 1.7 to 2 mm . the strain grows only under aerobic conditions at 25 , 28 and 37c , but optimal growth was observed at 37c after 48 hours of incubation . its growth also requires a ph ranging from 6.5 to 8.5 and a nacl concentration lower than 5nonmotile and non spore forming , strain marseille p2517 exhibits positive oxidase activity ; however , the catalase activity was negative . under the microscope , bacterial cells are gram negative and rod shaped ( fig . 4 ) , and individual cells have a diameter ranging 0.54 to 0.68 m and a length ranging 1.2 to 1.5 m ( fig . 5 , table 1 ) . using an api 20ne strip , we observed that nitrate and nitrite were not reduced , and urease and indole activities were absent . there was also no assimilation from d - glucose , l - arabinose , d - mannose , d - mannitol , d - maltose and n - acetyl - glucosamine . api 50ch showed that strain marseille p2517 metabolized only d - glucose ; and acid was not produced from other carbohydrates : arabinose , d - ribose , d - xylose , d - adonitol , d - galactose , d - fructose , d - mannose , l - rhamnose , d - mannitol , d - sorbitol , inositol , methyl - d - mannopyranoside , methyl - d - glucopyranoside , amygdalin , arbutin , esculin ferric citrate , salicin , d - cellobiose , d - maltose , d - lactose , d - melibiose , d - trehalose , inulin , d - melezitose , d - raffinose , starch , glycogen , xylitol , gentiobiose , d - turanose , d - lyxose , d - tagatose , fucose , arabitol , potassium gluconate , potassium 2 - ketogluconate and potassium 5 - ketogluconate . api zym revealed positive reactions for alkaline phosphatase , esterase , esterase lipase , lipase , leucine arylamidase , cystine arylamidase , valine arylamidase , trypsin , - chymotrypsin , acid phosphatase and naphtol - as - bi - phosphohydrolase . reactions for other enzymes such as galactosidase ( and ) and oxidases were negative . fame analysis demonstrated that the most abundant compound was 13 - methyl - tetradecanoic acid ( 60 % ) . this strain shows many saturated and unsaturated branched fatty acids ( iso and anteiso ) . several hydroxy fatty acids were also present ( table 2 ) . resistant to gentamicin ( cn 500 g ) and metronidazole ( met 4 ) , cells were sensitive to ceftriaxone ( cro 30 g ) , ciprofloxacin ( cip 5 g ) , clindamycin ( da 15 g ) , colistin ( ct 50 g ) , doxycycline ( do 30 g ) , erythromycin ( e 15 g ) , fosfomycin ( pos 50 g ) , oxacillin ( ox 5 g ) , penicillin ( p 10 g ) , rifampicin ( ra 30 g ) , teicoplasmin ( tec 30 g ) , trimethoprim / sulfamethoxazole ( sxt 25 g ) , vancomycin ( va 30 g ) and imipenem ( mp 10 ) . all the phenotypic characteristics of strain marseille p2517 were compared to those of the closely related flavobacteriaceae species , , , ( table 3 ) . the draft genome of strain marseille p2517 is 2434475 bp long with 38.16 mol % g + c content ( table 4 , fig . it is composed of nine scaffolds ( composed of ten contigs ) . on the 2395 predicted genes ,2324 were protein - coding genes and 71 were rnas ( five 5s rrna , four 16s rrna , two 23s rrna and 60 trna genes ) . a total of 1618 genes ( 69.62 % ) were assigned a putative function ( by cogs or by nr blast ) , and 123 genes were identified as orfans ( 5.29 % ) . comparison of the genome of our strain marseille p2517 with those of the closest species revealed that the draft genome sequence of strain marseille p2517 ( 2.34 mb ) was smaller than those of empedobacter falsenii ( 3.71 mb ) , empedobacter brevis ( 3.79 mb ) , elizabethkingia meningoseptica ( 3.84 mb ) and elizabethkingia anophelis ( 4.02 mb ) but larger than those of weeksella virosa ( 2.27 mb ) . the g + c content of strain marseille p2517 was larger than those of all the compared genomes : e. meningoseptica ( 36.4 % ) , w. virosa ( 35.9 % ) , e. anophelis ( 35.6 % ) , e. brevis ( 32.8 % ) and e. falsenii ( 32.1 % ) . the gene content of strain marseille p2517 ( 2395 ) was smaller than those of e. falsenii , e. brevis , e. anopheles and e. meningoseptica ( 3610 , 3633 , 4108 and 3500 respectively ) but larger than those of w. virosa ( 2192 ) . nevertheless , the distribution of genes into cogs categories was similar among all compared genomes ( fig . otherwise , the agios analysis showed that strain marseille p2517 shares between 1214 and 690 orthologous genes with its closely related species : 1214 , 1200 , 1142 , 702 and 690 with e. brevis , e. falsenii , w. virosa , e. anopheles and e. meningoseptica respectively ( table 6 ) . analysis of the average percentage of nucleotide sequence identity between strain marseille p2517 and other species ranged from 67.26 % with e. meningoseptica and 75.10 % with w. virosa ( table 6 ) . similar results were also observed for analysis of digital dna - dna hybridization ( table 7 ) . phenotypic , phylogenetic analyses and genomic results enable us to propose that strain marseille p2517 may be the representative of a novel genus , vaginella , with vaginella massiliensis as the type strain . the organism is an obligate aerobic , gram - negative and rod - shaped bacilli . it has negative catalase activity , and nitrate not reduced , with no urease production and positive oxidase activity . massiliensis , from massilia , the latin name of marseille , france , where the organism was first grown , identified , and characterized ) . the organism is obligate aerobic , nonmotile , nonsporulating and mesophilic , with optimal growth at 37c . vaginella cells are gram negative and rod shaped , with a mean diameter of 0.61 m and a length of 1.35 m ; it is oxidase positive and catalase negative ; the major fatty acid is 13 - methyl - tetradecanoic acid ( 60 % ) . on columbiaagar , colonies are yellow , opaque , circular , smooth and approximately 1.85 mm in diameter . nitrate reduction , urease and indole formation are negativecells are susceptible to ceftriaxone , ciprofloxacin , clindamycin , colistin , doxycycline , erythromycin , fosfomycin , oxacillin , penicillin , rifampicin , teicoplasmin , trimethoprim / sulfamethoxazole , vancomycin and imipenem but are resistant to gentamicin and metronidazole . the genome of vaginella massiliensis is 2434475 bp long and exhibits 38.16 % g + c content . its 16s rrna gene sequence and that of draft genome are both deposited in embl / ebi under accession numbers lt223570 and flmr00000000 , respectively . the type strain marseille p2517 ( = dsm 102346 = csur p2517 ) was isolated from the vaginal swab of a healthy frenchwoman .\noutput:\n" }, { "from": "agent", "value": "an obligate aerobic , gram - negative , nonmotile and nonsporulating rod designated marseille p2517 was isolated from the vaginal flora . we describe its features , annotate the genome and compare it to the closest species . the 16s rrna analysis shows 93.03 % sequence similarity with weeksella virosa , the phylogenetically closest species . its genome is 2 434 475 bp long and presents 38.16 % g + c . on the basis of these data , it can be considered as a new genus in the flavobacteriaceae family , for which we proposed the name vaginella massiliensis gen . nov . , sp . nov . the type strain is marseille p2517 t ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: chimeric antigen receptor ( car ) t cell therapy is a cellular therapy that redirects a patient s t cells to specifically target and destroy tumor cells . cars are genetically engineered fusion proteins composed of ( 1 ) an antigen recognition domain derived from a monoclonal antibody and ( 2 ) intracellular t cell signaling and costimulatory domains .1 , 2 , 3 , 4 , 5 use of car t cells as a treatment for cancer has been most extensively investigated in patients with b cell malignancies , and early results have been encouraging . for example , car t cell therapy has demonstrated complete response rates of 69 % 90 % in pediatric patients with relapsed or refractory acute lymphoblastic leukemia ( all ) in phase 1 trials .6 , 7 , 8 , 9 , 10 the development of car t cell therapy has now expanded beyond phase 1 trials and moved into phase 2 multi - site trials ( nct02435849 and nct02228096 ) , and a major consideration for academic institutions and industry is how to scale out the production of car t cells in an efficient , effective manner . herewe describe the process of manufacturing car t cells , and we discuss regulatory concerns that must be addressed to successfully produce car t cells for larger numbers of patients . the production of car t cells requires several carefully performed steps , and quality control testing is performed throughout the entire protocol . first , the process involves using leukapheresis to remove blood from the patient s body , separate the leukocytes , and return the remainder of the blood to the circulation . after a sufficient number of leukocytes have been harvested , the leukapheresis product is enriched for t cells ( figure 1 ) . this process involves washing the cells out of the leukapheresis buffer , which contains anticoagulants . enrichment of lymphocytes can be accomplished subsequently through counterflow centrifugal elutriation , which separates cells by size and density and maintains cell viability . separation of t cell subsets at the level of cd4 / cd8 composition using specific antibody bead conjugates or markers is an additional step that may be performed . purifying autologous antigen - presenting cells ( apcs ) from the patient to use for t cell activation would require several additional steps , making it labor intensive and difficult to obtain a potent car t cell product . for this reason , an approach was developed to activate t cells in a more standardized , efficient manner using , for example , beads coated with anti - cd3 / anti - cd28 monoclonal antibodies ( life technologies ) . while the use of anti - cd3 antibodies alone or in combination with feeder cells and growth factors , such as il - 2 , has been the practice for many years , in comparison to beads coated with anti - cd3 / anti - cd28 monoclonal antibodies or cell - based artificial apcs ( aapcs ) , the activation and ex vivo expansion are suboptimal .16 , 17 the beads , or aapcs , can be easily removed from the culture through magnetic separation . in the presence of interleukin - 2 and aapcs , t cells can grow logarithmically in a perfusion bioreactor for several weeks .11 , 16 , 18 , 19 , 20 the use of aapcs derived from the chronic myelogenous leukemia cell line k562 , which can be engineered to express the required costimulatory ligands , also has been investigated as a method of expanding t cells ex vivo .17 , 21 culture conditions may be further refined to polarize t cells to a specific phenotype ( i.e. , th2 or th17 ) during expansion . indeed , car t cells that were polarized to a th17 phenotype demonstrated efficacy in a preclinical model , suggesting that t cell polarization is a strategy that may enter the clinic in the future . during the activation process , the t cells are incubated with the viral vector encoding the car , and , after several days , the vector is washed out of the culture by dilution and / or medium exchange . the viral vector uses viral machinery to attach to the patient cells , and , upon entry into the cells , the vector introduces genetic material in the form of rna . in the case of car t cell therapy , this genetic material encodes the car . the rna is reverse - transcribed into dna and permanently integrates into the genome of the patient cells ; therefore , car expression is maintained as the cells divide and are grown to large numbers in the bioreactor . the car is then transcribed and translated by the patient cells , and the car is expressed on the cell surface . lentiviral vectors , which have a safer integration site profile than gammaretroviral vectors ,24 , 25 are commonly used in clinical trials of car t cell therapies , including ctl019 . other methods of gene transfer , including the sleeping beauty transposon system or mrna transfection , have been investigated as alternative approaches to express a car in t cells .26 , 27 car t cells generated using transient mrna transfection have been used in the clinic ; however , this approach requires several rounds of car t cell infusion . furthermore , while the sleeping beauty transposon system is considered to be inexpensive and has been tested in early - phase clinical trials , there are still several concerns , including efficiency relative to lentiviral vectors , the unknown potential of insertional mutagenesis , and remobilization of transposons . bioreactor culture systems are designed to provide the optimal gas exchange requirements and culture mixing necessary to grow large numbers of cells for clinical use ( figure 2 ) . the wave bioreactor ( now known as the xuri ; ge healthcare life sciences ) , which utilizes a rocking platform , has been used to expand the cd19 - targeted car t cell therapy ctl019 .11 , 20 , 30 another culture system that can be used is the g - rex ( wilson wolf ) , which has the ability to expand cells from low seeding densities .31 , 32 the g - rex uses gas - permeable membranes , allowing the flask to be placed directly in a cell culture incubator . one drawback of this system , however , is that the flask must be opened during cell inoculation . the clinimacs prodigy ( miltenyi biotec ) is a single device that accomplishes cell preparation , enrichment , activation , transduction , expansion , final formulation , and sampling . this contrasts with other methods , which use separate machines for the cell culture , cell washing , and other steps in the preparation . it was shown recently that the clinimacs prodigy is feasible for generating car t cells , and this device is expected to be used soon to prepare car t cells for clinical trials . when the cell expansion process is finished , the cell culture , which may reach a volume of up to 5 l , must be concentrated to a volume that can be infused into the patient .11 , 18 the washed and concentrated cells are cryopreserved in infusible medium , and , following product release , the frozen cells are transported to and thawed at the center where the patient will be treated . while aspects of cell washing , isolation , and culture are semi - automated , improving the throughput of currently manual parts of processing will be critical for developing car t cell therapies that can be used for a wider range of indications and larger populations . although protocols for manufacturing clinical - grade car t cells have now been established , car t cell therapies have been used to treat only a few hundred patients to date . when scaling out this complex manufacturing process to treat more patients in larger trials at an increased number of clinical centers , the process should be carefully evaluated to ensure production efficiency without compromising the integrity and potency of the final product . because car t cells can be used to target several types of cancer , the scale of production for the vector and the car t cells also will depend on the incidence of each indication . additional considerations include generating consistently high - quality vector for predictable genetic modification of cells , understanding the long - term safety of gene therapy , and anticipating global regulatory concerns . in the united states , the viral vector used to transduce the car into t cells is considered a key raw material of the car t cell manufacturing process , and the modified t cell is considered the investigational final product , also known as the medicinal product in the european union . in contrast to the final car t cell product , which must be individually generated for each patient , the viral vector encoding the car can be made in large quantities and stored at 80c for 4 years in our experience . other reports suggest that frozen viral vector stocks are stable for up to 9 years at this temperature .35 , 36 as with the car t cell manufacturing process , generation of the vector stocks must take place in good manufacturing practice ( gmp ) facilities . the sterility of the vector is crucial because the final car t cell product can not be sterilized by filtration ; manufacture of the vector under controlled , clean room conditions with minimal open processing and sterile filtration during the final aseptic stages of production , all supported and verified by an array of safety testing , ensures sterility and the absence of packaging cells from the final vector product . in addition , use of a third - generation minimal lentiviral vector , incorporating key safety features , enhances safety .37 , 38 in our experience , the batch manufacture of viral vector for cellular therapies takes a minimum of 2 weeks . most of this time is spent growing adequate numbers of cells , such as hek293 t cells , to produce large quantities of replication - defective viral vector . starting from a cryopreserved aliquot of an appropriate working cell bank , the cells are expanded in culture for several days to the appropriate number for production , allowing considerable expansion from the original number of cells seeded . the cells are then transfected with plasmids that collectively result in the production of the minimal lentiviral vector . these plasmids are typically ( 1 ) a gag / pol packaging construct that encodes the viral structural proteins ( gag ) and enzymes ( pol ) ; ( 2 ) a construct encoding a suitable envelope glycoprotein from a heterologous source , resulting in vector particle pseudotyping ( e.g. , vsv - g ) ; ( 3 ) a construct for the expression of viral accessory protein rev ; along with ( 4 ) a vector plasmid encoding the car construct as well as other sequences required for efficient reverse transcription , rna packaging , and integration . the vector systems should employ a number of key safety features that collectively prevent the reacquisition of replication competence ( e.g. , codon - optimized gag / pol that minimizes homology between vector components to prevent recombination , self - inactivating long terminal repeat sequences , and removal of all unnecessary sequences and accessory genes ) .41 , 42 , 43 within 48 hr of transfection , the production cells begin to release car - expressing lentiviral vector , which can be collected from the culture medium . over the course of several days , medium exchange allows for the harvest of multiple batches of vector - containing medium , typically two harvests . after filtration to remove production cells and debris , the viral vector is purified through downstream processing to enrich for the viral vector while removing impurities and to formulate the vector into an appropriate storage buffer . in our experience , the vector may be frozen at this point to allow for the production of multiple sub - batches to make larger quantities of the final vector product for increased economic efficiency . once the target quantity of vector is available , a further gmp process , involving sterilizing filtration and vialing under aseptic conditions , is performed . it is important to establish quality control testing for safety , sterility , purity , potency , identity , and titer so that manufacturing centers can be assured that each batch of vector meets defined standards before it is used to transduce t cells . safety testing , which can involve preclinical experimentation or toxicity studies in animals , aims to determine that the product is safe for humans when administered appropriately . the sterility of the product is tested to ensure that it is free of contaminating microorganisms ; in the case of gammaretroviral vectors and lentiviral vectors , assays for replication - competent retroviruses / lentiviruses ( rcrs / rcls ) and mycoplasma testing of the cells and media used in the process help determine that the final car t cell product is free from adventitious agents and safe for infusion into patients . impurities in the vector product are broadly tested to ( 1 ) verify consistent purification afforded by the vector manufacturing process , and ( 2 ) consequently ensure that the quality of the vector is consistent prior to its use in the t cell manufacturing process . impurity testing includes testing for process - related impurities , such as benzonase ( merck kgaa ; used to degrade and facilitate the removal of dna ) and bovine serum albumin ( originating from fetal bovine serum ) , and it also includes characterization of both residual host cell dna and residual plasmid dna . in addition , the t cells are tested for bacterial and fungal contamination from the cell culture process . the potency of the vector product is tested to assess whether it functions as anticipated , and its identity is proven through relevant physical , chemical , or biological tests . for example , the titer of viral vector can be measured by analyzing the percentage of healthy donor cells transduced by predefined mois , and this can verify whether a particular batch of vector is expected to optimally transduce patient cells . in early clinical trials performed at the university of pennsylvania , multiple vector suppliers were used during the generation of the cd19 - targeting therapy ctl019 . using vectors from different suppliers as starting material raises additional questions about the comparability of vector purity , stability , and function . therefore , it is desirable that a single vector source is used for the generation of ctl019 cells in current and future clinical trials . additionally , the vector supplier should be able to meet requirements , such as gmp compliance , as well as meet the large production demand . therefore , our approach was to adopt a lentiviral vector manufacturing process that can meet global health authority requirements and that has the appropriate supporting process validation ( figure 3 ) . in our experience with lentiviral vector manufactured by oxford biomedica ( oxb ) , we found that consistent vector quality minimized site - to - site variation in the subsequent car t cell manufacturing process . to provide batches of sufficient size to support clinical and commercial requirements , the process has been designed and optimized to manufacture vector in a series of multiple sub - batches within a given manufacturing campaign spanning several weeks . this approach relies on a purification and formulation step prior to cryopreservation and a subsequent hold period . once sub - batches have been demonstrated to meet a key subset of specifications for that manufacturing stage , specific sub - batches are selected for filling , and final processing is completed in a single day . the intermediate container closure system ( and associated fill volume ) , gmp processing parameters ( freeze / thaw conditions , further aseptic processing conditions , final container , etc . ) , and the formulation buffer have all been selected to ensure that any loss in titer is minimal and so that the resultant filled product meets target specifications and performs consistently and robustly in the t cell manufacturing process . in addition , the hold stage is supported by a stability testing program , which shows that vector titer is stable in storage for an extended period . the transduction efficiency of the oxb ctl019 vector was examined in a two - site study , and consistent , dose - dependent transduction efficiency was observed at both sites ( unpublished data ) . this study also provided an understanding of the variability in transduction efficiency among healthy donors , which provides a meaningful baseline to which we can compare patient data . the data demonstrated that the oxb vector can be used with equivalent performance across donors and manufacturing sites . these qualities are both desirable and necessary when choosing a vector that can be produced and used at large scale , and they reduce the risk in process validation . optimizing the vector for car t cell transduction before beginning large - scale manufacturing reduces variability and maximizes efficiency . the scale of vector production ultimately needs to take into account the potential size of the patient population on an indication - by - indication basis . on this basis , our strategy is to focus current clinical supply , as well as initial commercial supply , on current and well - established production platforms , while investing in the development of next - generation production processes that will provide an equivalent quality of functional vector on a significantly larger scale . the most common vectors used in car t cell manufacturing are replication - defective vector systems based on two types of retroviruses : gammaretroviruses and lentiviruses . both gammaretroviruses and lentiviruses deliver rna that is reverse - transcribed into dna in the target cell ; this dna , which encodes the car construct , then integrates into the host genome via a process catalyzed by the vector integrase enzyme and several key sequences within the vector construct . an additional advantage of lentiviral - derived vectors is that they retain the ability of lentiviruses to infect non - dividing cells , thus increasing their ability to transduce a wide variety of cells , including quiescent and difficult - to - transduce cells . however , as described previously , t cell activation is required for increased transduction efficiency , and the lentiviral vector is introduced during cell activation . insertional mutagenesis caused by the integration of vector dna into host cells near an oncogene is a potential concern with all integrating vectors .46 , 47 however , lentiviral integration patterns favor sites away from cellular promoters , while gammaretroviral integration more frequently occurs near transcriptional start sites , suggesting that lentiviral vectors may carry a lower risk of mutagenesis . risk for insertional mutagenesis also appears to be dependent on factors other than the vector system , such as the transgene that is encoded , the promoter , and the cell type or disease that is targeted . car t cell viral vector - mediated oncogenicity has not been observed in patients treated with car t cells in our experience nor in a decade - long study . oncogenic potential may be increased if rcrs / rcls are present in the vector products ; however , current vector designs make the generation of rcrs / rcls highly unlikely . the fda 2006 guidance considers lentiviral and retroviral vectors to be potentially oncogenic ; therefore , vectors used in the clinic for car t cell therapy are carefully tested for rcrs / rcls . in addition to testing for rcrs at multiple stages throughout the vector manufacturing process and the vector - modified cell product , the fda also recommends that patients be followed for rcrs / rcls for up to 15 years to monitor any potential delayed adverse event related to these vectors . evaluating the long - term safety of using viral vectors foras mentioned above , health authority guidelines also require long - term follow - up of studies using viral vectors ; however , requirements may differ depending on the individual countries involved . for example , a united states ( usa ) trial has been developed to monitor patients who received the cd19 car t cell therapy ctl019 for 15 years after treatment ( nct02445222 ) . this study will include patients of any age who have been treated with ctl019 for any b cell malignancy . the primary objective of this follow - up study is to describe delayed adverse events suspected to be related to cd19 car t cell therapy , such as the development of new malignancies , incidence or exacerbation of a preexisting neurologic or autoimmune disorder , or new incidence of a hematologic disorder . the secondary objectives of this study are monitoring the persistence of the ctl019 cells in peripheral blood and the long - term efficacy of the therapy . the persistence of ctl019 cells will be examined by using qpcr to detect the cd19 car transgene at specified time points . additionally , the proportion of patients who relapse or experience disease progression will be monitored , as well as the incidence of patient death from any cause . because the effects of persistent car t cells on pregnancy are unknown , reproductive health and pregnancy outcomes also will be followed in female patients who were treated with car t cells . thus , the careful design and manufacture of viral vectors for car t cell therapy to maximize safety , along with quality and safety testing and long - term patient follow - up , ensure that patient safety is the top priority . a major challenge with scaling out the production of car t cell therapies is the transition from a flexible process at a single academic institution to a highly controlled process that can be implemented across many collection , manufacturing , and treatment sites ( figure 4 ) . therefore , effective coordination among the collection , manufacturing , and treatment sites involved is crucial to ensure that the material is handled correctly and patients are appropriately scheduled throughout the therapeutic process . success in developing a global manufacturing process of car t cells will be driven by a robust understanding of both the product and the process in order to establish the target product profile and critical quality attributes . for ctl019 , the target product profile includes those qualities already discussed : target - specific , highly potent t cells that are capable of robust expansion and long - term persistence in vivo . using this product profile , cell number , transduction efficiency , growth rate , cellular phenotype , and functional analysis are all critical quality attributes of ctl019 that are well understood and controlled . cellular phenotype includes measures such as t cell subset distribution ( helper or cytotoxic , effector or memory , etc . ) and functionality ( cell killing , cytokine release , proliferative capacity , exhaustion , apoptosis , etc . ) . these critical quality attributes will be coordinated with process understanding to develop a consistent manufacturing process and control strategy that will ensure a uniform product . examples include the percentage of cd3 + t cells in the product and measurement of potency . however , it is to be noted that values for car positivity , viability , phenotype , and potency will vary from product to product . as more experience is gained and these data begin to be made public , fair comparisons on the utility and appropriate ranges may be assessed .51 , 52 vendor agreements , such as our agreement with oxb described previously , are critical for maintaining a controlled manufacturing process . in the case of car t cell therapy , product comparability has the additional challenge that variability between patient apheresis starting materials is likely to contribute much greater differences than factors related to the manufacturing site . therefore , we have controlled our processes for ctl019 manufacturing and vector production so that we minimize variability related to the manufacturing process . early results of car t cell therapy suggest significant patient benefit , and , thus , this therapy has the potential for clinical success , which could lead to greater global regulatory collaboration and harmonization . the patient benefit offered by car t cell therapies provides a promising opportunity to create a common ground between different regulatory authorities and improve international cooperation . ensuring regulatory compliance is a critical factor for the successful development of this novel therapeutic approach , and this will be an interesting challenge in a global environment . the fda has been regulating cell and gene therapies for many years and has developed a number of guidance documents regarding these products . however , these guidance documents are not harmonized with other countries or regions . in addition , each major country has a slightly different focus as they review clinical trial applications . for example , european union ( eu ) countries require cgmp compliance as determined by a qualified person , while the united states assesses cgmp compliance through a paper review . therefore , the more countries that are involved in clinical trials , the more robust the manufacturing process will need to be to meet all of the questions and regulatory requirements . to bring harmonization in the emerging area of cell and gene therapies , on october 11 , 2012 , nine members of the global regulatory community , including brazil anvisa ; european medicines agency ( ema ) ; health canada ; india national institute of biologicals ( nib ) ; japan ministry of health , welfare and labour / pharmaceutical and medical devices agency ; south korea ministry of food and drug safety ( previously known as food and drug administration [ kfda ] ) ; singapore health sciences authority ( hsa ) ; swissmedic ; and the u.s . food and drug administration , convened to form an integrated group with a goal to discuss best practices in the regulation of cell / gene - based therapies and support harmonization ( https://www.i-p-r-f.org/en/working-groups/gene-therapy-working-group/ ) . car t cell developers should have a thorough understanding of this diverse regulatory landscape . until harmonized regulations are established and there is common experience among regions , we can expect a significant level of uncertainty in product development and a greater reliance on subjective judgment by the regulators . for example , donor screening and testing , traceability and labeling , patient confidentiality , and apheresis requirements can vary widely among countries . this is particularly challenging if the donor starting material and final product are shipped across international borders . another example is that the definitions of the materials used ( i.e. , the starting or raw material ) and the requirements for quality control of these materials vary across regions . balancing different country requirements with starting material quality requirements can be challenging , but it is crucial for multi - national trials . therefore , the origin , traceability , composition , and certification of each reagent must be readily accessible . lastly , as each region has unique documents and recommendations related to materials used in cell and gene therapy manufacturing , the requirements for the human or animal serum used for cell culture differ among global regions . thus , to address some of these regulatory concerns , we are establishing protocols for car t cell manufacturing using reagents that comply with the quality requirements for major global regions ( e.g. , using the same international supplier across global regions ) . there are several preclinical areas of investigation designed to improve car t cell therapies and provide benefit to a larger patient population . one aspect under investigation is the subtype of t cells used for car t cell therapy . the starting cell population used for many car t cell therapies consists of cd4 and cd8 t cells at the ratio present in the peripheral blood of the patient . however , the use of a fixed 1:1 ratio of cd4 : cd8 car t cells in patients with all and non - hodgkin lymphoma has been investigated . if the ratio of t cell subsets becomes an important factor in car t cell therapy , manufacturing protocols may need to be altered to include the extra purification steps necessary to administer car t cells in a fixed subset ratio . other areas of consideration for the future of manufacturing a car t cell therapy include mitigating possible adverse events , both short and long term . for example , one adverse effect related to car t cell therapy is severe cytokine release syndrome ( crs ) , which occurs in a minority of patients . crs is caused by the release of proinflammatory cytokines directly from the car t cells and dying tumor cells . although most cases of crs are manageable with established treatment algorithms , it has been speculated that mechanisms to inactivate car t cells in patients experiencing adverse effects could be useful to improve the safety of car t cell therapy . using a suicide switch incorporated into the car construct is a strategy that is currently being investigated as a potential way to specifically deplete car t cells in a controlled manner , and it may become important as car t cell therapy is investigated in an ever - growing clinical population .55 , 56 for example , the icasp9 safety switch has been effectively used to reduce graft - versus - host disease ( gvhd ) in patients receiving allogeneic stem cell transplant . however , depletion of car t cells also may abrogate the potential benefit of long - term car t cell - mediated tumor surveillance . another method of potentially increasing the safety of car t cell therapy involves improving the specificity of the modified t cells . this approach may be especially important for car t cells targeting solid tumors , which often do not have antigens uniquely expressed on the tumor . a preclinical study showed that car t cells could be used to target tumors expressing two antigens , psca and psma ; the car t cells did not kill tumor cells expressing only one of these antigens . combinatorial antigen recognition strategies may , therefore , be important to consider when designing cars for the treatment of solid tumors . in our experience , crs has not yet been observed in clinical trials using car t cells to target solid tumors , perhaps because fewer tumor cells are rapidly killed at once due to the solid tumor mass . an additional strategy under investigation is the use of allogeneic off - the - shelf car t cells . this platform uses genome editing to inactivate the endogenous tcr gene , which limits the ability of the allogeneic cells to cause gvhd .59 , 60 off - the - shelf car t cells have shown efficacy in lymphoma xenograft models ; but , although there is a report of compassionate use in one patient , the results of controlled clinical trial use have not yet been reported .59 , 61 how the quality of the patient cells used for car transduction affects the efficacy of the final car t cell product also should be more thoroughly investigated . it has been shown recently that the reduction of an exhausted t cell phenotype is associated with improved car t cell efficacy . therefore , the choice of car - signaling domains , selection of cell subsets , and adjustment of cell culture conditions to decrease the percentage of cells that become exhausted during the transduction and expansion processes may be critical to generate the highest - quality car t cell product . given the success of car t cells in treating patients in the united states with b cell malignancies , scaling out car t cell manufacturing capacity will allow examination of the safety and efficacy of car t cell therapies in larger cohorts of patients around the globe . however , a number of manufacturing and regulatory challenges need to be considered when attempting to bring a cellular therapy with a complex manufacturing process to a larger , international patient population . we are currently manufacturing the cd19 car t cell therapy ctl019 in a way that will streamline the process of using the therapy globally . to accomplish this , we have established robust collaborations with academic institutions and vendors to thoroughly investigate both the product and process to ensure that our materials are controlled to maintain high quality . anticipating regulatory and manufacturing issues before they arise and proactively addressing these concerns help expedite the process of bringing this promising therapeutic approach to more patients . b.l.l . wrote , edited , reviewed , coordinated , and submitted the paper and j.m . , k.w . , andb.l.l . has commercial research grants from novartis pharmaceuticals and holds intellectual property assigned to the university of pennsylvania and licensed to novartis pharmaceuticals .\noutput:\n" }, { "from": "agent", "value": "immunotherapy using chimeric antigen receptor - modified t cells has demonstrated high response rates in patients with b cell malignancies , and chimeric antigen receptor t cell therapy is now being investigated in several hematologic and solid tumor types . chimeric antigen receptor t cells are generated by removing t cells from a patient s blood and engineering the cells to express the chimeric antigen receptor , which reprograms the t cells to target tumor cells . as chimeric antigen receptor t cell therapy moves into later - phase clinical trials and becomes an option for more patients , compliance of the chimeric antigen receptor t cell manufacturing process with global regulatory requirements becomes a topic for extensive discussion . additionally , the challenges of taking a chimeric antigen receptor t cell manufacturing process from a single institution to a large - scale multi - site manufacturing center must be addressed . we have anticipated such concerns in our experience with the cd19 chimeric antigen receptor t cell therapy ctl019 . in this review , we discuss steps involved in the cell processing of the technology , including the use of an optimal vector for consistent cell processing , along with addressing the challenges of expanding chimeric antigen receptor t cell therapy to a global patient population ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: sudden cardiac death ( scd ) accounts for almost 20 % of total mortality in western europe and the usa , and ventricular fibrillation ( vf ) is the most common underlying arrhythmia . vf arises through multiple mechanisms , depending on the underlying cardiac pathology . in the last decade , considerable progress has been made in the understanding of the genetic , molecular and electrophysiological basis of scd in the uncommon ( monogenic ) familial arrhythmia syndromes affecting the structurally normal heart and the rare inherited structural disorders associated with increased scd risk . however , the overwhelming majority ( ~ 80 % ) of scds in adults are caused by the sequelae of coronary artery disease , namely myocardial ischaemia or acute myocardial infarction ( mi ) , where scd is the first clinically identified expression of heart disease in up to half of cases . in contrast to the monogenic rhythm disorders , progress in understanding the molecular determinants of vf in these conditions , affecting a much greater proportion of the population , has been very limited . consequently , specific and sensitive risk predictors , as well as therapeutic targets for prevention , are currently missing . because of the magnitude of the problem , the opportunities for a real public health impact of improved risk stratification and novel preventive therapeutic strategies are enormous . the concept of a heritable component in the determination of risk for scd was first put forward by two epidemiological studies published in the late 1990s . in a population - based casecontrol study in the seattle area , the rate of mi or scd among first - degree relatives of cardiac arrest patients was almost 50 % higher than that in first - degree relatives of control patients . in the paris prospective study , parental sudden death increased the relative risk of scd among french men to 1.8 , and sudden death of both parents increased the relative risk of scd to 9.4 . we subsequently analysed further the concept of genetic predisposition to scd in a case control study in which we selectively included only patients with a first , acute st - elevation myocardial infarction ( stemi ) . in this population , recruited at multiple dutch heart centres , which we named the arrhythmia genetics in the netherlandsagnes study , we demonstrated that familial sudden death occurred significantly more frequently among stemi patients who suffered vf ( cases ) compared with stemi patients who did not suffer vf ( controls ) ( or 2.72 , 95 % ci 1.84 to 4.03 ) . this finding provided a strong rationale for the search of genetic modulators of risk in this specific cardiac pathology . there are two prevailing hypotheses as to the nature of the genetic variation modulating such common phenotypes . common variant hypothesis implicates common genetic variants , present at frequencies of 5 % in the general population , such as single nucleotide polymorphisms ( snps ) , each conferring a small to modest risk . rare variant hypothesis , proposes that susceptibility to common disease is due to low frequency ( 5 % ) variants , each conferring a moderate increase in risk . the advent of arrays in the second half of the last decade , capable of genotyping hundreds of thousands of snps in an individual in one single experiment , enabled the assessment of the contribution of common genetic variation spread throughout the genome to complex diseases . a clear advantage of these genomewide association studies ( gwas ) is that they are hypothesis - free , as there is no bias or list of candidate genes that are being tested . in order to identify common genetic variation underlying susceptibility to vf during a first acute mi , we recently conducted a genomewide association study in the agnes case control population . the selection of one highly specific arrhythmia phenotype ( mechanism ) for instance we excluded individuals with vf in the context of extensive pre - existing myocardial scarring from previous mis is critical in ensuring statistical power in such association studies . we genotyped 515 agnes cases with vf and 457 agnes controls without vf using the illumina human610 - quad array . non - genotyped snps throughout the genome were imputed by virtue of their degree of correlation to genotyped snps using data from the hapmap european ceu reference panel . the association of each snp with vf was then evaluated using logistic regression assuming an additive genetic model with adjustment for age and sex . over 2 million snps were evaluated in this way . the distribution of p values for the association of each snp with vf is shown in fig .1 . eight snps clustering on chromosome 21q21 ( the long arm of chromosome 21 ) showed the strongest association signal , passing the bonferroni - corrected p value threshold of p 510 . from these , the most significant association signals were found for rs2824292 and rs2824293 ( p = 3.310 ) . these two snps , which are highly correlated ( in strong linkage disequilibrium ) with each other , exhibited an odds ratio of 1.78 per copy of the g allele ( 95 % confidence interval , 1.472.13 ; risk allele was g for both snps ) . approximately 30 % of agnes cases were homozygous for these alleles in contrast to only 15 % of agnes controls . as expected , the frequency of the risk alleles in the general population was intermediate between those of cases and controls ( fig . 1 ) . control population . a manhattan plot of the genomewide association scan in the agnes population . each dot represents a different snp , with the alternating bands of colour showing different chromosomes of the human genome ( x axis ) . the negative logarithms of the p values , expressing the strength of the association , are displayed on the y axis . the horizontal red line indicates the preset threshold for genomewide significance , p 510 . data drawn from bezzina et al . . b distribution of rs2824292 genotypes in the discovery set , the replication set and a sample of the general population . c haploview plot of linkage disequilibrium ( d ) for all ceu hapmap snps in the region harbouring rs2824292 and the cxadr gene . colour scheme : d = 1 and lod 2 bright red , d 1 and lod 2 shades of pink / red , d = 1 and lod 2 blue , d 1 and lod 2 white results of genomewide association analysis in the agnes case control population . a manhattan plot of the genomewide association scan in the agnes population . each dot represents a different snp , with the alternating bands of colour showing different chromosomes of the human genome ( x axis ) . the negative logarithms of the p values , expressing the strength of the association , are displayed on the y axis . the horizontal red line indicates the preset threshold for genomewide significance , p 510 . data drawn from bezzina et al . . b distribution of rs2824292 genotypes in the discovery set , the replication set and a sample of the general population . c haploview plot of linkage disequilibrium ( d ) for all ceu hapmap snps in the region harbouring rs2824292 and the cxadr gene . colour scheme : d = 1 and lod 2 bright red , d 1 and lod 2 shades of pink / red , d = 1 and lod 2 blue , d 1 and lod 2 whiteone of the snps ( rs2824292 ) was then carried forward for replication in an independently recruited casecases for replication ( n = 150 ) were drawn from the amsterdam resuscitation study ( arrest - 11 ) . arrest - 11 is an ongoing prospective population - based study aimed at establishing the genetic , clinical and environmental determinants of scd in the general population . caucasian out - of - hospital cardiac arrest patients in the arrest - 11 dataset presenting with mi at hospital admission and with ecg - documented fast ventricular tachycardia or vf were included in the replication analysis . controls for the replication analysis were mi survivors drawn from the genetic determinants of restenosis ( gender ) study ( gender - mi ; n = 391 ) . the gender population comprises consecutive patients who underwent successful elective percutaneous transluminal coronary angioplasty at one of four dutch heart centres . as observed in the agnes casecontrol set , the risk g allele of snp rs2824292 at chromosome 21q21 was more abundant and the protective a allele was less abundant in the arrest - mi cases compared with the gender - mi controls . the chromosome 21q21 locus had not previously been linked to arrhythmia and the mechanism by which common genetic variation at this locus confers an increased risk to vf is unknown . common genetic variation is expected to impact on disease either by changing the amino acid sequence of a protein ( and thereby its function ) or by impacting on the level of gene expression and consequently protein level . the snps at chromosome 21q21 impacting on risk for vf are not located within a gene . inspection of a 1 megabase ( mb ) interval spanning both upstream and downstream of these snps identified three genes all located within a region of 0.5 mb downstream . one is btg3 , located at a distance of 179 kb from the association signal . this gene encodes b cell translocation gene 3 , a member of the pc3 , btg and tob family of growth inhibitory genes . its mrna expression level is relatively high in the testis , lung and ovary but is low in heart . another gene in the region is c21orf91 , located at 374 kb from the association signal ; it encodes the human orthologue of the chicken c21orf91 ( also known as eurl , encoding the early undifferentiated retina and lens protein ) , which is known to be expressed in the developing chick retina and lens and has been suggested to play a role in the development of these structures . the most plausible candidate gene in the region for the observed effect at this locus is , however , the cxadr gene , located 98 kb downstream of the association signal . this gene encodes the coxsackievirus and adenovirus receptor ( car ) protein , which is mostly expressed in the heart , brain and pancreas . car has a long - recognised role as viral receptor in the pathogenesis of viral myocarditis and its sequela of dilated cardiomyopathy . upon infection , the enteroviral ( as is the coxsackie b virus ) protease 2a cleaves dystrophin , resulting in disruption of the dystrophin glycoprotein complex , a component of the cytoskeleton of cardiac myocytes . interestingly , frequency of active coxsackie b virus infection has been reported to be high in a group of mi patients who died suddenly . it is expressed at the intercalated disc between cardiomyocytes , suggesting a role in conduction of the cardiac electrical impulse and cell cell communication . indeed , two studies have reported a physiological role for car in localisation of connexin 45 at the intercalated disks of atrioventricular node cardiomyocytes as well as its role in conduction of the cardiac impulse within this cardiac compartment . in addition , protein levels of connexin 43 , which is expressed in atrial and ventricular myocytes and in distal parts of the conduction system , were reduced in car - deficient mice , suggesting that loss of car could impact on ventricular conduction . however , providing support for a role of cxadr ( or any other gene ) in mediating the observed effect is a daunting task . the snps mediating the association signal on chromosome 21q21 are not linked to amino acid changing variants within the car coding region ( or any other gene in the region ) . this precludes an effect through functional variation of a gene product , implying that the role of these snps in modulation of arrhythmia risk is to be sought in effects on gene expression . effects of common genetic variation on gene expression is considered to be an important mechanism impacting on inter - individual variation in disease susceptibility , and many gwas studies have in fact identified many signals within non - coding ( intronic and intergenic ) regions . this will require studying gene expression as a function of genotype at this locus in the human heart . it is clear that other genetic variation in other areas of the genome will impact on risk of vf during acute ischaemia . these loci , as for the one we identified , are expected to carry small effect sizes , implying that increased numbers of agnes cases and controls will be required to uncover additional genes by gwas . the risk carried by the common genetic variation we identified at chromosome 21q21 is small , meaning that genotyping of this locus alone for risk stratification in patients will not reach the accuracy that is considered as clinically informative . nevertheless , if additional such loci are identified , one could envisage that by virtue of their additive effect , genotyping of such variants at multiple loci may in the future lead to their use in clinical practice . importantly , however , the gwas approach we used here has revealed a previously unsuspected involvement of chromosome 21q21 in arrhythmia risk . further research on the mechanism of this locus will ultimately provide novel insight into arrhythmia mechanisms in this condition .\noutput:\n" }, { "from": "agent", "value": "sudden cardiac death from ventricular fibrillation during myocardial infarction is a leading cause of total and cardiovascular mortality . this multifactorial , complex condition clusters in families , suggesting a substantial genetic cause . we carried out a genomewide association study ( gwas ) for sudden cardiac death , in the agnes ( arrhythmia genetics in the netherlands ) population , consisting of patients with ( cases ) and without ( controls ) ventricular fibrillation during a first st - elevation myocardial infarction . the most significant association was found at chromosome 21q21 ( rs2824292 ; odds ratio = 1.78 , 95 % ci 1.472.13 , p = 3.3 1010 ) , 98 kb proximal of the cxadr gene , encoding the coxsackie and adenovirus receptor . this locus has not previously been implicated in arrhythmia susceptibility . further research on the mechanism of this locus will ultimately provide novel insight into arrhythmia mechanisms in this condition ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the prolonged duration of orthodontic treatments is probably the chief complaint of both clinicians and patients . to reduce the treatment period , recent cellular , molecular , and tissue engineering studies affirmed that mechanical stimuli are the most important , though not the exclusive inducing factor for orthodontic tooth movement . accordingly , other stimuli such as surgical , laser , electromagnetic , pharmaceutical , and ultrasound have been used along with mechanical stimuli to accelerate tooth movements . resorption and formation of cortical bone are the two basic phenomena which make orthodontic tooth movement possible . all of the mentioned stimuli affect orthodontic movement by modulating the primary biological phenomena responsible for tooth movement . frost demonstrated that if there is sufficient noxious stimulus , a series of physiologic healing responses , termed as rap , can be induced , which are characterized with accelerated reorganizing activity in osseous and soft tissues . surgical injuries are potent stimuli in the induction of rap . based on this rationale , in addition , many clinicians like wilcko et al. suya , kole et al . , and badr et al . have attempted different methods of decortications ; they have all confirmed the effectiveness of these techniques . there are also some recent animal studies that investigated the effects of corticotomy facilitated orthodontics . for example , ren et al . , lino et al . , and mostafa et al . all reported that their methods of decortication after reflecting surgical flaps were effective in accelerating tooth movement compared to control . despite the repeated confirmation of the effectiveness of corticotomy - facilitated orthodontics through numerous case reports and animal studies , consequently , research into other less invasive procedures that may facilitate orthodontic treatment is required . kim et al . introduced corticision technique that is a surgical method with minimal intervention ; it is reportedly effective in accelerating tooth movement through induction of rap . despite its minimal intervention , four vertical incisions are required in this technique ; and transecting the mucogingival line could lead to postoperative complications . to reduce the treatment time with minimal invasiveness , we introduced a new technique called flapless bur decortication . instead , small holes are made along the buccal bone of the tooth that requires orthodontic movement using a fine surgical fissure bur . since the holes are located in the attached gingiva using lowspeed / high - torque rotary instrument , minimal complications are expected . the purpose of this study was to evaluate the effectiveness of this new technique in accelerating orthodontic tooth movement and its potential complications . ten premolar teeth of five adult german male dogs , weighting 20 - 25 kg with the age range of 18 - 24 months were used in this study . animals were supervised in the hospital of small animals ( tehran university , tehran , iran ) for one week prior to the study . their health status was evaluated by an experienced veterinary surgeon according to the animal welfare regulations . animals were surgically preanesthetized with ketamine ( 10 mg / kg , i m ) and 2 % xylazine ( 5 mg / kg ) and 5 % thiopental natrium ( 10 mg , iv ) . before the operation , the oral cavity was irrigated with 0.2 % povidine iodine and 0.02 % chlorhexidine mouthwash , respectively . the total of ten left and right maxillary first premolars were extracted [ figure 1 ] . first premolar tooth was extracted following local anesthesia miniscrews ( jeil medical corporation , korea .8 - mm length 1.4 mm diameter , self - drilling ) were placed mesial to left and right upper canines . a small groove was created in the most gingival part of clinical crown of right and left upper second premolars using a porcelain disk . a10 - mm a - niti closed coil spring ( orthotechnology corporation , usa ) was used for premolars protraction . the two ends of ligature wire were ligated ; one around the cervical groove of second premolar and one to the miniscrew head using steel ligature wire ( 3 m - unitek , 0.01 inch ) . the ligature wires were stabilized using nomix adhesive ( 3 m unitek corporation , usa ) [ figure 2 ] . the force system used for second premolar protraction ; the ligated wires were stabilized using nomix adhesive a 150 - gr orthodontic force was initially exerted for protraction of the second premolar . decortication was performed for one side of each arch and the other side was used as the control . during the process of decortication , small holes , without gingival flaps , were created through mesial and distal attached gingiva of each second premolar tooth . the holes were made on each side using a pointed tungsten carbide fissure bur ( the contouring fissure bur c1 , technicare dental supplies ltd . also , other holes were made on the buccal cortical table of the extracted tooth . small holes made mesial and distal to the second premolars and on the buccal table of extracted first premolar the holes ( all with 2 - mm depth ) were prepared using high torque , low speed surgical handpiece along with copious irrigation . antibiotic ( penicillin 633 , od ) , analgesics ( mephenamic acid 250 mg , bd / bid and tramadol 100 mg , bd / bid ) were prescribed for 5 days post - operatively . two 1 - mm depth pointed holes were made on the buccal surface of canines and second premolars with the same tungsten carbide fissure bur . the inter - points distances were recorded at the beginning of the experiment and one , two and three months thereafter by a digital caliper . the inter - points distances were measured with digital caliper ( accuracy = 0.01 mm ) two measurements were taken for each side by two independent examiners and the average was considered as the data . the condition of each miniscrew , attached gingiva , operation site , and the teeth were checked monthly . also , the coil springs were reactivated in the case of diminished forces ; oral cavity was irrigated with 0.02 % chlorhexidine . the decortication sites were evaluated for postsurgical complications such as fistula formation , ulceration , hematoma , and lack of proper healing . the experiment was performed according to the ethics committee of shahid beheshti university of medical sciences . the specimens were decalcified in 10 % formic acid and after preparation of paraffin blocks were sectioned mesiodistally ( 3 - 5 m thick ) and stained with hematoxylin and eosin technique . the amounts of tooth movements at the both sides during the first , second , and third months were calculated . descriptive statistics ( mean , standard deviation ) for velocity of monthly movement of second premolars in each group and accumulated distance of second premolar movement after each month were used in all groups . based on normal distribution of the data ( shapiro - wilk test ) , paired samples t - test was used for intergroup comparisons of mean tooth movements at each time . for intergroup and intragroup comparison of tooth movement by time period ( i.e. , monthly changes ) , we used the multivariate analysis of two - way repeated measures anova . because the sphericity was not assumed according to mauchly 's test of sphericity , the greenhouse - greisser correction was used for intergroup comparison of tooth movements by time . descriptive statistics ( mean , standard deviation ) for velocity of monthly movement of second premolars in each group and accumulated distance of second premolar movement after each month were used in all groups . based on normal distribution of the data ( shapiro - wilk test ) , paired samples t - test was used for intergroup comparisons of mean tooth movements at each time . for intergroup and intragroup comparison of tooth movement by time period ( i.e. , monthly changes ) , we used the multivariate analysis of two - way repeated measures anova . because the sphericity was not assumed according to mauchly 's test of sphericity , the greenhouse - greisser correction was used for intergroup comparison of tooth movements by time . the monthly movement and accumulated distance values for second premolars in study and control groups are shown in table 1 . comparison of the velocity and accumulated amount of second premolars movements in the study and control groups accordingly , during the first month , the movement of second premolars in the decortications side was 0.82 ( 0.56 ) mm greater than controls and this difference was statistically significant ( p = 0.031 ) . this difference was 0.04 ( 0.0.40 ) mm during the second month ; not statistically significant ( p = 0.826 ) . the difference between tooth movements during the third month of the experiment was 1.15 ( 0.58 ) mm . during this time , the second premolars in the decortications side moved less than the control side and this difference was significant ( p = 0.012 ) . considering the accumulated distance of tooth movement , the difference between accumulated tooth movement after two months was 0.86 ( 0.75 ) mm and this difference was not significant ( p = 0.063 ) . the difference between total amounts of tooth movement after three months between study and control groups was 0.29 ( 0.0.93 ) mm and this difference was not significant ( p = 0.527 ) [ table 1 ] . the results of this survey revealed that the differences between the amount of second premolar movement during the first , second and third months of the study were not significant for the control group ( p = 0.240 ) . in contrast , the velocity of this movement in the study group was significantly affected by the time ( p = 0.037 , greenhouse - geisser correction ) . the general patterns of monthly velocity of tooth movement in study and control groups were totally different [ figure 5 ] . comparative patterns of movement velocity related to second premolars during postoperative three months in the study group , the highest velocity of tooth movement was observed during the first month , followed by the second and third month in respect . contrarily , the related pattern for controls was increasing during 1 - 3 month , but not significantly different . considering the postsurgical complications , there was no findings of hematomas , ulcerations or oronasal fistulas during the study period . however , despite complete healing of the oral mucosa two weeks postsurgically , clinical appearance of decortications site was distinguishable . microphotographs of different decortication sites ; ( a ) , a site filled with woven bone with large marrow spaces ; ( b ) , more compact lamellar bone ( arrows ) has started to form from periphery , wb , woven bone ( h and e staining , 200 ) some of these sites were filled with the woven bone with large marrow spaces . the results of the present study indicated that in spite of effectiveness during the first month , flapless bur decortication technique had an inhibitory effect on orthodontic tooth movements in later stages . limited or less than enough area of decortications probably played an important role in limited acceleration of tooth movement during the first month . it can been proposed that the greater the amount of surgical intervention ( decortications ) , the greater the availability of biologic materials necessary for accelerating orthodontic tooth movement and the faster the velocity of tooth movement . frost observed a direct correlation between severity of surgical insult and intensity of regional acceleration phenomenon . reported a twice amount of accelerated tooth movement in study group compared to control group during the first month . in our study , 1.6 fold tooth movement in study group was found . this finding suggests that reducing the area of decortication negatively affects accelerated orthodontic tooth movement . in practice , few patients accept the risks of very wide area of decortication despite its effectiveness in reducing treatment time . then , the following questions will arise : 1 - what is the minimum amount of this intervention to successfully accelerate tooth movement ? 2 - does decortications in left side contribute to accelerating tooth movement in the right side ? 3 - does ( would ) local decortication around the teeth , which are subjected to orthodontic movement , effectively accelerate tooth movement ? another indistinct issue is the location of decortication to be either buccal and lingual or buccal . during the third month , the oldest sites of decortication went through the process of bone lamellation and maturation [ figures 6b and 7 ] and adversely affected tooth movement . biologic materials recruited because of decortication not only increased bone turn over , but also effectively contributed to accelerating bone maturation . as a result , the bone formed distal to the mesial root of second premolars on the experiment side was of the more mature lamellar bone in comparison with the relatively immature bone with wider marrow spaces on the control side . suggested this difference in quality of the newly formed bone as a reason for the reduced relapse tendency in the experiment side . this difference at the same time retarded tooth movement after the mesial side of distal root reached this bone in experiment side . recent clinical as well as animal studies support the declining pattern of tooth movement in study group at later stages of the treatment . phase contrast microphotography of two adjacent decortication sites ; ( a ) , woven bone ( wb ) ;( b ) , lamellar bone in the periphery ( arrow ) ( 40 ) during the second month the effect of decotication was neutralized by the resistance to tooth movement provided by the process of bone maturation . for more extended decortication in larger areas , there was the risk of nasal floor perforation due to the vicinity of this structure with the second premolar teeth in dogs . the available area of attached gingiva was the second limiting factor because decortication in the alveolar mucosa had the risk of tissue rupturing and unfavorable bleeding . in regard to using slow - speed hand - piece with copious irrigation and also the attached gingival as the holes site , minimal risk of complications was expected . that was achieved through the results of our study since no postoperative complications were observed during the three month observation of our experiment . if this technique would be tested in humans , the method of creating small holes between the roots of teeth could be modified by using hand instruments ; like the ones used for mini - implants , to improve safety of the method and decreasing the probability of complications . corticotomy facilitated orthodontic tooth movement is achievable with flapless bur decortication technique.velocity of tooth movement decreases in later stages of treatment due to maturation of newly formed bone at decortication sites . velocity of tooth movement decreases in later stages of treatment due to maturation of newly formed bone at decortication sites . as the timing of physiological events responsible for tooth movement in animal models differs from humans , future clinical trials with similar basis\noutput:\n" }, { "from": "agent", "value": "background : different surgical procedures that reduce orthodontic treatment time have been recommended . the aim of this study was to evaluate the effectiveness of a new less invasive surgical technique ( called flapless bur decortications ) for accelerating orthodontic tooth movement.materials and methods : this study was designed as a split - mouth study . the left and right maxillary first premolars of five dogs were extracted . an a - niti closed coil spring and an absolute anchorage was used for premolar protraction in both sides . in each dog , decortications were performed for one side and the other side was used as the control group . the distance between canine and second premolar was measured and the sites of decortication were evaluated histologically . the data was analyzed by paired samples t - test and multivariate analysis of two - way repeated measures anova.results : the study teeth moved more than their controls in the first month and less than their controls in the third month ( p < 0.05 ) . the total difference between study and control movements was not significant ( p < 0.05 ) . conclusion : ( 1 ) corticotomy facilitated orthodontic tooth movement is achievable with flapless bur decortication technique . ( 2 ) velocity of tooth movement decreases in later stages of treatment due to maturation of newly formed bone at decortication sites ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: criss - cross heart ( cch ) , or superoinferior ventricles , is a complex congenital rotational abnormality in which the systemic and pulmonary venous streams cross at the atrioventricular ( av ) level without mixing . its frequency is less than 8 / 1000000 and accounts for 0.1 % of congenital heart defects ( chd ) . in the normal heart , av structures are parallel to each other when viewed from the front , whereas in cch the av structures are not parallel but angulated by as much as 90 degrees .14 the atrium connects with the contralateral ventricle and the ventricular chambers are arranged in a superoinferior fashion , with the right ventricle ( rv ) superiorly and the left ventricle ( lv ) inferiorly located , regardless of whether the av connection is concordant or discordant . the diagnosis is made by using 2 - dimensional and color doppler echocardiography .35 here , we report a rare case of cch with concordant atrioventricular connections with dorv which was diagnosed by echocardiography . a 2 month old female infant , weighing 3.7 kg presented with history of breathlessness , feeding difficulty and cyanosis . she was a second product of non - consanguineous marriage and born by normal vaginal delivery . respectively . blood pressure was recorded at 75/35 mmhg and oxygen saturation 85 % in room air . cardiac auscultation revealed normal first and second heart sound along with a grade 3/6 ejection systolic murmur audible best at the left upper parasternal area . the two - dimensional echocardiography , subcostal coronal views demonstrated the connection of the left - sided left atrium and the right - sided left ventricle through the mitral valve and the right - sided right atrium to be connected to the left - sided right ventricle through the tricuspid valve by anterior angulation of the transducer . it also shows the two great arteries arising from the right ventricle ( figure 1 ) . subcostal coronal views shows the connection of the right - sided ra to be connected to the left - sided rv through the tricuspid valve , inlet vsd and the two great arteries arising from the rv . short - axis views shows the right ventricle was superior and left ventricle was inferior with horizontal position of the ventricular septum ( figure 2 ) . short - axis views shows the superior ( rv ) and inferior ( lv ) ventricle with horizontal position of the ventricular septum . the standard 4 - chamber view was not showing simultaneously all four chambers and both atrioventricular valves ( figure 3 ) . a large size inlet type of ventricular septal defect ( bidirectional shunt ) and a moderate size ostium secundum atrial septal defect ( bidirectional shunt ) were present . cch is a complex congenital anomaly produced by the rotation of ventricular mass along its long axis . this positional anomaly can coexist with a horizontal displacement of the ventricular mass along the horizontal plane of long axis , which produces superior - inferior ventricles . in 1961 , lev and rowlatt described unusual arrangement of the cardiac inlets that is ventricular chambers arranged in a superoinferior fashion , with the rv superiorly and the lv inferiorly .2 in 1974 , anderson et al used the term cch for cardiac anomaly producing the illusion of crossing of the systemic and pulmonary venous stream without mixing at the av level .3 in the later years , other cases was described with situs solitus or situs inversus or isomerism , mostly with av concordance .45 the physiology is determined by the concordant or discordant atrioventricular ( av ) and ventriculoarterial ( va ) connection and the associated cardiac defects .67 cch may be seen in three forms , that is complete transposition , corrected transposition , and normal hearts . in our case , there was av and va concordance with malposed great arteries . a review of the medical literature does not reveal any isolated presentation of cch cases . most patients with cch has other anomalies such as vsd , transposition of great vessels , right ventricular hypoplasia , subpulmonary stenosis , straddling av and others .78 the diagnosis should be suspected by echocardiography when the parallel arrangement of the av valves and ventricular inlets can not be achieved , and the two valves are not easily visualized simultaneously on apical 4 chamber view . color flow mapping can help in assessing the av connection , visualization of the direction of intracardiac blood flows and recognition of the crossover of the inflow streams .910 yang yl et al11 reported that the failure to obtain a characteristic 4 - chamber view was diagnostic for recognition of the cch . the echocardiographic features suggested by yang yl et al11 were present in our case . surgical options vary according to the exact sequential segmental analysis and associated abnormalities . in conclusion , cch is a rare cardiac anomaly than can be diagnosed by a transthoracic echocardiography by an alert echocardiographer to determine the relationships of the cardiac chambers and associated cardiac anomalies .\noutput:\n" }, { "from": "agent", "value": "crisscross heart ( cch ) is a rare cardiac malformation characterized by crossing of the inflow streams of the two ventricles due to an apparent twisting of the heart about its long axis . the developmental mechanisms and causes of cch are remaining unknown . neonates mainly presents with cyanosis and a systolic murmur . we herein present a case of cch with concordant atrioventriculo connections with double outlet right ventricle ( dorv ) which was diagnosed by echocardiography ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a 32 - year - old male of maltese heritage who was known to have electroretinogram - confirmed bietti crystalline retinal dystrophy presented with acute bilateral central visual impairment . upon examination , best - corrected visual acuity ( bcva ) was 6 / 60 in the right eye and 6 / 45 in the left eye . at an examination one year previously , bcva had been 6 / 7.5 in the right eye and 6 / 18 in the left . dilated retinal examination revealed the presence of peripheral corneal and retina crystalline changes characteristic of bietti dystrophy ( fig . no evidence of late leakage was observed , excluding the diagnosis of choroidal neovascularisation ( fig . time - domain ( td ) - oct was performed and demonstrated bilateral cystic macular lesions ( fig .1 g and 1h ) with a central foveal thickness ( cft ) of 242 m in the right eye and 253 m in the left . on the basis of the oct findings , the patient was diagnosed with cystoid macular oedema . acetazolamide therapy at a dose of 500 mg daily was initiated , and one month later , visual acuity improved to 6 / 18 bilaterally and cft reduced to 221 m in the right eye and 225 m in the left eye . following one year of acetazolamide therapy , bcva was 6 / 15 in the right eye and 6 / 24 in the left eye , and cft had stabilised at 221 m in the right eye and 219 m in the left eye ( fig . 1i and 1j ) . bietti crystalline retinal dystrophy is an uncommon , inherited , retinal degeneration associated with retinal crystal deposits and progressive visual decline . cystoid macular oedema is a rare complication of this disease , and may be associated with an acceleration of visual loss . the pathogenesis of the oedema in this disorder is not well understood , and therefore treatment options are limited . macular oedema has been documented in association with other inherited retinal dystrophies , notably retinitis pigmentosa . in thissetting , it is considered that the oedema may relate to impaired rpe function , resulting in a failure of the rpe pumping mechanism . inhibition of carbonic anhydrase with acetazolamide has previously been shown to result in increased retinal pump activity , and has been used in this regard to treat cystoid macular oedema associated with retinitis pigmentosa , x - linked retinoschisis and enhanced s - cone syndrome with some success . to our knowledge , this is the first case of cystoid macular oedema associated with bietti dystrophy that was successfully treated with acetazolamide therapy in the literature . given the reversible nature of this complication , it is important that potential treatments be recognised to preserve optimal vision . patients with bietti dystrophy who develop worsening central vision should be promptly assessed to diagnose cystoid macular oedema . this complication is responsive to therapy with acetazolamide , resulting in improved anatomical outcomes and preservation of visual function .\noutput:\n" }, { "from": "agent", "value": "bietti crystalline retinal dystrophy is a rare , inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration . this condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline . currently , treatment options for this complication of bietti dystrophy are limited and the visual prognosis is poor . here , we present a case of cystoid macular oedema associated with bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography . these modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation . in this patient , cystoid macular oedema was resolved with oral acetazolamide therapy , a treatment that has not been previously reported in this context . acetazolamide treatment resulted in oedema resolution and improvement in visual function , and can be considered a therapeutic option for other patients with bietti dystrophy who develop cystoid macular oedema ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the main pathophysiology in rheumatoid arthritis ( ra ) is found in the synovial tissues of peripheral joints as an extensive infiltration of immunocompetent cells and high levels of inflammatory mediators . one common outcome is that inflammatory pannus tissue invades the cartilage and bone surface and causes cartilage and bone tissue destruction . this process results in joint crepitus , which is considered to be a clinical sign of joint surface destruction in chronic arthritides that is correlated to radiographic such as cortical erosions in the temporomandibular joint ( tmj ) and hand joints . crepitus in knee osteoarthritis has been found to be the strongest clinical indicator of radiographic changes in osteoarthritis ( oa ) . however , another significant part of bone tissue resorption takes place within the subchondral bone marrow as a response to the systemic inflammation and mediators from the blood circulation . histologic studies of joint replacement specimens have shown that bone marrow resorptions with inflammatory cellular infiltrates can be detected on mri in 39 % 75 % of ra patients with disease duration of less than 1 year . this was further shown in chronic ra patients subjected to joint replacement surgery in finger joints comparing immunohistochemistry with mri . we recently showed that tmj bone tissue resorption is associated with plasma levels of glutamate , especially in patients with low - systemic inflammatory activity and low level of estradiol or testosterone . the mechanisms behind bone tissue resorption observed in the tmj in early ra may thus not be entirely related to systemic inflammation but also to other factors such as hormones . the question was therefore raised whether the glutamate - associated bone tissue resorption observed in the tmj in early ra is associated with bone tissue destruction involving inflammatory mediators such as serotonin ( 5 - ht ) and proinflammatory cytokines or whether it is associated with noninflammatory mechanisms . glutamate participates in normal bone turn over and bone tissue remodeling the glutamate level has been reported to be elevated in plasma and synovial tissues in ra , probably as a result of release from activated thrombocytes . continuous thrombocyte activation in the synovial tissues might be accomplished by proinflammatory cytokines such as tumor necrosis factor ( tnf ) since thrombocytes express cytokine receptors . serotonin may be involved in bone tissue resorption and the blood level of 5 - ht has been related to erosions of tmj bone tissue in patients with ra .5 - ht , which is mainly released from locally activated thrombocytes , is present in the bone marrow as well as the synovial membrane , synovial fluid , and blood plasma of patients with ra . estradiol is known to suppress inflammation by inhibiting tnf and to increase the expression of osteoprotegerin and thereby reduce bone resorption . the beneficial effects of estradiol on bone and inflammation may be neutralized and even antagonized by progesterone . the aim of this study was to investigate whether tmj bone tissue resorption in early ra is related to gender or proinflammatory mediators or markers or the sex steroid hormones depending on whether there are clinical signs of crepitus or not in the tmj . is bone resorption of the tmj related to crepitus as a clinical sign of articular cartilage and bone tissue damage ? is bone resorption in patients with or without crepitus related to glutamate , 5 - ht , cytokines ( tnf , il - 1 , il - 6 , vegf ) , crp , esr , rf , estradiol , progesterone or testosterone ? forty - seven patients , 29 females , and 18 males with ra were included in the study . the patients were consecutively invited to participate in the study after being diagnosed at the department of rheumatology , karolinska university hospital in huddinge , sweden . the inclusion criteria were diagnosis of ra according to the criteria of the american college of rheumatology , age above 18 , and verbal consent . exclusion criteria were current malignancies , tmj surgery or trauma within 2 years , recent intra - articular glucocorticoid injection in the tmj ( within 1 month ) , and conditions other than ra causing orofacial pain . this project was approved by the regional ethical committee at karolinska institutet ( 03 - 204 ) and by the local radiation committee at karolinska university hospital in huddinge ( 19/03 ) . eighty - one percent of the patients were on methotrexate treatment , which was initiated shortly before they entered the study at the time of diagnosis . sixty - two percent used nonsteroidal anti - inflammatory drug medication , 44 % received glucocorticoids , either by oral or intra - articular administration and 9 % used salazopyrine or received gold salt injection . the patients entered this study a median ( 25th75th percentile ) of 23 ( 1236 ) days after diagnosis . they were examined clinically for joint crepitus , blood samples were collected and radiographs were taken during the same day . tmj crepitus was assessed bilaterally as absent ( 0 ) , palpable ( 1 ) , or audible ( 2 ) and thus with an individual maximum score of 4 . the disease activity score comprising 28 joints ( das28 ) was assessed at the department of rheumatology , karolinska university hospital , huddinge , sweden , at the time of diagnosis . radiographic examination of the tmj region was performed with a cone - beam computer tomograph ( cbct ; newtom qr dvt mod 9000 , verona , italy ) . the newtom allowed a three - dimensional digital volume representation of the tmj region , enabling sections of this region in any desired plane . the examinations were performed with a standardized head position with the tmj located in the centre of the region of interest . the maximum size of the region of interest was 130130130 mm and scanning time was 70 seconds . the cbct sections were evaluated for presence of erosions , that is , radiographic signs of bone tissue resorption . erosion was defined as a local area with decreased mineral density of the articular cortical bone surface including or not including the adjacent subcortical bone or as subcortical bone tissue resorption under intact cortical bone . the erosions were assessed in 12 different regions of the condyle and temporal component of each tmj . the intraobserver consistency between repeated readings of bone erosion was tested on the images of 20 randomly selected joints from 10 of the patients . the scoring system was tested in a blinded fashion by the same radiologist at two occasions 2 - 3 years apart . on an individual levelthere was a total agreement in seven patients ( 70 % ) and a difference by one score unit in the other three patients . in order to assess the inflammatory activity the inflammatory markers esr ( normal range : 70 years : 15 mm / h and 70 years : 20 mm / h , 70 years : 20 mm / h and 70 years : 28 mm / h ) , crp ( normal range : 3 mg / l ) , rf ( normal range : 15 iu ) , thrombocyte particle count ( tpc ; normal range : 14534810 / l , 16538710 / l ) , leukocyte particle count ( lpc ; normal range : 8.810 / l ) , and anticyclic citrullinated peptide antibody titer ( anti - ccp ) ( normal range : 25 u / ml ) were analyzed in serum . all these analyses except for erythrocyte sedimentation rate were performed with standard procedures at the department of laboratory medicine ( clinical chemistry and immunology ) , karolinska university hospital , huddinge , sweden . venous blood sampled in edta tubes was immediately cooled and centrifuged ( 1500 g for 10 min at + 4c ) for analysis of glutamate , tnf , il - 1 , and il - 6 in plasma . other venous blood samples were stored without additives in room temperature for 1 hour to coagulate thereafter centrifuged ( 1500 g for 30 min at + 4c ) for analyses of 5 - ht serum levels . after preparation , the supernatants without cells were pipetted into polypropylene tubes except for serum samples that were stored in polystyrene tubes in 80c until analysis . the concentrations of all investigated mediators were determined by commercially available assays in our laboratory . glutamate in plasma was analysed by the amplex red glutamic acid / glutamate oxidase assay ( amplex , invitrogen , eugene , usa ) . this glutamate assay had a detection limit of 10 mol / l according to the manufacturer . the median ( 5th95th percentile ) plasma level of glutamate in 22 healthy individuals ( mean age 30 years , range 2054 years ) was found to be 6.2 ( 0.318 ) tnf , il - 1 , and il - 6 in plasma were analysed with the high - sensitivity human cytokine lincoplex kit for simultaneous multianalyte detection with luminex technology and instrumentation ( lincoplex kit , linco research , st charles , usa ) . the assay minimum detection concentration is 0.05 ( tnf ) , 0.06 ( il - 1 ) , and 0.10 ( il - 6 ) pg / ml , respectively . the intra - assay coefficients of variation are 3.5 % ( tnf ) , 3.1 % ( il - 1 ) , and 3.5 % ( il - 6 ) and the inter - assay coefficient are 3.8 % ( tnf ) , 2.2 % ( il - 1 ) , and 4.5 % ( il - 6 ) . the median ( 5th95th percentile ) levels of tnf ( n = 30 ) , il - 1 ( n = 30 ) and il - 6 ( n = 30 ) in a healthy control group have been reported to be 3.3 ( 1.27.8 ) , 0.33 ( 0.02.1 ) , and 187 ( 0.060 ) pg / ml , respectively . the healthy group referenced comprised 48 subjects ( 23 men and 25 women ; mean age 53 years , range 3969 years ) . vegf was analysed by a commercially available enzyme - linked immunoassay kit ( quantikine human immunoassays , r & d inc , minneapolis , usa ) in lysed whole blood . the median ( range ) vegf level in normal lysed whole blood is 298 ( 92 to 554 ) pg / ml .5 - ht was analyzed by a commercially available competitive enzyme immunoassay kit ( eia - kit . the intra - assay coefficient of variation is less than 9.4 % and the interassay coefficient of variation is less than 9.9 % , according to the manufacturer . normal serum 5 - ht has a median ( 25th75th percentile ) of 602 ( 339957 ) nmol / l , for males 626 ( 2711819 ; n = 19 , age = 35 ( 2741 ) and for females 882 ( 4371666 ) nmol / l ( n = 35 , age = 39 ( 3051 ) according to our data . the levels are not correlated to age ( rs = 0,112 , n = 52 , p = .427 ) . blood samples were also drawn to determine the serum levels of estradiol , progesterone and testosterone , according to standard procedures at the department of laboratory medicine ( clinical chemistry and immunology ) , karolinska university hospital , huddinge , sweden . the normal reference range according to the laboratory for estradiol levels in fertile women was 1001500pmol / l , in postmenopausal women 50 pmol / l and in men 50150 pmol / l . the normal reference intervall for progesterone levels in fertile women was at follicular phase 4.8 nmol / l and luteal phase 17 nmol / l and in postmenopausal women 3.0 median , min , max , and the 25th and 75th percentiles as well as mean and standard deviation were used for descriptive statistics . correlations between the variables were tested in all patients as well as prespecified subgroups according to gender and tmj crepitus by the spearman rank correlation coefficient ( rs ) . in order to select the strongest independent predictors to tmj bone erosion scoreinteraction analysis was performed by including an interaction term in addition to the main effects in the multiple linear regression model . the significance of differences according to gender and crepitus was tested with the mann - whitney u - test . the levels of the inflammatory mediators as well as the bone erosion and crepitus scores are shown in table 2 . bone erosion score was positively correlated to glutamate ( rs = 0.30 , p = .042 ) and tmj crepitus ( rs = 0.38 , p = .008 ) , while glutamate and tmj crepitus were not significantly related ( rs = 0.08 , p = .590 ) . multiple stepwise regression showed that the independent variables tmj crepitus ( p .001 ) , glutamate ( p = .005 ) , and esr ( p = .010 ) were positively related to and explained 41 % of the variation in the dependent variable tmj bone erosion score ( p .001 ) . gender , 5 - ht , tnf , il - 1 , il - 6 , vegf , estradiol , progesterone , testosterone , rf , crp , and esr were also included into the stepwise regression but did not significantly add to the ability of the model to predict erosion score . in the patients without tmj crepitus , bone erosion score was positively correlated to glutamate ( rs = 0.45 , n = 35 , p = .007 ; figure 1 ) . the corresponding correlation in the patients with crepitus was negative but did not reach statistical significance ( rs = 0.35 , n = 12 , p = .264 ; figure 1 ) . interaction analysis with multiple linear regression showed that there was a different relation ( p = .050 ) between bone erosion score and glutamate level in the patients without crepitus compared to those with crepitus . the bone erosion score was positively correlated to one of the investigated mediators of inflammation , 5 - ht ( rs = 0.54 , n = 16 , p = .030 ; figure 2 ) , in males . the corresponding correlation in the females was negative but did not reach statistical significance ( rs = 0.34 , n = 27 , p = .080 ; figure 2 ) . interaction analysis with multiple linear regression showed a significant ( p = .014 ) interaction between gender and 5 - ht . this implies a significant difference in relation between bone erosion and 5 - ht in males compared to females . this study shows that glutamate is related to articular bone tissue resorption in the tmj of patients with early ra without joint crepitus and that the presence bone resorption can be predicted by presence of joint crepitus and plasma level of glutamate . the crepitus in this study is mainly palpable ( 21 % ) and infrequently audible ( 2 % ) , which indicates a lower degree of tissue destruction in agreement with the short disease duration . the frequency of crepitus was lower in this study than in a previous study where 75 % of both male and female ra patients were reported to have crepitus . however , the majority of these patients had disease duration of more than 5 years . another study reported a weak but statistically significant relationship between crepitus and radiologic changes of the tmj in ra patients , where 80 % of joints with crepitus showed evidence of articular bone erosion while only 47 % of joints with radiologic erosion had crepitus . this latter finding is in agreement with ours and indicates that articular bone erosions develop with different mechanisms . the regression model also included esr as a predictor of bone resorption when the other variables were considered . esr was not significantly correlated to the bone erosion score in the non - parametric univariate analysis and this relationship should therefore be interpreted with great caution . however , such a relation can be expected for erosions of systemic inflammatory nature and strong association between serial measurements of esr and radiographic joint destruction has been found . the relationship between bone tissue resorption and serum level of 5 - ht seems to be positive and specific for men since there was a significant gender difference regarding this relationship . plasma and serum levels of 5 - ht have been reported to be associated with progression of tmj bone resorption during a 2546 month interval in patients with established ra , indicating a systemic influence by 5 - ht on local bone tissue resorption .5 - ht may modulate osteoblast bone formation via the 5 - ht2b receptor and the osteoclast differentiation through its transporter 5 - htt . the exact nature of the 5 - ht contribution to bone tissue resorption and the influence of gender is , however , still unclear . in this study , the observed bone tissue resorption can not be considered as normal remodeling due to the combination with active ra . however , 5 - ht may play an important role for articular bone tissue remodeling in both healthy individuals and in patients with ra since osteocytes and osteoblasts express receptors for 5 - ht and 5 - htt . a longitudinal study of mainly female patients with chronic ra remarkably showed that low - serum levels of 5 - ht were associated with progression of erosions , while high levels were associated with regression . whether glutamate or 5 - htis associated with continuing bone tissue resorption in the early stage of ra is not yet known . in this study , no dietary precautions like fasting were taken before blood sampling and quantification of 5 - ht and glutamate . the plasma level of glutamate found in this study is lower than that reported from a previous study of ra patients as well as in a sample of healthy individuals investigated in our clinic . a significantly higher nonfasting level of glutamate was found in the ra patients in comparison with healthy individuals . however , since no relation was observed between glutamate level and age nor disease duration in our patient sample , the discrepancies between the studies may be of methodological nature . the patients included had a recently diagnosed ra and most of them were examined for this study within less than one month after diagnosis and about 6 months after their report of debut of symptoms . most patients commenced anti - inflammatory medication shortly after diagnosis and before the start of this investigation . an influence of the medication on the levels of inflammatory markers and mediators is likely but the influence of the medication on the radiographic signs of bone tissue resorption can be expected to be minor or even insignificant . in conclusion , the results of this study show that presence of bone tissue resorption of the tmj can be predicted by presence of a combination of joint crepitus and elevated plasma level of glutamate in early ra . the relation between glutamate and tmj bone tissue resorption is different in patients with or without crepitus indicating that glutamate has a particular role in joints without surface destruction . the results also show that bone tissue resorption at this early stage is related to the inflammatory mediator 5 - ht in men but not in women .\noutput:\n" }, { "from": "agent", "value": "the aim was to investigate whether bone tissue resorption in early ra is related to crepitus of the temporomandibular joint ( tmj ) and systemic levels of inflammatory mediators and markers and sex steroid hormones . twentynine women and 18 men with recently diagnosed ra were examined for tmj bone erosions with computerized tomography and tmj crepitus was assessed . blood samples were analyzed for glutamate , 5 - ht , tnf , il - 1 , il - 6 , vegf , inflammatory markers , and estradiol , progesterone and testosterone . the tmj erosion score was positively correlated to glutamate , and tmj crepitus where crepitus , glutamate and esr explained 40 % of the variation in the bone erosion score . in the patients without crepitus , bone erosion score was positively correlated to glutamate , which was not the case in the patients with crepitus . in conclusion , the results of this study show that tmj bone tissue resorption can be predicted by tmj crepitus and glutamate in early ra ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: non - muscle - invasive bladder cancer ( nmibc ) generally has a good prognosis . nevertheless , the recurrence rate is 3080 % and the muscle - invasive disease develops within five years in 145 % of the cases .1 , 2 the goal of treatment is to eliminate the disease , prevent its recurrence , and improve the prognosis . one of the theories advanced to explain tumor recurrence is development of new tumors in tumor cells remaining after inadequate resection . another theory is seeding of tumor cells in damaged portions of the mucosa , resulting in tumor recurrence .3,4 therefore , intravesical therapy used in the early period could help to prevent tumor recurrence by eliminating floating tumor cells or residual neoplastic tissue .57 in a series of randomized studies , it was shown that treatment with a cytotoxic agent , such as epirubicin or mitomycin c ( mmc ) after transurethral resection of bladder tumor ( turbt ) decreases the risk of relapse .817 nowadays , single instillation of chemotherapy is used in the first 6 hours after turbt to reduce the likelihood of recurrence in low - risk nmibc , as recommended in the european association of urology guidelines for treatment of bladder cancer .18 in studies aiming to increase the effectiveness of intravesical chemotherapy , the most discussed methods are reduction of the volume of mmc solvent , reducing the amount of residual urine , fluid restriction to reduce production of urine , and urinary alkalinization .19 the effect of urinary alkalinization on intracavitary mmc as maintenance therapy has been evaluated in other studies , but there is no study reporting on early single instillation of mmc .20,21 in this prospective study , our objective was to determine the effectiveness of early single instillation of mmc treatment together with urinary alkalinization in patients with low - risk nmibc , diagnosed on the basis of pathology results and tumor properties , on increasing the effect of mmc , on time to relapse , and on recurrence rates . between february 2006 and november 2010 , 53 patients with a primary bladder tumor treated in our department by transurethral resection and single instillation of mmc were randomized into standard and optimized treatment groups . the patients , who were diagnosed to have low - risk nmibc post surgery depending on tumor pathology , number , and size ( tag1 , solitary , tumor size 3 cm ) , were prospectively enrolled in the optimized group . patients with medium - risk and high - risk nmibc , those with muscle - invasive bladder cancer , and those with suspected bladder perforation who could not be treated with mmc were excluded from the study . the control group was established retrospectively from patients with low - risk uroepithelial bladder cancer who had previously undergone turbt without mmc treatment . early single instillation of mmc is now the standard of care recommended in the guidelines , and all these patients had been treated prior to the current guidelines . in total , 49 patients with a diagnosis of primary bladder tumor treated with turbt and with records of regular follow - up in the postoperative period were included as the low - risk group . there were 11 patients in the standard treatment group , 15 in the optimized treatment group , and 23 in the control group . approval of the local ethics committee was obtained , and written informed consent forms were taken from patients before surgery . the patients in the standard treatment group received 40 mg of intracavitary mmc diluted with 40 ml of sterile saline , given into a completely empty bladder in the first 6 hours postoperatively via a foley catheter inserted during the operation , and the solution was kept in the urinary bladder for 2 hours . for alkalinization , 1.3 g of sodium bicarbonate was given orally the night before surgery , on the morning of surgery , and 30 minutes prior to administration of mmc , in three doses . patients in both the standard and optimized groups received 40 mg of mmc in the same way . in the control group , the patients were followed after surgery at months 3 and 12 , then annually for the first 5 years by cystoscopy . urinary ph was measured the night before and just prior to surgery in both the standard and optimized groups . the mean time to recurrence was calculated from the date of surgery to first recurrence in the control group and recorded in the patient files as months for both the standard and optimized groups . in addition , the groups were compared separately with respect to pathological features , demographic characteristics , and related environmental risk factors . the data analysis was performed using the statistical package for the social sciences version 11.5 for windows ( spss inc , chicago , il ) . descriptive statistics for continuous variables were expressed as the mean standard deviation or median ( minimum maximum ) , and categorical variables were given as number of cases and percentages . the relationship between recurrence - free survival rate and average life expectancy associated with the categorical variables was assessed by kaplan - meier survival analysis using the log - rank test . for each variable , survival rates at 1 , 3 , and 5 years , median survival time , and 95 % confidence intervals were calculated . the effect of the continuous variables on recurrence - free survival was evaluated using univariate cox proportional hazards regression analysis . hazard ratios and 95 % confidence intervals were calculated for each variable . a value of p 0.05 was considered to be statistically significant for the results . the data analysis was performed using the statistical package for the social sciences version 11.5 for windows ( spss inc , chicago , il ) . descriptive statistics for continuous variables were expressed as the mean standard deviation or median ( minimum maximum ) , and categorical variables were given as number of cases and percentages . the relationship between recurrence - free survival rate and average life expectancy associated with the categorical variables was assessed by kaplan - meier survival analysis using the log - rank test . for each variable , survival rates at 1 , 3 , and 5 years , median survival time , and 95 % confidence intervals were calculated . the effect of the continuous variables on recurrence - free survival was evaluated using univariate cox proportional hazards regression analysis . hazard ratios and 95 % confidence intervals were calculated for each variable . a value of p 0.05 was considered to be statistically significant for the results . the patients in the three treatment groups were compared with respect to demographic characteristics , tumor size , duration of follow - up , occupational risk factors , and smoking history . there were no statistically significant differences between the groups in this respect that may have affected the results of treatment ( table 1 ) . pre - alkalinization urinary ph values ( night before surgery ) were compared with post - alkalinization urinary ph values ( just before surgery ) in the optimized and standard groups . mean pre - alkalinization and post - alkalinization ph values were 5.880.71 and 6.400.50 versus 5.880.63 and 5.880.57 in the optimized and standard groups , respectively . the increase in mean urinary ph value was statistically significant in the optimized group ( p = 0.005 ) , but there was no statistically significant change in the standard group ( p = 0.750 ) . the effects of the variables in table 1 , on recurrence - free survival rates were assessed individually . the median age of the patients included in the study was 61 ( range 2584 ) years , and was found to have no effect on mean recurrence - free survival rate ( p = 0.720 ) . the recurrence - free survival rate in these men was 90.9 % and 85.9 % , respectively , at 1 and 3 years , while the recurrence - free survival rate of the five female patients was 100 % and 66.7 % , respectively , at 1 and 3 years . there was no significant difference between the genders in this regard ( table 2 ) . survival of patients with known occupational risk factors was 75 % at 1 and 3 years , whereas patients without occupational risk factors had recurrence - free survival rates of 93.3 % and 85.8 % at 1 and 3 years , respectively . thirty - nine patients with a history of smoking had recurrence - free survival rates of 89.7 % , 84.2 % , and 84.2 % at 1 , 3 , and 5 years , respectively . the 10 patients with no history of smoking had recurrence - free survival rates of 100 % , 85.7 % , and 85.7 % at 1 , 3 , and 5 years , respectively . the overall recurrence - free survival rates for all patients was 91.8 % , 84.7 % and 84.7 % at 1 , 3 and 5 years , respectively ( figure 1 and table 3 ) . the recurrence - free survival rates of the standard group at 1 , 3 , and 5 years were 100 % . in the optimized group , these rates were 86.7 % , 79.4 % , and 79.4 % at 1 , 3 , and 5 years , respectively . in the control group , the recurrence - free survival rates were 91.3 % , 82.6 % , and 82.6 % , at 1 , 3 , and 5 years , respectively . when the three groups were compared in terms of mean recurrence - free survival rates , no statistically significant difference was found ( table 3 ) . the mean time to recurrencewas compared between the study groups , and was 34.8 ( range 28.541.1 ) months in the optimized group , and 51.8 ( range 44.359.2 ) months in the control group , respectively . there was no recurrence during the follow - up period in the standard group ( table 3 ) . the groups had similar characteristics and were evaluated in terms of recurrence - free survival rate , time to recurrence , tumor size , demographic data such as age and gender , and risk factors such as smoking and occupational hazards , which might have an effect on the likelihood of recurrence . no statistically significant difference was found between the three treatment groups with respect to recurrence - free survival and time to recurrence . with regard to urinary alkalinization , the european association urology guidelines refer to the phase iii study by au et al , who reported that adaptation of urinary ph , reduced urinary output , and buffering of the intravesical solution all contribute to reduction in the recurrence rate .19 moreover , in another randomized trial , it is documented that the urinary drug concentration is more important than the duration of treatment .21 in light of these data , which all still need to be validated , the patient is asked to restrict their water intake on the morning of instillation , and it is recommended to dissolve the drug in an optimally buffered solution . on the other hand , in the american urological association guidelines , although it is stated that the optimal method of administration of mmc is unclear , reference is again made to the study by au et al , and dehydration , alkalinization , dose concentration , and bladder evacuation are recommended .19 there are no recommendations in the national comprehensive cancer network guidelines regarding adaptation of urinary ph . there are no studies in the literature on the use of urinary alkalinization in patients with primary bladder tumors , in addition to early postoperative single - dose instillation of mmc . the effectiveness of urinary alkalinization has been questioned in studies investigating induction treatment with mmc . in the study by au et al , performed on behalf of the international mmc consortium , it was predicted that when the physiological parameters of urine are under control , the mmc reaches higher concentrations in urine and therefore in the tumor .19 when the results of their study are compared with ours , their study showed a longer period of time to relapse and a greater disease - free survival rate in the optimized group . on the other hand , unlike our study , some measures other than urinary alkalinization were taken into account , including an increased dose of mmc , diluent volume reduction , and restriction of fluid . however , in our study , the only difference between the standard and optimized groups was in alkalinization of urine , and only the effectiveness of urinary alkalinization was monitored . in the au et al study , optimization for induction therapywas used in patients with a high - risk primary tumor or recurrence , whereas in our study , only early postoperative instillation of a single dose was used in low - risk patients with primary bladder tumors . therefore , in our study , the effect of urinary alkalinization was only measured after instillation of a single dose of mmc , whereas in the study by au et al , the cumulative effect of urinary alkalinization over an average period of 6 weeks before each mmc instillation may be responsible for the positive outcomes in the optimized group . maeda et al22 also showed that both the stability and activity of mmc are ph - dependent , and that a urinary ph greater than 5.5 heralds a good prognosis in mmc - treated patients . however , in in vitro studies , mmc has been shown to be more cytotoxic at acidic ph levels .23 in contrast , although the bladder tumor cells had a ph - dependent response in monolayer cultures , this reaction could not be demonstrated in multilayer cultures .24 in our study , it was demonstrated that effective urinary alkalinization could be achieved in the optimized group . nevertheless , a further contribution of preoperative urinary alkalinization to the benefits of early single - dose mmc instillation could not be demonstrated in terms of recurrence - free survival rate or time to recurrence . this study could not demonstrate the efficacy of urinary alkalinization before early single - dose mmc instillation following turbt in improving the effectiveness of mmc . however , although our study has some important limitations , including the small number of patients in the treatment and control groups , and a short follow - up period , it may have made a considerable contribution to the relevant literature , being an early study of the use of urinary alkalinization , in addition to single early mmc instillation following turbt in patients with nmibc . the results of this preliminary study did not demonstrate the efficacy of urinary alkalinization in increasing the effectiveness of a single dose of early mmc instillation following turbt , and discouraged us from continuing the practice . studies with larger numbers and longer follow - up periods are needed to confirm or refute our findings .\noutput:\n" }, { "from": "agent", "value": "backgroundthe purpose of this study was to determine the effectiveness of a single early instillation of mitomycin c ( mmc ) after transurethral resection of bladder tumor ( turbt ) together with urinary alkalinization in patients with low - risk non - muscle - invasive bladder cancer ( nmibc ) . methodsbetween february 2006 and november 2010 , patients diagnosed as having a primary bladder tumor were randomized into standard and optimized treatment groups . the treatment groups were formed prospectively from patients with nmibc according to results of pathological examination postoperatively , whereas the control group was formed retrospectively . patients in the standard group ( n = 11 ) were given intravesical mmc 40 mg in the first 6 hours after turbt , while the patients in the optimized group ( n = 15 ) underwent urinary alkalinization prior to mmc . in the control group ( n = 23 ) , no drug treatment was given . the patients were followed after surgery at months 3 and 12 , and then annually for the first 5 years using cystoscopy and ultrasound . time to recurrence and recurrence - free survival rates were calculated.resultsthere were no statistically significant differences between the standard and optimized groups , between the control and optimized groups , or between the control and standard groups in terms of mean recurrence - free survival rates ( p = 0.132 , 0.645 , and 0.173 , respectively ) . the mean time to recurrence was 34.8 ( range 28.541.1 ) months in the optimized group and 51.8 ( range 44.359.2 ) months in the control group . there was no recurrence during the follow - up period in the standard group.conclusionthe results of this preliminary study could not demonstrate the efficacy of urinary alkalinization before a single dose of early mmc following turbt to increase the effectiveness of the mmc , so we did not continue the study further ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: our study involved participants drawn from the whitehall ii epidemiological cohort ( 24 ) for psychophysiological testing between 2006 and 2008 . the criteria for entry into the study included no history or objective signs of clinical or subclinical cvd and no previous diagnosis or treatment for hypertension , inflammatory diseases , allergies , or kidney disease . cvd was defined as prior mi , stable or unstable angina , revascularization procedure , heart failure , transient ischemic attack , stroke , or electrocardiographic abnormalities ( resting 12 - lead electrocardiograms were taken ) . this information was confirmed by a telephone interview and verified from clinical data collected from the previous 7 phases of the whitehall ii study . volunteers were of white european origin , aged 53 to 76 years ; 56.5 % were in full - time employment . selection was stratified by grade of employment ( current or most recent ) to include higher and lower socioeconomic status participants . from the initially invited participants ( n = 1,169 ) ,27.6 % were not eligible ( mainly because of prescribed medications ) and 25.9 % declined to take part . participants were prohibited from using any antihistamine or anti - inflammatory medication for 7 days before testing and were rescheduled if they reported colds or other infections on the day of testing . participants gave full informed consent to participate in the study , and ethical approval was obtained from the university college london hospitals committee on the ethics of human research . we carried out psychophysiological stress testing in either the morning or afternoon in a light temperature - controlled laboratory . this procedure was based on a protocol previously used in this laboratory ( 25 ) . participants were instructed to refrain from drinking caffeinated beverages and smoking for at least 2 h before the study and not to have performed vigorous physical activity or consumed alcohol the previous evening . after a 30 - min rest period , baseline blood pressure ( using an automated ua - 779 digital monitor [ a & d instruments ltd . , oxford , united kingdom ] ) and a saliva sample were taken . two behavioral tasks , designed to induce mental stress , were then administered in random order . the tasks were a computerized version of the stroop task and mirror tracing , both of which have been used extensively in psychophysiological research ( 26 ) . the tasks each lasted for 5 min . saliva samples were collected immediately before and after the tasks for the assessment of salivary cortisol . the samples were collected using salivettes ( sarsted , leicester , united kingdom ) , which were stored at 30c until analysis . levels of cortisol were assessed using a time - resolved immunoassay with fluorescence detection at the university of dresden ( dresden , germany ) . the intra - assay and interassay coefficients of variation ( cvs ) were less than 8 % . nonfasting blood samples were collected in edta tubes and centrifuged immediately at 2,500 rpm for 10 min at room temperature . plasma was removed from the tube and aliquoted into 0.5 - ml portions and stored at 80c until analysis . we measured ctnt concentrations 75 min after the end of the mental stress test using a highly sensitive assay on an automated platform ( elecsys - 2010 troponin t hs stat , roche diagnostics , haywards heath , united kingdom ) , with a lower detection limit of 3 ng / l and a reported 99th percentile value in apparently healthy individuals of 13.5 ng / l , at which the cv is 9 % , confirmed by in - house studies ( 1719 ) . we assayed baseline plasma interleukin ( il ) - 6 using a quantikine high - sensitivity 2 - site enzyme - linked immunosorbent assay ( elisa ) from r & d systems ( oxford , united kingdom ) . the sensitivity of the assay ranged from 0.016 to 0.110 pg / ml , with intra - assay and interassay cvs of 7.3 % and 7.7 % , respectively . baseline c - reactive protein ( crp ) level was measured using a high - sensitivity elisa ( r & d systems ) . cac was assessed with electron - beam computed tomography ( imatron c - 150 , general electric , san francisco , california ) as previously described ( 27 ) . in brief ,40 contiguous 3 - mm slices were obtained during a single breath - hold starting at the carina and proceeding to the level of the diaphragm . scan time was 100 ms / slice , synchronized to 40 % of the r - r interval . agatston and volumetric calcium scores were calculated to quantify the extent of cac by a single experienced investigator blinded to the psychophysiological and clinical data on an aquarius workstation ( terarecon inc . , san mateo , california ) . because calcified volume was highly correlated with agatston score ( spearman rho 0.99 ) , we present data for agatston score only . participants reported current smoking levels , weekly alcohol intake ( units per week ) , employment grade ( as a marker of social position ) , and hours of moderate or vigorous physical activity per week . we measured height and weight in light clothing for calculation of body mass index ( bmi ) . total and high - density lipoprotein ( hdl ) cholesterol and triglycerides were measured within 72 h in serum stored at 4c using enzymatic colorimetric methods ( 28 ) . low - density lipoprotein ( ldl ) cholesterol level was derived using the friedewald equation ( 29 ) . glucose homeostasis was assessed from glycosylated hemoglobin ( hba1c ) concentration , assayed using boronate affinity chromatography , a combination of boronate affinity and liquid chromatography . we quantified the cortisol response to stress by subtracting the values of salivary cortisol concentration measured immediately after the behavioral tasks from the baseline . the resulting measure was normally distributed , and it was transformed for the main analyses into a binomial variable using a cut point at the value of 4 nmol / l , which corresponds to the mean value ( 0.54 nmol / l ) + 1 sd ( 3.47 nmol / l ) . hs - ctnt was highly right skewed and was undetectable for 83.3 % of the sample ( below the lower detection limit of 3ng / l ) ; therefore , it was transformed into a binomial variable ( detectable vs. undetectable ) . agatston score ( cac ) had a right - skewed distribution and was transformed for some analyses into a binomial variable by cutting at the value of zero ( 0 vs. 0 ) or 100 ( 100 vs. 100 ) . francis heart study , which demonstrated maximum sensitivity and specificity for detecting cardiovascular events at a threshold calcium score 100 ( 30 ) . we described the study sample according to the exposure ( salivary cortisol response to stress tasks ) and the outcome ( plasma detectable hs - ctnt ) variables . triglyceride and crp levels had right - skewed distributions and were described using medians and interquartile ranges . afterward we used multiple logistic regression to model the association between cortisol stress response and odds of detectable hs - ctnt . cortisol responses may differ according to baseline cortisol levels and time of testing ; therefore , these parameters were included as covariates . we also adjusted for age , sex , employment grade , and smoking because they are related to cvd and may confound the association between cortisol reactivity and cvd . additionally , we took into account clinical variables that are known to be linked to cvd such as systolic blood pressure , total cholesterol / hdl ratio , and hba1c . finally , we examined whether the association between cortisol reactivity and hs - ctnt was independent of underlying coronary atherosclerosis using several approaches : we adjusted for cac score as a binomial variable using both cut points separately ( 0 and 100 ) , carried out a subanalysis of participants with no detectable coronary calcification , and carried out a subanalysis of participants with positive cac scores and in this case further adjusted for cac score as a log - linear variable . we carried out sensitivity analyses on cortisol responses by testing several different methods of quantification . to test for dose - response associations , we analyzed the cortisol response as a continuous variable ; we tested a different cutoff for binomial analysis , defining positive responses as + 0.5 sd instead of 1 sd ; we calculated cortisol responses as the ratio between the post - stress and baseline values and tested the resulting variable as a linear variable and in binary analyses using both + 1 sd and + 0.5 sd as cut points . additionally , we checked for an association between the baseline levels of salivary cortisol and hs - ctnt using multivariate and time - stratified ( am / pm ) logistic regression models . as for the multiple adjustments , we further included additional variables such as physical activity , bmi , alcohol consumption , and ldl cholesterol , which were not included in the principal analyses . our study involved participants drawn from the whitehall ii epidemiological cohort ( 24 ) for psychophysiological testing between 2006 and 2008 . the criteria for entry into the study included no history or objective signs of clinical or subclinical cvd and no previous diagnosis or treatment for hypertension , inflammatory diseases , allergies , or kidney disease . cvd was defined as prior mi , stable or unstable angina , revascularization procedure , heart failure , transient ischemic attack , stroke , or electrocardiographic abnormalities ( resting 12 - lead electrocardiograms were taken ) . this information was confirmed by a telephone interview and verified from clinical data collected from the previous 7 phases of the whitehall ii study . volunteers were of white european origin , aged 53 to 76 years ; 56.5 % were in full - time employment . selection was stratified by grade of employment ( current or most recent ) to include higher and lower socioeconomic status participants . from the initially invited participants ( n = 1,169 ) ,27.6 % were not eligible ( mainly because of prescribed medications ) and 25.9 % declined to take part . participants were prohibited from using any antihistamine or anti - inflammatory medication for 7 days before testing and were rescheduled if they reported colds or other infections on the day of testing . participants gave full informed consent to participate in the study , and ethical approval was obtained from the university college london hospitals committee on the ethics of human research . we carried out psychophysiological stress testing in either the morning or afternoon in a light temperature - controlled laboratory . this procedure was based on a protocol previously used in this laboratory ( 25 ) . participants were instructed to refrain from drinking caffeinated beverages and smoking for at least 2 h before the study and not to have performed vigorous physical activity or consumed alcohol the previous evening . after a 30 - min rest period , baseline blood pressure ( using an automated ua - 779 digital monitor [ a & d instruments ltd . , oxford , united kingdom ] ) and a saliva sample were taken . two behavioral tasks , designed to induce mental stress , were then administered in random order . the tasks were a computerized version of the stroop task and mirror tracing , both of which have been used extensively in psychophysiological research ( 26 ) . the tasks each lasted for 5 min . saliva samples were collected immediately before and after the tasks for the assessment of salivary cortisol . the samples were collected using salivettes ( sarsted , leicester , united kingdom ) , which were stored at 30c until analysis . levels of cortisol were assessed using a time - resolved immunoassay with fluorescence detection at the university of dresden ( dresden , germany ) . the intra - assay and interassay coefficients of variation ( cvs ) were less than 8 % . nonfasting blood samples were collected in edta tubes and centrifuged immediately at 2,500 rpm for 10 min at room temperature . plasma was removed from the tube and aliquoted into 0.5 - ml portions and stored at 80c until analysis . we measured ctnt concentrations 75 min after the end of the mental stress test using a highly sensitive assay on an automated platform ( elecsys - 2010 troponin t hs stat , roche diagnostics , haywards heath , united kingdom ) , with a lower detection limit of 3 ng / l and a reported 99th percentile value in apparently healthy individuals of 13.5 ng / l , at which the cv is 9 % , confirmed by in - house studies ( 1719 ) . we assayed baseline plasma interleukin ( il ) - 6 using a quantikine high - sensitivity 2 - site enzyme - linked immunosorbent assay ( elisa ) from r & d systems ( oxford , united kingdom ) . the sensitivity of the assay ranged from 0.016 to 0.110 pg / ml , with intra - assay and interassay cvs of 7.3 % and 7.7 % , respectively . baseline c - reactive protein ( crp ) level was measured using a high - sensitivity elisa ( r & d systems ) . cac was assessed with electron - beam computed tomography ( imatron c - 150 , general electric , san francisco , california ) as previously described ( 27 ) . in brief , 40 contiguous 3 - mm slices were obtained during a single breath - hold starting at the carina and proceeding to the level of the diaphragm . scan time was 100 ms / slice , synchronized to 40 % of the r - r interval . agatston and volumetric calcium scores were calculated to quantify the extent of cac by a single experienced investigator blinded to the psychophysiological and clinical data on an aquarius workstation ( terarecon inc . , san mateo , california ) . because calcified volume was highly correlated with agatston score ( spearman rho 0.99 ) , we present data for agatston score only . participants reported current smoking levels , weekly alcohol intake ( units per week ) , employment grade ( as a marker of social position ) , and hours of moderate or vigorous physical activity per week . we measured height and weight in light clothing for calculation of body mass index ( bmi ) . total and high - density lipoprotein ( hdl ) cholesterol and triglycerides were measured within 72 h in serum stored at 4c using enzymatic colorimetric methods ( 28 ) . low - density lipoprotein ( ldl ) glucose homeostasis was assessed from glycosylated hemoglobin ( hba1c ) concentration , assayed using boronate affinity chromatography , a combination of boronate affinity and liquid chromatography . we carried out psychophysiological stress testing in either the morning or afternoon in a light temperature - controlled laboratory . this procedure was based on a protocol previously used in this laboratory ( 25 ) . participants were instructed to refrain from drinking caffeinated beverages and smoking for at least 2 h before the study and not to have performed vigorous physical activity or consumed alcohol the previous evening . after a 30 - min rest period , baseline blood pressure ( using an automated ua - 779 digital monitor [ a & d instruments ltd . , oxford , united kingdom ] ) and a saliva sample were taken . two behavioral tasks , designed to induce mental stress , were then administered in random order . the tasks were a computerized version of the stroop task and mirror tracing , both of which have been used extensively in psychophysiological research ( 26 ) . the tasks each lasted for 5 min . saliva samples were collected immediately before and after the tasks for the assessment of salivary cortisol . the samples were collected using salivettes ( sarsted , leicester , united kingdom ) , which were stored at 30c until analysis . levels of cortisol were assessed using a time - resolved immunoassay with fluorescence detection at the university of dresden ( dresden , germany ) . the intra - assay and interassay coefficients of variation ( cvs ) were less than 8 % . nonfasting blood samples were collected in edta tubes and centrifuged immediately at 2,500 rpm for 10 min at room temperature . plasma was removed from the tube and aliquoted into 0.5 - ml portions and stored at 80c until analysis . we measured ctnt concentrations 75 min after the end of the mental stress test using a highly sensitive assay on an automated platform ( elecsys - 2010 troponin t hs stat , roche diagnostics , haywards heath , united kingdom ) , with a lower detection limit of 3 ng / l and a reported 99th percentile value in apparently healthy individuals of 13.5 ng / l , at which the cv is 9 % , confirmed by in - house studies ( 1719 ) . we assayed baseline plasma interleukin ( il ) - 6 using a quantikine high - sensitivity 2 - site enzyme - linked immunosorbent assay ( elisa ) from r & d systems ( oxford , united kingdom ) . the sensitivity of the assay ranged from 0.016 to 0.110 pg / ml , with intra - assay and interassay cvs of 7.3 % and 7.7 % , respectively . baseline c - reactive protein ( crp ) level was measured using a high - sensitivity elisa ( r & d systems ) . cac was assessed with electron - beam computed tomography ( imatron c - 150 , general electric , san francisco , california ) as previously described ( 27 ) . in brief , 40 contiguous 3 - mm slices were obtained during a single breath - hold starting at the carina and proceeding to the level of the diaphragm . scan time was 100 ms / slice , synchronized to 40 % of the r - r interval . agatston and volumetric calcium scores were calculated to quantify the extent of cac by a single experienced investigator blinded to the psychophysiological and clinical data on an aquarius workstation ( terarecon inc . , san mateo , california ) . because calcified volume was highly correlated with agatston score ( spearman rho 0.99 ) , we present data for agatston score only . participants reported current smoking levels , weekly alcohol intake ( units per week ) , employment grade ( as a marker of social position ) , and hours of moderate or vigorous physical activity per week . we measured height and weight in light clothing for calculation of body mass index ( bmi ) . total and high - density lipoprotein ( hdl ) cholesterol and triglycerides were measured within 72 h in serum stored at 4c using enzymatic colorimetric methods ( 28 ) . low - density lipoprotein ( ldl ) glucose homeostasis was assessed from glycosylated hemoglobin ( hba1c ) concentration , assayed using boronate affinity chromatography , a combination of boronate affinity and liquid chromatography . we quantified the cortisol response to stress by subtracting the values of salivary cortisol concentration measured immediately after the behavioral tasks from the baseline . the resulting measure was normally distributed , and it was transformed for the main analyses into a binomial variable using a cut point at the value of 4 nmol / l , which corresponds to the mean value ( 0.54 nmol / l ) + 1 sd ( 3.47 nmol / l ) . hs - ctnt was highly right skewed and was undetectable for 83.3 % of the sample ( below the lower detection limit of 3ng / l ) ; therefore , it was transformed into a binomial variable ( detectable vs. undetectable ) . agatston score ( cac ) had a right - skewed distribution and was transformed for some analyses into a binomial variable by cutting at the value of zero ( 0 vs. 0 ) or 100 ( 100 vs. 100 ) . francis heart study , which demonstrated maximum sensitivity and specificity for detecting cardiovascular events at a threshold calcium score 100 ( 30 ) . we described the study sample according to the exposure ( salivary cortisol response to stress tasks ) and the outcome ( plasma detectable hs - ctnt ) variables . triglyceride and crp levels had right - skewed distributions and were described using medians and interquartile ranges . afterward we used multiple logistic regression to model the association between cortisol stress response and odds of detectable hs - ctnt . cortisol responses may differ according to baseline cortisol levels and time of testing ; therefore , these parameters were included as covariates . we also adjusted for age , sex , employment grade , and smoking because they are related to cvd and may confound the association between cortisol reactivity and cvd . additionally , we took into account clinical variables that are known to be linked to cvd such as systolic blood pressure , total cholesterol / hdl ratio , and hba1c . moreover , we adjusted for crp and il - 6 levels to account for vascular inflammation . finally , we examined whether the association between cortisol reactivity and hs - ctnt was independent of underlying coronary atherosclerosis using several approaches : we adjusted for cac score as a binomial variable using both cut points separately ( 0 and 100 ) , carried out a subanalysis of participants with no detectable coronary calcification , and carried out a subanalysis of participants with positive cac scores and in this case further adjusted for cac score as a log - linear variable . we carried out sensitivity analyses on cortisol responses by testing several different methods of quantification . to test for dose - response associations , we analyzed the cortisol response as a continuous variable ; we tested a different cutoff for binomial analysis , defining positive responses as + 0.5 sd instead of 1 sd ; we calculated cortisol responses as the ratio between the post - stress and baseline values and tested the resulting variable as a linear variable and in binary analyses using both + 1 sd and + 0.5 sd as cut points . additionally , we checked for an association between the baseline levels of salivary cortisol and hs - ctnt using multivariate and time - stratified ( am / pm ) logistic regression models . as for the multiple adjustments , we further included additional variables such as physical activity , bmi , alcohol consumption , and ldl cholesterol , which were not included in the principal analyses . a total of 543 participants participated in the study , but 34 ( 6.3 % ) had missing information for hs - ctnt and one had an hs - ctnt value 35the final analytic sample comprised 508 participants ( mean age of 62.95.7 years and 55.1 % men ) . the sample is described according to cortisol stress response in table 1 and according to hs - ctnt categories in table 2 . older and male participants were more likely to have detectable hs - ctnt and higher salivary cortisol responses to stress tasks . hs - ctnt , cortisol response , and cac appeared to be associated with each other : participants with detectable levels of hs - ctnt were more likely to have higher cortisol responses and cac ( table 2 ) , and participants having high cortisol responses were more likely to have cac 100 ( table 1 ) . participants with cortisol responses 4 nmol / l were more likely to be smokers , and those with detectable levels of hs - ctnt had higher il - 6 plasma concentrations ( tables 1 and 2 ) . baseline cortisol was not associated with hs - ctnt either in bivariate or multivariate models . we found a robust association between cortisol response and detectable hs - ctnt ( odds ratio [ or ] : 3.83 ; 95 % confidence interval [ ci ] : 1.86 to 7.90 ; p 0.001 ) . after adjustment for demographic variables and cardiovascular risk factors , the association between cortisol response and detectable hs - ctnt did not differ from that in the unadjusted analysis . after further adjustments for crp and il - 6 , the association remained ( or : 3.98 ; 95 % ci : 1.60 to 9.92 ; p = 0.003 ) . the adjustment for cac score as a binary variable did not change the effect estimates . in sensitivity analyses , the results remained unchanged after further adjustment for physical activity , bmi , alcohol consumption , and ldl cholesterol ( data not shown ) . we also performed sensitivity analyses using different approaches to quantify the cortisol stress response , although the same pattern of results emerged . for example , after treating the stress response as a linear proportional change in cortisol , the fully adjusted or for hs - ctnt was 1.38 ( 95 % ci : 1.10 to 1.73 ; p = 0.005 ) for each unit increase in change . when we restricted the analysis to participants without detectable coronary calcification , the evidence of association remained despite the 40 % drop in sample size ( n = 222 ; or : 4.77 ; 95 % ci : 1.22 to 18.72 ; p = 0.025 ) . when the analysis was restricted to participants with coronary calcification and adjusted for agatston cac score as a log - linear variable , the association between cortisol stress responses and ctnt concentration remained ( n = 286 ; or : 7.39 ; 95 % ci : 2.22 to 24.64 ; p = 0.001 ) ( table 3 ) . our results suggest that in healthy participants with no history of cvd , a heightened cortisol response to mental stress is associated with detectable concentrations of circulating ctnt when measured using a high - sensitivity assay . these findings add to previous data from our laboratory that demonstrate an association between cortisol reactivity and cac ( 12,13 ) . however , importantly , although this study confirms the findings from other work that stress responsivity is associated with increased cac ( 12 ) , the association between cortisol stress responses and circulating ctnt was independent of cac , a reliable indicator of subclinical coronary atherosclerosis . therefore , cortisol may be involved in structural and functional adaptations to the heart as well as in the atherosclerotic process . the prevalence of detectable hs - ctnt in our british sample was 16.7 % , which is similar to levels reported ( 15.7 % ) in a nationally representative cvd - free population sample in the united states ( 20 ) . to our knowledge , this is the first study to examine the association between mental stress and ctnt in humans . our data are consistent with research on stress - induced takotsubo cardiomyopathy , in which emotional stress increases troponin and cortisol levels in the absence of coronary artery disease ( 31,32 ) ( 33 ) , who showed that mental stress in laboratory animals increases troponin levels . although stress responses seem to be positively correlated with troponin , evidence for a direct or indirect glucocorticoid modulation of troponin is still scarce . the troponin gene contains a transcription factor binding site ( 34,35 ) , previously shown to bind the activated glucocorticoid receptor ( 36 ) . despite the presence of this binding site , the effect of glucocorticoids on troponin levels does not seem to be via direct modulation of gene expression ( 3741 ) . cortisol has a strong diurnal pattern that can cause difficulties in the interpretation of the data ; we dealt with this issue by considering stress response as the difference between the post - test and pre - test measurements and by adjusting for cortisol baseline level and day and time of testing at the data analysis stage . we also performed sensitivity analyses using different approaches to quantify the cortisol stress response , although the same pattern of results emerged . it is possible that the cortisol response to stress contributes to the increased levels of troponin t observed here by several indirect mechanisms . first , oxidative stress could play a role in cortisol - induced troponin release ( 42,43 ) . supporting this hypothesis , the temporal change in serum troponin levels matches the increase in the concentration of myocardial malondialdehyde , a marker of free radical lipid peroxidation ( 44 ) . second , stress - induced cortisol levels could increase troponin levels by modulating ion channels . for example , dexamethasone , a synthetic glucocorticoid , significantly increases the l - type ca currents in neonatal rat cardiomyocytes ( 45 ) and accelerates myocyte spontaneous contractions ( 46 ) . finally , cortisol responses to stress could induce troponin levels by potentiation of adrenergic signaling . corticosteroid - potentiated adrenergic signaling increases mineralocorticoid and glucocorticoid receptor expression and function in cardiomyocytes ( 47 ) . detectable hs - ctnt is associated with noncardiac conditions such as severe renal disease ( 48,49 ) , and theoretically , our results could be due to confounding if patients with renal disease are more likely to test positive on mental stress tests . however , it is unlikely that this mechanism underlies our results because the study participants were free from any chronic conditions at the time of testing , as explained in the methods section . the effect of stress - related cortisol release on cardiomyocytes may be mediated by atherosclerosis and consequent ischemia , although the adjustments for cac , which is a recognized index of atherosclerosis , did not attenuate the findings . cac and hs - ctnt do not appear to lie on the same causal pathway because their effect was not diminished by mutual adjustment , despite being correlated with each other . noncalcified coronary plaques are not detectable using cardiac computed tomography , and that may partly explain why cac did not attenuate the association between cortisol and hs - ctnt . however , there is a direct relationship between the number of calcified plaques present and total plaque burden , and cac correlates highly with the severity of coronary artery disease ; therefore , the absence of calcification implies that there is probably little significant coronary artery disease ( 50 ) . on the other hand , it has been argued that raised troponin t levels may be due to occult or undetected plaque rupture ( 51 ) , and it is known that plaque rupture is a relatively common event that is usually not followed by an acute cardiac event ( 52 ) . this process may have operated in our patients with minimal cac score levels and detectable hs - ctnt . a single measure of plasma hs - ctnt concentration can not be regarded as a robust test if it is not stable in time ( i.e. , if it shows remarkable intraindividual short - term variation ) . however , the results from the aric ( atherosclerosis risk in communities ) study showed that hs - ctnt intraindividual variability over 6 weeks is almost null , with a correlation coefficient of 0.94 ( 53 ) . thus , although our study collected hs - ctnt after a brief and moderately stressful behavioral challenge , it is improbable that troponin t was released in response to this task . to the contrary , we hypothesized that high cortisol responders are individuals who are hyperreactive to mental stress in everyday life . if these responses are elicited on a regular basis over extended periods of time , they might lead to chronic elevations in hs - ctnt concentrations . this was a cross - sectional study , and therefore , we can not determine the causal sequence . heightened cortisol stress responsivity may contribute to early signs of cvd , or people at an early stage of cardiac disease may be more prone to disturbed stress responses . in fact , cardiac troponins are the most sensitive and specific biochemical markers of myocardial damage ( 54 ) , but their elevation can be due to a variety of reasons such as pericarditis , myocarditis , pulmonary embolism , and others ( 55 ) . however , it is unlikely that the undetected presence of those conditions can explain our findings because no participants reported any symptoms or signs of cardiac disease ; had any previous diagnosis of or treatment for hypertension , inflammatory disease , or allergies ; and did not show any electrocardiographic indications of congenital heart disease on tests carried out over more than 20 years in the whitehall ii study . moreover , we found a strong association in people with and without coronary calcification , which is consistent with another study showing that hs - ctnt is predictive of cvd in healthy people and of secondary events in patients with cvd ( 56 ) . it is interesting to note that detectable levels of hs - ctnt were associated with salivary cortisol response to stress test but not with its baseline levels ( pre - test ) , corroborating its relationship with stress - induced neuroendocrine dysregulation . heightened cortisol responses to mental stress were associated with detectable levels of ctnt using high - sensitivity assays in the plasma of healthy people . heightened stress - induced cortisol release may increase the risk of chd through several pathways , including atherosclerotic processes , or other indirect effects on the cardiomyocytes . further research is needed to understand the role of psychosocial stress in the pathophysiology of cardiac cell damage .\noutput:\n" }, { "from": "agent", "value": "objectivesthe objective of this study was to examine the association between cortisol response to mental stress and high - sensitivity cardiac troponin t ( hs - ctnt ) in healthy older individuals without history of cardiovascular disease ( cvd ) . backgroundmental stress is a recognized risk factor for cvd , although the mechanisms remain unclear . cortisol , a key stress hormone , is associated with coronary atherosclerosis and may accentuate structural and functional cardiac disease.methodsthis cross - sectional study involved 508 disease - free men and women aged 53 to 76 years drawn from the whitehall ii epidemiological cohort . we evaluated salivary cortisol response to standardized mental stress tests ( exposure ) and hs - ctnt plasma concentration using a high - sensitivity assay ( outcome ) . we measured coronary calcification using electron - beam dual - source computed tomography and agatston scores.resultsafter adjustment for demographic and clinical variables associated with cvd as well as for inflammatory factors , we found a robust association between cortisol response and detectable hs - ctnt ( odds ratio [ or ] : 3.98 ; 95 % confidence interval [ ci ] : 1.60 to 9.92 ; p = 0.003 ) . the association remained when we restricted the analysis to participants without coronary calcification ( n = 222 ; or : 4.77 ; 95 % ci : 1.22 to 18.72 ; p = 0.025 ) or when we further adjusted for coronary calcification in participants with positive agatston scores ( n = 286 ; or : 7.39 ; 95 % ci : 2.22 to 26.24 ; p = 0.001 ) . conclusionswe found that heightened cortisol response to mental stress was associated with detectable plasma levels of ctnt using high - sensitivity assays in healthy participants , independently of coronary atherosclerosis . further research is needed to understand the role of psychosocial stress in the pathophysiology of cardiac cell damage ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: studies were approved by the ethics committee of the san raffaele scientific institute , milan , italy , and all participants signed an informed consent before any data collection or study procedure . duodenal biopsies ( two to three from each individual ) , obtained during an esophago - gastro - duodenal endoscopy , were collected in 10 % rpmi and rapidly processed . mucus and epithelial cells were removed from the tissue by incubation with 1 mmol / l dithiothreitol and 5 mmol / l edta in calcium - and magnesium - free hanks balanced salt solution ( hbss ) for 15 min at 37c . tissue samples were washed with hbss ; digested with 1 mg / ml collagenase a ( roche diagnostics ltd . , indianapolis , in ) in hbss supplemented with calcium , magnesium , and 5 units / ml dnase i ( roche diagnostics ltd . ) for 1 h at 37c ; and mechanically disrupted by gentle pipetting until dissociation was complete . after incubation , intestinal cells released from the tissue samples were passed through a 70 m cell strainer and washed with complete 10 % rpmi 1640 medium . peripheral blood mononuclear cells ( pbmcs ) intestinal cells and pbmcs were assessed for viability by trypan blue exclusion and stained with pacific blue conjugated anti - human cd4 , alexa fluor - 488conjugated anti - human foxp3 , pe - cy7conjugated anti - human cd25 , and apc - conjugated anti - human cd127 ( all from bd biosciences , san jose , ca ) . to stain for the foxp3 intracellular marker , cells were first stained with the monoclonal antibodies against surface molecules , fixed and permeabilized ( fix / perm solutions kit , bd pharmingen , san diego , ca ) , and then stained with anti - foxp3 monoclonal antibody . data were acquired using fluorescent - activated cell sorter ( facs ) canto system ii ( 3 laser system , becton dickinson , franklin lakes , nj ) and analyzed by using the facsdiva software ( bd biosciences ) . in parallel samples , intestinal cells were stained with percp - cy5conjugated anti - human cd11c , pacific blue conjugated anti - human cd4 , apc - conjugated anti - human nkg2d , fitc - conjugated anti - human tcr1 , and amcyan - conjugated anti - human cd3 monoclonal antibodies to analyze various gut immune cell subsets . to measure expression of the cd103 marker on the various gut lymphocyte subsets , cells were simultaneously stained with pacific blue conjugated anti - cd4 , apc - cy7conjugated anti - cd8 , amcyan - conjugated anti - cd3 , pe - cy5conjugated anti - cd11c , and pe - conjugated anti - cd103 ( all from bd biosciences ) . intestinal cells were isolated from the mucosa of duodenal fragments surgically removed from individuals affected by gastric carcinoma . cd4cd25 treg cells were isolated by magnetic sorting ( human cd4cd25 regulatory t cell selection kit , miltenyi biotec , bergisch gladbach , germany ) . cfse - stained cd4cd25 t effector ( teff ) cells ( either from blood or intestinal cells ) were cultured at 1:1 ratio with 10 intestinal or blood purified cd4cd25foxp3cd127 treg cells and stimulated with coated anti - human cd3 ( 10 g / ml ) and soluble anti - cd28 ( 1 g / ml ; bd biosciences ) monoclonal antibodies in the presence of recombinant human interleukin ( rhil ) - 2 ( 50 units / ml ; bd biosciences ) and irradiated pbmcs . proliferation of teff cells was measured by mean of cfse dilution using facs analysis over a culture period of 3 days . lpdcs or blood monocyte derived dcs ( bmdcs ) were obtained by culturing the adherent cell fraction ( 2 h adherence at 37c 5 % co2 ) of total intestinal cells or pbmcs for 10 days in the presence of rhil - 4 ( 20 units / ml ; miltenyi biotec ) and recombinant human granulocyte - macrophage colony - stimulating factor ( rhgm - csf ; 10 units / ml ; miltenyi biotec ) . mmol / l edta / pbs , extensively washed with cold pbs , and stained with anti - pe - cy5conjugated anti - cd11c and pe - conjugated anti - cd103 monoclonal antibodies to assess their cd11ccd103 tolerogenic phenotype through facs analysis . next , 510 cd11ccd103 lpdcs or cd11ccd103 bmdcs were cultured at 1:10 ratio ( dc to t cells ) with 510 autologous naive cd4cd25 t cells isolated from pbmcs by magnetic selection ( human cd4cd25 regulatory t cell selection kit , miltenyi biotec ) . cd4cd25 t cells were stimulated with soluble anti - human cd3 monoclonal antibody ( 1 g / ml ) in the presence of rhil - 2 ( 400 units / ml ; bd biosciences ) and recombinant human transforming growth factor - ( rhtgf - ; 5 ng / ml ; r & d systems , minneapolis , mn ) . after 4 days , cells were collected and stained with monoclonal antibodies anti - cd4 - pacific blue , anti - cd25 - pe - cy7 , anti - cd127 - apc , and anti - foxp3 - alexa fluor - 488 ( after fixation and permeabilization ) , and the percentage of cd4cd25foxp3cd127 treg cells obtained after stimulation with different dcs was measured by facs analysis . statistical differences were calculated with prism 4.0 software ( graphpad ) using an unpaired , two - tailed t test . studies were approved by the ethics committee of the san raffaele scientific institute , milan , italy , and all participants signed an informed consent before any data collection or study procedure . duodenal biopsies ( two to three from each individual ) , obtained during an esophago - gastro - duodenal endoscopy , were collected in 10 % rpmi and rapidly processed . mucus and epithelial cells were removed from the tissue by incubation with 1 mmol / l dithiothreitol and 5 mmol / l edta in calcium - and magnesium - free hanks balanced salt solution ( hbss ) for 15 min at 37c . tissue samples were washed with hbss ; digested with 1 mg / ml collagenase a ( roche diagnostics ltd . , indianapolis , in ) in hbss supplemented with calcium , magnesium , and 5 units / ml dnase i ( roche diagnostics ltd . ) for 1 h at 37c ; and mechanically disrupted by gentle pipetting until dissociation was complete . after incubation , intestinal cells released from the tissue samples were passed through a 70 m cell strainer and washed with complete 10 % rpmi 1640 medium . peripheral blood mononuclear cells ( pbmcs ) intestinal cells and pbmcs were assessed for viability by trypan blue exclusion and stained with pacific blue conjugated anti - human cd4 , alexa fluor - 488conjugated anti - human foxp3 , pe - cy7conjugated anti - human cd25 , and apc - conjugated anti - human cd127 ( all from bd biosciences , san jose , ca ) . to stain for the foxp3 intracellular marker , cells were first stained with the monoclonal antibodies against surface molecules , fixed and permeabilized ( fix / perm solutions kit , bd pharmingen , san diego , ca ) , and then stained with anti - foxp3 monoclonal antibody . data were acquired using fluorescent - activated cell sorter ( facs ) canto system ii ( 3 laser system , becton dickinson , franklin lakes , nj ) and analyzed by using the facsdiva software ( bd biosciences ) . in parallel samples , intestinal cells were stained with percp - cy5conjugated anti - human cd11c , pacific blue conjugated anti - human cd4 , apc - conjugated anti - human nkg2d , fitc - conjugated anti - human tcr1 , and amcyan - conjugated anti - human cd3 monoclonal antibodies to analyze various gut immune cell subsets . to measure expression of the cd103 marker on the various gut lymphocyte subsets , cells were simultaneously stained with pacific blue conjugated anti - cd4 , apc - cy7conjugated anti - cd8 , amcyan - conjugated anti - cd3 , pe - cy5conjugated anti - cd11c , and pe - conjugated anti - cd103 ( all from bd biosciences ) . intestinal cells were isolated from the mucosa of duodenal fragments surgically removed from individuals affected by gastric carcinoma . cd4cd25 treg cells were isolated by magnetic sorting ( human cd4cd25 regulatory t cell selection kit , miltenyi biotec , bergisch gladbach , germany ) . cfse - stained cd4cd25 t effector ( teff ) cells ( either from blood or intestinal cells ) were cultured at 1:1 ratio with 10 intestinal or blood purified cd4cd25foxp3cd127 treg cells and stimulated with coated anti - human cd3 ( 10 g / ml ) and soluble anti - cd28 ( 1 g / ml ; bd biosciences ) monoclonal antibodies in the presence of recombinant human interleukin ( rhil ) - 2 ( 50 units / ml ; bd biosciences ) and irradiated pbmcs . proliferation of teff cells was measured by mean of cfse dilution using facs analysis over a culture period of 3 days . lpdcs or blood monocyte derived dcs ( bmdcs ) were obtained by culturing the adherent cell fraction ( 2 h adherence at 37c 5 % co2 ) of total intestinal cells or pbmcs for 10 days in the presence of rhil - 4 ( 20 units / ml ; miltenyi biotec ) and recombinant human granulocyte - macrophage colony - stimulating factor ( rhgm - csf ; 10 units / ml ; miltenyi biotec ) . mmol / l edta / pbs , extensively washed with cold pbs , and stained with anti - pe - cy5conjugated anti - cd11c and pe - conjugated anti - cd103 monoclonal antibodies to assess their cd11ccd103 tolerogenic phenotype through facs analysis . next , 510 cd11ccd103 lpdcs or cd11ccd103 bmdcs were cultured at 1:10 ratio ( dc to t cells ) with 510 autologous naive cd4cd25 t cells isolated from pbmcs by magnetic selection ( human cd4cd25 regulatory t cell selection kit , miltenyi biotec ) . cd4cd25 t cells were stimulated with soluble anti - human cd3 monoclonal antibody ( 1 g / ml ) in the presence of rhil - 2 ( 400 units / ml ; bd biosciences ) and recombinant human transforming growth factor - ( rhtgf - ; 5 ng / ml ; r & d systems , minneapolis , mn ) . after 4 days , cells were collected and stained with monoclonal antibodies anti - cd4 - pacific blue , anti - cd25 - pe - cy7 , anti - cd127 - apc , and anti - foxp3 - alexa fluor - 488 ( after fixation and permeabilization ) , and the percentage of cd4cd25foxp3cd127 treg cells obtained after stimulation with different dcs was measured by facs analysis . statistical differences were calculated with prism 4.0 software ( graphpad ) using an unpaired , two - tailed t test . to test whether the gut environment impinges on human t1d by altering intestinal immune regulation , we analyzed the immune cell compartment in the small - intestinal mucosa and for comparison , peripheral blood of t1d patients , healthy control ( hc ) subjects , and individuals affected by celiac disease ( cd ) . we obtained duodenal biopsies and blood samples from 46 individuals , including 10 patients with t1d , 16 hc subjects , and 20 individuals with cd . age , sex , and clinical information for each group are summarized in table 1 . our multiparametric facs analysis showed that the percentages of various immune cell subsets , including cd4 t cells , cd8 t cells , nk cells , and t cells , in the lamina propria of the intestinal mucosa were similar among the three groups ( fig .1 ) revealed a significant reduction in the percentages of treg cells out of total lymphocytes residing in the small - intestinal mucosa of t1d patients compared with hc subjects ( p = 0.03 ) and individuals with cd ( p = 0.003 ) ( fig . the difference between t1d patients and control groups was evident also when cd4cd25foxp3cd127 treg cell percentages out of cd4 t cells ( rather than total lymphocytes ) , percentages of cd4cd25 treg cells out of cd4 t cells , and treg / teff cell ratio were considered ( supplementary figs . 2 and 3 ) . the quantitative defect observed in t1d patients regarded exclusively foxp3 treg cells residing in the gut . in fact , the number of cd4cd25foxp3cd127 treg cells in pbmcs of t1d patients was comparable to that of control subjects ( p 0.05 ) ( fig . because a high percentage of t1d patients were also affected by cd ( 50 % ) ( supplementary table 1 ) , to exclude the possibility that the celiac condition influenced the percentage of cd4cd25foxp3cd127 treg cells in the gut , we performed a multiple group comparison of treg cell percentages among patients affected by t1d only , patients affected by t1d in association with cd , individuals with cd only , and hc subjects .2 c , the celiac condition did not significantly alter the percentages of cd4cd25foxp3cd127 treg cells in the intestinal mucosa of both t1d and nondiabetic individuals , and the treg cell deficiency was exclusively associated with the t1d condition ( p 0.001 with anova ) . we also verified that the intestinal cd4cd25foxp3cd127 t cells that we enumerated were bona fide treg cells by isolating cd4cd25 t cells ( 70 % foxp3cd127 ) from normal surgical samples of small intestine ( the number of treg cells in bioptic material was not sufficient to perform such an experiment ) and assessing their suppressive capacity upon proliferation of teff cells ( fig . all patients ( n = 46 ) underwent esophago - gastro - duodenal endoscopy for a clinical suspect of cd . the diagnosis of cd was made out of the histological examination of the intestinal mucosa and of the presence of antitissue transglutaminase antibodies ( 95 % of celiac individuals were tissue transglutaminase igg and iga positive ) . hence , all the patients with cd were on a normal ( not gluten - free ) diet at the time of biopsy collection . hc subjects and patients affected only by t1d were all tissue transglutaminase igg / iga negative ( 100 % ) . the mean age in the t1d group was higher than that of control individuals ( healthy individuals and subjects with cd ) ; however , we found no statistical correlation between age and the percentage of cd4cd25foxp3cd127 treg cells in the gut mucosa ( r = 0.05 ) . early onset t1d , 6 months from diagnosis ; long - lasting t1d , 6 months from diagnosis . all samples analyzed were donated for research purposes and each individual signed an informed consent . the relative percentages of total cd4 t cells , cd8 t cells , nk cells , and t cells in the lamina propria of the small - intestinal mucosa were comparable in patients with t1d , hc subjects , and patients with cd . lamina propria cells were isolated from the small - intestinal mucosa ; simultaneously stained with pacific blue conjugated anti - human cd4 , apc - conjugated anti - human nkg2d , fitc - conjugated anti - human tcr1 , and amcyan - conjugated anti - human cd3 monoclonal antibodies ; and facs analyzed . means of percentages sem of cd4 t cells ( cd3cd4 cells ) , cd8 t cells ( cd3cd8 cells ) , t cells ( cd3 tcr1 cells ) , and nk cells ( cd3 nkg2d cells ) out of total lamina propria lymphocytes ( left ) and the means of percentages sem of cd4 t cells , cd8 t cells , and t cells out of cd3 t cells ( right ) are indicated . a : the percentages of cd4cd25foxp3cd127 treg cells out of total lymphocytes were measured in single cell suspensions isolated from the small - intestinal mucosa ( duodenal biopsies ) of patients with t1d ( n = 10 ) , hc subjects ( n = 16 ) , and individuals with cd ( n = 20 ) . the cd4cd25foxp3cd127 treg cells in gut mucosa were identified by multiparametric facs analysis . b : blood samples were collected from the same individuals simultaneously with the duodenal biopsy . pbmcs were isolated and analyzed as in a. data are presented as means sem of all experiments . c : the percentages of cd4cd25foxp3cd127 treg cells were compared among patients with t1d ( n = 5 ) , patients with t1d and cd ( t1d + cd , n = 5 ) , hc subjects ( n = 16 ) , and patients with cd only ( n = 20 ) . d : gut cd4cd25foxp3cd127 t cells were bona fide treg cells and showed a suppressive capacity similar to that of their blood counterparts . a suppression assay was used to test 10 cd4cd25 treg cells or cd4cd25 teff cells isolated from the mucosa of normal surgical samples of small intestine or pbmcs of hc subjects . briefly , treg or teff cells were added at 1:1 ratio to responder cfse - labeled cd4cd25 t cells stimulated with plate - bound anti - cd3 monoclonal antibody , soluble anti - cd28 monoclonal antibody , and rhil - 2 . the percentage of suppression was measured by the percent reduction of proliferation of responder teff cells ( measured by mean of cfse dilution ) . the reduced percentage of intestinal foxp3 treg cells in t1d patients could be due to defective gut homing of naturally occurring foxp3 treg cells that originate in the thymus . alternatively , the quantitative defect of foxp3 treg cells could be attributable to impaired de novo differentiation and / or expansion of foxp3 treg cells in the intestinal mucosa and / or gut - associated lymphoid tissue of t1d patients . small - intestinal lpdcs expressing the integrin e7 ( also called cd103 ) have the unique capacity to drive peripheral development and / or expansion ( from precursors of thymic origin ) of foxp3 treg cells ( 18,19 ) . although few reports on human lpdcs exist , those studies show that human lpdcs express classical dc markers such as cd11c , mhc class ii , and cd83as well as the typical marker of murine lpdcs , the cd103 molecule , and have some of their functional properties , such as ability to induce gut tropism on t cells ( 22 ) and foxp3 treg cell differentiation ( 23 ) . hence , we specifically analyzed percentages and tolerogenic antigen - presenting function ( i.e. , capacity to induce foxp3 treg cell differentiation / expansion ) of cd103cd11c lpdcs residing in the small - intestinal mucosa of t1d patients and control subjects . we did not detect any difference in the percentages of intestinal cd103cd11c lpdcs ( fig .3 a ) or in the percentages of lpdcs that expressed the cd103 marker ( fig . next , we performed conversion assays to test the capacity of lpdcs of t1d patients to induce foxp3 treg cell differentiation . because of the limited amount of bioptic material , we could not sort cd103cd11c lpdcs from total intestinal cellsalternatively , we enriched the cd103cd11c lpdcs from the small intestine of t1d patients and control subjects by culturing adherent intestinal cells with rhil - 4 and rhgm - csf for 10 days and evaluated their ability to induce de novo differentiation of cd4cd25foxp3cd127 treg cells ( supplementary fig . cultured dcs showed phenotypical features of cd11ccd103 dcs residing in the lamina propria ( ex vivo lpdcs ) , such as expression of dc markers cd11c and cd103 and maturation markers ( supplementary fig .3 c , human cd11ccd103 lpdcs from the intestinal mucosa of nondiabetic control subjects were able to convert cd4cd25 t cells into cd4cd25foxp3cd127 treg cells as previously demonstrated ( 23 ) . conversely , cd103cd11c lpdcs from t1d patients completely lacked that function and failed to induce treg cell differentiation / expansion ( fig . interestingly , we found that the addition of tgf - was necessary for human cd103cd11c lpdcs to promote treg cell conversion in control individuals ( supplementary fig . 5 ) . however , the addition of tgf - to lpdcs of t1d patients was not capable of restoring the capacity to induce de novo generation and / or expansion of cd4cd25foxp3cd127 treg cells ( fig . our data represent the first evidence that the tolerogenic properties of cd11ccd103 dcs from the gut mucosa are impaired in t1d patients . however , because the cd103 lpdc subset was enriched in vitro with a 10 - day culture period with il - 4 and gm - csf , we can not exclude that the reduced tolerogenic properties of t1d lpdcs were related to their defective response to those cytokines . cd103cd11c lpdcs are present in the small intestine of t1d patients but fail to induce foxp3 treg cell differentiation . a : percentages of cd103cd11c lpdcs in the gut mucosa of patients with t1d , hc subjects , and patients with cd . b : percentages of cells that express the gut receptor cd103 among various gut lymphocyte subsets ( cd4 t cells , cd8 t cells , and cd11c dcs ) in the three groups . c : the capacity of small - intestinal cd11ccd103 lpdcs of t1d patients and control subjects ( healthy or celiac individuals [ ctrs ] ) to induce cd4cd25foxp3cd127 treg cell differentiation was evaluated in conversion assays . bmdcs or small - intestinal cd11ccd103 lpdcs were obtained from t1d patients and ctrs and added at 1:10 ratio ( dc to t cells ) to autologous naive cd4cd25 t cells isolated from pbmc and stimulated with soluble anti - human cd3 monoclonal antibody in the presence of rhil - 2 and rhtgf - . cells were collected after 4 days and facs analyzed to measure percentages of cd4cd25foxp3cd127 treg cells . one representative experiment out of three ( t1d ) or four ( ctr ) is shown ( cells gated on cd4cd25cd127 cells ) . d : means sem of cd4cd25foxp3cd127 treg cell percentages obtained in conversion assays with bmdcs or lpdcs in three ( t1d ) or four ( ctr ) independent experiments are shown . * ( a high - quality color representation of this figure is available in the online issue . ) the identification and characterization of a specific defect of gut immune regulation in t1d patients could provide new insights in the current understanding of the disease pathogenesis . an immunological axis between the gastrointestinal tract and pancreatic tissues exists ( 20 ) , so that gut t cells continuously travel from the intestinal mucosa to pancreatic lymph nodes and tissues as documented by their expression of gut - homing receptors such as 47 and ccr9 on self - reactive t cells in t1d patients ( 24 ) and t cells infiltrating pancreatic islets of nod mice ( 25,26 ) . the existence of an immunological gutpancreas axis implies that the defective de novo generation of cd4cd25foxp3cd127 treg cells in the intestinal mucosa of t1d patients may have a direct negative influence on the teff / treg cell balance in pancreatic lymph nodes and islets and , thus , ultimately may promote teff cell responses against pancreatic self - antigens . further studies are necessary to dissect whether defective intestinal differentiation of foxp3 treg cells by cd103cd11c lpdcs in t1d patients is genetically determined or induced by environmental factors that alter the gut milieu , such as the intestinal microbiota . recent studies demonstrate that the enteric commensal microbiota modulate gut immunity and represent a key epigenetic factor modifying t1d predisposition ( 9,27 ) . it has been proposed that pathogenic microbiota promote t1d by activating self ( islet ) - reactive t cells in the gut ( 27 ) . however , it is now clear that intestinal bacteria are crucial to controlling immune regulation and dampening t - cell immunity in the intestine , either directly or through interaction with intestinal epithelial cells ( 28 ) . this raises the suggestive hypothesis that the microbiota , and possibly environmental factors such as diet and drugs that modify microbiota , impinge on t1d pathogenesis by altering tolerogenic dc function and impairing peripheral differentiation of cd4cd25foxp3cd127 treg cells .\noutput:\n" }, { "from": "agent", "value": "objectivethe gut environment modulates the pathogenesis of type 1 diabetes ( t1d ) , but how it affects autoimmunity toward pancreatic - cells , a self - tissue located outside the intestine , is still unclear . in the small intestine , lamina propria dendritic cells ( lpdcs ) induce peripheral differentiation of foxp3 + regulatory t ( treg ) cells . we tested the hypothesis that the intestinal milieu impinges on human t1d by affecting differentiation of foxp3 + treg cells.research design and methodswe collected duodenal biopsies of 10 t1d patients , 16 healthy subjects , and 20 celiac individuals and performed a fluorescent - activated cell sorter analysis to measure percentages of various immune cell subsets , including cd4 + and cd8 + t cells , nk cells , t cells , cd103 + cd11c + lpdcs , and cd4 + cd25 + foxp3 + cd127 treg cells . in parallel , we assessed the tolerogenic function ( i.e. , capacity to induce differentiation of foxp3 + treg cells ) by lpdcs of t1d patients and control subjects.resultsour analysis revealed a significant reduction in the percentage of intestinal cd4 + cd25 + foxp3 + cd127 treg cells in t1d patients compared with healthy subjects ( p = 0.03 ) and celiac individuals ( p = 0.003 ) . in addition , we found that lpdcs from t1d patients completely lacked their tolerogenic function ; they were unable to convert cd4 + cd25 t cells into cd4 + cd25 + foxp3 + cd127 treg cells.conclusionsour data indicate that t1d patients have a reduced number of intestinal foxp3 + treg cells as a result of their defective differentiation in the gut . these findings suggest that intestinal immune regulation is not only calibrated to tolerate commensal bacteria and food components but also is instrumental in maintaining immune tolerance toward pancreatic - cells and preventing t1d ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: trabeculectomy is commonly performed in patients with uncontrolled glaucoma and with the use of antimetabolites and surgical technique modification is successful in the majority of patients . the main reason for failure is episcleral fibrosis and thickening of the conjunctiva overlying the area of filtration . the inflammation and subsequent scarring are intense in the early postoperative period , in which most of the failures occur . the process of wound healing and tissue remodelling continues indefinitely after surgery and results in increasing failure rate with longer follow - up . risk factors which may influence the outcome of surgery include - previous surgery , long - term use of topical antiglaucoma medications , ocular inflammation , young age , ethnic origin , and postoperative suture lysis . to understand the mechanism of filtering surgery failure the research has mainly focused on conjunctiva . changes in the number of conjunctival fibroblasts and inflammatory cells were associated with increased risk of trabeculectomy failure . long - term use of antiglaucoma drops with preservative benzalkonium chloride ( bak ) induces subclinical inflammation of conjunctiva with over expression of human leukocyte antigen - ( hla - ) dr on epithelial cells . several cytokines were found to stimulate proliferation of tenon 's capsule fibroblasts , cells with a key role in scarring process , such as tgf - , tnf , and il - 1 . in trabeculectomy , also changes in the composition of this aqueous could influence the scarring process . in the prospective study we examined the effect of five cytokines in the aqueous humour on the outcome of trabeculectomy . we also investigated the superior bulbar conjunctiva overlying the area of filtration area for the expression of hla - dr , the markers of subclinical inflammation , on conjunctival epithelial cells and cd80 positive cells ( antigen - presenting cells ) during follow - up to determine whether changes in the expression of these molecules are associated with the outcome of surgery . thirty patients ( 30 eyes ) with uncontrolled intraocular pressure on maximal topical antiglaucoma medication who needed glaucoma surgery were included in this prospective study . the study protocol was approved by national ethics committee and all patients after receiving complete information signed informed consent form for inclusion in the study . at the beginning of surgery after local anaesthesia aqueous humour was obtained through the side incision made by 15 knife , avoiding any contact with limbal vessels and iris . aqueous humour ( 0.050.1 ml ) was drawn into a conventional tuberculin syringe and samples were stored at 70c , until tested . trabeculectomies were performed by a fornix - based conjunctival access and a scleral flap of 43 mm . in allpatients mitomycin c ( 0.3 mg / ml ) was topically applied for 3 minutes on a sponge beneath the conjunctiva . the sclerectomy was made by kelly 's punch using 23 bites to create an opening . scleral flap was closed with 24 sutures , of those 12 releasable . at the end of surgery , topical steroids and antibiotics were prescribed , and after 1 month only steroid eye drops were instilled and stopped 3 months after surgery . patients were scheduled for control visits 1 week , 1 month , 2 , 3 , 6 , and 12 months after surgery , and more often if deemed necessary . the collection of conjunctival cells was performed by the imprinting of the ocular surface onto millipore filter paper ( versus 0.22 m pore size ) after topical anaesthesia with 1 - 2 drops of oxybupropacaine . strips of filter paper approximately 36 mm were pressed firmly with a glass rod on the ocular surface for 5 seconds and peeled off with a forceps and put into 1 ml of phosphate buffered saline . three imprints were collected from superior bulbar conjunctiva 1 month and 3 months after surgery . surgical success was defined as intraocular pressure ( iop ) less than 21 mm hg without antiglaucoma medication and was evaluated at month 3 , 6 , and month 12 follow - up visits . a bd human inflammation cba ( cytometric bead array ) kitwas used to quantitate il - 8 , il - 1 , il - 6 , il - 10 , and tnf - and il - 12p70 protein levels in aqueous humour samples ( bd bioscience pharmingen san diego , ca , usa ) . briefly , aqueous humour samples were incubated for 3 hours , light protected at room temperature with the six cytokine capture beads and pe - conjugated detection antibodies . after incubation samples were washed and sample data were acquired using a facscanto flow cytometer ( bd bioscience , san diego cd , usa ) . sample results were generated using graphical and tabular format using the bd fcap array software ( bd bioscience , san diego , ca , usa ) . monoclonal antibodies conjugated with fluorochromes , cd80 ( fitc ) , anti - cytokeratin ( fitc ) and anti - hla - dr ( pe ) , were purchased from bd pharmingen ( san jose , ca , usa ) . a two - parameter analysis was performed to determine the expression of hla - dr on cytokeratin positive cells ( epithelial cells ) and on cd80 positive cells ( antigen - presenting cells ) . the facs data are reported as mean fluorescence intensities ( mfi ) and as percentages of positive cells . forstatistical analysis spss 15.0 software for windows was used . because the data were not normally distributed , median , minimum , and maximum values were calculated for the levels of cytokines and for the expression of hla - dr by epithelial and antigen - presenting cells . mann - whitney u test was used to test the hypothesis that there is no difference in the levels of cytokines and in the expression of inflammatory markers between the eyes with successful and failed surgery . the significance of the difference in the expression of hla - dr on epithelial and antigen - presenting cells 1 and 3 months after surgery was tested with paired sample t - test . aqueous humour specimens from 30 patients undergoing trabeculectomy ( 13 females , 17 males ) with the mean age 63.6 years ( standard deviation 10.3 years ) were analyzed for cytokines . the levels of cytokines in all patients as well as the values regarding the type of glaucoma are summarized in table 1 . at 3 months of follow - up23 eyes ( patients ) had successful surgery ( defined as iop less than 21 mm hg without antiglaucoma medication ) , and at 6 and 12 months there were 21 eyes with successful surgery . the median values and ranges for the percentages of hla - dr positive cytokeratin cells ( epithelial cells ) and cd80 positive cells ( antigen - presenting cells ) , with their median fluorescence intensity are shown in table 2 . mean fluorescence intensity of hla - dr molecules on epithelial cells at 1 month and 3 months was increased in eyes with successful surgery at 12 months , but there was large scatter of the data ( figures 1 and 2 ) . aqueous levels of cytokines in the eyes with surgical success and failure are summarized in table 3 . we found significantly higher levels of il - 6 and tnf - in eyes with surgical failure when compared to the eyes with surgical success ( figures 3 and 4 ) . the expression of hla - dr on epithelial cells was significantly lower 3 months compared to 1 month after surgery ( paired sample t - test ; p = .001 ) , both for the eyes with surgical success and failure ( figure 5 ) . there was no significant difference in the percentage of hla - dr positive epithelial and antigen - presenting cells as well as in the expression of hla - dr by antigen - presenting cells between 1 month and 3 months of follow - up ( not shown ) . several studies have investigated conjunctival biopsy specimens from patients with glaucoma receiving long - term antiglaucoma medication and after previous ocular surgery before undergoing filtration surgery . they have shown increased number of conjunctival fibroblasts and inflammatory cells when compared to eyes without previous ocular surgery or only briefly treated - primary surgery eyes . such preoperative subclinical inflammation was identified as a risk factor for failure of trabeculectomy and was attributed to the upregulation of the wound healing response caused by an increase in the number and degree of activation of these inflammatory cells . conjunctival epithelium has been studied in impression cytology specimens by flow cytometry . in eyes treated over long term without clinical inflammation , overexpression of inflammatory marker hla - dr and il - 6 , il - 8 , and il - 10it was demonstrated that the preservative benzalkonium chloride was the major component in the eye drops responsible for toxic and immunoinflammatory effects or both in the conjunctiva . in our study , we used impression cytology specimens from the superior bulbar conjunctiva and flow cytometry to measure ocular surface inflammation 1 month and 3 months after trabeculectomy in an attempt to correlate ocular surface changes with the outcome of surgery . there was a trend of increased number of hla - dr positive conjunctival epithelial cells collected one month after surgery in failures when compared to successes at 3 - month follow - up ( table 2 ) . in contrast to others , higher expression of hla - dr on conjunctival epithelial cells and antigen - presenting cells was not more common in failures . interestingly , the expression of hla - dr on epithelial cells at month 1 and 3 was higher in eyes with successful surgery than in failures , suggesting smaller ocular surface inflammation in failures ( figures 1 and 2 ) . this can not be explained by the difference in postoperative treatment regimen between the two groups , as all patients were receiving topical dexamethasone eye drops ( maxidex , alcon ) containing preservative benzalkonium chloride for up to 3 months after surgery that is , at the time points the specimens were collected . it was demonstrated that eyes with good intraocular pressure control have microcysts at the bleb surface containing aqueous humour , indicating a transcellular pathway of aqueous . hence , the different expression of hla - dr on epithelial cells in eyes with such functioning blebs may be also induced by the composition of aqueous . because the imprints of ocular surface were not collected before surgery , it remains unknown whether there was any difference in preoperative hla - dr expression between the eyes with successful and failed surgery . in both groupsthere was a reduction of hla - dr expression on epithelial cells over time , indicating diminished postoperative inflammation with longer follow - up ( figure 5 ) . the aqueous humour is known to contain several cytokines capable of affecting fibroblast activity . tgf - has been implicated in several ocular scarring processes including proliferative vitreoretinopathy , conjunctival wound healing , especially that occurring after trabeculectomy . it has been shown to be the most potent stimulator of human tenon 's fibroblast activity . in addition , aqueous concentrations of tgf - 2 are increased in glaucomatous eyes . in patients with exfoliative glaucoma previous argon laser trabeculoplasty ( alt ) increased the risk of scarring because of increased aqueous levels of activated tgf - 2 compared to patients without alt . a monoclonal antibody to tgf - 2 was developed to prevent the progression of fibrosis in patients undergoing trabeculectomy , but in a randomized multicentre study the subconjunctival application of the anti tgf -2-antibody was not different from placebo in preventing trabeculectomy failure . in this study , we used flow cytometry to measure cytokines in the aqueous humour of patients undergoing trabeculectomy to evaluate whether preoperative changes in the level of cytokines could predict the outcome of surgery . the proinflammatory cytokines il - 1 , il - 6 , il - 8 , il - 12 and tnf - , and il - 10 , an anti - inflammatory cytokine , were analyzed preoperatively . we found that higher preoperative levels of tnf - and il - 6 in the aqueous humour were present in eyes with surgical failure at 3 months ( table 3 , figures 3 and 4 ) . tumour necrosis factor - is synthesized by macrophages , monocytes , neutrophils , natural killer cells , and t cells . tnf - together with tgf - is a major proinflammatory and profibrogenic cytokine expressed by ocular surface tissues . during the inflammatory process , it orchestrates the initiation of further leukocyte infiltration via adhesion molecule upregulation , dendrite cell maturation and survival , macrophage activation , and driving th1 t cell responses in experimental autoimmune uveitis . tnf - together with il - 1 and vegf causes breakdown of blood - retinal barrier in a murine model of experimental autoimmune uveitis . have shown that tnf and il - 1 stimulated proliferation of tenon 's capsule fibroblasts in tissue culture . we propose that higher levels of tnf - in aqueous humour stimulate monocyte / macrophage - chemoattractant protein - 1 ( mcp - 1 ) gene and protein expression which could lead to an increase in the number of monocytes / macrophages from the subconjunctival tissue surrounding the fistula . these cells by producing proinflammatory and profibrogenic cytokines ( e.g. , tnf - and tgf - ) increase activation and transformation of conjunctival fibroblasts with accelerated extracellular matrix deposition and consequently intense scarring response . additionally , increased levels of tnf - in the aqueous stimulate neovascularisation and contribute to stronger wound healing response . interleukin - 6 is a macrophage - derived cytokine but is also thought to be produced by ocular parenchymal cells . readily induced by tnf - , ifn - , and il - 1 , il - 6 promotes differentiation of b cells to plasma cells and induces synthesis of acute phase proteins , such as fibrinogen and c - reactive protein . increased levels of il - 6 were found in aqueous humour in a murine model of experimental autoimmune uveitis demonstrating an increased local production at disease onset . also , in aqueous humour of patients with neovascular glaucoma , increased concentration of il - 6 correlated with the severity of iris neovascularisation . we suggest that higher levels of il - 6 in aqueous bathing the subconjuctival space after trabeculectomy may increase postoperative inflammation and lead to more intense fibrosis . both tnf - and il - 6 have been found elevated in aqueous humour of patients with idiopathic uveitis , behcet 's disease and fuchs ' heterochromic cyclitis . interleukin - 1 , il - 8 , il - 10 , and il - 12 were not found to be the risk factors for trabeculectomy failure . also , aqueous humour was collected at one time point only , at the beginning of trabeculectomy , and we do not know about the changes in cytokine levels during follow - up , which could support our results . other cytokines not investigated in our study may influence the outcome of surgery as well as interactions between different cytokines , which can not be studied in vivo . however , the study was prospective with a 12 - month follow - up , a period where most of the surgical failures occur and also studied ocular surface at the site of surgery . the increased percentage and expression of hla - dr on conjunctival epithelial cells and antigen - presenting cells were not associated with surgical failure . in contrast to other authors the expression of inflammatory marker hla - dr on epithelial cells was elevated in eyes with successful trabeculectomy when compared to eyes with surgical failure . in our study , inflammation of superior bulbar conjunctiva detected as overexpression of inflammatory molecules one and three months after surgery was not associated with subconjunctival fibrosis . lower levels of tnf - and il - 6 in aqueous humour were associated with better surgical outcome in patients undergoing trabeculectomy .\noutput:\n" }, { "from": "agent", "value": "purpose . to investigate the influence of inflammatory molecules in the aqueous humour and on the ocular surface on the outcome of glaucoma surgery . methods . thirty patients who needed antiglaucomatous surgery were included . the interleukin - ( il - ) 8 , il - 1 , il - 6 , il - 10 , tumour necrosis factor - ( tnf - ) ; and il - 12 were determined from aqueous humour preoperatively and the imprints of conjunctiva were analysed for expression of human leukocyte antigen - ( hla - ) - dr after surgery by flow cytometry . the success of trabeculectomy was defined as intraocular pressure less than 21 mmhg without antiglaucoma medication . results . eyes with trabeculectomy failure at 3 months showed significantly higher tnf - and il - 6 levels in the aqueous than eyes with successful surgery . increased expression of hla - dr on epithelial cells and antigen - presenting cells was not associated with the trabeculectomy outcome . conclusions . higher preoperative levels of tnf - and il - 6 in aqueous humour may contribute to the development of inflammatory milieu and were associated with worse outcome of glaucoma surgery ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: ciprofloxacin is a fluoroquinolone derivative in veterinary medicine with outstanding antibacterial activity primarily against gram - negative pathogens , but also gram - positive bacteria and some chlamydia , mycoplasma , and many mycobacterium species . the pharmacokinetics of ciprofloxacin has been investigated in dogs , rats and monkeys , rabbits , ponies , goats , cow calves , and buffalo calves . because of the lack of sufficient pharmacokinetic studies in goats and potential species differences , we evaluated the pharmacokinetics of ciprofloxacin after intravenous administration in goats . ten clinically healthy goats ( 15 - 20 kg ) were procured from a local breeding farm in jammu , india , and housed in a well - ventilated house . all de - wormed animals were housed in hygienic departmental shed for 20 d prior to experiments for acclimatization , and allowed free access to pasture , ad libitum water , and received once daily concentrated feed ration . one day prior to the experiment , the goats underwent thorough physical and clinical examinations . a single intravenous dose of 4 mg / kg body weight of ciprofloxacin hydrochloride monohydrate in sterile distilled water ( cadilla labs private , india ) was administered into the jugular vein of the six goats . blood samples of 6 - 7 ml were obtained directly from the jugular vein using disposable needles . the blood samples were collected in un - heparinized test tubes just prior to and at 2.5 , 5 , 10 , 20 , 30 , 45 , 60 and 90 min and 2 , 3 , 4 , 6 , 9 and 12 h after drug administration . the separated serum was then centrifuged for 15 min at 3,000 g to obtain clear supernatant fluid and stored at -20 until analysis , usually within 2 - 3 days . in phase ii , the urinary excretion of ciprofloxacin was investigated in four goats . the dose and route of administration were the same as in phase i. the animals were placed into metabolic stalls prior to start of the experiment and total urine was collected . the urine samples were collected at 0 - 3 , 3 - 6 , 6 - 9 , 9 - 12 , 12 - 24 , 24 - 36 , and 36 - 48 h after drug administration . the whole volume of urine was measured and 10 ml urine samples were taken for analysis . ciprofloxacin concentrations in serum and urine were determined using the agar well diffusion assay , using e. coli atcc - 25922 as test organisms grown on mueller hinton agar . standard concentrations ( 0.015 to 4 mg / ml ) were prepared in pooled untreated goat serum and urine , and showed a mean correlation coefficient ( r ) 0.99 % for both serum and urine . the serum concentration time profile showed a correlation coefficient ( r ) value of 0.9820.009 . the intra - assay and inter - assay precision variability were 10 % for standard concentrations in both serum and urine . the extent of protein binding was determined in vitro using an equilibrium dialyzing technique as described by kunin . to estimate the protein binding of ciprofloxacin , the drug was dissolved in 0.06 m phosphate buffer ( ph 7.0 ) and antibiotic - free healthy goat serum at 0.5 , 0.75 , 1.0 , 1.5 , and 2.0 g / ml . the differences in the diameters of the inhibition zone between the solution of the drugs in the buffer and serum were calculated . the compartment pharmacokinetics of serum concentration - time curves after single intravenous injection were analyzed for each goat by top - fit v. 2.0 . the best - fit model was selected based on akaike 's information criterion and the schwartz test . model - dependent pharmacokinetic parameters were obtained as described by baggot and gibaldi and perrier . the non - compartment model was used to determine the area under concentration - time curve ( auc ) , and area under the first moment curve ( aumc ) , using the linear trapezoidal rule with extrapolation to time infinity . mean residence time ( mrt ) and systemic clearance ( clb ) were calculated as mrt = aumc / auc and clb = dose / auc , respectively . the apparent volumes of distribution at steady state were calculated as vdss = ( dose aumc ) / auc . ten clinically healthy goats ( 15 - 20 kg ) were procured from a local breeding farm in jammu , india , and housed in a well - ventilated house . all de - wormed animals were housed in hygienic departmental shed for 20 d prior to experiments for acclimatization , and allowed free access to pasture , ad libitum water , and received once daily concentrated feed ration . one day prior to the experiment , the goats underwent thorough physical and clinical examinations . a single intravenous dose of 4 mg / kg body weight of ciprofloxacin hydrochloride monohydrate in sterile distilled water ( cadilla labs private , india ) was administered into the jugular vein of the six goats . blood samples of 6 - 7 ml were obtained directly from the jugular vein using disposable needles . the blood samples were collected in un - heparinized test tubes just prior to and at 2.5 , 5 , 10 , 20 , 30 , 45 , 60 and 90 min and 2 , 3 , 4 , 6 , 9 and 12 h after drug administration . the separated serum was then centrifuged for 15 min at 3,000 g to obtain clear supernatant fluid and stored at -20 until analysis , usually within 2 - 3 days . in phase ii , the urinary excretion of ciprofloxacin was investigated in four goats . the dose and route of administration were the same as in phase i. the animals were placed into metabolic stalls prior to start of the experiment and total urine was collected . the urine samples were collected at 0 - 3 , 3 - 6 , 6 - 9 , 9 - 12 , 12 - 24 , 24 - 36 , and 36 - 48 h after drug administration . the whole volume of urine was measured and 10 ml urine samples were taken for analysis . ciprofloxacin concentrations in serum and urine were determined using the agar well diffusion assay , using e. coli atcc - 25922 as test organisms grown on mueller hinton agar . standard concentrations ( 0.015 to 4 mg / ml ) were prepared in pooled untreated goat serum and urine , and showed a mean correlation coefficient ( r ) 0.99 % for both serum and urine . the serum concentration time profile showed a correlation coefficient ( r ) value of 0.9820.009 . the intra - assay and inter - assay precision variability were 10 % for standard concentrations in both serum and urine . the lower limit of quantification of the ciprofloxacin assay was 0.015 g / ml . the extent of protein binding was determined in vitro using an equilibrium dialyzing technique as described by kunin . to estimate the protein binding of ciprofloxacin , the drug was dissolved in 0.06 m phosphate buffer ( ph 7.0 ) and antibiotic - free healthy goat serum at 0.5 , 0.75 , 1.0 , 1.5 , and 2.0 g / ml . the differences in the diameters of the inhibition zone between the solution of the drugs in the buffer and serum were calculated . the compartment pharmacokinetics of serum concentration - time curves after single intravenous injection were analyzed for each goat by top - fit v. 2.0 . the best - fit model was selected based on akaike 's information criterion and the schwartz test . model - dependent pharmacokinetic parameters were obtained as described by baggot and gibaldi and perrier . the non - compartment model was used to determine the area under concentration - time curve ( auc ) , and area under the first moment curve ( aumc ) , using the linear trapezoidal rule with extrapolation to time infinity . mean residence time ( mrt ) and systemic clearance ( clb ) were calculated as mrt = aumc / auc and clb = dose / auc , respectively . the apparent volumes of distribution at steady state were calculated as vdss = ( dose aumc ) / auc . mean serum ciprofloxacin concentrations following a single intravenous administration of 4 mg / kg body weight are presented in fig .1 . the drug was detected in goat serum up to 12 h. following intravenous administration , the elimination half - life ( t1 / 2 ) , volume of distribution at steady state ( vdss ) , total body clearance ( clb ) , and area under curve from 0 ( auc0 ) were estimated to be 1.630.17 h , 2.0120.37 ml / min / kg , and 5.750.92 g.h / ml , respectively ( table 1 ) . the efficacy predictors , cp / minimum inhibitory concentration ( mic ) and auc0 - 24 / mic can predict antimicrobial efficacy of fluoroquinolones and to reduce selection for resistance . efficacy predictors for gram - negative bacteria at mic = 0.06 g / ml and gram - positive bacteria at mic = 0.5 g / ml were cp / mic = 74.5314.12 , auc0 - 24 / mic = 186.1175.91 and cp / mic = 17.891.69 , auc0 - 24 / mic = 22.339.11 , respectively ( table 3 ) . ciprofloxacin concentrations in urine were much higher than in serum ( table 2 , fig . urinary recovery of ciprofloxacin was 29.7010.34 % of the administered dose within 36 h post administration ( table 2 ) . the in vitro protein percentage of ciprofloxacin at different concentration ( 0.5 , 0.75 , 1 .1.5 , 2 g / ml ) was 20.5 , 35.2 , 49.3 , 51.0 , and 49.0 , respectively with the mean value 41.013.1 % . the in vitro protein binding of ciprofloxacin to serum protein was 41.013.10 % , and increased with increasing doses . following intravenous administration of ciprofloxacin ( 4 mg / kg ) , no adverse effect or toxic manifestation was observed . ciprofloxacin concentration versus time data is best described by a biphasic curve and was similar to the disposition in pre - ruminant calves and piglets , goats , dogs , ponies , sheep , buffalo calves and cats . the distribution of the ciprofloxacin appeared to be quite rapid , as indicated by short distribution half - life ( 0.1080.03 h ) and 2.11 fold reduction in the serum drug concentration within 30 min of its administration . the distribution half - life ( t1 / 2 ) in goats was similar to murrah buffalo calves . however , the values were lower than the observed distribution half - life in pre - ruminant calves , cats , and cow calves . higher values were reported in cats , horses , cow calves , buffalo calves , and men . l / kg ) that indicates the drug is well distributed to extra - vascular tissue , as a volume of distribution of one indicates good extra - vascular tissue distribution . this is supported by the high k12 / k21 ratio , which indicates that the drug moves freely between the body compartments , as reported in cats . the vdss values were similar in rabbits and horses , but lower than in cats and ponies . this value in goats was higher than reported in men , buffalo calves , and cat but lower than in lactating cow , and cow calves . ciprofloxacin was detected in urine following intravenous administration , with a mean of 29.70 % 10.34 % of the total administered dose of ciprofloxacin recovered in urine within 36 h. urine concentrations up to 36 h were above mic90 for both gram - positive and gram - negative pathogens responsible for urinary tract infections , suggesting that ciprofloxacin could be used to treat goats with urinary tract infections caused by bacterial strains resistant to other commonly used antimicrobials . ciprofloxacin ( 0.5 to 2.0 g / ml ) protein binding averaged 41.0 % , comparable with joos et al . and hoffken et al . who reported serum binding between 21.9 % and 39.6 % in human . an optimum dosage is derived by correlating the important pharmacodynamic variables like in vitro mic data with pharmacokinetic variables . the antibacterial activity of the fluoroquinolones is dependent on the drug concentration and the mic of the micro - organisms . antimicrobial drugs that act predominantly by concentration - dependent mechanisms generally exert significant post - antibiotic , sub - minimum inhibitory concentration effects . such drugs continue to inhibit bacterial growth for a period of hours after they have been completely removed from the system . optimal outcomes with this type of bactericide require high concentrations , with therapeutic success correlating with the auc / mic ratio , while prevention of the development of resistance correlating with the cp / mic ratio . accordingly , the cp / mic90 and auc24 / mic90 are the best parameters for predicting the antimicrobial effects of fluoroquinolones . for fluoroquinolones , a cp / mic90 higher than 3 produced 99 % reduction in bacterial count , and a cp / mic90 of 8 or higher prevented the emergence of resistant organisms . in addition , an auc24 / mic90 higher than 100 should give maximum clinical and bacteriology efficacy . the numerical values of cp / mic90 and auc24 / mic90 are substitute markers for predicting optimal dosage . the auc / mic for cattle , sheep , goats , and camels were lower than 100 - 125 . mic90 values of 0.015 and 0.06 g / ml were used for gram - negative bacteria ( e. coli , pasteurella spp . , klebsiella pneumonia , proteus mirabilis , bordetella bronchiseptica , and haemophilus spp . ) . however , values for gram - positive bacteria ( staphylococcus aureus , staphylococcus intermedius , staphylococcus spp . ) were 0.25 and 0.5 g / ml . mic90 values of 0.007 and 1 g / ml were used for selected veterinary bacterial pathogens . the efficacy predictors , auc0 - 24 / mic and cp / mic ratios ( table 3 ) are lower for gram - negative than gram - positive bacteria . however , for treatment of gram - positive bacteria with greater mic , the predicted efficacy is lower . the minimum therapeutic concentration of fluoroquinolones is 0.02 - 0.5 g / ml . here , ciprofloxacin concentration in serum was mic 1 g / ml up to 12 h , a level suitable for gram - negative bacteria , and levels in urine up to 36 h were sufficient for treating both gram - negative and gram - positive microorganisms . ciprofloxacin also shows post - antibiotic effects ( pae ) that persist for 4 to 8 h. we therefore recommend once daily , intravenous ciprofloxacin at 4 mg / kg to maintain effective levels in serum or 36 h intervals for treating urinary tract infections in goats . in conclusion , ciprofloxacin showed high efficacy predictors against gram - negative bacteria with pae . in addition , the high concentration of ciprofloxacin excreted in urine up to 36 h makes it a better therapeutic option for treating systemic infections , especially of gram - negative bacterial origin , as well as acute urinary tract infections of resistant strains .\noutput:\n" }, { "from": "agent", "value": "we evaluated the pharmacokinetics of ciprofloxacin in serum ( n = 6 ) and urine ( n = 4 ) in goats following a single intravenous administration of 4 mg / kg body weight . the serum concentration - time curves of ciprofloxacin were best fitted by a two - compartment open model . the drug was detected in goat serum up to 12 h. the elimination rate constant ( ) and elimination half - life ( t1 / 2 ) were 0.446 0.04 h - 1 and 1.630 0.17 h , respectively . the apparent volume of distribution at steady state ( vdss ) was 2.012 0.37 l / kg and the total body clearance ( clb ) was 16.27 1.87 ml / min / kg . urinary recovery of ciprofloxacin was 29.70 % 10.34 % of the administered dose within 36 h post administration . in vitro serum protein binding was 41 % 13.10 % . thus , a single daily intravenous dose of 4 mg / kg is sufficient to maintain effective levels in serum and for 36 h in urine , allowing treatment of systemic , gram - negative bacterial infections and urinary tract infections by most pathogens ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: this can cause alveolar ridges with a reduced width and height leading to a great challenge in prosthetic reconstruction as well as during endosseous dental implant placement . a lot of techniques have been developed to achieve alveolar ridge augmentation before dental implant placement . autogenous bone graft harvested from the patient s skeleton is considered the gold standard , and it seems to be the most predictable technique used in alveolar defects , although there are some limitations with it , such as the second surgical site involvement , inadequate donor site and the morbidity and discomfort along with it . another method for reconstruction of bone defects is guided bone regeneration , which has been successful based on animal and clinical studies . clot contraction under the membrane ; however , probably reduces its efficacy . graft materials such as allografts and xenografts are also proper alternatives for ridge augmentation , in order to overcome the autogenous bone restrictions . demineralized freeze - dried bone allograft ( dfdba ) is a type of bone graft that has been extensively used , although lack of osteoinductivity , getting washed out in bleeding sites and difficulty in handling have questioned the effectiveness of the material . to overcome this problem , dbm graft materials have been improved by using a carrier to maintain the particles together . it has some characteristics such as being hemostatic , expanding to fill the bony defect and having good stability . materials such as glycerol , polymers , polymeric gels , and collagen have been utilized as a carrier to keep up the integrity of the particles . irvine , ca ) is a trade name for a type of dbm combined with a carrier that exists in different forms of gel , matrix and putty depending on the type of vehicle used . poloxamer 407 is the carrier for the putty form of dynagraft . at low temperatures , based on histologic analysis , this material inhibits epithelial cell migration , playing the role of a barrier . in addition , it has been demonstrated to be guided tissue regenerative inherently , in human and animal studies . bio - oss ( geistlich biomaterials , wolhusen , switzerland ) is an inorganic osseous matrix that is produced after elimination of the organic components of medular bovine bone using a thermal treatment . after removal of the organic components , bio - oss preserves its trabecular artichecture and porosity and it acts as an osteoconductive material . the physical properties permit clot stabilization and revascularization to let osteoblast migration , leading to osteogenesis . the aim of this study was to evaluate the quality and quantity of bone healing after application of dynagraft and bio - oss in experimentally induced bone defects in rabbit calvaria compared to natural healing . the animal selection , management , and experimental protocol were approved by the animal care and use committee of tehran university of medical sciences . the study was performed strictly according to the advices of helsinki consensus for the use and care of animals . twelve new zealand white male rabbits with 2.5 kg mean weight were included in the study . the animals were kept on standard laboratory chow with free access to water for 2 weeks preceding the day of surgery . an intra - muscular injection of 2 % ( 5 mg / kg ) xylazine and 10 % ( 40 mg / kg ) ketamin ( alafason , woeden , holland ) was used to anesthetize the rabbits . subsequent to shaving the surgical sites on the calvaria , 7 % betadine was used to scrub the area for 5 minutes . a 10 cm anteroposterior incision15 surgical blade , and then the skin ( dermal and sub dermal tissues ) and the periosteum were reflected using a fine periosteal elevator . after that , a round bur was used to create three identical holes with an external diameter of 5 mm in the calvaria , under abundant irrigation with physiologic serum . anatomic landmarks such as the occipital process and craniocaudal sutures were used to standardize the location of the defects . in the center of the calvaria , these two landmarks meet each other and make a plus sign ( + ) . depending on the type of material , the defects were categorized into three groups : the control group , in which the defect was left without any treatmentthe bio - oss group , in which the defect was filled with bio - oss ( particles sized 0/25 mm1mm ) the dynagraft group , in which dynagraft was applied to fill the defect the control group , in which the defect was left without any treatment the bio - oss group , in which the defect was filled with bio - oss ( particles sized 0/25 mm1 mm ) the dynagraft group , in which dynagraft was applied to fill the defect the periosteum was closed using an absorbable 4/0 suture ( vicryl johnson & johnson somerville . ni ) , and the skin was sutured with a non - resorbable 4/0 suture ( monofil polyamid , surgi pro . the animals were transferred to a warm place , and they underwent medication with 3 days of narcotics ( ketoprofen 0/1 mg / day ) and 7 days of antibiotic therapy ( enrofloxacin 0/6 mg / day ) subcutaneously . the animals were sacrificed via pentobarbital overdose ( 100 mg / kg ) , injected intravenously after one month of healing . then , the calvaria was removed and placed in 10 % buffered formalin solution for 2 weeks and then it was de - calcified in 10 % formic acid for 14 days . subsequently , they were dried out in graded alcohols and surrounded in paraffin . before final preparation for sectioning , all samples were placed in formalin for 48 hours . ten histologic sections with a thickness of 6 m were prepared from each defect containing an intact border of the bone , and then the samples were routinely stained with hematoxylin and eosin . the amount of inflammation , foreign body reaction , bone vitality , type of bone formation ( sequence of collagen fibers ) were evaluated by a light microscope ( bx41 , olympus co. , tokyo , japan ) at a magnification of 40 . a five - tiered grading system was utilized to scale the inflammation as follows : 0 , without any inflammatory cells ; i , slight inflammation ; ii , focal inflammation containing 5 to 10 inflammatory cells ; iii , focal inflammation with 10 to 50 inflammatory cells ; and iv , focal inflammation with more than 50 inflammatory cells . in case of observing multinucleated giant cells in granulomatous response , the type of bone formation was characterized as woven bone alone ( type i ) , both woven and lamellar bone ( type ii ) , and lamellar bone alone ( type iii ) . collagen bundles in concentric form in the bony trabecules were determined as lamellar bone ; whereas , irregularly oriented collagen fibers in the trabeculae were considered as woven bone . the amount of bone formation ( percent ) and remaining biomaterial were evaluated by means of graphic software ( photoshop 8.0 cs , adobe photoshop cs ) . statistical analysis for the amount of inflammation and type of bone formationwilcoxon sign rank test was used to evaluate the intergroup differences ( two by two ) about the type of bone formation . repeated measure anova and paired lsd test were applied to analyze the amount of bone formation . in order to compare the remaining bone material between groups , paired t test was performed accordingly . the animals were sacrificed via pentobarbital overdose ( 100 mg / kg ) , injected intravenously after one month of healing . then , the calvaria was removed and placed in 10 % buffered formalin solution for 2 weeks and then it was de - calcified in 10 % formic acid for 14 days . subsequently , they were dried out in graded alcohols and surrounded in paraffin . before final preparation for sectioning , all samples were placed in formalin for 48 hours . ten histologic sections with a thickness of 6 m were prepared from each defect containing an intact border of the bone , and then the samples were routinely stained with hematoxylin and eosin . the amount of inflammation , foreign body reaction , bone vitality , type of bone formation ( sequence of collagen fibers ) were evaluated by a light microscope ( bx41 , olympus co. , tokyo , japan ) at a magnification of 40 . a five - tiered grading system was utilized to scale the inflammation as follows : 0 , without any inflammatory cells ; i , slight inflammation ; ii , focal inflammation containing 5 to 10 inflammatory cells ; iii , focal inflammation with 10 to 50 inflammatory cells ; and iv , focal inflammation with more than 50 inflammatory cells . in case of observing multinucleated giant cells in granulomatous response , the type of bone formation was characterized as woven bone alone ( type i ) , both woven and lamellar bone ( type ii ) , and lamellar bone alone ( type iii ) . collagen bundles in concentric form in the bony trabecules were determined as lamellar bone ; whereas , irregularly oriented collagen fibers in the trabeculae were considered as woven bone . the amount of bone formation ( percent ) and remaining biomaterial were evaluated by means of graphic software ( photoshop 8.0 cs , adobe photoshop cs ) . statistical analysis for the amount of inflammation and type of bone formationwilcoxon sign rank test was used to evaluate the intergroup differences ( two by two ) about the type of bone formation . repeated measure anova and paired lsd test were applied to analyze the amount of bone formation . in order to compare the remaining bone material between groups , the results are shown in table 1 . evaluating the amount of inflammation using friedman test , all specimens showed slight infiltration ( grade i and ii ) and there was no significant difference between groups ( p = 0/478 ) . seventy five percent of the control group , 66/66 % of bio - oss group and 58/33 % of dynagraft group showed grade i inflammation ; whereas , other specimens presented with grade ii inflammation . comparison of histologic characteristics in groups all specimens consisted of both lamellar and woven bone . consideringthe type of bone formation , in the control group , 16/67 % and 83/33 % of the specimens displayed type i and ii bone formation , respectively . in the dynagraft group , 41/67 % of the specimens showed type ii bone formation , and bone type iii was detected in 58/33 % of the defects in this group . in the bio - oss group , type i , ii and iii bone formation was observed in 16/66 % , 58/33 % , and 25/01 % of the specimens , respectively . according to friedman test , the difference between groups was statistically significant ( p value 0/05 ) . intergroup differences ( two by two ) were evaluated using wilcoxon sign rank test , and a significant difference was detected comparing dynagraft group with the control and bio - oss groups ( p value 0/017 ) ; whereas , there was no significant difference between bio - oss and the control group ( p value 0/017 ) . the mean amount of new bone formation was 28/6 % 11/2 in the control group , and the dynagraft and bio - oss groups demonstrated 56/1 % 15/1 and 53/55 % 13/5 mean amount of new bone formation , respectively . according to repeated measure anova , the difference between groups was statistically significant ( p value 0/001 ) . for evaluation ofthe two by two differences , lsd test showed a significant difference comparing the control group with dynagraft and bio - oss groups ( p value 0/05 ) . considering the remaining material , using paired t test , no significant difference was observed between bio - oss and dynagraft groups ( p value 0/1 ) . foreign body reaction was seen in two defects in the dynagraft group , and four specimens in the bio - oss group , and the difference was not statistically significant ( p value 0/342 ) . many experimental studies have been carried out to evaluate different techniques and materials in bone regeneration procedures . since the amount of bone formation and its quality are of significant importance , a large number of studies have compared the characteristics and treatment outcomes of a variety of materials and techniques . in the present study , we compared the effect of two types of bone grafts on the quality and quantity of bone healing in experimental defects in rabbit calvarium . the bone formation process of calvarium is intra membranous , similar to that of the alveolar bone . thus , we investigated the calvarium of the rabbit in order to make an appropriate comparison . this could be related to its good stability and its ability to act as a barrier membrane . moreover , these characteristics interpret the osteoinductive and osteoconductive effect of dynagraft in comparison to bio - oss with its osteoconductive properties . this is in accordance with the study of callan et al . in their case series study , four to six months prior to implant placement , they carried out a bone augmentation procedure . subsequent to material placement , a membrane barrier material was used in order to facilitate site closure . they established similar results about the new allograft material and they claimed it can be used in bone defects within a short time healing . they used the material for osseous reconstruction associated with dental implants . in their case series , they performed fresh socket implantation in the maxillary anterior segment . following extraction and fixture insertion , the residual defect was filled with the material . after approximately 6 months , at the second stage of implant surgery , a bone core was harvested from the distal aspect of the implant . . evaluated bone regeneration of critical sized calvarial defects in rabbits utilizing demineralized bone matrix putty . they established a complete bone fill and closure of the defects with vital bone at 12 weeks . since a true critical - sized cranial defect in the rabbit model is 15 mm , in the present study , due to the small size of the cranium , three critical - sized defects could not be prepared in the rabbit calvarium . moreover , many studies have shown that bio - oss is effective in bone regeneration procedures . the amount of new bone was comparable with bio - oss in conjunction with membrane . in the present study , we found similar results regarding bio - oss , but dynagraft group was better in amount of bone formation , although not statistically significant . investigated the healing of alveolar ridge defects augmented with cancellous bovine bone mineral and they found bio - oss an appropriate material for ridge reconstruction in humans . on the contrary , pinholt et al . implanted bio - oss subperiosteally for ridge construction purposes and heterotopically in the abdominal muscles of rats . in the microscopic evaluation , they found no osteoinduction or osteoconduction and a foreign body reaction was observed around the material . in their previous investigation , the authors of this study concluded that using dbbm alone in the bone defects of rabbit calvaria did not increase bone regeneration compared to the control group . they also showed that osteogenesis in rabbit calvarium may improve by adding prgf to dbbm . it seems that prgf accelerates the rate of degradation of the biomaterial . in the current study , regarding the negligible inflammatory and foreign body reaction in histological analysisthese characteristics were previously confirmed by hammerle et al . , slotte and lundgren , and khoshkhoonejad et al . displayed similar characteristics about dynagraft . in the present study , we did not use barrier membranes to cover the defects in order to eliminate its confounding effect ; therefore , we could evaluate the role of dynagraft as a barrier membrane in addition to its other properties . in the systematic review performed by khojasteh et al . moreover , khoshkhoonejad et al . demonstrated that using a membrane did not increase the amount of bone regeneration in their study . it is worth mentioning that membranes lack enough mechanical strength and they collapse into the defect , they separate the periosteum from the bone , and their early degradation and displacement may also contribute to their inefficacy . considering the amount of remaining biomaterialthe authors of this study , in their previous experiment showed a considerable amount of residual material in defects with bio - oss that reduced significantly when prgf was added . bio - oss is a hydroxyapatite compound and it is expected to have a slower rate of absorption . since our histological sections were prepared 4 weeks after the grafting procedure , this result could be different between groups if the samples were prepared after a longer period . according to the type of bone formation , the majority of new bone consisted of type ii in bio - oss and control groups ; whereas , dynagraft group mostly contained bone type iii . the difference between groups was statistically significant . as we mentioned earlier in the present study , dynagraft benefits from its osteoinductive and osteoconductive properties ; it can accelerate bone regeneration while playing the role of a membrane . our results were consistent with another study performed by khoshkhoonejad et al . , in which bio - oss group showed type ii bone formation in all specimens after one month . in the current study , considerable new bone formation was observed in both dbbm and dfdba groups in comparison with the control group . the dynagraft group showed slightly more bone formation compared to the bio - oss group .\noutput:\n" }, { "from": "agent", "value": "objectives : considering the importance of bone augmentation prior to implant placement in order to obtain adequate bone quality and quantity , many studies have been conducted to evaluate different techniques and materials regarding new bone formation . in this study , we investigated the bone healing capacity of two different materials deproteinized bovine bone mineral ( dbbm with the trade name of bio - oss ) and demineralized freeze - dried bone allograft ( dfdba with the trade name of dynagraft ) . materials and methods : this randomized blinded prospective study was conducted on twelve new zealand white rabbits . three cranial defects with an equal diameter were created on their calvarium . subsequently , they were distributed into three groups : 1 . the control group without any treatment ; 2 . the bio - oss group ; 3 . the dynagraft group . after 30 days , the animals were sacrificed for histologic and histomorphometric analysis.results : substantial new bone formation was observed in both groups . dynagraft : 56/1 % 15/1 and bio - oss : 53/55 % 13/5 compared to the control group : 28/6 % 11/2 . all groups showed slight inflammation and a small amount of residual biomaterial was observed.conclusion : considerable new bone formation was demonstrated in both dynagraft and bio - oss groups in comparison with the control group . both materials are considered biocompatible regarding the negligible foreign body reaction ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: eight cadaveric lumbar spine segments from t12 through the sacrum ( 4 female and 4 male cadavers ; mean age , 59.6 years ; age range , 5168 years ) were cleaned of muscle , loose connective tissue , and the anterior longitudinal ligament with special care given to preserving the remaining intervertebral ligamentous structures . each specimen underwent ct scanning with a slice thickness of 0.6 mm in a 64 - slice ct scanner ( somatom ; siemens , munich , germany ) . commercially available medical image analysis software ( scanip ; simpleware , exeter , england ) each specimen was segmented twice by each of 2 operators ( operator a and operator b ) . for ease of comprehension , the following scheme will be used throughout the remainder of this article : segmentation sessions will be abbreviated with operator name ( a or b ) followed by session number ( 1 or 2 ) ; for example , the second segmentation session by operator b will be abbreviated b2 . to ensure that each segmentation session was independent of bias related to memory , the first and second segmentations of each specimen by each operatorthe strategy of this segmentation process was to isolate the cortical bone of each vertebra and use this outline to develop a closed model of the vertebral body surface . operator a had completed more than 20 segmentations of the lumbar spine before the study . operator b had been trained in using the segmentation software before the study but had not otherwise segmented any spines . during importation of the ct data into the segmentation software , a custom window width and level were interactively applied to maximize contrast between bone and soft tissue . before segmentation of the ct volumetric data , a curvature anisotropic diffusion noise filter was applied to the image background . masks are defined as a delineation of voxels that define the shape of an anatomic component , such as a lumbar vertebra . a mask was created to contain an operator - specified threshold , defined as voxels contained between an upper and lower boundary of grayscale units . this threshold was interactively applied by the operator with the intent to maximize bone included in the mask , minimize the soft tissue , and create well - defined borders at the facet joints . . however , the thresholding mask often contains areas of connectivity , or bridges , between adjacent vertebrae in instances where no bony connectivity exists . these bridges are most commonly found at the facet joints where bone from adjacent vertebrae is in proximity and can be attributed to image blur . bridges were removed when the masked area did not correspond to bone per the judgment of the operator . because models of the vertebral surface were desired , the interior of each mask defined by thresholding was filled by use of a combination of morphologic closing filters and filling operations based on mask boundaries . manual definition and / or deletion of portions of masks was needed in instances where bone near the periphery of the vertebrae was not appropriately included in the initial threshold process . finally , all masks were visually evaluated to verify that the definition of the masks corresponded with the boundary of the vertebrae in the ct image space . a smoothing recursive gaussian filter was applied to each mask . during exportation , each model was decimated to a maximum of 70,000 triangular surface patches per part to reduce file size and computation time in subsequent processing while maintaining sufficient resolution of the surface model . because the models were limited to a maximum number of surface patches , the resolution was a function of the size of each vertebra . the average distance per side of each triangular surface patch across all vertebral levels was 0.70 mm . the minimum and maximum average distances for all vertebral levels were 0.66 mm ( l1 level ) and 0.72 mm ( l5 level ) , respectively . for an l3 vertebra representative of the population , the average distance per side of each triangular surface patch in a non - decimated model was 0.38 mm . the precision of the segmentation process was determined by registering vertebral models from 1 segmentation session with the corresponding vertebral models from another segmentation session and then determining the distances from each point on 1 model to the nearest point on the other model . although all segmentation sessions per specimen were completed using the same initial ct image , differences in cropping the image necessitated a translational registration process that was produced by the iterative closest point algorithm . distance calculations were also determined with custom - written matlab software ( math - works , natick , massachusetts ) . figures showing the models before and after registration , as well as color distance maps , were produced to visually verify that the process was successful . intra - user precision was determined by comparing segmentation session a1 with session a2 and session b1 with session b2 . ( d ) three - dimensional surface - rendered model produced from the ct scan of the vertebra depicted in c. ( e ) point cloud model of d registered with the corresponding operator a1 model . to determine the accuracy of the segmentation technique , 5 vertebrae ( l1 in 1 , l2 in 2 , and l3 in 2 ) from 2 lumbar segments that were used in the precision portion of this studythe specimens were disarticulated from adjacent vertebrae , were completely removed of soft tissue , underwent ct scanning , and were then segmented an additional time . the soft tissue was removed as follows : after disarticulation , a portion of the soft tissue was manually and conservatively removed ( to avoid damage to the bone ) with common surgical tools . , the vertebrae were macerated in water that was kept at room temperature between 2 and 14 days . the vertebrae were then individually simmered in a solution of water with 2 tablespoons of sodium borate ( 20 mule team borax ; dial , scottsdale , arizona ) per 1.5 l followed by manual tissue removal . both the endplates and articular cartilage were removed during this process . finally , the vertebrae were subjected to another round of maceration at room temperature for between 2 and 7 days before ct scanning . these steps were taken to produce 3d models that are less susceptible to segmentation error , particularly with regard to the facets . the lack of soft tissue and instrumentation allowed for the outer borders of the vertebrae to be easily identifiable without the use of judgment on the part of the operator . the methods used to determine segmentation accuracy alleviate this problem through disarticulation of the vertebrae . thus the goal of this procedure was to determine the error associated with the segmentation process itself by removing those elements associated with user judgment . this fifth accuracy segmentation was produced by operator a and compared with segmentation sessions a1 and b1 to determine segmentation accuracy . because of the difference in orientation between the first and second ct scans of these vertebrae , it was necessary to apply a rigid body registration transformation to superimpose associated models . models were registered by use of a freely available iterative closest point algorithm , written by per bergstrm , as part of custom - written matlab software .2 d shows a 3d model produced by segmentation of the ct image , and fig . eight cadaveric lumbar spine segments from t12 through the sacrum ( 4 female and 4 male cadavers ; mean age , 59.6 years ; age range , 5168 years ) were cleaned of muscle , loose connective tissue , and the anterior longitudinal ligament with special care given to preserving the remaining intervertebral ligamentous structures . each specimen underwent ct scanning with a slice thickness of 0.6 mm in a 64 - slice ct scanner ( somatom ; siemens , munich , germany ) . commercially available medical image analysis software ( scanip ; simpleware , exeter , england ) was used to generate a 3d model of each vertebra . each specimen was segmented twice by each of 2 operators ( operator a and operator b ) . for ease of comprehension , the following scheme will be used throughout the remainder of this article : segmentation sessions will be abbreviated with operator name ( a or b ) followed by session number ( 1 or 2 ) ; for example , the second segmentation session by operator b will be abbreviated b2 . to ensure that each segmentation session was independent of bias related to memory , the first and second segmentations of each specimen by each operatorthe strategy of this segmentation process was to isolate the cortical bone of each vertebra and use this outline to develop a closed model of the vertebral body surface . operator a had completed more than 20 segmentations of the lumbar spine before the study . operator b had been trained in using the segmentation software before the study but had not otherwise segmented any spines . during importation of the ct data into the segmentation software , a custom window width and level were interactively applied to maximize contrast between bone and soft tissue . before segmentation of the ct volumetric data , a curvature anisotropic diffusion noise filter was applied to the image background . masks are defined as a delineation of voxels that define the shape of an anatomic component , such as a lumbar vertebra . a mask was created to contain an operator - specified threshold , defined as voxels contained between an upper and lower boundary of grayscale units . this threshold was interactively applied by the operator with the intent to maximize bone included in the mask , minimize the soft tissue , and create well - defined borders at the facet joints . these bridges are most commonly found at the facet joints where bone from adjacent vertebrae is in proximity and can be attributed to image blur . bridges were removed when the masked area did not correspond to bone per the judgment of the operator . none of the spines used in this study exhibited fusion at the facet joints . because models of the vertebral surface were desired , the interior of each mask defined by thresholding was filled by use of a combination of morphologic closing filters and filling operations based on mask boundaries . manual definition and / or deletion of portions of masks was needed in instances where bone near the periphery of the vertebrae was not appropriately included in the initial threshold process . finally , all masks were visually evaluated to verify that the definition of the masks corresponded with the boundary of the vertebrae in the ct image space . , each model was decimated to a maximum of 70,000 triangular surface patches per part to reduce file size and computation time in subsequent processing while maintaining sufficient resolution of the surface model . because the models were limited to a maximum number of surface patches , the resolution was a function of the size of each vertebra . the average distance per side of each triangular surface patch across all vertebral levels was 0.70 mm . the minimum and maximum average distances for all vertebral levels were 0.66 mm ( l1 level ) and 0.72 mm ( l5 level ) , respectively . for an l3 vertebra representative of the population , the average distance per side of each triangular surface patch in a non - decimated model was 0.38 mm . the precision of the segmentation process was determined by registering vertebral models from 1 segmentation session with the corresponding vertebral models from another segmentation session and then determining the distances from each point on 1 model to the nearest point on the other model . although all segmentation sessions per specimen were completed using the same initial ct image , differences in cropping the image necessitated a translational registration process that was produced by the iterative closest point algorithm . distance calculations were also determined with custom - written matlab software ( math - works , natick , massachusetts ) . figures showing the models before and after registration , as well as color distance maps , were produced to visually verify that the process was successful . intra - user precision was determined by comparing segmentation session a1 with session a2 and session b1 with session b2 . ( d ) three - dimensional surface - rendered model produced from the ct scan of the vertebra depicted in c. ( e ) point cloud model of d registered with the corresponding operator a1 model . to determine the accuracy of the segmentation technique , 5 vertebrae ( l1 in 1 , l2 in 2 , and l3 in 2 ) from 2 lumbar segments that were used in the precision portion of this study were selected at random . the specimens were disarticulated from adjacent vertebrae , were completely removed of soft tissue , underwent ct scanning , and were then segmented an additional time . the soft tissue was removed as follows : after disarticulation , a portion of the soft tissue was manually and conservatively removed ( to avoid damage to the bone ) with common surgical tools . , the vertebrae were macerated in water that was kept at room temperature between 2 and 14 days . the vertebrae were then individually simmered in a solution of water with 2 tablespoons of sodium borate ( 20 mule team borax ; dial , scottsdale , arizona ) per 1.5 l followed by manual tissue removal . the total time each vertebra spent at simmering water temperature was approximately 2 hours . both the endplates and articular cartilage were removed during this process . finally , the vertebrae were subjected to another round of maceration at room temperature for between 2 and 7 days before ct scanning . these steps were taken to produce 3d models that are less susceptible to segmentation error , particularly with regard to the facets . the lack of soft tissue and instrumentation allowed for the outer borders of the vertebrae to be easily identifiable without the use of judgment on the part of the operator . the methods used to determine segmentation accuracy alleviate this problem through disarticulation of the vertebrae . thus the goal of this procedure was to determine the error associated with the segmentation process itself by removing those elements associated with user judgment . this fifth accuracy segmentation was produced by operator a and compared with segmentation sessions a1 and b1 to determine segmentation accuracy . because of the difference in orientation between the first and second ct scans of these vertebrae , it was necessary to apply a rigid body registration transformation to superimpose associated models . models were registered by use of a freely available iterative closest point algorithm , written by per bergstrm , as part of custom - written matlab software .2 d shows a 3d model produced by segmentation of the ct image , and fig . for each coupled session compared ( ie , a1 and a2 for intrauser precision ) , 2 sets of distance calculations were made . for example , distances were calculated from the a1 model to the a2 model and from the a2 model to the a1 model . this was performed to ensure that a distance for each point in both models was included in the analysis . the results for each subsection presented later are shown with the distance calculation that yielded the maximum root - mean - square ( rms ) between corresponding sets of points . all accounts of vertebral accuracy coupled comparisons had submillimeter rms values ( range , 0.360.39 mm ) . the 95th percentile values were submillimeter values in all instances ( range , 0.640.75 mm ) , whereas the 99th percentile values were near 1 mm ( range , 1.101.22 mm ) . the diagonal - lined bars show the maximum rms values for the precision comparisons of the vertebral models , and the solid bars show the maximum rms values for the accuracy comparisons of the vertebral models . all accounts of vertebral precision coupled comparisons had submillimeter rms values ( range , 0.320.35 mm ) with the interuser precision rms value being the largest . the 99th percentile values were also submillimeter values in all instances ( range , 0.780.96 mm ) .3 d solid modeling , using segmentation techniques similar to those described in this article , has become an important tool for biomechanical research as shown in the literature . applying kinematic data to solid models allows for the investigation of biomechanics and joint interaction in a noninvasive manner . as cripton et al outlined in an examination of the cervical spine , this technique allows researchers to visualize and interpret skeletal motion without obstruction from nonessential anatomic components . furthermore , cook and cheng used distance mapping between interacting facet surfaces that relied on the use of 3d solid models of the spine . although the utility of 3d models is apparent , the validity of the results garnered from model - based kinematic studies is dependent in part on the quality of the models produced , which is the focus of this study . the precision and accuracy of manual segmentation to create models of the lumbar spine have not been previously characterized . this information , in conjunction with error associated with kinematic tracking , is necessary for the analysis of data collected from model - based kinematic studies that use manual segmentation techniques . the accuracy of commercially available optoelectric tracking systems has been well characterized , and in many applications , it is on the submillimeter scale . it is desirable then to achieve segmentation accuracy of approximately the same magnitude . moreover , a priori knowledge of errors that are inherent to certain techniques equips researchers with necessary information for study design . in terms of the precision of the segmented models , this result was expected because manual corrections were made at the discretion of the operator and thus the resulting 3d models are dependent on the differences in judgment and manual segmentation techniques between operators . the low rms values ( range , 0.320.35 mm ) for all precision sessions indicate that the use of manual segmentation is robust enough to allow for highly precise segmentation sessions between operators , regardless of experience , given that each operator has been properly trained using image analysis software . the accuracy results for the full vertebrae are similarly promising because the rms values ranged from 0.36 to 0.39 mm . the accuracy segmentation sessions were a quality standard of accuracy because they incorporated the same imaging procedures as the precision models but did not contain soft tissue , instrumentation , or adjacent vertebrae and thus eliminated those components as potential sources of error . most importantly , the lack of adjacent vertebrae eliminated operator judgment at the facet joints . the technique presented for determining precision between 2 corresponding solid models encompasses variability across the entire model surface by investigating the distribution of distances between neighboring points on each surface after rigid body registration . to our knowledge , this is the first presentation of such a thorough technique in evaluating spinal segmentation . as a resultthe importance of calculating distances for each set of points defining their respective models is illustrated in fig . figure 4b shows registered point sets , with one depicted in red and the other in blue . it should be noted that part of the blue model exceeds the limits of the red model . figure 4a shows a color map of the distances calculated from the blue model to the red model , and fig .4 c shows a color map of the distances calculated from the red model to the blue model . the visible difference in the color maps indicates that results biased toward greater precision may be garnered if distances between both point sets are not included in analysis . ( c ) distance map from red model to blue model . for the distance maps , a limitation of this study is the use of maceration to remove soft tissue from the vertebrae used for the accuracy analysis . liquid - based tissue removal techniques have been shown to alter skull shape and dimensions in rodents . the amount of time that each vertebra used in the accuracy portion of the study spent in water for the purpose of maceration varied considerably . however , the use of the maceration techniques outlined in this article has not been characterized for human lumbar vertebrae . this process reduced surface resolution but was necessary to constrain file size and computation requirements . with an increase in computational power , analysis using non - decimated models should be considered . finally , this study assumes that the ct scanner used had been properly calibrated and produced images that were true to the actual dimensions of the vertebrae for both the scans used for precision and those used for accuracy . in conclusion , this study has shown that the reproducibility of lumbar vertebral models generated using manual segmentation is high and that these models accurately reflect the shape of the vertebra as indicated by submillimeter rms accuracy values . the magnitude of the error presented here should inform the design and interpretation of future studies using manual segmentation techniques to derive models of the lumbar spine .\noutput:\n" }, { "from": "agent", "value": "backgroundthe application of kinematic data acquired during biomechanical testing to specimen - specific , three - dimensional models of the spine has emerged as a useful tool in spine biomechanics research . however , the development of these models is subject to segmentation error because of complex morphology and pathologic changes of the spine . this error has not been previously characterized.methodseight cadaveric lumbar spines were prepared and underwent computed tomography ( ct ) scanning . after disarticulation and soft - tissue removal , 5 individual vertebrae from these specimens were scanned a second time . the ct images of the full lumbar specimens were segmented twice each by 2 operators , and the images of the individual vertebrae with soft tissue removed were segmented as well . the solid models derived from these differing segmentation sessions were registered , and the distribution of distances between nearest neighboring points was calculated to evaluate the accuracy and precision of the segmentation technique.resultsmanual segmentation yielded root - mean - square errors below 0.39 mm for accuracy , 0.33 mm for intrauser precision , and 0.35 mm for interuser precision . furthermore , the 95th percentile of all distances was below 0.75 mm for all analyses of accuracy and precision.conclusionsthese findings indicate that such models are highly accurate and that a high level of intrauser and interuser precision can be achieved . the magnitude of the error presented here should inform the design and interpretation of future studies using manual segmentation techniques to derive models of the lumbar spine ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: management of ao type c3 distal femur fractures with multifragmentary articular involvement is challenging , with most series reporting average to poor results and frequent complications such as malunion , knee stiffness , and secondary osteoarthritis .1234567891011 only a few studies123456 have exclusively reported the outcome of complex c3 type fractures of the distal femur , with only three such studies125 published in english literature . various surgical approaches have been suggested to achieve an adequate exposure of the distal femoral articular surface , including medial / lateral parapatellar approaches ,712 swashbuckler approach ,13 tibial tubercle osteotomy ,514 and combined medial and lateral approaches .3 external ring fixators have been used with mixed results by several previous authors12 to address the comminution in these complex injuries . some have used dual medial and lateral plates in these .345 most previous authors have employed primary bone grafting to enhance union in these complex fractures .1234 the use of swashbuckler approach for c3 fractures has not been reported yet in the literature . we have reported the results in a consecutive series of patients with c3 type distal femur fractures , operated by a single surgeon in a tertiary level trauma center , with a single lateral locked plate ( distal femur locking compression plate [ df - lcp ] ) , using a modified swashbuckler approach , without primary bone grafting .12 consecutive adult patients operated with open reduction and internal fixation of distal femur fractures with multifragmentary articular involvement ( ao / ota type 33c3 ) , between september 2012 and march 2014 were included in this prospective study . extraarticular fractures ( type a ) , partial articular fractures ( type b ) and simple articular fractures ( type c1 and c2 ) of the distal femur were not included in the study . patients with ipsilateral fractures in the same lower extremity and pathological fractures were excluded from the study to avoid confounding of results . all patients were initially managed according to advanced trauma life support guidelines .15 the fractured limb was splinted in a bohler - braun frame , with the application of skin traction . all the patients were operated within 10 days of the initial trauma . radiological evaluation included anteroposterior and lateral x - rays of the femur with knee , along with a pelvic x - ray to rule out proximal fractures . computed tomography ( ct ) scans with three - dimensional reconstruction were done , whenever feasible , to better delineate the fracture anatomy and to allow detailed subgroup classification . four of the 12 patients could not afford a ct scan and were operated based on plain films . the ao / ota classification16 was used to further classify the c3 fractures up to the subgroup level , based on the severity of extra - articular involvement [ figure 1 ] . the extra - articular component was also described according to the ao / ota subgroup classification of 33a fractures [ figure 2 ] , which is more detailed and useful in the management of the extra - articular component . ao / ota classification of distal femur type c fractures ao / ota classification of distal femur type a fractures all the patients were operated in the supine position on a radiolucent table by the senior author ( aa ) , who also has a considerable experience in knee arthroplasties [ figures 3 and 4 ] . if eversion of the patella was tight , the lateral attachment of the patellar tendon was released to ease eversion , similar to our practice in total knee arthroplasties . we used a leg - holding tray from our total knee arthroplasty set [ figure 3 ] to facilitate limb positioning in varying degrees of flexion . in full flexion , an excellent exposure of the distal articular surface of the femur ( including the posterior part of the medial femoral condyle ) is obtained [ figures 3 and 4 ] . ( a - c ) preoperative x - rays anteroposterior and lateral views of knee joint and computed tomography scans ( case no . ( d ) clinical photograph showing patient positioning and draping with leg - holding tray . ( f ) immediate postoperative anteroposterior and lateral x - rays of knee joint showing implant in situ . ( g ) three months postoperative x - rays anteroposterior and lateral views showing fracture consolidation . ( h and i ) clinical photograph showing range of motion of the knee at 3 months ( a - c ) preoperative x - rays anteroposterior and lateral views of knee joint and computed tomography scans ( case no . ( f ) immediate postoperative anteroposterior and lateral x - rays showing implant in situ . ( i and j ) clinical photographs of patient showing range of motion of the knee at 3 months the articular block was reconstructed first , which was subsequently reattached to the metadiaphysis . the distal femur articular surface was carefully inspected for all fracture lines , and the fracture classification was confirmed . the provisional reduction was done with pointed clamps and k - wires , followed by insertion of lag screws . the usual sequence of reduction was first , any sagittal split of posterior condyles , followed by the coronal splits ( hoffa / trochlear fragments ) , addressing the intercondylar component last . osteochondral fragments were fixed with headless or countersunk screws ( for large fragments 1 cm ) or k - wires ( for intermediate fragments 510 mm ) . our patient population can not afford biodegradable pins , otherwise we would have preferred them over k - wires . k - wires were put in a divergent fashion , preferably purchasing the far cortex ( bicortical ) and were cut flush with the articular surface ( lost k - wire technique ) . after anatomical reconstruction and rigid fixation of the articular block , attention was diverted to the extra - articular fracture , with repeat assessment of the fracture pattern . our philosophy of management of the extra - articular component in distal femur fractures is as follows . we prefer open reduction and compression plating ( hybrid fixation ) for simple metaphyseal fractures ( ao types a1 .2 , a1 .3 ) or those with an intact wedge ( ao type a2 .1 ) . fractures with wedge comminution ( ao type a2 .2 , a2 .3 ) or segmental comminution ( ao type a3 .1 , a3 .2 , a3 .3 ) were managed by indirect reduction and bridge plating using transarticular approach and retrograde plate osteosynthesis ( tarpo ) technique .7 the length , alignment , and rotation were carefully restored similar to the normal side . medial dissection was avoided in all cases to preserve the biology , and primary bone grafting was not done in any case . the anterolateral incision can be easily extended proximally , as in a standard lateral approach , if open compression plating of the fracture is to be done . the implant used was a distal femur lcp made of stainless steel ( ssepl , vadodara , india ) . it provides provision of inserting up to three 6.5 mm locking cancellous screws , and up to four additional 5 mm locking screws in the articular block . we aimed to put four to five locked screws in the articular block , and four bicortical screws in the metadiaphysis ( in case of compression plating ) or three to five locking screws ( in bridge plating ) . the working length of a bridge plate was kept at least 2.5 times the working length of the fracture , with a screw density ratio of 0.40.5 . the knee was mobilized on the 1 or 2 postoperative day , depending on the degree of postoperative pain . touchdown or partial weight - bearing was begun , depending on the fracture stability , and progressed to full weight bearing upon fracture union at 612 weeks . the patients were discharged only after 90 flexion of the knee was achieved , usually by the 4 or 5 postoperative day . the clinical and radiological evaluation was done by the junior author ( vk ) , who was not a part of the operating team . the patients were clinically examined at the time of discharge from hospital for any malrotation or limb length discrepancy . a limb malrotation 5 and a limb length discrepancy 5 mm were difficult to detect clinically and were considered normal . a repeat clinical examination was done at the final fracture healing to note any further change in limb length and rotation . ap and lateral radiographs of the femur with knee were taken immediately after surgery and were evaluated for fracture alignment , both in the coronal and sagittal planes . fracture alignment in the coronal plane was measured by the valgus angle between the anatomic axes of the femoral and tibial shafts . a 510 valgus angle was considered as normal as in the knee society score ( kss ) .17 the alignment in the sagittal plane was measured by noting the angulation between the anterior cortices of the proximal and distal fragments . the patients were followed up at every 6 weeks until bony union was achieved at both the articular and metaphyseal fracture sites , and the subsequent followup was done every 3 months for the 1 year , biannually in the 2 year , and annually thereafter . ap and lateral radiographs of the femur with knee were taken at each visit and evaluated for callus formation / progression and fracture union . in cases with simple articular and extra - articular fractures , managed by open compression plating , direct bone healing can be difficult to determine radiologically and was determined using clinical criteria such as painless weight - bearing and absence of pain / tenderness at the fracture site . any loss of reduction , plate lift - off , screw back - out or screw / plate breakage was recorded . any other complication such as superficial or deep infection was also recorded . at 1 year followup , a knee society knee score between 80 and 100 was regarded as excellent , between 70 and 79 was regarded as good , between 60 and 69 was regarded as fair , and 60 was regarded as poor .18 the 1 - year and subsequent radiographs were also evaluated for any change of secondary osteoarthritis , such as narrowing of joint space , development of osteophytes , and subchondral cysts or sclerosis , both in the tibiofemoral and patellofemoral compartments . statistical analysis was done using the spss 19.0 statistical software ( ibm spss , new york , usa ) . only descriptive analysis was done to calculate the mean and the standard deviation of the demographic and outcome variables . due to the limited number of patients in each ao subgroup ( there was only one patient in 33c3 .3 subgroup ) , no further subgroup analysis of the outcome parameters was done . all the patients were operated in the supine position on a radiolucent table by the senior author ( aa ) , who also has a considerable experience in knee arthroplasties [ figures 3 and 4 ] . if eversion of the patella was tight , the lateral attachment of the patellar tendon was released to ease eversion , similar to our practice in total knee arthroplasties . we used a leg - holding tray from our total knee arthroplasty set [ figure 3 ] to facilitate limb positioning in varying degrees of flexion . in full flexion , an excellent exposure of the distal articular surface of the femur ( including the posterior part of the medial femoral condyle ) is obtained [ figures 3 and 4 ] . ( a - c ) preoperative x - rays anteroposterior and lateral views of knee joint and computed tomography scans ( case no . ( d ) clinical photograph showing patient positioning and draping with leg - holding tray . ( f ) immediate postoperative anteroposterior and lateral x - rays of knee joint showing implant in situ . ( g ) three months postoperative x - rays anteroposterior and lateral views showing fracture consolidation . ( h and i ) clinical photograph showing range of motion of the knee at 3 months ( a - c ) preoperative x - rays anteroposterior and lateral views of knee joint and computed tomography scans ( case no . ( f ) immediate postoperative anteroposterior and lateral x - rays showing implant in situ . ( i and j ) clinical photographs of patient showing range of motion of the knee at 3 months the articular block was reconstructed first , which was subsequently reattached to the metadiaphysis . the distal femur articular surface was carefully inspected for all fracture lines , and the fracture classification was confirmed . the provisional reduction was done with pointed clamps and k - wires , followed by insertion of lag screws . the usual sequence of reduction was first , any sagittal split of posterior condyles , followed by the coronal splits ( hoffa / trochlear fragments ) , addressing the intercondylar component last . osteochondral fragments were fixed with headless or countersunk screws ( for large fragments 1 cm ) or k - wires ( for intermediate fragments 510 mm ) . our patient population can not afford biodegradable pins , otherwise we would have preferred them over k - wires . k - wires were put in a divergent fashion , preferably purchasing the far cortex ( bicortical ) and were cut flush with the articular surface ( lost k - wire technique ) . after anatomical reconstruction and rigid fixation of the articular block , attention was diverted to the extra - articular fracture , with repeat assessment of the fracture pattern . our philosophy of management of the extra - articular component in distal femur fractures is as follows . we prefer open reduction and compression plating ( hybrid fixation ) for simple metaphyseal fractures ( ao types a1 .2 , a1 .3 ) or those with an intact wedge ( ao type a2 .1 ) . fractures with wedge comminution ( ao type a2 .2 , a2 .3 ) or segmental comminution ( ao type a3 .1 , a3 .2 , a3 .3 ) were managed by indirect reduction and bridge plating using transarticular approach and retrograde plate osteosynthesis ( tarpo ) technique .7 the length , alignment , and rotation were carefully restored similar to the normal side . medial dissection was avoided in all cases to preserve the biology , and primary bone grafting was not done in any case . the anterolateral incision can be easily extended proximally , as in a standard lateral approach , if open compression plating of the fracture is to be done . the implant used was a distal femur lcp made of stainless steel ( ssepl , vadodara , india ) . it provides provision of inserting up to three 6.5 mm locking cancellous screws , and up to four additional 5 mm locking screws in the articular block . we aimed to put four to five locked screws in the articular block , and four bicortical screws in the metadiaphysis ( in case of compression plating ) or three to five locking screws ( in bridge plating ) . the working length of a bridge plate was kept at least 2.5 times the working length of the fracture , with a screw density ratio of 0.40.5 . the knee was mobilized on the 1 or 2 postoperative day , depending on the degree of postoperative pain . touchdown or partial weight - bearing was begun , depending on the fracture stability , and progressed to full weight bearing upon fracture union at 612 weeks . the patients were discharged only after 90 flexion of the knee was achieved , usually by the 4 or 5 postoperative day . the clinical and radiological evaluation was done by the junior author ( vk ) , who was not a part of the operating team . the patients were clinically examined at the time of discharge from hospital for any malrotation or limb length discrepancy . a limb malrotation 5 and a limb length discrepancy 5 mm were difficult to detecta repeat clinical examination was done at the final fracture healing to note any further change in limb length and rotation . ap and lateral radiographs of the femur with knee were taken immediately after surgery and were evaluated for fracture alignment , both in the coronal and sagittal planes . fracture alignment in the coronal plane was measured by the valgus angle between the anatomic axes of the femoral and tibial shafts . a 510 valgus angle was considered as normal as in the knee society score ( kss ) .17 the alignment in the sagittal plane was measured by noting the angulation between the anterior cortices of the proximal and distal fragments . the patients were followed up at every 6 weeks until bony union was achieved at both the articular and metaphyseal fracture sites , and the subsequent followup was done every 3 months for the 1 year , biannually in the 2 year , and annually thereafter . ap and lateral radiographs of the femur with knee were taken at each visit and evaluated for callus formation / progression and fracture union . in cases with simple articular and extra - articular fractures , managed by open compression plating , direct bone healing can be difficult to determine radiologically and was determined using clinical criteria such as painless weight - bearing and absence of pain / tenderness at the fracture site . any loss of reduction , plate lift - off , screw back - out or screw / plate breakage was recorded . any other complication such as superficial or deep infection was also recorded . at 1 year followup , a knee society knee score between 80 and 100 was regarded as excellent , between 70 and 79 was regarded as good , between 60 and 69 was regarded as fair , and 60 was regarded as poor .18 the 1 - year and subsequent radiographs were also evaluated for any change of secondary osteoarthritis , such as narrowing of joint space , development of osteophytes , and subchondral cysts or sclerosis , both in the tibiofemoral and patellofemoral compartments . statistical analysis was done using the spss 19.0 statistical software ( ibm spss , new york , usa ) . only descriptive analysis was done to calculate the mean and the standard deviation of the demographic and outcome variables . due to the limited number of patients in each ao subgroup ( there was only one patient in 33c3 .3 subgroup ) , no further subgroup analysis of the outcome parameters was done . the mechanism of injury was a high - energy trauma ( either road traffic accident or fall from height ) in ten patients . two of these patients had polytrauma and were transferred to us after the management of craniocerebral and chest trauma respectively . two patients with additional long bone fractures in the ipsilateral limb ( femoral neck in one and tibial fracture in one ) were excluded from the study . one other patient with a 33c3 .1 fracture was lost to followup after 12 weeks and was excluded from the study . the patient had attained a good range of motion ( rom ) of the knee , with no loss of reduction at followup . according to the ao classification , five fractures were type c3 .1 , six fractures were type c3 .2 , and one fracture was type c3 .3 [ table 1 ] . one patient had an associated avulsion of the anterior cruciate ligament , two patients had avulsion of the lateral collateral ligament , and one patient had avulsions of both the anterior cruciate and medial collateral ligaments . clinical details of the patients the patients were followed up for at least 1 year after the injury , with a mean followup of 17.6 months ( range 1225 months ) . all fractures united at a mean time of 14.3 weeks ( range 626 weeks ) .8 ) did not show any callus formation at the metaphyseal fracture site even after 12 weeks of surgery and was bone grafted secondarily . five of the patients had 90 flexion at 6 weeks followup , though all patients were discharged with 90 flexion after surgery .1 , 5 , and 7 ) returned at 1214 weeks with 90 flexion , with the fractures showing good union . their knees were manipulated under anesthesia , with audible adhesiolysis and restoration of full flexion ( 130 ) on table . two of the patients showed back out of one of the locking screws at 6 and 12 weeks followup , but their fractures were healing well and no screw exchange was needed . one patient developed a superficial infection , which settled with regular wound care and oral antibiotics . table 2 shows the immediate postoperative alignment of the operated leg in the coronal , sagittal and axial planes . the primary fixation in this case was in 510 varus and had to be accepted during the course of the fixation due to extensive medial comminution involving the epiphysis [ case no . the alignment was maintained at 6 weeks , but a further varus collapse to around 15 varus was noted at final fracture healing at 14 weeks . the alignment was maintained between the immediate postoperative and final assessments in all other patients . coronal , sagittal , and rotational alignment of the operated limbs immediately after surgery the outcome was rated as excellent in seven patients , good in three patients and fair in two patients according to the ksks [ table 3 ] at 1 year . three patients showed radiological changes of osteoarthritis , two in the tibiofemoral compartments [ table 3 , case no . 3 and 5 ] and one in the patellofemoral compartment [ table 3 , case no . only one of these patients experienced pain during routine day - to - day activities , while the other two were asymptomatic . one other patient [ table 3 , case no . 7 ] had asymptomatic osteoarthritis in the knee at the time of injury which showed no progression during followup . intraarticular fractures of the distal femur are challenging injuries . these require an extensive surgical approach to visualize and reduce the articular fragments , particularly in complex fractures . the insult to the periarticular soft tissues caused both by the initial trauma and subsequent surgical approach , causes difficulty in early postoperative rehabilitation predisposing to knee stiffness . hence , the outcome of intraarticular fractures of the distal femur remains unpredictable , and these are fraught with complications such as malunion , nonunion , stiffness , and secondary osteoarthritis . multiple surgical approaches have been described previously to obtain a good exposure of distal femoral articular surface , including medial parapatellar approach ,12 lateral parapatellar ( anterolateral ) approach ,7 tibial tubercle osteotomy ,514 and combined medial and lateral approaches .3 the latter two approaches are too extensive and frequently lead to complications , such as delayed wound healing , flap necrosis and delayed healing of osteotomy [ table 4 ] . the parapatellar approaches provide a sufficient articular exposure but involve splitting of the quadriceps mechanism , which may lead to scarring or adhesions . moreover , they are difficult to extend proximally , if open compression plating of the extra - articular fracture is planned . the proximal extension of a medial parapatellar approach , as described by henry ,19 involves cutting through the rectus tendon , which may not be desirable . results of c3 type fractures of distal femur fixed using different techniques starr et al. 13 described a modified anteriorapproach to the distal femur , which facilitated complete exposure of distal femur articular surface and quicker rehabilitation . we use an anterolateral skin incision for all distal femur fractures as a universalit can be limited to the standard lateral approach for simple fractures , extended distally as a swashbuckler approach in complex fractures , and extended proximally for open compression plating as in standard lateral approach . starr et al . , in their original report , had avoided the use of tourniquet , citing that it can prevent medial retraction of quadriceps muscle .13 however , with our modified technique , we did not face any difficulty in retraction of the quadriceps , even in cases in which a tourniquet was applied . the outcome of distal femur fractures has improved in recent times , with the use of biological and indirect reduction techniques and percutaneous osteosynthesis with bridge plates , usually locked ones . zlowodzki et al. 20 in a systematic review of different fixation techniques in the operative management of acute nonperiprosthetic distal femur fractures found that the use of locked plates is associated with a decreased relative risk of nonunions and infections as compared to compression plates . however , they found an increased relative risk of fixation failures and secondary surgical procedure with the use of locked plates .20 several other studies have expressed concerns that locking plates may cause callus inhibition , with reported nonunion rates up to 20 % in distal femur fractures .2122 furthermore , the precontoured locked plates may not conform to the bony contours in all patients and may lead to malalignment .23 bridge plating by tarpo technique requires a demanding surgical technique and extensive use of intraoperative imaging .7 in our experience , fractures of the distal femur ( both types a and c ) without extra - articular comminution ( a1 .2 , a1 .3 , and a2 .1 ) have a good outcome with open compression plating ( hybrid technique ) , which remains our procedure of choice for these , for reasons of technical ease , accurate pretraumatic alignment and more reliable healing . we reserve the use of bridge plating by tarpo technique for fractures with extra - articular comminution . we have analyzed the reported outcomes of complex c3 type fractures in previously published studies [ table 4 ] .123456 most of them reported a varying proportion of patients ( 7.7 % 16.7 % ) with poor results due to complications such as superficial infection , flap necrosis and stiffness . srbu et al. 6 in a study of c3 fractures fixed by a lateral locked plate using tarpo approach reported 100 % good to excellent results , though with a lower mean flexion of the knee ( 108 ) as compared to our series ( 120 ) . this may be explained by the different outcome scores employed in the two studies . as previously reported by other authors , patients knee function assessed by the kssis noted as less optimal as compared to the neer score .24 a standardized and validated outcome scoring system needs to be developed for distal femur fractures to allow comparability across studies . we attribute the good knee flexion obtained in our series to anatomical articular reduction , rigid fixation of articular fracture lines and early mobilization . concomitant addressal of ligament injuries , as was done in our series , is important for early rehabilitation as patients are apprehensive to move unstable joints . most previous studies1234 on c3 fractures of the distal femur have employed the use of primary bone grafting to enhance union . with the advent of minimally invasive reduction techniques and bridge plating , we used the tarpo technique for comminuted extra - articular fractures and did not employ primary bone grafting in our series . only one patient required secondary bone grafting at 3 months , which was due to technical reasons ( slight gap left at fracture site ) . in our experience , a single lateral locked plate gives sufficient stability for most distal femur fractures , even with extensive comminution . before the advent of locking plates , there was a propensity for varus collapse with a single lateral plate in comminuted fractures , and double plating with bone grafting was recommended .12 however , a single locked lateral plate gives sufficient axial and torsional rigidity ,25 even in cases with medial comminution , and the use of dual plates is no longer required . the strength of our study is the inclusion of only the most complex fractures of the distal femur ( ao type c3 ) . the study was a prospective one , with all cases operated by a single surgeon , using a single surgical approach , and the same type of implant , eliminating any confounding of results due to variation in surgical technique , reduction skills , or implant properties . since we have only included the complex c3 type distal femur fractures , the total number of patients was limited in our study , similar to other such studies .123456 another limitation in our study is the short followup period . the true incidence of posttraumatic osteoarthritis can be estimated only by a long term study though early trends are reflected in our study . our study shows a good to excellent functional outcome of complex c3 type distal femur fractures , fixed with a single lateral locked plate , using a modified swashbuckler approach .\noutput:\n" }, { "from": "agent", "value": "background : complex ao type c3 fractures of the distal femur are challenging injuries , fraught with complications such as malunion and stiffness . we prospectively evaluated a consecutive series of patients with complex ao type c3 distal femur fractures to determine the clinicoradiological outcome after fixation with a single locked plate using modified swashbuckler approach.materials and methods : 12 patients with c3 type distal femur fractures treated with a lateral locked plate , using a modified swashbuckler approach , were included in the study . the extraarticular component was managed either by compression plating or bridge plating ( transarticular approach and retrograde plate osteosynthesis ) depending on the fracture pattern . primary bone grafting was not done in any case . the clinical outcome at 1 year was determined using the knee society score ( kss ) . the presence of any secondary osteoarthritis in the knee joint was noted at final followup.results : all fractures united at a mean of 14.3 4.7 weeks ( range 626 weeks ) . there were no significant complications such as nonunion , deep infection , and implant failure . one of the patients underwent secondary bone grafting at 3 months . the mean range of motion of the knee was 120 14.8 ( range 105150 ) . seven patients had excellent , three patients had good and two patients had a fair outcome according to the kss at 1 year . at a mean followup of 17.6 months , three patients showed radiological evidence of secondary osteoarthritis of the knee joint . however , only one of these patients was symptomatic.conclusion : the results of complex c3 type distal femur fractures , fixed with a single lateral locked plate using a modified swashbuckler approach , are encouraging , with a majority of patients achieving good to excellent outcome at 1 year ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: cardiac troponin i ( ctni ) and its binding partner cardiac troponin t ( ctnt ) are the biomarkers of choice for the diagnosis of myocardial damage . upon myocardial injury , ctni is degraded by calcium - sensitive proteases such as calpain i and ctni fragments are released in the blood where they can be detected via the sensitive assays that are used in practice worldwide . inhibitor within the trimeric troponin complex , which together with cardiac troponin c ( ctnc , where calcium binds ) and ctnt , controls the position of tropomyosin on the thin actin filament in response to ca ( fig . 1 ) . in diastole ( low intracellular [ ca ] ) , ctni binds actin at multiple sites maintaining tropomyosin at the outer domain of actin , and thereby blocks myosin - binding sites on the thin filament and prevents force development . in systole ( high intracellular [ ca ] ) , this results in the release of ctni from actin and a shift of tropomyosin closer into the grove of the actin filament , thereby enabling actin - myosin interactions and cardiomyocyte force development . fig . . a schematic drawing of the thick and thin filaments , depicting exchange of endogenous troponin complex by exogenous troponin complex . the thick filament consists of myosin and myosin heads ( dark grey ) and the thin filament consists of actin monomers ( light grey ) spanned by tropomyosin ( black ) and the troponin complex : ctnc ( yellow ) , ctni ( blue ) and ctnt ( green ) . in this drawing , exogenous ctni is bisphosphorylated ( orange squares ) , for example at ser23 / 24 . the endogenous unphosphorylated troponin complex is exchanged by exogenous phosphorylated troponin complex ( arrows ) . to this endmembrane - permeabilised cardiomyocytes were immersed with an exchange solution containing a high concentration of recombinant troponin complex . the lower image shows a single human cardiomyocyte in relaxing solution attached between a force transducer and a piezoelectric motor [ this lower image has been published before : 18 ] schematic drawing of the thick and thin filaments exchanged with troponin complex . a schematic drawing of the thick and thin filaments , depicting exchange of endogenous troponin complex by exogenous troponin complex . the thick filament consists of myosin and myosin heads ( dark grey ) and the thin filament consists of actin monomers ( light grey ) spanned by tropomyosin ( black ) and the troponin complex : ctnc ( yellow ) , ctni ( blue ) and ctnt ( green ) . in this drawing , exogenous ctni is bisphosphorylated ( orange squares ) , for example at ser23 / 24 . the endogenous unphosphorylated troponin complex is exchanged by exogenous phosphorylated troponin complex ( arrows ) . to this endmembrane - permeabilised cardiomyocytes were immersed with an exchange solution containing a high concentration of recombinant troponin complex . the lower image shows a single human cardiomyocyte in relaxing solution attached between a force transducer and a piezoelectric motor [ this lower image has been published before : 18 ] because of its central role in the regulation of contraction and relaxation of the heart , ctni may also be a potential target for treatment of heart failure . alterations are known to occur in the phosphorylation status of ctni during acute cardiac events and in patients with heart failure . studies in rodent models of cardiac disease and human heart samples showed altered phosphorylation at various sites on ctni ( i.e. site - specific phosphorylation ) . this is caused by altered expression and / or activity of kinases and phosphatases during the development of heart failure . it is not known whether these ( transient ) alterations in ctni phosphorylation are beneficial or detrimental . knowledge of the effects of site - specific ctni phosphorylation on cardiomyocyte contractility is therefore of utmost importance for the development of new therapeutic strategies . in this reviewwe focus on the role of ctni phosphorylation in the healthy and diseased heart upon activation of the beta - adrenergic receptor pathway ( as occurs during increased stress and exercise ) and as a modulator of the frank - starling mechanism , which reflects the ability of the heart to increase stroke volume with an increase in ventricular filling ( end - diastolic volume ) . moreover , we provide an overview of recent studies which aimed to reveal the functional consequences of changes in ctni phosphorylation in cardiac disease . interactions within the troponin complex are regulated by kinases and phosphatases which , respectively , phosphorylate and dephosphorylate ctni at multiple phosphorylation sites and play a central role in tuning cardiomyocyte performance . during stress and exercise , sympathetic activation of theheart increases heart rate and stroke volume to meet the increased demands of the body . this is mediated via stimulation of 1 - adrenergic receptors , which leads to activation of a downstream kinase , protein kinase a ( pka ) . pka enhances cardiomyocyte contractility and relaxation by phosphorylation of proteins involved in ca handling and of myofilament proteins such as ctni , cardiac myosin - binding protein - c ( cmybp - c ) , and titin ( for reviews , see ) . pka - mediated phosphorylation of ca - handling proteins ( l - type ca channels , phospholamban and ryanodine receptor ) regulates intracellular ca fluxes , thereby controlling the amount of ca bound to ctnc . in addition to activated ( phosphorylated ) ca - handling proteins , pka - mediated ctni phosphorylation at serines 23 and 24 ( ser23 / 24 , human sequence ) represents a central mechanism controlling cardiomyocyte force development and relaxation , independent of the intracellular ca concentration . pka - mediated phosphorylation at ctni - ser23 / 24 reduces myofilament ca sensitivity and increases the speed of relaxation of the heart which is needed to maintain cardiac performance at increased heart rates . although ser23 / 24 are the so - called pka sites , multiple other kinases , pkc , pkd and pkg , are known to phosphorylate ctni at ser23 / 24 . the level of phosphorylation of these two serines will be determined by the balance between the kinase activity and phosphatase activity at the myofilaments , since ser23 / 24 are dephosphorylated by protein phosphatases ( pp ) pp1 and pp2a . in the end - stage failing heart , pka activity is reduced due to alterations in the - adrenergic signalling pathway . this results in decreased ctni - ser23 / 24 phosphorylation and increased myofilament ca sensitivity in patients with ischaemic and dilated heart failure compared with non - failing donors . although ctni - ser23 / 24 bisphosphorylation has been studied extensively , effects of site - specific phosphorylation of only ser23 or ser24 on cardiomyocyte contractility in the human heart were unknown . knowledge of functional consequences of monophosphorylated ctni is important , since recent studies in human post - mortem control hearts and fresh donor transplant hearts with normal cardiac function revealed that approximately 40 % of ctni is monophosphorylated . moreover , differences in the level of monophosphorylated ctni have been reported between donor and end - stage failing hearts . pka treatment of skinned porcine cardiac muscle preparations suggested that bisphosphorylation of ctni is required for the reduction in myofilament ca sensitivity . we recently studied the consequences of site - specific phosphorylation at ser23 or ser24 in human cardiomyocytes by exchange of endogenous ctn with site - specific phosphorylated ctni ( fig . 1 ) . this sophisticated protein engineering technique enabled us to study the effects of one specific ctni phosphorylation site . for this purpose , phosphorylation sites ( ser23 / 24 ) in human recombinant ctni were mutated to aspartic acid ( d ) to mimic phosphorylation or alanine ( a ) , which resembles the non - phosphorylatable state . various phosphorylated ctn complexes were introduced into human cardiomyocytes by protein exchange ( fig . 1 ) . using this method , we demonstrated that phosphorylation of both ser23 and ser24 of ctni is required to reduce ca sensitivity in human cardiomyocytes , as no change in ca sensitivity was observed upon exchange with ctn complexes containing monophosphorylated ctni . additionally , we demonstrated that the maximal reduction in myofilament ca sensitivity was reached at ~ 55 % bisphosphorylated ctni . defective - adrenergic signalling in heart failure may result in a higher myofilament ca sensitivity when ctni phosphorylation levels upon - adrenergic stimulation remain below ~ 55 % ctni bisphosphorylation . this may lead to an impaired diastolic function of the heart due to increased force development at low ca concentrations . comparison of cardiac samples from heart failure patients with different disease severity ( ranging from nyha class i to iv ) showed increased ca sensitivity only in the end - stage ( nyha class iv ) of cardiac disease , which suggested that detrimental effects of reduced ctni phosphorylation may only become evident at the end - stage of heart failure . however , a recent study in patients with obstructive hypertrophic cardiomyopathy ( hcm ) and normal systolic , but impaired diastolic function ( nyha class iii ) showed increased myofilament ca sensitivity and lower ctni phosphorylation in hcm compared with non - failing myocardium . in addition , a recent study showed that the level of ctni bisphosphorylation in post - mortem hearts with mild hypertrophy was significantly lower ( 4.1 % ) compared with control levels ( 18.4 % ) . collectively , these studies indicate that ctni bisphosphorylation and the associated impact on myofilament ca sensitivity depends on the stage of heart failure ( nyha class ) as well as on aetiology . frank - starling s law reflects the ability of the heart to increase stroke volume with an increase in ventricular filling ( end - diastolic volume ) , a property based on length - dependent activation ( lda ) of the myofilaments . an increase in sarcomere length within the working range of the heartenhances the maximal force generating capacity and the sensitivity of the myofilaments to ca ( fig .2 a ) ; i.e. for the same calcium concentration more force is generated by the sarcomeres . length - dependent myofilament activation thus represents an important cellular mechanism to adjust cardiac performance in response to increased preload of the heart . the role of ctni as a regulator of lda of the myofilaments was demonstrated more than a decade ago via replacement of endogenous ctni by slow skeletal troponin i ( sstni ) in cardiac muscle . this significantly blunted the increase in myofilament ca sensitivity upon an increase in sarcomere length . furthermore , ctni phosphorylation by pka was demonstrated to enhance length - dependent changes in the force - ca relation , since pka only enhanced lda in non - transgenic mice , and not in a transgenic murine model where ctni was replaced by sstni which misses the n - terminal region where the pka sites ser23 / 24 are located . recently , we demonstrated that pka treatment enhanced the length - dependent increase in myofilament ca sensitivity in human cardiomyocytes with low levels of phosphorylated ctni ( fig . in addition , we showed that phosphorylation at both ser23 and ser24 is needed to enhance the length - dependent increase in myofilament ca sensitivity . our data indicate that pka - mediated ctni - ser23 / 24 phosphorylation is an important mediator of length - dependent activation in human cardiac muscle tissue.fig .2 schematic representation of changes in length - dependent ca - sensitivity upon phosphorylation of ser42 / 44 , thr143 and / or ser23 / 24 . a an example of myofilament force development at short ( 1.8 m ) and long ( 2.2 m ) sarcomere length at various [ ca ] in human membrane - permeabilised cardiomyocytes . cardiomyocyte lengthening from 1.8 m to 2.2 m increases myofilament ca sensitivity ( white arrow ) . the ca sensitivity derived from the midpoint of the forceca relationship ( ec50 ) is demonstrated for both sarcomere lengths by a vertical line , and the difference represents the delta ec50 . an increase in left ventricular filling increases myofilament ca sensitivity and underlies , together with an increase in maximal force - generating capacity ( black arrow ) , increased cardiac output during the subsequent systolic phase . b data obtained in troponin - exchanged donor cells without and with treatment with exogenous pka were combined to illustrate the range at which myofilament ca sensitivity ( ec50 ) may vary in response to phosphorylation at ser23 / 24 and the pkc sites ser42 / 44 and thr143 . abbreviations : wild - type ( wt ) ; phosphorylated 42/44 ( 42d / 44d ) ; phosphorylated 143 ( 143d ) . boxes represent the range of ca sensitivity measured at a sarcomere length of 1.8 ( lower line ) and 2.2 m ( upper line ) . this figure demonstrates that the sarcomere length - dependent shift in ca sensitivity is relatively small in wt , 42d / 44d and 143d without pka ( i.e. low ctni - ser23 / 24 phosphorylation ) . pka treatment of wt and 143d increased the range in ca sensitivity at which the sarcomere is operating upon changes in sarcomere length between 1.8 and 2.2 m . however , pka treatment of 42d / 44d does not enhance the length - dependent increase in ca - sensitivity schematic representation of changes in length - dependent ca - sensitivity upon phosphorylation of ser42 / 44 , thr143 and / or ser23 / 24 . a an example of myofilament force development at short ( 1.8 m ) and long ( 2.2 m ) sarcomere length at various [ ca ] in human membrane - permeabilised cardiomyocytes . cardiomyocyte lengthening from 1.8 m to 2.2 m increases myofilament ca sensitivity ( white arrow ) . the ca sensitivity derived from the midpoint of the force ca relationship ( ec50 ) is demonstrated for both sarcomere lengths by a vertical line , and the difference represents the delta ec50 . an increase in left ventricular filling increases myofilament ca sensitivity and underlies , together with an increase in maximal force - generating capacity ( black arrow ) , increased cardiac output during the subsequent systolic phase . b data obtained in troponin - exchanged donor cells without and with treatment with exogenous pka were combined to illustrate the range at which myofilament ca sensitivity ( ec50 ) may vary in response to phosphorylation at ser23 / 24 and the pkc sites ser42 / 44 and thr143 . abbreviations : wild - type ( wt ) ; phosphorylated 42/44 ( 42d / 44d ) ; phosphorylated 143 ( 143d ) . boxes represent the range of ca sensitivity measured at a sarcomere length of 1.8 ( lower line ) and 2.2 m ( upper line ) . this figure demonstrates that the sarcomere length - dependent shift in ca sensitivity is relatively small in wt , 42d / 44d and 143d without pka ( i.e. low ctni - ser23 / 24 phosphorylation ) . pka treatment of wt and 143d increased the range in ca sensitivity at which the sarcomere is operating upon changes in sarcomere length between 1.8 and 2.2 m . however , pka treatment of 42d / 44d does not enhance the length - dependent increase in ca - sensitivity as mentioned above , reduced ctni - ser23 / 24 phosphorylation levels have been reported in end - stage heart failure relative to explanted donor tissue . since ctni - ser23 / 24 phosphorylation enhances the length - dependent increase in myofilament ca sensitivity , reduced phosphorylation levels may reduce lda in heart failure . this may explain why a reduced length - dependent increase in ca sensitivity was found in skinned fibres from terminally failing human myocardium . in our study replacement of endogenous ctn with exogenous bisphosphorylatedctni - ser23 / 24 enhanced the length - dependent increase in myofilament ca sensitivity in human failing cardiomyocytes . this suggests that the blunted length - dependent myofilament activation in end - stage heart failure may be at least partly caused by low bisphosphorylation at ctni - ser23 / 24 . while pka activity and phosphorylation of ctni - ser23 / 24 are reduced in heart failure , it has been demonstrated that protein kinase c ( pkc ) isoform expression ( , 1 , 2 ) and activity are increased in heart failure . higher ctni phosphorylation has been reported at several pkc sites in failing human myocardium . an increase has been found in ctni phosphorylation at the well - known pkc sites ser42 / 44 and thr143 in end - stage failing compared with donor myocardium . although pkc - mediated phosphorylation at ser42 / 44 and thr143 and its effects on muscle contractility have been studied in vitro and in rodent models , effects in humans were unknown . therefore , we recently studied the effects of site - specific phosphorylation at ser42 / 44 and thr143 in human cardiomyocytes . the reduction in maximal force generating capacity mediated by pkc might underlie the reduced cardiac performance observed in heart failure . however , treatment of human cardiomyocytes with the catalytic domain of pkc and different pkc isoforms ( pkc , pkc ) did not affect maximal force in non - failing donor and failing hearts . our recent study in human cardiomyocytes demonstrated that replacement of endogenous ctn with exogenous bisphosphorylated ctni - ser42 / 44 induces a relatively large decrease in myofilament ca sensitivity ( fig .3 ) without affecting maximal force development . interestingly , ser42 / 44 pseudo - phosphorylation largely blunted the pka - mediated increase in length dependence of myofilament ca sensitivity ( fig . since the drop in ca sensitivity at physiological ca levels was relatively large compared with phosphorylation of ser23 / 24 , pkc - mediated ctni - ser42 / 44 phosphorylation may result in a reduced force development in vivo , since the maximal intracellular ca concentration is ~ 3.98 m . fig . an example of myofilament force development at 2.2 m sarcomere length at various [ ca ] in human membrane - permeabilised cardiomyocytes in which endogenous troponin complex is exchanged with exogenous recombinant troponin complexes . compared with unphosphorylated wild - type ctni ( wt ) , ca sensitivity ( ec50 ) increases after exchange with phosphorylated ctni at thr143 ( 143d ) ( arrow to the left ) . this may result in higher cardiomyocyte force development during systole ( light grey : high intracellular ca concentrations ) and may result in increased cardiac output during the systolic phase , while the enhanced ca sensitivity may impair relaxation of the heart muscle during diastole ( dark grey : low intracellular ca concentrations ) . phosphorylation at ser23 / 24 ( 23d / 24d ) or at ser42 / 44 ( 42d / 44d ) decreases myofilament ca sensitivity compared with wt ( arrow to the right ) . this may contribute to enhanced muscle relaxation , which is required for proper filling of the heart during diastole , however , may result in a decrease in cardiac output during the systolic phase myofilament responses to phosphorylation of ctni at ser23 / 24 , ser42 / 44 and thr143 . an example of myofilament force development at 2.2 m sarcomere length at various [ ca ] in human membrane - permeabilised cardiomyocytes in which endogenous troponin complex is exchanged with exogenous recombinant troponin complexes . compared with unphosphorylated wild - type ctni ( wt ) , ca sensitivity ( ec50 ) increases after exchange with phosphorylated ctni at thr143 ( 143d ) ( arrow to the left ) . this may result in higher cardiomyocyte force development during systole ( light grey : high intracellular ca concentrations ) and may result in increased cardiac output during the systolic phase , while the enhanced ca sensitivity may impair relaxation of the heart muscle during diastole ( dark grey : low intracellular ca concentrations ) . phosphorylation at ser23 / 24 ( 23d / 24d ) or at ser42 / 44 ( 42d / 44d ) decreases myofilament ca sensitivity compared with wt ( arrow to the right ) . this may contribute to enhanced muscle relaxation , which is required for proper filling of the heart during diastole , however , may result in a decrease in cardiac output during the systolic phase phosphorylation of ctni - thr143 has been reported to increase myofilament ca sensitivity of contraction in rodents . in line with this finding , we found an increase in myofilament ca sensitivity in human cardiomyocytes exchanged with pseudo - phosphorylated ctni - thr143 ( fig . in addition , we studied whether phosphorylation of thr143 affects lda , since it has been demonstrated that the threonine residue 143 of the inhibitory region of ctni is essential for length - dependent alterations in myofilament ca sensitivity . although thr143 is essential for lda in rodents , exchange with phosphorylated ctni - thr143 did not alter lda ( in the absence or presence of pka ) in human cardiomyocytes ( fig . ctni phosphorylation thus affects cardiac performance and its impact differs between the failing and healthy heart . potentially ctni - ser23 / 24 phosphorylation may be a target for correcting high myofilament ca sensitivity and blunted length - dependent activation in heart failure . increased myofilament ca sensitivity may lead to an impaired diastolic function of the heart due to increased force development at low ca concentrations ( fig . also , a blunted length - dependent increase in ca sensitivity in end - stage heart failure has been found , which was restored to control levels after exchange with exogenous phosphorylated ser23 / 24 . length - dependent activation is the cellular basis of the frank - starling mechanism , which may be depressed in heart failure . therefore , increasing ctni - ser23 / 24 phosphorylation in failing cardiomyocytes may be beneficial for cardiac function . this is supported by our work in human hcm samples where we showed that restoring phosphorylation at the pka targets in vitro normalised myofilament function in sarcomere mutation - negative hcm and in hcm with truncating mybpc3 mutations . the effect of pkc - mediated phosphorylation of ctni in human depends on which sites are phosphorylated . phosphorylation of the pkc site thr143 did not affect lda properties of human heart muscle ( fig .2 b ) , but did increase ca sensitivity as illustrated in figs . 2 and 3 ( wt versus 143d , wt + pka versus 143d + pka ) . the high myofilament ca sensitivity may aid to maintain cardiac output of the failing heart , however , it may also contribute to diastolic dysfunction ( fig . ctni phosphorylation at ser42 / 44 reduces ca sensitivity of the myofilaments and blunts the enhanced length - dependent increase in ca sensitivity mediated by pka ( fig . while the low force development at physiological ca concentrations may reduce cardiac pump function ( fig . the decrease in force development coincides with a decrease in atp utilisation by the myofilaments , which may benefit the energy status of the failing heart . moreover , the decrease in myofilament ca sensitivity may also improve diastolic function , as was suggested previously ( fig . studying ctni phosphorylation in different disease phenotypes and at different disease stages will help us to gain a better understanding of the role of pkc - mediated ctni phosphorylation in cardiac disease . additionally , with this increasing knowledge about ctni phosphorylation in cardiac disease , ctni phosphorylation patterns at the different pka - and pkc - phosphorylation sites may become promising biomarkers since ctni phosphorylation status can be determined from blood samples after acute cardiac insult .\noutput:\n" }, { "from": "agent", "value": "cardiac troponin i ( ctni ) is well known as a biomarker for the diagnosis of myocardial damage . however , because of its central role in the regulation of contraction and relaxation in heart muscle , ctni may also be a potential target for the treatment of heart failure . studies in rodent models of cardiac disease and human heart samples showed altered phosphorylation at various sites on ctni ( i.e. site - specific phosphorylation ) . this is caused by altered expression and / or activity of kinases and phosphatases during heart failure development . it is not known whether these ( transient ) alterations in ctni phosphorylation are beneficial or detrimental . knowledge of the effects of site - specific ctni phosphorylation on cardiomyocyte contractility is therefore of utmost importance for the development of new therapeutic strategies in patients with heart failure . in this review we focus on the role of ctni phosphorylation in the healthy heart upon activation of the beta - adrenergic receptor pathway ( as occurs during increased stress and exercise ) and as a modulator of the frank - starling mechanism . moreover , we provide an overview of recent studies which aimed to reveal the functional consequences of changes in ctni phosphorylation in cardiac disease ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: this study is part of the school achievement study conducted by the university of agder and srlandet resource centre . in 2010 , 625 ninth - and tenth - grade students , from four different secondary schools in three different municipalities in vest - agder county , were invited to participate by filling in a questionnaire . of these , 482 students returned the questionnaires giving a participation rate of 77 % , and 475 students were included in the statistical analysis236 boys and 239 girls . the best suited participant schools in the county , representing both urban and rural municipalities , were selected by srlandet resource centre . all four schools that were contacted agreed to participate two schools from the main city ( kristiansand ) in the county and one secondary school each from the two rural municipalities were included . the students filled in the questionnaire during a school lesson in the presence of a master student and a project worker . beforethe questionnaires were handed out , the participants were informed that their responses would be treated as anonymous and that it was voluntary to participate . the students were given both oral and written instructions on how to fill in the questionnaire . the project worker helped the students with any questions . after filling out the questionnaire , the students returned it to the project worker in a sealed envelope . the questionnaire included questions about how students behave in school and their dietary intake and meal frequencies . to measure the students behavioral problem at school , we adopted items from roland ( 11 ) and developed a four - item , self - reported questionnaire . the four items were , do you make so much noise in class that the teachers yell at you ? , are you expelled from class because you make too much noise ? , does your teacher write down your name because of bad behavior ? , and do you disturb the class to such an extent that other students in your class ca n't pay attention ? all questions had five response categories , a sum score of these questions was made ( range : 420 ) with a high number indicating more problems . this sum score was dichotomized into those not having ( score : 411 ) and those having behavioral problems at school ( score : 1220 ) . in this study , the cronbach 's for the scale behavioral problems at school was 0.85 , indicating high reliability . diet was assessed by a food frequency questionnaire comprising 23 components , both food items and drinks . the questions had eight different response alternatives , ranging from never or seldom to four times or more per day for food items and seven glasses or more per day for beverages . the questionnaire had been validated in a national dietary study among norwegian children and adolescents ( 12 ) . having fruits and vegetables ( f & v ) twice a day or more often was categorized as often . having fish one three times per week or more was categorized as often . having candies , chocolate , and savory snacks four six times per week or more often was categorized as often . unhealthy food items included sugar - sweetened soft drinks , sweets , chocolate , savory snacks , pizza , and burger or hot dogs . meal frequency was assessed by questions like , how often do you have breakfast each week ? the same was asked for lunch , dinner , and evening meals . response alternatives ranged from never or seldom to seven days a week , and in the statistical analysis these were dichotomized into having meals five times a week or less and having meals six times a week or more , as done by verby et al . self - reported weight and height were used to calculate bmi ( kg / m ) . to estimate the prevalence of overweight , the international cutoff points for bmi for overweight were used ( 14 ) . in table 1 , the results are presented with means and standard deviations ( sd ) and percentage of participants . multiple logistic regressions were used to explore the relation between behavioral problems at school and meal patterns and unhealthy and healthy food items . the dependent variable was whether the respondent had behavioral problems at school and was dichotomized into having these or not . all meals ( breakfast , lunch , dinner , and evening meals ) and healthy and unhealthy food items were run in separate models adjusting for gender and bmi . all p - values are two - sided and a 5 % level of significance was used . description of participants proportion having behavioral problems at school , having meals regularlya and having healthy and unhealthy food items oftenb ( n [ % ] ) . having meals regularly was defined as having meals six times a week or more . having healthy foods often was defined as having f & v twice a day or more often , and having fish one three times per week or more . having unhealthy foods often was defined as having food four six times a week or more often . independent two - sample t - test continuous variables and chi - square for categorical variables . this study is part of the school achievement study conducted by the university of agder and srlandet resource centre . in 2010 , 625 ninth - and tenth - grade students , from four different secondary schools in three different municipalities in vest - agder county , were invited to participate by filling in a questionnaire . of these , 482 students returned the questionnaires giving a participation rate of 77 % , and 475 students were included in the statistical analysis236 boys and 239 girls . this study was conducted in january 2010 . the best suited participant schools in the county , representing both urban and rural municipalities , all four schools that were contacted agreed to participate two schools from the main city ( kristiansand ) in the county and one secondary school each from the two rural municipalities were included . the students filled in the questionnaire during a school lesson in the presence of a master student and a project worker . beforethe questionnaires were handed out , the participants were informed that their responses would be treated as anonymous and that it was voluntary to participate . the students were given both oral and written instructions on how to fill in the questionnaire . the questionnaire included questions about how students behave in school and their dietary intake and meal frequencies . to measure the students behavioral problem at school , we adopted items from roland ( 11 ) and developed a four - item , self - reported questionnaire . the four items were , do you make so much noise in class that the teachers yell at you ? , are you expelled from class because you make too much noise ? , does your teacher write down your name because of bad behavior ? , and do you disturb the class to such an extent that other students in your class ca n't pay attention ? all questions had five response categories , a sum score of these questions was made ( range : 420 ) with a high number indicating more problems . this sum score was dichotomized into those not having ( score : 411 ) and those having behavioral problems at school ( score : 1220 ) . in this study , the cronbach 's for the scale behavioral problems at school was 0.85 , indicating high reliability . diet was assessed by a food frequency questionnaire comprising 23 components , both food items and drinks . the questions had eight different response alternatives , ranging from never or seldom to four times or more per day for food items and seven glasses or more per day for beverages . the questionnaire had been validated in a national dietary study among norwegian children and adolescents ( 12 ) . having fruits and vegetables ( f & v ) twice a day or more often was categorized as often . having fish one three times per week or more was categorized as often . having candies , chocolate , and savory snacks four six times per week or more often was categorized as often . unhealthy food items included sugar - sweetened soft drinks , sweets , chocolate , savory snacks , pizza , and burger or hot dogs . meal frequency was assessed by questions like , how often do you have breakfast each week ? the same was asked for lunch , dinner , and evening meals . response alternatives ranged from never or seldom to seven days a week , and in the statistical analysis these were dichotomized into having meals five times a week or less and having meals six times a week or more , as done by verby et al . self - reported weight and height were used to calculate bmi ( kg / m ) . to estimate the prevalence of overweight , in table 1 , the results are presented with means and standard deviations ( sd ) and percentage of participants . multiple logistic regressions were used to explore the relation between behavioral problems at school and meal patterns and unhealthy and healthy food items . the dependent variable was whether the respondent had behavioral problems at school and was dichotomized into having these or not . all meals ( breakfast , lunch , dinner , and evening meals ) and healthy and unhealthy food items were run in separate models adjusting for gender and bmi . all p - values are two - sided and a 5 % level of significance was used . description of participants proportion having behavioral problems at school , having meals regularlya and having healthy and unhealthy food items oftenb ( n [ % ] ) . having meals regularly was defined as having meals six times a week or more . having healthy foods often was defined as having f & v twice a day or more often , and having fish one three times per week or more . having unhealthy foods often was defined as having food four six times a week or more often . independent two - sample t - test continuous variables and chi - square for categorical variables . overweight is defined by cole et al . more girls skip breakfast and evening meals compared to boys ( 77 % vs. 66 % , p = 0.01 ) . high intake of unhealthy foods was defined as having food four six times per week or more , whereas a high intake of f & v was defined as having food items twice a day or more often . more boys reported a high intake of vegetables ( 8 % vs. 4 % , p 0.05 ) and a low intake of fruits ( 84 % vs. 71 % , p 0.01 ) compared to girls . more boys than girls have a high intake of food items categorized as unhealthy , such as sugar - sweetened soft drinks , sweets , and savory snacks ( table 1 ) . table 2 presents adjusted results for meal frequencies association with behavioral problems at school . having breakfast regularly was significantly associated with decreased odds of behavioral problems at school ( or : 0.29 ( 0.150.55 ) , p0 .01 ) . having lunch , dinner , and eveningmeals regularly was not significantly associated with decreased odds of behavioral problems at school ( table 2 ) . adjusted results for healthy food items association with behavioral problemsthose who reported eating fruits ( or : 0.30 ( 0.100.87 ) , p = 0.027 ) and fish ( or : 0.47 ( 0.240.91 ) , p = 0.025 ) regularly had lower odds of behavioral problems at school . however , a high intake of unhealthy foods ( sugar - sweetened soft drinks , sweets , chocolate , savory snacks , pizza , and hotdogs ) was significantly associated with increased odds of behavioral problems at school ( table 4 ) . adjusted odds ratio ( or ) and 95 % ci for behavioral problems at school in relation to meal patterna having meals seldom is defined as having meals five times a week or less . having meals often is defined as having meals six times a week or more often . adjusted odds ratio ( or ) and 95 % ci for behavioral problems at school in relation to intake of healthy food itemsa adjusted for sex and bmi . adjusted odds ratio ( or ) and 95 % ci for behavioral problems at school in relation to intake of unhealthy food itemsa adjusted for sex and bmithis study shows that adolescents who frequently have breakfast and a moderate intake of fruit and fish have reduced odds of behavioral problems at school . further , the study shows that adolescents who have a high intake of unhealthy food items have increased odds of behavioral problems at school . to our knowledge , these relations have not been shown earlier in this age group of norwegian adolescents . few studies explore the relation between behavior problems and meal frequency or skipping of breakfast ( 9 ) . some studies state that having breakfast regularly has a positive impact on mental health ( 8 , 15 ) . the most accepted explanation for this relation is the benefits of energy intake after a night time fast . another benefit of having breakfast is the intake of essential micronutrients , which have a positive effect on likely health concerns , such as affective disorders , hyperactivity , and behavioral problems ( 1 , 4 , 17 ) . lien found that norwegian adolescents having breakfast regularly had reduced mental distress ( 9 ) . one explanation for this finding can be that having breakfast reduces cortisol levels ( at least in adults ) ( 18 ) . the finding that having breakfast reduces mental distress complements our finding of reduced odds for behavioral problems when having breakfast regularly . in addition to reducing mental distress , breakfast is associated with a range of positive outcomes , including better school attendance , academic performance , nutrient intake , and healthier body weight ( 19 , 20 ) . so , although causality can not be stated on the relation between breakfast and behavioral problems in the current study , promoting breakfast would be beneficial . a recent australian study found that children with behavior difficulties and low levels of prosocial behaviors and from poorly functioning households consumed fewer servings of f & v than children who did not experience any environmental stressors or behavioral problems ( 21 ) . this is in line with our findings regarding fruit intake , which is related to behavioral problems at school . however , we did not find an association between intake of vegetables and behavioral difficulties . this might be explained by the low intake of vegetables in norwegian children and adolescents in general ( 10 ) , leading to small differences in intake between groups . intake of fish and behavior problems has mostly been discussed in relation to omega -3-fatty acids . early studies by stevens et al . found that a greater number of behavior problems were reported in subjects with lower total omega -3-fatty acid concentrations ( 22 ) . a placebo - controlled trial with 166 schoolchildren in japan investigating whether fish oil supplements affected school children 's aggression levels found that there was a possibility that changes in fatty acid intake might affect physical aggression , especially in girls ( 23 ) . furthermore , a review on fish oils and aggression concludes that 11 of 14 studies found an association between fish oils and aggression ( 24 ) . the mechanisms as to how fish oils affect aggression or hostility is not yet clear ; however , a possible mechanism is activation of the serotonergic neuron system ( 24 ) . on exploring diet and attention deficit or hyperactivity disorder ( adhd ) , an australian study did not find any association between fatty acids and adhd symptoms but found that children with adhd consumed half the amount of fish or seafood compared to the controls ( 25 ) . this is in line with what is reported in this study in relation to fish consumption and behavioral problems . most controversy regarding diet and behavioral problems ( especially adhd ) has been found in relation to sugar and junk food ( 4 , 26 ) . for many years , teachers and parents have claimed that high sugar intake leads to attention and conduct problems in children ( 27 ) . in 2009 , junk food in early childhood were more likely to be in the top 33 % on the hyperactivity subscale at age 7 ( 2 ) ; however , this was not replicated in 2011 ( 28 ) . a norwegian study by lien et al . among adolescents agedfurthermore , intake of soft drinks was associated with higher odds of mental distress and conduct problems ( 27 ) . is one of the few studies assessing the relation between sugar intake and mental health problems ( 27 ) , not just focusing on adhd . the effect of sugar on mental health may not be direct but could be moderated by other nutritional factors , such as micronutrients ( 1 ) . a study in norwegian adolescents found that high intake of added sugar displaced intake of micronutrients ( 5 ) . with the cross - sectional design of this study , one can not state any causality , and well - designed longitudinal studies are needed . an australian longitudinal study from 2011 found that a healthy diet yielded better mental health , and that an unhealthy diet led to poor mental health ( 29 ) , supporting the results of this study . other longitudinal studies focusing more specifically on behavioral problems , including assessment of the whole diet , where one can calculate energy and micronutrient intake , are needed . there are several other limitations that need to be considered when interpreting the results of this study . first , the selection of schools was not done systematically , it was a convenient sample implicating that the generalization of the results may be limited . second , although validated , the dietary frequency questionnaires often report an overestimation of food intake . however , a validation study among 9 - and 13 - year olds showed that the food frequency questionnaire ( ffq ) was able to identify high and low consumers of food intake and had a moderate capability to rank individuals according to food intake ( 12 ) . finally , there was no assessment of socioeconomic status , physical activity , sleep , and drug abuse , which may be relevant factors regarding behavioral problems along with parenting style . however , the results from this study clearly show that having a healthy diet is related to having reduced odds of behavioral problems at school . the literature shows that behavioral problems at school are related to school dropout ( 30 ) . school dropout is a public health issue , as research shows that good education promotes good health and disparity in health and educational achievements are closely linked ( 31 ) . in addition , as a healthy diet is well known to be related to optimal health ( 32 ) , promoting a healthy diet , including both dietary intake and meal pattern , is important in these age groups , with regard to behavior , school achievement , and future health . this study shows that adolescents who frequently have breakfast and a moderate intake of fruit and fish have reduced odds of behavioral problems at school . furthermore , the study shows that adolescents who have a high intake of unhealthy food items have increased odds of behavioral problems at school . a longitudinal study to find causality between dietary intake and behavioral problems at schoolthe authors have not received any funding or benefits from industry or elsewhere to conduct this study .\noutput:\n" }, { "from": "agent", "value": "backgrounddiscussion about dietary factors in relation to behavioral problems in children and adolescents has been going on for a long time.objectivethe aim of this study was to investigate the cross - sectional relation between diet and self - reported behavioral problems at school in adolescents in the southern part of norway.designin total , 475 ninth - and tenth - grade students ( 236 boys and 239 girls ) out of 625 eligible students from four different secondary schools in three different communities in vest - agder county , norway , participated , giving a participation rate of 77 % . the students filled in a questionnaire with food frequency questions of selected healthy ( e.g. fruits , vegetables , and fish ) and unhealthy ( e.g. sweets , sugar - sweetened beverages , and crisps ) food items , questions of meal frequency , and four questions regarding behavioral problems at school.resultshaving breakfast regularly was significantly associated with decreased odds of behavioral problems ( or : 0.29 ( 0.15 0.55 ) , p0 .001 ) . a high intake of unhealthy foods , such as sugar - sweetened soft drinks ( or : 2.8 ( 1.06 7.42 ) , p = 0.03 ) and sweets ( or : 2.63 ( 1.39 4.98 ) , p = 0.003 ) , was significantly associated with increased odds of behavioral problems . at the same time , a high intake of fruits was associated with decreased odds of behavioral problems in norwegian adolescents ( or : 0.30 ( 0.10 0.87 ) , p = 0.03 ) . all ors are adjusted for sex and bmi.conclusionsthis study shows that having an optimal diet and not skipping meals are associated with decreased odds of behavioral problems at school in norwegian adolescents . hence , it is important to improve the dietary intake and meal pattern of norwegian adolescents . the cross - sectional design of this study limits any causal interpretations of the results of the study ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: evidence - based medicine aims to apply the best available evidence gained from the scientific method to medical decision making . striving towards evidence - based practice , in terms of evidence - based decision making , evidence - based guidelines and evidence - based interventions is widely accepted in the medical fields . different levels of evidence have been recognized , and based on careful compiling and consideration of the available evidence , health care or treatment protocols and directives have been established to promote evidence - based practice . in othernon - medical areas of health and medical practice , including health education and health promotion , the evidence - based paradigm is also advocated . however , for health education and health promotion interventions , no formal evidence - based registration , admission or directive systems are in place . in the netherlands , two important governmental or government - supported agencies for public health promotion , i.e. the centres for healthy living and youth health of the national institute for public health and the environment and the netherlands youth institute , initiated and coordinate a recognition system for health education and health promotion interventions to promote quality assurance and control . in this point of view article , the dutch recognition system , the recognition procedure and the first experiencesthis article is a point of view paper in the sense that we believe that more systematic quality assurance and control has been neglected and should be addressed in the health promotion field , but that the way to promote this , the quality criteria and the effects of such quality control and promotion may be controversial and should be debated . we hope that this point of view article leads to presentations of similar recognition systems or alternative systems for quality assurance and control that are in place or under construction in other countries . the dutch system is as follows : an organization or other entity that wishes to have an intervention formally recognized and submits a description of the intervention according to a standard submission form to the recognition registration desk at the national institute for public health or the youth institute . the submission also indicates for what level recognition is requested ( see next paragraph ) . the submission form demands information about the different steps of the model of planned promotion of population health ( fig .1 ) . a basic model of planned promotion of population health . for steps 13 , a brief epidemiological analysis is required outlining what the ultimate public health goals of the submitted intervention are , which behavioural or environmental risk factors are addressed and what the important and modifiable determinants of exposure to these risk factors are . this epidemiological analysis should result in a clear , preferably smart ( specific , measurable , attainable , relevant , time - bound ) , description of the goals of the intervention and of the target populations .1 , the intervention description should detail the intervention methods , strategies and materials and their theoretical and empirical foundation . for step 5 , finally , the evidence for efficacy and effectiveness and / or process evaluation results of the intervention should be summarized . more detailed descriptions of the intervention , intervention handbooks or protocols as well as research reports to underpin the epidemiological analysis , the interventions methods and strategies and / or the ( cost ) effectiveness of the intervention should be submitted as attachments to the recognition submission form . the registration desk checks the completeness and quality of the submitted forms and provides initial feedback to improve the submission if necessary . two subcommittees for recognition of health promotion interventions are in place , one for youth interventions and one for interventions for adults . both subcommittees consist of experts on health promotion and / or youth health care research , practice and policy . each submitted intervention is pre - evaluated by four committee members guided by a pre - structured evaluation form that lists all criteria for each recognition level . the submitted interventions are then discussed in a live committee meeting to come to a decision about the recognition level and to prepare feedback for further improvement of the intervention 's description and evidence base . if a consensus can not be reached , additional information may be requested , a lower level of recognition is considered or recognition is not granted . the committees meet approximately every 2 months for up to 3 h , in which usually a maximum of six interventions are discussed and evaluated . the chair 's role is to ensure that all members contribute to the evaluation , to summarize the evaluation results and to propose a conclusion . the results of the procedure are published online on the websites of the coordinating centres , and admitted interventions are registered in the so - called i - database ( http://www.loketgezondleven.nl/i-database/ and http://www.nji.nl/jeugdinterventies ) , where the intervention is described , the evidence is presented , contact details for the intervention 's ownership are provided as well as the recognition level that was granted . health promotion interventions are almost always complex interventions as indicated by the number of interacting intervention components , the number and difficulty of behaviours required by those delivering or receiving the intervention , the number of groups or organizational levels targeted by the intervention , the number and variability of outcomes and the degree of flexibility or tailoring of the intervention to individuals , subgroups or local circumstances . to establish the levels and criteria , three information sources have been used : previous experiences with existing admission systems in the netherlands in other fields ( preschool programs , youth care , forensic care ) , international literature and current views of researchers , politicians and practitioners on the requirements of a useful admission systems . the resulting admission levels concur strongly with the uk medical research council ( mrc ) 's framework for design and evaluation of complex interventions to improve health . four levels of recognition are distinguished : ( i ) theoretically sound , ( ii ) probable effectiveness , ( iii ) established effectiveness and ( iv ) established cost effectiveness . for each higher level of recognition , the criteria for the lower levels should also be met . for the first recognition level ( theoretically sound ) , the intervention should be well described , meaning that a formal description and manual for the intervention should be available as well as results of a process evaluation indicating that the intervention can be conducted with the reach , level of adoption , quality of implementation and maintenance that the intervention requires according to the description and manual . furthermore , the intervention 's methodologies and strategies and the process through which these are supposed to impact the targeted determinants or risk factors should be described , based on and with reference to established empirical health behaviour change theory , i.e. theories that describe , explain and / or guide health behaviour change that are supported by empirical evidence . a description and relevance of a range of such theories can be found elsewhere ( e.g. 1 ) . the criteria for the different levels of recognition for the second level ( probable effectiveness ) , all criteria for level i should be met , and additionally there should at least be preliminary evidence for effects of the intervention , based on exploratory studies , not necessarily of the strongest methodological rigor . the third level established effectiveness does require more than one study of strong internal validity conducted in the setting in which larger scale implementation is supposed to take place . for recognition at this level also evidence for generalizability of the results should be available . the evidence is not necessarily derived from results of randomized controlled trials ( rcts ) , despite the fact that rct - designed studies have the highest internal validity . as has been argued before , rct 's may not be a realistic or the best option for evaluation of certain kinds of complex health promotion interventions . for levels ii and iii , the studies with the best possible designs in terms of internal and external validity appropriate for the intervention at hand are required . for example , for nationwide mass media interventions , these can be interrupted time series designs ; for community interventions , community intervention trials may be most appropriate . for level iv ( established cost effectiveness ) the methodology to conduct economic evaluations of complex health promotion interventions is in its infancy , and no interventions have been submitted to date for evaluation at this level . the criteria and the possibility to submit for this recognition level will be in place in 2011 . the dutch system is as follows : an organization or other entity that wishes to have an intervention formally recognized and submits a description of the intervention according to a standard submission form to the recognition registration desk at the national institute for public health or the youth institute . the submission also indicates for what level recognition is requested ( see next paragraph ) . the submission form demands information about the different steps of the model of planned promotion of population health ( fig .1 ) . a basic model of planned promotion of population health . for steps 13 , a brief epidemiological analysis is required outlining what the ultimate public health goals of the submitted intervention are , which behavioural or environmental risk factors are addressed and what the important and modifiable determinants of exposure to these risk factors are . this epidemiological analysis should result in a clear , preferably smart ( specific , measurable , attainable , relevant , time - bound ) , description of the goals of the intervention and of the target populations .1 , the intervention description should detail the intervention methods , strategies and materials and their theoretical and empirical foundation . for step 5 , finally , the evidence for efficacy and effectiveness and / or process evaluation results of the intervention should be summarized . more detailed descriptions of the intervention , intervention handbooks or protocols as well as research reports to underpin the epidemiological analysis , the interventions methods and strategies and / or the ( cost ) effectiveness of the intervention should be submitted as attachments to the recognition submission form . the registration desk checks the completeness and quality of the submitted forms and provides initial feedback to improve the submission if necessary . two subcommittees for recognition of health promotion interventions are in place , one for youth interventions and one for interventions for adults . both subcommittees consist of experts on health promotion and / or youth health care research , practice and policy . each submitted intervention is pre - evaluated by four committee members guided by a pre - structured evaluation form that lists all criteria for each recognition level . the submitted interventions are then discussed in a live committee meeting to come to a decision about the recognition level and to prepare feedback for further improvement of the intervention 's description and evidence base . if a consensus can not be reached , additional information may be requested , a lower level of recognition is considered or recognition is not granted . the committees meet approximately every 2 months for up to 3 h , in which usually a maximum of six interventions are discussed and evaluated . the chair 's role is to ensure that all members contribute to the evaluation , to summarize the evaluation results and to propose a conclusion . the results of the procedure are published online on the websites of the coordinating centres , and admitted interventions are registered in the so - called i - database ( http://www.loketgezondleven.nl/i-database/ and http://www.nji.nl/jeugdinterventies ) , where the intervention is described , the evidence is presented , contact details for the intervention 's ownership are provided as well as the recognition level that was granted . health promotion interventions are almost always complex interventions as indicated by the number of interacting intervention components , the number and difficulty of behaviours required by those delivering or receiving the intervention , the number of groups or organizational levels targeted by the intervention , the number and variability of outcomes and the degree of flexibility or tailoring of the intervention to individuals , subgroups or local circumstances . to establish the levels and criteria , three information sources have been used : previous experiences with existing admission systems in the netherlands in other fields ( preschool programs , youth care , forensic care ) , international literature and current views of researchers , politicians and practitioners on the requirements of a useful admission systems . the resulting admission levels concur strongly with the uk medical research council ( mrc ) 's framework for design and evaluation of complex interventions to improve health . four levels of recognition are distinguished : ( i ) theoretically sound , ( ii ) probable effectiveness , ( iii ) established effectiveness and ( iv ) established cost effectiveness . for each higher level of recognition , the criteria for the lower levels should also be met . for the first recognition level ( theoretically sound ) , the intervention should be well described , meaning that a formal description and manual for the intervention should be available as well as results of a process evaluation indicating that the intervention can be conducted with the reach , level of adoption , quality of implementation and maintenance that the intervention requires according to the description and manual . furthermore , the intervention 's methodologies and strategies and the process through which these are supposed to impact the targeted determinants or risk factors should be described , based on and with reference to established empirical health behaviour change theory , i.e. theories that describe , explain and / or guide health behaviour change that are supported by empirical evidence . a description and relevance of a range of such theoriesthe criteria for the different levels of recognition for the second level ( probable effectiveness ) , all criteria for level i should be met , and additionally there should at least be preliminary evidence for effects of the intervention , based on exploratory studies , not necessarily of the strongest methodological rigor . the third level established effectivenessdoes require more than one study of strong internal validity conducted in the setting in which larger scale implementation is supposed to take place . for recognition at this level also evidence for generalizability of the results should be available . the evidence is not necessarily derived from results of randomized controlled trials ( rcts ) , despite the fact that rct - designed studies have the highest internal validity . as has been argued before , rct 's may not be a realistic or the best option for evaluation of certain kinds of complex health promotion interventions . for levels ii and iii , the studies with the best possible designs in terms of internal and external validity appropriate for the intervention at hand are required . for example , for nationwide mass media interventions , these can be interrupted time series designs ; for community interventions , community intervention trials may be most appropriate . for level iv ( established cost effectiveness ) , the criteria have not been detailed yet . the methodology to conduct economic evaluations of complex health promotion interventions is in its infancy , and no interventions have been submitted to date for evaluation at this level . the criteria and the possibility to submit for this recognition level will be in place in 2011 . in 2008 , the evaluations of recognitions were started , first only at level i. from june 2009 , the levels ii and iii were also considered . after a slow start in 2008 ( 18 health promotion interventions were evaluated ) , the number of evaluations increased in 2009 ( 36 interventions ) , and this number is expected to further increase in 2010 ( 45 interventions ) . until december 31 , 2009 ,54 health promotions interventions have thus been considered by the committees , with some interventions having been submitted more than once because after the first submission the committee regarded the information as insufficient to come to a decision . in table 2 , the topics and the recognition level granted of the interventions for which evaluation was completed in 2009 are presented . number of submitted interventions , per topic and recognition levels in 2008 and 2009 twelve interventions were re - submitted because recognition was not granted the first time , or the submitting organization re - submitted to obtain recognition at a higher level . mental health promotion interventions have been submitted most often , and two of these have been admitted at level iii . with 12 and 10 submitted interventions , the fields of sexual health and safety promotion are also well represented . for other topics of established importance for population health , such as healthy nutrition and physical activity promotion , obesity prevention , and prevention of alcohol and drug abuse , fewer interventions have been submitted . based on the committee 's evaluation of the submission forms , it appears to be difficult for health promotion organizations to describe the theoretical basis of their interventions , and interventions often appear not to have been systematically planned and developed based on established health behaviour change theory . the majority of the submitted interventions is individual counselling and health education - like interventions . fewer interventions have been submitted that take a broader health promotion perspective , i.e. directed at changing the physical , social cultural , economical or political environments . such health promotion interventions are often more difficult to evaluate in internally valid research designs and may therefore have more difficulties in being recognize at the established effectiveness level . most interventions have been submitted by national health promotion organizations , probably because their interventions are meant to be disseminated on a larger scale and because they have the means to more carefully prepare the submissions . promoting quality assessment and control in health promotion is of great importance in order to ensure that the most effective and efficient interventions are implemented and disseminated , i.e. to promote that the relatively meagre means for health promotion are invested in the best possible way . the dutch recognition system is an attempt to contribute to promotion of dissemination and implementation of the best available interventions in health promotion practice . the recognition system has been based on and inspired by an established health promotion planning model and an outline for evaluation of complex interventions . whether the dutch system is indeedthe way forward is debatable and experience with , discussion about and evaluation of the system and comparison with similar or alternative quality promotion attempts in other countries is needed and will take place within the next few years . one such system is the guide to community preventive services , from the us centers of disease control and prevention , which is a free resource to assist choosing programs and policies to improve health and prevent disease in community - based settings . this system has reviewed more than 200 interventions based on which recommendations for their use have been issued . another established example is the nice public health guidance of the uk national institute for health and clinical guidance . this system indeed provides guidance for health promotion institutes and actors to select appropriate well - described , evidence - based , best - practice interventions . we hope this point of view article will initiate reactions from the international health promotion research and practice community to help to evaluate and improve the dutch system . for example , the fact that the first step towards recognition is an epidemiological analysis to substantiate that the intervention addresses an important health issue does not recognize arguments made in the health promotion field to conduct a community analysis or a needs assessment that take more into account than epidemiological data to indentify health promotion priorities . the subcommittees evaluate which criteria are met , facilitated by evaluation forms provided by the registration desk personnel . the subcommittee members have been selected by the founding institutes , based on their expertise and experience in the relevant fields . the committees consist of professional experts who have received clear instructions on the procedures and purposes , but representation of lay people or health promotion intervention receivers . expanding the committee with such representativesfurthermore , the recognition process is internally monitored and evaluated , for example based on observations of subcommittee meetings , in order to adjust the procedures and processes when and where needed . the precision with which theoretical insights have been translated in intervention strategies and activities , the number and consistency of studies with positive results and the balance between internal and external validity in evaluations of complex interventions are issues that have been debated in developing the admission system , but that remains sometimes difficult to evaluate and assess . other critical points that have been debated include the reliance on probable or presumed determinants of health as effect indicators and what effect size can be regarded as relevant for population health . these issues are being and will be discussed in and between the evaluation committees as well as with the main stakeholders and should be further debated with international experts in the field . first , the criteria for recognition may favour certain interventions . relatively many mental health promotion interventions have been submitted and recognized . these interventions are often individually tailored counselling - like interventions , sometimes based on e - health approaches . such mainly individual and educational interventions are better suited for evaluation in rcts enabling internally valid effect estimates . interventions for , for example , obesity prevention , physical activity or healthy eating promotion typically require more integral approaches , combining health education with physical and policy environmental changes . evaluation of such interventions is more complex , requires long - term follow - up and is therefore costly . if the dutch recognition system leads an imbalance , with more recognition of interventions that can be tested in rcts , the system needs adjustments . practice - based research is needed to improve evidence - based practice in health promotion and for evaluation of such interventions , a broader range of evaluation designs need to be considered . the dutch recognition system accepts that rcts are often not applicable or not even desirable for evaluation of certain health promotion interventions , and recognition is not dependent on rct - based evaluation research . however , the strength of evidence from other research designs is often harder to interpret , and funding for evaluation studies with such alternative designs may be harder to obtain . the fact that most interventions to date were recognized at the level of theoretically sound illustrates that evidence for effectiveness is lacking for many interventions , many of which are already implemented and disseminated . the system has also been criticized by health promotion practitioners who claim that the system favours interventions developed by the larger , more established organization and interventions developed in or in collaboration with academia , where more manpower and more expertise on health promotion theory and systematically describing interventions in theory - based concepts and strategies is available . owner facilitates implementation and dissemination of the intervention , by providing clear implementation handbooks and protocols , as well as a description of what personnel and other ( financial ) means are necessary for implementing the intervention . the recognition system does not require active dissemination of interventions that were granted recognition , and careful monitoring should indicate if the recognition system does lead to dissemination of recognized interventions , or if and what other promotion dissemination activities are needed . the system may result in restricting implementations to recognized interventions , especially if financial support for intervention implementation is going to depend on the level of recognition . in 2012 , the netherlands health care inspectorate will evaluate the use of recognized interventions by the municipal health services in their inspection task . the main driver of intervention innovation and evaluation research is the netherlands is the netherlands organisation for health research and development and their prevention research funding programs . closer collaborations between this organization and the national institute for public health and environment to endorse continuity between development , evaluation and recognition are now being explored and experimented with .\noutput:\n" }, { "from": "agent", "value": "registration or recognition systems for best - practice health promotion interventions may contribute to better quality assurance and control in health promotion practice . in the netherlands , such a system has been developed and is being implemented aiming to provide policy makers and professionals with more information on the quality and effectiveness of available health promotion interventions and to promote use of good - practice and evidence - based interventions by health promotion organizations . the quality assessments are supervised by the netherlands organization for public health and the environment and the netherlands youth institute and conducted by two committees , one for interventions aimed at youth and one for adults . these committees consist of experts in the fields of research , policy and practice . four levels of recognition are distinguished inspired by the uk medical research council 's evaluation framework for complex interventions to improve health : ( i ) theoretically sound , ( ii ) probable effectiveness , ( iii ) established effectiveness , and ( iv ) established cost effectiveness . specific criteria have been set for each level of recognition , except for level 4 which will be included from 2011 . this point of view article describes and discusses the rationale , organization and criteria of this dutch recognition system and the first experiences with the system ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: since its appearance on the market in the second half of 2002 , the diagnostic properties of the ccp2 test have been studied by many laboratories . the accumulated data , including only papers that appeared in pubmed till december 2006 , are given in table 1 . it is clear that the accumulated data confirm the earliest reports on specificity and sensitivity of the ccp2 test . the anti - ccp2 test demonstrates an rf - like sensitivity with a very high specificity for ra ( see also recent reviews : ) . it is also commonly recognized that anti - ccp2 antibody may be present in up to 40 % of rf - negative ra sera . table 1cumulative anti - ccp2 diagnostic data published between 2002 and 2006patient groupnumberccp2 + sensitivity ( % ) specificity ( % ) ra total14 ,18310,13571.5 early3 ,8762,36561.0 established10 ,3077,77075.4 controls15 ,1566834.595.6 non - ra11 ,5026475.694.4 healthy3 ,654361.099.0 in total , 122 independent studies were included . cumulative anti - ccp2 diagnostic data published between 2002 and 2006 in total , 122 independent studies were included . the anti - ccp2 test enables clinicians to distinguish ra patients from other arthritic diseases , especially in cases where the rf test is not discriminative . this is , for example , the case with chronic hepatitis c virus ( hcv ) infection , a disease that can easily be misdiagnosed as it often reveals ra - like arthropathies and , in many cases , is accompanied by a positive rf . recently , there is also an interest to compare the diagnostic potential of anti - ccp2 with novel tests based on the use of a citrullinated antigen ( for example , mcv = anti - mutated citrullinated vimentin , cpa = citrullinated protein antibodies , vcp = anti - viral citrullinated protein , antihuman fibrinogen alpha , and ccp3 ) . for a reliable comparison of these tests , it is essential that their performance is assessed under the same conditions , e.g. , the sensitivities of the tests should be determined at the same level of specificity . good examples of such stratified studies have been carried out recently by van der cruijssen et al . and dejaco et al . . for example , dejaco et al . showed , in a large cohort of patients ( 600 ) , that at a specificity of 98.7 % , being the specificity of the anti - ccp2 test , the sensitivity of the anti - mcv test is 53.7 % as opposed to 70.1 % for the anti - ccp test . compared several commercial tests , including a very recent ccp3 test from inova . at the cut - offs recommended by the various manufacturers , the positive predictive value of the three commercial ccp2 tests is about 90 % with a specificity of around 96 % . the specificity of the other tests ( ccp3 = 88 % , mcv = 90 % , cpa = 94 % ) is lower as are their positive predictive values . these numbers may improve a little bit when the cut - off values are adjusted to more realistic data ; nevertheless , the data allow the statement that , in absolute percentages , none of the tests performs better than the anti - ccp2 test . they also seem to indicate that some tests detect ra patient groups that are negative in the anti - ccp test , illustrating again that the autoantibody repertoire of ra patients is very heterogeneous . another risk forthe specificity of a test that is based on a citrullinated antigen is the possibility that antibodies are not directed exclusively to the citrulline - containing epitope but also to other possibly overlapping epitopes present in the substrate antigen . this is particularly important when citrullinated versions of proteins like vimentin or fibrinogen are used . for example , it is known that antibodies to vimentin are present in several diseases different from ra . they used elisa plates containing the control ccp2 antigens ( arg instead of cit in the same peptide context ) , produced and made available by euro - diagnostica , arnhem , the netherlands , in parallel to the normal ccp2 test . the results of these comparative studies showed that in ra and most non - ra rheumatic disease sera , anti - ccp reactivity indeed is citrulline - dependent . however , in some patients , particularly autoimmune hepatitis patients , citrulline - independent reactivity with the antigen may occur . a positive ccp test in a rheumatic disease ( almost always citrulline - specific ) may thus suggest the future development of ra as has been suggested by several studies . a positive test in a nonrheumatic disease ( very often not citrulline - specific ) , for example , liver disease , should be interpreted with care . because ra patients at first presentation often do not fulfill the criteria for the diagnosis / classification of ra , an early , highly predictive marker would greatly assist the clinician in reaching an early diagnosis . there are several studies indicating that the anti - ccp2 test provides this help ( reviewed by ) . in the recently published eular recommendations for the management of early arthritisthese factors include : number of swollen and tender joints , esr or crp , level of rf and anti - ccp antibodies , and radiographic erosions . most of these factors were also mentioned as being important in the prediction of early erosive ra ( visser et al . ) . subsequent studies by the same group gave an indication of the relative importance of these factors . when expressed as odds ratios ( or ) , the data was as follows : arthritis of three or more joints , 5.0 ; radiographic erosions , 8.7 ; positive igm - rf , 1.7 ; and positive anti - ccp2 , 38.6 . these and other data ( see also ) clearly show that the presence of anti - ccp antibodies is an important and independent prognostic factor for radiographic progression in not only early arthritis but also in early rheumatoid arthritis . recently , it has also been shown that igm - ccp is present in early samples from both patients with undifferentiated arthritis ( ua ) and patients with ra as well as in follow - up samples from patients with ra . these data indicate the development of the anti - ccp isotype repertoire into full usage early in the course of arthritis and a continuous ( re ) activation of the ra - specific anti - ccp response during the further development of the disease . it is , however , evident that besides the clinical and laboratory parameters mentioned above , some genetic factors are important as well . the effect of the hla shared - epitope alleles on the development of acpa has been firmly established . because such dying cells are generally removed from the environment via clearance by phagocytes , a process that is regulated by many genes , the immune system will normally not encounter citrullinated proteins . however , it has been shown that during inflammation , citrullinated proteins are detectable in the inflamed tissue , both in ra and non - ra patients . this is probably caused by inefficient clearance of the massive numbers of dying cells , a process already described to occur in sle . this inefficient clearing could , in principal , also be the consequence of altered genes , i.e. , the genetic background . the mere presence of citrullinated antigens in inflamed synovial tissue does not necessarily result in the occurrence of anti - ccp antibodies in serum or synovial fluid , neither in humans nor in mouse models of arthritis . hill et al. showed that the generation of anticitrulline antibody in mice actually is linked to the expression of the ra shared epitope ( se ) , and a similar link was also found in patients because the combination of se , and anti - ccp has a very high predictive value for the future development of ra . the specific structure of hla molecules obviously plays an important role in the induction of autoimmunity to citrullinated proteins . these studies were extended by huizinga et al . who found that hla - drb1 alleles encoding the se were only associated with anti - ccp positive ra and not with anti - ccp negative ra . in contrast , anti - ccp negative ra appeared to be associated with hla - dr3 . therefore , the presence of citrullinated antigens , together with the appropriate genetic background ( the se and probably other types of hla ) , appears to be the minimum requirement for an immune response to citrullinated polypeptides to be generated . next to that , other sensitizing genetic settings resulting from polymorphisms ( e.g. , ptpn22 ) might , given their association , aid in triggering of acpa . the present literature describes and confirms that the anti - ccp2 test is a very useful marker for the early and accurate diagnosis of ra . anti - ccp antibody is very specific for ra and has a sensitivity comparable to that of rf . these antibodies can be detected very early in disease and may be used as an indicator for the progression and prognosis of ra . initially , the test was available principally as a manual elisa method through euro - diagnostica and axis - shield and their partners . more recently , fully automated anti - ccp assays have also been made available from phadia ( unicap elia ccp ) and abbott diagnostics ( axsym anti - ccp ) . a very novel format is the ccpoint , a point - of - care test for the detection of these antibodies in whole blood in 10 min . a small drop of whole blood is applied onto the sample well followed by the addition of four drops of running buffer . after 10 min , the result is read by visual inspection of the detection zone for staining of the antigen line . as no special equipmentis required to perform the assay , this test will bring the detection of anti - ccp antibodies into the office of the family doctor , facilitating a very fast referral to the rheumatologist when the test gives a positive answer . such new applications will undoubtedly further enhance the utility of the anti - ccp autoantibody system in clinical practice .\noutput:\n" }, { "from": "agent", "value": "the literature of the last 4 years confirms that the anti - ccp2 test is a very useful marker for the early and specific diagnosis of rheumatoid arthritis ( ra ) . the anti - ccp2 test is very specific for ra ( 9599 % ) and has sensitivity comparable to that of the rheumatoid factor ( 7075 % ) . the antibodies can be detected very early in the disease and can be used as an indicator for the progression and prognosis of ra . in this review , these interesting properties and some future possibilities of this diagnostic test are discussed ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: crustaceans like other invertebrates only have innate immunity , including many immune molecules to eliminate exogenous pathogens . to date , many studies have verified that hemocyanin is an important nonspecific innate immune defense molecule and can provide an effective immune defense in arthropods . its primary function is to transport and store oxygen and also to participate in osmoregulation , molt cycle , exoskeleton formation , and melanin synthesis . so far , studies on the immunologic function in crustacean are mainly focused on the hemocyanin itself or its degraded peptides , which have hemolytic activity , agglutination property , and antiviral function . hemocyanin genes have been cloned and characterized in certain crustacean species such as litopenaeus vannamei , eriocheir sinensis , cherax quadricarinatus , homarus americanus , and caridina multidentata and atyopsis moluccensis . copper is a central component of hemocyanin and a cofactor of many other enzymes , like superoxide dismutase , cytochrome oxidase , and lysyl oxidase . the dietary copper level can affect crustacean immune responses in penaeus monodon and e. sinensis . it was found that the expression of hemocyanin mrna in e. sinensis was affected by dietary copper level . investigation of the functional relationship between dietary copper and hemocyanin mrna expressions can provide better understanding on crustacean innate immunity and offer insight into disease control through dietary management in shrimp farming . we hypothesize that copper as a major component of hemocyanin can impact prawn innate immunity through dietary copper manipulation . oriental river prawn ( macrobrachium nipponense ) is an important aquaculture species in china and other southeast asian countries . various diseases have been found in the m. nipponense farming population due to intensive culture and environmental pollution . for example , the bacterial disease induced by aeromonas hydrophila is one of the major diseases which can cause 30 % death of prawn , sometimes as high as 70 % . as a result , the investigation on the m. nipponense innate immune mechanism against a. hydrophila has become a key issue of health management in crustacean farming . the hemocyanin subunit is a functional group for crustacean immunity , and a hemocyanin subunit has been cloned and characterized in the freshwater prawn m. nipponense . in this study , we discovered another hemocyanin subunit in m. nipponense ( mnhc - 1 ) . to understand the role of mnhc - 1 in m. nipponense immunization , ( 1 ) the full - length cdnas of mnhc - 1was cloned , ( 2 ) the distribution of mnhc - 1 in different tissues was examined , ( 3 ) the mrna expression of mnhc - 1 in immune defense after prawn challenge with a. hydrophila was examined , and ( 4 ) the relative expression level of mnhc - 1 in the hepatopancreas of m. nipponense fed different levels of copper was quantified . all adult oriental river prawns ( m. nipponense ) were obtained from a local farm in shanghai . the hepatopancreas , muscle , gill , ovary , intestine , heart , and stomach were collected from healthy prawn , flash - frozen in liquid nitrogen , and stored at 80c until rna extraction . a total of 1 ml hemolymph was collected from the ventral sinus using a sterile syringe and diluted using half volume of anticoagulant solution , then centrifuged at 8000 g for 10 min at 4c to collect the hemocyte , and stored at 80c immediately until rna extraction . prior to the challenge experiment , the adult prawns were acclimatized in the laboratory for 2 weeks . a total of 300 healthy prawns were randomly divided into two groups with five replicates . according to the preliminary experiment , the prawn in the bacterial challenge trial was injected with 100 l a. hydrophila in saline suspension ( 110 cfu / ml ) obtained from shanghai ocean university , while each prawn in the control group received the same volume of saline injection . after injection , prawns were put back to the rearing tanks , and hemocyte samples were collected at 0 , 3 , 6 , 12 , 24 , and 48 h after injection , centrifuged , and stored at 80c for rna extraction . the juvenile m. nipponense were obtained from the same farm as the adults and acclimated for two weeks in the laboratory conditions prior to the feeding trial . the basal diet was supplemented with copper sulphate ( analytical reagent , shanghai chemical co. , shanghai , china ) at 0 , 10 , 20 , 30 , 40 , 80 , and 160 mg cu kg diet , respectively . the actual copper concentrations in the feeds were analyzed to be 2.8 , 12.2 , 20.9 , 29.8 , 43.1 , 78.9 , and 157.1 mg kg , respectively , by the flame atomic absorption photometry . prawn juveniles ( 0.1010.001 g ) were randomly placed in 21 of 300 - l tanks with 30 prawns per tank in triplicate . prawns were fed to apparent satiation twice daily ( 8:00 and 17:00 h ) for 56 days . to maintain water quality , one - third of the tank water was exchanged daily . during the feeding period , l , and total ammonia nitrogen 0.1 mg l. the cu concentration in rearing water was 1.41.7 g cu l. at the end of the feeding trial , all prawns were counted and gained survival rate ( survival rate = 100 ( final prawn number ) / ( initial prawn number ) ) . total rna was isolated using rna extraction kit ( aidlab biotech , beijing , china ) following manufacture protocol . in reverse transcription reaction , 3 g of total rna was used for synthesis of first - strand cdna by the primescript rt - pcr kit ( takara , dalian , china ) . acquired cdna was stored at 20c for subsequent quantitative real - time pcr ( qrt - pcr ) . to get the full length of mnhc - 1 cdna sequence , smart race cdna amplification kit ( clontech , usa ) gene - specific primers of mnhc - 1 were designed based on the known fragments initially identified from the est cdna library of m. nipponense . reaction volume was 50 l containing 5.0 l 10x ex taq buffer ( mg plus ) , 5.0 l 10x upm , 4.0 l cdna template , 4.0 l dntps mix ( 2.5 mm each ) , 1.0 l gsp ( 10 m ) , 0.26 l ex taq hs ( takara , dalian , china ) , and 30.74 l of sterile deionized water . the pcr conditions were set as follows : 5 cycles of 94c for 30 s and 72c for 3 min , then 5 cycles of 94c for 30 s and 70c for 30 s , and 25 cycles of 94c for 30 s , 68c for 30 s , and 72c for 3 min . primers of mnhc - s1 and mnhc - a1 were used to confirm the mnhc - 1 fragment from the est cdna library .5 - cds primer a ( as the rt primer ) , gene - specific primer of mnhc - 5gsp , and the upm ( universal primer a mix ) were used for the 5 - race .3 - cds primer a ( as the rt primer ) , gene - specific primer of mnhc - 3gsp , and the upm were used for the 3 - race . the pcr products were purified by the uniq - 10 gel extraction kit ( sangon , shanghai , china ) and cloned into the pucmt vector ( sangon , shanghai , china ) . the transformed bacteria were identified , confirmed by blue / white screening , and validated by pcr . more than two recombinant plasmids were sequenced using bigdye terminator v3 .1 cycle sequencing kit operating on an automatic dna sequencer ( abi 3730xl dna analyzer ) . the online orf finder program ( http://www.ncbi.nlm.nih.gov/gorf/ ) was used to predict the gene 's putative open reading frame . the blast algorithm at the national center for biotechnology information ( http://www.ncbi.nlm.nih.gov/blast/ ) was applied to search for sequence homology . smart ( simple modular architecture research tool , http://smart.embl-heidelberg.de/ ) was used to predict conserved motifs . the deduced amino acid sequence of mnhc - 1 from m. nipponense and other invertebrate hemocyanin sequences acquired from ncbi database were aligned by software clustalx . a neighbor - joining ( nj ) phylogenetic relationship was established based on amino acid sequences of the hemocyanin using the mega 5.1 program ( http://www.megasoftware.net/ ) . the mrna expression of mnhc - 1 in the hepatopancreas , muscle , gill , ovary , intestine , heart , and stomach was detected by qrt - pcr with - actin as internal control . the synthesis of the first - strand cdna was the same as that described above . gene - specific primers of mnhc - s2 , mnhc - a2 , - actin - s , and - actin - a were used in qrt - pcr ( table 2 ) . the qrt - pcr liquid compositions and conditions were according to the manufacturer instructions of sybr premix ex taq ( takara , dalian , china ) . the qrt - pcr was conducted on the cfx96 real - time system ( bio - rad , usa ) according to the manufacturer 's protocols . during the detection , the melt curve of the amplification products was analyzed to ensure that only one pcr product was amplified and detected at the end of each pcr . the mrna expression of mnhc - 1 in the hemocytes of m. nipponense injected with a. hydrophila or saline water was , respectively , detected at 0 , 3 , 6 , 12 , 24 , and 48 h after injection by a quantitative real - time rt - pcr . at the feeding experiment , mrna expression of mnhc - 1 in hepatopancreas of m. nipponense from the feeding treatment at seven copper levels was analyzed by qrt - pcr . the results of relative mrna expression in challenge test were analyzed by t - test , while other results were subjected to one - way anova and post hoc duncan multiple range tests . the full length of mnhc - 1 cdna from the m. nipponense was 2,163 bp ( genbank accession number jx456149 .1 ) , containing a 20 bp 5 - untranslated region , a 115 bp 3 - untranslated region with poly a tail , and a 2,028 bp open reading frame ( orf ) ( figure 1 ) . the orf encoded a polypeptide of 675 amino acids with a calculated molecular weight of 78.060 kda and an isoelectric point of 5.45 . a putative signal peptide of 21 amino acids was found in the n - terminus by using signalp 4.1 program . smart program predicted that the mnhc - 1 belongs to the hemocyanin family , including n terminal domain ( ser24 - val150 ) , typical copper - containing domain ( pro154 - glu411 ) , and c terminal domain ( pro417 - his667 amino acid ) . six histidine residues ( h212 , h216 , h242 , h362 , h366 , and h402 ) of copper - binding sites were identified . homology analysis with blast algorithm showed that mnhc - 1 amino acid sequences had 75 % , 73 % , 70 % , and 68 % similarity to that of the a. moluccensis gamma subunit , p. monodon , c. quadricarinatus , and e. sinensis , respectively . the mnhc - 1 exhibited 64 % identity with another subunit of hemocyanin in m. nipponense ( mnhc - 2 , genbank accession number jf683437 .1 ) . a phylogenetic tree was constructed with the 24 full - length hemocyanin sequences from arthropod based on the neighbor - joining method ( figure 2 ) . the result of phylogenetic analysis revealed that mnhc - 1 was more closely related to the hemocyanin gamma subunit 1 of freshwater shrimps a. moluccensis and c. multidentata . the mrna transcripts of mnhc - 1 were analyzed in the tissues of hepatopancreas , gill , muscle , hemocytes , intestine , ovary , and stomach . in prawn , the highest expression was found in hepatopancreas ( p 0.05 ) ; the expression value is 20.32 , which is 20 times higher or more compared with other tissues . the value is as low as 0 so that the gene is not expressed in muscle ( figure 3 ) . figure 4 exhibits the expression profile of mnhc - 1 in the hemocytes challenged by a. hydrophila from 0 to 48 h. the expression of mnhc - 1 showed a distinct time - dependent pattern . the mrna expression level significantly dropped at 3 h after injection ( 0.6 times ) ( p 0.05 ) and then started to significantly increase and reached the peak in 12 h ( 6.2 times ) ( p 0.05 ) , followed by a recovery to the initial level in 24 h and 48 h. survival rate ( 7081 % ) of prawns was not affected by the dietary copper levels . as shown in figure 5 , the response of mnhc - 1 expression in the hepatopancreas was affected by the dietary copper level . with the dietary copper level increasing from 43.1 to 157.1 mg cu kg diet , the level of mnhc - 1 mrna in hepatopancreas of prawns significantly increased ( 1.9-fold to 5.8-fold ) ( p 0.05 ) and was significantly higher compared to that fed 2.829.8 mg cu kg diet ( p 0.05 ) , but differences in 2.829.8 groups were not significant ( p 0.05 ) . those subunits differ considerably in their primary structures and are encoded by distinct genes . in this study , we cloned and characterized the expression pattern of one hemocyanin subunit from m. nipponense ( mnhc - 1 ) . mnhc - 1 was a polypeptide of 675 amino acids with a 21 - amino acid putative signal peptide . the signal peptide ends ala - x - ala motif , which is a frequent accordance prior to the cleavage site of signal peptides , suggesting that a cleavage site is located at the 21 - 22 amino acids . structurally , mnhc - 1 has conservative copper - binding domains including six histidine residues ( h212 , h216 , h242 , h362 , h366 , and h402 ) of the copper - binding sites ; this domain agrees with other crustaceans . based on immunological methods , the crustacean hemocyanin subunits are classified into three distinct subunit types : alpha , beta , and gamma . the phylogenetic analysis showed that mnhc - 1 and mnhc - 2 belong to separate clade ; mnhc - 1 belongs to the gamma subunit which has evolved at a later time compared to alpha and beta subunits in freshwater shrimps . the present study showed that the highest level of mnhc - 1 mrna expression occurred in the hepatopancreas . the result is the same as the findings in other crustaceans , such as h. americanus , fenneropenaeus chinensis , and e. sinensis , and consistent with the report that hemocyanin synthesis occurs mainly in the hepatopancreas . mnhc - 1 expression was detected in all the examined tissues except for muscle , which is different from another subunit of hemocyanin in m. nipponense ( mnhc - 2 ) expressed in the muscle . we also found that mnhc - 1 was expressed in ovary , whereas mnhc - 2 was hardly expressed in ovary . the discrepant expression patterns of these two subunits of hemocyanin may be owing to their functional specialization in different tissues . hemocyanin is an important multifunctional protein in mollusks and arthropods . besides its role as an oxygen carrier , its immune functions including antibacterial activities , agglutination property , and po activity have become hot topics of immunological research . zhang et al . found that the main protein directly bound to the vibrio alginolyticus , vibrio harveyi , a. hydrophila , and staphylococcus aureus in l. vannamei serum was hemocyanin , suggesting that hemocyanin possesses antibacterial functions . the c - terminus of l. vannamei hemocyanin is possibly related to the immunity in shrimp to different pathogens . gram - negative bacteria a. hydrophila are a common species of the aeromonas genus in water and water habitants . the infection of a. hydrophila in fish and prawn including m. nipponense has been one of the major diseases under farming conditions . sun et al . showed that the hemocyanin gene expression of e. sinensis was significantly upregulated by a. hydrophila infection . in our study , temporal and spatial expressions of mnhc - 1 in the hemocytes of prawn infected with a. hydrophila showed a clear time - dependent pattern . the level of mnhc - 1 mrna expression significantly decreased at 3 h after injection , then started to significantly increase after 6 h and 12 h , and then reached the peak at 12 h , implying that the hemocyanin is involved in the antibacterial defense of prawn . in another study , the level of mnhc - 2 mrna expression in prawn significantly increased over time and peaked at 3 h after the a. hydrophila challenge . lei et al . found a similar result in p. japonicus that pjhcl transcriptional upregulation occurred after 4 h of injection of the active wssv . it is possible that pjhcl may be triggered by the fast expressed proteins in virus . it is also likely that mnhc - 1 may be induced by fast expressed protein in bacteria , but the detailed defensing mechanism of hemocyanin against bacterial infection needs further study . the expression of hemocyanin subunits varies with environmental or nutritional changes . our present study showed that the level of dietary copper affected the hemocyanin gene expression in prawn . the level of mnhc - 1 mrna in hepatopancreas of the prawn fed 43.1157.1 mg cu kg diet was significantly higher compared to that fed 2.829.8 mg cu kg . the increase of dietary cu concentration also increased the cu content in hepatopancreas , especially in the 43.1157.1 mg cu kg groups . therefore , we suggest that the high level of copper content in the hepatopancreas can trigger mnhc - 1 mrna expression , whereas the optimal level of dietary copper ( 2040 mg kg diet ) can increase hemocyanin mrna expression in the hepatopancreas and hemocytes of crab . these studies suggest that the effect of dietary copper level on hemocyanin mrna expression is species - specific . it seems that the two subunits of hemocyanin may have structural functions in their own hemocyanin and show different response to the level of dietary copper . dietary copper may be first used for hemocyanin synthesis as low dietary copper did not reduce the level of mnhc - 1 mrna . in conclusion , we cloned the hemocyanin subunit gene ( mnhc - 1 ) from the hepatopancreas of m. nipponense . our results suggest that mnhc - 1 may play a critical role in antibacterial defense in prawn . these results provide the foundation for further studies in biological function and regulation of hemocyanin in crustacean .\noutput:\n" }, { "from": "agent", "value": "hemocyanin is a copper - containing protein with immune function against disease . in this study , a hemocyanin subunit named mnhc - 1 was cloned from macrobrachium nipponense . the full - length cdna of mnhc - 1 was 2,163 bp with a 2,028 - bp open reading frame ( orf ) encoding a polypeptide of 675 amino acids . the mnhc - 1 mrna was expressed in the hepatopancreas , gill , hemocytes , intestine , ovary , and stomach , with the highest level in the hepatopancreas . in the infection trial , the mnhc - 1 mrna transcripts in the hemocytes were significantly downregulated at 3 h after injection of aeromonas hydrophila and then upregulated at 6 h and 12 h , followed by a gradual recovery from 24 to 48 h. the mnhc - 1 transcriptional expression in the hepatopancreas was measured after m. nipponense were fed seven diets with 2.8 , 12.2 , 20.9 , 29.8 , 43.1 , 78.9 , and 157.1 mg cu kg1 for 8 weeks , respectively . the level of mnhc - 1 mrna was significantly higher in the prawns fed 43.1157.1 mg cu kg1 diet than in that fed 2.829.8 mg cu kg1 diet . this study indicated that the mnhc - 1 expression can be affected by dietary copper and the hemocyanin may potentially participate in the antibacterial defense of m. nipponense ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the term polytrauma is mainly used to describe blunt trauma patients whose injuries involve multiple body regions or cavities , compromise patient 's physiology , and potentially cause dysfunction of uninjured organs . polytrauma is one of the main causes of death in the world . since young people are frequently involved , trauma is the leading cause of death under the age of 40 . fractures are frequently components of polytrauma patterns . these lesions must be considered as wounds of bone and soft tissue , giving rise to stress , pain , and hemorrhage . they can be contaminated and cause compartment syndromes with ischemia - reperfusion injury . patients are at risk of higher morbidity and mortality than the summation of expected morbidity and mortality of each individual injury . although polytrauma patients represent a major therapeutic challenge , improved results can be achieved in dedicated institutions with efficient triage and focused trauma specialist care . the treatment of polytrauma patients noted a significant development as a result of better understanding of the physiopathological mechanisms of injury , development of a network of prehospital trauma management , institution of multispecialist integrated groups , and improved intensive care resuscitation . the ideal approach to orthopedic injuries is to perform definitive fixation of all fractures in one trip to the operating room . this approach , called early total care ( etc ) , was widely used in the 80 's ; not only does it allow the most efficient employment of the operating room and orthopedic surgeons , but also permits patients to be promptly mobilized for tests and therapies . however , there are several scenarios in which immediate definitive fixation of all fractures is not feasible because of patient instability , preventing lengthy operation with associated blood loss . these patients have a primary indication for damage control orthopedics ( dco ) , a procedure developed since the 90 's . regardless of the preferred approach , a careful evaluation of preoperative patient conditions represents the key factor for selecting the type of initial treatment . the aim of this paper is to review the most recent literature on orthopedic polytrauma patient in order to provide a practical flowchart . early stabilization of major skeletal injuries was the mainstay of treatment in trauma surgery in the 80 's and early 90 's . etc involves definitive surgical stabilization of all long - bone fractures during the early phase of treatment ( 2448 h ) . the concept of the etc holds the merit to focus the attention of the international medical community on the need to stabilize long - bone lesions ; this constituted the first step in the development of the modern management of multiple traumas . previously , these patients were considered too sick to undergo surgery , and the manipulation of the fracture stumps was discouraged because of the fear of the so - called fat embolism syndrome . in the early 70s , the operative stabilization of femur fractures has been demonstrated to reduce pulmonary complications , promote early patient mobilization and discharge , when compared to traditional nonoperative fracture management . the development of the etc was made possible by the progressive improvement of osteosynthesis techniques and trauma resuscitation , involving better cardiorespiratory monitoring and the ability to perform prolonged artificial ventilation . in the late 80s , bone et al . further strengthened this movement with their prospective study , showing the basic role of early surgery . multi - injured patients treated with etc appeared to have less pulmonary complications , reduced length of intensive care unit ( icu ) and hospital stay ( los ) , compared to patients with delayed surgery . even though several studies highlighted this concept and its benefits , opposite views started to emerge during the 90s . etc was not considered suitable for all polytrauma patients , since in unstable patients it was associated with an unexpectedly high rate of pulmonary complications . the term damage control was originally coined by the us navy , in reference to keeping afloat a badly damaged ship by procedures to limit flooding , stabilize the vessel , isolate fires and explosions , and avoid their spreading . in abdominal surgery , it is a staged strategy for the treatment of severe bleeding injury occurring from either blunt or penetrating mechanisms . the same principle , named damage control orthopedics ( dco ) , was applied to the management of multi - injured patients with long bone and pelvic fractures . the priorities of the second phase are the control of hemorrhage , the temporary stabilization of major skeletal fractures , and the management of soft tissue injuries , while minimizing the degree of surgical insult to the patient . phase three consists of a monitoring period in icu , while phase four focuses on definitive fracture fixation . the shift from etc to the dco came after significant advances in the understanding of pathophysiological and immunological mechanisms regulating the host responses to injury . traumatic injuries lead to the systemic inflammatory response syndrome ( sirs ) followed by a period of recovery mediated by a counter - regulatory anti - inflammatory response ( cars ) . a mild inflammatory response followed by an excessive cars may induce a prolonged , deleterious immunosuppressed state . this initial traumatic injury is called the first hit and predisposes the patient to a potential risk of deterioration after surgery . in this scenariothe impact of surgery on the patient biological reserve depends on its type and timing . fat emboli and hypoxic events , which may result from early surgery , can add damage to the lungs , already injured by pulmonary contusions or rib fractures . as far as the emergency orthopedic treatment is concerned , the type of initial stabilization and timing of definitive osteosynthesis modulate these adverse events . external fixation has become the dco workhorse , because of its rapidity , as well as reduced blood loss and invasiveness . however , less invasive procedures such as splinting and skeletal traction can still play an important role in the initial stabilization of the multi - injured patient . for most upper extremity injuries , simple stabilization with splints orsplinting without traction is not effective because the joint above the fracture ( the hip ) can not be immobilized . in these fractures , skeletal traction was found to be equal to external fixation in terms of acute respiratory distress syndrome ( ards ) , multiple organ dysfunction syndrome ( mods ) , pneumonia , deep venous thromboembolism ( dvt ) , pulmonary embolism ( pe ) development , as well as icu stay , and death rate . regardingthe timing of definitive osteosynthesis , the period - defined window of opportunity has been set between the 5th and the 10th days . the posttrauma days 2 to 4 have been reported to be unsuitable for performing definitive osteosynthesis . at this time , sustained immunologic changes are ongoing and fluid shifts , increasing generalized tissue edema , are not yet normalized . in a large survey of over 4000 cases , definitive osteosynthesis in patients who later developed mods was performed between days 2 and 4 , whereas patients without mods were operated on between days 6 and 8 ( p 0.0001 ) . therefore , the need for a waiting period of several days before definitive osteosynthesis has emerged . however , the waiting period should preferably be shorter than 15 days , since it has been shown that contamination rates in external fixator pin sites rose substantially after 2 weeks . in conclusion , dco seeks to avoid provoking a severe inflammatory response and confines itself to more modest goals : sufficient stabilization of fractures to prevent further tissue damage and the potential compartment syndrome , while allowing the patient to be mobilized for tests and improved pulmonary care . severely injured patients should be assessed on the basis of the advanced trauma life support ( atls ) criteria . according to these criteria , a primary survey of airway , breathing , circulation , neurological status , and core temperaturethe following conditions must be identified and treated : airway obstruction , inadequate ventilation for tension pneumothorax , open pneumothorax , massive hemothorax , mobile chest flap , hemorrhagic shock , or cardiac tamponade . the next step is based on identification of factors that discourage immediate surgery and lead to selection for dco . diabetic patients are subjected to peripheral vascular deficiency and increased risk of limb ischemia following high - energy fracture . consequently , similar anatomical injuries may lead to different outcomes , based on preexisting patient conditions . the first criteria ascertaining the suitability of blunt trauma patients for orthopedic surgery were published in 1978 . the authors recommended the use of systolic blood pressure , heart rate , central venous pressure , and hematocrit for basic evaluation . in addition , cardiac index , pulmonary arterial pressure , coagulation status , and acid - base balance were found to be of value during the early period after trauma . improved knowledge of the pathophysiological mechanisms of trauma allowed identification of four significant clinical factors . three of them correspond to the so - called lethal triad : hypothermia , coagulopathy , and acidosis . hypothermia begins at the traumatic insult and is thereafter exacerbated by hypoperfusion , prolonged exposure , and inactivity . studies have shown that up to 21 % of trauma patients are hypothermic at presentation ; this figure increases to 46 % when patients leave the operating room . coagulopathy is caused by multiple factors including dilution due to aggressive fluid resuscitation , hypothermia , acidosis , and calcium levels , which have all been shown to affect both the intrinsic and extrinsic clotting cascades . soft tissue injuries are the fourth parameter and may affect the extremities , lung , abdomen , and pelvis . starting from these parameters , pape described four classes of patients , based on their clinical status : stable , borderline , unstable , and in extremis . a patient is classified into one of these four classes , if he or she meets the criteria in at least three of the four pathophysiological parameters , as reported in table 1 . currently , dco is the preferred approach in unstable and in extremis patients . in these patients , immediate surgery would be the cause of the second hit , which may lead to ards , mods , or even death . accordingly , dco should be adopted in patients with a body temperature below 33c , blood pressure less than 90 mmhg , increased lactate levels , platelets count below 90,000 , and major soft tissue injuries . fortunately , the majority of patients fall into the stable or borderline categories . patients , a condition where subjects have no life - threatening injuries , respond to initial therapy , and are hemodynamically stable without inotropic support . these patients have also no evidence of coagulopathy , ongoing occult hypoperfusion , abnormalities of acid base status , or hypothermia . borderline patients represent the most controversial category in which the choice between etc and dco remains uncertain . pape coined the term borderline to describe a patient who is apparently in stable condition before surgery , but who deteriorates unexpectedly and develops organ dysfunction postoperatively . in these patients , the presence of one of the criteria listed in table 2 is an adverse prognostic factor , which recommends dco approach . these criteria include the injury severity score ( iss ) and specific clinical and radiological findings . the iss is an anatomical score system that provides an overall score for patients with multiple lesions and correlates with mortality , morbidity , and hospitalization time after trauma . in addition , the hypothesis of a long duration of surgery argues in favor of dco . elevated mechanical ventilation time , increased mods , and mortality rates have been documented after operations exceeding 6 hours , in comparison to shorter operative procedures . finally , advances in molecular biology might significantly contribute to the development of future therapeutic algorithms . the importance of mediators of the inflammatory response , such as il - 6 , il - 8 , il - 10 , hla - dr class - ii molecules and many other markers , has been recently highlighted . surgery has been shown to cause a variety of subclinical inflammatory alterations that may result in a cumulative effect as a function of preexisting comorbidity and the time elapsed from trauma to surgery . in polytrauma patients , the recognition of high levels of inflammatory markers could favor the dco application , in order to prevent the effects of the second hit inflammatory reaction . il - 6 is considered the most specific prognostic indicator : early high levels of il - 6 have been associated with the development of organ failure . in fact , il - 6 measurement has already been implemented as a routine laboratory test in several trauma centers . the fixation of femoral shaft fractures ( fsf ) in polytrauma patients remains a controversial issue , despite the large number of articles published in the last recent decades . in the 70s and 80s several studies demonstrated that etc of fsf reduces pulmonary complications , mortality , and los . subsequently , this concept was denied by the proponents of the dco , suggesting that external fixation offers the advantage of early skeletal stability , while minimizing blood loss and anesthesia time of the surgical second hitit was also found that patients with serious abdominal injury and chest trauma benefit the most from delayed treatment . in patients with head injuries , etc leads to excessive fluid administration , with consequent increased rates of hypoxemia and hypotension , contributing to a poor neurological outcome . however , in the recent literature , opposing views emerged , questioning the advantages of the dco . in 2007 , weninger et al . concluded that early unreamed intramedullary nailing ( imn ) of femoral fractures is a safe procedure in multiple injury patients with severe thoracic trauma and seems to be justified to achieve early definitive care . likewise , brundage et al . showed that chest and head trauma are not contraindications to early fixation with reamed imn . in this series of 674 patients with multiple injuries , femur fixation within 24 hours ( n = 399 ) , 24 to 48 hours ( n = 79 ) , 48 to 120 hours ( n = 23 ) , and greater than 120 hours of injury ( n = 15 ) was associated with pneumonia in 15 % , 24 % , 35 % ( p 0.05 ) , and 13 % of cases , respectively . this demonstrated the relationship between fixation of femur fractures at days 2 to 5 and the development of pulmonary complications . the conflicting results reported in the literature depend , at least in part , on the different management of multi - injured patients carried out in american and european trauma centers . . observed that dco is applied in only 12 % of patients with multiple traumatic injuries and iss 17 . the rate of dco performed in american centers is much lower ( p 0.05 ) than in european centers ( 36 % to 47 % ) . some european centers aggressively attempt to stabilize femoral fractures in patients with multiple injuries within the first hours after admission . in pape series , only 2 % of patients underwent surgery more than 8 hours after admission to the trauma center . this contrasts with american data : 48 % of patients with femoral fractures underwent surgical intervention more than 8 hours after admission ( average 14 hours ) . the differences in the initial management to polytrauma patient with femur fracture may explain the different outcomes experienced by the centers . the european polytrauma study group on the management of femur fractures performed a randomized multicenter study , comparing etc and dco . amongpatients , the incidence of ards was 16.7 % in the etc group and 11.1 % in the dco group ( p = 0.618 ) . a lower incidence of ards is usually reported in north american studies . in the recent northamerican retrospective series , the incidence of ards was 1.5 % in the etc group and 0.0 % in the dco group ( p = 1.000 ) . from these data , we may conclude that an adequate resuscitation before surgery is essential . finally , bilateral femoral fractures represent a separate entity with different prognosis and therapeutic options . this is a unique scenario associated with a higher mortality and ards rates . in addition , these patients have an increased number of associated injuries ( up to 80 % ) , thus worsening the prognosis . although there is a paucity of literature data on this subset of patients , dco seems to be the ideal strategy . the management of polytrauma patient with pelvic fracture is a major diagnostic and therapeutic challenge both in the immediate postinjury and subsequent definitive fixation phase . pelvic and acetabular fractures are rare injuries and account for approximately 3 % to 8 % of all fractures . however , these fractures , often the result of high - energy trauma , are at high risk of associated injuries , which strongly influence the outcome and survival rates . the poor prognosis of pelvic fractures is related to the high incidence of hemorrhagic shock , due to the anatomical proximity of arteries and veins . fracture and vascular injury can cause the formation of hematoma in the pelvis and retroperitoneum . this space can hold up to 4 liters of blood before the pressure within the hematoma dabs further hemorrhage . in most of the cases ( 90 % ) , the bleeding originates from venous disruption or from cancellous bone , while bleeding is due to an arterial injury in only 10 % of cases . the mortality of polytrauma patients with pelvic fracture and unstable hemodynamics has been reported to be as high as 50 % in one series . early mortality is usually secondary to uncontrolled hemorrhage , whereas late mortality is due to associated injuries and sepsis - induced mods . with advances in resuscitation , a first classification distinguishes stable fractures ( where the pelvic ring is intact or dislocation is minimal and where physical examination did not detect abnormal mobility ) from unstable fractures ( interruption in the continuity of the pelvic ring with abnormal mobility on physical examination ) . fractures are also classified into open or closed depending on whether or not the fracture is in continuity with the skin , the rectum , or the vagina . open fractures , unstable fractures with displacement greater than 5 mm , and fractures with vertical instability associated with structural lesions of the posterior pelvic ring have a higher risk of bleeding . the young - burgess classification is the most widely used , as far as the mechanism of injury , prediction of resuscitation , hemorrhage severity , and associated injuries are concerned . anteroposterior compression injuries ( apc , in which an anteriorly directed force exerts external rotation deformities to the pelvic ring ) are associated with the highest mortality and blood transfusion requirements : on average 20 % and 14.8 units , respectively . in lateral compression injuries ( lc , in which an internal rotation force is directed to the hemi - pelvis ) the decision making in the polytrauma patient with a pelvic ring injury can be divided into two phases : detection and treatment of life - threatening situations ( emergency algorithm ) , followed by diagnosis , classification of the osteoligamentous injury , and operative planning , if required . after initial resuscitation according to atls protocols , the hemodynamic stability should be immediately evaluated . in fact , resuscitation volume as required in hemodynamically unstable patient is unproductive in the long run without an adequate control of the bleeding site . to quickly identify the source of hemorrhage , the efast ( extended focused assessment sonography for trauma ) technique is nowadays crucial . this ultrasound technique allows a rapid examination of lungs , heart , and abdominal organs in search of the source of bleeding . in the absence of a clear extrapelvic bleeding ( that could explain the hemodynamic instability ) , the orthopedic surgeon should assume that the cause of the shock is a retroperitoneal hematoma related to the pelvic fracture . at this point , every effort should be aimed at stabilization of the fracture in order to reduce the volume of the open pelvic ring and to dab the venous bleeding . a method that has proved useful over the years is wrapping of the pelvis . this method consists in binding the pelvis with a commercial device , such as the tpod , or with a sheet , which allows to reduce pelvic volume . this application is rapidly accomplished , is free from side effects , and is usually able to effectively staunch vein bleeding ; these patients can then be safely subjected to total - body ct scan . pelvic binders have largely replaced external fixation and pelvic c - clamp as the best initial means of controlling the hemorrhage associated with unstable fractures of pelvis . in spite ofthe fact that pelvic external fixation can be rapidly applied , reduces the pelvic volume , and provides temporary fracture stabilization , this fixation is located in front of the patient , while pelvic ring instability is predominantly posterior . by compressing the front , external fixationthe pelvic c - clamp also allows rapid reduction and stabilization of the posterior pelvic ring , through the positioning of two nails in the coccyx and sacroiliac joint . this device does not prevent operators ' access to the abdomen but can be burdened with neurological complications , particularly in the presence of sacral fractures . if the patient remains hemodynamically unstable , despite the attempt of external stabilization of the pelvis , the hemorrhagic shock probably has an arterial origin . these patients benefit most from angiographic embolization , a procedure requiring the immediate availability of skilled personnel and highly specialized trauma centers . in a metaanalysis including 26 studies , karadimas et al . although , the effectiveness of arteriographic embolization varied from 59 % 100 % the mortality from pelvic hemorrhage was as high as 25 % . alternatively , pelvic packing is a dco workable strategy in the presence of pelvic fractures and hemoperitoneum ; this approach is especially supported by some european trauma centers . temporary pelvic packing via laparotomy could significantly aid in pelvic bleeding control and provide crucial time for a more selective management of hemorrhage . however , complication rates were significant , including infection ( 35 % ) , mods ( 9 % ) , and an overall mortality rate of 23 % . the subsequent definitive fixation can be performed using different techniques depending on the fracture pattern . for example , injuries of the anterior ring are best treated by open reduction and internal fixation with a plate on the symphysis pubis . disruptions to the sacroiliac ligament can be managed by closed reduction and percutaneous screw fixation , aiming the screw from posterior to anterior across the sacroiliac joint in order to reach the midline of sacrum without emerging anteriorly . in any case , the orthopedic surgeon has to operate only with the final goal of preventing deformities and reducing complications . . as previously mentioned , the main benefits result from earlier mobilization , pulmonary rehabilitation , pain control , and therapy . finally , figure 1 suggests a possible algorithm that summarizes the previous concepts of pelvic fracture management . the variety of clinical presentations in multiple trauma patients makes it difficult to formulate treatment algorithms suitable for each case . the treatment of any individual patient should be tailored according to many variables , such as general medical conditions , fracture patterns , and associated injuries . stable to in extremis proved to be useful in guiding treatment , as summarized in figure 2 . although dco reduces the risk of complications related to the second hit , it requires a second operation and delays patient mobilization . etc should be preferred when the clinical condition of the patient and the presence of well - trained surgical teams permit it . for isolated bone lesions , especially the long ones , early stabilization ensures the reduction of complications , resulting in shorter hospitalization and reduced costs . before deciding the type and timing of surgery , efforts must be focused on optimizing ventilatory and hemodynamic parameters and normalizing lactate levels , by means of an adequate resuscitation strategy . the tumultuous progress in the field of molecular biology and genetics is likely to guide future treatment protocols , as suggested by the discovery of a close relationship between blood inflammatory marker levels and the risk of posttraumatic complications .\noutput:\n" }, { "from": "agent", "value": "the management of the polytraumatized orthopedic patient remains a challenging issue . in recent years many efforts have been made to develop rescue techniques and to promote guidelines for the management of these patients . currently controversies persist between two orthopedic approaches : the early total care and the damage control orthopedics . an overview of the current literature on the orthopedic management of polytrauma patient is provided . subsequently , femoral shaft fractures , representing extremely common lesions , and pelvic ring injuries , that are associated with a high mortality rate , are analyzed in detail ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: models of the geographical range of plant species predict that climate change will have profound impacts ( e.g. 1 , 2 ) . the best - known and most used models to evaluate the influence of climate change on species range fall into two classes : statistical climate envelope models and process - based dynamic vegetation models . both classes assume , firstly , that the range margins of species are determined by macroclimatic factors and , secondly , that the current species range is in equilibrium with the current climate . the explanatory variables used in envelope models include a large array of climatic variables that are assumed to be important , and possible statistical interactions among these variables . the dynamic models commonly include physiological limiting variables that assess cold tolerance , the duration of the growing season and drought tolerance , and competition between species for light , nutrients , water and space . based on this set of explanatory variables , both approaches can result in a very good match between predicted and observed ranges , thus supporting the two basic assumptions of the species range modelling indicated above . this gives confidence to predict the potential future area of a species , based on climate change scenarios provided by global circulation models . potential then refers in most dynamic models to the condition without dispersal limitation , whereas envelope models usually present the results of both unlimited dispersal and of complete dispersal limitation . in some cases , however , species - specific dispersal is estimated 3 . however , many dynamic forest succession models assume that the maximum growth rate is attained at the core of the geographic distribution of a species and decreases toward its limits 4 . this is the consequence of using a parabolic relationship between growth rate and thermal time ( accumulation of days exceeding a temperature threshold , also referred to as growing degree days , gdd ) estimated at these limits . thus , in a warmer climate , the growth rate may locally decline concomitantly with increasing temperature sum . consequently , the model predicts local extinction , even though the growing conditions may actually improve due to the extended growing season . in this paperwe begin by reviewing two major classifications of biogeographical models : envelope models and dynamic models . we show that both the envelope and some dynamic approaches of species area modelling may predict that in the northern hemisphere the southern limit of the species range moves north and the species goes locally extinct on its former southern border even though the growing conditions apparently improve . secondly , we outline a methodology for modelling biogeographical distributions of perennial plants that would in the future avoid the potential modelling error that we have drawn attention to . bioclimatic envelope models assume that climate exerts dominant control over the natural distribution of species 5 , 6 and that the current species range is in equilibrium with its climatic potential area . if valid , time independent , statistical correlations between climate variables at the limits of the species ' geographical distribution can be used to describe current ranges . the potential future range of a species can subsequently be assessed by using future projections of climate change obtained from global circulation models ( see 7 for a review ) . the approach is based on the concept of the fundamental niche 8 which is defined by the abiotic conditions where the species can survive , grow and reproduce ( see 9 for an extensive discussion ) . hence , biotic interactions such as competition or predation are not directly considered . moreover , if only climatic variables are used , what is described is the climatic niche rather than the fundamental niche , as the latter is also determined by local abiotic pedological features , such as the ph . the climate envelope is , however , based on observed ranges obtained from presence / absence or abundance data : it is based on the realised niche of a species and does not explicitly consider the conditions the species requires for survival , growth and reproduction . biotic interactions are thus implicit in the correlation between the species area and the climate 6 . various advanced statistical techniques are deployed to correlate climate variables with species ranges 10 - 12 . additionally , techniques have been developed to refine the climatic envelope to allow more detailed environmental description of fragmented habitat of a species . for example by including generic soil and topographical features 13 . two important advantages of these techniques are that only the current geographical distribution of the species is required ( presence / absence data per grid cell ) and that the only climate variables required are long - term meteorological averages or variability , and the changes to these predicted by global circulation models . as both data sources are currently widely available , the analysis can be applied to a large number of species and over large areas . however , davis and co - workers 14 , 15 argue that the method is essentially invalid as it fails to consider biotic interactions . these interactions might be essentially true at local scales if neutral assemblages are not the rule 16 . moreover , if a species has a limited dispersal capacity , its current range might not be in equilibrium with its potential range as determined by climate 17 . a final drawback of correlative envelope models is that they do not include physiological information and hence do not assess differential responses of species to an increased concentration of atmospheric co214 . firstly , they point out that bioclimatic envelope models can be highly successful in predicting current species ranges . secondly , they indicate that for species dispersal it is the rare long - term dispersal events that critically determine the rate of change of geographical areas 18 . these rare events can be assumed to continue and may be becoming less unusual , as humans act as powerful dispersal vectors . thirdly , pearson and dawson argue that envelope models should be seen within a hierarchy of increasingly detailed models when assessing the presence of a species at the scale of the continent , region , landscape or plot . fourthly , they find that the response of species to elevated co2 is too complex and uncertain to be included in the models and therefore should be ignored for the time being 5 , 19 . but see rickebusch et al . 20 and hickler et al . 21 for a recent attempt to account for hydrological effects of increasing atmospheric co2 . the potential prediction error of local extinction with improving growing conditions that we signal here , in addition to those described above , does not seem to have received attention in the literature . figure 1 presents an example of a future projection of climate change impact ( a2 - scenario , 22 ) on a species area of european beech ( fagus sylvatica l. ) using an ensemble approach of statistical envelope models implemented in the biomod r - package 12 , 23 for details ) . the model predicts a northward shift of the southern limit of beech distribution . for this ensemble of models , the most important factor that cause beech to go extinct locally is growing degree days in august ( figure 2 ) . dynamic biogeographical models use bioclimatic variables to constrain the environmental space based on adaptive traits related to a species ' ability to survive , and the capacity to gain resources for growth and reproduction , i.e. survival and capacity adaptation 24 . survival adaptation refers to the physiological traits that improve the likelihood of a species surviving potentially fatal conditions ; examples are frost hardiness , drought tolerance , resistance to fire , tolerance to grazing and dormancy of seeds . winter cold requirements expressed as chilling requirements during the dormant period ( together these determine the start of the growing season ) , and iii . these three physiological limiting processes related to the survival of plants are discussed in more detail below . i. tolerance of winter cold is described by isotherms of the minimum temperature , or the mean temperature of the coldest month 25 . winter tolerance represents a potential mortality factor , hence a climate change entailing warmer winters means that new habitat will become available and a potential northward shift of the northern limits of a species range can reliably be predicted . the winter cold requirement ( number of chilling days , with mean temperature below 5c ) for bud burst , is often assumed to reduce the thermal time at an exponential rate 26 . as this so - called alternating model 28is not constrained by a minimum thermal time , it may predict bud burst in the absence of forcing temperature 27 . additionally , the alternating model is very sensitive to a small variation in the parameter in the exponent , which is difficult to estimate accurately 28 , and overestimates the advance of bud burst with increasing temperature 29 . drought tolerance is often expressed as the ratio of actual evapotranspiration to potential evapotranspiration , which represents moisture availability 30 . alternatively , in some models drought tolerance is expressed as the relative water content in the soil between wilting point and field capacity during the growing season 31 . drought stress is a mortality factor that determines the southern and eastern margins of the range of european plant species 32 - 34 . capacity adaptation refers to traits that promote resource gain , such as harvesting of light , uptake of nutrients and water , and occupancy of space , all of which improve a species ' ability to compete for limiting resources . dynamic models include extensive process - based descriptions of the uptake and release of carbon , water and nutrients in relation to morphological traits such as growth form and leaf habit , and to physiological traits such as shade tolerance , photosynthetic pathway ( c3 or c4 ) and allocation pattern . dynamic models usually take a mass - balance approach to resources in the ecosystem . consequently , actual plant growth is the result of the most limiting resource , given the constraints of the plant 's morphological and physiological traits . dynamic models that are based on the above described principle of physiologically limiting factors ( related to survival and the capacity to gain resources ) , constrained by morphological features , fall in two broad categories : dynamic vegetation models and dynamic species models . the detail in which these models describe physiological limiting factors , morphological features , population dynamics and competition varies greatly , however , depending on the purpose for which the model has been developed . these models focus on the distribution of plant functional types or biomes at the global scale that are characterised by their physiognomy , such as evergreen vs. deciduous ; needle - leaved vs. broad - leaved and different life forms ( grass ; shrubs ; trees ) 34 - 38 . for this paper , however , we focus on the models of perennial plant species . dynamic species models almost exclusively address woody species and are referred to as forest succession models 4 , 39 - 41 . they include much mechanistic detail and are therefore more often used to assess a species ' response to climate change at a particular location 42 rather than to evaluate climate change impacts on species ranges . forest succession models are usually based on gap phase replacement of trees , and therefore explicitly take into account conditions for regeneration , competition for light , water and nutrients , and mortality 43 . they may also take into account responses ( e.g. growth , seed production and phenology ) to elevated co2 and temperature 33 , 44 . moreover , they allow the impacts of disturbances and changes in disturbance regimes to be explicitly modelled and analysed 45 - 47 . in the latest generation of forest succession models , sometimes referred to as process - based forest models , growth is modelled as the outcome of physiological processes such as photosynthesis , respiration , leaf and fine root turnover , and allocation of carbon gains to different tissues ( e.g. fine roots , sapwood , and leaves ) 33 , 39 , 47 . the different processes are parameterised on the basis of independent measurements , rather than fitted to species ranges . models of this type preclude the unrealistic prediction that a species will go extinct locally as growing conditions improve . however , they require many parameters that are not easily obtainable from the literature or fieldwork . they do not usually take account of the process of spatial seed dispersal ; if they do , they demand much processor time 46 . the dynamic approach based on physiological limiting factors as applied in the process - based forest models has the advantage that responses to climate change have a mechanistic basis and therefore future projections can be assumed to be more reliable than the statistical correlative approach . in addition , these models provide the basis for the analysis of ecosystem functioning in terms of cycling of carbon , water and nutrients and the importance of trait diversity for the maintenance and resilience of these functions in the face of climate and land use change 48 - 52 . however , the species - specific parameters defining the bioclimatic limits are usually not independently determined empirically or by observation , but instead are fitted to the observed species range 53 . this procedure assumes equilibrium between current species occurrences and climate factors , as in envelope models . a classic example is that of relating optimal growth to thermal time ( expressed as gdd5 ) based on a parabolic curve 54 with minimum and maximum gdd5 values fitted to the northern and southern limits of the species area , respectively . the potential risk of this approach is that with increasing growing degree days , the growth rate may decline and attain zero value , thereby producing a predicted northward shift of the southern limit of the species . this can have dramatic consequences for future projections of climate change on a species area depending on the critical upper gdd5 value and the current species distribution ( figure 3 ) . yet despite this , the approach is still often used to scale up forest succession models developed for the stand scale , to species area 4 . the predicted northward shift of a southern limit is realistic only if the relative competitive ability of the given species decreases with improved environmental conditions , which implies that the southern limit of plant species adapted to warmer climates is determined by biotic interactions 55 . the latest generation of process - based models does determine whether a change in species boundary is caused by physiological constraints ( i.e. caused by traits related to survival adaptation ) and / or is due to competition ( i.e. caused by traits related to capacity adaptation ) . as an example of such a model outcome , figure 4 presents the future projection of climate change impact ( a2 - scenario , 22 ) on a species area of european beech ( fagus sylvatica l. ) using the dynamic species model lpj - guess 33 , 47 . the model predicts a reduction of leaf area index ( lai , figure 4a ) not only in the south and south - east of europe , but also in the north - west . in this case , the decrease is not caused by higher temperature but by decreasing soil water ( figure 4b ) and milder winters , which delays budburst in western beech populations 26 ( results not shown ) . changes in soil water have a direct effect because in the model the establishment of european beech is constrained by a threshold for the average growing - season soil water content . milder winters have an indirect effect through competition with other species , which can take more advantage of the warmer climate because budburst is less delayed by the milder winters . thus in this example , the capacity adaptation of beech is less than that of its competitors . in other words , the process model confirms the results obtained from the statistical model ( see figure 1 ) , but for entirely different reasons . to avoid predicting local extinction despite improved growing conditions for perennial plants , we propose a method in which the future projections of the envelope models are constrained by changes in the geographical distribution of dominant plant species assessed by a dynamic species model on dominant plant species . the null - model , without biotic interactions , can be tested on a species ' current range that provides data for validating the model . a mismatch between the observed and predicted species ranges indicates the importance of biotic interactions with other species : if these turn out to be important , the null model is not a suitable tool for assessing the impacts of climate change on the future range of the species , and species interactions should be taken into account . the statistical bioclimatic envelope models could be applied to a large number of the plant species within the future projection of dominant species made by the dynamic species models . the importance of biotic explanatory factors can be assessed by examining how much the model 's goodness - of - fit improves when supposedly important biotic variables are added to the bioclimatic model 56 , 57 . in addition , consistency between statistical and dynamic modelling approaches can be tested if the species is actually physiological constrained by the particular climate envelope . though both dynamic models of dominant species and statistical envelope models are well - established , there is little harmonisation in the current attempts to refine their selection of explanatory variables . to avoid the potential modelling error that local species extinction is predicted despite improved growing conditions , data can be exchanged between models in order to assess the importance of biotic interactions and to check for consistency of the models ' forecasts 58 , 59 . moreover , it is useful to analyse the models ' responses to changes in climatic drivers in terms of changes in morphological and physiological traits and diversity thereof : such an analysis can be based on the current theory on ecosystem functioning based on functional trait diversity ( i.e. diversity of response and effect traits ) 48 - 50 , 52 , 60 , 61 instead of on a particular species composition . in that way , predictions of range shift of the geographic distribution of dominant plant species can be downscaled to assess changes in functional trait diversity within ecosystems and their consequences for the functioning and resilience of ecosystems in the face of climate change . we believe that for policy making that anticipates climate change it is important to model the range shifts of species in a consistent way , as only then will the implications of climate change for the functioning of ecosystems be properly understood . this requires closer collaboration between research communities working with different modelling approaches . instead of building a model that integrates dynamic species modelling and statistical species modelling it will be necessary for these research communities to co - ordinate the selection of driving variables and to exchange compatible data . bioclimatic envelope models assume that climate exerts dominant control over the natural distribution of species 5 , 6 and that the current species range is in equilibrium with its climatic potential area . if valid , time independent , statistical correlations between climate variables at the limits of the species ' geographical distribution can be used to describe current ranges . the potential future range of a species can subsequently be assessed by using future projections of climate change obtained from global circulation models ( see 7 for a review ) . the approach is based on the concept of the fundamental niche 8 which is defined by the abiotic conditions where the species can survive , grow and reproduce ( see 9 for an extensive discussion ) . hence , biotic interactions such as competition or predation are not directly considered . moreover , if only climatic variables are used , what is described is the climatic niche rather than the fundamental niche , as the latter is also determined by local abiotic pedological features , such as the ph . the climate envelope is , however , based on observed ranges obtained from presence / absence or abundance data : it is based on the realised niche of a species and does not explicitly consider the conditions the species requires for survival , growth and reproduction . biotic interactions are thus implicit in the correlation between the species area and the climate 6 . various advanced statistical techniques are deployed to correlate climate variables with species ranges 10 - 12 . additionally , techniques have been developed to refine the climatic envelope to allow more detailed environmental description of fragmented habitat of a species . for example by including generic soil and topographical features 13 . two important advantages of these techniques are that only the current geographical distribution of the species is required ( presence / absence data per grid cell ) and that the only climate variables required are long - term meteorological averages or variability , and the changes to these predicted by global circulation models . as both data sources are currently widely available , the analysis can be applied to a large number of species and over large areas . however , davis and co - workers 14 , 15 argue that the method is essentially invalid as it fails to consider biotic interactions . these interactions might be essentially true at local scales if neutral assemblages are not the rule 16 . moreover , if a species has a limited dispersal capacity , its current range might not be in equilibrium with its potential range as determined by climate 17 . a final drawback of correlative envelope models is that they do not include physiological information and hence do not assess differential responses of species to an increased concentration of atmospheric co214 . firstly , they point out that bioclimatic envelope models can be highly successful in predicting current species ranges . secondly , they indicate that for species dispersal it is the rare long - term dispersal events that critically determine the rate of change of geographical areas 18 . these rare events can be assumed to continue and may be becoming less unusual , as humans act as powerful dispersal vectors . thirdly , pearson and dawson argue that envelope models should be seen within a hierarchy of increasingly detailed models when assessing the presence of a species at the scale of the continent , region , landscape or plot . fourthly , they find that the response of species to elevated co2 is too complex and uncertain to be included in the models and therefore should be ignored for the time being 5 , 19 . but see rickebusch et al . 20 and hickler et al . 21 for a recent attempt to account for hydrological effects of increasing atmospheric co2 . the potential prediction error of local extinction with improving growing conditions that we signal here , in addition to those described above , does not seem to have received attention in the literature . figure 1 presents an example of a future projection of climate change impact ( a2 - scenario , 22 ) on a species area of european beech ( fagus sylvatica l. ) using an ensemble approach of statistical envelope models implemented in the biomod r - package 12 , 23 for details ) . the model predicts a northward shift of the southern limit of beech distribution . for this ensemble of models , the most important factor that cause beech to go extinct locally is growing degree days in august ( figure 2 ) . dynamic biogeographical models use bioclimatic variables to constrain the environmental space based on adaptive traits related to a species ' ability to survive , and the capacity to gain resources for growth and reproduction , i.e. survival and capacity adaptation 24 . survival adaptation refers to the physiological traits that improve the likelihood of a species surviving potentially fatal conditions ; examples are frost hardiness , drought tolerance , resistance to fire , tolerance to grazing and dormancy of seeds . winter cold requirements expressed as chilling requirements during the dormant period ( together these determine the start of the growing season ) , and iii . drought tolerance . these three physiological limiting processes related to the survival of plants are discussed in more detail below . i. tolerance of winter cold is described by isotherms of the minimum temperature , or the mean temperature of the coldest month 25 . winter tolerance represents a potential mortality factor , hence a climate change entailing warmer winters means that new habitat will become available and a potential northward shift of the northern limits of a species range can reliably be predicted . ii . the winter cold requirement ( number of chilling days , with mean temperature below 5c ) for bud burst , is often assumed to reduce the thermal time at an exponential rate 26 . as this so - called alternating model 28is not constrained by a minimum thermal time , it may predict bud burst in the absence of forcing temperature 27 . additionally , the alternating model is very sensitive to a small variation in the parameter in the exponent , which is difficult to estimate accurately 28 , and overestimates the advance of bud burst with increasing temperature 29 . drought tolerance is often expressed as the ratio of actual evapotranspiration to potential evapotranspiration , which represents moisture availability 30 . alternatively , in some models drought tolerance is expressed as the relative water content in the soil between wilting point and field capacity during the growing season 31 . drought stress is a mortality factor that determines the southern and eastern margins of the range of european plant species 32 - 34 . capacity adaptation refers to traits that promote resource gain , such as harvesting of light , uptake of nutrients and water , and occupancy of space , all of which improve a species ' ability to compete for limiting resources . dynamic models include extensive process - based descriptions of the uptake and release of carbon , water and nutrients in relation to morphological traits such as growth form and leaf habit , and to physiological traits such as shade tolerance , photosynthetic pathway ( c3 or c4 ) and allocation pattern . dynamic models usually take a mass - balance approach to resources in the ecosystem . consequently , actual plant growth is the result of the most limiting resource , given the constraints of the plant 's morphological and physiological traits . dynamic models that are based on the above described principle of physiologically limiting factors ( related to survival and the capacity to gain resources ) , constrained by morphological features , fall in two broad categories : dynamic vegetation models and dynamic species models . the detail in which these models describe physiological limiting factors , morphological features , population dynamics and competition varies greatly , however , depending on the purpose for which the model has been developed . these models focus on the distribution of plant functional types or biomes at the global scale that are characterised by their physiognomy , such as evergreen vs. deciduous ; needle - leaved vs. broad - leaved and different life forms ( grass ; shrubs ; trees ) 34 - 38 . for this paper , however , we focus on the models of perennial plant species . dynamic species models almost exclusively address woody species and are referred to as forest succession models 4 , 39 - 41 . they include much mechanistic detail and are therefore more often used to assess a species ' response to climate change at a particular location 42 rather than to evaluate climate change impacts on species ranges . forest succession models are usually based on gap phase replacement of trees , and therefore explicitly take into account conditions for regeneration , competition for light , water and nutrients , and mortality 43 . they may also take into account responses ( e.g. growth , seed production and phenology ) to elevated co2 and temperature 33 , 44 . moreover , they allow the impacts of disturbances and changes in disturbance regimes to be explicitly modelled and analysed 45 - 47 . in the latest generation of forest succession models , sometimes referred to as process - based forest models , growth is modelled as the outcome of physiological processes such as photosynthesis , respiration , leaf and fine root turnover , and allocation of carbon gains to different tissues ( e.g. fine roots , sapwood , and leaves ) 33 , 39 , 47 . the different processes are parameterised on the basis of independent measurements , rather than fitted to species ranges . models of this type preclude the unrealistic prediction that a species will go extinct locally as growing conditions improve . however , they require many parameters that are not easily obtainable from the literature or fieldwork . they do not usually take account of the process of spatial seed dispersal ; if they do , they demand much processor time 46 . the dynamic approach based on physiological limiting factors as applied in the process - based forest models has the advantage that responses to climate change have a mechanistic basis and therefore future projections can be assumed to be more reliable than the statistical correlative approach . in addition , these models provide the basis for the analysis of ecosystem functioning in terms of cycling of carbon , water and nutrients and the importance of trait diversity for the maintenance and resilience of these functions in the face of climate and land use change 48 - 52 . however , the species - specific parameters defining the bioclimatic limits are usually not independently determined empirically or by observation , but instead are fitted to the observed species range 53 . this procedure assumes equilibrium between current species occurrences and climate factors , as in envelope models . a classic example is that of relating optimal growth to thermal time ( expressed as gdd5 ) based on a parabolic curve 54 with minimum and maximum gdd5 values fitted to the northern and southern limits of the species area , respectively . the potential risk of this approach is that with increasing growing degree days , the growth rate may decline and attain zero value , thereby producing a predicted northward shift of the southern limit of the species . this can have dramatic consequences for future projections of climate change on a species area depending on the critical upper gdd5 value and the current species distribution ( figure 3 ) . yet despite this , the approach is still often used to scale up forest succession models developed for the stand scale , to species area 4 . the predicted northward shift of a southern limit is realistic only if the relative competitive ability of the given species decreases with improved environmental conditions , which implies that the southern limit of plant species adapted to warmer climates is determined by biotic interactions 55 . the latest generation of process - based models does determine whether a change in species boundary is caused by physiological constraints ( i.e. caused by traits related to survival adaptation ) and / or is due to competition ( i.e. caused by traits related to capacity adaptation ) . as an example of such a model outcome , figure 4 presents the future projection of climate change impact ( a2 - scenario , 22 ) on a species area of european beech ( fagus sylvatica l. ) using the dynamic species model lpj - guess 33 , 47 . the model predicts a reduction of leaf area index ( lai , figure 4a ) not only in the south and south - east of europe , but also in the north - west . in this case , the decrease is not caused by higher temperature but by decreasing soil water ( figure 4b ) and milder winters , which delays budburst in western beech populations 26 ( results not shown ) . changes in soil water have a direct effect because in the model the establishment of european beech is constrained by a threshold for the average growing - season soil water content . milder winters have an indirect effect through competition with other species , which can take more advantage of the warmer climate because budburst is less delayed by the milder winters . thus in this example , the capacity adaptation of beech is less than that of its competitors . in other words , the process model confirms the results obtained from the statistical model ( see figure 1 ) , but for entirely different reasons . to avoid predicting local extinction despite improved growing conditions for perennial plants , we propose a method in which the future projections of the envelope models are constrained by changes in the geographical distribution of dominant plant species assessed by a dynamic species model on dominant plant species . the null - model , without biotic interactions , can be tested on a species ' current range that provides data for validating the model . a mismatch between the observed and predicted species ranges indicates the importance of biotic interactions with other species : if these turn out to be important , the null model is not a suitable tool for assessing the impacts of climate change on the future range of the species , and species interactions should be taken into account . the statistical bioclimatic envelope models could be applied to a large number of the plant species within the future projection of dominant species made by the dynamic species models . the importance of biotic explanatory factors can be assessed by examining how much the model 's goodness - of - fit improves when supposedly important biotic variables are added to the bioclimatic model 56 , 57 . in addition , consistency between statistical and dynamic modelling approaches can be tested if the species is actually physiological constrained by the particular climate envelope . though both dynamic models of dominant species and statistical envelope models are well - established , there is little harmonisation in the current attempts to refine their selection of explanatory variables . to avoid the potential modelling error that local species extinction is predicted despite improved growing conditions , data can be exchanged between models in order to assess the importance of biotic interactions and to check for consistency of the models ' forecasts 58 , 59 . moreover , it is useful to analyse the models ' responses to changes in climatic drivers in terms of changes in morphological and physiological traits and diversity thereof : such an analysis can be based on the current theory on ecosystem functioning based on functional trait diversity ( i.e. diversity of response and effect traits ) 48 - 50 , 52 , 60 , 61 instead of on a particular species composition . in that way , predictions of range shift of the geographic distribution of dominant plant species can be downscaled to assess changes in functional trait diversity within ecosystems and their consequences for the functioning and resilience of ecosystems in the face of climate change . we believe that for policy making that anticipates climate change it is important to model the range shifts of species in a consistent way , as only then will the implications of climate change for the functioning of ecosystems be properly understood . instead of building a model that integrates dynamic species modelling and statistical species modelling it will be necessary for these research communities to co - ordinate the selection of driving variables and to exchange compatible data .\noutput:\n" }, { "from": "agent", "value": "two assumptions underlie current models of the geographical ranges of perennial plant species : 1 . current ranges are in equilibrium with the prevailing climate , and 2 . changes are attributable to changes in macroclimatic factors , including tolerance of winter cold , the duration of the growing season , and water stress during the growing season , rather than to biotic interactions . these assumptions allow model parameters to be estimated from current species ranges . deterioration of growing conditions due to climate change , e.g. more severe drought , will cause local extinction . however , for many plant species , the predicted climate change of higher minimum temperatures and longer growing seasons means , improved growing conditions . biogeographical models may under some circumstances predict that a species will become locally extinct , despite improved growing conditions , because they are based on an assumption of equilibrium and this forces the species range to match the species - specific macroclimatic thresholds . we argue that such model predictions should be rejected unless there is evidence either that competition influences the position of the range margins or that a certain physiological mechanism associated with the apparent improvement in growing conditions negatively affects the species performance . we illustrate how a process - based vegetation model can be used to ascertain whether such a physiological cause exists . to avoid potential modelling errors of this type , we propose a method that constrains the scenario predictions of the envelope models by changing the geographical distribution of the dominant plant functional type . consistent modelling results are very important for evaluating how changes in species areas affect local functional trait diversity and hence ecosystem functioning and resilience , and for inferring the implications for conservation management in the face of climate change ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: invasive candidiasis is the most common fungal infection reported in healthcare - associated infections . depending on the series , candida albicans is the 3rd or 4th cause of catheter - associated blood stream infections in children . in recent years , non - albicans species have been more frequently isolated , including candida parapsilosis in neonates and others such as , c. glabrata , c. krusei , c. guillermondi all of these important because of their resistance to azoles , . kodamaea ohmeri , formerly named pichia ohmeri , corresponds to the telemorphic ( sexual ) state of candida guilliermondii var . it is a yeast which was initially isolated in cucumber salts used in the food industry for the fermentation of pickled foods , tree barks and fruits . it has also been isolated from environmental sources such as , pools , sand , floors and sea water . in the past , kodamaea ohmeri , was considered a contaminant , but at present some species are recognized as emerging opportunistic pathogens which can cause infection in patients with special underlying conditions including prematurity , immunosuppression , prolonged hospitalizations , prosthetic valves , cvl 's or other medical devices such as peritoneal catheters . a male infant 54 days old , developed fever , tachycardia , leukocytosis , high reactive c protein and thrombocytopenia while he was hospitalized since 21 days ago because diarrhoea , respiratory distress and hypovolemic shock that needed nicu admission , with diagnosis of acute necrotizing enterocolitis ( nec ) . he was born at 35 weeks , delivered at home and small for gestational age . during the hospitalizationhe had required mechanical ventilation and treatment with ampicillin , vancomycin , meropenem and fluconazole for 9 days because suspect of fungemia and had also bacteremia by s. epidermidis , multilobar pneumonia and cytomegalovirus pneumonitis treated with ganciclovir . at time of clinical worsening , yeasts were isolated from peripheral and central line blood cultures , caspofungin was started and cvl was removal . further identification of the yeast by the automatic system vitek - 2 ( yst biomrieux , marcy - letoile , france ) was kodamaea ohmeri ( pichia ohmeri ) . subsequently , it was subcultured in sabouraud dextrose agar in which white , rugged colonies were observed , which did not grow in mycosel culture media . in addition , it was also plated in chromagar media for candida withgrowth of pink colonies that later turned to a blue - green color ( fig . 1 , fig . susceptibility testing revealed resistance to fluconazole with the following minimal inhibitory concentrations ( mic 's ) : fluconazole = 8 g / dl , amphotericin b = 0.5 g / ml and voriconazole = 0.12 g / ml ( see table 1 ) . treatment with amphotericin b deoxicolate ( amb - doc ) iv at a dose of 1 mg / kg / day was started along with good clinical response . follow up blood cultures on the 5th day of treatment were negative and antifungal treatment was continued for a total of 14 days since the first negative blood culture . the first clinical isolate of kodamaea ohmeri was reported in 1984 from a pleural fluid sample but at that time it was considered a contaminant . that same year , fungemia in a 48 year old diabetic patient with immunosuppression due renal transplantation was reported , who subsequently died from the infection . since then , more infections with this yeast have been reported considering it a true clinical pathogen , especially in patients with underlying immunosuppression . the most of those case reports are from asia ( korea , turkey , india ) . there are a few from north america , some from brazil and none from colombia . the largest series reported in the same site included 38 patients from a tertiary care hospital in north india , with 78.9 % of these cases corresponding to neonates in intensive care units . in that series , the attributed mortality from this infection was 31.8 % , but there are other reports of mortality as high as 50 % in the pediatric population , , . of the 5 species recognized in the kodamaea genus , only k. ohmeri has the capacity to grow at 37 c and cause human disease . the clinical relevance of the other species of kodamaea ( k. anthrophila , k. kakaduensis , k. laetipori , k. nitidulidarum ) has not been established . one of the methods currently available for identification is the api 20c test for carbohydrate fermentation , which is considered the gold standard for identification of yeasts . in this testthis method can have false positive results identifying some species of c. haemulonii or c.parapsilosis as k. ohmeri . another method is the vitek 2 id - yst system which identifies with more accuracy this species of candida , although there have been some missed identifications with c. haemulonii . . the chromagar candida ( bbl , beckton dickinson , sparks , md ) method allows species identification according to the color changes of the colonies in the agar , in which k. ohmeri changes from pink to blue in a period of 48 h , as was observed in our case . molecular diagnosis is available through the amplification and sequencing of the its2 region localized on the rrna gen of the 5.8 s and 28s subunit . it can also be typed through restriction endonucleases by pulsed field gel electrophoresis for analysis of genomic dna . the latter is one of the most reliable methods for the correct identification of this yeast but only available in research laboratories or for epidemiological purposes . dominguez et al . , reported the identification of k. ohmeri by maldi - tof with an accuracy comparable to pcr but better than the one obtained through api20c . k. ohmeri has been described as causing fungemias , catheter associated infections , phlebitis , wound infections , peritonitis , endocarditis as well as outbreaks in intensive care units table 2 . all : acute lymphoblastic leukemia , nec : necrotizing enterocolitis , cvl : central venous line , tpn : total parenteral nutrition , amb : amphotericin b , fcz : fluconazole . risk factors reported in children are : prematurity , low birth weight , prolonged icu stay , use of medical devices , prosthetic valves , use of broad spectrum antibiotics , total parenteral nutrition , immunosuppression ( leukemias , lymphomas ) and neutropenia . therefore , k. ohmeri can be considered an opportunistic pathogen that can cause severe infections in patients with underlying conditions . to date , there is only one case reported of infection in a previously healthy child with no predisposing conditions except for encephalitis . other risk factors reported in adults are : diabetes , malignancies , intravenous drug use , cardiac prosthetic valves and chronic renal disorders . no intrinsic resistance of k. ohmeri to antifungals has been reported to date . there have been several reports of fluconazole resistance , some reports of echinocandin resistance and only one report of an isolate with high mic 's to amphotericin b. therefore , antifungal treatment should be adjusted according to susceptibility reports of the clinical isolates . treatment of infections caused by k. ohmeri is similar to fungemias due to candida spp . and other yeasts . removal of cvl 's or other medical devices is mandatory , as well as , treatment with parenteral antifungals adjusted to fungal susceptibility reports . k. ohmeri , is frequently resistant to fluconazole , therefore , it should not be used for empirical therapy due to the risk of clinical failure . amphotericin b is the treatment of choice , with echinocandins as second line therapy . in cases with dose - dependent susceptibility to fluconazole , treatment may be successful using high doses of fluconazole . clinical and laboratory standards institute ( clsi ) has defined that fungal susceptibility break points for this yeast are the same as those for c. albicans isolates : fluconazole mic 2 g / l susceptible , 4 g / ml dose - dependent susceptibility , and 8 g / l resistant . for amphotericin b , mic 1 g / ml susceptible and 1 g / ml resistant . for caspofungin = 0.25 g / ml susceptible , 0.5 g / ml intermediate and = 1 g / ml resistant , with no category for dose - dependent susceptibility . in the study reported by lee et al . eventhough , susceptibility data to equinocandins is scarce , it seems that micafungin and anidulafungin are good treatment options in patients with isolates that are resistant to azoles and in whom treatment with amphotericin b is contraindicated . there are reports of clinical failures with fluconazole , in which case therapy has been continued with amphotericin b or caspofungin , . chakrabarti et al . , describes the largest pediatric series to date from a hospital in north india . this series included 38 isolates of k. ohmeri of which 37 were susceptible to azoles with mic 's between 0.5 and 32 ( according to break points available at that time ) , and only one resistant isolate with an mic of 64 mg / ml . all the isolates were also susceptible to caspofungin with mic 's between 0.12 and 1 mg / ml . interestingly , 86.8 % of the isolates had high mic 's to amphotericin b ( mic 1 mg / ml ) , in contrast to most of the other cases reported in the literature to date . catheter - associated fungemias are an important cause of morbidity and mortality in neonates and critically ill children . kodamaea ohmeri is a yeast that belongs to the species of candida guillermondi which is an infrequent cause of infections in children , but the mortality associated with these infections can be as high as 50 % . high rates of resistance to azoles has been reported , therefore , empirical treatment with amphotericin b or echinocandins should be started and adjusted according to antifungal susceptibility tests .\noutput:\n" }, { "from": "agent", "value": "fungal infections have become an important cause of morbidity and mortality in hospitalized children due to many complicating and underlying conditions . we present the case of a newborn infant with fungemia due to kodamaea ohmeri who had a good outcome of the infection after using the combination of antifungal treatment and central venous catheter removal ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: phlegmonous gastritis ( pg ) is an uncommon and fatal disease characterized by suppurative bacterial infection of the stomach wall .12 it can progress rapidly and even form grossly suppurative exudate or pus within several days . thus , strong clinical suspicion and rapid diagnosis are important to the prognosis . with antibiotic therapy , the mortality rate has decreased . however , the overall mortality is still about 27 % .3 although there are several reports about pg , to the best of our knowledge , there has been no report of its development during the diagnostic evaluation and following treatment of early gastric cancer ( egc ) after diagnosis of pg . herein , we report a case of pg that developed after performing a biopsy for the diagnosis of egc . the patient had multiple comorbidities of alcoholic liver cirrhosis , diabetes mellitus , hypertension , and a history of right posterior liver sectionectomy for hepatocellular carcinoma . after successful treatment of pg with antibiotics , endoscopic ablation therapy ( argon plasma coagulation , apc ) was performed for the treatment of gastric cancer . however , local recurrence was found after two years , and the patient underwent subtotal gastrectomy with lymph node dissection . a 74 - year - old man with alcoholic liver cirrhosis underwent esophagogastroduodenoscopy ( egd ) for varix evaluation . the patient had diabetes mellitus , hypertension , and alcoholic liver cirrhosis with child - pugh class a liver function . on egd , two lesions were noted : a 1.2 - cm ill - defined erythematous depression at the distal antrum and a 0.5 - cm erythematous mucosal area at the proximal antrum ( fig . biopsy specimens were obtained from the two lesions . because of continuous bleeding at the proximal antrum after biopsy , endoscopic saline was administered and the bleeding stopped . nine hours later , he visited the emergency department of a local hospital because of upper abdominal pain and vomiting and was transferred to our hospital . blood pressure was 141/71 mmhg and the heart rate was 99 beats per minute ; his body temperature was 36.7 . bowel sounds were normoactive , and the upper abdomen was tender to palpation , but there was no evidence of peritonitis . the blood test showed leukocytosis with neutrophilic left shift ( white blood cell count , 18,490 / l , 88.5 % neutrophils ) . the patient did not have anemia , and serum alanine aminotransferase , total bilirubin , alkaline phosphatase , lactate dehydrogenase , amylase , and lipase were within normal ranges . abdominal computed tomography ( ct ) showed marked edematous wall - thickening in the gastric antrum , with an air bubble . egd performed on the same day showed diffuse thickening of mucosal folds , which was compatible with pg and biopsy - induced mucosal erosion ( fig . histologic results of the biopsies showed well - differentiated adenocarcinoma at the distal antrum and chronic gastritis at the proximal antrum . after 9 days of hospitalization , we tried to perform endoscopic submucosal dissection ( esd ) for egc . however , the attempt failed , because the stomach was still diffusely edematous and purulent discharge made the procedure difficult ( fig . esd seemed to be impossible in the near future because of submucosal pus and subsequent fibrosis . in addition , surgical resection such as subtotal gastrectomy was considered a high - risk procedure because the stomach wall was filled with pus and the patient had multiple comorbidities . apc was performed as previously described .4 the equipment for apc included an argon gas source ( apc300 ; erbe elektromedizin , tbingen , germany ) and high - frequency generator ( vio 300d ; erbe elektromedizin ) . the argon gas flow rate was 2.0 l / min , with the current set at 60 w. culture of the purulent discharge was not attempted . the egd at 14 days after apc still showed a whitish purulent discharge but improved mucosal edema . three months after apc , egd showed apc scars without discharge or edematous mucosa ( fig . six months after apc , egd biopsy showed adenocarcinoma in the apc scars and we repeated the apc ( fig .3 b ) . at the 9 - , 12 - , and 18 - month follow - ups after the initial apc , egd biopsy showed chronic gastritis . at the 24 - month follow - up after initial apcthus , we decided to perform subtotal gastrectomy with lymph node dissection ( d1 plus alpha ) for recurrent egc . final pathology revealed a 2.2 - cm egc with tubular , well differentiated adenocarcinoma confined within the muscularis mucosa . about 500 cases have been published worldwide , with 15 cases in korea .356 pg is caused by bacterial infection spreading through the stomach wall . the inflammation invades the submucosa or muscle layer and creates a suppurative abscess and infectious emphysema of the gastric wall . it can even spread to the esophagus or entire gastrointestinal tract .7 the most common symptom is abdominal pain ( 95 % ) , followed by nausea or vomiting ( 68 % ) , fever ( 57 % ) , and hematemesis ( 14 % ) .89 the progression is rapid , and even sepsis was reported at diagnosis .10 the most common pathogen is streptococcus spp . , klebsiella pneumoniae , staphylococcus spp . , haemophilus influenzae , proteus , and clostridia .311 mucormycosis has been reported as an etiologic agent . the main predisposing factor for pg is an immunocompromised state including alcoholism , diabetes mellitus , human immunodeficiency virus infection , chronic hepatitis , and achlorhydria .81213 pg has also been reported after endoscopic procedures like esd ,14 endoscopic ultrasound - guided fine - needle aspiration ,15 and endoscopic mucosal resection .16 in this report , we presented a case with pg after biopsy for the diagnosis of egc . the patient had comorbidities of alcoholic liver cirrhosis , diabetes mellitus , hypertension , and a history of liver resection for hepatocellular carcinoma . in a previous reportpg can be diagnosed by endoscopy with culture of the purulent discharge , endoscopic ultrasound , and ct scan .1718 endoscopic findings can show gastric wall edema , purulent exudate , or gangrene . ct or ultrasound shows thickening of the gastric wall , abscess , or an air bubble in the gastric wall . in our case , the purulent discharge , edematous gastric wall , and air bubble were seen on egd and ct at diagnosis . the edematous gastric wall improved , but a whitish purulent discharge was still present 23 days after diagnosis . more recent data , however , indicate that the mortality has been decreasing ; for example , rada - palomino et al. 3 reported 27 % ( 12/45 ) mortality in 2014 . patients with predisposing conditions showed higher mortality ( 33 % ) than patients without predisposing conditions ( 17 % ) . in addition , early recognition of the condition and prompt treatment lead to better survival .1 antimicrobial agents are a mainstay of treatment , with surgical resection of infected tissue when necessary . the diversity of causative organisms and the natural history of the disease make it crucial to urgently initiate empirical broad - spectrum antimicrobial therapy . it is not feasible to compare the results of medical treatment with surgery because available data are based on case series that are outdated . there is a broad range of reported postoperative mortality ( 18 % ~ 75 % ) , as well as of response to medical treatment ( 0 % ~ 100 % ) .16811 in korea , 10 reports with 15 cases of pg have been published .5619 the mortality rates for surgically or medically treated patients were 44.4 % ( 4/9 ) and 0 % ( 0/6 ) , respectively . the difference in mortality rates could be because of a milder disease state in medically - treated cases , but this is uncertain . if the disease is diagnosed at an early phase and is localized , it can be treated with antibiotics and supportive management . to our knowledge , the present case is the first report of treatment of egc after diagnosis of pg . immediate surgical resection could treat gastric cancer and pg simultaneously , but previous surgical treatments of pg have shown high mortality rates .5619 our case showed that endoscopic treatment ( esd or apc ) for egc immediately after recovery from pg has the risk of incomplete treatment . because recurrent disease can be more difficult to manage , delaying treatment and evaluation of the gastric cancer until after full recovery from pg might be a better option in this particular clinical situation . in summaryafter improvement of pg with antibiotics , esd for egc was attempted but failed because of submucosal pus , and apc was performed . during regular 6 - month follow - upsconsidering the risk of incomplete treatment immediately after recovery from pg , and that recurrent disease can be more difficult to manage , as well as the characteristics of the tumor ( small , well - differentiated mucosal cancer ) , delaying treatment and evaluation until after full recovery of pg ( i.e. , 3 months later ) might be a better option in this particular clinical situation .\noutput:\n" }, { "from": "agent", "value": "phlegmonous gastritis is a rare and rapidly progressive bacterial infection of the stomach wall , with a high mortality rate . antibiotics with or without surgical treatment are required for treatment . we present a case in which phlegmonous gastritis occurred during the diagnostic evaluation of early gastric cancer . the patient showed improvement after antibiotic treatment , but attempted endoscopic submucosal dissection failed because of submucosal pus . we immediately applied argon plasma coagulation since surgical resection was also considered a high - risk procedure because of the submucosal pus and multiple comorbidities . however , there was local recurrence two years later , and the patient underwent subtotal gastrectomy with lymph node dissection . considering the risk of incomplete treatment immediately after recovery from phlegmonous gastritis and that recurrent disease can be more difficult to manage , delaying treatment and evaluation until after complete recovery of pg might be a better option in this particular clinical situation ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the organism in this study is bacillus okhensis strain kh10 - 101 t ( here after b. okhensis ) , a gram - positive , strictly aerobic , rod like bacterium . the b. okhensis was first isolated from a salt pan in india , near port of okha by nowlan et al . , 2006 . b. okhensis is tolerant to both high salt and high ph , can grow from neutral to high ph ( ph 711 ) and from low to high salt ( 0.512 % nacl ) concentrations . the genomic dna was extracted from an active log phase culture ( grown in cmb medium , ph 10 and 5 % nacl ) as per sambrook et al . the genome of kh10 - 101 t was sequenced using roche 454 gs ( flx titanium ) pyrosequencing platform . functional annotation was carried out using rast tool , identification of trna genes by trnascan - se and rrna genes by rnamerr . genome sequencing resulted in a total of 3,18,628 high quality reads with approximately 28 coverage of the entire genome . n50 contig size is 115,121 bp and the largest contig size is 349,697 bp . total 98 high quality contigs , with size greater than 500 bp were assembled . final assembled draft genome size is 4,865,284 bp ( 4.86 mb ) with 38.2 % gc content . the genome size of b. okhensis is relatively larger than its closest and sequenced relatives , bacillus halodurans ( 4.2 mb ) and b. pseudofirmus ( 3.85 mb ) showing its evolutionary significance . annotation with rast has shown a total of 4952 coding sequences , ( 45 % annotated and 55 % hypothetical ) ( fig .1 ) . 165 rna coding genes and 8 rrna ( 6 numbers of 5s rrna , one 23s rrna and one 16s rrna ) genes were present ( table 1 ) . of the total protein coding genes , genes involved in carbohydrate metabolism , amino acid metabolism , cofactors , vitamins , prosthetic groups , protein metabolism , nucleic acid metabolism , respiration were dominant ( fig . however , none of these stress responsive genes coded for acid stress responsive proteins . further , despite the fact that b. okhensis is aerobic , genes involved in fermentation and acid production were identified . in addition , 145 genes code for the proteins that are involved in transport across the membrane , such as abc transporters and cation transport proteins . interestingly , it was observed that though spore formation does not occur in high salt and high ph conditions in b. okhensis , its genome has 131 genes encoding proteins related to spore formation and dormancy . the b. okhensis strain kh10 - 101 t whole genome shot gun ( wgs ) project has been deposited at ddbj / embl / genbank under the project accession jrju00000000 . the project ( 01 ) has the accession number jrju01000000 and consists of sequences jrju01000001 : jrju01000098 . comparative genome analysis and genome wide transcriptomic analysis of this halo - alakli tolerant strain will be helpful in better understanding of the mechanisms involved in salt and high ph tolerance . the authors declare that there is no conflict of interest on any work published in this paper .\noutput:\n" }, { "from": "agent", "value": "we report the 4.86 - mb draft genome sequence of bacillus okhensis strain kh10 - 101 t , a halo - alkali tolerant rod shaped bacterium isolated from a salt pan near port of okha , india . this bacterium is a potential model to study the molecular response of bacteria to salt as well as alkaline stress , as it thrives under both high salt and high ph conditions . the draft genome consist of 4,865,284 bp with 38.2 % g + c , 4952 predicted cds , 157 trnas and 8 rrnas . sequence was deposited at ddbj / embl / genbank under the project accession jrju00000000 ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the conventional morphologic features on common palmar digital nerve and artery is well - documented3 ) . the median and ulnar nerve divided into three common palmar digital nerves , then descending with common palmar digital arteries without any branch before finger webs . in this present study , we describe a rare and unreported variation in the course and distribution of the common palmar digital nerves and its relation to the common palmar digital arteries . knowledge of the frequency of anatomical variations of the neural and arterial pattern of the hand is crucial for safe and successful hand surgery . as the number of hand surgical interventions increase a better understanding of the anatomy of hand nerves and arteries gain in importance . herewe describe a rare anatomic variation of the common palmar digital nerves and arteries in a 42 - year - old yellow male cadaver right palm fixed in 10 % formalin . that cadaver specimen was detected during dissections performed in a routine gross anatomy course . the skin of the bottoms of palm was removed , and the vessels and nerves were exposed . the superficial palmar arch and three unusual anatomic variation pairs of the common palmar digital nerves and arteries were identified . each common palmar digital nerve divided into 2 or 3 branches and clamped the corresponding common palmar digital artery ( fig . the variation of common palmar digital arteries went through palmar digital nerves have so far not been described . to understand the rare anatomic variation and collect new anatomical data , now it is reported as follows . we set the line connecting the scaphoid node with the pisiform bone as a reference line . we show here three common palmar digital nerves originated from the median nerve or ulnar nerve divided into 2 or 3 smaller branches , and clamped the corresponding common palmar digital artery . the distance from the crotch of nerves to the reference line were 53.12 mm , 54.70 mm , 54.46 mm , respectively . the distance from the concourse to the reference line were 65.60 mm , 67.76 mm , 58.80 mm , respectively . each common palmar digital nerve downward to the finger weds , and then divided into two branches named proper palmar digital nerves . besides , from intersection of each common palmar digital artery and nerve we also detected the vascular impression with the diameter of 1.38 mm , 1.18 mm , 1.26 mm , respectively . the diameter of proximal vascular impressions were 1.52 mm , 1.73 mm , 1.56 mm , respectively ( fig . bozkurt et al. 2 ) described an unusual termination of the ulnar nerve in the palm . vollala et al. 8 ) observed formation of superficial palmar arch solely by superficial branch of ulnar artery without any contribution from the radial artery or median artery . meals and shaner6 ) in their comprehensive study on the common palmar digital nerves of 50 palms did not find the variation of common palmar digital nerves divided into 2 or 3 smaller branches , and clamped the corresponding common palmar digital artery . the injury of common palmar digital nerves and arteries are the center of attraction for most of the surgical procedures and traumatic events in the hand . the hand surgeon should keep in mind this kind of variations before performing surgical procedures such as , neurosuture , arterial repairs , replantation of severed limbs4 ) . the knowledge of the variations of the common palmar digital nerves and arteries is useful in clinical as well as surgical practice . they may be the cause of nerve entrapment syndrome , ischemia because of variable relations of nerves with the surrounding muscles and the vessels . the presence of anatomical variations in the common palmar digital nerves and arteries is used to explain unexpected signs and symptoms useful in medical practice . the present case revealed the common palmar digital arteries went through the common palmar digital nerves . this variation can cause anomalies of the sensory innervations of the hand . with the deepening of cognition on peripheral nerve compression , the incidence of nerve entrapment syndrome of common palmar digital nerve has been increasing year by year . as one of reasons , thus , these variations are important to note by the anatomist and clinicians . knowing the existence of the abnormal case of the common palmar digital nerves and arteries is very essential , as it may be damaged during surgery , in trauma in these area .\noutput:\n" }, { "from": "agent", "value": "variations in the course and distribution of common palmar digital nerves and arteries are rare . a classic common palmar digital nerves and arteries are defined as concomitant . during routine dissection classes to undergraduate medical students we observed formation of each common palmar digital nerve divided into 2 or 3 branches and formed a ring enclosing the corresponding common palmar digital artery . knowledge of the anatomical variations of the common palmar digital nerves and arteries is crucial for safe and successful hand surgery ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: thymus - parathyroid unit ( tpu ) ( parathymus ) occurring in adults is rare , reported in the perithyroid / thyroid and cervical location when extrathoracic and extrathymic . rare cases of parathyroid adenomas , in the context of parathyroid hyperfunction or thymic cyst , have been reported as developing in such units . in the present study , we discuss the features observed in 2 cases where tpu was noted in the perithyroid site ( diagnosed during thyroid surgery for basedow graves disease ) , as well as 2 cases wherein tpu was located in the neck . two patients ( a woman and a man , aged 28 and 27 years , respectively ) diagnosed with basedow graves disease presented with perithyroid tpu . the basedowgraves disease was diagnosed at the age of 25 and 24 years , respectively ; both patients showed tachycardia , loss of body weight , and bilateral exophtalmia . for the first patient ( woman ) , the serum anti - tsh antibodies were 32.1 ( positive , 1.5 ui / l ) , the antithyroperoxidase antibodies 123 ui / ml ( normal , 34 ) , and thyroid function tests showed 0.01 mu / l ; 9.93 and 59 pmol / l for tsh , t3 and t4 , respectively ( normal ranges , 0.274.20 mu / l , 3.106.80 and 1222 pmol / l , respectively ) . this patient also showed persistent hypoleucocytemia with neutropenia ( without positivity for hiv , viral hepatitis virus or tuberculosis tests ) as well as a history of hyperprolactinemia in relation with a hypophysal microadenoma diagnosed on magnetic - resonance - imaging at the age of 25 and treated by cabergoline . furthermore , ultrasound examination showed a normally sized thyroid with heterogeneous echogenicity and with several hypoechogenic nodules ( 2 - mm ) . for the second case , the serum levels of anti - tsh antibodies was 4.7 both patients were treated by neomercazole ( and propranolol for the female patient ) , but the anti - tsh antibodies remained high , although fluctuating . macroscopic and microscopic features were consistent with basedow graves disease ; the thyroid parenchyma showed dystrophic vesicles , multifocal inflammation , fibrosis , and rare calcifications . the parathyroid and the thymus were focally separated from the thyroid capsule by sparse adipocytes ( figure 1 ) . the parathyroid tissue appeared normal and showed some adipocytes and chief cells ( some with water - clear cytoplasm ) . the parathyroid , which was surrounded almost entirely by a capsule was focally in contact with the thymic tissue ( figure 1 ) . in addition , the thymic tissue , which was also almost completely surrounded by a capsule appeared normal ( with both cortical and medulla ) . several hassal corpuscles were noted , some of which were calcified . in one of the cases , one other parathyroid , ( normal ) , was detected in the perithyroid adipose tissue at distance from the tpu . postoperatively , both patients showed hypocalcemia ( 1.72 and 1.64 mmol / l , respectively ) thereby requiring medication . in the 2 cases of perithyroid tpu ( cases 1 and 2 ) ( a , b , c , and d , e , f , respectively ) , the thymic tissue was situated in the perithyroid tissue , focally separated either by parathyroid tissue or by fibroadipose tissue ( a and d , respectively ) . thymic and parathyroid tissues were focally separated by an inconspicuous fibrous layer or a calcified hassal corpuscle ( b ) or adipose tissue ( d and e ) . the thymic tissue contains several hassal corpuscles , some of them calcified ( a , b , c , and f ) . the white arrows indicate hassal corpuscles ( calcified ) , the black arrows uncalcified hassal corpuscles . hematoxylin - and - eosin stain , original magnification2 .5 ( a and d ) and 20 ( b , c , e , and f ) . the tpu was observed on the central neck dissection specimen , which was performed in the third case during thyroidectomy for thyroid papillary carcinoma ( woman , 42 - years ) and in the fourth , for thyroid medullary carcinoma extension . for the third case , the ultrasound - examination showed a homogeneous right thyroid lobe and 2 adjacent hypoechogenic nodules ( 3 and 1.6 - cm ) with microcysts , microcalcifications , and hypervascularisation . further , in the fourth case , the follow - up positron - emission - computed - tomography showed 3 hypermetabolic foci of paratracheal and right hilar , subcarina location . the parathyroid tissue , which was situated between the thymic lobules ( figure 2 ) , showed an incomplete capsule and comprised chief cells and focally oncocytic cells . in addition , an epithelial microcyst was found in the fourth case and another parathyroid . in the other case , parathyroid cells , some of which had clarified cytoplasm , were focally found in direct contact with or intermingled within the thymus ( figure 2 ) . in the 2 cases of cervical tpu ( cases 3 and 4 ) ( a , b , c and d , e , f , respectively ) , the parathyroid tissue was situated between thymic lobules ( a f ) , separated either by a thin fibrous capsule , or at contact or intermingled with thymic tissue ( b , c , e , and f ) . the white arrows indicate hassal corpuscles ( uncalcified ) , hematoxylin - and - eosin stain , original magnification2 .5 ( a ) , 5 ( d ) , 20 ( b , c , and e ) , and 40 ( f ) . here we report the features observed for 2 cases of tpu at a perithyroid location , both of which were incidentally diagnosed upon the inspection of thyroidectomy specimens obtained for basedow graves disease . features were similar to those previously observed in the cases reported in 1928 and in 2001 , occurring in the context of basedow disease and lymphocytic thyroiditis with adenoma . however , in one of the cases presented here , both parathyroid and thymic tissues were observed in direct proximity to the thyroid capsule . the 2 cases showing perithyroid thymus were both young adults and had been diagnosed with basedow graves thyroiditis . in the report of a large series of patients with basedow graves disease , ectopic thymus was observed in 1.8 % of patients but at a cervical location . one hypothesis suggests that the incomplete migration of the thymus during embryogenesis results in its ectopic presence within the perithyroid tissue , along with the parathyroid . furthermore , the fact that the tpu may occur in adults in the neck at a distance from the thyroid ( as observed in 2 cases ) , in addition to the presence of intermingled parathyroid cells in the thymic lobule , also favors the hypothesis of developmental abnormalities of the third and / or fourth pharyngeal pouches . a direct fusion of thymus and parathyroid has been reported in 65 - mm - fetus and older fetus , being known as the parathymus . water - clear cell buds , similar to the clear cells we observed in the cervical thymus of patient 3 , were already mentioned in 1937 as rudiments present in the embryofetal life . moreover , the coexistence of thymic and parathyroid tissues has been reported in the subangulomaxillary region , incidentally , or in the context of hyperparathyroidism in esophageal and jaw sites , in association or not with the adenomatous parathyroid . however , one may question whether metabolic factors related to iodine intake could also be involved in the development of abnormal perithyroid thymus because increased iodine has been reported to result in perithyroid thymic tissue occurrence as demonstrated in rat models wherein the perithyroid / thyroid lymphoid tissue with thymus - like cd4 / cd8 / tdt immunophenotype and without hassal corpuscles appeared more frequently after consuming enriched - iodine than after normal - iodine or low - iodine diets . the presence of a normal ioduria in one patient , with basedow graves disease , in which this analysis was performed , does not favor the hypothesis of iodine - induced thymic tissue . however , the finding of high levels of anti - tsh antibodies in both patients could be representative of an increased tolerance toward thyroid autoantigens , including during neomercazole treatment . moreover , the presence of persistent neuropenia may suggest a specific immunological profile with regard to the evolution of the disease and response type to treatments . the clinical significance of tpu diagnosed on thyroidectomy specimens performed for a benign inflammatory , autoimmune disease is limited except the postsurgical hypocalcemia , which may occur similarly to patients having the cervical unit and which may require treatment . however , the differential diagnosis with perithyroid lymph node metastases of thyroid tumors , such as papillary or medullary carcinomas may rise as thymic hassal corpuscles may also show calcifications on imaging procedures . although rare , the presence of parathyroid cells intermingled with thymic tissue ( as we have observed in one of the cervical units ) warrants further interest because of eventual abnormalities related to an parathyroid hormone secretion or , to a lesser extent , immunological disturbances , since in adults .\noutput:\n" }, { "from": "agent", "value": "abstractthe thymus - parathyroid unit ( tpu ) occurring in adults is rare.the main symptoms and important clinical findings are as follows : 2 patients presented with neomercazole - resistant basedow graves disease . a third patient presented with thyroid nodules and a fourth patient with a neck mass after thyroid resection for medullary thyroid carcinoma.the main diagnoses were those of thyroid nodules ( either in the context of goiter , or not ) . in the fourth case the diagnosis was of thyroid medullary carcinoma recurrence in the neck.thyroidectomy was performed in the 2 cases of basedow graves disease and in the third case ( wherein selective neck dissection was also performed ) . in the fourth case , a neck dissection was performed for a possible medullary carcinoma recurrence.a tpu was microscopically detected in 2 cases with perithyroid location , on thyroidectomies for basedow graves disease and in the 2 other cases with neck soft tissue location ( associated with thyroid papillary carcinoma and thyroid medullary carcinoma extension ) . postsurgical hypocalcemia requiring treatment occurred in both patients with basedow graves disease and in the fourth patient.the presence of tpu should be acknowledged because such lesions can be misdiagnosed as suspect lymph nodes during thyroid surgery for malignant tumors ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a great number of studies suggests that migration is a risk factor for schizophrenia and other psychotic disorders . elevated risk was observed for a variety of ethnic groups , mostly for minorities and migrants experiencing cultural barriers . the reasons for this remain unclear and generally vary , from genetic explanations of neurodevelopment to social rationalizations . in 1932odegard developed in europe the first theory concerning the relationship between the migration status and mental illnesses . astonished by the increasing number of mental disorders among norwegian migrants in usa , he formulated the theory of selective migration through which he considered that those deciding to emigrate belonged to the weakest segment of population and more prone to mental illnesses . later , this theory was refuted and scholars attention focused on post - emigration social factors , such as racial discrimination , reduced opportunities , lack of friends , unemployment , legal matters , acculturation and lack of ability to understand the host country language . the meta - analysis study conducted by cantor - graae and selten reported a relative risk to develop schizophrenia of 2.9 at first - generation migrants , and of 4.5 at the second generation , compared with non - migrants and of 3.3 for migrants from developing countries . of the risk factors , in this study we paid a special attention to discrimination , defined as a separation , difference , clear distinction between more elements . it is a restrictive differentiation of legal rights for a part of a country s population , for an organization or for some countries towards others . because of discrimination , a category of citizens of a country are deprived of certain rights on the basis of unfounded considerations . a recent meta - analysis has revealed that discrimination is associated with an increased probability to develop clinical mental illness . social defeat , defined as a chronic experience of social exclusion or an inferior position in society may lead to dopaminergic hyperactivity in the mesocorticolimbic system , which is also sensitized in schizophrenia . perceived discrimination is a major stressor , associated with a high risk of developing psychoses , contributing to the feeling of alienation from the majority culture . on the grounds of these observations , the aim of this study was to investigate whether the perceived discrimination is associated with psychotic symptom severity as well as the level of social functioning among the romanian migrants included in the study . in addition , it attempts to identify the features of romanian migrants group more prone to feel discriminated . the present study is part of the phd thesis onset and evolution of psychosis in romanian emigrants temporarily abroad . the assessment included 70 patients admitted to the cluj psychiatric hospital , between january 2007 april 2010 , diagnosed with acute psychotic disorder , schizophrenia and other schizophrenia - spectrum disorders , according to icd10 diagnostic criteria , recently arrived home from work or studies abroad . the inclusion of the patients in the study was done after the approval of the ethical commitee of iuliu haieganu university of medicine and pharmacy cluj - napoca and following the patient informed consent . exclusion criteria were : substance induced psychosis , patients with relatives temporarily abroad , other types of psychotic disorders such as adaptation disorder , depression or bipolar disorder . participants were individually tested . they filled in the migration questionnaire for socio - demographic variables and migration history and the psychiatrist completed the psychotic symptoms assessment scales ( panss ) and the global assessment of functioning scale ( gaf ) . this is divided in positive symptoms ( delirious ideas , hallucinations ) , negative symptoms ( blunted emotion , lack of spontaneity , difficulties in abstract thinking ) and general ( anxiety , depression , social avoidance , lack of attention ) . social , occupational and psychological functioning was assessed through gaf scale which is a numeric scale ( 0 through 100 ) . in order to assess the level of discrimination perceived by the patients , they were asked whether they had felt unfairly treated or insulted because of one s cultural background . the descriptive study in the first part was conducted in order to define the sample of patients as regards the homogeneity , clarifying the following aspects : gender ( men / women ) , the age of sample patients at the age at illness onset , the number of hospitalizations , the area of residence , the level of education , the marital status , the legal status , the family medical history , the discharge diagnosis distribution , the country where illness occurred , the country where they have worked , the period spent abroad and the type of work performed abroad versus country of origin . subsequently , we followed the psychotic symptom evolution from the admission through panns and gaf scales and we correlated the panns symptoms , with the social functioning and the discrimination perceived . pearson s r coefficient of parametric correlation was used , which has variations between -1 and 1 . the gender distribution was 78.57 % males and 21.43 % women , almost half of them ( 45.71 % ) between 2635 years , 70 % from the urban area and generally from middle and lower class . the most frequent diagnosis was acute psychotic disorder - 42.86 % of cases , 55 ( 71 % ) of patients were at their first admission , closely followed by paranoid schizophrenia . the first episode began while they were at work / studies abroad for most of the subjects , 74.29 % in spain . as to the level of education , 40 % of the group had graduated from a vocational school and only 27.14 % had higher education . while in their native country 44.29 % did qualified labor , 68.57 % registered social regression abroad , performing non - skilled exhausting labour . as for the period spent abroad before developing the illness , most of them had spent less than 6 months - 34.29 % , followed by those who had spent between 15 years - 32.06 % . the majority of the subjects were single , did not have relatives abroad and worked without a job contract . the level of discrimination perceived by the subjects correlated neither with panns symptoms ( r = 0.051 , p 0.05 ) nor with the social functioning level ( r = 0.029 , p 0.05 ) . moreover , it can be noticed that the level of social functioning correlated significantly negatively with the panns general symptom level ( r = 0.41 , p 0.05 ) ( table i ) . the results of the study evidenced a dependence on the categories of age , gender or the country where the illness occured . from table ii it can be observed that there are statistically significant differences between categories of education regarding the general symptoms on panns scale ( f = 2.84 , p 0.05 ) , respectively the level of discrimination perceived ( f = 4.96 , p 0.01 ) . as f test is omnibus ( it identifies only the significant differences without identifying the pairs of significantly different categories ) , we used the post - hoc analysis to identify the education groups , among which the significant difference showed by the f test value was found . thus , it was reported that , as regards the panns symptoms , differences appear in the primary school - vocational school , primary school - higher education , respectively , for the variable perceived discrimination , the differences appear for the couples primary school - higher education , vocational school - high school , and vocational school - higher education respectively , in all cases the low level of education being associated with a higher level of discrimination perceived . we can also observe that ( table iii ) the area of residence was only associated with differences regarding the level of discrimination perceived ( t = 2.31 , p 0.05 ) . the subjects from the rural area perceived themselves as discriminated at a greater extent than those from the urban area this result is in accordance with the one obtained in case of the variable level of education . the subjects who worked abroad without job contract ( table iv ) presented a more reduced level of social functioning ( m = 22.87 , sd = 4.10 ) as compared to those who held a job contract ( m = 27.42 , sd = 5.26 ) and this difference was statistically significant ( t = 4.06 , p 0.01 ) . the discrimination itself is not such an important risk factor to justify a psychosis outbreak , but we can not rule out its important contribution in the psychopathogenetic process . although it does not correlate with psychotic symptom severity , most of the patients felt discriminated at different levels , as resulted from the questionnaires completed individually . in the specific literature , the minority status of the psychotic migrants is associated with the perceived discrimination and with the severity of psychotic , anxious and depressive symptoms , suggesting that social stressors may influence the expression of particular psychotic symptoms . at presentthere is a consensus concerning the multifactorial etiology of schizophrenia , an individual may carry a genetic predisposition but this vulnerability is expressed only in presence of certain environmental factors ( in our case , the migration with its different alleged stressors ) which may produce mutations or influence the genetic expression . a first study performed on the same sample of patients reported that subjects had a low educational level , financial difficulties , lack of family support , regressed professionally , were not accustomed with physical effort and did not benefit from medical care abroad , so they were exposed to multiple stressors . from a psychoanalytic point of view , we can explain the reaction resulted from emigration also through identification . the child identifies with his mother and , as he grows , he identifies with his parents , family , caste , community and his country . the persons who identify themselves with their country can not handle appropriately the separation from it . the poorer the social integration , the more difficult is to deal with this mourning . apparently , the patients of rural origin have a more intense perception of the social isolation consequent to discrimination . as they live in an environmentwhere belonging to a community and to the group rules is important , the fear of rejection and of loss of interpersonal relationship leaves traces on their mental stability . if for the subjects from the urban area , with higher education but with no experience in the work field , the professional regression is a major risk factor , the subjects from the rural area are more often prone to lose their family point of reference and feel excluded from the new cultural environment . the low educational level of most of the patients coming from the rural area contributes to the reinforcement of the perception of discrimination and is correlated negatively with the ability to adapt to the new environment . furthermore , the lack of a job contract seems to play an unsettling role in the life of psychotic emigrants , leading to the reduction of social functioning level . discrimination is perceived more intensely by subjects from the rural area and with a lower level of education but this does not correlate with psychotic symptom severity . discrimination is an important stressor but can not justify by itself the outbreak or the severity of a psychotic episode which involves a multifactorial etiology .\noutput:\n" }, { "from": "agent", "value": "aiminvestigating the relationship between the perceived discrimination and the psychotic symptom severity as well as the level of social functioning in romanian migrants with psychotic disorders , considering that this is a major stressor which contributes to the feeling of alienation from the majority culture.materials and methodsthe assessment included 70 patients admitted to the cluj psychiatric hospital , from january 2007 to april 2010 , diagnosed with acute psychotic disorder , schizophrenia and other schizophrenia - spectrum disorders , according to icd 10 diagnosis criteria . the patients completed the migration questionnaire for socio - demographic variables and the level of discrimination perceived , the psychotic symptom severity being assessed through panns and gaf scales.resultsthe level of discrimination perceived by the subjects correlated neither with panns symptoms ( r = 0.051 , p > 0.05 ) nor with the social functioning level ( r = 0.029 , p > 0.05 ) . the social functioning level had significant negative correlations with the panns level of general symptoms ( r = 0.41 , p > 0.05 ) . there are no differences between panns symptoms , social functioning and perceived discrimination according to age , gender or illness onset country . there are significantly statistical differences between education categories concerning the general symptoms on panns scale , respectively the level of discrimination perceived , the lower level of education being associated with a highly perceived discrimination level . the subjects of rural origin perceived discrimination at a higher level than those from urban area ( t = 2.31 , p < 0.05 ) . conclusionsdiscrimination is perceived more intensely by the subjects from the rural area and with a poorer educational level but this does nt correlate with psychotic symptom severity ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: musculoskeletal problems are commonly experienced by musicians .1,2 these problems may have a significant impact upon the individual , with musicians who have been injured reporting a negative impact upon social relationships ,3 the loss of a form of expression ,3 loss of identity ,3 and an impact on financial well - being .4 furthermore , musicians are reportedly reluctant to discuss their injuries for fear of destroying their reputations ,4 and may avoid seeking care from health and medical professionals , as they fear they will be told to stop playing , and because they perceive these professionals to lack the experience required to treat musicians .4,5 it is important to determine the management sought by university woodwind students for musculoskeletal problems and their views towards it , as well as the consequences of such problems to enable appropriate management and support to be implemented . a systematic search ( see supplementary materials for the search strategy ) was conducted to identify studies investigating the experiences of university woodwind students with musculoskeletal symptoms . throughout the published literature , various terms and definitionshave been used to describe these musculoskeletal symptoms ; 2,6 hence any musculoskeletal symptoms were considered relevant . seven studies713 were identified ( figure s1 ) ; all investigated the prevalence of musculoskeletal symptoms ( table 1 ) . this revealed that there is a particular need to better understand instrument - , location - , and duration - specific prevalence of musculoskeletal problems in this population . no studies investigated the incidence of musculoskeletal problems or the impact of these on the individual or their playing . ackermann et al7 was the only study to report on the management strategies utilized , as well as the strategy that was perceived to be the most effective . this study aims to fill some of the gaps identified in this systematic search by investigating the following questions : what is the prevalence of playing - related injuries ( pris ) in university woodwind students , specific to instrument , location , duration , and point prevalence ? what is the impact of pris for university woodwind students ? what percentages of university woodwind students with a history of pri have trialed various conservative management strategies ? what is the perceived effectiveness of pri conservative - management strategies trialed by the university ? for the purpose of this study , pris refer to musculoskeletal symptoms , like pain , discomfort , tingling , numbness , or weakness that prevent musicians from playing at their normal level . initially , the term playing - related musculoskeletal disorder ( prmd ) was to be used along with zaza et als4 definition , for it differentiated between the mild symptoms that one may expect with playing , and those that impact upon playing and may require treatment . during the pilot testing of the survey used in this project ( described in the materials and methods section ) , the term pri was selected and the definition modified based upon feedback from the participants during the pilot testing of the survey , to make the term and definition easier to understand for the population . this project had ethics approval from the university of south australia s human ethics committee ( protocol number p060 / 10 ) . during may 2012 , an email was sent to all classical woodwind students at a tertiary training institution who were currently enrolled in one of their vocational education and training ( vet ) or undergraduate courses ( n = 40 ) . this email was sent to students by a staff member at the conservatorium , and included the study information sheet and a link to the online survey , which was open for 1 week . only students under the age of 18 years were excluded , as their parental consent could not be obtained online . no existing published survey included the items required to fulfill the requirements of this study . this survey was also used to obtain information on students perceptions regarding risk factors , prevention strategies , experience with prevention strategies , attitudes regarding injury prevention , injuries , and injured musicians , as well as their interest in injury - prevention programs . the survey was piloted with woodwind musicians who were not currently vet or undergraduate students . a semi - structured interview was conducted with each to determine the utility and validity of the survey . after each interview , the survey was modified and then tested with another individual , until there were no further issues identified . this led to the use of the term pri and the definition musculoskeletal symptoms , like pain , discomfort , tingling , numbness , or weakness , that prevent you from playing at your normal level . surveymonkey ( palo alto , ca , usa ; www.surveymonkey.com ) was the platform used for this survey , and the survey has been included in the supplementary materials . this project had ethics approval from the university of south australia s human ethics committee ( protocol number p060 / 10 ) . during may 2012 , an email was sent to all classical woodwind students at a tertiary training institution who were currently enrolled in one of their vocational education and training ( vet ) or undergraduate courses ( n = 40 ) . this email was sent to students by a staff member at the conservatorium , and included the study information sheet and a link to the online survey , which was open for 1 week . only students under the age of 18 years were excluded , as their parental consent could not be obtained online . no existing published survey included the items required to fulfill the requirements of this study . this survey was also used to obtain information on students perceptions regarding risk factors , prevention strategies , experience with prevention strategies , attitudes regarding injury prevention , injuries , and injured musicians , as well as their interest in injury - prevention programs . the survey was piloted with woodwind musicians who were not currently vet or undergraduate students . a semi - structured interview was conducted with each to determine the utility and validity of the survey . after each interview , the survey was modified and then tested with another individual , until there were no further issues identified . this led to the use of the term pri and the definition musculoskeletal symptoms , like pain , discomfort , tingling , numbness , or weakness , that prevent you from playing at your normal level . surveymonkey ( palo alto , ca , usa ; www.surveymonkey.com ) was the platform used for this survey , and the survey has been included in the supplementary materials . fourteen students commenced the survey ; however , one did not complete any questions relating to their experiences with pri , and thus their data were excluded . as no data could be obtained regarding the number of students who were eligible for the survey ( ie , the number aged 18 years or older ) , a response rate could not be calculated ; however , the sample represented 35 % of all classical woodwind students enrolled in undergraduate or vet courses . the sample reflected a range of ages , levels of study , and instruments , with both male and female students represented ( table 2 ) . ten ( 77 % ) participants played the instruments of their majors , and nine ( 62 % ) participants played instruments unrelated to their majors . this indicates that an instrument - specific analysis would not be appropriate , for the impact of additional instruments could not be accounted for . the lifetime prevalence of pri was 62 % ( n = 8 ) , and the point prevalence was 38 % ( n = 5 ) . four participants ( 31 % ) reporting having a pri that lasted for longer than 3 months . the most commonly experienced consequence of a pri was reduced practice time by half ( n = 4 , 50 % ) , and missed playing commitments ( n = 3 , 38 % ) , followed by missed opportunities for work / study ( n = 2 , 25 % ) , stopping them from playing for 3 months ( n = 2 , 25 % ) , financial problems ( n = 1 , 13 % ) , and stopping them from playing for a month ( n = 1 , 13 % ) . interestingly , two participants reported that they had stopped playing for 3 months ; however , they did not report stopping playing for 1 month , this accounting for the lower percentage having 1 month off from playing than for 3 months off . while multiple responses were encouraged , this appears to have been an error . in general , playing - related management strategies , like taking breaks , were the most commonly utilized , with a relatively even spread of active and passive nonplaying - related strategies . ofthe health professionals listed , physiotherapists were the most commonly consulted ( 63 % of those with a history of pri ) ( figure 1 ) . in general , playing - related and passive nonplaying - related management strategies were perceived to be most effective ( figure 2 ) . one participant reported that they saw a chinese doctor who treated them with acupuncture and homeopathy . the lifetime prevalence of pris in this cohort was 62 % , which is within the range of the reported literature for university woodwind students ( 58 % 87 % ) .8,10,12 variation may be due to differences in the populations , as well as the terms used to define the musculoskeletal symptoms ( pri , pain , musculoskeletal problems , playing - related physical problem ) . the lifetime prevalence is less than that of woodwind musicians in australian professional orchestras , which was reported as 88.1 % .1 the point prevalence of pri in this population is arguably the most important prevalence to consider . not only is it more accurate to report , as it is not retrospective , it gives a better indication of the risks involved in playing at this level , as previous injuries , which may have occurred during their early stages of learning , are not considered . there was no existing literature with which to compare this finding that specifically investigated university woodwind students ; however , in australian professional orchestras , 49.3 % were reported to have current pain or injuries ,1 which is considerably higher than in university students . thirty - one percent of participants reported having pris that had lasted for at least 3 months . as this means that the musician s playing was affected for at least 3 months this could have a dramatic impact upon the student s education and future career , through decreased practice time or missed opportunities for work or study . it is important that we understand why these disorders have persisted for so long , and to improve the effectiveness of management to decrease their duration . the lifetime prevalence of pri was highest for the wrist / hand / finger regions ( 31 % for left , 43 % for right ) , as well as the lower back on the left side ( 23 % ) , neck on the right side ( 31 % ) , and right shoulder ( 23 % ) . similarly , ackermann et al7 found the hand / wrist / elbow regions ( 65 % ) , either shoulder ( 65 % ) , and the lumbar spine ( 40 % ) to be commonly affected by playing - related musculoskeletal disorders ( prmds ) ( no definition reported ) . this higher prevalence may be due to potential differences in the definition of prmds / pris , differences in the regions investigated , or the small sample size in our study . furthermore , ackermann et als7 study was specific to flautists , which may have altered the results . the prevalence reported by hartsell and tata11 found the prevalence of injuries in flute , clarinet , and saxophone students to be lower in general , which may be due to use of the termhowever , after combining the results for these instruments , prevalence was highest for the hand ( 10 % ) , wrist ( 6 % ) , and face ( 6 % ) . whilst there are differences in the prevalence rates across the three studies , the wrist / hand / finger regions appear to be the most commonly affected by pris . pris lasting for longer than 3 months were most commonly reported in the lower back region on the left side ( 15 % ) in our study . ackermann et als7 study of flautists revealed that either shoulder ( 40 % ) was at the highest risk of long term prmds ( greater than 3 months ) , whereas the lower back only had a prevalence of 25 % for this time period . again , this may be due to differences in the population or body regions reported . this does however indicate that pris in the shoulder and lower back regions are most likely to impact upon a musician s studies and career because of their longer durations . the neck ( left side 15 % , right side 23 % ) and wrist / hand / finger regions ( left side 15 % , right side 23 % ) had the highest point prevalence . given that the prevalence of pri for longer than 3 months was not high , it is hypothesized that pris occur more frequently in these regions ; however , the duration of bouts is relatively short . pratt et al13 also found point prevalence for the fingers and wrist to be the highest ( 64 % and 71 % , respectively ) , with neck pain experienced by 52 % of participants at the time of the survey . the higher prevalence in pratt et als13 study may be because they investigated playing - related pain , which did not have to impact upon playing . we decided not to investigate the instrument - specific prevalence of pri because of the high proportion of participants ( 62 % ) who played other instruments that were unrelated to their majors . none of the previous literature reporting instrument - specific data7 ,9,11 reported whether their participants played other instruments . with the exception of the middle and lower back and the jaw , this may be due to the right thumb supporting the weight of the clarinet , saxophone , bassoon , and oboe , and depending on hand position , the flute . given the small sample and the lack of instrument - specific analysis , conclusions regarding the potential ergonomic reasons for these asymmetrical symptoms can not be made . hypotheses regarding this could be drawn from a larger - scale study of a similar nature , where instrument - specific analysis can occur . this was the first study to investigate the consequences of pris for university woodwind students . the most commonly reported consequence of a pri was reducing playing time by half ( 50 % ) . whilst this may be problematic , this question did not account for how long their playing time was limited for ( eg , the number of days ) . of greater concernis that 38 % had missed playing commitments , followed by missed opportunities for work / study ( 25 % ) and 3 months off from playing ( 25 % ) . moreover , time off from playing and missed opportunities for study and work may have longer - term implications for the musician , as their exposure to potential employers is decreased , and they effectively lose practice time . additionally , time off may lead to deskilling that they will later have to make up . it is possible that these musicians may be too eager to get back to their previous level of playing , and therefore not pace themselves , thus potentially increasing their risk of reinjury . this is positive , in that many of these , if continued beyond the pri bout , may assist in preventing future injury . participants in our study were most likely to consult a physiotherapist for advice ( 60 % ) , which is in contrast with ackermann et als7 finding of only 15 % of university flute students consulting a physiotherapist . they found that their participants would more commonly consult an alexander - technique teacher ( 30 % ) or a chiropractor ( 20 % ) . this indicates differences between the institutions , which may originate from the types of health professionals in contact with the institutions and the beliefs of the teachers and other students regarding which type of health professional may be most appropriate to consult . in general , passive techniques appeared to be rated as the most effective , whereas more active strategies tended to rate lower . this may be because active strategies require more work on the part of the student , and thus their expectations of effectiveness may be higher . it is possible that the improvement in pri is more subtle with active strategies , or that participants are not committed to these in the long term , thus decreasing their effectiveness . the management preferences of this population , as well as their perceived effectiveness , are of great importance in terms of understanding the population , as well as prioritizing the management strategies that should be investigated in future research . it will also be important to gain an understanding of the management goals and definitions of effectiveness of this population , as these may reveal that different strategies will be preferred for different goals . the greatest limitation of this study is the poor response rate , drawn from a small population . this may be because this population had not previously been approached for this type of research , which may have limited their interest in participating . as we were investigating pri , those with a history of pri may have been more interested in participating ; however , in contrast , some may have been eager to leave their pri in the past , and therefore reluctant to participate in a survey that would make them reflect on their experiences . this may account for differences in the prevalence findings of our study in comparison with those in the literature . this was a pilot study utilizing a convenience sample , which limits the generalizability of the study findings , and thus the study should be repeated with a larger sample using probabilistic sampling . the findings of this study are primarily applicable to the institution from which the sample was drawn , rather than all university woodwind students . the comparison with ackermann et als7 study , particularly with respect to management preferences , revealed differences between institutions within the same country . the survey used was developed specifically for this project , and only has face validity , as it was not formally tested for content and construct validity . furthermore , it is acknowledged that the term pri and its definition also have face validity only . the greatest limitation of this study is the poor response rate , drawn from a small population . this may be because this population had not previously been approached for this type of research , which may have limited their interest in participating . as we were investigating pri , those with a history of pri may have been more interested in participating ; however , in contrast , some may have been eager to leave their pri in the past , and therefore reluctant to participate in a survey that would make them reflect on their experiences . this may account for differences in the prevalence findings of our study in comparison with those in the literature . this was a pilot study utilizing a convenience sample , which limits the generalizability of the study findings , and thus the study should be repeated with a larger sample using probabilistic sampling . the findings of this study are primarily applicable to the institution from which the sample was drawn , rather than all university woodwind students . the comparison with ackermann et als7 study , particularly with respect to management preferences , revealed differences between institutions within the same country . the survey used was developed specifically for this project , and only has face validity , as it was not formally tested for content and construct validity . furthermore , it is acknowledged that the term pri and its definition also have face validity only . this study supports previous works that suggest that university woodwind students are at high risk of pri , particularly in regions of the back , neck , and upper limbs . furthermore , half of these were reported to last for longer than 3 months , which may have a significant impact on their career . this was the first study to investigate such consequences for university woodwind students , finding that many had to reduce their playing time by half and / or miss playing commitments due to a pri . most chose to use playing - related management techniques , with passive nonplaying - related strategies generally rated as the most effective . this was a pilot study with a small sample size , and so should be repeated with a larger sample to improve the generalizability and accuracy of the findings . furthermore , it is recommended that future research investigate why musicians select a particular management approach , and what makes them effective . a systematic search of scopus , cumulative index to nursing and allied health literature ( cinahl ) ( ebscohost ) , medline ( ovidsp ) , and embase ( ovidsp ) was conducted in october 2012 using the search terms reported in table s1 . woodwind terms were searched in the title field , whilst the other terms were searched in the title , abstract , and keyword fields , where permitted by the databases . these terms were combined as woodwind terms and university student terms and musculoskeletal symptoms terms and ( prevalence / incidence terms or impact terms or management terms ) . searches were limited to english - language articles for all databases , as well as peer - reviewed articles in cinahl , and journal articles in scopus . studies were excluded if they were not published in english , in peer - reviewed journals , did not report relevant data ( prevalence / incidence of musculoskeletal symptoms , impact of musculoskeletal symptoms , management utilized , or perceptions of effectiveness of management utilized ) specific to university woodwind students , or were opinion papers ( eg , non - systematic narrative reviews , editorials ) . indicates a truncation symbol ( the symbol may be replaced by any number of characters by the search engine ) . prior to participating in this survey , please ensure that you have read and understood the information sheet ( attached to the email which included this link ) . we are interested in the thoughts of those who are not interested in an injury prevention program , as much as we are those who are interested . throughout the surveythese are defined as musculoskeletal symptoms , like pain , discomfort , tingling , numbness , or weakness , that prevent you from playing at your normal level . compulsory questions are marked * after many of the questions , there is a comments section . you may use this to add any extra information , ie , other suggestions , thoughts , or to explain your views . participants were also provided with a contact email if they experienced difficulties in completing the survey . * have you read and understood the information sheet , and provided your consent ? no ( survey completed at this point ) * are you aged 18 years or over ? no ( survey completed at this point ) * have you completed this survey previously ? list all of the instruments you regularly play , with your university major listed first ( include detail , ie , alto saxophone , bass clarinet ) which degree / diploma are you enrolled in ? ( include detail , ie , performance and pedagogy , classical performance ) which year are you in for your performance subject ? do you think there should be a whole subject devoted to musicians health at university ? ( tick all that apply ) [ order of statements was randomized ] instrument - specific sessions ( ie , practical sessions specifically for clarinet players ) one - on - one sessions ( ie , one - on - one session with a health professional ) interactive webpage comments ( open response ) how likely do you think you are to experience an injury in the next : no chanceextremely likely6 months12 months5 yearsever if you had an injury , how likely do you think the following would be ? [ order of statements was randomized ] no chanceextremely likelymissed playing commitmentsa negative impact on your playing reputationa week off from playingending your careerreducing your playing time by halffinancial problemsthree months off from playinga month off from playingsocial isolation comments ( open response ) how much do you think the following factors would increase your risk of an injury ? [ order of statements was randomized ] not at allextreme impactnot enough breaks when practicingpoor posture / hand positionsudden increase in playing intensity ( eg , harder pieces ) sudden increase in playing timecarrying your instrumentoverpracticingplaying with discomfortinsufficient warm up ( eg , playing long notes , slow scales ) poor general physical fitnesscramped playing conditionspoor awareness of injury preventionstress ( eg , performance anxiety ) moving equipment ( chairs , stands ) facilities ( eg , chairs , temperature , lighting ) instrument setup ( eg , thumb rests , reeds , neck straps , key height ) comments ( open response ) how effective do you think the following are in preventing an injury ? ( if you do nt know what these strategies are , leave the line blank ) [ order of statements was randomized ] no effectwill completely prevent an injurywarm - up ( eg , long tones , slow scales ) yogaregular massagestop playing as soon as you experience discomfortpilatesaerobic exercise ( eg , running , rowing ) stretchingmuscle - resistance exercises ( eg , weights , thera - band ) alexander techniqueosteopathbowen therapyphysiotherapyrelaxation techniquesfeldenkraisregular practice breakschiropractor comments ( open response ) have you tried or are you currently doing any of these to help prevent an injury ? ( tick all that apply ) [ order of statements was randomized ] have donecurrently doingpilatesstop playing as soon as you experience discomfortalexander techniquerelaxation techniquesstretchingyogafeldenkraisaerobic exercise ( eg , running , rowing ) physiotherapychiropractorosteopathwarm - up ( eg , long tones , slow scales ) regular practice breaksmuscle - resistance exercises ( eg , weights , thera - band ) bowen therapyregular massage comments ( open response ) what has or would prompt you to make changes to reduce your risk of injury ? ( tick all that apply ) [ order of statements was randomized ] has prompted a changewould prompt a changereading about injuriesadvice from a health / medical professionalexperiencing an injury that impacts on your playingstarting to get symptoms ( before they start impacting on your playing ) having a class / workshop about injuriesknowing someone who has experienced an injuryadvice from your teacheradvice from other students / colleagues comments ( open response ) how important is it for musicians to : [ order of statements was randomized ] not at all importantextremely importanthave a no pain , no gain attitudeunderstand the physical requirements of playinghave a good posture / hand positionunderstand injury preventioncarefully structure practice sessionshave good playing techniquedo exercises ( stretches and strengthening to reduce injuries ) comments ( open response ) rate your agreement with the following statements [ order of statements was randomized ] completely disagreeneutralcompletely agreeinjury prevention is the responsibility of the teacherinjury prevention is the responsibility of the individual musicianinjury prevention is the responsibility of the universityinjuries can be preventedif i had an injury , i would tell my teacherif a musician has an injury , it reflects poorly on their teachermusicians should understand injury preventiondiscomfort is a normal part of playinghealth professionals need a good musical understanding to advise and treat musiciansi would not tell another musician if i had an injurymusicians who have had an injury are at higher risk of future injurymusicians who have had an injury should not be professional musiciansmusicians who have had to have time off because of an injury must not want to be musicians bad enoughteachers should teach injury preventioninjuries are an excuse for time off comments ( open response ) to what extent do you agree with the following statements regarding strategies to prevent injuries ? [ order of statements was randomized ] completely disagreeneutralcompletely agreechanging my posture / hand position would have a positive effect on my playing long termlearning more about good posture / hand position will make me a better teacherit is too difficult to change my posture / hand positionchanging my practice structure will help improve my playingchanging my posture / hand position will help prolong my careerthe discomfort and fatigue from doing exercises will make it hard to practice afterwardshaving a good posture / hand position will improve the way in which my performance is perceived , even if the sound is the samedoing exercises will help decrease my injury riskdoing exercises is embarrassingchanging my practice structure will help decrease my injury riskdoing exercises will improve my playing reputationi need to practice for long durations to be able to perform for long durationschanging my practice structure will help prolong my careerit is too difficult to change my practice structuredoing exercises will help improve my posturedoing exercises will improve my playingif i found time to do exercises , i may as well practiceit would take too much time to change my posture / hand positionchanging my posture / hand position would affect my playing negatively in the short termdoing exercises will help prolong my careerchanging my posture / hand position will help decrease my injury riskthere is not the space to do exercises at universitymy duration of practice in one session is dictated by practice room availabilityi do nt have the time to do exercises comments ( open response ) have you ever experienced an injury ? no ( progress to item 26 ) mark all the areas you have experienced an injury in , and whether it has lasted more than 3 months , or if you currently have it ever experiencedlonger than 3 months at a timecurrentlyneck ( left side ) neck ( right side ) upper back ( left side ) upper back ( right side ) middle back ( left side ) middle back ( right side ) lower back ( left side ) lower back ( right side ) left shoulderright shoulderleft armright armleft wrist / hand / fingersright wrist / hand / fingersjaw ( left side ) jaw ( right side ) comments ( open response ) how have your injuries affected your playing / career ? ( tick all that apply ) [ order of statements was randomized ] reduce practice time by half stop you from playing for a month missed opportunities for work / study stop you from playing for 3 months missed playing commitments comments ( open response ) how effective have you found the following in treating injuries ? ( only mark those you have tried ) [ order of statements was randomized ] no helpextremely helpfulrelaxation techniquesmassageheatcortisone injectionsstretchingalexander techniqueyogabowen therapypilatesgeneral body trainingwarm - upstop playing as soon as you experience discomfortregular practice breakstime off from playingmedicationsmuscle resistance exercises ( eg , weights , thera - band ) reduce playing hoursfeldenkraischiropractorphysiotherapyosteopathice comments ( open response ) if there is anything else you would like to tell us about injuries or injury prevention , including anything in particular you would like taught in an injury prevention program , please write this in the space belowa systematic search of scopus , cumulative index to nursing and allied health literature ( cinahl ) ( ebscohost ) , medline ( ovidsp ) , and embase ( ovidsp ) was conducted in october 2012 using the search terms reported in table s1 . woodwind terms were searched in the title field , whilst the other terms were searched in the title , abstract , and keyword fields , where permitted by the databases . these terms were combined as woodwind terms and university student terms and musculoskeletal symptoms terms and ( prevalence / incidence terms or impact terms or management terms ) . searches were limited to english - language articles for all databases , as well as peer - reviewed articles in cinahl , and journal articles in scopus . studies were excluded if they were not published in english , in peer - reviewed journals , did not report relevant data ( prevalence / incidence of musculoskeletal symptoms , impact of musculoskeletal symptoms , management utilized , or perceptions of effectiveness of management utilized ) specific to university woodwind students , or were opinion papers ( eg , non - systematic narrative reviews , editorials ) . indicates a truncation symbol ( the symbol may be replaced by any number of characters by the search engine ) . the survey was administered using surveymonkey ( palo alto , ca , usa ) . thank you for your interest in this survey . prior to participating in this survey , please ensure that you have read and understood the information sheet ( attached to the email which included this link ) . we are interested in the thoughts of those who are not interested in an injury prevention program , as much as we are those who are interested . throughout the surveythese are defined as musculoskeletal symptoms , like pain , discomfort , tingling , numbness , or weakness , that prevent you from playing at your normal level . compulsory questions are marked * after many of the questions , there is a comments section . you may use this to add any extra information , ie , other suggestions , thoughts , or to explain your views . participants were also provided with a contact email if they experienced difficulties in completing the survey . * have you read and understood the information sheet , and provided your consent ? no ( survey completed at this point ) * are you aged 18 years or over ? no ( survey completed at this point ) * have you completed this survey previously ? list all of the instruments you regularly play , with your university major listed first ( include detail , ie , alto saxophone , bass clarinet ) which degree / diploma are you enrolled in ? ( include detail , ie , performance and pedagogy , classical performance ) which year are you in for your performance subject ? do you think there should be a whole subject devoted to musicians health at university ? ( tick all that apply ) [ order of statements was randomized ] instrument - specific sessions ( ie , practical sessions specifically for clarinet players ) one - on - one sessions ( ie , one - on - one session with a health professional ) interactive webpage comments ( open response ) how likely do you think you are to experience an injury in the next : no chanceextremely likely6 months12 months5 yearsever if you had an injury , how likely do you think the following would be ? [ order of statements was randomized ] no chanceextremely likelymissed playing commitmentsa negative impact on your playing reputationa week off from playingending your careerreducing your playing time by halffinancial problemsthree months off from playinga month off from playingsocial isolation comments ( open response ) how much do you think the following factors would increase your risk of an injury ? [ order of statements was randomized ] not at allextreme impactnot enough breaks when practicingpoor posture / hand positionsudden increase in playing intensity ( eg , harder pieces ) sudden increase in playing timecarrying your instrumentoverpracticingplaying with discomfortinsufficient warm up ( eg , playing long notes , slow scales ) poor general physical fitnesscramped playing conditionspoor awareness of injury preventionstress ( eg , performance anxiety ) moving equipment ( chairs , stands ) facilities ( eg , chairs , temperature , lighting ) instrument setup ( eg , thumb rests , reeds , neck straps , key height ) comments ( open response ) how effective do you think the following are in preventing an injury ? ( if you do nt know what these strategies are , leave the line blank ) [ order of statements was randomized ] no effectwill completely prevent an injurywarm - up ( eg , long tones , slow scales ) yogaregular massagestop playing as soon as you experience discomfortpilatesaerobic exercise ( eg , running , rowing ) stretchingmuscle - resistance exercises ( eg , weights , thera - band ) alexander techniqueosteopathbowen therapyphysiotherapyrelaxation techniquesfeldenkraisregular practice breakschiropractor comments ( open response ) have you tried or are you currently doing any of these to help prevent an injury ? ( tick all that apply ) [ order of statements was randomized ] have donecurrently doingpilatesstop playing as soon as you experience discomfortalexander techniquerelaxation techniquesstretchingyogafeldenkraisaerobic exercise ( eg , running , rowing ) physiotherapychiropractorosteopathwarm - up ( eg , long tones , slow scales ) regular practice breaksmuscle - resistance exercises ( eg , weights , thera - band ) bowen therapyregular massage comments ( open response ) what has or would prompt you to make changes to reduce your risk of injury ? ( tick all that apply ) [ order of statements was randomized ] has prompted a changewould prompt a changereading about injuriesadvice from a health / medical professionalexperiencing an injury that impacts on your playingstarting to get symptoms ( before they start impacting on your playing ) having a class / workshop about injuriesknowing someone who has experienced an injuryadvice from your teacheradvice from other students / colleagues comments ( open response ) how important is it for musicians to : [ order of statements was randomized ] not at all importantextremely importanthave a no pain , no gain attitudeunderstand the physical requirements of playinghave a good posture / hand positionunderstand injury preventioncarefully structure practice sessionshave good playing techniquedo exercises ( stretches and strengthening to reduce injuries ) comments ( open response ) rate your agreement with the following statements [ order of statements was randomized ] completely disagreeneutralcompletely agreeinjury prevention is the responsibility of the teacherinjury prevention is the responsibility of the individual musicianinjury prevention is the responsibility of the universityinjuries can be preventedif i had an injury , i would tell my teacherif a musician has an injury , it reflects poorly on their teachermusicians should understand injury preventiondiscomfort is a normal part of playinghealth professionals need a good musical understanding to advise and treat musiciansi would not tell another musician if i had an injurymusicians who have had an injury are at higher risk of future injurymusicians who have had an injury should not be professional musiciansmusicians who have had to have time off because of an injury must not want to be musicians bad enoughteachers should teach injury preventioninjuries are an excuse for time off comments ( open response ) to what extent do you agree with the following statements regarding strategies to prevent injuries ? [ order of statements was randomized ] completely disagreeneutralcompletely agreechanging my posture / hand position would have a positive effect on my playing long termlearning more about good posture / hand position will make me a better teacherit is too difficult to change my posture / hand positionchanging my practice structure will help improve my playingchanging my posture / hand position will help prolong my careerthe discomfort and fatigue from doing exercises will make it hard to practice afterwardshaving a good posture / hand position will improve the way in which my performance is perceived , even if the sound is the samedoing exercises will help decrease my injury riskdoing exercises is embarrassingchanging my practice structure will help decrease my injury riskdoing exercises will improve my playing reputationi need to practice for long durations to be able to perform for long durationschanging my practice structure will help prolong my careerit is too difficult to change my practice structuredoing exercises will help improve my posturedoing exercises will improve my playingif i found time to do exercises , i may as well practiceit would take too much time to change my posture / hand positionchanging my posture / hand position would affect my playing negatively in the short termdoing exercises will help prolong my careerchanging my posture / hand position will help decrease my injury riskthere is not the space to do exercises at universitymy duration of practice in one session is dictated by practice room availabilityi do nt have the time to do exercises comments ( open response ) have you ever experienced an injury ? no ( progress to item 26 ) mark all the areas you have experienced an injury in , and whether it has lasted more than 3 months , or if you currently have it ever experiencedlonger than 3 months at a timecurrentlyneck ( left side ) neck ( right side ) upper back ( left side ) upper back ( right side ) middle back ( left side ) middle back ( right side ) lower back ( left side ) lower back ( right side ) left shoulderright shoulderleft armright armleft wrist / hand / fingersright wrist / hand / fingersjaw ( left side ) jaw ( right side ) comments ( open response ) how have your injuries affected your playing / career ? ( tick all that apply ) [ order of statements was randomized ] reduce practice time by half stop you from playing for a month missed opportunities for work / study stop you from playing for 3 months missed playing commitments comments ( open response ) how effective have you found the following in treating injuries ? ( only mark those you have tried ) [ order of statements was randomized ] no helpextremely helpfulrelaxation techniquesmassageheatcortisone injectionsstretchingalexander techniqueyogabowen therapypilatesgeneral body trainingwarm - upstop playing as soon as you experience discomfortregular practice breakstime off from playingmedicationsmuscle resistance exercises ( eg , weights , thera - band ) reduce playing hoursfeldenkraischiropractorphysiotherapyosteopathice comments ( open response ) if there is anything else you would like to tell us about injuries or injury prevention , including anything in particular you would like taught in an injury prevention program , please write this in the space below , please ensure that you have read and understood the information sheet ( attached to the email which included this link ) . we are interested in the thoughts of those who are not interested in an injury prevention program , as much as we are those who are interested . throughout the surveythese are defined as musculoskeletal symptoms , like pain , discomfort , tingling , numbness , or weakness , that prevent you from playing at your normal level . compulsory questions are marked * after many of the questions , there is a comments section . you may use this to add any extra information , ie , other suggestions , thoughts , or to explain your views . participants were also provided with a contact email if they experienced difficulties in completing the survey . * have you read and understood the information sheet , and provided your consent ? no ( survey completed at this point ) * are you aged 18 years or over ? no ( survey completed at this point ) * have you completed this survey previously ? list all of the instruments you regularly play , with your university major listed first ( include detail , ie , alto saxophone , bass clarinet ) which degree / diploma are you enrolled in ? ( include detail , ie , performance and pedagogy , classical performance ) which year are you in for your performance subject ? do you think there should be a whole subject devoted to musicians health at university ? what format do you think information about preventing injuries should be provided in ? ( tick all that apply ) [ order of statements was randomized ] instrument - specific sessions ( ie , practical sessions specifically for clarinet players ) one - on - one sessions ( ie , one - on - one session with a health professional ) interactive webpage comments ( open response ) how likely do you think you are to experience an injury in the next : no chanceextremely likely6 months12 months5 yearsever if you had an injury , how likely do you think the following would be ? [ order of statements was randomized ] no chanceextremely likelymissed playing commitmentsa negative impact on your playing reputationa week off from playingending your careerreducing your playing time by halffinancial problemsthree months off from playinga month off from playingsocial isolation comments ( open response ) how much do you think the following factors would increase your risk of an injury ? [ order of statements was randomized ] not at allextreme impactnot enough breaks when practicingpoor posture / hand positionsudden increase in playing intensity ( eg , harder pieces ) sudden increase in playing timecarrying your instrumentoverpracticingplaying with discomfortinsufficient warm up ( eg , playing long notes , slow scales ) poor general physical fitnesscramped playing conditionspoor awareness of injury preventionstress ( eg , performance anxiety ) moving equipment ( chairs , stands ) facilities ( eg , chairs , temperature , lighting ) instrument setup ( eg , thumb rests , reeds , neck straps , key height ) comments ( open response ) how effective do you think the following are in preventing an injury ? ( if you do nt know what these strategies are , leave the line blank ) [ order of statements was randomized ] no effectwill completely prevent an injurywarm - up ( eg , long tones , slow scales ) yogaregular massagestop playing as soon as you experience discomfortpilatesaerobic exercise ( eg , running , rowing ) stretchingmuscle - resistance exercises ( eg , weights , thera - band ) alexander techniqueosteopathbowen therapyphysiotherapyrelaxation techniquesfeldenkraisregular practice breakschiropractor comments ( open response ) have you tried or are you currently doing any of these to help prevent an injury ? ( tick all that apply ) [ order of statements was randomized ] have donecurrently doingpilatesstop playing as soon as you experience discomfortalexander techniquerelaxation techniquesstretchingyogafeldenkraisaerobic exercise ( eg , running , rowing ) physiotherapychiropractorosteopathwarm - up ( eg , long tones , slow scales ) regular practice breaksmuscle - resistance exercises ( eg , weights , thera - band ) bowen therapyregular massage comments ( open response ) what has or would prompt you to make changes to reduce your risk of injury ? ( tick all that apply ) [ order of statements was randomized ] has prompted a changewould prompt a changereading about injuriesadvice from a health / medical professionalexperiencing an injury that impacts on your playingstarting to get symptoms ( before they start impacting on your playing ) having a class / workshop about injuriesknowing someone who has experienced an injuryadvice from your teacheradvice from other students / colleagues comments ( open response ) how important is it for musicians to : [ order of statements was randomized ] not at all importantextremely importanthave a no pain , no gain attitudeunderstand the physical requirements of playinghave a good posture / hand positionunderstand injury preventioncarefully structure practice sessionshave good playing techniquedo exercises ( stretches and strengthening to reduce injuries ) comments ( open response ) rate your agreement with the following statements [ order of statements was randomized ] completely disagreeneutralcompletely agreeinjury prevention is the responsibility of the teacherinjury prevention is the responsibility of the individual musicianinjury prevention is the responsibility of the universityinjuries can be preventedif i had an injury , i would tell my teacherif a musician has an injury , it reflects poorly on their teachermusicians should understand injury preventiondiscomfort is a normal part of playinghealth professionals need a good musical understanding to advise and treat musiciansi would not tell another musician if i had an injurymusicians who have had an injury are at higher risk of future injurymusicians who have had an injury should not be professional musiciansmusicians who have had to have time off because of an injury must not want to be musicians bad enoughteachers should teach injury preventioninjuries are an excuse for time off comments ( open response ) to what extent do you agree with the following statements regarding strategies to prevent injuries ? [ order of statements was randomized ] completely disagreeneutralcompletely agreechanging my posture / hand position would have a positive effect on my playing long termlearning more about good posture / hand position will make me a better teacherit is too difficult to change my posture / hand positionchanging my practice structure will help improve my playingchanging my posture / hand position will help prolong my careerthe discomfort and fatigue from doing exercises will make it hard to practice afterwardshaving a good posture / hand position will improve the way in which my performance is perceived , even if the sound is the samedoing exercises will help decrease my injury riskdoing exercises is embarrassingchanging my practice structure will help decrease my injury riskdoing exercises will improve my playing reputationi need to practice for long durations to be able to perform for long durationschanging my practice structure will help prolong my careerit is too difficult to change my practice structuredoing exercises will help improve my posturedoing exercises will improve my playingif i found time to do exercises , i may as well practiceit would take too much time to change my posture / hand positionchanging my posture / hand position would affect my playing negatively in the short termdoing exercises will help prolong my careerchanging my posture / hand position will help decrease my injury riskthere is not the space to do exercises at universitymy duration of practice in one session is dictated by practice room availabilityi do nt have the time to do exercises comments ( open response ) have you ever experienced an injury ? no ( progress to item 26 ) mark all the areas you have experienced an injury in , and whether it has lasted more than 3 months , or if you currently have it ever experiencedlonger than 3 months at a timecurrentlyneck ( left side ) neck ( right side ) upper back ( left side ) upper back ( right side ) middle back ( left side ) middle back ( right side ) lower back ( left side ) lower back ( right side ) left shoulderright shoulderleft armright armleft wrist / hand / fingersright wrist / hand / fingersjaw ( left side ) jaw ( right side ) comments ( open response ) how have your injuries affected your playing / career ? ( tick all that apply ) [ order of statements was randomized ] reduce practice time by half stop you from playing for a month missed opportunities for work / study stop you from playing for 3 months missed playing commitments comments ( open response ) how effective have you found the following in treating injuries ? ( only mark those you have tried ) [ order of statements was randomized ] no helpextremely helpfulrelaxation techniquesmassageheatcortisone injectionsstretchingalexander techniqueyogabowen therapypilatesgeneral body trainingwarm - upstop playing as soon as you experience discomfortregular practice breakstime off from playingmedicationsmuscle resistance exercises ( eg , weights , thera - band ) reduce playing hoursfeldenkraischiropractorphysiotherapyosteopathice comments ( open response ) if there is anything else you would like to tell us about injuries or injury prevention , including anything in particular you would like taught in an injury prevention program , please write this in the space below\noutput:\n" }, { "from": "agent", "value": "backgroundthis study aimed to determine the experiences of university classical woodwind students with playing - related injuries ( pris ) , the impact of these pris , the management selected by students with pris , and the perceived effectiveness of this management.materials and methodsall classical woodwind students enrolled in vocational education training or undergraduate courses at a university were sent an email with a link to an online survey . only those aged 18 years and older were eligible . the survey obtained data regarding demographic information , details of pri experienced ( location , if they lasted for more than 3 months , and if they were current ) , and the impact of these , as well as the types of management strategies tried and their perceived effectiveness . data were analyzed using descriptive statistics , and comments were reported descriptively.resultsfourteen students returned the survey ; however , one of these only completed the questions regarding demographics , and was therefore excluded . a total of 62 % of participants reported having experienced a pri . common locations for pri were the wrist / hand / fingers , lower back , and neck . reducing practice time by half and missing playing commitments were the most commonly reported consequences of pris . playing - related management strategies were most frequently trialed , with these and passive nonplaying - related strategies perceived to be the most effective.conclusionpris are common in this population , with a range of consequences reported . while it is encouraging that students had tried and found effective playing - related management strategies , active nonplaying - related strategies should be encouraged , particularly in preference to passive nonplaying - related strategies . this was a small - scale study , and the results are only applicable to the institution investigated ; therefore , similar larger - scale studies are recommended to determine the generalizability of these findings ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: brugada syndrome ( bs ) was first described in 1992 as a new autosomal dominantly inherited channelopathy caused by a defective gene located on chromosome 3 in a structurally normal heart . it is characterized by st - segment elevation in the right precordial leads and increases susceptibility to ventricular tachyarrhythmias . importantly , fluctuations in ecg patterns seem to be common among bs patients . for instance , vagotonic agents , - adrenergic agonists , fever and bradycardia are some of the conditions that may reveal the abnormality on a surface ecg . subarachonoid hemorrhage results in repolarisation abnormalities and changes in autonomic nervous system activity . in this report , we present the case of a patient with subarachonoid hemorrhage who was admitted to the emergency department after suffering an out - of - hospital cardiac arrest with typical st - segment elevation and an ecg pattern characteristic of bs . a 48 - year - old man with no past medical history was presented to our emergency department after collapsing suddenly while shopping . a store employee trained in basic life support was the first to assist the patient and started to cardiopulmonary resuscitation ( cpr ) . upon arrival to the local emergency medical service , the paramedics commenced ventricular fibrillation ( vf ) and an automated external defibrillator was used to defibrillate the patient . after two separate defibrillations and 5 min of cpr the patient regained spontaneous circulation , but remained unconscious . he was flaccid , non - febrile and comatose ( glasgow coma scale of 4 ) , with a heart rate of 75 bpm and blood pressure of 110/75 mmhg . meanwhile , vf was performed several times and the patient was defibrillated successfully to a normal sinus rhythm . electrocardiography revealed bizarre coved - type st - segment elevation in leads v1 through v3 , with t wave inversion consistent with the type 1 brugada pattern ( fig . 1 ) and reciprocal st depression in inferior and lateral leads . emergent cardiac catheterization was performed , which revealed no stenosis or flow abnormalities in his coronary arteries . after contrast injection into those coronary arteries , st - segment elevation was resolved and did not recur ( fig . 2 ) . laboratory tests , including cardiac biomarkers and coagulation studies , produced results that were within normal reference limits . since the patient was not responding , a non - contrasted brain computed tomography scan was performed and revealed a diffuse subarachnoid hemorrhage . he was admitted to the intensive care unit and determined to be brain dead after further neurological testing . brugada syndrome is characterized by st - segment elevation in the right precordial ecg leads , specifically v1 - v3 , and a high incidence of sudden death due to ventricular tachyarrhythmias in patients with structurally normal hearts . the syndrome is generally thought to be responsible for 412 % of all sudden deaths and at least 20 % of deaths in patients with structurally normal hearts ; the most common presentation is syncope . the syndrome is inherited and auotosomally dominant , and in 25 % of the cases the responsible mutation is found on the cardiac sodium transport gene ( scn5a ) , located on chromosome 3 . because the ecgs of patients with brugada syndrome are complex and often conceal the condition , it is difficult to estimate the true incidence of the disease in the general population . however , three types of repolarisation patterns in the right precordial leads are currently recognized . type 1 is diagnostic of bs and is characterized by a coved st - segment elevation 2 mm ( 0.2 mv ) , followed by a negative t wave . type 2 has a saddleback appearance with a high take - off st - segment elevation of 2 mm , followed by a trough displaying 1 mm st - segment elevation and either a positive or biphasic t wave . type 3 has either a saddleback or coved appearance with an st - segment elevation of 1 mm . sodium - channel blockers , vagotonic agents , - adrenergic agonists , - adrenergic blockers , tricyclic antidepressants , glucose - induced insulin secretion , fever , bradycardia , ischemia , hypothermia , hyperkalemia , hypokalemia , hypercalcemia , alcohol and cocaine can expose or induce these ecg patterns . additionally , st - segment elevation in the brugada patients is significantly influenced by heart rate and autonomic tone . the ventricular myocardium is composed of at least three electrophysiologically distinct cell types : epicardial , endocardial and m cells . the st - segment elevation and t wave inversions seen in the right precordial leads of those with bs are thought to be due to an alteration in the action potential of the epicardial and possibly the m cells , but not the endocardial cells . the resulting dispersion of repolarisation across the ventricular wall , which is most pronounced in the right ventricle , results in a transmural voltage gradient that is manifested in the electrocardiogram as st - segment elevation . this dispersion of repolarisation facilitates the development of phase 2 reentry , which generates a phase 2 reentrant extrasystole that takes advantage of the window of opportunity to precipitate the ventricular tachycardia and / or fibrillation that often results in sudden cardiac death . a bs diagnosis is confirmed when a type 1 st - segment elevation is observed in more than one right precordial lead ( v1 - v3 ) , in the presence or absence of a sodium channel block , and in conjunction with one of the following : documented ventricular fibrillation , self - terminating polymorphic ventricular tachycardia , a family history of scd ( 45 years ) , coved type ecgs in family members , inducibility of vt with programmed electrical stimulation , syncope or nocturnal agonal respiration . cardiac arrhythmias or repolarisation abnormalities occur after a stroke in approximately 6070 % of patients and may have important prognostic implications . in one report , investigated the circulatory collapse mechanisms in patients who experienced out - of - hospital cardiac arrest ( ohca ) due to subarachnoid hemorrhage . pulseless electrical activity and asystole were common among study patients , but no ventricular fibrillation was observed . found that the return of spontaneous circulation rate was higher than other etiologies of ohca , but long - term survival was poor . a rate of vf similar to the initial cardiac rhythm was observed in a study by inamasu et al . researchers concluded that the prognosis was more favourable if the initial rhythm causing circulatory collapse was vf , but not brainstem damage . in another study , brouwers et al . demonstrated that ecg changes were most prominent 2472 hours after subarachnoid hemorrhage . specifically , this event leads to repolarisation and several electrocardiographic abnormalities , including qt segment prolongation , aberrant q waves , non - specific st - segment changes , t wave abnormalities and the appearance of u waves . evidence of subendocardial infarction or anterolateral ischemia is common after a stroke , especially after subarachnoid hemorrhage . myocardial injury during a stroke is most likely the result of a centrally mediated release of catecholamines , due to hypoperfusion of the posterior hypothalamus . transient coronary vasospasm secondary to increased sympathetic tone during a stroke has also been described . the depression of ica and activation of ik - atp during ischemia associated with vasospasm involving right ventricular outflow tract results in st - segment elevation similar to that observed in cases of bs . in our patient , subarachnoid hemorrhage created a transmural voltage gradient due to its effect on repolarisation or increased - adrenergic activity and resulted in a bs - like ecg pattern . subarachnoid hemorrhage may be one of the factors predisposing the patient to the electrocardiographic and arrhythmic manifestations of bs . to conclude , when a patient without known structural heart disease presents with ventricular tachyarrhythmia and bs - like st - segment elevation , subarachnoid hemorrhage should be kept in mind , since its prompt and accurate treatment could be life saving .\noutput:\n" }, { "from": "agent", "value": "brugada syndrome is an autosomal dominantly inherited channelopathy estimated to be responsible for 412 % of all sudden deaths , particularly among middle - aged men . it is characterized by st - segment elevation in the right precordial leads , in the absence of acute coronary syndrome . this report discuses a patient with subarachonoid hemorrhage who developed the characteristic electrocardiographic features of brugada syndrome ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: prior to the advent and subsequent popularity of the internet , biological databases and scientific publications were necessarily separate entities . however , now that scientists rely on cyberinfrastructure in the course of their daily research , it is startling that databases and publications are still so distinct from each other . while databases have matured and grown in complexity in the digital age , publications have fared poorly ; the traditional concept of an article as a static , independent unit of information persists , albeit in an electronic version . there are myriad ways in which the content of an electronic version of an article can be used in a computational manner and the technology and infrastructure to make this happen already exists ; this is demonstrated by , among other things , the existence of biological databases and related data mining tools . indeed , one hallmark of a successful biological database is integration via data mining with other related databases or resources . yet integration with literature , which is unquestionably the primary medium through which scientists communicate their research , is conspicuously lacking . significant progress in taking advantage of article content is finally being made , perhaps most notably as a result of the open access literature movement pioneered by , among others , the public library of science ( plos ) ( 1 ) . articles that are published under an open access license are available for download in toto immediately upon publication and can be distributed freely providing that the original citation is maintained . the deposition of open access life sciences articles has been centralized with the creation of pubmed central ( 2 ) and it is especially important to note that pubmed central stores many of these articles in a standardized and machine - readable format , which conforms to the national library of medicine ( nlm ) dtd ( http://dtd.nlm.nih.gov/ ) . all pubmed central articles deposited as a result of this movement are thus freely available as xml files , which contain the full - text of the article and some semantic mark - up of the content . though a major advantage to both authors and readers , a large segment of the life sciences community remains unaware of the opportunities that are now available due to the existence of pubmed central as a digital repository , or even of the existence of open access literature altogether . hopefully , this will change with the recent nih directive , which mandates the deposition of all findings of nih - funded research in pubmed central ( http://publicaccess.nih.gov/ ) and with novel open access - driven applications such as pubnet ( 3 ) and scivee ( 4 ) . admittedly , challenges do present themselves when considering the use of open access literature beyond that of a reader or distributor they have been described elsewhere ( 47 ) but opportunities abound and the tenor of current scientific policy and inquiry suggests that the open access corpus will continue to grow significantly ( 810 ) . biolit aims to take advantage of the opportunities offered by open access literature by making it possible to include full text or excerpts of these articles directly within existing biological databases and to add newly generated metadata to the articles in order to increase their informative value , tasks which are both made possible by having free access to the full text of the article . these tasks are accomplished by mining the full article text for terms of interest , indexing the terms found , and then including these terms in both machine - readable and human - readable forms that are an enhancement of the original article xml file . we have prototyped this particular aspect of the effort using a clone of the rcsb protein data bank ( pdb ) ( 11 ) , a database of macromolecular structures , and have consequently focused on finding pdb identifiers and gene ontology ( 12 ) terms as these are both major resources in the structural biology community and the life sciences community as a whole . several groups have made significant contributions in applying ontologies to both open - and closed - access biomedical literature . for example , the biocreative initiative has spawned a number of tools with the aim of annotating genes and proteins in articles using ontologies and other vocabularies ( 13 ) . gopubmed ( 14 ) and the more recent segopubmed ( 15 ) both aim to add gene ontology - based semantic data to pubmed abstracts in order to improve literature searches . the textpresso team has also focused on improving the classification and searchability of articles by inferring semantic relationships in articles using customized ontologies ( 16,17 ) . another excellent resource is the national center for biomedical ontology ( ncbo ) whose overarching aim is to render biomedical information into machine - readable data ( 18 ) . one of their major contributions is the unification and integration of biomedical ontologies into a single resource , the obo foundry , which makes projects such as these and biolit feasible . the ncbo consortium is also developing a number of web - based tools , in order to make the machine - readable biomedical information available and useful to the community . finally , the conceptual open hypermedia service ( cohse ) , perhaps the most broadly applicable semantic mark - up project , runs as a portlet and adds hyperlinks to existing web pages by allowing a user to select an ontology with terms that can be matched to the page to create links to other pages ( 19 ) . several of the aforementioned tools allow manual curation of the marked - up result in order to increase the accuracy of the mark - up , and hence , the literature search results . this is the ideal approach towards semantic mark - up since the author , or at least an expert human , is providing input . however , the uptake of such an approach in the community has been fairly unsuccessful owing to time limitations on the part of the putative curators and , presumably , lack of demonstrable value to justify the time and effort . biolit shares many attributes with these projects but is unique in that it offers a searchable web database of the full text of all pubmed central research articles with automated mark - up from multiple biomedical ontologies and identifiers from multiple biological databases . no downloading of software is required and all searchable terms belong to established biomedical resources . the focus of this resource is specific to life sciences literature but broad within that realm . the database supporting the biolit web server contains data from a subset of the pubmed central holdings . article archives , including full - text xml files and figures , were retrieved via the pubmed central ftp site ( ftp://ftp.ncbi.nlm.nih.gov/pub/pmc ) . the articles were first filtered to remove articles that were not labeled as review - article , case - report , research - article , brief - report , retraction and article - commentary , and documents which contained only scanned content since these are generally advertisements . the remaining articles were stored in a local mysql database both in the original and parsed formats . when possible , data included in the medline record for an article were retrieved from pubmed using ncbi 's e - utilities ( 2 ) . the full text of each article was then parsed to find pdb ids and gene ontology terms . currently , 51667 articles exist in the database . the database is updated weekly . biolit uses a customized viewer for the articles in order to display the original text inline with the added metadata . the full text of the paper can be displayed in a tabbed format or the traditional linear article format and the metadata are highlighted with color and a menu of options when the user clicks on a term . in the case of pdb ids , an image of the 3d structure identified by the pdbi d is displayed along with links to the macromolecular sequence , the pdb record and other related features . we also generate statistics describing ontology term usage across all articles and these terms can be used for searching or finding related articles . this customized viewer not only displays the full text of an article as it was originally published but also displays integrated metadata from the biolit database . pdb ids can be seen highlighted in yellow and gene ontology terms are highlighted in lavender . clicking on a highlighted terms brings up information , a list of options or links associated with each term . this customized viewer not only displays the full text of an article as it was originally published but also displays integrated metadata from the biolit database . pdb ids can be seen highlighted in yellow and gene ontology terms are highlighted in lavender . clicking on a highlighted terms brings up information , a list of options or links associated with each term . in order to use the biolit article viewer , the user enters a search term on the biolit homepage . this term can be an author name , title , keyword , etc . the web server then returns a list of matching articles ; clicking on an article invokes the customized viewer . alternatively , a user could bypass the web - based viewer and retrieve biolit xml files using a script by appending a pubmed central i d ( pmcid ) , pubmed i d ( pmid ) or article digital object identifier ( doi ) to the following url template : http://biolit.ucsd.edu/biolit/getbiolitxml?source=id where , source isthe machine - readable version of an article is available as an xml file through the viewer and via a post http query . the xml markup enrichment performed by biolit consists of inserting metadata into the original xml file . the biolit tag appears as the top - level child node of article , a tag in the nlm namespace . the additional metadata includes markup revision data ( markup - version and markup - date ) as well as derived identification content ident , which specifies the doi and pubmed central i d of the article . throughout the text of the article , biolit - term marks semantic content that has been discovered during the data mining process where attributes typeone example of how the biolit data might be used in an existing biological web resource is illustrated by the biolit pdb clone , a stand - alone clone of the protein data bank which runs independently from the pdb and has direct access to the biolit database ( http://biolit.ucsd.edu/pdb ) . the clone maintains much of the original functionality , including access to the latest release of the pdb database , while providing access to features unique to biolit . a simple browser has been integrated to display data excerpts from the article as well as structure ids and ontology terms identified in the article . thus , when an entry in the pdb is displayed , all articles in the biolit database that mention that entry are included as citations in the pdb record . in contrast , the pdb currently only displays the citation associated with the entry in which the solved structure is reported . figure 2 shows an entry from the biolit pdb clone which has citations in the biolit database . because we find all mentions of pdb ids in an article , we can also report which pdb ids are mentioned in the same article . all ontology terms are parsed from an obo file ( http://obofoundry.org/ro/ro.obo ) and loaded into a tree structure such that each letter in any given term links to the letter succeeding it . the full - text of the xml article is then read beginning with the abstract and ending with the end of the article body . the parser jumps to the beginning of every word in the article text , reading character by character . this structure is advantageous as it allows a search for all words in a single read of the document and it allows the reading to stop as soon as a word fails to have a character in the tree . the longest parse time that we have observed of parsing an article through a large ontology , such as the gene ontology , are about 30 s , although most articles are processed in under 1 s.the biolit web server is staged from a single dell poweredge sc145 , which is hosted at the skaggs school of pharmacy and pharmaceutical sciences at ucsd . the machine is a dual - opteron 2216 ( dual core at 2.4 ghz ) with 8 gb of ram and 750 gb of raided storage , which runs redhat enterprise linux 5 . at the present time , this machine is responsible for data mining , markup , front - end functionality , as well as serving a modified clone of the pdb web application . in an effort to maximize performance and scalability of the software , the data mining portion is handled by a suite of in - house parsing scripts . the front - end searching and visualization functionality is delivered by a j2ee web application running on apache tomcat 6 . much of the web - based , event - driven functionality is structured upon the yui api . the dynamic data storage and sharing is handled by mysql , while large static data are locally archived . the value of the biolit web server resides in the amount of metadata it can provide and in the ease in which those metadata can be retrieved . to increase the value of biolit , we plan to parse the articles through all ontologies in the open biomedical ontologies foundry ( 20 ) and allow the user to specify the inclusion or exclusion of metadata by ontology . we also plan to expand our search for database identifiers to other major biological databases . in order to make these data more accessible to biocurators and text miners , we are implementing web services - based protocols that allow fetching of articles or metadata by source ( database , ontology ) and by term or i d . we recognize that we are not experts in natural language processing and that the markup we provide is not truly semantic in nature ( e.g. we do not infer relationships between terms and identifiers ) . we hope that the biolit web server will establish an informative , yet transparent , connection between the data and the article describing the data and that effective use of this resource will provide new perspectives on both traditional literature and biological databases . we expect that literature will simply become another interface to biological data in a database and the database will recall appropriate literature not in abstract or complete paper size chunks , but knowledge objects that annotate the data being examined . as authors become more aware of the possibilities offered by open access literature and by tools that can be used to standardize and highlight semantic content , we hope this awareness will manifest itself in the writing process and contribute to the accessibility of literature - based knowledge .\noutput:\n" }, { "from": "agent", "value": "biolit is a web server which provides metadata describing the semantic content of all open access , peer - reviewed articles which describe research from the major life sciences literature archive , pubmed central . specifically , these metadata include database identifiers and ontology terms found within the full text of the article . biolit delivers these metadata in the form of xml - based article files and as a custom web - based article viewer that provides context - specific functionality to the metadata . this resource aims to integrate the traditional scientific publication directly into existing biological databases , thus obviating the need for a user to search in multiple locations for information relating to a specific item of interest , for example published experimental results associated with a particular biological database entry . as an example of a possible use of biolit , we also present an instance of the protein data bank fully integrated with biolit data . we expect that the community of life scientists in general will be the primary end - users of the web - based viewer , while biocurators will make use of the metadata - containing xml files and the biolit database of article data . biolit is available at http://biolit.ucsd.edu ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: integration is the goal of many human service organizations , policymakers , theorists , and professionals . integrated health services hold the promise of improved efficiency , capacity , performance / quality , cost - effectiveness , and enhanced working environment with improved communication and cooperation . the canadian council on health services accreditation ( 2006 ) offers a definition of integration which encapsulates the many definitions found in the limited health literatureservices , providers , and organizations from across the continuum working together so that services are complementary , coordinated , in a seamless unified system , with continuity for the client . in ontario , there are increasing efforts to promote health services integration especially in local health integration networks ( lhins ) . in a synthesis of reviews of . concluded that comprehensive interventions address multiple risk and protective factors , operate across multiple environments such as school , home , and community , and provide a mix of universal , targeted , and clinical services that are often proactive . this can be achieved by providing integrated care coordination ( adjusting one provider 's care because of what other providers do ) or collaboration ( jointly planning the type of care , provided how and by whom ? ) . recently the children 's treatment network ( ctn ) of simcoe county and york region , ontario created integrated child and family teams of rehabilitation provider 's from different and autonomous organizations whose providers work together using network interdisciplinary teams and a single plan of care to address the range and mix of any client 's problems . recently , the children 's treatment network ( ctn ) in ontario was formed with funding from the ontario ministry of children and youth services to create network interdisciplinary teams that target the needs of each child and their families with complex disabilities in simcoe county and york region of ontario . the ctn model is a new approach for care of children and their families with complex needs that is based on local service providers from different agencies and organizations collaborating and taking a team approach to the comprehensive rehabilitation and psychosocial needs of both children and their families without the use of a single children 's treatment centre organization and building . the ctn model of team service provision consists of an integrated package with the following key elements . single point of access , service navigation , and a comprehensive child and family interview , assignment of a service coordinator , development of the individual child and family team , and development of a single plan of care recorded in the shared electronic client record . this integrated network incorporates the key principles necessary for success as outlined by suter et al . in their comprehensive health systems integration review . common services available to families in the ctn model of delivery are developmentally appropriate physiotherapy , occupational therapy , speech therapy , augmentative communication , in - home family support worker , child behavior therapy , inclusive recreation , parenting instruction , family therapy , psychology , early childhood educator , or special educational resource teacher depending on the child 's school age ( http://www.ctn-simcoeyork.ca/ ) . to date , evaluation of health service integration efforts has been largely cross - sectoral in nature with some reported benefits to the system . system - level positive outcomes include reduction in nonemergency cases using the emergency room ; reduction in the average length of stay in hospital ; better financial performance ; a flatter organizational structure ( fewer management tiers ) . some of the positive program / provider - level outcomes include increased job satisfaction ; increased cooperation with other agencies ; a blending of professional cultures into one shared culture . our team took the bioecological and biopsychosocial perspectives of human development that it is not possible to fully understand quality of life in children with complex needs by considering only simple associations between child / parent / family / social or health service provider factors . a multitude of levels of factors and interactions between these factors are simultaneously present as in figure 1 , and care of these families requires a holistic approach . the purpose of this paper was to test the value of the integrated efforts of a team of rehabilitation providers from networked organizations that can be moderated by child and parent variables and relate these interactions to the change in the child 's physical function after two years . we hypothesized that the effects of current integrated child and family team function would be more pronounced or stronger among families with fewer parent and child risk characteristics because the physical rehabilitation providers are not educated to deal with cumulative parent or child risk factors . when integrated teams are able to manage dysfunctional parents and child behaviors , there would be improvements in child physical function two years later . parents and children interact and can moderate the effectiveness of integrated team function whereby either the child or the parent in interaction with service providers either facilitates or inhibits the success of physical rehabilitation efforts . this descriptive study is part of a prospective cohort study examining the effects and expense of the ctn . ethics approval was obtained for the study by the research ethics board of mcmaster university . the depth of integration of ctn service providers on each child and family team was also measured at the 2 - year followup . completed integration measures were obtained from service providers on 110 ctn child and family teams . this was a 2 - year longitudinal survey of families with a special needs child enrolled in the ctn from may to december 2007 . families were deemed eligible if the child was aged 019 years , were residents of simcoe / york , and there were , in addition to the child 's physical rehabilitation needs , multiple other needs within the family ( child 's special cognitive , communication , and behavioral needs and families ' needs e.g. parenting style , a parent 's medical or mental health problem ) . the consenting parent / guardian most knowledgeable ( pmk ) returned a signed consent form to mcmaster university indicating their willingness to participate . the pmk then completed a baseline telephone interview ( 1 hour ) by one of three trained interviewers from mcmaster university . a followup telephone interview was completed after 2 years by the same mcmaster interviewer who was masked to the child and family receipt of integration care . integration of the ctn teams among families enrolled in this research was measured using the integration of human services measure . this measure evaluates observed and expected depth of integration among service providers on each ctn child and family team . depth of integration represents the perceived and expected self - reported degree of exchange between all service providers along a continuum of involvement from nonawareness = 0 , awareness = 1 , communication = 2 , cooperation = 3 , collaboration = 4 . the total observed integration score is the mean of the average group observed depth of integration scores . the total expected integration score is the mean of the average group expected depth of integration scores . both observed and expected depth of integration scores about the service coordinator for each team were calculated by the average of individual members ' inputs on a four - point scale from 0 ( nonawareness ) to 4 ( collaboration ) . the number of team members who responded to the study and the corresponding response rate were also calculated . the shortened version consists of 15 items comprising three core scales and addresses the physical ( 5 items ) , emotional ( 4 items ) , social ( 3 items ) , and school functioning ( 3 items ) . parent proxy report formats were used for children ages from 2 to 18 due to the inclusion of children with limited cognitive or communicative abilities . each item for ages from 8 to 18 asks how much of a problem it has been during the past month on a five - point scale ( 0never a problem to 4almost always a problem ) . for children aged 5 to 7items are reverse - scored and linearly transformed to a 0100 scale so that higher scores indicate better quality of life . psychosocial quality of life ( psychql ) is computed as the sum of the emotional , social , and school scale scores ( 10 items , range 0100 ) . behavior was measured using the child behavior checklist ( cbcl ) questionnaire for children ages 219 also used in the canadian longitudinal survey of children and youth ( nlscy ) . the questionnaire asks about how the child seems to feel or act regarding age - specific behaviors such as getting into fights , inability to sit still , and worrying . the parent is asked to rate the specific behavior from 1never to 3often . behavior subscales include hyperactivity / inattentive , prosocial , anxiety / emotional disorder , conduct disorder / physical aggression , indirect aggression , and property offence . items differ for age groups 0 - 1 years , 25 years , and 619 years . specifically , questions pertaining to aggression , property offense , and prosocial behavior do not apply to the younger age groups . internal consistency is reported by subscale and age group ( cronbach 's alpha 0.680.84 ) . the kessler scale ( k10 ) measures pmk symptoms of depression and anxiety , a frequent accompaniment of depression . ten questions measure the frequency of feeling : sad , nervous , restless , hopeless , worthless , everything was an effort , tired for no good reason , so nervous that nothing could calm down , fidgety , so restless could not sit still , or depressed during the past month . chronic aspects of distress in the past month are examined on a five - point scale ( 1all of the time to 5none of the time ) . scores range from 10 to 50 where 19 indicates no clinically important level of distress , 2024 indicates mild distress , 2529 indicates moderate distress , and 3050 severe distress . parents were asked to rate their mental , physical health and general life satisfaction on a five - point scale ( 1very satisfied orthese questions were taken from the canadian community health survey ( cchs 2.2 ) that allowed comparisons with national samples . the impact on family ( iof ) scale determines the effects of a chronic illness on parents and families . parents respond on a four - point scale about the degree to which statements apply to their family ( 1strongly agree to 4strongly disagree ) . the revised iof scale ( 15 items ) has been validated . statements cover four dimensions : financial burden , family / social impact , personal strain , and mastery ( e.g. , fatigue is a problem , see family and friends less , need to change plans at last minute , little desire to go out ) . the nlscy parenting scale was used and consists of twenty - five questions adapted from the validated parenting practices scale . the following four parenting behaviors were measured : positive interaction ( praise , play ) , hostility / ineffective ( anger , ineffective discipline ) , consistency ( follow through ) , and punitive ( yelling , physical punishment ) . pmk rated each item ( e.g. , do something special with your child that he / she enjoys ) in terms of frequency from 0never to 4many times each day . internal consistency is reported by subscale and age group ( cronbach 's alpha 0.390.75 ) . the level of social support of the pmk was assessed using an eight - item shortened version of the social provisions scale . different social support constructs were measured : guidance , reliable alliance ( i.e. , feeling assured that others would be available to offer practical help ) , and attachment . pmk rated each item along a four - point scale from 0strongly disagree to 3strongly agree . thirteen items from the nlscy population survey , based on a subscale of the mcmaster family assessment device , were used to gather information on various aspects of family functioning ( problem solving , communication , roles , affective responsiveness , affective involvement , behavior control ) . pmk rated each item ( e.g. , we avoid discussing our fears or concerns ) along a four - point scale from 0strongly agree to 3strongly disagree . the measure of processes of care ( mpoc - 20 ) is a 20 - item , well - validated , and reliable self - report measure of parents ' perceptions of the extent to which the services they and their child receive are family - centered . respondents use a seven - point scale to describe the extent to which they experience service provider behaviors across five domains with response options ranging from 1never to 7 - to a great extent . the five domains are . enabling and partnerships , providing general information , providing specific information , comprehensive and coordinated care , and respectful and supportive care . they include , child age , gender , grade and pmk report of the main medical and other important diagnosis . a standard form including spiritual or faith orientation , ethnicity , and languages was selected from the nlscy that also includes community dwelling disabled children . sociodemographic data were gathered on the pmk gender , age , and educational level as well as on household income and family status . descriptive statistics ( numbers , percentages , means , and standard deviations ) were calculated for all child and family variables , team integration , and team functioning scores . specifically , prosocial , indirect aggression , and property offence behavior scale items are applicable for children and youth from 6 to 19 years old . the behavior scales for different age groups were transformed using the interpolation technique where the mean of the behavior scale scores for children from 2 to 5 years old with fewer items were multiplied times the number of items for older children . there were reports of two or three children with complex needs in the same family and only one report of parent variables . in these instances , the pmk was counted multiple times to ensure a matched number of children and parents in the analysis . a multiple linear regression model was used to study the interactions among the integrated team variables with other child / family / health services variables to explain the variation in the child 's physical quality of life ( ql ) at followup . variables consistent with the ecological conceptual framework that showed high correlation with and strong prediction on the followup child 's physical ql in the exploratory regression were selected . the selected child / family / health services / integration variables ( i.e. , independent variables ) were then studied for all 2 - way interactions with the outcome followup child physical ql ( i.e. , dependent variable ) . the fit of the model was assessed by the regression coefficient ( r ) , as it measures the percentage of variation of the dependent variable explained by the model . in the final model , all possible 2 - way interactions of variables were tested , and interactions that were not statically significant were removed using the forward stepwise selection technique , where the inclusion significance level and exclusion significance level were chosen to be 0.05 and 0.10 respectively . the variables in the final model were centralized to adjust for possible multicolinearity . the normal probability plot for the residualsthe association between one variable and the outcome was plotted as a regression line under three conditions of the other variable . the literature suggested applying one standard deviation from the mean to approximate scores of different conditions . in our analysis , the three conditions were conventionally defined as high ( any score more than 1 standard deviation above the mean ) , moderate ( any score within 1 standard deviation of the mean ) , and low ( any score more than 1 standard deviation below the mean ) . the majority of pmk surveyed were mothers of the children ( 80 % ) , born in canada ( 74 % ) , and spoke english ( 88 % ) . the average pmk was 40 years , 86 % were female ( as 6 % of the female respondents were not the child 's mother ) , 84 % were married / common - law , 69 % were employed , and the median household income was $ 60 $ 69,000 . there was an even split between families residing in simcoe region ( 50 % ) and york county . the average child age at interview was 7 years with 63 % of the sample being male . forty - four percent of the children were in pre - school ( up to and including kindergarten ) , 34 % in grades 15 ( elementary ) , and 22 % in grades 6 to 12 ( junior and high school ) . fifty - seven percent of children were receiving service from community care access centers and school boards at time of entry into the ctn . the top diagnoses for the children reported by pmk ( table 2 ) were mental and behavioral disorders ( 82 % ) including autism ( 29 % ) , diseases of the nervous system ( 45 % ) including cerebral palsy ( 22 % ) , and congenital malformations , deformations , and chromosomal abnormalities ( 26 % ) . fifty - four percent of children had more than one reported medical problem . in table 3 , it can be seen that the ctn study sample included children with complex needs with very low physical and low psychosocial quality of life as indicated by the pmk compared to varni 's children and adolescents with other chronic diseases . generally , this sample of children exhibited prosocial behavior and low levels of anxiety , aggression , and property offence behaviors . pmk positive interaction and consistency parenting practices were moderate , and pmk hostile or ineffective parenting and punitive parenting were generally low in this sample . on average pmk report having social supports without family dysfunction and good overall life satisfaction . forty - five percent , however , were exhibiting mild to severe symptoms of depression and anxiety ( k1019 ) . for measures of processes of care , respectful and supportive care received the highest rating , and providing general informationreceived the lowest rating by pmk . observed levels of ctn team depth of integration indicate teams were currently functioning at a communication level while team members expect to be cooperatingthe service coordinators were on average observed to be functioning at an awareness level and expected to be communicating . ctn teams were rated on their high ( 3.0 to 4.0 ) and low ( 2.5 ) observed depth of team collaboration and expected team collaboration . of 110 teams measured 43 were deemed high functioning ( high observed and expected integration levels bolded cells in table 4 ) . sixty - seven teams were deemed low functioning based on low observed and expected integration scores ( table 4 ) . a comparison of the children 's characteristics , family functioning , and extent of health services received by families between the families engaged by high and low functioning teams is shown in table 5 . the difference in quality of life , although not statistically significant , is clinically important . higher functioning teams were serving more physically and medically fragile functioning children with higher psychosocial quality of life , less aggression , and less prosocial behavior . in addition higher integrated teams were serving parents with more positive and less hostile parenting . finally , the observed and expected service coordinator depth of integration scores were higher in teams scored as highly integrated . table 6 presents the summary interaction regression analysis on the child 's physical ql at followup . eighty - nine percent of the variability in the child physical ql score at followup was explained by the model . a total of sixteen 2 - way interactions among child / family / health services / integrative team variables were found to be statistically significant . three tested the hypothesized health services / integration team variables interacting with child / family variables : child psychosocial ql interacting with integrated team function ; child emotional disorder interacting with comprehensive and coordinated care ; hostile parenting interacting with integrated team function . the interaction effect between two variables ( e.g. , a and b ) was comprised of the main effects ( a and b ) and the cross effect ( ab ) . therefore , the regression coefficients of both components were included when interpreting a complete interaction effect . figures 24 display the aforementioned three hypothesized interactions and show how integration was interacting with child / family variables . child physical ql at followup was positively associated with child psychosocial ql at baseline ( figure 2 ) . the strength of such association , however , interacted with the functioning of an integrative team . when the child and family team was highly by integrated , one additional unit of child psychosocial ql at baseline was associated with an average 1.7 score increase in child physical ql at followup . it was only associated with an average 0.9 score increase in child physical ql when the integrative team was low functioning . in other words , for each additional unit in children 's psychosocial ql at baseline , there could be an average 82 % improvement on the child 's physical ql score at followup for children engaged by a high integrated team versus a low integrated team . more hostile or ineffective parenting was not always positively associated with better child 's physical ql ( figure 3 ) . when the child and family team had low integration , for each unit increase in the baseline hostile ineffective parenting score on average , there was a deterioration of 1.1 in child 's 2 - year followup physical ql score . when the team was high functioning , there was on average a 0.79 improvement in the child 's physical ql at followup . for each unit increase in hostile parenting at baseline , the high integration team effect could account for about 170 % improvement in child physical ql at followup compared to the case of a similar situation receiving care from a low integrated team . for each additional unit in child emotional disorder at baseline , there was an average 1.6 score increase in child physical ql at followup when the family received good comprehensive and coordinated care ( figure 4 ) . in families receiving moderate and poor comprehensive and coordinated care at baseline , for each unit increase in child emotional disorder there were , on average , 0.13 and 1.83 decreases in child 's physical ql scores at followup , respectively . the level of comprehensive and coordinated care received by the family interacted with the child 's emotional status at baseline in its effect on the child 's physical ql at followup . for families that received little to moderate comprehensive and coordinated care , the child 's physical ql deteriorated at followup as their emotional status at baseline was worse . contrarily , the child 's physical ql improved at followup with poorer emotional function at baseline when the families received good comprehensive and coordinated support from service providers . this study provides original information about the effect of integrative efforts of individual child and family service teams for children with complex needs and reaffirms the value of a bioecological perspective . the primary hypothesis was corroborated about the effect of integrated team function on the improvement in child physical function after 2 years being more pronounced among families with fewer parent / child risk factors . teams with higher integration scores worked with children with higher levels of psychosocial function and parents with more positive and less hostile ineffective parenting style at baseline . the physical function of these children improved more with the higher integrated team compared to the improvement in a similar child with less integrated team function . further , when highly integrated teams worked with parents endorsing hostile - ineffective parenting styles at baseline , there was greater improvement in the child 's physical function and quality of life two years later . a less integrated team working with parents with similar hostile - ineffective parenting styles at baseline resulted in the child 's physical functioning actually deteriorating after 2 years . this same improvement in the child 's physical function after 2 years was observed when parents of children with high emotional disorder at baseline reported receiving a high level of comprehensive coordinated care at followup compared to similar children receiving less comprehensive coordinated care . generally , ctn child and family teams rated themselves as functioning at a communication level of integration . this combined with the response rate of moderate among service providers reflects the complexity of integrating service providers from different agencies all at differing locations . the ctn network is also still in its infancy with respect to organization , planning , and system support . higher expected integration scores reflect the recognition from service providers of improving integration efforts over time . this study also provides information about the physical quality of life of children with complex needs and the associations and interactions of system integration variables . the low ql scores in this sample compared to others , particularly for physical quality of life , illustrate the multifaceted needs and issues faced by this heterogeneous group of children and youth with multiple diagnoses . this study supports previous findings and confirms that reports of simple associations between research outcomes do not give a comprehensive picture of the issues . a multitude of factors ( e.g. , child behavior , child quality of life , parenting practices , provider processes of care , health service integration ) and interactions among these factors are simultaneously present ; therefore , care of these families requires a holistic approach that addresses all aspects of the child 's environment . finally , this study informs service planners of the positive characteristics of children and families more likely to be served by highly integrated teams , the risk variables at intake most likely to impair progress from children 's rehabilitation services , and the need for teams to have behavioral mental health members . results and findings are difficult to generalize outside of this study population because other contexts may differ . this study may be missing important information from working , lower educated , single parents and their children likely those with greater need . highly integrated teams had already been working with a greater proportion of medically fragile children at intake into the study . while these families had less pronounced risk factors at intake into the study , this could have been due to the services of this team prior to the outset of the study . due to the cross - sectional nature of the team integration measure in of this research , we do not understand the causation or directional influence of integration on child quality of life . longitudinal followup is needed to determine whether documented improvements in integrative team function can improve the well - being of the child or if in fact providers need to engage actively those difficult to reach families ( i.e. , families with low child psychosocial ql and unfavorable parenting practices ) . of course randomized clinical trialswould be the ideal design to address this question , but these are complex to undertake in circumstances like these . these questions are also important in order that team integration efforts can be targeted and evaluated to include the needs of parents so that child quality of life can be maximized . in this study , generally , parents underestimate their child 's quality of life compared to child self - reports . therefore , the associations and interactions may vary when child self - report data are used . it was not feasible to obtain self - report data from this complex needs group due to the wide range of limitations present in the children and budget constraints of the study . finally , clinically important change was difficult to quantify in this patient population . research to date has not determined the minimally important difference in quality of life in a diverse group of children with complex needs . rehabilitation providers working with children with complex needs need preparation to address child and parent problematic behaviors that limit progress in physical functioning . when this was the case in high integrated teams , the child 's physical quality of life improved after two years .\noutput:\n" }, { "from": "agent", "value": "purpose . to explore the interactions between child and parents psychosocial factors and team integration variables that may explain improvements in physical dimensions of the peds ql quality of life of children with complex needs after 2 years . methods . in this 2 - year study , parents were identified by the children 's treatment network . families were eligible if the child was aged 019 years , had physical limitations , resided in either simcoe county or the region of york , ontario , and there were multiple other family needs . regression analysis used to explore associations and interactions ; n = 110 . results . a child 's physical quality of life was affected by interacting factors including child 's behavior , parenting , and integrated care . statistically significant interactions between team integration , processes of care , and child / parent variables highlight the complexity of the rehabilitation approach in real - life situations . conclusions . rehabilitation providers working with children with complex needs and their families should also address child and parent problematic behaviors . when this was the case in high integrated teams , the child 's physical quality of life improved after two years ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: common clinical manifestations of large granular lymphocyte leukemia ( lgl leukemia ) include cytopenias , recurrent infections , splenomegaly , and autoimmune disorders . diagnosis can be difficult , and is usually based on clinical presentation , persistent peripheral lgl lymphocytosis , and morphologic / immunophenotypic analysis . for t - lgl leukemia , a t - cell receptor ( tcr ) gene rearrangement study is performed to confirm the presence of the monoclonal t - cell population . an abnormal killer - cell ig - like inhibitory receptor ( kir ) expression pattern has been reported in some of the nk - lgl leukemia patients , although this is not routinely employed . chronic exposure to antigen or virus has been postulated to be the initial trigger in lgl leukemia pathogenesis . recent studies demonstrated that jak / stat pathway deregulation may promote clonal expansion of the activated lgl population . to further understand lgl leukemia pathogenesisthe cdr3 sequences , tcrv profiles , stat3 mutation profile and the underlying signaling pathway were examined throughout the disease . the institutional review board of hershey medical center , pennsylvania state university approved this study . deep sequencing , the tcr cdr3 regions were amplified and sequenced by adaptive biotechnologies corp ( seattle , wa ) using the immunoseq assay on cdnas . real - time quantitative pcr ( qrt - pcr ) was employed to examine the tcrv profile , using primers and methods described previously , except that sybrgreen ( life technologies ) was used and target specificity was confirmed within the imgt primer database . deep sequencing results for one clone were validated using pcr - based cdr3 sequencing with primers designed from the imgt primer database ( tbv9 , 5 - cac tct gaa cta aac ctg a-3 ; cb1a , 5 - ggg tgt ggg aga tcc tg ( c ) - 3 ) . conventional sanger stat3 mutation testing was carried out as previously described by koskela et al . . primer pairs were designed to cover exons 2021 encoding the stat3 src homology 2 ( sh2 ) domain . droplet digital pcr ( ddpcr ) assays were designed to detect individual mutations d661y , y640f and s614r . assays were designed to the following context sequences : d661y ggatattggtagcat ( a / c ) catgatcttatagcc , y640f agctgctgctttgtg ( a / t ) atggttccacggact , and s614r gacgcctccttcttt ( t / g ) ctgctttcactgaat . assays were performed in duplicate on the qx200 droplet reader and generator ( bio - rad , hercules , ca ) . western immunoblotting utilized antibodies to stat3 ( # 9139 ) , py705 - stat3 ( # 9131 ) , mcl - 1 ( # 5453 ) and gapdh ( # 2118 ) ( cell signaling , danvers ma ) a 77 - year - old male presented in 2002 with mild macrocytic anemia and splenomegaly . based on the peripheral blood morphology , bone marrow biopsy , flow cytometry and positive tcr gene rearrangement assay , cd3 + / cd8 + t - lgl leukemia was diagnosed . he did not require any therapy other than routine follow - up , which showed stable blood counts ( table 1a ) . in 2011 , his follow - up cbc revealed worsening anemia and moderate neutropenia with increased lymphocytosis . repeated flow cytometry showed a marked increase in the cd3 / cd16 + / cd56 population that represents the nk - cell phenotype , with a smaller cd3 + / cd8 + t - cell population . these results suggested that his leukemia had evolved to nk - predominant disease with a residual of previous t - lgl leukemia ( table 1a ) . despite the progression of his leukemia , he has remained asymptomatic and clinically stable to date , and no treatment has been required . antigen exposure has been postulated as the initial stimulus for ctl expansion in t - lgl leukemia pathogenesis . we employed qrt - pcr to study the dynamic change of tcrv profile using primers designed to amplify each of the human tcrv genes ( hbv ) . as shown in table 1a , shortly after his initial diagnosis there was a predominant expression in the tcrv9 region with smaller expansions in the tcrv3 and tcrv21 regions . tcrv3 and tcrv21 usages persisted and later became predominant , while tcrv9 expression was lost , revealing a drift in tcrv usage that correlated with the t - lgl to nk - lgl phenotypic switch . cdr3 is a hypervariable region on the tcr that is critical for antigen recognition and clonal t - cell expansion . sequencing of this region in t - lgl leukemia was recently enabled by utilizing deep sequencing technology . three cdr3 sequences were detected at very high frequencies in the diagnostic t - lgl leukemia sample of 2003 ( table 1b ) . all three clones persisted throughout the disease ; however , the clone represented by the cdr3 sequence casstgdnqpqhf , which had the highest copy number initially , was significantly decreased to an extremely low copy number when the nk - lgl clone emerged . meanwhile , the other two clones became more dominant as the disease evolved , similar to oligoclonal tcrv distribution depicted in table 1a . the cdr3 sequences identified in this case appeared to be unique compared to the sequences reported in other t - lgl leukemia studies . clonal drift was previously reported in one third of t - lgl leukemia cases , although it is not strongly associated with clinical features . the worsening of cytopenias , such as this patients anemia at later dates , implies an important role of clonal drift in disease evolvement . therefore , long - term immunophenotypic monitoring may provide clinical relevance and guide medical management . it has been reported that 4070 % of t - lgl and 30 % of nk - lgl leukemia patients carry activating stat3 mutations . to investigate whether a deregulated stat3 pathway was associated with the patients disease progression , we searched for mutations in the stat3 sh2 domain before and after the t - lgl to nk - lgl phenotype switch . a stat3 s614r mutation was identified by sanger sequencing later in the illness in the nk - cells , but not the t - cells ( fig .1 a , data not shown for early stage ) . an elevated phosphorylated stat3 level and an increase in its transcriptional target mcl - 11b ) , consistent with enhanced transcriptional activity of the mutant protein . in order to determine if the s614r - mutated clone had been present all along , we tested unsorted genomic dna samples from 2003 and 2011 for s614r and for two common mutations y640f and d661y by ddpcr . both samples contained approximately 35,000 copies of the stat3 locus , yielding approximately 9000 positive droplets for the wild - type allele .1 c ) exceeded the 12 positive droplets found in similar amounts of normal dna by at least 10-fold ( not shown ) . s614r mutations were not detected in the earlier sample ( no copies mutated in a background of roughly 35,000 wild - type copies ) . small but non - negligible amounts of d661y and y640f mutations suggested the presence of 8.52 % and 0.68 % clones , respectively , assuming heterozygous mutation . these contracted to roughly 0.1 % ( 1:500 cells ) in the follow - up sample , shadowing the decrease in the t cell compartment . in contrast , s614r dominated in the follow - up specimen with a mutation rate of 33.3 % and a clone size of roughly 67 % , which is identical to the cd3 / cd16 + population reported in table 1a . therefore , this patient developed a dominant nk - lgl clone harboring the s614r mutation , while a population of cells with a strongly - activating y640f mutation remained a minority clone . this clearly suggests that the capacity of particular stat3 mutations to drive clonal dominance can not be predicted a priori , rather it is likely to be dependent upon the genetic context of these mutations such as co - existent activating mutations or loss of suppressive checkpoint mechanisms . our findings here not only complement the known mutational mechanism for nk - lgl leukemogenesis , but also suggest that t and nk - lgl leukemia can result from the same underlying pathological process , with mutations in stat3 able to support the expansion of either cell type . in 2009 , the world health organization recognized a provisional category of chronic lymphoproliferative disorder of nk cells to distinguish it from t - cell lgl leukemia as well as aggressive nk - lgl leukemia . the clinical and molecular data presented here suggests that this distinction amongst the chronic lgl diseases may need to be reconsidered . a 77 - year - old male presented in 2002 with mild macrocytic anemia and splenomegaly . based on the peripheral blood morphology , bone marrow biopsy , flow cytometry and positive tcr gene rearrangement assay , cd3 + / cd8 + t - lgl leukemia was diagnosed . he did not require any therapy other than routine follow - up , which showed stable blood counts ( table 1a ) . in 2011 , his follow - up cbc revealed worsening anemia and moderate neutropenia with increased lymphocytosis . repeated flow cytometry showed a marked increase in the cd3 / cd16 + / cd56 population that represents the nk - cell phenotype , with a smaller cd3 + / cd8 + t - cell population . these results suggested that his leukemia had evolved to nk - predominant disease with a residual of previous t - lgl leukemia ( table 1a ) . despite the progression of his leukemia , he has remained asymptomatic and clinically stable to date , and no treatment has been required . antigen exposure has been postulated as the initial stimulus for ctl expansion in t - lgl leukemia pathogenesis . we employed qrt - pcr to study the dynamic change of tcrv profile using primers designed to amplify each of the human tcrv genes ( hbv ) . as shown in table 1a , shortly after his initial diagnosis there was a predominant expression in the tcrv9 region with smaller expansions in the tcrv3 and tcrv21 regions . tcrv3 and tcrv21 usages persisted and later became predominant , while tcrv9 expression was lost , revealing a drift in tcrv usage that correlated with the t - lgl to nk - lgl phenotypic switch . cdr3 is a hypervariable region on the tcr that is critical for antigen recognition and clonal t - cell expansion . sequencing of this region in t - lgl leukemia was recently enabled by utilizing deep sequencing technology . three cdr3 sequences were detected at very high frequencies in the diagnostic t - lgl leukemia sample of 2003 ( table 1b ) . all three clones persisted throughout the disease ; however , the clone represented by the cdr3 sequence casstgdnqpqhf , which had the highest copy number initially , was significantly decreased to an extremely low copy number when the nk - lgl clone emerged . meanwhile , the other two clones became more dominant as the disease evolved , similar to oligoclonal tcrv distribution depicted in table 1a . the cdr3 sequences identified in this case appeared to be unique compared to the sequences reported in other t - lgl leukemia studies . clonal drift was previously reported in one third of t - lgl leukemia cases , although it is not strongly associated with clinical features . the worsening of cytopenias , such as this patients anemia at later dates , implies an important role of clonal drift in disease evolvement . such drift may precede changes in the disease course . therefore , long - term immunophenotypic monitoring may provide clinical relevance and guide medical management . it has been reported that 4070 % of t - lgl and 30 % of nk - lgl leukemia patients carry activating stat3 mutations . to investigate whether a deregulated stat3 pathway was associated with the patients disease progression , we searched for mutations in the stat3 sh2 domain before and after the t - lgl to nk - lgl phenotype switch . a stat3 s614r mutation was identified by sanger sequencing later in the illness in the nk - cells , but not the t - cells ( fig .1 a , data not shown for early stage ) . an elevated phosphorylated stat3 level and an increase in its transcriptional target mcl - 11b ) , consistent with enhanced transcriptional activity of the mutant protein . in order to determine if the s614r - mutated clone had been present all along , we tested unsorted genomic dna samples from 2003 and 2011 for s614r and for two common mutations y640f and d661y by ddpcr . both samples contained approximately 35,000 copies of the stat3 locus , yielding approximately 9000 positive droplets for the wild - type allele . all1c ) exceeded the 12 positive droplets found in similar amounts of normal dna by at least 10-fold ( not shown ) . s614r mutations were not detected in the earlier sample ( no copies mutated in a background of roughly 35,000 wild - type copies ) . small but non - negligible amounts of d661y and y640f mutations suggested the presence of 8.52 % and 0.68 % clones , respectively , assuming heterozygous mutation . these contracted to roughly 0.1 % ( 1:500 cells ) in the follow - up sample , shadowing the decrease in the t cell compartment . in contrast , s614r dominated in the follow - up specimen with a mutation rate of 33.3 % and a clone size of roughly 67 % , which is identical to the cd3 / cd16 + population reported in table 1a . therefore , this patient developed a dominant nk - lgl clone harboring the s614r mutation , while a population of cells with a strongly - activating y640f mutation remained a minority clone . this clearly suggests that the capacity of particular stat3 mutations to drive clonal dominance can not be predicted a priori , rather it is likely to be dependent upon the genetic context of these mutations such as co - existent activating mutations or loss of suppressive checkpoint mechanisms . our findings here not only complement the known mutational mechanism for nk - lgl leukemogenesis , but also suggest that t and nk - lgl leukemia can result from the same underlying pathological process , with mutations in stat3 able to support the expansion of either cell type . in 2009 , the world health organization recognized a provisional category of chronic lymphoproliferative disorder of nk cells to distinguish it from t - cell lgl leukemia as well as aggressive nk - lgl leukemia . the clinical and molecular data presented here suggests that this distinction amongst the chronic lgl diseases may need to be reconsidered . yiyi yan designed and performed experiments , analyzed the data , wrote the manuscript and provided figures . thomas olson designed the tcr qrt - pcr experiments and stat3 mutation detection , analyzed the data , and wrote the manuscript . susan bell nyland designed the tcr deep sequencing experiments , analyzed the data , wrote the manuscript and provided figures .\noutput:\n" }, { "from": "agent", "value": "large granular lymphocyte ( lgl ) leukemia is a chronic clonal lymphoproliferative disorder . here , a t - lgl leukemia patient developed nk - lgl leukemia with residual leukemic t - lgl . tcrv usage and cdr3 sequence drifts were observed with disease progression . a stat3 s614r mutation was identified in nk but not t - cells in the mixed leukemic stage . multiple , non - dominant t - cell clones with distinct stat3 mutations were present throughout . our results suggest that t and nk - lgl leukemia may share common pathogenesis mechanisms and that stat3 mutation alone is insufficient to bring about clonal expansion . mutational and immunological monitoring may provide diagnostic and therapeutic significance in lgl leukemia ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: striae or pregnancy stretch marks are a form of linear scarring on the abdomen and breast , which usually appear in 50 % - 90 % of all pregnant women . the remaining marks are an aesthetic concern for most women ( 1 , 2 ) . striae often appear as reddish or purplish streaks during the 24th week of pregnancy ( 1 ) and fade gradually after delivery and finally change into wrinkled silvery scars and remain forever ( 3 ) . these include genetic factors , family history , skin type , skin color , mother s young age , gestational age , the newborn s weight , malnutrition , body mass index , and gestational diabetes ( 4 , 5 ) . it seems that disorder in fibroblast synthesis and connective tissue is the main cause of the problem ( 5 ) . ( 2011 ) showed that 73.8 % of women are disgusted by striae during pregnancy ( 6 ) . although striae do not endanger the mother and the fetus , they may cause a desire to scratch the region leading to small wounds , induce stress over beauty , decrease self - confidence , and create psychological disorders ( 7 - 9 ) . these make primiparous women or those who decide to become pregnant inquire about striae and its prevention measures ( 1 , 10 ) . they may try various treatments and often refer to dermatology clinics and receive long - term treatments ; these time - consuming and costly behaviors will affect their quality of life indirectly ( 1 , 10 - 13 ) . therefore , striae make women both mentally and socially vulnerable . in other words , women s physical , mental , and social health orrather their quality of life is endangered ( 1 , 3 , 10 - 13 ) . thus , determining quality of life , concerning the skin , gains significance for skin changes , though not directly life - threatening , could affect people s life in various ways such as pain and itching , tension , social and family relation problems and health care problems ( 1 ) .2013 ) suggested that striae leads to reduced quality of life and is a limiting factor in life ( 14 ) . yamaguchi et al . ( 2012 ) showed there was no significant association between striae and general life quality , the dimension of symptoms and functions of skin quality of life index ( 15 ) . yamaguchi et al . ( 2014 ) showed pregnant women with striae had a lower quality of life in the dimension of emotion ; the preventive steps were associated with the level of quality of life in the dimension of emotion , in pregnant women with striae ( 16 ) . therefore , investigating quality of life can play an important role in determining the severity of striae , offering appropriate health care , planning life quality improving programs , and providing health consultation to prevent further problems . the aim of this study was to evaluate the quality of life in iranian postpartum women with and without striae gravidarum . this cross - sectional study was conducted on 145 primiparous and multiparous women referring to health centers of mashhad during year 2013 . the sample size was calculated as 145 based on prevalence ( confidence coefficient = 95 % ) . multi - stage random sampling was applied . from among five health centers in khorasan razavi province , one center ( cluster ) was randomly selected and based on the number of referrals , 10 affiliate centers were selected . in every center , using simple sampling , subjects were selected from women referring to receive health care during their sixth week after delivery . inclusion criteria included provision of consent , iranian nationality , lack of diagnosis of adrenal disease , lupus , connective tissue , cushing syndrome as well as auditory , speech and mental disorders . the tools applied included a demographic questionnaire , fitzpatrick classification scale , atwal scale , skindex29 scale and quality of life sf - 36 questionnaire . validity of the forms and questionnaires was confirmed through the content validity test . to identify skin type , this is a four - point likert questionnaire in which six skin types are categorized . a score of 0 - 6 presents type one skin ; a score of 7 - 13 indicates type 2 skin ; 14 - 20 type 3 ; 21 - 27 type 4 ; 28 - 34 type 5 ; and 35 type 6 ( 17 ) . severity of striae was determined by the color and number of streaks on breast , abdomen , thighs , and hips measured by atwal scale ranging from zero to 24 . a score of zero indicated lack of striae ; 4 - 9 , mild ; 10 - 15 , average ; and more than 15 , severe striae . the reliability was confirmed by correlation coefficient of 0.86 . to determine skin quality of life , skindex29 was used , which was composed of three dimensions : emotion ( 10 questions ) , symptoms ( 7 questions ) and function ( 12 questions ) . one question , which is not considered in scoring , was asked using a five - point likert scale . the reliability was demonstrated with cronbach s alpha coefficient of 0.84 for emotion , 0.80 for symptoms , and 0.86 for functioning . to investigate quality of life and health , the sf - 36 questionnaire of life qualitypain and general health included physical functioning , role limitations due to physical health , role limitations due to emotional problems , energy / fatigue , emotional well - being , social functioning . scores range from 0 - 100 and a higher score indicates higher quality of life . the reliability was demonstrated with internal consistency coefficient for the eight subscales , which was 0.76 to 0.82 . upon approval of the university research ethics committee , and after briefing the subjects on the purpose of the study and acquiring their written consent and observing all ethical codes , sampling was performed . firstly , the demographic information questionnaires , general quality of life questionnaire and skindex29 were completed , through an interview by the researcher assistant . next to complete the atwal scale , breasts , thighs , hips , and abdomens were observed in private , during the subject s sixth week of delivery by the research assistant . data were analyzed using the spss v. 11.5 software with descriptive statistics , mann - whitney and kruskal wallis . in this analysis , normality of quantitative variables was determined by kolmogorov - smirnov test in which variables had a non - normal distribution . , the participants were provided with an informed consent form ; the subjects were assured about the confidentiality of their personal information . before sampling , permission to conduct the study was granted from the university ethics committee and also , a letter of recommendation from mashhad university of medical sciences was provided for the healthcare centers . in this study , the participants were provided with an informed consent form ; the subjects were assured about the confidentiality of their personal information . before sampling , permission to conduct the study was granted from the university ethics committee and also , a letter of recommendation from mashhad university of medical sciences was provided for the healthcare centers . subjects mean age was 26.35.7 years ( women with striae 28.275.37 years , women without striae 25.935.73 ) , body mass index ( bmi ) was 25.945.69 kg / m , women without striae25 .482.61 kg / m ) , and pregnancy over weightiness was 12.324.91 kg ( women with striae 10.635.78 kg , women without striae 12.544.75 kg ) . there was no significant difference between mean age ( p = 0.057 ) , bmi ( p = 0.828 ) , pregnancy over weightiness ( p = 0.103 ) in women with and without striae . striae were seen in 84.8 % ( n = 123 ) of the subjects . around 72.2 % had abdomen striae . skin type in 40.0 % ( n = 58 ) was type 2 . mean and standard deviation ( sd ) for general quality of life and subscales : physical function , physical role , mental health , physical pain , social function , emotional role , vitality , general health were 49.438.28 , 29.2534.23 , 68.1331.91 ,90.1826.87 , 33.4224.37 , 27.9523.57 , 63.8816.10 , 41.2815.17 and 42.478.39 , respectively . mann - whitney test showed that there was a significant difference between means of skindex29 and its dimensions , general life quality in women with and without striae ( p 0.05 ) . also , mann - whitney test showed no significant difference between mean of general quality of life except for physical function in women with and without striae ( p 0.05 ) ( table 1 ) . mann - whitney test showed a significant difference between means concerning mental dimension of general quality of life ( p = 0.025 ) and emotional dimension of skindex29 ( p = 0.036 ) in primiparous and multiparous pregnant women ( table 2 ) . kruskal wallis test showed no significant difference between mean of general quality of life ( p = 0.717 ) and skindex29 ( p 0.05 ) , according to striae severity ( table 3 ) . the findings indicated that frequency distribution of striae gravidarum is 87.4 % and the commonest striae site is the abdomen . therefore , the findings of the present study suggested that general quality of life and skin quality of life are significantly better in women without striae than in women with it . ( 2012 ) indicated that the score for dimension of emotion regarding skin quality of life in women without pregnant striae was significantly better than women with striae . however , there was no significant difference considering dimensions of function and symptoms and also general life quality between women with and without striae . this discrepancy between the findings might be due to striae prevalence ( about 39.1 % ) ( 15 ) . though striae gravidarum does not impose any life - threatening risk , their ugly - looking appearance may cause stress , decrease self - confidence , create mental problems and make women worried about their husbands losing interest in them , which can lead to psychological problems after delivery ( 1 , 3 , 7 - 9 ) . in the present study , there was not a significant relationship between striae severity and general life quality and skin life quality . balkrishnan et al . ( 2006 ) studied quality of life in women with facial spots referring to wake forest university school of medicine ( wfusm ) in north california . the findings showed facial spots significantly decrease quality of life , self - image , and self - confidence , but there is no relationship between the type and severity of the spot and quality of life ( 18 ) . facial spots clearly affect people s look ; patient s evaluation of his / her skin is not positive , which as a result generally lowers quality of life . ( 2009 ) showed that skin diseases such as chronic dermatitis decrease skin quality of life ( 19 ) . . showed that in patients with skin problems , severity alone is not the main concern and non - fatal skin diseases may lower life quality more than other diseases . skin problems of head and face cause the most decrease in life quality dimensions of all other disorders , which is statistically significant regarding dimensions of mental health , social function , body pain , general health and vitality ( 20 ) . moreover , according to the findings of this study , the mean score for mental dimension of general life quality and emotional dimension of skin quality of life in primiparous women is significantly lower than those of multiparous women .2013 ) investigated stress factors after delivery in primiparous and multiparous women in mashhad , iran . their findings indicated stress from striae and pregnancy chloasma in primiparous is significantly higher than that of multiparous women ( 21 ) . the period after delivery is a potentially stressful time during which women should accept their motherhood role and the subsequent body changes . during this period , various anatomical , physiological and psychological changes occur in mothers , which are difficult to cope with . skin changes and striae affect one s body image negatively ( 1 - 7 , 21 ) . though striae rarely influence physical well - being , their psychological effects affect general health and skin dramatically . the strength of this study was the use of numerical scoring system for the severity of striae at account the number of striae present and the degree of erythematic , while other studies used the number of striae to measure severity . further research aimed at striae preventive measures or their treatment is recommended ; although they are not dangerous , they affect general life standard and skindex29 in many mothers after delivery . therefore , the findings of the present study , general quality of life and the quality of skin , significantly worsen in women with striae .\noutput:\n" }, { "from": "agent", "value": "backgroundstriae are a common change during pregnancy , leaving striae in various body parts after delivery , which most women find unpleasant . they create a big aesthetic concern for most women . although striae do not endanger the mother and the fetus , they may cause a desire to scratch the region leading to small wounds , induce stress over beauty , decrease self - confidence , and create psychological disorders . they may try various treatments and often refer to dermatology clinics and receive long - term treatments ; these time - consuming and costly behaviors and may affect their quality of life.objectivesthe aim of this study was to evaluate the quality of life in iranian postpartum women with and without striae gravidarum.materials and methodsthis cross - sectional study was conducted on 145 women who had referred to health centers of mashhad to receive post - delivery health care six weeks after delivery during year 2013 . multi - stage sampling was applied to select the participants . the tools used were demographic , sf - 36 quality of life , skindex29 , atwal and fitzpatrick classification questionnaires . data were analyzed using the spss v. 11.5 software.resultsthe subjects mean age was 26.3 5.7 . mann - whitney test showed there was a significant difference between mean of skindex29 and its dimensions ( p < 0.001 ) , general life quality ( p < 0.001 ) in women with and without striae . mann - whitney test showed no significant difference between mean general quality of life dimension , except physical function in women with and without striae ( p > 0.05 ) . conclusionsthe results showed that striae lead to reduced quality of general life and reduced skin quality index in women postpartum ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: chemokines are a subgroup of cytokines with the specific function of chemoattraction ( chemotactic cytokines ) and a molecular weight between 7 and 12 kda . they are small molecules of approximately 70 amino acid residues derived from a single ancestral gene about 650 million years ago . chemokines are characterized by several features including the presence of four conserved cysteine residues and vertical receptor signal transduction . these receptors often promote rapid and reversible changes in cellular metabolism or migration , in contrast to horizontal cytokines receptors which usually cause slower and irreversible cellular changes , such as proliferation and apoptosis . members of the chemokine family are divided into four groups depending on the spacing of their first two cysteine residues : cc chemokines , which have two adjacent cysteines , cxc chemokines , with the two cysteines separated by one amino acid , c chemokines , characterized by the presence of only two cysteines , and cx3c chemokines with three amino acids separating the initial pair of cysteines . among the fifty - two chemokines discovered to date , nineteen are presently considered to be relevant in heart disease , seven of them belonging to the class of cc chemokines , ten to the cxc family , one to the cx3c chemokines , and one to c chemokines . some chemokines play a role in the early stages of cardiovascular disease like atherosclerosis or acute ischemia . others are involved in both early and late response to injury and are strongly associated with cardiac arrhythmias , heart failure , and chronic rejection of a transplanted heart ( figure 1 ) . the chemokines associated with cardiovascular disease discussed in the present review are listed in table 1 . myocardial ischemia ( mi ) is a state of myocardial impairment due to an imbalance between the level of coronary perfusion and myocardial energy demand . although atherosclerosis is a central part of cardiovascular disease , reviewing the role of chemokines in its development is beyond the scope of the review . we will discuss chemokines involvement in cardiovascular disease from the first event which changes dramatically the metabolism and the homeostasis of the heart , that is , myocardial ischemia . the mechanical work of the myocardium is driven by aerobic metabolism , which produces energy in the form of adenosine triphosphate ( atp ) . myocardial ischemia is followed by the progression from reversible to irreversible myocardial cell injury within about thirty minutes . after this period , histologic features of coagulation necrosis appear , with nuclear pyknosis , karyolysis , and exudative inflammation . sudden death of the whole heart as such does not occur ; every cell of the heart singularly responds to the injury ( ischemia ) and to the removal of the injury ( reperfusion ) with biochemical changes moving toward life or death ( figure 2 ) . the severity of the damage depends on time , on the coronary artery involved , and on the entity of the inflammatory response . two different scenarios are possible after ischemia : permanent occlusion or reperfusion . in case of permanent occlusion , potential causes of irreversibility are catabolism without new synthesis of macromolecules , reduced transmembrane gradients of na and k , ca overload , catabolite and oxygen radicals accumulation , enzyme denaturation , cell swelling , and membrane rupture . early reperfusion , on the other hand , is associated with rapid cellular infiltration of neutrophils and monocytes mainly into the jeopardized border zone surrounding the infarcted area . neutrophils migrate from the perivascular area and remain primarily in the border zone whereas monocyte migration into the infarct proceeds very rapidly . a possible evolution of both scenarios is cardiac hypertrophy , a thickening of the ventricular walls in the heart , which is an adaptive response to pressure overload , volume stress , mutations of proteins involved in the structure or loss of cardiomyocytes , and contractility , all possible consequences of myocardial ischemia . hypertrophy can be physiological , present as normal response to healthy exercise , characterized by a concentric aspect , or pathological , leading to remodeling and changes in the shape and structure of the myocardium . concentric hypertrophy is believed to have a compensatory function by diminishing wall stress and oxygen consumption whereas pathological hypertrophy can lead to heart failure ( hf ) and is associated with major arrhythmias . pathological hypertrophy activates the expression of genes related to collagen , chemokines , and actin which are not stimulated by physiological hypertrophy . myocardial hypertrophy is associated with persistent inflammation , irrespective of the cause of the disease . indeed a similar pattern of inflammatory activation is present in patients with aortic valve stenosis or mi , as well as in animals subjected to different stimuli leading to the development of pathological hypertrophy . at the cellular level , cardiomyocyte hypertrophy is characterized by an increase in cell size , enhanced protein synthesis , and heightened organization of the sarcomere . this pathological condition is associated with fibrosis development , characterized by monocytes infiltration and activation of matrix - metalloproteinase ( mmp ) in extracellular matrix ( ecm ) . in animal models , myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy and can evolve in decompensated remodeling , with myocytes slippage and wall thinning . if the loss of viable myocardium has been massive , wall stress increases further and the final result can be left ventricular ( lv ) dilation and hf a condition in which cardiac function is seriously impaired . this vicious circle results in increased blood pressure and lv mechanical overload , which further worsens the condition . one chemokine - one function way , in modulating this cardiac response to injury . this characteristic is well known in the field of immunology and is one of the causes of the typical redundancy seen in several inflammatory processes . the complexity of this network is far from being completely understood and described , but recent studies are trying to reassemble the pieces of the puzzle . recently a small clinical study for risk stratification ( a tool for identifying and predicting which patients are at high risk of cardiovascular events ) performed in patients after mi evaluated the prognostic significance and the clinical relevance of a cluster of 27 serum cytokines , including the chemokines cxcl8 , ccl11 , ccl2 , ccl3 , ccl4 , and ccl5 . the authors did not identify a single inflammatory cytokine capable of predicting adverse events in a long term follow - up , but they suggested that the presence of more than 13 cytokines above the median value was useful for risk stratification . another clinical study enrolled 28 patients undergoing pci , 20 undergoing coronary angiography , and 28 healthy controls , with the aim of analyzing the plasma levels of ccl2 and ccl11 in all groups . the results showed a significant increase of both ccl2 and ccl11 in patients suffering heart disease as compared to healthy subjects . moreover , the plasma levels of the two chemokines rose significantly after pci ; notably ccl2 rose after 3 and 6 months following pci and ccl11 rose 24 h but not 3 months after pci . when the process degenerates toward failure , the inflammatory pathway appears to be almost the same irrespectively of the initial cause of pathology . some of the most common signaling pathways , relevant in the crosstalk between innate immune response and ischemic heart , include the following : tlr - 4 , responsible for macrophage homing and inflammatory cytokine production ; hmgb1 / tlr - 4 for monocytes recruitment and activation of cxcl12 - cxcr4 pathway in the leukocytes ; gp130 / jnk / stat3 and tlr - 4 / myd88 / camkii / nf - b for monocytes and monocyte / neutrophils recruitment and activation ; cgmp / enos , through cxcl12 - cxcr4 axis , for neutrophils recruitment and matrix remodeling after ischemic injury.these pathways underline the presence of communication between cardiovascular and immune systems through several mediators including chemokines . therefore , we will discuss in detail their role in the progression from ischemia to heart failure . tlr - 4 , responsible for macrophage homing and inflammatory cytokine production ; hmgb1 / tlr - 4 for monocytes recruitment and activation of cxcl12 - cxcr4 pathway in the leukocytes ; gp130 / jnk / stat3 and tlr - 4 / myd88 / camkii / nf - b for monocytes and monocyte / neutrophils recruitment and activation ; cgmp / enos , through cxcl12 - cxcr4 axis , for neutrophils recruitment and matrix remodeling after ischemic injury . ccl2 ( monocyte chemoattractant protein or mcp - 1 ) has been the subject of numerous investigations in the field of cardiovascular research . it is produced by a variety of cells including macrophages , fibroblasts , and epithelial and endothelial cells and it is thought to play a key role in several pathophysiological processes , such as atherosclerosis and remodeling after mi . in a large cohort of patients with acute coronary syndrome , an elevated baseline level of ccl2was associated both with traditional risk factors for atherosclerosis and with an increased risk for death or mi . ccl2 was found to increase in the rat heart during reperfusion but not after 1 or 2 hours of permanent infarction . it was also detected in human cardiac myocytes and human cardiac fibroblasts which revealed ccl2 production under cytokine stimulation , but not under hypoxia , in vitro . in patients with ischemic cardiomyopathy , polymorphism in ccl2 gene ( ccl2 - 2518 a / g single nucleotide polymorphism ) was correlated with c - reactive protein ( crp ) level . altogether these findings suggest that this chemokine is more associated with inflammation than with hypoxia / ischemia , being strongly regulated by reperfusion and correlated with a known inflammatory marker such as crp . to investigate the mechanism of action of ccl2 and other chemokines in the myocardial response to injuryentman , frangogiannis , and their coworkers extensively explored this topic and unveiled the connection between ccl2 and cardiac fibrosis in a mouse model of ischemia without necrosis . in particular ccl2 , identified in the ischemic myocardium after repetitive cycles of brief ischemia / reperfusion ( ir ) , was associated with increased collagen content , macrophages infiltration , interstitial remodeling , and lv dysfunction , phenomena which were attenuated in ccl2 mice . moreover , fibroblasts isolated from wild type ( wt ) mice exposed to repetitive ir exhibited increased proliferative capacity , which was abrogated in fibroblasts from ccl2 null - hearts . it was found that the profibrotic actions of ccl2 are probably associated with decreased macrophage recruitment since at a molecular level no altered expression of genes associated with cardiac fibrosis was observed . in a different study , using the same experimental model , same group also discovered that reactive oxygen species generation in the reperfused myocardium rapidly induced ccl3 , ccl4 , and cxcl2 upregulation in the venular endothelium in the absence of infarction or irreversible cellular injury . in this study , the chemokines induction correlated with nuclear translocation of nf - b , c - fos , and c - jun in cardiac venules . since angiogenesis begins in the venular endothelium , these experiments could indicate a potential role of chemokines as angiogenetic agents during a transient ischemia without necrosis . interestingly , tarzami and colleagues found a protective effect of cxcl2 dependent ccl2 expression in cardiac ischemia without reperfusion , a survival pathway in target cardiac myocytes themselves . indeed , ccl2 markedly decreased hypoxia - induced cell death in cultured cardiac myocytes . among chemokines modulating these processes , ccl2 and its receptor ccr2 seem to be one of the keys of the shift from physiological to pathological conditions in both heart and vessels . ccl2 chemotactically attracts mononuclear cells which are source of fibrogenic mediators like tgf - and fibroblast growth factor . activation of the ccl2 / ccr2 pathway induces monocyte - mediated inflammation and several related processes ; enhanced ccr2 fluorescence intensity on monocytes was observed in hypertensive patients as well as in rat models . in ccr2 mice , angiotensin ii - ( ang - ii - ) induced vascular inflammation and remodeling were blunted compared to wt animals ; in a model of fibrosis and hypertrophy secondary to suprarenal aortic constriction , chronic treatment with an antibody against ccl2 led to myocyte hypertrophy without fibrosis and to an improvement in diastolic dysfunction , in the absence of an effect on blood pressure or systolic function . in contrast , control rats showed hypertrophy and reactive fibrosis . ang - ii infusion is a well - established model of myocardial hypertrophy and it has been used to characterize chemokine expression and cellular element involvement . kuwahara and colleagues showed mrna - ccl2 upregulation from day 1 to day 3 after treatment , followed by tgf - induction at day 3 to day 28 . the results were confirmed by sopel and colleagues who measured chemokines expression using quantitative real time pcr . they also showed that fibrocytes ( fibroblast progenitor cells ) were recruited into the myocardium prior to the development of myocardial fibrosis and were probably recruited out of the circulation by gradients of cxcl12 , ccl21 , and ccl2 . a further demonstration of ccl2 involvement in the progression from hypertrophy to fibrosis originates from a model of genetic deletion of ccl2 in mice . ccl2 - knock - out ( ko ) animals receiving infusion of ang - ii were prevented from fibrosis development , induction of collagen , induction of tgf - 1 , and tnf mrna expression . in this model , , an interesting clinical study found that patients with heart failure had higher level of circulating ccl2 as compared with healthy controls despite treatment with a high - dose of ace - inhibitor . on the other hand , angiogenic and cardioprotective effects of ccl2have also been reported , suggesting distinct effects of this chemokine on remodeling after mi . morimoto and colleagues investigated the effect of cardiac ccl2 overexpression on lv dysfunction and remodeling in a murine model of mi . the interesting findings were that cardiac overexpression of ccl2 reduced infarct area and scar formation improving lv dysfunction and remodeling , thus suggesting a controversial role of ccl2 in response to mi . at the same time dewald and colleagues found that inhibition of ccl2 could have the same deleterious effect observed with corticosteroid treatment in patients with mi , that is , impairing the repair processes , after injury . altogether , the role of ccl2 appears therefore to go beyond the simple recruitment / proinflammatory effect and is clearly involved in the fine and critical modulation of cardiac homeostasis after a detrimental insult . recently , two studies showed the effects of chemokine inhibition on mi . in the first work , treatment with a monoclonal antibody anti - ccl5 ( rantes ) significantly reduced both infarct size and postinfarction hf in a murine model which was correlated with a decreased leukocyte recruitment within the infarcted hearts . in the second study , mice subjected in vivo to left coronary artery permanent ligation and followed up for different times ( up to 21 days ) showed a beneficial reduction in infarct size as compared to controls when treated with chemokine inhibitors , in particular with ccl5 inhibition , which reduced cardiac injury / inflammation and improved survival . this treatment was associated with a decrease in postinfarction myocardial leukocyte infiltration , reactive oxygen species release , and circulating levels of cxcl1 and ccl2 . cxcl8 ( il - 8 ) is a chemokine attracting neutrophils , which plays a key role in the early phase of reperfusion injury as well as in heart failure . cxcl8 expression was found to increase in ischemic reperfused myocardium suggesting a role in neutrophil - induced myocardial injury by promoting ligand - specific adhesion to cardiac myocytes . dams and colleagues showed that circulating levels of cxcl8 , cxcl1 ( gro - ) , and cxcl5 ( ena - 78 ) gradually increased in patients with congestive heart failure ( chf ) in parallel with an increase in nyha functional class . recently , high levels of cxcl8 in patients suffering st elevation myocardial infarction , complicated by hf , were associated with less improvement in lv function during the first 6 weeks after pci , suggesting a possible role of cxcl8 in the reperfusion - related injury . in 2001 , chandrasekar and colleagues found that myocardial ir in the rat activates nf - b and induces neutrophil infiltration via a homologous of cxcl8 in rats called lix ( lipopolysaccharide - induced cxc chemokine ) . lix was found to be expressed by resident myocardial cells during ir and induced in cultured cardiomyocytes by oxidative stress or tnf - via nf - b activation . moreover , in a further study , they discovered that lix , in addition to attracting and activating neutrophils , also amplified the inflammatory cascade , stimulating local production of cytokines that had negative inotropic and proapoptotic effects . dams and colleagues examined the circulating levels of cxcl8 , cxcl1 , and cxcl5 in patients with various degrees of hf , finding that they had a significant increase in the levels of all three chemokines and that both cxcl8 and cxcl1 correlated with the nyha class . an additional chemokine involved in cardiac hypertrophy and remodeling is cxcl12 , also known as stromal cell - derived factor 1 ( sdf - 1 ) . this chemokine has a key role in hematopoiesis , cardiogenesis , vasculogenesis , and neurogenesis . the increased expression of cxcl12 in ischemic tissue is considered a beneficial signal attracting stem cells into the heart . the main receptor for cxcl12 is cxcr4 which is expressed in several cells including those from megakaryocytic lineage . the main function of cxcl12 interaction with cxcr4 is the mobilization of stem cells from bone marrow . larocca and colleagues demonstrated that cxcr4 physically interacts with the 2 adrenergic receptor and modulates the subsequent downstream signaling . cxcl12 / cxcr4 are expressed on cardiac myocytes and inhibit contractility in response to the - adrenergic receptor agonist , isoproterenol . recently , it was reported that cxcr4 expression prevented cardiac hypertrophy induced by isoproterenol : cxcr4 - ko and wt mice were subjected to chronic administration of isoproterenol for 3 weeks ; biochemical as well as echocardiographic and hemodynamic measurements were performed . ko mice showed worsened fractional shortening and ejection fraction as compared with wt animals , as well as upregulation of apoptotic markers and reduced mitochondrial function . there was also an increase in myocardial fibrosis . a cxcr4 gene transfer performed in ko animals reduced apoptosis and improved mitochondrial and cardiac function . however , controversies exist over the protective versus harmful effects of cxcl12 and cxcr4 in models of cardiac injury . . found that cxcl12 is constitutively secreted by cardiomyocytes and upregulated by ang - ii and reported an increase in fibroblast migration in a mouse model of dilated cardiomyopathy , suggesting a profibrotic role of this chemokine in the chronically failing heart . in contrast , two authors reported that the cxcl12 / cxcr4 axis was the mechanism of the protective effect of apelin - 13 , an isolated bioactive peptide from bovine extract , and of erythropoietin ( epo ) , respectively . apelin - 13 increased angiogenesis and cardiac repair by the upregulation of cxcl12 / cxcr4 and homing of vascular progenitor cells . epo , known for its protective properties after ir injury , attenuated remodeling , enhanced neovascularization , and diminished apoptotic cells in the peri - infarct area 6 and 30 days after permanent infarction . moreover , epo treatment mobilized bone marrow - derived stem cells ( bmcs ) and enhanced homing of sca1 ( + ) and cxcr4 ( + ) bmcs toward a cxcl12 gradient into the ischemic myocardium . interestingly , epo had no beneficial effects on resident cardiac stem cells . finally , in an interesting work , hwang and kloner investigated the potential benefit of simultaneous administration of multiple soluble factors ( sfs ) , including cxcl12 , in rats subjected to permanent coronary ligation . the rationale of this work was based on the knowledge that in the clinical setting delivery of a single sf to the ischemic heart had limited effects . their results revealed no enhancements in cardiac function or reduction in infarct size . among the possible explanations for the negative results , the authors reported that coronary artery occlusion might have prevented access of intraperitoneal administered sfs to the ischemic region of the myocardium . waehre and colleagues studied the chemokines associated with alteration of the structure in extracellular matrix ( ecm ) , in particular with the function of slrps ( small leucine - rich proteoglycans ) proteins . slrps are proteins capable of binding various types of collagens regulating kinetics , assembly , and spatial organization of fibrils . they found that the interaction between cxcl13 and its receptor cxcr5 was involved in myocardial remodeling , probably regulating proteoglycans and quality of myocardial ecm . this interaction was found to be protective since genetic deletion of the receptor cxcr5 exacerbated dilatation and increased mortality , probably via lack of the increase of slrps . moreover , in a model of pressure overload dependent right ventricle remodeling , they found that cx3cl1 ( also known as fractalkine ) , ccl5 , and cxcl16 regulated expression and posttranslational modifications of slrps in cardiac fibroblasts . therefore these inflammatory mediators may play a role in the development and progression of right - sided myocardial remodeling during pressure overload . recently , two chemokines were found to be associated with hf , namely , cx3cl1 and xcl1 / 2 ( also known as lymphotactin ) . cx3cl1 is a chemokine with a polypeptide structure different from the typical structure of other chemokines and represents the only member of the cx3c group . its expression is modulated by tnf - and it is thought to promote cardiac injury and hf by activating mapks pathway ( mitogen - activated protein kinases pathway ) . in a rat heart transplant model , both cx3cl1 and xcl1 / 2 were found to be involved in the rejection of transplanted hearts secondary to cytomegalovirus infection . the authors suggested that rejection was due to an increase in vascular infiltration of inflammatory cells in the graft through enhanced chemokine expression . its concentration in serum from hf patients was higher than in controls and was independently associated with mortality in chronic and acute post - mi hf . interestingly , mice lacking ccl21 receptor , ccr7 , showed improved survival and attenuated increase in markers of myocardial dysfunction and wall stress in post - mi hf after 1 week but in the long term presented myocardial dysfunction and increased wall stress . repair for recovery or decompensated remodeling appears like a crossroad for mediators involved in the process and it is not clear which input could tilt the balance in favor of recovery . the autonomic nervous system ( ans ) may play a critical role in this setting . the best definition for the crosstalk between innate immunity and autonomic nervous system is likely to be allostasis , that is , maintaining stability through change . the signals travelling throughout the body create a network of information fine - tuned by the incessant dialog between the systems , aimed at directing the necessary mutual changes . during the late nineties , armour andcolleagues identified intrinsic cardiac ganglia in the heart , especially in the posterior surface of the atria and superior surface of the ventricle , and showed that processes occurring in such an intrinsic cardiac nervous system involve afferent neurons , local circuit neurons , and both sympathetic and parasympathetic efferent postganglionic neurons . when an injury occurs , the heart signals the damage to the nervous system , which responds by leading an orchestrated reaction involving neurohormones , chemokines , cytokines , neuropeptides , and other mediators . after mi , sensory afferent neurons , which respond to hypoxia - induced changes in the heart , are also responsible for pain perception and the sympathetic nervous system modulates activation / proliferation of progenitor cells from bone marrow . it is becoming increasingly clear that there is both plasticity and integration at many peripheral anatomical sites in the cardiovascular - immune - neural axis : innate immune system stimulates autonomic nervous system through cytokines , chemokines , platelet - activating factor , and arachidonate metabolites released from immune cells and this activation is integrated at the hypothalamic level . mutually , sympathetic system , through the release of norepinephrine ( ne ) , can modulate the functions of immune system cells through receptors expressed on their surface . other peptides like neuropeptide y ( npy ) and substance p ( sp ) colocalize with ne or are associated with its function and were found to be relevant to heart disease . sp is a neuropeptide belonging to the family of tachykinins , widely distributed in the nervous system , including the stellate ganglia . it is also localized in the heart and released by sensory nerve endings and immune cells . macrophages and neutrophils are found to express preprotachykinin gene - i ( ppt - i ) mrna and are modulated by sp biological actions . in the emerging role of chemokines , cxcl2 , ccl3 , ccl2 , andcxcl12 seem to be involved in the crosstalk with the ans and organs . in an in vitro model using isolated primary mouse neutrophils , sp primed neutrophils for chemotactic responses to the chemokines cxcl2 and ccl3 and induced both mrna and protein expression of ccl3 and cxcl2 in neutrophils and upregulated the chemokine receptors cc chemokine receptor 1 ( ccr1 ) and cxc chemokine receptor 2 ( cxcr2 ) . in a recent study it was found that sp seems also to act as a primer for cardiac fibroblasts , transiently upregulating genes related to ecm regulation and proteins rather than directly converting fibroblasts to myofibroblasts or increasing collagen synthesis . moreover , in cd34 - derived human mast cells , production of ccl2 , the potent profibrotic chemokines , was significantly increased by sp treatment , both at protein and at mrna level . interestingly vagal nerve stimulation ( vns ) , which decreases infarct size and adverse lv remodeling and hf in several experimental models , suppressed sp in a rat model of cardiac ischemia and decreased ccl2 and lix plasma levels in the rat after ir injury . cxcl12 seems to be involved in the remodeling of stellate ganglion neurons , a phenomenon occurring in several cardiomyopathies . after mi , neural remodeling was associated with an increase in npy immune - reactivity ; npy , like sp , is a neuropeptide colocalized and coreleased with ne from sympathetic nerve terminals . wang and colleagues showed that remodeling after mi could be reversed with a therapy combining npy and mesenchymal stem cells ( msc ) in a rat model of mi through a npy dependent upregulation of cxcl12 gene and others required for mitosis in msc . finally , it was very recently demonstrated that a potent neurotrophin , nerve growth factor ( ngf ) , attracted human bone marrow - derived mononuclear cells similarly to what was observed with cxcl12 , used as positive control . in this model ngf promoted progenitor cells homing from the bone marrow to the infarcted heart improving myocardial blood flow and cardiac function . the interaction between parasympathetic system and innate immunity has been clarified by tracey at the beginning of this century with the discovery of cholinergic anti - inflammatory pathway , an axis of neuroimmune modulation where acetylcholine ( ach ) , -7 nachr , and macrophages are the main players with anti - inflammatory properties . when activated , this pathway protected organs , including heart , from the consequences of the ischemic injury , decreased levels of ccl2 and lix after reperfusion injury , and downregulated the expression of ccl2 , ccl4 , ccl5 , ccr1 , ccr2 , and ccr5 in murine autoimmune myocarditis . both these pathways , immune - sympathetic and immune - parasympathetic , are involved in the beginning and in the progression of heart disease and are reciprocally connected , affecting and modulating each other 's functions . it is becoming evident that the mutual crosstalk within the autonomic nervous system between sympathetic and parasympathetic fibers is represented by the ability to reciprocally modulate neurotransmitters release and that these molecules have the ability to modulate the innate immune response . despite these intriguing hints , to our knowledgethe mutual effects of chemokines , substance p , npy , ngf , and ans in the progression of heart disease remain largely unknown . it is increasingly clear that the individual autonomic responses already characterized before the development of cardiovascular disease could determine the outcome and the progression of cardiac dysfunction . it is conceivable that ans activation , through neurotransmitters , neurotrophins , and immune mediators , could act as a primary imprinting which orchestrates the response to injury in sense of compensated repair or decompensated progression toward dysfunctional heart disease . the heart is a highly innervated organ and the link between the autonomic nervous system and ventricular arrhythmias is universally acknowledged : an increased sympathetic tone is a trigger for arrhythmic events in several conditions including patients with ion - channel diseases , ischemic heart disease , and hf . although the knowledge of inflammation role in the context of cardiac arrhythmia diseases is still scanty , some evidence suggesting its contribution in favoring an arrhythmogenic substrate has been provided . one of the most intriguing hypotheses is that inflammatory mediators may have a direct effect on the electrical properties of cardiomyocytes . this hypothesis is in agreement with the finding that cytokines and chemokines act as modulators of excitability in neurons . left cardiac sympathetic denervation ( lscd ) is an established additional treatment for patients with long qt syndrome ( lqts ) and catecholaminergic polymorphic ventricular tachycardia ( cpvt ) nonprotected by - blocker ( bb ) therapy . the presence of inflammatory activity in stellate ganglia of genetically confirmed lqts and cpvt patients , who underwent lscd because of malignant ventricular arrhythmias resistant to bb therapy , was evaluated by rizzo et al . . inflammatory infiltrates composed of t lymphocytes and macrophages and degeneration of adjacent ganglion cells suggestive of chronic ganglionitis were found in all lqts / cpvt patients as compared to none of ten control subjects who died in accidents . they proposed that t cell - mediated cytotoxicity toward sympathetic ganglionic cells may increase adrenergic firing and enhance electrical instability in patients already genetically predisposed to ventricular arrhythmias . a very recent study identified a chemokine that can influence electrical stability and directly modulate action potential duration ( ap ) : cxcl9 has been shown to shorten cardiac ap by reducing sarcolemmal l - type ca current via the g protein - coupled receptor cxcr3 , in lv myocytes isolated from male mice . also in the context of common cardiac diseases such as mi , a proinflammatory condition seems to be associated with an increased risk of developing life - threatening arrhythmias . elmas and colleagues studied the levels of matrix - degrading metalloproteinases , their inhibitors ( timps ) , and cxcl8 , the predominant chemokine interacting with them , in patients with mi complicated or not by ventricular fibrillation ( vf ) . levels of timp - 1 and cxcl8 were found to be significantly higher in patients with mi complicated by vf as compared to mi patients without vf . since high timp levels are related to the degree of fibrosis which is a substrate for electrical instability , the presence of these circulating inflammatory mediators may contribute to the occurrence of vf . in addition cxcl8 is a powerful chemoattractant responsible for the recruitment of neutrophils ; the adhesion of neutrophils to ischemic cardiomyocytes may result in excitation - contraction disturbances and development of arrhythmias in inflamed cardiac tissue . a high degree of fibrosis is also documented in arrhythmogenic ventricular cardiomyopathy ( arvc ) , a heart muscle disease characterized by fibrofatty replacement of the right and , less frequently , of the left ventricle . the presence of elevated levels of serum inflammatory mediators including cxcl8 , il - 6r , ccl2 , and ccl4 and an altered balance between circulating proinflammatory and anti - inflammatory factors have been found in patients with arvc compared to controls . the same study additionally showed that some inflammatory molecules , either circulating or derived from the myocardium , may lead to disruption of desmosome structure through dislocation of plakoglobin from desmosomes to intracellular space , myocyte injury , and arrhythmogenesis . there is growing evidence of chemokine mediators involvement also in the context of atrial fibrillation ( af ) . to elucidate the role of circulating inflammatory factors in atrial fibrillation , wu et al. conducted a meta - analysis based on observational studies and evidenced that the presence of increased inflammation molecules ( crp , il - 6 , and tnf - ) was significantly associated with a greater af risk in the general population . high levels of crp , ccl2 , and cxcl8 among patients with af were found by several investigators . notably , elevated levels of cxcl8 detected in patients with permanent af but not in patients with paroxysmal af suggested a link between low - grade inflammatory reaction and long - lasting af . the west birmingham atrial fibrillation project disclosed in a large cohort of af patients the independent correlation between low plasma levels of cx3cl1 and low risk of major cardiovascular events . although these studies on af are only observational and do not explain the molecular mechanisms linking inflammation with af risk , they suggest the assessment of plasma concentrations of chemokines as a potential application to improve the risk stratification in af patients . the presence of inflammatory chemokine mediators appears to be associated with an increased arrhythmic risk both in patients affected by inherited cardiac diseases and in patients with high degree of fibrosis due to nongenetic causes . inflammatory molecules are significantly more prevalent in patients with heart diseases and documented cardiac arrhythmias than in patients free of arrhythmia . it is likely that in most cases inflammation may act as a trigger in subjects already susceptible to developing arrhythmia . it must be mentioned that it has not been conclusively shown whether the inflammatory component plays a primary pathogenic role or whether it is rather the consequence of the myocyte injury . the fact that many studies showed ongoing active inflammation in a symptom - free time , remote from any acute event , suggests inflammation may be a trigger of arrhythmia for already susceptible subjects . however , further efforts are required to elucidate the specific molecular mechanisms involving chemokines and other inflammatory mediators in the development of cardiac arrhythmia . dilated cardiomyopathy ( dcm ) is a myocardial disease characterized by an increase in lv size and volume with normal lv wall thickness , associated with a progressive decline of lv contractile function leading to hf . being the third most common cause of hf worldwide , dcm is the underlying disease leading to up to 25 % of chf cases in the us and the most common cause of heart transplantation . with a prevalence of 1 : 2500 , dcm is a common and largely irreversible form of heart muscle disease . familial cases account for about 2035 % of all dcm and have been reported linked to a diverse group of 20 loci and genes . although a specific cause for the disease is found in almost 3035 % of dcm cases the others receive an exclusion diagnosis , idiopathic dilated cardiomyopathy ( idc ) . multifactorial genetic traits , associated with persistent viral infection and immunological abnormalities including autoimmunity , have been postulated as potential causes in the pathogenesis of idc since the late 1980s . experimental and clinical data suggest a causal relationship between myocarditis and idc , confirming that a chronic inflammatory process may underlie the development of idc . being the most frequent cardiomyopathy phenotype , dcm appears to be the final common pathway of many cardiac injuries . it appears that the pathways involved with this condition tend to be more disease specific in the initial phases of myocardial injury , but they involve progressively more stereotyped mechanisms in the later phases of myocardial remodeling , progressively leading to dcm and heart failure . several sources including the natural history of patients with particular conditions such as chagas disease provided a strong evidence of the process leading from myocardial inflammation to dilated cardiomyopathy . chagas disease is a well - characterized example of how the immune response meant to avoid the dissemination of trypanosoma cruzi , the parasite responsible for the disease , results in the development of a potentially fatal cardiomyopathy in 30 % of the infected cases , years after the acute infection . in the context of this disease , t. cruzi triggers an innate immune response involving the production of cytokines ( il - 1 , il - 6 , and tnf - ) , chemokines ( ccl2 , ccl5 , and cxcl9 ) , and an adaptative th1 t cell lymphocyte / antibody response . this response leads to control but not to elimination of the infection , causing the progressive development of chagas cardiomyopathy resulting from this sustained inflammation in susceptible individuals . these susceptible subjects have been identified as patients showing a smaller t reg lymphocyte compartment producing il - 10 and il - 17 , resulting in a deficient suppressive activity leading to uncontrolled production of th1 cytokines and , among others , of the chemokines ccl2 , ccl5 , and cxcl9 . several recent studies supported this finding , demonstrating that gene polymorphism associated with increased or decreased production of the above - mentioned chemokines exerts favoring or protective effects , respectively , on the development of chagas cardiomyopathy . chemokines causing leukocyte infiltration and cytotoxicity were investigated as potential mechanisms of cardiomyocyte damage also in chronic myocarditis and in sporadic idc . macrophages appear to be one of the key cells causing cardiac myocyte damage ; ccl2 and other chemokines are a major signal for the recruitment and activation of monocytes / macrophages . in 1995seino et al . reported for the first time that the ccl2 mrna is expressed in the myocardium of patients with idc . shortly after , kolattukudy and colleagues demonstrated in a transgenic murine model that ccl2 leads to increased myocardial leukocyte infiltration and to the phenotype of dilated cardiomyopathy . therefore , since the late 1990s , ccl2 has been known to be dynamically regulated in dcm and to possibly contribute to the deterioration in lv function . in 2007 the group of ohe confirmed that the expression of ccl2 was present in all myocardial samples from each of the 13 dcm patients analyzed in their study , but not in those from control subjects . moreover , the expression level of ccl2 in the myocardium was correlated with the degree of impairment of cardiac function . these experiments proved once more that augmented expression of specific chemokines was associated with adverse ventricular remodeling with their homeostasis with the maintenance of cardiac structure and function . ccl3 , acting through their receptors ccr2 and ccr5 , are key chemokines for the development of experimental autoimmune myocarditis and proved that inhibition of ccl2 with 7nd gene transfection significantly reduced disease severity in an experimental model of autoimmune myocarditis . interestingly , it may induce also stem cells homing in the dilated myocardium , thus proving that chemokine signaling may be a useful adjuvant for stem cell therapy . altogether , these experiments show the important role of chemokines , especially of ccl2 , in dilated cardiomyopathy and also in myocarditis , providing further clues supporting the existence of a common inflammatory pathway leading to the dilated cardiomyopathy phenotype . furthermore , some experiments carried out in animal models of autoimmune heart inflammation showed a favorable response in terms of reduction of inflammatory t cells infiltration and cardiomyocyte damage following the administration of some chemokines ( e.g. , cxcl1 , acting through toll - like - receptor 4 ) . these results show that further knowledge of the mechanisms underlying the chemokine network may be useful to understand the pathophysiological basis of a broad range of conditions leading to dcm and thus to favorably influence the inflammatory conditions underling this widespread heart disease . the parameters used to stratify the risk come from clinical practice and from laboratory results . the prediction of the risk of cardiovascular events in apparently healthy people as well as in patients with a previous cardiac event has been the focus of very active research in the last decades . the more the research progresses , the more it becomes clear that the risk stratification process , due to its complexity , can be effectively addressed only through a polyparametric approach . this means that only a combination of a clinical , instrumental , laboratory , and eventually invasive evaluations exploring different biological conditions and pathways can be really helpful in trying to identify and stratify the risk of each individual subject . although conventional risk prediction algorithms are made available based on the presence of major cardiovascular risk factors identified in diseased populations , authentic and accurate biomarkers of cardiovascular diseases are still lacking . among themchemokines are of particular interest because as already described they seem to act as a working - network involved in all stages of cardiovascular response to injury , in deep linkage with the autonomic nervous system ( ans ) . since they work as a network it is difficult to associate only one or few of them with cardiovascular risk . nevertheless , through the assessment of a predefined setting of chemokines we could have the possibility to evaluate and quantify pathological deviations of cardiovascular system homeostasis even at very initial stages . the incremental prognostic value of a polyparametric approach including an evaluation of inflammatory markers has been clearly demonstrated by correia and colleagues in 2010 in the setting of acute coronary syndromes . five cytokines [ interleukin - ( il - ) 1 , il - 6 , il - 10 , il - 12p70 , and tumor necrosis factor - ( tnf - ) soluble receptor i ] , five chemokines ( cxcl8 , ccl5 , cxcl9 , ccl2 , and cxcl10 ) , and crp were measured at admission in 87 patients with non - st segment elevation acute coronary syndrome ( nste - acs ) . individuals who developed events ( death , nonfatal acute mi , and refractory unstable angina ) during hospitalization had significantly greater levels of crp , il - 1 , il - 12 , tnf - , cxcl8 , cxcl9 , and ccl2 compared with patients without events . these markers were used to create an inflammatory score ( by inputting one point for each of these variables above the 75th percentile ) to be further adjusted for another score , called grace . grace score consists of 8 variables , 5 semiquantitative ( age , systolic blood pressure , heart rate , plasma creatinine , and killip class ) and 3 dichotomic ( positive necrosis markers , st segment deviation , and cardiac arrest at admission ) . after adjustment for the grace risk score ( considered as the most accurate one in the setting of nste - acs and largely used in clinical practice ) , the inflammatory score independently predicted events ( or = 1.80 ; 95 % ci = 1.121.88 ) . the incorporation of the inflammatory score into the grace score promoted a c - statistics improvement from 0.77 ( 95 % ci = 0.580.96 ) to 0.85 ( 95 % ci = 0.711.0 ) , with a net reclassification improvement of 13 % ( p = 0.007 ) ; on the other hand , when only crp was incorporated into grace , the increase on c - statistics was not relevant ( from 0.77 to 0.80 ) . when we look at the plasmatic levels of each of the 11 markers analyzed in the score , we found very interesting results . cxcl8 was the most varied chemokine between patients with and patients without events ; indeed cxcl8 levels were almost 4 times higher in patients with events ( median 37this is not surprising considering the well - known cxcl8 neutrophils attracting properties and their key role in the development of reperfusion injury . among the other chemokines analyzed , both ccl2 and cxcl9 levels were significantly higher in patients with events ( p = 0.02 ) . on the other hand , ccl5 and cxcl10 levelswere not different in the two groups . while cxcl10 has never been evaluated in the setting of acute coronary syndromes before , the negative results for ccl5 ( lack of association with events ) were not expected . however , considering the limited sample size , the possibility of type ii error as an explanation of these negative findings could not be ruled out . finally , the authors clearly demonstrated that although the inflammatory score was related with both peak troponin t and peak creatine kinase mb , it remained a significant predictor of events even after the adjustment for these parameters . the results of these studies , although very preliminary , speak in favor of a multimarker strategy ( including chemokines ) as opposed to a single - marker approach . unfortunately , the proposed inflammatory score ( in addition to grace score ) , although very appealing for the early management of nste - acs , has never been evaluated in other populations and the majority of the studies performed in the last years focused on the evaluation of a single chemokine , therefore missing the central point of the network . in 2012 , de jager and colleagues studied a larger population of 609 acs patients ( 56 % infarcted patients with st elevation or stemi , 33 % non - stemi , and 11 % with unstable angina ) and demonstrated a significant prognostic value of a pool of three chemokines ( ccl3 , ccl5 , and ccl18 ) for the short - term outcome . the average follow - up time was 189 days ( 18914.1 days ) and patients were monitored for the occurrence of fatal ( n = 48 ) and nonfatal ( n = 22 ) cardiovascular events ( new acute coronary syndrome , acs , and / or coronary revascularization including both pci and cabg techniques ) . high levels of ccl3 , ccl5 , and ccl18 were found to be independently associated with short - term fatal events in patients with acs . furthermore , the risk increased with a growing number of chemokines in the highest concentration tertile , reaching hazard ratio of 2.52 ( 95 % ci : 1.115.65 ) in case of all of them in the upper tertile . interestingly , no relationships were observed between chemokine levels and the risk of nonfatal events during follow - up and a large difference between the timing of fatal and nonfatal events during follow - up was noticed . namely , the majority of the fatal events occurred already shortly after the start of follow - up . the median time - to - event of fatal events was merely 5 days , whereas nonfatal events occurred much later during follow - up with a median time - to - event of 120 days . considering the known predictors of short - term fatal events ( including clinical variables and crp levels ) , the combination of ccl3 , ccl5 , and ccl18 , if added simultaneously to the model , improved the c - statistics from 0.74 to 0.81 ( p = 0.007 ) . obviously , the question of whether this increased prognostic value is also of clinical relevance deserves further investigation in studies with larger patient populations . altogether , the results of these few studies , although very preliminary , speak in favor of a multimarker strategy as opposed to a single - marker approach . furthermore , the fact that scores including chemokine were found to be consistently related to acute / subacute clinical outcome rather than to middle term follow - up in the setting of acute coronary syndromes seems to have a strong biological rationale and point out the importance of the shift of the chemokine homeostasis in driving the evolution of an acute myocardial ischemia . being so , by assessing a pool of chemokine we could have the possibility to predict an adverse biological response ( e.g. , reperfusion injury ) immediately before it is taking place and we could identify high risk patients who may require a more aggressive treatment and / or new experimental interventions ( e.g. , vns ) . in the past two decades the evidence suggesting a role for inflammation in the pathogenesis of cardiovascular diseases has been progressively increasing . most data were related initially to the development of atherosclerosis and to the acute instability of atherosclerotic plaques . as reviewed in this paper , numerous studies now demonstrate a profound involvement of inflammatory processes in a variety of cardiovascular manifestation of diseases such as myocardial ischemia , heart failure , atrial fibrillation , and malignant ventricular arrhythmias . parallel with the increased understanding of the role of inflammation , data have been gathered on the implication of chemokines in these processes . chemokines act as a complex network connecting the cardiovascular system with the immune system and the autonomic nervous system . although the original goal of this extensive crosstalk is to maintain homeostasis and to coordinate the best response to injury , it appears that unbalanced or exaggerated responses may actually lead to a progression of the disease and contribute to an acute and potentially life - threatening manifestation . many aspects of the involvement of chemokines must still be elucidated before their role can be considered clarified . moreover , further data are required before their evaluation can be used clinically in the prediction of the disease , in risk stratification of patients , and possibly in paving the way to new therapeutic strategies . in many circumstancesthe chicken and egg question has not been solved , being still uncertain whether specific chemokines are involved in favoring the disease or rather are the result of the disease , being triggered by it . also , it has become increasingly evident that chemokines represent a very complex network and that it would be nave to believe that by simply assessing a single one of them a significant improvement in the comprehension of a disease process or in the risk stratification of individual subjects may be derived . this goal may be possibly achieved using a multidimensional evaluation in which multiple markers including panels of appropriately selected chemokines are assessed together . should we achieve this goal we would have probably reached the heart of the problem for a better understanding , diagnosis , and therapeutic strategy of cardiovascular diseases .\noutput:\n" }, { "from": "agent", "value": "among the chemokines discovered to date , nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury . chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets . moreover , they could have a role as mediators of crosstalk between immune and cardiovascular system , since they seem to act as a working - network in deep linkage with the autonomic nervous system . in this paper we will describe the single chemokines more involved in heart diseases ; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems . finally , some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: natural proteins with over 35 % sequence similarity tend to fold into similar conformations , yet several evolutionarily related natural protein pairs with up to 40 % similarity have been observed to produce substantially different topologies . two sequences bearing the same length and only three nonidentical residues were posted as sequential targets in the recent 8th community - wide experiment on the critical assessment of techniques for protein structure prediction ( casp8 ) . targets t0498 and t0499 therefore posed a riddle for the international protein fold prediction community to determine whether the conformations of these 95 % identical sequences maintain the same topological folds or adopt different ones . the proteins were artificially produced in the group of john orban and philip bryan as a study of the tolerance of sequence identity to maintain the 3 - and / folds of streptococcal protein g domain a ( ga ) and domain b ( gb ) , respectively . the two 16 % identity domains of protein g were brought together in sequence space first by adding terminal tails to ga to make it equal in length to gb and then by progressively mutating sites of nonidentity . the key in this approach was linking each fold to its natural function : human serum albumin binding for the 3 - ga fold and igg binding for the / gb fold . this linkage of fold to function allowed the application of powerful biologic selection methods to determine clusters of sites in each protein , which could be substituted with the corresponding amino acid in the other protein . more recently , two 95 % identical sequences possessing the same fold , ga95 and gb95 , were designed and provided as the two casp8 targets discussed here . the designed protein pairs maintain the fold and specific binding function of the proteins from which they were derived , with immeasurable structural or functional character of the domain represented in the alternate protein . structural genomics consortia contribute thousands of new protein structures each year , yet previously unobserved folds are seldom found . this pattern seems to indicate that the majority of folds that can be detected by current laboratory techniques have already been observed . the completeness of the structural fold space has been addressed using a subset of 1,489 proteins covering the protein data bank at the level of 35 % sequence identity ; all but two folds can be resolved using templates found within the same set . thus , template - based modeling appears to be feasible given the best template ( s ) within the set . the best performing freely available fold recognition web server methods are maintained by yang zhang within the local meta - threading server ( lomets ) fold recognition pipeline of i - tasser ( iterative threading assembly refinement algorithm ) , the best performing protein structure prediction server in the past two casp experiments . as an isolated meta - threading server , lomets uses local implementation to avoid the destructive aspects of internet dynamic regulation corrupting so many meta - servers . the nine methods of lomets are representative of the fold recognition field ( normally targeted toward naturally occurring proteins ) and can be summarized as various combinations of the following : comparing target to known structure sequence profiles , secondary structure preferences , environmental fitness , pairwise contact probabilities , structure profiles , simulated mutations , single - body or residue - specific knowledge - based potentials , and profile hidden markov models ( hmms ) . most web server groups predicted both t0498 and t0499 to adopt the / fold of protein gb ( figure 1a ) . for example , our own predictions for t0498 did not significantly resemble the target structure [ 37.2 global distance test total score ( gdt - ts ) ; figure 1b , left ] , yet all five of our predictions for t0499 were within the top 10 total predictions ( 88.4 gdt - ts ; figure 1b , right ) . the models for t0499 exemplify progress in another major challenge in protein structure prediction : refinement of model quality from the best template . ( a ) only four out of over 150 contributing team groups recognized the difference in fold caused by three nonidentical residues in the 56 residue proteins : hhpred ( cyan ) , feig ( black ) , foldpro ( blue ) , and coma ( others are in orange ) . the results are shown in global distance test ( gdt ) plot format , in which the alpha carbon atoms of the predicted model and experimental structure are spatially aligned within distance cutoffs of 0.5 , 1 , and 1.5 up to 10 , such that lower lines denote higher accuracy . a common trend of these four groups was to predict the alternate fold as a lower confidence model . most groups correctly identified the gb95 t0499 fold , yet most models were no better than random for ga95 t0498 . the ability for four automated servers to disentangle this riddle provides a positive outlook for the fold recognition field . ( b ) predictions made by our group ( purple ) for t0498 and t0499 compared with the experimental structures for ga95 and gb95 ( cyan ) , respectively . while our predictions were among the very best for t0499 / gb95 ( the only group with all five submissions in the top 10 ) , the incorrect fold assignment led to highly inaccurate predictions for t0498 / ga95 . as with so many other protein structure prediction groupsca , alpha carbon ; ga95 , the artificial protein with ga fold and 95 % sequence identity to gb95 ; gb95 , the artificial protein with gb fold and 95 % sequence similarity to ga95 . the side chain interactions visible in the experimental structures of ga95 and gb95 , as well as the simulated mutant models depicted in figure 2 , demonstrate interactions within a relatively stable , folded state , which are not necessarily illustrative of those interactions occurring during the folding process . even when the structures are known , it is difficult to ascertain exactly what makes the two proteins follow different fold trajectories . rather , they rely on calculated interactions within simulated mutants of these folded structures to test the accuracy of fit for a possible template ; thus , even with a perfect energy function , mistakes in fold recognition could occur . a sequence - to - structure cross of ga95 and gb95 is presented to demonstrate determinants of fold recognition from side chain packing of the nonidentical residues ( red ) . the lack of profound steric clashes created by applying the side chain identities from t0498 to the structure of gb95 ( left ) misleads predictors to identify an incorrect fold topology . conversely , the clash that occurs between f30 and a20 when applying the side chain identities from t0499 to the structure of ga95 ( right ) illustrates an incorrect fold for predictors . ga95 , the artificial protein with ga fold and 95 % sequence identity to gb95 ; gb95 , the artificial protein with gb fold and 95 % sequence similarity to ga95 . in this case , a multitude of experimentally derived structures for ga and gb and detectable sequence similarity within this group reasonably limit the fold search to these topologies . crossing fold assignments for ga95 and gb95 enables interrogation of side chain packing for the three nonidentical residues ( figure 2 ) . the clash occurring between f30 and a20 when the nonidentities from t0499 are applied to the structure of ga95 ( figure 2 , right ) implicates an incorrect fold to predictors . conversely , minimal steric clashes emerge when the t0498 sequence is applied to the structure of gb95 ( figure 2 , left ) . this absence of incriminating evidence for the t0498 gb95 sequence fold pair could mislead predictors to select this fold topology . out of over 150 contributing teams , four groups recognized the difference in fold caused by three nonidentical residues in the 56 amino acid proteins : hhpred , foldpro , feig , and coma . the accurate predictions of these groups demonstrate sensitivity to subtle changes affecting folding not previously demonstrated in a bona fide blind prediction scenario . the emission sequence of hmms includes position - specific insertion and deletion probabilities along with the sequence distributions found in multiple sequence alignment profiles . hhsearch specifically includes secondary structures via a substitution matrix derived from comparing measurements on the template to target predictions and to the confidence thereof . to interrogate alignments , the hhsearch method maximizes the coemission log - odds probability for the pair of hmms derived for a given protein pair . hhsearch directs the structural similarity search hierarchically by searching databases of alignments organized by fold family rather than lists of disconnected sequences . the csi - blast ( context - specific iterative basic local alignment search tool ) sequence similarity search method recently published by the group was likely used to build the profile input to the hmms for each alignment . the cheng group uses a supervised classification approach previously used for fold classification , invoking support vector machines to combine global profile - profile alignment , secondary structure , solvent accessibility , contact map , and strand hydrogen bond pairing . the feig group used a very typical set of methods , including fold recognition functions overlapping those in lomets ( including hhsearch / hhpred ) , standard model construction , and a modified cluster calculation using a standard discriminatory potential function . other promising work by this group in the refinement category includes the use of an implicit continuum dielectric solvent based on generalized born theory to drive lattice - based course grain searches , monte carlo molecular dynamics , and restrained normal mode sampling . the venclovas group invokes a profile comparison method for detection of distant evolutionary relationships across profile databases , adding a modified two - level seg ( segment sequences by local complexity ) algorithm to filter noninformative profile regions , variable gap penalties , and adaptive parameterization . the underlying sequence similarity search is driven by their psi - blast - iss ( position - specific iterative blast intermediate sequence search ) , which evaluates and refines output profile alignments . the emission sequence of hmms includes position - specific insertion and deletion probabilities along with the sequence distributions found in multiple sequence alignment profiles . hhsearch specifically includes secondary structures via a substitution matrix derived from comparing measurements on the template to target predictions and to the confidence thereof . to interrogate alignments , the hhsearch method maximizes the coemission log - odds probability for the pair of hmms derived for a given protein pair . hhsearch directs the structural similarity search hierarchically by searching databases of alignments organized by fold family rather than lists of disconnected sequences . the csi - blast ( context - specific iterative basic local alignment search tool ) sequence similarity search method recently published by the group was likely used to build the profile input to the hmms for each alignment . the cheng group uses a supervised classification approach previously used for fold classification , invoking support vector machines to combine global profile - profile alignment , secondary structure , solvent accessibility , contact map , and strand hydrogen bond pairing . the feig group used a very typical set of methods , including fold recognition functions overlapping those in lomets ( including hhsearch / hhpred ) , standard model construction , and a modified cluster calculation using a standard discriminatory potential function . other promising work by this group in the refinement category includes the use of an implicit continuum dielectric solvent based on generalized born theory to drive lattice - based course grain searches , monte carlo molecular dynamics , and restrained normal mode sampling . the venclovas group invokes a profile comparison method for detection of distant evolutionary relationships across profile databases , adding a modified two - level seg ( segment sequences by local complexity ) algorithm to filter noninformative profile regions , variable gap penalties , and adaptive parameterization . the underlying sequence similarity search is driven by their psi - blast - iss ( position - specific iterative blast intermediate sequence search ) , which evaluates and refines output profile alignments . a handful of the automated algorithms were able to recognize the fold switch caused by the three nonidentical residues of ga95 and gb95 ( figure 2 ) . however , the experimentally unobserved 60 % of naturally occurring proteins and the prospect of designing new folds heralded by top7 demand more methods sensitive enough to detect subtle triggers in fold switching and predict previously unobserved topologies . developments in the protein fold prediction field can often be limited to incremental engineering optimizations . in this fold recognition problem , the proper application of support vector machines and hmm methods enabled success for two groups . also , two groups created their own improvements on psi - blast : csi - blast and psi - blast - iss , which both enhance quality and relevance of a search by interrogating low - quality regions in the alignment by context and together comprise the first significant improvements on the enormously popular algorithm in a decade . the novel algorithmic adjustments in fold recognition used in casp8 demonstrate significant progress amounting to new tools for the field . future developments are anticipated to include the steady stream of mathematical enhancements observed since the inception of the protein structure prediction field but also include new conceptual paradigms such as functional signatures and the use of template - free modeling to drive the difficult fold recognition problems .\noutput:\n" }, { "from": "agent", "value": "we examine the ability of current state - of - the - art methods in protein structure prediction to discriminate topologically distant folds encoded by highly similar ( > 90 % sequence identity ) designed proteins in blind protein structure prediction experiments . we detail the corresponding prognosis for the protein fold recognition field and highlight the features of the methodologies that successfully deciphered this folding riddle ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: determinar se h associaes entre o nvel de atividade fsica na vida diria ( afvd ) e a funo pulmonar em tabagistas adultos . foram selecionados 62 tabagistas adultos de um estudo epidemiolgico , realizado na cidade de santos ( sp ) . o nvel de afvd foi avaliado pelo questionrio internacional de atividade fsica e por acelerometria triaxial ( aparelho utilizado por sete dias ) . o nvel mnimo de afvd , em termos de quantidade e intensidade , foi definido como 150 min / semana de atividade fsica moderada a vigorosa durante o monitoramento . as correlaes entre as variveis estudadas foram avaliadas pelo coeficiente de correlao de pearson ou de spearman conforme a distribuio das variveis . a influncia de afvd nas variveis espiromtricas foi avaliada por meio de anlise de regresso mltipla linear . o nvel de significncia foi estipulado em 5 % . quando avaliados todos os preditores corrigidos para fatores de confuso e utilizando dados da funo pulmonar como variveis de desfecho , no foram observadas associaes significativas entre a inatividade fsica avaliada por acelerometria e os ndices espiromtricos . as anlises mostraram valoresinferiores da cvf em participantes com hipertenso arterial e da relao vef1 / cvf nos participantes com diabetes mellitus . nossos resultados sugerem que a inatividade fsica apresenta associao pouco consistente com a funo pulmonar de tabagistas adultos . a carga tabgica , assim como comorbidades cardiovasculares e metablicas , deveriam ser priorizadas em estratgias preventivas da dpoc . smoking is a major public health problem worldwide . in the 20th century , tobacco use killed 100 million people worldwide . smoking accounts for 5.4 million deaths per year worldwide , and it is estimated that it will account for more than 8.0 million deaths per year in 2030 . approximately 80 % of these deaths will occur in developing countries , and smoking is currently the leading cause of preventable death worldwide . 1the impact of tobacco use on health is well known , tobacco use accounting for 90 % of all cases of lung cancer , 75 % of all cases of chronic bronchitis , and 25 % of all cases of ischemic heart disease .2 individuals who smoke more than 20 cigarettes per day are significantly different from nonsmokers in terms of their fev1 . 3this is due to the fact that smoking causes acute lung changes , including changes in airflow resistance , cough , and airway irritation .4 lung function decline is less pronounced in smokers who engage in moderate - to high - intensity physical activity .5 studies have shown that regular physical activity is effective in preventing chronic diseases such as cardiovascular disease , diabetes , cancer , hypertension , obesity , depression , and osteoporosis . it has been suggested that there is a significant association between physical activity and health status , increased physical fitness resulting in additional health benefits .6 other studies have shown that endurance training in nonsmokers results in adaptations of the cardiorespiratory and neuromuscular systems that increase the supply of oxygen to the mitochondria , thus contributing to maintaining physical fitness . 78910 in addition , significant differences have been found between physically active and physically inactive smokers regarding fatigue immediately after the six - minute walk test and during the recovery period , at two minutes after the test . 11 regular physical exercise can counter the negative effects of smoking through an anti - inflammatory and antioxidant mechanism . physical activity and smoking interact antagonistically : inflammatory markers that are produced in the lung and are related to a decline in cardiorespiratory fitness are suppressed by physical exercise .5 physical activity can be assessed by a variety of methods , including direct observation , questionnaires , self - report diaries , and motion sensors , such as pedometers and accelerometers .12 objective assessment is performed by motion sensors , which are instruments that are used in order to detect body motion and determine the level of physical activity in daily life ( padl ) over a period of time . accelerometers are real - time motion capture sensors that are sensitive to acceleration . 13 few studies have examined the preventive effect of physical activity on the lung function of smokers , the level of padl having been determined on the basis of self - reports , face - to - face interviews , or physical activity questionnaires . using pedometers , furlanetto et al .11 found that the mean number of daily steps was significantly lower in adult smokers than in adult controls , the former also having lower physical capacity , worse lung function , and greater sensation of fatigue . however , there is a lack of studies in which the level of padl in smokers is more accurately determined with the use of triaxial accelerometers . however , there is a need for further clarification of the association between the level of padl and lung function in smokers . longitudinal studies of the role that a higher level of objectively measured padl has in preventing lung function decline in smokers could contribute to preventing smoking - related complications , which consume a significant proportion of health care resources in brazil and the world . 14 we hypothesized that smokers who have a higher level of padl ( more accurately determined by triaxial accelerometry ) have relatively preserved lung function , regardless of their smoking history . confirmation of our hypothesis would support the need for strategies to increase the level of padl in smokers in order to reduce the damage caused by smoking . therefore , we sought to determine whether the level of padl , as determined by triaxial accelerometry , was associated with lung function in adult smokers . this was a cross - sectional study involving a convenience sample of adult smokers selected from among the participants of a study conducted in the federal university of so paulo laboratory of epidemiology and human movement , located in the city of santos , brazil . the study included 62 adult smokers who were 20 years of age or older and had no cardiac , respiratory , or metabolic diseases limiting their exercise capacity . in brief , this was a population - based epidemiological study whose primary objective was to determine the association of sedentary behavior and physical inactivity with the development of chronic diseases . the exclusion criteria were as follows : a spirometric diagnosis of copd ; problems indicating inability to perform padl adequately ; being a smoker with a smoking history of fewer than 1.5 pack - years or more than 50 pack - years ; and being a former smoker .15 the following demographic variables were analyzed : age ; gender ; race ; place of birth ; level of education ; and socioeconomic status . after being selected for inclusion , all participants were informed of the procedures , discomfort , and risks associated with the present study and gave written informed consent . the study project was approved by the federal university of so paulo human research ethics committee ( protocol no . the risk of cardiovascular events was determined on the basis of the following risk factors : age ; family history ; smoking history ; hypertension ; dyslipidemia or hypercholesterolemia ; diabetes or hyperglycemia ; obesity ; and sedentary lifestyle . smoking status was determined by self - report , and smoking history was calculated by multiplying the duration of smoking in years by the number of cigarettes smoked per day and dividing the result by 20 ( the number of cigarettes in one pack ) . individuals who reported current smoking and having smoked 100 or more cigarettes in their lifetime at the time of the study were defined as smokers .15 after anthropometric measurements , including weight , height , and bmi calculation , all participants were evaluated as described below . lung function was assessed by forced spirometry ( quark pft ; cosmed , rome , italy ) . fev1 , fvc , fev1 / fvc , and pef were determined in accordance with the american thoracic society criteria .16 spirometric indices were expressed as absolute values and as a percentage of reference values .17 the level of padl was determined by the international physical activity questionnaire ( ipaq ) , which assesses total energy expenditure in metabolic equivalent task - minutes per week ( met - min / wk ) and time spent in daily physical activity . padl was classified as vigorous , moderate , or light , measured in met - min / wk , and divided into four domains : work ; transport ; household chores ; and recreation and leisure . the ipaq - long form was used , consisting of 27 questions regarding physical activity . the participants were instructed to answer the questions on the basis of the week prior to the administration of the ipaq . 18 the level of padl was also assessed with a widely used triaxial accelerometer ( gt3x actigraph ; mti , pensacola , fl , usa ) . 1922 a triaxial accelerometer measures the duration and intensity of physical activity . the participants were instructed to wear the device on an elastic belt placed on their dominant hip and left in place for seven days . all participants were instructed to remove the device before engaging in water - based activities , such as bathing and swimming , and at bedtime . only the data from the participants who used the accelerometer for at least four valid days were analyzed .19 on the basis of its intensity , physical activity was classified as follows : physical inactivity or light physical activity , fewer than 3.00 met - min / wk ; moderate physical activity , 3.00 - 5.99 met - min / wk ; hard physical activity , 6.00 - 8.99 met - min / wk ; and very hard physical activity , 9.00 met - min / wk .23 the minimum level of padl , in terms of quantity and intensity , was defined as 150 min / week of moderate to vigorous physical activity .24 the participants who were unable to achieve that level of padl were considered to be physically inactive . in the present study , statistical analysis was performed with the ibm spss statistics software package , version 23 ( ibm corporation , armonk , ny , usa ) . the kolmogorov - smirnov test was used in order to determine the normality of continuous variables . data are presented as mean standard deviation or as median ( interquartile range ) . the study sample size was calculated on the basis of the number of independent variables of interest for inclusion in the multiple regression model . the models were adjusted for age , gender , weight , height , and six other variables . after the bivariate analysis , the variables that were found to be significantly associated with the spirometric indices were included in the multiple regression model , as follows : age ; gender ; presence of hypertension ; presence of diabetes mellitus ; ipaq household chores domain score ; daily energy expenditure in kcal ; and physical inactivity . the student 's t - test or the mann - whitney test was used in order to compare the spirometric indices between males and females according to the presence of comorbidities , such as hypertension , diabetes mellitus , dyslipidemia , obesity , and physical inactivity . correlations between the studied variables were tested with pearson 's or spearman 's correlation coefficient , depending on the distribution of the variables . among the 62 volunteers in the study sample , obese individuals and females predominated ( table 1 ) . there were significant differences between males and females regarding smoking history , weight , and bmi . variable males females ( n = 20 ) ( n = 42 ) age , years4714538smoking history , pack - years12 .7 ( 3.2 - 20.0 ) * 22.5 ( 11.7 - 40.0 ) weight , kg80 .212.3 * 74.619.9 height , cm1 .710.07 * 1.570.07 bmi , kg / m27 .44.5 * 29.87.07 risk factors , n ( % ) hypertension4 ( 20 ) 13 ( 31 ) obesity5 ( 25 ) 20 ( 47 ) diabetes2 ( 10 ) 10 ( 23 ) dyslipidemia5 ( 25 ) 18 ( 42 ) physical inactivity7 ( 35 ) 14 ( 33 ) data presented as mean sd or median ( interquartile range ) , except where otherwise indicated . * p 0.05 . data presented as mean sd or median ( interquartile range ) , except where otherwise indicated . table 2 shows the correlations between padl and lung function , fvc having been found to correlate significantly with the ipaq household chores domain score , energy expenditure in kcal / day , and hard physical activity in h ( p 0.05 for all ) . the household chores domain scores were the only ipaq domain scores that correlated significantly with lung function . pef was found to correlate significantly with the ipaq household chores domain score , light physical activity , and hard physical activity . fvc was found to be reduced in the participants with arterial hypertension , and the fev1 / fvc ratio was found to be reduced in those with diabetes mellitus . no significant associations were found between physical inactivity , as determined by accelerometry , and spirometric indices . table 2 . statistical correlations between lung function and physical activity in daily life . lung function physical activity in daily life ipaq - hc ee , kcal / day wst , h wlpa , h wmpa , h wvpa , h wvvpa , h fvc , l0 .432 * 0.320 * 0.1820.2030.1040.375 * 0.034 fev1 , l0 .400 * 0.330 * 0.2180.1860.1030.346 * 0.036 fev1 / fvc0 .1100.0640.2050.0640.0230.0710.018 fev1 / fvc , % predicted0 .0570.0460.2410.0590.0120.0840.001 pef , l / min0 .451 * 0.1910.2460.264 * 0.0520.392 * 0.008 ipaq - hc : international physical activity questionnaire household chores domain score ; ee : energy expenditure ; wst : weekly sedentary time ; wlpa : weekly light physical activity ; wmpa : weekly moderate physical activity ; wvpa : weekly vigorous physical activity ; and wvvpa : weekly very vigorous physical activity . energy expenditure measured in metabolic equivalent task - minutes per week . * p 0.05 . ipaq - hc : international physical activity questionnaire household chores domain score ; ee : energy expenditure ; wst : weekly sedentary time ; wlpa : weekly light physical activity ; wmpa : weekly moderate physical activity ; wvpa : weekly vigorous physical activity ; and wvvpa : weekly very vigorous physical activity . energy expenditure measured in metabolicrisk factors lung function data fvc , l fvc , % predicted fev1 , l fev1 , % predicted fev1 / fvc , % predicted arterial hypertensionyes2 .810.62 * 86142.220.538416786 no3 .720.10 * 94122.880.899512825 diabetes mellitusyes2 .740.8583102.290.698610842 * no3 .471.0394122.800.879415806 * dyslipidemiayes2 .980.67 * 92122.440.52 * 9313825no3 .531.16 * 92132.850.98 * 9215806obesityyes2 .940.59 * 88112.410.52 * 8914816no3 .581.19 * 95132.900.99 * 9414805physical inactivityyes3 .271.1192152.620.979118796 no3 .351.0092122.740.81931282 corrected for confounding factors , and using lung function data ( fvc and fev1 , both in % of predicted ) as outcome variables , we found that the variables that remained in the model as predictors of lung function were smoking history and the presence of diabetes , as predictors of fvc , and smoking history and the presence of arterial hypertension , as predictors of fev1 ( table 4 ) . outcome predictors coefficient standard error p r r fvc , % predictedsmoking history0 .2180.0650.0010.1100.246 diabetes mellitus12 .2663.7630.0020.136 fev1 , % predictedsmoking history0 .2020.0740.0090.1350.225 arterial hypertension9 .8833.7810.0110.090 model adjusted for age , gender , weight , height , hypertension , diabetes , physical inactivity ( determined by triaxial accelerometry ) , and international physical activity questionnaire score . model adjusted for age , gender , weight , height , hypertension , diabetes , physical inactivity ( determined by triaxial accelerometry ) , and international physical activity questionnaire score . the present study investigated the association between the level of padl and lung function in adult smokers without respiratory disease . the level of padl was directly assessed by triaxial accelerometry over the course of seven days . to our knowledge , there is little information regarding the use of triaxial accelerometry for determining the level of padl . after adjustment for the main confounding factors , no association was found between an adequate level of padl and better lung function . as expected , smoking history was a predictor of worse fvc and fev1 , even after having been adjusted for confounding factors . studies have shown that smoking history is the main predictor of reduced fev1 in smokers with a normal fev1 / fvc ratio .25 smoking is also associated with dysregulation of gene expression in the small airway epithelium and accelerates the aging of the airways , as well as being the principal factor responsible for progressive lung function decline .27 conducted a cohort study and concluded that smoking and physical inactivity are associated with disability retirement and that even hard physical activity is not sufficient to eliminate the adverse effects that smoking has on health . elderly smokers have reduced exercise capacity when compared with elderly never - smokers , and tobacco exposure is associated with reduced quality of life regardless of the level of physical activity .28 smoking is associated with evidence of mild obstruction and accelerates lung function decline in adolescents . female adolescents are possibly more vulnerable to the effects of smoking on lung function than are male adolescents . 29 we believe that the benefits of padl were not enough to make up for the damage caused by smoking . we observed a crucial association between the presence of diabetes mellitus and lung function in our participants .3031 lung volume changes reducing lung compliance and dlco have been described in patients with diabetes . this is probably due to a reduction in pulmonary capillary blood volume as a result of diabetes mellitus . impaired lung function in individuals with diabetes suggests that the lung is a \" target organ \" in diabetes mellitus .32 systematic reviews have examined lung function in patients with diabetes mellitus . reduced fev1 and fvchave been found to be associated with type 1 diabetes and type 2 diabetes .33 our results suggest that this association remains significant even in smokers with varying history of smoking . therefore , diabetes mellitus should be considered a major risk factor for lung function decline and , eventually , copd . according to the aforementioned studies , moderate to high levels of regular physical activityare associated with reduced lung function decline and reduced risk of copd in smokers .534 this difference can be attributed to the methods used in order to determine the level of padl . in the present study , we used triaxial accelerometry , which precisely measures the amount and intensity of padl . the aforementioned studies involved the use of questionnaires . despite the size of those studies , the major limitation of questionnaires is that they overestimate the level of padl . triaxial motion sensors can overcome some of the limitations of self - report instruments , are not affected by random and systematic errors introduced by interviewees and interviewers , and provide valid and reliable estimates of basic features such as the frequency , duration , and intensity of physical activity , as well as the pattern of physical activity .35 an accurate assessment of physical activity is extremely important when the relationship between exposure to physical activity and a range of health outcomes ( e.g. , cardiovascular disease , hypertension , and obesity ) is examined .36 in addition , self - reported physical activity is highly susceptible to inaccuracy because self - report instruments depend on the ability of individuals to recall and report their physical activity .23 our results suggest the need for longitudinal epidemiological studies to investigate the association between lung function and padl , the latter being more accurately assessed by motion sensors . the major limitation of the present study is its convenience sample , which can explain the predominance of females and the difference in smoking history between males and females . however , the sample size was sufficient to adjust the regression models to the main confounders of clinical interest . our results suggest that there is no association between physical inactivity and lung function in adult smokers , as well as reinforcing the importance of smoking cessation and preventing comorbidities such as diabetes mellitus and arterial hypertension in order to prevent lung function decline and copd . therefore , health professionals should focus on health promotion instructions and strategies , as well as on preventing comorbidities in smokers and the general population .\noutput:\n" }, { "from": "agent", "value": "objective : to determine whether the level of physical activity in daily life ( padl ) is associated with pulmonary function in adult smokers . methods : we selected 62 adult smokers from among the participants of an epidemiological study conducted in the city of santos , brazil . the subjects underwent forced spirometry for pulmonary function assessment . the level of padl was assessed by the international physical activity questionnaire and triaxial accelerometry , the device being used for seven days . the minimum level of padl , in terms of quantity and intensity , was defined as 150 min / week of moderate to vigorous physical activity . correlations between the studied variables were tested with pearson 's or spearman 's correlation coefficient , depending on the distribution of the variables . we used linear multiple regression in order to analyze the influence of padl on the spirometric variables . the level of significance was set at 5 % . results : evaluating all predictors , corrected for confounding factors , and using pulmonary function data as outcome variables , we found no significant associations between physical inactivity , as determined by accelerometry , and spirometric indices . the values for fvc were lower among the participants with arterial hypertension , and fev1 / fvc ratios were lower among those with diabetes mellitus . obese participants and those with dyslipidemia presented with lower values for fvc and fev1 . conclusions : our results suggest that there is no consistent association between physical inactivity and pulmonary function in adult smokers . smoking history should be given special attention in copd prevention strategies , as should cardiovascular and metabolic comorbidities ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a 42 - year - old male patient reported to our institution with a chief complaint of a swelling in the right side of the mandible in the region of 43 , 44 and 45 . extraorally , there was a diffuse swelling on the right side of the face with associated facial asymmetry [ figure 1 ] . on inspection , the diffuse extra oral swelling on the left side of face extending approximately posteriorly 4 cm from the angle of mandible , anteriorly 3 cm from the symphysis menti and inferiorly up to the inferior border of mandible . intraorally , there was an exophytic soft tissue overgrowth in the region of 43 and 44 . on palpation , the intraoral swelling was smooth , firm , and nontender with bicortical expansion of both buccal and lingual cortical plates . there was displacement of 42 and 44 with grade iii mobility [ figure 2 ] . orthopantomograph revealed missing 43 , 44 with a multilocular radiolucency , sclerotic borders and displacement of 42 and 45 . mandibular occlusal view radiographs revealed bicortical expansion of both buccal and lingual cortical plates [ figure 4 ] . computed tomography scan with three - dimensional reconstruction showed an expansile soft tissue mass with areas of calcification [ figure 5 ] . histopathological slide incisional biopsy was done [ figure 6 ] and a small bit of lesional tissue was given for histopathological examination . histopathology of the incisional biopsy specimen showed eosinophilic homogenous , acellular areas resembling amyloid and leisegang ring type of calcifications , which was suggestive of ceot . histopathological slide considering the intrabony mandibular location of the lesion and its limited size , we opted for a more conservative surgery under general anesthesia . the tumor was surgically removed completely as a mass by enucleation with removal of a thin layer of bone adjacent to the lesion , followed by curettage [ figures 7 and 8 ] . during surgery , the lesion proved to be primarily cystic in nature and could be easily enucleated from the surrounding bone . after enucleation , the specimen was fixed in a 4 % neutral formalin solution and submitted for histopathologic examination . histopathology of the excised specimen showed islands and strands of polyhedral epithelial cells with prominent intercellular bridges . leisegang ring type of calcifications was also seen [ figure 9 ] . from the histopathology , healing was uneventful , except for a transitory decrease in sensitivity in the region of the right inferior alveolar nerve , which regressed progressively during the next several months . the patient was advised to come for regular follow - up to monitor the healing and prognosis . the follow - up of 1 - month revealed good healing of the site and obturator had been fabricated to cover the defect [ figures 1013 ] . it was first described by the oral pathologist pindborg , and hence ceot is also called pindborg tumor . the tumor occurs over a wide range of age the youngest being reported as 1 - year and the oldest as 82 years . the present case was reported in a 42 - year - old patient with a painless swelling in the mandibular premolar region . the radiographic features of the tumor may be unilocular or multilocular radiolucency . in our caseapproximately 50 % of the cases are associated with an unerupted tooth or odontome , but was not so with our case . histopathologic feature usually show islands and strands of polyhedral epithelial cells with nuclear pleomorphism , prominent nucleoli and intercellular bridges . one of the characteristic microscopic features of this tumor is the presence of amorphous , eosinophillic hyalinized and acellular areas resembling amyloid within or adjacent to epithelial islands . these epithelial islands and amyloid - like materials were seen in our case also . the presence of amyloid can be confirmed with congo red stains . many histologic , histochemical , immunohistochemical and electron microscopic investigations were done to identify the nature of the amyloid - like material in pindborg tumor . yamaguchi et al . and page et al . studied the histologic , histochemical , fluorescent and ultrastructural study of ceot and found that the eosinophilic substance was not amyloid . it is now identified that this material has a unique protein that has similarity with enamel proteins and is produced by this tumor cell . another characteristic feature of this tumor is the presence of concentric ring of basophilic calcifications called leiesegang rings within the amyloid - like masses . these lisegang ring calcifications were thought to be a form of dystrophic calcification and cemental masses . various treatment options ranging from simple enucleation to segmental resections have been proposed to treat ceots . based on clinical similarities between ceot and the solid ameloblastoma , several authors initially advocated aggressive treatment , but newer evidence that ceot does not infiltrate into the intertrabecular bony spaces , rather supports the fact that conservative surgery is the treatment of choice of intrabony mandibular forms of ceots . moreover , mandibular tumors in general tend to grow slower than their maxillary counterpart and remain usually well confined , allowing a less radical surgical approach . however , occurrence of clear cells may prove to be a sign of increased tumor aggressiveness necessitating a more radical surgical approach . nevertheless , the 11 cases of clear cell ceot with limited follow - up information reported to date do not allow any definite conclusions in terms of biological behavior , treatment , and prognosis . the follow - up of 1 - year showed good healing of the site and no recurrence . the ceot and its clear cell variant are rare , and benign odontogenic tumors of still controversial origin can be locally aggressive in nature and have an unpredictable clinical behavior . if the clinical , radiologic , and histologic profiles of the ceot are now well defined , other questions such as treatment strategy or incidence of recurrence are still debatable , mostly because of the small number of lesions reported in the literature and lack of long - term follow - up . we have reported a rare case of ceot or pindborg tumor which was diagnosed and confirmed as ceot by incisional and excisional biopsy . it is an extremely rare odontogenic tumor and included in the differential diagnosis of all the odontogenic tumors . treatment should be individualized for each lesion because of variations in the clinical and histologic features . the absence of recurrence seen in our patient almost 1 - year after treatment is encouraging and so far brings one more argument for a conservative surgical approach for intrabony mandibular ceots of limited size .\noutput:\n" }, { "from": "agent", "value": "calcifying epithelial odontogenic tumor ( ceot ) also known as pindborg tumor is a rare odontogenic epithelial neoplasm . so far nearly 200 cases have been reported in literature . we are reporting a case of ceot in a 42 - year - old male patient with painless bony swelling in the mandible . approximately , 50 % of the cases are associated with an unerupted tooth or odontome , but was not so with our case . considering the intrabony mandibular location of the lesion and its limited size , we opted for a more conservative surgery . the clinical , radiographic and histopathologic features and the surgical treatment done are discussed with relevant references ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: asthma is a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms , airflow obstruction , bronchial hyper responsiveness , and underlying inflammation . asthma may be classified clinically on the basis of various parameters including the atopic status of the individual , the degree of airway obstruction , or the nature of trigger factors . by convention , the classification into atopic or nonatopic asthma is based on the presence or absence of clinical symptoms precipitated by one or more common aeroallergens , supported by the presence of allergen - specific antibodies as evidenced by skin prick + / serological tests . the airways epithelium likely plays a key role in the pathogenesis of asthma , as it is a key interface with the external environment . there is ongoing debate as to whether atopic and nonatopic asthma are immunopathologically two distinct entities or if both are driven by similar mechanisms , and the answer to this question is still not clear . the entity of intrinsic or nonatopic asthma continues to raise questions about the possible role of ige - mediated mechanisms in asthma pathogenesis . the clarification of this issue becomes more relevant with the current availability of anti - ige therapy for the treatment of atopic asthma . the main theme of this paper is to address airway epithelium as central to the theatre of asthmatic inflammation and to compare the airways microenvironment in atopic and nonatopic asthma . the airway epithelium is the first site of contact for both inflammatory and physical environmental stimuli . interaction of epithelial cells with such stimuli may contribute substantially to inflammation and the airways obstruction and oedema seen in asthma and a number of other respiratory diseases . they are ciliated columnar cells , mucous cells ( goblet cells ) , clara cells , serous cells , neuroendocrine cells , basal cells , intraepithelial nerves and immune cells . on the basis of ultrastructural , functional , and biochemical criteria , these may be classified into three categories : basal , ciliated , and secretory . immune cells , inflammatory cells , and phagocytic cells migrate to and remain within the epithelium or transit through to the lumen . asthma is a condition characterised by variable airways obstruction , airways hyper - responsiveness , and chronic airways inflammation . there is increasing evidence suggesting that the airway epithelium has an important role in orchestrating this inflammatory response , as a consequence of constant interaction with multiple environmental agents resulting in tissue injury and aberrant repair . it has an important role in the origin and progression of asthma as well as in exacerbations . according to holgate , in asthma , the epithelial - mesenchymal trophic unit ( emtu ) , which controls the local tissue microenvironment and maintains tissue homeostasis , becomes deregulated . on the basis of this concept , epithelial damage by environmental agents such as biologically active allergens , air pollutants , irritants , environmental tobacco smoke , and respiratory viruses , results in the production of signals that act on the underlying mesenchyme to propagate and amplify inflammatory and remodelling responses in the submucosa . this concept is further strengthened by the fact that many asthma susceptibility genes identified so far are expressed in the epithelium and mesenchyme . there is also a strong evidence base supporting the proposition that ige - mediated mechanisms play a crucial role in asthma pathogenesis . ige synthesis may take place in the bronchial mucosal epithelium of patients with both atopic and nonatopic asthma . rackemann first introduced the terms extrinsic and intrinsic asthma in 1947 . the author observed in a study of a limited number of patients a form of the disease in which extrinsic factors were triggering the symptoms and another in which no specific triggering factor could be found . he called the former extrinsic asthma and the latter intrinsic asthma . according to rackemann , the first type was easier to diagnose , associated with vasomotor rhinitis and allergy and of onset before the age of 30 . more recently , and not necessarily in line with rackemann 's view of external triggers , the differentiation between the two entities has been focussed on the presence or absence of positive skin prick ( + / serological ) tests to common aero allergens rather than purely on the basis of history of allergies . a series of studies designed to analyse the immunopathological differences between atopic and nonatopic asthma resulted in the conclusion that both kinds of asthma share more similarities than differences . nieves et al . conducted a relatively large population study in 751 asthmatics to understand the discriminating characteristics between the two groups and concluded that despite the immunopathological similarities , atopic and nonatopic asthma reflect distinct clinical phenotypes . age , age of onset of asthma , and female / male ratio were higher in nonatopic than in atopic asthmatics . younger age , early onset , male sex , rhinitis , and smoking were independent factors discriminating atopic from nonatopic asthma . in the above survey , about a quarter of patients were nonatopic , whereas an earlier swiss sapaldia survey found that a third of total asthmatics were nonallergic ( intrinsic ) . ever since the first description of intrinsic asthma , there has been debate about its pathogenesis . it has been suggested that nonatopic asthma may represent a form of autoimmunity possibly triggered by a viral infection like influenza which often precedes its onset . this is further supported by the recent observation that nonatopic asthmatics frequently demonstrate positive autologous serum skin tests , evidence of circulating histamine releasing factors and positive ana autoantibodies . it is also always possible that nonatopic asthmatics manufacture ige against as yet undetected or unidentified allergen and , therefore , may benefit from allergen avoidance . the airway epithelium in atopic or nonatopic asthma may sometimes be colonized by microbes such as staphylococci which produce superantigens . superantigens produced locally in the airways may lead to class switching of local b - cells , resulting in polyclonal ige production in the airways and also the production - specific ige against the super antigens . this leads to sensitization of mast cells , which can be activated by the usual asthma triggers such as exercise . superantigens can also stimulate clonal expansion of t - cells , resulting in increased th2 cells and cd8 cells while suppressing regulatory t cells . asthma is characterised by the presence of bronchial mucosal infiltrate with eosinophils and elevated expression of eosinophil active chemokines and cytokines , indicating local t - cell activation . early comparisons of epithelial cellular infiltrates in atopic and nonatopic asthma showed remarkable similarities , except for increased tissue macrophages in the bronchial mucosa of the nonatopic patients . this is linked to the fact that bronchoalveolar lavage cells expressing the - subunit of the granulocyte macrophage colony stimulating factor receptor ( gm - csfr ) , expressed by alveolar macrophages , were increased in nonatopic but not in atopic asthma . the majority of the studies comparing atopic and nonatopic asthma have been focussed on the inflammatory and / or immune cells at the submucosal level rather than the resident cells in the mucosal epithelium . in this paper , we bring together what few comparisons have been made between atopic and nonatopic asthma at the epithelial and submucosal level . shahana and colleagues compared the ultrastructural changes in the airway epithelium in bronchial biopsies using transmission electron microscopy in a relatively small group of patients with allergic ( n = 11 ) and nonallergic ( n = 7 ) asthma . interesting similarities and differences between the two groups were noted from the results of this study and another study by amin et al . epitheliumepithelial damage mainly affecting columnar cells was found to be extensive in both allergic and nonallergic asthmatics compared to controls in the electron microscopic study using a semiquantitative scoring system . the damage was slightly higher in atopics ; however , the difference was not significant . the columnar cells had been lost over larger areas in severe cases , with only few basal cells left covering the basement membrane in extreme cases . areas with flattened rather than columnar cells were observed only in nonallergic asthma . by contrast , the degree of epithelial damage was significantly higher in the atopic asthma group in the study by amin et al . . in the damaged areas , cylindrical ciliated epithelial cells were absent , whereas the layer of cuboidal basal cells was often intact . differences in the criteria for defining epithelial damage and the techniques used ( transmission electron microscopy versus immunohistochemistry ) may explain these disparities . epithelial damage mainly affecting columnar cells was found to be extensive in both allergic and nonallergic asthmatics compared to controls in the electron microscopic study using a semiquantitative scoring system . the damage was slightly higher in atopics ; however , the difference was not significant . the columnar cells had been lost over larger areas in severe cases , with only few basal cells left covering the basement membrane in extreme cases . areas with flattened rather than columnar cells were observed only in nonallergic asthma . by contrast , the degree of epithelial damage was significantly higher in the atopic asthma group in the study by amin et al . . in the damaged areas , cylindrical ciliated epithelial cells were absent , whereas the layer of cuboidal basal cells was often intact . differences in the criteria for defining epithelial damage and the techniques used ( transmission electron microscopy versus immunohistochemistry ) may explain these disparities . desmosomesdesmosomes are specialized major cell - cell adhesive junctions of epithelial tissue and play an important role in maintaining tissue integrity via intermediate filaments . they also play a role in the transduction of intracellular signals that regulate cell behaviour . in the bronchial epithelium , desmosomes were present between columnar cells , columnar and basal cells , and between basal cells . the relative length of the desmosomes was reduced in both types of asthma , more so in the columnar cells in allergic asthma . half desmosomes were also common in this group consisting of a single plaque in one of the adjacent cells . the authors speculated that asthma patients have an intrinsic or acquired deficiency in the synthesis of desmosomes , which would make the epithelium more prone to loss of columnar cells . desmosomes are specialized major cell - cell adhesive junctions of epithelial tissue and play an important role in maintaining tissue integrity via intermediate filaments . they also play a role in the transduction of intracellular signals that regulate cell behaviour . in the bronchial epithelium , desmosomes were present between columnar cells , columnar and basal cells , and between basal cells . the relative length of the desmosomes was reduced in both types of asthma , more so in the columnar cells in allergic asthma . half desmosomes were also common in this group consisting of a single plaque in one of the adjacent cells . the authors speculated that asthma patients have an intrinsic or acquired deficiency in the synthesis of desmosomes , which would make the epithelium more prone to loss of columnar cells . basal cellsin the basal cells , the relative desmosomal lengths were significantly reduced both in allergic and nonallergic asthma compared to controls . basal cells were also lost in asthma , however , less so compared with columnar cells , probably due to the presence of stronger desmosomes in basal cells . in the basal cells , the relative desmosomal lengths were significantly reduced both in allergic and nonallergic asthma compared to controls . basal cells were also lost in asthma , however , less so compared with columnar cells , probably due to the presence of stronger desmosomes in basal cells . goblet cellsgoblet cell hyperplasia , partly responsible for increased mucus secretion , was observed only in allergic asthmatics . as mast cell chymase is one stimulus for mucus secretion , increased mast cell degranulation in allergic asthma may at least partly account for this . goblet cell hyperplasia , partly responsible for increased mucus secretion , was observed only in allergic asthmatics . as mast cell chymase is one stimulus for mucus secretion , increased mast cell degranulation in allergic asthma may at least partly account for this . basal laminathe subepithelial basement membrane in human airways is composed of a basal lamina and reticular basement membrane . subepithelial fibrosis is thought to cause basement membrane thickening in asthma . under the electron microscope , thickening of lamina densa ofmany other studies describe an increase in the thickness of basement membrane in asthmatics , more so in atopic asthma , on the basis of the light microscopic immunohistochemical examination of the bronchial mucosa . the significance of these changes is still not clear . the subepithelial basement membrane in human airways is composed of a basal lamina and reticular basement membrane . subepithelial fibrosis is thought to cause basement membrane thickening in asthma . under the electron microscope , thickening of lamina densa ofmany other studies describe an increase in the thickness of basement membrane in asthmatics , more so in atopic asthma , on the basis of the light microscopic immunohistochemical examination of the bronchial mucosa . eosinophilsin asthmatics , many studies show a correlation between eosinophilic infiltration and epithelial damage . studies comparing the numbers of mucosal epithelial eosinophils in atopic and nonatopic asthmatics show disparate findings . some studies noted a significant increase in eosinophil numbers in the atopic compared to nonatopic asthmatics by immunohistochemistry ( eg1 and eg2 positivity ) . on the other hand , other studies reported that eosinophils were more abundant in the bronchial submucosa of nonatopic than atopic asthmatics for a given degree of disease severity . in asthmatics , many studies show a correlation between eosinophilic infiltration and epithelial damage . studies comparing the numbers of mucosal epithelial eosinophils in atopic and nonatopic asthmatics show disparate findings . some studies noted a significant increase in eosinophil numbers in the atopic compared to nonatopic asthmatics by immunohistochemistry ( eg1 and eg2 positivity ) . activated eosinophils were also more numerous in atopic asthmatics . on the other hand , other studiesreported that eosinophils were more abundant in the bronchial submucosa of nonatopic than atopic asthmatics for a given degree of disease severity . neutrophilsone study reported elevated airways epithelial neutrophils ( hnl - and mpo - positive cells ) in nonatopic asthmatics compared to atopics and nonasthmatic control groups . increased neutrophilic infiltration of the airwayshas been reported in some studies to be a more generalised feature of severe asthma ( an observation which may also reflect the effects of corticosteroid therapy ) . one study reported elevated airways epithelial neutrophils ( hnl - and mpo - positive cells ) in nonatopic asthmatics compared to atopics and nonasthmatic control groups . increased neutrophilic infiltration of the airwayshas been reported in some studies to be a more generalised feature of severe asthma ( an observation which may also reflect the effects of corticosteroid therapy ) . mast cellsmast cell numbers appear to be increased in the airways in atopic and nonatopic asthma and found to be similarly increased in both groups by immunohistochemical staining of antitryptase antibody - 1 ( aa1 ) . in one study , the total number and the number of degranulating mast cells were higher in allergic asthmatics by electron microscopy though the difference was not statistically significant . however , there lack evidence showing differences in infiltrated inflammatory cells in epithelium between atopic and nonatopic asthma . mast cell numbers appear to be increased in the airways in atopic and nonatopic asthma and found to be similarly increased in both groups by immunohistochemical staining of antitryptase antibody - 1 ( aa1 ) . in one study , the total number and the number of degranulating mast cells were higher in allergic asthmatics by electron microscopy though the difference was not statistically significant . however , there lack evidence showing differences in infiltrated inflammatory cells in epithelium between atopic and nonatopic asthma . lymphocytesprofuse lymphocyte infiltration was observed equally in both atopic and nonatopic asthmatics by electron microscopy . other studies are disparate , with some suggesting intense mononuclear cell infiltration with an increase in the number of cd45 cells ( total leukocytes ) , cd3 , and cd4 t lymphocytes in nonatopic asthmatics , but others showing elevated total numbers t - lymphocyte of all subsets ( cd3 , cd4 , cd8 , and cd25 ) in the bronchial epithelium of atopic as compared with nonatopic asthmatics by immunohistochemical staining . profuse lymphocyte infiltration was observed equally in both atopic and nonatopic asthmatics by electron microscopy . other studies are disparate , with some suggesting intense mononuclear cell infiltration with an increase in the number of cd45 cells ( total leukocytes ) , cd3 , and cd4 t lymphocytes in nonatopic asthmatics , but others showing elevated total numbers t - lymphocyte of all subsets ( cd3 , cd4 , cd8 , and cd25 ) in the bronchial epithelium of atopic as compared with nonatopic asthmatics by immunohistochemical staining . macrophagessome studies have shown an increased number of cd68 tissue macrophages in the bronchial mucosa of nonatopic , as compared with atopic asthmatics . there was an increased number of cells expressing the - subunit of the gmcsf receptor , reflecting the elevated number of these tissue macrophages . some studies have shown an increased number of cd68 tissue macrophages in the bronchial mucosa of nonatopic , as compared with atopic asthmatics . there was an increased number of cells expressing the - subunit of the gmcsf receptor , reflecting the elevated number of these tissue macrophages . atopic and nonatopic asthmatics had higher numbers of cells expressing il - 4 , il - 5 and il - 8 than control subjects according to amin et al . . the numbers of cells expressing il - 4 and il - 5 were higher in atopic asthmatics , whereas il - 8 expression was higher in bronchial epithelial cells and neutrophils in nonatopic asthmatics by immunohistochemistry . on the other hand , studies by our group suggested that il - 4 and il - 5 protein positive cells and m - rna were equally and significantly elevated in both atopic and nonatopic asthmatics compared to controls . il - 4 and il - 5 receptors ( il - 4r andthere are also reports of elevated numbers of epithelial cells and eosinophils expressing il - 8 in atopic asthma . two separate studies reported marked increase in cd68 macrophages in nonatopic , compared with atopic asthma as shown by an increase in cd68 or in gmcsf receptor subunit cells . however , according to the observations made by another group , there were no differences in the amounts of mrna encoding gmcsf , il - 3 , or il - 13 by in situ hybridization between the two groups . concentrations of il - 2 and - ifn were observed to be elevated in the bal or sputum fluid of nonatopic compared to atopic asthmatics ; however , il - 2 receptors were equally expressed in both groups . the expression of il - 10 and il - 12 m - rna was increased in the sputum of atopic asthmatics compared to nonatopics , suggesting the presence of a homeostatic mechanism to reduce lung inflammation ( table 2 ) . according to multiple studies , both atopic and nonatopic asthmatics showed enhanced expression of the cc chemokines eotaxin , eotaxin - 2 , rantes , monocyte chemotactic protein 3 ( mcp - 3 ) , and mcp - 4 in the bronchial epithelium and submucosa with no differences between them . in one study , the mean concentration of rantes in bal cell supernatants was increased in nonatopic asthmatics compared to controls but very low in atopic asthmatics . many c - c chemokines are potent eosinophil chemoattractants and act predominantly via the ccr3 receptor , the expression of which was also similar in the two groups , either in epithelium or submucosa ( table 3 ) . the th2 cytokines il - 4 and il - 13 , overproduced in asthma , are the only known cytokines which can induce b cell switching to ige synthesis , but precisely where and when such switching occurs is unclear . in addition to mediating acute degranulation of mast cells and basophils through its binding to fcri , which may at least exacerbate asthma in some individuals , ige may play important , less well - defined roles in the genesis of asthmatic mucosal inflammation , for example , by facilitating antigen capture and presentation by subjects of mucosal dendritic cells expressing fcri and b cells themselves which express fcrii ( cd23 ) . these mechanisms may operate regardless of whether allergen - specific ige in detectable in the periphery ( by skin - prick testing or in vitro tests on the serum ) . epidemiologically , individuals who overproduce ige ( of any specificity ) are more likely to develop asthma , but this does not necessary indicate cause and effect . perhaps the clearest evidence for a role for ige in asthma pathogenesis comes from the therapeutic success of anti - ige strategies in asthma . omalizumab , for example , which prevents ige binding to fcri and fcrii ( cd23 ) , reduces asthma exacerbations and mucosal inflammation at least in atopic asthmatics , and its possible effects in nonatopic asthma remain to be seen . in a series of bronchial biopsy studies using in situ hybridization and / or immunohistochemistry , both atopic and nonatopic asthma were characterised by increased infiltration of th2 cells secreting il - 4 , the presence of fcrii cells and cells that expressed mrna for the germ - line transcript ( i ) , and heavy chain of ige ( c ) compared to nonasthmatic controls ( table 4 ) . interestingly , there were no differences in the numbers of cd20 b - cells between asthmatics ( atopic and nonatopic ) and nonasthmatic controls . these observations combined with that of upregulation of fcr1 expression on mast cells , macrophages , and eosinophils in the epithelial submucosa of asthmatics irrespective of their atopic status support the notion that localised ige synthesis and class switching take place in the asthmatic bronchial epithelium regardless of the conventional atopic status of the individual . in another study from our group , - glt and aid mrna were detectable in the bronchial mucosa of asthmatics and nonasthmatic controls , by rt - pcr ; however , circle transcripts ( i - c , i - ) and - mrna were detectable mainly in asthmatics , but rarely in nonasthmatics . these findings further strengthen our hypothesis that the asthmatic epithelium is primed for localised ige switching and ige synthesis , irrespective of the subject 's atopic status . even though subtle differences exist between atopic and nonatopic asthma at the mucosal and submucosal levels , the fact is that the similarities invariably outweigh the differences . having said this , many aspects of the pathogenesis of nonatopic asthma still remain incompletely resolved , in particular the role of ige .\noutput:\n" }, { "from": "agent", "value": "asthma is an inflammatory disorder of the airways , and the airway epithelium has the central role in its pathogenesis . in general , the airway inflammation is characterised by the infiltration of the epithelium and submucosa by a range of inflammatory cells driven largely by th - 2 lymphocytes , eosinophils , and mast cells . the pathogenic mechanisms of nonatopic asthma in comparison to its atopic counterpart have always been a subject of debate . although clinically are two distinct entities , more similarities than differences have been observed between the two in terms of immunopathogenesis , underlying ige mechanisms , and so on . in a number of previous studies . more information has become available in recent years comparing the ultrastructure of the epithelium in these two types of asthma . a comparison of airway epithelium in atopic and nonatopic asthma is presented here from the available information in the literature . similarities outnumber the differences , until we unravel the mystery surrounding these two important phenotypes of asthma in more detail ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: trauma and ptsd in children occur in the context of the ongoing parent - child relation , and this lens may offer insights to the correlations which previous studies have uncovered , integrating the findings and adding a fuller contour to the picture of pediatric ptsd . this paper aims to review and integrate an understanding of ptsd in children and adolescents in an attachment context and organizes the article in several sections : defining ptsd in children ; a review of parental influences on pediatric ptsd ; psychological mechanisms for how attachment relations affect trauma responses ; the link between ptsd and juvenile delinquency ; a few take - away points for pediatricians . trauma is a profound experience of the loss of security and welfare evoking feelings of fear , helplessness , horror , and possibly disorganized agitation in children . the description of ptsd in the diagnostic and statistical manual of mental disorders has increasingly taken into account child - specific features of ptsd , and ptsd has evolved from a disorder first associated with vietnam veterans in the 1970s to one which has now been well documented in the general population at an estimated 7.8 % and in specific groups of children , particularly high - risk children such as adolescent delinquents , though an estimate of ptsd in the population of children and adolescents is still forthcoming . in fact , ruchkin et al . found 25 % of adolescent delinquents met dsm - iii ptsd criteria and 42 % fulfilled partial ptsd criteria , percentages comparable to and exceeding those found in the population of vietnam veterans , suggesting the vulnerability of childhood or adolescent experiences and the subjective nature of trauma . the latest dsm - iv - tr outlines the diagnostic criteria for ptsd following the occurrence of a traumatic event , including symptoms for longer than one month of ( 1 ) reliving the trauma , ( 2 ) avoiding associations related to the trauma , and ( 3 ) increased arousal resulting in clinically significant distress or impairment in social , occupational , or other important areas of functioning . the description is keen to note the impact of childhood development on the triad of symptoms ; for instance , in children , the response to the trauma may be expressed as disorganized and agitated behavior rather than intense fear , horror , and helplessness , and the reexperiencing may be expressed through repetitive play with traumatic themes , frightening dreams without recognizable meaning , and trauma - specific reenactment . children may suffer from trauma in many significant ways including developmental delays ; numerous social , behavioral , and academic difficulties ; somatic complaints ; lower self - esteem ; attachment issues . thus , ptsd should be understood as one clinically significant effect of trauma that may occur in the context of and be linked to many other subtle or explicit effects on the child 's functioning and development . to more deeply understand the nature of post traumatic stress disorder ( ptsd ) , including the impact of the etiological event of the trauma and the manifestation and trajectory of its symptoms , some scholars have turned to the influence of attachment figures and attachment styles on ptsd . this focus occurs in the larger context of the growing interest in emotions and their social function in the psychological sciences and psychopathology . unhealthy attachment styles have been correlated to greater ptsd symptoms in adults , and scheeringa and zeanah review 17 studies which consistently found undesirable parental variables linked to elevated child ptsd or other detrimental symptoms following trauma . other pools of research which suggest the influence of parents on pediatric ptsd include papers on the interpersonal aspects of trauma and ptsd , the effects of abuse and neglect on development , social support and ptsd , parent psychopathology and child behavioral problems , parent child reporting of child ptsd symptoms , and the benefits of parent participation in child psychotherapy . much of the highlighted literature is guided by the primacy of the parent - child relationship and the strong influence of parent variables and behaviors on child outcomes . research in developmental and evolutionary psychology as well as neuroanatomy and neuroendocrinology has converged in validating the safety and well - being that parenting can provide , as well as the negative consequences caused by attachment disruptions , an intuitive result of the primacy of that relation . and parenting literature , which pertains more to parenting in a normative context , has consistently demonstrated correlations between certain types of parenting and child competence ; for instance , authoritative parenting characterized by high emotional responsiveness as well as high behavioral goals , yet lower psychological control , has been associated with high child competence . it is interesting that both literature in trauma and that in attachment relations discuss the role of ( 1 ) core schemas and ( 2 ) emotional engagement as relevant psychological mechanisms . first , if attachment relations shape core schemas , and ptsd is caused by negative schemas of the self and world formed through trauma , then it is plausible that attachment figures can play a role in influencing ptsd . schemas are a conceptual framework based on life experiences that help the individual organize information and interpret and adapt to the environment . trauma can cause damage either by negatively changing one 's positive schemas of one 's self as competent and the world as safe or by priming existing knowledge of one 's self as incompetent and the world as dangerous . though the first pathway is intuitive , the latter pathway applies to trauma victims with previous traumatic experiences and pretrauma psychological disturbances . foa cites studies which provide evidence for both these pathways , such as an earlier study by the author which found that individuals who had ptsd 3 months after trauma showed a less positive view about the world and themselves just after the trauma than those who recovered ( as cited in ) . attachment theory founder bowlby conceived of attachment as an evolutionarily crucial form of behavior distinct from feeding and sex with the purpose of gaining proximity , care , and protection from the attachment figure , the infant caregiver or mother . bowlby believed that repeated interactions with attachment figures shaped children 's dynamic and increasingly complex internal working models of the world , self , and important relations ; comforting behavior by attachment figures results in internal working models of the self as worthy and the world as safe versus the self as unworthy and the world as dangerous . according to developmental psychologist jean piaget , who is commonly known for introducing and popularizing the term schema , thus , behaviors by attachment figures ( as well as childhood trauma ) should have a stronger impact during this time in schema formation , providing the foundational schema which can be further tweaked . following the line of thought of the core schema theory , attachment figures that strengthen the child 's schemas of the self as competent and the world as safe can play a role in mitigating the negative effects of trauma and the likelihood of ptsd . second , if emotional engagement with the trauma facilitates trauma resolution , then the healthy attachment relationship , which can elicit strong feelings of engagement and comfort , should help process trauma feelings and mitigate ptsd . conversely , trauma occurring in the context of an unhealthy attachment relationship which hinders emotional engagement with the trauma should increase ptsd . research points to early emotional engagement with the trauma as crucial for trauma processing and recovery and emotional withholding , avoidance , or disassociation as linked to ptsd severity . indeed , complex ptsd , occurring after long - term trauma , first , it is within the context of the attachment relation that infants first learn about emotional engagement , as both the receiver and giver of it , developing styles of engagement ( secure , anxious avoidant , or anxious ambivalent ) based on patterns of the attachment figure 's sensitivity , responsiveness , timeliness , and availability . for the infant , physical bonding is an essential aspect of emotional engagement ; in lieu of verbal vocabulary , touch can communicate emotions and information to the infant based on the qualities of the interaction and facilitate state regulation and coping with stress and arousal . ainsworth found that the most significant commonality for those infants developing an avoidant style was mothers with an aversion for physical contact . disengagement is then a strategy by the infant to cope with the mother 's expected rejection and hostility . in fact , an independent emotional system characterized by feelings of calm , comfort , and emotional engagement , with a discrete system of brain circuits , evolved to support attachment in human evolution for parenting , just as separate emotional systems of lust and attraction evolved to foster the other two primary behaviors of mating and reproduction . attachment theory holds that this attachment style , though first shaped by the attachment figure , extends beyond the primary relation and is correlated with later responses and psychopathology . on the same note , found that adult former prisoner war veterans with secure attachment styles scored significantly lower on measures of ptsd than did those with insecure styles , and that ptsd symptom intensity was predicted better by attachment style than trauma severity . this resonates with the idea that the style of emotional engagement , first shaped by the attachment figure , is used to process later events such as trauma . second , attachment figures can help children emotionally engage with and process the relevant trauma . though attachment style is relevant throughout the lifespan , the facilitation of emotional engagement by attachment figures like parents is especially pertinent for children facing childhood trauma ; attachment theory holds that attachment behaviors are most visible during early childhood and during times of distress and uncertainty , both of which are relevant for pediatric trauma . the evolutionary purpose of attachment is protection , and it is in such moments requiring that the attachment dynamic becomes more salient , offering a reassurance distinct from and beyond social support or peer approval . attachment figures can help children emotionally engage with their presence , providing a secure base and reliable boundaries amidst unpredictable and disruptive situations , through attentiveness to and inquiries of the child 's experiences and needs ; nonjudgment and acceptance of strong feelings ; offering empathetic validations . attachment figures can also help with sense making of traumatic events , negotiating implications of traumatic situations to less distressing ones . the most empirically supported pediatric trauma treatment , trauma - focused cognitive behavioral therapy ( tf - cbt ) , incorporates all of the previously discussed aspects , aiming to support positive core schemas and correct maladaptive ones , foster emotional engagement , and strengthen the parent child bond . this treatment for children of ages 3 to 17 suffering from trauma - related negative feelings and behaviors consists of implementing a therapeutic sequence summarized by the acronym practice , including psychoeducation about trauma ; relaxation skills ; affect or emotional processing and management ; cognitive processing and management ; trauma narration and processing ; conjoint child - parent discussion ; finally , enhancing well - being , safety , and development . it is important to note that the parent undergoes treatment and training along with the child ( in individual sessions for the first four phases , preparing the parent to be as supportive as possible following the trauma narration and later joint parent - child sessions ) . the complexity of trauma situations and degree and nature of parent involvement in the trauma , from less involved , witness , victim similar to the child , enabler , or perpetrator , will affect the parent - child dynamic , parent and child symptomatology , and healing of the trauma . as discussed in the literature review , relational traumas are more influential , and thus , traumas in which parents are involved in a more negative light will likely be more challenging . however , as discussed above , tf - cbt provides a general method for addressing childhood trauma , and with the assumption that the involved caregiver is not a current threat to the child , it utilizes the strength of the parent - child attachment dynamic in facilitating cognitive and emotional trauma processing for healing . while tf - cbt is empirically supported , it is less certain which phase or combination of phases lends to its efficacy . tested tf - cbt variations ( 8 weeks versus 16 weeks and trauma narration vs. no trauma narration ) and found that though all variations effectively improved symptoms , parenting skills , and children 's personal safety skills , the 8 - week trauma narrative version most decreased parent and child abuse - related anxiety , while the 16 - week no narrative condition most increased effective parenting practices and decreased child externalizing problems . perhaps a trade - off occurs in how time is utilized in therapy , with focusing on parenting skills decreasing the child 's acting - out behaviors , while talking about the trauma may relieve some of the anxiety associated with it . overall , the paper seems to suggest that healing occurs more through the processing of emotions and beliefs in context of the strengthened parent - child bond rather than formal trauma narration or an extended length of therapy . as an anxiety disorder , one may imagine ptsd to be a source of strife for the victim and perhaps close a circle of contacts . however , rather than being a quietly contained disorder , the violence and chaos experienced by the victim through trauma may manifest as outward acts of aggression , delinquency , and conduct disorder ; conduct disorder behaviors and the like may be considered as symptoms of ptsd , rather than isolated problems . ryan and testa 's finding resonates with this point : substantiated victims of maltreatment averaged 47 % higher delinquency rates relative to nonabused children . similarly , steiner et al . found 31.7 % of severely delinquent juvenile offenders with ptsd and 20 % meeting partial criteria , compared to the 9.3 % in nonclinical sample of youth . in youth with conduct disorder , reebye et al . found ptsd more frequently in girls , who reported more sexual assault trauma than the physical trauma and witnessing death described by boys . similarly , in the general population at large , the national comorbidity survey found that although men were more likely to experience one trauma overall , women were both more likely to experience a trauma more correlated with ptsd in that gender ( like rape for females ) and more affected by traumas in general , with women more than twice as likely to develop ptsd after a described trauma . this point is important because the number of crimes by female adolescents rose 23 % between 1989 and 1993 compared to the 11 % in males with severely violent crimes rising by a staggering 55 % in females compared to 33 % in males , and trauma in girls could help make sense of this increase . the environmental factors conducive to juvenile delinquency such as parental psychopathology , drug use , and criminal activity ; neighborhoods with criminal subculture , low participation , and frequent mobility among residents ; poor school conditions with chaotic environments are also likely factors conducive to trauma and characteristic of environments that are less supportive following trauma . furthermore , once trauma has occurred , ptsd itself devoid of these environmental influences can lead to juvenile delinquency . steiner et al . theorizes that ptsd creates possible pathways for aggression in four distinct ways : arousal - driven interference with relaxation and learning , inappropriate reliving - driven hostile reactions , intrusion - driven continuous trauma reenactment , and unnecessary avoidance of triggers . thus , children in the previously mentioned negative environments who have also experienced trauma are at greatest risk for juvenile offending , and care should be taken to view aggressive actions in context of trauma history and environment rather than as merely innately malicious acts . individual risk factors associated with juvenile delinquency such as low social conformity , drug use , low self - esteem , antisocial attitudes , noncompliance , and poor school achievement are all eerily familiar with the summary of research findings on the impact of childhood abuse and neglect , suggesting that traumatized children are also at greater risk for delinquency due to the impact of the trauma to one 's attitudes and skills . tarolla et al . describe juvenile delinquency as one of our most urgent social issues , with offenders using a large share of child welfare , juvenile justice , special education , and mental health resources . understanding , preventing , and treating childhood ptsd are of importance not only to emotionally benefit the victim , the primary focus of mental health professionals , but also to avoid costs and reap benefits on a societal level throughout the course of the child 's development into adulthood . the less than established effectiveness of many of the available juvenile delinquency prevention and treatment plans may be due to the lack of relational and trauma focus of these plans . 's paper finds longer community - based interventions that improve family functioning , incorporate behavioral intervention , and improve social networks more useful for treatment . the child 's advocates include the family , teachers , pediatrician , and mental health care specialists such as social workers , therapists , psychologists , and psychiatrists , and in light of the previous research , measures taken by these members to resolve trauma are in themselves a preventative measure against juvenile delinquency . though mental health care specialists will be responsible for the formal psychological assessment and treatment , pediatricians aware of trauma symptoms and treatment will have a more comprehensive understanding of the patient and can also effectively make referrals if needed . based on this paper , a few take - away points regarding childhood trauma for pediatricians include the chaotic environmental factors conducive to both trauma and juvenile delinquency described in the previous section ; the earlier described dsm - iv criteria for ptsd , noting child - specific features ; the fact that trauma can affect the child without the child meeting full ptsd criteria and that these effects may subtly or explicitly affect the child 's functioning and development , manifesting as developmental delays , behavioral or academic difficulties , or somatic complaints and may also resemble symptoms traditionally associated with adhd , conduct disorder , or juvenile delinquency ( see for a fuller description of the developmental effects of childhood maltreatment ) ; findings that traumas of an interpersonal nature are more associated with ptsd ; the potential for the healthy attachment relation to heal trauma . further , a mental health specialist skilled in tf - cbt , the most empirically supported treatment for childhood trauma , would be the first line of recommended treatment . understanding trauma history and strengthening attachment relations will be a critical piece in addressing and healing delinquent children and adolescents .\noutput:\n" }, { "from": "agent", "value": "the present paper reviews pediatric posttraumatic stress disorder , emphasizing the relational basis of the disorder and highlighting the missing link between juvenile delinquency and trauma . the first part of the paper defines trauma and the diagnostic criteria for ptsd , noting child - specific features . the second part reviews the literature emphasizing the relational and attachment relevant nature of trauma . the third part explores psychological mechanisms for how attachment relations could affect trauma responses . attachment relations ( 1 ) shape core schemas of the world , others , and the self and ( 2 ) foster emotional engagement or disengagement , both of which have been associated with traumatic responses . the most empirically supported pediatric trauma treatment , trauma - focused cognitive behavioral therapy ( tf - cbt ) , acknowledges the attachment figure 's influence and includes treating and training the parent and conjoint child - parent discussion . the next section reviews the noteworthy link between juvenile delinquency and trauma history . more awareness of trauma and ptsd in children and adolescents is recommended to effectively address juvenile delinquency . the review ends with a few helpful points for practicing pediatricians regarding childhood trauma ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: local analgesia , which allows a virtually pain - free treatment , plays a crucial role in paediatric dental practice . articaine is a commonly used local analgesic that was introduced to the german market in 1976 . experts have said that it may be the analgesic of choice in children over 4 years of age ( nizharadze et al .2011 ) . for younger children , a current meta - analysis could not find recommendations for its use , since no data supporting such were found ( katyal 2010 ) . to avoid the risk of toxicity , especially when treating small children , a body weight - based dosage has to be calculated ( ahmed and martinez 2009 ) and the use of a vasoconstrictor is recommended ( lipp et al . the vasoconstrictor of choice in most cases is epinephrine ( paxton and thome 2010 ) . for articaine , it was shown that adverse reactions occur mainly due to the amount of epinephrine in the analgesic solution ( santos et al . it may lead , especially at sites with increased resorption of the local analgesic or in cases of intravascular injection , to an increased heart rate , ejection volume , blood pressure , body temperature and blood supply of the skeletal muscles . further systemic side - effects of the vasoconstrictor may be nausea , agitation , dizziness and tremor . a higher amount of epinephrine is equated with an increased analgesic duration ( kmmerer et al .2011 ) . as result of the longer loss of sensation after dental analgesia especially in smaller children , self - induced lesions of the soft tissues such as biting of the tongue , the lips and the cheeks may occur ( ram and amir 2006 ; adewumi et al . there are no special recommendations about the vasoconstrictor concentration for the treatment of children and it has been demonstrated that even a low concentration of epinephrine ( 1:400,000 ) leads to a significant prolongation of the systemic absorption of a local analgesic solution ( hansen et al . the systemic as well as local risks may increase ( kmmerer et al . 2011 ) . altogether , a limitation of the amount of epinephrine in combination with articaine in paediatric patients should be discussed . an adaption of local analgesia to the respective treatment time may enhance the child s wellbeing . articaine , with the minor adjunct of epinephrine 1:400,000 , has already been shown to be safe and effective in short dental procedures in adult patients ( daublnder et al . therefore , the aim of this study was to conduct a non - interventional , multi - centre assessment of an articaine solution with reduced epinephrine concentration in dental paediatric practice . a prospective clinical study was performed at a dental clinic ( university of giessen ) and four private dental practices for paediatric or general dentistry ( munich and herrsching ) between 2009 and 2010 . a non - interventional study is defined as a study where the respective product is used in the usual manner and the assignment of the patient to a particular therapeutic strategy falls within current practice . this type of trial usually reflects normal clinical practice with a quality close to those from clinical and interventional trials ( worz and hundt 2011 ) . the study was conducted with the approval of the ethics committee of the medical association of rhineland - palatinate and in accordance with the declaration of helsinki . after taking the medical history of the patient , the procedures , possible discomforts or risks , as well as possible benefits were explained fully to the patients and their legal guardians . the legal guardians of the patients signed an informed consent prior to the initiation of the dental treatment . inclusion criteria were : patients aged 417 years requiring routine dental treatment under local analgesia . exclusion criteria were the following : contra - indications for one of the components of the analgesic solution ( articaine , epinephrine , or sodium sulphite ) , limited activity of plasma cholinesterases , patients with american society of anaesthesiologists classification 2 , lack of compliance and infections in the area of injection . if the respective criteria were met , each patient attending at one of the study centres for treatment was included in the study . the local analgesic solution was supplied in 1.7 ml carpules by 3 m espe ( seefeld , germany ) containing 4 % articaine plus epinephrine 1:400,000 ( ubistesin lite 1:400,000 ) . it was used in the technique chosen by the dentist ( infiltration , nerve block , periodontal ligament injection ( pdl ) , combinations ) with the instrument chosen by the dentist . routine dental treatment ( cavity preparations , extractions , endodontic treatment ) , was performed , mostly on primary teeth . the main indication for the epinephrine - reduced solution was for a shorter treatment time . additional sedation was performed if and when needed in accordance to the normal and everyday routine procedures of the clinic or practices . if needed , the dentist used nitrous oxide as an inhalation technique or orally administered midazolam and / or additional analgesics . prior treatment , affected teeth , region as well as the respective indication were documented . if there were more than one area to be treated , the region that was treated first was documented . for each patient , the duration of the treatment as well as the achieved analgesia ( complete , sufficient , insufficient , none ) after a period of 57 min was noted . if the analgesia was ratedin addition , the injection technique as well as dosage of the local analgesic ( primary and secondary injection as well as total dose ) were documented . if sedation was needed , the character of the sedation as well as the special drug and its concentration were recorded . complete , sufficient , insufficient and no rating possible . if insufficient or no rating possible , failed analgesia was documented . one day after treatment , a structured telephone interview with the patient or the parents was conducted to examine the duration of subjective soft tissue analgesia recorded in minutes by the patients and / or legal guardians while touching the tissues as well as potential side - effects . the patients remained on a follow - up schedule for 14 days after treatment . all patients ( respectively , legal guardians ) that gave informed consent and were treated with ubistesin 1:400,000 were evaluated in the study . a prior power calculation showed a sample size of n = 918 patients to be sufficient to reveal potential side - effects with an incidence of 0.5 % or more with a likeliness of 99 % . to find possible associations between side - effects and age and to obtain information about the influence of prior sedation on duration of soft tissue analgesia , students t tests were conducted . to assess an association between side - effects and injection technique as well as prior sedation , tests were used . a difference between the groups was seen to be statistically significant if p 0.05 . to show a possible correlation between dose of local analgesic agent and soft tissue analgesia , all other data were descriptive only . for statistical evaluation , the statistical analysis system software ( sas , version 8.2 ; sas institute inc . a prospective clinical study was performed at a dental clinic ( university of giessen ) and four private dental practices for paediatric or general dentistry ( munich and herrsching ) between 2009 and 2010 . a non - interventional study is defined as a study where the respective product is used in the usual manner and the assignment of the patient to a particular therapeutic strategy falls within current practice . this type of trial usually reflects normal clinical practice with a quality close to those from clinical and interventional trials ( worz and hundt 2011 ) . the study was conducted with the approval of the ethics committee of the medical association of rhineland - palatinate and in accordance with the declaration of helsinki . after taking the medical history of the patient , the procedures , possible discomforts or risks , as well as possible benefits were explained fully to the patients and their legal guardians . the legal guardians of the patients signed an informed consent prior to the initiation of the dental treatment . inclusion criteria were : patients aged 417 years requiring routine dental treatment under local analgesia . exclusion criteria were the following : contra - indications for one of the components of the analgesic solution ( articaine , epinephrine , or sodium sulphite ) , limited activity of plasma cholinesterases , patients with american society of anaesthesiologists classification 2 , lack of compliance and infections in the area of injection . if the respective criteria were met , each patient attending at one of the study centres for treatment was included in the study . the local analgesic solution was supplied in 1.7 ml carpules by 3 m espe ( seefeld , germany ) containing 4 % articaine plus epinephrine 1:400,000 ( ubistesin lite 1:400,000 ) . it was used in the technique chosen by the dentist ( infiltration , nerve block , periodontal ligament injection ( pdl ) , combinations ) with the instrument chosen by the dentist . routine dental treatment ( cavity preparations , extractions , endodontic treatment ) , was performed , mostly on primary teeth . the main indication for the epinephrine - reduced solution was for a shorter treatment time . additional sedation was performed if and when needed in accordance to the normal and everyday routine procedures of the clinic or practices . if needed , the dentist used nitrous oxide as an inhalation technique or orally administered midazolam and / or additional analgesics . prior treatment , affected teeth , region as well as the respective indication were documented . if there were more than one area to be treated , the region that was treated first was documented . for each patient , the duration of the treatment as well as the achieved analgesia ( complete , sufficient , insufficient , none ) after a period of 57 min was noted . if the analgesia was ratedin addition , the injection technique as well as dosage of the local analgesic ( primary and secondary injection as well as total dose ) were documented . if sedation was needed , the character of the sedation as well as the special drug and its concentration were recorded . complete , sufficient , insufficient and no rating possible . if insufficient or no rating possible , failed analgesia was documented . one day after treatment , a structured telephone interview with the patient or the parents was conducted to examine the duration of subjective soft tissue analgesia recorded in minutes by the patients and / or legal guardians while touching the tissues as well as potential side - effects . the patients remained on a follow - up schedule for 14 days after treatment . all patients ( respectively , legal guardians ) that gave informed consent and were treated with ubistesin 1:400,000 were evaluated in the study . a prior power calculation showed a sample size of n = 918 patients to be sufficient to reveal potential side - effects with an incidence of 0.5 % or more with a likeliness of 99 % . to find possible associations between side - effects and age and to obtain information about the influence of prior sedation on duration of soft tissue analgesia , students t tests were conducted . to assess an association between side - effects and injection technique as well as prior sedation , tests were used . a difference between the groups was seen to be statistically significant if p 0.05 . to show a possible correlation between dose of local analgesic agent and soft tissue analgesia , all other data were descriptive only . for statistical evaluation , the statistical analysis system software ( sas , version 8.2 ; sas institute inc . the study recruited 999 patients ( 50.5 % male , 49.5 % female ) with a mean age of 7.92.34 years that were treated between 04/2009 and 04/2010 in five study centres . contrary to the treatment protocol , five children under 4 years of age ( 0.5 % ) were treated as well . accordingly , 101 patients ( 10.1 % ) weighed less than 20 kg , 496 patients ( 49.6 % ) 20 to 30 kg , 333 patients ( 33.3 % ) 3045 kg and 69 patients ( 6.9 % ) 45 kg . concomitant diseases were known in 18 patients ( 1.8 % ) ; ( in detail : neurodermatitis n = 3 , attention deficit hyperactivity disorder n = 2 , asthma n = 2 , thyroid hypofunction n = 2 , diabetes typei n = 1 , allergic coryza n = 1 , sore throat n = 1 , slight cough n = 1 , purpura anaphylactoids n = 1 , congenital heart disorder n = 1 , mucopolysaccharidosis n = 1 , cardiac dysrhythmia n = 1 , photodermatosis n = 1 ) . in all patients , no prior allergic reactions towards local analgesic agents were recorded . in nine patients ( 0.9 % ) , a prior pain medication ( ibuprofen n = 6 , paracetamol ( acetaminophen ) n = 2 , talvosilen ( codeine and paracetamol ) n = 1 ) was self - prescribed . in 795 patients primary teeth and in 204 patients permanent teeth were treated . in 816 cases ( 81.7 % ) dental cavity preparation and treatment with intra - coronal restorations were undertaken , in 230 cases ( 23 % ) simple extractions of primary teeth and in 60 cases ( 6.4 % ) endodontic treatments ( pulpectomy , pulpotomy ) on primary teeth were conducted . in 29 cases ( 2.9 % ) , other indicated treatment had a frequency of less than 3 % ( fig . 1 ) . in 602 patients ( 60.3 % ) one tooth , in 357 patients ( 35.7 % ) two teeth and , in 40 patients ( 4 % ) three teeth were treated.fig . n = 999 ) pie chart showing the different indications for treatment in % ( n = 999 ) two hundred seventy six patients ( 27.6 % ) received sedation prior to treatment [ nitrous oxide n = 119 ( 11.9 % ) , midazolam + analgesics + other sedative n = 102 ( 10.2 % ) , midazolam + analgesic n = 31 ( 3.1 % ) ] . in 93.5 % of cases ( n = 934 ) the initial local analgesia was complete or at least sufficient to perform the planned treatment . a second injection was necessary in 3.4 % ( n = 34 ) before , in 2.7 % ( n = 27 ) during treatment and in 0.4 % of cases ( n = 4 ) at both times . the major technique used was infiltration ( 50.2 % , n = 501 ) , followed by a combination with pdl ( 25.8 % , n = 258 ) , block analgesia ( 14.3 % , n = 143 ) , pdl only ( 9.3 % , n = 93 ) as well as block analgesia and pdl ( 0.4 % , n = 4 ) ( fig . 2 ) . the mean volume of the initial injection was 1.1 ml ( sd 0.43 ) , the mean additional volume was 0.9 ml 0.46 . the mean body weight - based dosage was 1.50.69 mg / kg ; in very young and frail children an increase up to 3.43 mg / kg was documented . between first injection and start of treatment a mean time of 64 min elapsed , and between first injection and second injection a mean time of 169 min was measured .2 pie chart showing the frequency of each injection technique in the study in % ( n = 999 ) pie chart showing the frequency of each injection technique in the study in % ( n = 999 ) in 99 % of cases ( n = 989 ) the planned treatment could be completed . only 1 % of the patients ( n = 10 ) were either non - compliant ( n = 7 ) or very anxious ( n = 1 ) or had insufficient response to repeated local analgesia ( n = 1 ) or sedation ( n = 1 ) . in 98.7 % of cases , the quality of local analgesia was rated to be at least sufficient ( fig . 3 ) . fig . 3bar charts showing the quality of local analgesia rated by the dentist . a subdivision into the different injection techniques is given bar charts showing the quality of local analgesia rated by the dentist . a subdivision into the different injection techniques is given fifty five unwanted side - effects occurred in 42 ( 4.3 % ) of patients . a possible or likely coherence with the solution was stated in 3.1 % ( n = 31 ) . of these , 71 % were light and all were transient . the main side - effects were unspecific systemic [ nausea ( 1.1 % , n = 11 ) , exhaustion ( 0.9 % , n = 9 ) and headache ( 0.5 % , n = 5 ) ] . post - operative soft tissue injury occurred in four patients ( 0.4 % ) ; all were younger than 7 years ( mean 5.41.2 ) . side - effects were evaluated significantly more often in the group of children younger than 6 years of age ( p = 0.001 ) . neither an association between side - effects and injection technique ( p = 0.53 ) nor between side - effects and prior sedation ( p = 0.78 ) was observed . for n = 997 patients ( drop - out rate was 0.2 % ) , a mean duration of soft tissue analgesia of 2.191.01 h ( total time from injection to end of numbness ) was measured . the longest duration was seen for block analgesia with 2.430.55 h , the shortest for pdl with 1.220.47 h only . it could be shown that for infiltration , the duration of soft tissue analgesia tended to ascend with increasing volume of the local analgesic solution ( pearson s correlation coefficient 0.26 ; fig . sedation increased the duration of analgesia in a small amount for all techniques , statistically relevant only in the infiltration plus pdl group ( p = 0.049 ) . fig .4 scatter plot showing the weak correlation between the amount of local analgesic solution and the duration of soft tissue analgesia after infiltration scatter plot showing the weak correlation between the amount of local analgesic solution and the duration of soft tissue analgesia after infiltrationthe study recruited 999 patients ( 50.5 % male , 49.5 % female ) with a mean age of 7.92.34 years that were treated between 04/2009 and 04/2010 in five study centres . contrary to the treatment protocol , five children under 4 years of age ( 0.5 % ) were treated as well . accordingly , 101 patients ( 10.1 % ) weighed less than 20 kg , 496 patients ( 49.6 % ) 20 to 30 kg , 333 patients ( 33.3 % ) 3045 kg and 69 patients ( 6.9 % ) 45 kg . concomitant diseases were known in 18 patients ( 1.8 % ) ; ( in detail : neurodermatitis n = 3 , attention deficit hyperactivity disorder n = 2 , asthma n = 2 , thyroid hypofunction n = 2 , diabetes typei n = 1 , allergic coryza n = 1 , sore throat n = 1 , slight cough n = 1 , purpura anaphylactoids n = 1 , congenital heart disorder n = 1 , mucopolysaccharidosis n = 1 , cardiac dysrhythmia n = 1 , photodermatosis n = 1 ) . in all patients , no prior allergic reactions towards local analgesic agents were recorded . in nine patients ( 0.9 % ) , a prior pain medication ( ibuprofen n = 6 , paracetamol ( acetaminophen ) n = 2 , talvosilen ( in 795 patients primary teeth and in 204 patients permanent teeth were treated . in 816 cases ( 81.7 % ) dental cavity preparation and treatment with intra - coronal restorations were undertaken , in 230 cases ( 23 % ) simple extractions of primary teeth and in 60 cases ( 6.4 % ) endodontic treatments ( pulpectomy , pulpotomy ) on primary teeth were conducted . in 29 cases ( 2.9 % ) , other indicated treatment had a frequency of less than 3 % ( fig . 1 ) . in 602 patients ( 60.3 % ) one tooth , in 357 patients ( 35.7 % ) two teeth and , in 40 patients ( 4 % ) three teeth were treated.fig .1 pie chart showing the different indications for treatment in % ( n = 999 ) pie chart showing the different indications for treatment in % ( n = 999 ) two hundred seventy six patients ( 27.6 % ) received sedation prior to treatment [ nitrous oxide n = 119 ( 11.9 % ) , midazolam + analgesics + other sedative n = 102 ( 10.2 % ) , midazolam + analgesic n = 31 ( 3.1 % ) ] . in 93.5 % of cases ( n = 934 ) the initial local analgesia was complete or at least sufficient to perform the planned treatment . a second injection was necessary in 3.4 % ( n = 34 ) before , in 2.7 % ( n = 27 ) during treatment and in 0.4 % of cases ( n = 4 ) at both times . the major technique used was infiltration ( 50.2 % , n = 501 ) , followed by a combination with pdl ( 25.8 % , n = 258 ) , block analgesia ( 14.3 % , n = 143 ) , pdl only ( 9.3 % , n = 93 ) as well as block analgesia and pdl ( 0.4 % , n = 4 ) ( fig . 2 ) . the mean volume of the initial injection was 1.1 ml ( sd 0.43 ) , the mean additional volume was 0.9 ml 0.46 . the mean body weight - based dosage was 1.50.69 mg / kg ; in very young and frail children an increase up to 3.43 mg / kg was documented . between first injection and start of treatment a mean time of 64 min elapsed , and between first injection and second injection a mean time of 169 min was measured .2 pie chart showing the frequency of each injection technique in the study in % ( n = 999 ) pie chart showing the frequency of each injection technique in the study in % ( n = 999 ) in 99 % of cases ( n = 989 ) the planned treatment could be completed . only 1 % of the patients ( n = 10 ) were either non - compliant ( n = 7 ) or very anxious ( n = 1 ) or had insufficient response to repeated local analgesia ( n = 1 ) or sedation ( n = 1 ) . in 98.7 % of cases , the quality of local analgesia was rated to be at least sufficient ( fig .3 bar charts showing the quality of local analgesia rated by the dentist . a subdivision into the different injection techniques is given bar charts showing the quality of local analgesia rated by the dentist . fifty five unwanted side - effects occurred in 42 ( 4.3 % ) of patients . a possible or likely coherence with the solution was stated in 3.1 % ( n = 31 ) . of these , 71 % were light and all were transient . the main side - effects were unspecific systemic [ nausea ( 1.1 % , n = 11 ) , exhaustion ( 0.9 % , n = 9 ) and headache ( 0.5 % , n = 5 ) ] . post - operative soft tissue injury occurred in four patients ( 0.4 % ) ; all were younger than 7 years ( mean 5.41.2 ) . side - effects were evaluated significantly more often in the group of children younger than 6 years of age ( p = 0.001 ) . neither an association between side - effects and injection technique ( p = 0.53 ) nor between side - effects and prior sedation ( p = 0.78 ) was observed . for n = 997 patients ( drop - out rate was 0.2 % ) , a mean duration of soft tissue analgesia of 2.191.01 h ( total time from injection to end of numbness ) was measured . the longest duration was seen for block analgesia with 2.430.55 h , the shortest for pdl with 1.220.47 h only . it could be shown that for infiltration , the duration of soft tissue analgesia tended to ascend with increasing volume of the local analgesic solution ( pearson s correlation coefficient 0.26 ; fig . 4 ) . sedation increased the duration of analgesia in a small amount for all techniques , statistically relevant only in the infiltration plus pdl group ( p = 0.049 ) . fig .4 scatter plot showing the weak correlation between the amount of local analgesic solution and the duration of soft tissue analgesia after infiltration scatter plot showing the weak correlation between the amount of local analgesic solution and the duration of soft tissue analgesia after infiltrationin paediatric dentistry , local analgesia offers virtually pain - free treatment , providing comfort for children and increasing their cooperation . to reduce plasma levels of the local analgesic and to enhance the analgesic effect ,1994 ; yagiela 1995 ) , although , the vasoconstrictor may produce its own adverse side - effects ( meechan et al . 2001 ; santos et al . 2007 ) . to minimise those and to balance risk and benefit , therefore , the aim of this non - intervention clinical study was an evaluation of efficacy , tolerance and safety of 4 % articaine with an adjunct of 1:400,000 epinephrine in dental treatment of children aged 417 years . for adult patients , our group could prove in a similar clinical setting that epinephrine - reduced articaine is safe and effective in short dental treatments ( daublnder et al . 2012 ) . though , to the best of our knowledge , this is the first study evaluating 4 % articaine with 1.400,000 epinephrine in paediatric dentistry . with a primary analgesia success rate of 93.5 % of cases ,99 % of all treatments were completed , although no self - reporting by the patients was included in the analysis . for latency with 4 % articaine with 1.200,000 epinephrine , a shorter time has been reported ( ram and amir 2006 ) . the influence of the vasoconstrictor concentration on analgesic diffusion due to a slower absorption rate may explain this difference ( lima - junior et al .2012 ) , although , this effect was not seen in infiltration analgesia ( moore et al . 2006 ) . the volumes used in this study ( mean = 1.1 ml ) were generally very low ; however , in smaller children , dosages up to 3.46 mg / kg of articaine were recorded . those could be potentially dangerous when using a local analgesic without vasoconstrictor ( lipp et al . altogether , we could demonstrate that with the low concentration of the vasoconstrictor used in the present study , efficacy as well as mean duration of analgesia was sufficient in nearly all cases . efficacy and safety of 4 % articaine with the higher epinephrine concentrations of 1:100,000 and 1:200,000 in dental treatment of children have been studied before ; showing a safe and efficient effect of the respective solution . there was also no higher incidence of adverse reactions following 4 % articaine with epinephrine 1:100,000 in children under the age of 4 years , although the manufacturer does not recommend this use ( wright et al . a study on the pharmacokinetics of articaine with epinephrine 1:200,000 in children ( 312 years old ) showed drug serum levels comparable to adults and no relevant differences between the 2 and 4 % solution . the maximum plasma levels were distinctly earlier and the plasma clearance increased in comparison to adult subjects ( jakobs et al . a major disadvantage of local analgesia in children is the prolonged numbness after treatment , which may increase the chance of self - inflicted soft tissue lesions . the effect of numbness has been reported to be longer after articaine use than other local analgesics such as lidocaine ( ram and amir 2006 ) . as described by adewumi et al . nevertheless , due to the small number of such side - effects in the present study , this result may be seen controversial . we recommend further trials with narrower age limits , basing the studies on the younger age group . within the limitations of the present study ( phone call 24 h later with an increased chance of recall bias ) , the mean duration of soft tissue analgesia was 2.19 h. compared to adults using the same epinephrine - reduced articaine solution , the duration was approximately 20 min shorter in the paediatric population ( daublnder et al . ram and amir ( 2006 ) reported for 4 % articaine with epinephrine 1:200,000 a mean duration of total soft tissue analgesia of 3.43 h. accordingly , the reduction of vasoconstrictor results in a shorter time of numbness . this may explain the smaller number of soft tissue injuries in our study ( 0.4 % ) compared to the 14 % reported by adewumi et al . similar to prior studies , the duration of soft tissue numbness for local infiltration was shorter than the duration of nerve block injections ( malamed et al . we also found a weak but clinical relevant correlation with the injected volume when using infiltration . after administration of 4 % articaine with different epinephrine concentrations ( 1:100,000 and 1:200,000 ) , no severe adverse effects in children were observed . therefore , our data concerning the safety of 4 % articaine with 1:400,000 epinephrine tested in 999 children with a low rate of minor side - effects reflect the already known risk benefit profile of articaine solution . due to a high efficacy , tolerance and safety , articaine 4 % solution with reduced epinephrine concentration ( 1:400,000 ) is a safe and suitable drug in paediatric dentistry for routine treatment . for longer and very painful procedures and in treatments that require ischaemia , solutions with higher concentrations of epinephrine are preferable .\noutput:\n" }, { "from": "agent", "value": "aimin paediatric dentistry , epinephrine may contribute to systemic and local side - effects . on the other hand it is necessary to provide good and safe local analgesia . therefore , an articaine solution with reduced epinephrine concentration was tested in a clinical setting.methodsin a non - interventional clinical study , dental treatment was performed in children and adolescents ( 417 years ) . for local analgesia , articaine 4 % plus epinephrine 1:400,000 was used in the technique chosen by the dentist . efficacy and tolerance as well as duration of soft tissue analgesia and side - effects were evaluated.results999 patients ( 50.5 % male , 49.5 % female ) with a mean age of 7.9 ( sd 2.34 ) years were treated . two hundred seventy six patients ( 27.6 % ) received sedation prior to treatment . the mean treatment time was 15 min ( sd 10 ) . in 93.5 % of cases , initial local analgesia was sufficient to perform the planned treatment . in 99 % of cases ( n = 989 ) the planned treatment could be completed . a second injection was necessary in 6.5 % of cases . a mean duration of soft tissue analgesia of 2.19 h ( sd 1.01 ) was seen . slight side - effects occurred in 3.1 % of subjects.conclusionsdue to high efficacy , tolerance and safety , the articaine 4 % solution with the reduced epinephrine concentration ( 1:400,000 ) was a safe and suitable drug for paediatric routine treatment ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: generalized lymphangiomatosis is an uncommon developmental disorder characterized by abnormal proliferation and dilatation of lymphatic channels involving multiple systems . systemic manifestations include multiple low - density or cystic lesions within the neck , mediastinum and abdomen , pulmonary interstitial thickening , and lytic bone lesions . poor knowledge of this condition among radiologists and clinicians often leads to a delayed diagnosis . in this case report , we discuss the radiological findings in a young man with generalized lymphangiomatosis and systematically arrive at the diagnosis . a 19 - year - old student presented with complaints of productive cough and progressive dyspnea for 18 months and hemoptysis for 6 months . he was extensively evaluated in multiple centres and was diagnosed with probable tuberculosis based on computed tomography ( ct ) findings of probable necrotic mediastinal lymphadenopathy and pericardial effusion . histopathological examination of ct - guided and mediastinoscopy - guided nodal biopsies and thoracoscopy - guided pericardial and lung biopsies done elsewhere were inconclusive . he was treated with empirical anti - tubercular therapy ( att ) for 6 months following which there was no clinical improvement . he required repeated pericardial drainages and , therefore , underwent pleuropericardial shunt insertion for recurrent hemorrhagic pericardial effusions . because there was no clinical improvement , he presented to our institution for further evaluation . chest radiograph showed mediastinal widening , bilateral pleural effusions ( left more than right ) , prominent interstitial lung markings , and kerley b lines [ figure 1 ] . ct thorax and abdomen with intravenous contrast showed confluent , sheet - like , hypodense mediastinal lesion ( hu - 28 ) encasing the mediastinal viscera without mass effect [ figure 2 ] . extensive interlobular septal thickening , peribronchovascular interstitial thickening , and patchy , lobular areas of ground glass density were seen in both the lungs with relative sparing of the lung apices [ figure 3 ] . a few well - defined lytic lesions with prominent primary trabeculae were seen in the sternum [ figures 2 and 4 ] and a few vertebrae . mottled lucencies with a coarse trabecular pattern were seen in a few vertebral bodies , a few ribs , and pelvic bones [ figure 4 ] . minimal , ill - defined , hypodense soft tissue was also seen in the lesser omentum along with a few dilated retroperitoneal lymphatics [ figure 5 ] . lab investigations revealed iron deficiency anemia , normal total and differential white blood cell counts , negative sputum acid - fast bacilli , and negative xpert polymerase chain reaction for mycobacterium tuberculosis . pleural fluid was hemorrhagic and analysis showed multiple red blood cells , lymphocytosis , elevated lactate dehydrogenase , elevated protein , and low glucose . combination of the lung findings ( smooth interlobular septal thickening , peribronchovascular interstitial thickening , and lobular areas of ground glass density ) and hypodense soft tissue lesion insinuating around the mediastinal viscera made us consider the following differentials : pulmonary lymphoma , pulmonary veno - occlusive disease ( pvod ) , erdheim chester disease , lymphangiomatosis , and histiocytosis . the fluid - density nature of the mediastinal lesion , lack of infiltration and absence of mass effect on the mediastinal structures made lymphoma less likely . pvod and erdheim chester disease could show similar lung findings , but the mediastinal lesion and the lack of ct findings of pulmonary arterial hypertension excluded pvod . erdheim chester disease typically shows a rind of soft tissue around the kidneys , adrenal fossa , and aorta which were not seen in our patient . although langerhans cell histiocytosis ( lch ) can also present with multiple lytic lesions in the bones , the lesions in lch tend to be ill - defined , with adjacent bone marrow edema , periosteal reaction , and enhancing soft tissue . skeletal lesions in lymphangiomatosis are typically well - defined lytic lesions similar to our case . finally , generalized lymphangiomatosis was thought to be the most likely diagnosis because of the multi - system involvement ( mediastinal , pulmonary and bone involvement , retroperitoneal dilated lymphatics , and pericardial effusion ) , typical lung findings , and the low - density , nonenhancing nature of the mediastinal lesion . chest radiograph showing mediastinal widening , bilateral pleural effusion ( open arrows ) , prominent interstitial lung markings ( oval ) , and kerley b lines ( curved arrows ) images of ct thorax in mediastinal window , axial ( a , b ) and coronal ( c ) images showing confluent , sheet - like , hypodense ( hu - 28 ) mediastinal lesion ( straight solid arrows ) encasing the mediastinal viscera with no mass effect . left pleural effusion ( star ) and pericardial effusion ( curved arrow ) are also evident on coronal image ( c ) . a well - defined lytic lesion is seen in the sternum ( open arrow ) in image 2a coronal ( a , b ) and axial ( c ) ct images of chest in lung window , showing interlobular septal thickening ( solid arrows ) , peribronchovascular interstitial thickening ( open arrows ) and patchy lobular areas of ground glass density ( oval ) in both lungs with relative sparing of the lung apices axial ( a , b ) and coronal ( c ) ct images in bone window , showing the lytic lesion in sternum ( open arrow in a ) , mottled lucencies with coarse trabecular pattern in vertebrae and pelvic bones ( solid arrows in b and c ) axial ( a , b ) and coronal ( c ) ct images of abdomen showing dilated lesser omental lymphatics ( open arrow in a ) and retroperitoneal lymphatics ( solid arrows in b and c ) list of differentials with their imaging features , in the context of our index case well - defined , lytic lesions with prominent primary trabeculae like in our patient could represent hemangiomas or lymphangiomas which can not be differentiated on ct or mri . however , in view of the nature of the systemic lesions , these were presumed to be lymphangiomas . it showed elevated pleural fluid triglyceride ( 225 mg / dl ) and was positive for chylomicrons , confirming chylothorax . review of the histopathology slides from the lung biopsies ( thoracotomy and open lung biopsies done earlier ) showed congested blood vessels with dilated lymphatic channels lined by endothelial cells , which were positive for d2 - 40 and cd31 . the walls of the vascular channels focally contained spindle cells with elongated nuclei and eosinophilic cytoplasm . our patient was initiated on medium chain fatty acid diet , even though the usefulness of the same has been disputed . a multidisciplinary team involving pulmonologists , radiation oncologists , medical oncologists , and radiologists met to discuss the treatment options . he was started on 5 mg propranolol which was gradually increased to 20 mg per day while monitoring the heart rate . he received 10 fractions of 20 gy external beam radiotherapy to the thorax which he tolerated well . few days later , he presented to the emergency department with complaints of small volume hemoptysis , rapidly worsening breathlessness over a few hours , and two episodes of generalized tonic , he was found to have metabolic acidosis and hypoxic respiratory failure , either of which could have caused the seizures . although hypoxia improved with mechanical ventilation , he had worsening hemodynamic compromise requiring inotrope infusions . generalized lymphangiomatosis / diffuse lymphangiomatosis is a rare developmental disease involving the lymphatic system characterized by abnormal proliferation , dilatation , and thickening of lymphatic channels . it forms a part of the spectrum of lymphatic disorders and clinical presentation depends on the extent and site of involvement . imaging findings include pericardial effusion , low - density mediastinal and neck masses , which encase the large vessels and other viscera without compressing them . less commonly , centrilobular , small , ground glass - density nodules and patchy , lobular areas of ground glass density may be seen in the lungs . skeletal involvement is seen in 75 % of the cases and is characterized by lytic lesions involving multiple bones . abdominal findings include confluent , low - density lesions , mottled appearance of splenic parenchyma , and cystic lesions within the spleen . lymphangiomatosis can also extensively involve other abdominal viscera and retroperitoneum , as described by cutillo et al . lymphangiomatosis is a distinct entity , separate from pulmonary lymphangiectasia which is thought to be due to the pathologic dilatation of pulmonary lymphatics either due to the failure of pulmonary interstitial connective tissues to regress ( primary or congenital form ) or secondary lymphangiectasia , which is due to a variety of processes that impair pulmonary lymph drainage or increase lymph production . on pathological examination , lymphangiomatosis shows proliferation of complex , anastomosing , endothelial - lined spaces with asymmetrically spaced bundles of spindle - shaped cells and collagen , surrounding the endothelial - lined channels . on immunohistochemical staining , the endothelial cells in lymphangiomatosis are positive for d2 - 40 , cd 31 , and factor viii - related antigen . in addition , the spindle cells in lymphangiomatosis stain positive for sma and negative for hmb - 45 while the spindle cells in lymphangioleiomyomatosis are positive for both sma and hmb - 45 . there is no specific treatment for diffuse lymphangiomatosis that is universally accepted . palliative options that have been reported to be useful in the literature include radiotherapy , medical therapy with interferon - alpha , corticosteroids , and other chemotherapy drugs , which may be associated with systemic toxicity . more recently , propranolol has been used with promising results and without any significant systemic side effects . chylothorax associated with multiple bone lesions is reported to have a poor prognosis . in summary , multi - system involvement with low - attenuation cystic lesions in the neck , thorax , and abdomen along with pulmonary interstitial thickening , chylothorax , and skeletal lesions in a young patient should raise the possibility of generalized lymphangiomatosis .\noutput:\n" }, { "from": "agent", "value": "we present the case of a 19 - year - old man who was extensively evaluated in multiple centres for long - standing cough , dyspnea , and hemoptysis without a definitive diagnosis . his chest radiograph at presentation showed mediastinal widening , bilateral pleural effusions , and kerley b lines . computed tomography of the thorax showed a confluent , fluid - density mediastinal lesion enveloping the mediastinal viscera without any mass effect . there were bilateral pleural effusions , prominent peribronchovascular interstitial thickening , interlobular septal thickening and lobular areas of ground glass density with relative sparing of apices . there were a few dilated retroperitoneal lymphatics and well - defined lytic lesions in the bones . in this case report , we aim to systematically discuss the relevant differentials and arrive at a diagnosis . we also briefly discuss the treatment options and prognosis along with our patient 's course in the hospital and final outcome ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a 39 - year - old man presented with diplopia and ptosis that was characterized by diurnal variation . three years previously a mediastinal tumor was diagnosed on a chest x - ray during a routine medical examination . chest computed tomography ( ct ) confirmed the presence of a demarcated anterosuperior mediastinal mass , leading to the diagnosis of a thymoma . anti - achr antibodies were not detected and an electromyogram was not performed . at that timethe patient was asymptomatic , and there were no clinical signs of mg before surgery . he received a median sternotomy , and an anterosuperior , well - encapsulated tumor was found that was not adherent to the mediastinal structures . his postoperative course was satisfactory . on admission , bilateral ptosis and diplopia were present , but the physical examination was otherwise normal . the titer of anti - achr antibody was high , at 43.7 nmol / l . the diagnosis of mg was confirmed by the findings of both the anti - achr antibody and electrophysiological test . pyridostigmine bromide administration ( 180 mg per day ) was started , which resulted in the prompt improvement of myasthenic symptoms . at a 2 - year follow - up , the patient was doing well on pyridostigmine , with a chest ct revealing no evidence of a recurrent or metastatic tumor . the thymus plays a key role in the immunologic status of an individual , and disease of the thymus can be associated with autoimmune disorders . mg first appearing many years following the removal of a thymoma reportedly occurs in 1.5 - 28 % of cases .8 the interval between a thymectomy and the onset of postoperative mg has varied between studies . two of the studies involving an adequate number of cases and obtaining detailed clinical data found that the mean interval between thymectomy and the onset of postoperative mg was 19 and 18 months . reported that patients with a shorter onset of postoperative mg had a better prognosis , but other study did not find this relationship .3,8 the rarity of postoperative mg cases has meant that it remains unclear whether the interval between thymectomy and the onset of postoperative mg influences the prognosis . most reports demonstrate that postoperative mg responds to anticholinesterase drugs and / or steroids , and that the prognosis is relatively good .5,8 although a thymectomy does not prevent the onset of postoperative mg , this procedure is associated with a good prognosis . one study found that 63 % , 25 % , and 12 % of thymomas were of mixed histological type , predominantly lymphocytic type , and predominantly epithelial type , respectively ,3 and the corresponding percentages in another study were 65 % , 22 % , and 13 % .8 these distributions of the histological types were similar to that in patients with thymoma and preoperative mg . in the study of kondo and monden , the anti - achr antibody at onset varied between 1.8 and 91 nmol / l. 8 the majority of patients show a clinical severity of type i or type iia on osserman 's classification . however , they found that the titer of anti - achr antibody did not correlate with clinical severity , as was the case in our patient . the various time periods between a thymectomy and the onset of postoperative mg raise doubts as to whether a thymectomy directly triggers mg onset . found using t - cell - proliferation assays for a fragment of the achr that the thymoma released mature auto - antigen - specific t - cells into the periphery .9 buckley et al . found that t - cells in a thymoma were exported to the peripheral blood , and that these t - cells could persist in the periphery for many years .10 these studies suggest that a thymoma actively exports large numbers of mature t - cells into the peripheral blood , with these cells persisting in the periphery , potentially stimulating autoantibody production and subsequent autoimmune diseasethe late onset of mg and other autoimmune disorders should be kept in mind as possible complications of surgical treatment for thymoma . therefore postoperative follow - up care with consideration of postoperative mgrecurrent or metastatic thymoma should be ruled out because reoperation can be effective even in the treatment of mg .\noutput:\n" }, { "from": "agent", "value": "a small proportion of thymoma patients without myasthenia gravis ( mg ) have been observed to develop mg after total removal of the thymoma . however , the underlying cause is not yet known due to the rarity of postoperative mg patients . we report a 39 - year - old man in whom mg appeared after surgical removal of a thymoma . computed tomography and magnetic resonance imaging showed no signs of recurrent or metastatic thymoma . administration of pyridostigmine bromide resulted in the prompt improvement of myasthenic symptoms . our observations indicate that postoperative follow - up care with monitoring of possible postoperative mg is necessary after resecting a thymoma ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: liraglutide is a once - daily injectable glucagon - like peptide - 1 ( glp - 1 ) analog approved for the treatment of type 2 diabetes mellitus ( t2 dm ) . liraglutide treatment led to significant reduction in glycosylated hemoglobin ( hba1c ) and weight in patients with t2 dm in various liraglutide effect and action in diabetes ( lead ) trials . however , the duration of all lead trials was short ( 26 weeks , except lead 3 , which was 52 weeks ) . long - term data on efficacy and safety of liraglutide in real - world clinical practice is limited . few countries have published their data recently , on efficacy and safety of liraglutide in t2 dm , but the duration of these studies was mostly 6 months , which might not truly reflect long - term effects . our group has demonstrated the beneficial effects of liraglutide on body weight and glycemic control in the real life clinical practice setting until 3 months after liraglutide initiation in indian obese t2 dm subjects . however , it is not known in indian t2 dm subjects whether the effect of liraglutide on body weight and glycemic control would be sustained for a longer period . in this study , we present 1 year follow - up data on effectiveness and tolerability of liraglutide in indian patients with t2 dm in the real - world clinical setting . aim of the study was to evaluate the effect of liraglutide on glycemic control and weight in obese patients with t2 dm for 1 year after liraglutide introduction . this was an observational study conducted at the outpatient clinic of a tertiary care hospital . liraglutide was prescribed to 96 patients with t2 dm and obesity and followed up at 3 months intervals up to 1 year . of 96 patients , 22 patients discontinued liraglutide before completion of 1 year for a variety of reasons ; adverse events ( n = 10 ) , financial constraints ( n = 2 ) , lost to follow - up ( n = 6 ) , and lack of weight loss ( n = 4 ) . therefore , 1 year data were available for 74 patients . clinical parameters including , body weight , body mass index ( bmi ) , and metabolic parameters ( fasting plasma glucose [ fpg ] , postprandial plasma glucose [ ppg ] and hba1c ) were assessed at baseline and 3 months , 6 months , 9 months , and 1 year after liraglutide introduction . dosage adjustment of other antidiabetic medications and up - titration of liraglutide dose ( 0.6 mg / day , 1.2 mg / day or 1.8 mg / day ) was done according to clinical judgment . data analysis was done using spss software ( sas 9.1.3 , sas institute inc . , comparison between mean pretreatment and posttreatment value of various parameters was done using paired t - test . comparison between two groups was done using student 's t - test . the significance level was set at p 0.05 . data analysis was done using spss software ( sas 9.1.3 , sas institute inc . , comparison between mean pretreatment and posttreatment value of various parameters was done using paired t - test . the mean age of patients was 50.99.6 years and mean duration of diabetes was 11.66.3 years . at baseline , mean hba1c was 8.91.3 % and mean body weight was 98.916.0 kg . table 2 shows the clinical outcomes for liraglutide at 6 and 12 months follow - up . a significant decline in mean hba1c , fpg , ppg , and body weightmean hba1c levels at 6 and 12 months of follow - up were 7.31.1 % and 7.41.2 % , respectively [ figure 1 ] . the mean absolute decline in hba1c levels at 6 and 12 months of follow - up were 1.51.2 % and 1.41.6 % ( both p 0.01 ) compared with baseline , respectively . similarly , significant reduction in mean body weight was observed at 6 months and 12 months of follow - up [ figure 2 ] . average body weight at 6 and 12 months of follow - up were 94.114.9 kg and 93.815.0 kg , respectively . baseline characteristics various parameters at 6 months and 12 months after liraglutide introduction ( mean standard deviation ) change in mean glycosylated hemoglobin from baseline to 1 year after liraglutide introduction . * difference from baseline is significant ( p 0.05 ) , difference between 6 months and 12 months not significant ( p 0.05 ) change in mean body weight from baseline . * difference from baseline is significant ( p 0.05 ) we further categorized the patients into six groups based on the response to liraglutide treatment at 6 months and 12 months . group 1 included patients who showed continued lowering of mean hba1c from baseline up to 1 year ( n = 32 ) . group 2 included patients in whom mean hba1c declined initially from baseline up to 6 months but subsequently increased ( n = 30 ) . group 3 included patients in whom mean hba1c did not lower at all or continued rising from baseline ( n = 12 ) . group 4 included patients who showed continued lowering of mean weight from baseline up to 1 year ( n = 37 ) . group 5 included patients in whom mean weight declined initially from baseline up to 6 months but subsequently increased ( n = 33 ) . group 6 included patients in whom mean weight did not lower at all or continued rising from baseline ( n = 4 ) . tables 3 and 4 show a comparison between groups 1 and 2 and groups 4 and 5 , respectively . groups 3 and 6 were not compared due to small numbers . group 1 patients had significantly higher mean hba1c at baseline as compared to group 2 patients ( 9.4 % vs. 8.7 % p = 0.04 ) . there was no significant difference in any of the parameters between groups 4 and 5 . figure 3 shows the change in mean hba1c from baseline in group 1 and group 2 . mean hba1c was significantly higher at 12 months as compared to 6 months in group 2 ( 6.80.9 % vs. 7.91.2 % , p 0.001 ) , however , it was significantly lower compared to baseline ( 8.71.1 % vs. 7.91.2 % , p = 0.001 ) . mean weight was significantly higher at 12 months as compared to 6 months in group 5 ( 92.414.1 kg vs. 94.514.6 kg , p 0.001 ) , however , it was significantly lower compared to baseline ( 97.214.7 kg vs. 94.514.6 kg , p 0.001 ) . reduction of hba1c at 1 year was associated positively with baseline hba1c ( r = 0.336 , p 0.001 ) and body weight reduction at 1 year was associated positively with baseline weight ( r = 0.664 , p = 0.003 ) . comparison of various parameters ( meanstandard deviation ) between group 1 ( patients with consistent lowering of glycosylated hemoglobin ) and group 2 ( patients in whom glycosylated hemoglobin lowered initially but again increased ) comparison of various parameters ( meanstandard deviation ) between group 4 ( patients in whom weight declined consistently ) and group 5 ( patients in whom weight declined initially but increased again ) comparison of mean glycosylated hemoglobin between group 1 ( patients with consistent lowering of glycosylated hemoglobin ) and group 2 ( patients in whom glycosylated hemoglobin lowered initially but again increased ) . * significant difference between the groups ( p 0.05 ) , significant difference from baseline and 6 months ( p 0.05 ) adverse events were ; diarrhea ( n = 11 ) , nausea ( n = 14 ) , vomiting ( n = 2 ) , pain abdomen ( n = 1 ) , dizziness ( n = 2 ) , and lethargy ( n = 2 ) . none of the subjects had major hypoglycemia . the maximal daily dose of liraglutide , i.e. , 1.8 mg was reached in 18/74 patients , and in the rest , the dose was maintained at 1.2 mg daily . present study for the first time demonstrates the efficacy of liraglutide on weight reduction and fair glycemic control over 1 year in indian t2 dm subjects . we found that initiating liraglutide was associated with significant reductions in mean hba1c and mean weight at 12 months of follow - up . liraglutide treatment for 1 year resulted in 1.4 % decline in mean hba1c level and mean weight loss of 5.1 kg . however , in significant proportion of patients ( 30/74 ) , mean hba1c decreased initially from baseline until 6 months after initiating liraglutide ( 8.71.1 % at baseline vs. 6.80.9 % at 6 months , p 0.001 ) but increased thereafter ( 6.80.9 % at 6 months vs. 7.91.2 % at 12 months , p 0.001 ) . similarly , in subset of patients ( n = 33/74 ) , mean weight decreased initially from baseline until 6 months ( 97.214.7 at baseline vs. 92.414.1 kg at 6 months , p 0.001 ) but increased thereafter ( 92.414.1 kg at 6 months vs. 94.514.6 kg at 12 months , p 0.001 ) . significant reductions in body weight and hba1c were obtained with liraglutide in all lead trials . the duration of all lead trials was 26 weeks , except lead 3 , which was 52 weeks . real world clinical effectiveness of liraglutide has been evaluated by others where liraglutide was shown to be effective in reducing hba1c and weight in t2 dm subjects . however , follow - up of most of these studies was up to 6 months . recently , our group has demonstrated the beneficial effects of liraglutide on body weight and glycemic control in the real life clinical practice setting until 3 months after liraglutide initiation in indian obese t2 dm subjects . short - term results ( until 6 months ) on hba1c and weight of the current study are in accordance with earlier studies evaluating the efficacy of liraglutide in t2 dm patients over 1224 weeks follow - up . however , we found the fading effect of liraglutide on glycemic control and body weight after 6 months of initiation , in significant proportion of patients . studies describing the effect of liraglutide on glycemic control and body weight over long - term , in different populations have started appearing recently in literature . the lead - 3 sub - analysis showed the significant weight reduction by liraglutide treatment for 2 years . similarly long - term liraglutide treatment ( over 2 years ) in japanese t2 dm subjects , effectively maintained the reduction of body weight and the fair glycemic control . another observational study concluded that adding liraglutide to insulin in daily clinical practice reduced hba1c significantly within 6 months ; however , there was nonsustainable effect during long - term treatment . in this study , median hba1cre - increased ( 7.7 % at baseline , 6.9 % at 6 months , and 7.5 % at 12 months ) and median weight rose again ( 99.8 kg at baseline , 97.5 kg at 6 months , and 100.5 kg at 12 months ) , after 6 months of liraglutide initiation . our study similarly showed a rise in hba1c ( n = 30/74 ) and body weight ( n = 33/74 ) after an initial decline , following 6 months of liraglutide initiation in a subset of patients . nevertheless , their hba1c and body weight stayed significantly lower at 12 months compared to baseline . we compared the group of patients who continued to show decline in mean hba1c from baseline up to 1 year with the group of patients in whom hba1c increased after 6 months of initial decline . patients who showed a continuous decline in mean hba1c after liraglutide initiation had higher mean hba1c at baseline , but there was no significant difference in any other parameter including weight or duration of diabetes , compared to the group of patients in whom hba1c increased after 6 months of initial decline . although mean hba1c re - increased in the latter group , weight continued to decline up to 1 year . we found significant positive association between baseline hba1c and reduction of hba1c at 1 year and between baseline weight and body weight reduction at 1 year . magnitude of reduction of hba1c at 1 year was not associated with duration of diabetes or baseline weight . similarly , magnitude of reduction of weight at 1 year was not associated with duration of diabetes or baseline hba1c . these results may imply that liraglutide has an independent effect on body weight and glycemic control , may be by different mechanisms in glp - 1 actions . furthermore , it suggests that liraglutide effectiveness is not influenced by duration of diabetes , and good glycemic control can be achieved with liraglutide even in patients with long - standing t2 dm . our results are consistent with that of a recent study evaluating long - term impact of liraglutide use on body weight and glycemic control in japanese t2 dm subjects which showed that significant determinants for the reduction of body weight or hba1c from baseline to 2 years were baseline bmi and insulin dose , or baseline hba1c , respectively . other studies have also shown that baseline bmi and hba1c may be important predictors for weight reduction and glycemic control , respectively , before liraglutide therapy . patients nonadherence regarding dietary restrictions could be one of the reasons accounting for the fading effect of liraglutide on body weight and hba1c beyond 6 months in a subset of patients presented here . in our observation , patients do not tend to adhere to a diet plan , once the gastrointestinal side effects of liraglutide disappear after few months of liraglutide initiation . limitations of the study ; this is an observational study , not a randomized clinical trial study . our study demonstrated the effectiveness of liraglutide at 6 and 12 months follow - up in real - world clinical practice in indian t2 dm subjects . a significant proportion of patients showed a fading effect of liraglutide on weight reduction and glycemic control after 6 months ; however , their weight and hba1c still remained significantly lower compared to baseline . baseline hba1c and baseline weight were significant predictors of glycemic control and weight reduction respectively at 1 year suggesting that liraglutide may be more effective in patients who are obese and have poor glycemic control on oral antidiabetic drugs with or without insulin .\noutput:\n" }, { "from": "agent", "value": "background : long - term efficacy of liraglutide , a glucagon - like peptide - 1 analog , on body weight and glycemic control has not been studied in indian type 2 diabetes mellitus ( t2 dm ) subjects.aim : to evaluate the effect of liraglutide on glycemic control and body weight for 1 year in indian t2 dm patients.methods : liraglutide was prescribed to 96 obese patients with t2 dm and followed up for 1 year . clinical parameters were measured at baseline and 3 , 6 , 9 , and 12 months . dosage of liraglutide and other medications was adjusted according to clinical judgment.results : 1 year data were available for 74 patients . mean age was 50.9 9.6 years . mean duration of diabetes was 11.6 6.3 years . glycosylated hemoglobin ( hba1c ) significantly decreased from 8.9 1.3 % at baseline to 7.4 1.2 % at 1 year . body weight significantly declined from 98.9 16.0 kg at baseline to 93.8 15.0 kg at 1 year . after an initial decline , subset of patients had an increase in mean hba1c ( n = 30/74 ) and mean body weight ( n = 33/74 ) after 6 months of liraglutide initiation . baseline hba1c and baseline body weight were positively associated with a reduction of hba1c and body weight at 1 year , respectively . no major side effects occurred.conclusion : liraglutide treatment resulted in a significant and sustained reduction in hba1c and body weight over 1 year in indian t2 dm patients . magnitude of reduction of hba1c and body weight at 1 year was positively associated with baseline hba1c and baseline weight , respectively ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the main aim of periodontal surgery is to achieve a good function of the periodontium and an aesthetically satisfying gingiva . over the past few years surgical techniquesthese techniques are based on the transplantation of free tissue grafts14 or the application of membranes ,510 the transposition of periodontal flaps ,1119 or a combination of both techniques .2023 the rate of success has increased continuously and individualized techniques for achieving the best results in different kinds of recessions have been presented . the morphology of the recession dictates the best technique for root coverage which in turn leads to the best clinical results . the aim is to achieve long - term coverage of the root surface with attached gingiva of normal height and in the correct position . the gingival margin as well as the color and texture of tissue should resemble that of the healthy neighbouring teeth . in other words , the scars of the surgery should not be visible . to gain an objective assessment of the clinical results , the percentage of root coverage should be ascertained .21,2429 clinical success depends on the extent of biological regeneration .3032 complete biological regeneration is only seen in the apical and lateral part of the former recession in this case , while a long epithelial attachment is seen in the other parts of the root when conventional surgical techniques are used .30,33 this biological examination requires histological specimens that should only be taken during second - look surgery so as to avoid further periodontal damage in a patient who is likely to have a good result . an important parameter for judging the success of a new surgical technique is good clinical results . therefore , it can be stated that the best clinical results for covering extended denuded root surfaces are achieved by surgical techniques using a free soft tissue graft but this results in donor - site morbidity .33 to avoid donor site - related problems on the one hand and to exploit the advantages of a connective tissue graft on the other , a new surgical technique for root coverage has been developed over the last few years . the technique is based on transposition of the local periosteum in combination with a mucoperiosteum transpositional flap . herein , the new periosteum eversion technique used in this study is described and a report on the first clinical trial is presented . periodontal recessions of the upper or lower front teeth were to be covered surgically in 30 patients . the periodontal defects were all located at the upper or lower canines in six and four patients and the upper or lower incisors in eight and 12 patients , respectively . miller class i defects were registered in 10 patients , miller class ii defects in seven patients , and miller class iii defects in 13 patients .34 a periodontal probe ( pcp12 ) was used by one examiner . an intensive oral hygiene program was carried out in the first stage of treatment to reduce preoperative plaque contamination to less than 30 % all over the dentition which is a precondition for surgery .35 three months after achieving an approximal plaque index value of less than 30 % , the preoperative findings of the periodontal area and the teeth which were to be treated surgically were recorded . periodontal bleeding after mild probing , attachment loss , and the height of the attached gingiva were recorded . the loss of periodontal attachment was identified at three different locations for each root , namely mesially , centrally , and distally at the labial root surface ( figure 1 ) and the highest value of attachment loss was noted . the width of the keratinized gingiva was measured at the same positions as the attachment loss after retracting the lip manually and the lowest value was recorded . no plaque contamination was seen before surgery , whereas some gingival bleeding was seen preoperatively in nine patients . the new technique of periosteoplasty was then used for every patient ( figures 2a , 2b , 2c , 2d , 2e ) . the root surface was cleaned mechanically by scaling and disinfected with chlorhexidine solution ( chlorhexamed 0.06 % , blend - a - dent ; proctor & gamble , schwalbach , germany ) . the root surface was then conditioned with 40 % acetic acid solution for 20 s and washed with physiologic saline solution for 60 s ( figure 3 ) . the periosteum was incised at the baseline and in the lateral part and was separated from the submucous connective tissue up to the border of the attached gingiva ( figure 4 ) . the crestally pedicled periosteum was everted and transposed coronally where it was fixed with interdental resorbable stitches ( figure 5 ) . a coronal transposition of the mucoperiosteum was then performed and the mucoperiosteum flap was also fixed with interdental resorbable stitches ( figure 6 ) . chlorhexidine solution was used twice a day for six weeks after surgery for plaque decontamination . clinical follow - up was performed once a week in the first postoperative month , every two weeks in the second postoperative month and once a month thereafter . the clinical examination was repeated 3 , 6 , and 12 months after surgery , and the results were compared to the preoperative values . in other words , gingival bleeding , attachment loss , and the height of the attached gingiva were examined and compared to the preoperative findings . by comparing the attachment loss mesially , centrally , and distally before and after the operation , the percentage of root surface coverage was calculated for each position . the mean percentage of these three values was stated to be the percentage of the whole root coverage . epithelialization of the everted periosteum used for root coverage was seen 14 days after surgery ( figures 7a , 7b ) . an improvement in the clinical situation was seen in all the patients ( figure 7c ) . there was no bleeding on periodontal probing at 3 , 6 , and 12 months postoperatively . the mean periodontal probing depth was 1.2 mm preoperatively and 0.4 mm at three and six months postoperatively . twelve months after surgery , the mean probing depth was 0.3 mm ( 0.1 sd ) . after three months no attachment loss was registered , while mean values of 0.3 mm ( 0.1 sd ) were seen at six and 12 months after surgery . the mean height of attached gingiva was 2.3 mm ( 0.2 sd ) three months after surgery and 2.2 mm ( 0.1 sd ) on average at six and 12 months postoperatively . in comparison to the neighbouring teeth , the height of attached gingiva was 0.3 mm less on average for the surgically treated teeth . a mean value of 94.8 % root coverage was calculated six and 12 months after surgery , which shows a relapse in recession of 5.2 % . the main aim of periodontal surgery is to achieve complete restitution of all periodontal tissue resulting in healthy and aesthetically satisfying periodontal conditions . covering denuded root surfaces is one of the important goals of surgical periodontal treatment and the best results can be achieved by choosing the most appropriate technique . while small and flat recessions on single teeth can be treated successfully by using surgical flap techniques alone , in the case of large and deep defects with no attached gingiva , the use of free gingiva or connective tissue grafts or membranes becomes more important for achieving the best possible results .36 the main advantage of techniques using guided tissue regeneration with membranes ( gtr ) over techniques using tissue grafts is avoidance of donor site problems . these gtr techniques are used most successfully in periodontal recessions of between 4.5 and 5.5 mm if keratinized gingiva is still present .510 using these techniques , the percentage of root surface coverage is between 60 % and 84 % in a follow - up period of six to 18 months . medium - and long - term recessions of between 0.75 and 1.7 mm have been ascertained in the literature . the main problem arises if there is wound dehiscence followed by bacterial contamination of the membrane . the defect has to be covered after membrane removal by flap surgery ,36 which is not successful in every case . furthermore , gtr techniques are not so successful if there is little or no attached gingiva . in this case , new keratinized gingiva has to be created and other surgical techniques using connective tissue or free gingiva grafts have to be used which bring about a good regeneration of attached gingiva .37,38 when using free connective tissue grafts , residual recessions of between 0.1 mm and 1.27 mm can be achieved and the percentage of root coverage is between 70 % and 97 % .3947 the results vary considerably depending on the surgical techniques used for transplant coverage or preparation and vascularization of the transplant bed . the better the vascularization of the transplant bed , the higher the resulting percentage of keratinized gingiva .38 furthermore it can be assumed that there is a lower extent of root surface coverage when recessions of more than 5 mm in depth have to be treated .38 in these cases , root coverage of between 70 % and 92 % is reported .40,44 when comparing combined techniques of graft transplantation and flap surgery , transpositional flaps have better results than the envelope technique .40,44 in this study , periodontal recessions of more than 5 mm were also treated by the new periosteum eversion technique . it was first reported in 2001 , and was originally used to cover onlay grafts in augmentative alveolar ridge surgery48 and adapted for use in periodontal surgery in this study . the technique is based on using the local periosteum as a vascularized transplant for defect coverage . in comparison to other techniques of periosteum transposition , the periosteum is separated from the mucoperiosteum flap after baseline incision , so that the basal part of the periosteum is used for defect coverage after eversion . the periosteum remains pedicled in the crestal part and can be elongated and coronally transposed without retraction forces . the vascularized periosteum can be used for defect coverage in a similar way to a connective tissue graft and can be epithelialized by the neighbouring mucosa as a vital and well vascularized tissue , although it may not be covered by a mucoperiosteum flap . the principle of tissue regeneration in this new technique is therefore similar to the conventional technique of using connective tissue grafts in combination with a transpositional flap . therefore the results of periosteum eversion technique should be compared with the results of the conventional technique as described in the literature . in thisstudy the periosteum eversion technique resulted in a rate of defect coverage of 94.8 % and a mean residual denuded root surface of 5.2 % one - year postoperatively . this result is very similar to the results of defect coverage in recessions of between 4 and 6 mm using a combination of connective tissue grafts and a mucoperiosteum flap and surpasses the results of the envelope technique in this kind of defect .40,44 furthermore the periosteum eversion technique and the combined connective tissue graft and flap technique both show better long - term results for root coverage than gtr techniques for these special defects . when using membrane techniques , the extent of root coverage is between 72.7 % and 82 % .49,50 an improvement in attached gingiva is similar for both the periosteum eversion technique and the combined connective tissue graft and flap technique .50 the main advantage of the periosteum eversion technique in comparison to all other techniques using free grafts is that there is no donor - site morbidity .33 although connective tissue grafts are only associated with minor donor site problems , they may only be harvested to a limited extent ,51 whereas periosteum exists in every location of the alveolar ridge and can also be used for covering multiple recessions in the same patient . furthermore there is only a low risk of transplant necrosis in well vascularized tissue .4 although the incidence of necrosis is low in free connective tissue grafts , the well vascularized periosteum flap has the possibility to react to bacterial contamination like any other vital tissue and the danger of necrosis and infection in this kind of flap is low . the risk of necrosis and infection is at the lowest if a vascularized graft is used and therefore there is a low risk for graft removal with the associated difficulties of second - flap surgery for defect coverage .5255 it can be concluded that the periosteum eversion technique is highly suitable for covering extended denuded roots caused by recession . the technique is similar to a combined therapy of connective tissue graft and flap transposition . its main advantage is that the periosteum remains vascularized and there are no donor site problems . the biological mechanisms of tissue regeneration caused by this technique need to be examined in subsequent studies .\noutput:\n" }, { "from": "agent", "value": "this is a case series in which a new technique for the surgical treatment of periodontal recessions is presented along with the results of the first clinical trial . a new technique of periodontal flap surgery was performed on 30 patients with severe periodontal recessions of the upper or lower front teeth . root and soft tissue scaling was carried out with an open approach , then the periosteum was incised and mobilized at the apical part of the mucoperiosteum flap to cover the defect before the mucoperiosteum was reattached and fixed by sutures . sulcus bleeding , periodontal probing depths , attachment loss and the length of the attached gingiva of the affected teeth were recorded preoperatively and at 3 , 6 , and 12 months postoperatively . every clinical parameter was improved by surgery . no sulcus bleeding was observed at any time during the postoperative follow - up . a mean reattachment of 5.5 mm was noticed 12 months postoperatively at a mean probing depth of 0.3 mm . the mean height of the attached gingiva was 0 mm before surgery , 2.3 mm at three and six months postoperatively , and 2.2 mm at 12 months . the periosteum eversion technique is suitable for the treatment of gingival recessions resulting in good gingival function and a clear improvement in aesthetics ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: in all well developed societies there tend to be barriers between different organizations and different professions , even when those professions want to co - operate to help individuals to satisfy their needs . health and social services today face groups of patients who have composite problems and are often unstable . they include , very obviously , elderly persons with multiple problems , chronically ill children , and persons suffering mental ill - health . they have continuing need of care and in search of care they move between primary care , hospital care and municipality care , such as that provided for elderly persons . their situation demands some form of integration between health and social services , the benefits of which have been identified as including reduced hospital use , a strong focus on prevention and keeping patients healthy , and the provision of care closer to home . from the perspective of the person seeking care , medical and social needs are connected . individuals do not see themselves as multi - ill , but as needing support for their needs as they know them . it must be said that from the 1970s onwards a number of integrative approaches have been tried out , not least in education . although there are exceptions to learn from , generally speaking european health and social services are fragmented and poorly equipped to take care of patients with composite needs . so far , and to a great extent , the task of integrating different delivery systems , of managing the transitions from one provider to another , has fallen on the shoulders of patients themselves or their relatives . much of the evidence indicates that the problem we face is a result of the prevailing mindset . how can we increase our understanding of health and social services that are located in different organizations ? in all well developed societies there tend to be barriers between different organizations and different professions , even when those professions want to co - operate to help individuals to satisfy their needs . health and social services today face groups of patients who have composite problems and are often unstable . they include , very obviously , elderly persons with multiple problems , chronically ill children , and persons suffering mental ill - health . they have continuing need of care and in search of care they move between primary care , hospital care and municipality care , such as that provided for elderly persons . their situation demands some form of integration between health and social services , the benefits of which have been identified as including reduced hospital use , a strong focus on prevention and keeping patients healthy , and the provision of care closer to home . from the perspective of the person seeking care , medical and social needs are connected . individuals do not see themselves as multi - ill , but as needing support for their needs as they know them . it must be said that from the 1970s onwards a number of integrative approaches have been tried out , not least in education . although there are exceptions to learn from , generally speaking european health and social services are fragmented and poorly equipped to take care of patients with composite needs . so far , and to a great extent , the task of integrating different delivery systems , of managing the transitions from one provider to another , has fallen on the shoulders of patients themselves or their relatives . much of the evidence indicates that the problem we face is a result of the prevailing mindset . how can we increase our understanding of health and social services that are located in different organizations ? lindberg observed examples of meaningful co - operation at the local level , with colleagues from different organizations meeting and pooling their knowledge of local conditions with the patient or user as the focal point . the phenomenon has been variously called the chain of care , integrated care , seamless care or shared care . this co - operation aims at creating a continuing relationship with the patient / user regardless of who at a given moment is the responsible provider . edgren and stenberg found these practical attributes of co - operation in cass : a common task is shared among the co - working agents.collaboration is in people s minds , it is instinctive behaviour.each actor s capabilities are known and respected.a combination of monetary and non - monetary incentives exists in order to create lasting mutually acceptable solutions . collaboration is in people s minds , it is instinctive behaviour . each actor s capabilities are known and respected . a combination of monetary and non - monetary incentives exists in order to create lasting mutually acceptable solutions . according to brommels in his presentation to the ehma - conference 2006 , the cas approach means , among other things : identifying and supporting constructive relations between agents within the system and understanding tensions and conflicts.avoiding strict definitions of roles and concentrating on agreed actions.giving agents their freedom to organize current activities . identifying and supporting constructive relations between agents within the system and understanding tensions and conflicts . avoiding strict definitions of roles and concentrating on agreed actions . giving agents their freedom to organize current activities . if we are to improve our understanding of how a health or social service provider functions as an integrated part of a locally driven health and social service system , we need an innovative , in terms of changing practice , model to guide our thinking . traditional models view systems as machines . it helps us understand what happens in dynamic living systems , where many agents are interconnected . in order to make clear its significance let us first recapitulate the machine model . for a long time effective organizationsthe machine has a constructor , the top manager , who describes the integral parts and how they are supposed to co - operate . hospitals and other health services organizations are usually designed to function according to principles of scientific management . rationality , objectivity , stability and predictability are the terms we associate with this approach . rationality , for example , requires that all integral parts act on perfect information , have the same background and similar values and work towards the same goals , and that there is a system designer , the top manager , who is from outside the system . change is seen as a linier and predictable process , controlled by top managers and carried out by works managers . plans are made and are to be followed , and the intended change , takes place as a direct consequence . if problems do arise during the implementation of change , then either there is wrong expectations or there is an inability or refusal to take prescribed action . the change takes time and energy and the outcome is difficult to take in . when political decisions setting precise goals are centralized and detailed rules are laid down and lines of action specified , and when there is constant top - down monitoring and assessment , there is a very real risk of destroying capacity and motivation at the so - calledand then , when the unforeseen happens , the whole system breaks down , because there is no readiness or capability to adapt all solutions have been pre - programmed beforehand . from thiswe learn that when there is no motivation to renew the system , when there is an inability to innovate , the survival of the system is threatened . if health and social service providers are to meet changing demands and expectations from patients or users , they must be able to move quickly to find mutually acceptable , locally developed forms of integration at their points of intersection , that is , where their separate services should be coming together . instead of theories assuming cause and effect linkages between separate details , we need theories to deal with patterns and principles . a few years ago concepts such as the knowledge society and learning organizations , and the associated mechanisms and technologies the internet , e - mail , mobile phones and digital imaging were all unknown . davis coined the expression any time , any place when he describes how time and space restrictionsthis has given us enormous possibilities to communicate , to become connected , to network . as we advance in the knowledge society , the basic assumptions behind much of what is taught and practiced in the name of management are now hopelessly out of date . indeed , most of our assumptions about organizations are at least fifty years old . so why turn to complexity science and to complex adaptive systems ( cas ) ? according to zimmerman et al . they provide an alternative to traditional management principles , that is they offer patterns and principles whereby we can better act in an increasingly complex world , as when we attempt to harness health and social care and other services to meet the particular needs of the individual . in such a way complexity science can serve as a sense making tool . it also enables us to develop locally adapted solutions in order to manage complex tasks , such as we find in advanced home health care . complexity can be expressed as the amount of information needed to describe or understand something . andthe term complex emphasizes that the necessary competence to perform a task is not owned by any one part , but comes as a result of co - operation within the system . a cas consists of several subsystems called agents , which act in dependence of one another . . they may either compete or co - operate according to their sense of their interests and what will bring them an advantage . self - organization is about creating order or increasing the regularity of the system without help from the outside . good examples would be the ant - hill , the human immune defence , the financial market and the surgical operating theatre team . important work has been carried out at the new england complex system institute and the santa fe institute and elsewhere . researchers in chemistry , physics , biology , medicine , anthropology economics , and sociology have been asking fundamental questions about living systems , living systems that are not fixed , but change , grow , heal up , adjust , renew and develop organically . prominent figures in the field include nobel laureates ilya prigogine in chemistry and murray gell - mann in theoretical physics . within medicinewe find stuart kauffman and physics russ marion and mary uhl - bien . according to augustinsson , one way to explain the phenomenon of complexity is by reference to the possibility to apply routines to carry out a particular task . the more a task is characterized by regularities the more we can think in terms of applying routines . when everyday work is characterized by both regularities and irregularities , by a mix of the predictable and the unpredictable , then we have the highest degree of complexity . although more research is needed to achieve greater understanding of complex adaptive systems and to strengthen the knowledge base for action , we do have a growing number of examples that show the cas concept gaining ground within the health and social services . the agents see the point , because they create order out of many local interactions . complexity science offers new ways to understand how complementary knowledge organizes for co - operation . we can regard integrated care partners as partners in a common system and we can regard them logically as agents in this system . emergency treatment is a clear example of independent agents interacting locally with other independent agents . another example comes from elderly care where the cas concept has been applied to secure agreement between politicians and civil servants . the objective was to identify how local politicians and managers understand problems and goals regarding the structures and processes involved in the care of the elderly . a common vision , easy to understand and to communicate , there is no external constructor , no superior centrally located source to govern the design of the system . when we study a cas , the focus is on the interaction and communication between agents . rewriting the old clich , that the whole is greater than the sum of the parts , the whole is the relations between the parts . whether between two persons or between human being and machine or between machine and machine , it is the intensity of relations that determines the complexity of the system , the constant change , adaptation and development of the system , which will be in an unforeseeable non - linear way . todaydigital imaging as a diagnostic technology brings together the specialist radiologist and the primary practitioner treating the patient in a way that was virtually impossible previously . andthereby generate new possibilities of professional interaction and patient involvement as well as new forms of inter - organizational collaboration . complexity science emphasizes the inherent power of development and self - organizing nature of the system . attempts from above to reduce the complexity of the system in order to gain control , are often counterproductive . in practice we assume that any provider s top down attempt at specifying tasks will risk more complexity for the patient . such top down attempts are usually made in order to make it simpler for the provider not the person seeking care . when we address a given community s health and social problems , the process is local : both in intelligence gathering , using multiple local sources to build up the knowledge base for action , and in connecting all those locally based agencies / institutions and individuals with competence to do something about them . one important aspect of complexity science is that it has shown how complementary knowledge organizes for co - operation . later studies of cass have emphasized how the interplay between the environment and the system results in a sort of co - development , whereby each influences the other . so , for example , a hospital inpatient can at the same time be a part both of the hospital system and another system at his workplace . positive feedback loops enhance or amplify changes and tend to move a system away from equilibrium stage . for example in general terms , there is a positive feedback loop between income and consumption in an economy . the bigger the income of the individuals , negative feedbacks tend to dampen or buffer changes and hold a system to some equilibrium state , like a thermostat in a fridge . these loops are carriers of information , material and energy between the agents of the system , and facilitate the adaptability of the entire system . in complexity science positive and negative feedbackthere is not much sense in agents spending time separately on detailed planning since the functioning of the system is a result of their interactions . instead holden talks about direction without directives . it has been found that for purposes of fostering connectivity among diverse agents , effective coupling of structures , ideas and innovations , and ensuring that they are neither too loose nor too tightly interdependent , complex systems are better led by indirect than by direct leadership behaviours . the cas approach helps agents to see themselves as co - workers , part of an innovative team with great potential . with their local knowledge of needs , they are so much better placed to act than any centrally located management ever could be . they sense that they have control over their own work situation , perhaps the most important change needed to create the good workplace . in this waywe see that the cas approach satisfies the fundamental human need to participate , to have a feeling of solidarity , to be part of a greater whole . general criticisms of the cas approach coming from practitioners concern a lack of recommendations as to how they should behave being part of a cas . others may argue that this is only one of several possible approaches to promote integrated care . communication - and co - ordination conflicts among participating agents , or rather free riding agents , have been noted . a certain level of system inertia may also develop over time . to learn to use a different approach to organizing may mean insecurity and risk similar to being expected to accept new technology . seen from a staff perspective the cas approach may mean increased insecurity , greater responsibility , more decision - making and more elements of risk management . the cas approach raises some ethical concerns that refer to decision making that can neither be supported by science nor by objective criteria . first this is due to the nature of the system which is determined by the sum of choices made in it . secondly , when there appears to be no simple final objective or calculable ground for our decisions , we can not shift the responsibility for the decision onto something or somebody else do nt blame me ; the genetic algorithm said we should sell ! we know that all our choices to some extent represent a step in the dark , and therefore , we can not but be responsible for them . but the cas approach lays out the considerations to be taken into account more clearly than the alternatives . for a long time effective organizations have been looked upon like well - oiled machines . the machine has a constructor , the top manager , who describes the integral parts and how they are supposed to co - operate . hospitals and other health services organizations are usually designed to function according to principles of scientific management . rationality , objectivity , stability and predictability are the terms we associate with this approach . rationality , for example , requires that all integral parts act on perfect information , have the same background and similar values and work towards the same goals , and that there is a system designer , the top manager , who is from outside the system . change is seen as a linier and predictable process , controlled by top managers and carried out by works managers . plans are made and are to be followed , and the intended change , takes place as a direct consequence . if problems do arise during the implementation of change , then either there is wrong expectations or there is an inability or refusal to take prescribed action . the change takes time and energy and the outcome is difficult to take in . when political decisions setting precise goals are centralized and detailed rules are laid down and lines of action specified , and when there is constant top - down monitoring and assessment , there is a very real risk of destroying capacity and motivation at the so - calledand then , when the unforeseen happens , the whole system breaks down , because there is no readiness or capability to adapt all solutions have been pre - programmed beforehand . from thiswe learn that when there is no motivation to renew the system , when there is an inability to innovate , the survival of the system is threatened . if health and social service providers are to meet changing demands and expectations from patients or users , they must be able to move quickly to find mutually acceptable , locally developed forms of integration at their points of intersection , that is , where their separate services should be coming together . instead of theories assuming cause and effect linkages between separate details , we need theories to deal with patterns and principles . a few years ago concepts such as the knowledge society and learning organizations , and the associated mechanisms and technologies the internet , e - mail , mobile phones and digital imaging were all unknown . davis coined the expression any time , any place when he describes how time and space restrictionsthis has given us enormous possibilities to communicate , to become connected , to network . as we advance in the knowledge society , the basic assumptions behind much of what is taught and practiced in the name of management are now hopelessly out of date . indeed , most of our assumptions about organizations are at least fifty years old . so why turn to complexity science and to complex adaptive systems ( cas ) ? according to zimmerman et al . they provide an alternative to traditional management principles , that is they offer patterns and principles whereby we can better act in an increasingly complex world , as when we attempt to harness health and social care and other services to meet the particular needs of the individual . in such a way complexity science can serve as a sense making tool . it also enables us to develop locally adapted solutions in order to manage complex tasks , such as we find in advanced home health care . complexity can be expressed as the amount of information needed to describe or understand something . and an important part of complexity science is the complex adaptive system ( cas ) . the term complex emphasizes that the necessary competence to perform a task is not owned by any one part , but comes as a result of co - operation within the system . a cas consists of several subsystems called agents , which act in dependence of one another . . they may either compete or co - operate according to their sense of their interests and what will bring them an advantage . self - organization is about creating order or increasing the regularity of the system without help from the outside . good examples would be the ant - hill , the human immune defence , the financial market and the surgical operating theatre team . important work has been carried out at the new england complex system institute and the santa fe institute and elsewhere . researchers in chemistry , physics , biology , medicine , anthropology economics , and sociology have been asking fundamental questions about living systems , living systems that are not fixed , but change , grow , heal up , adjust , renew and develop organically . prominent figures in the field include nobel laureates ilya prigogine in chemistry and murray gell - mann in theoretical physics . within medicinewe find stuart kauffman and physics russ marion and mary uhl - bien . according to augustinsson , one way to explain the phenomenon of complexity is by reference to the possibility to apply routines to carry out a particular task . the more a task is characterized by regularities the more we can think in terms of applying routines . when everyday work is characterized by both regularities and irregularities , by a mix of the predictable and the unpredictable , then we have the highest degree of complexity . although more research is needed to achieve greater understanding of complex adaptive systems and to strengthen the knowledge base for action , we do have a growing number of examples that show the cas concept gaining ground within the health and social services . the agents see the point , because they create order out of many local interactions . complexity science offers new ways to understand how complementary knowledge organizes for co - operation . we can regard integrated care partners as partners in a common system and we can regard them logically as agents in this system . emergency treatment is a clear example of independent agents interacting locally with other independent agents . another example comes from elderly care where the cas concept has been applied to secure agreement between politicians and civil servants . the objective was to identify how local politicians and managers understand problems and goals regarding the structures and processes involved in the care of the elderly . a common vision , easy to understand and to communicate , was created to connect the two groups . there is no external constructor , no superior centrally located source to govern the design of the system . when we study a cas , the focus is on the interaction and communication between agents . rewriting the old clich , that the whole is greater than the sum of the parts , the whole is the relations between the parts . whether between two persons or between human being and machine or between machine and machine , it is the intensity of relations that determines the complexity of the system , the constant change , adaptation and development of the system , which will be in an unforeseeable non - linear way . todaydigital imaging as a diagnostic technology brings together the specialist radiologist and the primary practitioner treating the patient in a way that was virtually impossible previously . and thereby generate new possibilities of professional interaction and patient involvement as well as new forms of inter - organizational collaboration . complexity science emphasizes the inherent power of development and self - organizing nature of the system . attempts from above to reduce the complexity of the system in order to gain control , are often counterproductive . in practicewe assume that any provider s top down attempt at specifying tasks will risk more complexity for the patient . such top down attempts are usually made in order to make it simpler for the provider not the person seeking care . working in isolation the burden of coordination passes to the patient . when we address a given community s health and social problems , the process is local : both in intelligence gathering , using multiple local sources to build up the knowledge base for action , and in connecting all those locally based agencies / institutions and individuals with competence to do something about them . one important aspect of complexity science is that it has shown how complementary knowledge organizes for co - operation . later studies of cass have emphasized how the interplay between the environment and the system results in a sort of co - development , whereby each influences the other . so , for example , a hospital inpatient can at the same time be a part both of the hospital system and another system at his workplace . positive feedback loops enhance or amplify changes and tend to move a system away from equilibrium stage . for example in general terms , there is a positive feedback loop between income and consumption in an economy . the bigger the income of the individuals , the more the whole population consume , which further increasing their income as individuals . negative feedbacks tend to dampen or buffer changes and hold a system to some equilibrium state , like a thermostat in a fridge . these loops are carriers of information , material and energy between the agents of the system , and facilitate the adaptability of the entire system . in complexity sciencethere is not much sense in agents spending time separately on detailed planning since the functioning of the system is a result of their interactions . instead holden talks about direction without directivesit has been found that for purposes of fostering connectivity among diverse agents , effective coupling of structures , ideas and innovations , and ensuring that they are neither too loose nor too tightly interdependent , complex systems are better led by indirect than by direct leadership behaviours . the cas approach helps agents to see themselves as co - workers , part of an innovative team with great potential . with their local knowledge of needs , they are so much better placed to act than any centrally located management ever could be . they sense that they have control over their own work situation , perhaps the most important change needed to create the good workplace . in this waywe see that the cas approach satisfies the fundamental human need to participate , to have a feeling of solidarity , to be part of a greater whole . general criticisms of the cas approach coming from practitioners concern a lack of recommendations as to how they should behave being part of a cas . some theorists would claim that cas is nothing but the emperor s new clothes . others may argue that this is only one of several possible approaches to promote integrated care . communication - and co - ordination conflicts among participating agents , or rather free riding agents , have been noted . a certain level of system inertia may also develop over time . to learn to use a different approach to organizing may mean insecurity and risk similar to being expected to accept new technology . seen from a staff perspective the cas approach may mean increased insecurity , greater responsibility , more decision - making and more elements of risk management . the cas approach raises some ethical concerns that refer to decision making that can neither be supported by science nor by objective criteria . first this is due to the nature of the system which is determined by the sum of choices made in it . secondly , when there appears to be no simple final objective or calculable ground for our decisions , we can not shift the responsibility for the decision onto something or somebody else do nt blame me ; the genetic algorithm said we should sell ! we know that all our choices to some extent represent a step in the dark , and therefore , we can not but be responsible for them . but the cas approach lays out the considerations to be taken into account more clearly than the alternatives . when the competence necessary for carrying out a given task does not lie within one individual provider organization , co - operation between agents within the system comes into play to discharge that task . we are no longer talking about the individual organization / agent but shaping overall workable solutions taking a patient / user perspective . this applies to matching care with the needs of different patient groups and of individual patients . the cas approach helps the management to understand why the traditional top down way of managing may meet with problems in organizations with complex tasks . an important discussion is about how the top management in fact executes its steering function . leaders may consider accepting complexity instead of trying to reduce it , formulate few simple and concrete goals , communicate and give feedback and measure performance . when we perceive health and social service organizations as cass we should gain more insight into the processes that go on within and between organizations . are we willing to face the interdependence between health and social services , the dependence on collaboration to deliver appropriate integrated care ? if we do , complexity science could be an important step towards fresh thinking in order to fulfil our patients and users presently unfulfilled needs . edgar borgenhammar , phd ( economics ) , mba ( berkeley ) , dsi ( lund ) , professor emeritus , from the nordic school of public health in gteborg , former hospital chief executive , sweden peter carswell , dr . , centre for health services research and policy , faculty of medical and health sciences , university of auckland , auckland , new zealand alene hokenstad , project director , united hospital fund , new york , usa\noutput:\n" }, { "from": "agent", "value": "introductionorganizations can be regarded as systems . the traditional model of systems views them as machines . this seems to be insufficient when it comes to understanding and organizing complex tasks . to better understand integrated care we should approach organizations as constantly changing living organisms , where many agents are interconnected in so - called complex adaptive systems ( cas ) . theory and discussionthe term complex emphasizes that the necessary competence to perform a task is not owned by any one part , but comes as a result of co - operation within the system . adaptive means that system change occurs through successive adaptations . a cas consists of several subsystems called agents , which act in dependence of one another . examples would be the ant - hill , the human immune defence , the financial market and the surgical operating theatre team . studying a cas , the focus is on the interaction and communication between agents . although these thoughts are not new , the cas - approach has not yet been widely applied to the management of integrated care . this helps the management to understand why the traditional top down way of managing , following the machine model thinking , may meet with problems in interdependent organizations with complex tasks.conclusionwhen we perceive health and social services as cass we should gain more insight into the processes that go on within and between organizations and how top management , for example within a hospital , in fact executes its steering function ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: endoscopic submucosal dissection ( esd ) has been accepted as an established procedure for superficial esophageal neoplasms .1 although the most important advantage of esd is its effectiveness in resecting lesions regardless of size , postoperative stricture occasionally becomes a problem after esd for large lesions , especially in the esophagus . to avoid unnecessary complications , an accurate diagnosis of the horizontal extent of the tumor is very important . at present , lugol chromoendoscopy is the golden standard for detection and demarcation of esophageal squamous cell neoplasms ( escn ) .2 - 5 however , it is also reported to occasionally cause mucosal irritation and induce erosions or ulcers in the esophagus .6,7 we report a case of escn in which intraoperative demarcation of tumor became difficult due to re - epithelialization after mucosal damage by preoperative iodine staining . his alcohol consumption was low ( 350 ml beer every day ) and he did not have a history of smoking . he underwent esophagogastroduodenoscopy as part of a medical checkup and an iodine - unstained area through lugol chromoendoscopy was pointed out . conventional endoscopy using a high - resolution upper gastrointestinal endoscope ( gif - h260z ; olympus medical system corp . , tokyo , japan ) showed a reddish rough mucosal area on the right side of the middle thoracic esophagus , occupying one third of the circumference of the esophagus ( fig . the lesion was evaluated as a clearly distinguishable brownish area by narrow band imaging ( nbi ) endoscopy ( fig . dilated and irregular intraepithelial papillary capillary loop ( ipcl ) pattern was observed in the whole lesion through magnifying endoscopy with nbi . although elongation of the ipcl was observed partially in the lesion , severe destruction of the vessels was not observed . these findings suggested that it was either high grade intraepithelial neoplasia or invasive squamous cell carcinoma limited to the lamina propria .8 after noninvasive observation , 20 ml of 3 % lugol 's solution was applied on the esophageal mucosa . the lesion was identified as a clearly distinguishable iodine - unstained area measuring about 40 mm or less in diameter ( fig . a targeted biopsy from the center of the lesion was performed , and the histopathological assessment was atypical squamous cells suggesting squamous cell carcinoma . gif - h260z was used for evaluation of the horizontal extent of the tumor and marking , and gif - q260j for resection of the tumor , respectively . at the time of treatment , the oral border of the tumor was unclear by conventional endoscopy although we used the same endoscope , gif - h260z , as in the previous endoscopy ( fig . the lesion was observed as a brownish area with a vague border and could be barely demarcated by magnifying endoscopy with nbi ( fig . after that , intraoperative iodine staining with 3 % lugol 's solution was performed , and it revealed a 25 mm unstained area as well as many other small unstained areas scattered on the oral side ( fig . 2c ) . we put marking dots around the identified tumor border including small unstained areas with a 5 mm margin at 2 to 3 mm interval by dual knife ( olympus medical system corp . ) because they seemed to concur with the brownish area identified through magnifying endoscopy with nbi and also with the iodine - unstained area observed in the preoperative endoscopy .3 ) .9 histopathological assessment revealed proliferation of atypical squamous cells limited to the mucosal epithelium , indicating high - grade intraepithelial neoplasia . both lateral and vertical margins were tumor - free , and there was no vessel infiltration . tumor cells were also found in the basal - parabasal layers of the mucosa where small unstained areas were scattered , although superficial layers showed well - differentiation containing glycogen in cytoplasm . he was pathologically judged to be completely cured , and follow - up endoscopy has detected neither local recurrence nor metachronous lesion so far . since the 1960s when lugol 's solution was first used to evaluate esophageal diseases ,10 it has been widely used in the detection and demarcation of superficial esophageal neoplasms . lugol chromoendoscopy is based on a chemical reaction between iodine , and the glycogen contained in normal epithelial cell microgranules in the stratum spinosum .11 dysplastic and cancerous cells are not stained by lugol 's solution because they do not contain glycogen . for this reason , it is reported that endoscopic screening with lugol 's solution is useful for the detection of superficial escn in high risk populations , such as patients with a history of head or neck cancers .2 - 4 additionally , lugol chromoendoscopy has also been reported to be beneficial in the evaluation of horizontal extent of these lesions ,12 and is often used to determine the extent of resection during esd . on the other hand , lugol 's solution often causes mucosal irritation leading to retrosternal discomfort .6 in addition , it is reported to cause chemical esophagitis and gastritis and to induce erosions and ulcers .7,13,14 sreedharan et al. 14 reported that the biopsies from gastric mucosa of chemical gastritis due to lugol 's solution confirmed acute edema of the lamina propria with loss of the superficial epithelium . we speculate that the same phenomenon occurs in patients with chemical esophagitis . in this case , mucosal damage by preoperative lugol chromoendoscopy may have complicated intraoperative demarcation of tumor . at the time of treatment , a part of the previously unstained area showed an affinity to lugol 's solution , and consequently a 25 mm unstained area with many small unstained areas scattered on the oral side could be observed . histological assessment of this area revealed atypical squamous cells in the basal - parabasal layers of the mucosa although superficial layers showed well - differentiation containing glycogen in cytoplasm . these results suggested that a portion of atypical squamous cells in the superficial layers desquamated because of the damage by preoperative lugol chromoendoscopy , and re - epithelialization with normal squamous epithelial cells occurred there , then morphological change of iodine - unstained area was observed at the time of treatment . lesions should be resected with necessary and sufficient tumor - free margins to minimize local recurrence and unnecessary stricture . to minimize the influence of preoperative lugol chromoendoscopyfirst , the concentration of lugol 's solution is an important factor . considering that lugol chromoendoscopyis based on a chemical reaction , large amounts of free iodine may increase the mucosal damage . sreedharan et al. 14 reported that higher concentrations ( 3 % to 5 % ) of lugol 's solution might be associated with a higher risk of complications . for the same reason , routine use of sodium thiosulfate solution soon after lugol chromoendoscopy may theoretically be effective . kondo et al. 6 reported that spraying 20 ml of 5 % sodium thiosulfate solution could neutralize free iodine and reduce side effects of lugol 's solution . second , the interval from preoperative endoscopy with iodine staining to endoscopic treatment is another important factor . in this case , demarcation of the tumor was clear at first endoscopy in our hospital although he had undergone lugol chromoendoscopy in another hospital the previous day , indicating that re - epithelialization did not occur immediately after lugol chromoendoscopy . on the other hand , a sufficient interval from preoperative endoscopy to endoscopic treatment may also be helpful because tumor cells in the basal - parabasal layers of the mucosa is hypothesized to proliferate and replace well - differentiated cells in the superficial layer along with time . however , setting too long interval is a risk for leading tumor progression and resulting noncurative resection by esd . further researches are needed to determine the optimal interval from preoperative endoscopy including lugol chromoendoscopy to endoscopic treatment . magnifying endoscopy with nbi has recently been reported to be useful in the detection of escn .5,15,16 i - scan , which is another image enhanced endoscopy ( iee ) technology , has also been reported to be helpful in the detection and the demarcation of gastrointestinal tumors including escn .17 if the progress of these new iee technologies makes it possible for endoscopists to detect escn and to diagnose the horizontal extent of escn without spraying lugol 's solution in preoperative endoscopy , the problem of re - epithelialization at the time of treatment may be resolved . however , further studies are required to compare the diagnostic ability of these new technologies and lugol chromoendoscopy in detecting and demarcating escns . we encountered a case of escn where demarcation of the tumor was complicated by preoperative lugol chromoendoscopy . detailed evaluation about the optimal concentration of lugol 's solution and interval from preoperative endoscopy to endoscopic treatment , and further studies about diagnostic ability of iees are desirable .\noutput:\n" }, { "from": "agent", "value": "a 53 - year - old man was suspected of having an esophageal neoplasm . an endoscopic examination including lugol chromoendoscopy suggested an esophageal squamous cell neoplasm limited to the lamina propria . a targeted biopsy showed atypical squamous cells , and an endoscopic submucosal dissection was performed 22 days after the previous endoscopy . although a single 40 mm unstained area was observed by preoperative lugol chromoendoscopy , intraoperative endoscopy revealed a 25 mm iodine - unstained area , with small unstained areas scattered on the oral side . we included the small unstained areas in the extent of the resection through assessment by preoperative endoscopy . histopathologically , the tumor extent appeared to coincide with the preoperative assessment . tumor cells were found in the basal - parabasal layers of the mucosa , in which small unstained areas were scattered , although the superficial layers exhibited well - differentiated cells containing glycogen in the cytoplasm . although lugol chromoendoscopy , which can induce chemical esophagitis , is widely used , re - epithelialization after mucosal damage by preoperative iodine staining may complicate the intraoperative demarcation of tumors ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the volunteer participants of this study were recruited by announcements in gambling - related internet sites ( www.ray.fi , www.pakkopeli.fi , www.a-klinikka.fi , www.peluuri.fi , www.suomi24.fi , www.paihdelinkki.fi ) and by two announcements in a widely distributed , free newspaper ( metro ) during the first quarter of 2009 . in the announcements , those who experienced gambling as a problem were advised to visit the study s webpage and complete the finnish version of the south oaks gambling screen ( sogs ) and a dsm - iv - based screen ( lesieur and blume 1987 ; apa 1994 ) . sogs includes 16 questions about problems associated with gambling and is used to measure the pathology of gambling . the total score on the sogs ranges from 0 to 20 ( higher values are indicative of worse psychopathologic states : a value of 5 or more indicates probable pathological gambling ) . the dsm - iv screen for pathological gambling includes 10 questions relating to persistent and recurrent maladaptive gambling behavior . the total score on the dsm - iv screen ranges from 0 to 10 ( higher values are indicative of worse gambling - related problems ; a value of 5 or more indicates pathological gambling ) . those respondents who scored five or more on both the sogs and dsm - iv screens were informed about their possible suitability for the study and given the e - mail address to contact the research team . those who contacted the research team were invited to a visit with a study doctor , who assessed their suitability for the research . the inclusion criteria were : a score of 5 or more on the sogs and dsm - iv screens and an ability to use the internet and e - mail . the exclusion criteria were : acute hepatitis , severe liver or kidney dysfunction , suicide risk , severe depression or other untreated mental health problem , participation in other gambling research at the same time , the use of drugs ( especially opiates ) , pregnancy ; also excluded were prisoners and people with mental illness or mental retardation . the ethics board of the helsinki & uusimaa hospital district gave permission for this study ( permission # eudract # 2008 - 004102 - 14 and ethical permission # 259 / 13/03/00 / 2008 ) . all participants had to be able to read and understand the patient information sheet and sign the informed consent . the socio - demographic variables of the subjects were based on the following questions : what is your age , gender , relationship status , education , employment status , and residence ? in addition to these , we asked if the subjects smoked or if they had incurred debts due to their gambling . to record the lag - times between their first gambling experience , active gambling and pathological gambling , we asked the subjects to report the corresponding ages for these stages . the games gambled and gambling behavior were analyzed from the answers given for the sogs and dsm - iv screens . we used multivariate linear regression modeling to study the effects of relevant socio - demographic variables on sogs and dsm - iv scores , and on the initiation age of active gambling . the subjects ( n = 39 ) were finnish adults aged 2078 years ( average age 39 years ) , with 80 % being male ( average age 36 years ) and 20 % female ( average age 51 years ) . most of the subjects were married or cohabited ( 59 % ) , lived with their family or with friends ( 72 % ) , had at least a secondary education degree ( 69 % ) , and were employed ( 87 % ) ( fig . 1 ) .1 socio - demographic variables of the subjects socio - demographic variables of the subjects according to sogs , all of the subjects ( 100 % ) had some times gambled more than they had originally planned . the highest amount of money spent on gambling was usually eur 100999 per day ( 44 % ) ( table 1 ) . money loaned for gambling was most often loaned from household funds ( 69 % ) ( table 1 ) . regression estimates of socio - demographic factors on gambling behavior ( sogs , dsm - iv and initiation age of active gambling ) are shown in table 2 . the higher the subject s score on sogs , the higher the debts they had incurred due to gambling ( = 2.85 , se = 1.19 , p = 0.02 ) . the association between gambling debts and dsm - iv was only of marginal significance ( = 0.81 , se = 0.47 , p = 0.10 ) . men had incurred debts due to gambling significantly more often than women ( fisher s exact test , p = 0.02 ) . other basic variables ( gender , age , education , marital status , residence , or smoking ) had no effect on the sogs or dsm - iv screen scores.table 1money and gambling : highest daily bets and sources of gambling loanshighest daily bets ( % of subjects ) 109910099910009999100005 % 44 % 38 % 13 % sources of loans ( % of subjects ) household fundsbank / quick loanscredit cardspouse or relativesgambling on creditprivate loan giverspawnshops or selling propertyselling shares69 % 68 % 67 % 56 % 49 % 33 % 31 % 21 % table 2multivariate linear regression model estimates and standard errorsexplanatory variablemodel 1model 2model 3sogsdsm - ivstarting age of active gambling ( se ) ( se ) ( se ) ( intercept ) 14.77 ( 2.74 ) 7.00 ( 1.13 ) 3.84 ( 0.32 ) male gender0 .57 ( 1.42 ) 0.89 ( 0.57 ) 0.56 ( 0.23 ) age ( years ) 0.04 ( 0.04 ) 0.01 ( 0.01 ) - elementary school1 .13 ( 0.97 ) 0.00 ( 0.40 ) 0.02 ( 0.17 ) married1 .13 ( 1.37 ) 0.13 ( 0.56 ) 0.19 ( 0.24 ) living alone1 .61 ( 1.57 ) 0.35 ( 0.65 ) 0.11 ( 0.28 ) smoker0 .82 ( 0.93 ) 0.01 ( 0.39 ) 0.21 ( 0.16 ) gambling debts2 .85 ( 1.19 ) 0.81 ( 0.47 ) 0.01 ( 0.20 ) 0.10.05 logarithmic transformationthere is a self - evident correlation between age and starting age of active gambling , and therefore age is not included as an explanatory variable in model 3 money and gambling : highest daily bets and sources of gambling loans multivariate linear regression model estimates and standard errors logarithmic transformation there is a self - evident correlation between age and starting age of active gambling , and therefore age is not included as an explanatory variable in model 3 according to the sogs results , most of the subjects argued about gambling with their families ( 95 % ) and felt guilt ( 97 % ) due to gambling . thus most of the subjects 84 % tried to hide their gambling from significant others according to sogs . the results from the dsm - iv screen also supported this observation . in the dsm - iv screen ,92 % of the subjects reported that they were telling lies to hide their gambling losses , and 74 % had even jeopardized or lost a significant relationship , job , or educational or career opportunity because of gambling . the percentages of responses to the different dsm - iv questions are listed in table 3 . table 3percentage of subjects giving affirmative answers to questions made in dsm - iv . percentages are presented separately for female ( n = 8 ) and male ( n = 31 ) populations and for the whole group ( n = 39 ) dsm - ivfemalemaleallthoughts preoccupied with gambling88 % 100 % 97 % need to gamble with increasing amounts of money in order to achieve desired excitement63 % 81 % 77 % repeated unsuccessful efforts to control , cut back , or stop gambling100 % 97 % 97 % restless or irritable when attempting to cut down or stop gambling88 % 100 % 97 % gambling is a way of escaping from problems or of relieving a dysphoric mood50 % 94 % 85 % after losing money gambling , often returns another day in order to get even100 % 100 % 100 % lies to family members , therapist , or others to conceal the extent of involvement with gambling63 % 100 % 92 % committed illegal acts , such as forgery , fraud , theft , or embezzlement , in order to finance gambling0 % 10 % 8 % jeopardized or lost a significant relationship , job , or educational or career opportunity because of gambling25 % 87 % 74 % relies on others to provide money to relieve a desperate financial situation caused by gambling50 % 77 % 72 % percentage of subjects giving affirmative answers to questions made in dsm - iv . n = 31 ) populations and for the whole group ( n = 39 ) the subjects started active gambling ( gambling at least 3 times per week ) usually before the age of 30 . however , there was a significant gender - difference in the initiation ages : men started active gambling significantly earlier than women ( = 0.56 , se = 0.23 , p = 0.02 ) ( table 2 ) . other basic variables ( education , marital status , residence , smoking , or debts ) were not significantly associated with the age of active gambling . in contrast , active gambling very rapidly led to gambling problems . within 2 years of active gambling , 62 % of the subjectsreported having such a serious problem with the gambling , that they started to seek help ( figlag 2 is the time between active gambling and gambling problem according to sogs , the most popular games were slot machines ( table 4 ) . men tended to gamble more with sports and race betting , whereas weekly lotteries and scratch cards were preferred by women.table 4games gambled by the subjects more than once a week ( according to sogs ) . the number of respondents ( female : male ) and the relative % is described separately for both sexes ( female n = 8 , male n = 31 ) n ( female : male ) % of females % of males % of allslot machines6 : 2375 % 74 % 74 % scratch cards2 : 425 % 13 % 15 % sports betting1 : 2113 % 55 % 56 % horse races0 : 30 % 10 % 8 % casino games at finnish casino0 : 40 % 10 % 10 % casino games elsewhere0 : 40 % 10 % 10 % weekly lotteries4 : 1350 % 42 % 44 % daily lotteries3 : 838 % 26 % 28 % veikkaus lottery tickets from internet0 : 40 % 10 % 10 % paf internet poker1 : 913 % 29 % 26 % paf online games ( except poker ) 2:725 % 23 % 23 % international internet netpoker0 : 70 % 23 % 18 % international online games ( except poker ) 1:613 % 19 % 18 % private gambling0 : 30 % 10 % 8 % speculation with investments or shares0 : 10 % 3 % 3 % paf is an internet gambling provider in the finnish ahvenanmaa islands games gambled by the subjects more than once a week ( according to sogs ) . the number of respondents ( female : male ) and the relative % is described separately for both sexes ( female n = 8 , male n = 31 ) paf is an internet gambling provider in the finnish ahvenanmaa islandsone of the most interesting findings of this study was that pathological gambling behavior developed very rapidly after active gambling was initiated . gambling that disturbed their life so much that they started to seek help to quit gambling was reported by 62 % of the subjects to have begun within 2 years of the onset of active gambling . in the case of drug addiction , the time from initiation to developing an addiction differs with different drugs : drugs that produce addiction more rapidly are generally considered to be more addictive . the development of addiction depends often upon the amount of reinforcement arising from the addictive behavior and how soon after the behavior the reinforcement occurs . however , certain drugs , e.g. , heroin , cocaine and nicotine , can bring about addiction in the user very rapidly , probably because they produce a stronger reinforcement . similar to certain drugs , gambling also seems able to cause strong and rapid reinforcement , which may lead to a rapid development of addiction . another interesting finding of this study was the gender - specific difference in the initiation ages . men started active gambling ( gambling at least 3 times per week ) significantly earlier than women ( p = 0.02 ) .2009 ; crisp et al . 2004 ; ladd and petry 2002 ; grant and kim 2002 ; tavares et al2004 ) , boys seem to be at higher risk of developing pg . this should be taken into account in the planning of prevention programs for youth . the higher the subjects scored on sogs , the more often they had gambling debts ( p = 0.02 ) . to fund their gambling , subjects borrowed money from various sources ( table 1 ) . according to our results , the subjects borrowed money from banks and other external sources rather than from their spouses or relatives . similarly , according to sogs , 84 % of the subjects were hiding gambling from significant others , and the answers in the dsm - iv screen confirmed this : 92 % of the subjects reported telling lies and hiding gambling losses . earlier studies have also reported that gambling often causes conflicts inside families ( johansson et al . this is in agreement with our findings : 95 % of the subjects reported in sogs that they often have conflicts with significant others about gambling . pathological gamblers have often made many unsuccessful attempts to quit gambling before seeking treatment for the problem . this phenomenon was also demonstrated in our study : the thoughts of the subjects were preoccupied with gambling ( 97 % ) , and they felt restless or irritable when attempting to cut down or quit gambling ( 97 % ) . most of the subjects ( 97 % ) had made unsuccessful attempts to try to control or stop gambling . thus in many ways gambling seems to resemble other addictions in how it affects the life and behavior of the addicted person : the pg s have withdrawal symptoms , try to hide their behavior , experience feelings of guilt and shame , and even borrow money to continue the injurious behavior . these symptoms are similar to those used in the diagnosis of substance use disorders . however , pg not only resembles substance use disorders , it often co - occurs with them ( park et al . both men and women used slot machines weekly but certain sex - specific differences were also seen : men preferred sports betting , the races , and casinos more than women did ( table 4 ) . on the other hand , women gambled more with scratch cards , and entered more weekly and daily lotteries than men did . most studies suggest that women prefer non - strategic games , such as slot machines , whereas men tend to choose strategic games , such as sports betting and horse races ( granero et al . our results partly support these earlier observations : the men had a higher tendency towards strategic games whereas the women preferred luck - based , nonstrategic games . also earlier studies have reported that internet gamblers are more likely to be young men ( griffiths et al . second , the patients were recruited by announcements , and this may have caused bias among the study subjects . it has been suggested that older pg s do not seek help as often as younger pg s ( grant et al . this may , in part , explain why most of our subjects ( 54 % ) were fairly young : under the age of 35 . third , in addition to the age bias , there was a gender bias , with four times as many men in the study . the uneven age and gender ratios probably affected the results , thus limiting the strength of the interpretations . the findings of this study need replication and extension among larger groups of treatment - seeking gamblers .\noutput:\n" }, { "from": "agent", "value": "this article describes the socio - demographic characteristics and gambling behavior of 39 pathological gamblers who participated in our treatment study in 2009 . the inclusion criteria of the study were : score of five or more on both the south oaks gambling screen ( sogs ) and a pathological gambling screen based on the diagnostic and statistical manual of mental disorders ( dsm - iv ) . the first 39 patients meeting the inclusion criterion were recruited into the study . the average age of the subjects was 39 years , and 80 % were males . the lag - time between active gambling ( at least three times per week ) and the onset of a pathological gambling problem was short : within 2 years of active gambling , 62 % of the subjects reported having become pathological gamblers . our results also indicated certain gender - specific differences in the age at initiation and in the severity of the gambling problem ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: adductor spasmodic dysphonia is a disorder characterized by involuntary contractions of the adductor muscles of the larynx during phonation , resulting in strained , strangled , or forced voice quality , as well as intermittent voice breaks12 . the use of botulinum toxin for the treatment of spasmodic dysphonia was described by blitzer in 19863 . since this report , botulinum toxin injection has been the treatment of choice for spasmodic dysphonia in various centers worldwide . the toxin blocks presynaptic acetylcholine release at the neuromuscular junction , causing a partial and reversible chemodenervation leading to muscle weakness , which reduces spasms in patients with dystonia4 . the most widely used method for injecting botulinum toxin into the thyroarytenoid ( ta ) muscle is electromyography - guided injection4 . at our facility , botulinum toxin is typically injected with a flexible needle , which is passed through the biopsy channel of a fiberoptic laryngoscope and guided by video - assisted endoscopy25 . the reported side effects of botulinum toxin injection into the ta muscle include dysphagia , aspiration , and transient dyspnea , effects that vary in terms of incidence and severity610 . another factor observed in clinical practice is a change in glottal configuration , including vocal fold bowing and incomplete glottal closure ( with or without ventricular fold paralysis ) . studies in ophthalmology and gastroenterology have shown that paralysis of adjacent muscles is the most serious complication of the use of botulinum toxin and is probably caused by excessive diffusion of the toxin111213 . this probably accounts for the wide variability in laryngeal function and configuration after injection of botulinum toxin into the ta muscle , given that the adjacent ( non - targeted ) muscles include the lateral cricoarytenoid ( lca ) muscle and the ventricular portion of the ta muscle itself . therefore , the objective of the present study was to evaluate the diffusion of aniline blue , a stain specific to muscle fibers , after its injection into the ta muscles of larynges excised from human cadavers . the larynges were obtained from the university of so paulo school of medicine , so paulo municipal department of death certification , located in the city of so paulo , brazil . all larynges were obtained from adult individuals of 3087 years of age ( mean age , 55.5 years ) . the cause of death was not taken into consideration , given that all larynges were macroscopically intact . in the present study , we used aniline blue , a water - soluble stain that targets muscle fibers , at a concentration of 2 % . the methodology employed was similar to that used for the injection of botulinum toxin in the clinical otolaryngology department of the university of so paulo school of medicine hospital das clnicas5 . the needle was introduced into the ta muscle and middle third of the vibratory portion of the vocal fold , approximately 1 mm lateral to junction of the vibratory portion and the floor of the laryngeal vestibule ( figure 1 ) . we injected 0.2 ml of aniline blue into the right and left vocal folds of each larynx . this volume ( 0.2 ml ) is the volume that is used for botulinum toxin injections at our facility . the larynges remained in an anatomical position for 30 min , after which they were immersed in 10 % buffered formalin and left for 7 days . the larynges were then placed in 7 % nitric acid for 24 h for decalcification , being subsequently immersed in the same buffered formalin solution . the larynges were removed from the buffered formalin solution and stored at -10 c . in order to standardize the laryngeal sections , we drew a line ( corresponding to the projection of the right vocal fold ) on the ipsilateral thyroid cartilage lamina , parallel to the lower border of the cartilage . after measuring the width of the lamina along this line , we divided the line into 4 equal parts . the larynges were coronally sectioned with a microtome blade at 3 points ( at the demarcated levels ) , resulting in 4 sections ( designated sections i , ii , iii , and iv , from posterior to anterior ) . all sections were examined under a surgical microscope in order to identify the regions and muscles that showed aniline blue staining . for subsequent analyses , the sections were photographed with a digital camera ( dsc - s30 ; sony corporation , tokyo , japan ) at a resolution of 640480 pixels . we examined the ta , lca , cricothyroid ( ct ) , and posterior cricoarytenoid ( pca ) muscles for aniline blue staining . we examined both sides of the sections because of the possibility of finding different degrees of aniline blue staining at different depths . stained muscles were defined as those in which the entire length of the muscle ( in at least one of the sections ) showed aniline blue staining . partially stained muscles were defined as those in which part of the muscle , however small , did not show staining . in order to analyze the pca musclewe compared the genders in terms of dye diffusion to the muscles studied , each cadaver being considered as one case . dye diffusion was defined as the presence of aniline blue staining on at least one side ( right or left ) . we then measured the ta muscle in the section in which it was at its largest , using a ruler divided into millimeters . the ta muscle was measured in the lateromedial direction ( width ) and in the craniocaudal direction ( height ) , as shown in figure 2 . points at which the width and height of the thyroarytenoid muscle were measured . in order to compare the muscles in terms of dye diffusion , we used the mcnemar 's test for paired proportions . in order to compare the genders in terms of dye diffusionwhether ta muscle width and height had any influence on dye diffusion to non - injected muscles , we adjusted the logistic regression model , testing the parameters with the wald test . in order to compare the genders in terms of laryngeal sizethe left vocal fold of one of the larynges was damaged during the sectioning process , and the larynx was therefore excluded from the study sample . table 1 shows the analysis of aniline blue staining of the ta , lca , ct , and pca muscles . note : ta , thyroarytenoid ; lca , lateral cricoarytenoid ; ct , cricothyroid ; pca , posterior cricoarytenoid . aniline blue staining was observed most often in the lca muscle , followed by the ct and pca muscles . we found statistically significant differences between the lca and ct muscles and between the lca and pca muscles in terms of the frequency of dye diffusion ( p 0.00001 ) . we also found a statistically significant ( albeit weaker ) difference between the ct and pca muscles in terms of the frequency of dye diffusion ( p 0.0013 ) . table 2 shows the results of the comparison between the genders in terms of the frequency of dye diffusion . since there was dye diffusion to the lca muscle in all larynges , it was impossible to perform a statistical analysis of this variable for the lca muscle . we found that neither the width nor the height of the ta muscle had a significant influence on aniline blue diffusion to the lca , ct , and pca muscles ( table 3 ) . note : lca , lateral cricoarytenoid ; ct , cricothyroid ; pca , posterior cricoarytenoid p = 0.622 for the ct muscle ; p = 1.000 for the pca muscle . since there was dye diffusion to the lca muscle in all larynges , it was impossible to perform a statistical analysis for this muscle . note : ta , thyroarytenoid ; lca , lateral cricoarytenoid ; ct , cricothyroid ; pca , posterior cricoarytenoid . botulinum toxin injections into the ta muscle have been widely used in the treatment of spasmodic dysphonia . botulinum toxin is produced by the anaerobic bacterium clostridium botulinum , and botulinum toxin type a is the form that is used therapeutically . botulinum toxin blocks presynaptic acetylcholine release at the neuromuscular junction , causing partial and reversible chemodenervation leading to muscle weakness , thereby reducing spasticity in patients with dystonia4 . the most serious complication of botulinum toxin injection in the treatment of dystonia has been reported to be paralysis of muscles other than the target muscle , which is most likely attributable to toxin diffusion from the injected muscle to adjacent muscles . various authors141516 have reported botulinum toxin diffusion to pharyngeal and laryngeal muscles after injection of the toxin into the sternocleidomastoid muscle for the treatment of spasmodic torticollis . according to these authors , the complications were dysphagia , hoarseness , and vocal fold paralysis . ludlow et al9 noted that , after injection of botulinum toxin into the ta muscle , there was transient dysphagia for liquids , breathiness , transient dyspnea , and aspiration , all of which were attributed to diffusion of the toxin to adjacent muscles . the use of excised larynges allows the larynx to be cut into several sections after dye injection . however , an excised larynx has the disadvantage of being a devitalized tissue , which is immobilized ( not subject to the motion that accompanies breathing , swallowing , and phonation ) and without blood circulation or lymph flow . therefore , it does not accurately reflect normal laryngeal function . in the excised larynges used in the current study , dye diffusion occurred passively , i.e. , without the aid of circulation or active motion , and was probably due to hydrostatic pressure on the fluid - filled compartment of the muscle . in the present study , the lca muscle , which is the muscle that is closest to the ta muscle , was the most affected by diffusion ( figure 3 ) . the lca muscle is an important adductor muscle that positions the vocal processes along the midline through the rotation of the arytenoids . therefore , lca muscle involvement can lead to inadequate closure of the posterior third of the glottis , with incorrect positioning of the vocal process , leading to breathiness and aspiration . aniline blue diffusion to the ct muscle was observed in 42.86 % of the cases ( figure 4 ) . it is known that ct muscle involvement can lead to decreased fundamental frequency of phonation and , when accompanied by lca and ta muscle paralysis , can decrease vocal intensity . the pca muscle is the only abductor muscle of the larynx . in the present study , aniline blue diffusion to the pca musclealthough the risk of bilateral diffusion is small , it should be taken into consideration when botulinum toxin is used in the treatment of patients with spasmodic dysphonia , particularly when the toxin is injected bilaterally , because bilateral toxin diffusion can lead to a clinical situation that is similar to bilateral adductor vocal fold paralysis . although it is a rare complication , bilateral paralysis following botulinum toxin injection has been reported in patients with adductor spasmodic dysphonia17 . therefore , different degrees of muscle paralysis and paresis ( in isolation or in combination ) can explain the different laryngeal configurations observed in such patients . another parameter analyzed in our study was the influence of gender on aniline blue diffusion to non - injected muscles . this was tested for each muscle individually . for the lca muscle , it was impossible to analyze this parameter because all of the larynges studied showed dye diffusion to the lca muscle , with the exception of 2 hemi - larynges . with regards to the ct and pca muscles , we found that gender had no statistically significant influence on dye diffusion to these muscles . other authors have also found that there are no significant gender - related differences in diffusion . in addition , we tested whether the height and width of the ta muscle influenced dye diffusion to non - injected muscles . we found that neither the height nor the width of the ta muscle had any influence on dye diffusion to any of the adjacent muscles studied . based on the results of the present study , we can conclude that the probability of botulinum toxin diffusion to muscles that are adjacent to the ta muscle is nearly 100 % for the lca muscle and nearly 50 % for the ct muscle . in addition , it seems that neither gender nor laryngeal size has any significant influence on the pattern of diffusion .\noutput:\n" }, { "from": "agent", "value": "summary introduction : endolaryngeal injection of botulinum toxin into the thyroarytenoid ( ta ) muscle is one of the methods for treatment of focal laryngeal dystonia . however , after treatment , there is variation in laryngeal configuration as well as the side effects reported by patients . as a consequence of the functional variability of results , it was hypothesized that botulinum toxin diffuses beyond the limits of the muscle into which it is injected . objectives : after injection of botulinum toxin into the ta muscle for the treatment of focal laryngeal dystonia , patients differ in terms of laryngeal configuration and side effects . we hypothesized that this toxin diffuses from the target muscle to adjacent muscles . method : the ta muscles of 18 cadaver larynges were injected with aniline blue ( 0.2 ml ) . after fixation in formaldehyde and nitric acid decalcification , the larynges were sectioned in the coronal plane and the intrinsic muscles were analyzed . results : we found diffusion of aniline blue to the lateral cricoarytenoid muscle , cricothyroid muscle , and posterior cricoarytenoid muscle in 94.3 % , 42.9 % , and 8.6 % of the cases , respectively . in terms of the degree of diffusion to adjacent muscles , we found no differences related to the size ( height and width ) of the ta muscle or to gender . conclusions : our findings suggest that diffusion of botulinum toxin from its injection site in the ta muscle to the lateral cricoarytenoid muscle is likely in most cases . on the other hand , diffusion to the cricothyroid muscle occurs in approximately half of cases and diffusion to the posterior cricoarytenoid muscle occurs in very few cases ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: cardiac diseases are the primary cause of death worldwide and their associated pathologies have their origins in alterations of gene expression . though many causes of cardiac injury have been identified , the key molecular mechanisms of their pathogenesis have not been understood . the molecular processes within the cardiac cell are controlled by transcription factors such as nuclear factor - kappa b ( nf - b ) . in many heart diseasesin particular , nf - b activation is involved in congestive heart failure , myocardial hypertrophy , diabetic cardiomyopathy ( dc ) and coronary artery disease , including acute coronary syndromes and ischemic reperfusion . in this paperthis entity includes the direct effect of diabetes mellitus , as one of the most prevalent diseases , on the myocardium . nf - b activation may act in dc via canonical and non - canonical pathways , by controlling different set of genes and being involved in related processes such as oxidative stress , inflammation , endothelial dysfunction , fibrosis , hypertrophy and apoptosis . nf - b is a ubiquitous family of inducible dimeric homodimer or heterodimer transcription factors including five members : rel ( c - rel ) , rela ( p65 ) , relb , nf - b1 ( p50 / p105 ) and nf - b2 ( p52 / p100 ) . all of these proteins share a highly conserved rel homology region of about 300 amino acids , composed of two immunoglobulin - like domains . this region is responsible for the interaction with other members of the family , inhibitory proteins and dna . in non - stimulated cells , homodimers or heterodimers of nf - b family membersthus , the nf - b - nuclear localization sequences are masked , and nf - b remains sequestered in the cytoplasm . among the different tissues , two principal signaling cascades , the classical / canonical nf - b activation and the alternative / non - canonical pathway , can control nf - b activation and nuclear transport in the heart . the canonical pathway proceeds via phosphorylation , ubiquitination , and proteasomal degradation of specific ib , in particular ib , ib , ib or bcl - 3 ( figure 1 ( a ) ) . the phosphorylation occurs at two serines ( s32 and s36 ) in the aminoterminus of ib and is catalyzed by ib kinases ( ikks ) - and mostly , complexed with the regulatory subunit nemo ( nf - b essential modulator ) . phosphorylation promotes lysine 48 - ( k48 - ) linked polyubiquitination at adjacent lysine residues initiated by the ubiquitin e3 ligase complex scf . free nf - b dimers , commonly the rela / nf - b1 ( p50 ) heterodimer , translocate into the nucleus through interaction with karyopherins ( nuclei - cytoplasmic transporters ) . activated nf - b bind nf - b - dna sites ( named b sites ) to regulate gene transcription . interestingly , knockout mice for all of the nf - b subunits have been obtained , but only the rela knockout is non - viable , suggesting some functional redundancy among other members of the family . the non - canonical route starts through the phosphorylation , ubiquitination , and proteasomal degradation of inhibitory nf - b1 ( p105 ) and nf - b2 / p100 proteins ( figure 1 ( b ) ) . this pathway is much slower and weaker than the former and depends on ikk but not ikk or nemo . nf - b1 ( p105 ) and nf - b2 / p100 are phosphorylated at their carboxyl - terminus and then k48 - polyubiquitinated by scf ligase . subsequent proteasomal processing of nf - b1 ( p105 ) or nf - b2 / p100 generates mature p50 or p52 , respectively , which heterodimerizes with relb . ikk complexes appear to be the most likely point of convergence of many nf - b regulators . some nf - b inhibitors target ikks competing for their atp binding site , abrogating ib phosphorylation and degradation , and thereby nf - b activation . in this sense , deubiquitinating enzymes such as cyld and a20 can also block nf - b activation by removal of ubiquitinated chains . ikk can even directly phosphorylate rela subunit , which increases its transactivation strength . in addition , ikk - phosphorylated targets , ibs , play critical roles in the regulation of nf - b . as an example , the absence of ikb in knockout mice produces a lethal increase of skin inflammation and proinflammatory molecules . nf - b was initially identified as a nuclear factor bound to the enhancer of the immunoglobulin - light chain gene of b - lymphocytes . however , it is clear that several dozens of nf - b : ib complexes may exist within the cells , providing an enormous diversity of options and allowing for specific regulations in the nf - b system . thus , different activated nf - b dimers bind with distinct affinity to a variety of consensus b sites in the heart . the b sites [ 5 - ggg ( a / g ) nn ( c / t ) ( c / t ) cc - 3 ; where n is any base ] can be uneven resulting in subtle cell and gene - specific modulations of gene expression . importantly , nf - b dimers do not promote gene transcription by themselves , but as a part of a complex of several coactivators such as the camp response element binding protein or signal transducers and adaptors of transcription . moreover , nf - b interacts with a variety of other transcription factors in a positive or negative manner . in some cases , like nuclear factor - il - 6 and activator protein - 1 ( ap - 1 ) , the interaction results in a synergistic stimulation of inflammatory genes [ 1 , 3 , , the physical association of nf - b and the glucocorticoid receptor ( another transcription factor ) inhibits nf - b dna binding ( and enhances ib levels ) . peroxisome proliferator activated receptor ( ppar ) is another transcription factor able to avoid the nf - b nuclear translocation . many of them are involved in inflammation , such as adhesion molecules , interleukins , chemokines , acute phase response genes and cytokines . some of these cytokines are tnf - and il - 1 , closing the circle of a self - sustained loop ( table 1 ) . also nf - b regulates a large number of immune responses , stress , surface receptors , cell survival , growth factors , proliferation and ubiquitin - proteosome system genes . interestingly , the relb , c - rel , nf - b1 ( p105 ) and ib gene expression is under nf - b control . type - i and type - ii diabetic patients are at increased risk of cardiomyopathy and heart failure is a major cause of death for these patients . two - thirds of the diabetic patients die because of cardiovascular complications . in the framingham heart study , the risk of heart failure was increased in diabetic men and women by two - and fivefold , respectively . this could not be explained by looking at several other diabetes mellitus - associated risk factors such as obesity , dyslipidemia , infarction , autonomic neuropathy , or endothelial dysfunction . thus , diabetes mellitus alters cardiac structure and function independently of coronary artery disease and systemic hypertension , a condition known as diabetic cardiomyopathy ( dc ) . here , the associated hyperglycemia and hyperlipidemia induce severe cardiac alterations ( metabolic and structural ) that lead to ventricular diastolic and systolic dysfunction , typically a delayed relaxation pattern and presence of left atrial enlargement . however , there is an uncompleted knowledge of the dc - associated cellular mechanisms , including nf - b signalling . nf - b can be activated by a large number of both physiological and non - physiological stimuli , including cytokines , mitogens , viruses , mechanical and oxidative stress ( table 1 ) . however , at present it is unclear how various intracellular and extracellular stimuli converge to trigger nf - b activation . myocardial tissue from patients with heart failure of various etiologies exhibits activation of nf - b and overexpression of nf - b - regulated genes . in dc , the high concentrations of circulating glucose and ldl / vldl lipoproteins stimulate myocardial nf - b activation . also they lead to the release of vasoactive peptides ( i.e. , angiotensin - ii , endothelin - 1 , phenylephrine ) and growth factors ( tgf , connective tissue growth factor ) from the circulating and local cells . these molecules could stimulate nf - b activity directly or by cytokine - mediated expression ( figure 2 ) . in the canonical pathway , under potent stimulus such as cytokines ( tnf , il - 1 ) or lipopolysaccharide , ib is rapidly degraded within minutes . tnf and il - 1 activate nf - b primarily through interaction with their respective type - 1 receptors , which bind to adapter molecules such as tnf receptor - associated factors . then , these adapters can interact with mitogen - activated protein - ( map - ) kinase , which transphosphorylate and activate ikk . in the non - canonical pathway , cellular receptors such as receptor activator of nf - b , cd40 and lymphotoxin - r stimulate nf - b . other stimuli like double - stranded rna result also in nf - b activation . in these cases , a common interacting protein ( nf - b inducing kinase ) can transphosphorylate to ib proteins . most information on pathogenic mechanisms in dc is derived from animal models . an increase of nf - b activity in a diabetic or diabetic - hypertensive rat heart has been described . in cultured cardiomyocytes , incubation with high - glucose promotes nf - b activation through the diacylglycerol - pkc signal transduction pathway . this route increased pkc and pkc2 , which phosphorylated map - kinase and lately ib . the cardiac responses to dc are oxidative stress , inflammation , endothelial dysfunction , fibrosis , hypertrophy and apoptosis , in which nf - b could participate . hyperglycemia and subsequently generation of advanced glycation end - products ( ages ) are major promoting sources of reactive oxygen species ( ros ) within the cardiomyocytes ( figure 2 ) . another cause of ros accumulation in the cardiomyocyte can be the excess of mitochondrial oxidation , mainly from fatty acid degradation ( almost the unique origin of fuel in dc ) . some ros , as superoxide , react with nitric oxide lacking its beneficial signalling action , or are converted to hydroxyl radical , which damages proteins , lipids and dna . the elevation of free radicals ( and ages ) also impairs ca translocation ( by ca - pump decrease ) and triggers nf - b activation , reducing cardiac contractibility and modifying the overall gene expression program in the diabetic cardiomyocytes . in particular , pkc - and pkc - 2 overexpression may be mediating the nf - b activation induced by high content of ros . importantly , as well as hyperglycemia , cytokine stimulation ( tnf , il - 1 ) may activate nf - b via ros formation . thus , oxidative stress will become a common mediator involved in the initiation and development of the cardiac responses to dc . the inflammatory response is a significant process in the progression of heart failure in dc . although cardiac inflammation is not present in chronic experimental models of diabetes mellitus ( by the local expression of anti - inflammatory and anti - oxidant molecules ) , it has been demonstrated as an early response to the diabetic insult . in human myocardial biopsies or necropsieshowever , non - specific serum inflammatory markers such as mcp - 1 , il - 6 , tnf , troponin or c - reactive protein , have been linked to cardiovascular dysfunction in diabetic patients . nf - b is clearly one of the most important regulators of pro - inflammatory gene expression . cardiac cells express receptors for pro - inflammatory cytokines , il - 1 and tnf and also contain the ikk complex needed for nf - b signal activation . interestingly , ib knockout mice are born normally , but usually die a few days after birth because of extensive skin inflammation consistent with persistent nf - b activation . in early experimental models of dc , activation of nf - b was correlated with an increased of il - 1 and tnf . thus , nf - b could lead to or enhance expression of host genes , including cytokines , leukocyte adhesion molecules , cyclooxygenase - 2 and inducible nitric oxide synthase , ending to a positive feedback loop ( figure 2 ) . in addition , pro - inflammatory cytokines produced by macrophages , t - cells and cardiac cells may exert their actions on cardiomyocytes and fibroblasts via nf - b activation . although inflammation in human cardiac tissue has not been entirely demonstrated , animal studies indicate that the presence of leukocytes in the diabetic heart and nf - b activation could play a crucial control . accordingly , most of the beneficial effects of dc treatments improve inflammatory events and nf - b alleviation ( see later ) . endothelial dysfunction is primary cause of atherogenesis initiation in the coronary vasculature that enforces the direct deleterious effect of diabetes mellitus on the heart . elevation of circulating glucose , ros , lipoproteins and cholesterol damages the endothelial cell layer increasing the attraction and adhesion / rolling / extravasation of inflammatory cells . cytokines ( il - 6 , tnf ) , angiotensin - ii and adhesion molecules ( icam - 1 , vcam - 1 , e - selectin ) are released from endothelial cells . as a result , more leukocytes migrate to subendothelial sites of inflammation . once there , they promote vascular smooth muscle cells attraction ( by chemokines mcp - 1 and il - 8 ) from the media layer and fibrosis ( by collagen deposition ) , leading to atherosclerotic plaque formation . the regulation of all these factors by nf - b has been well described in human and animal models . finally , the stability of the plaque and thrombosis can depend on the ecm turnover and presence of pro - thrombotic factors . in this sense , as well as mmps , nf - b also regulates pro - thrombotic genes . in the heart , vasoactive peptides and growth factors ( angiotensin - ii , tgf ) released in diabetes mellitus can activate nf - b . tgf stimulates the synthesis of extracellular matrix ( ecm ) proteins including collagens , fibronectin , tenascin and proteoglycans ( figure 2 ) . interestingly , a close relationship between tgf and nf - b signaling has been suggested and nf - b can also interact with ap - 1 to overexpress collagens , fibronectin and tgf , enhancing the ecm accumulation . cardiac injury after dc may result in acute loss of a large number of myocardial cells leading to the formation of a scar . in human biopsies , interstitial and perivascular fibrosis were present in the diabetic heart . in short - and long - term diabetic models , fibrosis and fibronectin expressionthis glycoprotein possess in its promoter region a specific sequence to be regulated by nf - b dna binding . nevertheless , fibrotic deposition depends on the balance between ecm proteins and ecm - degradation enzymes . interstitial metalloproteases ( mmps ) have the ability to completely degrade collagen and most other ecm components . tgf suppresses matrix degradation through down - regulation of proteinases , such as plasminogen activators and collagenases ( i.e. , mmps ) , and increases synthesis of proteinase inhibitors , such as plasminogen activator inhibitor - 1 and tissue inhibitors of metalloproteases ( timps ) . however , paradoxically at least mmp - 1 , 3 , and 9 can be also up - regulated by nf - b , and timps are either up or down - regulated by nf - b activity . nevertheless the balance of pro - over anti - fibrotic factors will promote ecm deposition in dc . the up - regulation of profibrotic cytokines and deposition of ecm proteins ( via nf - b , among others ) impair contractibility of cardiomyocytes and lead to cardiac stiffness and heart failure progression in dc . in other hypertrophic cardiomyopathy such as dilated cardiomyopathy , there was not genotype or allelic association between a promoter polymorphism [ linked to inactivation of nf - b1 ( p50 / p105 ) ] and the occurrence of heart failure . however , this polymorphism may worsen the onset of the disease by promoting cardiac remodeling . in dc , as initial compensatory response to stress ( glucose osmolarity , ros oxidation ) , cardiomyocytes increase cellular size through stimulation of contractile proteins like myosins and overexpression of embryonic genes such as the atrial natriuretic peptide . we previously demonstrated also an increase of cell size and atrial natriuretic peptide expression in the rat diabetic heart . nf - b activation can be necessary and sufficient to induce myocardial hypertrophy via g - proteins stimulation or toll - like receptors ( tlrs ) . the later mediate their cellular responses by pi3k / akt / mtor signaling and stimulation of nfb ( figure 2 ) . in particular , tlr4 up - regulation has been observed in human heart failure and ischemic hearts , and tlr4 - deficient mice showed reduced cardiac hypertrophy following pressure overload . another potential mechanism involved in the cardiac prohypertrophic nfb - dependent pathway includes the map - kinases / ppar activation . cardiac hypertrophy induced by angiotensin - ii ( via map - kinases ) was attenuated in p50 null mice . in concordance , tnf - overexpressing mice with cardiac hypertrophy and tnf - induced hypertrophic cardiomyocytes showed reduction of ppar coactivator - 1 expression and its targets ( ppar isoforms ) . interestingly , by nf - b inhibition or incubation with a specific inhibitor of p38 - map - kinase , cardiac hypertrophy and glucose - induced oxidation were reverted . thus , the shift in glucose metabolism to fatty acid degradation during cardiac hypertrophy may be also improved by map - kinase and nf - b blockade ( or ppar activation ) . in consonance , we have preliminary found hypertrophy inhibition in glucose - treated cardiomyocytes after ppar / agonist incubation ( unpublished data ) . of note , mice lacking the nf - b interacting protein - 1 , a repressor of nf - b , showed a severe and rapidly progressive dilated cardiomyopathy but not ventricular hypertrophy . cardiac remodeling might function as an adaptive mechanism to replace dead cells and maintain the heart contractile function . however , hypertrophy can be a bona fide apoptosis trigger since the increase of cytoskeleton proteins is a major cause of cell stiffness , contractile dysfunction and death . cardiomyocytes rarely proliferate within the adult heart , and cardiomyocyte loss plays an essential role in both animal and human dc . nf - b signalling can increase the pro - apoptosis gene expression depending on the stimuli and cellular context . in particular , nf - b is required for endoplasmic reticulum stress - mediated apoptosis . the anti - apoptotic effect of nf - b is very likely to be induced by tnf , although the genes involved in this action are not well characterized . this il - 6 family member activates nf - b through map - kinases and akt to mediate cytoprotective effects in cardiomyocytes . nf - b up - regulates also the inhibitor of apoptosis proteins , x - linked inhibitor of apoptosis proteins , and anti - apoptotic factors bcl2 and cflip and indirectly prevents mitochondrial - mediated apoptosis by induction of mn - superoxide dismutase ( an ros neutralizer ) . these data are in concordance with the fact that rela and ikk knockout mice die from extensive liver apoptosis . in dc , we found an increase of apoptosis and pro - apoptotic factors in the chronic diabetic rat heart . activation of caspase cascade may be in part responsible for nf - b abrogation . in this sense , caspase - 8 degrades rip - kinase , a mediator needed for tnf - induced nf - b activation . thus , in contrast to the other events , activation of nf - b may be appropriate to attenuate the dc - associated apoptosis . since nf - b plays critical roles in the pathophysiology of several process of dc , it is plausible that exogenous modulation of nf - b activation may be effective to develop new therapeutic strategies . however , due to nf - b ubiquity , systemic nf - b inhibitors are likely to have deleterious side effects , particularly if used for long periods . when the original or ongoing stimuli for nf - b activation can not be fully controlled , it is still possible to decrease their effects by interfering with the associated pathways . nf - b could be retained inactive in the cytoplasm by the use of drugs or genetic manipulations in the cardiac cell . treatment with specific inhibitors against the proteasome degradation of ib has shown favourable effects in preventing nf - b activation . downstream , by using immunosuppressive agents such as cyclosporine - a , ib degradation is attenuated and nf - b remains also sequestered in the cytosol . also , the therapies with anti - oxidants like pyrrolidine dithiocarbamate , vitamins c or e , or atp competitors as aspirin have been extensively used in heart injury research . further , once active nf - b enters into nucleus , it would be still feasible to modulate its transcriptional activity by lacking any interactive coactivator ( i.e. , other transcription factors ) . also , genetic delivery of ib and genetic manipulations with small interfering rna , oligodeoxynucleotides or dominant negative against ikk subunits , may be promising strategies for nf - b lessening in dc . lastly , some apparently nf - b - unrelated agents show a potential modulation of the nf - b pathway . for instance , angiotensin receptor blockers , angiotensin converting enzyme inhibitors and statins , exhibit beneficial effects in cardiac diseases although neither hypertension nor hyperlipidemia are present , possibly by nf - b attenuation . however , all of these are unselective attempts to block nf - b activation that may be hazardous . moreover , most of the beneficial effects have been shown for inflammation , but is uncertain the improvement of nf - b blockers in other dc - linked pathologies such as fibrosis , hypertrophy or apoptosis . it would be crucial to describe each one of the multiple ways through which nf - b can become activated in the different responses to dc , and specific alterations may be blocked selectively with reduced side effects . in this regard , we could profit from the anti - apoptotic role of nf - b and develop strategies in which anti - apoptotic pathways can be triggered in cardiomyocytes that are on their way to apoptosis , like in dc . also , a further knowledge of the composition of the nf - b dimers and nf - b interacting partners would help to select the appropriate blockade . in this regard , increasing ppar proteins , such as the and / isoforms , could mitigate the nf - b actions in the diabetic heart . both classical and alternative pathways of nf - b activation may participate in the deleterious responses of the cardiac cells to dc . oxidative stress , inflammation , endothelial dysfunction , fibrosis , hypertrophy and apoptosis seem to be attractive processes for nf - b gene regulation . thus , nf - b or , preferentially , any of its specific related pathways may be of highly interest for pharmaceutical target . a local tissue delivery of inhibitors that target a specific subunit or cofactor of nf - b or selective pathway ( s ) that leads to its modulation may work in dc . this paper is funded by ministerio de sanidad y consumo ( saf 2007 / 63648 , 2007 / 60896 and 2009/8367 ) , cam ( s2006 / gen - 0247 ) , instituto de salud carlos iii ( fis pi050451 , ps09 / 01405 and cp04 / 00060 ) , european network ( health f2 - 2008 - 200647 ) , eurosalud ( eus2008 - 03565 ) , red recava ( rd06 / 0014/0035 ) , fundacin espaola del corazn , sociedad espaola de arteriosclerosis , fundacin mutua madrilea , msd and pfizer .\noutput:\n" }, { "from": "agent", "value": "diabetic cardiomyopathy entails the cardiac injury induced by diabetes independently of any vascular disease or hypertension . some transcription factors have been proposed to control the gene program involved in the setting and development of related processes . nuclear factor - kappa b is a pleiotropic transcription factor associated to the regulation of many heart diseases . however , the nuclear factor - kappa b role in diabetic cardiomyopathy is under investigation . in this paper , we review the nuclear factor - kappa b pathway and its role in several processes that have been linked to diabetic cardiomyopathy , such as oxidative stress , inflammation , endothelial dysfunction , fibrosis , hypertrophy and apoptosis ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: tumors are masses of cells that replicate in an increasingly uncontrollable way ( 1 ) . they are able break out in different tissues and organs of the body and fall into two categories : benign and malignant ( 2 , 3 ) . brain tumors that are rooted in the brain parenchyma are referred to as intra - axial . if the origin of the tumor is outside of the brain ( or it is due to metastasis ) , it is called extra - axial ( 4 , 5 ) . since the brain is completely covered by skull , it is possible to make a timely diagnosis if only para - clinical equipment and appropriate diagnostic tools are available to identify the state of the brain ( 6 , 7 ) . however , brain tumor diagnosis is usually made when unexplainable patient symptoms are reported ( 810 ) . the extent of tumor threats depend upon a set of factors , including the type of the tumor , size of the tumor , its origin , cellularity of the tumor , and the way it develops ( 11 , 12 ) . however , brain tumor diagnosis is usually made when unexplainable symptoms in the patient are brought about by the tumor ( 13 , 14 ) . in addition , surgery plans and designs play a contributing role in the extent and intensity of post - surgery side effects ( 15 ) . therefore , if the surgeon can acquire exhaustive information regarding tumor characteristics via para - clinical equipment ( mri in particular ) , neurosurgeons may be able to modify their surgery plan to minimize the side effects of the operation ( 16 ) . making timely diagnosis of a brain tumorhas a considerable impact on the process of the affected patient s treatment . to accomplish this , para - clinical methods , mri in particular , play a significant role ( 17 , 18 ) . mri is able to answer many significant questions regarding tumors characteristics , as well as aid neurosurgeons . yet there are some mysterious and unknown aspects in mri , including cellularity of tumor . in order to detect the tumor cellularity , the current methods require specimens taken through biopsy and then send them to the pathology unit , after they directly encounter the unknown cellularity of the tumor during the operation ( 1921 ) . the aim of the present study is to identify important information regarding tumor cellularity by using specific mri protocols before the surgery . a group of 32 patients ( 18 males and 14 females from 1877 y / o ) were randomly selected from patients suffering intra - axial brain tumors were admitted to the neuro surgery department of shohada - e - tajrish hospital in tehran ( iran ) and gave permission to undergo an operation from april 2012 to february 2014 . to ensure the accurate functioning of the software , a different group of 8 patientsmri pulse sequences were performed using a siemens avanto mri 1.5 t. it was used on a quadrature coil of brain and particular holding pads to perform mri pulse sequences of the brain . we conducted the initial analysis of the images with the aid of mri syngo b17 software and final analysis was completed using matlab software . the matlab analysis program ( below program ) was written to extract t2 relaxation times : the patients initially underwent mri which comprised of a routine sequence , as well as the intended sequence of the study , specifically t2 multi echoes ( 16 echo ) ( table 1 ) . they were initially processed by using the mri scanner and the final process and analysis of the images were conducted using matlab software . finally , matlab outputs were registered next to the tumor cellularity identified by the surgeon during the surgery . the patient entered the mri scanner head first and supine on the bed . after setting up a quadrature coil to taking image of the brain and holding pads , the patient was sent into the magnet and the scanning processes began . using parameters already optimized and saved ( table 1 ) , brain routine pulse sequences , including flair , t1w , t2w in the axial plane , t2w in the coronal plane , t1w in the sagittal plane , and t2w multi echo pulse sequence in the axial plane ( figure 1 ) were provided . parallel imaging techniques , generalized auto calibrating partially parallel acquisition ( grappa ) with a speed factor of 2 was used in all sequences for time reduction . to begin the final analysis , data from the mri , along with the results of tumor cellularity were sorted into three individual files until retrieved by matlab . files 1 through 3 concerned information about the patients whose tumor cellularity degrees were between 1 to 3 . for each filethe related table illustrates the mean signal intensity per echo , ranging from 22 to 352 milliseconds with echo intervals of 22 milliseconds . the surgeon , who is one of the main project assistants , assesses the cellularity of tumor during surgery by dividing it into three classes : a tumor that ca nt be suctioned , razor sharp tools are required to cut them . tumors that can be suctioned , but they are not liquid or necrotic in structure . the intended matlab software program consists of four functions , which include main , feature , train , and weight . the functions take the features and vectors from the file of images and extracts the features . the features include t2 relaxation time , the slope of the graph for t2 relaxation time , and the maximum slope of the for graph t2 relaxation time . in this study , the extracted feature of matlab software indicated that the best feature , compared with biopsy results , to separate the extent of cellularity from among the features above is t2 relaxation time . another effective extracted feature is the slope of the t2 relaxation time , which exhibits a 81 % diagnostic accuracy compared to biopsy . finally , the maximum slope of the t2 relaxation time feature had a 79 % diagnostic accuracy compared to biopsy . as mentioned earlier , the greater the weight of a feature , the higher capability it possesses to distinguish between classes of tumor cellularity ( p 0.05 ) . as is shown in the roi in figure 2 and the signal intensity in the roi in figure 3 , t2 relaxation time has a direct relationship between the structures and inter - molecule bond type of each substance and tissue . it is evident that an increase in the tissue intensity , as well as in the strength of inter - molecule relations , brings about a reduction in t2 relaxation times . this occurs because of the increasing inter - actions among the spins or hydrogen of that tissue , and the tissue diffuses quicker and appears to be darker on images with t2 weighted contrast . the main focus of this research was finding the relationship between the effective criteria for tissue cellularity and mri images . therefore , se multi echo sequences and matlab software were used in order to find the t2 relaxation time of tumoral tissue and discover the relationship between cellularity and t2 relaxation times . the features extracted using matlab software during this study showed that t2 relaxation has the highest diagnostic accuracy of all features , due to a direct relation to tissue cellularity , compared with biopsy results . to separate the extent of cellularity among the features above , t2 relaxation time was extracted from optimized sequences , such as se - multi echo , and is capable of correlating with molecular cellularity . it appears that when the extent of cellularity for a tissue or lesion is higher , the t2 relaxation time curve of the tissue or lesion shows a steeper slope ( 22 ) . it should be noted that similar studies in other works that are quantitative and observation base confirm this result ( 17 , 20 , 23 ) . in some similar studies , tumor cellularity was evaluated based on quantitative results and , according to the signal intensity of tumors in pdw and t2w , the diagnostic accuracy result has been low ( 24 , 25 ) . signal intensity with t2 contrast directly relates to the molecule structure of each substance and / or tumoral tissues . with regards to the t2 relaxation time , it can be said that the cellularity of a tissue or lesion correlates directly with the steepness of the slope of the t2 relaxation time curve of the tissue or lesion . the main problem in this study was the relatively small number of patients , though the number of patients for this clinical trial is sufficient . the results of this research demonstrated that , of the features or characteristics defined for the software , t2 relaxation time feature is the best indicator to distinguish and present the degree of intra - axial brain tumors cellularity ( 85 % accuracy compared to biopsy ) . it is because this feature , as opposed to other features , has the highest weight . in other words , the higher the weight of the feature , the higher the capability and certainty it has in distinguishing the classes of tumor cellularity . these findings showed that if the t2 relaxation time of highly consistent tumors is less and the t2 relaxation time curve has a steeper slope , with a maximum peak , and can be based on the tumor cellularity classification , the tumor falls into a low class . in contrast , an increase in t2 relaxation time is accompanied by a reduction in tumor cellularity . the most clinical application of this study involves reducing the number of biopsy of brain tumors to determine tumor cellularity . this study can be continued in some other area , including the pituitary gland and liver lesions .\noutput:\n" }, { "from": "agent", "value": "introductiontimely diagnosis of brain tumors could considerably affect the process of patient treatment . to do so , para - clinical methods , particularly mri , can not be ignored . mri has so far answered significant questions regarding tumor characteristics , as well as helping neurosurgeons . in order to detect the tumor cellularity , neuro - surgeons currently have to sample specimens by biopsy and then send them to the pathology unit . the aim of this study is to determine the tumor cellularity in the brain.methodsin this cross - sectional study , 32 patients ( 18 males and 14 females from 1877 y / o ) were admitted to the neurosurgery department of shohada - e tajrish hospital in tehran , iran from april 2012 to february 2014 . in addition to routine pulse sequences , t2w multi echo pulse sequences were taken and the images were analyzed using the matlab software to determine the brain tumor cellularity , compared with the biopsyresultsthese findings illustrate the need for more t2 relaxation time decreases , the higher classes of tumors will stand out in the designed table . in this study , the results show t2 relaxation time with a 85 % diagnostic weight , compared with the biopsy , to determine the brain tumor cellularity ( p < 0.05 ) . conclusionour results indicate that the t2 relaxation time feature is the best method to distinguish and present the degree of intra - axial brain tumors cellularity ( 85 % accuracy compared to biopsy ) . the use of more data is recommended in order to increase the percent accuracy of this techniques ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: platinum analogs have been the standard of care in management of advanced stage epithelial ovarian and fallopian tube carcinoma . platinum and taxane combination has shown a survival benefit in the firstline as well as in relapse setting . carboplatin being equally efficacious and with better toxicity profile has replaced cisplatin as first choice chemotherapy . however , with increasing use of carboplatin , especially in relapsed settings , there is a notable increase in hypersensitivity reactions ( hsrs ) . severe hsrs may cause panic among nursing staff and at times can be frightening even for physicians . further , in usual combination regimen with taxanes , differentiating acute hsr between the two is also a difficult task . a 56 - year - old postmenopausal woman without known comorbidities was diagnosed with stage iii c ovarian carcinoma 6 months back . she had serological response with ca125 decreasing from 1285 u / ml to 90 u / ml post nact . subsequently , she underwent interval cytoreduction ( r0 ) with histological evidence of residual viable serous adenocarcinoma and omental metastasis . however , in cycle six , although paclitaxel infusion was uneventful on day 1 , on day 2 immediately after starting carboplatin infusion she developed severe hsr . oxygen saturation plummeted to 85 % with hypotension ( blood pressure [ bp ] 80/40 mm hg ) and tachycardia up to 125 / min . infusion was stopped immediately and she was administered intravenous ( iv ) injections of diphenhydramine 25 mg , hydrocortisone 100 mg , along with iv fluid ( bolus normal saline ) , and salbutamol nebulization 2.5 mg despite of above measures she deteriorated and became pulseless with unrecordable bp . subsequently , she received mephentermine 15 mg iv and then within a minute she regained consciousness with vital parameters returning to baseline in next few minutes . she was shifted to ward for observation and was discharged the next morning after ensuring stable general condition . further chemotherapy was abandoned and she was suggested to be on regular follow - up . incidence of carboplatin induced hsr have been reported widely ranging from 1 % to 35 % depending upon the severity and grade . it has been observed more frequently in women receiving carboplatin in the second line with peak incidence at median number of seven cycles . these reactions could be acute , which manifests within a couple of minutes or delayed , which happens after a couple of hours or days after the inciting drug . pattern of hypersensitivity constitutes broad spectrum , which may be varied from mild to severe life - threatening reactions . flushing , rash , itching , diaphoresis , facial edema , fever , chills , nausea , and backache without any cardiorespiratory instability constitute mild nature of reactions , which is one end of the spectrum while hypertension / hypotension , tachycardia , breathlessness , chest pain , palpitation , altered sensorium , wheezing , stridor , laryngeal edema , shock could be serious and life - threatening . these reactions have been reported not only for iv , but also for intraperitoneal route . however , repeated exposure to low dose free platinum metal , which is present as impurity or contaminant in the drug is the likely culprit . this analogy hold true from allergic manifestation in platinum mining workers and why allergic manifestation develop after median seven cycles of carboplatin due to gradual exposure to low metal concentration . immunologically , immediate type 1 ige mediated hsr or anaphylactoid reaction mediated by release of vasoactive cytokines and histamines from basophils and mast cells have been postulated . majority of carboplatin hsr have been reported after a couple of minutes to hour after the administration ; however , it is not uncommon to develop a reaction within minutes of starting infusion . this is paradox of paclitaxel induced hsr which typically manifest within few drops or 10 min of infusion . platinum analogs have better outcomes in the second line or recurrent ovarian carcinomas with response rates up to 50 - 70 % in platinum sensitive relapses ; in . hence , it is pertinent to evolve strategies to counter the carboplatin hsr , which may deprive the patient of an effective drug . lack of clinical or biochemical marker to stratify patients into high risk for hsr are yet to be defined . however , patients receiving carboplatin after 12 months of platinum free interval have much higher incidence of hsr ( 50 % ) as compared with otherwise ( 25 % ) . previous history of environmental or drug allergies have been shown to increase the risk of carboplatin hsr in a study with limited sample size . several methods have been evaluated including skin testing , specific immunoglobulin levels , desensitizing , increasing infusion duration with aggressive premedication and replacing carboplatin with cisplatin with modest success . skin testing with prick or intradermal testing with stratified dilution has been useful in predicting patients likely to have hsr to carboplatin . it has high negative predictive value of more than 76 % thus helpful in identify patients less likely to have a reaction . skin test done independently for carboplatin and cisplatin can help in identifying patients who have cross resistance to platinum analogs where cisplatin can not be recommended . however , atypical hsr with negative skin test have been identified . limitation to skin testing is that it can not predict the severity of reaction and correlates more with early reaction than late reaction . in a patient with recent suspicion of carboplatin hypersensitivity , it is advisable to consider skin testing . if test is positive avoid carboplatin or consider desensitization before subsequent planned dose . prick test - it is done on a volar surface of forearm with a drop of carboplatin ( 10 mg / ml ) . if prick test is negative then intradermal test with 0.02 ml of 0.1 mg / ml of carboplatin is done . concentration is increased by 10 times as long as intradermal test remains negative to a maximum of 10 mg / ml , each time on different areas of forearm . prick test is positive if more than 3 mm of wheal is seen , while intradermal test is positive if more than 5 mm of wheal is identified . patients with recent history of carboplatin hsr if re - challenged without desensitization are likely to have severe reaction in more than 75 % of patient population . in one of largest series100 % of patients tolerated subsequent carboplatin without any allergic reaction post iv or oral desensitization . in another series by rose et al . , rate of successful desensitization was more than 90 % . however , markman suggested some reservations regarding the above finding as any significant hsr could potentially be life - threatening even after desensitization in a small group of patients and suggested alternate drugs instead of carboplatin . it is recommended to formulate institutional desensitization protocols , which should be strictly followed for effective , consistent , and safe results . commonly used methods for desensitization include : premedication regimes , dilution chemotherapy escalation [ table 1 ] , andincreasing duration of drug infusion . premedication regimes , dilution chemotherapy escalation [ table 1 ] , and increasing duration of drug infusion . desensitization protocols for carboplatin hypersensitivity reactions prophylactic extended infusion schedule over 3 h in a large prospective study has shown to decrease the incidence of hsr to 4 % when compared to 21 % in standard infusion time schedules . in a patient with platinum sensitive relapse with good evidence of response during previous treatmentone can consider desensitization before carboplatin as it can reduce subsequent hsr in the majority of patients . risk of cross sensitivity to platinum analogs is of concern in patients with hsr to carboplatin . use of desensitization before substituting carboplatin to cisplatin is a viable option . even without desensitizationmore than 75 % patients do tolerate cisplatin without any hsr , however in 20 % of such patients have subsequent reactions to cisplatin after 3 and 4 cycles . in a small series of patients reported by mskcc , 5 out of 7 patient successfully received cisplatin with adequate premedication and slower infusion rates . skin testing for cisplatin - carboplatin allergy is an alternate option before starting patients on cisplatin with known hsr to carboplatin . overall , replacing cisplatin to carboplatin can be attempted preferably after desensitization with adequate premedication and slower infusion rate under strict medical supervision . despite of abovethere is a small risk of cross sensitivity , hence substitution can be attempted , but with due caution . carboplatin hypersensitivity is one of the major clinical challenges in treating patients with relapse / recurrent ovarian malignancies . incidence increase to more than one - third when used in the second line setting with increasing risk with each subsequent cycle . there is a paucity of data to suggest that delivering carboplatin on next rather than same day of paclitaxel affects the incidence of hypersensitivity . some of these hypersensitive reactions could be serious and life - threatening if not dealt urgently especially among less vigilant and untrained personnel . hence , it is prudent to consider following factors in descending order of importance before deciding to continue treatment with platinum analogs . severity of observed reaction.strong evidence of current platinum responsive disease / predicted high likelihood of response.presence of significant comorbidity that might increase the risk of death with subsequent hsr e.g. , recent myocardial infarction , stroke , and arrhythmia.availability of other rational alternative therapeutic options.individual patient willingness to treatment with platinum in view of potential risks and possible benefits . presence of significant comorbidity that might increase the risk of death with subsequent hsr e.g. , recent myocardial infarction , stroke , and arrhythmia . individual patient willingness to treatment with platinum in view of potential risks and possible benefits . considering the significance of hsr to carboplatin itis strongly recommended that institution should formulate model protocols to handle severe life - threatening reaction in busy day care or inpatient care . certain suggestions aimed at preemptive , prophylactic , and primary prevention of hsr are listed in table 2 . skin testing with prick or intradermal testing with stratified dilution has been useful in predicting patients likely to have hsr to carboplatin . it has high negative predictive value of more than 76 % thus helpful in identify patients less likely to have a reaction . skin test done independently for carboplatin and cisplatin can help in identifying patients who have cross resistance to platinum analogs where cisplatin can not be recommended . however , atypical hsr with negative skin test have been identified . limitation to skin testing is that it can not predict the severity of reaction and correlates more with early reaction than late reaction . in a patient with recent suspicion of carboplatin hypersensitivity , it is advisable to consider skin testing . if test is positive avoid carboplatin or consider desensitization before subsequent planned dose . prick test - it is done on a volar surface of forearm with a drop of carboplatin ( 10 mg / ml ) . if prick test is negative then intradermal test with 0.02 ml of 0.1 mg / ml of carboplatin is done . concentration is increased by 10 times as long as intradermal test remains negative to a maximum of 10 mg / ml , each time on different areas of forearm . prick test is positive if more than 3 mm of wheal is seen , while intradermal test is positive if more than 5 mm of wheal is identified . prick test - it is done on a volar surface of forearm with a drop of carboplatin ( 10 mg / ml ) . if prick test is negative then intradermal test with 0.02 ml of 0.1 mg / ml of carboplatin is done . concentration is increased by 10 times as long as intradermal test remains negative to a maximum of 10 mg / ml , each time on different areas of forearm . prick test is positive if more than 3 mm of wheal is seen , while intradermal test is positive if more than 5 mm of wheal is identified . patients with recent history of carboplatin hsr if re - challenged without desensitization are likely to have severe reaction in more than 75 % of patient population . in one of largest series100 % of patients tolerated subsequent carboplatin without any allergic reaction post iv or oral desensitization . in another series by rose et al . , rate of successful desensitization was more than 90 % . however , markman suggested some reservations regarding the above finding as any significant hsr could potentially be life - threatening even after desensitization in a small group of patients and suggested alternate drugs instead of carboplatin . it is recommended to formulate institutional desensitization protocols , which should be strictly followed for effective , consistent , and safe results . commonly used methods for desensitization include : premedication regimes , dilution chemotherapy escalation [ table 1 ] , andincreasing duration of drug infusion . premedication regimes , dilution chemotherapy escalation [ table 1 ] , and increasing duration of drug infusion . desensitization protocols for carboplatin hypersensitivity reactions prophylactic extended infusion schedule over 3 h in a large prospective study has shown to decrease the incidence of hsr to 4 % when compared to 21 % in standard infusion time schedules . in a patient with platinum sensitive relapse with good evidence of response during previous treatmentone can consider desensitization before carboplatin as it can reduce subsequent hsr in the majority of patients . risk of cross sensitivity to platinum analogs is of concern in patients with hsr to carboplatin . use of desensitization before substituting carboplatin to cisplatin is a viable option . even without desensitizationmore than 75 % patients do tolerate cisplatin without any hsr , however in 20 % of such patients have subsequent reactions to cisplatin after 3 and 4 cycles . in a small series of patients reported by mskcc , 5 out of 7 patient successfully received cisplatin with adequate premedication and slower infusion rates . skin testing for cisplatin - carboplatin allergy is an alternate option before starting patients on cisplatin with known hsr to carboplatin . overall , replacing cisplatin to carboplatin can be attempted preferably after desensitization with adequate premedication and slower infusion rate under strict medical supervision . despite of abovethere is a small risk of cross sensitivity , hence substitution can be attempted , but with due caution . carboplatin hypersensitivity is one of the major clinical challenges in treating patients with relapse / recurrent ovarian malignancies . incidence increase to more than one - third when used in the second line setting with increasing risk with each subsequent cycle . there is a paucity of data to suggest that delivering carboplatin on next rather than same day of paclitaxel affects the incidence of hypersensitivity . some of these hypersensitive reactions could be serious and life - threatening if not dealt urgently especially among less vigilant and untrained personnel . hence , it is prudent to consider following factors in descending order of importance before deciding to continue treatment with platinum analogs . severity of observed reaction.strong evidence of current platinum responsive disease / predicted high likelihood of response.presence of significant comorbidity that might increase the risk of death with subsequent hsr e.g. , recent myocardial infarction , stroke , and arrhythmia.availability of other rational alternative therapeutic options.individual patient willingness to treatment with platinum in view of potential risks and possible benefits . presence of significant comorbidity that might increase the risk of death with subsequent hsr e.g. , recent myocardial infarction , stroke , and arrhythmia . individual patient willingness to treatment with platinum in view of potential risks and possible benefits . considering the significance of hsr to carboplatin itis strongly recommended that institution should formulate model protocols to handle severe life - threatening reaction in busy day care or inpatient care . certain suggestions aimed at preemptive , prophylactic , and primary prevention of hsr are listed in table 2 .\noutput:\n" }, { "from": "agent", "value": "carboplatin and paclitaxel as doublet are the standard therapeutic option for advanced stage ovarian carcinoma in the first line as well as relapse . carboplatin with its better toxicity profile has replaced cisplatin as the first line drug . however , increase in incidence of carboplatin hypersensitivity is alarming . severity of carboplatin hypersensitivity varies from a mild rash to life - threatening reactions . with an increase in the number of cycles the risk of hypersensitivity reactions increase , which jeopardizes the use of this highly effective drug in a significant proportion of patients . prompt diagnosis and rapid therapeutic rescue are the key in severe life - threatening reactions . managing patients with carboplatin hypersensitivity and planning subsequent therapy is thus a therapeutic challenge ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: some attempts have been made to describe the geographic distribution of molds in united states of america ( usa ) homes and buildings . horner et al . quantified culturable molds from air and dust samples obtained from 50 single family residences in atlanta , ga , usa . shelton et al. reported on the analysis of culturable indoor and outdoor air samples from 1,717 buildings in the usa . us epa and hud researchers recently standardized the analysis of molds in us housing based on settled dust . as part of the 2006 hud american healthy home survey ( ahhs ) , standardized dust samples were obtained from a statistically representative set of homes across the usa . each of these dust samples was prepared in the same way and then analyzed using mold - specific quantitative pcr ( msqpcr ) . the 36 molds include the 26 group 1 species which we have shown to be associated with homes with water damage and the 10 group 2 species which are found in homes independent of water damage . if the sum of the logs of the group 2 ( slg2 ) molds is subtracted from the sum of the logs of the group 1 ( slg1 ) molds , a unitless environmental relative moldiness index ( ermi ) value is obtained which describes the mold burden in a home with a single numeric value relative to a national ermi scale . the ermi scale ranges from about 10 to 20 or even higher and is divided into quartiles . the development of the ermi , its components and calculations , has recently been reviewed . the analysis of molds in dust by msqpcr has been used by us to estimate the mold burden in homes , defined by both the concentrations of the molds as well as the diversity of species in the home . by using a standard protocol for sampling homes and a dna - based method of analysis , the distribution of the 36 molds that make up the environmental relative moldiness index ( ermi ) can be described for the usa . the american healthy homes survey ( ahhs ) targeted a nationally representative sample of permanently occupied homes or housing units . a housing unit is defined as a house , apartment , mobile home , a group of rooms , or a single room that is occupied as separate living quarters . separate living quarters are those in which the occupants live and eat separately from any other persons in the building and which have direct access from the outside or through a common hall . for this survey , lists of households in the sampled segments were acquired from commercially available sources . a sample of four residential addresses , plus two backup addresses , was randomly selected from the list in a typical segment to determine which households were eligible to be included in the sample . these lists were validated by a modified listing process in which interviewers visited the sampled segments with the acquired lists to compare them with the housing units actually present to validate a list for each designated segment within each primary sampling unit ( psu ) . this comparison resulted in some housing units being added to the lists and others being deleted from the lists . because of low population density , no samples were obtained from the states of oregon , montana , nevada , utah , wyoming , north dakota , or south dakota . dust samples were collected by vacuuming 2 m of the living room floor and 2 m of a bedroom floor ( whether carpeted or not ) , directly adjacent to the sofa or bed , respectively , for 5 min each with a mitest sampler - fitted vacuum . the analysis of 5 mg of sieved dust from each sample was completed by epa licensed commercial laboratories , as previously described . all primer and probe sequences , as well as known species comprising the assay cluster and the list of epa licensed commercial laboratories , are published at the epa website : http://www.epa.gov/microbes/moldtech.htm . the ahhs set of data included concentrations of each of the 36 molds for each of the 1083 homes in the continental us . home locations were converted to latitude and longitude coordinates prior to data exploration and reduction . the data were initially inspected for evidence of geographical influence on mold burden using regression analysis on the 1083 home data set . separate regressions were run for each species and ermi - related index ( slg1 , slg2 , and ermi ) using a maximum likelihood regression procedure with log10 - transformed mold concentrations and nontransformed ermi indices as the response variable and latitude and longitude as predictors . data were then assessed for the presence of distinct spatial partitions of homes on the basis of standardized concentration values for the 36 mold species . spatially mediated partitions were generated using the clusttool package for r , with multiple combinations of distance metric , partitioning algorithm and number of partitions being tested and compared to obtain optimal partitioning . after the partitioning , data reduction was carried out in two separate stages in order to create a manageable visual representation based on a small number of relatively homogeneous mold groups by clustering together those species with similar patterns of abundance as a function of geographic distribution . once molds were assigned to clusters , the abundance measures for each of the molds in a cluster were combined to form a single cluster component , preferentially weighted on those molds with greatest information content . this reduction step was carried out using the sas 9.2 varclus procedure ( sas inst . , inc . , cary , nc ) , resulting in a first principal component ( fpc ) for each cluster that , for mapping purposes , was representative of concentrations and geographical distributions of the subset of molds belonging to that cluster . the second data reduction step prerequisite to mapping was carried out in order to collapse fpc scores across sampling locales , that is , across groups of geographically - related homes that were sampled as representatives of a metropolitan population along the lines of the original psus . this step served to provide a local estimate of the mold burden in the community being sampled . sampling clusters were identified on the basis of a disjoint cluster analysis carried out on latitude and longitude data using the sas fastclus procedure , which reduced the number of plotting positions from 1083 to 82 . the univariate procedure was used to calculate the mean latitude and longitude of each of the 82 sampling locales for plotting purposes , as well as mean fpc scores and ermi - related indices for each locale . first principal component scores and ermi - related values were plotted by latitude and longitude as an x , y event - layer using the software program arcgis desktop 9.3.1 ( esri inc . , redlands , ca ) . for each map , the values were classified using a five category natural break classification . the five categories were indicated by combined grey scale and graduated symbol size , with the smallest size and lightest color representing the category with the smallest values . the initial regression analyses suggest that for at least some of the 36 mold species , a significant , systematic relationship exists between the concentration of the mold and the geographic gradient ( table 1 ) . thirteen of the 26 group 1 species and 8 of the 10 group 2 species fall into this category , as do the indices sum of the logs of group 2 and ermi . the nature of these relationships , however , was inconsistent even among the species within groups 1 or 2 : positive longitude coefficients coupled with negative latitude coefficients are found for species in both groups 1 and 2 molds , as are negative longitude coefficients coupled with positive latitude coefficients ( table 1 ) . the partitioning analyses based on the full set of 1083 homes and 36 mold species failed to uncover a valid partitioning that yielded compact , well - separated partitions with systematic spatial distributions , either on global or local criteria ( data not shown ) . irrespective of variations in distance metric , partitioning algorithm or predefined number of partitions , validity measures remained relatively stable within a very small range , inconsistent with the presence of true partitions that become increasingly distinct as the optimal number of partitions is reached : average silhouette widths , for example , were consistently low , most on the order of 0.050.07 , and very few reaching as high as 0.1 ( data not shown ) . these results , combined with those from individual mold species , suggest that while some species ' concentrations may generally increase / decrease to some ( variable ) extent along a preferred geographical gradient , the individual trends do not intersect to form patterns that represent coherent species communities in association with spatially distinct subsets of individual homes . thus species concentrations , when seen as an integrated multispecies system , are heterogeneously distributed across the continental us . given the apparent absence of statistically valid partitions of this type , we focused instead on results from the data reduction techniques employed for mapping purposes and provide a more broad scope description of those findings in light of the single - species results . the variable clustering analysis of the 36 molds ' standardized concentrations produced seven disjoint clusters at criterion , as shown in table 2 . the r values associated with each mold listed in table 2 represent the squared correlations between the molds themselves and , respectively , the cluster to which they were assigned and the next closest cluster . a large r value for a given mold with its own cluster indicated a better fit of the mold data to the cluster component and was in turn associated with greater weighting of that mold in the calculation of fpc scores . cluster 1 was dominated by aspergillus , and the distribution appeared strongest in the eastern half of the country ( figure 1 ) , as expected given the positive longitude coefficients associated with cluster 1 and lack of significant negative longitude coefficients . cluster 2 fpc scores had a wide distribution ( figure 2 ) except in the desert southwest . consistent with the mix of positive and negative coefficients , cluster 3 fpc scores were distributed more widely in the western us ( figure 3 ) than were scores from some of the other exclusively group 1 clusters . cluster 4 was specifically penicillium purpurogenum , concentrations of which did not pattern significantly with either longitude or latitude , and it was found as expected randomly distributed across the entire us ( figure 4 ) . cluster 5 was made up exclusively of group 2 molds ( 6 of the 10 group 2 molds ) , 4 of which were significantly associated with geographical gradients ( figure 5 ) . clusters 6 ( figure 6 ) and 7 ( figure 7 ) were mixtures of group 1 and 2 molds . the distribution of the sum of the logs of the group 1 ( slg1 ) molds ( figure 8 ) showed a mix of high and low values scattered across the usa . the distribution of the sum of the logs of the group 2 ( slg2 ) molds ( figure 9 ) was fairly uniform across the usa with most locales in the darker shades of gray . the ermi values themselves were heterogeneously distributed across the continental us ( figure 10 ) . this representative national survey of us homes is the first attempt to apply a standardized sampling procedure and dna - based quantification of molds in settled dust to describe the geographic distribution of specific molds . the metric for understanding the mold burden in homes is the ermi scale which is made up of 36 molds , 26 indicators of water damage and 10 outdoor molds . in fact , these 36 molds have been shown to also occur from the uk to singapore . humidity and precipitation are the natural phenomena that can alter the moisture conditions in a home but it is primarily the homes ' internal and external structural integrity that controls moisture and mold growth . therefore , the slg1 molds ( figure 8 ) will vary not only by geography but based on natural and man - made moisture conditions in each home , dominated by the latter . the result is group 1 mold populations being speckled across the usa as in figure 8 , with a mix of high and low values indicating that water problems are national in scope . on the other hand group2 molds accumulate as a function of outdoor conditions ( soil , vegetation , etc . ) and the habits of the home 's occupants , for example , how often do they clean , do they leave the windows open , are there pets and so forth . most areas of the usa showed a fairly uniform distribution of group 2 molds with few extremes ( figure 9 ) . only in the desert southwest and the southeastdoes it appear that group 2 molds are less abundant than in the rest of the usa . desert outdoor conditions in the southwest or the subtropical southeast conditions may distinguish these home outdoor mold populations to some extent . the ermi calculation ( subtracting slg2 from slg1 ) adjusts for these variations in order to provide a relative scale for comparison of homes . the resulting ermi values demonstrate the heterogeneous distribution of mold in homes across the usa ( figure 10 ) . of course , this is a simplification , and any particular house may or may not support the growth of any of these molds . so the origins of a particular mold population could be a mixture of both inside and outside sources . however , in general group 1 and group 2 molds segregated into separate clusters . this suggests that their population sources are largely separate , that is , group 1 from indoors ( figures 1to 4 ) and group 2 ( figure 5 ) from outdoors . the cooccurrence of certain species in the fpc clusters demonstrates that specific molds tend to colonize homes in common patterns . for example , aspergillus , dominating cluster 1 , appears to populate homes in the eastern usa and penicillium , dominating cluster 3 , populates homes in the western usa . perhaps these differences are a function of different types of building practices , age of housing , and so forth . more intense investigation of these locale differences may help explain specific health issues associated with molds . . reported on the analysis of over 9,000 indoor air samples and 2,400 outdoor air samples from 1717 buildings . they found that cladosporium , penicillium , nonsporulating fungi , and aspergillus were the most common molds . however , these samples were not collected at random but came from buildings with employee health complaints , in the evaluation of visible mold growth or odors , or from a proactive indoor air quality program . so there was a bias in the sampling locations . also , the samples were short - term air samples , and these types of samples have many inherent limitations . the overall goal of our mold research is to place mold analysis on a firmer , more objective basis . however , any methodology also has to be practical . of the possible hundreds of molds in a home , only monitoring 36is a limitation but the results described here suggest that these 36 molds are nationally distributed . the ermi values in homes were found to be widely and heterogeneously distributed across the usa indicating that the 36 molds that make up the ermi are broadly distributed with only limited geographic selection .\noutput:\n" }, { "from": "agent", "value": "objective . the objective of this study was to quantify and describe the distribution of the 36 molds that make up the environmental relative moldiness index ( ermi ) . materials and methods . as part of the 2006 american healthy homes survey , settled dust samples were analyzed by mold - specific quantitative pcr ( msqpcr ) for the 36 ermi molds . each species ' geographical distribution pattern was examined individually , followed by partitioning analysis in order to identify spatially meaningful patterns . for mapping , the 36 mold populations were divided into disjoint clusters on the basis of their standardized concentrations , and first principal component ( fpc ) scores were computed . results and conclusions . the partitioning analyses failed to uncover a valid partitioning that yielded compact , well - separated partitions with systematic spatial distributions , either on global or local criteria . disjoint variable clustering resulted in seven mold clusters . the 36 molds and ermi values themselves were found to be heterogeneously distributed across the united states of america ( usa ) ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: , the cervical spine is exposed to increased stress and loads that can lead to various conditions such as degenerative or herniated discs , stenosis , and osteoarthritis . depending on the disease severity , patients can be treated conservatively or surgically . for most of the patientsthe first line of treatment is usually the nonoperative management including oral medication , physical therapy , bracing , and changes in the activity . it has been shown that in the 70 % to 80 % of the patients with cervical radiculopathy , nonsurgical treatments were successful . common primary goals of cervical spine surgery are to decompress spinal cord and nerves and stabilize the spine when needed . although the clinical success of cervical procedures is very high , several complications have been reported . it has been show that the type of surgical approach can contribute to the complication onset . fager reported that patients who were treated anteriorly for cervical degenerative conditions with myelopathy had a 10 % higher chance for developing neurological complications . intraoperative complications associated with both anterior and posterior approaches include esophageal and tracheal perforation ; injury of main arteries ; hematoma , wound infections ; spinal cord and nerve injury ; dura leak ; and improper positioning of instrumentation and graft . a 5 - year report done by the cervical spine research society ( 1982 to 1987 ) on the death incidence after cervical spinal surgery demonstrated low mortality rates , ranging from 0.34 % to 0.96 % , with 1982/1983 and 1985/1986 having the highest rates ( 0.95 % and 0.96 % , respectively ) . they further reported that the cord - related complications were more prevalent with the posterior approach and nerve root with the anterior approach . even though death is a secondary adverse event there are several variables that can influence the mortality rates . second , there are reports that demographic factors ( age and race ) play an important role . skolasky and coworkers have shown an overall 0.42 % mortality rate and found that african americans had 59 % higher odds of dying after cervical spine surgery compared to caucasian patients . in addition , alosh et al found that african americans had 57 % higher odds of death as a terminal complication after anterior cervical spine surgery . last , an overall mortality incidence will be directly linked to the patient s medical condition . although there is literature on the death incidence with spine surgeries , most of the studies focused on the postoperative mortality rates or on the complications leading to death . the purpose of our multicenter study was to determine the incidence of intraoperative death in patients undergoing cervical spine surgery . we also sought to address the correlation between patient demographics , surgical approach , and intraoperative death rates . we have conducted a retrospective multicenter case series study involving 21 high - volume surgical centers from the aospine north america clinical research network , selected for their excellence in spine care and clinical research infrastructure and experience . medical records for 17625 patients who received cervical spine surgery between january 1 , 2005 , and december 31 , 2011 , inclusive , were reviewed to identify occurrence of 21 predefined treatment complications . the complications included reintubation requiring evacuation , esophageal perforation , epidural hematoma , c5 palsy , recurrent laryngeal nerve palsy , superior laryngeal nerve palsy , hypoglossal or glossopharyngeal nerve palsy , dural tear , brachial plexopathy , blindness , graft extrusion , misplaced screws requiring reoperation , anterior cervical infection , carotid artery injury or cerebrovascular accident , vertebral artery injuries , horner s syndrome , thoracic duct injury , quadriplegia , intraoperative death , revision of arthroplasty , and pseudomeningocele . trained research staff at each site abstracted the data from medical records , surgical charts , radiology imaging , narratives , and other source documents for the patients who experienced one or more of the complications from the aforementioned list . copies of case report forms were transferred to the aospine north america clinical research network methodological core for processing , cleaning , and data entry . from the initial 17625 patients , 258 patients met the inclusion / exclusion criteria and were used in the study . there were 141 male ( 54.7 % ) and 117 female ( 45.3 % ) patients ( table 1 ) . the average age was 57.113.2 years , and the mean body mass index was 28.86.5 . fifty - two patients were current smokers , 69 were previous smokers and 111 never smoked ( table 1 ) . the most common procedure was the anterior approach 139 ( 53.9 % ) , followed by posterior 101 ( 39.1 % ) and circumferential 18 ( 7 % ) approaches ; and for most of the cases surgery was done on the left side ( 65.4 % ; table 2 ) . average length of surgery was 212.7110.8 minutes , and the average blood loss was 461.1725.5 ( table 2 ) . there was no intra - operative death in our study , and the total incidence of other rare complications was low ( table 3 ) . total incidence ( % ) = ( number of patients with given complication / total number of patients undergoing cervical surgery ) 100 . in the past decades , there has been immense progress in understanding the link between pathophysiological changes and spine biomechanics , leading to defined cervical surgical approaches . the risk of complications is inevitable but it can be reduced with the proper surgical indications that are appropriate for the pathology present . our data shows that among 21 centers , there was no case of intraoperative deaths in elective cervical spine surgeries . we did not measure the mortality rate of postoperative deaths in our series of patients . goz and coworkers indicated that the mortality rates after spine surgery remained constant over a 10 - year period . thoracic spine surgery had the highest death incidence ( 1.2 % ) , followed by cervical ( 0.46 % ) and lumbar ( 0.14 % ) . a similar pattern was observed in another database study , with the mortality incidence being 0.57 % , 0.13 % , and 0.11 % for the thoracic , cervical , and lumbar regions , respectively . both studies found that older age ( 65 years ) , male patients , and various comorbidities ( congestive heart failure , chronic pulmonary disease , neurological disorders , metastatic cancer , renal failure , weight loss ) strongly correlated with the risk of in - hospital death . in our study , the mean patient age was 54 years , and 54.7 % were male patients . one of the key factors that can lead to an increase in death incidence is the nature of the surgery , whether it is emergent or elective . a prospective study on spinal surgery with 471 patients receiving elective surgery and 471 patients receiving emergency surgery reported an overall 2.1 % mortality rate . in the study by street et al , there was only one death in the elective surgery group , and 19 in the emergency group , mainly in patients with trauma or spinal tumors . in our retrospective study , all the surgeries were elective and no intraoperative death was observed . furthermore , a retrospective database study reported 0 % postoperative mortality rates after ambulatory cervical surgeries over a 5 - year time period . the majority of these cases ( 68 % ) were done using the anterior cervical discectomy and fusion , similar to our study where 53.9 % of the patients underwent an anterior approach . the impact of teaching and nonteaching hospitals on the death incidence rates after spine surgery has been an extensive ongoing debate . numerous studies have shown that teaching hospitals in general perform better when it comes to the more complex surgeries and that mortality rates are lower or similar to nonteaching hospitals . however , fineberg et al found a significant difference in mortality rates between teaching and nonteaching hospitals ( 1.2 vs 0.6 per 1000 ) . some of the predictors for this high incidence were patient age , weight loss , neurological , pulmonary , and cardiac comorbidities and complications . another contributing factor in this study was the surgery complexity , which was higher at the teaching hospitals . our data is in agreement with these reports ; all the centers in our study were teaching institutions and the complication rates were low . one of the most common complications after cervical surgery occurs in the region of the esophagus . patients with anterior cervical discectomy and fusion procedures in particular are at a higher risk of dysphagia , laryngeal nerve injury , and pharynx wall swelling . fineberg et al looked at the influence of aspiration on the death incidence after anterior fusion , posterior fusions , or posterior decompression . the aspiration incidence was 5.3 per 1000 , and it was more common in older patients and male patients . mortality rates were significantly higher in patients with aspiration compared to those without ( 34.4 vs 0.7 per 1000 ) . the highest mortality rates were observed in multilevel surgeries ( 3 or more levels ) and in posterior cervical fusions . the aspiration and mortality rates were strongly correlated with older age and male gender . in our study , the incidence of esophageal perforation was very low ( 0.02 % ) , and most of the cases were done using the anterior approach . another study looking at the trends of cervical surgery with and without human recombinant bone morphogenetic protein 2 ( rhbmp2 ) found that posterior cervical fusion had the highest mortality rate of 12.6 per 1000 compared to 2.9 per 1000 for anterior cervical fusion and 3.2 per 1000 for posterior cervical decompression . injury of the vertebral artery during anterior cervical fusion can lead to a fatal outcome . a systematic review done by park and jho found that among 39 cases ( 17 studies ) that underwent anterior cervical approach only one case ended up fatally due to excessive bleeding and 45 % of the patients had delayed vascular complications . myelopathy is possibly the comorbidity with the highest influence on morbidity rates associated with cervical surgery . patients who had myelopathy and an anterior cervical procedure had a higher mortality rate compared to nonmyelopathy patients ( 0.52 % vs 0.05 % ) . the posterior approach was not strikingly different , but the mortality rates were higher overall in myelopathy patients ( 0.67 % vs 0.36 % respectively ) . one of the most probable explanations is that myelopathy can lead to a sequel of perioperative complications obstructing vital functions . wang and coauthors further found that patients over 75 years of age and with myelopathy had a 19 times higher chance of dying after cervical spine surgery , posterior or circumferential . even though there is data on death after cervical spine surgery , several reports have shown that those trends are stable or declining . patil et al have shown that despite the 2-fold increase in the number of cervical procedures over a decade , the average mortality and length of stay decreased , suggesting improvement in surgical approach and patient care . the major limitation was the study size , as only 258 patients met the inclusion criteria . within each center , cases originated from a single surgeon potentially introducing bias due to the highly defined surgical setting . furthermore , other demographic data known to affect mortality rates such as ethnicity or previous conditions was not collected . despite those limitations and no death cases , our study suggests that using an adequate surgical approach for patient diagnosis and comorbidities may prevent the occurrence of this intraoperative death . death after cervical spine surgery is a very rare complication . in our multicenter study , there was no incidence of intraoperative death . our findings further strengthen the notion that low complication rates and proper surgical skills can diminish the circumstances that could lead to intraoperative death .\noutput:\n" }, { "from": "agent", "value": "study design : a retrospective multicenter study.objective : routine cervical spine surgeries are typically associated with low complication rates , but serious complications can occur . intraoperative death is a very rare complication and there is no literature on its incidence . the purpose of this study was to determine the intraoperative mortality rates and associated risk factors in patients undergoing cervical spine surgery.methods : twenty - one surgical centers from the aospine north america clinical research network participated in the study . medical records of patients who received cervical spine surgery from january 1 , 2005 , to december 31 , 2011 , were reviewed to identify occurrence of intraoperative death.results : a total of 258 patients across 21 centers met the inclusion criteria . most of the surgeries were done using the anterior approach ( 53.9 % ) , followed by posterior ( 39.1 % ) and circumferential ( 7 % ) . average patient age was 57.1 13.2 years , and there were more male patients ( 54.7 % male and 45.3 % female ) . there was no case of intraoperative death.conclusions : death during cervical spine surgery is a very rare complication . in our multicenter study , there was a 0 % mortality rate . using an adequate surgical approach for patient diagnosis and comorbidities may be the reason how the occurrence of this catastrophic adverse event was prevented in our patient population ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: left atrial myxoma is a benign primary cardiac tumor and a cause of embolic stroke . nearly half of the benign heart tumors are myxomas , making it the most common heart tumor . although classified as benign tumors , myxomas seem to grow and spread , but there is still debate as to whether they metastase or fragments simply embolize . there is a 2:1 female preponderance and the age at onset is usually between 3060 years . although atrial myxoma is largely sporadic , at least 7 % of cases are familial . stroke appears to be responsible for 80 % of the neurological presentations of myxomas , and only 40 % of these have a typical pattern of cardioembolism involving several vascular territories . myxoma usually causes ischemic stroke by embolism of tumor or thrombus , but aneurismal dilations at sites of earlier embolic vascular occlusion can cause intracerebral or subarachnoid hemorrhage . cerebral imaging often demonstrates multiple infracts suggestive of an embolic cause , but in some cases it may show only small subcortical ischemic lesions , as seen in lacunar infracts . transthoracic echocardiography has approximately 90 % sensitivity in the detection of left atrial myxoma , while the sensitivity of transesophageal examination is 100 % . transesophageal examination is also preferred because of its ability to detect other cardioemoblic sources , such as intracardiac thrombus , vegetations , or aortic arch plaque . general or constitutional manifestations , such as fatigue , fever , erythematous rash , arthralgia , myalgia , and weight loss , as well as laboratory abnormalities , such as anemia and elevated esr and serum c reactive protein and globulin levels , have been observed in many patients irrespective of the site and size of the myxoma . the risk of recurrent myxoma is 13 % for sporadic cases , and it is usually attributed to multifocal myxoma embolization or incomplete resection . it has not yet been established as to whether transcranial doppler ( tcd ) can be used as a means to examine the emboliogenic potential of cardiac myxoma in patients with acute stroke . a 43 - year old woman from the philippines was brought to the emergency department of rambam medical center in haifa , israel because of acute onset of generalized tonic - clonic seizures and left hemiplegia . her vital signs were normal , and cardiac exam revealed sinus rhythm without heart murmurs . neurological examination showed left central facial palsy , eye deviation to the right , left hemiplegia , brisk deep tendon reflexes , and extensor plantar reflex on the left . a ct scan of the brain on admission revealed a small old right parietal lobe infraction . another ct was performed 24 hours later and revealed a large acute infraction in the territory of the right middle cerebral artery ( mca ) and another smaller one in the territory of the posterior cerebral artery on the same side . carotid duplex , including common , internal and external carotid arteries and vertebral arteries , was normal . tcd ( pioneer , tc 8080 , viasys , nicolet ) microemboli monitoring was performed for 30 minutes , with both mcas monitored . cardiac holter showed a sinus rhythm average of 74 ( 62119 ) without tachy or brady - arrhythmia or conduction disturbances . transesophagial echocardiography ( tee ) identified a 5 cm left atrial mass , which was highly suspected to be an atrial myxoma ( figure 1 ) attached to the interatrial septum and prolapsed through the mitral valve ( without significant lv inflow obstruction in the supine position ) . after the tee results were obtained , another tcd monitoring was performed and continued this time for one hour . transthoracic echocardiography was performed three days after surgery and showed no evidence of residual myxoma or atrial septal defect . figure 1multiple trans - esophageal images of a large left atrial myxoma ( marked by * ) . long - axis mid - esophageal views of the heart ( a systole , b early diastole , c mid - diastole ) demonstrating prolapse of the myxoma from the left atrium into the left ventricle during diastole . multiple , mobile , finger - like projections of the tumor were evident ( thin arrows ) . four - chamber mid - esophageal view ( d ) showing the connection of the tumor to the interatrial septum ( thick arrow ) . la = left atrium , lv = left ventricle , ao = ascending aorta , aov = aortic valve , rv = right ventricle . multiple trans - esophageal images of a large left atrial myxoma ( marked by * ) . long - axis mid - esophageal views of the heart ( a systole , b early diastole , c mid - diastole ) demonstrating prolapse of the myxoma from the left atrium into the left ventricle during diastole . multiple , mobile , finger - like projections of the tumor were evident ( thin arrows ) . four - chamber mid - esophageal view ( d ) showing the connection of the tumor to the interatrial septum ( thick arrow ) . la = left atrium , lv = left ventricle , ao = ascending aorta , aov = aortic valve , rv = right ventricle . this technique provides useful information about possible sources of embolism , as well as their activity . acute ischemic stroke , carotid stenosis , and cardiac diseases are the most studied areas in the field of mes monitoring . the significance of mes in patients with cerebrovascular diseases has been the subject of many studies . the short pubmed literature search by combination of mes and stroke retrieved 122 related items . the first line of research is devoted to revealing the prevalence and timing of mes appearance in patients with acute ischemic stroke . it is now well established that mes is a frequent phenomenon in patients with ischemic stroke and that the amount of mes is related to stroke onset , with the peak occurring in the first hours and days after stroke . many other important studies have been devoted to the key issue of using the presence and amount of mes as predictors of the short - and long - term clinical outcomes during the index event , as well as possible predictors of recurrent ischemic stroke . studies exploring the correlation between prevalence and amount of mes and the etiology of ischemic stroke can also be found in the literature . another line of research estimates the impact of mes in both symptomatic and asymptomatic carotid disease . in patients suffering from carotid stenosis , the presence of mes can be indicative of an unstable structure of carotid plaque that is prone to be a source of emboli . the existence of mes in patients with carotid disease is also an important indicator of the substantial danger of the first and recurrent cerebrovascular event . another area in which the presence of mes determines the increased risk of peri - and post - procedural complications is that of carotid surgery and stenting . in both cases , the appearance of a significant amount of mes reflects damage of the plaque , resulting in multiple emboli with neurological and cognitive impairment . in cardiology , tcd is a reliable technique for the detection of mes from cardiac embolic sources , such as prosthetic cardiac valves , aortic plaques , and atrial fibrillation . it is also used as an especially sensitive technique for detecting right - to - left cardiac or pulmonary shunts . the microembolic signals obtained from patients with artificial heart valves and during examinations for pfo detection have also been used as a model , alongside other methods , in an attempt to differentiate between gaseous and solid microemboli . the results of mes monitoring may also be found in some other clinical situations , where their presence or absence helps us to better understand the role of embolism in the development of the disease . our case emphasizes that mes monitoring may be useful not only in detecting the emboliogenic nature of the disease , but also in exploring the precise timing of embolization ( i.e. , either permanent , as in the many clinical situations mentioned above , or sporadic , as in our case ) . although cardiac myxoma is a rare disease , it should be considered in young patients with stroke and elevated esr , even without systemic symptoms . there are no data in the literature about tcd monitoring in patients with atrial myxomas . our findings showed the absence of mes on two consecutive tcd examinations , suggesting a spontaneous occurrence , rather than the permanent presence , of embolization , even in the most acute phase of stroke . these data are compatible with literature sources pointing to the simultaneous appearance of multiple emboli at different target sites in patients presenting with cardiac myxomas . another line of evidence supporting our data is the large number of silent lesions commonly found in patients with stroke and myxomas , as in the case of the patient presented here . thus , it seems that in many cases , despite silent embolic events , the patient may remain clinically intact for years until a symptomatic event occurs . the tendency of myxomas to spontaneously produce severe and multiple emboli emphasizes the need for the surgical excision of myxomas when possible anticoagulation seems to be doubtful .\noutput:\n" }, { "from": "agent", "value": "this is the first reported attempt to examine the emboliogenic potential of cardiac myxoma in patients with acute stroke through the monitoring of microembolic signals ( mes ) by transcranial doppler . a 43 - year old woman was brought to the emergency department because of acute onset of generalized tonic - clonic seizures and left hemiplegia . a ct scan of the brain demonstrated a large acute infraction in the territory of the right middle cerebral artery ( mca ) and another smaller one in the territory of the posterior cerebral artery on the same side . trans - cranial doppler ( tcd ) microemboli monitoring did not reveal mes . transesophagial echocardiography ( tee ) identified a 5 cm left atrial mass , which was highly suspected to be an atrial myxoma attached to the interatrial septum and prolapsed through the mitral valve . after the tee results were obtained , another tcd monitoring was performed . again , there were no mes found in either of the mcas.our findings showed the absence of mes on two consecutive tcd examinations , suggesting a spontaneous occurrence , rather than the permanent presence , of embolization , even in the most acute phase of stroke . thus , the tendency of myxomas to spontaneously produce multiple emboli emphasizes the need for the surgical excision of myxomas ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the amphibole group of asbestos includes crocidolite , amosite , anthophyllite , tremolite , and actinolite varieties . the use of crocidolite and products containing this fibre and spraying of all forms of asbestos are prohibited under the international labour organisation ( ilo ) convention concerning safety in the use of asbestos ( no . more than 50 countries , including all member states of the european union , have banned the use of not only crocidolite but also all other forms of asbestos . chrysotile , which is not prohibited under the ilo , is still used in many developing countries , accounting for 90 % of world 's asbestos production . although chrysotile is safer than crocidolite , significant mortality has been associated with exposure to chrysotile asbestos . we studied chrysotile asbestos workers of a small - scale clutch plate - manufacturing factory as one of their colleagues had expired 1 year ago ( sentinel case ) due to asbestosis . a prospective evaluation of 14 workers from a small - scale clutch plate - manufacturing factory was performed after obtaining institutional review board clearance . as per the industrial laws , hence , a report from social security officer was taken and the workers were called to the hospital for evaluation . as per the report , these workers worked in a 200 m area with adequate ventilation , but without protective gears on hydraulic machine with the material , as shown in figure 1 . the asbestos string and powder used for making clutch the aims of the study were to evaluate ( 1 ) if the workers were well - informed about asbestos and its handling in a small scale - clutch manufacturing factory , ( 2 ) the prevalence and type of asbestos - induced lung disease from a small scale - clutch manufacturing factory , and ( 3 ) the sensitivity and specificity of residual volume ( rv ) to total lung capacity ( tlc ) ratio , i.e. , rv / tlc and diffusion capacity of lung for carbon monoxide ( dlco ) in detecting nonmalignant asbestos - induced lung disease . all the 14 workers underwent a detailed history taking and examination . the history included the following : ( 1 ) information that the substance they are working with is a hazardous substance and the extent of its hazardousness ; ( 2 ) information about preventive measures ; ( 3 ) if any checkup was advised by the employer ; ( 4 ) respiratory symptoms ; ( 5 ) duration of work ; ( 6 ) smoking index : one bidi was taken as one cigarette in bidi smokers ; and ( 7 ) atopy . spirometry with diffusion test was performed with medisoft / morganscientific spiroair in all the patients . it was performed and interpreted as per the american thoracic society ( ats ) guidelines . parameters noted were forced vital capacity ( fvc ) , forced expiratory volume at 1 second ( fev1 ) , fev1 / fvc ratio , maximal mid - expiratory flow at 2575 % ( mmef2575 % ) , rv / tlc , and dlco . chest radiograph and high resolution computed tomography ( hrct ) was also carried out in all the cases . the diagnosis of the possible absence or presence of lung disease was based on hrct . patients were classified as small airway disease ( sad ) if the hrct showed mosaic attenuation and / or centrilobular nodules , ild if there was interseptal thickening and / or honeycombing , and chronic obstructive pulmonary disorder ( copd ) if there was centrilobular emphysema . if hrct showed evidence of airway and / or interstitial involvement , the workers were subjected to bronchoscopy and transbronchial lung biopsy ( tblb ) . the asbestos - induced lung disease was confirmed if there was presence of asbestos bodies on tblb . asbestos bodies indicate that there was significant asbestos exposure , thereby indicating asbestos - induced lung disease . none of the workers had any information about preventive measures . none of the workers had ever done preventive health checkup . none of the workers were aware about detrimental effects related to smoking combined with asbestos . their mean age was 42.314.16 years , and the mean duration of exposure in the factory was 24.234.2 years . eight out of 11 patients were symptomatic , and majority had complaints of cough with or without expectoration along with breathlessness ranging from few months to 18 years [ table 2 ] . four out of 11 patients had atopic tendencies , 2 patients had significant smoking index , 6 patients had insignificant smoking history ( smoking index 5 pack years ) , and 3 patients had never smoked . on general examination , 8 patients had post - exercise desaturation of more than 4 % and 7 patients had clubbing . on respiratory system examination , 7 patients had basal crackles , 2 patients had rhonchi as well as crackles , and 2 had no respiratory abnormality . details of workers affected with asbestos induced lung disease the spirometry of 11 affected workers showed mean fvc of 2.3690.467 l and 62.3612.26 % predicted , the mean fev1 / fvc ratio of 75.10913.52 % , and the mean of mmefr2575 % of 53.0928.96 % predicted . the diffusion studies in these patients showed a dlco of 18.755.45 ml / mm of hg / min and 69.8118.88 % predicted , and the mean rv / tlc of 45.389.98 % . fvc was reduced in all 11 patients , 5 patients showed reduced fev1 / fvc ratio , 7 patients had reduced mmefr . the dlco was reduced in 8/8 patients , and ild and rv / tlc ratio was increased in 10/11 patients with sad [ table 3 ] . pulmonary function test findings out of 11 patients with asbestos - induced lung disease , 5 patients had bilateral lower zone haziness along with reticulonodular opacities , 1 patient had hyperinflated lung field , 1 had shaggy lung fields , and 4 had normal chest radiograph . on hrct , all 11 workers with asbestos - induced lung disease had an evidence of sad . three patients had sad alone , 6 workers had sad with ild , and 2 patients had ild , copd , and sad . in patients with sad and copd , it was difficult to pinpoint that the etiology of sad was due to asbestos - induced injury or small airways involvement because of copd . the hrct and histopathology images of few of the patients are presented in figures 3 and 4 . venn diagram showing spectrum of presentation in patients of asbestos - induced lung disease ( a ) high - resolution computed tomography thorax transverse section lung window of case 4 showing presence of centrilobular nodule and interstitial thickening ; ( b ) high - resolution computed tomography thorax transverse section lung window of case 2 showing interstitial thickening and subpleural honey combing ; ( c ) high - resolution computed tomography thorax transverse section mediastinal window of case 2 showing bilateral pleural thickening ; ( d ) high - resolution computed tomography of thorax transverse section mediastinal window of case 3 showing mosaic attenuation ( a ) asbestos body covered by golden brown pigment ( 100objective ) ; ( b ) asbestos body stained by prussian blue iron stain . ( 20objective ) the remaining 3 asymptomatic workers who did not have asbestos - induced lung disease had a mean age of 38.332.3 years , and mean duration of exposure of 22.664.04 years . the mean fvc was 2.700.046 l ( 70.334.16 % predicted ) . all 3 patients had low fvc due to poor performance ; obesity and kyphoscoliosis in 1 patient each . the patients had normal chest radiograph and hrct except for features of kyphoscoliosis in one of the workers . it should be noted that 3 of the workers with asbestos - induced lung disease did not have symptoms , 2 workers did not have any clinical finding , and 4 workers had normal chest radiograph . all those who were diagnosed to have asbestos - induced lung disease had low fvc , but even those without asbestos - induced lung disease had low fvc due to various reasons . predicting the probability of various diagnostic modalities in patients with asbestos - induced lung disease in our studychest radiograph and spirometery were not useful for screening of asbestos - induced lung disease . however , rv / tlc and dlco had good sensitivity and specificity for detecting nonmalignant asbestos - induced lung disease . predicting probability of various diagnostic modalities in patients with asbestos induced lung disease in our study . workers suffering from the disease as well as those without the disease have been advised to quit smoking and / or not to smoke ever . they have also been informed about the harmful effects of asbestos and have been advised to use protective gears . all the workers with asbestos - induced lung disease have been given influenza and pneumococcal vaccine . workers suffering from the disease as well as those without the disease have been advised to quit smoking and / or not to smoke ever . they have also been informed about the harmful effects of asbestos and have been advised to use protective gears . all the workers with asbestos - induced lung disease have been given influenza and pneumococcal vaccine . the small - scale factory that we studied is covered under the employee state insurance scheme ( esis ) , which is tailored to provide socioeconomic protection to worker population and their dependents covered under the scheme . though the factory workers were covered under esis , most of the workers were uninformed about asbestos and its ill effects . it has been documented earlier that workers remain uninformed and untrained in dealing with asbestos exposure . in india , the use of asbestos has doubled in the decade 2000 - 2010 to approximately 300,000 tonnes a year by the industry that employs an estimated 100,000 workers . the health and safety legislations do not cover 93 % of the workers in the unorganized sector where asbestos exposure is extremely high . if the workers covered under the esis do not know about asbestos and its handling , the state of the other workers must be dismal ! has shown that there is a significant mortality risk , particularly from lung cancer and nonmalignant respiratory diseases , associated with exposure to chrysotile asbestos . our study shows that chrysotile not only causes mortality ( sentinel case ) it also leads to significant morbidity if handling is improper . overall , our study shows a glaring reality toward steps that are required to be taken for small - scale asbestos worker 's well - being in india if not ban the chrysotile variety of asbestos altogether ! chrysotile variety of asbestos is used for a lot of items , e.g. , roofing shingles , water supply lines , fire blankets , insulation materials , clutch and brake linings , gaskets , and pads for automobiles . the process of clutch manufacturing requires steels , graphite , phenolic resin , and chrysotile asbestos fiber as raw materials . subsequently , asbestos string is soaked and removed from graphite mixture , and then the string is bonded to the clutch facing . however , an exclusive evaluation of workers working in clutch manufacturing has never been done . the factory workers we analyzed for work - related injuries were evaluated because an index case had died of asbestosis . there have been large - scale studies evaluating the risk of asbestosis in exposed workers in various asbestos industries from india . one of the studies from india done by programme objective series ( probes ) in 2008 among asbestos workers showed exposure - wise prevalence of symptoms , signs , obstruction , and restriction . the prevalence was high in unorganized sector such as ours possibly due to the high level of exposure . in yet another study with a sample size of 625 where brake lining workers were included along with other asbestos workers showed that 6/153 ( 3.9 % ) , 20/153 ( 13.1 % ) , and 1/153 ( 0.7 % ) of brake workers had restrictive , obstructive , and combined defect , respectively . another study from mumbai with a sample size of 182 showed that the prevalence rate of asbestosis in asbestos industry workers was 23 % . in this study , the restrictive abnormality was shown to be higher ( 62 % ) than the obstructive abnormality ( 15 % ) . in our group of workers , 11/14 ( 71.42 % ) there could be five reasons for the overall high prevalence of asbestos induced lung disease : ( 1 ) the sample size in our study was small because of which we could study them in much more detail with hrct . ( 2 ) our workers belonged to the small scale unorganized sector , and hence possibly the level of asbestos at workplace was high . sad was in the form of mineral dust bronchiolitis or obliterative bronchiolitis causing centrilobular nodules and / or air trapping and / or mosaic attenuation on hrct . however , no studies have demonstrated a very high prevalence of sad in asbestos workers . in fact , one of the studies had questioned sad in asbestos workers . in this study , it was shown that there was absence of relationship of pulmonary function ( fev1 , fev1 / fvc , or fef2575 % ) and cumulative exposure to asbestos . in the accompanying editorial , it was argued that possibly these workers were resistant to asbestos or the exposure was miniscule . workers resistance to asbestos was argued on the basis that the mean fvc of the population studied was 99.6 % predicted after 27.7 years of exposure . the editor has also stated that such an unimpacted population would not show a dose - response relationship ! further , it was noted by the editor that with exposure greater than 20 years , only 10 workers had asbestos bodies . thus , the hypothesis that asbestos does not cause sad seems to be incorrect . in our study , sad was more common compared to ild . this high prevalence of sad could be due to the following factors : ( 1 ) smoking : smoking has been found to have compounding effect on small airway obstruction . had suggested that individuals probably differ in their susceptibility to asbestos - induced lung disease based on respiratory clearance . eight out of 11 patients were ex - smokers , though only 2 of them had significant smoking index . possibly small amount of smoke inhalation also leads to trapping of asbestos making them susceptible to small airway injury . had also stated that there could be other unidentified hosts or environmental factors . in our study , 4 of the patients were atopic and one of these atopic individual was a nonsmoker . ( 3 ) phenolic resin : it is possible that phenolic resin which is known to cause airway disease had an additive effect . the study described earlier with a subgroup of brake manufacturing workers using phenolic resin also had high prevalence of obstructive airway disease . ( 4 ) small sample size : due to small sample size , our group of patients could be studied in detail with rv / tlc and hrct . ( 5 ) hrct : some of the studies done earlier have not used hrct , and the studies which have used hrct did not aim to evaluate sad . hence , sad was not picked up which is otherwise easy to miss . thus , smoking , atopy , phenolic acid , small sample size , and careful observation on hrct possibly made us diagnose sad more than the others studies . this finding also helped us in treating the patients with bronchodilators who were symptomatically better after the treatment . hrct has been evaluated for screening of nonmalignant asbestos - induced lung disease and is considered to be a more sensitive tool . the recent literature has also documented that chest hrct findings significantly correlate with pulmonary function and mortality . however , its routine use for this purpose is not been recommended so far for nonmalignant asbestos - induced lung disease . spirometry as a screening parameter for detecting nonmalignant asbestos - induced lung involvement is likely to miss both sad and ild . this is because mmefr2575 % measured during conventional spirometry for detecting sad has very poor sensitivity and specificity . the sensitivity of chest radiograph , fvc % predicted , fev1 / fvc , and mmefr2575 % was 63.6 % , 100 % , 45 % , and 63.6 % , respectively . the specificity of the same parameters was 66.6 % , 0 % , 66.6 % , and 100 % , respectively . on the contary , sensitivity of rv / tlc and dlco was 90.9 % and 100 % , respectively , and the specificity of both the parameters was 100 % . these studies have found them to be useful in assessing the severity . however , none have assessed their specificity and sensitivity for diagnosing nonmalignant asbestos - induced lung disease . because the specificity and sensitivity of rv / tlc and dlco is good , it can be very useful for screening of ild and sad , i.e. , nonmalignant asbestos - induced lung disease if hrct is not feasible . to conclude , we would like to state that chrysotile is not safe and requires to be regulated . especially in small - scale industry strict guidelines regarding its handling and workers protectionclutch manufacturing workers are possibly more prone to sad and we can label this type of lung involvement , i.e. , small airway , interstitial , and pleural involvement combined as clutch plate manufacturing worker 's disease . studies on screening of asbestos - induced lung disease should include at least rv / tlc and dlco . our study made asbestos workers aware about the harmful effects of asbestos and its preventive measures , which were not very well known to them earlier .\noutput:\n" }, { "from": "agent", "value": "background : the crocidolite variety of asbestos is banned . however , chrysotile , which is not prohibited , is still used in developing countries in making products such as clutch plate . fourteen workers from a small - scale clutch plate - manufacturing factory were analyzed for asbestos - induced lung disease as one of their colleagues had expired due to asbestosis.aims : this study was conducted to evaluate the awareness of workers , the prevalence and type of asbestos - induced lung disease , and the sensitivity and specificity of diffusion test.materials and methods : history , examination , chest radiograph , spirometry with diffusion , and high resolution computed tomography ( hrct ) thorax was performed in all the workers . the diagnosis of asbestos - induced lung disease was suspected on the basis of hrct . this was subsequently confirmed on transbronchial lung biopsy ( tblb ) . results : none of the workers had detailed information about asbestos and its ill effects . eleven out of 14 ( 71.42 % ) workers had asbestos - induced lung disease . all 11 had small airway disease ( sad ) . three had sad alone , 6 had additional interstitial lung disease ( ild ) , and 2 patients had additional ild and chronic obstructive pulmonary disease . sensitivity and specificity of residual volume ( rv ) or total lung capacity ( tlc ) for detecting sad was 90 % and 100 % , respectively , and that of diffusion capacity of lung for carbon monoxide ( dlco ) for detecting ild was 100 % . conclusion : the awareness about asbestos in small - scale clutch - plate manufacturing industry is poor . the usage of chrysotile should be strictly regulated as morbidity and mortality is high . dlco and rv / tlc are sensitive and specific in detecting nonmalignant asbestos induced lung disease ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: a 57 - year - old male patient presented with a sudden onset of low back pain radiating to the left lower leg after running on a treadmill . magnetic resonance imaging revealed a posterior herniated ruptured disc between the fourth and fifth vertebrae in the lumbar spine . a neurosurgeon evaluated the patient 's condition , which indicated the need for a microdiscectomy of the left l4 - l5 intervertebral disc . an emergency operation was decided because the patient complained of severe pain and numbness . inside the operating room , the non - invasive blood pressure ( nibp ) , electrocardiography ( ecg ) and pulse oximeter ( spo2 ) were connected to the patient . general anesthesia was induced with propofol 120 mg and endotracheal intubation was facilitated using rocuronium 60 mg as a muscle relaxant . anesthesia was maintained with desflurane in a 50 % n2o and o2 mixture , and rocuronium . the lungs were ventilated mechanically with a semiclosed circuit system to maintain the end - tidal co2 ( etco2 ) at approximately 35 mmhg . intraoperative monitoring included the heart rate , nibp , ecg , spo2 , etco2 , anesthetic gases analysis and the airway pressures . a sudden spurt of blood occurred when the disc was almost completely removed . as the blood continued to gush out , the systolic bp decreased to 50 mmhg , the nibp was not detectable and patient began to have tachycardia ( 156 bpm ) . three 16 g cannulas were quickly secured on the dorsum of the other hand and both external jugular veins . arterial cannulation was achieved with a 20 g cannula on the left radial artery . under the suspicion of a large vessel injury , the laminectomy wound was closed immediately and the patient was turned to the supine position for a laparotomy . at that time , the patient showed an inflating abdomen . a 16 g double lumen central line was placed in the right internal jugular vein and fluids were infused . dopamine and dobutamine infusions were started but they had no effect , so a norepinephrine infusion was also started . the neurosurgeons , anesthesiologists and cardiothoracic surgeons agreed about the necessity of cardiopulmonary bypass ( cpb ) due to the suspicion of severe bleeding from an iatrogenic large vessel injury . a right iliac artery injury was suspected so the left femoral artery and vein were used for cannulation . an arterial cannula was cannulated into the left femoral artery , with a flow of 2,000 ml / m / min , and partial cpb was started . , a wedge - shape rent was found in the right external iliac artery around the l4 - 5 level . during the operation , the intravascular volume was replaced with 9 liters of crystalloid , 0.5 liters of colloid , 18 units of packed red blood cells , 14 units of fresh frozen plasma and 8 units of platelet concentrates . as soon as the external iliac artery injury had been repaired , the hemodynamic parameters of the patient began to improve . after the bleeding was controlled , and the cpb was stopped , and protamine ( 185 mg ) was administrated . postoperatively , the patient was sent intubated and ventilated to the intensive care unit ( icu ) . in the icu , the patient was extubated on the fourth postoperative day . under the appropriate treatment for seven daysfour weeks later , the patient was discharged from hospital neurologically intact and with a healthy laparotomy wound . the aorta is ventral to the vertebral column , which transverses the diaphragm at the level of the l1 intervertebral space and bifurcates at the level of the l4 intervertebral space into the common iliacs . the inferior vena cava is located to the right of the aorta in these segments , and is divided further into left and right common iliac veins , also at the level of the l4 intervertebral space . the incidence of major vascular injury during lumbar disc operations is 0.01 - 0.05 % with an overall mortality of 10 - 65 % [ 2 - 4 ] . the broad range of the mortality is associated with the diameter of the injured vessels , size of the tear , speed of diagnosis , laparotomy and control of bleeding . many factors predisposing the patients to vascular injury during lumbar surgery have been reported , including anterior disc rupture , preexisting defects in the anterior annulus fibrosus and anterior longitudinal ligaments , vertebral anomalies , body habitus , patient positioning , use of different techniques , use of a surgical microscope , prior intraabdominal surgery , surgery for recurrent disc herniation , and the surgeon 's experience . major vascular injuries can manifest as acute life - threatening hemorrhage , chronic arteriovenous fistula or pseudoaneurysm formation . acute blood loss can lead to an intractable and progressive decrease in blood pressure due to hypovolemia , wide pulse pressure , tachycardia , a decrease in haematocrit , pallidness , and a decrease in skin temperature . an arteriovenous fistula and aneurysms may often be undetected initially and patients may present with symptoms months or years later . the mortality rate for lacerations , the most common injury among them is on the right common iliac artery , which is located immediately anterior to the l4 - l5 lumbar disc space . next in order of frequency is an arteriovenous fistula between the right common iliac artery and left common iliac vein . the most common surgical techniques for repair of these complication include the following techniques : primary suturing , interposition grafting , excision with end - to - end anastomosis , suturing from within the vessel , patch angioplasty , ligation and endovascular embolisation or stent - graft placement . laceration of a major artery or vein will result in life - threatening bleeding complications that should be treated by rapid fluid resuscitation and immediate vascular surgical intervention . the surgical decision and repair of the arterial wall injury in patients presenting with an acute and rapid course of deterioration should be made as early as possible . the mortality rate approaches 100 % when surgery is not performed immediately in arterial injuries . during lumbar disc surgery , ureteral and intestinal injuries can also occur but , the diagnosis can be more difficult due to a lack of specific diagnostic signs . generally , cpb with the femoral artery and vein is indicated for an aneurysm of the ascending aorta , or severe atherosclerosis or difficult cannulation in the ascending aorta during cardiac surgery due to the complex surgical technique . in addition , it can be used when difficult airway management is predicted or , like this case , when severe bleeding caused by a major vessel injury occurs . in summary , correct crisis resolution protocols , such as proper massive transfusion algorithms and successful surgical intervention , are quite effective during the critical period . a high index of suspicion , prompt diagnosis and action will result in improved patient salvage .\noutput:\n" }, { "from": "agent", "value": "iatrogenic vascular injury during lumbar disc surgery is a rare but serious complication . this paper reports a patient who sustained an injury to the iliac artery while undergoing intervertebral disc surgery at the lumbar region . he suffered from massive bleeding and shock . an urgent laparatomy was performed under cardiopulmonary bypass , and the vascular injuries were repaired successfully . this case shows that a rapid diagnosis and immediate intervention can result in a favorable outcome ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: 90 % of those aged 81 - 90 have pathological bph .5 the prevalence of bph among iranian men above 40 years is estimated to be 23.6 % .6 bph would present with luts . the progression of luts can result in aur .1 it is well - recognized by both urologists and pathologists that bph and prostatitis can coexist .78 twenty percent of patients with luts associated with bph might also have symptoms suggestive of prostatitis .15 but , the relationship between bph and prostatic inflammation , and how one can influence the presentation , diagnosis , treatment and treatment outcome of the other , is under controversy .9 histopathologically , inflammation would be detected in most pathological specimens of patients with bph , who do not necessarily have symptoms of prostatitis .17 incidental asymptomatic prostatic inflammation is defined in the usa national institute of health classification of prostatitis ( category iv ) and has been showed to be present in 43 - 98 % of surgically resected prostates due to bph .1011 a subanalysis of the medical therapy of prostatic symptoms ( mtops ) study suggested that inflammation detected in baseline prostatic biopsies was highly predictive of progression of bph to aur and the need for more invasive therapy .12 if inflammation and bph had a causal relationship , by derivation the incidence of inflammation would be higher in aur , the most severe symptom in bph than in those patients with bph who do not present with aur .1 in the present study , we investigated the patients with bph who were scheduled to undergo turp or open prostatectomy with the aim of determining whether the incidence of prostatic inflammation was significantly different in patients presented with aur than in those presented with luts . this was a cross - sectional study done at a hospital in guilan , the northern province of iran . the studied population was consisted of patients undergoing turp or open prostatectomy from 1999 to 2002 . histopathologic prostatic samples from both groups were fixed in formalin and examined by two consultant histopathologists . aci was diagnosed by the presence of edema , vascular congestion and numerous neutrophils within prostatic acini infiltrating the lining epithelium and extending to a lesser extent into the surrounding stroma . the term aci was used for lymphocyte and plasma cell dominant stromal infiltrations with lesser admixture of neutrophils and macrophages .1 the studied sample was consisting of 300 patients , of whom complete data was available for 280 patients . the patients who had bladder stones or prostate cancer or complained of prostatitis manifestations or any other pathology of prostate were excluded . the mean age sd of the patients was 66.877.13 years , with the range of 45 to 85 years old . the mean sd prostate weight was 44.889.50 g. among the studied subjects , 150 and 130 patients ( 53.6 % and 46.4 % , respectively ) undertook surgery due to aur and luts , respectively ; 130 out of 280 patients ( 46.4 % ) showed aci in their pathologic exams and 150 patients ( 53.6 % ) did not ( table 1 ) . t - test analysis showed that the patients who had aur were significantly older than the patients who presented with luts ( 68.146.97 and 65.416.05 years , respectively ) ( p 0.05 ) ( table 2 ) . also , patients with aci were significantly older than patients without it ( 67.966.34 and 65.927.64 years , respectively ; p 0.05 ) ( table 1 ) . bivariate analysis showed that aci was significantly associated with aur ( p 0.05 ) . the mean prostate weight was significantly higher in aur group compared the luts group ( 48.088.39 g versus 41.219.13 g , respectively ; p 0.05 ) ( table 2 ) . also , patients who showed aci according to pathologic exams had heavier prostates than those who did not showed aci ( 46.868.70 versus 43.239.90 g , respectively ; p 0.05 ) ( table 1 ) . the differences between patients with and without aci the differences between patients with aur or lutsafter mishra et al study ,1 this was the first study carried out in asia showed that aci is specifically more reported in patients present with aur than luts . the overall incidence of aci in the present study was 46.4 % , which was lower than that reported in the study of mishra et al ( 51 % ) 1 and also some other studies .711 as mishra et al said in their study , the reason might be an underestimation of inflammation in histopathologic sections . but , this phenomenon would be attributable to all samples in both groups , and therefore is unlikely to influence the validity of the last results .1 the present study showed that the weight of prostates with aci was almost 3.7 g higher than the prostates without aci . this difference of the weights between the two groups may be due to several reasons , including the experience and speed of the sonologist , but the most important reason might be related to the higher degrees of bph present in aci . this can support the argument that aci might be a factor in the pathogenesis of bph . in the present study , a high incidence of aci was reported in bph patients and aci was significantly more prevalent in patients whose presentation was aur ( the most severe symptom in bph ) . this supports the hypothesis that patients with aci are more likely to show aur symptoms than those without it . the obstruction in symptomatic bph is hypothesized to be caused by a combination of dynamic and static components . the dynamic component of obstruction is determined by the tone of the prostate and bladder neck smooth muscle , and the static component is related to the mechanical obstruction caused by the enlarged gland .17 symptoms of bph would progress despite medical therapy with - blockers which balance dynamic component .113 similarly , anti - androgen therapy ( against static component ) is only moderately effective .1415 some patients deteriorate even on combined therapy .16 thus , there should be other causative factors exists for bph , one of which could be inflammation . histological evidence of prostatic inflammation is often present in biopsy , surgical and autopsy samples . inflammation in autopsy samples of prostates is reported as high as 5 - 15.3 % in patients over 60 years of age ,17 while mcneal found inflammation in 40 of 91 ( 44 % ) prostates samples obtained at autopsy .18 evidence of prostatic inflammation was noted in 45 % of aspiration biopsy specimens taken because of suspicion of carcinoma .19 kohnen and drach mentioned that up to 98 % of surgically resected prostates removed for bph contained at least some foci of significant inflammatory reaction .11 some of the studies7 have confirmed the histological association of prostatic inflammation and bph , while others2021 have characterized some of the specific inflammatory cells associated with bph . a study by sauver et al showed that using daily nsaids was inversely associated with onset of moderate and severe urinary symptoms , low maximum flow rate , increased prostate volume and elevated prostate specific antigen ( psa ) . results suggested that using nsaids may prevent or delay development of bph .2 nsaids may inhibit proliferation and induce apoptosis in hyperplasic cells .22 this mechanism may have therapeutic effect on bph . in a similar study , falahatkar et al showed that nocturia improved or disappeared in 82.5 % of bph patients who received celecoxib .23 if prostate inflammation truly has a role in the development and progression of benign prostatic hyperplasia , including aur , the hypothesized role of nsaids in aur must be challenged in a randomized trial ( you did not mention anything about the role of nsaids in your introduction or method ; so it is not appropriate to mention it in discussion ) . the main finding of the present study was that aci may be associated with more advanced urinary obstruction . this might have an implication in the future medical management of bph , considering the extent of attention which is currently paid to therapy directed with the aim of reducing the size of the prostate and thus , to reduce the risk of aur . use of nsaids in bph patients may probably decrease risk of urinary retention through reduction of edema and inflammation in the prostate , although randomized trials are suggested to support this .\noutput:\n" }, { "from": "agent", "value": "objectives : almost 20 % of patients with lower urinary tract symptoms ( luts ) due to benign prostatic hyperplasia ( bph ) might also have symptoms of prostatitis . but , the interrelationship between bph and prostatic inflammation , and how one can influence the other , is under controversy . the aim of our study was to determine the incidence of prostatic inflammation in bph patients presented with acute urinary retention ( aur ) . methods : this crosssectional study was conducted in a hospital at guilan , the northern province of iran . a total of 280 patients undergoing transurethral resection of the prostate ( turp ) or open prostatectomy from 1999 to 2002 were enrolled . histopathologic samples of prostate were examined for existence of acute and / or chronic intraprostatic inflammation ( aci ) . results : overall , 150 ( 536 % ) of patients undertook surgery for aur and 130 ( 464 % ) for luts . among them , 130 patients ( 46.4 % ) showed aci in the pathologic examinations whereas 150 patients ( 53.6 % ) did not . the patients with aur were significantly older than those with luts . aci was significantly associated with aur . the mean prostate weight was significantly higher in aur group compared the luts group . those patients who showed aci according to pathologic examinations had heavier prostates than those who did not . the association of aci and aur should be considered in secondary prevention for bph patients.conclusions : aci may increase the degrees of urinary obstruction and aur ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: there may also be bulging of the fetal amniotic membranes through the uterine cervix and vagina . in severe cases the fetal membranes could be seen protruding through the external genitalia . in such cases rupture of the fetal membranescould occur resulting in painless preterm labour and delivery of a live - born fetus . however , this condition usually leads to the empiric use of tocolytic agents and cerclage . furthermore , some studies have advocated early transvaginal sonographic follow - up with or without application of fundal pressure with the aim of detecting cases with occult cervical insufficiency , thereby indicating early cerclage . cervical incompetence can occur after operations ( e.g. , conisation for cervical intraepithelial neoplasia and forceful cervical dilatation for advanced abortions ) or as a result of congenital weakness ( e.g. , after intrauterine exposure to diethylstilboestrol ) . uterine malformations may also give rise to preterm labour , but common ones such as a bicornuate shape are often compatible with term labour , while those such as a thin uterine septum that renders implantation insecure are rare . the equivocal results of trials of cervical cerclage , however , indicate that genuine cervical insufficiency is rare , being implicated in less than 5 % of cases . since the introduction of the cervical stitch procedure in clinical practice over 50 years ago , the efficacy of the operation has not been established by evidence - based standards for many indications . at present , five randomized clinical trials have offered significant information about elective cerclage performed for clinical indications , and the expected neonatal survival rate with properly selected elective cerclage is about 87 % . the 312 % incidence of preterm labor and preterm delivery varies widely with different populations , including risk factors such as low maternal prepregnancy weight , socioeconomic status , racial and ethnic factors , maternal education , maternal work patterns , physical effort during pregnancy and especially during the third trimester , maternal sexual activity , tobacco use , interval between pregnancies , bacterial vaginosis , and other types of bacterial colonization , uterine abnormalities , number of fetuses , and more . finally , other studies have not found any benefits with cerclage compared with expectant management . the purpose of this report is to show the feasibility of emergency late second trimester cerclage in cases with advanced cervical dilatation and bulging of fetal membranes . this is an observational study carried out at the department of obstetrics and gynecology of the douala general hospital , cameroon , between the periods june 2002 and june 2010 . it is noteworthy that the douala general hospital is a tertiary care centre in cameroon covering the central african subregion with patients coming for treatment from neighbouring countries ( chad , gabon , congo republic , equatorial guinea , and central african republic ) including those coming from other towns in cameroon . the patients sociodemographic data were collected including age , occupation , marital status , gravidity and gestational age based on last normal menstrual period and / or ultrasound scanning . furthermore , data regarding the current pregnancy follow - up and any other medical conditions including smoking habits were recorded . the diagnosis of cervical incompetence was by physical examination because all the patients were referred to our department from other centres already with advanced cervical effacement and dilatation , some with bulging of fetal membranes . during hospitalization , blood samples were taken for full blood count , coagulation studies , hiv , syphilis , toxoplasma , and rubella serum titres . furthermore , thick and thin film for malaria , c - reactive protein , urinalysis and culture , electrolytes , fasting blood glucose levels . high vaginal swaps and cultures for gonococcal , chlamydiae , mycoplasma , beta - haemolytic streptococcus , and bacterial vaginosis were taken and transabdominal ultrasound scans were done for estimating gestational age , fetal weight , position , amniotic fluid volume , placenta , fetal viability , and morphologic studies . furthermore , all our patients who underwent cerclage did not present with signs of uterine contractions , chorioamnionitis or bleeding , and preterm premature rupture of membranes ( pprom ) . on admission to hospital , the patients were put to bed rest preferably in the lateral recumbent position and hydration with iv fluids 2000 ml ringers lactate per day was commenced . furthermore , they received prophylactic tocolysis with terbutaline ( bricanyl lp ) 5 mg orally twice daily and betamethazone 12 mg in two doses 12 hours apart for enhancement of fetal lung maturity . the fetal wellbeing was monitored with a hand held huntleigh sonicaid fd2 ( fetal dopplex ii ) containing a 2 mhz probe until 28 - week gestation when we switched to twice daily external cardiotocographic monitoring . were also monitored and finally the patients were programmed for emergency late second trimester cerclage . during the procedure patients were placed in the trendelenberg position under general anesthesia , bladder emptied , and antibiotic prophylaxis begun intraoperatively with ceftriaxone 2 gm intravenous bolus . using vaginal retractors for exposure , the bulging membranes were pushed into the uterus using a gauze mounted to a sponge holding forceps ( figure 1 ) . the bladder was mobilized cephalad ( figure 2 ) with submucosal placement of a mersilene band ( ethicon france ) anterior to posterior bilaterally at the level of the internal os , tying posteriorly and burying the anterior knot at 6 o'clock ( figure 3 ) . finally , all our patients were hospitalized for 48 hours after the modified shirodkar procedure . during this period they received tocolysis ( salbutamol 5 mg in 500 ml 5 % dextrose solution ) and antibiotic prophylaxis with ceftriaxone 1 gm every 12 hours for 24 hours . we usually removed the cervical stitch at 36 - week gestation or when indicated because of complications ( rupture of membranes , chorioamnionitis , or uterine contractions ) . ethical clearance to carry out this study was obtained from the ethical board of the douala general hospital , cameroon . altogether , six patients were analyzed during the study period and their average age was 27.6 years ( range 2235 years ) while their gestational ages on admission ranged between 24 and 26 weeks . there were a total of 17 ( 100 % ) pregnancies recorded during this period . among these pregnancies , the global number of deliveries and miscarriages in the study group between the period 2002 and 2010 was 5 ( 29.4 % ) and 12 ( 70 % ) , respectively . furthermore , most of the pregnancies 12 ( 70 % ) and abortions 8 ( 66.7 % ) were from the older ( 3035 years ) age group . their mean gravidity was 2.83 ( 17/6 ) pregnancies with a mean parity of 0.29 ( 5/17 ) . the six patients who underwent cerclage in our department , 4 ( 66.7 % ) carried their pregnancy to term and had normal vaginal deliveries while , in two patients ( 33.3 % ) , we had to undo the stitch at 24 - week , 2 - day , and 26 - week gestation because of preterm premature rupture of membranes ( pprom ) and chorioamnionitis , respectively . these two patients were also positive for chlamydiae and mobiluncus species infection , respectively , and also had bulging of fetal membranes for over 4 days prior to admission into our department ( table 1 ) . all the other patients who took their pregnancy to term had bulging of fetal membranes into the vagina for a period no more than one day before the cerclage procedure . the two babies from the spontaneous abortions succumbed in the neonatal intensive care unit two and six days later , respectively . on discharge from hospital , the two patients were prescribed roxithromycin 300 mg orally per day to be taken for three consecutive weeks and metronidazole 1500 mg per day for 10 days , respectively . late second trimester cervical stitch is not a common procedure in current gynecologic practice in cameroon . the diagnosis of cervical insufficiency is usually clinical in our country where ultrasonography is not accessible to all the regions . cameroon being one of the low income economies , our neonatal intensive care units may not be as equipped as in the developed economies . this could explain why the two babies delivered at 24 wks 2 days and 26 weeks succumbed a few days later . on the contrary , according to literature reports from the united states , about 50 % of infants born as early as 2225 weeks of gestation may survive , and half of the survivors were without moderate to profound impairment at 1822 months of age . furthermore , it has been estimated that 9.6 % of all births worldwide were preterm in 2005 . approximately , 85 % of this burden was concentrated in africa and asia , where 10.9 million births were preterm . about 0.5 million preterm births occurred in europe and the same number in north america , while 0.9 million occurred in latin america and the caribbean . the incidence of cervical insufficiency is very difficult to determine in cameroon because there are no studies made towards that direction and the diagnostic criteria are ( facility based ) not homogeneous . the limitations of this study are that the study population is too small to draw meaning conclusions of stastistical significance . therefore , a multicentric study becomes imperative in cameroon . a meta - analysis of trials regarding cerclage for short cervix diagnosed by ultrasonography identified four properly conducted trials . in the total population , preterm birth at less than 35 weeks of gestation occurred in 29.2 % ( 89/305 ) of the cerclage group , compared with 34.8 % ( 105/302 ) of the no - cerclage groups ( relative risk [ rr ] 0.84 , 95 % confidence interval [ ci ] 0.671.06 ) . it was concluded that cerclage does not prevent preterm birth in all women with short cervical length on transvaginal ultrasonography . in the subgroup analysis of singleton gestations with short cervical length , especially those with a prior preterm birth , cerclage may reduce preterm birth , and a well - powered trial should be carried out in this group of patients . in contrast , in twins , cerclage was associated with a significantly higher incidence of preterm birth . in other literature reports 225 women were studied , 152 underwent a physical examination with indicated cerclage , and 73 were managed expectantly without cerclage . cervical dilatation , gestational age at presentation , and antenatal steroid use differed between groups . in the adjusted analyses , cerclage was associated with longer interval from presentation until delivery , improved neonatal survival , birthweight greater than 1500 g , and preterm birth less than 28 weeks , compared with expectant management . similar results were obtained in the analyses of women with cervical dilatation between 2 and 4 cm ( n = 122 ) . twenty - two women with bulging membranes after primary cerclage were offered repeat cerclage ; 11 chose a repeat cerclage and 11 chose bed rest . the median gestational age at delivery , birthweight and survival rates were significantly higher in the repeat cerclage group compared to the bed rest group ( mean 26.8 weeks versus 21.7 weeks , p = 0.04 , mean birthweight 1180 g versus 491 g , p = 0.01 odds ratio for survival 22.0 , 95 % ci , 2.1236 ) . they concluded that early repeat cerclage under antibiotic cover may be beneficial in women with bulging membranes after a prior failing cerclage attempt . in our serieswe had to undo the cerclage in two patients 33 % because of complications leading to late second trimester abortions . other authors have reported laparoscopic abdominal cerclage with good results compared with patients put on expectant management . nevertheless , these techniques are not well known in developing nations . if silent membrane prolapse to or past the external os occurs at 22 weeks or before , the incidence of intrauterine bacterial colonization is 20 % to 50 % as reported by romero et al . this is in conformity with our study where two patients were diagnosed to have vaginal infection with c. trachomatis and mobiluncus species . the above - mentioned studies elucidate the fact that late second trimester cerclage could be beneficial in some selected cases with true cervical insufficiency . the use of prophylactic antibiotics , tocolysis , and corticosteroids for fetal lung maturity is mandatory in such cases . we recommend that salvage cervical cerclage should be considered in patients with advanced cervical dilatation and bulging membranes in the second trimester . despite overall poor prognosis in such cases successful outcomes may be obtained in selected cases especially when bulging of membranes has occurred no later than 24 hours and in the absence of maternal vaginal infection . we would recommend facility based introduction of ultrasound scanning for the diagnosis of the short cervix and clinical risk factors for cervical insufficiency inorder to fight against the poor morbidity / mortality related to this condition . follow - up of these patients after the cervical stitch with sonography could be an adjunctive modality to predict the outcomes of these pregnancies . finally , the development of strategies for improving access to effective care in developing countries must remain a top research and operational priority .\noutput:\n" }, { "from": "agent", "value": "purpose . to show the feasibility of emergency late second trimester cerclage with advanced cervical dilatation and bulging of amniotic membranes . setting . department of obstetrics and gynecology of the douala general hospital . method . this is a retrospective study of case files of patients who underwent emergency late second trimester cerclage with advanced cervical dilatation , some with bulging of fetal membranes between june 2003 and june 2010 . the modified shirodkar technique was employed in all the cases . results . altogether , six patients ( 100 % ) underwent late second trimester cervical cerclage between 24 and 26 weeks of gestational age . four cases ( 66.7 % ) carried on their pregnancies to term that resulted in healthy live - born babies all delivered vaginally . the other two cases ( 33.3 % ) presented with preterm premature rupture of fetal membranes ( pprom ) which led us to undo the stitch with eventual delivery of live - born premature fetuses which died in the neonatal intensive care unit because of complications of prematurity and neonatal infection . conclusion . in experienced hands and in the absence of other risk factors like infection , the success rates of this procedure are encouraging with improved prognosis . finally , the modified shirodkar technique yielded excellent results in our series ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: our study population consisted of 482 patients with ftd , 22 of whom had concomitant als ( ftd - als ) , and 147 patients with als ascertained in belgium through an ongoing multicenter collaboration of neurology departments and memory clinics partnering in the belgian neurology ( belneu ) consortium . additional patients were included who had initially been referred to the diagnostic service facility for medical genetic testing . postmortem neuropathologic analysis confirmed diagnosis in 25 patients with ftd , 3 patients with ftd - als , and 6 patients with als . a positive familial history , i.e. , at least one first - degree relative with a ftd - als spectrum disease , was recorded in 132 patients with ftd ( 28.7 % ) , 4 patients with ftd - als ( 36.4 % ) , and 18 patients with als ( 12.2 % ) . of these familial index patients , 93 cases of ftd ( 70.5 % ) , 1 case of ftd - als ( 25.0 % ) and 7 cases of als ( 38.9 % ) were not explained by mutations in the known ftld and als genes ( mapt , grn , c9orf72 , vcp , chmp2b , fus , tardbp , sod1 ) , in the ad genes ( psen1 , psen2 , app ) , or in the prion gene ( prnp ) . one patient with unexplained ftd - als was the index patient of a 4 - generation family ( family dr158 ) , of which we collected genomic dna and generated lymphoblast cell lines of 38 individuals including 4 patients in generation iii ( figure 1 and table 1 ) . a belgian control cohort of 1,044 persons free of personal and familial history of neurodegenerative or psychiatric diseases and with a mini - mental state examination score 26 was also analyzed . to protect the privacy of the participants , we masked the sex of each person , scrambled the pedigree of family dr158 , and did not specify the number of at - risk individuals tested shown in the white diamonds . filled symbols represent patients , with their age at onset ( aao ) in years below their symbol . age at death ( aad ) is shown for individuals who died in old age without symptoms . in family dr663 , 3 of the 4 childrenalso carry a repeat expansion mutation in c9orf72 , 2 affected ( i - 1 and ii - 2 ) and 1 asymptomatic ( ii - 4 ) , for whom the age at last examination ( aale ) is given . an asterisk identifies the family members for whom genomic dna was available . the glu643del mutation is shown as . the 5 polymorphic markers , including the tbk1 - ( gt ) n repeat polymorphism located 400 kb upstream of tbk1 , are indicated at the left and flank the tbk1 mutation p.glu643del at both sites . the 3 different disease haplotypes are shown with colored bars : green haplotype of at least 7.5 mb , purple haplotype of at least 8.7 mb , and orange haplotype of at least 3.0 mb . haplotypes based on segregation data are indicated in regular font , those based on allele sharing are in italics , and those that were inferred are between brackets . als = amyotrophic lateral sclerosis ; ftd = frontotemporal dementia . clinical characteristics of patients of family dr158 and tbk1 mutation carriers all participants provided written informed consent for participation in clinical , pathologic , and genetic studies . clinical study protocols and informed consent formsgenetics study protocol and informed consent forms were approved by the medical ethics committees of the university hospital antwerp and the university of antwerp . nineteen coding tbk1 exons were amplified in multiplex pcr reactions using mastr technology ( http://www.multiplicom.com ) and sequenced on a miseq platform ( illumina ; san diego , ca ) and 1 exon was analyzed by sanger sequencing . tbk1 transcripts were measured in lymphoblast cells of 8 mutation carriers and frontal cortex of 2 carriers using real - time pcr amplification of a tbk1amplicon , quantified against 2 housekeeping genes . we sequenced real - time pcr products to establish the transcribed alleles based on the coding mutation or the coding polymorphism rs7486100 . we used western blotting of protein lysates of lymphoblast cells and brain with a monoclonal antibody against tbk1 and quantified against gapdh . our study population consisted of 482 patients with ftd , 22 of whom had concomitant als ( ftd - als ) , and 147 patients with als ascertained in belgium through an ongoing multicenter collaboration of neurology departments and memory clinics partnering in the belgian neurology ( belneu ) consortium . additional patients were included who had initially been referred to the diagnostic service facility for medical genetic testing . postmortem neuropathologic analysis confirmed diagnosis in 25 patients with ftd , 3 patients with ftd - als , and 6 patients with als . a positive familial history , i.e. , at least one first - degree relative with a ftd - als spectrum disease , was recorded in 132 patients with ftd ( 28.7 % ) , 4 patients with ftd - als ( 36.4 % ) , and 18 patients with als ( 12.2 % ) . of these familial index patients , 93 cases of ftd ( 70.5 % ) , 1 case of ftd - als ( 25.0 % ) and 7 cases of als ( 38.9 % ) were not explained by mutations in the known ftld and als genes ( mapt , grn , c9orf72 , vcp , chmp2b , fus , tardbp , sod1 ) , in the ad genes ( psen1 , psen2 , app ) , or in the prion gene ( prnp ) . one patient with unexplained ftd - als was the index patient of a 4 - generation family ( family dr158 ) , of which we collected genomic dna and generated lymphoblast cell lines of 38 individuals including 4 patients in generation iii ( figure 1 and table 1 ) . a belgian control cohort of 1,044 persons free of personal and familial history of neurodegenerative or psychiatric diseases and with a mini - mental state examination score 26 was also analyzed . to protect the privacy of the participants , we masked the sex of each person , scrambled the pedigree of family dr158 , and did not specify the number of at - risk individuals tested shown in the white diamonds . filled symbols represent patients , with their age at onset ( aao ) in years below their symbol . age at death ( aad ) is shown for individuals who died in old age without symptoms . in family dr663 , 3 of the 4 childrenalso carry a repeat expansion mutation in c9orf72 , 2 affected ( i - 1 and ii - 2 ) and 1 asymptomatic ( ii - 4 ) , for whom the age at last examination ( aale ) is given . an asterisk identifies the family members for whom genomic dna was available . the glu643del mutation is shown as . the 5 polymorphic markers , including the tbk1 - ( gt ) n repeat polymorphism located 400 kb upstream of tbk1 , are indicated at the left and flank the tbk1 mutation p.glu643del at both sites . the 3 different disease haplotypes are shown with colored bars : green haplotype of at least 7.5 mb , purple haplotype of at least 8.7 mb , and orange haplotype of at least 3.0 mb . haplotypes based on segregation data are indicated in regular font , those based on allele sharing are in italics , and those that were inferred are between brackets . als = amyotrophic lateral sclerosis ; ftd = frontotemporal dementia . clinical characteristics of patients of family dr158 and tbk1 mutation carriersall participants provided written informed consent for participation in clinical , pathologic , and genetic studies . clinical study protocols and informed consent formsgenetics study protocol and informed consent forms were approved by the medical ethics committees of the university hospital antwerp and the university of antwerp . nineteen coding tbk1 exons were amplified in multiplex pcr reactions using mastr technology ( http://www.multiplicom.com ) and sequenced on a miseq platform ( illumina ; san diego , ca ) and 1 exon was analyzed by sanger sequencing . tbk1 transcripts were measured in lymphoblast cells of 8 mutation carriers and frontal cortex of 2 carriers using real - time pcr amplification of a tbk1amplicon , quantified against 2 housekeeping genes . we sequenced real - time pcr products to establish the transcribed alleles based on the coding mutation or the coding polymorphism rs7486100 . we used western blotting of protein lysates of lymphoblast cells and brain with a monoclonal antibody against tbk1 and quantified against gapdh . we screened the coding region of tbk1 and identified 2 frameshift , 1 nonsense , 1 splice site mutation , and 2 single amino acid deletions in 11 unrelated index patients ( table 1 , table e-1 , and figure e-1 ) . copy number variation analysis of all tbk1 exons did not reveal exonic or whole gene deletions or duplications . we predicted that the nonsense and frameshift mutations resulted in a premature termination codon leading to mrna degradation by nonsense - mediated decay . cdna sequencing of tbk1 in lymphoblast cells of the ser398profs * 11 carrier , and in brain of the p.ser518leufs * 32 carrier , did not identify the mutant allele , suggesting a complete loss of the mutant transcript . quantification of tbk1 transcripts demonstrated a highly reduced gene expression that was restored to normal levels using an inhibitor of protein synthesis ( figure 2 ) . western blot analysis demonstrated near 50 % reduction of protein expression in lymphoblast cells and in brain ( figure 3 ) . quantitative pcr quantification of tbk1 transcripts from lymphoblast cells ( a ) and frontal cortex ( b ) of lof mutation carriers ( blue bars ) compared to control persons without mutation ( black bars ) normalized to different housekeeping genes . is indicated if cells were treated ( + , dark blue bars ) or not treated ( , light blue bars ) with cycloheximide ( chx ) , a protein synthesis inhibitor . sequence traces are obtained by real - time pcr from the lymphoblast cells of the p.ser398profs * 11 mutation carrier treated or not treated with chx using primers in exon 6 and exon 21 . ( c ) real - time pcr with primers in exon 6 and 10 of cdna of brain of the p.gly272_thr331del mutation carriers is shown on agarose gel , with the respective sequence traces from the aberrant transcripts . western blot analysis of protein extracts from lymphoblast cells ( a ) and frontal cortex ( b ) of loss - of - function ( lof ) mutation carriers compared to control persons without mutation . of the p.glu643del mutation , the upper band represents tbk1 ( 84 kda ) and the lower band the housekeeping protein gapdh ( 37 kda ) . the graphs below ( c ) show the quantification in control samples ( black ) and patient samples ( blue ) of the tbk1 signal normalized to the signal of gapdh . error bars represent the sd ; * * indicates a significant p value of 0.01 compared to controls . in dr189 , a mutation affecting the intron 8 splice donor site resulted in in - frame skipping of exon 8 in lymphoblast cells and brain . in addition , use of a cryptic splice site in exon 8 resulted in an out - of - frame transcript ( figure 2 ) . quantitative pcr analysis showed 30 % reduced expression in lymphoblast cells and 50 % reduced expression in brain ( figure 2 ) . western blot analysis detected only the normal - sized protein band with 45 % reduced expression in lymphoblast cells and 34 % in brain lysates , suggesting that no stable protein was produced from the mutant transcripts ( figure 3 ) . in lymphoblast cells of patients carrying the in - frame deletion mutations , p.asp167del and p.glu643del ( n = 5 ) however , we observed a significantly reduced protein level of 44 % in the p.glu643del carriers ( p = 0.0017 ) . in the p.asp167del carrier , the 5 missense mutations were scattered over the 4 functional domains ( table e-1 and figure e-1 ) . we observed p.ala535thr in 1 male control ( age at inclusion 63 years ) , and p.lys291glu in a male control and a female control ( age at inclusion 67 and 69 years ) . two mutations , p.arg271leu and p.ala535thr , were predicted neutral , while the other 3 mutations received variable effects using 3 prediction algorithms . missense mutation carriers did not show reduced transcript and protein expression levels ( figure e-2 ) . six unrelated index patients carried the p.glu643del mutation ( table 1 ) , among them index patient iii - 8 of autosomal dominant ftd - als family dr158 , containing 13 patients ( table 1 and figure 1 ) . ten patients of family dr158 were diagnosed with a dementia syndrome , i.e. , ftd ( n = 4 ) or unspecified dementia ( n = 6 ) , while 2 patients had a diagnosis of als . the mean onset age was 69.17.7 years , with a mean disease duration of 6.43.9 years . the 5 patients with ftd or ftd - als presented with bvftd ( table e-2 ) . remarkably , memory loss and disorientation were present relatively early in the disease in most of the p.glu643del mutation carriers ( table e-2 ) . one patient with als ( iii - 1 ) and 1 patient with ftd - als ( iii - 8 ) presented with als with spinal onset ( table e-2 ) , both showing signs of motor neuron disease on emg . analysis of all family members indicated that the disease segregated with the p.glu643del mutation on a disease haplotype of minimal 7.5 mb ( figure 1 ) . seven mutation carriers were without symptoms at age 70 years , including obligate carrier ii - 5 and 2 children of ii - 5 who , at their last clinical evaluation , were 79 , 81 , and 82 years of age , respectively ( figure 1 ) . given the frequent occurrence of psychiatric disease in family dr158 , it can not be excluded that symptoms of ftd were not recognized ( table e-2 ) . carrier ii - 5 and one of her children with a current age of 81 years had repeated depression . one of the asymptomatic children of patient ii - 1 had alcohol abuse and has a current age of 70 years . among the other 5 carriers of the p.glu643del mutation and their relatives , we identified 2 distinct disease haplotypes that differed from that in dr158 ( figure 1 and table e-3 ) . in family dr663 , als patient ii - 1 and ii - 2 carried , besides the tbk1 mutation , a c9orf72 repeat expansion , as did the asymptomatic sib ii - 4 without the tbk1 mutation , age 63 years ( figure 1 ) . the mean onset age in the 11 patients carrying a lof mutation ( table 1 ) was 59.68.6 years . in 4 p.glu643del carriers , excluding the 2 patients carrying a c9orf72 repeat expansion , we calculated a mean onset age of 66.33.9 years , which was significantly later ( p = 0.04 ) than in the 5 patients with another lof mutation , with a mean onset age of 57.46.0 years . when we included all affected carriers of family dr158 , the significance became stronger ( p = 0.004 ) . also , the mean disease duration of 8.31.8 years was significantly longer ( p = 0.016 ) than the mean disease duration of 2.62.2 years in the patients with another lof mutation with an increasing effect if all dr158 patients were included ( p = 0.002 ) . four of 5 ftd mutation carriers and the patient with ftd - als had behavioral variant ftd ( bvftd ) ( table e-2 ) . the 3 patients with ftd with a p.glu643del mutation expressed extrapyramidal symptoms , while the patients with ftd with another tbk1 mutation did not ( table e-2 ) . in 1 patient with bvftd ( dr1120 ) , muscular fasciculations were observed in 1 limb ( table e-2 ) . the proband of dr158 presented with spinal onset als ; in the 3 other documented patients with als ( dr663 , dr1123 , dr1124 ) , the site of onset was bulbar ( table e-2 ) . of 3 tbk1 mutation carriers with als or ftd - als ( dr158.iii - 8 , dr1123 , dr1124 ) , we had emg reports , while of 3 other patients with als ( dr663 , dr1044 , dr1127 ) , no detailed information was available . based on a clinical examination , there was no cognitive evidence for ftd in the majority of als cases . however , in als patient dr1124 memory deficits and the impression of behavioral disinhibition were reported ( table e-2 ) , but we did not have sufficient information to determine if the criteria for possible ftld were fulfilled . neuropathologic brain examination of ftd patient dr189 ( p.gly272_thr331del ) showed mild neuronal loss of the frontal cortices . we found a moderate amount of tdp - 43 and p62 neuronal cytoplasmic inclusions ( nci ) and short dystrophic neurites but no intraneuronal intranuclear inclusions ( figure 4 , a , b , d , and e ) compatible with a tdp type b proteinopathy . in als patient dr1124 ( p.ser518leufs * 32 ) , pathologic signs of lower and upper motor neuron disease were apparent . the tdp - 43 positive nci were mainly restricted to the hypoglossal nucleus and the ventral horn neurons of cervical and thoraco - lumbar spinal cord ( figure 4 , c , f ) . staining withthe nissl substance of the neurons in the ventral horn of the spinal cord was stained . immunohistochemistry of frontal cortex ( a , d , g ) and hippocampus ( b , e , h ) of 1 patient with frontotemporal lobar degeneration with the p.gly272_thr331del mutation ( dr189 ) and spinal cord ( c , f , i ) of 1 patient with amyotrophic lateral sclerosis ( als ) with the p.ser518leufs * 32 mutation ( dr1124 ) compared to a control individual without mutation ( j l ) . in frontotemporal dementia patient dr189 , a mild neuronal loss of the frontal cortices and to a lesser extent of the temporal neocortex and the hippocampus was shown . a moderate amount of tdp - 43 and p62 neuronal cytoplasmic inclusions ( nci ) ( arrows ) and short dystrophic neurites , but no intraneuronal intranuclear inclusions , were found throughout all layers of the frontal ( a , d ) and temporal neocortices , in the dentate gyrus of the hippocampus ( b , e ) , the parahippocampal transentorhinal cortex , the neostriatum , and the pallidum , but not in the cerebellum . in als patient dr1124 , no explicit cortical abnormalities were present , but pathologic signs of lower and upper motor neuron disease were apparent . severe demyelination of the pyramidal tract in mesencephalon , pons , medulla oblongata , and the entire spinal cord and severe neuronal loss in the hypoglossal nucleus , as well as in the ventral horns of the cervical and thoracic spinal cord , were observed . the tdp -43-positive ( c ) and p62 - positive ( f ) nci were mainly restricted to the hypoglossal nucleus and the ventral horn neurons of cervical and thoraco - lumbar spinal cord ( arrows ) . cytoplasmic tbk1 immunoreactivity ( arrows ) in cortical neurons of the frontal cortex ( g , j ) , in the dentate gyrus of the hippocampus ( h , k ) , and in the cervical ventral horn neurons ( i , l ) showed no differences between patients and controls . we screened the coding region of tbk1 and identified 2 frameshift , 1 nonsense , 1 splice site mutation , and 2 single amino acid deletions in 11 unrelated index patients ( table 1 , table e-1 , and figure e-1 ) . copy number variation analysis of all tbk1 exons did not reveal exonic or whole gene deletions or duplications . we predicted that the nonsense and frameshift mutations resulted in a premature termination codon leading to mrna degradation by nonsense - mediated decay . cdna sequencing of tbk1 in lymphoblast cells of the ser398profs * 11 carrier , and in brain of the p.ser518leufs * 32 carrier , did not identify the mutant allele , suggesting a complete loss of the mutant transcript . quantification of tbk1 transcripts demonstrated a highly reduced gene expression that was restored to normal levels using an inhibitor of protein synthesis ( figure 2 ) . western blot analysis demonstrated near 50 % reduction of protein expression in lymphoblast cells and in brain ( figure 3 ) . quantitative pcr quantification of tbk1 transcripts from lymphoblast cells ( a ) and frontal cortex ( b ) of lof mutation carriers ( blue bars ) compared to control persons without mutation ( black bars ) normalized to different housekeeping genes . is indicated if cells were treated ( + , dark blue bars ) or not treated ( , light blue bars ) with cycloheximide ( chx ) , a protein synthesis inhibitor . sequence traces are obtained by real - time pcr from the lymphoblast cells of the p.ser398profs * 11 mutation carrier treated or not treated with chx using primers in exon 6 and exon 21 . ( c ) real - time pcr with primers in exon 6 and 10 of cdna of brain of the p.gly272_thr331del mutation carriers is shown on agarose gel , with the respective sequence traces from the aberrant transcripts . western blot analysis of protein extracts from lymphoblast cells ( a ) and frontal cortex ( b ) of loss - of - function ( lof ) mutation carriers compared to control persons without mutation . of the p.glu643del mutation , the upper band represents tbk1 ( 84 kda ) and the lower band the housekeeping protein gapdh ( 37 kda ) . the graphs below ( c ) show the quantification in control samples ( black ) and patient samples ( blue ) of the tbk1 signal normalized to the signal of gapdh . error bars represent the sd ; * * indicates a significant p value of 0.01 compared to controls . in dr189 , a mutation affecting the intron 8 splice donor site resulted in in - frame skipping of exon 8 in lymphoblast cells and brain . in addition , use of a cryptic splice site in exon 8 resulted in an out - of - frame transcript ( figure 2 ) . quantitative pcr analysis showed 30 % reduced expression in lymphoblast cells and 50 % reduced expression in brain ( figure 2 ) . western blot analysis detected only the normal - sized protein band with 45 % reduced expression in lymphoblast cells and 34 % in brain lysates , suggesting that no stable protein was produced from the mutant transcripts ( figure 3 ) . in lymphoblast cells of patients carrying the in - frame deletion mutations , p.asp167del and p.glu643del ( n = 5 ) however , we observed a significantly reduced protein level of 44 % in the p.glu643del carriers ( p = 0.0017 ) . in the p.asp167del carrier , the 5 missense mutations were scattered over the 4 functional domains ( table e-1 and figure e-1 ) . we observed p.ala535thr in 1 male control ( age at inclusion 63 years ) , and p.lys291glu in a male control and a female control ( age at inclusion 67 and 69 years ) . two mutations , p.arg271leu and p.ala535thr , were predicted neutral , while the other 3 mutations received variable effects using 3 prediction algorithms . missense mutation carriers did not show reduced transcript and protein expression levels ( figure e-2 ) . six unrelated index patients carried the p.glu643del mutation ( table 1 ) , among them index patient iii - 8 of autosomal dominant ftd - als family dr158 , containing 13 patients ( table 1 and figure 1 ) . ten patients of family dr158 were diagnosed with a dementia syndrome , i.e. , ftd ( n = 4 ) or unspecified dementia ( n = 6 ) , while 2 patients had a diagnosis of als . the mean onset age was 69.17.7 years , with a mean disease duration of 6.43.9 years . the 5 patients with ftd or ftd - als presented with bvftd ( table e-2 ) . remarkably , memory loss and disorientation were present relatively early in the disease in most of the p.glu643del mutation carriers ( table e-2 ) . one patient with als ( iii - 1 ) and 1 patient with ftd - als ( iii - 8 ) presented with als with spinal onset ( table e-2 ) , both showing signs of motor neuron disease on emg . analysis of all family members indicated that the disease segregated with the p.glu643del mutation on a disease haplotype of minimal 7.5 mb ( figure 1 ) . seven mutation carriers were without symptoms at age 70 years , including obligate carrier ii - 5 and 2 children of ii - 5 who , at their last clinical evaluation , were 79 , 81 , and 82 years of age , respectively ( figure 1 ) . given the frequent occurrence of psychiatric disease in family dr158 , it can not be excluded that symptoms of ftd were not recognized ( table e-2 ) . carrier ii - 5 and one of her children with a current age of 81 years had repeated depression . one of the asymptomatic children of patient ii - 1 had alcohol abuse and has a current age of 70 years . among the other 5 carriers of the p.glu643del mutation and their relatives , we identified 2 distinct disease haplotypes that differed from that in dr158 ( figure 1 and table e-3 ) . in family dr663 , als patient ii - 1 and ii - 2 carried , besides the tbk1 mutation , a c9orf72 repeat expansion , as did the asymptomatic sib ii - 4 without the tbk1 mutation , age 63 years ( figure 1 ) . the mean onset age in the 11 patients carrying a lof mutation ( table 1 ) was 59.68.6 years . in 4 p.glu643del carriers , excluding the 2 patients carrying a c9orf72 repeat expansion , we calculated a mean onset age of 66.33.9 years , which was significantly later ( p = 0.04 ) than in the 5 patients with another lof mutation , with a mean onset age of 57.46.0 years . when we included all affected carriers of family dr158 , the significance became stronger ( p = 0.004 ) . also , the mean disease duration of 8.31.8 years was significantly longer ( p = 0.016 ) than the mean disease duration of 2.62.2 years in the patients with another lof mutation with an increasing effect if all dr158 patients were included ( p = 0.002 ) . four of 5 ftd mutation carriers and the patient with ftd - als had behavioral variant ftd ( bvftd ) ( table e-2 ) . the 3 patients with ftd with a p.glu643del mutation expressed extrapyramidal symptoms , while the patients with ftd with another tbk1 mutation did not ( table e-2 ) . in 1 patient with bvftd ( dr1120 ) , the proband of dr158 presented with spinal onset als ; in the 3 other documented patients with als ( dr663 , dr1123 , dr1124 ) , the site of onset was bulbar ( table e-2 ) . of 3 tbk1 mutation carriers with als or ftd - als ( dr158.iii - 8 , dr1123 , dr1124 ) , we had emg reports , while of 3 other patients with als ( dr663 , dr1044 , dr1127 ) , no detailed information was available . based on a clinical examination , there was no cognitive evidence for ftd in the majority of als cases . however , in als patient dr1124 memory deficits and the impression of behavioral disinhibition were reported ( table e-2 ) , but we did not have sufficient information to determine if the criteria for possible ftld were fulfilled . neuropathologic brain examination of ftd patient dr189 ( p.gly272_thr331del ) showed mild neuronal loss of the frontal cortices . we found a moderate amount of tdp - 43 and p62 neuronal cytoplasmic inclusions ( nci ) and short dystrophic neurites but no intraneuronal intranuclear inclusions ( figure 4 , a , b , d , and e ) compatible with a tdp type b proteinopathy . in als patient dr1124 ( p.ser518leufs * 32 ) , pathologic signs of lower and upper motor neuron disease were apparent . the tdp - 43 positive nci were mainly restricted to the hypoglossal nucleus and the ventral horn neurons of cervical and thoraco - lumbar spinal cord ( figure 4 , c , f ) . staining withthe nissl substance of the neurons in the ventral horn of the spinal cord was stained . immunohistochemistry of frontal cortex ( a , d , g ) and hippocampus ( b , e , h ) of 1 patient with frontotemporal lobar degeneration with the p.gly272_thr331del mutation ( dr189 ) and spinal cord ( c , f , i ) of 1 patient with amyotrophic lateral sclerosis ( als ) with the p.ser518leufs * 32 mutation ( dr1124 ) compared to a control individual without mutation ( j l ) . in frontotemporal dementia patient dr189 , a mild neuronal loss of the frontal cortices and to a lesser extent of the temporal neocortex and the hippocampus was shown . a moderate amount of tdp - 43 and p62 neuronal cytoplasmic inclusions ( nci ) ( arrows ) and short dystrophic neurites , but no intraneuronal intranuclear inclusions , were found throughout all layers of the frontal ( a , d ) and temporal neocortices , in the dentate gyrus of the hippocampus ( b , e ) , the parahippocampal transentorhinal cortex , the neostriatum , and the pallidum , but not in the cerebellum . in als patient dr1124 , no explicit cortical abnormalities were present , but pathologic signs of lower and upper motor neuron disease were apparent . severe demyelination of the pyramidal tract in mesencephalon , pons , medulla oblongata , and the entire spinal cord and severe neuronal loss in the hypoglossal nucleus , as well as in the ventral horns of the cervical and thoracic spinal cord , were observed . the tdp -43-positive ( c ) and p62 - positive ( f ) nci were mainly restricted to the hypoglossal nucleus and the ventral horn neurons of cervical and thoraco - lumbar spinal cord ( arrows ) . cytoplasmic tbk1 immunoreactivity ( arrows ) in cortical neurons of the frontal cortex ( g , j ) , in the dentate gyrus of the hippocampus ( h , k ) , and in the cervical ventral horn neurons ( i , l ) showed no differences between patients and controls . the overall tbk1 lof mutation frequency is 1.7 % ( 11/629 ) , with 1.1 % ( 5/460 ) in ftd , 4.5 % ( 1/22 ) in ftd - als , and 3.4 % ( 5/147 ) in als . in patients with ftd , tbk1 lof mutations explained 3.2 % of the unexplained familial ftd cases and were the third most common genetic cause after c9orf72 and grn mutations ( figure e-3 ) , consistent with the findings in a ftld - tdp cohort . in the als cohort , all described lof mutations , except 1 , are different from those in the other published reports . the p.glu643del mutation that was present in 6/629 ( 1 % ) unrelated belgian patients was also found in 2/1 ,010 german patients with sporadic als . the presence of 3 different disease haplotypes of at least 3 mb among the p.glu643del carriers might be explained by a mutation hotspot due to a repetitive ( gaa ) 3 sequence encoding 3 glu residues ( codons 641643 ) or because of an extreme distant common founder . expression studies in lymphoblast cells and in brain of 3 lof mutation carriers confirmed the loss of transcript and of protein leading to 50 % reduced protein levels , as previously reported . a novel finding is that the p.glu643del mutation had no effect on transcript levels but resulted in a near 50 % reduced protein expression in blood , possibly due to loss of protein stability . the p.asp167del mutation andthe missense mutations did not show reduced transcript or protein levels , but we can not exclude their pathogenicity by mechanisms like reduced kinase activity or hampered protein dimerization . tbk1 has a 4 - domain structure with an n - terminal kinase domain ( kd ) , a ubiquitin - like domain , an - helical scaffold dimerization domain , and a c - terminal domain ( figure e-1 ) . tbk1 is activated by trans - autophosphorylation of serine 172 ( ser172 ) , for which homodimerization is required . ser172 is located in a kinase activation loop of the kd starting at the conserved dfg motif ( residues 157159 ) and extending to residue 198 . interestingly , the p.asp167del mutation is located in this activation loop and hence might hamper the conversion of tbk1 to the active state . in other tbk1 reports , some missense mutations were found to be pathogenic . since at least one of the used prediction algorithms predicted that some of our missense mutations are pathogenicclinical heterogeneity among the tbk1 mutation carriers was apparent since all different phenotypes of the ftd - als spectrum and a wide range in age at onset and disease duration were present , comparable to what was observed in c9orf72 expansion carriers . however , remarkably , 5 of 6 ftd or ftd - als index patients with a tbk1 mutation presented with bvftd . the later onset age and longer disease duration associated with the p.glu643del mutation suggested that this mutation has a milder pathogenic effect . since amnestic deficits and orientation problems were apparent early in the disease process , it might be interesting to screen tbk1 in patients with clinically diagnosed ad , also since in another study 2 of 4 patients with ftld - tdp with a tbk1 mutation presented with clinical ad . in alsfamily dr663 , we found both the tbk1 p.glu643del mutation and a c9orf72 repeat expansion ( 80 repeat units ) segregating with disease . the 2 sibs who carried both mutations had a remarkably younger onset age ( 41 and 51 years ) and a shorter disease duration ( 1 and 2 years ) compared to the other p.glu643del mutation carriers . also , one other index patient of the als cohort , dr1044 , carried both the tbk1 p.glu643del mutation and a c9orf72 repeat expansion of only 59 repeat units . this patient had later onset age of 63 years , corroborating our recent findings that patients with a short repeat expansion ( 4580 units ) have a later age at onset compared to patients with a longer expansion . further , the disease penetrance in p.glu643del mutation is highly variable , with 7 carriers of family dr158 still unaffected at age 70 years , with 2 at age 81 and 82 years , nearly 2 sds beyond the mean onset age . the 7 unaffected carriers were not homozygous for the minor protective allele of tmem106b rs1990622 . the observed tdp - 43 type b pathology in brain or spinal cord could be distinguished from that in patients with a c9orf72 mutation by the absence of p62 - positive inclusions containing dipeptide repeats . this pathology was previously reported in 1 patient with ftd - als while another study reported ftld - tdp type a in 3 mutation carriers . the observation that tbk1 mutations were present in a significant part of sporadic and late - onset patients is not uncommon in adult - onset neurodegenerative diseases because of reduced penetrance , similar to what is described for c9orf72 mutations and to a lesser extent for grn mutations . a relatively high de novo mutation rate may be another explanation , supported by the observation that the p.glu643del mutation occurred on 3 different haplotype backgrounds . also , as proposed by others , more than 1 gene might be involved in some patients , as observed in family dr663 segregating both a tbk1 and a c9orf72 mutation . tbk1 is an important serine / threonine kinase of the ikk family phosphorylating a wide range of substrates involved in several cellular processes , including innate immune response / inflammation , autophagy , and cell proliferation . substrates of tbk1 include optineurin ( optn ) , another gene with lof mutations in als , and p62 , a major component of pathologic depositions and showing mutations in ftld and als . moreover , tbk1 targets the vps37c protein of the endosomal sorting complex required for transport - i , thereby regulating the vesicular retroviral budding system , which is also involved in neurodegeneration , e.g. , chmp2b . as other ftd / als genes , including vcp , are also involved in autophagy , and since mutations in optn and tbk1 are also involved in glaucoma , our findings emphasize the major role of autophagic defects in neurodegeneration . also , in the antiviral innate immune response both tbk1 and optn are involved through the nf - kb complex pathway . in this study , we demonstrated that lof mutations in tbk1 are associated with ftd - als spectrum disorders in a belgian clinical patient cohort , can segregate in families according to an autosomal dominant pattern , and are present in a significant part of sporadic cases . the identification of tbk1 emphasizes the convergence of ftd and als in 1 continuum and will accelerate effective drug development . ilse gijselinck : literature search , figures , study design , genetic data collection , data analysis , data interpretation , writing . sara van mossevelde : patient samples collection , clinical data collection , data analysis , data interpretation , writing . julie van der zee : patient data collection , genetic data collection , data analysis , data interpretation . anne sieben : patient samples collection , clinical data collection , neuropathology data collection , figures , data analysis , data interpretation , writing . bavo heeman : literature search , experimental data collection , data analysis , data interpretation . sebastiaan engelborghs : patient samples collection , clinical data collection , data analysis , data interpretation . mathieu vandenbulcke : patient samples collection , clinical data collection , data analysis , data interpretation . greet de baets : literature search , figures , protein structure data collection , data analysis , data interpretation . rik vandenberghe : patient samples collection , clinical data collection , data analysis , data interpretation . peter de jonghe : patient samples collection , clinical data collection , data analysis , data interpretation . patrick cras : patient samples collection , clinical data collection , data analysis , data interpretation . de deyn : patient samples collection , clinical data collection , data analysis , data interpretation . jean - jacques martin : patient samples collection , neuropathology data collection , data analysis , data interpretation , writing . marc cruts : literature search , study design , data interpretation , writing , study supervision . christine van broeckhoven : literature search , figures , study design , genetic data collection , genealogy data collection , data analysis , data interpretation , writing , study supervision . the sponsors of the study had no role in study design , data collection , data analysis , data interpretation , or writing of the report . the research was funded in part by the belgian science policy office interuniversity program ; the flemish government - supported european initiative on centers of excellence in neurodegeneration ( coen ) ; the flemish government - initiated methusalem excellence program ; the flemish government - initiated flanders impulse program on networks for dementia research ( vind ) ; the alzheimer research foundation ( sao - fra ) ; the medical foundation queen elisabeth ( qemf ) ; the research foundation flanders ( fwo ) ; the agency for innovation by science and technology flanders ( iwt ) and the university of antwerp research fund , belgium ; and the metlife foundation award for medical research to c.v.b . the fwo provided a phd fellowship to s.p . and a postdoctoral fellowship to i.g . the article processing charge was paid by the flanders impulse program on networks for dementia research ( vind ) .\noutput:\n" }, { "from": "agent", "value": "objective : to assess the genetic contribution of tbk1 , a gene implicated in amyotrophic lateral sclerosis ( als ) , frontotemporal dementia ( ftd ) , and ftd - als , in belgian ftd and als patient cohorts containing a significant part of genetically unresolved patients.methods : we sequenced tbk1 in a hospital - based cohort of 482 unrelated patients with ftd and ftd - als and 147 patients with als and an extended belgian ftd - als family dr158 . we followed up mutation carriers by segregation studies , transcript and protein expression analysis , and immunohistochemistry.results : we identified 11 patients carrying a loss - of - function ( lof ) mutation resulting in an overall mutation frequency of 1.7 % ( 11/629 ) , 1.1 % in patients with ftd ( 5/460 ) , 3.4 % in patients with als ( 5/147 ) , and 4.5 % in patients with ftd - als ( 1/22 ) . we found 1 lof mutation , p.glu643del , in 6 unrelated patients segregating with disease in family dr158 . of 2 mutation carriers , brain and spinal cord was characterized by tdp -43-positive pathology . the lof mutations including the p.glu643del mutation led to loss of transcript or protein in blood and brain.conclusions : tbk1 lof mutations are the third most frequent cause of clinical ftd in the belgian clinically based patient cohort , after c9orf72 and grn , and the second most common cause of clinical als after c9orf72 . these findings reinforce that ftd and als belong to the same disease continuum ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: the use of phenotypic methods has been limited in identifying closely related candida species . using genotypic methods , the clonally related species of candida orthopsilosis complex was subsequently divided into groups 1 , 2 and 3 identified under the corresponding names ; candida parapsilosis , c. orthopsilosis and candida metapsilosis . these were of sufficient differences to make them distinctly different species and should be viewed as separate clinical and epidemiological entities . these species have been implicated in several clinical conditions but with varying frequencies , including sex and age related differences . c. parapsilosis is a major cause of disease in the immuno - compromised individual while c. orthopsilosis is comparatively rare in human infection despite its isolation from several clinical specimens , , , , . identified 5700 protein coding genes in c. orthopsilosis , the majority of which were similar to those found in c. parapsilosis . these findings suggest that virulence of this species may be associated with expansion of gene families . up to 1992 only eight c. parapsilosis associated cases of septic arthritis were reported in the literature , seven of which followed replacement of a joint prosthesis , joint injection , or arthrocentesis . to date , after an extensive literature search , no cases of septic arthritis caused by c. orthopsilosis have been reported . we present a case of c. orthopsilosis infection associated with septic arthritis in a 28 year - old male presented at uhwi with a history of sle . to the best of our knowledgethis was the first case seen at the uhwi with no previously reported cases in jamaica or in the literature . in march 2001 a 17 - year - old jamaican male diagnosed with systemic lupus erythematosus ( sle ) presented to the university hospital of the west indies ( uhwi ) rheumatology clinic with high fever , severe joint pains , proteinuria , and bilateral ankle edema . at that time , tests for both ana and anti - dna antibodies were positive , and a renal biopsy showed class i glomerulonephritis . he was treated with high dose steroids , which were quickly tapered because of steroid induced diabetes . the patient was therefore kept on prednisone 20 mg daily with mycophenolate mofetil ( mmf ) . the patient was readmitted in january 2002 and was regularly monitored with frequent blood cultures for sepsis , which yielded sterile cultures for microbiological investigations . his third admission in may 2002 was subsequent to a diagnosis of pylonephritis and skin sepsis . between january 2001 and may 2004 the patient had several clinic visits including sixth admissions to wards for fever and joint pains , pleurisy and renal flare . he also experienced another renal flare with significant proteinuria ( 3.7 g per 24 h ) but normal serum creatinine . from 2006 until 2009he had frequent clinic visits and admissions because of fever , increased proteinuria and knee swelling . following recurrent painful swelling of the left knee in 2008 , several aspirations of joint fluid were collected , yielding inflammatory fluid with negative bacterial cultures . each aspiration was followed by a corticosteroid injection . radiographs of the knees showed flattened condyles , presumably due to previous avascular necrosis ( fig .1 ) . aspirations and steroid injections did not have any lasting effect as the left knee became increasingly painful several weeks after each aspiration . despite negative cultures , however , this treatment did not stabilize the renal inflammation and the patient was started on dialysis after another renal flare with acute renal failure . between march 2011 and february 2012 , repeated cultures of tissue and joint fluids of the left knee on saboraud dextrose agar and mycobiotic agar , yielded yeast in pure cultures and were reported as candida sp ( not candida albicans ) . these cultures , were subsequently identified by remel and api 32 c as c. parapsilosis ( biomerieux api 32 c assimilation kit , reference code 6752175 ) . growth on cornmeal agar was characteristic of c. parapsilosis with yeast cells and philamentous hyphae . in april 2012 empiric treatment was commenced with fluconazole , and continued on a dosage of 200 mg twice per week , given after each dialysis . representative isolates of c. parapsilosis and subsequent isolate recovered from tissue and joint fluid in may 2012 were submitted to the center of disease control and prevention ( mycology branch ) for genotyping . these isolates were confirmed as c. orthopsilosis using pcr primers d1 : gca tat caa taa gcg gag ga and d2 : ttg gtc cgt gtt tca aga cg for amplification and sequence analysis of the ribosomal large subunit , d1 / d2 and the internal spacer region of the rrna as outlined by deak et al . . a candida - specific luminex - based assay using probe co ( c. orthopsilosis ) with a nucleotide sequence ( 5 to 3 ) of aa aat tct tcc aaa ttc gac was used for rapid identification of the present isolate . primers used in the luminex - based assay were its 3 : gca tcg atg aag aac gca gc and its4 - biotin : tc ctc cgc tta ttg ata tgc . among the many matches of c. orthopsilosis in genbank we provide two strains including 100 % match to genbank # hm 755978.1 and hm 755977.1 ( respectively equal to c. orthopsilosis strain atcc 20504 and c. orthopsilosis strain attc 20503 ) . the minimal inhibitory concentration micro - dilution assay described by the national committee for clinical laboratory standards ( nccls ) was performed on the c. orthopsilosis isolate and yielded susceptibilities to amphotericin b ( amb ) 0.03 mg / l ; fluconazole 0.25 mg / l ; itraconazole 0.03 mg / l ; flucytosine ( 5 - fc ) 0.125 mg / l ; and ketoconazole 0.25 mg / l . c. orthopsilosis remains a rare entity in fungal associated human infections . before 2005 , c. orthopsilosis ( group 2 strain ) was yet to be differentiated from its closely related group 1 , c. parapsilosis , and understandably so , as all previously associated infections were assigned to this species . several studies to adjust the number of infections previously attributed to c. parapsilosis , revealed estimated frequencies varying from 1.4 % with c. orthopsilosis and 1.7 % with c. metapsilosis in spain to 10 . to date however , there has been no reported case of c. orthopsilosis associated arthritis following an extensive literature search . it is interesting to note that the present case is similar to previous cases where c. parapsilosis was implicated in arthritis in which there were persistent infections over several months despite antifungal treatment . consistent with these findings , is the prolonged period of treatment with fluconazole in the present case , but with no signs of improvement and the continued isolation of the yeast in pure culture . the prognosis therefore remains unclear , as the patient continues on fluconazole without any signs of resolution over the several months since antifungal therapy was first initiated . current reports on epidemiological studies have described c. orthopsilosis in only a few sporadic cases of clinical relevance , , , , . however , its ability to infect and cause human diseases , appear to be similar to closely related candida spps . c. parapsilosis for example , is closely related to c. orthopsilosis with many of their protein - coding genes having an ortholog in c. parapsilosis . they reported c. orthopsilosis as producing severe attenuation and morphological changes on reconstituted human tissue models . majority of the c. parapsilosis associated arthritis cases reported in the literature occurred with elderly patients ( 60 years ) following instrumentation of joints for placement of a joint prosthesis , joint injection , or arthrocentesis , , . comparatively , our patient is much younger ( 24 years at diagnosis ) with a pre - compromised immune system apparently resulting from autoimmune disease sle , and the frequent use of cortico - steroids introduced in patient therapy . the persistence of infection seen in a number of candida affected cases , appear to be more likely , the result of biofilm formation . biofilm formation confers significant resistance to antifungal therapy by limiting the penetration of antifungal drugs , as well as , protect cells from host immune responses . some strains of c. orthopsilosis are able to form biofilms on silicone elastomer discs , which would increase the ability of the yeast to infect and cause disease . production of biofilms is a primary virulence factor of c. parapsilosis and apparently of greater significance than the small amount produce by c. orthopsilosis and c. metapsilosis . interestingly , the mortality rate of patients at an italian university hospital from whom were isolated c. parapsilosis which form biofilm in vitro , was 71.4 % compared to 28 % from those with biofilm - deficient isolates . it is important to note that filamentous c. parapsilosis phenotypes generated more biofilm , and were more invasive into agar than strains , which remained predominantly in yeast forms . the present c. orthopsilosis isolate is notably , a pseudohyphal yeast , observed on cornmeal agar . the virulence of c. orthopsilosis and its capacity to produce disease has not been extensively studied . however , its closely genetically related c. parapsilosis would reasonably suggest a strong possibility of similar invasiveness and clinical relevance of the two species . the prolonged treatment with fluconazole in the present case is similar to other cases of septic arthritis associated with c. parapsilosis . failure to carry out early investigations for fungal arthritis in our patient was probably due to the apparent lack of clinical suspicion . presumably , as also seen in c. parapsilosis related cases , the source and dissemination of c. orthopsilosis , may have resulted from multiple injections of steroids in the joint including aspirations of joint fluid . the source of the organism may also have resulted from the contaminated hands of healthcare providers , which have been implicated in the transmission of c. parapsilosis . a hematogenous spread of the yeast may have followed severe renal impairment , hemodialysis and avascular necrosis . after 12 months of fluconazole therapy , c. orthopsilosis was isolated from joint fluid and tissue in pure cultures of the organism . mics on repeated isolations of the fungus at different times , did not show any significant changes and remained at a low level of concentration for all the mics done . the repeated isolation of c. orthopsilosis in pure cultures followed by prolonged fluconazole therapy was consistent with the persistence of infection seen with other arthritic cases due to c. parapsilosis . it is in our view , that the persistency of infection is a consequence of biofilm formation decreasing the concentration of fluconazole in the synovial fluid , . we believe that the resolution of this fungal infection will require the full course of continued treatment with fluconazole over a prolonged period of up to two years of antifungal therapy , , . however , in the event of non - responsiveness to fluconazole , the echinochandins antifungals may prove useful , as they have shown high activity against biofilm forming candida species , . together with the appropriate management of the patient and the timely monitoring with cultures , may also play an important role in achieving complete clearance of the yeast . written informed consent was obtained from the patient for publication of this case report and any accompanying images . a copy of the written consent is available for review from the series editor of this journal .\noutput:\n" }, { "from": "agent", "value": "we report a case of persistent candida orthopsilosis associated septic arthritis . repeated isolation of c. orthopsilosis from tissue and joint fluid was confirmed by identification of the its region of the rrna gene using a candida - specific luminex based assay and gene sequencing of the d1 / d2 regions . this was the first case of c. orthopsilosis associated septic arthritis reported in jamaica and in the literature ." } ]

[ { "from": "human", "value": "***task***\nthe task is to summarize an input biomedical literature in six sentences\n\n***input***\nthe input is a biomedical literature\n\n***output***\nthe output is the summary of an input biomedical literature in six sentences\n\n***documentation***\n\n***examples***\n\ninput: sulfur dioxide is one of the most important pollutants in urban areas which have caused numerous cases of respiratory diseases and deaths in many communities . some studies show that there is a significant relationship between daily mortality and exposure to sulfur dioxide . studies on asthma have not yet determined the safe limit of so2 not causing respiratory malfunctioning . in fact , even very low concentrations of sulfur dioxide can cause respiratory capacity reduction . maantay declared that people living in industrialized area of the bronx and new york city were more susceptible for asthma ( 66 % ) due to sulfur dioxide . previous studies have revealed that oil refineries were one of the major sources of emitting so2 around and in the city . the size of the industry , its distance from the neighboring town , and direction of the wind were among the most important parameters causing air pollution in cities . having a thorough knowledge on these sources is an important tool in controlling and managing them . geographic information system ( gis ) software is a powerful tool to determine the contribution levels of such sources . so far , many studies on controlling air pollution have been carried out using this software . in order to monitor geographical dispersion of a pollutant in an area , it is required that sample pollutant is to be examined at different stations simultaneously . due to low cost and easy operation of diffusive method , this technique has been widely used to monitor air pollution with high precision in large scales . diffusive sampling is a powerful tool to take samples of atmospheric gas using molecular diffusion with controlled speed that has no need to pump air during sampling . many studies on the accuracy of passive sampling of so2 have shown that this method had an acceptable error rate compared to other methods of sampling . adame et al . used k - mean cluster technique to measure daily cycles for so2 pollutant at different air quality regimes in a heavily industrialized area in spain . while two of the clusters showed a low mixing ratio , the others exceeded the thresholds limits of air quality . used a comprehensive emission inventory and dispersion modeling approaches to determine the contribution of so2 from different types of pollution sources in jamshedpur in india . although the first approach showed that industrial sources account for 77 % of the total emissions of so2 , the second approach demonstrated that more than 50 % of so2 was emitted from industrial sources . studying the effect of emission sources and meteorological conditions on so2 pollution in mongolia was done by luvsan and his colleagues using multiple regression models . data revealed that so2 concentrations in industrialized area increased with the decrease of wind speed and temperature and with the increase of relative humidity . so2 distribution to air quality in hong kong was assessed by the multilayer , non - steady - state puff dispersion model . the results showed that the contribution of the power plant located in marine sources regions is significant during both summer and winter times . since the industrial regions of zarghan ( northeast of shiraz ) are affected by numerous air pollution sources , suitable monitoring systemstherefore , the main objectives of this study were to ( i ) determine preliminary assessment of the dispersion level of so2 using passive sampling and gis software and ( ii ) assess the contribution level of generating sources of so2 in urban areas . in order to study the dispersion level of so2 in zarghan , knowing the information about the local climatic condition is very essential . zarghan average annual temperature is 16c , and the total average annual rainfall is 330.2 mm . more than 56 % of the precipitation falls during winter , and the number of rainy days is 48 days . the average annual humidity is 42 % . based on domarten climate classification , the city is located on the semiarid area . monthly average wind speed at the time of air sampling is 0.9 ms . at first , zarghan is located 25 km northeast of shiraz , nearby shiraz - tehran highway . many industrial complexes are located about 10 km from zarghan among which one can name oil refinery , industrial park with more than 35 industries , ceramic industry , loab industry , and chemical industry . besides , due to a rocky wall of 300 m height in the east side of the town , the air flow through the town is often blocked . each of the above sources individually could be the cause of air pollution in zarghan . a diffusive sampler consisted of a tube in which the adsorbent material adsorbed the pollutant . speed - controlled pollutant entered the adsorbent tube by molecular diffusion with no need for electrical power or pumping . therefore , so2 sampling was based on the adsorbent molecular diffusion . in this research , sampling tubes were sealed and carried to the lab for analysis of samples after two weeks of adsorption period . the tubes were of 20 mm diameters and made of polypropylene . to reduce the turbulence effects of the wind and rain , the sampling was taken by a metal clamp inside a fiberglass container as shown in figure 1 . after collecting the specimens , they were sent to pasam company in switzerland for the determination of so2 . mixture of potassium carbonate and glycerin was used to extract so2 and the total amount of extracted so2 determined by ion chromatography . according to various sources , which are believed to be effective in zarghan air pollution , boundary conditions for creating a mesh net andgeographical coordinates , names , and reasons for choosing the sampling points are given in table 1 . due to the small size of the study area , 10 points were selected and one sample was collected at each point . moreover , it should be mentioned that statistical methods were not used in choosing the number of samples . sampling adsorbents were installed by a crane at a height of 3 to 4 meters from the ground adjacent to electrical towers . the adsorbents were exposed to outdoor so2 for 17 days from the second to the nineteenth of january , 2012 . at the beginning , geographical coordinates of 4 points of suitable dispersion were determined by the software and used in an excel file as the ground reference ( figure 2 ) . using arcgis software , the image was processed as the ground reference and the result saved in tiff format with a pixel size of 5 m. the data obtained from sampling of so2 were interpolated using the passive sampling method with different methods such as inverse distance weighing ( idw ) , natural nearest neighbor . kriging format ( tiff ) is a raster image format with a pixel size of 5 m for each specimen being prepared ( with at least 10 sample points ) . then , all interpolated layers were cut into the size of sample point 's area to perform interpolation for all layers . table 2 shows the results of so2 measurements in different stations in the industrial regions of zarghan . due to the importance of wind direction , maps of the wind rose of the sampling season and zarghan are shown in figure 3 . as shown in figure 4 , geographic concentration coverage area of so2 has been studied using different methods of nearest neighbor , iwd , and kriging . so2 pollution maps were prepared using passive sample interpolation . who ( world health organization ) guideline value for 24 hours of so2 concentration was set as 20 gm . since in this study the passive sampling method was used and the specimens were exposed to the air pollution in many of the studied stations for 17 days , the data were comparable to the average 24 - hour so2 guideline . in general , many of the stations where samples were collected had acceptable so2 levels except the following 4 stations which had considerable pollution levels . the station of oil refinery with the value of 63.3 gm.the station near street with the value of 29.7 gm.the station of industrial park with the level of 24.4 gm.the station with the level of 19.3 gm.figure 5 shows so2 concentration in different stations . as it can be seen in this figure , so2 concentration in zarghan residential areas is within standard limits . the station of oil refinery with the value of 63.3 gm . the station near street with the value of 29.7 gm . the station of industrial park with the level of 24.4 gm . the station with the level of 19.3 gm . as gis pictures showed , among generating sources of so2 pollution , the oil refinery and the highway were of more importance . in general , the concentration of so2 was much greater around the oil refinery than near the highway . although the prevailing wind direction at the time of sampling was not toward zarghan , it could affect point located 3 km away . in addition the industries located in the industrial park could not have a major effect on so2 concentration in zarghan . the concentration of so2 in the industrial park with 4000 - meter distance from the - oil refinery was 24 gm showing a higher concentration compared to point located 3 km away . on the other hand , so2 concentration at the distance of 200 meters from the highway inside the industrial park was greater than the one at station adjacent to the highway . it was concluded that the industrial park had intensified air pollution caused by the oil refinery by an amount of 5 gm . although the prevailing wind in the highway blew toward zarghan , it could have affected only 150 meters around . the 24 - hour concentration of so2 was just on standard border line in point located 3 km away , while it was within standard limits in zarghan urban areas . the reason for higher level of so2 in point located 3 km away was its adjacency to the oil refinery . according to the simulation of pollutants concentration in the atmosphere , using calpuff nonstationary gaussian model at rio grande city , the concentration of co reached 28.019 mg / m , the so2 reached 4.8623 mg / m , and no2 reached 40.8490 mg / m . similar study showed that most areas of dallas county only experienced small variations of so2 concentration over the period from 1996 to 2002 and that annual so2 concentration in some areas of the county greatly increased over this period . in addition , results from the source - contribution analysis indicated that the spatial - temporal variations in so2 concentration in dallas county from 1996 to 2002 were not attributed to any particular type of emission source , but industrial emission sources could be the origin of extreme variations in so2 concentrations in some areas . application of the sim - air modeling tool in six indian cities estimated that 21,400 premature deaths will be in the six cities in 2020 ; implementation of the six interventions in the transport and brick kiln sectors can potentially save 5870 lives ( 27 % ) annually and result in an annual reduction of 16.8 million tons of carbon dioxide emissions in the six cities . as seen from the images , the nearest neighbor interpolation method showed the linear effects of pollution on the highway clearly . as shown , zarghan has been located in the green zone , and so2 could not be accumulated in the town despite the existence of wind . according to the wind rose map , during january , the prevailing direction was not toward zarghan . therefore , it would be possible to record higher level of so2 concentration in zarghan if samples were collected during windy months blowing toward the city . on the contrary , the pollution due to the highway was affected by prevailing winds blowing toward the city , and , as seen in the gis images , the highway pollution could not affect the city . it would be highly recommended to repeat the experiment during other months of the year , especially october , in which the prevailing wind direction is toward zarghan .\noutput:\n" }, { "from": "agent", "value": "the city of zarghan is located 25 km northeast of shiraz , southern iran . zarghan is affected by numerous pollution sources such as oil refinery , an industrial park , and shiraz - tehran highway . the numerous contaminating sources around zarghan can cause serious local air pollution . sulfur dioxide gas is an important index of air pollution in cities . therefore , in order to control and manage zarghan air quality , it is important to monitor sulfur dioxide concentration in the surrounding area . it is also essential to know about the contribution level of other sources of pollution as well as dispersion radius of pollutants in the area . in this study , the concentration of sulfur dioxide was measured by passive sampling at 10 different stations . these values were interpolated in other parts of the city using arcgis software . the results of sampling showed that the concentration of the gas was 60 gm3 around oil refinery . the level was 19 gm3 in region located about 3 km from the oil refinery . it was also demonstrated that the gas concentration was not higher than the standard limit within residential area . on the other hand , the role of the local highway and industrial park was not significant in contaminating air in urban areas ." } ]