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[ { "content": "You are a medical writer. Summarize the following article: histone acetyltransferases ( hats ) transfer acetyl groups from acetyl coa to specific lysine residues in the amino terminal histone tails to form -n - acetyl lysine promoting an \n several transcriptional coactivators , including cbp / p300 and src , have intrinsic hat activity [ 1 , 2 ] . \n histone deacetylases ( hdacs ) , in contrast , catalyze the removal of acetyl groups on target lysines [ 3 , 4 ] creating a condensed , transcriptionally repressed , chromatin organization . of the various hdac inhibitors ( hdaci ) , \n several exhibit more or less specificity for individual members of the four classes ( i - vi ) of human hdacs [ 6 , 7 ] . \n a major mode of action of hdaci ( i.e. , the transcription - dependent mechanism ) affects gene reprogramming as a consequence of hdaci type , concentration , and duration of exposure [ 8 , 9 ] . \n recent estimates place the number of hdaci - impacted genes at 210% of the total expressed repertoire , several of which negatively regulate cell cycle progression [ 1013 ] such as p21 and plasminogen activator inhibitor type-1 ( pai-1 ; serpine1 ) [ 1421 ] . \n pai-1 is particularly relevant in this context as this serpin complexes with both urokinase ( upa ) and tissue - type ( tpa ) plasminogen activators to limit pericellular plasmin generation effectively attenuating upa-/plasmin - dependent growth factor activation and cellular proliferative responses [ 22 , 23 ] . \n pai-1 , in fact , is both necessary and sufficient for p53-dependent growth arrest [ 2326 ] and required for tgf-1-mediated antiproliferative effects in human keratinocytes and mouse embryo fibroblasts . \n activated ras or raf oncogenes trigger the initiation of a senescence - like growth arrest program , with induction of pai-1 , in several cell types [ 2831 ] . \n at least some cells transformed as a consequence of chronic oncogenic ras expression , and that escape ras - induced senescence can also undergo proliferative arrest upon exposure to certain hdaci ( e.g. , sodium butyrate ; nab ) with concomitant high - level pai-1 induction [ 16 , 17 , 32 ] . \n it is not known , however , if hdaci - associated growth inhibition of immortalized ras - transformants , like entrance of normal cells into replicative senescence , also requires pai-1-induction . \n this paper details the involvement of pai-1 expression during hdaci - induced growth restriction in several well - characterized v - ki - ras and ha - ras -transformed epithelial cell lines [ 15 , 16 ] . \n nab was selected for this study as this hdaci is a potent stimulator of pai-1 expression [ 14 , 20 ] and cytostasis in ras - transformed renal cells . \n nab - mediated growth inhibition was not evident in pai-1 knockdown ( i.e. , anti - sense ) cells , but the hdaci - dependent proliferative block could be rescued by vector - driven pai-1 overexpression . \n the various ras - transformed renal epithelial cell lines used in this study [ 15 , 16 ] grow in serum - free dmem ( at least over the short time frame used in this study ; 35 days ) facilitating assessments of the proliferation - modulating effects of nab ( 110 mm ) and exogenous pai-1 ( 0.02100 nm stable mutant 14 - 1b , t1/2 = 145 hours ; n150h , k154 t , q319l , m354i ) in both the presence and absence of fbs . the derivation of the pai-1 functionally null knockdown ( pai-1 ) 4hh cell line by transfection of a 2.6 kb rat pai-1 ecor1/hindiii cdna fragment ( representing nucleotides 118 to + 2572 ) cloned in anti - sense orientation ( rc / cmviap ) has been described [ 34 , 35 ] . \n v - ras - transformed cells were also transfected with the rc / cmvpai sense vector to initiate high - level pai-1 expression in the absence of nab or with the empty rc / cmv construct . \n coupled in vitro transcription / translation assay confirmed that a full - length immunoreactive pai-1 protein was synthesized using the rc / cmvpai vector as a template . in some cases , \n c - ha - ras oncogene - expressing human hacat ii-4 keratinocytes were described previously [ 33 , 36 ] as were the pai-1-deficient and reconstituted renal cell lines . \n cytoplasmic rna was separated by electrophoresis on denaturing 1% agarose/2.2 m formaldehyde gels , transferred to nitrocellulose and blots hybridized with a p - labeled ecori - hindiii fragment of rat pai-1 cdna ( specific activity 1 - 2 10 cpm/g dna ) for 48 hr at 4c . \n the recombinant pbluescript ( sk(- ) phagemid prpaiss1 - 3 , containing a 3.0-kb ecori / sstii - flanked cdna insert encoding pai-1 , was used for isolation of the prpaimr1 - 4 probe used for hybridization . \n briefly , prpaiss1 - 3 was digested with ecori / hind iii at 37c for 1 hr and fragments separated in 1% agarose gels . after staining with ethidium bromide , \n bands representing the pai-1 cdna insert were excised and electroeluted . this insert fragment ( prpaimr1 - 4 ) was labeled with p - dctp by random priming . \n following hybridization , membranes were washed sequentially for 20 minutes each in 2x ssc/0.1% sds ( twice ) and then in 1x ssc/0.1% sds , all at 55c . \n growth media ( in 35-mm diameter cultures ) were aspirated , cells washed twice with hbss and 1 ml of labeling medium ( fbs- and methionine - free rpmi 1640 medium containing 50 ci s - methionine ( specific activity = 1100 ci / mmol ) added to each culture . at the end of a 6 hr labeling period , the substrate adherent - enriched ( sap ) \n cellular fraction was collected , clarified at 13,000 g , and solubilized in lysis buffer ( 9.8 m urea , 2% nonidet p-40 , 2% ampholytes , and 100 mm dithiothreitol ) . \n 50,000 cpm s - methionine - labeled protein were loaded onto prerun 1.5 mm diameter tube gels ( 9.1 m urea , 2% nonidet p-40 , 6% ph 57 ampholytes , 1.2% ph 310 ampholytes , 4% acrylamide / bisacrylamide for isoelectric focusing ( ief ) for 18 hr prior to separation on sds-10% acrylamide slab gels . \n individual protein spots were mapped and quantitated with a bio - image investigator 2-d electrophoresis analysis system interfaced to a sun sparc workstation . \n limited expression profiling previously indicated that pai-1 was among the most abundant of the nab - upregulated genes in ras - transformed renal epithelial cells [ 14 , 15 ] consistent with microarray and bioinformatic analyses of genetic networks responsive to nab in colonic epithelial cells . \n 1-d electrophoresis ( figure 1(a ) ) , northern blotting ( figure 1(b ) ) , and 2-d proteomic mapping ( figure 1(c ) ) , moreover , confirmed a significant and rather selective pai-1 induction in nab - stimulated v - ras - transformants ( involving both the 50-kd and mature 52-kd glycosylated pai-1 species ) , using 1-d/2-d mobility and immunochemical identification criteria established previously [ 16 , 38 , 41 ] , relative to nondetectable pai-1 levels in control v - ras populations . \n pai-1 upregulation correlated with a prominent nab - associated g1 arrest increased cell size ( figure 2 ) and concentration - dependent proliferative inhibition resulting in a 63% ( figure 3(a ) ) and 48% ( figure 3(b ) ) decrease in population density in serum - free and 10% serum - supplemented medium , respectively ( summarized in figure 4 ) . \n collectively , these findings ( figures 1 and 4 ) are consistent with the conclusion that v - ras - transformants that escape ras oncogene - initiated cellular senescence [ 29 , 42 , 43 ] are essentially pai-1 null . \n since targeted suppression of pai-1 leads to bypass of both replicative senescence and tgf--induced growth arrest [ 23 , 27 ] , it was important to determine if exogenously - delivered pai-1 could similarly regulate the proliferative response of pai-1-deficient ras transformants in the absence of nab . \n the addition of a long half - life recombinant pai-1 mutant ( pai-1 14 - 1b ) effectively suppressed growth of v - ras - transformed cells in a concentration - dependent manner with an 80% reduction in final population density after a 5-day exposure to 100 nm pai-1 ( figure 5(a ) ) . \n indeed , the level of growth inhibition in cultures exposed to 20 nm pai-1 ( 45% reduction in population density relative to the corresponding control ) ( figure 5(a ) ) approximated the 47.5% decrease induced by 10 mm nab even in the presence of serum ( figure 4(b ) ) . \n ha - ras - transformed hacat cells , which express low levels of pai-1 in response to egf , were also growth inhibited by exposure to pai-1 14 - 1b in the presence of fbs or egf ( figures 5(b ) and 5(c ) ) largely due to g1 arrest ( figure 5(c ) ) . to assess this effect more critically in a genetic context , antisense knockdown ( pai-1 ; 4hh ) cells ( figure 6(a ) ) , which are resistant to nab - dependent proliferative inhibition , were incubated in pai-1-supplemented medium with or without , addition of nab . \n recombinant pai-1 , at a final concentration of 20 nm , effectively suppressed pai-1 cell proliferation ; the combination of pai-1 + nab did not significantly impact the extent of cytostasis compared to pai-1 alone ( figure 6(b ) ) . \n transient vector - driven re - expression of pai-1 in rc / cmvpai v - ras transfectants ( figure 6(a ) ) similarly reduced cell growth relative to cells transfected with the empty rc / cmv construct ( figure 6(b ) ) . \n mass cultures of rc / cmvpai - expressing cells and , in particular , their g418-selected clonal isolates , but not cells transfected with rc / cmv without the 2.6 kb pai-1 cdna insert , had significant numbers of very well - spread cells ( a hallmark of the growth arrest phenotype in renal epithelial cells [ 1416 ] ) compared to rc / cmv populations . \n the marked reduction in cell proliferation ( figure 6(b ) ) and increased spreading in rc / cmvpai as compared to rc / cmv transfectants correlated with an approximately 22-fold increase in pai-1 expression . \n data mining of microarray and serial analysis of gene expression profiles consistently identified increased pai-1 levels as characteristic of specific growth arrest states ( e.g. , [ 23 , 27 , 35 , 36 , 39 , 4246 ] ) . similar to other hdaci - regulated genes , several of which negatively regulate cell cycle progression [ 1013 ] , pai-1 is a particularly relevant candidate as this serpin attenuates upa-/plasmin - dependent growth factor activation and cellular proliferative responses [ 22 , 23 ] , mediates p53-dependent cytostasis [ 2326 ] , and is required for tgf-1-mediated antiproliferative responses . in cells expressing activated ras or raf oncogenes , moreover , induced pai-1 initiates the engagement of a senescence - like phenotype [ 2831 ] while , for those cells that escape ras - induced senescence , the growth arrest program can be rescued upon exposure to certain hdaci ( e.g. , nab ) with concomitant high - level pai-1 induction [ 16 , 17 , 32 ] . \n while molecular events underlying nab - stimulated pai-1 expression is unclear , nab enhances smad3 phosphorylation and potentiates tgf--induced pai-1 expression , concomitant with nab - induced g1 arrest . \n indeed , overexpression of smad3 in v - ha - ras - transformed keratinocytes induced a cytostatic response , stimulated pai-1 promoter ( 3tp - lux reporter)-dependent transcription , and increased the incidence of senescent epithelial cells . \n the present findings are consistent with these and previous data that tgf--initiated growth inhibition as well as senescence arrest is pai-1-dependent [ 23 , 27 ] and establish , moreover , pai-1 as a mediator of nab - initiated cytostasis . whether this response can be adapted for directed senescence therapy of human cancers , \n nab upregulates the cell cycle inhibitors p21 and p16 in human fibroblasts although targeted disruption of p21 only weakly impacted hdaci - induced senescence - like growth arrest . \n p53 mouse embryo fibroblasts ( mefs ) , moreover , are resistant to nab - initiated cytostasis indicating that this tumor suppressor is a major senescence determinant in mefs , and nab - mediated apoptosis in human melanoma cells is p53-dependent . \n indeed , nutlin-3 , an mdm2 inhibitor which restores p53 function in tumor cells that retain a wild - type p53 , cooperate with several hdacis ( including nab ) to induce cell death in p53 wild - type tumor cell lines but not in p53-null pc-3 prostatic carcinoma likely by hdaci - induced p53 hyperacetylation and/or mdm2/mdm4 downregulation . \n this may be dependent , in part , on the extent of increased p53 expression in response to nab . \n similarly , nab - stimulated p53 transcriptional activity initiated irreversible g1/s cell cycle arrest in c - ha - ras - transformed rat embryo fibroblasts that were p53 wild - type but not in cells with an inactivated p53 . \n while the actual contribution of p21 versus ink4a / arf - encoded genes ( e.g. , p19 ) in nab - induced growth arrest is uncertain [ 55 , 56 ] , the role of p53 ( at least in mefs ) may be more relevant since p53 is required for pai-1 expression and growth arrest ( see [ 27 , 57 ] ; and overstreet et al . \n . p53 status , therefore , may be a major aspect of hdaci - induced cell cycle arrest through its transcriptional control of pai-1 and , thereby , pai-1-dependent cytostasis .", "role": "user" }, { "content": "malignant transformation of mammalian cells with ras family oncogenes results in dramatic changes in cellular architecture and growth traits . \n the generation of flat revertants of v - k - ras - transformed renal cells by exposure to the histone deacetylase inhibitor sodium butyrate ( nab ) was previously found to be dependent on transcriptional activation of the pai-1 ( serpine1 ) gene ( encoding the type-1 inhibitor of urokinase and tissue - type plasminogen activators ) . \n nab - initiated pai-1 expression preceded induced cell spreading and entry into g1 arrest . to assess the relevance of pai-1 induction to growth arrest in this cell system more critically , two complementary approaches were used . \n the addition of a stable , long half - life , recombinant pai-1 mutant to pai-1-deficient v - k - ras-/c - ha - ras - transformants or to pai-1 functionally null , nab - resistant , 4hh cells ( engineered by antisense knockdown of pai-1 mrna transcripts ) resulted in marked cytostasis in the absence of nab . \n the transfection of ras - transformed cells with the rc / cmvpai expression construct , moreover , significantly elevated constitutive pai-1 synthesis ( 10- to 20-fold ) with a concomitant reduction in proliferative rate . \n these data suggest that high - level pai-1 expression suppresses growth of chronic ras - oncogene transformed cells and is likely a major cytostatic effector of nab exposure .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: primary dysmenorrhea ( pd ) is the most prevalent gynecological condition experienced in women of reproductive age.1 it is defined as a colicky , low abdominal pain associated with menstruation in the absence of any obvious pelvic pathology . \n pd first occurs usually during adolescence after ovulatory cycles become established , and pain severity decreases with increasing age.2 the contributing risk factors include younger age , low and high body mass index , earlier age at menarche ( aam ) , smoking , prolonged or aberrant menstrual flow , family history of dysmenorrhea , nulliparity , high caffeine intake , and a history of sexual abuse.13 it negatively affects daily life activities , academic performance , and socializing with peers and is reported to be associated with psychiatric conditions such as depression and anxiety.4 autism spectrum disorder ( asd ) is characterized by deficits in social communication and social interaction across contexts , as well as restricted and repetitive patterns of behavior , interests , or activities.5 according to the report of autism and developmental disabilities monitoring network , the current estimated prevalence of asd is 14.7/1,000 ( one in 68 ) children aged 8 years.6 males are approximately four times more likely than females to receive the diagnosis.7 although the underlying etiology remains unclear , recent findings suggest that asd is a polygenetic disorder with interaction of genetic and environmental factors.8 the androgen theory of asd proposes that elevated prenatal androgens may have masculinizing effects on fetal brain and may be a precursor for autistic traits.7 previous studies have shown that higher fetal testosterone levels , measured in amniotic fluid , were positively correlated with autistic traits in typically developing children.7,9 lower second - to - fourth digit length ratio ( 2d:4d ) was reported in individuals with asd , indicating greater fetal testosterone exposure.10 several studies have also demonstrated that excessive androgens have been related to menstrual problems , including amenorrhea , irregular menstrual cycles , and dysmenorrhea.1113 the androgen theory also suggests that women with asd might be more vulnerable to medical conditions associated with elevated androgens , including severe acne , hirsutism , and menstrual problems.14,15 limited literature indicates that women with asd experience higher rates of menstrual difficulties , including premenstrual syndrome , irregular menstrual cycles ( amenorrhea ) , unusually painful periods ( dysmenorrhea ) , and excessive menstrual bleeding.1418 in an observer - rated study , obaydi and puri18 have found a markedly increased prevalence of premenstrual syndrome in a group of women with autism compared to age- and intelligence - matched controls ( 92% vs 11% ) . \n ingudomnukul et al14 have demonstrated that significantly more women with asd experienced menstrual problems , including irregular menstrual cycles ( 57.4% vs 28.6% ) and dysmenorrhea ( 44.4% vs 28% ) compared to controls . \n pohl et al15 have also reported higher rates of irregular menstrual cycles ( 46.3% vs 34% ) and dysmenorrhea ( 39.3% vs 26.3% ) among women with asd than those among healthy controls . \n asd is a clinical diagnosis ; however , behavioral and cognitive traits linked to asd ( autistic traits ) are common and follow a continuous distribution in the general population.19,20 previous studies have reported associations between autistic traits and other factors , including white matter connectivity , facial features , and genetic polymorphisms.2123 lundstrm et al24 have demonstrated that both asd and autistic traits share etiological similarity , and they have suggested that they differ from each other in terms of severity and functional impairment . in this study , we aimed to investigate the association between autistic traits and pd in a group of university female students . based on the above literature , indicating that dysmenorrhea was more frequent in women with asd than controls , we predicted that women with pd would have higher autistic traits than women without pd . \n the participants of the study were female medical students , recruited from a public university , necmettin erbakan university ( konya city , middle of turkey ) . \n menstruation pain was first measured in each individual by a visual analog scale ( vas ) , coded from 0 to 10 . \n subjects who had a history of dysmenorrhea , starting shortly after menarche , and who rated menstrual pain as severe , defined as a score 6 on the vas,25 were included in the study group ( sg ) . \n subjects were enrolled into the control group ( cg ) if they rated their menstrual pain as 2 on the vas . \n dysmenorrhea was defined as a 1272 hours colicky pain in the lower abdomen during each menstrual cycle ( for three consecutive menses ) , with or without nausea , diarrhea , fatigue , or headache.1 the inclusion criteria for all the participants were as follows : 1 ) 18- to 25-year - old females ; 2 ) a regular menstrual cycle of ~2732 days ; and 3 ) nulliparity . \n the exclusion criteria were as follows : 1 ) acute or chronic pelvic disease ; 2 ) physical illness causing pain ; 3 ) smoking ; 4 ) pregnancy or / and a history of childbirth ; and 5 ) use of any psychotropic drugs and hormonal contraception within last 6 months . before entering the study , purpose and procedure of the study were explained to the participants . upon their agreement , \n all the subjects were clinically examined by a gynecologist and completed a comprehensive evaluation , including medical history , pelvic manual examination , and pelvic ultrasonography in the obstetrics and gynecology outpatient clinic to exclude secondary dysmenorrhea caused by organic pelvic diseases . \n subjects who showed no evidence of a medical condition that would explain pd were considered eligible for the study . \n the participants did not use any pain - relieving medication on the day of assessment . \n they were then invited to complete a data form about their demographic characteristics and menstrual patterns and to rate their current menstruation pain by using vas . \n afterward , they filled out two self - report questionnaires , brief symptom inventory ( bsi ) for measuring their anxiety and depression levels and autism spectrum quotient ( aq ) to evaluate their autistic traits . \n weight and height were measured in all participants , and their body mass index was calculated . \n this procedure was conducted in the same order and took ~2530 minutes to complete for each subject during the menstruation phase . \n the study and the study protocol were reviewed and approved by the ethics committee of the necmettin erbakan university , faculty of medicine , konya , turkey . \n the participants of the study were female medical students , recruited from a public university , necmettin erbakan university ( konya city , middle of turkey ) . \n menstruation pain was first measured in each individual by a visual analog scale ( vas ) , coded from 0 to 10 . \n subjects who had a history of dysmenorrhea , starting shortly after menarche , and who rated menstrual pain as severe , defined as a score 6 on the vas,25 were included in the study group ( sg ) . \n subjects were enrolled into the control group ( cg ) if they rated their menstrual pain as 2 on the vas . \n dysmenorrhea was defined as a 1272 hours colicky pain in the lower abdomen during each menstrual cycle ( for three consecutive menses ) , with or without nausea , diarrhea , fatigue , or headache.1 the inclusion criteria for all the participants were as follows : 1 ) 18- to 25-year - old females ; 2 ) a regular menstrual cycle of ~2732 days ; and 3 ) nulliparity . \n the exclusion criteria were as follows : 1 ) acute or chronic pelvic disease ; 2 ) physical illness causing pain ; 3 ) smoking ; 4 ) pregnancy or / and a history of childbirth ; and 5 ) use of any psychotropic drugs and hormonal contraception within last 6 months . \n before entering the study , purpose and procedure of the study were explained to the participants . upon their agreement , \n all the subjects were clinically examined by a gynecologist and completed a comprehensive evaluation , including medical history , pelvic manual examination , and pelvic ultrasonography in the obstetrics and gynecology outpatient clinic to exclude secondary dysmenorrhea caused by organic pelvic diseases . \n subjects who showed no evidence of a medical condition that would explain pd were considered eligible for the study . \n the participants did not use any pain - relieving medication on the day of assessment . \n they were then invited to complete a data form about their demographic characteristics and menstrual patterns and to rate their current menstruation pain by using vas . \n afterward , they filled out two self - report questionnaires , brief symptom inventory ( bsi ) for measuring their anxiety and depression levels and autism spectrum quotient ( aq ) to evaluate their autistic traits . \n weight and height were measured in all participants , and their body mass index was calculated . \n this procedure was conducted in the same order and took ~2530 minutes to complete for each subject during the menstruation phase . \n the study and the study protocol were reviewed and approved by the ethics committee of the necmettin erbakan university , faculty of medicine , konya , turkey . \n this is a self - reported form , prepared for the purpose of this study , that included questions about the demographic characteristics ( age , duration of education ) and menstrual patterns ( aam , duration of the menstruation cycles and bleeding , duration of the menstruation pain ) of the subjects . during their menstruation phase , the participants rated the intensity of their current menstrual pain on a 10 cm vas , from no pain ( 0 ) to the worst pain i have ever experienced ( 10 ) . \n the aq is a 50-item self - report questionnaire that measures autistic traits in adults with normal intelligence.20 individuals are asked to indicate how well each statement applies to them on a 4-point scale : strongly agree , \n each item is rated with a score of 1 to a response indicating an autistic trait and 0 to a response nonindicative of an autistic trait . \n it consists of five subscales , each comprising ten items : social skills , attention to detail , attention switching , communication , and imagination . \n items within each subscale are summed to provide a quantitative measure of that particular autistic trait , with higher scores indicating increased autistic traits . \n the reliability and validity of the aq in the turkish population was done by kse et al.26 they reported the internal consistency as =0.64 . in the current study , internal consistency for the aq was =0.55 . \n the bsi is a 53-item , self - report inventory that measures symptoms of psychopathology in adults.27 the participants were asked to rate the degree to which they were affected by and experienced distress from symptoms during the previous 7 days . \n each question was rated on a 5-point likert scale ranging from not at all ( 0 ) to extremely ( 4 ) . \n the turkish version of bsi was reported to be reliable and valid for use in the turkish population.28 for the current study , only subscales measuring depression and anxiety were used . in this sample , bsi \n depression and bsi anxiety had good internal consistency ( bsi depression , =0.89 ; bsi anxiety , =0.88 ) . \n statistical analyses were done using spss for windows , version 22.0 ( ibm corporation , armonk , ny , usa ) . \n smirnov test was performed to test distribution of the data , and according to the results , an independent t - test or mann whitney u - test was used to compare continuous variables between the groups . \n . a p - value of < 0.05 ( two tailed ) was considered as statistically significant . \n this is a self - reported form , prepared for the purpose of this study , that included questions about the demographic characteristics ( age , duration of education ) and menstrual patterns ( aam , duration of the menstruation cycles and bleeding , duration of the menstruation pain ) of the subjects . \n during their menstruation phase , the participants rated the intensity of their current menstrual pain on a 10 cm vas , from no pain ( 0 ) to the worst pain i have ever experienced ( 10 ) . \n the aq is a 50-item self - report questionnaire that measures autistic traits in adults with normal intelligence.20 individuals are asked to indicate how well each statement applies to them on a 4-point scale : strongly agree , \n each item is rated with a score of 1 to a response indicating an autistic trait and 0 to a response nonindicative of an autistic trait . \n it consists of five subscales , each comprising ten items : social skills , attention to detail , attention switching , communication , and imagination . \n items within each subscale are summed to provide a quantitative measure of that particular autistic trait , with higher scores indicating increased autistic traits . \n the reliability and validity of the aq in the turkish population was done by kse et al.26 they reported the internal consistency as =0.64 . in the current study , internal consistency for \n the bsi is a 53-item , self - report inventory that measures symptoms of psychopathology in adults.27 the participants were asked to rate the degree to which they were affected by and experienced distress from symptoms during the previous 7 days . \n each question was rated on a 5-point likert scale ranging from not at all ( 0 ) to extremely ( 4 ) . \n the turkish version of bsi was reported to be reliable and valid for use in the turkish population.28 for the current study , only subscales measuring depression and anxiety were used . in this sample , bsi \n depression and bsi anxiety had good internal consistency ( bsi depression , =0.89 ; bsi anxiety , =0.88 ) . \n statistical analyses were done using spss for windows , version 22.0 ( ibm corporation , armonk , ny , usa ) . \n smirnov test was performed to test distribution of the data , and according to the results , an independent t - test or mann whitney u - test was used to compare continuous variables between the groups . \n . a p - value of < 0.05 ( two tailed ) was considered as statistically significant . \n one hundred forty female students met the criteria for participation and were enrolled into the study . \n they were divided into two groups based upon their vas score : the sg ( n=70 ) had severe painful menstruation ( vas 6 ) and the cg ( n=70 ) had no pain during menstruation ( vas 2 ) . \n statistical tests confirmed that the two groups were well matched for age , education , anthropometric variables , and menstrual characteristics ( table 1 ) . according to the vas , \n women in the sg reported significantly more severe menstrual pain compared to controls ( 7.441.14 vs 0.990.81 ; p<0.000 ) . \n the menstrual pain duration of the subjects in the sg was 2.230.94 days and their history of dysmenorrhea was 7.772.80 years . \n the mean scores in all subscales of aq were higher in the sg than cg ; however , only attention switching subscale reached significance . \n there were no significant differences between groups in terms of depression and anxiety levels ( table 2 ) . \n spearman analysis showed that vas score was positively correlated with only aq total ( r=0.190 , p=0.025 ) and aq attention switching subscale ( r=0.205 , p=0.015 ) . \n multiple linear regression analysis was performed to determine the factors affecting menstrual pain intensity , measured by vas . \n anxiety scores , and clinical characteristics included age , education , aam , and duration of the menstruation cycle . \n in this case control study , we investigated the relationship between pd and autistic traits in female university students . according to our knowledge , \n this is the first study examining autistic features in young females with pd by using the aq , an established measure to screen autistic traits in the general population . \n we found that subjects with pd reported more autistic traits than age - matched healthy controls and aq attention switching subscale was associated with menstruation pain intensity , as measured by vas . \n our results are in line with findings of two prior studies indicating an association between dysmenorrhea and asd.14,15 ingudomnukul et al have examined a number of medical conditions and behavioral traits , seen as associated with elevated androgen levels , in women with asd using an electronically distrubuted questionnaire , the testosterone medical questionnaire . \n several medical conditions , including polycystic ovary syndrome , hirsutism , severe acne , and menstrual problems were found at a higher rate in the asd group ( n=54 ) than healthy controls ( n=183 ) . in the study of ingudomnukul et al,14 significantly more women with asd reported dysmenorrhea ( 44.4% vs 28% ) . \n pohl et al15 replicated these findings in a larger sample and similarly reported that dysmenorrhea was more frequent in women with asd ( n=415 ) than controls ( n=415 ; 39.3% vs 26.3% ) . \n they suggested elevated androgen levels as the common link between the following two conditions : asd and dysmenorrhea.14,15 several studies have suggested that excessive androgens were related to menstrual problems , including amenorrhea , irregular menstrual cycles , and dysmenorrhea.1113 association between increased androgens and menstrual irregularities has been reported in both clinical and nonclinical samples.13,29 van anders and watson13 have found significant positive correlations between salivary testosterone levels and menstrual irregularities in healthy women . \n hart et al12 have demonstrated that fetal androgen exposure had an influence on reproductive function of female offspring . \n our finding , higher autistic traits in women with pd , raises the possibility that a common biological mechanism , elevated androgens , underlies both conditions . \n the androgen theory suggests that certain groups within the general population may be predisposed to have higher autistic traits.7 a previous study showed that women with polycystic ovary syndrome , which is associated with menstrual irregularities , had higher autistic traits than controls.30 recently , an association between higher autistic traits and delayed menarche was reported in nonclinical female university students.31 ingudomnukul et al14 and pohl et al15 have demonstrated the relationship between autism and dysmenorrhea in clinically diagnosed asd samples . \n two prior findings , association between early aam and pd1,2 and positive correlation between autistic traits and aam,31 would suggest finding lower autistic traits in women with pd , contrary to the results of this study . in our sample , aam was lower in women with pd ; however , this difference was not significant . \n the mean menarcheal age was 13.01 in the cg , which is in line with previous studies conducted in turkey.32 we also did not find any correlations between autistic traits and aam in this sample . \n therefore , the associations between aam , pd , and asd should be further investigated . \n previous studies have demonstrated sensory processing ( eg , vision , hearing , touch , smell , proprioception ) problems in individuals with asd.33 sensory disturbances in autism may present as hypersensitivity ( occurring as there is an overload of stimuli ) and hyposensitivity ( occurring as an underreaction to the sensory stimuli).34 tavassoli et al35 have reported that adults with asd had more sensory over - responsivity to stimuli in the environment and within their body . \n robertson and simmons36 have demonstrated strong link between autistic traits and sensory processing difficulties in the general population . \n our finding , positive correlation between autistic traits and menstrual pain intensity , is in line with the existing literature . in the current study , \n total scores than controls and scored significantly higher on only one of the five subscales of aq , attention switching . \n this subscale of the aq covers behaviors such as having strong interests , an adherence to routine , and anxiety surrounding new situations . \n these findings may suggest that pd patients experience difficulties similar to those with asds , at least in attention switching domain measured by the aq . \n attention switching subscale might be indicative of a relationship between restricted interests and desire for sameness , and painful menstruation . \n one other finding of the current study was association between menstrual pain intensity , measured by vas , and attention switching subscale of the aq , meaning that females with pd might have poor attention switching abilities . \n this is consistent with the study of keogh et al37 concluding that menstrual - related pain was related with greater attentional interference , including attentional switching . \n craner et al38 have also reported that women with premenstrual disorders had lower abilities to shift their attention . \n the perception of pain depends on attention that is allocated to a stimulus , and directing attention away from that stimulus reduces pain.39,40 these findings suggest that attention switching might be a vulnerability factor by contributing to more painful menstruation . \n first , although our sample was homogeneous , as consisting of medical students , it does not represent all women and we can not generalize our findings to the general population . \n second , as this was a cross - sectional study , we can not determine the causal relationships between autistic traits and dysmenorrhea . \n finally , we did not consider several possible confounding factors , including family history of asd and pd and history of sexual abuse , that might be expected to have an impact on our findings . \n this is the first investigation reporting an association between autistic traits and pd in neurotypical female university students . \n although the biological underpinning of this relationship is unclear , these preliminary findings require further exploration .", "role": "user" }, { "content": "objectivesrecent studies have shown that women with autism spectrum disorder have higher rates of menstrual problems , including irregular menstrual cycles , unusually painful periods ( dysmenorrhea ) , and excessive menstrual bleeding . in this study \n , we investigated the autistic traits in female university students with primary dysmenorrhea ( pd).methodsseventy females with pd and 70 females without pd were enrolled in the study . the autism spectrum quotient ( aq ) \n was used to measure autistic traits and the brief symptom inventory was used for evaluating anxiety and depression levels . \n the dysmenorrheal pain was assessed by visual analog scale ( vas ) , coded from 0 to 10 . \n weight and height were measured , and the body mass index was calculated.resultsthere were no statistical differences between the groups in terms of age , duration of education , and body mass index . \n women with pd had higher aq total , and aq attention switching subscale scores than subjects without pd . \n spearman analysis revealed that aq \n total and aq attention switching scores were correlated with vas . according to the linear regression analysis , vas was predicted only by aq \n attention switching subscale.conclusionour findings showed an association between autistic traits and dysmenorrhea in typically developing females .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: traumatic dental injuries in children and adolescents are frequently associated with the avulsion of tooth . \n immediate tooth reimplantation of the avulsed tooth is considered as the ideal clinical treatment . for successful reimplantation of an avulsed tooth , \n it is most important to preserve the vitality of periodontal ligament ( pdl ) cells attached to the root surface to re - establish nutrient supply to the cells . \n when an avulsed tooth is reimplanted after 15 min , damaged pdl cells cause partial root resorption . \n moreover , a 30 min delayed reimplantation can cause fatal damage to cells and a 60 min delayed reimplantation in dry condition can cause pdl necrosis , leading to extensive root resorption . \n however , the lack of specific dental knowledge may lead a patient to fail to reimplant an avulsed tooth in a timely manner \n . the ability of transport medium to support cell viability can be more important than the extra oral time for preventing ankylosis and resorption . \n various storage media such as tap water , saliva , milk , and culture media have been investigated for the ability to maintain cell viability . \n the purpose of this study was to compare and evaluate the efficacy of ringer 's lactate , hank 's balanced salt solution ( hbss ) , tender coconut water , and green tea extract in maintaining the cell viability for transportation of an avulsed tooth within time intervals of 15 min , 30 min , 60 min , and 90 min , by using the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide ( mtt ) assay . \n ten grams of green tea leaves was soaked in 100 ml of boiling distilled water for 5 min and filter sterilized by using a whatman filter paper [ figure 1 ] . \n filter sterilized whatman filter paper in this in vitro experimental study , cell culture of human gingival fibroblast cells was obtained from clinically healthy premolars extracted for orthodontic purposes from the department of oral and maxillofacial surgery , sri hasanamba dental college , hassan . \n the protocol was reviewed and approved by the ethical review committee of sri hasanamba dental college . \n extraction was performed as atraumatically as possible , and the tooth was washed with sterile solution to wash out residual blood . the tooth was held with forceps at the coronal region and the pdl cells were obtained by scraping with a no . 2 scalpel blade from the lower third of the root surfaces . \n the teeth were stored in air - tight vials containing antibiotic solutions under aseptic conditions . \n these vials were transported to the international stem cells private limited , sri raghavendra biotechnologies , bangalore to harvest and culture the human gingival fibroblasts . \n the tissues were split into small pieces and cultivated in dulbecco 's modified eagle medium supplemented with 10% fetal bovine serum in a humidified atmosphere containing 5% co2 at 37c . after incubation \n the 96-well culture plates were incubated at 37c for 24 h with a layer of fibroblasts attached to the well culture plates and they were seeded at a density of 40,000 cells / well onto the 96-well culture plates using a microlittre pipette [ figures 2 and 3 ] . \n 96 well culture plates the storage media tested in the study were divided into four major groups to be inoculated into the 96-well culture plates as follows [ figure 4 ] : the four storage medias used in the present study \n group i : hbssgroup ii : ringer 's lactate solutiongroup iii : tender coconut watergroup iv : green tea extract \n group ii : ringer 's lactate solution group iii : tender coconut water group iv : green tea extract the four groups were then divided to denote the storage time periods of 15 min , 30 min , 60 min , and 90 min , respectively . \n these time periods are considered because one of the sequelae following replantation of avulsed tooth includes inflammatory or replacement resorption . \n the development of replacement resorption depends on both the degree of damage to the periodontium at the time of avulsion and the extent to which the viability of periodontal ligament cells remaining on the tooth surface is maintained . \n hence , the prognosis of an avulsed tooth is largely dependent on the status of the periodontal ligament cells at replantation . \n when an avulsed tooth is reimplanted after 15 min , the damaged pdl cells cause partial root resorption . \n moreover , a 30 min delayed reimplantation can cause fatal damage to the cells and a 60 min delayed reimplantation in dry condition can cause pdl necrosis , leading to extensive root resorption . \n the best prognosis of tooth reimplantation is obtained when the extra - alveolar time does not exceed 5 min . to standardize the number of cells , a cell suspension was made to get a cell count of 40,000 cells / ml . \n one milliliter of each of the storage media was inoculated into the 96-well culture plates containing the fibroblasts cells and placed in an incubator of 5% co2 at 37c for 24 h. then 50 l of mtt dye was added to each well and the contents were incubated for 4 h at 37c . \n after incubation , the mtt dye was removed and dimethyl sulfoxide ( dmso ) solvent was added to solubilize the colored products . \n the viable fibroblast cells absorbed the dye and a purplish residue containing formazan crystals was formed in most of the wells . \n the absorbance was measured using an optical microplate reader or called as optical calorimeter [ figure 5 ] at a wavelength of 540 nm and the percentage of viable cells was calculated for 15 min , 30 min , 60 min , and 90 min . \n in this in vitro experimental study , cell culture of human gingival fibroblast cells was obtained from clinically healthy premolars extracted for orthodontic purposes from the department of oral and maxillofacial surgery , sri hasanamba dental college , hassan . \n the protocol was reviewed and approved by the ethical review committee of sri hasanamba dental college . \n extraction was performed as atraumatically as possible , and the tooth was washed with sterile solution to wash out residual blood . the tooth was held with forceps at the coronal region and the pdl cells were obtained by scraping with a no . 2 scalpel blade from the lower third of the root surfaces . \n the teeth were stored in air - tight vials containing antibiotic solutions under aseptic conditions . \n these vials were transported to the international stem cells private limited , sri raghavendra biotechnologies , bangalore to harvest and culture the human gingival fibroblasts . \n the tissues were split into small pieces and cultivated in dulbecco 's modified eagle medium supplemented with 10% fetal bovine serum in a humidified atmosphere containing 5% co2 at 37c . after incubation , the fibroblasts migrated out of the tissue pieces and started proliferating . \n the 96-well culture plates were incubated at 37c for 24 h with a layer of fibroblasts attached to the well culture plates and they were seeded at a density of 40,000 cells / well onto the 96-well culture plates using a microlittre pipette [ figures 2 and 3 ] . \n 96 well culture plates the storage media tested in the study were divided into four major groups to be inoculated into the 96-well culture plates as follows [ figure 4 ] : the four storage medias used in the present study \n group i : hbssgroup ii : ringer 's lactate solutiongroup iii : tender coconut watergroup iv : green tea extract \n group ii : ringer 's lactate solution group iii : tender coconut water group iv : green tea extract the four groups were then divided to denote the storage time periods of 15 min , 30 min , 60 min , and 90 min , respectively . \n these time periods are considered because one of the sequelae following replantation of avulsed tooth includes inflammatory or replacement resorption . \n the development of replacement resorption depends on both the degree of damage to the periodontium at the time of avulsion and the extent to which the viability of periodontal ligament cells remaining on the tooth surface is maintained . \n hence , the prognosis of an avulsed tooth is largely dependent on the status of the periodontal ligament cells at replantation . \n when an avulsed tooth is reimplanted after 15 min , the damaged pdl cells cause partial root resorption . \n moreover , a 30 min delayed reimplantation can cause fatal damage to the cells and a 60 min delayed reimplantation in dry condition can cause pdl necrosis , leading to extensive root resorption . \n the best prognosis of tooth reimplantation is obtained when the extra - alveolar time does not exceed 5 min . to standardize the number of cells , a cell suspension was made to get a cell count of 40,000 cells / ml . the cells were counted with a neubauer counting chamber under light microscope . \n one milliliter of each of the storage media was inoculated into the 96-well culture plates containing the fibroblasts cells and placed in an incubator of 5% co2 at 37c for 24 h. then 50 l of mtt dye was added to each well and the contents were incubated for 4 h at 37c . \n after incubation , the mtt dye was removed and dimethyl sulfoxide ( dmso ) solvent was added to solubilize the colored products . \n the viable fibroblast cells absorbed the dye and a purplish residue containing formazan crystals was formed in most of the wells . \n the absorbance was measured using an optical microplate reader or called as optical calorimeter [ figure 5 ] at a wavelength of 540 nm and the percentage of viable cells was calculated for 15 min , 30 min , 60 min , and 90 min . \n table 1 shows the cell viability of human periodontal cells at different time intervals with four experimental transport media . \n the mean and standard deviation were estimated from the results that were statistically analyzed using one - way analysis of variance ( anova ) to identify the significant groups at p 0.5 . \n cell viability of human periodontal cells at different time intervals with four experimental transport media percentage of cell viability found using mtt assay figure 6 shows the scanning electron microscopic analysis . \n scanning electron microscopic analysis results indicated that there was no statistically difference in the cell viability of ringer 's lactate , hbbs , and tender coconut water . \n green tea extract showed lower viability after 90 min , when compared to the other three media . \n two of the most crucial factors affecting the prognosis of an avulsed tooth are extraoral dry time and the storage medium in which tooth is placed before reimplantation . \n experimental studies have indicated that storage medium is a more critical prognostic factor than the extra - alveolar period . physiological storage media such as saliva , milk , hbss , and viapan \n tap water was found to be unsuitable due to its hypotonicity leading to rapid cell lysis . \n tap water showed a decrease in periodontal ligament cell viability and increased external root resorption . \n saliva was found to be more effective than tap water , but also has the potential for bacterial contamination . \n osm / l ) was found to be much lower than the normal range ( 230400 osm / l ) required for cell growth . \n saliva is a hypotonic solution , causing periodontal cells to swell and burst . practically speaking , \n hbss is not commonly available to a majority of the people at the time of an accident , hence milk has been advocated as an appropriate storage medium . \n apart from maintaining the cell viability , a medium should be easily available , inexpensive , and simple to use . \n tender coconut water has been proved to be a blood plasma substitute because of its sterility and biocompatibility . \n green tea was chosen as a test solution because people in asia generally drink green tea and it is easily available in the event of an accident . \n substance in green tea used as allograft material and for cell study . in the dental field \n , green tea extract was known to protect alveolar bone resorption from periodontal disease because it inhibited the expression of matrix metalloproteinase-9 ( mmp ) in osteoblasts and the formation of osteoclasts . \n the commercial green tea used in this study showed very low osmolality , which might lead to cell death . \n the human gingival fibroblasts are the predominant cell type in the soft connective tissues of the periodontium and consequently play a central role in normal function and in pathologic alterations . \n fibroblasts used in the present study were cultured from atraumatically extracted premolar tooth with clinically healthy periodontium . \n browne et al . postulated that established cell lines such as bhk-21/c13 ( baby hamster kidney fibroblasts ) , l929 fibroblasts , and human cervical carcinoma epithelial cells were used commonly for endodontic research . in the present study , \n human gingival fibroblasts were used at a density of 40,000 cells / ml , as they are easily cultured and are consistent in quality . \n barnhart et al . conducted an in vitro study to determine the cytotoxicity of various irrigating solutions using the cy - quant assay . \n this non - radioactive assay provides the potential to evaluate cytotoxicity in terms of cell proliferation . in the present study \n viable cells with active mitochondria cause cleavage of mtt dye into water - insoluble dark blue formazan crystals , whereas dead cells remain uncolored . \n the main advantages of mtt assay are its rapidity , accuracy , and not requiring the use of radioisotopes . \n therefore , it is a useful tool for evaluating the toxicity of newly developed drugs . in the present study , \n the results obtained from the scanning electron microscopic analysis were similar to the cytotoxicity results . \n numerous vacuoles occurred in the cell cytoplasm with changes in cell shape and attachment , indicating cell death . \n with the limitations of this in vitro study , the following conclusions are drawn : \n within 15 min , 30 min , and 60 min , hbss , ringer 's lactate , tender coconut water , and green tea extract were the most effective storage mediaviability of cells in green tea extract after 90 min was slightly statistically inferior to the other three mediadue to superior osmolarity , easier availability , and cost effectiveness , green tea extract , ringer 's lactate solution , and coconut water can be advocated as alternate and viable storage media . \n within 15 min , 30 min , and 60 min , hbss , \n ringer 's lactate , tender coconut water , and green tea extract were the most effective storage media viability of cells in green tea extract after 90 min was slightly statistically inferior to the other three media due to superior osmolarity , easier availability , and cost effectiveness , green tea extract , ringer 's lactate solution , and coconut water can be advocated as alternate and viable storage media .", "role": "user" }, { "content": "objectives : the study was performed to compare and evaluate the efficacy of four experimental storage media ( hank 's balanced salt solution , ringer 's lactate solution , tender coconut water , and green tea extract ) for maintaining cell viability of human periodontal cells at different time intervals of 15 min 30 min , 60 min , and 90 min.materials and methods : human periodontal cells were cultured and stored in the four media . \n after 15 min 30 min , 60 min , and 90 min , the different media were examined under optical microscope and viabilities analyzed using an optical calorimeter . \n mean and standard deviation were estimated from the results that were statistically analyzed using one - way analysis of variance ( anova ) to identify the significant groups.results:the results indicated that there was no difference in cell viability between the four media up to a period of 60 min , whereas green tea extract showed a lower cell viability after 90 min.conclusion:within the limitations of the present study , it appears that due to superior osmolality , cost effectiveness , and easier availability , ringer 's lactate , tender coconut water , and green tea extract can be used as alternate storage media for avulsed tooth .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: copd is characterized by progressive and partially reversible airflow limitation , and it is among the leading causes of death worldwide.1 the disease is complicated by exacerbation , which is associated with a poor prognosis,2,3 and places a considerable economic burden on health services and society.4,5 it has also been recognized that some patients with copd are particularly prone to exacerbations , and these patients have been termed \n frequent exacerbators.6,7 exacerbations are categorized into mild , moderate , and severe ones in terms of either clinical presentation ( number of symptoms ) or utilization of health care resources.810 most of the published studies have surveyed moderate - to - severe exacerbation that required a change in regular medication or hospital admission.2,3,11 however , one observational study found that about half of all exacerbations remain unreported , yet the recovery periods are similar to those of moderate or severe exacerbations.12 other studies have also shown that unreported exacerbations might negatively affect the health - related quality of life ( qol ) of patients13,14 and underline the importance of early detection of exacerbations and appropriate therapy . \n the reported frequency of moderate or severe exacerbation is low among japanese patients with copd,1517 and lower than that in other countries.7 however , the frequency , risk factors , and impact of mild exacerbation on copd status in a japanese population of patients with copd have not yet been clarified . \n we have been conducting a multicenter , observational cohort study to longitudinally examine the comorbidities of copd in japan , called the keio copd comorbidity research ( k - ccr ) . \n we recently reported the findings of cross - sectional studies at enrollment showing associations between comorbidities and various aspects of copd.1820 here , we aimed to compare the impact on the health - related qol and pulmonary function between mild exacerbation and moderate or severe exacerbation in japanese patients with copd . \n the reported longitudinal changes in st george s respiratory questionnaire ( sgrq ) categories and their determinants are markedly different between its categories.21 therefore , we hypothesized that such differences would be more markedly seen when patients were classified based on the severity of exacerbation . \n we retrospectively reviewed the medical records of patients with copd to detect the severity of all exacerbation events and applied a robust definition of exacerbation based on symptomatic and treatment criteria . \n an observational cohort study has been established at keio university and affiliated hospitals to prospectively determine the optimal management of copd comorbidities and register the findings with the university hospital medical information network ( umin000003470 ) . \n we enrolled 572 patients between april 2010 and december 2012 , including those who had been diagnosed with copd by pulmonary physicians and those referred for the assessment of possible copd based on symptoms and/or presence of emphysematous changes on computed tomography ( ct ) images as described.18,19 we analyzed only data from patients who had copd confirmed by spirometry , had completed annual examinations and questionnaires , and had visited outpatient clinics at the participating hospitals monthly or bimonthly for regular clinical checkups for 2 years ( n=311 ) . \n the ethics committees of keio university and affiliated hospitals approved the study protocol , and each patient provided written informed consent to analyze and present their data . \n the study conforms in all respects to the declaration of helsinki adopted by the 59th wma general assembly , seoul , korea , october 2008 . \n doctors assessed whether copd symptoms had worsened since the last assessment and required treatment during scheduled appointments or emergency presentation . \n symptoms constituting an exacerbation were identified based on strict criteria adapted from the original definition of previous reports.10,22 independent investigators in the present study retrospectively judged number and severity of exacerbations from reviews of physicians medical records . \n mild copd exacerbation was defined as worsening of symptoms that were self - managed ( by measures such as an increase in salbutamol use ) and resolved without systemic corticosteroids or antibiotics . \n moderate copd exacerbation was defined as a requirement for treatment with systemic corticosteroids or antibiotics or both . \n severe copd exacerbation was defined as hospitalization , including an emergency admission for > 24 hours . \n all patients were clinically stable and without exacerbations for at least 1 month before study enrollment and the day of annual examinations . \n all questionnaires of health status , including all categories of sgrq2325 and the copd assessment test ( cat),26,27 were completed at home while the disease was stable at baseline and then annually thereafter . \n the extent of emphysema was quantified as the ratio of low attenuation area ( laa%)28 and the ratio of airway wall area ( wa%)29 on ct images using custom - made software ( aze ltd . \n , tokyo , japan).19 images of a multipurpose chest phantom n1 ( kyoto kagaku , kyoto , japan ) were acquired at the start of the study to calibrate ct instrument from various manufacturers , which also enabled the assessment of longitudinal changes in laa%.19 comorbid diagnoses were established using clinical history and examination findings based on a review of available medical records as reported previously.18,19 ophthalmological examinations were performed to estimate the prevalence of cataract . \n data were compared between two groups using t - test , mann whitney u - test , and test and among three groups using analysis of variance and the tukey \n the effects of factors on minimal clinical important changes in cat ( cat 2 per year ) were assessed using univariate and multivariate logistic regression analyses.30 differences in levels of cat , sgrq , forced expiratory volume in 1 second ( fev1 ) , laa% , and in rates of change over time among three groups classified according to the severity of exacerbation were estimated using mixed - effects modeling31 with bonferroni correction . \n two - sided p - values of < 0.05 were considered significant for all tests . \n the mixed - effect model was applied using spss 23 ( ibm corporation , armonk , ny , usa ) . \n an observational cohort study has been established at keio university and affiliated hospitals to prospectively determine the optimal management of copd comorbidities and register the findings with the university hospital medical information network ( umin000003470 ) . \n we enrolled 572 patients between april 2010 and december 2012 , including those who had been diagnosed with copd by pulmonary physicians and those referred for the assessment of possible copd based on symptoms and/or presence of emphysematous changes on computed tomography ( ct ) images as described.18,19 we analyzed only data from patients who had copd confirmed by spirometry , had completed annual examinations and questionnaires , and had visited outpatient clinics at the participating hospitals monthly or bimonthly for regular clinical checkups for 2 years ( n=311 ) . \n the ethics committees of keio university and affiliated hospitals approved the study protocol , and each patient provided written informed consent to analyze and present their data . \n the study conforms in all respects to the declaration of helsinki adopted by the 59th wma general assembly , seoul , korea , october 2008 . \n doctors assessed whether copd symptoms had worsened since the last assessment and required treatment during scheduled appointments or emergency presentation . \n symptoms constituting an exacerbation were identified based on strict criteria adapted from the original definition of previous reports.10,22 independent investigators in the present study retrospectively judged number and severity of exacerbations from reviews of physicians medical records . \n mild copd exacerbation was defined as worsening of symptoms that were self - managed ( by measures such as an increase in salbutamol use ) and resolved without systemic corticosteroids or antibiotics . \n moderate copd exacerbation was defined as a requirement for treatment with systemic corticosteroids or antibiotics or both . \n severe copd exacerbation was defined as hospitalization , including an emergency admission for > 24 hours . \n all patients were clinically stable and without exacerbations for at least 1 month before study enrollment and the day of annual examinations . \n all questionnaires of health status , including all categories of sgrq2325 and the copd assessment test ( cat),26,27 were completed at home while the disease was stable at baseline and then annually thereafter . \n the extent of emphysema was quantified as the ratio of low attenuation area ( laa%)28 and the ratio of airway wall area ( wa%)29 on ct images using custom - made software ( aze ltd . \n , tokyo , japan).19 images of a multipurpose chest phantom n1 ( kyoto kagaku , kyoto , japan ) were acquired at the start of the study to calibrate ct instrument from various manufacturers , which also enabled the assessment of longitudinal changes in laa%.19 comorbid diagnoses were established using clinical history and examination findings based on a review of available medical records as reported previously.18,19 ophthalmological examinations were performed to estimate the prevalence of cataract . \n data were compared between two groups using t - test , mann whitney u - test , and test and among three groups using analysis of variance and the tukey \n the effects of factors on minimal clinical important changes in cat ( cat 2 per year ) were assessed using univariate and multivariate logistic regression analyses.30 differences in levels of cat , sgrq , forced expiratory volume in 1 second ( fev1 ) , laa% , and in rates of change over time among three groups classified according to the severity of exacerbation were estimated using mixed - effects modeling31 with bonferroni correction . \n two - sided p - values of < 0.05 were considered significant for all tests . \n the mixed - effect model was applied using spss 23 ( ibm corporation , armonk , ny , usa ) . \n the proportions of patients without exacerbation , with only mild exacerbations , and with moderate or severe exacerbations during the first and second years of follow - up were similar ( 61.7% , 19.0% , and 19.3% vs 68.2% , 14.5% , and 17.4% , respectively , p=0.2029 ) . \n the frequency of moderate or severe exacerbation during follow - up ( events per person per year ) was 0.28 . \n only seven patients , comprising three patients in gold stage ii , three patients in gold stage iii , and one patient in gold stage \n iv , had more than two moderate or severe exacerbations per year . among 59 patients with mild exacerbations during the first year of follow - up , 19 ( 32.2% ) patients also experienced only mild exacerbations during the second year , and among 60 patients with moderate or severe exacerbations during the same period , 24 ( 40.0% ) patients also experienced the same severity of exacerbations during the second year ( figure 1 ) . \n we compared the characteristics among three groups of patients to determine the impact of exacerbation severity on copd status during 2 years of follow - up . \n patients were grouped according to whether they were exacerbation free ( n=154 ) , had only mild exacerbation ( mild exacerbator , n=67 ) , or had at least one moderate or severe exacerbation ( moderate / severe exacerbator ; n=90 ) . \n the ratio of predicted forced expiratory volume in 1 second ( % fev1 ) was significantly lower , and the laa% was higher in the moderate / severe exacerbator compared with the mild exacerbator and exacerbation - free groups at baseline ( % fev1 : 53.3 vs 65.4 and 67.4 , p=0.0006 and p<0.0001 , respectively ; laa% : 20.3 vs 9.0 and 10.6 , p=0.0013 and p=0.0004 , respectively ) . \n table 3 shows that the frequency of some comorbidities differed among the exacerbation - free , mild exacerbator , and moderate / severe exacerbator groups . \n the prevalence of gastroesophageal reflux disease ( gerd ) was higher in the mild exacerbator group than in the exacerbation - free group ( 46.2% vs 30.4% , p=0.0281 ) . \n in contrast , the prevalence of anemia , cataracts , and prostatic hypertrophy was higher in the moderate / severe exacerbator group than in the exacerbation - free group ( anemia : 29.7% vs 17.5% , p=0.0286 ; cataract : 63.6% vs 40.4% , p=0.0044 ; prostatic hypertrophy : 20.7% vs 8.7% , p=0.0100 ) . \n the frequency of cardiovascular disease and depression did not significantly differ among the three groups . \n the fev1 was significantly lower in the moderate / severe exacerbator group than in the mild exacerbator and exacerbation - free groups during follow - up ( p=0.001 and p<0.001 , respectively ) but did not differ between the mild exacerbator and exacerbation - free groups ( p=1.000 ; figure 2 ) . \n the rate of change in fev1 did not differ among the three groups during follow - up ( p=0.5446 ) . \n we analyzed only data from patients who underwent annual ct assessment more than twice and provided comparable quantitative laa% data to determine annual changes in laa% ( n=179 ) . \n the values for laa% and rates of change in laa% did not significantly differ among the three groups during 2 years of follow - up ( p=0.0887 and p=0.3013 , respectively ; figure 3 ) . \n not only did the moderate / severe exacerbator group significantly differ in total cat scores during 2 years of follow - up compared with the exacerbation - free group ( p<0.001 ) , but the mild exacerbator group also exhibited significant difference compared with the exacerbation - free group ( p=0.014 ) . \n there was no difference between mild and moderate / severe exacerbator groups ( figure 4 ) . \n the moderate / severe exacerbator group included seven patients who experienced more than two moderate or severe exacerbations during each year , and their cat scores at baseline were 16.5 ( interquartile range , 5.7528.75 ) . among the eight items comprising cat scores , a significant difference persisted in the respiratory symptom components of cough , sputum , and dyspnea and their activity ( p=0.0002 , p=0.0006 , p<0.0001 , and p=0.0045 , respectively ) . \n we assessed the effect of mild exacerbation on cat scores using multivariate logistic regression analysis that included risk factors that either reached significance or trended toward an association on univariate analysis . \n severe airflow limitation ( % fev1 < 50% ) and mild exacerbation independently advanced the likelihood of cat 2 per year ( p=0.042 and p=0.028 , respectively ; table 4 ) . \n the 2-year follow - up also revealed a significant difference in all categories of sgrq scores between moderate / severe exacerbator groups and exacerbation - free groups ( total , p<0.001 , figure 5 ; symptoms ; p<0.001 , figure 6 ; activity , p<0.001 , figure 7 ; impact , p<0.001 , figure 8) . \n however , the mild exacerbator group exhibited significant difference compared with the exacerbation - free group only in total score and symptoms category of sgrq ( total , p=0.041 , figure 5 ; symptoms ; p=0.002 , figure 6 ; activity , p=0.226 , figure 7 ; impact , p=0.064 , figure 8) . \n the proportions of patients without exacerbation , with only mild exacerbations , and with moderate or severe exacerbations during the first and second years of follow - up were similar ( 61.7% , 19.0% , and 19.3% vs 68.2% , 14.5% , and 17.4% , respectively , p=0.2029 ) . \n the frequency of moderate or severe exacerbation during follow - up ( events per person per year ) was 0.28 . \n only seven patients , comprising three patients in gold stage ii , three patients in gold stage iii , and one patient in gold stage \n among 59 patients with mild exacerbations during the first year of follow - up , 19 ( 32.2% ) patients also experienced only mild exacerbations during the second year , and among 60 patients with moderate or severe exacerbations during the same period , 24 ( 40.0% ) patients also experienced the same severity of exacerbations during the second year ( figure 1 ) . \n we compared the characteristics among three groups of patients to determine the impact of exacerbation severity on copd status during 2 years of follow - up . \n patients were grouped according to whether they were exacerbation free ( n=154 ) , had only mild exacerbation ( mild exacerbator , n=67 ) , or had at least one moderate or severe exacerbation ( moderate / severe exacerbator ; n=90 ) . \n the ratio of predicted forced expiratory volume in 1 second ( % fev1 ) was significantly lower , and the laa% was higher in the moderate / severe exacerbator compared with the mild exacerbator and exacerbation - free groups at baseline ( % fev1 : 53.3 vs 65.4 and 67.4 , p=0.0006 and p<0.0001 , respectively ; laa% : 20.3 vs 9.0 and 10.6 , p=0.0013 and p=0.0004 , respectively ) . \n table 3 shows that the frequency of some comorbidities differed among the exacerbation - free , mild exacerbator , and moderate / severe exacerbator groups . \n the prevalence of gastroesophageal reflux disease ( gerd ) was higher in the mild exacerbator group than in the exacerbation - free group ( 46.2% vs 30.4% , p=0.0281 ) . \n in contrast , the prevalence of anemia , cataracts , and prostatic hypertrophy was higher in the moderate / severe exacerbator group than in the exacerbation - free group ( anemia : 29.7% vs 17.5% , p=0.0286 ; cataract : 63.6% vs 40.4% , p=0.0044 ; prostatic hypertrophy : 20.7% vs 8.7% , p=0.0100 ) . \n the frequency of cardiovascular disease and depression did not significantly differ among the three groups . \n the fev1 was significantly lower in the moderate / severe exacerbator group than in the mild exacerbator and exacerbation - free groups during follow - up ( p=0.001 and p<0.001 , respectively ) but did not differ between the mild exacerbator and exacerbation - free groups ( p=1.000 ; figure 2 ) . \n the rate of change in fev1 did not differ among the three groups during follow - up ( p=0.5446 ) . \n we analyzed only data from patients who underwent annual ct assessment more than twice and provided comparable quantitative laa% data to determine annual changes in laa% ( n=179 ) . \n the values for laa% and rates of change in laa% did not significantly differ among the three groups during 2 years of follow - up ( p=0.0887 and p=0.3013 , respectively ; figure 3 ) . \n not only did the moderate / severe exacerbator group significantly differ in total cat scores during 2 years of follow - up compared with the exacerbation - free group ( p<0.001 ) , but the mild exacerbator group also exhibited significant difference compared with the exacerbation - free group ( p=0.014 ) . \n there was no difference between mild and moderate / severe exacerbator groups ( figure 4 ) . \n the moderate / severe exacerbator group included seven patients who experienced more than two moderate or severe exacerbations during each year , and their cat scores at baseline were 16.5 ( interquartile range , 5.7528.75 ) . among the eight items comprising cat scores , a significant difference persisted in the respiratory symptom components of cough , sputum , and dyspnea and their activity ( p=0.0002 , p=0.0006 , p<0.0001 , and p=0.0045 , respectively ) . \n we assessed the effect of mild exacerbation on cat scores using multivariate logistic regression analysis that included risk factors that either reached significance or trended toward an association on univariate analysis . \n severe airflow limitation ( % fev1 < 50% ) and mild exacerbation independently advanced the likelihood of cat 2 per year ( p=0.042 and p=0.028 , respectively ; table 4 ) . \n the 2-year follow - up also revealed a significant difference in all categories of sgrq scores between moderate / severe exacerbator groups and exacerbation - free groups ( total , p<0.001 , figure 5 ; symptoms ; p<0.001 , figure 6 ; activity , p<0.001 , figure 7 ; impact , p<0.001 , figure 8) . \n however , the mild exacerbator group exhibited significant difference compared with the exacerbation - free group only in total score and symptoms category of sgrq ( total , p=0.041 , figure 5 ; symptoms ; p=0.002 , figure 6 ; activity , p=0.226 , figure 7 ; impact , p=0.064 , figure 8) . \n previous studies have shown that patients with moderate or severe exacerbations have a rapid decline in lung function32,33 and emphysema progression,16 an inferior health - related qol,11 and decreased exercise performance.34 however , the influence of mild exacerbation on qol , lung function , and emphysema has remained unclear . \n this study shows that steady - state cat scores and the symptom component of sgrq remained worse in the mild exacerbator group than in the exacerbation - free group during 2 years of follow - up , although the severity of fev1 did not significantly differ . \n however , mild exacerbations did not change the levels of activity or impact scores of sgrq at steady state . \n the cat and other sgrq scores also remained worse in the moderate / severe exacerbator compared with the exacerbation - free group during 2 years of follow - up , but they were concomitant with a lower fev1 . \n to ascertain , mild exacerbation is limited because perception of the actual symptoms is subjective . \n many studies have tried to establish standardized methods , but some issues have arisen.35,36 independent investigators in this study selected most of the patients with mild copd exacerbation from detailed retrospective reviews of individual clinical records , in which patients reported issues such as having had a common cold since the last consultation with a respiratory physician . \n the physicians then assumed that the health status of the patient had been restored to normal without intervention with antibiotics and/or steroid . \n sometimes , copd exacerbation was objectively judged during an unscheduled primary care assessment or when a patient walked into an emergency center . \n reliability depends on self - reported previous illness that patients need to recall over various periods . \n the investigators were aware of the limitation that the frequency of mild exacerbations might be underestimated because patients might forget episodes if they were very mild or very frequent or when they recognized that reporting was not needed . \n on the other hand , the risk of overestimating exacerbation severity must be minimal because patients report it after understanding the consequences of recovery from such episodes compared with the patient diary approach.14,22 one of the major strengths of this study is the comprehensive assessment of comorbid factors in the k - ccr cohort study , which has been characterized in detail . \n generally , it was reported that comorbidities of conditions , such as cardiac disease,37,38 gerd,39,40 and depression41 are associated with moderate or severe exacerbations . \n however , the frequency of these comorbidities did not significantly differ between moderate / severe exacerbator and exacerbation - free groups in the present study , which could be explained as follows . \n japanese patients with copd have different characteristics , such as more advanced age , lower bmi , emphysema - dominant type,15,42 and a different profile of comorbidities , compared with non - japanese , as well as a lower prevalence of cardiovascular disease and metabolic syndrome and a higher frequency of osteoporosis and malnutrition.18,43 this study finds that symptoms of gerd are associated with mild exacerbations but not with moderate or severe exacerbations . \n thus , gerd might cause mild exacerbations or comorbid gerd could worsen cat and sgrq scores . \n whether or not treatment for gerd contributes to improve these scores in patients with mild exacerbations or decrease the frequency of mild exacerbations should be worth investigating . \n interactions between host factors , bacteria , viruses , and air pollution are thought to exacerbate copd.44 human rhinovirus prevalence and load increased at copd exacerbation and resolved during recovery.45 the etiology might be associated with differences in exacerbation severity . \n our cohort study showed that the current frequency of moderate or severe exacerbations of copd is as low as that found in previous studies of japanese patients with copd1517 and lower than that found in other countries7 and in some recent clinical trials.46,47 this discrepancy could be explained as follows . \n this study includes patients with mild airflow limitation ( gold 1 , 22.2% ) , unlike previous clinical studies that did not recruit such patients . \n our patients were mostly past smokers ( 87.5% ) and were regularly treated with bronchodilators ( 72.3% ) . \n although the reasons for the difference in exacerbation frequency remain to be defined , the difference in the low rate of exacerbation might not be unique to japan , and they might have important implications for clinical trials of exacerbation . \n this study is limited by the short observational period of only 2 years , and the fact that qol scores , lung function , and chest ct images were only monitored annually . a longer follow - up with more frequent measures \n is required to develop a more thorough understanding of the long - term impact of mild exacerbation on the progression of clinical parameters . \n large clinical trials of patients with copd have shown that current treatments have significantly reduced moderate or severe exacerbations46,47 and early intervention also improves outcomes of exacerbations.13,48 however , the effectiveness of such treatments on mild exacerbations remains unknown . \n appropriate intervention for mild exacerbations , as well as moderate or severe ones , would be important for improving outcomes for patients with copd .", "role": "user" }, { "content": "backgroundpatients with copd might not report mild exacerbation . the frequency , risk factors , and impact of mild exacerbation on copd status \n are unknown.objectivesthe present study was performed to compare features between mild exacerbation and moderate or severe exacerbation in japanese patients with copd.patients and methodsan observational copd cohort was designed at keio university and affiliated hospitals to prospectively investigate the management of copd comorbidities . \n this study analyzes data only from patients with copd who had completed annual examinations and questionnaires over a period of 2 years ( n=311).resultsamong 59 patients with mild exacerbations during the first year , 32.2% also experienced only mild exacerbations in the second year . among 60 patients with moderate or severe exacerbations during the first year , 40% also had the same severity of exacerbation during the second year . \n findings of the copd assessment test and the symptom component of the st george s respiratory questionnaire at steady state were worse in patients with mild exacerbations than in those who were exacerbation free during the 2-year study period , although the severity of the ratio of predicted forced expiratory volume in 1 second did not differ between them . \n severe airflow limitation ( the ratio of predicted forced expiratory volume in 1 second < 50% ) and experience of mild exacerbations independently advanced the likelihood of an elevated copd assessment test score to 2 per year.conclusionthe severity of copd exacerbation seemed to be temporally stable over 2 years , and even mild exacerbations adversely impacted the health - related quality of life of patients with copd .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: we tested 2,637 nasopharyngeal swabs or nasal washes ( from patients 1 day to 88 years of age ) submitted to the virology laboratory at st . \n louis children s hospital for routine respiratory virus detection from july 2003 through june 2004 . of these samples , \n 2,263 were from children < 4 years of age ( including 419 newborns ) and 374 were from children > 4 years of age . \n the specimens were extracted with the automated roche magna pure lc extractor and magna pure lc total nucleic acid isolation kit ( roche diagnostics , indianapolis , in , usa ) . for real - time pcr , amplification primers wu - tab02-f 5- tgttgcatccatttgttacattcat-3 and wu - tab03-r 5-gaaagaactgttagacaaatatataggcctta-3 and the minor groove binder probe wu - tab04-pro 5-6famatgtcagcaaattcmgbnfq-3 were used with a commercially available universal taqman real - time pcr master mix and abi 7500 real - time thermocycler ( applied biosystems , foster city , ca , usa ) . \n all wu polyomavirus positive specimens were screened for 17 additional viruses ( influenza a and b ; rsv a and b ; piv 14 ; human metapneumovirus ; adenovirus subgroups b , c , and e ; rhinovirus ; and coronaviruses oc43 , 229e , and nl63 ) by using the eragen multicode - plx respiratory virus panel as described previously ( 1 ) . \n pertinent demographic , historical , and clinical information , when available , was collected by using a standard collection form . \n statistical significance was determined by using 2-tailed fisher exact tests with epi info software version 3.4 ( centers for disease control and prevention , atlanta , ga , usa ) seventy ( 2.7% ) of the 2,637 tested specimens were positive for wu polyomavirus ; 71% of the positive samples were also positive for > 1 other respiratory virus . of the 70 positive samples , 5 were omitted from analysis because of chart unavailability . \n the remaining 65 samples were collected from 60 individual patients ( 5 specimens were serial samples associated with distinct clinical syndromes in 2 immunocompromised patients ) . \n the ethnic breakdown was as follows : 50% african - american , 47% caucasian , 3% other . \n positive specimens were noted for patients 1 day to 15 years of age ( appendix table ) . \n the highest and lowest rates of infection are displayed in the figure , panel a. a ) percentage of samples positive for wu polyomavirus by age group . \n a small peak was observed in july 2003 , and a second small peak was observed in april and may 2004 ( figure , panel b ) . \n wu polyomavirus was the only virus detected in a 1-day - old full - term infant delivered by cesarean section who had been transferred to st . \n they included a 12-year - old with evans syndrome and a 15-year - old with severe combined immunodeficiency syndrome ( both post bone marrow transplant ) and a 14-year - old with end - stage renal disease and asthma . \n the most common clinical findings in the patients with wu polyomavirus are listed in the table . \n the most frequent diagnoses were pneumonia ( 31% ) ( although 40% had positive bacterial cultures ) , bronchiolitis ( 25% ) , and upper respiratory tract infections ( 15% ) . \n we also compared all the measured parameters from the patients who were infected with wu alone to the patients who were co - infected with other viruses . in most cases , no statistically significant differences occurred between the co - infected and wu polyomavirus only patients , except that more co - infected patients than wu polyomavirus only patients had rhinorrhea ( 23/47 vs. 2/18 ; p = 0.005 ) and upper respiratory tract symptoms ( 30/47 vs. 6/18 ; p = 0.049 ) . \n in addition , significantly more children with co - infection than with only wu polyomavirus had prior daycare exposure ( 18/45 vs. 1/15 ; p = 0.02 ) . * \n the cohort of 2,637 samples included several sets of sequential samples taken from the same patient during the course of prolonged illness . in 2 patients , \n the first patient was a 4-year - old girl with hemophagocytic lymphohistiocytosis , who had 4 distinct respiratory specimens that tested positive during a 2-month period . \n her first positive specimen was obtained while she was asymptomatic during admission for a bone marrow transplant in september 2003 . \n a second sample was obtained during a clinic visit for nasal congestion and cough in november 2003 . \n her third sample ( also positive for coronavirus oc43 ) was obtained during an admission 5 days later for pneumonia . \n finally , a fourth sample ( negative for the previously detected coronavirus oc43 ) was taken 7 days later during the same admission after an episode of apnea . \n the second patient was a 16-month - old child with biliary atresia admitted for a liver transplant in september 2003 . \n his blood cultures were now also positive for klebsiella and enterobacter spp . , and his third respiratory sample demonstrated both wu polyomavirus and rhinovirus . \n two weeks later , fever , hypoxia , and increasing secretions developed , with his fourth sample positive only for wu polyomavirus . \n patients infected with wu polyomavirus in this cohort were primarily hospitalized with pneumonia , bronchiolitis , and upper respiratory tract infections . \n one new observation is that multiple respiratory specimens sampled from the same patient over 68 weeks were positive for wu polyomavirus , which suggests that wu polyomavirus may persistently infect humans . \n both patients were immunocompromised , although they were able to clear infections with other viruses ( coronavirus oc43 , rhinovirus , adenovirus ) , which suggests that the continued detection of wu polyomavirus was not due to a completely incapacitated immune system . sequence analysis of a 250-bp fragment of the vp2 gene of wu polyomavirus amplified from multiple samples from the 2 patients showed no sequence polymorphisms between the initial and later samples ( data not shown ) . \n as some sequence variation has previously been reported in this locus ( 1 ) , these data are consistent with the model of persistent infection . \n the detection of wu polyomavirus in the respiratory secretions of a 1-day - old infant suggests that vertical transmission of wu polyomavirus from mother to fetus may occur , although further studies are needed to verify this suggestion . in conclusion , \n a high percentage of coinfection with other respiratory viruses was detected , complicating interpretation of the clinical findings . \n however , wu polyomavirus was the sole virus detected in 20 specimens from patients with respiratory illness , which suggests that it may be a respiratory pathogen . \n finally , the observed persistence of this virus suggests analogy to bk and jc viruses in this regard ( 2 ) . \n ", "role": "user" }, { "content": "wu polyomavirus is a recently described polyomavirus found in patients with respiratory infections . \n of 2,637 respiratory samples tested in st . \n louis , missouri , 2.7% were positive for wu polyomavirus by pcr , and 71% were coinfected with other respiratory viruses . \n persistent human infection with wu polyomavirus is described .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: tuberculosis ( tb ) remains the most widespread and deadly infectious disease worldwide , and it has been recently declared as a great emergency by the world health organization ( who ) . unfortunately , 8.99.9 million new cases of tb were reported in 2008 , while 1.11.7 million human immunodeficiency virus ( hiv)-negative patients died from this disease . \n the factors which are mainly responsible for this evolving incidence are : ( i ) the migration of individuals from regions with high tb incidence to those with low incidence , ( ii ) the increasing number of hiv - positive individuals , and ( iii ) the emergence of multidrug - resistant tb due to unwise use of antibiotics . in a total population of approximately \n 11 million people , the incidence of tb in greece is estimated at 18/100,000 persons and the mortality rate at 2 /100,000 annually [ 24 ] . \n the spread of mycobacterium tuberculosis in the majority of humans is inhibited after the development of an effective immune response . \n interestingly , only a minority of these patients have an identifiable risk factor , such as hiv infection , advanced age , alcohol abuse , chronic corticosteroid therapy , diabetes and poor nutrition / socio - economic status . in the remaining patients , \n studies in twins strongly suggest that host genetic factors play a major role in the susceptibility to development of tb . \n intense efforts are therefore being made to discover any possible genetic factors that may have a role in the host defense system and explain the increased susceptibility to overt m. tuberculosis infection . in 1981 a gene was found in mice that played an essential role in the determination of resistance to mycobacteria and other intracellular pathogens . \n the human homologue of the nramp1 gene , designated nramp1 , now known as slc11a1 , is located on the long arm of chromosome 2 ( 2q35 ) . \n nramp1 protein seems to play an important role in regulation of cytoplasmic cation levels , especially iron . \n iron is an essential mycobacterial nutrient , and has a major role in generating reactive oxygen and nitrogen intermediates in macrophages ; hence , it affects the intracellular growth of mycobacteria . \n although it was believed that the gene is expressed solely in reticuloendothelial cells , it was recently shown to be expressed in cd11c dendritic cells , and exerts its pleiotropic effects on cytokine transcription , major histocompatibility complex ( mhc ) class ii molecule expression , and presentation of protein antigens to t lymphocytes . \n the possible association of nramp1 polymorphisms with susceptibility to development of tb has been studied in different countries . \n a case - control study , conducted in west africans , showed a positive association of the gene with pulmonary tb . \n a similar study , conducted in koreans , detected a significant association for the 3utr polymorphism , but not for the int4 locus . on the other hand , \n studies conducted in denmark , mexico , morocco , japan , brazil and china suggested that the gene is not associated with an increased risk for developing tb [ 1517 ] . in a study conducted in the chinese population , \n nramp1 allelic polymorphisms at the int4 and d543n loci were each significantly associated with severe forms of pulmonary tb . \n the aim of the present study was to explore the association between nramp1 polymorphisms and the susceptibility to develop active pulmonary tb after a latent m. tuberculosis infection , in the greek population . \n the inclusion criteria for the patients group were : ( i ) greek origin ; ( ii ) all patients should be genetically unrelated ; and ( iii ) diagnosis of pulmonary tb based on suggestive radiological findings , a microscopic examination of sputum smears from an experienced microscopist , and documented in all patients with the presence of positive sputum cultures for m. tuberculosis infection . \n the exclusion criteria for the patients group were : ( i ) presence of extrapulmonary tb ; ( ii ) patients known to have an hiv infection were not recruited ( all the other patients who agreed to participate were screened for hiv antibodies and hiv - positive patients were not enrolled in the study ) ; and ( iii ) presence of any immunodeficiency syndrome or systemic disease . \n a 5 ml blood sample was drawn from 142 greek patients with pulmonary tb who were hospitalized in the sotiria general hospital of thoracic diseases from january 2004 until december 2008 . \n the ethics committee of sotiria general hospital , athens , greece , accepted the study protocol . \n currently , in the athens area of greece , sotiria general hospital of thoracic diseases is the health institution where the majority of tb cases are diagnosed and monitored . \n the sample size was considered to be adequate for the study , taking into consideration the size of the greek population and the incidence of tb in greece . moreover , during the study period , cases of pulmonary tb were diagnosed , but were excluded from the study because most of these tb cases were diagnosed in immigrants of foreign origin and due to the patient s co - morbidities . \n the inclusion criteria for the control group were : ( i ) ethnically matched volunteers who visited sotiria hospital for a routine check - up ; and ( ii ) the presence of a latent m. tuberculosis infection . \n latent m. tuberculosis infection was defined as a positive tuberculin skin and at least 2 negative sputum cultures , combined with the absence of suggestive radiological findings for pulmonary tb . \n , healthy subjects who visited sotiria hospital for a routine check - up were enrolled . \n a 5 ml blood sample was drawn from every healthy volunteer , and was handled identically to the patients group . in all controls \n specifically , 0.1 ml of purified protein derivative ( ppd ) , which contained 5 tuberculin units , was injected intradermally in the volar surface of the forearm . \n the transverse width of induration in millimetres ( mm ) at the skin test site was measured after 4872 hours . \n a positive tuberculin skin test was defined as skin transverse width 12 mm . in all of the controls enrolled , a chest - x - ray ( cxr ) and sputum cultures for m. tuberculosis \n one hundred forty - four ethnically matched volunteers with latent m. tuberculosis infection were included . \n the exclusion criteria for the control group were : ( i ) hiv - positive subjects ; ( ii ) history of prior tb ; ( iii ) evidence of current or prior tb in the cxr ; and ( iv ) presence of any immunodeficiency syndrome or systemic disease . \n the kit used for the extraction was purelink genomic dna kit catalog no.s k1820 - 01 , k1820 - 02 , k1821 - 04 , from invitrogen . \n the nramp1 polymorphisms typed were : ( i ) a single - nucleotide change in intron 4 ( int4 ) ( 469 + 14g / c ) ; ( ii ) d543n , a non - conservative single - base substitution at codon 543 , which changes aspartic acid to asparagine ; and ( iii ) 3utr , a tgtg deletion in the 3untralsated region ( 1729 + 55del4 ) . \n the pcr primers for the int4 polymorphism were 5ctctggctgaaggctctcc3 and 5tgtgctatcagttgagcctc3. the primers for d543n and 3utr were 5gcatctccccaattcatggt3 and 5aactgtcccactctatcctg3 , respectively . \n real - time pcr studies were performed in a lightcycler 480 instrument , roche . for each of the 3 polymorphisms analyzed , \n a lightsnip kit was designed from the constructor company , tib - molbiol , germany . \n the pcr reaction mixture contained 14.410.4 l pcr grade h20 , 1.0 l reagent mix 2.0 l lightcycler faststart dna master hyprobe 1.6 l mgcl2 and 1.05.0 l dna template . \n initially , variants at 3 polymorphisms ( 3 utr , int4 , d543n ) in the nramp1 gene were compared between tuberculosis cases and controls with fisher s exact test . to assess the differences in demographic characteristics , we used chi - square ( for categorical data ) and t test ( for continuous data ) . \n deviations from hardy - weinberg equilibrium ( hwe ) were assessed using the chi - square test . \n subsequently , the 3 nramp1 polymorphisms were each independently associated with tuberculosis through logistic regression analysis after adjustment for age and sex . \n the sas statistical package ( version 9.1 , sas institute inc , cary , nc ) was used to analyze the data . \n the inclusion criteria for the patients group were : ( i ) greek origin ; ( ii ) all patients should be genetically unrelated ; and ( iii ) diagnosis of pulmonary tb based on suggestive radiological findings , a microscopic examination of sputum smears from an experienced microscopist , and documented in all patients with the presence of positive sputum cultures for m. tuberculosis infection . \n the exclusion criteria for the patients group were : ( i ) presence of extrapulmonary tb ; ( ii ) patients known to have an hiv infection were not recruited ( all the other patients who agreed to participate were screened for hiv antibodies and hiv - positive patients were not enrolled in the study ) ; and ( iii ) presence of any immunodeficiency syndrome or systemic disease . \n a 5 ml blood sample was drawn from 142 greek patients with pulmonary tb who were hospitalized in the sotiria general hospital of thoracic diseases from january 2004 until december 2008 . \n the ethics committee of sotiria general hospital , athens , greece , accepted the study protocol . \n currently , in the athens area of greece , sotiria general hospital of thoracic diseases is the health institution where the majority of tb cases are diagnosed and monitored . \n the sample size was considered to be adequate for the study , taking into consideration the size of the greek population and the incidence of tb in greece . moreover , during the study period , cases of pulmonary tb were diagnosed , but were excluded from the study because most of these tb cases were diagnosed in immigrants of foreign origin and due to the patient s co - morbidities . \n the inclusion criteria for the control group were : ( i ) ethnically matched volunteers who visited sotiria hospital for a routine check - up ; and ( ii ) the presence of a latent m. tuberculosis infection . \n latent m. tuberculosis infection was defined as a positive tuberculin skin and at least 2 negative sputum cultures , combined with the absence of suggestive radiological findings for pulmonary tb . \n , healthy subjects who visited sotiria hospital for a routine check - up were enrolled . \n a 5 ml blood sample was drawn from every healthy volunteer , and was handled identically to the patients group . in all controls \n specifically , 0.1 ml of purified protein derivative ( ppd ) , which contained 5 tuberculin units , was injected intradermally in the volar surface of the forearm . \n the transverse width of induration in millimetres ( mm ) at the skin test site was measured after 4872 hours . \n a positive tuberculin skin test was defined as skin transverse width 12 mm . in all of the controls enrolled , a chest - x - ray ( cxr ) and sputum cultures for m. tuberculosis \n one hundred forty - four ethnically matched volunteers with latent m. tuberculosis infection were included . \n the inclusion criteria for the patients group were : ( i ) greek origin ; ( ii ) all patients should be genetically unrelated ; and ( iii ) diagnosis of pulmonary tb based on suggestive radiological findings , a microscopic examination of sputum smears from an experienced microscopist , and documented in all patients with the presence of positive sputum cultures for m. tuberculosis infection . \n the exclusion criteria for the patients group were : ( i ) presence of extrapulmonary tb ; ( ii ) patients known to have an hiv infection were not recruited ( all the other patients who agreed to participate were screened for hiv antibodies and hiv - positive patients were not enrolled in the study ) ; and ( iii ) presence of any immunodeficiency syndrome or systemic disease . \n a 5 ml blood sample was drawn from 142 greek patients with pulmonary tb who were hospitalized in the sotiria general hospital of thoracic diseases from january 2004 until december 2008 . \n the ethics committee of sotiria general hospital , athens , greece , accepted the study protocol . \n currently , in the athens area of greece , sotiria general hospital of thoracic diseases is the health institution where the majority of tb cases are diagnosed and monitored . \n the sample size was considered to be adequate for the study , taking into consideration the size of the greek population and the incidence of tb in greece . moreover , during the study period , cases of pulmonary tb were diagnosed , but were excluded from the study because most of these tb cases were diagnosed in immigrants of foreign origin and due to the patient s co - morbidities . \n the inclusion criteria for the patients group were : ( i ) greek origin ; ( ii ) all patients should be genetically unrelated ; and ( iii ) diagnosis of pulmonary tb based on suggestive radiological findings , a microscopic examination of sputum smears from an experienced microscopist , and documented in all patients with the presence of positive sputum cultures for m. tuberculosis infection . \n the exclusion criteria for the patients group were : ( i ) presence of extrapulmonary tb ; ( ii ) patients known to have an hiv infection were not recruited ( all the other patients who agreed to participate were screened for hiv antibodies and hiv - positive patients were not enrolled in the study ) ; and ( iii ) presence of any immunodeficiency syndrome or systemic disease . \n a 5 ml blood sample was drawn from 142 greek patients with pulmonary tb who were hospitalized in the sotiria general hospital of thoracic diseases from january 2004 until december 2008 . \n the ethics committee of sotiria general hospital , athens , greece , accepted the study protocol . \n currently , in the athens area of greece , sotiria general hospital of thoracic diseases is the health institution where the majority of tb cases are diagnosed and monitored . \n the sample size was considered to be adequate for the study , taking into consideration the size of the greek population and the incidence of tb in greece . moreover , during the study period , cases of pulmonary tb were diagnosed , but were excluded from the study because most of these tb cases were diagnosed in immigrants of foreign origin and due to the patient s co - morbidities . \n the inclusion criteria for the control group were : ( i ) ethnically matched volunteers who visited sotiria hospital for a routine check - up ; and ( ii ) the presence of a latent m. tuberculosis infection . \n latent m. tuberculosis infection was defined as a positive tuberculin skin and at least 2 negative sputum cultures , combined with the absence of suggestive radiological findings for pulmonary tb . \n , healthy subjects who visited sotiria hospital for a routine check - up were enrolled . \n a 5 ml blood sample was drawn from every healthy volunteer , and was handled identically to the patients group . in all controls \n specifically , 0.1 ml of purified protein derivative ( ppd ) , which contained 5 tuberculin units , was injected intradermally in the volar surface of the forearm . \n the transverse width of induration in millimetres ( mm ) at the skin test site was measured after 4872 hours . \n a positive tuberculin skin test was defined as skin transverse width 12 mm . in all of the controls enrolled , a chest - x - ray ( cxr ) and sputum cultures for m. tuberculosis \n one hundred forty - four ethnically matched volunteers with latent m. tuberculosis infection were included . \n the inclusion criteria for the control group were : ( i ) ethnically matched volunteers who visited sotiria hospital for a routine check - up ; and ( ii ) the presence of a latent m. tuberculosis infection . \n latent m. tuberculosis infection was defined as a positive tuberculin skin and at least 2 negative sputum cultures , combined with the absence of suggestive radiological findings for pulmonary tb . \n , healthy subjects who visited sotiria hospital for a routine check - up were enrolled . \n a 5 ml blood sample was drawn from every healthy volunteer , and was handled identically to the patients group . in all controls \n specifically , 0.1 ml of purified protein derivative ( ppd ) , which contained 5 tuberculin units , was injected intradermally in the volar surface of the forearm . \n the transverse width of induration in millimetres ( mm ) at the skin test site was measured after 4872 hours . \n a positive tuberculin skin test was defined as skin transverse width 12 mm . in all of the controls enrolled , a chest - x - ray ( cxr ) and sputum cultures for m. tuberculosis \n one hundred forty - four ethnically matched volunteers with latent m. tuberculosis infection were included . \n the exclusion criteria for the control group were : ( i ) hiv - positive subjects ; ( ii ) history of prior tb ; ( iii ) evidence of current or prior tb in the cxr ; and ( iv ) presence of any immunodeficiency syndrome or systemic disease . \n dna samples were extracted from human whole blood collected into tubes containing edta . the kit used for the extraction was purelink genomic dna kit catalog no.s k1820 - 01 , k1820 - 02 , k1821 - 04 , from invitrogen . \n the nramp1 polymorphisms typed were : ( i ) a single - nucleotide change in intron 4 ( int4 ) ( 469 + 14g / c ) ; ( ii ) d543n , a non - conservative single - base substitution at codon 543 , which changes aspartic acid to asparagine ; and ( iii ) 3utr , a tgtg deletion in the 3untralsated region ( 1729 + 55del4 ) . \n the pcr primers for the int4 polymorphism were 5ctctggctgaaggctctcc3 and 5tgtgctatcagttgagcctc3. the primers for d543n and 3utr were 5gcatctccccaattcatggt3 and 5aactgtcccactctatcctg3 , respectively . \n real - time pcr studies were performed in a lightcycler 480 instrument , roche . for each of the 3 polymorphisms analyzed , \n a lightsnip kit was designed from the constructor company , tib - molbiol , germany . \n the pcr reaction mixture contained 14.410.4 l pcr grade h20 , 1.0 l reagent mix 2.0 l lightcycler faststart dna master hyprobe 1.6 l mgcl2 and 1.05.0 l dna template . \n initially , variants at 3 polymorphisms ( 3 utr , int4 , d543n ) in the nramp1 gene were compared between tuberculosis cases and controls with fisher s exact test . to assess the differences in demographic characteristics , we used chi - square ( for categorical data ) and t test ( for continuous data ) . \n deviations from hardy - weinberg equilibrium ( hwe ) were assessed using the chi - square test . \n subsequently , the 3 nramp1 polymorphisms were each independently associated with tuberculosis through logistic regression analysis after adjustment for age and sex . \n the sas statistical package ( version 9.1 , sas institute inc , cary , nc ) was used to analyze the data . \n all patients who were enrolled had a culture - positive pulmonary tb , combined with suggestive radiological findings . \n positive acid - fast bacilli ( afb ) sputum smear for m. tuberculosis was observed in 108 ( 76% ) patients ; the remaining 34 ( 24% ) patients had a negative afb smear test . \n the demographic characteristics and the frequency of the 3 nramp1 polymorphisms ( 3utr , d543n , int4 ) between patients and controls are shown in table 1 . \n there was no evidence for deviation from hwe regarding the polymorphisms d543n ( p=0.07 ) and int4 ( p=0.08 ) , whereas the 3 utr ( p=29.11 ) was found to deviate significantly from hwe . \n the nramp1 allelic frequencies for the d543n and 3utr variants were not found to differ significantly between patients with pulmonary tb and controls . \n d543n associated g / g and g / a variants were observed in 138 and 4 samples in the patients group , respectively . in controls , d543n - associated g / g and g / a genotypes \n the genotype a / a was absent in both groups . in the patients group , \n the 3utr - associated tgtg / tgtg , tgtg / del and del / del variants were observed in 137 , 4 and 1 sample , respectively . in the control group , \n the numbers of samples with positive 3utr variants were 139 , 4 and 1 sample , respectively . \n however , we identified an increased incidence of int4 polymorphism in the patients group compared to the control group , which was close to the borderline of statistical significance ( p=0.058 ) . \n three separate logistic regression analyses were performed , after adjustment for age and sex , in order to further investigate the possible association of tb patients with the allelic frequencies of the 3 nramp1 polymorphisms ( table 2 ) . \n no significant association was found in patients with pulmonary tb for the d543n and 3utr allele variants . \n specifically , when gg allele genotype was used as baseline value , cc homozygotes were found to be at higher risk for developing pulmonary tb ( or=7.31 , 95% ci : 1.3340.17 , p=0.022 ) . \n a more detailed analysis was performed by creating 8 categories of genotype combinations : g / tgtg / g , g / tgtg / c , g / del / g , a / del / g , a / tgtg / g , g / del / c , a / tgtg / c and a / del / c ( table 3 ) . \n significant differences among the frequencies between patients and controls were found regarding g / tgtg / g and g / tgtg / c genotype combinations \n . specifically , lower expression of g / tgtg / g combination ( p=0.005 ) was found in the patients group compared to the control group , while higher expression of the g / tgtg / c combination ( p=0.004 ) was found in the patients group compared to the controls . from a total of 8 genotype combinations , 5 ( g / tgtg / g \n , g / tgtg / c , g / del / g , a / del / g , a / tgtg / g ) were included in a multivariate model ( table 4 ) . \n the remaining 3 combinations ( g / del / c , a / tgtg / c , a / del / c ) were excluded because of their extremely low frequencies . \n g / tgtg / c was found to be associated with a 36% higher risk for developing pulmonary tb ( or=1.36 ; 95% ci : 1.111.66 ; p=0.004 ) compared to the baseline expression of g / tgtg / g . \n an association between pulmonary tb and g / del / g , a / del / g and a / tgtg / g genotype combinations , compared to the baseline expression of g / tgtg / g , was not observed . \n to our knowledge this is the first study in greece that examines the possible association of nramp1 polymorphisms and the susceptibility to develop culture - positive pulmonary tb . \n our study demonstrated that there was not any significant difference in the incidence of nramp1 d543n and 3utr polymorphisms between patients with pulmonary tb and ethnically matched healthy controls having latent m. tuberculosis infection . \n an increased incidence of int4- nramp1 polymorphism was found in the patients group , which was close to the borderline of statistical significance . \n a positive association of 3utr variant allele and the susceptibility to develop tb was reported in a small caucasian population . however , several studies performed in european populations suggested no statistically significant association between nramp1 polymorphisms and the susceptibility to develop tb . \n this was also confirmed in the biggest meta - analysis of published trials to date . in this analysis , \n the odds ratios ( ors ) among 3utr , d543n , int4 locus and tb susceptibility , in the european population , were 1.81 ( 95%ci : 0.664.93 ; p=0.25 ) , 1.88 ( 95%ci : 0.754.67 ; p=0.18 ) and 0.87 ( 95%ci : 0.611.22 ; p=0.41 ) , respectively . \n it is believed that the european origin population has a high level of genetical resistance to m. tuberculosis infection , due to natural selection over the last 300 years . \n the lower proportion of tb cases in the european population , compared to asian and african populations , could be another reason for the lack of association . \n we found a lack of correlation among d543n and 3utr nramp1 polymorphisms and an increased susceptibility to develop pulmonary tb , according to results of the majority of studies in european populations . \n although our results are close to statistical significance , there is a trend for a higher incidence of int4-nramp1 polymorphism in patients with pulmonary tb , compared to ethnically matched volunteers with latent m. tuberculosis infection . \n this possible association appears for the first time in a european population , and can be possibly attributed to the diverse genetic background among various ethnic populations of the same descent . \n specifically , the int4-nramp1 polymorphism can be found in approximately 20% of the chinese population , whereas the frequency in white europeans is about 50% , with significant variation among different european populations . \n the int4-cc homozygotes variants were found to have an increased risk for developing pulmonary tb , compared to their corresponding common gg alleles . when a more detailed analysis was performed by creating 8 categories of genotype combinations , higher expression of g / tgtg / c combination ( p=0.004 ) was found in the patient s group as compared to the controls . \n this combination was associated with a 36% higher risk for developing pulmonary tb ( or=1.36 ; 95% ci : 1.111.66 ; p=0.004 ) compared to the baseline expression of g / tgtg / g . \n however , the limited number of patients and controls found to carry the int4-cc genotype must be taken into consideration in the interpretation of our results . whether the incidence of int4-cc variant or any nramp1 genotype combination is correlated to the development of active disease \n most of the studies exploring the possible role of nramp1 polymorpisms in the development of tb did not distinguish between susceptibility to infection with m. tuberculosis and susceptibility to progression to active disease , since the control groups consisted of healthy volunteers without active disease . \n our study design distinguishes between susceptibility to infection with m. tuberculosis and susceptibility to progression in an active m. tuberculosis pulmonary disease . \n all volunteers in the control group had a latent m. tuberculosis infection without developing the disease . \n this fact suggests that int4-nramp1 polymorphisms may have a role in the development of overt pulmonary disease after a latent m. tuberculosis infection . the main limitations of our study are the lack of data in both study groups that can be associated with a higher risk of developing pulmonary tb ( alcohol abuse , chronic corticosteroid therapy , diabetes , poor nutrition / socio - economic status ) , and the relatively small sample size of the population enrolled . \n int4-nramp1 polymorphism may be associated with a higher rate of culture - positive pulmonary tb in the greek population compared to ethnically matched healthy controls with latent m. tuberculosis infection . \n a lack of association was observed for the other 2 nramp1 polymorphisms ( d543n , 3utr ) . \n an increased incidence of g / tgtg / c genotype combination was found in the patients group compared to controls . \n g / tgtg / c genotype combination was associated with a 36% higher risk for developing pulmonary tb compared to the baseline expression of g / tgtg / g genotype combination . \n the possible role of int4-nramp1 polymorphism in the development of active pulmonary tb , after an initial latent m. tuberculosis infection , needs further investigation .", "role": "user" }, { "content": "summarybackgroundample evidence suggests that host genetic factors affect human susceptibility to tuberculosis . the natural resistance associated macrophage protein 1 ( nramp1 ) gene seems to play a role in the pathophysiology of a number of intracellular infections , including mycobacteria . \n a case - control study was conducted in the greek population to determine whether nramp1 polymorphisms affect the susceptibility to development of overt pulmonary tuberculosis.material/methodsnramp1 polymorphisms ( 3utr , d543n , int4 ) were evaluated among 142 patients with culture - positive pulmonary tuberculosis and 144 ethnically matched healthy controls having latent m. tuberculosis infection . \n patients with human immunodeficiency virus infection were excluded.resultsout of the 3 nramp1 polymorphisms , a trend of increased incidence of int4 polymorphism was found in the patients group compared to the control group . \n a lack of association was observed between the 2 groups as far as the other 2 polymorphisms ( d543n , 3utr ) are concerned . \n int4-cc homozygotes were found to have a higher risk to develop pulmonary tuberculosis compared to gg homozygotes ( p=0.022 ) . \n an increased incidence g / tgtg / c genotype combination was found in the patients group as compared to controls . \n g / tgtg / c genotype combination was associated with a 36% higher risk of developing pulmonary tuberculosis ( p=0.004 ) compared to the baseline expression of g / tgtg / g combination.conclusionsint4-nramp1 polymorphism may have a role in the development of culture - positive pulmonary tuberculosis after an initial m. tuberculosis latent infection . \n the possible role of int4-nramp1 polymorphism in the development of active pulmonary tuberculosis needs further investigation .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: every year , more than one million cases of scorpion stings are reported in the world ( 1 ) . \n most of these cases are reported in mexico , tunisia , and brazil ( 2 ) . \n the hemiscorpius genus of scorpions is distributed throughout asia ( iran , iraq , oman , pakistan , saudi arabia , yemen , and the united arab emirates ) and africa ( eritrea , somalia , and egypt ) ( 37 ) . in iran , \n about 40,000 to 50,000 scorpion sting cases are reported annually , resulting in about 19 deaths ( 8) . to date , 1,500 species of scorpions have been identified throughout the world , and about 50 of these species can be dangerous to humans . \n these 50 species include androctonus , buthus , mesobuthus , tityus , leiurus , and hemiscorpius ( 9 ) . \n the scorpion s venom contains various toxins , including neurotoxin , cardiotoxin , nephrotoxin , and hemolytic toxin ( 14 ) . \n children and elderly patients are at increased risk of complications from scorpion envenomation ( 15 ) . \n it is well known that the potent cytotoxin , venom in h. lepturus , causes cutaneous necrosis , necrotic ulcers , psychological problems , ankylosis of the joints , hemoglubinuria , fatal haemolysis , hematuria , renal failure , and even death ( 9 , 11 , 12 , 1618 ) . in southern \n this paper presents and discusses the first report of death as a result of h. acanthocercus envenomation in a 15-year - old male in southern iran . \n a 15-year - old male resident of a rural area in the bandar abbas district in southern iran was stung by an h. acanthocercus scorpion on his right arm ( figure 1 ) , and he was admitted to the hospital 12 hours later due to weakness , fever , chills , and pain at the site of the sting . \n the patient was conscious at the time of admission , and he was not ill , icteric . on the first day , \n the clinical signs included fever , lethargy , abdominal pain , chills , active bleeding , and hematuria . \n the patient s vital signs were bp ( 115/75 mm hg ) , pr 68/min , rr ( 18/min ) , and body temperature ( 39.5 c ) ; his heart and lung functions were normal . \n erythema and local necrosis were observed at the site of the sting . on the second day after admission \n , the patient s fever increased to 40 c , and active bleeding and hematuria continued . \n on the third day , there was no change in the clinical status of the patient . \n table 1 provides the results of the patient s laboratory tests . on the second day , his data showed increases in ptt ( 56 sec ) , wbc ( 2410/l ) , urea ( 86 mg / dl ) , creatinine ( 2.1 mg / dl ) , sgot ( 240 \n u / l ) , sgpt ( 180 u / l ) , total and direct bilirubin ( 9 and 2 mg / dl , respectively ) , and there were decreases in his rbc ( 2.8310/l ) , hgb ( 8.8 g / dl ) , and plt ( 2010/l ) . \n the patient also received 400 mg of ciprofloxacin twice a day and 600 mg of clindamycin three times a day for treatment of cellulitis . \n also , intravenous paracetamol was used to control the patient s fever , and he received fresh frozen plasma ( ffp ) , platelets , and cryoprecipitate for correction of coagulation factors . in spite of these treatments , the patients died due to his impaired coagulation status and hemodynamic status . \n a 15-year - old male resident of a rural area in the bandar abbas district in southern iran was stung by an h. acanthocercus scorpion on his right arm ( figure 1 ) , and he was admitted to the hospital 12 hours later due to weakness , fever , chills , and pain at the site of the sting . \n the patient was conscious at the time of admission , and he was not ill , icteric . on the first day , \n the clinical signs included fever , lethargy , abdominal pain , chills , active bleeding , and hematuria . \n the patient s vital signs were bp ( 115/75 mm hg ) , pr 68/min , rr ( 18/min ) , and body temperature ( 39.5 c ) ; his heart and lung functions were normal . \n erythema and local necrosis were observed at the site of the sting . on the second day after admission \n , the patient s fever increased to 40 c , and active bleeding and hematuria continued . \n on the third day , there was no change in the clinical status of the patient . \n table 1 provides the results of the patient s laboratory tests . on the second day , his data showed increases in ptt ( 56 sec ) , wbc ( 2410/l ) , urea ( 86 mg / dl ) , creatinine ( 2.1 mg / dl ) , sgot ( 240 u / l ) , sgpt ( 180 u / l ) , total and direct bilirubin ( 9 and 2 mg / dl , respectively ) , and there were decreases in his rbc ( 2.8310/l ) , hgb ( 8.8 g / dl ) , and plt ( 2010/l ) . \n the patient also received 400 mg of ciprofloxacin twice a day and 600 mg of clindamycin three times a day for treatment of cellulitis . \n also , intravenous paracetamol was used to control the patient s fever , and he received fresh frozen plasma ( ffp ) , platelets , and cryoprecipitate for correction of coagulation factors . in spite of these treatments , the patients died due to his impaired coagulation status and hemodynamic status . \n h. lepturus envenomation has resulted in a significant number of mortalities in iran ( 19 , 20 ) . \n the hemiscorpius scorpion s sting does not cause immediate or severe pain ( 1 , 19 ) , so most people who are stung do not get medical care . the delay in seeking medical care may be due to the fact that there are few early symptoms associated with h. lepturus envenomation , and those that do occur are mild ( 18 ) . \n the patient did not seek medical care until 12 days after envenomation , and by that time he had developed severe complications . \n the severe symptoms of envenomation caused by h. lepturus venom in children are attributable to their low body mass and their limited physiological reserves ( 19 ) . \n very severe renal complications have been observed in children who had not sought medical care ( 21 ) . in rahmani & jalali s study , \n all patients who died also had been stung by h. lepturus scorpions and sought medical care days later ( 18 ) , as was the case for the patient in our study . \n h. lepturus venom causes various symptoms , such as macular erythema , necrosis , ulcers , fever , and others ( 22 ) . \n the clinical symptoms caused by h. acanthocercus envenomation were similar to those of h. lepturus . \n studies have shown that hemiscorpius venom is highly cytotoxic and can cause cutaneous necrosis , severe hemolysis , hematuria , renal failure , and death ( 18 , 23 ) , and our observations in the case in question were similar to the findings of those studies . \n table 1 shows laboratory findings that indicate the changes in a patient s hematology and biochemistry parametrics as the result of being stung by an h. acanthocercus scorpion . \n these data were in good agreement with the findings of other similar studies in iran ( 10 , 16 , 18 , 2426 ) . \n the most severe hemoglobinuria , i.e. , + 4 , that has been observed in people stung by h. lepturus scorpions was reported in mohseni s study ( 27 ) . \n other studies has shown a rapid reduction in the level of hct with acute hemolysis among patients who were referred to hospital emergency departments ( 16 , 28 ) . \n in addition , emam s report indicated that the measurement of hematologic parameters , such as ptt , hb , rbc , and plt , was important because they are important indicators in patients who have been stung by h. lepturus scorpions ( 29 ) . \n in contrast to the above results , the results of mohseni s study indicated that the ptt and pt factors were not important indices in cases involving scorpion stings ( 27 ) . \n dehghani showed that the venom from the h. lepturus scorpion causes an increase in wbc count ( 30 ) . \n the results of hematology tests and urine analyses in this case were similar to the above results . \n the results of this report showed that , when people are stung by hemiscorpius scorpions , their laboratory test results change , including the results associated with hematology , biochemistry , and urine analysis . therefore these tests can be useful in the early detection and treatment of victims . \n the specific anti - venin made by the razi vaccine and serum research institute is a polyvalent antivenom ( 5-ml ampoule ) against six species of scorpions , i.e. , h. lepturus , androctonus crassicauda , mesobuthus eupeus , odonthobothus doriae , hottentotta saulcyi and hottentotta zagrozensis ( 31 ) . in iran , \n the current treatment of patients who have been stung by h. lepturus is the intravenous ( iv ) or intramuscular ( i m ) injection of anti - venom ( 12 ) . \n the specific polyvalent anti - venom injection as early as possible after the sting is fundamentally important with respect to the effectiveness of the anti - venom ( 19 ) . in severe cases following envenomation , \n death can occur as a result of delaying the administration of the anti - venom , especially in children and elderly patients ( 32 ) . \n the venom of h. acanthocercus such as h. lepturus venom represents serious clinical symptom such as hemoglobinuria , proteinuria , hematuria , hemolysis of blood cells and increased creatinine excretion . \n urine analysis , hematology and biochemistry data are the most important factors in the follow - up of scorpion victims . \n this report showed that the anemia and hemoglobinuria in patients who stung by hemiscorpius scorpions should be considered . \n finally , the results of this report indicate that h. acanthocercus is one of the most dangerous scorpions in south of iran . \n further studies are recommended due to lack of sufficient information on the toxicology of these scorpions done .", "role": "user" }, { "content": "scorpion stings are significant causes of death in the western and southern regions of iran . to date \n , reports have indicated that the h. lepturus species is the main cause of mortality due to scorpion stings . \n one of the species that belongs to this genus is hemiscorpius acanthocercus ( h. acanthocercus ) . \n this scorpion s venom is cytotoxic , and it causes pathological changes in the blood and can cause severe damage to the kidneys . \n the pain of hemiscorpius sting is mild and asymptomatic in the early hours . \n delays in the treatment of these victims can cause hemolysis , hematuria , kidney failure , and even death . in this paper , we report the first known death due to an h. acanthocercus sting in iran .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: hypertension is a major risk factor for cardiovascular ( cv ) and cerebrovascular morbidity and mortality . \n achieving blood pressure ( bp ) goal rapidly , as well as sustaining this level of control , is important to reduce cv risk and prevent organ damage . \n treatment guidelines generally recommend treatment of hypertension with a bp goal < 140/90 mm hg for the majority of patients . \n more aggressive targets of < 130/80 mm hg in patients with diabetes or renal disease have also been suggested [ 3 , 4 ] , although such low bp targets have been recently questioned following inconclusive results from several trials [ 2 , 57 ] . despite these recommendations , less than one - third of patients taking hypertensive treatment \n reach the desired goal of < 140/90 mm hg , and many of these will be taking only one antihypertensive agent . combining two drugs from different classes with complementary mechanisms of action \n is likely to result in additional reductions in bp compared with either agent used alone [ 9 , 10 ] . \n for this reason and based upon evidence from many antihypertensive studies , most guidelines agree that the majority of patients need combination therapy to achieve bp goals , and so initial combination therapy is now more frequently recommended [ 3 , 4 , 11 , 12 ] . \n single - pill combinations ( spcs ) can also help overcome the poor treatment adherence that has been associated with free combination therapies with multiple antihypertensive agents , administered at different time intervals , and , therefore , patients are more likely to reach and maintain their bp goal and reduce their cv risk . \n a calcium channel blocker ( ccb ) combined with a renin - angiotensin system ( ras ) inhibitor ( such as an angiotensin ii receptor blocker [ arb ] or an angiotensin - converting enzyme inhibitor ) is one such complimentary combination . \n indeed , based on outcomes from the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension ( accomplish ) trial , in which a ras inhibitor / ccb was superior to a ras inhibitor / diuretic , this combination was particularly effective in reducing cv risk and is recommended by guidelines [ 3 , 4 , 12 ] . \n telmisartan is the longest acting of all arbs with a half - life of 24 hours and has been shown to reduce cv risk , leading to an indication for the reduction of cv morbidity in patients with manifest atherothrombotic cv disease ( history or coronary heart disease , stroke , or peripheral arterial disease ) or type 2 diabetes mellitus with documented target organ damage . when combined with the ccb , amlodipine , additive bp \n this telmisartan / amlodipine combination has also been demonstrated to be effective in patients at all stages of hypertension , as well as in those with added risk factors including obesity , diabetes , or metabolic syndrome [ 1924 ] . \n several published studies have demonstrated the efficacy of the telmisartan / amlodipine combination in patients uncontrolled on amlodipine monotherapy [ 20 , 25 ] ; however , a pooled analysis incorporating a large population is currently lacking . \n this paper presents a post hoc analysis of data from the boehringer ingelheim clinical trials database comparing telmisartan / amlodipine in combination therapy versus amlodipine monotherapy in patients who were uncontrolled with amlodipine alone . \n only trials from the boehringer ingelheim database were chosen as no other relevant studies could be found using other databases . \n this also enabled access to patient - level data and to ensure consistency in the recording of outcomes . \n the boehringer ingelheim trial database was searched for all studies investigating the telmisartan / amlodipine spc therapy in hypertensive patients uncontrolled on any ccb monotherapy . \n four randomized , double - blind studies , completed between september 2008 and august 2011 , were identified , and these are detailed in table 1 . \n all studies included a 68-week amlodipine monotherapy ( 5 or 10 mg ) run - in period , and patients who had not reached the diastolic bp ( dbp ) goal of 90 mm hg following this run - in period were then randomized to amlodipine monotherapy or telmisartan / amlodipine spc therapy for a further 8 weeks . \n three of the studies ( telmisartan / amlodipine single - pill study to assess the efficacy in patients with essential hypertension not controlled on a5 [ teamsta-5 ] , t40/a5 in a5 nonresponders , and t80/a5 in a5 nonresponders ) included patients uncontrolled on amlodipine 5 mg ( a5 ) at the end of the run - in period of 6 weeks , and the fourth study ( telmisartan / amlodipine single - pill study to assess the efficacy in patients with essential hypertension not controlled on a10 [ teamsta-10 ] ) included patients uncontrolled on amlodipine 10 mg ( a10 ) at the end of the run - in period . in the teamsta-10 study , the run - in period was longer as patients began treatment with a5 for 2 weeks before being uptitrated to a10 for a further 6 weeks . during the randomized phases of the studies , \n the treatment regimens used were a5 , a10 , telmisartan 40 mg ( t40)/a5 , telmisartan 80 mg ( t80)/a5 , t40/a10 , and t80/a10 . in all studies , patients took their trial treatments once daily , in the morning . \n bp was measured at baseline ( week 0 ) , week 4 , and week 8 in the three studies involving patients uncontrolled on a5 , at baseline , and at weeks 2 , 6 , and 8 in the one study that included patients uncontrolled on a10 . \n the change from reference baseline ( i.e. , after amlodipine monotherapy ) in seated trough dbp was the primary endpoint in all four studies . \n due to the similarities in trial design , data from the three trials in patients uncontrolled on a5 were pooled and analyzed . however , data from the one study in patients uncontrolled on a10 were analyzed separately . \n the mean changes in seated dbp and systolic bp ( sbp ) from reference baseline , adjusted for baseline bp and study ( where appropriate ) , were calculated , and treatments were compared using analysis of covariance . \n other measures included bp goal ( < 140/90 mm hg ) , dbp goal ( < 90 mm hg ) , and sbp goal ( < 140 mm hg ) attainment rates , in addition to response rates for dbp ( < 90 mm hg or a reduction 10 mm hg ) and sbp ( < 140 mm hg or a reduction 20 mm hg ) . \n the goal and response rates were compared between treatments using logistic regression adjusted for baseline bp and study . \n a total of 2812 patients were included in this analysis1891 not achieving dbp goal < 90 mm hg on a5 monotherapy and 921 not achieving the same dbp goal on a10 . \n for the analysis in patients not at goal on a5 monotherapy , groups were generally well matched for most demographic characteristics ( table 2 ) . \n however , the t80/a5 group had slightly more females ( 39.9% compared with 34.736.7% in the other groups ) ; the a5 and t40/a5 groups had higher proportions of asian patients ( 69.9% and 60.0% , resp . ) than the a10 and t80/a5 groups ( 20.3% and 49.1% ) , due to the inclusion of two asian studies that did not contain a10 as a treatment . \n the baseline sbp in the a10 group was lower than in the other groups ( 140.9 mm hg versus 147.2147.9 mm hg ) . \n the baseline sbp in the a10 group was lower than in the other groups ( 140.9 mm hg versus 147.2147.9 mm hg ) . \n considering those patients not at goal on a10 monotherapy , the groups were very well matched , with only the a10 group having fewer females ( 41.3% ) compared with the t40/a10 and t80/a10 groups ( 47.1% and 46.1% , resp . ) \n all patients achieved significantly greater reductions in dbp and sbp when switched to telmisartan / amlodipine spc therapy , compared with patients who continued on monotherapy ( p < 0.0001 ) . \n after 8 weeks of randomized treatment , patients not at dbp goal ( < 90 mm hg ) on a5 monotherapy who were maintained on a5 achieved dbp changes ( from reference baseline ) of 6.7 mm hg ( 95% confidence interval [ ci ] , 7.2 , 6.1 ) , and those who were uptitrated to a10 achieved dbp reductions of 8.8 mm hg ( 95% ci , 9.8 , 7.8 ; p = 0.0003 versus a5 ) . those patients who switched to t40/a5 and t80/a5 achieved dbp reductions of 10.7 mm hg ( 95% ci , 11.4 , 10.0 ; p < 0.0001 versus a5 ; p = 0.0011 versus a10 ) and 10.9 mm hg ( 95% ci , 11.6 , 10.1 ; p < 0.0001 versus a5 ; p = 0.0005 versus a10 ) , respectively \n . adjusted mean changes in sbp from baseline at 8 weeks were 7.8 mm hg ( 95% ci , 8.6 , 6.9 ) for patients maintained on a5 monotherapy , 12.1 mm hg ( 95% ci , 13.6 , 10.6 ; p < \n 0.0001 versus a5 ) for patients uptitrated to a10 monotherapy , 14.6 mm hg ( 95% ci , 15.7 , 13.6 ; p < 0.0001 versus a5 ; p = 0.0032 versus a10 ) for patients switched to t40/a5 , and 15.2 mm hg ( 95% ci , 16.3 , 14.0 ; p < 0.0001 versus a5 ; p = 0.0005 versus a10 ) for patients switched to t80/a5 ( figure 1 ) . \n in those patients who had not reached goal ( dbp < 90 mm hg ) with a10 monotherapy , dbp was reduced by 6.1 mm hg ( 95% ci , 6.8 , 5.4 ) when maintained on a10 for a further 8 weeks ; 8.9 mm hg when switched to t40/a10 ( 95% ci , 9.6 , 8.1 ; p < 0.0001 versus a10 ) ; and 8.9 mmhg when switched to t80/10 ( 95% ci , 9.6 , 8.2 ; p < 0.0001 versus a10 ) . \n adjusted mean changes in sbp from baseline at 8 weeks were 6.9 mm hg ( 95% ci , 7.9 , 5.8 ) for patients remaining on a10 monotherapy , 10.5 mm hg ( 95% ci , 11.6 , 9.5 ; p < \n 0.0001 versus a10 ) for patients switched to t40/a10 , and 10.7 mm hg ( 95% ci , 11.8 , 9.7 ; p < 0.0001 versus a10 ) for patients switched to t80/a10 ( figure 2 ) . a greater proportion of patients not at dbp goal ( < 90 mm hg ) with amlodipine monotherapy achieved the goals of bp < 140/90 mm hg , dbp < 90 mm hg , and sbp < 140 mm hg when switched to telmisartan / amlodipine spc therapy for 8 weeks compared with those who continued with amlodipine monotherapy ( figures 3(a ) and 3(b ) ) . indeed , patients who switched to the telmisartan / amlodipine spc therapy were significantly more likely to achieve goals than patients maintained on monotherapy ( table 3 ) . in those patients who had not previously achieved goal with a5 monotherapy , dbp goal ( < 90 mm hg ) was achieved by only 46.6% of patients remaining on a5 and \n 56.6% of patients uptitrated to a10 compared with 62.3% patients who were switched to t40/a5 and 66.9% of patients who were switched to t80/a5 . \n similarly , sbp goal ( < 140 mm hg ) was achieved by 51.6% of those patients remaining on a5 monotherapy and 54.4% of those uptitrated to a10 compared with 68.9% of patients switched to t40/a5 and 69.7% who were switched to t80/a5 . \n overall bp goal ( < 140/90 mm hg ) was achieved by only 33.8% of patients remaining on a5 monotherapy and 39.5% of patients uptitrated to a10 compared with 52.5% and 56.1% of patients who switched to t40/a5 and t80/a5 , respectively ( \n in patients not at goal with a10 monotherapy , dbp < 90 mm hg was achieved in only 51.1% of patients remaining on a10 compared with 63.7% of patients switched to t40/a10 and 66.5% of patients switched to t80/a10 ( p = 0.0002 for overall treatment differences ) . \n sbp < 140 mm hg was achieved in 50.2% of those remaining on a10 monotherapy compared with 58.8% switched to t40/a10 and 60.3% switched to t80/a10 ( p = 0.0012 for overall treatment differences ) . \n overall bp goal ( < 140/90 mm hg ) was achieved by only 37.0% of patients remaining on a10 monotherapy compared with 47.7% and 52.3% of patients who switched to t40/a10 and t80/a10 , respectively ( \n patients not at goal with amlodipine monotherapy who received telmisartan / amlodipine spc therapy were significantly more likely to achieve response targets than patients maintained on either monotherapy ( table 4 ) . \n response rates ( dbp < 90 mm hg or a reduction 10 mm hg or sbp < 140 mm hg or a reduction 20 mm hg ) were higher in patients randomized to telmisartan / amlodipine spc therapy compared with response rates of patients who continued amlodipine monotherapy . in patients not at goal on a5 monotherapy , dbp response was achieved in only 51.6% of patients remaining on a5 and 62.5% of those uptitrated to a10 compared with 70.0% patients on t40/a5 and 73.0% of patients on t80/a5 ( p < 0.0001 for overall treatment differences ) . \n sbp response was achieved in 57.8% of those remaining on a5 and 63.6% of those uptitrated to a10 compared with 74.3% on t40/a5 and 77.7% on t80/a5 ( p < 0.0001 for overall treatment differences ) . in patients not at goal on a10 monotherapy , dbp response was achieved in only 53.4% of patients remaining on a10 compared with 66.0% patients on t40/a10 and 68.7% of patients on t80/a10 ( p = 0.0002 for overall treatment differences ) . \n sbp response was achieved in 54.1% of those remaining on a10 compared with 64.7% on t40/a10 and 65.8% on t80/a10 ( p = 0.0013 for overall treatment differences ) . in patients not at goal with a5 monotherapy , those who continued on a5 monotherapy experience a similar rate of drug - related adverse events and discontinuations due to adverse events compared with those who switched to either spc dose ( table 5 ) . \n however , those who switched to a10 monotherapy experienced numerically more drug - related adverse events and discontinuations due to adverse events . in patients not at goal with a10 monotherapy , the rates of respective aes were similar in all three treatment groups . \n the number of serious adverse events reported in all groups was very low , irrespective of run - in medication . \n interestingly , peripheral oedema mainly occurred in the european studies ( a5 and a10 nonresponder trials ) , whereas in the asian studies ( t40/a5 in the a5 nonresponder trial and t80/a5 in the a5 nonresponder trial ) , peripheral oedema was not reported as frequently . in the a5 nonresponder trial , peripheral oedema was reported as follows : a10 : 74 ( 26.8% ) , a5 : 22 ( 8.2% ) , t40/a5 : 14 ( 5.1% ) , and t80/a5 : 10 ( 3.6% ) . in the a10 nonresponder trial , \n the respective numbers were a10 : 22 ( 7.0% ) , t40/a10 : 21 ( 6.7% ) , and t80/a10 : 27 ( 8.5% ) . \n in this analysis of 2812 patients who failed to reach dbp goal ( < 90 mm hg ) with amlodipine monotherapy after 68 weeks of treatment , use of telmisartan / amlodipine spc therapy was associated with significantly greater reductions in dbp and sbp compared with maintenance on , and uptitration of , amlodipine monotherapy . \n this is to be expected due to the complimentary modes of actions of the two drugs . \n adding an arb to ccb therapy should promote arterial and venous dilation by blocking the ras system and attenuate renal hyperfiltration and peripheral edema induced by ccbs . \n in addition , the negative sodium balance promoted by ccbs may further reinforce the antihypertensive effect of the arb [ 2830 ] . \n the greatest treatment differences noted , 7.4/4.2 mm hg , were between continuation on a5 monotherapy and switching to t80/a5 . \n slightly smaller treatment differences of 2.83.8 mm hg were observed when patients not at goal with a10 switched to spc therapy compared with those who continued with a10 monotherapy . \n this may be expected as patients who are unresponsive to higher doses of monotherapy are often considered more difficult to treat . \n these small differences in bp may be clinically relevant , as a large meta - analysis found that reductions in sbp even as small as 2 mm hg reduced mortality from stroke by 10% and mortality from other cv causes by 7% in middle - aged individuals . in this analysis , patients switched to spc therapy were more likely to respond to treatment and achieve bp goal than those maintained on monotherapy . in patients not at goal with a5 monotherapy , the odds ratio ( or ) of achieving bp goal ( < 140/90 mm hg ) was 3.43 ( 95% ci , 2.54 , 4.64 ) for t80/a5 versus continuing a5 therapy , and for dbp goal ( < 90 mm hg ) , the corresponding or was 3.00 ( 95% ci , 2.22 , 4.07 ) . however , approximately half of all patients not at goal ( dbp \n < 90 mm hg ) on either dose of amlodipine monotherapy after 68 weeks of treatment achieved dbp goal following a further 8 weeks of continued monotherapy treatment , and 56.7% of patients achieved dbp goal on switching to more potent monotherapy ( uptitration to a10 ) . \n this suggests that some patients initially unresponsive to monotherapy may eventually achieve bp goal if continued on the same treatment at the same or a higher dose of monotherapy . \n however , the time taken to achieve bp goal is also an important risk factor [ 3236 ] . \n therefore , due to greater likelihood of goal attainment and greater sbp / dbp reduction , early treatment with spc therapy may be preferable to quickly achieve and maintain bp goal . \n the bp reductions observed with telmisartan / amlodipine spc therapy in patients not at goal with amlodipine monotherapy are similar to those observed with other arb / ccb combinations . \n for example , a study investigating olmesartan / amlodipine in patients with moderate - to - severe hypertension , not at goal with amlodipine monotherapy , adds further support for switching to combination therapy . following 8 weeks of a5 monotherapy , nonresponders were randomized to receive either placebo plus a5 or a combination of olmesartan ( 10 , 20 , or 40 mg ) plus a5 for a further 8 weeks \n . adjusted mean changes in dbp versus placebo / amlodipine therapy were 2.0 mm hg ( p = 0.0207 ) for olmesartan 10 mg / a5 , 3.7 mm hg ( p < \n 0.0001 ) for olmesartan 20 mg / a5 , and 3.8 mm hg ( p < \n adjusted mean changes in sbp were 3.5 mm hg ( p = 0.0103 ) , 5.8 mm hg ( p < 0.0001 ) , and 7.1 mm hg ( p < 0.0001 ) , respectively . \n this is the first pooled analysis of telmisartan / amlodipine spc therapy in a large number of patients ( n = 1891 ) not at goal with a5 monotherapy , in addition to the retrospective analysis of another study ( n = 921 ) in patients not at goal with a10 monotherapy \n . limitations of these analyses are that they are retrospective and incorporate boehringer ingelheim - sponsored studies only \n . however , the endpoints stipulated in the individual trials are mostly identical to those used in this pooled and retrospective analysis , and results from the two separate analyses are similar . \n in addition , the use of the boehringer ingelheim studies enabled the study of patient - level data . in each study , criteria for randomization was dbp > 90 mm hg . a significant proportion of randomized patients ( 15.830.2% ) already had sbp < 140 mm hg , which partly confounds the analysis of sbp data ; however , the analysis of dbp is robust . \n the results are clinically relevant in terms of the doses investigated and the study design , investigating bp goal attainment with combination therapy in patients not at goal with monotherapy . \n patients not at goal with a5 or a10 monotherapy achieved significantly greater dbp and sbp reductions compared with continuing with amlodipine monotherapy , and the majority of patients achieved bp goal when switched to telmisartan / amlodipine spc therapy . reported adverse events with spc therapy were similar to or less than those experienced with continued monotherapy \n therefore , the early use of combination therapy , such as the telmisartan / amlodipine spc , may be considered as an approach to quickly reach bp targets . \n this is of particular relevance to the more difficult - to - treat , added - risk , hypertensive patients .", "role": "user" }, { "content": "hypertensive patients unable to reach blood pressure ( bp ) targets with antihypertensive monotherapy may be switched to a combination of two medications with complementary modes of action for improved treatment response . \n this post hoc analysis pools data from 2812 patients , 1891 of whom were not at goal ( diastolic bp [ dbp ] < 90 mm hg ) with amlodipine 5 mg ( a5 ) monotherapy who subsequently switched to telmisartan 40 or 80 mg ( t80)/a5 single - pill combination ( spc ) or amlodipine 10 mg ( a10 ) monotherapy , and considers an additional 921 patients , 616 of whom were not at goal with a10 monotherapy who switched to telmisartan / amlodipine spc . patients switched to telmisartan / amlodipine spc achieved significantly greater bp reductions compared with continued monotherapy ( p < 0.0001 ) with reductions of 15.2/10.9 mm hg seen with t80/a5 after 8 weeks in patients switched from a5 . \n bp goal ( < 140/90 mm hg ) , systolic bp goal ( < 140 mm hg ) , and dbp goal ( < 90 mm hg ) were reached by significantly more patients with telmisartan / amlodipine than with monotherapy ( p < 0.0001 for all comparisons ; 56.1% , 69.7% , and 66.9% , resp . , in patients who switched from a5 to t80/a5 ) . \n early use of such combination therapy should be considered to quickly reach bp targets , particularly in patients with added risk .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the income , prestige , and authority of doctors in most western countries reflects their omnipotence amongst health care professionals and their power within our society . \n however , concurrent with the increasing number of women entering medicine , there has been a recent decrease in that power . \n for example , a significant proportion of female family physicians reports being sexually harassed by male patients . \n sexual harassment is an abusive behaviour perpetrated by those with power on the more vulnerable . \n the victimization of female doctors could only occur if the offending male patients saw their physicians as vulnerable women rather than powerful professionals , that is , if gender rather than professional role was the primary determinant of power in the relationship . \n if female physicians are \" women first \" in the eyes of some male patients , do their overwhelmingly female nurse colleagues also view them through a gender lens ? \n how will the increasing percentage of women in medicine change professional relationships between doctors and nurses ? \n this study examines whether the traditional authority of doctors over nurses is eroded when that authority arises solely from profession and not from gender . \n historically both the gendered role of nursing and the sex of nurses was almost exclusively female . \n the profession primarily attracted working class or immigrant women whose background fostered unquestioning obedience to authority . \n the \" doctor nurse \" game described by stein ( 1967 ) indicated that despite the passage of time , roles had not changed substantially . by showing initiative and making important recommendations , while appearing to defer passively to the doctor 's authority \n stein revisited the nurse - doctor game in 1990 and argued that nurses had unilaterally decided to stop playing . \n the change was , in part , attributed to an increasing number of female physicians and male nurses , both of whom were unable to play . \n nurses ' recent overt refusal to be dominated by physicians is also a reflection of the decrease in power differentials between men and women in western society at large . \n in contrast to nursing , the gender role and the practitioners of medicine one hundred years ago were male . \n many nurses and physicians still overtly and covertly resist the equalization of power that true teamwork requires . \n salvage and smith argue that while assertive nurses resent being put down by doctors , physicians resent being challenged by nurses . \n obstacles to collaboration include gendered thinking , different styles of learning , models of working , regulatory mechanisms , role ambiguity , and incongruent expectations . \n nurses generally experience greater satisfaction when communicating with female rather than male physicians and prefer a female managerial style . \n nurses doubt that physicians ' sex affects their behaviour , although some admit anger or disappointment when female physicians do not exceed the standards nurses set for male physicians . \n they deny any sexual chemistry that favours male physicians , despite the female doctors ' impression to the contrary . \n some female nurses describe female doctors in stereotypic terms such as \" demanding \" , \" domineering \" , and \" bitchy \" . \n female physicians , on the other hand , resent both having to make extra efforts to be nice to nurses , and devising conscious strategies to cultivate egalitarianism and friendship . \n more than 80% feel that at some time in their careers they have experienced unequal treatment , more intense scrutiny , or a lack of respect from nurses because they ( the doctors ) were female . \n a recent norwegian study examined the physician 's perspective on what happens to the doctor - nurse relationship when both are women . \n both male and female physicians thought the relationship was influenced by the doctor 's gender . \n female doctors perceived that they received less respect or help than did their male colleagues . \n the physicians interpreted this in two ways , thinking that either nurses ' wishes to reduce status differences between nurses and physicians affect female doctors more than male , or that there is an \" erotic game \" taking place between male doctors and female nurses . \n hypothesizing that the sex of the physician could affect nurses ' behaviour , we examined differences in the interaction between female nurses and female and male physicians . a self selected population of nurses working in an urban , university based hospital was asked to complete one of two forms of a three page questionnaire in jan . 2000 . \n the questionnaire included four clinical vignettes reflecting some previously identified areas of strain in the doctor nurse relationship . in form 1 of the questionnaire the physicians described were female , male , female , and male . in form 2 \n participants were asked five point likert type questions about nurse physician interactions , their expectations , probable actions , and feelings about the physicians . \n the questionnaire was pre - tested amongst a small group of hospital nurses to assess face and content validity . \n letters explaining that the accompanying study 's aim was to examine teamwork in a hospital setting , that participation was voluntary , and that responses would be confidential were left at all patient care planning areas ( nursing desks ) of the hospital . \n all surveys left at a specific patient care planning area were of the same form . \n nurses were asked to return questionnaires , whether completed or not , to an identified collection envelope , and to complete only one questionnaire . following the final collection date , letters explaining that responses to the two forms of the questionnaire would be compared to identify differences in interactions between nurses and physicians based on the doctor 's sex , and describing the \" nurse - doctor game \" were distributed . \n the analysis compared the responses to each question based on the sex of the physician in the particular vignette ( ie responses to form 1 and form 2 of the questionnaire ) . \n pearson chi - square analysis was used to test for statistical significance ( p < 0.05 ) . \n of the three hundred surveys printed , 265 were taken , 197 were returned completed , 2 were returned with no responses , and 66 were not returned . \n the overall response was 74% ( 199 of 265 taken ) and included approximately 22% of the 900 nurses employed by the hospital . \n the inpatient nursing specialties were broadly represented amongst the 95% ( n = 177 ) who indicated they were female , the 5% ( n = 9 ) who were male , and the 11 respondents who did not specify . based on the overall sex ratio of respondents these \n 11 were assumed to be female and included in the analysis .. responses from men were excluded , leaving 188 surveys for inclusion ( 95 surveys of form 1 and 93 of form 2 ) . in the first vignette a physician leaves a suture tray with needles at the bedside , despite a department policy assigning cleanup responsibility to the user of any \" sharps \" . \n female nurses expected physicians of either sex , to dispose of the needles ( 85.3% female physician , 86.0% male physician , p = 0.97 ) but were significantly less likely to remove the needles for female physicians ( p < 0.05 ) . nurses expectations of , and conflicts with physicians varied by sex . \n those surveyed were more likely to feel indifferent about a male physician , and negative about a female physician when the nurse ultimately removed the needles herself ( p < 0.01 ) . in vignette two , \n the nurse was interrupted while checking a patient 's vital signs and asked to do the same check on the doctor 's patient . \n nurses were equally unlikely to immediately stop and help a female or male physician ( p = 0.69 ) . \n however assertive requests by physicians were more likely to be acted upon if the physician were male ( p < 0.03 ) despite near universal resentment of this aggression ( 80% toward females , and 77% toward males , p = 0.89 ) . \n when physician requests for help were polite , nurses felt positive toward both male and female physicians ( 68.5% toward females , and 65.1% toward males , p = 0.33 ) but , as in vignette 1 , were less likely to help the female physician ( p = 0.17 ) . \n the nurse wonders if the physician remembers that the mother received meperidine ( a medication that could depress the baby 's breathing and that could be reversed by giving the baby naloxone ) two hours previously . \n nurses were more likely to suggest to the physician that the newborn needed naloxone , ( 99% were likely or very likely to suggest to female physicians and 97.8% for male physicians , p = 0.24 ) , than they were to tell the physician that the newborn needed naloxone ( 31.8% were likely or very likely to tell a female physician and 26.1% for a male physician , p = 0.21 ) . again , though not statistically significant in this case , there was a trend for nurses to be more forward with female doctors . \n they were less likely to wait for a female doctor to make her own decision about giving naloxone ( p = 0.15 ) , and more likely to suggest ( p = 0.21 ) or tell ( p = 0.20 ) the female doctor to give the medication . \n nurses also expected female doctors would respond more positively to their suggestions ( p < 0.04 ) . in the final vignette \n a doctor on call has just gone to sleep in her / his call room . \n nurses were asked if they would call the physician for an acetaminophen ( an analgesic ) order . \n there was , however , a consistent and contrary trend to that observed in the other scenarios . \n nurses were less likely to call a female physician than a male , regardless of whether the physician had given the nurse a complement earlier in the day ( p = 0.24 ) , or had been rude earlier on ( p = 0.63 ) . \n nurses were more likely to feel that a male physician 's anger was inappropriate ( p = 0.39 ) . \n they were less comfortable approaching a female doctor to discuss her anger ( p = 0.38 ) . in this vignette \n our findings suggest , however , that the process of , and feelings around nurse physician interactions are informed by gender stereotypes . in addition to professional hierarchy , gender appears to account for physicians ' perceived power over nurses . \n although physicians may well reinforce these same stereotypes this study did not examine their beliefs . \n overall , nurses ' behaviour was influenced by the sex of the physician . in vignette 1 , those surveyed expected both male and female physicians to remove needles left on a suture tray . \n they were , however , more willing to clean up after male physicians , and to do so with indifference rather than with the hostility they directed toward female doctors . \n findings that nurses are statistically less likely to remove needles for female doctors , and to feel somewhat more resentful toward female doctors for whom they have cleaned up , speaks to the primacy of sex over hierarchy in defining the doctor nurse relationship . \n perhaps nurses feel role confusion because female physicians do not fit into their learned male stereotypes , and instead better fit into traditionally female roles such as \" cleaner \" . \n these results corroborate pringle 's subjective findings that nurses do more for male physicians and expect more of female physicians . that nurses were unlikely to drop everything to assist either a male or female physician take a blood pressure is consistent with the increasing autonomy of the nursing profession . \n assertive physician requests met with resistance from these increasingly confident nurses who commented , \" many times doctors feel they have the right to interrupt with little to no consideration for the rns . \n they feel their job is more important ! \" and , \" she is perfectly capable of doing vital signs . \n \" pleasant requests for nursing help were more effective . again , however , sex role stereotypes appeared to enter the relationship as nurses accepted aggressive male behaviour and acquiesced more readily to male requests for help . \n responses to the third scenario suggest that the ' doctor - nurse game ' is alive and well . \n nurses deferred to the physicians ' status despite knowing what was medically necessary , and would suggest , but not dictate , treatment for the unresponsive baby . \n as one respondent wrote , \" i would be more likely to phrase it in a way that would make him feel in control . \n \" nevertheless , there was again more deference to the authority of male doctors . in the final vignette \n , respondents showed a non - significant trend toward a more kindly association with female than male physicians . at first this \n this vignette , however was the only one of the four requiring a nurse to initiate , rather than respond to an action . \n perhaps nurses are hostile and reactive to female physicians in situations where their expectations ( often based on sex stereotypes ) are not met , such as when women fail to clean up after themselves . however \n , when the nurse is in control , her less hierarchical relationship with another female , despite the power differential of profession , may foster collegiality . when doctors and nurses are both female , elimination of the power differential of gender diminishes nurses ' perceptions of professional power inequalities . \n as a result , female nurses appear more comfortable approaching and communicating with female doctors , but are also more hostile toward female physicians ' use of medical authority . \n these paradoxical behaviours will confuse female physicians if they view themselves as doctors first , rather than as women , and expect nurses to interact with all physicians equally . as females \n these same physicians may anticipate appreciation for their increased collaboration and egalitarianism , and not understand the nurses ' confusion at the lack of traditional professional hierarchy . \n perhaps the perception that female physicians are more caring and compassionate than their male counterparts creates conflicts with nurses , who define caring as their function , and may feel their role in health care delivery is threatened by women physicians . in general , the nurses surveyed said they would resist being controlled by physicians . \n this decrease in the power of medicine over nursing is concurrent with an increase in the number of women physicians in north america . \n although the feminization of medicine could diminish the power and prestige of all physicians within the health care system , our findings suggest that nurses are more resistant to domination by female , rather than male doctors . \n changes in power differentials between medicine and nursing appear to be shaped by gender , suggesting that the traditional omnipotence of physicians in the health care hierarchy arose from gender roles , and not solely from profession . \n written responses may define socially desirable values rather than actual behaviours in clinical situations , however the hostility toward physicians expressed in many of the nurses ' written comments ( not reported here ) mitigates against this concern . because the study was limited to hospital nurses and the scenarios were hospital based \n as with any study in which participants are self - selected rather than randomly surveyed , selection bias is possible . \n our relatively high response rate ( 74% ) minimizes , but does not preclude this limitation . \n written responses may define socially desirable values rather than actual behaviours in clinical situations , however the hostility toward physicians expressed in many of the nurses ' written comments ( not reported here ) mitigates against this concern . because the study was limited to hospital nurses and the scenarios were hospital based \n as with any study in which participants are self - selected rather than randomly surveyed , selection bias is possible . \n our relatively high response rate ( 74% ) minimizes , but does not preclude this limitation . \n historically , the power held by a predominantly male medical profession may have arisen primarily from gender rather than from hierarchical position . \n current relationships between doctors and nurses appear to be shaped by gender as well as by profession . when nurses and doctors are female the traditional power imbalance between the two diminishes . \n the effects of this change on the authority of the medical profession , the role of nurses , and on patient care remain undefined .", "role": "user" }, { "content": "backgroundthe nurse - doctor relationship is historically one of female nurse deference to male physician authority . \n we investigated the effects of physicians ' sex on female nurses ' behaviour.methodsnurses at an urban , university based hospital completed one of two forms of a vignette - based survey in january , 2000 . \n each survey included four clinical scenarios . in form 1 of the questionnaire \n the physicians described were female , male , female , and male . in form 2 , vignettes were identical but the physician sex was changed to male , female , male , and female . \n differences in responses to questions based on the sex of the physician in each vignette were studiedresults199 self - selected nurses completed the survey . \n the responses of 177 female respondents and 11 respondents who did not specifiy their sex , and were assumed to be female based on the overall sex ratio of respondents , were analysed . \n persistent sex - role stereotypes influenced the relationship between female nurses and physicians . \n nurses were more willing to serve and defer to male physicians . \n they approached female physicians on a more egalitarian basis , were more comfortable communicating with them , yet more hostile toward them.conclusionwhen nurses and doctors are female , traditional power imbalances in their relationship diminish , suggesting that these imbalances are based as much on gender as on professional hierarchy . \n the effects of this change on the authority of the medical profession , the role of nurses , and on patient care merit further exploration .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: linacs operated in a flattening filter - free ( fff ) mode is becoming of increasing interest in recent years \n . started in the 1990s , the early research work was focused on the increased dose rate for radiosurgery or the physics characteristics of unflattened beams . in 2000s \n rotational imrt or vmat has recently become a promising and commercial treatment option . during the past years , feasibility of treating various cancers including prostate , lung , larynx , chest wall , and esophagus using unflattened beams have been reported . also exclusive use of a linear accelerator in fff mode in 3d crt planning \n a reduced beam on time ( bot ) and comparable plan quality seem to have been confirmed for vmat plan with unflattened beams . \n nevertheless , studies published so far are limited to cases with relatively small planning target volume ( ptv ) with less peripheral organs at risk ( oars ) . \n nasopharyngeal carcinoma ( npc ) is one of the most frequently occurred cancers in certain regions of east asia and africa . \n although radiotherapy is the choice of npc treatment , more treatment fractions and longer treatment time per fraction makes it prominent to further improve the treatment efficiency . at the same time , planning of npc cases proved to be challenging due to the large ptv volumes and the numerous close proximity normal structures . in the present work , using of fff beams in npc - vmat is studied to evaluate whether and to what extent the higher dose rate of fff beams could be of a solution to the efficiency problem and , to illustrate the performance of fff - vmat for npc cases . \n our work was carried out in three steps : ( 1 ) a fff photon beam was modeled in a commercial tps using the measured beam data from a linac operated in fff mode . \n ( 2 ) ten npc cases previously treated in our department were randomly selected . for each case \n , a vmat plan using flattened beams ( ff - vmat ) and unflattened beams ( fff - vmat ) were designed , respectively . \n ( 3 ) plan quality and delivery efficiency between fff - vmat plans and ff - vmat plans were compared . \n an elekta synergy linac ( elekta , crawley , uk ) was used for beam data collection and treatment delivery undertaken in this study . \n beam data of 6 mv photon with and without ff were collected and used to model the linac in the pinnacle ( v9.0 ) ( philips radiation oncology , fitchburg wi ) tps . \n the usual method of obtaining a fff beam was to replace the ff with a thin plate composed of various materials . \n as an exploratory study , an easier and safer way was adopted in our study : the 6mv photon ff was replaced with the 6mev electron scatter foil . \n in such a way , only the configurations of the linac control software needed to be changed and the linac could be easily restored to its original clinical mode when the research work done . \n the fff beam in our study was not suitable for clinical use , but it should be sufficient for exploratory studies . in order to enable the fff beam delivery in the linac , flatness \n beam data with and without the ff were collected according to the pinnacle photon beam data collection ( philips radiation oncology , fitchburg wi ) using a scanditronix rfaplus phantom ( scanditronix ab , husbyborg , sweden ) with a compact ionization chamber ( scanditronix / wellhofr rk compact chamber ) for depth dose - curve measurements and a diode detector ( pfd iba dosimetry gmbh , germany ) for profile measurements . \n data including percent depth dose curves , output factors ( scp ) and profiles were measured at various depths for a range of field sizes . the ff beam used in our department \n was calibrated according to the iaea trs-277 protocol using dose1 electrometer and fc65-g 0.6cc farmer ion - chamber ( scanditronix medical ab ) . as xiong et al . concluded that when ff was removed , the original stopping - power ratios as function of % dd(10 ) x can still be used but with a slightly higher uncertainty . \n the fff beam in the present work was thus calibrated using the same methods as ff beam . modeling \n similar process had been adapted in our study except that the relative incidence fluence was defined by an arbitrary profile in the tps to account for the conical shape of the unflattened beam . \n the cases selected were diagnosed with early stage carcinoma ( t1 ) and were clinically treated with nine fields imrt by means of a simultaneously integrated boost ( sib ) technique . \n two planning target volumes were defined : ptv1 , the target volume of the primary lesion , which was given to 60.06 gy in 33 fractions , and ptv2 , the target volume of electively treated region , which was given to 50.96 gy in 28 fractions or 60.06 gy in 33 fractions depends on the clinical observation ( only the latter case was examined in our study ) . the boost target volume , including the planning primary tumor ( pgtvnx , gtv extended 2 mm ) and the involved periphery lymph nodes ( gtvnd ) , were treated to 69.96 gy in 33 fractions . typical targets layout and corresponding dose levels were exemplified in figure 1 . \n typical target layout and corresponding dose levels oar constraints for npc cases the planning process was started by optimizing a 2-arc ( 360 deg per arc ) fff - vmat plan according to the clinical requirements . \n depending on the optimization results , fine - tuning of optimization parameters and re - optimizing of the plan might also be applied . \n finally , the resulting set of optimization parameters were then applied to a fff - vmat plan and ff - vmat plan using the same process : beams were reset and plan was optimized for 70 iterations followed by a \n optimization ( optimization was started from the plan 's current photon fluence ) of 30 iterations . \n as can be seen , this study did not optimize treatment delivery parameters specifically for flattened beams . \n treatment plans with flattened beams used the same number of arcs , dose constraints , and planning priorities as used for unflattened beams . \n when the planning process was done , the collapsed cone convolution superposition algorithm was employed for the final dose calculation . \n dry runs of all plans were performed on the linac to check the real deliverability of the treatment . \n target dose , dose to organs at risk ( oars ) , and normal tissue ( nt ) , plan delivery efficiency were compared using two - tailed , paired t - tests . \n for ease of comparison , plans were renormalized such that 95% of pgtvnx received 100% of the prescription dose . \n finally , all plans were delivered on the linac and the delivery efficiency was evaluated using the actually measured bot . \n dose homogeneity index ( hi ) and conformity index ( ci ) were used as comparison metrics between plans generated with and without a flattening filter . \n the hi as described by wu et al . was used : where dp , d2 , and d98 represent the prescription dose , dose to 2% and 98% of the target , respectively . by this definition , \n lower hi value indicates better dose homogeneity . as the dose distribution inside ptv was non - uniform , the hi was only calculated for pgtvnx . \n the ci used to evaluate the dose conformity was defined as : where ptv_p is the percentage of ptv volume receiving a dose no less than the prescription dose , and iso_p is the portion of the prescribed iso - dose volume account for by the target . \n the ci values range from 0 to 1 , where 1 is the ideal value . in this work , \n ptv1 and ptv2 were merged together to create a new target ( ptv1 + ptv2 ) for conformity evaluation . in the evaluation of oar dose , \n parameters for comparison were selected accordingly : percent of volume covered by the clinically concerned threshold dose were used for parallel organs and maximum dose were used for serial organs . \n if no volume of a parallel organ received the threshold dose , mean dose was applied . \n the maximum dose was defined as the dose to 1cc or 1% of the organ volume , whichever is less . \n percent volume covered by 35 gy iso - dose lines ( v35 ) was used for left and right parotid , and maximum dose was used for spinal cord , brain stem , left and right lens , left and right optic nerves . \n the usual method of obtaining a fff beam was to replace the ff with a thin plate composed of various materials . \n as an exploratory study , an easier and safer way was adopted in our study : the 6mv photon ff was replaced with the 6mev electron scatter foil . in such a way , only the configurations of the linac control software needed to be changed and the linac could be easily restored to its original clinical mode when the research work done . \n the fff beam in our study was not suitable for clinical use , but it should be sufficient for exploratory studies . in order to enable the fff beam delivery in the linac , flatness \n beam data with and without the ff were collected according to the pinnacle photon beam data collection ( philips radiation oncology , fitchburg wi ) using a scanditronix rfaplus phantom ( scanditronix ab , husbyborg , sweden ) with a compact ionization chamber ( scanditronix / wellhofr rk compact chamber ) for depth dose - curve measurements and a diode detector ( pfd iba dosimetry gmbh , germany ) for profile measurements . \n data including percent depth dose curves , output factors ( scp ) and profiles were measured at various depths for a range of field sizes . the ff beam used in our department \n was calibrated according to the iaea trs-277 protocol using dose1 electrometer and fc65-g 0.6cc farmer ion - chamber ( scanditronix medical ab ) . as xiong et al . concluded that when ff was removed , the original stopping - power ratios as function of % dd(10 ) x can still be used but with a slightly higher uncertainty . \n the fff beam in the present work was thus calibrated using the same methods as ff beam . modeling \n similar process had been adapted in our study except that the relative incidence fluence was defined by an arbitrary profile in the tps to account for the conical shape of the unflattened beam . \n the cases selected were diagnosed with early stage carcinoma ( t1 ) and were clinically treated with nine fields imrt by means of a simultaneously integrated boost ( sib ) technique . \n two planning target volumes were defined : ptv1 , the target volume of the primary lesion , which was given to 60.06 gy in 33 fractions , and ptv2 , the target volume of electively treated region , which was given to 50.96 gy in 28 fractions or 60.06 gy in 33 fractions depends on the clinical observation ( only the latter case was examined in our study ) . \n the boost target volume , including the planning primary tumor ( pgtvnx , gtv extended 2 mm ) and the involved periphery lymph nodes ( gtvnd ) , were treated to 69.96 gy in 33 fractions . \n typical target layout and corresponding dose levels oar constraints for npc cases the planning process was started by optimizing a 2-arc ( 360 deg per arc ) fff - vmat plan according to the clinical requirements . \n depending on the optimization results , fine - tuning of optimization parameters and re - optimizing of the plan might also be applied . \n finally , the resulting set of optimization parameters were then applied to a fff - vmat plan and ff - vmat plan using the same process : beams were reset and plan was optimized for 70 iterations followed by a \n optimization ( optimization was started from the plan 's current photon fluence ) of 30 iterations . \n as can be seen , this study did not optimize treatment delivery parameters specifically for flattened beams . \n treatment plans with flattened beams used the same number of arcs , dose constraints , and planning priorities as used for unflattened beams . \n when the planning process was done , the collapsed cone convolution superposition algorithm was employed for the final dose calculation . \n dry runs of all plans were performed on the linac to check the real deliverability of the treatment . \n target dose , dose to organs at risk ( oars ) , and normal tissue ( nt ) , plan delivery efficiency were compared using two - tailed , paired t - tests . \n for ease of comparison , plans were renormalized such that 95% of pgtvnx received 100% of the prescription dose . \n finally , all plans were delivered on the linac and the delivery efficiency was evaluated using the actually measured bot . \n dose homogeneity index ( hi ) and conformity index ( ci ) were used as comparison metrics between plans generated with and without a flattening filter . \n the hi as described by wu et al . was used : where dp , d2 , and d98 represent the prescription dose , dose to 2% and 98% of the target , respectively . by this definition , \n lower hi value indicates better dose homogeneity . as the dose distribution inside ptv was non - uniform , the hi was only calculated for pgtvnx . \n the ci used to evaluate the dose conformity was defined as : where ptv_p is the percentage of ptv volume receiving a dose no less than the prescription dose , and iso_p is the portion of the prescribed iso - dose volume account for by the target . \n the ci values range from 0 to 1 , where 1 is the ideal value . in this work , \n ptv1 and ptv2 were merged together to create a new target ( ptv1 + ptv2 ) for conformity evaluation . in the evaluation of oar dose , \n parameters for comparison were selected accordingly : percent of volume covered by the clinically concerned threshold dose were used for parallel organs and maximum dose were used for serial organs . \n if no volume of a parallel organ received the threshold dose , mean dose was applied . \n the maximum dose was defined as the dose to 1cc or 1% of the organ volume , whichever is less . \n percent volume covered by 35 gy iso - dose lines ( v35 ) was used for left and right parotid , and maximum dose was used for spinal cord , brain stem , left and right lens , left and right optic nerves . \n with respect to beam modeling in the tps , errors between the measured profiles and tps calculated profiles were usually used to evaluate fitness of the resulting model . \n figure 2 illustrated the comparison results of a 20 20 cm field pdd and profiles ( dashed line was the calculated ) . \n the maximum differences were 0.7% and 1.2% for pdd beneath the buildup region and profile at 10-cm depth , respectively . \n figure 3 was the resulting relative energy spectrum of ff and fff beam ( normalized at 2 mev ) . \n the enhanced lower energy component of the dashed line indicated a softer fff beam resulting from the absence of the hardening effects of the ff . \n the maximum value of the fff beam spectrum was shifted approximately 1 mv toward the lower energy , making it resembles a 4 - 5mv ff beam . \n the absolute dose output ratio of fff beam to ff beam measured in a 30s beam on duration ( ssd 90 cm , 10 10 cm field ) was 2.225 . \n comparison between the calculated and measured pdd ( a ) and profiles at depth 5 cm ( b ) , 10 cm ( c ) , 20 cm ( d ) of 20 cm 20 cm field for fff beam energy spectrum of ff and fff beam table 2 listed the average values , standard deviations and t - test p values of the selected parameters for both groups of plans . \n the listed averaged bot was calculated from the plan dry - run process in which all plans were delivered successfully . \n plan comparison results of npc cases as for target dose coverage , the maximum difference of averaged dose ( for ptv2 ) was less than 1% and the difference was close to statistically significant . for other targets , \n although the difference of ci was statistically significant , the averaged ci values are very close to each other . \n visual check of the dvh curves also confirmed that the dose conformity of targets is close . \n in general , target dose coverage of fff - vmat plan was similar to ff - vmat plans . \n for dose to normal organs , though p values for some of the metrics ( parotid glands , brain stem , right lens , and nt ) indicated a statistically significant difference , the average values were relatively close to each other . \n the most notable difference was observed for the right parotid gland , in which the percent volume covered by 35 gy iso - dose lines of fff - vmat plans was decreased by 4.9% . \n max dose to other organs was also decreased to some extent . for nt mean dose , \n overall , although the difference was slight , plans were consistently better with the filter removed , and surely they were no worse . concerning the plan delivery efficiency , averagely ~24% of the bot decrease was observed for fff - vmat plans and the difference was statically significant . \n with respect to beam modeling in the tps , errors between the measured profiles and tps calculated profiles were usually used to evaluate fitness of the resulting model . \n figure 2 illustrated the comparison results of a 20 20 cm field pdd and profiles ( dashed line was the calculated ) . \n the maximum differences were 0.7% and 1.2% for pdd beneath the buildup region and profile at 10-cm depth , respectively . \n figure 3 was the resulting relative energy spectrum of ff and fff beam ( normalized at 2 mev ) . \n the enhanced lower energy component of the dashed line indicated a softer fff beam resulting from the absence of the hardening effects of the ff . \n the maximum value of the fff beam spectrum was shifted approximately 1 mv toward the lower energy , making it resembles a 4 - 5mv ff beam . \n the absolute dose output ratio of fff beam to ff beam measured in a 30s beam on duration ( ssd 90 cm , 10 10 cm field ) was 2.225 . \n comparison between the calculated and measured pdd ( a ) and profiles at depth 5 cm ( b ) , 10 cm ( c ) , 20 cm ( d ) of 20 cm 20 cm field for fff beam energy spectrum of ff and fff beam \n table 2 listed the average values , standard deviations and t - test p values of the selected parameters for both groups of plans . \n the listed averaged bot was calculated from the plan dry - run process in which all plans were delivered successfully . \n plan comparison results of npc cases as for target dose coverage , the maximum difference of averaged dose ( for ptv2 ) was less than 1% and the difference was close to statistically significant . for other targets , dose to 95% of the target was almost the same . \n although the difference of ci was statistically significant , the averaged ci values are very close to each other . \n visual check of the dvh curves also confirmed that the dose conformity of targets is close . \n in general , target dose coverage of fff - vmat plan was similar to ff - vmat plans . \n for dose to normal organs , though p values for some of the metrics ( parotid glands , brain stem , right lens , and nt ) indicated a statistically significant difference , the average values were relatively close to each other . \n the most notable difference was observed for the right parotid gland , in which the percent volume covered by 35 gy iso - dose lines of fff - vmat plans was decreased by 4.9% . \n max dose to other organs was also decreased to some extent . for nt mean dose , \n overall , although the difference was slight , plans were consistently better with the filter removed , and surely they were no worse . concerning the plan delivery efficiency , averagely ~24% of the bot decrease \n clinical use of unflattened beams has been investigated from different perspectives ; mainly beam modeling , plan verification , and case planning . \n the most particular work of modeling an unflattened beam in tps is obviously the way to account for the conical shape of the beam profile . \n this has been previously accomplished by replacing the conical reduction which simulating the ff with a negative reduction . in the present work , \n the energy fluence was modeled by an easier way of providing the tps with an arbitrary profile . \n although no modeling details presented , successful modeling of fff beam in other tps had also been exemplified . \n it seems that handling unflattened beams in today 's tps is no longer a problem . \n several groups working on fff beams have presented imrt verification using various phantoms and measurement devices in their work . \n from all these investigations , it could be extrapolated that dose calculation accuracy in state - of - the - art tps will certainly not be impaired when removing the ff . \n considering that the fff - vmat plans are not intended for clinical use , dosimetric verification was thus not presented in this work . in a whole , for the npc cases used in the present work , \n as the flattening filter ( ff ) is one of the main scattering elements in the treatment head , a better oar sparing is reasonably expected when applying fff beam in clinical treatment . \n peripheral doses in imrt and sbrt treatment were reported to be significantly decreased in anthropomorphic phantom measurements . as dose to organs close to the target , \n though the extent of improvement was much less , a better oar protection for unflattened beams had also been confirmed by a number of authors . \n according to table 2 , the results in our study generally support these reported data . whereas , a similar planning study of advanced npc cases using eclipse tps and varian truebeam linac performed by zhuang et al . showed that oar sparing of unflattened beam vmat plans was somewhat inferior to that of flattened beam . \n this may indicate that in a comparison planning study of vmat technique , patient characteristics , planning processes , tpss , and linacs can affect the comparison results . \n as vmat and fff are relatively new techniques in radiotherapy , to further explore their potentials , planning experiences may need to be accumulated and inter - comparison of various tpss and linacs may also needed to be carried out . \n the increase in dose rate is one of the most obvious and attractive effects when removing the ff . due to the variety in treatment techniques , \n experimental data from various authors can serve as good references . up to now , bot reduction of more than 70% had been reported in srt treatment and ~33% in breast and prostate treatment . \n the bot in our study was ~24% less for fff - vmat plans , which was remarkably lower than the above mentioned data . \n obviously , in terms of treatment time , treatments with small target size and less mlc movement could benefit more from the increased dose rate of the fff beam . \n planning study of various cases using field in field technique illustrated that segments number ratio of fff beam to ff beam increase with an increased ptv volume . \n this explains why the relative time decreasing of fff beam in npc vmat cases is less than the reported value . \n although the percentage reduction of bot in complicated npc case was relatively less , the actual time saved was still beneficial in terms of patient comfort as well as patient outcome . in our study \n , the optimization parameters were changed over multiple iterations in order to produce the fff - vmat plan that meets all the dvh criteria . \n one issue of such planning process is termed the weight paradox by deasy , whereby the optimal choices for the relative weights of different ptv and oar optimization criteria are not known and may take many iterations of trial and error to determine . \n choosing criteria that are too constraining for the oar can compromise the target coverage , or vice versa . in the optimizing of a ff - vmat plan using parameters \n derived from a fff - vmat plan in our study , there 's always a possibility that the resulting ff - vmat plan was suboptimal . our way to avoid this problem \n was tried to make the optimization parameters as general as possible in the optimization process . to be specific \n , the number of optimization parameters and iterations of trial and error were kept as fewer as possible . to achieve this goal , \n our results showed that almost all the doses to targets and oars of the ff - vmat plans met the clinical requirements . \n the beam modeling and planning process demonstrated that commercial tps used in our study was able to handle unflattened beams . \n the plan comparison results revealed that in the npc treatment , the fff beam when compared to the ff beam , prone to improve the normal sparing while achieving similar target dose distribution . \n decreasing of beam - on time in npc cases was less notable but remains beneficial .", "role": "user" }, { "content": "purpose : to explore the dosimetric effects of flattening filter - free ( fff ) beams in volumetric modulated arc therapy ( vmat ) of nasopharyngeal carcinoma via a retrospective planning study.materials and methods : a linear accelerator ( linac ) was prepared to operate in fff mode and the beam data were collected and used to build a model in tps . for 10 nasopharyngeal carcinoma ( npc ) cases , vmat plans of fff beams and normal flattened ( ff ) beams were designed . \n differences of plan quality and delivery efficiency between fff - vmat plans and filter filtered vmat ( ff - vmat ) plans were analyzed using two - tailed paired t-tests.results:removal of the flattening filter increased the dose rate . averaged beam on time ( bot ) of fff - vmat plans \n was decreased by 24.2% . \n differences of target dose coverage between plans with flattened and unflattened beams were statistically insignificant . for dose to normal organs , up to 4.9% decrease in v35 of parotid grand and 4.5% decrease in averaged normal tissue ( nt ) dose was observed.conclusions:the tps used in our study was able to handle fff beams . the fff beam prone to improve the normal tissue sparing while achieving similar target dose distribution . \n decreasing of bot in npc cases was valuable in terms of patient 's comfort .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: use of antiepileptic drugs ( aeds ) during pregnancy presents the dilemma of minimising the risk of seizure and avoiding adverse effects in the unborn child . \n various studies revealed that prenatal exposure of aeds imparts serious effects on infants [ 13 ] . \n further , prenatal exposures to aeds were also reported to produce cognitive impairment [ 4 , 5 ] . \n janz and fuchs reviewed that exposure to aed during pregnancy increases the risk of miscarriage and stillbirth rate . \n however , little attention was paid to the cellular effects of aeds during postnatal development and in adulthood . \n lamotrigine ( ltg ) , a phenyltriazine derivative , is one of the most widely used second - generation antiepileptic agents used for both partial and generalised seizures . in pregnant women , \n ltg is reported to produce side effects such as rash , mania , memory and cognitive problems , mood changes , runny nose , cough , nausea , indigestion , abdominal pain , weight loss , vaginitis , and leukopenia and retardation in development of fetus [ 810 ] . \n recently , exposure to ltg during pregnancy was shown to impart adverse outcome within different developmental domains . \n on the other hand its use in pregnancy is associated with risk of seizure deterioration , because its clearance is accelerated in pregnancy . \n this reveals the need of additional information on the therapeutic window of ltg or its possible toxic effects in pregnancy . \n prenatal exposure to ltg ( 520 mg / kg / day ) alone and in combination with mx-801 , phenobarbital , or phenytoin resulted in cell death in the neonatal rat brain . \n but , katz et al . showed no such effects in the same corresponding dose . \n thus the effects of ltg during pregnancy , offspring development , and behaviour are still needed to be studied . \n the present study was undertaken to investigate the effects of prenatal exposure of ltg on postnatal development and its impact on offspring behaviour in rats . \n ltg was a kind gift from m / s sun pharmaceutical pvt . ltd . , \n trizol reagent was purchased from sigma aldrich , usa . unless mentioned , all other chemicals and reagents were of analytical grade . \n animals were housed in polypropylene cages in a well - ventilated room ( air cycles : 1215 air changes / min , recycle ratio : 70 : 30 ) under an ambient temperature of 23 2c and 4065% relative humidity , with an artificial photoperiod of 12 h light / dark cycle . \n they were provided with rodent feed ( provimi animal nutrition india pvt . ltd . ) and purified water ad libitum . \n animals were acclimatized for a period of 7 days to the laboratory conditions prior to initiation of the experiment \n . guidelines of guide for the care and use of laboratory animals ( institute of laboratory animal resources , national academic press 1996 , nih publication number 85 - 23 , revised 1996 ) were strictly followed throughout the study . \n institutional animal ethics committee ( iaec ) , sri ramachandra university , chennai , india , approved the study protocol ( iaec / xiv / sru/99/2008 ) . \n following acclimatization , female rats were introduced with proven breeder during night time ( 18:00 ) and were isolated during day hours ( 09:00 ) in the ratio of 3 : 1 , respectively , for copulation . \n vaginal smear test was performed for each female rat every 24 h and the pregnancy were confirmed by the existence of diestrum stage for three consecutive days . \n the day of confirmation of pregnancy was designated as gnd 3 and the pregnant rat was isolated into a separate cage . \n the dose of ltg was arrived from the maximum recommended human dose ( 500 mg ) in the management of epilepsy ( http://www.drugs.com/ ) . \n pregnant rats were randomized into 4 groups ( 6 in each ) based on stratified body weight . \n group - i received vehicle ( 0.5% cmc ; 10 ml / kg , p.o . ) ; group - ii , iii , and iv received ltg at 11.5 , 23 , and 46 mg / kg , p.o . \n , respectively ( three - dose regimen was selected to investigate the dose dependent response ) . \n body weight gain was measured on postnatal days once in a week till the study termination . \n the day of occurrence for pinna detachment , incisor eruption , eye opening , vaginal opening , and testes descent was also recorded . \n offspring were allowed to mature for 90 days with free access to food and water ad libitum . \n elevated plus maze was constructed of black painted wood with two open arms ( 50 10 1 cm ) and two closed arms ( 50 10 40 cm ) extending from a common central platform ( 10 10 cm ) and elevated to 45 cm above floor level . \n experiments were carried out in a sound - attenuated , temperature - controlled room and illuminated by two 60 w fluorescent light . \n on pnd 91 , rats were individually placed in the center of the maze facing open arm . \n number of entries into open and closed and time spent in open and closed arms were recorded for a period of 5 min [ 1619 ] . \n open field apparatus consisted of a plywood floor ( 96 96 cm ) with high walls . \n the entire apparatus was painted black except for 6 mm thick white lines which divided the floor into 16 squares . \n on pnd 91 , each animal was placed at one corner of the apparatus and observed for next 5 min . \n the number of squares crossed , immobility period ( in seconds ) , and number of rearing and grooming were recorded . \n radial arm maze was made of black painted wood finished with a polyurethane coating and consisted of 8 arms with a center platform of 60 cm in diameter . \n a disposable plastic cup was placed at each end of the arm to reinforce the sweet smash and all arms were baited with either a food cup or an empty cup . \n the offspring were food - restricted to 8590% and maintained for the duration of training and testing period . \n the maze task was divided into three phases : adaptation , training , and retention phases . in adaptation phase , \n the rats were allowed to explore the radial arm maze by 3 5 min trials . during this period , \n all of the arms of the maze were baited with the food so that the rats received experience in gaining a feed reinforcement by completely traversing an arm and reaching into the food cup . \n time taken by the animal to move from the starting point ( lag period ) , number of working memory errors , and time taken by the animal to munch the food in all arms were recorded . during the training period , four \n the trial was terminated when the rat has entered and eaten from all the four baited arms . at the end of the three trials of each day , \n lag time , number of reference memory errors , working memory errors , correct entries , and total time taken by the animal to munch the food were recorded . \n after behavioural assessment , all the experimental animals were euthanized using co2 exposure and cortical brain structures were collected for gaba - a and gaba - b mrna expression . \n briefly , the total rna was extracted using trizol reagent ( sigma , usa ) . \n after homogenization , the tubes were incubated for 10 min and centrifuged at 1000 rpm for 5 min . \n 200 l of chloroform was added to the supernatant , allowed to incubate for 5 min at room temperature , and centrifuged at 12000 rcf for 20 min . \n then 500 l of isopropyl alcohol was added to the supernatant to precipitate total rna and centrifuged at 12000 rcf for 15 min following the incubation period of 10 min . \n supernatant was decanted carefully and pellet was washed thrice with 75% alcohol and centrifuged at 12000 rcf for 15 min and the pellet was dried . \n the pellet was resuspended in rnase - free water and stored in 80c until use . \n the isolated rna was allowed to undergo reverse transcription and polymerization reaction to get cdna using rt - pcr master cycler gradient ( genet bio , korea ) . \n the gene expression was analyzed using the bands formed in agarose gel electrophoresis , captured using gel documentation unit ( vilber laumar , germany ) and quantified by bio i d software . \n primers sequence used were as follows : gaba - a : sense , 5-aag gac cca tga cag tgc tc-3 ; antisense , 5-ggc tcc ctt gtc cac tca ta-3. gaba - b : sense , 5-gct gga tgg tta cca cat ag-3 ; antisense 5-ggt cac agg agc agt gat g-3 and -actin : sense , 5-tgc tgt ccc tgt atg cct ct-3 ; antisense , 5-agg tct tta cgg atg tca acg-3 . \n mean differences between the groups were analysed by one way anova followed by tukey 's multiple comparison as post - hoc test . \n administration of ltg , at 46 mg / kg , p.o , produced severe signs of toxicity such as hyperesthesia , vocalisation , recumbency , vaginal bleeding , nasal discharge , and finally death of the dam between gnd 15 and 17 . \n a significant decrease in body weight , food , and water consumption was observed in ltg ( 11.5 and 23 mg / kg , p.o ) administered dam on gnd 14 ( f(3,20 ) = 5.81 , p < \n 0.01 ; f(3,20 ) = 43.11 , p < 0.01 and f(3,20 ) = 15.51 , p < 0.01 , resp . ) and 21 ( f(2,15 ) = 6.74 , p < 0.01 ; f(2,15 ) = 55.23 , p < 0.01 and f(2,15 ) = 13.08 , p < 0.01 , resp . ) when compared to control ( table 1 ) . ltg ( 11.5 and 23 mg / kg , p.o ) significantly increased ( f(2,15 ) = 23.83 , p < 0.01 ) the gestational period when compared to control rats . no significant difference in litter size between the groups was observed . \n however , a nonsignificant decrease in pups viability index was observed in ltg administered group when compared to control group ( table 2 ) . \n ltg ( 11.5 and 23 mg / kg , p.o ) produced a significant delay in incisor eruption in both male ( f(2,15 ) = 6.96 , p < 0.05 ) and female ( f(2,9 ) = 6.36 , p < 0.05 ) offspring when compared to control offspring . a similar observation was recorded in vaginal opening in female offspring ( f(2,9 ) = 286.5 , p < 0.01 ) . \n there were no significant differences in the day of pinna detachment , eye opening , and testes decent observed between ltg and control offspring ( table 3 ) . \n no significant difference in body weight was observed in both male and female offspring in comparison to control offspring throughout the study ( figures 1 and 2 ) . \n ltg male showed no significant difference in number of entries and time spent between open and closed arms . \n however , ltg female ( 23 mg / kg , p.o ) showed a significant increase in number of entries ( f(2,9 ) = 5.14 , p < 0.05 ) and time spent ( f(2,9 ) = 58.57 , p < 0.01 ) in open arms and decreased number of entries ( f(2,9 ) = 20.88 , p < 0.01 ) and time spent ( f(2,9 ) = 58.57 , p < 0.01 ) in closed arms when compared to control rats ( table 4 ) . \n no significant difference was observed in number of squares crossed , immobility period , and between the experimental groups . \n however , a significant ( f(2,9 ) = 4.07 , p < 0.05 ) increase in rearing behaviour was observed in ltg ( 23 mg / kg , p.o ) female offspring when compared to control group ( table 5 ) . \n there was no significant difference in lag period , number of reference and working memory errors , number of correct entries , and total time taken by the animal to munch the food recorded between the experimental groups ( table 6 ) . \n mrna expression of gaba - a was found to be significantly ( f(2,3 ) = 17.07 , p < 0.05 ) downregulated in ltg female offspring ( 23 mg / kg , p.o ) when compared to counterparts ; whereas , no difference in gaba - b expression was observed between the experimental groups ( figure 3 ) . \n use of antiepileptic drugs , such as ltg and levetiracetam , during pregnancy has become challenging these days as they have toxic effects on the developing embryo . \n administration of ltg in the form of single therapy or polytherapy is at a high risk of developing signs and symptoms of fetal toxicity . \n the present study demonstrates that prenatal exposure of ltg in rats produced severe signs of toxicity in dam and gender differential behavior in female offspring . \n various studies demonstrated that prenatal ltg exposure at a dose of 250 mg / kg ( half the human equivalent dose ) increases stillbirth and postnatal death of the offspring [ 25 , 26 ] . in the current study , \n gestational ltg exposure at 46 mg / kg produced severe toxic signs such as hyperesthesia , vocalisation , recumbency , vaginal bleeding , nasal discharge , and finally death of the dam . \n . showed that lamotrigine administration increases the follicle stimulating hormone ( fsh ) and luteinizing hormone ( lh ) which in turn stimulated estrogen secretion . \n increased estrogen secretion results in maturation of graaffian follicle followed by ovulation which leads to embryo detachment . \n this may be the possible reason for the observed fetal death in the present study . \n in addition , ltg induces the secretion of parathyroid hormone ( pth ) thereby modulating calcium homeostasis leading to osteoporosis . \n it is well known that osteogenesis of the embryo occurs at gnd 1521 in rats . increased serum calcium levels by pth reduce the fetal osteogenesis during embryonic development which could also be one of the possible factors for observed fetal death at gnd 1517 in ltg high dose administered rats . decreased body weight gain and feed and water intake of dam treated with ltg revealing its possible maternal toxic effects . \n further , delayed vaginal opening and incisors eruption in offspring of ltg lower doses group might also be due to its maternal toxic effects . \n on the other hand , it is reported that ltg administration along with the estrogen - containing hormonal contraceptives reduces the serum ltg concentration . \n hence the dose has to be increased when administered with such contraceptives to maintain its level of action . \n in addition , increased estrogen level induces fsh and secretes progesterone and testosterone by feedback control process thereby lengthening the gestational period . \n although progesterone and testosterone levels were not measured in dams , the increased gestational length observed in our study of rats who administered ltg at lower doses may be due to impaired luteolysis and increased progesterone levels . \n earlier studies have shown that blockade of gaba - a receptor in rat brain induces hyperexcitability / anxiolytic behaviour in elevated plus maze [ 30 , 31 ] . \n further , estrogen suppresses gaba - a receptor expression thereby slowing down the gaba mediated inhibition . in the present study , the observed decrease in gaba - a expression and hyperactivation behaviour ( as evidenced by the elevated plus maze and open field test ) may be due to the overactivation of g - protein - coupled receptor 30 ( gpr30 ) by estrogen hormone in the female offspring . put together , the observations showed that the anxiolytic behaviour in female offspring but not the male may be due to the defect in gaba - a expression and also the alterations in gpr30 mediated estrogen secretion . \n in conclusion , the present study demonstrates the potential untoward effects of ltg in pregnant rats and also its influence on the postnatal development and gender based differential behavioural effects in offspring . \n our lab is further investigating the mechanisms and reason for these untoward effects so as to utilise the therapeutic benefits of ltg in a safer way .", "role": "user" }, { "content": "use of antiepileptic drugs ( aeds ) in pregnancy warrants various side effects and also deleterious effects on fetal development . \n the present study was carried out to assess the effects of prenatal exposure to lamotrigine ( ltg ) on postnatal development and behavioural alterations of offspring . \n adult male and female sprague dawley rats weighing 150180 g b. wt . were allowed to copulate and pregnancy was confirmed by vaginal cytology . \n pregnant rats were treated with ltg ( 11.5 , 23 , and 46 mg / kg , p.o ) from gestational day 3 ( gnd 3 ) and this treatment continued till postnatal day 11 ( pnd 11 ) . \n offspring were separated from their dam on day 21 following parturition . \n ltg , at 46 mg / kg , p.o , produced severe clinical signs of toxicity leading to death of dam between gnd 15 and 17 . \n ltg , at 11.5 and 23 mg / kg , p.o , showed significant alterations in offspring 's incisors eruption and vaginal opening when compared to age matched controls . \n ltg ( 23 mg / kg , p.o ) exposed female offspring expressed hyperactive behaviour and decreased gaba - a receptor expression when compared to control rats . \n these results reveal that prenatal exposure to ltg may impart differential postnatal behavioural alterations between male and female rats which paves way for further investigations .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: obesity prevalence has grown dramatically in recent decades and shows no signs of decline . according to the world health organization ( who ) , it is estimated that 1.5 billion people are overweight , of which 500 million are obese.1 obesity and overweight result from a combination of genetic background , environmental , and lifestyle factors , and are intrinsically associated with increased risk of associated disease , such as hypertension , dyslipidemia , and type 2 diabetes.2 several gene - association studies have led to the identification of different loci ( single nucleotide polymorphisms [ snps ] ) that contribute to obesity and overweight.3 one of these snps , rs9939609 , in the fat - mass and obesity - associated ( fto ) gene , has been described as a risk factor to obesity , and strongly associated with body mass index ( bmi ) increments in european adults.4 frayling and colleagues4 demonstrated that the presence of the risk allele a is cumulative and represent a 20% higher risk for the development of obesity and 13% for the development of overweight . \n this association was later confirmed by several other studies in different populations.57 another gene playing an important role in obesity is peroxisome proliferator - activated receptor gamma ( pparg ) , which regulates the adipocyte differentiation , thus influencing bmi , as well as glucose metabolism.8 in particular , snp rs1801282 has been associated with obesity in different populations , with a clear identification of the risk allele g.911 to date , there are no data on the involvement of either of these snps in obesity in the adult portuguese population , and whether the same pattern of risk alleles is present . \n here , we report on the first association study between these snps and obesity for the adult portuguese population , which can provide useful data for the clinical management and risk assessment of obesity . \n all 194 subjects participating in the study were premenopausal caucasian portuguese females between 18 and 50 years old duly informed about the study and having signed an informed consent . as a control group were 99 healthy subjects showing a bmi ranging between 18.5 and 24.9 kg / m with body - weight variation inferior to 10% in the last year . these subjects were either selected during a routine health check or belonged to the staff of curry cabral hospital ( lisbon , portugal ) . \n the case group was composed of 95 subjects showing a bmi 30 kg / m with body - weight variation inferior to 10% in the last year . \n samples were collected from peripheral total blood and preserved at 80c . for analysis , 2 ml of blood was transferred to individual fta ( whatman , maidstone , uk ) microcards , and dna was purified according to the manufacturer s protocol . polymerase chain reaction ( pcr ) \n amplifications were performed on a biometra tgradient thermocycler ( gttingen , germany ) in 25 l final volume with master mix and dna surf hot taq polymerase ( 10 u/l ) ( stab vida , lisbon , portugal ) with the following thermal cycling conditions : initial 15-minute denaturation at 96c , followed by 30 amplification cycles of denaturation at 94c for 1 minute , annealing at 59c for 1 minute , elongation at 70c for 1 minute , and a final elongation at 70c for 5 minutes . \n primers for pparg locus ( genbank accession no nc_000003.11 ) : pparg - f 5-caattcaagcccagtccttt-3 and pparg - r 5-ttatctctgtgcatggctcc-3. primers for fto locus ( genbank accession no nc_000016.9 ) : fto - f 5-gcaaaatggcaacacacact-3 and fto - r 5-aacaccatccttgggctg-3. snp identification was performed via direct sequencing . \n sequencing reactions were carried out with 100 ng/100 bp of the previously pcr - amplified product using big dye version 3.1 technology ( life technologies , carlsbad , ca , usa ) in an applied biosystems 3730xl dna analyzer . to determine the normality of the continuous variables ( age ) , student s t - test was used . to determine the differences between genotype groups of each snp and anthropometric traits , one - way analyses of variance and a post hoc bonferroni test were used . all odds ratio ( or ) \n analysis was performed using binary logistic regression with 95% confidence interval ( ci ) to determine the risk of each loci to obesity and the respective p - value . \n all statistical analyses were carried out using spss software version 20 ( ibm , armonk , ny , usa ) . \n all 194 subjects participating in the study were premenopausal caucasian portuguese females between 18 and 50 years old duly informed about the study and having signed an informed consent . as a control group were 99 healthy subjects showing a bmi ranging between 18.5 and 24.9 kg / m with body - weight variation inferior to 10% in the last year . these subjects were either selected during a routine health check or belonged to the staff of curry cabral hospital ( lisbon , portugal ) . \n the case group was composed of 95 subjects showing a bmi 30 kg / m with body - weight variation inferior to 10% in the last year . \n samples were collected from peripheral total blood and preserved at 80c . for analysis , 2 ml of blood was transferred to individual fta ( whatman , maidstone , uk ) microcards , and dna was purified according to the manufacturer s protocol . \n polymerase chain reaction ( pcr ) amplifications were performed on a biometra tgradient thermocycler ( gttingen , germany ) in 25 l final volume with master mix and dna surf hot taq polymerase ( 10 u/l ) ( stab vida , lisbon , portugal ) with the following thermal cycling conditions : initial 15-minute denaturation at 96c , followed by 30 amplification cycles of denaturation at 94c for 1 minute , annealing at 59c for 1 minute , elongation at 70c for 1 minute , and a final elongation at 70c for 5 minutes . \n primers for pparg locus ( genbank accession no nc_000003.11 ) : pparg - f 5-caattcaagcccagtccttt-3 and pparg - r 5-ttatctctgtgcatggctcc-3. primers for fto locus ( genbank accession no nc_000016.9 ) : fto - f 5-gcaaaatggcaacacacact-3 and fto - r 5-aacaccatccttgggctg-3. snp identification was performed via direct sequencing . \n sequencing reactions were carried out with 100 ng/100 bp of the previously pcr - amplified product using big dye version 3.1 technology ( life technologies , carlsbad , ca , usa ) in an applied biosystems 3730xl dna analyzer . \n to determine the normality of the continuous variables ( age ) , student s t - test was used . to determine the differences between genotype groups of each snp and anthropometric traits , one - way analyses of variance and a post hoc bonferroni test \n analysis was performed using binary logistic regression with 95% confidence interval ( ci ) to determine the risk of each loci to obesity and the respective p - value . \n all statistical analyses were carried out using spss software version 20 ( ibm , armonk , ny , usa ) . \n figure 1 shows the population characterization by allele and genotype frequencies for fto and p parg snps . \n significant differences ( p<0.05 ) were found only among the different genotypes of fto rs9939609 for bmi , fat mass , and waist circumference . \n genotype frequencies for fto rs9939609 were 24.74% t / t , 56.70% a / t , and 18.56% a / a . when comparing case and control groups , no significant deviation from the hardy weinberg equilibrium of allele frequencies \n was observed for this locus ( p=0.053 ) , with a majority of individuals being heterozygous ( a / t ) . \n data showed that the t allele is more frequent in subjects with bmi values between 18.5 and 24.9 kg / m , whereas the a allele is preeminent in subjects with bmi 30 kg / m . \n for pparg rs1801282 , the allele frequencies were 80.93% for homozygous c / c , 1.03% for homozygous \n again , no significant deviation from the hardy weinberg equilibrium of allele frequencies was observed for pparg rs1801282 ( p=0.97 ) . \n the presence of the a allele in fto rs9939609 does not per se confer risk for obesity in the studied population . \n however , significant differences in allele frequencies between the control and case groups were found for fto rs9939609 ( p<0.05 ) , indicating a 2.5-fold higher risk for obesity for homozygous a / a individuals ( or=2.571 , ci 1.0486.308 ; p=0.039 ) . comparison of homozygous a / a individuals with t allele carriers ( either homozygous t / t or heterozygous a / t ) clearly shows a significant association of homozygous a / a with obesity ( or=2.451 , ci 1.1455.243 ; p=0.021 ) ( table 2a ) . what is more striking is the allelic expression of a / a homozygosity in subjects with a bmi 40 kg / m , ie , class iii obesity \n considering this subgroup of obese women compared to those with class i and class ii obesity , an or=4.044 ( ci 1.09914.878 ; p=0.035 ) was found ( table 2b ) . \n analysis of pparg rs1801282 showed no association with obesity ( p>0.05 ) within the studied population . \n the worldwide prevalence of obesity has been increasing dramatically in the last few decades , and portugal is no exception , where a 13.8% prevalence of obesity has been recorded.12 association studies have highlighted the influence of snps in obesity , with particular focus on fto rs9939609.13,14 thus far , no data on the possible association of this snp to obesity in the adult portuguese population has been reported . here , for the first time , we demonstrate an association between the fto rs9939609 homozygous aa genotype and increased bmi when compared to homozygous tt . \n significant differences were found between control and case group confirming the increased risk for obesity of homozygous aa at this locus . also , with the post hoc bonferroni test , it was possible to determine that individuals with both a alleles in fto rs9939609 show 6.372.35 ( p=0.022 ) higher bmi , 11.994.86 kg ( p=0.043 ) higher body - fat mass and 13.314.87 cm ( p=0.020 ) higher waist circumference compared to t - allele carriers . \n these data are in clear agreement with what has been reported for other populations of european origin.57,15,16 our data show that in the adult portuguese population , this polymorphism confers an even higher risk for class iii obesity ( bmi > 40 kg / m ) \n . this may allow identification of those individuals at increased risk and target them for an earlier clinical and lifestyle intervention . \n this idea has been recently reinforced by the report of albuquerque and colleagues showing a strong association of fto rs9939609 with obesity in portuguese children.17 together , these data may prove useful for a structured public health strategy within the european union . \n conversely , pparg rs1801282 showed no association with obesity within the studied population , as no significant difference was found between control and case subjects ( p>0.05 ) . in european populations , \n pparg rs1801282 has shown association with obesity and higher bmi for homozygous carriers of the g allele ( p<0.05).10 nevertheless , no association was found in other studies,1820 indicating that this snp may differ between populations and probably should not be considered as a strong genetic marker to evaluate risk for obesity as fto rs9939609 is . despite reports on a relation between pparg rs1801282 and diabetes type 2,21 we observed no relation in our study ( p>0.05 ) . \n the relevance of pparg rs1801282 as a genetic marker to assess risk for obesity and high insulin levels in premenopausal portuguese women is , therefore , negligible . \n thus far , this is the first association study involving obesity - related genetic polymorphisms in the adult portuguese population . \n data show that fto rs9939609 could be useful for the clinical management of obese women . \n nevertheless , additional data are required , namely inclusion of males and youth subjects , to fully characterize the involvement of these loci in the development of obesity within the portuguese population .", "role": "user" }, { "content": "purposewe evaluated the association between risk of obesity in the portuguese population and two obesity - related single - nucleotide gene polymorphisms : fat - mass and obesity - associated ( fto ) rs9939609 and peroxisome proliferator - activated receptor gamma ( pparg ) rs1801282.patients and methodsa total of 194 portuguese premenopausal female caucasians aged between 18 and 50 years ( 95 with body mass index [ bmi ] 30 g / m2 , 99 controls with bmi 18.524.9 kg / m2 ) participated in this study . \n the association of the single - nucleotide polymorphisms with obesity was determined by odds ratio calculation with 95% confidence intervals.resultssignificant differences in allelic expression of fto rs9939609 ( p<0.05 ) were found between control and case groups , indicating a 2.5-higher risk for obesity in the presence of both risk alleles when comparing the control group with the entire obese group . \n a fourfold - higher risk was found for subjects with class iii obesity compared to those with classes i and ii . no significant differences in bmi were found between the control and case groups for pparg rs1801282 ( p>0.05).conclusionfor the first time , a study involving an adult portuguese population shows that individuals harboring both risk alleles in the fto gene locus are at higher risk for obesity , which is in agreement to what has been reported for other european populations .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: marburg disease is an acute form of multiple sclerosis ( ms ) that is marked by rapid onset and often continual progression of the demyelination process . \n the national multiple sclerosis society estimates the prevalence of ms to be around 135 per 100,000 population in the u.s . , and a total ms population of approximately 400,000 . \n fortunately , marburg disease is very rare and may be encountered once in a neurosurgeon s career . \n our patient is a 38-year - old african american male who was admitted because of right footdrop . \n his past medical history was significant for hypertension , diabetes mellitus , and rheumatoid arthritis . \n he was given a medication for rheumatoid arthritis back in the early 2000s but discontinued it shortly after because of side effects . \n he could not remember what it was . on physical exam , strength was 5/5 in the upper extremities and left lower extremity and 2/5 in the right lower extremity . \n sensation to light touch and pinprick was intact . on mri of the brain , there was a 2.9 x 2.5 x 2.3 cm cystic mass in the left superior medial frontal lobe . \n the patient underwent bone scan and ct of the chest , abdomen , and pelvis . \n the final pathology report came with the diagnosis acute demyelinating disease , known as marburg 's disease or marburg 's variant of multiple sclerosis . \n hematoxylin and eosin sections revealed a process exclusively involving the white matter with sharp demarcation between the gray and white matter . \n the white matter appeared mostly replaced by histiocytes and reactive astrocytes ( figure 2a ( fig . \n 2 ) ) . there was an accompanying perivascular lymphocytic infiltrate ( figure 2a ( fig . \n cd68 immunohistochemistry demonstrated the histiocytes exclusively in the white matter with sparing of the gray matter ( figure 2b ( fig . \n the differential diagnosis would have been subacute ischemic process , however , neurofilament immunohistochemical tests revealed preserved axons within the lesion consistent with a demyelinating disease . \n grocott 's methenamine silver ( gms ) special stain and culture were negative for fungal infection . \n the patient was discharged home and a year and a half later is happily alive and doing well . \n marburg disease , an acute , fulminant , monophasic variant of multiple sclerosis , typically kills within a year , . \n distribution of the lesions is usually indistinguishable from classical multiple sclerosis , but unlike classical ms , they occur simultaneously in all affected areas . on histological examination , lesions are generally similar to those of classical ms though they tend to have more inflammatory infiltrates and appear more destructive . if marburg disease occurs in the form of a sole big lesion it can be radialogically indistinguishable from a brain tumor or abscess . in our case \n , there was no fever , the erythrocyte sedimentationr rate and white blood count were not elevated at admission , and culture of the biopsied material was negative . \n the patient was withdrawn from antibiotics when the final pathology report came confirming a demyelinating disease . \n it is known that multiple sclerosis is more common in whites ; however , when the disease happens in african americans it is usually more severe . \n nobody yet knows for sure why these racial differences exist but many researchers think it is due to differences in the immune system . \n the rheumatoid arthritis in our patient s history is a strong indicator of an autoimmune process going on in the patient s organism . \n although the pathological picture in our case was consistent with the marburg variant of multiple sclerosis , the diagnosis would depend on the progression of the disease . \n the diagnosis will be downgraded to multiple sclerosis - chronic form if the patient follows a remitting course . \n three learning points can be extracted from this case : the marburg variant of multiple sclerosis is rare and requires high index of suspicion.the marburg variant of multiple sclerosis should be included in the differential diagnosis of abscess- and tumor - like lesions on mri.the diagnosis of the marburg variant of multiple sclerosis should be made based on disease course . \n the marburg variant of multiple sclerosis should be included in the differential diagnosis of abscess- and tumor - like lesions on mri . \n the diagnosis of the marburg variant of multiple sclerosis should be made based on disease course . \n \n ", "role": "user" }, { "content": "marburg disease , the fulminant form of multiple sclerosis , is a rare disease that typically kills within a year . \n we had a 38-year - old african american male who presented with right footdrop and was pathologically diagnosed with marburg disease . \n the patient recovered clinically after surgery and stayed stable for more than a year . \n the diagnosis of marburg disease was thus degraded .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: infertility is medically defined as the inability to conceive after a year or more of regular , unprotected sexual intercourse ( 1 ) . with an estimated prevalence , 812% of couples around the world experience difficulty conceiving a child ( 2 ) . \n although the extent of infertility varies considerably among countries , infertility has been recognized as a public health issue worldwide by the world health organization ( who ) , and has the potential to threaten the stability of individuals , relationships and communities ( 3 , 4 ) . \n research has proved the quality of marital relationship is a significant predictor of overall happiness and well - being , while poor marital quality is associated with many family and community problems ( 57 ) . \n infertility has been associated with marital problems and conflicts , and has serious implications for the mental and social well - being of those involved . \n this can be problematic as the marital relationship is seen as the most important source of support in the context of infertility treatment ( 1 , 8) . \n furthermore , the who guidelines concerning the psycho - social aspects of infertility , clearly state that the task of medical staff goes beyond diagnosis and clinical interventions and should include attention to the psychological aspects of fertility disorders and that attention should be paid to enhance the quality of life of infertile couples ( 9 ) . \n therefore , it is necessary to have better understanding of marital relationship in infertility , and an examination of its associated factors . referring to the quality of marital relationship \n , it has frequently been described by marital benefit , marital distress , marital satisfaction and marital adjustment ( 1013 ) . \n though , there were some studies ( 1416 ) assessing the quality of marital relationship in infertility , but they did not have valid outcome due to weak and simple items used as quantitative measures , making it difficult to make comparison and draw general conclusion . \n in addition , while there were some studies with standard measures about marital relationship in infertility , the reported results were unclear and conflicting . \n some research suggested that infertile individuals ( both infertile males and females ) experienced greater dissatisfaction with themselves , their marriages , and infertility - related stress and its treatment had a negative effect on the relationship both directly or indirectly ( 17 , 18 ) . \n other authors indicated infertility might be stressful , but their shared condition made closer mutual support in the couple 's thoughts and feelings , thus had positive effect on their relationship ( 1921 ) . \n findings from earlier studies on marital relationship in infertile individuals , showed a significant correlation between stressful life events and marital quality ( 22 ) . \n in addition , family studies indicated there was difference between the male 's and female 's perceptions of the aspects of marital relationship ( 23 , 24 ) . \n moreover , the individual 's marital relation was related to other characteristics such as socio - economic status ( 25 ) , personality ( 26 ) , mental health ( 27 ) , communication ( 28 ) and duration of marriage ( 29 ) . \n for both the infertile males and females , their marital relationship could be influenced by the above factors directly or indirectly . \n the reason for the latter finding was due to infertility as a mutual condition , and both partners shared the experience of childlessness ( 30 ) . \n however , considering the interactions between couples that may be more important for marital quality than social or personal traits ( 31 ) , the change in martial relationship in infertile couples should be given more attention to the couple 's interaction patterns on relationship , not only analyze discrepant or congruent views in managing infertility stress . on the other hand , husbands and wives marital quality have been found to be significantly and positively correlated with ( 32 ) , which suggested partner 's marital quality should be discussed to explore its considerable effect on the other side . in order to have a clear understanding of marital relationship in infertility , it is necessary to examine the determinants that might be involved differently affect marital relationship . \n the aim of this systematic review is to summarise the published findings on marital relationship and infertile subjects , specifically the original data were based on standardized instruments in infertile males , infertile females or both infertile couples . \n to be included in the review , the selected articles had to meet the following criteria : ( 1 ) peer - reviewed articles published in english between 1990 and 2011 ; ( 2 ) the primary or secondary objective was to assess marital relationship in the context of infertility ; ( 3 ) the study participants comprised of infertile individuals , or infertile couples comprised infertile subjects and their partners . \n all participants were not in marital separation ; ( 4 ) a relevant , validated instrument was used to assess marital relationship . \n thus , reviews , editorials , debates , letters , case reports , non - peer - reviewed articles , meeting abstracts and brief communications were excluded . in this study , \n a systematic literature review was conducted using the following electronic databases as the most appropriate resources to identify published studies : medline ( ovid ) , psycinfo ( ovid ) and scopus . \n the search was compiled using keywords and phrases separated by the boolean word or \n : marital relationship or marital quality or marital satisfaction or marital adjustment or marital distress in combination with infert * or childless * in the title , abstract , or keywords . \n since some studies linked with marital relationship are explored in the context of clinical treatment , we included the following terms too : in - vitro fertilization ( ivf ) or intra - cytoplasmic sperm injection ( icsi ) or assisted reproduction ( ar ) . \n many of the searches generated duplicate articles , or articles which were unrelated to the study , these were not considered in the review . in the process of extraction , one of the investigators reviewed both the tile of the citation and the abstract to determine its suitability for inclusion . \n firstly , the titles and abstracts following with the search strategy were evaluated for the selection of eligible studies . \n some studies were excluded at this stage as they were scarce of evidence with regard to the inclusion criteria . \n secondly , the full - text of selected studies were further evaluated to decide whether they fulfilled the inclusion criteria . \n the quality of the included studies was assessed using the criteria checklist ( table 1 ) , which was derived from some systematic review studies ( 3338 ) , and adjusted to fit the research questions . \n the criteria for evaluating the quality of studies included in our study were : the quality of the measure instrument , the profile of study participants , study design and main results . \n the criteria checklist comprised 16 items ; each item was scored with one point if the study met a criterion , and a score of zero if the study had an insufficient or no description of the item . \n studies scoring 75% or more of the maximum attainable score ( 12 points ) were considered to be of high quality . \n studies scoring between 50 and 75% ( between 8 and 12 points ) were rated as moderate quality , and scores lower than 50% ( 7 points ) were considered as low - quality studies . \n list of criteria for assessing the quality of studies on marital relationship in the infertile and/or their spouse / partners * the criteria checklist was based on an established criteria for systematic review reported in the literature ( 1520 ) \n to be included in the review , the selected articles had to meet the following criteria : ( 1 ) peer - reviewed articles published in english between 1990 and 2011 ; ( 2 ) the primary or secondary objective was to assess marital relationship in the context of infertility ; ( 3 ) the study participants comprised of infertile individuals , or infertile couples comprised infertile subjects and their partners . \n all participants were not in marital separation ; ( 4 ) a relevant , validated instrument was used to assess marital relationship . \n thus , reviews , editorials , debates , letters , case reports , non - peer - reviewed articles , meeting abstracts and brief communications were excluded . \n in this study , a systematic literature review was conducted using the following electronic databases as the most appropriate resources to identify published studies : medline ( ovid ) , psycinfo ( ovid ) and scopus . \n the search was compiled using keywords and phrases separated by the boolean word or \n : marital relationship or marital quality or marital satisfaction or marital adjustment or marital distress in combination with infert * or childless * in the title , abstract , or keywords . \n since some studies linked with marital relationship are explored in the context of clinical treatment , we included the following terms too : in - vitro fertilization ( ivf ) or intra - cytoplasmic sperm injection ( icsi ) or assisted reproduction ( ar ) . in addition , citations from these articles which appeared particularly relevant were also sought . \n many of the searches generated duplicate articles , or articles which were unrelated to the study , these were not considered in the review . in the process of extraction , one of the investigators reviewed both the tile of the citation and the abstract to determine its suitability for inclusion . \n firstly , the titles and abstracts following with the search strategy were evaluated for the selection of eligible studies . \n some studies were excluded at this stage as they were scarce of evidence with regard to the inclusion criteria . \n secondly , the full - text of selected studies were further evaluated to decide whether they fulfilled the inclusion criteria . \n the quality of the included studies was assessed using the criteria checklist ( table 1 ) , which was derived from some systematic review studies ( 3338 ) , and adjusted to fit the research questions . \n the criteria for evaluating the quality of studies included in our study were : the quality of the measure instrument , the profile of study participants , study design and main results . \n the criteria checklist comprised 16 items ; each item was scored with one point if the study met a criterion , and a score of zero if the study had an insufficient or no description of the item . \n studies scoring 75% or more of the maximum attainable score ( 12 points ) were considered to be of high quality . \n studies scoring between 50 and 75% ( between 8 and 12 points ) were rated as moderate quality , and scores lower than 50% ( 7 points ) were considered as low - quality studies . \n list of criteria for assessing the quality of studies on marital relationship in the infertile and/or their spouse / partners * the criteria checklist was based on an established criteria for systematic review reported in the literature ( 1520 ) \n as can be seen in figure 1 , the initial search in the online databases identified 910 citations , comprising 65 articles from med - line ( ovid ) , 329 from psycinfo ( ovid ) and 516 from scopus . \n 116 articles were excluded due to the extraction of duplicates . after applying the study inclusion criteria , \n flowchart of study selection progress table 2 \n provided a summary of the 18 published studies that met the inclusion criteria . \n they included studies that investigated the status of marital relationship and its influence across different infertility types . \n all studies had been conducted in a clinical setting , of which , thirteen studies ( 3951 ) were cross - sectional , and five ( 5256 ) were longitudinal . \n the sample sizes differed due to variations in research protocols . in the studies on infertile couples , the sample sizes ranged from 20 ( 43 ) to 525 ( 46 ) ; and in studies on infertile individuals , the sample sizes ranged from 18 ( 47 ) to 520 ( 48 ) . \n the instruments were reliable and valid for the assessment of marital relationship in all of the reviewed studies . \n studies examining marital relationship in infertility in total , all studies described at least two demographic variables and most described at least two clinical variables of interest . the most reported demographic variables were age , ethnicity , economical status , education and duration of the marital relationship . frequently represented clinical variables were type of infertility , type of treatment , time interval since diagnosis and time of medical attention . \n quality scores ranged from 8 ( low quality ) ( 47 ) to 15 ( high quality ) ( 56 ) . \n six studies ( 33% ) were graded as high and twelve ( 67% ) as moderate . among these 18 studies , \n over half had some limitations in methodological quality , 12 ( 66% ) studies could not meet the criteria h participation rates for the infertile groups and/or their spouses were described ( defined as the percentage of eligible patients who gave informed consent ) and they exceeded 70% , 13 ( 72% ) studies could not meet the criteria i information was given about the ratio of non - responders versus responders , 13 ( 72% ) studies could not meet the criteria k the collection of data was prospectively gathered , 13 ( 72% ) \n studies could not meet the criteria l the design was longitudinal ( more than 1 year ) \n , 13 ( 72% ) studies could not meet the criteria n the follow - up period was at least 6 months , 17 ( 94% ) studies could not meet the criteria o the loss to follow - up was described and was less than < 20% . \n three studies were on infertile males marital relationship among the 18 studies , using a cross - sectional design . \n methodological assessment of study quality one study demonstrated that male factor infertility did not have a negative marital impact after controlling for male age , partner 's age , race , religion , educational level , employment status , prior pregnancy , duration of infertility , and prior paternity ( 51 ) . \n another study presented the incidence of partnership disorders within marriage was not different between infertile and fertile males , but the marital dysfunction of infertile males should be given more attention in males over 30 , lower education and infertility lasting 36 years ( 50 ) . \n findings of a third study on the effects of infertility diagnosis on martial relationship in chinese society , indicated no significant differences between infertile males and their spouse regarding infertility stress , but infertile males expressed more marital satisfaction than their partners ( 45 ) . \n studies on marital relationship of infertile females are reported either in specific studies ( five papers ) ( 41 , 49 , 50 , 53 , 55 ) or as part of investigations in couples ( one paper ) ( 45 ) . among infertile females referred for art , the findings indicated infertile females had less stable relationships than fertile females , and the condition \n was negatively correlated with advanced age , increased duration of infertility , and failed ivf - icsi attempts in the past ( 49 ) . \n moreover , more partnership disorders seen within marriage in infertile females appeared to be due to age over 30 , lower education and infertility lasting 36 years ( 50 ) . \n however , those women who became biological mothers through ivf were significantly more satisfied with their marital lives than women who were unsuccessful in ivf and remained childless ( 53 ) , even though marital satisfaction changed in both pregnant and non - pregnant women after the first treatment cycle due to an increase in sexual dissatisfaction ( 55 ) . \n as for the inferile female 's marital satisfaction in different treatment periods , one study demonstrated that marital satisfaction during treatment was significantly lower compared with the periods before and after the treatment . \n in addition , the study found female initiation of treatment , partner 's embarrassment for treatment termination , female 's age and length of treatment period were negatively correlated with marital satisfaction in infertile females for all the three aforesaid periods , but no significant relationship was found between type of infertility ( primary vs. secondary ) and marital satisfaction ( 41 ) . apart from the above studies , which directly selected infertile females as research subjects , another study selected infertile females from infertile couples as research subjects to explore marital relationship . \n the findings indicated that infertile females experienced significantly more distress than their husbands , and were less satisfied with their marriage than their husbands ( 45 ) . amongst the studies on marital relationship in infertile couples , one study ( 45 ) examined marital relationship affected by a gender - specific infertility diagnosis in chinese society , and made comparison between husbands and wives . \n the findings indicated when both partners were infertile women expressed less marital satisfaction than their husbands . \n no differences in marital satisfaction between wives and husbands with unexplained infertility were seen , and only wives with a diagnosed female infertility expressed higher distress than their husbands . \n in other studies , the data on marital relationship were mixed without differentiating gender - specific infertility diagnosis . \n one study suggested marital adjustment of the wives of infertile couples were significantly lower than the scores of controls , but no differences were noted in husbands of infertile couples ( 47 ) . \n however , some studies further demonstrated various factors contributing to marital dissatisfaction in infertile couples , e.g. , age of partners above 30 years , individuals with greater stress , higher emotional distress , lower education , lower income , lengthier treatment , and unsuccessful treatment ( 39 , 43 , 44 , 56 ) . \n in addition , the level of sexual satisfaction in female partners was positively correlated to their marital satisfaction , but the level of infertility - related stress did not contribute significantly to fluctuations in their marital satisfaction . \n by contrast , marital satisfaction of male partners was influenced by the level of infertility stress , and not by their own degree of sexual satisfaction , nor by their wives becoming pregnant ( 52 ) . \n furthermore , coping strategies were emphasized to be correlated with marital relationship and coping strategies such as self - blame , were emphasized to be correlated with marital difficulties in both male and female partners ( 54 ) . \n both escape / avoidance and accepting responsibility coping strategies could diminish marital adjustment in both males and females , but seeking social support and planful problem - solving coping strategies could enhance or did not diminish their marital satisfaction ( 48 ) . considering that infertility is a condition shared by both couples , \n other studies have suggested the intra - couple coping concordance might have different effects on marital relationship . \n one study demonstrated couples with high levels of congruence concerning infertility stress reported significantly higher levels of marital adjustment when compared to couples with different infertility - related stress ( 46 ) . \n another study showed that marital satisfaction was highest in couples where the males were using low levels of emotion - oriented coping , specifically the least satisfaction for women was evident when the woman was using less emotion - oriented coping than her partner or than when both partners were using more emotion - oriented coping strategies ( 42 ) . \n as can be seen in figure 1 , the initial search in the online databases identified 910 citations , comprising 65 articles from med - line ( ovid ) , 329 from psycinfo ( ovid ) and 516 from scopus . \n 116 articles were excluded due to the extraction of duplicates . after applying the study inclusion criteria , \n table 2 \n provided a summary of the 18 published studies that met the inclusion criteria . \n they included studies that investigated the status of marital relationship and its influence across different infertility types . \n all studies had been conducted in a clinical setting , of which , thirteen studies ( 3951 ) were cross - sectional , and five ( 5256 ) were longitudinal . \n the sample sizes differed due to variations in research protocols . in the studies on infertile couples , the sample sizes ranged from 20 ( 43 ) to 525 ( 46 ) ; and in studies on infertile individuals , the sample sizes ranged from 18 ( 47 ) to 520 ( 48 ) . \n the instruments were reliable and valid for the assessment of marital relationship in all of the reviewed studies . \n studies examining marital relationship in infertility in total , all studies described at least two demographic variables and most described at least two clinical variables of interest . \n the most reported demographic variables were age , ethnicity , economical status , education and duration of the marital relationship . \n frequently represented clinical variables were type of infertility , type of treatment , time interval since diagnosis and time of medical attention . \n quality scores ranged from 8 ( low quality ) ( 47 ) to 15 ( high quality ) ( 56 ) . \n six studies ( 33% ) were graded as high and twelve ( 67% ) as moderate . among these 18 studies , \n over half had some limitations in methodological quality , 12 ( 66% ) studies could not meet the criteria h participation rates for the infertile groups and/or their spouses were described ( defined as the percentage of eligible patients who gave informed consent ) and they exceeded 70% , 13 ( 72% ) studies could not meet the criteria i information was given about the ratio of non - responders versus responders \n , 13 ( 72% ) studies could not meet the criteria k the collection of data was prospectively gathered , 13 ( 72% ) \n studies could not meet the criteria l the design was longitudinal ( more than 1 year ) \n , 13 ( 72% ) studies could not meet the criteria n the follow - up period was at least 6 months , 17 ( 94% ) studies could not meet the criteria o the loss to follow - up was described and was less than < 20% . \n three studies were on infertile males marital relationship among the 18 studies , using a cross - sectional design . \n methodological assessment of study quality one study demonstrated that male factor infertility did not have a negative marital impact after controlling for male age , partner 's age , race , religion , educational level , employment status , prior pregnancy , duration of infertility , and prior paternity ( 51 ) . \n another study presented the incidence of partnership disorders within marriage was not different between infertile and fertile males , but the marital dysfunction of infertile males should be given more attention in males over 30 , lower education and infertility lasting 36 years ( 50 ) . \n findings of a third study on the effects of infertility diagnosis on martial relationship in chinese society , indicated no significant differences between infertile males and their spouse regarding infertility stress , but infertile males expressed more marital satisfaction than their partners ( 45 ) . \n studies on marital relationship of infertile females are reported either in specific studies ( five papers ) ( 41 , 49 , 50 , 53 , 55 ) or as part of investigations in couples ( one paper ) ( 45 ) . among infertile females referred for art , the findings indicated infertile females had less stable relationships than fertile females , and the condition was negatively correlated with advanced age , increased duration of infertility , and failed ivf - icsi attempts in the past ( 49 ) . \n moreover , more partnership disorders seen within marriage in infertile females appeared to be due to age over 30 , lower education and infertility lasting 36 years ( 50 ) . \n however , those women who became biological mothers through ivf were significantly more satisfied with their marital lives than women who were unsuccessful in ivf and remained childless ( 53 ) , even though marital satisfaction changed in both pregnant and non - pregnant women after the first treatment cycle due to an increase in sexual dissatisfaction ( 55 ) . \n as for the inferile female 's marital satisfaction in different treatment periods , one study demonstrated that marital satisfaction during treatment was significantly lower compared with the periods before and after the treatment . \n in addition , the study found female initiation of treatment , partner 's embarrassment for treatment termination , female 's age and length of treatment period were negatively correlated with marital satisfaction in infertile females for all the three aforesaid periods , but no significant relationship was found between type of infertility ( primary vs. secondary ) and marital satisfaction ( 41 ) . \n apart from the above studies , which directly selected infertile females as research subjects , another study selected infertile females from infertile couples as research subjects to explore marital relationship . \n the findings indicated that infertile females experienced significantly more distress than their husbands , and were less satisfied with their marriage than their husbands ( 45 ) . \n amongst the studies on marital relationship in infertile couples , one study ( 45 ) examined marital relationship affected by a gender - specific infertility diagnosis in chinese society , and made comparison between husbands and wives . \n the findings indicated when both partners were infertile women expressed less marital satisfaction than their husbands . \n no differences in marital satisfaction between wives and husbands with unexplained infertility were seen , and only wives with a diagnosed female infertility expressed higher distress than their husbands . \n in other studies , the data on marital relationship were mixed without differentiating gender - specific infertility diagnosis . \n one study suggested marital adjustment of the wives of infertile couples were significantly lower than the scores of controls , but no differences were noted in husbands of infertile couples ( 47 ) . \n however , some studies further demonstrated various factors contributing to marital dissatisfaction in infertile couples , e.g. , age of partners above 30 years , individuals with greater stress , higher emotional distress , lower education , lower income , lengthier treatment , and unsuccessful treatment ( 39 , 43 , 44 , 56 ) . \n in addition , the level of sexual satisfaction in female partners was positively correlated to their marital satisfaction , but the level of infertility - related stress did not contribute significantly to fluctuations in their marital satisfaction . \n by contrast , marital satisfaction of male partners was influenced by the level of infertility stress , and not by their own degree of sexual satisfaction , nor by their wives becoming pregnant ( 52 ) . \n furthermore , coping strategies were emphasized to be correlated with marital relationship and coping strategies such as self - blame , were emphasized to be correlated with marital difficulties in both male and female partners ( 54 ) . \n both escape / avoidance and accepting responsibility coping strategies could diminish marital adjustment in both males and females , but seeking social support and planful problem - solving coping strategies could enhance or did not diminish their marital satisfaction ( 48 ) . \n considering that infertility is a condition shared by both couples , other studies have suggested the intra - couple coping concordance might have different effects on marital relationship . \n one study demonstrated couples with high levels of congruence concerning infertility stress reported significantly higher levels of marital adjustment when compared to couples with different infertility - related stress ( 46 ) . \n another study showed that marital satisfaction was highest in couples where the males were using low levels of emotion - oriented coping , specifically the least satisfaction for women was evident when the woman was using less emotion - oriented coping than her partner or than when both partners were using more emotion - oriented coping strategies ( 42 ) . \n in studies on infertility , marital issues are increasingly reported to be in part due to the impact of infertility per se , and also due to the importance of mutual support provided during the process of infertility treatment ( 8) . the purpose of this systematic review was to provide an overview of studies that addressed the impact infertility diagnosis and subsequent treatment on marital relationship . in all of the selected studies \n the reasons might be related to the sampling methods in inferile males with newly diagnosed infertility or the short duration of marriage which might not develop infertility stress or marital strain . on the other hand , \n the infertile males perception of infertility could be anther mediator and infertile men undergoing treatment held the optimism for conceiving a child ( 57 ) . from therotical perspective , infertility may place significant stress on a man 's social and marital relationships ( 58 ) , however , the insufficient response of infertile males in the selected studies was not helpful for correlation analysis on infertility and marital relationship . therefore study on infertile males marital relationship should be given more attention via increasing participants response and implementing longitudinal studies to explore the marital relationship and factors influencing it . \n regarding marital relations in infertile females , most studies mainly focused on the effect of treatment , which indicated lower marital satisfaction to be very common in infertile females in comparison with their partners or with fertile females . \n however , only two longitudinal studies made comparison between successful and unsuccessful treatment in infertile female participants . since unsuccessful treatment \n is frequently seen in infertility , longitudinal studies would be necessary to examine marital relationship and its determinants , specifically , among infertile females with treatment failure . \n correlation analysis was also used to explore certain factors related to marital relationship affected by infertility diagnosis or treatment but studies with multivariate analyses controlling for interaction among various variables were very few . therefore , though coping strategies were proved to be crucial in marital adjustment for infertile females with different treatment results , this conclusion might be weak if the studies neglect the effect from infertile females sexuality , infertility experience , social - demographics and psychological well - being , etc . of infertile females . \n as for the related studies on infertile couples , some findings showed treatment ( process and outcome ) to be related to the couples level of marital satisfaction , but some were not ; some findings reflected infertility - related stress could influence the males level of marital satisfaction , but some suggested no relationship between females marital satisfaction and infertility - related stress . \n the above conflicts or ambiguities could be explained by adoption of coping strategies , level of education , economical status , or the age of infertile couples . \n regarding the couple as the research unit , there is merit in analysing how each partner is both influenced by and influences the response by their partners . \n we recommend future studies further explore marital relationships of infertile couple with male factor , female factor , a combination of male and female factors and unexplained factors through using marital pairs as the unit , especially exploring the congruency of couples perceptions of infertility , intra - couple coping , and dyadic relationships . in retrieving the literature , we found most studies had a predominately medical focus , and few studies explored the impact of infertility diagnosis on marital relationship from psychosocial , emotional and sexual perspectives \n . obviously , further research on intimacy , sexuality , marriage and social functions is necessary to understand and provide improved services to infertile couples . \n moreover , there were other limitations in this systematic review , firstly the reviewed papers were confined to the english language literature , thus , some relevant non - english language studies were missed . \n secondly , the papers were reviewed by title , abstract , or keywords ; therefore studies containing relevant marital relationship and infertility - related information as a minor part of the results could have been neglected . \n thirdly , while all studies were selected strictly according to the inclusion criteria , there may still have been some bias due to the lack of a second , independent reviewer . \n fourthly , most data were obtained from clinical settings and the study results might not be representative of the general infertile population . \n given these methodological limitations , it is important to consider all aspects of a systematic review when evaluating their applicability . \n the current review found most studies of high quality , but few studies were scarce of rigor in sample size and study design . \n however , these selected studies provide an outline for understanding the marital relationship in the context of infertility . \n we expect the future studies on marital relationship in infertility can be broadly implemented from both the perspective of infertile couples , across a range of different infertility types , extended sample sizes and longitudinal research , specifically using qualitative methodologies to contribute information to this work .", "role": "user" }, { "content": "backgroundinfertility is a complex issue that affects individuals and groups , and also it has serious implications for the mental and social well - being of those involved . the aim of this review was to assess marital relationship in the context of infertility , using data from infertile individuals or both couples.methodsa literature search was undertaken using multiple databases ( medline , psycinfo and scopus ) to identify and synthesize all relevant literature published from 1990 to 2011 . \n all studies in the systematic review were confirmed using specific inclusion criteria ; the methodological quality of these studies were examined according to a checklist.resultsof the potential 794 articles , 18 studies were included in the final analysis , of which 6 were graded as high quality and 12 as moderate . \n the results indicated male factor infertility did not have a negative marital impact . \n in addition , infertile male participants expressed higher marital satisfaction than their wives . \n infertile females had significantly less stable marital relationship compared to fertile females , which was associated with their socio - demographics and treatment experience . for infertile couples , \n the infertile subjects or their partners marital relationship was affected by either member 's infertility , experience specifically coping strategies . moreover other factors such as sexual satisfaction , age of the infertile couples , education level , and congruency of couples perceptions of infertility were associated with the quality of martial relationship.conclusionalthough the review can provide an outline of marital relationship in infertility , future studies should focus on the perspective from both infertile couple , across a range of different infertility types , including extended sample sizes and longitudinal study designs . \n in addition , more consideration should be given to qualitative study .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: pulpal necrosis is a frequent sequale of trauma to the anterior teeth and if it occurs in young permanent teeth , this will result in the cessation of root development . \n cessation of root development results in teeth with open apex , thin root walls and poor crown root ratio that are difficult to instrument and impossible to seal . \n various treatment options exist to manage non - vital young permanent teeth which includes non - surgical root canal treatment ( apexification ) , single visit apexification , apical surgery and extraction . \n traditionally customized gutta - percha cone was used to obturate immature canal space , but there is a danger of root fracture during lateral condensation . \n long - term calcium hydroxide therapy was considered as the ideal treatment for such teeth , but this therapy has its own disadvantages , like multiple visits , relatively long period of time and alteration of mechanical properties of dentin . \n recently , single visit apexification using mineral trioxide aggregate ( mta ) has gained popularity . \n although this technique is faster compared to traditional apexification , but leaves the tooth with poor crown root ratio and prone to fracture . \n recently maturogenesis or pulpal revascularization is considered as the ideal treatment for non - vital immature permanent teeth . \n maurogenesis stimulates regeneration of a functional pulp dentin complex that allows continued root development , thickening of dentinal walls and apical closure . \n obtaining and maintaining sterile root canal is one of the most important steps during maturogenesis . \n combination of antibiotic drugs , i.e. , ciprofloxacin , metronidazole and minocycline ( 3 mix ) has been used to maintain sterile root canal due to its broad spectrum antibacterial property , low toxicity and biocompatibility . \n the present case reports describe successful maturogenesis of permanent maxillary right central incisor in a 10-year - old child , which sets another example to the mainstream of such treatment option . \n a 10-year - old girl with non - contributory medical history reported to the department of pediatric dentistry , government dental college and hospital , nagpur for the treatment of pain and swelling in maxillary anterior region . \n soft - tissue examination in relation to permanent maxillary right central incisor showed soft - tissue swelling of 1 1 cm . \n the tooth was tender to vertical percussion and showed negative response to thermal ( cold test [ polfofluorange pharma dental handelsges ] ) and electric pulp testing ( parkell farmingdate ) . \n intraoral periapical radiograph of permanent maxillary right central incisor revealed incompletely formed apex with periapical rarefaction [ figure 1 ] . \n after rubber dam isolation and gaining access to the root canal system , the canal debris was loosen with minimal instrumentation and the root canal system was slowly irrigated with 0.5% sodium hypochlorite to prevent further damage to the survived apical papilla . \n minimal instrumentation within the root canal system prevents further weakening of the root canal system . \n a light plain cotton pellet was placed in the pulp chamber for 48 h to facilitate purulent drainage . at the next visit \n working length was measured using diagnostic radiograph , followed by very minimal instrumentation and copious irrigation with normal saline and the canal was dried with sterile paper points . \n mixture of ciprofloxacin , metronidazole and minocycline ( 3 mix ) was placed in the canal and coronal access was sealed with zinc oxide eugenol cement ( dentifiss india ltd . \n patient was recalled after 1 week , the tooth was asymptomatic and the canal was found to be dry . \n intraoral periapical radiograph of 11 showing incompletely formed apex with periapical rarefaction a 23 gauge sharp sterile needle was pushed with a sharp stroke beyond the working length of the canal into the periapical tissue to intentionally induce bleeding into the canal . \n when frank bleeding was evident at the cervical portion of the root canal system , a tight sterile dry cotton pellet was inserted at a depth of 3 - 4 mm into the canal and held there for 10 min to allow clot formation . \n thick paste of calcium hydroxide base ( deepti dental product , raigad ) was placed over the clot and the excess opening was sealed with zinc oxide eugenol cement ( dentifiss india ltd . \n a 23 gauge sharp sterile needle was pushed with a sharp stroke beyond the working length of the canal into the periapical tissue to intentionally induce bleeding into the canal . \n when frank bleeding was evident at the cervical portion of the root canal system , a tight sterile dry cotton pellet was inserted at a depth of 3 - 4 mm into the canal and held there for 10 min to allow clot formation . \n thick paste of calcium hydroxide base ( deepti dental product , raigad ) was placed over the clot and the excess opening was sealed with zinc oxide eugenol cement ( dentifiss india ltd . \n five months radiograph showed thickening of lateral dentinal walls , increased root length [ figure 2 ] . \n nine months radiograph showed increased root length , complete apical closure and thickening of lateral dentinal walls [ figure 3 ] . \n thereafter , the tooth is under follow - up of 15 months without any signs of endodontic failure clinically and radiographically [ figure 4 ] . \n five months periapical radiograph showed thickening of lateral dentinal walls and increased root length nine months periapical radiograph showing maturogenesis fifteen months follow - up periapical radiograph showing no signs of endodontic failure \n maturogenesis is a relatively new treatment modality for non - vital necrotic immature permanent teeth , which allows continued thickening of root dentin and apical closure . \n this biologically based endodontic procedure has several advantages over conventional methods such as ; ( 1 ) continued root development increases the crown root ratio , ( 2 ) continued thickening of root dentin strengthens the thin and week root , ( 3 ) reduces the risk of root fracture during lateral condensation and ( 4 ) easy to obtain apical seal . \n although the exact mechanism of action of maturogenesis is not known , different hypotheses have been proposed : ( a ) presence of few vital pulp cells apically , ( b ) abundance of multipotent dental pulp cell in immature permanent teeth , ( c ) stem cells from periodontal ligament or bone marrow , ( d ) stem cell from apical papilla ( scap ) and ( e ) growth factors releasing from the blood clot . of the above hypothesis scap shows promising results . \n it has been experimentally shown that the removal of an apical papilla halted the development of that particular root despite the pulp tissue being intact . \n in contrast , the root of the tooth containing apical papilla showed normal growth and development . \n so far , different treatment protocols have been presented for creating a favorable disinfecting condition within the root canal system of non - vital immature permanent teeth . \n most of the authors recommended the use of tri - antibacterial paste ( ciprofloxacin , metronidazole and minocycline ) to creating a favorable disinfecting condition in the root canal system . in the present case \n , complete disinfection was obtained using tri - antibacterial paste that resulted in successful maturogenesis . \n studies have shown the tri antibacterial paste is effective in killing the bacteria in the deep layers of root canal dentin and are almost effective against all the pathogens responsible for endodontic failure . \n it is assumed that ones the infection is subsided survived scap under the influence of the hertwig 's epithelial root sheath give rise to formation primary odontoblast to complete root formation . \n we also noticed that maturogenesis in permanent maxillary right central incisor was faster than the physiologic root development of permanent maxillary left central incisor . \n the exact reason for rapid maturogenesis is not known but following hypothesis can be made ; ( 1 ) wide root canals allow rapid transfer of small blood vessels which aid in pulp revascularization by stimulating undifferentiated mesenchymal cells to odontoblast , ( 2 ) young children have high healing potential with more stem cell regenerative potential ; thus , maximized the chances of faster and successful maturogenesis . \n however , in the present case , we placed thick paste of calcium hydroxide over the blood clot . \n the reasons are ( 1 ) calcium hydroxide is time tasted medicament for pulpotomy of primary and young permanent tooth ; ( 2 ) secondly calcium hydroxide is economical compared to mta ; ( 3 ) in the developing countries like india where majority of population can not afford mta . \n although the calcium hydroxide can be used for placement over blood clot , it should not be used as root canal disinfectant because ; ( 1 ) it might damage the cells of apical papilla due to its high ph and tissue dissolving property , ( 2 ) it might alters the mechanical properties of dentin which further increases the chance of tooth fracture , ( 3 ) tightly filled calcium hydroxide reduces the space available for scap to proliferate into the canal . although the clinical and radiographic findings ( continued root development , thickening of dentinal walls and apical closure ) are suggestive of regeneration of pulp dentin complex , human histologic studies are still needed to further evaluate whether maturogenesis procedure truly replicate the pulp dentin complex . \n ( 1 ) tri antibacterial paste ( 3 mix ) can be used as an intra - canal medicament to obtain sterile root canal system during maturogenesis .", "role": "user" }, { "content": "pulpal necrosis in young permanent teeth often results in teeth with open apex , thin root walls and poor crown root ratio . out of the available treatment options maturogenesis \n has been the most conservative option that exploits full potential of pulp for dentin deposition . \n maturogenesis involves disinfecting the root canal system followed by stimulation of blood clot from the periapical tissue , which provides a matrix into which the cell could grow and sealing the coronal excess . in the present case report , \n tri antibacterial paste ( 3 mix ) was used as an intracanal medicament that proved successful in stimulating vital pulp cells of the periapical region for maturogenesis . \n five months radiograph follow - up showed thickening of lateral dentinal walls , which progress until 15 months resulting in apical closure , thickening of lateral dentinal walls and increase root length .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: \n otitis media ( om ) is prevalent in infants , especially those 6 - 18 months old . \n the disease itself can be classified into three types : acute om , om with effusion ( ome ) , and chronic om ( 1 , 2 , 3 ) . \n typically , otoscopy is used to assess the condition of the tympanic membrane ( tm ) surface or its mobility using pneumatic pressure . \n the optics of an otoscope can visualize only the tm surface or if the tm is translucent , the presence of any effusion that might be present immediately behind the tm . \n this subjective observation can be problematic and no quantitative depth - resolved imaging technology exists for imaging the middle ear and assessing the characteristics of any effusion that might be present . \n these weaknesses often result in an incorrect diagnosis , which can subsequently affect treatment and outcomes . to address these weaknesses of standard otoscopy , we have developed the use of optical coherence tomography ( oct ) for non - invasive assessment and quantification of the microstructure of the tm and middle ear , including the presence of bacterial biofilms ( 4 , 5 ) . \n a new primary care imaging system has been developed using advanced oct optical imaging technology ( 6 ) . \n oct is a non - invasive , non - contact optical imaging technology that can effectively reconstruct a depth - resolved high - resolution cross - sectional image of tissues ( 1 - 15 m ) using interferometry and a near - infrared light source ( 7 , 8 , 9 , 10 ) . in ophthalmology , \n oct has become the gold standard for retinal imaging , and can detect disease by measuring the thickness of the retina or retinal nerve fiber layer ( 7 , 11 ) . \n recently , oct applications have focused primarily on characterizing cancer and other disease processes in the larynx ( 12 ) , because oct is ideal for imaging the thin , layered structures of the vocal fold epithelium and lamina propria . \n most oct applications in otolaryngology of the middle and inner ear have been either animal investigations or human temporal bone studies ( 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ) . \n in addition , various research groups worldwide have performed otolaryngology imaging studies using oct ( 13 , 21 , 22 , 23 ) . in this study \n , we demonstrate the wider application of oct technology for non - invasive detection of changes and diagnosing disease associated with the human tm and various types of om . \n in addition , specific features were identified in two - dimensional ( 2d ) oct images of abnormal tms , compared to images of normal tms . \n analysis of a - scan ( axial depth scan ) data successfully identified unique patterns of constituents within effusions . \n among the patients with otological symptoms who visited the department of otorhinolaryngology at kyungpook national university hospital between july and october 2012 , a total of 39 patients who were diagnosed with om using a standard otoendoscopic examination and audiological tests were enrolled and the acquisition of oct images was tried . from oct images , \n six volunteers with normal tm on otoendoscopy were also included and oct images of tm were acquired as a control . \n we examined the clinical use of spectral domain - oct ( sd - oct ) . \n 1a shows a schematic of the sd - oct system and the handheld probe used for these clinical studies . \n a 12-bit complementary metal oxide semiconductor ( cmos ) line - scanning camera ( aviiva em4 2048 pixels , e2v , essex , uk ) with an effective line rate of 70,000 lines / s in 2048-pixel mode was used as the sd - oct detector . a transmission - type diffraction grating ( spatial frequency 1,800 lpmm , nominal aoi / aod 46.05 ; wasatch photonics , north carolina , usa ) was adapted to enhance the light efficiency in the detection path . \n the source was a superluminescent light - emitting diode ( sled ) operating in high - power mode ( sld-35-hp , superlum , schlieren , switzerland ) . \n the sled has a center wavelength of ~870 nm and a spectrum with a full width at half maximum ( fwhm ) of ~65 nm . \n the sled was connected to one end of a 22 ( 50:50 ) fiber - fused coupler ( fc850 - 40 - 50-apc , thorlabs , new jersey , usa ) . \n the sled power measured after the objective lens ( an achromatic lens with a focal length of 75 mm ) was ~6 mw . \n the detected oct signals were transferred to host memory in a computer with four core 2 quad q8200 central processing units ( 2.33-ghz clock rate , intel , california , usa ) via a frame grabber ( pcie-1433 , 850-mb / s bandwidth , national instruments , texas , usa ) over two camera - link cables . \n the computer drove a galvanometer scanner using a data acquisition board ( pcie-6321 , national instruments ) that could provide two analog outputs . to generate the depth - resolved sample reflectivity or a - line , \n the interferogram was transformed using full - range k - domain linearization ( 24 ) . \n real - time , high - resolution oct imaging is possible with this system at a display speed exceeding a 250 khz a - scan rate , and the software used was written in labview ( labview 2011 , national instruments ) . to process signals from the camera , a frame grabber ( ni : pcie-1429 ) with an acquisition rate of 680 \n mb / s was used . to drive the galvanometer scanner , a data acquisition board ( pcie-6115 , national instruments ) with a maximum sampling rate of 10 ms \n 1 shows the handheld oct probe used to acquire the tm . a miniaturized charge - coupled device ( ccd)-based video camera with a size of 16 mm21 mm and 0.27 megapixel was integrated in the handheld oct probe . a white light - emitting diode ( led ) \n was located behind the focusing lens to illuminate the target site . through this system , \n the orientation of oct beam could be identified and a real image of tm surface and cross - sectional oct image could be acquired simultaneously . \n the system sensitivity was approximately 101 db near zero optical delay when the camera was set at an exposure time of 14.1 s . \n the theoretical sensitivity was approximately 116 db because the ideal efficiency of the spectrometer was 73% , and the power at the sample path was 1.8 mw . \n the sensitivity of the system was lower than the theoretical value , mainly because of the insertion loss ( -11.6 db ) between the fiber optics and the 2d galvanometer scanner in the sample path . \n the research protocol was approved by the institutional review board ( 2012 - 12 - 006 ) of kyungpook national university hospital . \n among the patients with otological symptoms who visited the department of otorhinolaryngology at kyungpook national university hospital between july and october 2012 , a total of 39 patients who were diagnosed with om using a standard otoendoscopic examination and audiological tests were enrolled and the acquisition of oct images was tried . from oct images , \n six volunteers with normal tm on otoendoscopy were also included and oct images of tm were acquired as a control . \n we examined the clinical use of spectral domain - oct ( sd - oct ) . \n 1a shows a schematic of the sd - oct system and the handheld probe used for these clinical studies . \n a 12-bit complementary metal oxide semiconductor ( cmos ) line - scanning camera ( aviiva em4 2048 pixels , e2v , essex , uk ) with an effective line rate of 70,000 lines / s in 2048-pixel mode was used as the sd - oct detector . \n a transmission - type diffraction grating ( spatial frequency 1,800 lpmm , nominal aoi / aod 46.05 ; wasatch photonics , north carolina , usa ) was adapted to enhance the light efficiency in the detection path . \n the source was a superluminescent light - emitting diode ( sled ) operating in high - power mode ( sld-35-hp , superlum , schlieren , switzerland ) . \n the sled has a center wavelength of ~870 nm and a spectrum with a full width at half maximum ( fwhm ) of ~65 nm . \n the sled was connected to one end of a 22 ( 50:50 ) fiber - fused coupler ( fc850 - 40 - 50-apc , thorlabs , new jersey , usa ) . \n the sled power measured after the objective lens ( an achromatic lens with a focal length of 75 mm ) was ~6 mw . the detected oct signals were transferred to host memory in a computer with four core 2 quad q8200 central processing units ( 2.33-ghz clock rate , intel , california , usa ) via a frame grabber ( pcie-1433 , 850-mb / s bandwidth , national instruments , texas , usa ) over two camera - link cables . \n the computer drove a galvanometer scanner using a data acquisition board ( pcie-6321 , national instruments ) that could provide two analog outputs . to generate the depth - resolved sample reflectivity or a - line , \n the interferogram was transformed using full - range k - domain linearization ( 24 ) . \n real - time , high - resolution oct imaging is possible with this system at a display speed exceeding a 250 khz a - scan rate , and the software used was written in labview ( labview 2011 , national instruments ) . to process signals from the camera , a frame grabber ( ni : pcie-1429 ) with an acquisition rate of 680 \n mb / s was used . to drive the galvanometer scanner , a data acquisition board ( pcie-6115 , national instruments ) with a maximum sampling rate of 10 ms \n 1 shows the handheld oct probe used to acquire the tm . a miniaturized charge - coupled device ( ccd)-based video camera with a size of 16 mm21 mm and 0.27 megapixel was integrated in the handheld oct probe . a white light - emitting diode ( led ) \n was located behind the focusing lens to illuminate the target site . through this system , \n the orientation of oct beam could be identified and a real image of tm surface and cross - sectional oct image could be acquired simultaneously . \n the system sensitivity was approximately 101 db near zero optical delay when the camera was set at an exposure time of 14.1 s . \n the theoretical sensitivity was approximately 116 db because the ideal efficiency of the spectrometer was 73% , and the power at the sample path was 1.8 mw . \n the sensitivity of the system was lower than the theoretical value , mainly because of the insertion loss ( -11.6 db ) between the fiber optics and the 2d galvanometer scanner in the sample path . \n the research protocol was approved by the institutional review board ( 2012 - 12 - 006 ) of kyungpook national university hospital . \n of the 39 patients , oct images were acquired from 16 patients ( 41.0% ) . the most common cause of failure to acquire an image was a narrow or curved external auditory canal ( n=5 ) . \n other causes were the presence of obstacles , such as profuse otorrhea ( n=3 ) , cholesteatoma material ( n=4 ) , and cerumen ( n=7 ) , and poor compliance ( n=4 ) . \n the thickness of a normal tm in typical region was estimated from six volunteers using a - scan . \n the mean thicknesses ( sd ) were 12211.08 m ( normal tm ) , 32630.28 m ( chronic om ) , 25125.37 m ( adhesive om ) , and 1089.72 m ( ome ) . \n 2 shows representative oct images and data acquired from the normal tms of two volunteers , showing the b - mode ( cross - sectional ) image and an a - scan plot from the central part of the tm after image processing to obtain the thickness and structural information on the tm . while there were small differences among individuals , the normal tm was approximately 122 m thick , which is similar with reported values ( 25 ) . \n in addition , the epidermal , fibrous , and mucous layers of the tm were clearly identified , as reported previously ( fig . \n 3a ) , while the left tm is retracted and turbid on the otoendoscopic examination and non - uniformly thick in the oct examination ( fig . \n the a - scan analysis indicated that the left tm was approximately four times thicker than right tm . \n the pure tone average of four frequencies ( 0.5 , 1 , 2 , and 3 khz ) was 5 db hl in the right ear and 25 db hl in the left . \n the results of the speech reception threshold ( right , 5 db ; left , 30 db ) and speech discrimination ( right , 100% [ 35db ] ; left , 100% [ 60db ] ) tests were comparable with the pure tone average . the right ear has a normal hearing level , while the left is between normal hearing and mild hearing loss . \n the diagnosis for the left tm was chronic om based on the otoendoscopic and oct findings , and the hearing status suggested that the disease was not severe . \n in addition to the size and location of the perforation in the otoscopic image , the thickness and characteristics of the perforation margin was evaluated with the oct image . as seen in the a - scan , thickening and blunting of tm margin \n was detected in all patients with chronic om , although the extent differed . in the case of adhesive om , \n the tm is retracted and in partial contact with the tympanic mucosa on otoendoscopy , as shown in fig . 6a . \n the decrease in the air gap between the tm and tympanic mucosa due to the retraction is shown ( fig . \n the oct scattering signal intensity decreases rapidly in the low - scattering air layer after the strong peak scattering value from the tm , and a weaker scattering signal can be seen from the tm mucosa , as shown graphically by the a - scan . \n 6b is an image of the tm of a patient with ome ; the pattern is similar to that of adhesive om in b - mode . \n however , unlike chronic om , the scattering signal is attenuated gradually with increasing depth into the highly scattering effusion in the a - scan ( fig . \n the most favorable clinical characteristics of oct are its noninvasiveness , lack of radiation , high resolution , and ease of office - based use . however , there are few reports on the clinical application of oct to otology , which might be limited by the difficulty securing a light pathway for the oct device and the diagnostic efficiency of otoendoscopy . in this study , \n real and oct images were acquired simultaneously in real time , so that the findings of each imaging modality supplemented the drawbacks of the other . \n most studies of oct in otology have involved basic research of the middle and inner ear ( 15 , 16 , 19 , 20 , 21 ) or cadaveric temporal bone ( 26 ) . \n ( 27 ) , who coupled an oct system to an operating microscope and they suggested that oct is a useful measurement tool in the middle ear during ossiculoplasty . \n djalilian et al . ( 13 ) obtained images of normal and pathological tms using an oct system coupled with an operating otoscope . \n they obtained cross - sectional images at one frame per second . due to the acquisition speed \n , no tm images could be obtained when the patients moved . with our oct system , \n images were obtained at 42 frames per second , which gave the clinician the ability to examine the tm and middle ear structure . \n nguyen et al . ( 4 ) performed a clinical study using a handheld oct otoscope and focused on the in vivo detection of biofilms , not the utility of a handheld oct otoscope as a diagnostic tool for middle ear disease . in this study \n , we evaluated normal and pathological tms and demonstrated the advantages of the oct images . \n the thickness of normal tms was measurable and the three layers were distinguishable in the high - resolution oct images . \n the mean thickness of a specific region of the normal tms could be used as a standard parameter for evaluating abnormal tms . \n 5 are otoendoscopic and oct images of chronic om , which is commonly seen in outpatient departments . \n the pathological changes in this disease result from either acute or chronic inflammatory reactions , including edematous changes , the infiltration of inflammatory cells , and the presence of persistent bacterial biofilms . \n the oct images provide tomographic information on the pathological region and facilitate evaluation of the extent or severity of disease . \n given the small amount of data , we can not draw conclusions about the relationship between the oct image features and hearing status . however , a study of the clinical role of oct images in finding structural differences related to the hearing level might be valuable . \n long - standing eustachian tube dysfunction can create a negative pressure and resulting effusion in the middle ear cavity . \n ome is often recurrent due to the long - term negative pressure , and the fibrous layer of the tm is thought to become weak and overly compliant . as a result \n , the normal shape and position of the tm can not be maintained , and it collapses and retracts medially . \n 6a is a typical finding of severe retraction . if this progresses , the inner surface of the tm attaches to the middle ear mucosa and fibrous tissue replaces the mucosa , a condition called adhesive om . in ome , \n the effusion liquid and scattered suspended material are distributed evenly in the middle ear cavity , as in fig . \n these examples demonstrate the added information that oct can provide by performing depth - resolved imaging through the tm and into the middle - ear cavity , which is impossible with standard otoscopy or otoendoscopy . as a traditional method for diagnosing om and monitoring the treatment response , \n otoscopy is used to observe only the surface features of the tm , and the findings are combined with the patient 's symptoms and audiometry measurements to direct therapy . \n these diagnostic methods using otoscopy are limited by the information that a surface image of the tm can provide . in this study , we observed sections of the tm in vivo with oct . \n we demonstrated that oct could easily confirm structures behind the tm that are invisible using standard otoscopy . \n the s - shaped external auditory canal is 2.5 - 3 cm in length and 7 - 9 mm in diameter . \n the tm is tilted in the direction of the external auditory meatus by 55 ( 5 , 26 ) . the extent of the curvature and the diameter of the canal influenced the acquisition of oct images , as described in the results . \n therefore , the anterior margin of the tm was not evaluated in the case of anterior perforation and the region of attic retraction or attic cholesteatoma was not visualized using the oct system in some cases . a system with various interchangeable speculums and miniaturized components for the handheld oct probe \n the optic pathway should not be interrupted by obstacles , such as cerumen , otorrhea , or keratin debris ; thus meticulous cleaning is needed . \n lastly , the resolution and brightness of the ccd - based camera , integrated with handheld oct probe , must be upgraded . \n based on our results , oct has the potential to facilitate diagnosis of om by primary care clinicians and otologists . \n although further clinical trials are necessary , this groundwork shows that oct has the potential to be the next - generation detection , diagnostic , and monitoring method for om , and that it can complement or even potentially replace the more traditional otorhinolaryngology instruments .", "role": "user" }, { "content": "we report the application of optical coherence tomography ( oct ) to the diagnosis and evaluation of otitis media ( om ) . whereas conventional diagnostic modalities for om , including standard and pneumatic otoscopy , are limited to visualizing the surface of the tympanic membrane ( tm ) , oct effectively reveals the depth - resolved microstructure below the tm with very high spatial resolution , with the potential advantage of its use for diagnosing different types of om . \n we examined the use of 840-nm spectral domain - oct ( sd - oct ) clinically , using normal ears and ears with the adhesive and effusion types of om . \n specific features were identified in two - dimensional oct images of abnormal tms , compared to images of healthy tms . \n analysis of the a - scan ( axial depth scan ) identified unique patterns of constituents within the effusions . \n the oct images could not only be used to construct a database for the diagnosis and classification of om but oct might also represent an upgrade over current otoscopy techniques.graphical abstract", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the formulation of composite resins has been modified during the past years with the purpose of improving their physical , mechanical and handling characteristics . among the main factors related to the clinical outcome of composite resin restorations , \n the quality of the restorative material - tooth interfacial seal and absence of microleakage are definitely considered1,16 . \n this is largely determined by the degree of polymerization shrinkage of the composite resin and the quality of bonding to tooth structures20 \n . however , other critical factors are well known to contribute to the quality of marginal sealing , such as configuration factor , filling technique , bonding system and modulation of light - curing6 . \n the decrease in shrinkage strain can sometimes be attributed to reduced binding in the polymer network caused by less conversion or to an increased flexibility of the materials . \n however , research in resin formulation has led to structural modification by the development of new acrylic molecules . \n the changes in the organic matrix of the composite resins , therefore , may contribute to the magnitude of polymerization shrinkage . \n the main component of most composite resins used in dentistry is bisgma in its linear form18 . \n the synthesis of bisgma , by the addition of two molecules of glycidylmethacrylate to one bisphenol - a , results in a molecule with two free hydroxyl - groups , which are slightly hydrophilic . in order to make bisgma hydrophobic , \n its structure has been modified by ethoxylation of bisphenol - a at various ethoxylation degrees and final methacrylation , which leads to a more hydrophobic molecule . \n thus , less hydroxyl groups were present in the composite resin and consequently the material became less susceptible to the absorption of liquids12 . among other modifications , it can be mentioned the replacement of bisgma and tegma of the organic matrix by an organic silicium compound known as ormocers7 , which is the acronym of organically modified ceramic . \n therefore , the purpose of this study was to analyze the magnitude of the volumetric polymerization shrinkage of 7 contemporary composite resins to determine whether there are differences among them . \n the null hypothesis is that no significant differences will be detected among the tested materials . \n seven medium- and high - density hybrid composite resins were selected for this experiment : two with organic silicium matrix , two with ethoxylated bisgma and three with bisgma ( as declared by the manufacturers ) . \n the tests were carried out in a standard laboratory under controlled room temperature ( 233c ) and relative humidity ( 505% ) . a scale ( mark and a & d weighing , series hr-200 , the usa ) accurate to 0.0001 g and 0.05% was used . \n one receptacle was empty and the other was immersed in a beaker containing distilled water . \n the water level was kept 1 cm above the specimen5 . to perform the test , 1 g of composite resin , as recommended by astm : d792 specification2 , was placed in a teflon split mould between two strips of silliconated polyethylene and pressed manually with two flat glass plates resulting in a thin disc ( 1.0 mm thick ) . \n the plastic strips and the split mould were carefully removed and the resin was weighed in order to determine the mass of the resin in air ( m1 ) . \n the disc was carefully removed from the scale receptacle in air and was transferred to the receptacle immersed in water and weighed ( m2 ) . according to puckett ; smith14 , no alteration in the weight of resins occurs when they are submerged in water for up to 2 minutes before polymerization . \n five specimens of non - polymerized resins were separately weighed in air and water and the values were used to calculate the specific gravity ( sp gr ) of composite resins before polymerization . at the moment of each weighing , the water temperature was measured with a precision thermometer with accuracy of 0.1c . for this water temperature \n the following equation was used : sp gr = m1/ ( m1-m2 water density ) , where : m1 = mass of resin in air and m2 = mass of resin in water the specimen was removed from water , dried with absorbent paper and then polymerized with a light - curing unit ( led blue star 1 , microdont , so paulo , sp , brazil ) for 20 seconds with light intensity of 1250 mw / cm . \n the densities of the specimens were used to calculate the corresponding volumes as follows : v1= m1/d1 and v2 = m2/d2 , where : v1= volume of unpolymerized resin ; v2= volume of polymerized resin ; m1= mass of unpolymerized resin in air ; m2= mass of polymerized resin in air ; d1= density of unpolymerized resin ; d2= density of polymerized resin after obtaining the pre- and post - polymerization volumes of the specimens , the percentage of volumetric contraction was calculated as follows : % shrinkage= ( v1v2 / v2 ) 100 . \n one - way anova ( =0.05 ) was used to determine statistically significant difference in volumetric shrinkage among the tested composite resins . \n table 2 displays the means and standard deviation of percent volumetric shrinkage for each material . \n suprafill and definite presented the least volumetric polymerization shrinkage , both significantly different ( p>0.05 ) when compared to the other composites . \n surefil , filtek z250 and fill magic were not significantly different ( p<0.05 ) from each other and presented intermediate volumetric shrinkage . \n solitaire and alert presented higher polymerization shrinkage and both were significantly different ( p>0.05 ) from the other resins . \n studies on the matrix formation of the resin complex have shown that bisgma is the main monomer and that the degree of conversion decreases with the increase of its proportion in the composition . \n the authors concluded that the decrease in the conversion rate due to the increase in bisgma content does not decrease the magnitude of strength or hardness of the resin . following the calculation according to the rules for mixtures to keep proportion in these co - monomers \n bisgma is present in most of formulations as the main part of the organic matrix of composite resins due to its low contraction rate when compared to other similar monomers . \n the high viscosity ( 628 pa*s 25c ) of bisgma indicates that there are less degrees of freedom in the bisgma molecule than in the least viscous monomers . \n this leads kinetically to a low degree of conversion , thus resulting in a lower shrinkage . \n due to its high viscosity , it requires dilution with other low - viscosity dimethacrylates such as the oligomers tegma ( triethyleneglycoldimethacrylate ) and edgma ( ethyleneglycoldimethacrylate ) or functional monomers , like hpma ( hydroxypropylmethacrylate ) or aromatics , such as bisema ( bisphenol - a ethoxylated dimethacrylate ) or bisma ( bisphenol - a dimethacrylate ) . as a consequence of polymerization , \n the resin system shrinks mainly because the intermolecular distance of the monomer molecules in the network shortens from 0.3 - 0.4 nm to 0.15 nm , when the double - bonds are polymerized to covalent main - chain bonds11,13 . \n solitaire , a silicon - organic resin ( ormocer ) , showed the highest shrinkage in the present study . in this case , the silicon - backbone is intrinsically connected to four acrylate monomer - groups . \n this material has bisgma ( bifunctional ) , hpma and etma ( ethylenentriglycol methacrylate ) ( nonfunctional ) as co - monomers . \n these nonfunctional monomers show a lower degree of conversion in fotoactivated systems and are able to reduce total contraction . \n however , according to labella , et al.10 , hpma has to be added in approximately 40% in weight to be considered a good mixture with bisgma and , at this level , volumetric contraction is promoted . \n the content of low viscosity monomers and the low filler content may contribute to the high shrinkage level of the solitaire resin . \n watts and hindi19 concluded that a lower initial contraction may be achieved either by special light irradiation regimes ( low to high , or ramped ) or in favorable cases by novel monomer - composite formulations and setting chemistry ( e.g. solitaire ) . \n in other words , these authors consider that light - activation at high intensity would promote the same effect as short - term or low - intensity irradiation in conventional bisgma - based resins . \n alert , with 84% of filler , showed 2.33% contraction , significantly higher ( 15% . ) than that of surefil . \n the matrix of the alert resin is based on ethoxylated bisgma . due to its low viscosity , this monomer has some more polymerization degrees of freedom than bisgma . \n even the use of the fibers that manufacturers recommend to interweave within monomers to improve the material s strength can not compensate the greater intimacy among free radicals , leading to a higher contraction . \n the matrixes of fill magic ( bisgma , bisema , uedma and tegma ) , surefil resin ( bisgma , tegma and udema ) and filtek z250 ( bisgma , bisema and uedma ) have in common the main monomer , bisgma . \n however , it is difficult to determine the conversion rate of each material without knowing proportions of the mixture ( 4 ) . \n therefore , it is difficult to determine the effects of the mixtures of bisgma , tegma , bisema and uedma on the mechanical properties of these resins . \n filtek z250 ( 3 m ) has in its matrix uedma ( urethaneethylenedimethacrylate ) and bisema , two monomers of different viscosities when compared to tegma . \n the extension of contraction , among other factors , depends on the molecular degree of freedom and on the functionality of monomers of the resin complex to form the composite resin matrix ( 14 ) . comparing the monomers of similar viscosity , the polymerization shrinkage increases with their functionality and , when comparing monomers with the same functionality , the polymerization shrinkage increases as the viscosity decreases . \n tegma , due to its long and flexible chain , is often selected as a diluent of bisgma , in such a way that the resulting mixture will have plasticity , resulting in optimal handling characteristics of the resin without reducing the material s strength or hardness . \n alternatively , urethaneacrylates can be added to the resins to improve their resistance to wear and to reduce their absorption of water . \n however , a total replacement of tegma by uedma leads to a decrease in the elasticity modulus , in flexural strength and in tensile strength . \n this is possibly associated to the capacity of urethaneacrylate resins to form hydrogenionic links with copolymers which , presumably , restricts the mobility of polymers3 . \n definite composite resin has a silicon organic matrix linked to methacrylate radicals and siloxanes ( si - o - si ) . \n first as an organic filler and second as a low degree - of - freedom - monomer . \n this can explain , in part , the lower volumetric contraction rate presented by definite resin . \n in the present study the lowest values of contraction were found for suprafill , which could be attributed to the relation of bisgma and diluents , or others factors . \n further studies about filler type and shape also than initiation system have to be carried out . \n the resins that have ebisgma ( ethoxylated - bisgma ) as basic monomer present a great filler content . \n the matrix has at least 20% less monomer and usually requires a higher amount of diluters to improve the handling characteristic of the material , which affect the volumetric contraction . \n ebisgma is a less viscous molecule than bisgma and , thus , has more degrees of freedom . \n consequently , it has a greater conversion rate and greater plasticity . on the other hand , it will have an increased contraction during the polymerization process . \n the water absorption in hydrophobic monomers is reduced , preventing the required hygroscopic expansion . for this reason , \n it is possible that resins containing ebisgma may show a greater and more significant contraction than bisgma - based resins . \n however , surefil ( with 82% filler ) , showed 2.01% of shrinkage , which is similar to other bisgma - based resins . \n this demonstrates that volumetric contraction depends on the resin - filler complex that forms the resin and only a well - balanced mixture will produce a satisfactory and adequate product . \n although it unquestionably depends on the basic monomers present in the matrix , there are also other external factors that should be studied in order to obtain the real value for polymerization contraction . \n the authors believe that possible influences on the volumetric shrinkage could be the conversion rate , filler type and shape , and cavity configuration . \n however , the composite resins evaluated in this study showed significantly different shrinkage values and the null hypothesis is therefore rejected . \n the variability in polymerization shrinkage may be related to the differences in matrix formulation and filler content , type and shape . \n the percentage of volumetric polymerization shrinkage was smaller for suprafill and definite followed by filtek z250 , while surefil and fill magic showed intermediate values . \n knowing the polymerization shrinkage rates of the commercially available composite resins , the dentist would be able to choose between using composite resins with lower polymerization shrinkage rates or adopting technical or operational procedures to minimize the adverse effects deriving from resin contraction during light - activation .", "role": "user" }, { "content": "the polymerization shrinkage of composite resins may affect negatively the clinical outcome of the restoration . \n extensive research has been carried out to develop new formulations of composite resins in order to provide good handling characteristics and some dimensional stability during polymerization . \n the purpose of this study was to analyze , in vitro , the magnitude of the volumetric polymerization shrinkage of 7 contemporary composite resins ( definite , suprafill , surefil , filtek z250 , fill magic , alert , and solitaire ) to determine whether there are differences among these materials . \n the tests were conducted with precision of 0.1 mg . \n the volumetric shrinkage was measured by hydrostatic weighing before and after polymerization and calculated by known mathematical equations . \n one - way anova ( =0.05 ) was used to determine statistically significant differences in volumetric shrinkage among the tested composite resins . \n suprafill ( 1.870.01 ) and definite ( 1.890.01 ) shrank significantly less than the other composite resins . \n surefil ( 2.010.06 ) , filtek z250 ( 1.990.03 ) , and fill magic ( 2.020.02 ) presented intermediate levels of polymerization shrinkage . alert and solitaire presented the highest degree of polymerization shrinkage . knowing the polymerization shrinkage rates of the commercially available composite resins , the dentist would be able to choose between using composite resins with lower polymerization shrinkage rates or adopting technical or operational procedures to minimize the adverse effects deriving from resin contraction during light - activation \n .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: according to mantini et al . , the left hepatic vein ( lhv ) draining into the coronary sinus ( cs ) is an extremely rare finding classified as type ia2 of congenital abnormalities involving the coronary sinus . \n the anomalous vein is usually a single vessel that arises from the left hepatic lobe , passes through the diaphragm and joins the body of the coronary sinus close to its orifice . in most published cases , \n the anomaly is of no clinical or hemodynamic significance , unless the patient is qualified for heart surgery . \n we report a case of an anomalous connection of lvh to cs in the child operated on for partial anomalous ( right ) pulmonary vein drainage ( papvd ) . \n a two - year - old male patient was admitted for open heart surgery with preliminary diagnosis of a partial anomalous connection of the middle and inferior right pulmonary veins to the right atrium and 9 mm atrial septal defect ( asd ) , based on ultrasound and computed tomography ( ct ) scan evaluation . \n the transthoracic echocardiography performed in our department found posterior rotation of the right margin of the intraatrial septum resulting in papvd , but did not confirm the presence of asd . \n the left pulmonary veins as well as right superior pulmonary vein were found to drain in a normal way to the left atrium . during surgery , while dissecting the inferior vena cava for direct bi - caval cannulation , we found a 5 mm diameter vein passing through the diaphragm and draining into the coronary sinus . \n it was located leftward and parallel to the inferior vena cava ( ivc ) within the distance of 1.5 cm . \n any major tension applied to the vein resulted in cardiac rhythm disturbances and drop in blood pressure . after commencing moderate hypothermic cardiopulmonary bypass ( cpb ) ( 31c ) , the aorta was cross - clamped for a single period of 21 minutes , and the right atrium was opened and inspected . \n the intracardiac findings consisted of two right pulmonary vein orifices within the right atrium and no atrial septal defect . \n ostium of the coronary sinus was markedly enlarged , whereas the orifice of the anomalous ( left hepatic ) vein was clearly visible in the most distal part of the coronary sinus , close to the right atrial chamber . \n a large part of the atrial septum was resected and a patch of autogenous pericardium was then used to re - direct the right pulmonary veins to return to the left atrium . \n the postoperative period was uneventful and the patient was discharged home on the 9 day after surgery . considering the intraoperative findings and possible surgical consequences of unrecognized anomalous connection of the hepatic vein into the coronary sinus , we decided to reevaluate the patient and look for the morphological evidence of the left hepatic vein to the coronary sinus connection . \n the purpose of this procedure was to determine whether it was possible to make the proper diagnosis prior to surgery . \n the analysis of preoperative echocardiographic recordings carried out anew did not show the vein directly . \n it was most likely due to the markedly increased , turbulent flow caused by an abnormal connection of the right pulmonary veins joining the lowermost part of the right atrium close to the ivc - ra junction and cs ostium . \n we expected that redirecting the flow from both right pulmonary veins to the left atrium with the patch would diminish blood turbulence within the area of interest and make the task easier . \n indeed , the four - chamber apical view revealed the dilatation of the distal ( closest to the ostium ) part of the coronary sinus , whereas more proximal parts of the cs were normally narrow ( fig . \n the thorough , gradual inspection of the cs , seen in transverse cut with modified parasternal short axis views , revealed the ostium of the abnormal vein joining the dilated part of the coronary sinus . \n the 3 mm diameter vein that originated from the liver , was passing the diaphragm , and joined the coronary sinus perpendicularly ( fig . 2 and 3 ) \n proximal part of coronary sinus is narrow while distal segment is enlarged ( asterisk ) . \n right ventricle , lv left ventricle modified parasternal short axis view showing transversal cut of distal ( ostial ) coronary sinus . \n 2 . cs normal sized proximal part of coronary sinus ( dotted circle ) , mpl posterior leaflet of mitral valve , thao thoracic aorta , \n sinus venosus ( sv ) , which comprises two horns , is located on the caudal end of the primary heart tube and receives blood from three different sources : vitelline or omphalomesenteric veins , umbilical veins , and common cardinal veins . in the complex process of normal heart development , during the 5 week of gestation \n , the left horn of the sinus venosus is reduced to the coronary sinus and oblique vein of the left atrium . \n persistent patency of connections between the left vitelline vein system and left horn of sv could be the main reason for the left hepatic vein to the coronary sinus communication . \n inferior vena cava , lhv left hepatic vein , cs ostium of coronary sinus , tv tricuspid valve , fo \n right ventricle direct venous drainage of a single hepatic vein into the coronary sinus should not have any clinical or hemodynamic consequences . \n nevertheless , it has been suggested that it may be associated with atrial arrhythmias and could lead to technical difficulties during coronary sinus approach procedures . while undiagnosed prior to surgery , the anomaly might be found during inspection of the inferior vena cava region either by placing a loop around the vessel , or preparing the site for direct caval cannulation . \n it is worth mentioning that any excessive tension of lhv should be avoided because of possible rhythm disturbances as well as reduced cardiac output , due to cs blood flow changes . \n the blood inflow through lvh during the intracardiac procedure is easily controlled by temporary occlusion with tourniquet ( like in the reported case ) , or direct cannulation . \n the lvh to cs connection is an important issue in patients qualified for fontan type surgery because of the significant right to left shunt 's volume into low - pressure pulmonary venous atrium . \n ", "role": "user" }, { "content": "left hepatic vein ( lhv ) that drains blood into a coronary sinus ( cs ) is an extremely rare congenital anomaly of systemic vein drainage with only single reports published . in most of these cases \n the unusual venous connection was found incidentally during diagnostics or surgery.the case of a two - year - old boy in whom the anomaly was discovered during open heart surgery for partial anomalous pulmonary venous drainage ( papvd ) is presented . \n difficulties in obtaining proper diagnosis preoperatively are confronted with postoperative echo findings.embryology and evolution of sinus venosus are discussed to explain the persistent connection between hepatic venous circulation and a coronary sinus . \n the authors attempt to recapitulate the possible surgical consequences of lhv - cs continuity .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: boron ( b ) is a critical micronutrient in the growth of plant , which was undoubtedly considered as a part of the structure in the cell wall [ 13 ] . \n more increasing evidence was present for a possible role of b in metabolism processes , such as the maintenance of plasma membrane function and several metabolic pathways . \n park and schlesinger reported that most b is fixed into cell wall and is not recycled internally once used by plant , but some b would be emitted to atmosphere in plant aerosol or during the biomass burning . \n the global uptake of b by plant from soils can be calculated as 4.5 tg b / yr . all of these indicated that the cycling of b and the equilibrium of b isotope in the process between plant and soil would be changed . in nature , b has two stable isotopes : b and b. because b shows a large variation in the stable isotopic composition ( ~90 ) [ 58 ] , b and its isotope have been used to investigate a wide range of geochemical , cosmochemical , and geophysical problems . \n recent concerns about the use of b isotope in biological systems have been taken into consideration for its important role in embryonic development and organogenesis in plant growth [ 1 , 3 ] and its isotopic fractionation in the cycling of b in the uptake by plant from soil and processing within plant by a series of chemical or biochemical reactions . \n the presence of lots of organic matters in plant can influence the emission of cs2bo2 \n ion current in the chamber of tims [ 9 , 10 ] . in plant , the appropriate pretreatment of sample should effectively remove organic contaminants and meanwhile keep b isotopic composition stable . \n the method using amberliter ira 743 resin coupled with cation and anion ion - exchange mixing resin developed by xiao et al . and wang et al . was applied as a proxy for the separation of b , especially in the water samples . \n the techniques of microsublimation [ 1315 ] and digestion with h2o2 were fit for the samples with few organic matters . \n the wet chemical digestion with hno3/h2o2 in common was used to digest plant sample ; however , this method would produce the isobaric cs2cno ion of m / z 308 and 309 , which affected the determination of b isotope . \n wei et al . developed a method using hf , h2o2 , and mannitol mixed solution to separate b from the silicate rock sample successfully , and b isotope ratio was determined by multicollector inductively coupled plasma mass spectrometry ( mc - icp - ms ) . \n these techniques mentioned above were not suitable to eliminate large number of organic matters in plant sample . \n attempted b isotopic composition for biogeochemical plant - soil interaction and provenance on the coffee bean . \n however , methods for determining b isotopic composition in different plant tissues are scarce . in this study , \n a series of dry ashing experiments coupled with ion - exchange resin chromatography were performed to separate b in plant tissue sample . the b isotopic composition in plant tissue \n the recoveries of b separation in dry ashing , ion - exchange chromatography , and the whole procedure were examined . and \n the characteristics and fractionation in the b isotope composition of plant tissue samples were investigated and discussed . \n to examine the fractionation of b isotopes in different plant species and within plant tissues , plant samples investigated in this study include various tissues of swertia mussotii franch . and \n halenia elliptica d. don collected in the qinghai - tibet plateau area , weigela florida cv . \n red prince and echinacea angustifolia in shandong area and cynomorium songaricum ruper . in inner mongolia area , china . \n the samples of s. mussotii and h. elliptica were collected in september and october ( the flowering and fruiting period ) , 2012 , in yushu and banma counties of qinghai , china , respectively . \n the root holoparasite c. songaricum , known in chinese herbal medicine as suoyang , is a classic mongolian pharmaceutical plant and usually parasitizes the roots of nitraria spp . . \n the collected samples include the root , stem , leaf , and flower tissues of w. florida , s. mussotii , and h. elliptica , stem , leaf , and flower tissues of e. angustifolia , and stem and flower of c. songaricum . \n the information about sample site , plant species , and soil conditions in the regions is summarized in table 1 . \n hydrochloric acid ( guaranteed reagent ) was redistilled in a sealed vessel to remove the exogenous b. the cesium carbonate ( spectroscopic pure ) was of 99.994% purity . \n high - purity graphite was added to a mixture of ethanol solution ( 80% ) to obtain the final solution corresponding to 13 mg / g graphite . \n the isotopic reference standard used in this study was nist srm 951 boric acid ( gaithersburg , md , usa ) . \n a solution of mannitol of 1.82% ( w / v ) and cs2co3 solution containing 12.3 mg / ml of cs was also prepared . \n sodium carbonate , ammonia hydroxide , and sodium chloride were of the analytical grade reagent . \n the resins , b specific resin amberlite ira 743 , strong cation exchange resin dowex 50w x8 , and weakly anion exchange resin amberlite ira 67 , were purchased from sigma - aldrich co. llc , china . \n high purity water with a b blank less than 0.008 g was redistilled by subboiling distillation and passed through a resin column filled with b specific resin ( amberlite ira 743 ) , which was used to prepare the standard solution and working solution . \n an inductively coupled plasma optical emission spectrometer ( icp - oes , vista mpx , varian , usa ) with a 40 mhz radio frequency generator and a charge coupled device detector ( vista chip ) was used to detect b. dry ashing was also used to decompose plant sample to eliminate the organic impurities . \n traditionally , plant sample was decomposed using wet chemical digestion method of hno3/h2o2 , which can lead to the formation of the isobaric interference cs2cno ions of 308 ( cs2 \n bo2 \n ) and 309 ( cs2 \n bo2 \n ) in the ionization chamber in tims . \n about 0.30.5 g of dried plant sample was weighted and placed into a quartz crucible . \n the crucible together with plant sample was placed in a closed microwave - assist muffle burner . to avoid the bubbling in sample from rapid heating , at first the temperature \n then , the temperature was raised to 550c for 4 h until the ash was whitish to black . \n after cooling down , 1 ml of 0.5 mol / l hcl solution was used to dissolve the ash and the solution was transferred to a polypropylene tube . \n the b specific resin was used to selectively extract b and to remove the remaining impurities meanwhile . \n the ph in the sample solution was adjusted to 8 - 9 using 0.1 mol / l nh3h2o solution and then transferred to the conditioned b specific resin at a flow rate of 2.5 ml / min . after rinsing with ultrapure water , 10 ml of 0.1 mol / l hcl at 75c \n was used to elute b in the resin ; then , the collected eluates were evaporated under a clear air flow at 60c until 0.5 ml solution was left . \n finally , the 0.5 ml concentrated solution was transferred to a mixing ion exchange resin column , which consists of a strong cation exchange resin ( 200400 mesh ) and a weak anion exchange resin ( 100120 mesh ) . \n all collected eluates were transferred to a 15 ml teflon beaker . following the addition of cs2co3 solution and mannitol solution , evaporation of the solution continued until about 0.2 ml solution was left . \n the solution was transferred to a 0.5 ml centrifuge tube and continued evaporating to the approximate concentration of 1 mg b / ml . the solution was stored at 4c for mass spectrometric analysis . \n an outline of the general workflow of b separation in plant sample mentioned above is expressed in table 2 . \n the measurement of the b isotopic ratio was performed using a triton tims ( thermo fisher scientific inc . , \n usa ) , which was equipped with a special double cup system allowing static multicollection of cs2 \n bo2 \n /cs2 \n tantalum filament was degassed at a current of 3 a for 1 h and then coated with a 2.5 l of graphite slurry solution . \n when the slurry solution was almost dried , 1 l sample solution was loaded on top of the graphite and evaporated to dryness . \n the b / b ratio was calculated as r \n 309/308 0.00078 [ 23 , 24 ] . \n the b isotopic composition of the sample is expressed as \n b ( ) relative to that of the nist srm 951 standard:(1)11b=b11/b10samb11/b10std11000 . \n here , ( b / b)sam and ( b / b)std were the b isotopic ratio of sample and nist srm 951 h3bo3 , respectively \n . the measured average b / b ratio of nist srm 951 h3bo3 was 4.0564 0.0098 ( 2 = 0.03% , n = 5 ) . \n most attention has been given to the b loss and subsequent isotope fractionation in dry ashing and two - step ion - exchange chromatography in biological samples . \n have reported the effects of ph , acidity and salinity , and temperature of hcl solution on the recoveries of b using amberlite ira 743 resin combine with mixing ion - exchange resin . \n the results indicated that the recovery of b in the two - step ion - exchange chromatography reached to 100% , which means there is no b loss in the process . \n so , in the following experiments , the recoveries of b in dry ashing and in whole procedure were investigated . to examine the b recovery in dry ashing , \n borax was used as the reference standard to evaluate the loss of b and the isotopic fractionation in the process . in the five replicates , \n the mean recovery of 100.2% was obtained , which means that there was no loss of b except the crystal water lost . \n however , when h3bo3 was used for the recovery test in dry ashing , there was no b remaining in the tube , which indicated that all b in the format of h3bo3 would evaporate to air . \n this suggests that when drying ash at temperatures less than 550c , b in the form of borate will not lose in the sample , which indicated the conservative behavior of b. concurrently , low oxygen supply appears to inhibit the variation of b formation in dry ashing . \n the two - step ion exchange chromatography method used for b extraction from environmental sample is based on the modification reported by wang et al . and xiao et al . . \n the introduction of the b blank in dry ashing and the chromatography may change the recovery and isotopic composition of b. reference standard borax was used to pass through the procedure to quantify b recovery and to explore the fractionation of b isotope . \n the total b blank demonstrated here was 0.008 g b , which indicates that the variation of b isotopic composition in the procedure should be within the external precision of the isotopic measurement and therefore ignored . \n the results showed that the recovery of b in the whole procedure ranged from 95.6 to 110.2% , suggesting b was not lost in the process . \n the comparison of the b isotopic composition in borax before ( \n b = 5.08 , n = 5 ) and after the procedure ( \n b = 5.10 , n = 5 ) with an error deviation of 0.35 suggests b isotopic composition was not fractionated in the procedure . \n the recovery yields of b in the complete procedure as well as for two - step ion - exchange resin chromatographic separation of born in the matrix are shown in figure 1 . the dried amount of b in plant tissue samples ranged from 2.87 to 40.6 g / g . \n the results listed in figure 2 showed that the dried amount of b was lowest in the stem and highest in flower . in general , the mean dried amounts of b in leaf ( 26.39 g / g ) and flower ( 26.85 g / g ) were larger than those in root ( 15.71 g / g ) and stem ( 12.89 g / g ) . in calculating the average of b in stem and flower , the results of c. songaricum were not taken into consideration for the different behavior of b in dried amounts of stem and flower . \n the dried amounts of b in these plant tissue samples were similar to those in other plants ( 10100 g / g ) based on the dry weight reported by power and woods . \n in vascular plants , b moves from the roots with transpiration , accumulating in the growing points of leaves and stems [ 1 , 26 ] . in most plant species , \n huang et al . demonstrated that b was transported from leaves into actively growing reproductive organs in white lupin ( lupinus albus ) . \n these findings suggest that , during plant growth , especially in the flowering stage and fruiting period , a large amount of b is needed to promote growth and development of plant reproductive tissues , which leads to the accumulation of b in leaves and flowers . \n the \n b values in the tissue of these plant samples are shown in figure 3 . \n the \n b ( ) values range from 19.45 to + 28.13 ( total range : 47.58 ) , with a mean value of 2.61 11.76 sd . \n when c. songaricum was taken into consideration for calculation , the \n b values range from 19.45 to 12.09 ( range scope : 31.54 ) , with a mean of 0.4 10.10 sd . \n these results were similar to those reported by serra et al . with the \n b values from 11.60 to 17.20 ( mean value : 4.23 7.57 sd ) . \n except for the stem and flower tissue of c. songaricum ( figure 3 ) , the maximum mean \n b values occurred in the leaf ( + 7.58 ) and flower tissue ( + 7.90 ) , with the minimum \n b occurring in stem ( 12.11 ) and then in root ( 2.74 ) . in figures 2 and 3 , \n the variation of \n b is similar to that of dried amount of b , which may be relative to the uptake and transportation of b within plant . in plant growth , \n the uptake of b by root is in the form of b(oh)3 or b(oh)4 \n . \n b(oh)3 can be taken up by plants through passive diffusion or an energy dependent high - affinity transport system . \n borate can form the most stable diesters with cis - diols on a furanoid ring [ 1 , 27 ] . \n the heavier isotope of b is favored in b(oh)3 and b(oh)4 \n is depleted in b ; thus , the variation of \n b in root is lower and closely associated with that in the soil . \n b can be also transported to reproductive and vegetative tissues [ 30 , 32 ] , although this capacity varies among species [ 33 , 34 ] . \n after b is transported from the root to the stem , the \n b value in the root is greater than that in stem as different velocities influence b mobility by transportation or ion exchange . during plant growth , a large number of sugar alcohols such as sorbitol , mannitol , and fructose , which are utilized by the combination of hydroxyls of b(oh)3 , \n thus , much b will preferentially go into the leaves and flowers along with b(oh)3 , resulting in higher \n b values in the leaf and in flower . \n the fractionation between two components i and j was determined as follows : ( 2)11bij=11bi11bj . \n the variations of \n b in the plant tissue samples w. florida , s. mussotii , and h. elliptica are illuminated in figure 4 . \n b isotopic composition is significantly fractionated in the plant species and in different tissues of the same plant . \n broot - stem , \n broot - leaf , and \n broot - flower in h. elliptica were of 3.46 , 2.19 , and 2.05 , in w. florida were of 2.87 , 0.83 , and 1.09 , and in s. mussotii were of 1.46 , 2.25 , and 0.1. the maximum of \n b ( > + 0 ) was found in the root - stem , root - leaf , and root - flower of h. elliptica , which means that relative to that in w. florida and s. mussotii , more b was used by h. elliptica from the region where it grows . \n the minimum of those values ( < 0 ) observed in s. mussotii , which indicates that more b was accumulated in the tissues of s. mussotii , may be caused by the different manner of uptake and transference or by the biophysiological effect of b on plants . \n this presence would be another important channel for the variation of b isotope composition in the global cycle of b by further uptake and translocation of b in the tissues of plants . \n a proposed method using dry ashing combined with two - step chromatography was developed for the separation of b in plant sample , which enables applications of b isotopes in biogeochemistry , behavior of plant and soil , and plant metabolism . within the plant , \n b isotope is fractionated by the mechanism of diffusion , transportation , or a biological effect between tissues . \n moreover , knowledge of cycling and fractionation mechanism of b isotope in the uptake of plants will contribute to better understanding of the global biogeochemical cycle of b.", "role": "user" }, { "content": "knowledge of boron and its isotope in plants is useful to better understand the transposition and translocation of boron within plant , the geochemical behavior in the interface between soil and plant , and the biogeochemical cycle of boron . \n it is critical to develop a useful method to separate boron from the plant for the geochemical application of boron and its isotope . \n a method was developed for the extraction of boron in plant sample , whose isotope was determined by thermal ionization mass spectrometry . \n the results indicated that this method of dry ashing coupled with two - step ion - exchange chromatography is powerful for the separation of boron in plant sample with large amounts of organic matters completely . \n the ratios of boron isotope composition in those plant tissue samples ranged from 19.45 to + 28.13 ( total range : 47.58 ) with a mean value of 2.61 11.76 sd . \n the stem and root isotopic compositions were lower than those in flower and leaf . \n the molecular mechanism of boron isotope may be responsible for the observed variation of boron isotopic composition and are considered as a useful tool for the better understanding of boron cycling process in the environment and for the signature of living systems .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: f - box and wd40 domain - containing protein 7 ubiquitin - specific protease 28 skp1cullin1f - box protein \n fbw7 , the substrate recognition subunit of the scf ( skp1cullin1f - box protein ) ubiquitin ligase , promotes ubiquitination and turnover of multiple oncoproteins . \n mutations in fbw7 frequently occur in human cancers ( most notably in colorectal carcinomas and t - cell leukemias ) and compromise substrate ubiquitination . \n accumulation of fbw7 substrates , such as myc , mcl1 , and cyclin e , fuels tumorigenesis by driving cell proliferation , survival , and genomic instability . \n fbw7 also promotes its own degradation via autocatalytic ubiquitination , either in response to signaling or when substrate levels become low . \n fbw7-dependent substrate ubiquitination is countered by the usp28 deubiquitinating enzyme . in human tumor cell lines , shrna - mediated depletion of usp28 \n downregulates myc levels and attenuates proliferation . as a cysteine protease that stabilizes myc , a key driver of cancer progression , \n interestingly , however , recent studies have revealed a range of genetic alterations in usp28 in human tumors , including amplifications , deletions , and point mutations . \n for example , usp28 is overexpressed in colorectal and ovarian carcinomas , whereas prostate carcinomas and melanomas harbor recurrent focal deletions at the usp28 locus . furthermore \n , usp28 protein expression is downregulated in several cancer types relative to normal tissue , suggesting that loss of usp28 may also be beneficial during tumorigenesis . \n analysis of usp28 knockout mice may help reconcile these controversial observations . as expected from in vitro studies , ablation of one allele of usp28 \n in contrast , complete loss of usp28 produces tissue - specific effects in the intestine fbw7 substrates are further downregulated whereas in other tissues , including lung , liver , and pancreas , they match or exceed the wildtype levels . \n interestingly , fbw7 is regulated reciprocally ; it remains stable upon loss of usp28 in the intestine but is downregulated in most other tissues and in cultured mouse embryonic fibroblasts ( mefs ) , suggesting that usp28 controls fbw7 stability in a tissue - specific manner . \n indeed , experiments in mefs and human tumor cells demonstrate that usp28 directly deubiquitinates and stabilizes fbw7 . \n importantly , deubiquitination of fbw7 requires significantly lower levels of usp28 than needed for fbw7 substrates , explaining the differential response to mono- and biallelic deletion of usp28 . \n apparently , half of the normal dose of usp28 maintains stable fbw7 , but is not sufficient for fbw7 substrate stabilization . \n in contrast , complete knockout of usp28 triggers autocatalytic ubiquitination and degradation of fbw7 , sparing fbw7 substrates . autocatalytic ubiquitin transfer by fbw7 \n consistent with these findings , inhibition of pin1 restores fbw7 levels and drives fbw7 substrate degradation in usp28-null mefs . in tissues of usp28 knockout mice , \n pin1 expression inversely correlates with fbw7 levels , suggesting that the abundance or activity of pin1 may determine the outcome of usp28 loss for fbw7 substrates . \n usp28-dependent control of fbw7 and its substrates closely resembles regulation of mdm2 and p53 by the hausp deubiquitinase . \n hausp stabilizes both mdm2 and p53 , but its higher affinity for mdm2 results in a biphasic response to the loss of hausp . \n other deubiquitinase ligase pairs will likely exhibit a similar relationship , revealing a common regulatory paradigm in ubiquitin networks . \n we propose that dual control of fbw7 activity by usp28 maintains physiological levels of fbw7 substrates during homeostasis ( fig . 1 ) . \n activation of usp28 will stabilize both fbw7 substrates and fbw7 , suppressing prolonged accumulation of proto - oncoproteins . \n a similar principle is observed in the regulation of several oncogenic transcription factors ; for example , phosphorylation events that activate myc and jun simultaneously prime them for degradation , creating a time - restricted window of activity . \n potentially , such mechanisms evolved as safeguards against unscheduled activation of proto - oncoproteins and the emergence of cancer - initiating cells . \n usp28 limits fbw7-mediated ubiquitination of proto - oncogenic substrates , but primarily deubiquitinates and stabilizes fbw7 . during homeostasis , the fbw7usp28 complex maintains low levels of fbw7 substrates . \n loss of usp28 triggers autocatalytic ubiquitination and turnover of fbw7 , leading to the accumulation of fbw7 substrates and promoting oncogenic transformation . \n overexpression ( oe ) of usp28 blocks both autocatalytic and substrate - directed ubiquitination by fbw7 and equivalently enhances cell transformation . \n usp28 limits fbw7-mediated ubiquitination of proto - oncogenic substrates , but primarily deubiquitinates and stabilizes fbw7 . during homeostasis , the fbw7usp28 complex maintains low levels of fbw7 substrates . \n loss of usp28 triggers autocatalytic ubiquitination and turnover of fbw7 , leading to the accumulation of fbw7 substrates and promoting oncogenic transformation . \n overexpression ( oe ) of usp28 blocks both autocatalytic and substrate - directed ubiquitination by fbw7 and equivalently enhances cell transformation . \n in a cell culture model of oncogenic transformation , loss of usp28 strongly upregulates fbw7 substrates and promotes anchorage - independent growth ( fig . 1 ) . \n intriguingly , ectopic expression of usp28 in this system equivalently stabilizes fbw7 substrates and promotes transformation , despite highly increased levels of fbw7 . \n thus , opposite extremes of usp28 abundance produce equivalent phenotypes through opposite mechanisms : complete loss destabilizes fbw7 , whereas overexpression stabilizes both fbw7 and its substrates . \n a prediction derived from our analysis is that usp28 may function as a tumor promoter or suppressor in different tissues , depending on whether the signaling context favors autocatalytic ubiquitination of fbw7 . in the intestine \n accordingly , in a mouse model of apc - driven driven intestinal cancer , ablation of usp28 attenuates tumorigenesis and prolongs survival . in tissues where the signaling favors autocatalytic turnover of fbw7 , deletion of usp28 may functionally mimic fbw7 loss - of - function and promote tumorigenesis . \n our observations in mefs predict that under these conditions , loss and overexpression of usp28 may equivalently upregulate fbw7 substrate levels and help establish or maintain the malignant state . \n we imagine that bifunctional regulatory motifs , similar to the usp28fbw7fbw7 substrate circuit , are widespread in signaling networks and could explain the occurrence of opposite genetic alterations of a single gene in cancer . \n \n work in the popov laboratory is supported by the german research foundation ( dfg research grant po14583/1 and po14584/1 ) and by an institutional grant from the deutsche krebshilfe .", "role": "user" }, { "content": "the usp28 deubiquitinase antagonizes fbw7-mediated turnover of multiple oncoproteins , including myc , jun , and notch , and promotes tumorigenesis in the intestine . \n our recent study reveals that usp28 also counteracts autocatalytic ubiquitination of fbw7 , suggesting a complex role for usp28 in the regulation of fbw7 activity and tumor development .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: herpes simplex virus type 2 ( hsv-2 ) can be transmitted without any symptoms during the viral revital period through genital mucus membrane by sexual contact . \n it can also be transmitted vertically from an infected mother to the fetus ( 1 - 4 ) . \n once infected , it is impossible to cure completely : it is hidden in the neural system and revitalized with the weakening of immune system or by a stimulus such as uvs to secrete infectious hsv-2 ( 5 , 6 ) . \n most of infected persons do not know information about the transmission mode or the fact that continuing sexual contacts could trigger transmission of hsv-2 , eventually increasing the cumulative number of infected persons ( 3 , 7 ) . \n sexually transmitted infections ( stis ) should be reported to the related authority in korea within 7 days when verified by public health centers or clinics of any kind . \n stis can be classified according to its cause or the type of infected bacteria and virus : syphilis , gonorrhea , chlamydia , non - gonococcal urethritis , condyloma acuminata , and genital herpes . \n although hsv-2 infection is detected , it is not required to report its occurrence to health authorities in most countries , so that it is difficult to figure out the magnitude of its incidence . \n each year 600 - 700 hsv-2 infected persons or pseudo - infected persons are reported but information on the magnitude of infection and the transmission rate is insufficient ( 8) . since hsv-2 infection itself is not fatal , \n prevention and treatment can be neglected , which increases the risk of other stis and the possibility of its transition to other fatal diseases . for human papilloma virus ( hpv)-infected women with hsv-2 , \n the incidence rate of cervical cancer is 2 to 3 times higher than that of women infected with hpv only . \n furthermore , it is reported that ulcer incurrence by hsv-2 increases human immunodeficiency virus ( hiv ) infection rate by 3 to 9 times ( 9 - 11 ) . \n the aims of this study were to investigate the magnitude in hsv-2 infection in the general public in korea and to compare it with the magnitude of infection of risk groups for stis . \n in 2004 , we selected 1,768 persons from the public health centers in the region p , a big harbor city , and 882 in the region j , an inner rural area , both of which are located in the southern part of korea and conducted hsv-2 igg antibody test for physical examination . \n all of them were visitors to pubic health centers . in order to verify whether the seroprevalence data of the southern part in korea represents generality \n , we used the stratified random sampling to select 455 sera from 40,000 samples obtained by the project of \" national survey of health and nutrition ( nshn ) \" conducted between 6 april 2005 and 30 june 2005 . \n the nshn was a nationwide big project to analyze the state of health and nutrition on a regular basis under the supervision of the ministry of health and welfare in korea . \n we also investigated 304 commercial sex workers ( csws ) , a high - risk group of stis , who were to make regular visits to health centers in two big cities , s and p , for a periodical stis examination . \n furthermore , we examined hsv-2 seroprevalence in 196 persons infected with hiv by sexual contact in 2003 . \n the separated serum was aliquotted and then frozen at -20. we used sera for igg antibody test . to examine a hsv-2 specific antibody , herpeselect 2 elisa igg ( focus technologies , memphis , tn , u.s.a . ) \n we processed the data with excel and used the statistical analysis system for windows ( ver . \n the seroprevalence of the study group was defined as the number of positive persons per one of the tested persons . \n test was used to assess the difference of seroprevalence by age , sex , and region . \n the stratified random sample selection by age and sex was used for sampling the general public who represented the korean population . \n serological test results in child and youth in the region p are in the table 2 , which indicates that the seroprevalence of hsv-2 under the 20s was 2.8% ( 2.7% for men , 3.0% for women ) , rendering no difference in seroprevalence for age ( p= 0.4979 ) or for sex ( p=0.7056 ) . \n table 3 shows that the seroprevalence of adults aged 20 and above was 24.9% and women ( 28.0% ) were recorded higher than men ( 21.7% ) ( p=0.0053 ) ; 7.4% for aged 20 - 29 ( men 6.8% and women 8.0% , p=0.6817 ) , 22.6% for aged 30 - 39 ( men 13.8% and women 30.9% , p= 0.0004 ) , 29.6 - 34.9% for aged 40 and above . \n overall , the seroprevalence in the 30s ( 22.6% ) significantly increased compared with that of the 20s ( 7.4% ) ( p<0.0001 ) , and in the 40s ( 32.7% ) than the 30s ( p=0.0066 ) , respectively . \n women 's seroprevalence greatly increased in the 30s ( 30.9% ) than in the 20s ( 8.0% ) ( p<0.001 ) , while men 's increasing rate of seroprevalence in the 20s ( 6.8% ) compared to the 30s ( 13.8% ) and the 30s to the 40s ( 31.0% ) was significantly higher in the older groups ( p=0.0497 and p=0.0005 , respectively ) . \n women 's seroprevalence was higher than that of men in the 30s , while the other age groups showed no difference among the groups or gender ( p=0.0004 ) . \n the comparison by region showed a contradictory difference in the 20s and the 60s ( p=0.0012 , p=0.0209 ) , but there was no difference after adjusted by age . \n seroprevalence of in the 20s and above was not significant by region under the standardized age ( p=0.3949 ) . \n we selected samples from the national pool to verify whether the age - specific hsv-2 seroprevalence of sexually active age group in the southern part of korea represents generality . \n the hsv-2 seroprevalence among 455 adults aged between 10 and 35 in the nshn was 8.8% ; 4.7% for aged 10 - 19 , 7.5% for aged 20 - 24 , 12.9% for aged 25 - 29 , and 9.8% for aged 30 - 34 . \n the women 's seroprevalence was 12.7% and showed a significant difference compared with the seroprevalence in men , 4.8% ( table 4 , p<0.0001 ) . \n as shown in table 5 , the seroprevalence of hsv-2 in korean csws was 81.6% , which was remarkably different with those of the 20s ( 8.0% ) and the 30s ( 30.9% ) in the general public of the southern part of korea ( p=0.0054 ) . \n the age - specific hsv-2 seroprevalence of hiv - infected men was 23.9% for the 20s , 48.6% for the 30s , 57.1% for the 40s and \n 69.2% for the 50s , respectively , showing an increasing trend by age ( p<0.0001 ) . \n the seroprevalence of the hiv infected women ( 63.6% ) was higher than that of the infected men ( 47.6% ) . due to the unbalance between the sexes \n in the seroprevalence of women of age 20 - 39 , csws ( 81.6% ) were recorded remarkably higher than the general women of the southern part ( 18.5% ) ( p<0.0001 ) . \n 1 shows that the seroprevalence of 186 hiv - infected men ( 47.3% ) was also significantly higher than that of the general men in the southern part ( 21.7% ) ( p<0.0001 ) . \n this is the first voluminous study in korea which investigated the seroprevalence of hsv-2 in age close to being sexually active or in its peak in the two groups , csws and hiv - infected persons . in a group of the general public in korea , \n the seroprevalence of the 1,855 subjects aged 13 and above in the southern part was 20.1% ( 20.9% for men , 22.4% for women ) , similar to that of the united states ( 12 ) . in the united states , the seroprevalence of age 12 and above in the general public was 21.9% , 17.8% for men and 25.6% for women \n however , korea 's seroprevalence for the aged 13 - 19 ( 2.3% ) showed a significant difference with that of the united states ( 5.6 % ) and even it was lowered than 4.5% among white people in the united states . \n the age - specific seroprevalence of hsv-2 in the united states was 17.2% for the 20s , 27.8% for the 30s , 26.6% for the 40s , 25.1% for the 50s , and 24.3% for the 60s . \n as shown above the 20s , the seroprevalence of age 20 - 30 in korea was lower than that of the same ages in the united states , but in the 40s and above in korea showed a higher seroprevalence compared with the counterpart in the united states ( 7 , 12 ) . \n the seroprevalence of koreans under the 20s was 2.8% , which was similar to that of bangladesh ( age 1 - 12 , 2.5% ) and that of the united kingdom ( 16 - 19 , 2 - 3% ) ( 13 , 14 ) . \n the hsv-2 seroprevalence of women in the 20s in the southern part of korea was 8.0% , while that of the 30s was sharply increasing to 30.9% , which consolidated the importance of a sti prevention program . \n considering the average age of the first marriage is 27 in korea , the hsv-2 seroprevalence in the 30s can be an important indicator to trace vertical transmission as women are likely give birth to their first babies in their 20s or 30s ( 15 ) . \n it was reported that the hsv-2 seroprevalence of pregnant women in the united states was 32% and transmission rate of birth infected by primary hsv was 30 - 50% , and recurred hsv was 1 - 4% ( 12 ) . \n the prevalence of herpes infection for newborn babies was less than 10 per 100,000 persons in europe , 15 - 48 in the united states , and more than 85% of the infection 's pathogen was hsv-2 . \n age - specific hsv-2 seroprevalence in the general public in korea showed that the seroprevalence of people under the 20 was the lowest , less than 5% , despite their sexual experience rate of 7.1 - 31.7% in age 13 - 19 according to the juvenile sexual activity study , which was lower than that of the group under 13 ( 16 ) . \n this contradiction necessitated the further study on the relation between hsv-2 seroprevalence and sexual activity . \n regardless of the fact that people in the 20s are sexually active and have sexual experience ( 57.3% ) , it was found that hsv-2 seroprevalence was very low . \n however , the regional difference between region p and j was reported to be substantial ( 17 , 18 ) . we aimed at understanding the nationwide state of age - specific hsv- 2 infection notwithstanding the limited sampling region in this study , so we conducted an investigation on the hsv-2 seroprevalence of 455 sera from the nhsn as a pilot study for generalization of hsv-2 seroprevalence in korea . \n we still found a low seroprevalence rate of 4.7% for age 10 - 19 , 7.5% for 20 - 24 , 12.9% for 25 - 29 , and 9.8% for 30 - 34 . \n however , in age 30 - 34 , the hsv-2 prevalence of nhsn was rather lower than that of subjects of the southern part . \n we intended to observe a dynamic change by age and to compare data collected from the southern part of korea as a seroprevalence study on sera from the national survey of health and nutrition , but there was no difference in the 20s and in the early 30s . since a different pattern in the southern part has known , it is necessary to study hsv-2 seroprevalence in korea to cover more regions with a bigger sample size . \n conducted a study for university students ( age 18 - 25 ) in 2005 and showed the prevalence rate of chlamhydia trachomatis was 8.4% for men , 10.6% for women , and that of neisseria gonorrhea was 0.8% for men and 0.0% women . \n these figures were lower than those of the australian counterparts ; 16.4% and 4.9% for subjected age 20 - 24 , 18.2% and 5.5% for subjected age 30 - 34 ( 19 , 20 ) . in this study , \n the hsv-2 seroprevalence in women was higher than in men , and that the hsv-2 prevalence rate of women in the 30s was four times higher than in the 20s . \n this fact could be verified the necessity of intensive stis prevention programs and publicity to target people in the 20s in order to reduce the current 30 - 40% rate . \n furthermore , the seroprevalence of hsv-2 of csws , a high - risk group of stis , was much higher than that of the general public . \n since the high seroprevalence of csws could accelerate transmission of sexually - transmitted virus such as hiv , it is necessary to launch education programs to prevent any transmission of stis . \n the seroprevalence of csws in japan , germany , and thailand ranges betweens 60% and 80% ( 21 - 23 ) . \n blood testing is encouraged to people suspected of hsv-2 infection , even though they have no symptoms . \n the hsv-2 seroprevalence of hiv infected persons was lower than that of csws , but much higher than the general public . \n the seroprevalence of hsv-2 in hiv - infected brazilians was 73% , which was higher than that of koreans , 48.5% ( 24 ) . \n it was reported that ulcerous stis such as hsv could increase hiv infection rate by 3 to 9 times ( 20 ) . \n therefore , prevention of hsv-2 infection is related to the prevention of hiv infection . according to the fisman 's study , without intervention , \n the prevalence of hsv-2 infection among individuals aged 15 to 39 in the united states was projected to increase up to 39% among men and 49% among women by 2025 . \n in addition , the annual cost of new infections could be risen from $ 1.8 billion in 2000 to $ 2.7 billion in 2025 ( 25 ) . \n . the much lower seroprevalence rate of hsv-2 in teenagers and the 20s compared with the remarkably high rate in the 30s showed that it is necessary to develop a stis prevention program of education and publicity for the 20s as well as for teenagers . \n this study is the first report to investigate the magnitude of hsv-2 infection in the general public as compared with a high - risk group ( csws ) and the hiv - infected group for the advanced understanding of hsv-2 infection status . \n it provides basic data for consistent and systematic hsv-2 studies and information about the target groups for stis vaccine program .", "role": "user" }, { "content": "to determine the characteristics of seroprevalence of herpes simplex virus type 2 ( hsv-2 ) infection among korean people , a cross - sectional study was conducted on three groups in 2004 . \n the three groups consisted of the general public who visited public health centers , commercial sex workers ( csws ) , and human immunodeficiency virus ( hiv)-infected persons . among the general public , hsv-2 seroprevalence rates for age under the 20s , in the 20s , 30s , 40s and the above 22.6% , 32.7% and 32.3% , respectively , which showed rapid increase of the rate in the 30s ( p<0.0001 ) . in case of the above of 19 yr old , \n women ( 28.0% ) was higher than men ( 21.7% ) ( p<0.0001 ) . \n the rate of csws ( 81.6% ) was about 10 times higher than that of general women . in case of hiv - infected men ( 47.6% ) , \n the figure was about 2 - 3 times higher than that of general men . \n the low rate in the teens and the 20s proved that it is essential to develop sexually transmitted infections ( stis ) prevention programs of education and publicity for them as a precaution measure . \n this study is the first major study of its kind on hsv-2 and would provide basic data for prevention of stis including information about target groups subject to vaccination program .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: brain - derived neurotrophic factor ( bdnf ) is a member of the neurotrophic factor family and is well known as a survival factor and chemoattractant during development of the central nervous system . in recent years , however , it has been shown that bdnf also plays a significant role modulating synaptic plasticity in the hippocampus [ 26 ] . \n these functions include the enhancement of synaptic transmission at excitatory synapses and alterations of dendritic architecture , for example , increasing dendritic spine density [ 912 ] . \n bdnf exerts its effects both at the presynapse and the postsynapse : at the presynaptic level , bdnf modulates quantal synaptic transmission , and at hippocampal ca3-ca1 pyramidal neuron synapses , this is manifested as transient increases in the frequency of miniature synaptic currents . \n acute application of bdnf enhances spontaneous and evoked glutamatergic excitatory postsynaptic currents in cultured neurons [ 1317 ] . \n long - term treatment of postnatal hippocampal slice cultures with bdnf increases the frequency of miniature excitatory postsynaptic currents ( mepscs ) recorded from ca1 pyramidal neurons , without affecting their amplitude or kinetics . \n indeed , bdnf selectively increased the density of synaptic vesicles docked at the active zone of asymmetric spine synapses , without affecting those in the main vesicle cluster . \n furthermore , bdnf selectively enhanced evoked and spontaneous fm1 - 43 destaining in acute hippocampal slices , but only when presynaptic terminals were dye - loaded with a hyperosmotic shock using sucrose , a manipulation that only engages the readily releasable pool of vesicles [ 19 , 20 ] . \n two potential mechanisms mediating the bdnf - induced increase in transmitter release include synapsin - i phosphorylation and trkb - initiated plc activation leading to ca mobilization from ip3-sensitive stores . \n previous studies have suggested that ca influx following ca store depletion may contribute to spontaneous vesicular release . \n however , studies regarding bdnf - mediated increases in mepsc frequency in dissociated cultured neurons have concluded that this effect is dependent upon ca release from intracellular stores only . \n we herein report that bdnf activation of trkb receptors rapidly enhances spontaneous quantal transmitter release in ca1 pyramidal neurons of hippocampal slice cultures by ca mobilization from intracellular stores , a signal further amplified by ca entry through trpc plasma membrane channels . \n additionally , bdnf causes immediate fm dye destaining in the absence of action potentials , directly proving its presynaptic effect and the vesicular origin of postsynaptic quantal responses . \n the rate of bdnf - induced destaining was similar for two fm dyes with different membrane departition rates , suggesting that bdnf increases mepsc frequency by either full - fusion events or through fusion pores with limited fm dye permeability . \n all animal procedures strictly adhered to national and international guidelines for the ethical use of research animals . \n the institutional animal care and use committee ( iacuc ) of the university of alabama at birmingham ( uab ) reviews and approves all animal procedures described in the present paper on an annual basis . \n briefly , hippocampi were dissected from anesthetized postnatal days 711 sprague - dawley rats ( harlan , indianapolis , in , or charles river laboratories , wilmington , ma , usa ) and cut transversely into 400 m thick slices using a custom - made wire slicer fitted with 20 m thick gold - coated platinum wire . \n hippocampal slices were individually plated on millicell - cm filter inserts ( millipore , billerica , ma , usa ) and cultured in 36c , 5% co2 , 98% relative humidity incubators ( thermo - forma , waltham , ma , usa ) . \n slices were maintained in culture media ( neurobasal - a plus b27 ; invitrogen , carlsbad , ca ) , containing 20% equine serum for the first 4 days in vitro ( div ) . to avoid the confounding effects of hormones and growth factors in the serum , its concentration \n was gradually reduced over a period of 48 h starting at 4 div ( 24 h each in 10 and then 5% serum ) . after a period of 24 h in serum - free media ( \n neurobasal - a plus b27 ) , 710 div slices were used for electrophysiology . \n individual 710 div slices were transferred to a recording chamber mounted on a fixed - stage upright microscope ( axioskop fs ; zeiss , oberkochen , germany ) and continuously perfused ( 2ml / min ) with artificial csf ( acsf ) at room temperature ( 24c ) containing the following ( in mm ) : 124 nacl , 2 kcl , 1.24 kh2po4 , 1.3 mgso4 , 17.6 nahco3 , 2.5 cacl2 , 10 glucose , and 29.2 sucrose ( 310320 mosm ) . \n superficial ca1 pyramidal neurons were visualized with a water - immersion 63x objective ( 0.9 numerical aperture ( na ) ) using infrared differential interference contrast ( ir - dic ) microscopy . \n whole - cell intracellular recordings were performed as previously described [ 10 , 24 ] . \n human recombinant mature bdnf ( supplied by amgen , thousand oaks , ca , or purchased from promega , madison , wi , usa ) was pressure applied to hippocampal slices from glass pipettes ( ~5 m ) using a picospritzer iii ( parker hannifin , cleveland , oh , usa ) as described [ 10 , 22 ] . \n hippocampal slices , maintained in serum - free medium for 10 to 12 days , were labeled with either fm1 - 43 or fm2 - 10 dyes . \n the total recycling pool of vesicles was loaded via endocytosis by incubating slices in 40 mm k acsf containing 0.5 m ttx and either 15 m fm1 - 43 or 100 m fm2 - 10 ; the solution had been prewarmed to 37c and was under constant aeration ( 95% o2/5% co2 ) throughout the 15 min incubation . \n individual slices were then placed in standard acsf containing 0.5 m ttx and either 5 m fm1 - 43 or 100 m fm2 - 10 for 3 minutes , then in dye - free , nominally zero ca acsf containing 0.5 m ttx for a 30-minute washout . \n imaging was conducted in standard acsf containing 0.5 m ttx , and fm dye fluorescence intensity was monitored during pressure application of bdnf from glass pipettes ( ~5 m ) using a picospritzer - iii ( parker hannifin , cleveland , oh , usa ) . \n fm dye fluorescence images were collected with a 60x , 0.9 na water - immersion objective ( lumplanfi / ir2 ; olympus , melville , ny , usa ) , using a custom - built multiphoton excitation laser scanning microscope consisting of an upright bx50wi microscope and a modified fv300 scanhead ( olympus ) . a ti - sapphire laser pumped by a 12 w diode ar laser ( chameleon ; coherent , santa clara , ca , usa ) was tuned to 840 nm center wavelength . \n infrared laser intensity was controlled by an external pockels cell ( conoptics , danbury , ct , usa ) before entering the scanhead . \n infrared - filtered fm dye fluorescence emission was detected by a gaasp photomultiplier ( pmt ) ( h7422p-40 ; hamamatsu ) in nondescanned mode . \n the lowest intensity necessary for adequate signal - to - noise ratio was used to avoid photodamage and fm dye bleaching . \n average power in the back focal plane of the objective never exceeded 50 mw . \n ir - filtered fm dye fluorescence was detected by laser - scanning microscopy and time - lapse image acquisitions were controlled by fluoview - tiempo software ( olympus ) . \n full - frame images ( 512 512 pixels , ~72 72 m ) were acquired every 1.1 second . \n all image fields were obtained from within ~200 m of the slice surface , typically ~25150 m deep . \n ten image frames were acquired before stimulation and used to determine baseline fluorescence ( fb ) . \n once stimulation was delivered , fm dye emission intensity was measured , and changes were expressed as f / fb . \n fm dye bleaching was measured by image sequences of similar duration but without stimulation and was less than 5% over the 30-minute long movies . \n fm dye fluorescence intensity was measured from visually identified puncta or clusters of several puncta that could be individually tracked in a single z - plane ( focal ) section over time . \n the fluorescence intensity of each of these regions - of - interest ( roi ) was individually measured , normalized , and plotted over time , after background and bleaching subtraction [ 18 , 2528 ] . \n all data analyses were performed blindly and included only those fm puncta , whose fluorescence intensity was more than two times the sd of the baseline fm dye fluorescence intensity . \n identical rois with a constant diameter of 1 m ( seven pixels ) were used to select individual puncta and ensure consistent analysis over time and regions in a slice . \n data from experiments where lateral displacement ( x - y ) or focal drift in the z - axis of fm dye puncta occurred , were discarded . to avoid imaging nonselective fm staining , only puncta that showed stimulus - dependent destaining \n data were analyzed using paired student 's t - test for comparing bdnf effects on mepsc mean frequency in the same cells , kolmogorov - smirnov test for comparing median mepsc frequencies , and unpaired student 's t - test for comparing fm dye destaining rates ( prism ; graph - pad software , san diego , ca , usa ) . \n long - term ( minutes to hours ) exposure to bdnf induces varied effects on hippocampal neurons , ranging from modulation of synaptic transmission and plasticity to structural changes of dendrites , spines , and presynaptic terminals [ 3 , 4 , 6 , 30 ] . in order to investigate whether short - term exposure has similar effects \n , we applied bdnf from picospritzer - controlled pipettes placed 100 m above hippocampal slice cultures , a configuration that prevents pressure and mechanical artifacts . \n bdnf - containing pipettes were positioned over ca1 neuron dendrites within stratum radiatum , 200 m away from their cell bodies , to reproduce the spatiotemporal profile of a paracrine neuropeptide released from dense - core vesicles acting on perisynaptic receptors . under these conditions , \n a single bdnf puff of 30 sec duration increased the mean mepsc frequency from 3.6 0.6 hz to 44.8 6.6 hz measured at 70 10 sec following bdnf application ( n = 3 , p = 0.0262 ) ( figures 1(a ) and 1(b ) ) , which is a ~14 fold increase over the baseline levels . \n the bdnf - induced elevation of mepsc frequency was evident within seconds , and lasted 176.7 11.6 sec before returning to baseline levels . \n the median baseline mepsc frequency was 3.9 hz , while the peak median mepsc frequency following bdnf application reached 21.3 hz . a kolmogorov - smirnov test for differences between baseline mepsc frequency and bdnf - induced mepsc frequency yielded a z value of 14.6 0.7 , which was highly significant ( p < 0.05 ) ( figure 1(c ) ) . \n the inward current observed in the representative example shown in figure 1(a ) is mediated by trpc3-containing channels and was fully characterized in amaral and pozzo - miller . \n the amplitude of individual mepscs before and after bdnf exposure was not statistically different ( 20.9 0.9 pa versus 22.6 0.5 pa , n = 3 , p > 0.05 ) ( figure 1(c ) ) . \n similarly , the kinetics of individual mepscs was not affected by bdnf ( rise time : 1.7 0.3 ms versus 2 0.3 ms , n = 3 , p > 0.05 ) . \n the bdnf - induced increase in mepsc frequency was mediated by trk receptors , as the effect did not occur after bath application of k-252a , an inhibitor of tyrosine kinases ( mean : 2.4 0.6 hz versus 2.6 0.8 hz , n = 3 , p = 0.51 ; median : 2.6 hz versus 3.3 hz ; kolmogorov - smirnov z value : 1.9 1.3 ) ( figure 2(a ) ) . on the other hand , intracellular application of k-252b ( an analog of lower membrane permeability ) reduced but not fully prevented the bdnf effect on mepsc frequency ( mean : 1.41 0.4 hz versus 9.6 2.7 hz , \n n = 3 , p = 0.1250 ; median : 1.94 hz versus 3.59 hz ; kolmogorov - smirnov z value : 4.31 3.7 ) , which was a 6.77 fold increase over the baseline ( figure 2(b ) ) . the bdnf response in k-252b - loaded neurons peaked at 80 40 sec following bdnf application ( not different in control conditions ) but lasted significantly less ( 76.67 37.86 sec versus 176.7 11.6 sec ; n = 3 , p = 0.0289 ) . the persistence of such response albeit attenuated reflects the contribution of presynaptic trk receptors ( which are not inhibited in k-252b - loaded neurons ) to the overall effect measured under control conditions . \n the fact that intracellular k-252b application reduced the amplitude and duration of the bdnf effect on mepsc frequency suggests the intriguing possibility that postsynaptic trk receptors signal retrogradely to modulate presynaptic transmitter release . \n alternatively , k-252b could simply leak out of the postsynaptic cell to act on nearby presynaptic terminals . \n both of these pharmacological agents were used at a concentration of 200 nm in 0.01% dmso , which is specific for receptor tyrosine kinases of the trk gene family . \n vehicle controls revealed no effects of either extracellular or intracellular dmso on mepsc frequency , amplitude , and kinetics . since the frequency of asynchronous synaptic transmission is sensitive to changes in ca and bdnf signaling engages intracellular \n ca signaling , we next examined whether the bdnf effect on mepsc frequency was sensitive to manipulations of ca levels . \n indeed , bdnf failed to increase the mean mepsc frequency in the absence of extracellular ca ( 2.26 1.2 hz versus 2.94 1.3 hz , \n the median baseline frequency was 0.69 hz , which briefly reached a median frequency of 6.41 hz ( kolmogorov - smirnov z value : 1.9 1.3 ) , demonstrating that influx of extracellular ca is required for the effect of bdnf on mepsc frequency . \n next , intracellular ca stores were depleted by bath application of the serca pump inhibitor thapsigargin ( 1 m ) . under this condition , \n the magnitude of the bdnf effect on mepsc frequency ( 0.87 0.3 hz versus 14.11 3.5 hz , n = 3 ) was significantly smaller than that observed under control conditions ( p < 0.05 ) . \n the median mepsc frequency changed from 1.1 hz to 3.7 hz ( kolmogorov - smirnov z value was 6.6 2.6 ) ( figure 3(b ) ) . \n the temporal features of this significantly smaller response , which peaked at 102.5 63.1 sec after bdnf application , and lasted 135 90.37 sec , are not significantly different from control conditions . \n such significantly smaller bdnf response in the presence of thapsigargin may reflect incomplete store depletion , or the contribution by capacitative ca entry triggered by store depletion . \n consistent with a presynaptic mechanism , the inclusion of 20 mm bapta in the neurons under recording did not affect the ability of bdnf to increase the mean mepsc from 1.58 0.59 hz to 20.04 4.73 hz ( n = 5 , p = 0.0196 ) ( figure 3(c ) ) . \n the median mepsc frequency increased from 0.93 hz to 8.68 hz following bdnf application , and a kolmogorov - smirnov test yielded a z value of 9.51 1.93 . \n taken together , these results suggest that an elevation of intracellular ca in presynaptic terminals mediated by both ca influx and mobilization of intracellular stores is necessary for bdnf to increase mepsc frequency . \n the requirement of both ca influx and intracellular ca stores suggested the involvement of trpc channels , which are activated by the plc cascade and mediated the activation of postsynaptic currents and dendritic ca signals by bdnf in ca1 and ca3 pyramidal neurons [ 10 , 22 , 35 ] . \n bath application of the trpc inhibitor skf-96365 completely prevented the effect of bdnf on mepsc frequency ( 3.04 2.29 hz versus 2.29 0.78 hz ; n = 3 , p = 0.4256 ) ( figure 4(a ) ) . \n the median mepsc frequency changed from 2.75 hz to 2.28 hz after bdnf application ( kolmogorov - smirnov test z value 2.3 1.9 ) . to directly demonstrate that the elevated mepsc frequency evoked by bdnf represents vesicular transmitter release , we performed multiphoton imaging of fm dyes in slice cultures . \n the total pool of recycling synaptic vesicles was labeled by exposing slices to a depolarizing solution ( 40 mm k ) containing 5 m fm1 - 43 ( figure 5(a ) ) [ 18 , 26 ] . following fm1 - 43 dye washout in a zero ca solution ( to prevent fm1 - 43 destaining by spontaneous vesicle fusions ) \n , slices were imaged by multiphoton excitation microscopy ( 840 nm excitation ) in ca - containing acsf with ttx to block na - dependent action potentials . \n bdnf was applied to apical dendrites in area ca1 using a picospritzer in the same manner as for whole - cell recordings of mepscs , and fm1 - 43 fluorescence intensity was followed over time ( 0.9 frames per second , 30 min movies ) . \n figure 5(a ) shows a representative example of bdnf - induced fm1 - 43 destaining in the presence of ttx to block spike - dependent transmitter release . \n the rate of the exponential decay of fm1 - 43 fluorescence intensity immediately following bdnf application was 506 62 sec ( n = 6 slices ) . \n these observations were confirmed with fm2 - 10 , a styryl lipophilic dye with lower membrane - binding affinity ( figure 5(b ) ) . the exponential decay rate of fm2 - 10 intensity evoked by bdnf in ttx was 403 118 sec ( n = 4 slices ) , which was not significantly different that that observed using fm1 - 43 ( p > 0.05 ) . \n these results show that bdnf induces fm dye loss by a vesicular fusion mechanism that is independent of the membrane affinity and molecular size of fm1 - 43 and fm2 - 10 dyes . \n furthermore , these imaging results directly demonstrate that the elevated mepsc frequency caused by bdnf represents vesicular transmitter release from presynaptic terminals . \n the present study demonstrates that the bdnf - induced increase in mepsc frequency recorded in hippocampal ca1 pyramidal neurons represents ca - dependent vesicle release from presynaptic terminals . \n the bdnf - induced increase in mepsc frequency is prevented by bath application of the tyrosine kinase inhibitor k-252a . \n depletion of intracellular ca stores with thapsigargin also inhibited the bdnf - induced mepsc frequency increase , as did the removal of extracellular ca . \n these results demonstrate the critical requirement of trkb - initiated ca - dependent signaling in the bdnf - induced increase in mepsc frequency . \n one of the signaling cascades activated by trk receptors , the hydrolysis of pip2 by plc leading to ip3 formation , has long been known to cause intracellular ca mobilization in neurons . \n indeed , bdnf increased ca levels within presynaptic terminals of xenopus neuromuscular junctions in culture , leading to a transient enhancement of transmitter release that was dependent on extracellular ca levels and presynaptic depolarization [ 38 , 39 ] . \n similarly , extracellular ca was required for bdnf to increase the frequency of mepscs and somatic ca levels in cultured hippocampal neurons . \n in addition to well - established voltage- and ligand - gated mechanisms of ca influx , ca signals mediated by depletion of intracellular ca stores are fundamental component of neuronal ca signaling . in non - excitable cells , \n the depletion of ca stores activates plasma membrane channels often called store - operated channels ( socs ) , allowing ca entry for the replenishment of emptied stores ; this process is called capacitative ca entry [ 41 , 42 ] . \n recent evidence suggests that cultured hippocampal neurons exhibit such capacitative ca entry [ 23 , 43 , 44 ] . \n furthermore , we recently demonstrated that bdnf evokes postsynaptic currents and dendritic ca signals in ca1 and ca3 pyramidal neurons through the activation of trkb / plc and mediated by trpc3-containing channels [ 10 , 22 , 35 ] . here \n , we present evidence consistent with the model that the source of ca that contributes to the bdnf - induced increase in mepsc frequency originates from presynaptic er stores . the contribution of intracellular er stores as a source of ca to asynchronous ( spontaneous ) quantal transmitter release has been a highly debated issue . \n although some reports demonstrate that store depletion in hippocampal pyramidal neurons leads to ca - induced ca release ( cicr ) and subsequent paired - pulse facilitation of excitatory postsynaptic potentials , other reports are to the contrary . using thapsigargin , which empties er stores by poisoning the serca pump , or ryanodine , which blocks ryanodine receptors \n , it has been demonstrated that er stores and cicr do not affect paired - pulse facilitation of excitatory postsynaptic potentials . \n these studies were conducted at four different excitatory synapses in the brain : hippocampal ca3-ca1 synapses ; mossy fiber synapses between the dentate granule cells and ca3 pyramidal cells ; synapses between ca3 neurons ; cerebellar parallel fiber to purkinje cell synapses . \n still others have shown that immediate mepsc frequency increases are dependent upon mitochondrial excitatory postsynaptic potentials . \n our studies have directly demonstrated that the elevated frequency of mepscs evoked by brief and local bdnf application indeed reflects vesicular fusion events from presynaptic terminals . \n we also attempted to determine whether the vesicular fusions underlying fm1 - 43 loss from terminals represented kiss - and - run or full - fusion events by comparing them to fm2 - 10 loss , which has a slower departition rate from lipid membranes [ 47 , 48 ] . \n however , the kinetics of bdnf - induced fm2 - 10 destaining was not different than that of fm1 - 43 . \n this suggests that bdnf caused dye loss either via full - fusion events or through fusion pores with a permeability for styryl dyes that is not affected by the molecular sizes of fm1 - 43 and fm2 - 10 . \n recently , it has been determined that the fm family of dyes is not suitable for determining whether vesicle release occurs via full - fusion or kiss - and - run events . \n taken together , these results demonstrate that bdnf increases mepsc frequency by enhancing vesicular fusion through a presynaptic ca - dependent mechanism involving trkb receptors , ca stores , and trpc channels .", "role": "user" }, { "content": "brain - derived neurotrophic factor ( bdnf ) is well known as a survival factor during brain development as well as a regulator of adult synaptic plasticity . \n one potential mechanism to initiate bdnf actions is through its modulation of quantal presynaptic transmitter release . in response to local bdnf application \n to ca1 pyramidal neurons , the frequency of miniature excitatory postsynaptic currents ( mepsc ) increased significantly within 30 seconds ; mepsc amplitude and kinetics were unchanged . \n this effect was mediated via trkb receptor activation and required both full intracellular ca2 + stores as well as extracellular ca2 + . \n consistent with a role of ca2 + -permeable plasma membrane channels of the trpc family , the inhibitor skf96365 prevented the bdnf - induced increase in mepsc frequency . \n furthermore , labeling presynaptic terminals with amphipathic styryl dyes and then monitoring their post - bdnf destaining in slice cultures by multiphoton excitation microscopy revealed that the increase in frequency of mepscs reflects vesicular fusion events . \n indeed , bdnf application to ca3-ca1 synapses in ttx rapidly enhanced fm1 - 43 or fm2 - 10 destaining with a time course that paralleled the phase of increased mepsc frequency . \n we conclude that bdnf increases mepsc frequency by boosting vesicular fusion through a presynaptic , ca2 + -dependent mechanism involving trkb receptors , ca2 + stores , and trpc channels .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: although evolutionarily distant , humans and microorganisms of the candida genus are closely related from a health perspective . c. albicans is a commensal organism that colonizes mucosal surfaces of the digestive tract and oral and vaginal cavities , and is able to cause superficial or systemic infections ( candidiasis ) , particularly in the light of immunological host defects . \n nonetheless , other candida species including c. glabrata , c. krusei , c. parapsilosis and c. tropicalis have also emerged as important causative agents of candidiasis . \n intact glycosylation pathways in both , the human host and the fungal pathogen , are important , if not essential , for their development ; thus , the knowledge of commonalities and divergences of these metabolic processes , as well as their functions , could help define pharmacological targets to suppress the pathogenicity of candida and other fungal pathogens . \n the n - glycosylation pathway involves attachment of glycans to the amide nitrogen atom in the side chain of asparagine ( asn ) residues of eukaryotic , archaeal , and bacterial glycoproteins . \n the best described model where the eukaryotic n - glycosylation pathway has been characterized in detail is the baker yeast saccharomyces cerevisiae . through the years \n this model has helped to identify and characterize various human and fungal orthologs involved in this pathway . \n the synthesis of the dolichol - linked glycan and its transfer to proteins are identical in both , human cells and c. albicans [ 3 , 4 ] ( see table 1 and figure 1 ) . \n in fact , these processes are quite conserved among eukaryotic cells and there are only a handful of organisms where these stages are slightly different , such as trypanosomatids , some protists , and the fungal pathogen cryptococcus neoformans [ 5 , 6 ] . \n the eukaryotic n - linked glycosylation pathway is divided in two sequential stages : ( a ) synthesis in the rough endoplasmic reticulum ( rer ) of the dolichol - linked glycan precursor dol - pp - glcnac2man9glc3 and its transfer to a nascent protein and ( b ) the n - linked glycan processing and maturation in the rer and golgi ( figure 1 ) . \n both stages require the action of different glycosyltransferases ( gts ) and an adequate supply of donor substrates , which can be , depending on the gt family , nucleotide - activated sugars or dolichol - activated sugars . \n the lipid dolichol used as a carrier in the first stage of n - glycosylation is a polymer of isoprene units ( ch3c(ch3)=ch ch2 ) predominantly of 1417 units in the baker yeast , 1922 in humans , and of undetermined length in candida . \n dolichol is modified in the rer cytosolic face by human and c. albicans orthologue gts alg7 , alg13/14 , alg1 , alg2 , and alg11 , using the nucleotide sugars udp - glcnac and gdp - man as donor substrates to synthesize the dol - pp - glcnac2man5 intermediate . \n this intermediate is then flipped from the cytosol to the rer lumen , where synthesis proceeds by gts alg3 , alg9 , alg12 , alg6 , alg8 , and alg10 that use the dolichol - linked sugars dol - pp - glc and dol - pp - man as donors to synthesize the glycan precursor dol - pp - glcnac2man9glc3 . \n the flippase that translocates dol - pp - glcnac2man5 has not been identified yet in any organism , although a critical accessory protein in yeast , rft1 , and its human ortholog have been proposed to participate in this process [ 9 , 10 ] . \n nonetheless , a recent work in trypanosoma brucei , an early diverging eukaryote , has pointed that rft1 is not the much sought after flippase , although it is critical for allowing maturation of the dol - pp - glcnac2man5 intermediate once it is flipped to the rer lumen . \n a putative ortholog of rtf1 has been also found in c. albicans ( table 1 ) . \n once synthesized , the dol - pp - glcnac2man9glc3 precursor glycan is transferred en bloc by the oligosaccharyl transferase complex ( ost ) to asn residues by linkage to carboxamide nitrogens . \n the asn residues targeted for n - linked glycosylation are located , with rare exceptions , within the consensus sequence asn - x - ser / thr ( where x is any amino acid except proline ) . \n however , not all consensus sequences are n - linked glycosylated , because this protein modification is a co - translational process , and thus other factors are involved in selecting consensus sequences , such as accessibility of ost to the consensus sequence during the unfolded state of the protein . \n the ost complex has not been characterised in detail in c. albicans ; however , the fungus encodes all the subunit orthologs found in s. cerevisiae ost , which is comprised of nine different transmembrane subunits : wbp1 , swp1 , stt3 , ost1 , ost2 , ost3 , ost4 , ost5 , and ost6 , where stt3 is the catalytic subunit ( table 1 ) . \n albicans ost subunits are known and include : ribophorin i ( ost1 ) and ii ( swp1 ) , ost48 ( wbp1 ) , defender against apoptotic cell death or dad1 ( ost2 ) , n33 ( ost3 ) , magnesium transporter 1 ( ost6 ) , and ost4 ( ost4 ) [ 1416 ] , ( table 1 ) . \n in addition , two stt3 protein orthologs ( stt3a and stt3b ) have been identified in plants , insects , and vertebrates [ 15 , 17 , 18 ] . \n the human stt3a isoform is primarily responsible for cotranslational modification of sequons when the nascent polypeptide enters the rer lumen . \n the stt3b isoform is less competent for cotranslational glycosylation , but mediates the posttranslational modification of skipped glycosylation sites in unfolded proteins . \n the mammalian ost has been found in three complexes that exhibit different ribosome affinities and subunit compositions : ostc(i ) , ostc(ii ) , and ostc(iii ) . \n furthermore , two additional components found in the mammalian ost complex have been reported : kcp2 and dc2 [ 16 , 20 ] . \n once transference onto the protein is achieved , the pathway continues with the processing and maturation stage . \n processing is carried out , in both human and c. albicans , by rer enzymes : the mannosyl oligosaccharide glucosidase i ( mogs / cwh41 ) that removes the outermost 1,2-glucose unit , and the mannosyl oligosaccharide glucosidase ii which trims the following 1,3-glucose residue exposing the glc1man9glcnac2 epitope ( figure 1 ) . in humans \n / candida , glucosidase ii is a heterodimer composed of two subunits , the hydrolytic-subunit ( ganab / rot2 ) and the -subunit ( glu2b / gtb1 ) , see table 1 . \n the glc1man9glcnac2 epitope is a key point of er quality control of glycoproteins , as it binds to the calnexin / calreticulin ( cnx / crt ) lectin that is a folding sensor associated to erp57 . at this point \n , glucosidase ii removes the last glucose residue and , if correctly folded , the glycoprotein exits the rer after the 1,2-mannosidase removes one man residue from the middle branch of the n - linked glycan core , generating glcnac2man8 ( figure 1 ) . \n if the protein is misfolded , the glycan is reglucosylated by the action of the uggt1 glucosyltransferase in humans and its ortholog kre5 in c. albicans . \n uggt is a conformational sensor , regenerating the acceptor substrate for the calnexin / calreticulin lectin , starting a new deglucosylation step by glucosidase ii . \n this cycle continues until the protein is correctly folded or targeted for er - associated degradation . \n in contrast to candida , humans code for an endomannosidase ( manea ) located in the golgi / ergic compartment that provides a glucosidase i and ii independent pathway for n - linked glycan maturation . \n manea is able to remove the inner most glc residue along with the man residue attached to it , generating the glcnac2man8 structure ( figure 1 ) . \n the further processing of the glcnac2man8 structure is the divergence point between humans and c. albicans ( figure 1 ) . in humans , \n the n - linked glycans are processed by golgi - resident mannosidase ia , ib , and ic , which have different hydrolytic patterns but all generate man5glcnac2 . \n this glycan is then acted upon by glycosyltransferase glcnact - i to generate a glcnacman5glcnac2 structure that is acted upon by type ii -mannosidases . \n the type ii -mannosidases include the golgi mannosidase ii ( man2a1 ) , and in some cell types , additional mannosidases man2a2 and mannosidase iii have been described as bypassing enzymes when mannosidase ii fails to hydrolyse the n - linked glycan core [ 2426 ] . \n the type ii -mannosidases remove the terminal 1 - 3man and 1 - 6man residues allowing addition of a second glcnac residue to give way to complex glycans . \n the glcnac residues can be extended with additional monosaccharide linkages involving galactose , fucose , or sialic acid residues . \n furthermore , the hybrid and complex n - linked glycans found in humans may exist with two or more glcnac - bearing branches or antennae . in forming multiantennary n - linked glycan structures , \n glcnac residues may be added to the trimannosyl core by six different glcnac transferases ( i vi ) . \n if type ii -mannosidases do not act or glcnact - iii bisects the glcnacman5glcnac2 structure , hybrid glycans are then generated ( figure 1 ) . in animals , \n n - linked glycans are terminated by sialic acid in 2,3- , 2,6- , or 2,8- linkages by specific sialyltransferases . in humans , \n sialic acid is mostly of the n - acetylneuraminic acid form , in contrast to most mammalian species , where a mixture of n - glycolylneuraminic acid and n - acetylneuraminic acid is generally found . \n this monosaccharide in view of its terminal position , linkages , and negative charge has been an important element in the evolution of animal glycan function . \n although 2,3- and 2,6- sialic acid have been identified in the cell wall of c. albicans [ 33 , 34 ] , no ortholog to vertebrate sialyltransferase or ability to synthesize sialic acid has been characterized in this fungus . \n however , evidence of sialic acid synthesis has been reported in aspergillus fumigatus and c. neoformans , where sialyltransferase activity has been identified . \n another frequent modification of human n - linked glycans not seen in c. albicans is 1,6- core fucosylation of the first glcnac residue , as well as terminal fucosylation on gal or glcnac residues . \n nonetheless , fucose has been identified as a component of the cell wall of c. albicans and binds the uea - i lectin that is specific for l - fucose , more particularly to 1,2-fucose . \n mass spectrometry identified 1,6-fucose residues in oligomannosylated n - linked glycans of the fungi cantharellus cibarius . \n this raises the question on how this type of glycans are presented in the surface of mushrooms , as no fut8 family member of fucosyltransferases responsible for this linkage has been identified in yeast nor mushrooms . although little is known about fucosylation and sialylation mechanisms in c. albicans or fungi in general , more information is hinting at their role in pathological human host interactions through molecular mimicry . \n furthermore , human n - glycans can be phosphorylated to target glycoproteins to the lysosomes , through interaction with the man-6-p receptor . \n phosphorylation occurs by modification of the glcnac2man8 structure by a udp - glcnac - dependent glcnac-1-phosphotransferase ( figure 1 ) . \n a glcnac phosphodiester is added to n - linked glycans on one of three mannose residues on the arm with the 1,6- linkage to the core mannose . \n a second phosphodiester can then be added to the other side of the n - glycan or onto other mannose residues ( figure 1 ) . \n afterwards , the phosphodiester glycosidase in the trans - golgi removes the glcnac to generate man-6-p residues . \n the phosphate residues partially block the action of processing mannosidases , maintaining the n - glycans in an oligomannosyl form . \n this sorting system of soluble proteins does not exist in c. albicans or other yeast species , but interestingly they contain the gene mrl1 , which seems to be the ortholog of that encoding the human man-6-p receptor . in c. albicans , \n the n - linked glycan glcnac2man8 is modified by proteins that have no human orthologs ( see table 2 ) . \n the glcnac2man8 core is recognised by och1 , an 1,6-mannosyltransferase that adds the first mannose residue of the n - linked glycan outer chain ( figure 1 ) . \n this mannose residue works as a molecular primer to build the 1,6-mannose backbone , which in s. cerevisiae is elongated by the m - pol i complex ( a heterodimer composed of mnn9 and van1 ) that adds 3 to 7 mannose residues and then by m - pol ii , a multimeric complex composed of mnn9 , anp1 , mnn10 , mnn11 , and hoc1 [ 46 , 47 ] ( figure 1 ) . \n both , in vivo and in vitro studies have shown that mnn10 and mnn11 contribute to most of the 1,6-mannosyltransferase activity of m - pol ii . \n thus far , there is only experimental evidence about mnn9 role in c. albicans ; however , the encoding genes for all members of both complexes are present within c. albicans genome and it is likely they work as described in the baker yeast . \n parallel to this process , the 1,6-mannose polymer works as a molecular scaffold where branches of 1,2-mannose residues are added by mnn5 [ 49 , 50 ] . \n these are further elongated by the mannosyltransferases mnt4 and mnt5 , and members of the mnn2-like gene family . in s. cerevisiae , \n the branches are terminated with 1,3-mannose residues added by action of the mannosyltransferase mnn1 . in c. albicans , these mannose residues are also present and are likely to be incorporated to glycans via the same protein ; however , it is most frequent that the 1,2-mannose branches are further decorated and capped with 1,2-mannose units . \n the 1,2-mannosylation is characteristic of this pathogenic yeast species and is carried out by members of the bmt gene family . \n another decoration attached to the 1,2-mannose branches is the phosphomannan , which is a mannose residue attached to the n - linked glycan by a phosphodiester bond ( figure 1 ) . \n this phosphorylation is not related to that found in humans and is partially synthesized by phosphomannosyltransferases mnt3 and mnt5 . \n the identity of the enzymes involved in the addition of the rest of the phosphomannan remains unknown , although it is likely that members of the mnn4-like family contribute to this activity [ 57 , 58 ] . \n as the n - linked glycan , the phosphomannan can be further 1,2-mannosylated with up to 14 1,2-mannose units , by action of bmt2 , bmt3 , and bmt4 . \n the n - linked glycans associated to glycoproteins participate in the calnexin / calreticulin er quality control system of glycoprotein folding . \n furthermore , n - linked glycans are involved in protein stabilization and trafficking and serve as moieties recognized by receptors , thereby modulating binding by increasing or decreasing affinity . \n the n - linked glycans play from trivial to essential roles in glycoprotein function and are involved in most , if not all , cellular processes . \n there is clear evidence that this posttranslational modification is essential for homeostasis in multicellular organisms as has been demonstrated by clinical phenotypes , mostly multisystemic , of patients affected by congenital disorders of glycosylation , indicating that n - linked glycan integrity is required for normal tissue function . \n the n - linked mannans are essential for c. albicans viability , as demonstrated by treatment with tunicamycin , a drug that inhibits the action of alg7 during n - linked glycan core synthesis . \n furthermore , they are quite important for cell fitness : defects in either the processing step by rer -glycosidases or elongation by golgi mannosyltransferases lead to longer duplication times , swollen cells , inability to perform proper cell separation , abnormal colony morphology , and impaired ability to undergo dimorphism [ 21 , 44 , 51 , 63 ] . \n these pleiotropic defects are likely consequences of loss of the cell wall plasticity : mutant cells with defects in the n - linked mannan biosynthesis have rearrangements in the wall composition , including low mannan levels and high chitin and glucan contents , which led to increasing the sensitivity to cell wall perturbing agents such as tunicamycin , congo red , calcofluor white , hygromycin b , and caffeine [ 4 , 21 , 44 , 5052 , 63 ] . \n protein modification by n - linked mannans also modulates protein secretion , but surprisingly in a negative form , as shown in mutants lacking rer -glycosidases , which display increased cell wall protein content . \n in addition , biofilm formation seems to depend on n - linked mannans , as shown by the inability of tunicamycin - treated cells to form this kind of microbial consortiums . finally , and most important , n - linked mannosylation is required for normal cell adhesion and virulence [ 4 , 21 , 44 , 50 , 51 , 63 , 6569 ] . \n the extent to which fucosylation and sialylation play a role in pathogenicity through the adhesion to the host surface , particularly extracellular matrix components , still requires further characterization in c. albicans . \n in contrast to c. albicans that only synthesizes o - linked mannosyl glycans ( o - man ) , six additional types of o - linked glycans are found in humans , and are classified based on the first sugar attached to the amino acid residue : glcnac , galnac , galactose , xylose , glucose , or fucose . \n the o - man glycans were identified on brain proteoglycans more than 30 years ago , and the o - mannosylation of -dystroglycan ( dg ) has been the most studied . \n in contrast to c. albicans , human o - man glycans contain only one mannose residue ( linked to the protein ) and are extended with other monosaccharides ( figure 2 ) . in c. albicans , \n most of the mammalian o - mannosyl glycans are variations of the common tetrasaccharide core neuac2 - 3gal1 - 4glcnac1 - 2man1-ser / thr , although branched structures with 2,6-di - substituted mannose ( glcnac - linked 1,2 and 1,6 ) have been described in brain glycoproteins . in humans \n , the first mannose residue is added in the rer by protein - o - mannosyl - transferase 1 ( pomt1 ) and 2 ( pomt2 ) , homologous to c. albicans pmt4 and pmt2 , respectively ( table 3 ) . \n both enzymes perform their function in an essential complex that uses dol - p - man as sugar donor . in humans , \n elongation of o - man glycans is initiated in the golgi complex by transfer of glcnac to the man residue in the 2-oh position , mediated by the protein - o - mannosyl n - acetylglucosaminyltransferase 1 ( pomgnt1 ) that uses udp - glcnac as donor substrate ( figure 2 ) . \n alternatively , n - acetylglucosaminyltransferase ix ( gnt - ix ) can make branched structures transferring glcnac in 1,6-linkage to the o - man glycan . \n further enzymes directly involved in the elongation of o - man glycans remain to be identified among families of 1,4-galactosyltransferases and 2,3-sialyltransferases . another o - linked glycan structure ( \n galnac1 - 3glcnac1 - 4man1-ser / thr ) has been reported in dg ( figure 2 ) . \n this structure is further phosphorylated in the 6-position of o - mannose by the action of the protein - o - mannose kinase ( pomk ) . \n the large and large2 bifunctional glycosyltransferases act on the phosphomannose structure producing repeating units of [ -3-xylose-1,3-glucuronic acid-1- ] ( figure 2 ) [ 79 , 80 ] . \n two other proteins , fukutin and fkrlp , with glycosyltransferase characteristics , are also involved in the formation of human o - man glycans , but their function remains unknown . \n as in humans , in c. albicans , this pathway starts in the rer and finalises in the golgi complex . \n the synthesis begins with the addition of one -linked mannose residue to ser or thr residues via an ester bond . \n this reaction takes place in the rer lumen and is catalysed by the protein - mannosyl transferases that use dol - p - man as sugar donor . \n this enzyme activity is performed by a family composed of five members that are subclassified in three groups : the pmt1 ( pmt1/5 ) , pmt2 ( pmt2/6 ) , and pmt4 subfamilies ( figure 2 ) . \n the proteins encoded by these subfamilies do not have redundant activity in vivo , as each member has specific substrates [ 8183 ] . \n in addition , these enzymes interact among them generating protein - protein interactions . in s. cerevisiae , \n pmt1 interacts in vivo with pmt2 , and combined disruption of pmt1 and pmt2 results in more than 90% less enzyme activity in vitro . \n another predominant complex includes pmt5 and pmt3 , but in the absence of pmt5 , pmt3 can form a complex with pmt1 , and pmt2 can form a complex with pmt5 when pmt3 is disrupted . \n once the glycoproteins are transported to the golgi complex , the o - linked glycans are further elongated by the golgi 1,2-mannosyltransferases mnt1 and mnt2 that have redundant activities to fully elongate the glycans [ 71 , 85 ] . \n this mannan structure can also be phosphomannosylated , and in fact , the phosphosugar attached to o - linked mannans represents about 20% of total cell wall phosphomannan content . \n however , the machinery involved in this process is different of that described for n - linked mannans , as mnt3 and mnt5 do not add phosphomannose to o - linked mannans . \n as mentioned before , sialic acid has been described in c. albicans [ 33 , 36 ] , and sialidase treatment has been shown to increase binding of the peanut agglutinin that has specificity for the gal1,3galnac sequence present in human core 1 o - glycans which has not been described in c. albicans . \n this suggests that sialic acid could be part of c. albicans o - linked mannans and the presence of uncharacterized galactosyltransferases . \n the best characterized mammalian o - linked man glycoprotein is dg ( figure 2 ) . \n this protein is a glycosylated peripheral membrane protein involved in linking the cytoskeleton of neurons and muscle cells to the basal lamina through interactions with extracellular proteins ; glycosylation of dg is essential for its function . to date , mutations in seven glycosyltransferase or glycosyltransferase - like genes have been reported to affect the o - linked mannosylation pathway and are causative for various forms of autosomal recessive congenital muscular dystrophies associated with variable brain and ocular abnormalities . as it was mentioned earlier , o - man glycans in humans are not highly mannosylated structures ; they only possess a single man residue . \n this divergence is functionally important in the immune systems recognition of pathogenic yeast and fungal microorganisms , including c. albicans . \n highly mannosylated structures , as those found in yeast and fungi , are recognized as foreign by both circulating antibodies and elements of the complement system , including both the classical and alternative pathways . \n loss of pmt2 or combined disruption of pmt1 and pmt4 led to nonviable cells , indicating that o - linked mannosylation is essential for growth and cell viability . \n in addition , incomplete o - linked mannan elaboration has been associated with rearrangements in the cell wall composition , increasing sensitivity to cell wall perturbing agents , defects in morphogenesis , reduced tissue adhesion , defective biofilm formation , and virulence attenuation [ 71 , 81 , 8991 ] . \n the o - linked mannans are key cell wall elements during the c. albicans sensing by immune cells . \n this cell wall component is sensed by tlr4 receptor , and loss of either o - linked mannans or tlr4 receptor has a negative impact on cytokine production by human pbmcs , on the proinflammatory response of oral epithelial cells , and on yeast killing by human polymorphonuclear cells . indeed , \n tlr4 knockout mice are more susceptible to infections caused by c. albicans due a defective immune response against the fungus [ 94 , 95 ] . \n furthermore , it has been demonstrated that simultaneous stimulation of dectin-1 and either tlr2 or tlr4 significantly enhances cytokine production in both human monocytes and macrophages [ 96 , 97 ] . \n therefore , it has been hypothesized that recognition of o - linked mannans plays a pivotal role , along with 1,3-glucan sensing , in the establishment of a protective anti - candida immune response . \n however , the relevance of o - linked mannans during c. albicans sensing is not the same for different kinds of immune cells , as yeast cells lacking both mnt1 and mnt2 , and therefore expressing truncated o - linked mannans at the cell wall surface , are as good as the wild type control cells to stimulate binding and cytokine production by human dendritic cells . \n moreover , there are some c. albicans strains whose immune sensing is independent of recognition via tlr4 , suggesting that the fungus might be able to modulate the production of this cell wall component . \n the gpi anchors are complex structures that comprise a phospholipid tail , a glycan core , and a phosphoethanolamine linker ( figure 3 ) . \n this structure is attached to the c - terminus of some eukaryotic proteins , allowing their anchoring to cell membranes or the wall . \n the core glycan , mannose(1 - 2)mannose(1 - 6)mannose(1 - 4)glucosamine(1 - 6)myo - inositol is highly conserved in eukaryotes , but it can be modified with other residues such as mannose , phosphoethanolamine ( etn - p ) , galactose , sialic acid , and others . the gpi synthetic pathway ( figure 3 ) initiates on the cytoplasmic side of the rer with the transfer of glcnac from the udp - glcnac donor to phosphatidylinositol . \n this step requires several proteins that form complex ( gpi - gnt ) , pig - a / gpi3 , pig - c / gpi2 , pig - h / gpi15 , pig - p / gpi19 , pig - q / gpi1 , and pig - y / eri1 ( mammals / yeast ) [ 100107 ] ; see table 4 . \n next , glcnac - pi is deacetylated by pig - l / gpi12 , generating glcn - pi , which requires crossing the rer membrane to continue the synthetic pathway within the lumen . \n this transport , as in the other protein modification described above , is carried out by a rer flippase . \n then , inositol acylation takes place due to the acyltransferase activity of pig - w / gwt1 , being the donor acyl - coa [ 109 , 110 ] . \n gpi mannosylation takes place using dol - p - man as mannose donor and begins with action of the mannosyltransferase pig - m / gpi14 in complex with pig - x / pbn1 that adds the first mannose ( 1,4-linked ) to glcn . \n the second ( 1,6-linked ) and third ( 1,2-linked ) mannose units are transferred by pig - v / gpi18 and pigb / gpi10 mannosyltransferases , respectively [ 112115 ] . \n the enzyme smp3 catalyses the addition of a fourth mannose residue ( 1,2-linked ) to man-3 of the glycan core , being an essential step in yeast and candida cells , as it is required for subsequent attachment of phosphoethanolamine [ 116 , 117 ] . \n mammalian cells mostly transfer trimannosyl - gpis to proteins and do not require the addition of a fourth mannose residue , but a human ortholog of the yeast mannosyltransferase smp3 that adds a fourth , 1,2-linked man to trimannosyl gpi precursors has been identified , displaying high expression in brain and colon , suggesting that man4-gpis elaboration could be tissue - specific . in c. albicans , smp3 and is essential for viability and has been proposed to be a potential antifungal target . an etn - p unit can be attached to the first mannose of the glycan core as a side branch by pig - n / mcd4 and also to the second mannose by a complex of pig - f / gpi11 and pig - g / gpi7 [ 119121 ] . \n finally , a moiety of etn - p is added to the third mannose of the core , being this residue the one bound to the protein through an amide link . \n a transferase association between pig - o / gpi13 and pig - f / gpi11 is responsible for this step [ 122 , 123 ] . \n the gpi synthetic pathway is highly conserved , but gpis can be further modified in the lipid and glycan moieties depending on genus , species , and protein type . \n the gpi - anchored proteins have a c - terminal sequence that directs the attachment of a gpi anchor . \n the removal of the c - terminal gpi signal sequence and its replacement with gpi on the lumen of rer are catalyzed by the gpi transamidase ( gpit ) , which is a complex consisting of the membrane proteins pig - k / gpi8 , gaa-1 , pig - s / gpi-17 , pig - t / gpi16 , and pig - u / cdc91 [ 125 , 126 ] . in the first step of the gpit - catalyzed reaction , the gpi signal sequence is cleaved and the newly generated -carbonyl group is attached via a thioester linkage to the pig - k subunit of gpit . \n nucleophilic attack on the activated carbonyl by the amino group of the terminal etn - p residue of gpi regenerates gpit and yields a gpi - anchored protein . after transfer , \n the inositol group introduced before mannosylation of the gpi precursor is removed in humans and yeast by the orthologous pgap1/bst1 deacylase er proteins . \n yeast is able to remodel the shorter acyl chains of the diacylglycerol shortly after transfer to either base - labile c26:0/c26:0 diacylglycerols or to a base - stable ceramide consisting of c18:0 phytosphingosine and a hydroxy - c26:0 fatty acid . \n the remodeling initiates with the removal by pgap3/per1 of the acyl chain at the sn-2 position of the diacylglycerol [ 128 , 129 ] . \n pgap3-dependent removal of unsaturated fatty acyl chains at the sn-2 position occurs predominantly in the golgi , whereas per1 activity is located in the rer . \n next , a c26:0 acyl chain is introduced at sn-2 by the o - acyltransferase gup1 that is the only enzyme involved in gpi anchor synthesis in c. albicans that has no human ortholog . \n the mammalian pgap2 protein is involved in the subsequent introduction of a saturated ( c18:0 ) fatty acid at sn-2 . \n mutations in the yeast gene that encodes a homolog of pgap2 , cwh43 , albeit a much larger protein , cause cell wall abnormalities consistent with defects in cell surface anchorage of gpi proteins . in mammals , remodeling at sn-2 requires prior inositol deacylation by pgap1 . \n the pgap3- and pgap2-dependent remodeling activities , in turn , are necessary for the gpi - anchored proteins to associate with lipid rafts . \n the obvious role for gpi - anchors is the attachment of proteins to cell surface . \n examples include cell surface receptors ( e.g. , folate receptor , cd14 ) , cell adhesion molecules ( e.g. , neural cell adhesion molecule ) , cell surface hydrolases ( e.g. , alkaline phosphatase ) , and complement regulatory proteins ( e.g. , decay - accelerating factor [ cd55 ] ) . \n human diseases arise by failures in this posttranslational process , stressing its importance for proper function of human cells . \n the paroxysmal nocturnal hemoglobinuria is a consequence of lower surface expression of gpi - proteins , due to clonal acquired mutations in pig - a . \n inherited mutation in the promoter region of pig - m impairs the binding of the transcription factors , resulting in abrogation of gpi mannosylation , leading to propensity to venous thrombosis and seizures . \n other congenital diseases involving defective pig anchoring have been recently described . as in human cells , \n gpi synthesis is essential for s. cerevisiae growth [ 101 , 135 ] . c. albicans has 115 putative gpi - proteins , with diverse predicted functions , including adhesion to host tissues . c. albicans gpi7 leads to an aberrant cell wall composition with increased chitin content and less protein abundance , while cells lacking smp3 mannosyltransferase are nonviable . \n propose that gpi2 and gpi19 subunits of the gpi - gnt complex regulate ergosterol synthesis and ras signaling , which explains the influence of gpi synthesis in the dimorphic switch . \n adhesins of the als family are known to be gpi - proteins , so it is not surprising that virulence is attenuated in gpi mutants . \n the information gathered in the last decades about the human glycosylation pathways has helped to differentiate the normal processes from those found in neoplastic cells , and these are now explored as potential strategies to treat cancer [ 141 , 142 ] . since protein glycosylation is a key process for c. albicans fitness and virulence attributes [ 4 , 143 ] , it is assumed that the development of inhibitors for any of the glycosylation pathways may assist in treatment of candidiasis . \n tunicamycin is one of the oldest n - linked glycosylation inhibitors that has been thoroughly characterised over the last decades . \n it affects the elaboration of the n - linked glycan core , and tunicamycin - treated cells of c. albicans lose the viability and the ability to generate biofilms , making this molecule a potential anti - c . \n however , the udp - n - acetylglucosamine , dolichol phosphate glcnac-1-p transferase , the molecular target of this compound , is equally sensitive in both human and fungal cells . a promising strategy for treatment of c. albicans infections could be found in the rer glucosidase inhibitors , which have been used in the experimental control of some viruses [ 145149 ] . \n we have previously shown that c. albicans cells require processing of the n - linked glycan core in order to elongate their n - linked mannans , and loss of either glucosidase i or ii led to virulence attenuation . \n since the human cells have a bypassing strategy for glucosidase trimming via the endomannosidase enzyme activity , it is feasible to conceive the potential low cytotoxicity of these drugs on the host cells . \n celgosivir , pbdnj0804-a deoxynojirimycin derivative , and cm-10 - 18 are rer glucosidase i inhibitors that could show anti - c . \n it was recently demonstrated that the rhodanine-3-acetic acid derivative ogt2468 is a pmt inhibitor in s. cerevisiae and that it likely affects the same biosynthetic pathway in c. albicans . whether this compound affects or not the elaboration of o - linked man glycoprotein in human cells remains to be addressed . \n the enzymes involved in gpi synthesis are also potential targets to develop new antifungal drugs . \n gepinacin and e1210 were found to inhibit the fungal acyltransferase gwt1 , impairing the growth of fungal pathogens . despite the functional similarity \n assays on c. albicans cells treated with gepinacin indicate that they overexpose -glucans on the wall surface , which triggers a better macrophage response [ 152154 ] . \n development of smp3 or gup1 inhibitors would be of value in view of their nonessential nature or absence in humans , respectively . \n metazoa ( animals ) and fungi derive from a common ancestor that existed ~1 billion years ago , nonetheless the basis of protein glycosylation pathways is strikingly conserved in spite of this period . in this review \n , we can look at the common bases and differences that emerge when comparing glycosylation mechanisms in c. albicans and humans . \n the study of c. albicans glycosylation machinery is an important step to identify pharmacological targets to treat local or systemic candidiasis . \n ideal pharmacological targets are represented by those elements only present in candida . in the n - linked glycosylation pathway at least 16 gts participate in mannan synthesis and \n are not present in humans ( see table 2 ) , making this pathway an attractive alternative for drug design . \n thus far , some promising approaches have been done with glucosidase inhibitors , but their toxicity in human cells remains to be addressed . \n in addition , rer - mannosidase inhibitors could be used as an alternative approach , as fungal cells only contain one mannosidase class i within the rer , and its loss is associated with virulence attenuation . \n the above data indicate that fungal glycosylation pathways are promising for inhibitory compound screening that are species specific , both because of the presence of many nonhomologous proteins identified in c. albicans , particularly in the n - glycosylation pathway , and also because of the presence of homologous proteins that have a low degree of identity . \n further studies should focus on developing compounds to inhibit the essential functions of glycosylation pathways taking into account these facts .", "role": "user" }, { "content": "protein glycosylation pathways are present in all kingdoms of life and are metabolic pathways found in all the life kingdoms . \n despite sharing commonalities in their synthesis , glycans attached to glycoproteins have species - specific structures generated by the presence of different sets of enzymes and acceptor substrates in each organism . in this review \n , we present a comparative analysis of the main glycosylation pathways shared by humans and the fungal pathogen candida albicans : n - linked glycosylation , o - linked mannosylation and glycosylphosphatidylinositol - anchorage . \n the knowledge of similarities and divergences between these metabolic pathways could help find new pharmacological targets for c. albicans infection .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the high prevalence of obstructive sleep apnea ( osa ) among patients with chronic obstructive pulmonary disease ( copd ) parallels the recent increase in obesity in western societies . \n the prevalence of osa among patients with copd is similar to that of the general population ( 22% and 25%29% , respectively ) while the prevalence of obstructive airway disease among patients with osa is even higher ( 29%40% ) ( young et al 1993;de miguel et al 2002 ; sanders et al 2003 ; obrien et al 2005 ) . \n although the clear common risk factors for such strong association are incompletely understood , the sheer number of patients with copd and osa accounts for their frequent coexistence . despite well documented high prevalence of both copd and osa , the coexistence of both conditions remains frequently unrecognized . \n nocturnal arterial oxyhemoglobin desaturation and diurnal hypoxemia and hypercapnia are more pronounced in patients with coexistent copd and osa than in patients with either condition alone ( chaouat et al 1995 ; sanders et al 2003 ) . \n patients with both conditions have a greater risk for pulmonary hypertension and right heart failure compared with patients with copd or osa alone ( bradley et al 1985 ; chaouat et al 1995 ) . \n most importantly , patients with coexistent copd and osa have increased mortality compared with patients with osa alone ( lavie et al 1995 ; chaouat et al 1999 ) . \n treatment with continuous positive airway pressure ( cpap ) reduces the risk of fatal and nonfatal cardiovascular events in patients with osa ( marin et al 2005 ) . \n therefore , early recognition and prompt treatment of coexistent osa in patients with copd is essential for reducing morbidity and mortality in these patients . \n the present review discusses the diagnostic challenges presented by the coexistence of copd and osa , and emphasizes the importance of timely identification and treatment of osa in patients with copd . \n patients with osa experience repetitive episodes of hypoxia / reoxygenation during apneas and hypopneas while asleep resulting in increased arterial stiffness , blood pressure , and sympathetic activity ( carlson et al 1993 ; nieto et al 2000 ; jelic et al 2002 ) . \n untreated osa increases risk for hypertension , heart failure , stroke , and increased mortality ( he et al 1988 ; peker et al 1999 ; peppard et al 2000 ; yaggi et al 2005 ) . \n patients with untreated severe osa have a higher incidence of fatal and nonfatal cardiovascular events than patients treated with cpap after adjustment for pre - existing cardiovascular risk factors ( marin et al 2005 ) . \n forced expiratory volume in 1 second ( fev1 ) is as good a predictor of cardiovascular mortality as serum cholesterol ( hole et al 1996 ) . \n ischemic heart disease , and not respiratory failure , is the leading cause of death in copd patients ( pauwels et al 2001 ) . \n while right heart failure is a well established complication of copd , the high prevalence of left ventricular ( lv ) systolic dysfunction in patients with copd remains unclear . \n patients with copd are not at increased risk for hypertension or lv hypertrophy ; however , they consistently show evidence of low - grade systemic inflammation that plays a major role in the pathogenesis of atherosclerosis ( sin et al 2004 ) . \n patients with severe copd and unknown osa status are 2.18 and 2.74 times more likely to have elevated and highly elevated , respectively , circulating c - reactive protein levels than control subjects ( sin et al 2003 ) . \n untreated osa is associated with systemic inflammation as well ( shamsuzzaman et al 2002 ) . \n the presence of unrecognized osa may potentiate systemic inflammation and accelerate progression of coronary atherosclerosis leading to increased cardiovascular morbidity and mortality in copd patients . furthermore \n , untreated osa causes excessive daytime sleepiness that leads to increased risk of accidents at work and while operating a motor vehicle ( sassani et al 2004 ) . \n utilization of healthcare resources and economic cost are 23% to 50% greater among untreated osa patients compared with the age - matched subjects ( bahammam et al 1999 ; smith et al 2002 ) . \n efficacious treatment of osa reduces the cardiovascular morbidity and mortality as well as cost of care ( marin et al 2005 ) . despite its significant negative impact on public health , \n identifying patients who experience osa - related arterial oxyhemoglobin desaturation is especially important in copd patients since more pronounced nocturnal desaturation correlates with the development of pulmonary hypertension and adverse outcomes ( mcnicholas et al 1984 ; bradley et al 1985 ) . \n the prevalence of osa among patients with mild copd equals that among general middle - age population ( 22% vs 29% ) ( sanders et al 2003 ) . \n an additional quarter of copd patients with mild daytime hypoxemia suffer from nocturnal oxyhemoglobin desaturation even in the absence of osa ( fletcher et al 1987 ) . \n progressive decline in fev1 and forced vital capacity ( fvc ) ratio to below 65% is associated with accelerated increase in risk of oxyhemoglobin desaturation during sleep ( sanders et al 2003 ) . taken together , these epidemiological data suggest that nocturnal oxyhemoglobin desaturation either related or unrelated to osa is present in at least a half of copd patients without significant daytime hypoxemia . \n current guidelines for evaluation of nocturnal oxyhemoglobin saturation in copd patients without significant daytime hypoxemia are somewhat restrictive . measuring nocturnal oxyhemoglobin saturation in copd patients who have daytime arterial partial pressure of oxygen ( pao2 ) of 5559 mm hg is not recommended , except in patients with unexplained polycythemia or cor pulmonale ( celli et al 2004 ) . \n this includes copd patients who have daytime hypercapnia with only moderately reduced fev1 , those who are obese snorers , or those who develop headache after nocturnal oxygen therapy ( flenley 1985 ; celli et al 2004 ) . \n witnessed apneas while asleep and daytime sleepiness are highly suggestive of osa ( hiestand et al 2006 ) . \n however , the presence of concomitant osa is often difficult to predict from daytime symptoms in patients with copd . \n a majority of patients with osa do not have daytime hypercapnia or headache and some of them are not obese and have no daytime sleepiness ( young et al 1993 ; resta et al 2000 ; netzer et al 2003 ; bradley et al 2007 ) . \n pulmonary function testing correlates poorly with nocturnal hypoxemia while moderate oxyhemoglobin desaturation during exercise has a weak predictive value for reduced nocturnal mean and nadir oxyhemoglobin saturation ( mulloy et al 1996 ) . \n significant cardiovascular morbidity and mortality associated with untreated osa that is reversible with cpap treatment strongly support a more aggressive approach to diagnosis of coexistent osa among patients with copd ( marin et al 2005 ; bradley et al 2007 ) . \n while the paucity of data regarding prevalence of unrecognized osa in patients with copd presents a major challenge , the prevalence of unrecognized copd among patients with known osa has seldom been addressed . \n daytime hypercapnia , pulmonary hypertension , and nocturnal tachyarrhythmias may suggest the presence of unrecognized copd in patients with osa ( fletcher et al 1987 ; chaouat et al 1995 ; resta et al 2002 ; olmetti et al 2007 ) . among 265 patients with osas , \n the prevalence of daytime hypercapnia was 27% in the 30 patients with an associated copd and 8% in the 235 patients without copd ( chaouat et al 1995 ) . \n similarly , daytime hypercapnia was observed in 11% of 1141 osa patients who were free of copd and was related to the severity of obesity ( laaban et al 2005 ) . \n pulmonary hypertension is observed in 75% of patients with coexistent osa and copd ( fletcher et al 1987 ) and in only 12%20% of unselected osa patients ( bradley et al 1985 ; krieger et al 1989 ) . \n patients with coexistent osa and copd are 2.53 times more likely to experience tachyarrhythmias during sleep that patients with osa alone ( olmetti et al 2007 ) . patients with osa who do not carry the diagnosis of copd but experience daytime hypercapnia , pulmonary hypertension , and/or nocturnal tachyarrhythmias should be screened for the presence of coexistent copd including the pulmonary function testing . considering that approximately half of patients with copd who have nocturnal hypoxemia have coexistent osa , clinicians should be vigilant in establishing the diagnosis of osa in these patients . \n readily available and inexpensive nocturnal oxymetry should be performed in copd patients with mild daytime hypoxemia and/or fev1/fvc ratio below 65% . \n patients with copd who are diagnosed with nocturnal hypoxemia by nocturnal oxymetry should undergo attended nocturnal polysomnography to exclude coexistent osa as a treatable cause of nocturnal hypoxemia ( figure 1 ) . \n timely diagnosis and treatment of coexistent osa may reduce cardiovascular morbidity and mortality in patients with copd . \n prospective studies of long - term cpap therapy reported reduction in airway obstruction and improvement in gas exchange and respiratory muscle strength in patients with copd and osa ( mezzanotte et al 1994 ; mansfield et al 1999;de miguel et al 2002 ) . cpap therapy for 6 months reduces daytime arterial paco2 and increases daytime pao2 and fvc and fev1 in these patients ( de miguel et al 2002 ) . \n improvement in spirometry and gas exchange persisted after 18 months of cpap therapy ( de miguel et al 2002 ) . \n in contrast , one retrospective study reported decrease in fvc and fev1 after initiation of long - term cpap therapy in patients with coexistent copd and osa ( obrien et al 2005 ) . \n however , study sample was small ( n = 35 ) and less than a third of enrolled patients were included in the final analysis . the reasons for incomplete sample analysis and the precise timing of baseline and follow - up pulmonary function testing were not specified making the results of this study difficult to interpret . \n the addition of long - term cpap therapy to standard treatment of copd patients improves gas exchange , and airflow obstruction while reducing hospitalization rates in patients with copd and osa ( mansfield et al 1999 ; pauwels et al 2001 ; gold 2005 ) . \n an improvement in gas exchange with cpap has important implications when considering long - term oxygen therapy in patients with coexistent copd and osa . among 55 middle - aged men with daytime hypoxemia and coexistent copd and osa \n , only 22% continued to have daytime pao2 < 60 mmhg after 6-month cpap therapy ( de miguel et al 2002 ) . \n furthermore , cpap therapy reduces elevated pulmonary and systemic arterial pressure in osa ( arias et al 2006 ; campos - rodriguez et al 2007 ) . \n this emphasizes the importance of timely diagnosis and treatment of coexistent copd and osa to prevent development of severe cardiovascular complications . \n possible mechanisms responsible for cpap mediated improvement in lung function in patients with coexistent copd and osa includes counteraction of auto - positive end - expiratory pressure , decreasing respiratory muscle load , and respiratory work of breathing ( petrof et al 1990 ; mezzanotte et al 1994 ) . \n in addition , cpap may have a mild bronchodilatory effect by ameliorating chronic irritation and hyperresponsiveness of the upper airway caused by snoring and repetitive closing and opening in osa ( chan et al 1988 ) . \n reduction in chronic airway edema results in increased airway diameter after cpap therapy ( chan et al 1988 ; mansfield et al 1999 ) . \n polysomnography identifies previously unrecognized osa - related severe nocturnal hypoxemia in copd patients that requires combined treatment with cpap and supplemental oxygen . \n the number of prescriptions for long - term oxygen therapy increased 4-fold among 70 copd patients after nocturnal polysomnography uncovered previously unrecognized osa - related nocturnal hypoxemia ( obrien et al 2005 ) . \n patients with coexisting copd and osa who require long - term oxygen therapy have less severe copd than patients receiving oxygen therapy due to copd alone ( obrien et al 2005 ) . \n therefore , all patients with mild to moderate copd and concomitant daytime hypoxemia should undergo nocturnal oxymetry and/or polysomnography to establish the diagnosis of possible coexistent osa . while cpap therapy is effective in most osa patients with or without coexistent copd , bilevel positive airway pressure ( pap ) may be useful when patients experience difficulty exhaling against a fixed pressure or have persistent intermittent nocturnal hypoxemia during cpap titration despite adequate airflow ( kushida et al 2006 ) . \n bilevel pap delivers a lower expiratory pap and higher inspiratory pap thereby augmenting ventilation ( sanders et al 1990 ; schafer et al 1998 ) . some patients with coexistent osa and copd experience persistent intermittent nocturnal hypoxemia during cpap and bilevel pap titration despite adequate airflow ( sampol et al 1996 ) . \n if increased pap is ineffective or poorly tolerated , supplemental oxygen can be added to pap to eliminate persistent intermittent nocturnal hypoxemia ( kakkar et al 2007 ) . \n the current guidelines suggest the initial follow - up within 1 month after the start of pap treatment and subsequent yearly and as needed follow - up visits , as well as objective monitoring of cpap compliance ( ats 1994 ; kushida et al 2006 ) . \n close follow - up that includes patient education , adjustment of facial interface , and treatment of nasal conditions improves adherence with pap therapy ( kushida et al 2006 ) . \n patients with a resting daytime pao2 < 55 mm hg are candidates for continuous home oxygen therapy ( celli et al 2004 ) . \n copd patients with mild daytime hypoxemia ( pao2 > 60 mm hg ) do not qualify for home supplemental oxygen ; however , more than a quarter of these patients experience nocturnal arterial oxyhemoglobin desaturation without evidence of osa ( fletcher et al 1987 ) . \n nocturnal arterial oxyhemoglobin desaturation occurs mostly during rem sleep ( fletcher et al 1987 ) . \n transient oxyhemoglobin desaturation in copd probably results from a combination of alveolar hypoventilation and gas exchange abnormalities augmented by rem sleep - related muscular atonia and changes in respiratory control ( weitzenblum et al 1997 ) . \n possible contribution of airflow limitation has been suggested by a modest improvement in oxyhemoglobin desaturation during rem sleep after tiotropium use for 4 weeks in copd patients without osa ( mcnicholas et al 2004 ) . \n repetitive alveolar hypoxia and hypoxic vasoconstriction may lead to sustained pulmonary hypertension ( sajkov et al 1999 ; fagan 2001 ) . \n these patients have a greater mortality compared with copd patients who do not experience nocturnal arterial oxyhemoglobin desaturation ( fletcher et al 1992 ) . \n nasal oxygen therapy for 3 years significantly reduced pulmonary artery pressure in copd patients with nocturnal desaturation ( fletcher et al 1992 ) . \n the effect of long - term oxygen therapy on mortality in copd patients with isolated nocturnal oxyhemoglobin desaturation remains unclear . \n one study reported a trend toward increased survival among copd patients with nonapneic nocturnal desaturation who were treated with long - term oxygen therapy ( fletcher et al 1992 ) . \n others reported no overall survival benefit with nasal oxygen therapy in these patients ( gorecka et al 1997 ; chaouat et al 1999 ) . \n low mortality rate in a small study sample precluded definitive conclusion about the effect of nocturnal nasal oxygen therapy on survival in copd patients with nocturnal arterial oxyhemoglobin desaturation in one study ( chaouat et al 1999 ) . \n copd patients with nocturnal arterial oxyhemoglobin desaturation were not identified in another cohort of copd patients receiving long - term oxygen therapy for mild daytime hypoxemia ( gorecka et al 1997 ) . \n pooling together copd patients with and without nocturnal oxyhemoglobin desaturation may mask a beneficial effect of long - term oxygen therapy on survival in copd patients with nocturnal oxyhemoglobin desaturation . in summary , \n patients with coexistent copd and osa have increased morbidity and mortality compared with patients with copd or osa alone . \n clinicians should be vigilant in establishing the diagnosis of osa in patients with copd who have nocturnal hypoxemia \n . timely diagnosis and treatment of coexistent osa may reduce cardiovascular morbidity and mortality in patients with copd . \n prospective studies of long - term cpap therapy reported reduction in airway obstruction and improvement in gas exchange and respiratory muscle strength in patients with copd and osa ( mezzanotte et al 1994 ; mansfield et al 1999;de miguel et al 2002 ) . cpap therapy for 6 months reduces daytime arterial paco2 and increases daytime pao2 and fvc and fev1 in these patients ( de miguel et al 2002 ) . \n improvement in spirometry and gas exchange persisted after 18 months of cpap therapy ( de miguel et al 2002 ) . \n in contrast , one retrospective study reported decrease in fvc and fev1 after initiation of long - term cpap therapy in patients with coexistent copd and osa ( obrien et al 2005 ) . \n however , study sample was small ( n = 35 ) and less than a third of enrolled patients were included in the final analysis . the reasons for incomplete sample analysis and the precise timing of baseline and follow - up pulmonary function testing were not specified making the results of this study difficult to interpret . \n the addition of long - term cpap therapy to standard treatment of copd patients improves gas exchange , and airflow obstruction while reducing hospitalization rates in patients with copd and osa ( mansfield et al 1999 ; pauwels et al 2001 ; gold 2005 ) . \n an improvement in gas exchange with cpap has important implications when considering long - term oxygen therapy in patients with coexistent copd and osa . among 55 middle - aged men with daytime hypoxemia and coexistent copd and osa \n , only 22% continued to have daytime pao2 < 60 mmhg after 6-month cpap therapy ( de miguel et al 2002 ) . \n furthermore , cpap therapy reduces elevated pulmonary and systemic arterial pressure in osa ( arias et al 2006 ; campos - rodriguez et al 2007 ) . \n this emphasizes the importance of timely diagnosis and treatment of coexistent copd and osa to prevent development of severe cardiovascular complications . \n possible mechanisms responsible for cpap mediated improvement in lung function in patients with coexistent copd and osa includes counteraction of auto - positive end - expiratory pressure , decreasing respiratory muscle load , and respiratory work of breathing ( petrof et al 1990 ; mezzanotte et al 1994 ) . \n in addition , cpap may have a mild bronchodilatory effect by ameliorating chronic irritation and hyperresponsiveness of the upper airway caused by snoring and repetitive closing and opening in osa ( chan et al 1988 ) . \n reduction in chronic airway edema results in increased airway diameter after cpap therapy ( chan et al 1988 ; mansfield et al 1999 ) . \n polysomnography identifies previously unrecognized osa - related severe nocturnal hypoxemia in copd patients that requires combined treatment with cpap and supplemental oxygen . \n the number of prescriptions for long - term oxygen therapy increased 4-fold among 70 copd patients after nocturnal polysomnography uncovered previously unrecognized osa - related nocturnal hypoxemia ( obrien et al 2005 ) . \n patients with coexisting copd and osa who require long - term oxygen therapy have less severe copd than patients receiving oxygen therapy due to copd alone ( obrien et al 2005 ) . \n therefore , all patients with mild to moderate copd and concomitant daytime hypoxemia should undergo nocturnal oxymetry and/or polysomnography to establish the diagnosis of possible coexistent osa . while cpap therapy is effective in most osa patients with or without coexistent copd , bilevel positive airway pressure ( pap ) may be useful when patients experience difficulty exhaling against a fixed pressure or have persistent intermittent nocturnal hypoxemia during cpap titration despite adequate airflow ( kushida et al 2006 ) . \n bilevel pap delivers a lower expiratory pap and higher inspiratory pap thereby augmenting ventilation ( sanders et al 1990 ; schafer et al 1998 ) . some patients with coexistent osa and copd experience persistent intermittent nocturnal hypoxemia during cpap and bilevel pap titration despite adequate airflow ( sampol et al 1996 ) . \n if increased pap is ineffective or poorly tolerated , supplemental oxygen can be added to pap to eliminate persistent intermittent nocturnal hypoxemia ( kakkar et al 2007 ) . \n the current guidelines suggest the initial follow - up within 1 month after the start of pap treatment and subsequent yearly and as needed follow - up visits , as well as objective monitoring of cpap compliance ( ats 1994 ; kushida et al 2006 ) . \n close follow - up that includes patient education , adjustment of facial interface , and treatment of nasal conditions improves adherence with pap therapy ( kushida et al 2006 ) . \n patients with a resting daytime pao2 < 55 mm hg are candidates for continuous home oxygen therapy ( celli et al 2004 ) . \n copd patients with mild daytime hypoxemia ( pao2 > 60 mm hg ) do not qualify for home supplemental oxygen ; however , more than a quarter of these patients experience nocturnal arterial oxyhemoglobin desaturation without evidence of osa ( fletcher et al 1987 ) . \n nocturnal arterial oxyhemoglobin desaturation occurs mostly during rem sleep ( fletcher et al 1987 ) . \n transient oxyhemoglobin desaturation in copd probably results from a combination of alveolar hypoventilation and gas exchange abnormalities augmented by rem sleep - related muscular atonia and changes in respiratory control ( weitzenblum et al 1997 ) . \n possible contribution of airflow limitation has been suggested by a modest improvement in oxyhemoglobin desaturation during rem sleep after tiotropium use for 4 weeks in copd patients without osa ( mcnicholas et al 2004 ) . \n repetitive alveolar hypoxia and hypoxic vasoconstriction may lead to sustained pulmonary hypertension ( sajkov et al 1999 ; fagan 2001 ) . \n these patients have a greater mortality compared with copd patients who do not experience nocturnal arterial oxyhemoglobin desaturation ( fletcher et al 1992 ) . nasal oxygen therapy for 3 years significantly reduced pulmonary artery pressure in copd patients with nocturnal desaturation ( fletcher et al 1992 ) . \n the effect of long - term oxygen therapy on mortality in copd patients with isolated nocturnal oxyhemoglobin desaturation remains unclear . \n one study reported a trend toward increased survival among copd patients with nonapneic nocturnal desaturation who were treated with long - term oxygen therapy ( fletcher et al 1992 ) . \n others reported no overall survival benefit with nasal oxygen therapy in these patients ( gorecka et al 1997 ; chaouat et al 1999 ) . \n low mortality rate in a small study sample precluded definitive conclusion about the effect of nocturnal nasal oxygen therapy on survival in copd patients with nocturnal arterial oxyhemoglobin desaturation in one study ( chaouat et al 1999 ) . \n copd patients with nocturnal arterial oxyhemoglobin desaturation were not identified in another cohort of copd patients receiving long - term oxygen therapy for mild daytime hypoxemia ( gorecka et al 1997 ) . \n pooling together copd patients with and without nocturnal oxyhemoglobin desaturation may mask a beneficial effect of long - term oxygen therapy on survival in copd patients with nocturnal oxyhemoglobin desaturation . in summary , \n patients with coexistent copd and osa have increased morbidity and mortality compared with patients with copd or osa alone . \n clinicians should be vigilant in establishing the diagnosis of osa in patients with copd who have nocturnal hypoxemia . \n timely diagnosis and treatment of coexistent osa may reduce cardiovascular morbidity and mortality in patients with copd .", "role": "user" }, { "content": "the high prevalence of both obstructive sleep apnea ( osa ) and chronic obstructive pulmonary disease ( copd ) in western societies is well documented . \n however , osa frequently remains unrecognized and untreated among patients with copd . \n patients with both conditions have a greater risk for fatal and nonfatal cardiovascular events compared with patients with copd or osa alone . \n efficacious treatment with continuous positive airway pressure reduces the risk of cardiovascular complications in patients with osa . \n the aim of the present review is to discuss the diagnostic approach to patients with both conditions and to delineate the benefits of timely recognition and treatment of osa in patients with copd .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: in drug discovery projects , the three - dimensional ( 3d ) structure of the receptor is not always available . in such cases , \n pharmacophore model building , 3d quantitative structureactivity relationship ( qsar ) , comparative molecular field analysis ( comfa),(1 ) and ligand - based virtual screening all depend on a good algorithm to flexibly align small molecules . in light of the importance of the subject \n on top of the methods mentioned in the comprehensive review of lemmen and lengauer,(2 ) new efforts have continued to appear . \n similar to docking , the small molecule alignment problem can be divided into two parts . \n second , a scoring function needs to be able to distinguish good alignment poses from other possibilities . \n the current work is about obtaining a good scoring function for this purpose . in principle , a scoring function that can distinguish the correct alignment pose from incorrect ones is not necessarily the same as a scoring function that upon minimization gives poses that resemble the correct one as much as possible . in practice , a good scoring function probably performs well for both purposes . in this work , \n we are primarily interested in a scoring function for distinguishing good poses . in any case , we believe that the exact answer to the molecular alignment problem may not be simple . \n for example , using only carbons in the binding pocket for superposition may give a slightly different answer from that using all the pocket atoms or using the pharmacophore elements involving the ligand and the pocket . \n moreover , the ligand may have some freedom of movement inside a pocket . hence trying to nudge down the geometric difference between a proposed alignment hypothesis and the correct alignment all the way to zero \n may not be necessary , or even meaningful , as long as the correct alignment mode is obtained . for scoring functions used in docking , one can use molecular mechanics force fields derived from first principles . \n such functions need to be derived from some statistical analysis of a training set of known molecular alignments . \n the protein data bank(17 ) ( pdb ) is an obvious source to obtain such a training set . \n just in the five years since 2003 , the number of entries has more than doubled ( see http://www.pdb.org ) . moreover , many old entries have been revisited and cleaned up , and many low - resolution structures have been superseded by better ones . by \n now , there are hundreds of systems of entries with identical proteins but different ligands . \n we believe that now is a good time to make use of the growth in the pdb to revisit the derivation of a scoring function for molecular alignment . \n for the problem of small molecule alignment , there are two main types of scoring functions . \n the first type is atom based : when two molecules are being aligned , the score consists of a sum of terms that are based on intermolecular atom pairs ( i.e. , each pair has one atom coming from each molecule ) . \n the second type of score is field based : the electrostatic or steric fields of the molecules or their surfaces are compared to arrive at a score \n . this would be somewhat slower to compute since the fields or the molecular surfaces need to be calculated from the atomic coordinates . \n hence it would be difficult to flexibly refine an ensemble of aligned molecules or to deal with a huge number of conformers . \n indeed several of the field - based alignment methods rely on an independent conformational search engine to generate good conformers ( e.g. , shapelets,(6 ) brutus,(13 ) the molecular field extrema method,(11 ) and mimic(18 ) ) . \n since our scoring function will be used to distinguish good binding poses among a huge number of possibilities , it needs to be calculated quickly . \n an atom - based function would hence be more appealing than a molecular field - based function . when creating a hypothesis for an alignment of molecules , it is desirable for atoms ( from different molecules that are being aligned ) with similar properties to be near to each other . intermolecular atom pairs that are far away should have little influence on the goodness of an alignment . \n this can be achieved by associating each intermolecular atom pair with similar properties with a gaussian scoring term : w exp(r ) , where r is the distance between the two atoms , is a parameter controlling the range of the interaction , and w is the weight of this term . \n it is also desirable for the alignment hypothesis for atoms with incompatible properties ( e.g. , hydrophobic vs hydrophilic ) to not superpose . \n this can be achieved using the same functional form but with a negative value for w. besides atoms , hydrogen - bond projected features can also be considered . \n these features represent the expected positions of the hydrogen - bonding partner on the binding pocket based on the ligand geometry \n . the overlap of hydrogen - bond projected features of the same type should be favorable for an alignment hypothesis . \n again , the same gaussian score can work , with r being the distance between the intermolecular features . \n while the gaussian function is widely used in molecular alignment methods ( e.g. , fap,(4 ) pharao,(5 ) moe,(16 ) sq,(19 ) and seal(20 ) ) , there are other functional forms that can provide a similar effect . \n these include piecewise linear functions ( e.g. , flame),(12 ) and piecewise linear and quadratic functions ( e.g. , tfit).(21 ) it can be construed that indeed any bell - shaped function can work in a similar fashion . in their pioneering work 20 years ago , kearsley and smith(20 ) noticed that the lorentzian function ( 1/(1 + r ) ) yielded similar results to the gaussian but was significantly faster to compute . \n however , the advance in computational technology to calculate exponents has eliminated this advantage of the lorentzian function . \n for this work we chose the gaussian because it involves a minimal number of tunable parameters and has a simple , continuous shape . \n another consideration is that function optimization procedures often require the first and second derivatives of the function . in the case of the gaussian , \n once the function has been calculated , its first and second derivatives can be obtained without much extra work . \n a scoring function s could thus be constructed based on a sum of gaussian terms : \n in the formula , tk is a term encouraging / discouraging the overlap of a particular pair of types ( ak , bk ) of atoms / features ; wk is the weight of the term ; i and j are atoms / features from the two molecules ; rij is the distance between the intermolecular atom / feature pair ; and is a parameter controlling the range of this type of interaction . \n ligands binding in the same mode are expected to have substantial volume overlap . the first term in the scoring function , t0 \n the terms t1 and t2 encourage the overlap of pairs of intermolecular donors and acceptors . \n after these attractive terms come the repulsive terms that discourage the overlap of intermolecular atom pairs of incompatible types . \n first , hydrophobic and hydrophilic atoms ( atoms capable of hydrogen bonding ) are not expected to occupy the same part of the binding pocket , as reflected by t4 and t5 . \n second , hydrogen - bond acceptors that are not also donors are expected to avoid positions of donors that are not also acceptors . \n the last two terms , t8 and t9 , are based on hydrogen - bond projected features . \n the scoring function consists of a summation of terms , tk s , each of which has the form : \n\n each row of the table corresponds to one term , tk , and i and j denote atoms ( for t0t7 ) or features ( for t8 and t9 ) coming from the first and second molecule , respectively . these atoms / features have to be of certain types , ak and bk , as given in the second and third columns of the table , and rij is the distance between the atoms / features . \n the names of the various constants for the different terms , wk and , are given in the fourth and fifth columns of the table . \n all the atom - based terms have the same value for , namely a , while all hydrogen - bond projected feature - based terms have another value for , namely p . to keep the number of parameters low , the same value of , a , \n the projected feature terms used a different value of , p , allowing these terms to be more diffuse than the atom - based terms if necessary . \n atom - based terms were followed by projected feature terms . for the atom - based terms , \n based on this order , the scoring function was built up term by term . at each stage , the one or two parameter(s ) of the newly added term was / were optimized . \n a series of scoring functions were created using different values for the newly added parameter(s ) . \n the parameter value(s ) corresponding to the best scoring function in the series would be picked . \n after the scoring function was optimized , it was incorporated into the flexible alignment functionality in molecular operating environment ( moe).(22 ) molecular alignment results were compared with two recent publications . \n proschak et al.(6 ) performed rigid - body alignments for eight thermolysin ligands using their shapelets method and compared their result with two previous alignment methods . \n we performed validation runs on these thermolysin ligands to see how our scoring function fared . \n chen et al.(23 ) studied the geometric accuracy of aligning small molecules using rocs(26 ) and flexs.(27 ) they used eight protein targets as test sets : hiv protease , cyclin - dependent kinase 2 ( cdk2 ) , estrogen receptor 1 ( esr1 ) , mitogen - activated protein kinase 14 ( p38 ) , thermolysin , human rhinovirus capsid , elastase , and trypsin . \n six of these ( all but thermolysin and elastase ) consist exclusively of structures from the publicly accessible pdb.(17 ) we used these six systems for validation runs . \n both rigid - body alignments and flexible alignments were compared . for training a scoring function for \n the validation runs , all systems that contain any pdb entries involved in the test sets were naturally excluded . \n ligands from identical or almost identical pockets ( see below for details ) from the pdb were used for training the scoring function . only pdb entries with a resolution of better than 2.5 were used . \n ligands were defined as freestanding molecules with no more than 300 heavy atoms and 10 residues . in order to exclude waters and very small molecules , \n each ligand must have at least one pair of heavy atoms separated by three bonds . \n ligands without carbon atoms or with exotic elements ( elements other than c , h , n , o , s , p , f , cl , br , and i ) were discarded . \n atp analogs were excluded because their large population in the pdb would likely skew the data . \n ligands without any rings were also excluded so as to remove the lipids without excluding any drug - like compounds . \n we first obtained a list of protein domains from structural classification of proteins ( scop).(28 ) for each domain , all pdb entries containing that domain were superposed using the protein backbone of that domain . \n overlapping ligands were clustered into groups so that each group would correspond to one pocket . for each pocket , \n since we started from scop domains , it was possible that pockets within a group could involve different residues or have different geometries . for our purpose of scoring function training \n , it may not be very meaningful to study the alignment of ligands in different pockets . \n a table was then constructed with each row corresponding to one protein and each column corresponding to one carbon cluster . \n a cell of the table has the residue type as the entry if the protein contributes to that cluster . \n the pocket similarity between a pair of proteins was defined to be the fraction of table columns that are identical ( i.e. , same residue type , or empty cell , for all cells in the column ) . after the pocket similarities between all protein pairs were determined , the proteins were clustered , using complete linkage and pocket similarity as the metric , with a cutoff of 0.8 . in other words , \n any two pockets in the same group had at least 80% of the table columns identical . \n each original pocket group might thus be divided into multiple groups . for each resulting group , \n a fine superposition on the 3d structures was performed again using carbons common to all pockets , since the definition of the pocket might have changed due to the change in the content of the ligand set . \n this whole procedure was repeated until there was no new division of the pocket groups . upon inspection \n , some systems were found to be uninteresting in the sense that the aligned ligands only displayed one type of structure at most regions of the pocket . \n studying this type of system would not give us more information than studying self - alignments . \n . therefore the training ligands were restricted to those having no more than 12 rotatable bonds . \n finally , to ensure diversity , a set of representative ligands was chosen for each system such that no pair of representatives had a tanimoto similarity of over 0.8 on their maccs fingerprints . \n only 100 systems remained after these final filters , and 85 systems had no more than 20 representative ligands . \n this is our comprehensive aligned small molecules data set . for training a scoring function for the validation runs , 11 of the 100 systems in the comprehensive data set were excluded because they contained entries that would be used in the runs . \n this was more than the number of test systems ( 7 ) because some test systems ( e.g. , the 57 ligands in the cdk2 system ) had variations in the pocket residue composition or geometry and were hence subdivided into more than one pocket group when our comprehensive data set was constructed . to keep things simple , \n the training of the scoring function was based on trying to align a flexible source ligand onto a rigid target ligand . \n dummy poses were generated by making small adaptations to the moe docking engine,(22 ) as described below . \n n aligned ligands , all n n pairs of ligands were considered with the following requirement . \n the fraction of heavy atoms in the target that lie within 2 of any heavy atom of the source must exceed 0.5 , and the fraction of heavy atoms in the source that lie within 2 of any heavy atom of the target must exceed 0.75 . \n this excluded ligands with different binding modes and ensured that no source ligand was substantially larger than the target . \n if this resulted in more than 5000 conformers , a random subset of the systematically generated conformers would be used . only conformers with severe atomic overlaps \n this is because we envisioned that when the scoring function is used to distinguish poses with the correct binding mode , any poses that are fished out can be refined to improve the pose geometry and any atomic overlap within the molecule will be relieved . for each sourcetarget pair , \n each time , a random set of three heavy atoms on the target ligand was chosen , together with a random conformer of the source ligand . \n triplets of heavy atoms on the source ligand , which formed a triangle similar to that formed by the three chosen target atoms , were used to align the source ligand onto the target ligand . \n poses whose root - mean - square deviation ( rmsd ) for the heavy atoms was under 1.5 were considered duplicated , and only one copy was kept . \n for each scoring function , the scores for all dummy poses were calculated . for each set of alignments involving a particular pair of source and target ligands \n , we counted the number of good poses , n25 , among the top 25 scoring poses . \n as for whether a pose is good or not , we used fuzzy logic \n . poses with an rmsd ( heavy atoms only ) from the correct pose of under 2.0 were considered good . \n poses with an rmsd between 2.0 and 3.0 were considered partial good poses , with the partiality decreasing linearly from 1 to 0 . for each system ( i.e. , same pocket ) , we averaged the number of good poses for all sourcetarget pairs in the system . \n the receiver operating characteristic ( roc ) curve is often used to measure the success of scoring functions for virtual screening.(29 ) in short , the roc curve plots the fraction of true positives recovered ( out of all active compounds ) against the fraction of false positives obtained ( out of all inactive compounds ) , as the cutoff value varies . \n it is generally considered that the bigger the area under the curve , the better is the scoring function . \n we felt that , for our purpose , using the area under the roc curve was not as suitable as using \n the number of good poses amongst the top 25 , since we generally can only afford to consider a limited number of top scoring poses . \n hence all but the very beginning part of the roc curve would be of significance to us . \n we think that human inspection can typically handle 10 or so poses . on the other hand , if a thorough refinement is desired as part of an automatic process , then it would be reasonable to intensively process up to about 100 poses per ligand . \n hence here we used the top 25 poses . as a precaution , we repeated all the calculations and validation runs using the top 100 poses instead of the top 25 . \n it turned out that only one out of the six optimized parameters for the scoring function would come out different , and the quality of the of validation runs remained very similar . \n the details are given in section a of the supporting information . as mentioned previously , \n the scoring function was built up term by term . at each stage , only one ( or two ) parameter was introduced . \n each table corresponds to one stage of optimization where one ( or two ) parameter was optimized . \n the resulting numbers of good poses among the top 25 , n25 , corresponding to the various values of the parameter being optimized are given in the tables . \n the optimal value of the parameter and its corresponding value of n25 are highlighted in bold . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of a . \n we started by including only the volume overlap term ( t0 in table 1 ) in the scoring function . \n in other words , to a first approximation , the bigger the volume overlap between two molecules , the better was the score . in order to make the scoring function quick to calculate , \n the only parameter to be optimized was . obviously a smaller value for would result in a more diffuse gaussian function . \n consider the simple case to align one atom ( the source ) onto a diatomic molecule ( the target ) . \n this is similar to trying to align methane , with one heavy atom , onto ethane , with two heavy atoms . \n suppose the internuclear distance of the diatomic molecule is 1.5 ( for comparison , a cc bond in a benzene ring is about 1.40 , and a cc bond in an ethane is about 1.54 ) . \n the shapes of the scoring function for three different values of are plotted in figure 2 . for large values of , \n the source atom will see a score with two distinct peaks located very close to the two target atoms . \n it will have a strong tendency to align with either one of the target atoms . \n for example , if is 2.0 ( the blue curve of figure 2 ) , then the distance between the peaks will be 1.46 \n . the value of the score at the trough midway between the peaks will be 64% of the height of the peaks . \n when decreases to 1.2 ( the black curve of figure 2 ) , the peaks will move toward each other , away from the atomic positions . \n the distance between the peaks will drop to 1.18 , and the trough to peak height ratio of the score will increase to 94% \n . in other words , the score has already very much smoothed out the atomic positions . \n the source atom can settle for any position between the two atoms with little change on the score . \n how the scoring function is controlled by the parameter , for the case of a target molecule consisting of two atoms , located at positions 0.75 and 0.75 . for a source atom to be superimposed onto the target molecule , \n the scoring function is exp(r12 ) + exp(r22 ) , where r1 and r2 are the distances from the source atom to the two target atoms . \n the scoring functions corresponding to values of 2.0 , 1.5 , and 1.2 are plotted in blue , red , and black , respectively . given a scoring scheme and an initial aligned pose between two rigid ligands , one can refine the alignment by optimizing the score . \n when we did this with many starting poses , we found that we ended up with fewer resulting aligned poses when we used smaller values of ( unpublished results ) . \n this is in line with our expectation that smaller values of smooth out the score landscape . according to previous works of gaussian function - based alignment scores , values of of between 0.1 and 0.5 \n , we tried out a total of 7 values for a , from 0.06 to 0.7 . \n the corresponding numbers of good poses among the top 25 are tabulated in table 2a . \n it can be seen that for the values of a tested , a value of 0.5 was the best , with an average of 4.83 good poses among the top 25 . after establishing a value for a \n , the relative weights of the atom - based terms were optimized one by one . \n we first looked at the weight wda for the hydrogen - bonding atoms ( donor and acceptor ) similarity terms ( t1 and t2 in table 1 ) . for this \n we tried out 7 values for wda , from 0.5 to 32 , in logarithmic intervals . \n the corresponding numbers of good poses among the top 25 are tabulated in table 2b . \n a value of 4 turned out to be the most favorable , with an average of 6.10 good poses among the top 25 . \n the new terms are t1 and t2 , which correspond to the attraction between hydrogen - bond donor / acceptor atoms . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of wda . \n after this , we turned to the similarity term between hydrophobic atoms ( t3 in table 1 ) . besides trying to establish the optimal weight whh for this term , we also tried out two schemes of defining hydrophobic atoms . \n one used the conventional hydrophobic atom assignment in moe.(22 ) the other scheme was based on how far topologically an atom was from any hydrogen - bonding atom . \n atoms that were two or more bonds away from any hydrogen - bond acceptors or donors were considered hydrophobic . \n tables 2c and 2d give the numbers of good poses among the top 25 for various values of whh using the two schemes . \n it can be seen that the two schemes gave very similar results , with the optimal weighting factor whh to be around 1.0 for both schemes . \n the scoring function at this stage is ( t0 + t1 + t2 + t3 ) . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of whh . \n the scoring function at this stage is ( t0 + t1 + t2 + t3 ) . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of whh . \n next we considered the repulsion term between hydrogen - bonding atoms and hydrophobic atoms ( t4 and t5 in table 1 ) . \n here we see that the first scheme of defining hydrophobicity was slightly better and that the optimal weight for the repulsion term , wr1 , was around 1.0 . \n the scoring function at this stage is ( t0 + t1 + t2 + t3 + t4 + t5 ) . \n the new terms t4 and t5 correspond to the repulsion between hydrophobic and hydrogen - bonding atoms . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of wr1 . \n the scoring function at this stage is ( t0 + t1 + t2 + t3 + t4 + t5 ) . \n the new terms t4 and t5 correspond to the repulsion between hydrophobic and hydrogen - bonding atoms . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of wr1 . \n after this we investigated a repulsion term between hydrogen - bond donor and acceptor atoms ( t6 and t7 in table 1 ) . \n perhaps surprisingly , it was found that this term did not seem to improve the scoring function ( see table 2 g ) . \n the scoring function at this stage is ( t0 + t1 + t2 + t3 + t4 + t5 + t6 + t7 ) . \n the new terms t6 and t7 correspond to the repulsion between hydrogen - bond donor atoms that are not acceptors and hydrogen - bond acceptor atoms that are not donors . refer to table 1 for the details of these terms . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of wr2 . \n finally the projected acceptor and donor feature points were considered ( t8 and t9 in table 1 ) . \n these points correspond to the expected positions of donors and acceptors on the binding pocket . in this sense \n so we tried out different values of as well as different weights , wpf , for this term . \n it can be seen that an p value of 0.125 coupled with a weight of 2.0 was a good combination . \n otherwise an p value of 0.0625 coupled with a weight of 1.0 was also respectable . \n the scoring function at this stage is ( t0 + t1 + t2 + t3 + t4 + t5 + t8 + t9 ) . \n the new terms t8 and t9 correspond to the attraction between hydrogen - bond donor / acceptor projected features . refer to table 1 for the details of these terms . \n this table gives the average number of good poses , n25 , within the top 25 scoring poses for various values of wpf and p . \n to summarize , it was found that a good scoring function is of the form given by the terms of table 1 , except terms t6 and t7 , with the values of the various coefficients given in table 3 . \n the optimal scoring function consists of the terms t0t5 , t8 , and t9 , as given in table 1 , with the various parameters as given by this table . for each of the parameters considered \n however , there was a considerable number of ligandpocket systems , and in each system , there was a considerable number ( at least 25 , but often much more ) of pairs of sourcetarget ligands . \n more importantly , the fact that there are smooth trends in the numbers in tables 2a2h , as the parameters were varied , serves to confirm that the numbers are accurate enough for our purpose of locating the optimal values for the parameters . \n moe s flexible alignment ( flexalign ) functionality(22 ) was used for the validation runs . for rigid - body alignments , conformers from the pdb \n flexalign generated random poses of the source molecule superposed onto the target molecule and optimized the alignment score s , while keeping the molecules rigid . \n for the flexible alignments , for each source molecule , one randomized conformation was used as input . \n flexalign generated a random conformer from this input , randomly superposed it onto the target molecule , and then optimized this pose under the influence of the alignment score between the source and target molecules . \n the target molecule remained fixed throughout the process . in order to avoid unrealistic conformations , \n the internal energy u of the source molecule must also be considered alongside the alignment score s. for the internal energy , we used the mmff94 force field with a distance - dependent dielectric . \n pose optimization was carried out by minimizing the effective energy , e , which was defined by \n alignment solutions were also ranked according to their e values . \n a value of 4 kcal / mol was used for k. this value seemed to give a good balance between the internal energy u and the alignment score s. the difference in the force field energy u between the conformation of the source molecule in the top scoring ( i.e. , the one with the lowest e value ) solution and its corresponding local energy minimum was generally small . \n the average of this difference ( over the n n cross - alignments for each system ) for the cdk2 , hiv , p38 , esr1 , trypsin , and rhinovirus systems were , respectively , 0.32 , 0.76 , 0.25 , 0.33 , 0.25 , 0.25 kcal / mol per heavy atom . \n in contrast , the average of the difference in the internal energy u between the ligand conformer in the crystal structure and its corresponding local energy minimum is over 1 kcal / mol per heavy atom for all the six systems . \n we also investigated whether the value of the alignment score s or the effective energy e gives an indication of the goodness of the alignment . \n our results were first compared with those in table 4 of proschak et al.(6 ) this involved pairwise rigid - body alignments on a system of eight thermolysin ligands . \n for each ligand pair , one ligand was used as the target , while the other was used as the source . \n an alignment was considered successful if the top scoring pose had a heavy atom rmsd of under 2 from the correct answer . \n our results , together with those obtained by proshak et al.,(6 ) are tabulated in table 4 . according to proshak \n when surfcomp(24 ) was used with the electrostatic potential , the success rate was 75% . \n in contrast , our scoring function yielded a success rate of 93% ; there were only 2 failed cases out of 28 alignments . \n our scoring function returned the correct answer as the second best scoring solution ( figure 3 , bottom ) . in any case \n , our best scoring solution looks highly plausible with heavy overall volumetric overlap as well as the overlap of the aromatic ring and two carbonyl groups ( figure 3 , top ) . \n carbons of our solutions ( top and bottom are best and second best scoring , respectively ) are in cyan . \n the eight thermolysin ligands have pdb i d s 1thl , 1tlp , 1tmn , 3tmn , 4tmn , 5tln , 5tmn , and 6tmn . for each pair of nonidentical ligands , \n one ligand was chosen as the template , and the other ligand was aligned onto the template . \n if the top scoring solution yielded an rmsd of under 2 with the crystallographic pose for the heavy atoms , then it was considered successful . \n this table gives the success rates for the 28 cases , as reported on table 4 of proschak et al.(6 ) tests were also run on six systems mentioned in chen et al.,(23 ) where rocs(26 ) and flexs(27 ) were used . \n an alignment was considered correct if the top scoring solution had a heavy atom rmsd of under 2 with the crystallographic overlay . \n except for the rhinovirus system , which will be examined in more details below , and for the flexible alignment of the cdk2 system , our results are significantly better than those obtained by chen et al . using flexs or rocs . for rigid - body alignments , \n our fraction of correct results was at least 40% and reached 80% or more in two systems . \n naturally , flexible alignment is more difficult than rigid - body alignment , and so the percentages of correct results are lower for all systems except rhinovirus ( see analysis below ) . \n for each of the six systems , pairwise cross - alignments were carried out for all n n ligand pairs , where n is the number of ligands in the system . \n if the top scoring result yielded an rmsd of under 2 for the heavy atoms , then it was considered correct . \n this table gives the percentage of correct results for the n n ligand pairs in the system , as reported on table 2a of chen et al.(23 ) for the cdk2 system , our results for the rigid - body alignments but not for the flexible alignments are significantly better than those of chen et al . \n cdk2 is a large system ( 57 ligands ) with a complex pharmacophore model.(31 ) if the six ligands 1di8 , 1p5e , 1pkd , 1pxi , 1pxj , and 1wcc were excluded , then our results would improve from 39.6% to 47.6% correct for the rigid - body alignments and from 22.4% to 26.6% correct for the flexible alignments . of the 57 ligands in the system , only 7 ligands have more than 33 or less than 17 heavy atoms , and 1p5e , 1pkd \n , 1pxi , 1pxj , and 1wcc are among them , with 13 , 36 , 14 , 14 , and 8 heavy atoms , respectively . \n since the pharmacophore model is complex,(31 ) it seems that volumetric overlap is an important factor for alignment . \n hence ligands that are much smaller or much larger than average would be difficult to align . moreover , an important pharmacophore element is the set of two hydrogen - bond donors and one acceptor interacting with the hinge region of the protein . \n these correspond to pharmacophore features d1 , d2 , and a1 mentioned in zou et al.(31 ) and are shown in figure 4 . out of the 57 ligands , only 4 do not have at least 2 out of these 3 features , and ligands 1di8 , 1p5e , and 1wcc are among them . \n important pharmacophore features for the cdk2 ligands include two hydrogen - bond donors ( magenta sphere ) and one acceptor ( cyan sphere ) . \n the fact that they are relatively comparable in size ( all but three have between 39 and 61 atoms ) , do not have a homogeneous ( spherical ) shape , and have rich feature sets might have helped the rigid - body alignment result , because there are not that many possibilities for the molecules to align well . \n one possibility for our superior results is that we have trained our scoring function using a significantly larger data set from the pdb than the version of flexs or rocs that were used . of all six test systems , \n the drop in performance in going from the rigid - body to the flexible mode is most pronounced for the hiv system . \n of the 28 hiv ligands , 5 have 10 rotatable bonds . 7 have between 12 and 16 rotatable bonds . \n for the 13 ligands of the p38 system , our scoring function produced an overall correct rate of 43% and 30% for the rigid - body and flexible alignments , respectively ( table 5 ) . \n it is worth noting that one of the ligands , 1wbo , is significantly smaller than the others ( figure 5 ) . \n it can be seen that the ligand 1di9 ( magenta in figure 6 ) binds in a mode different from the others . \n the four ligands 1m7q , 1ouk , 1ouy , and 1ove ( yellow in figure 6 ) also bind in a mode somewhat different from the others . for the remaining 7 ligands , \n our scoring function actually got 73% of the pairwise cross - alignments correct in the rigid - body mode , and 53% correct in the flexible mode . and for the 16 pairwise cross - alignments of the four ligands 1m7q , 1ouk , 1ouy , and 1ove , our scoring function got them all , 100% , correct in the rigid - body mode and 94% ( all but one of the 16 ) correct in the flexible mode . \n ligands within each group have comparable sizes and can be considered to bind in a similar mode , as can be seen in figure 7 . for the pairwise cross - alignments of all 13 ligands , our scoring function got 59% and 41% correct in the rigid - body and flexible modes , respectively . \n however , for the group of 6 smaller ligands , we got 94% of the 36 rigid - body cross - alignments correct and 72% of the flexible alignments correct . for the group of 7 larger ligands , we got 92% of the 49 rigid - body cross - alignments correct and 65% of the flexible alignments correct . \n the 6 smaller ligands ( 1a52 , 1gwq , 1l2i , 1x7e , 1x7r , and 3erd ) are in cyan . the 7 larger ligands ( 1r5k , 1sj0 , 1uom , 1xp1 , 1xp9 , 1xqc , and 2bj4 ) are in magenta . the crystallographic alignment of the 7 trypsin ligands is given in figure 8 . \n ligand 1tni ( cyan in figure 8) assumes a binding mode different from the others . for the remaining 5 ligands , \n our scoring function got all 25 cross - alignments correct in both the flexible and rigid - body modes . \n figure 9 gives our result for flexibly aligning 1tnj onto the much larger ligand 1pph . \n our second best scoring solution ( figure 9 , bottom ) yielded the correct alignment mode . \n as for our best scoring solution ( figure 9 , top ) , it involves a perfect atom to atom matching for all atoms of 1tnj . \n the aromatic ring is mapped to an aromatic ring of 1pph , all aliphatic carbons are mapped to aliphatic carbons on 1pph , and the nitrogen atom is mapped to a nitrogen on 1pph . \n our third best scoring solution ( figure 10 , bottom ) roughly yielded the correct binding mode . \n our best scoring solution ( figure 10 , top ) involves a matching of atoms similar to that of the best scoring solution of aligning 1tnj onto 1pph ( figure 9 , top ) . \n our second best scoring solution ( figure 10 , middle ) also involves a good matching of atoms , with the phenyl ring of 1tnl aligned to a six - membered ring of 1pph . \n the remaining ligands are 1tnh , 1tnj , 1tnk , 1tnl , 3ptb . flexibly aligning 1tnj onto 1pph ( carbons in green ) . \n carbons of our solutions ( top and bottom : best and second best scoring ) are in cyan . flexibly aligning 1tnl onto 1pph ( carbons in green ) . \n carbons of our solutions ( from top to bottom : first , second , and third best scoring ) are in cyan . for the 8 rhinovirus ligands , our scoring function got 50% of the pairwise cross - alignments correct in both the rigid - body and flexible modes . \n as shown in figure 11 , all eight ligands have a long shape and are almost symmetric . \n there is a heterocyclic ring on either end of each ligand , connected by a long , flexible linker chain . \n as noted in the original publication for the x - ray structures,(32 ) the ligands have two binding modes , one being the inverse of the other , as shown in figure 11 . \n it is easy for the alignment algorithm to superpose the two rings on either end but difficult to distinguish between the two binding modes . \n hence all the cross - alignments within a binding mode were obtained correctly , but the inverse binding mode was obtained for each pair across the different binding modes . \n the carbons are in magenta for one mode ( 2rm2 , 2rr1 , 2rs1 , and 2rs3 ) and in cyan for the other mode ( 2r04 , 2r06 , 2r07 , and 2rs5 ) . \n when the scoring function was trained for the validation runs , systems involved in the test sets were excluded . after the validation runs , the training process was repeated to make use of all data , including systems involved in the test sets . \n it turned out that using all the data did not lead to any change in the scoring function . \n the updated tables 2a2h are given in tables ah of section b of the supporting information . \n although the numbers of good poses among the top 25 ( n25 ) have changed slightly , the positions for the optimal values for all the parameters have not . \n based on the pdb(17 ) and scop,(28 ) a comprehensive set of aligned ligands binding in the same pocket has been compiled . \n we used only high - resolution structures and considered only pockets that are highly similar and have diversified , drug - like ligands . for each pair of ligands binding in the same pocket , \n one ligand was used as the target , and dummy aligned poses of the other ligand were generated . by studying the correlation between the score of these dummy poses and their similarities with the correct answer , a small molecule alignment scoring function was built up term by term . \n eventually we obtained the scoring function composed of terms given by table 1 , except terms t6 and t7 , with parameters as given by table 3 . \n we verified our scoring function by comparing results of rigid - body and flexible alignments performed using the flexible alignment functionality in moe(22 ) with those reported in the literature . \n we found that our results are superior to those of five methods reported in two recent publications . \n we are happy to share our comprehensive aligned small molecules data set with other scientists so that they can use it to optimize their own scoring functions .", "role": "user" }, { "content": "a comprehensive data set of aligned ligands with highly similar binding pockets from the protein data bank has been built . \n based on this data set , a scoring function for recognizing good alignment poses for small molecules has been developed . \n this function is based on atoms and hydrogen - bond projected features . \n the concept is simply that atoms and features of a similar type ( hydrogen - bond acceptors / donors and hydrophobic ) tend to occupy the same space in a binding pocket and atoms of incompatible types often tend to avoid the same space . \n comparison with some recently published results of small molecule alignments shows that the current scoring function can lead to performance better than those of several existing methods .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the dpp was a randomized clinical trial performed at 27 centers involving 3,234 subjects who were at high risk for diabetes . \n the detailed methods have been reported ( 10 ) , and the protocol is available at http://www.bsc.gwu.edu/dpp . \n institutional review boards at each center approved the protocol , and all participants gave written informed consent prior to participation . \n eligibility criteria included being age 25 years , having a bmi 24 kg / m ( 22 kg / m in asian americans ) , having a fasting plasma glucose concentration of 5.36.9 mmol / l ( 6.9 mmol / l in the american indian clinics ) , and attaining a 2-h glucose of 7.811.0 \n subjects were excluded if they were taking medications known to alter glucose tolerance or had significant illness . \n eligible participants were randomly assigned to one of three interventions : 1 ) ils , 2 ) 850 mg metformin twice daily and standard lifestyle recommendations , or 3 ) placebo twice daily and standard lifestyle recommendations . \n the goal for participants assigned to ils was to achieve and maintain a weight reduction of at least 7% of their initial body weight through a healthy low - calorie , low - fat diet and physical activity of moderate intensity , such as brisk walking , for at least 150 min per week . \n self - reported levels of leisure physical activity were assessed semiannually with the modifiable activity questionnaire ( 10 ) . \n the physical activity level was calculated as the product of the duration and frequency of each activity ( in hours per week ) weighted by an estimate of the metabolic equivalent ( met ) of that activity and summed for all activities performed with the result expressed as the average met hours per week for the previous year . \n usual daily caloric intake during the previous year , including calories from fat , carbohydrate , protein , and other nutrients , was assessed at baseline and at 1 year with the use of a modified version of the block food frequency questionnaire ( 10 ) . \n weight was measured using a standardized calibrated scale , and blood pressure was measured using a manual sphygmomanometer . \n venous blood was obtained and processed at each clinical site using a standardized manual of operations . \n 20c for several days and then shipped in batches on dry ice to a single central laboratory . \n measurement methods for glucose , insulin , triglycerides , and hdl cholesterol have been published ( 11 ) . \n measures of insulin secretion ( corrected insulin response [ cir ] = [ 100 30 min insulin]/[30 min glucose { 30 min glucose 70 } ] ) and insulin sensitivity ( 1/fasting insulin ) were calculated using validated indices ( 12 ) . \n of 3,234 participants in the dpp , 2,528 had a baseline fasting glucose concentration > 5.6 mmol / l ( and < 7.0 mmol / l ) and , thus , according to american diabetes association ( ada ) criteria were considered to have ifg in addition to igt ( 13 ) . \n the primary outcome measure was regression from combined ifg / igt to ngr ( fasting glucose < 5.6 mmol / l and 2-h glucose \n < 7.8 mmol / l ) , with secondary outcome measures such as regression from ifg / igt to isolated ifg ( fasting glucose 5.66.9 mmol / l and 2-h glucose \n < 7.8 mmol / l ) or isolated igt ( fasting glucose < 5.6 mmol / l and 2-h glucose 7.811.1 \n analyses also examined predictors for regression from ifg / igt to ngr , isolated ifg , or isolated igt within each treatment group . \n another set of models was constructed analyzing regression in the dpp cohort ( those who had igt with a fasting plasma glucose concentration > 5.3 mmol / l [ and < 7.0 \n mmol / l ] [ n = 3,143 ] and regressed to ngr [ n = 468 ] , isolated ifg [ n = 1,150 ] , or isolated igt [ n = 279 ] ) . \n quantitative characteristics are presented as the median ( 25th and 75th percentiles ) and qualitative characteristics as n ( % ) . \n the effect of baseline characteristics , as well as the effect of weight change , ils , and metformin versus placebo , on the incidence of regression was estimated using cox proportional hazards modeling . in circumstances where variables had significant colinearity ( e.g. , weight and bmi ) , \n cox proportional hazards models included only participants with ifg / igt and modeled time to first incidence of regression to ngr , isolated ifg , or isolated igt using yearly visits . those who had progressed to diabetes , had missing data , or , depending on the outcome measure of the model , regressed to ngr , isolated ifg , or isolated igt were censored from subsequent analyses ( fig . \n 1 ) . hazard ratios ( hrs ) for continuous variables are presented per sd for each variable of interest ( except age , which is for an increase of 5 years ) . \n an hr > 1 indicates greater risk for regression ( i.e. , favors regression ) , whereas the opposite is true for hr < 1 ( i.e. , impedes regression ) . \n p values for individual covariates were calculated using the wald test and the likelihood ratio test for the overall model . \n stratified analyses were conducted first by treatment group with a test for heterogeneity , checking whether the effect of a covariate is the same across treatment groups . \n all analyses were conducted using sas software ( version 8.01 ; sas institute , cary , nc ) . \n flowchart for primary data analysis illustrating handling of the data from years 1 to 3 . \n ifg , fasting glucose = 5.66.9 mmol / l ; igt , 2-h glucose = 7.811.1 \n mmol / l ; ngr , fasting glucose < 5.6 mmol / l ; and 2-h glucose \n were censored from subsequent analyses due to regression to ngr ( in year prior ) , isolated ifg or igt , progression to diabetes , or missing data . \n eligible participants were randomly assigned to one of three interventions : 1 ) ils , 2 ) 850 mg metformin twice daily and standard lifestyle recommendations , or 3 ) placebo twice daily and standard lifestyle recommendations . \n the goal for participants assigned to ils was to achieve and maintain a weight reduction of at least 7% of their initial body weight through a healthy low - calorie , low - fat diet and physical activity of moderate intensity , such as brisk walking , for at least 150 min per week . \n self - reported levels of leisure physical activity were assessed semiannually with the modifiable activity questionnaire ( 10 ) . \n the physical activity level was calculated as the product of the duration and frequency of each activity ( in hours per week ) weighted by an estimate of the metabolic equivalent ( met ) of that activity and summed for all activities performed with the result expressed as the average met hours per week for the previous year . \n usual daily caloric intake during the previous year , including calories from fat , carbohydrate , protein , and other nutrients , was assessed at baseline and at 1 year with the use of a modified version of the block food frequency questionnaire ( 10 ) . \n weight was measured using a standardized calibrated scale , and blood pressure was measured using a manual sphygmomanometer . \n venous blood was obtained and processed at each clinical site using a standardized manual of operations . \n 20c for several days and then shipped in batches on dry ice to a single central laboratory . \n measurement methods for glucose , insulin , triglycerides , and hdl cholesterol have been published ( 11 ) . \n measures of insulin secretion ( corrected insulin response [ cir ] = [ 100 30 min insulin]/[30 min glucose { 30 min glucose 70 } ] ) and insulin sensitivity ( 1/fasting insulin ) were calculated using validated indices ( 12 ) . \n of 3,234 participants in the dpp , 2,528 had a baseline fasting glucose concentration > 5.6 mmol / l ( and < 7.0 mmol / l ) and , thus , according to american diabetes association ( ada ) criteria were considered to have ifg in addition to igt ( 13 ) . \n the primary outcome measure was regression from combined ifg / igt to ngr ( fasting glucose < 5.6 mmol / l and 2-h glucose \n < 7.8 mmol / l ) , with secondary outcome measures such as regression from ifg / igt to isolated ifg ( fasting glucose 5.66.9 mmol / l and 2-h glucose \n < 7.8 mmol / l ) or isolated igt ( fasting glucose < 5.6 mmol / l and 2-h glucose 7.811.1 \n analyses also examined predictors for regression from ifg / igt to ngr , isolated ifg , or isolated igt within each treatment group . \n another set of models was constructed analyzing regression in the dpp cohort ( those who had igt with a fasting plasma glucose concentration > 5.3 mmol / l [ and < 7.0 \n mmol / l ] [ n = 3,143 ] and regressed to ngr [ n = 468 ] , isolated ifg [ n = 1,150 ] , or isolated igt [ n = 279 ] ) . \n quantitative characteristics are presented as the median ( 25th and 75th percentiles ) and qualitative characteristics as n ( % ) . \n the effect of baseline characteristics , as well as the effect of weight change , ils , and metformin versus placebo , on the incidence of regression was estimated using cox proportional hazards modeling . in circumstances where variables had significant colinearity ( e.g. , weight and bmi ) , \n cox proportional hazards models included only participants with ifg / igt and modeled time to first incidence of regression to ngr , isolated ifg , or isolated igt using yearly visits . those who had progressed to diabetes , had missing data , or , depending on the outcome measure of the model , regressed to ngr , isolated ifg , or isolated igt were censored from subsequent analyses ( fig . \n hazard ratios ( hrs ) for continuous variables are presented per sd for each variable of interest ( except age , which is for an increase of 5 years ) . \n an hr > 1 indicates greater risk for regression ( i.e. , favors regression ) , whereas the opposite is true for hr < 1 ( i.e. , impedes regression ) . \n p values for individual covariates were calculated using the wald test and the likelihood ratio test for the overall model . \n stratified analyses were conducted first by treatment group with a test for heterogeneity , checking whether the effect of a covariate is the same across treatment groups . \n all analyses were conducted using sas software ( version 8.01 ; sas institute , cary , nc ) . \n flowchart for primary data analysis illustrating handling of the data from years 1 to 3 . \n ifg , fasting glucose = 5.66.9 mmol / l ; igt , 2-h glucose = 7.811.1 \n mmol / l ; ngr , fasting glucose < 5.6 mmol / l ; and 2-h glucose \n were censored from subsequent analyses due to regression to ngr ( in year prior ) , isolated ifg or igt , progression to diabetes , or missing data . \n baseline characteristics for the ada - defined ifg / igt cohort ( fasting glucose 5.66.9 mmol / l and 2-h glucose 7.811.1 mmol / l as opposed to fasting glucose 5.36.9 mmol / l and 2-h glucose 7.811.1 \n mmol / l for the entire dpp cohort ) are summarized in table 1 by treatment group . \n no significant differences were observed between the randomized groups by treatment assignment for the variables shown , except for diastolic blood pressure and hdl cholesterol that were borderline significant . \n further , there was no significant difference between the treatment groups in baseline characteristics ( except hdl cholesterol ) using a fasting glucose cut point of 5.3 mmol / l ( data not shown ) . \n baseline characteristics of participants with both ifg and igt , defined by the ada data are n ( % ) for categorical variables and median ( 25th75th percentile ) for continuous variables . \n insulin secretion was estimated using the cir ( [ 100 30 min insulin]/[30 min glucose { 30 min glucose 70 } ] ) . \n results from the final multivariate model , shown in table 2 , included treatment group , age , sex , ethnicity , baseline weight and change in weight , baseline fasting and 2-h plasma glucose concentrations , and indices of the -cell 's insulin response and tissue insulin sensitivity , as each were significantly and independently predictive of regression to ngr in a univariate analysis . \n as expected , lower baseline fasting and 2-h glucose predicted regression to ngr , as did younger age and a greater insulin secretion to the oral glucose load . \n ils and greater weight loss had significant and independent effects on regression . a nonsignificant trend for metformin , male sex , and greater insulin sensitivity on incidence of regression was also observed . \n the cumulative incidence of regression to ngr in each treatment group is shown in fig . \n 2 . when the model was run using the entire dpp cohort ( fasting glucose 5.36.9 vs. 5.66.9 mmol / l ) , the results were similar ( data not shown ) . \n predictors of regression to ngr , isolated ifg , or isolated igt using ada criteria in a multivariate model hrs for continuous variables are per 1 sd ( or per 5 years for age ) . \n cumulative incidence of ngr according to treatment group , adjusted for baseline age , sex , ethnicity , weight , fasting and 2-h glucose concentrations , as well as insulin sensitivity ( 1/fasting insulin ) and secretion ( cir ) . \n when examining the data by treatment group , caucasian self - reported ethnicity was significantly associated with less likelihood of regression ( hr 0.68 , p = 0.02 ) , but only in the metformin group , and therefore is of uncertain significance . \n contribution from a positive family history of diabetes , lipids , blood pressure , use of lipid- and/or blood pressure lowering medications , selective serotonin reuptake inhibitors , or hormone replacement therapy , dietary calories from fat , and met / h per week of physical activity were also explored and found to not be significantly related to regression to ngr ( data not shown ) . \n higher fasting and lower 2-h glucose , as well as male sex and greater insulin sensitivity , were associated with regression to isolated ifg , as defined by ada ( table 2 ) . \n when the entire dpp cohort was analyzed , higher fasting glucose ( hr 1.14 , p < 0.01 ) , lower 2-h glucose ( 1.43 , p < 0.01 ) , male sex ( 1.35 , p < 0.01 ) , and greater insulin sensitivity ( 1.08 , p = 0.02 ) remained similarly predictive . \n the power gained by using the entire cohort increased the ability to detect an effect of ils ( 1.28 , p < 0.01 ) and revealed a tendency for younger age ( 1.03 , p = 0.07 ) to positively influence regression to isolated ifg . within \n treatment group comparisons noted a stronger effect of low 2-h glucose on regression in placebo ( hr 1.64 ) and metformin ( 1.61 ) groups than in the ils group ( 1.25 ) ( test for interaction , p = 0.03 ) . lower fasting and higher 2-h glucose , female sex , a greater insulin secretion , as well as both ils and metformin were associated with regression to isolated igt in the ada - defined ifg / igt cohort ( table 2 ) . \n greater weight loss was marginally associated with regression to isolated igt . when the same analysis was performed in the entire dpp cohort , \n lower fasting glucose ( hr 2.36 , p < 0.01 ) , higher 2-h glucose ( 1.15 , p = 0.02 ) , female sex ( 1.54 , p < 0.01 ) , ils ( 1.46 , p = 0.02 ) , and metformin ( 1.89 , p < 0.01 ) remained similarly predictive . \n in contrast , insulin response was no longer significantly related ( 1.01 , p = 0.86 ) , but younger age was ( 1.06 , p = 0.05 ) . \n in addition , marginal associations emerged for lower baseline weight ( 1.13 , p = 0.09 ) and greater weight loss ( 1.17 , p = 0.07 ) influencing regression to isolated igt . \n baseline characteristics for the ada - defined ifg / igt cohort ( fasting glucose 5.66.9 mmol / l and 2-h glucose 7.811.1 mmol / l as opposed to fasting glucose 5.36.9 mmol / l and 2-h glucose 7.811.1 \n mmol / l for the entire dpp cohort ) are summarized in table 1 by treatment group . \n no significant differences were observed between the randomized groups by treatment assignment for the variables shown , except for diastolic blood pressure and hdl cholesterol that were borderline significant . \n further , there was no significant difference between the treatment groups in baseline characteristics ( except hdl cholesterol ) using a fasting glucose cut point of 5.3 mmol / l ( data not shown ) . \n baseline characteristics of participants with both ifg and igt , defined by the ada data are n ( % ) for categorical variables and median ( 25th75th percentile ) for continuous variables . \n insulin secretion was estimated using the cir ( [ 100 30 min insulin]/[30 min glucose { 30 min glucose 70 } ] ) . \n results from the final multivariate model , shown in table 2 , included treatment group , age , sex , ethnicity , baseline weight and change in weight , baseline fasting and 2-h plasma glucose concentrations , and indices of the -cell 's insulin response and tissue insulin sensitivity , as each were significantly and independently predictive of regression to ngr in a univariate analysis . \n as expected , lower baseline fasting and 2-h glucose predicted regression to ngr , as did younger age and a greater insulin secretion to the oral glucose load . \n ils and greater weight loss had significant and independent effects on regression . a nonsignificant trend for metformin , male sex , and greater insulin sensitivity on incidence of regression was also observed . \n the cumulative incidence of regression to ngr in each treatment group is shown in fig . \n 2 . when the model was run using the entire dpp cohort ( fasting glucose 5.36.9 vs. 5.66.9 \n predictors of regression to ngr , isolated ifg , or isolated igt using ada criteria in a multivariate model hrs for continuous variables are per 1 sd ( or per 5 years for age ) . \n cumulative incidence of ngr according to treatment group , adjusted for baseline age , sex , ethnicity , weight , fasting and 2-h glucose concentrations , as well as insulin sensitivity ( 1/fasting insulin ) and secretion ( cir ) . \n when examining the data by treatment group , caucasian self - reported ethnicity was significantly associated with less likelihood of regression ( hr 0.68 , p = 0.02 ) , but only in the metformin group , and therefore is of uncertain significance . \n contribution from a positive family history of diabetes , lipids , blood pressure , use of lipid- and/or blood pressure lowering medications , selective serotonin reuptake inhibitors , or hormone replacement therapy , dietary calories from fat , and met / h per week of physical activity were also explored and found to not be significantly related to regression to ngr ( data not shown ) . \n higher fasting and lower 2-h glucose , as well as male sex and greater insulin sensitivity , were associated with regression to isolated ifg , as defined by ada ( table 2 ) . \n when the entire dpp cohort was analyzed , higher fasting glucose ( hr 1.14 , p < 0.01 ) , lower 2-h glucose ( 1.43 , p < 0.01 ) , male sex ( 1.35 , p < 0.01 ) , and greater insulin sensitivity ( 1.08 , p = 0.02 ) remained similarly predictive . \n the power gained by using the entire cohort increased the ability to detect an effect of ils ( 1.28 , p < 0.01 ) and revealed a tendency for younger age ( 1.03 , p = 0.07 ) to positively influence regression to isolated ifg . within \n treatment group comparisons noted a stronger effect of low 2-h glucose on regression in placebo ( hr 1.64 ) and metformin ( 1.61 ) groups than in the ils group ( 1.25 ) ( test for interaction , p = 0.03 ) . \n lower fasting and higher 2-h glucose , female sex , a greater insulin secretion , as well as both ils and metformin were associated with regression to isolated igt in the ada - defined ifg / igt cohort ( table 2 ) . \n when the same analysis was performed in the entire dpp cohort , lower fasting glucose ( hr 2.36 , p < 0.01 ) , higher 2-h glucose ( 1.15 , p = 0.02 ) , female sex ( 1.54 , p < 0.01 ) , ils ( 1.46 , p = 0.02 ) , and metformin ( 1.89 , p < 0.01 ) remained similarly predictive . \n in contrast , insulin response was no longer significantly related ( 1.01 , p = 0.86 ) , but younger age was ( 1.06 , p = 0.05 ) . \n in addition , marginal associations emerged for lower baseline weight ( 1.13 , p = 0.09 ) and greater weight loss ( 1.17 , p = 0.07 ) influencing regression to isolated igt . \n as the epidemic of diabetes continues to worsen , developing and implementing preventive strategies has become critical . \n a number of clinical trials ( 2,49 ) have demonstrated the effectiveness of lifestyle and/or drug therapy at preventing diabetes in people with pre - diabetes , but none have examined the effectiveness of an intervention on returning those with pre - diabetes to ngr . to expand the paradigm of diabetes prevention , the aim of the current study was to examine the effect of basal biologic factors , weight change , and prevention strategies ( ils or metformin ) on the incidence of regression from pre - diabetes to ngr . \n the major findings from this analysis were that 1 ) insulin secretion , and other biologic processes that are retained with younger age , are key in the restoration of ngr in people with pre - diabetes ; however , 2 ) ngr may also be attained through weight loss and additional aspects of ils , such as healthy eating and exercise . \n ils and metformin both have been shown to be effective strategies for diabetes prevention , but in the dpp only ils restored ngr significantly more frequently than did placebo ( 2 ) . \n different impact of ils versus metformin on parameters of insulin sensitivity or secretion did not explain these results . \n this observation lends support for the notion that aspects of ils beyond insulin sensitization per se are key in truly reducing diabetes risk . \n weight loss appears to be the most important component of ils predicting regression , with every 1 kg lost associated with a 16% reduction in diabetes risk ( 14 ) . \n weight loss strategies inclusive of exercise preferentially mobilize fat from the visceral depot , inducing more favorable metabolic results than would fat mobilized from the subcutaneous depot ( 15 ) . \n interestingly , however , ils , independent of weight loss , also predicted regression to ngr in our study . \n this finding implies a role for the other aspects of ils , such as healthy eating or exercise , in restoring ngr . \n indeed , healthy eating ( 16 ) and exercise ( 17 ) without weight loss have been previously and independently demonstrated as positive effectors on the metabolic milieu ; however , we found no predictive effect toward regression for either in the current analysis . \n the combination of healthy eating with exercise or other pleiotropic effects of exercise may explain these findings but were not assessed in dpp participants . \n in contrast to lifestyle change , some predictors of regression to ngr are not modifiable . \n for example , younger age was associated with regression to ngr in the current study . \n this was seen despite the previous finding that older dpp participants had greater success meeting ils goals and with it the beneficial effect of lower diabetes incidence ( 18 ) . \n considerable controversy exists as to whether age by itself ( 19 ) ( versus age - related body composition change ) leads to the deterioration of insulin action and/or secretion . \n greater insulin secretion also predicted regression to ngr and may reflect the critical link between ils , weight loss , and age in restoring and maintaining ngr . \n weight loss and younger age either resulted in , or were associated with , lower baseline 2-h glucose levels in the dpp , likely reflecting the more robust -cell responsiveness in these groups . \n insulin sensitivity and secretion are integrally related , and the deterioration of each is felt to be requisite in the development of type 2 diabetes ( 21 ) . \n nevertheless , longitudinal data ( 22 ) clearly demonstrate the failure of the -cell as the seminal event in this process . \n therefore , one could surmise that the maintenance of insulin secretion is vital , as insulin sensitivity may be modified more readily than insulin secretion by ils , weight loss , and/or age - related body composition changes . \n all participants in the dpp had elevated 2-h and high - normal fasting glucose concentrations . as the combination of increasing fasting and 2-h glucose levels confers greater risk for diabetes than either in isolation ( 3 ) , there is reason to believe that regression from ifg / igt to isolated ifg or igt may also decrease diabetes risk . \n other than the expected predictive effects of glucose concentration itself ( high fasting and low 2-h glucose for ifg and the converse for igt ) and intervention effects on glucose concentration ( ils on fasting and 2-h glucose , metformin on fasting ) , we observed distinct predictors for reversion to isolated ifg and isolated igt , likely reflecting their different pathophysiology ( 23 ) . \n consistent with some , but not all , cross - sectional studies , those with isolated ifg were more likely to be insulin sensitive and male , whereas those with isolated igt were more likely to have retained insulin secretion and be female ( 24,25 ) . \n first , the primary analyses were conducted using the ada definition of ifg , which reduced the sample size and power to find differences . \n second , by virtue of our analysis plan , the fate of those who may have changed glucose tolerance status more than once , spontaneously regressed , or were incorrectly classified due to the inaccuracy of the oral glucose tolerance test , was not captured . \n finally , analyses were post hoc and exploratory with the intention of generating hypotheses and discussion on this topic . \n , true diabetes prevention likely resides in the restoration of ngr rather than in the maintenance of a high - risk state , such as pre - diabetes . \n for example , age - related changes , particularly when leading to diminished insulin secretion , may permanently impede restoration of ngr . \n in other circumstances , however , ngr may be attained through weight loss and the combined aspects of ils . establishing healthy habits early in life , \n before age - related changes occur , is most likely the best strategy for diabetes prevention . \n ", "role": "user" }, { "content": "objectiveparticipants in the diabetes prevention program ( dpp ) randomized to intensive lifestyle modification ( ils ) or metformin had a significantly reduced incidence of diabetes compared with those randomized to placebo , yet most were still at risk because they had pre - diabetes . \n we explored the effect of baseline characteristics , weight change , ils , and metformin on regression from pre - diabetes to the lowest - risk state of normal glucose regulation ( ngr ) defined by american diabetes association criteria.research design and methodsthe dpp was a prospective randomized trial . \n cox proportional hazards modeling was used to identify predictors of regression from pre - diabetes to ngr over 3 years of follow-up.resultslower baseline fasting ( hazard ratio 1.52 , p < 0.01 ) and 2-h ( 1.24 , p < 0.01 ) glucose predicted regression to ngr , as did younger age ( 1.07 , p < 0.01 ) and greater insulin secretion ( 1.09 , p = 0.04 ) . \n ils ( 2.05 , p < 0.01 ) and weight loss ( 1.34 , p < 0.01 ) had significant and independent effects on regression . a nonsignificant trend for regression \n was also observed for metformin ( 1.25 , p = 0.06 ) , male sex ( 1.17 , p = 0.08 ) , and insulin sensitivity ( 1.07 , p = 0.09 ) . in those entering the study with both impaired fasting glucose ( ifg ) and impaired glucose tolerance ( igt ) , \n male sex and insulin sensitivity predicted regression to isolated ifg , whereas ils , metformin , female sex , and greater insulin secretion predicted regression to isolated igt.conclusionsinsulin secretion , and other biologic processes retained with younger age , are key in restoring ngr in people with pre - diabetes . \n however , ngr may also be attained through weight loss and additional aspects of ils .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: cardiac myxoma is the most common benign heart tumor which can arise in any of the cardiac chambers , valves or related great veins . \n we present a rare case of myxoma in a tricuspid valve attached to papillary muscle . \n a 45-year - old man was referred to our center for the evaluation dyspnea and chest pain . during work - up by transthoracic echocardiography ( tte ) \n , a mass was found on the corda tendinea of the anterior papillary muscle of the tricuspid valve . \n coronary angiography revealed normal coronary artery . during open heart surgery , an oval and non - pedunculated mass was detected on tricuspid corda tendinea and resected . \n this experience illustrates a rare case of myxoma which originated from tricuspid corda tendinea , diagnosed by echocardiography , suggesting fibroelastoma . \n however , the mass was not clear enough but dyspnea and sign and symptom of probably embolization to lung urged us to treat it surgically . no complications attributable to the mass developed in the postoperative course . \n in the first year of follow - up , non - recurrence of the mass was detected on tee , and the patient was asymptomatic . \n cardiac myxoma is the most common benign heart tumor which can arise in any of the cardiac chambers , valves or related great veins . \n most of this myxoma presents with constitutional sign and symptom as well as hemodynamic disturbances by the tricuspid valve obstruction or pulmonary emboli but minority of them were found incidentally on routine echocardiography ( 1 ) . \n the myxoma arising from tricuspid valve apparatus has a potential to cause life - threatening embolic events . \n surgical excision of the tumor is recommended for all patients with or without sign or symptom ( 2 ) . \n a 45-year - old man was referred to the imam ali hospital of the kermanshah university of medical science in the west of iran in february 2015 for evaluation and management of cardiac mass that was found on a transthoracic echocardiogram ( tte ) and his dyspnea . \n the echocardiogram revealed no tricuspid regurgitation , and no mass was noted on the tricuspid valve . \n laboratory data , including work - up for infective endocarditis and autoimmune disease were unremarkable . \n the tte showed a 1.5 1 cm mass attached to the corda tendinea of the anterior leaflet of the tricuspid valve ( fig . \n 1 ) . we consideredsurgical removal of this mass ( figure 2 ) . under cardiopulmonary bypass and bicaval \n cannulation , the right atrium was opened and a tumoral lesion that attaches to the corda tendinea was resected and the corda tendinea repaired . in pathological exam of tumor , myxoid stroma with typical spindle cell was observed ( fig . \n 3 ) . the patient was followed - up with medical treatment , including anticoagulation with heparin for two weeks . \n the patient was also followed - up at three month intervals for one year after discharge from the hospital . \n modified four - chamber apical view showing an oval mass having refractive appearance with echolucent areas on corda tendinea of the papillary muscle of tricuspid valve gross view of tumor from tricuspid corda microscopic finding of myxoid stroma with typical spindle cells \n the myxoma is the most common primary tumor of the heart and most frequently involves the interatrial septum and the left atrium ( 3 ) . \n it always has a sign and symptom of the mitral valve disease or presents with thromboembolic events ( 4 ) . \n myxoma originates from the right atrium in 18% of cases ( 5 ) , and its the signs and symptoms of are variable ( 6 ) . \n the primary origin of myxoma from the cardiac valve apparatus is rare , and tumor arising from the corda tendinea is an exceedingly rare phenomenon . \n this myxoma must be differentiated from other cardiac mass - like lesions such as thrombosis , protuberant pectinate muscle around the tricuspid annulus , rare case of lipoma , sarcoma , schwannoma , paraganglioma , fibroelastoma , libman - sacks vegetations , loeffler 's syndrome , neurofibroma ( 7 ) and lamble 's nodules ( 8) . in this patient , \n the case was unlikely to be a thrombus because of absence of predisposing factors and the location and features of the mass ( 9 ) . \n loeffler 's vegetations were differentiated from myxoma by their small , rounded and sessile contours . \n as opposed to myxoma , loeffler masses are exclusively seen on the mitral , aortic valves and rarely seen on the tricuspid valve . in the majority of patients , involvement of the cardiac valves with any mass may be associated with stenosis or regurgitation ( 10 ) . \n however , the small size of the tumor in our case , with absence of obstructive symptom , led to dyspnea by breaking off a small piece of the tumor or overlying thrombosis and emboli to the pulmonary system . according to previous studies , \n the clinical symptoms and signs of the tricuspid valve myxoma are dyspnea , pulmonary embolism , cyanotic episodes , congestive heart failure and arrhythmias(1113 ) . however , in this patient , the mass was not clear but dyspnea and sign and symptom of probably embolization to lung urged us to treat it surgically . \n this patient illustrates a rare case of myxoma which originated from the tricuspid corda , diagnosed by echocardiography , suggesting fibroelastoma . \n however , in pathology , it was a myxoma . there is some controversy about the appropriate method of surgery in tricuspid valve myxoma . in small masses , despite resection of the tumor , \n valve apparatus was repairable and resected corda tendinea may be reconstructed with such synthetic corda . in some cases \n , some portion of the tricuspid valve needs to resected and extended with fresh pericardial patch . in huge , the tricuspid valve myxoma with destruction of valve , \n our cases present a rare case of myxoma in the tricuspid valve attached to the papillary muscle that pathological examination confirmed this diagnose . \n his postoperative findings indicate improvement in clinical symptom of embolization to lung and dyspnea after surgery .", "role": "user" }, { "content": "backgroundcardiac myxoma is the most common benign heart tumor which can arise in any of the cardiac chambers , valves or related great veins . \n diagnosis of a myxoma arising from the tricuspid valve apparatus is exceptional . \n we present a rare case of myxoma in a tricuspid valve attached to papillary muscle.case detailsa 45-year - old man was referred to our center for the evaluation dyspnea and chest pain . during work - up by transthoracic echocardiography ( tte ) , a mass was found on the corda tendinea of the anterior papillary muscle of the tricuspid valve . \n coronary angiography revealed normal coronary artery . during open heart surgery , an oval and non - pedunculated \n mass was detected on tricuspid corda tendinea and resected . \n pathological examination revealed the presence of a myxoma.conclusionthis experience illustrates a rare case of myxoma which originated from tricuspid corda tendinea , diagnosed by echocardiography , suggesting fibroelastoma . \n however , the mass was not clear enough but dyspnea and sign and symptom of probably embolization to lung urged us to treat it surgically . \n no complications attributable to the mass developed in the postoperative course . in the first year of follow - up , \n non - recurrence of the mass was detected on tee , and the patient was asymptomatic .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: men and women with type 2 diabetes , aged 1877 years , were enrolled between september 2007 and july 2008 at 85 sites in the u.s . , \n eligible patients were treatment - naive subjects whose hyperglycemia was inadequately controlled with diet and exercise alone . \n entry criteria included bmi 45 kg / m and fasting c - peptide 1.0 ng / ml . \n patients were excluded if they had a history of type 1 diabetes , serum creatinine 133 mol / l ( men ) or 124 mol / l ( women ) , urine albumin - to - creatinine ratio > 200 mg / mmol , aspartate transaminase and/or alanine transaminase > 3 times the upper limits of normal , creatine kinase 3 times the upper limit of normal , symptoms of severely uncontrolled diabetes ( including marked polyuria and polydipsia with > 10% weight loss during the last 3 months before enrollment ) ; significant renal , hepatic , hematological , oncological , endocrine , psychiatric , or rheumatic diseases , a cardiovascular event ( including new york heart association class iii / iv congestive heart failure ) within 6 months of enrollment , and severe uncontrolled blood pressure ( systolic blood pressure 180 mmhg and/or diastolic blood pressure 110 mmhg ) . \n this was a 24-week randomized , parallel - group , double - blind , placebo - controlled phase 3 trial with a 2-week diet / exercise placebo lead - in ( 1 week for patients with enrollment a1c 10.112.0% ) . \n the respective institutional review board or independent ethics committee approved the study protocol , and all patients gave informed consent . \n patients with a1c 7.010% were randomly assigned equally to one of seven arms to receive once - daily placebo or 2.5 , 5 , or 10 mg dapagliflozin , administered once daily either in the morning ( main cohort ) or evening ( exploratory cohort ) for 24 weeks . \n patients with a1c 10.112% ( high - a1c exploratory cohort ) were assigned randomly in a 1:1 ratio to receive blinded treatment with a morning dose of 5 or 10 mg / day dapagliflozin ( a placebo group was not included because of the high a1c levels ) . \n patients with fasting plasma glucose ( fpg ) > 270 mg / dl at week 4 , > 240 mg / dl at week 8 , or > 200 mg / dl at weeks 1224 were eligible for open - label rescue medication ( 500 mg metformin , titrated as needed up to 2,000 mg ) . \n patients with a1c > 8.0% for 12 weeks despite a maximum tolerated metformin dose were discontinued . throughout the study , patients received diet / exercise counseling per american diabetes association recommendations . \n the primary efficacy end point was change from baseline in a1c at week 24 in the main patient cohort . \n secondary efficacy measures included change from baseline at week 24 in fpg and body weight . \n efficacy measures assessed in the exploratory evening dose and high - a1c cohorts included change from baseline at week 24 in a1c , fpg , and body weight . for patients requiring rescue medication , data obtained after rescue were excluded from efficacy analyses . \n fractional renal glucose excretion was calculated as the ratio of urine to plasma glucose multiplied by the ratio of plasma to urine creatinine . \n safety assessments included vital signs , laboratory measurements , and adverse events ( coded using preferred terms of the medical dictionary for regulatory activites [ meddra version 11.1 ] ) . \n in addition , at each visit , patients were actively monitored for clinical signs and symptoms suggestive of urinary tract infections ( utis ) and genital infections . \n utis and genital infections are reported here as an adverse event of special interest and include any of the prospectively defined 20 preferred terms relating to possible upper uti events , 44 preferred terms relating to possible non upper uti events , and 49 preferred terms relating to possible genital infections ( including bacterial and mycotic infections ) . \n patients were instructed to self - monitor their blood glucose daily and to report any unusually high or low blood glucose event or any symptoms suggestive of hypoglycemia . \n analyses of change from baseline in a1c , fpg , and body weight were performed using an ancova with treatment group as effect and baseline value as covariate . \n point estimates and 95% ci were calculated for the mean change from baseline within each treatment group as well as for the difference in mean change from baseline between treatment groups . per the study design , \n the primary efficacy end point was change from baseline in a1c at week 24 in the main patient cohort . \n secondary efficacy measures included change from baseline at week 24 in fpg and body weight . \n efficacy measures assessed in the exploratory evening dose and high - a1c cohorts included change from baseline at week 24 in a1c , fpg , and body weight . for patients requiring rescue medication , data obtained after rescue were excluded from efficacy analyses . \n fractional renal glucose excretion was calculated as the ratio of urine to plasma glucose multiplied by the ratio of plasma to urine creatinine . \n safety assessments included vital signs , laboratory measurements , and adverse events ( coded using preferred terms of the medical dictionary for regulatory activites [ meddra version 11.1 ] ) . \n in addition , at each visit , patients were actively monitored for clinical signs and symptoms suggestive of urinary tract infections ( utis ) and genital infections . \n utis and genital infections are reported here as an adverse event of special interest and include any of the prospectively defined 20 preferred terms relating to possible upper uti events , 44 preferred terms relating to possible non upper uti events , and 49 preferred terms relating to possible genital infections ( including bacterial and mycotic infections ) . patients were instructed to self - monitor their blood glucose daily and to report any unusually high or low blood glucose event or any symptoms suggestive of hypoglycemia . \n analyses of change from baseline in a1c , fpg , and body weight were performed using an ancova with treatment group as effect and baseline value as covariate . \n point estimates and 95% ci were calculated for the mean change from baseline within each treatment group as well as for the difference in mean change from baseline between treatment groups . per the study design , \n a total of 485 patients were randomly assigned to the main morning dose and exploratory evening dose cohorts ( fig . \n , 74 patients were randomly assigned to the exploratory , high - a1c cohort , of which 73 patients took at least one dose of study medication . \n demographics and baseline characteristics data are means sd , n ( % ) , or median ( quartile 1 , quartile 3 ) . \n in the main cohort , mean a1c reductions were dose ordered and apparent by week 4 and maintained thereafter ( fig . \n mean a1c reductions from baseline at week 24 in the main cohort ranged from 0.58 to 0.89% with dapagliflozin compared with 0.23% with placebo . \n the reductions were statistically significant with 5 and 10 mg dapagliflozin ( p = 0.0005 and p < 0.0001 , respectively , vs. placebo ) . at the end of study \n , a higher proportion of patients in dapagliflozin arms reached the american diabetes association / european association for the study of diabetes target a1c of < 7% ( 41 , 44 , and 51% with 2.5 , 5 , and 10 mg dapagliflozin , respectively , vs. 32% with placebo ) . \n error bars represent 95% cis . reductions in fpg were apparent as early as week 1 . throughout the study , \n fpg reductions were more marked in 5 and 10 mg dapagliflozin arms and were statistically significant at week 24 ( fig . \n mean body weight decreases were greater with all dapagliflozin doses than with placebo , although they did not reach statistical significance ( fig . \n changes from baseline at week 24 in efficacy parameters , vital signs , and laboratory values data are means sem unless otherwise indicated . \n na , not assessed . * assessed in patients without missing baseline and week 24 values with last observation carried forward . \n ratio from morning fasting spot urine test . # p < 0.0001 ( = 0.019 [ two - sided ] applying dunnett adjustment ; secondary end points were tested using a sequential procedure ) . in the exploratory evening dose cohort , changes from baseline in a1c , fpg , and body weight at week 24 were similar to those seen in the main patient cohort ( table 2 ) . \n in the exploratory high - a1c cohort ( 10.112% at enrollment ) , treatment with dapagliflozin for 24 weeks led to numerically greater reductions in mean a1c and fpg from baseline than those observed in other cohorts ( table 2 ) . \n subgroup analyses of the main patient cohort by baseline a1c were consistent with the ability of dapagliflozin to cause greater a1c reductions in patients with high baseline a1c . in patients with baseline a1c 9% , \n changes in mean a1c from baseline at week 24 were 1.23 0.98 , 1.98 0.90 , and 1.90 0.79% with 2.5 , 5 , and 10 mg dapagliflozin groups , respectively , compared with 0.16 2.50% with placebo . \n treatment with dapagliflozin did not result in any clinically meaningful changes from baseline in serum electrolytes including serum sodium ( table 2 ) . \n there were no clinically relevant changes in any renal function parameter including serum creatinine , blood urea nitrogen , or cystatin c. in addition , there were no clinically relevant changes in mean serum albumin with dapagliflozin treatment . \n small , numerical decreases from baseline in high - sensitivity c - reactive protein ( placebo - subtracted adjusted mean change from baseline value [ se ] ranged from 1.53 [ 1.06 ] to 2.67 [ 1.10 ] \n small , dose - ordered mean increases in hematocrit ( up to 2.4% ) were observed with dapagliflozin . a decrease in mean \n seated blood pressure with no notable increase in orthostatic hypotension was observed in the dapagliflozin arms ( table 2 ) . \n treatment with dapagliflozin did not alter the lipid profile of patients , although small numerical increases in hdl cholesterol were noted in all dapagliflozin arms ( placebo - subtracted adjusted mean change from baseline value [ se ] ranged from 0.02 [ 0.07 ] to 0.17 [ 0.08 ] mmol / l ) . \n glucose - to - creatinine ratios were higher with dapagliflozin than with placebo ( table 2 ) . \n higher values with the evening dose presumably reflect the pharmacokinetic half - life of dapagliflozin . in pooled data from the morning and evening cohorts , changes from baseline in fractional renal glucose excretion at week 24 \n were significantly related ( r = 0.13 , p = 0.008 ) with the corresponding changes in body weight , such that across all study arms greater renal glucose losses were associated with larger decrements in body weight . \n a similar trend was found for changes in glucose excretion and changes in a1c ( p = 0.11 ) . \n there was one death due to a motor vehicle accident in the 10 mg dapagliflozin group . \n there were no major episodes of hypoglycemia in this study , and none of the patients discontinued the study medication due to hypoglycemia . \n an increased incidence in signs and symptoms and other reports suggestive of utis and genital infections was noted with dapagliflozin treatment . \n safety data in the exploratory evening dose cohort were similar to those in the morning dose cohort . \n a small number of patients ( n = 6 ) experienced nocturia with the evening dose ( one , two , and three patients in the 2.5 , 5 or 10 mg dapagliflozin evening dose arms , respectively , and none with the morning dose ) . \n there were no other notable differences in the number or type of adverse events reported with the evening dose . \n n ( % ) and include data after rescue . * additional adverse events ( aes ) with 5% incidence in any of the primary cohort and exploratory evening dose arms were arthralgia , pharyngitis , upper respiratory infection , uti , back pain , dizziness , constipation , influenza , myalgia , peripheral edema , pain in extremity , and insomnia . \n none of the hypoglycemic events led to discontinuation from the study , and none was a major episode , defined as a symptomatic episode requiring third - party assistance due to severe impairment in consciousness or behavior , with a capillary or plasma glucose value < 54 mg / dl , and prompt recovery after glucose or glucagon administration . \n these events included signs , symptoms , and other reports suggestive of genital infections . # not placebo controlled . \n administration of dapagliflozin as monotherapy to treatment - naive patients with type 2 diabetes resulted in clinically meaningful decreases in a1c and fpg , along with favorable effects on weight , blood pressure , and other metabolic parameters . \n although the decrease in body weight in our study did not reach statistical significance compared with placebo , dapagliflozin treatment did lead to increased renal glucose excretion . \n this glucose excretion persisted for the full 24-week study period and was consistent with the urinary loss of 200300 calories / day as reported previously ( 17 ) . \n a factor that may have lessened the effect of dapagliflozin on weight was the large placebo effect in this study , which was probably due to a greater impact of diet / exercise counseling on motivated patients with newly diagnosed diabetes in a clinical trial setting . \n it should also be noted that the progressive decrease in weight over time had not reached a plateau by the end of study ; thus , long - term studies are needed to more precisely gauge the effect of dapagliflozin on weight in the monotherapy setting . \n furthermore , in exploratory analysis of pooled data greater increments in fractional renal glucose excretion were associated with greater decrements in body weight , suggesting a link between the mechanism of action of dapagliflozin and clinical outcome . \n data from the high - a1c cohort are of particular relevance given the mechanism of action of dapagliflozin as an sglt2 inhibitor . \n patients with high a1c at enrollment are likely already to present with glycosuria as their filtered glucose load may exceed the absorption capacity of the kidney . however , dapagliflozin was able to elicit a considerable improvement in glycemia in the exploratory high - a1c cohort . \n results from subgroup analysis of patients with baseline a1c 9% were also consistent with the observation that dapagliflozin continues to be efficacious in patients who present with higher a1c levels . \n after prospectively defined monitoring ( see research design and methods ) , signs and symptoms suggestive of utis and genital infections were more frequently reported in the dapagliflozin arms . \n the reported signs / symptoms / events of utis and genital infections resolved with standard care and rarely led to discontinuation . \n the decrease in mean systolic and diastolic blood pressure noted in this study is in keeping with the diuretic effect of dapagliflozin . also consistent with this effect is the increase in hematocrit levels noted in the dapagliflozin arms . \n in addition to blood pressure , favorable , albeit small , effects were also noted in several other clinical parameters including hdl cholesterol , uric acid , and high - sensitivity c - reactive protein . \n although effects on weight , blood pressure , and other metabolic risk factors were small , they may have a cumulative benefit in the long term . \n most notably , lowering of plasma glucose with dapagliflozin is accompanied by a urinary loss of calories , suggesting a shift toward negative net energy balance . \n this effect of dapagliflozin is unlike that of other antidiabetic agents , which often cause weight gain as they lower plasma glucose concentrations . given its effect on net energy balance and its insulin - independent mechanism , dapagliflozin is likely to have beneficial effects in a wide spectrum of patients with diabetes ( 17,18 ) .", "role": "user" }, { "content": "objectivedapagliflozin , a highly selective inhibitor of the renal sodium - glucose cotransporter-2 , increases urinary excretion of glucose and lowers plasma glucose levels in an insulin - independent manner . \n we evaluated the efficacy and safety of dapagliflozin in treatment - naive patients with type 2 diabetes.research design and methodsthis was a 24-week parallel - group , double - blind , placebo - controlled phase 3 trial . \n patients with a1c 7.010% ( n = 485 ) were randomly assigned to one of seven arms to receive once - daily placebo or 2.5 , 5 , or 10 mg dapagliflozin once daily in the morning ( main cohort ) or evening ( exploratory cohort ) . \n patients with a1c 10.112% ( high - a1c exploratory cohort ; n = 73 ) \n were randomly assigned 1:1 to receive blinded treatment with a morning dose of 5 or 10 mg / day dapagliflozin . \n the primary end point was change from baseline in a1c in the main cohort , statistically tested using an ancova.resultsin the main cohort , mean a1c changes from baseline at week 24 were 0.23% with placebo and 0.58 , 0.77 ( p = 0.0005 vs. placebo ) , and 0.89% ( p < 0.0001 vs. placebo ) with 2.5 , 5 , and 10 mg dapagliflozin , respectively . \n signs , symptoms , and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the dapagliflozin arms . \n there were no major episodes of hypoglycemia . \n data from exploratory cohorts were consistent with these results.conclusionsdapagliflozin lowered hyperglycemia in treatment - naive patients with newly diagnosed type 2 diabetes . \n the near absence of hypoglycemia and an insulin - independent mechanism of action make dapagliflozin a unique addition to existing treatment options for type 2 diabetes .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: among the patients who were diagnosed with cnv due to armd and underwent pdt from april of 2003 to the present , the authors selected three patients ( three eyes total ) for retrospective analysis . with each patient , visual acuity with and without correction was measured , and the anterior segment of the patients ' eyes were examined with a slit - lamp . a dilated retinal exam was also done with contact lenses and an indirect ophthalmoscope , and fag was done in order to identify cnv . \n the patients were asked about allergic reactions to iodine , shellfish , and crustaceans , all of which were negative . \n pdt was conducted by intravenously injecting icg dye with concentration of 50 mg/2.5 cc ( diagnogree , cheil pharmaceutical co. , japan ) . in order to allow the dye to reach the eye without dilution , \n then , the diode laser with a wavelength of 805 nm was mounted on the slit - lamp and applied to the retina with the spot size of 3000 m for 90 seconds . \n the patients were then followed - up for one month after the pdt , and then three months after that . \n afterwards , the authors examined the patients once every three months and measured the best - corrected visual acuity with the etdrs chart , conducted a dilated retinal examination , and performed fag . with the natural progression of cnv in mind , the authors defined stabilization of visual acuity after pdt as the visual acuity decreasing by less than two lines on etdrs chart . \n the authors defined progress of visual acuity as the patient obtaining more than one line of improvement on etdrs chart . \n when there was no leakage compared to the previous findings identified by fag , the patient was said to have \" no leakage \" . \n the patient was said to have \" minimal leakage \" when the area of leakage was no more than fifty percent of the original leakage , and \" moderate leakage \" when the area was more than fifty percent . finally , \n when the leakage exceeded the original area of the lesion , the progression \" label was given to the patient 's leakage , and the analysis was completed . \n a 74-year - old male patient reported a decrease in visual acuity in his left eye that began six months before his initial visit to the hospital . \n his vision with or without correction on his left eye was 20/2000 , and his vision with and without correction on his right eye was 20/25 and 20/50 , respectively . \n the patient had no past history of hypertension or diabetes , and the anterior segment of his eye appeared normal . \n dilated retinal examination showed atrophy as well as hypertrophy of the retinal pigment epithelial ( rpe ) layer in the left foveal region . \n fag showed classic cnv the size of an optic disc , located in the subfoveal region . \n the lesion showed hyperfluorescence at first ; the area of hyperfluorescence increased towards the end of the fag due to leakage ( fig . \n the diode laser was then applied to the patient 's retina with the spot size of 3000 m for 90 seconds . \n there were no allergic or adverse effects due to icg dye during or after the therapy session . \n the patient was followed - up for three months , and his best - corrected visual acuity one month after the treatment increased by one line to 20/800 . however , his visual acuity showed no additional improvement three months after the treatment . \n the authors looked at his fag taken three months after the treatment , and found \" no leakage \" on both occasions ( fig . \n during his final visit , the authors found atrophy of the retinal pigment epithelial layer , and there was no evidence of rpe detachment . \n a 66-year - old female patient complained of metamorphopsia beginning three months before her initial visit to the hospital . \n her visual acuity with or without correction was 20/400 in her right eye and 20/25 in her left eye . \n the patient had no past history of hypertension or diabetes , and the anterior segment of her eyes appeared normal . \n dilated retinal examination showed atrophy as well as hypertrophy of right foveal region , and the patient also had a soft drusen and exudate . \n the patient 's fag showed occult cnv the size of an optic disc located in the subfoveal region , and an area of hyperfluorescence increased towards the end of the fag due to leakage ( fig . \n icg dye was injected intravenously , and a diode laser was applied to the patient 's retina with the spot size of 3000 m for 90 seconds . \n the patient was followed up for nine months , and her best - corrected visual acuity improved by more than two lines to 20/250 . \n the degree of metamorphopsia also decreased . according to fag taken nine months after the treatment \n , the patient showed \" minimal leakage \" , involving an area no more than 50% of the original leakage ( fig . \n dilated retinal examination done in her final visit showed atrophic changes in the retinal epithelial layer , and there was no evidence of retinal hemorrhage or rpe detachment . \n the patient did not experience any allergic or adverse reactions to the icg dye during or after the treatment session . \n a 56-year - old male patient reported decreased visual acuity and metamorphopsia beginning six months prior to the initial visit to the hospital . \n his visual acuity with or without correction was 20/2000 in his right eye , and 20/25 in his left eye . \n the patient had no past history of hypertension or diabetes , and the anterior segment of his eyes appeared normal . \n dilated retinal examination showed atrophy as well as hypertrophy of the retinal epithelial layer in his right macular region . \n there was no evidence of a soft drusen or small areas of retinal hemorrhage in the macula . \n fag revealed a hyperfluorescent area located in the nasal macular region due to atrophy of the rpe layer , and a subfoveal occult cnv the size of an optic disc showed increase in the area of hyperfluorescence towards the end of the fag due to leakage ( fig . \n 3a - c ) . icg dye with a concentration of 50 mg/5 cc was injected intravenously , and a diode laser was applied to the patient 's retina with the spot size of 3000 m for 90 seconds . \n the patient was then followed up for nine months , and his final best - corrected visual acuity of the right eye worsened by one line on the chart at 20/1333 . \n 3d ) . dilated retinal examination done in his final visit revealed atrophy of the rpe layer , and there was no evidence of retinal hemorrhage or rpe detachment . \n the patient also reported no allergic or adverse reactions to icg dye during or after the treatment session . \n cnv occurs underneath the retina or rpe layer , and leakage or hemorrhage because of neovascularization , ischemia , or fibrosis can damage the retina , decreasing visual acuity.1,2 causative factors of cnv include armd , ocular histoplasmosis , high myopia , and other idiopathic causes.3 among these causes , armd is a degenerative disease of the macula which occurs in patients in their fifties and older . \n it is characterized by soft drusen , hyper- or hypopigmentation of the rpe layer , detachment of the sensory retina , retinal hemorrhage , geographic atrophy of the rpe , and cnv or fibrotic changes of the retina . in the western hemisphere , \n armd has become a main cause of blindness in the elderly population over 60 years of age . \n its prevalence is also increasing in korea.4 it can be classified into atrophic or exudative degeneration , and most cases of severe visual loss occur in patients with exudative armd with accompanying cnv . \n many different treatment modalities have been tried in order to cure cnv , including pharmaceutical or radiological therapy , subfoveal surgery , or laser photocoagulation.5 different pharmaceutical treatments have also been tried ( e.g. , thalidomide , interferon -2a , and anti - vegf ) but they were generally ineffective ; research is still ongoing.6 radiological therapy was known to reduce proliferation of vascular endothelial cells ex vivo , thereby preventing proliferation of neovascular vessels in vivo . \n however , there have been contrasting reports regarding maintenance or amelioration of visual acuity after treatment.7 subfoveal surgery has been tried in patients who have severe subfoveal hemorrhage and cnv , in patients with large cnv where laser photocoagulation can not be done , and in patients with cnv which has ambiguous margin . \n however , there have been reports of serious complications such as the development of cataract , the recurrence of cnv , and retinal detachment . \n finally , laser photocoagulation can decrease the incidence of severe visual loss , but in cases of subfoveal cnv , hyperthermia caused by laser can also damage healthy sensory retina . \n cases are limited where laser treatment can be effective , and recurrence after five years is more than 50%.8 thus , in patients with subfoveal cnv , there are no satisfactory treatments . however , while studying agents that can selectively work with cnv , pdt ( which employs photosensitive agents ) has been developed . \n pdt has been clinically proven in the treatment against cancer , and research has been conducted in order to prove its efficacy in the treatment against cnv . \n schmidt - erfurth and hasan reported that photosensitive agents can be absorbed into neovascular vessels , and they successfully demonstrated photothrombosis in an experiment involving animals.9 among photosensitive agents , the second - generation agent verteporfin has been proven to selectively induce cnv regression , and because the agent can also prevent laser - induced hyperthermia , it has become a widely used agent during photodynamic therapy.10,11 verteporfin can bind with tumors that have multiple low - density lipoprotein ( ldl ) receptors and can also selectively unite with neovascular vessels , thereby giving out singlet oxygen and free radical . \n as a result , new vessels may become clogged due to photothrombosis.12 pdt , which employs verteporfin , has been proven in the treatment of cnv due to armd after a random prospective study of the treatment of amd with photodynamic therapy ( tap ) was published , and this study included two years of clinical results.13 in the phase i and ii study that examined the safety of verteporfin , short - term visual outcome and effectiveness was exemplified by fag : hyperfluorescent leakage decrease - dafter a short period of time ( one to four weeks ) , and normal retinal vessels or visual acuity remained intact . \n the study also showed that the leakage coming out of cnv recurred after 12 weeks.14,15 however , after injecting verteporfin , patients reported photosensitive symptoms such as rash , eczema , facial edema and flushing . \n the patients were instructed not to expose their skin , eyes , or other organs directly to sunlight , artificial tanning machines , bright halogen light , or other sources of bright indoor lighting . \n furthermore , when verteporfin is injected along with other photosensitizing agents such as tetracycline , sulfonamides , phenothiazines , sulfonylurea , hypoglycemic agents , thiazide diuretics , and griseofulvin , a photo - allergic reaction may be amplified . additionally , when verteporfin is used with free radical oxygen , anticoagulants , agents which constrict vessels , thromboxane a2 , dimethyl sulfoxide , betacarotene , ethanol , formate , or mannitol , its therapeutic effect decreased markedly . \n when the patient is taking calcium channel blockers or polymyxin - b or is receiving ultraviolet therapy , the therapeutic effects of verteporfin will also decrease because these agents decrease selectivity to neovasculature . in order to overcome these defects of verteporfin \n , some studies started to employ icg dye in pdt because the dye does not cause photosensitivity.16 icg is an anionic tricarbocyanine lavender - hued dye , and , ever since it was introduced by an american fox in 1957 , it has been widely used in liver and heart function tests . \n it has also been used in fag of the retina and choroid for more than thirty years.17 after the dye is injected intravenously , it combines with blood proteins and spreads throughout the body . because it is absorbed by the liver \n twenty minutes after injection , 97% of the dye is digested by the liver and excreted through the gallbladder . \n this makes the dye a very stable agent when measuring liver and circulatory function , because one can freely determine the residual amount in the blood or its loss thereof , and the amount of blood flow into the liver . with the exception of patients who are allergic to iodine ( which is included in the icg ) , \n the dye is safe to use , and it poses no toxicity to skin . when icg is diluted into a solution , its maximum wavelength changes from 780 nm to 805 nm after it combines with blood proteins , and such a property can be used in pdt . \n pdt consists of two parts : the injection of a photosensitive agent and the application of a non - thermal laser to the sensitized tissue . \n after the injection of icg , the dye unites with blood proteins ( e.g. ldl , albumin , etc . ) and among these proteins , ldl increases in number within vascular endothelial cells of rapidly proliferating cells ( such as choroidal neovascular vessels ) . \n thus , the combined unit of icg and ldl accumulates within cnv , and when the non - thermal laser is applied to the site , this unit changes from a ground singlet form to an excited triplet form . \n icg makes a photochemical reaction with this triplet form , giving rise to free radicals or transforming it into singlet oxygen . \n these singlet oxygen and free radicals can damage the endothelial cells , expose the basement membrane of vessels , and activate the platelets , thereby making the platelets combine and coagulate . \n these activated platelets can secrete vasoactive mediators , causing thrombosis and constriction of vessels , thereby clogging the new vessels . among non - thermal lasers employed in the pdt , the icg enhanced diode laser photocoagulation \n was first used by puliafito et al . for the treatment of cnv.18 the wavelength of the diode laser varies between 780 and 840 nm , and the laser \n , maximum absorption wavelength of icg dye is identical to that of the laser at 805 nm , enabling the laser to penetrate deep into the tissue.19 furthermore , the wavelength is within that of the infra - red light , making penetration through cornea and lens easy , and since the laser is not absorbed by other pigments such as xanthophylls , flavoprotein , and glutathion peroxidase , it can be very useful in the treatment of subfoveal lesions.20 in one study published obana et al . , which examined the effectiveness of icg dye and diode laser , obana reported the therapeutic effect in regression of macular cnv to be up to 92%.21 while obana conducted his clinical study with humans , the authors of this study previously took pigmented rats , and , after creating artificial cnv in the retina of rats , injected icg dye , applied a diode laser , and observed the regression of cnv . \n the authors found that the therapeutic effect of such treatment to be up to 85%.22 when the authors analyzed the clinical results of this study , one month after the treatment , there was visual improvement of 0.3 lines . \n the visual acuity did not continue to improve six months and nine months after the treatment , and the overall average increase in visual acuity was 0.2 lines . \n as fag data were analyzed , two eyes had \" no leakage \" while one eye had \" minimal leakage . in the tap study that studied the effectiveness of pdt with verteporfin , improvement of visual acuity \n was defined as improving more than a line on etdrs chart after taking into account the natural progression of cnv . \n one can argue that the authors ' study failed to prove that the therapy with icg failed to bring about improvements in visual acuity . \n however , the visual acuity can be defined as stable when there is deterioration of no more than two lines on the chart , and the authors concluded that the therapy with icg at least can stabilize the progression of cnv . \n also , when the authors looked at the changes in the amount of leakage on fag , \" moderate leakage \" ( greater than 50% of the original leakage ) or \" progression \" did not occur in all patients , further exemplifying the cnv - stabilizing effect of pdt with icg . \n the location of cnv in all three cases was either directly subfoveal or near the area , and because there was no massive hemorrhage , the final visual outcome of pdt could have been good . \n this study does have its limitations that , unlike the tap study that studied the effectiveness of pdt with verteporfin , the authors did not attempt to treat the patient when there was further leakage on fag , and the patient pool was rather small . \n also , in one patient 's eye , only a short period of follow - up ( three months ) was possible , making a direct comparison of icg to verteporfin difficult . \n however , compared to the tap study , the visual acuity stabilizing effect of icg was comparable to that of verteporfin , making the dye useful in the treatment of armd with cnv . \n furthermore , compared to verteporfin , icg is safer because it does not give rise to any allergic or adverse reactions to light , and is cost effective . \n thus , the authors concluded that in patients with decreased visual acuity due to armd with concomitant cnv , pdt with icg can be employed with expectation of improving the visual acuity at a relatively cheaper cost . \n further studies are necessary in order to compare both the short- and long - term visual outcomes of pdt with icg dye , and also to study whether such treatment can be employed with other causes of cnv such as pathologic myopia , ocular histoplasmosis , and idiopathic cnv . \n a 74-year - old male patient reported a decrease in visual acuity in his left eye that began six months before his initial visit to the hospital . \n his vision with or without correction on his left eye was 20/2000 , and his vision with and without correction on his right eye was 20/25 and 20/50 , respectively . \n the patient had no past history of hypertension or diabetes , and the anterior segment of his eye appeared normal . \n dilated retinal examination showed atrophy as well as hypertrophy of the retinal pigment epithelial ( rpe ) layer in the left foveal region . \n fag showed classic cnv the size of an optic disc , located in the subfoveal region . \n the lesion showed hyperfluorescence at first ; the area of hyperfluorescence increased towards the end of the fag due to leakage ( fig . \n the diode laser was then applied to the patient 's retina with the spot size of 3000 m for 90 seconds . \n there were no allergic or adverse effects due to icg dye during or after the therapy session . \n the patient was followed - up for three months , and his best - corrected visual acuity one month after the treatment increased by one line to 20/800 \n . however , his visual acuity showed no additional improvement three months after the treatment . \n the authors looked at his fag taken three months after the treatment , and found \" no leakage \" on both occasions ( fig . \n during his final visit , the authors found atrophy of the retinal pigment epithelial layer , and there was no evidence of rpe detachment . \n a 66-year - old female patient complained of metamorphopsia beginning three months before her initial visit to the hospital . \n her visual acuity with or without correction was 20/400 in her right eye and 20/25 in her left eye . \n the patient had no past history of hypertension or diabetes , and the anterior segment of her eyes appeared normal . \n dilated retinal examination showed atrophy as well as hypertrophy of right foveal region , and the patient also had a soft drusen and exudate . \n the patient 's fag showed occult cnv the size of an optic disc located in the subfoveal region , and an area of hyperfluorescence increased towards the end of the fag due to leakage ( fig . \n icg dye was injected intravenously , and a diode laser was applied to the patient 's retina with the spot size of 3000 m for 90 seconds . \n the patient was followed up for nine months , and her best - corrected visual acuity improved by more than two lines to 20/250 . \n the degree of metamorphopsia also decreased . according to fag taken nine months after the treatment \n , the patient showed \" minimal leakage \" , involving an area no more than 50% of the original leakage ( fig . \n dilated retinal examination done in her final visit showed atrophic changes in the retinal epithelial layer , and there was no evidence of retinal hemorrhage or rpe detachment . \n the patient did not experience any allergic or adverse reactions to the icg dye during or after the treatment session . \n a 56-year - old male patient reported decreased visual acuity and metamorphopsia beginning six months prior to the initial visit to the hospital . \n his visual acuity with or without correction was 20/2000 in his right eye , and 20/25 in his left eye . \n the patient had no past history of hypertension or diabetes , and the anterior segment of his eyes appeared normal . dilated retinal examination showed atrophy as well as hypertrophy of the retinal epithelial layer in his right macular region . \n there was no evidence of a soft drusen or small areas of retinal hemorrhage in the macula . \n fag revealed a hyperfluorescent area located in the nasal macular region due to atrophy of the rpe layer , and a subfoveal occult cnv the size of an optic disc showed increase in the area of hyperfluorescence towards the end of the fag due to leakage ( fig . \n icg dye with a concentration of 50 mg/5 cc was injected intravenously , and a diode laser was applied to the patient 's retina with the spot size of 3000 m for 90 seconds . \n the patient was then followed up for nine months , and his final best - corrected visual acuity of the right eye worsened by one line on the chart at 20/1333 . \n 3d ) . dilated retinal examination done in his final visit revealed atrophy of the rpe layer , and there was no evidence of retinal hemorrhage or rpe detachment . \n the patient also reported no allergic or adverse reactions to icg dye during or after the treatment session . \n cnv occurs underneath the retina or rpe layer , and leakage or hemorrhage because of neovascularization , ischemia , or fibrosis can damage the retina , decreasing visual acuity.1,2 causative factors of cnv include armd , ocular histoplasmosis , high myopia , and other idiopathic causes.3 among these causes , armd is a degenerative disease of the macula which occurs in patients in their fifties and older . \n it is characterized by soft drusen , hyper- or hypopigmentation of the rpe layer , detachment of the sensory retina , retinal hemorrhage , geographic atrophy of the rpe , and cnv or fibrotic changes of the retina . in the western hemisphere \n , armd has become a main cause of blindness in the elderly population over 60 years of age . \n its prevalence is also increasing in korea.4 it can be classified into atrophic or exudative degeneration , and most cases of severe visual loss occur in patients with exudative armd with accompanying cnv . \n many different treatment modalities have been tried in order to cure cnv , including pharmaceutical or radiological therapy , subfoveal surgery , or laser photocoagulation.5 different pharmaceutical treatments have also been tried ( e.g. , thalidomide , interferon -2a , and anti - vegf ) but they were generally ineffective ; research is still ongoing.6 radiological therapy was known to reduce proliferation of vascular endothelial cells ex vivo , thereby preventing proliferation of neovascular vessels in vivo . \n however , there have been contrasting reports regarding maintenance or amelioration of visual acuity after treatment.7 subfoveal surgery has been tried in patients who have severe subfoveal hemorrhage and cnv , in patients with large cnv where laser photocoagulation can not be done , and in patients with cnv which has ambiguous margin . \n however , there have been reports of serious complications such as the development of cataract , the recurrence of cnv , and retinal detachment . \n finally , laser photocoagulation can decrease the incidence of severe visual loss , but in cases of subfoveal cnv , hyperthermia caused by laser can also damage healthy sensory retina . \n cases are limited where laser treatment can be effective , and recurrence after five years is more than 50%.8 thus , in patients with subfoveal cnv , there are no satisfactory treatments . however , while studying agents that can selectively work with cnv , pdt ( which employs photosensitive agents ) has been developed . \n pdt has been clinically proven in the treatment against cancer , and research has been conducted in order to prove its efficacy in the treatment against cnv . \n schmidt - erfurth and hasan reported that photosensitive agents can be absorbed into neovascular vessels , and they successfully demonstrated photothrombosis in an experiment involving animals.9 among photosensitive agents , the second - generation agent verteporfin has been proven to selectively induce cnv regression , and because the agent can also prevent laser - induced hyperthermia , it has become a widely used agent during photodynamic therapy.10,11 verteporfin can bind with tumors that have multiple low - density lipoprotein ( ldl ) receptors and can also selectively unite with neovascular vessels , thereby giving out singlet oxygen and free radical . \n as a result , new vessels may become clogged due to photothrombosis.12 pdt , which employs verteporfin , has been proven in the treatment of cnv due to armd after a random prospective study of the treatment of amd with photodynamic therapy ( tap ) was published , and this study included two years of clinical results.13 in the phase i and ii study that examined the safety of verteporfin , short - term visual outcome and effectiveness was exemplified by fag : hyperfluorescent leakage decrease - dafter a short period of time ( one to four weeks ) , and normal retinal vessels or visual acuity remained intact . \n the study also showed that the leakage coming out of cnv recurred after 12 weeks.14,15 however , after injecting verteporfin , patients reported photosensitive symptoms such as rash , eczema , facial edema and flushing . \n the patients were instructed not to expose their skin , eyes , or other organs directly to sunlight , artificial tanning machines , bright halogen light , or other sources of bright indoor lighting . \n furthermore , when verteporfin is injected along with other photosensitizing agents such as tetracycline , sulfonamides , phenothiazines , sulfonylurea , hypoglycemic agents , thiazide diuretics , and griseofulvin , a photo - allergic reaction may be amplified . \n additionally , when verteporfin is used with free radical oxygen , anticoagulants , agents which constrict vessels , thromboxane a2 , dimethyl sulfoxide , betacarotene , ethanol , formate , or mannitol , its therapeutic effect decreased markedly . \n when the patient is taking calcium channel blockers or polymyxin - b or is receiving ultraviolet therapy , the therapeutic effects of verteporfin will also decrease because these agents decrease selectivity to neovasculature . in order to overcome these defects of verteporfin \n , some studies started to employ icg dye in pdt because the dye does not cause photosensitivity.16 icg is an anionic tricarbocyanine lavender - hued dye , and , ever since it was introduced by an american fox in 1957 , it has been widely used in liver and heart function tests . it has also been used in fag of the retina and choroid for more than thirty years.17 after the dye is injected intravenously , it combines with blood proteins and spreads throughout the body . because it is absorbed by the liver \n twenty minutes after injection , 97% of the dye is digested by the liver and excreted through the gallbladder . \n this makes the dye a very stable agent when measuring liver and circulatory function , because one can freely determine the residual amount in the blood or its loss thereof , and the amount of blood flow into the liver . with the exception of patients who are allergic to iodine ( which is included in the icg ) , \n the dye is safe to use , and it poses no toxicity to skin . when icg is diluted into a solution , its maximum wavelength changes from 780 nm to 805 nm after it combines with blood proteins , and such a property can be used in pdt . \n pdt consists of two parts : the injection of a photosensitive agent and the application of a non - thermal laser to the sensitized tissue . \n after the injection of icg , the dye unites with blood proteins ( e.g. ldl , albumin , etc . ) and among these proteins , ldl increases in number within vascular endothelial cells of rapidly proliferating cells ( such as choroidal neovascular vessels ) . \n thus , the combined unit of icg and ldl accumulates within cnv , and when the non - thermal laser is applied to the site , this unit changes from a ground singlet form to an excited triplet form . \n icg makes a photochemical reaction with this triplet form , giving rise to free radicals or transforming it into singlet oxygen . \n these singlet oxygen and free radicals can damage the endothelial cells , expose the basement membrane of vessels , and activate the platelets , thereby making the platelets combine and coagulate . \n these activated platelets can secrete vasoactive mediators , causing thrombosis and constriction of vessels , thereby clogging the new vessels . among non - thermal lasers employed in the pdt , the icg enhanced diode laser photocoagulation \n was first used by puliafito et al . for the treatment of cnv.18 the wavelength of the diode laser varies between 780 and 840 \n nm , and the laser has maximum output of 2~3 w , making photocoagulation of retina possible . also , maximum absorption wavelength of icg dye is identical to that of the laser at 805 nm , enabling the laser to penetrate deep into the tissue.19 furthermore , \n the wavelength is within that of the infra - red light , making penetration through cornea and lens easy , and since the laser is not absorbed by other pigments such as xanthophylls , flavoprotein , and glutathion peroxidase , it can be very useful in the treatment of subfoveal lesions.20 in one study published obana et al . , which examined the effectiveness of icg dye and diode laser , obana reported the therapeutic effect in regression of macular cnv to be up to 92%.21 while obana conducted his clinical study with humans , the authors of this study previously took pigmented rats , and , after creating artificial cnv in the retina of rats , injected icg dye , applied a diode laser , and observed the regression of cnv . \n the authors found that the therapeutic effect of such treatment to be up to 85%.22 when the authors analyzed the clinical results of this study , one month after the treatment , there was visual improvement of 0.3 lines . \n the visual acuity did not continue to improve six months and nine months after the treatment , and the overall average increase in visual acuity was 0.2 lines . \n as fag data were analyzed , two eyes had \" no leakage \" while one eye had \" minimal leakage . in the tap study that studied the effectiveness of pdt with verteporfin , improvement of visual acuity \n was defined as improving more than a line on etdrs chart after taking into account the natural progression of cnv . \n one can argue that the authors ' study failed to prove that the therapy with icg failed to bring about improvements in visual acuity . \n however , the visual acuity can be defined as stable when there is deterioration of no more than two lines on the chart , and the authors concluded that the therapy with icg at least can stabilize the progression of cnv . \n also , when the authors looked at the changes in the amount of leakage on fag , \" moderate leakage \" ( greater than 50% of the original leakage ) or \" progression \" did not occur in all patients , further exemplifying the cnv - stabilizing effect of pdt with icg . \n the location of cnv in all three cases was either directly subfoveal or near the area , and because there was no massive hemorrhage , the final visual outcome of pdt could have been good . \n this study does have its limitations that , unlike the tap study that studied the effectiveness of pdt with verteporfin , the authors did not attempt to treat the patient when there was further leakage on fag , and the patient pool was rather small . \n also , in one patient 's eye , only a short period of follow - up ( three months ) was possible , making a direct comparison of icg to verteporfin difficult . \n however , compared to the tap study , the visual acuity stabilizing effect of icg was comparable to that of verteporfin , making the dye useful in the treatment of armd with cnv . \n furthermore , compared to verteporfin , icg is safer because it does not give rise to any allergic or adverse reactions to light , and is cost effective . \n thus , the authors concluded that in patients with decreased visual acuity due to armd with concomitant cnv , pdt with icg can be employed with expectation of improving the visual acuity at a relatively cheaper cost . \n further studies are necessary in order to compare both the short- and long - term visual outcomes of pdt with icg dye , and also to study whether such treatment can be employed with other causes of cnv such as pathologic myopia , ocular histoplasmosis , and idiopathic cnv .", "role": "user" }, { "content": "purposeto evaluate the diode laser photodynamic therapy efficacy on choroidal neovascularization ( cnv ) in the treatment of three patients with age - related macular degeneration ( armd).methodsthe authors selected three patients with armd whose vision has decreased due to cnv , and applied diode laser treatment after injecting an indocyanine green ( icg ) solution . \n the patients were followed for at least three months after treatment , and examinations included evaluating vision changes and possible leakage on fluorescein angiography ( fag).resultsthe final vision of two patients improved by more than one line on the early treatment diabetic retinopathy study ( etdrs ) chart after at least three months of follow - up . however , the final vision of the third patient decreased by one line on etdrs chart . \n fag was done in all patients , and in two of the patients , there was no evidence of leakage at the laser - applied site . in the other patient \n , there was evidence of minimal leakage , with the area of leakage decreasing by more than fifty percent . \n side effects of icg were not found during or after the photodynamic therapy sessions.conclusionsthe photodynamic usage of icg treatment of cnv in patients with armd , was effective in preventing or improving the visual outcome . compared to the widely used verteporfin , icg is more stable and is more cost effective . \n the authors therefore came to a conclusion that icg can be very useful in the treatment of cnv . \n however , further studies are necessary .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: hypertension is the major risk factor for cardiovascular disease ( cvd),1 which is the leading cause of mortality worldwide.2,3 studies have shown that developing countries have the largest absolute number of people with hypertension and suffer a greater impact from the growing burden of chronic diseases like hypertension.4,5 in sub - saharan africa , the prevalence of hypertension has been increasing,6,7 and it is one of the risk factors that showed the highest increase from 1990 to 2010 in this region.8 in parallel , from 1990 to 2013 , an increase of 81% in cardiovascular mortality occurred in this region.9 however , sub - saharan africa remains the region of the world where published data on the prevalence , treatment , and control of hypertension are lacking.10,11 in angola , estimates show that 9% of 301,000 deaths occurred due to cvds in 2012,12 with 24.2% of probability of premature death ( aged between 30 and 70 years ) due to noncommunicable diseases ( ncds).12 little is known about the prevalence of hypertension ( and prehypertension ) in the general population . in the few existing studies , the prevalence varied between 23% and 45.2%,13,14 but in clinical practice , it is undiagnosed and undertreated , often presenting as a hypertensive emergency , with target organ damage ( tod ) in early ages compared to the world average.13,15,16 in huambo , south of angola , no published study to date has assessed hypertension and its associated risk factors . \n the current population context in the province is characterized by increased life expectancy and unhealthy lifestyle habit adoption , which in interaction with the racial factor and other health determinants force toward epidemiological transition . \n therefore , it is important to study this condition in the population , principally in the setting of 25 25 global target , which aimed a 25% relative reduction in premature mortality from main ncds between 2010 and 2025.17 the aim of this study was to assess the prevalence , awareness , treatment , and control of hypertension , as well as associated factors in patients attending an outpatient clinic at south angolan hospital . \n a cross - sectional study was conducted with 265 subjects aged 18 years and older , attending the outpatient medical service of the general hospital of huambo , in september 2015 . \n huambo is a province of southern angola , with an area of 34.274 km and about 1.8 million inhabitants.18 the general hospital of huambo is a tertiary hospital , whose outpatient service attends about 2400 to 5000 patients aged 18 years and older each month , most of them from the peri - urban area . despite being a tertiary hospital , \n most patients in the outpatient service are of primary care profile , due to patient flow diversion that arises from the system deficiency , with a defective flow regulation between primary care and reference services . \n thus , most patients are attended based on subacute and mild symptoms and seek services spontaneously . since they do not meet the criteria to be evaluated in the emergency services , they are attended by this outpatient service . \n most patients seek assistance without previously diagnosed chronic comorbidities and are seen in a general medicine or surgery consultation . among the few with a previous diagnosis are those with surgical pathology , in evaluation for elective surgery , and those in postorthopedic trauma follow - up . \n therefore , the study subjects are more a non - representative fraction of the general population than an appropriately referenced tertiary hospital population . \n a sample size was calculated , expecting a hypertension prevalence of 24% , based on the adjusted estimate for the average age,6 assuming precision of 5% , 95% confidence interval ( ci ) , and a design effect of 1 . \n all individuals aged 18 years and older , who attended a consultation during the period of data collection ( in september ) , were invited to participate and were included consecutively until to complete the calculated sample . \n pregnant women were excluded because their inclusion would cause a significant difficulty in separating those with chronic hypertension , from those with gestational hypertension and/or preeclampsia , in a population where the knowledge of chronic ncd is low . \n this is reinforced in the context of limited resources , from basic laboratory tests such as proteinuria , technological resources such as a computerized system to retrieve information about previous health of the woman , until human resource limitations . during data collection \n , 276 patients completed the evaluation , but 11 patients were excluded because of erroneous or incomplete data . \n data were collected using a questionnaire , with questions about age , gender , personal medical history , medication use , and smoking history . \n the questionnaire also included questions about knowing to be hypertensive , told by a health - care professional after blood pressure ( bp ) measurement , and prescribed medication for hypertension . \n those who reported being on antihypertensive medication were evaluated whether they had bp < 140/90 mmhg on study measurement , in which situation we considered that they were with controlled bp . \n bp was evaluated according to the seventh report of the joint national committee on prevention , detection , evaluation , and treatment of high blood pressure ( jnc 7 ) recommendations,19 at the arm level , by the oscillometric method , with digital automatic device , omron m6 comfort ( hem-7221-e ; omron healthcare co. , ltd . ) , tested and calibrated by the manufacturer , and validated according to the european society of hypertension international protocol.20 we categorized the population into three subgroups based on a single measurement bp value : normotensives ( bp below 120/80 mmhg ) , prehypertensives ( systolic bp between 120 and 139 mmhg and/or diastolic bp between 80 and 89 mmhg ) , and hypertensives ( systolic bp 140 mmhg and/or diastolic bp 90 mmhg).19 those on medication for previously diagnosed hypertension were considered as hypertensives , regardless of bp value . \n the data were stored in a common database and subjected to descriptive statistical analysis according to specific variables . \n we calculated the prevalence of prehypertension and hypertension in the general sample and specific by age and gender . \n the association between independent and dependent variables was evaluated by odds ratios ( or ) with 95% ci , accepting a level of significance for p < 0.05 . \n the study procedures were performed only after informed verbal consent was obtained from participants or those responsible for them , without any registration , because a considerable portion of the subjects were illiterate , so they do not know how to sign . \n all research procedures were evaluated and approved by the scientific and pedagogical board of the hospital , that is , the organ responsible for ethical issues in research at the institution , in the absence of formal ethical committee in the province . \n a cross - sectional study was conducted with 265 subjects aged 18 years and older , attending the outpatient medical service of the general hospital of huambo , in september 2015 . \n huambo is a province of southern angola , with an area of 34.274 km and about 1.8 million inhabitants.18 the general hospital of huambo is a tertiary hospital , whose outpatient service attends about 2400 to 5000 patients aged 18 years and older each month , most of them from the peri - urban area . despite being a tertiary hospital , \n most patients in the outpatient service are of primary care profile , due to patient flow diversion that arises from the system deficiency , with a defective flow regulation between primary care and reference services . \n thus , most patients are attended based on subacute and mild symptoms and seek services spontaneously . since they do not meet the criteria to be evaluated in the emergency services , they are attended by this outpatient service . \n most patients seek assistance without previously diagnosed chronic comorbidities and are seen in a general medicine or surgery consultation . among the few with a previous diagnosis are those with surgical pathology , in evaluation for elective surgery , and those in postorthopedic trauma follow - up . \n therefore , the study subjects are more a non - representative fraction of the general population than an appropriately referenced tertiary hospital population . \n a sample size was calculated , expecting a hypertension prevalence of 24% , based on the adjusted estimate for the average age,6 assuming precision of 5% , 95% confidence interval ( ci ) , and a design effect of 1 . \n all individuals aged 18 years and older , who attended a consultation during the period of data collection ( in september ) , were invited to participate and were included consecutively until to complete the calculated sample . \n pregnant women were excluded because their inclusion would cause a significant difficulty in separating those with chronic hypertension , from those with gestational hypertension and/or preeclampsia , in a population where the knowledge of chronic ncd is low . \n this is reinforced in the context of limited resources , from basic laboratory tests such as proteinuria , technological resources such as a computerized system to retrieve information about previous health of the woman , until human resource limitations . during data collection \n , 276 patients completed the evaluation , but 11 patients were excluded because of erroneous or incomplete data . \n data were collected using a questionnaire , with questions about age , gender , personal medical history , medication use , and smoking history . \n the questionnaire also included questions about knowing to be hypertensive , told by a health - care professional after blood pressure ( bp ) measurement , and prescribed medication for hypertension . \n those who reported being on antihypertensive medication were evaluated whether they had bp < 140/90 mmhg on study measurement , in which situation we considered that they were with controlled bp . \n bp was evaluated according to the seventh report of the joint national committee on prevention , detection , evaluation , and treatment of high blood pressure ( jnc 7 ) recommendations,19 at the arm level , by the oscillometric method , with digital automatic device , omron m6 comfort ( hem-7221-e ; omron healthcare co. , ltd . ) , tested and calibrated by the manufacturer , and validated according to the european society of hypertension international protocol.20 we categorized the population into three subgroups based on a single measurement bp value : normotensives ( bp below 120/80 mmhg ) , prehypertensives ( systolic bp between 120 and 139 mmhg and/or diastolic bp between 80 and 89 mmhg ) , and hypertensives ( systolic bp 140 mmhg and/or diastolic bp 90 mmhg).19 those on medication for previously diagnosed hypertension were considered as hypertensives , regardless of bp value . \n the data were stored in a common database and subjected to descriptive statistical analysis according to specific variables . \n we calculated the prevalence of prehypertension and hypertension in the general sample and specific by age and gender . \n the association between independent and dependent variables was evaluated by odds ratios ( or ) with 95% ci , accepting a level of significance for p < 0.05 . \n the study procedures were performed only after informed verbal consent was obtained from participants or those responsible for them , without any registration , because a considerable portion of the subjects were illiterate , so they do not know how to sign . \n all research procedures were evaluated and approved by the scientific and pedagogical board of the hospital , that is , the organ responsible for ethical issues in research at the institution , in the absence of formal ethical committee in the province . \n a total of 265 patients were included , the median age was 36 years ( range 1891 years ) , and 60% ( 159 ) were women , without significant age difference between genders , and all black africans . \n the overall prevalence rates of hypertension and prehypertension were 38.5% ( n = 102 ; 95% ci : 32.83%44.90% ) and 30.2% ( n = 80 ; 95% ci : 24.52%36.22% ; fig . \n the occurrence of hypertension was significantly associated with age ( > 35 years ; or = 10.09 ; 95% ci : 5.4618.66 , p < 0.01 ) and female gender ( 44.03% vs. 30.19% ; or = 1.81 , 95% ci : 1.083.05 , p = 0.02 ) . \n figure 2 displays the prevalence of prehypertension and hypertension by age , among subjects aged 18 years and older . among total hypertensive patients , 54.9% ( 56/102 ) \n were aware of the diagnosis , 28.43% were in treatment , and only 7.84% had controlled bp . \n considering those who were aware of the diagnosis , 51.78% ( 29/56 ) were in treatment , and of these , only 27.6% had controlled bp ( table 1 ) . \n aldosterone system inhibitors , alone , or in combination with diuretics and/or calcium channel antagonists . \n lack of awareness about diagnosis was significantly higher in younger ( 37 years ) than in older ( 68.42% vs. 39.76% ; or = 3.28 , 95% ci : 1.139.49 , p = 0.02 ) , and in men than in women ( 59.38% vs. 38.57% ; or = 2.32 ; 95% ci : 0.995.46 , p = 0.05 ) . \n table 2 displays the univariate analysis of factors associated with the prevalence of hypertension and lack of awareness of diagnosis among subjects aged 18 years and older . in the sample , 3.39% and 4.15% self - reported diabetes and active smoking , respectively , without significant association with hypertension prevalence . \n the prevalence of hypertension found in this study ( 38.5% ) is consistent with that of other studies in africa , being 38.2% and 38.9% in nigeria and south africa , respectively.21,22 however , it was relatively lesser than that found ( 45.2% ) in the study done in the country s capital with workers from a university,14 which can be explained mainly by the significant difference in age between the two studies ( 44.5 10.6 years in the previous study vs. 38.67 15.36 years in this study ) \n . moreover , to a lesser extent , the social class difference may be another reason , by factors like higher access to industrialized food among workers compared with the population of the current study , most of them from lower social class and peri - urban area . in this study \n , only 31.3% of the population had normal bp and 68.7% had high bp ( prehypertension or hypertension ) . \n these data are relevant , considering the median age of the study , and the parallel knowledge that around 78.61% of prehypertensive patients can progress to hypertension within four to five years , if no intervention is implemented.23 in this way , approximately 62.22% of the economically active population can become hypertensive within this period , which is a real alert for an imminent explosion of cardiovascular events , if no action is taken . the prevalence increased with age , which corroborates with data from the literature.24 the association with the female gender \n is also found in most of the literature,25,26 which has been attributed to the higher prevalence of obesity in females.27 obesity may have also contributed to higher cardiovascular mortality observed in women in sub - saharan africa from 1990 to 2013.9 no significant association was found between hypertension and diabetes or smoking , most likely due to the low number of smokers and diabetics in the sample . \n a low awareness rate was also found in the study carried out in the north of the country13 and was emphasized in most studies in this region.28 the treatment rate was even lower so that among total hypertensives , only 28.43% ( 29 of 102 patients ) were in treatment and 7.84% had controlled bp , which is in accordance with the rates found in other studies.23,28 it is even more worrying when considering that this is a sample of patients with some contact with health professionals , and the problem may be greater in the general population , particularly from rural area , as found in madagascar where only 1.7% and 5.3% of hypertensive patients were in treatment in rural and urban areas , respectively.29 this scenery is favorable to the occurrence of tod at an earlier age compared to the world average , as has been found by other studies.16,30,31 in this study , it was impossible to screen for most tod , due to resources limitations , and there are no previously reported data in this population . \n the only existing data are about peripheral arterial disease , whose prevalence was 42.6% among those aged 40 years and older , using the ankle - brachial index as diagnostic criteria , in a study carried out in parallel with this.32 it is worth to highlight that in a study done in the country s capital with 123 patients aged 45 years ( mean 36.62 5.49 years ) , admitted with hypertensive emergencies , the most frequent presentations were hemorrhagic stroke ( 82.1% ) and hypertensive encephalopathy ( 9.8% ) , with 25.2% inhospital mortality.15 these data from the few available studies can be the closest reflection of the overall picture of cvd in the country . \n additionally , even among those with previous diagnosis , only 51.78% was under treatment , and of these , only 27.6% had controlled bp . \n this raises concern about the need for training of health professionals on the importance of an appropriate approach to hypertension.33 this includes diagnosis , treatment institution , adjustments of drug dosages to achieve the desired goals , and adherence check , knowing that the latter is the leading cause of noncontrol among those with established treatment , as found in adherence check study in congo , where 54.2% were nonadherent and only 15.6% had controlled bp.34,35 professional training is necessary , because even those with the diagnosis confirmed by a professional were likely to be released without treatment , reflecting a lack of preparedness of health system , at this level , for the care of hypertensive outpatients as found in tanzania.36 this may be occurring because of the little attention that is given to ncd , during training , in a medium where acute communicable diseases are still the leading cause of mortality.12 however , it is worthy to emphasize that ncds have shown increasing prevalence and growing space on morbidity and mortality.12,15 therefore , they should also be worthy of focus during training . \n another important element is that young people and men , although less affected , are the groups more unaware of the diagnosis , reaching 66.66% in young people and 59.37% in men . \n this has also been shown in other studies , where the unawareness rate ranged from 72% to 81.3% , and higher in younger.24,37 this context of unawareness , favours the little implementation of lifestyle changes by most of them , as shown in relation to salt intake among university students in the capital,38 and stay without pharmacologic treatment.22 even in treatment , these subgroups tend to have higher rates of nonadherence and low control.22,24,25 this confluence of factors is the substrate for the occurrence of early cardiovascular events and premature mortality , as shown in other studies.16,39 finally , analyzing in the setting of 25 25 global target , the results of this study are in line with a study of current trends , showing that africa is the region of the world with greater difficulty to achieve this target.40 among the risk factors to address , hypertension is the factor whose reduction could cause the greatest impact to achieve this global target.31,41 therefore , the low awareness , treatment , and control are points to take into account in the planning , implementation , evaluation , and adjustment of strategies aimed to decrease these issues and achieve such target at the local level . \n the prevalence of hypertension found in this study ( 38.5% ) is consistent with that of other studies in africa , being 38.2% and 38.9% in nigeria and south africa , respectively.21,22 however , it was relatively lesser than that found ( 45.2% ) in the study done in the country s capital with workers from a university,14 which can be explained mainly by the significant difference in age between the two studies ( 44.5 10.6 years in the previous study vs. 38.67 15.36 years in this study ) \n . moreover , to a lesser extent , the social class difference may be another reason , by factors like higher access to industrialized food among workers compared with the population of the current study , most of them from lower social class and peri - urban area . in this study \n , only 31.3% of the population had normal bp and 68.7% had high bp ( prehypertension or hypertension ) . \n these data are relevant , considering the median age of the study , and the parallel knowledge that around 78.61% of prehypertensive patients can progress to hypertension within four to five years , if no intervention is implemented.23 in this way , approximately 62.22% of the economically active population can become hypertensive within this period , which is a real alert for an imminent explosion of cardiovascular events , if no action is taken . \n the prevalence increased with age , which corroborates with data from the literature.24 the association with the female gender is also found in most of the literature,25,26 which has been attributed to the higher prevalence of obesity in females.27 obesity may have also contributed to higher cardiovascular mortality observed in women in sub - saharan africa from 1990 to 2013.9 no significant association was found between hypertension and diabetes or smoking , most likely due to the low number of smokers and diabetics in the sample . \n a low awareness rate was also found in the study carried out in the north of the country13 and was emphasized in most studies in this region.28 the treatment rate was even lower so that among total hypertensives , only 28.43% ( 29 of 102 patients ) were in treatment and 7.84% had controlled bp , which is in accordance with the rates found in other studies.23,28 it is even more worrying when considering that this is a sample of patients with some contact with health professionals , and the problem may be greater in the general population , particularly from rural area , as found in madagascar where only 1.7% and 5.3% of hypertensive patients were in treatment in rural and urban areas , respectively.29 this scenery is favorable to the occurrence of tod at an earlier age compared to the world average , as has been found by other studies.16,30,31 in this study , it was impossible to screen for most tod , due to resources limitations , and there are no previously reported data in this population . \n the only existing data are about peripheral arterial disease , whose prevalence was 42.6% among those aged 40 years and older , using the ankle - brachial index as diagnostic criteria , in a study carried out in parallel with this.32 it is worth to highlight that in a study done in the country s capital with 123 patients aged 45 years ( mean 36.62 5.49 years ) , admitted with hypertensive emergencies , the most frequent presentations were hemorrhagic stroke ( 82.1% ) and hypertensive encephalopathy ( 9.8% ) , with 25.2% inhospital mortality.15 these data from the few available studies can be the closest reflection of the overall picture of cvd in the country . \n additionally , even among those with previous diagnosis , only 51.78% was under treatment , and of these , only 27.6% had controlled bp . \n this raises concern about the need for training of health professionals on the importance of an appropriate approach to hypertension.33 this includes diagnosis , treatment institution , adjustments of drug dosages to achieve the desired goals , and adherence check , knowing that the latter is the leading cause of noncontrol among those with established treatment , as found in adherence check study in congo , where 54.2% were nonadherent and only 15.6% had controlled bp.34,35 professional training is necessary , because even those with the diagnosis confirmed by a professional were likely to be released without treatment , reflecting a lack of preparedness of health system , at this level , for the care of hypertensive outpatients as found in tanzania.36 this may be occurring because of the little attention that is given to ncd , during training , in a medium where acute communicable diseases are still the leading cause of mortality.12 however , it is worthy to emphasize that ncds have shown increasing prevalence and growing space on morbidity and mortality.12,15 therefore , they should also be worthy of focus during training . \n another important element is that young people and men , although less affected , are the groups more unaware of the diagnosis , reaching 66.66% in young people and 59.37% in men . \n this has also been shown in other studies , where the unawareness rate ranged from 72% to 81.3% , and higher in younger.24,37 this context of unawareness , favours the little implementation of lifestyle changes by most of them , as shown in relation to salt intake among university students in the capital,38 and stay without pharmacologic treatment.22 even in treatment , these subgroups tend to have higher rates of nonadherence and low control.22,24,25 this confluence of factors is the substrate for the occurrence of early cardiovascular events and premature mortality , as shown in other studies.16,39 finally , analyzing in the setting of 25 25 global target , the results of this study are in line with a study of current trends , showing that africa is the region of the world with greater difficulty to achieve this target.40 among the risk factors to address , hypertension is the factor whose reduction could cause the greatest impact to achieve this global target.31,41 therefore , the low awareness , treatment , and control are points to take into account in the planning , implementation , evaluation , and adjustment of strategies aimed to decrease these issues and achieve such target at the local level . \n the study revealed a high prevalence , with low awareness , treatment , and control rates . \n greater efforts and studies , with representative samples , are necessary to overcome these challenges and better understand about the disease and associated factors in this population . \n this is a single - center and hospital - based study ; hence , it does not represent the general population of huambo . \n the single measurement is another evident limitation of this study , an option that was chosen because resource limitations , at the local level , extend to the number of available monitors for bp measurement and the number of collaborators to carry out this research .", "role": "user" }, { "content": "objectivethis study aimed to assess the prevalence , awareness , treatment , and control of hypertension in patients attending an outpatient clinic at a general hospital in huambo , south angola.methodsa total of 265 subjects aged 18 years and older were included . \n evaluation included complete interview and blood pressure measurement using a validated automatic device.resultsthe prevalence rates of hypertension and prehypertension were 38.5% ( 95% confidence interval [ ci ] : 32.83%44.90% ) and 30.20% ( 95% ci : 24.52%36.22% ) , respectively . \n hypertension was associated with age ( > 35 years ; odds ratio [ or ] = 10.09 , 95% ci : 5.4618.66 , p < 0.01 ) and female gender ( or = 1.81 , 95% ci : 1.083.05 , p = 0.02 ) . among total hypertensive patients , \n 54.9% were aware of their diagnosis , 28.43% were in treatment , and 7.84% had controlled blood pressure . \n lack of awareness was significantly higher in younger ( age 37 years ; or = 3.28 , 95% ci : 1.139.49 , p = 0.02).conclusionthis study revealed a high prevalence of hypertension , with low awareness , treatment , and control rates . \n greater efforts are necessary to overcome these challenges .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: main determinants in the clinical care of patients with urolithiasis are the location , size , and chemical composition of the calculi , the latter being particularly important in the presence of uric acid ( ua ) stones , since ua stones may be dissolved by urinary alkalinization . \n the imaging modality of choice for the detection of urinary stone disease is unenhanced computed tomography ( ct ) , offering high specificity and sensitivity . \n however , despite promising in vitro results , the transferability of results to an in vivo setting was hampered by misregistration problems . \n symptomatic urinary stone disease affects approximately 900,000 persons in the united states each year , resulting in annual medical costs of $ 5.3 billion . \n the morbidity associated with urolitiasis includes colic pain and kidney obstruction , which can lead to renal failure and severe urinary tract infections such as pyonephrosis and septic shock . \n moreover , the institution of further prophylactic measures to prevent recurrences is of utmost importance . \n this necessitates a thorough metabolic workup and an accurate quantitative stone analysis . without an appropriate workup , stone analysis and proper follow up \n , the recurrence rates may be as high as 1023%/year and may reach to 50% within 5 years . among all types of urinary stones , \n the frequency of calcium stone is 7080% , struvite stone 510% , uric acid stone 510% , and cystine stone 1% . in general , stones composed of ua are broken up easily by shock waves , whereas stones of calcium oxalate monohydrate ( com ) , brushite , or cystine are difficult to break . \n previous attempts [ 911 ] to predict stone composition using spiral ct were based on the analysis of ct attenuations . \n . demonstrated that high resolution spiral ct yields unique ct attenuations for common types of stones if proper window settings are used to localize homogeneous regions within the stones . \n currently , the following methods are available for stone analysis : ( 1 ) chemical analysis , ( 2 ) emission spectroscopy , ( 3 ) polarizing spectroscopy , ( 4 ) x ray diffraction , ( 5 ) x ray coherent scatter / crystallography , ( 6 ) thermogravimetry , ( 7 ) scanning electron microscopy , and ( 8) infrared spectroscopy [ 6 , 2 ] . chemical analysis was traditionally used most widely due to its ease and low cost . however , this is time consuming , necessitates large stone samples and can not distinguish between the two commonly occurring calcium stones ( monohydrate / dihydrate ) . with the exception of infrared spectroscopy \n contradictory findings were published in literature regarding the ability of helical ct to accurately assess the chemical composition of urinary stones . \n two in vivo studies [ 9 , 10 ] , both conducted at 120 kv with 35 mm collimation , concluded that ct density ( attenuation / stone size ) was the best predictor of stone composition and could differentiate ua from calcium oxalate stones . \n most in vitro studies [ 14 , 15 ] placed human calculi in a water bath to evaluate ct attenuation values as parameters predicting stone composition ; they could distinguish ua stones from other stones . \n the aim of the present study was to investigate retrospectively the impact of urinary stone volume on computed tomography stone attenuations measured in hounsfield units in 253 patients with urolithiasis using postoperative in vitro infrared spectroscopy ( 100 ftir , perkinelmer ) . \n this retrospective study was approved by the institutional ethics board of our university . from 2008 to 2010 , 253 consecutive patients ( 189 men , 64 women ) with urolithiasis were included into our analysis . children and pregnant women were excluded from the study . in patients with acute flank pain , suspected of having urinary stones , we performed so called stone ct , which is an unenhanced low \n participants were scanned using a 64slice computed tomography unit ( siemens ag , somatom , sensation 64 , erlangen , germany ) . one unenhanced scan ( acquisition : 64x0.6 mm , 120 kv , 150 mas ) of the abdomen and the pelvis with a slice thickness of 3 mm was made . \n this protocol is routinely used at our institution to evaluate patients with acute flank pain suspected to have renal colic . \n a region of interest ( roi ) was drawn on each stone , and the attenuation was measured . \n the sizes and positions of the regions of interest were validated by an experienced abdominal radiologist ( a.l ) by using a conventional soft tissue window and narrow bone windows . when the calculi had irregular contours , special attention was given not to include any surrounding soft tissue , which has much lower ct attenuation values than calculi . \n the average , highest , and lowest ct attenuation values in hounsfield units were calculated . \n our abdominal radiologist , who was blinded to the chemical composition of the stones , retrospectively reviewed the imaged and analyzed data to determine the hu of the calculi . \n spss software package version 13 ( spss , ibm , chicago , illinois ) was used . \n hereby , the p values were based on levene 's test of equality of means . \n all statistical tests were two sided . according to the european association of urology the size of a concrement ( stone burden ) \n the most common way of expressing size in the literature is to use the largest diameter , i.e. the length of the stone as measured on a plain film . \n the stone surface area ( sa ) can be estimated for most stones from the length ( l ) and width ( w ) of the stone using the following formula sa = l. w. . 0.25 ( =3.14159 ) with the more common use of ct examinations , it is possible to get an even better estimate of the stone volume ( sv ) by combining measures of length ( l ) , width ( w ) and depth ( d ) using the formula : sv = l. w. d. . 0.167 ( = 3.14159 ) . \n the biochemical composition of the stone was established after spontaneous passage , operation or shock wave lithotripsy . \n stone analysis was based on infrared spectroscopy , which determines the molecular and crystalline composition of the stone . \n infrared spectroscopy is the spectroscopy that deals with the infrared region of the electromagnetic spectrum , that is light with a longer wavelength and lower frequency than visible light . \n it covers a range of techniques , mostly based on absorption spectroscopy . as with all spectroscopic techniques \n , it can be used to identify and study chemicals . a common laboratory instrument that uses \n we used perkinelmer spectrum 100 ftir spectrometer ( perkinelmer , shelton , usa ) to analyse urinary stones after passage or operation . \n this retrospective study was approved by the institutional ethics board of our university . from 2008 to 2010 , 253 consecutive patients ( 189 men , 64 women ) with urolithiasis were included into our analysis . children and pregnant women were excluded from the study . in patients with acute flank pain , suspected of having urinary stones , we performed so called stone ct , which is an unenhanced low \n participants were scanned using a 64slice computed tomography unit ( siemens ag , somatom , sensation 64 , erlangen , germany ) . one unenhanced scan ( acquisition : 64x0.6 mm , 120 kv , 150 mas ) of the abdomen and the pelvis with a slice thickness of 3 mm was made . \n this protocol is routinely used at our institution to evaluate patients with acute flank pain suspected to have renal colic . \n a region of interest ( roi ) was drawn on each stone , and the attenuation was measured . \n the sizes and positions of the regions of interest were validated by an experienced abdominal radiologist ( a.l ) by using a conventional soft tissue window and narrow bone windows . when the calculi had irregular contours , special attention was given not to include any surrounding soft tissue , which has much lower ct attenuation values than calculi . \n the average , highest , and lowest ct attenuation values in hounsfield units were calculated . \n our abdominal radiologist , who was blinded to the chemical composition of the stones , retrospectively reviewed the imaged and analyzed data to determine the hu of the calculi . \n spss software package version 13 ( spss , ibm , chicago , illinois ) was used . \n variables were compared by anova . hereby , the p values were based on levene 's test of equality of means . \n all statistical tests were two sided . according to the european association of urology the size of a concrement ( stone burden ) \n the most common way of expressing size in the literature is to use the largest diameter , i.e. the length of the stone as measured on a plain film . \n the stone surface area ( sa ) can be estimated for most stones from the length ( l ) and width ( w ) of the stone using the following formula sa = l. w. . 0.25 ( =3.14159 ) with the more common use of ct examinations , it is possible to get an even better estimate of the stone volume ( sv ) by combining measures of length ( l ) , width ( w ) and depth ( d ) using the formula : sv = l. w. d. . 0.167 ( = 3.14159 ) . \n the biochemical composition of the stone was established after spontaneous passage , operation or shock wave lithotripsy . \n stone analysis was based on infrared spectroscopy , which determines the molecular and crystalline composition of the stone . \n infrared spectroscopy is the spectroscopy that deals with the infrared region of the electromagnetic spectrum , that is light with a longer wavelength and lower frequency than visible light . \n it covers a range of techniques , mostly based on absorption spectroscopy . as with all spectroscopic techniques \n , it can be used to identify and study chemicals . a common laboratory instrument that uses this technique \n we used perkinelmer spectrum 100 ftir spectrometer ( perkinelmer , shelton , usa ) to analyse urinary stones after passage or operation . \n we included 253 patients from 2008 to 2010 into our analysis ( 189 men and 64 women ) with the mean age being 51.2 years and the median age 49.6 years ( see table 1 ) . \n according to urinary stone incidence in relation to gender , we found a male predominance ( 2.9 higher risk ) . \n patients and study objects there were 134 pure calcium oxalate monohydrate ( whewelit , com ) calculi , 29 stones with 50% uric acid and 50% whewelit , 29 stones with 80% whewelit and 20% cystine and 12 pure calcium oxalate dihydrate ( whedelit , cod ) . there were 49 mixed calculi according to their chemical compositions : struvite , carbonate , and xanthine , as well as protein . the calculi were divided into 4 groups according to their clinical relevance : calcium oxalate monohydrate and dihydrate , uric acid stones , struvite , cystine . \n calcium oxalate monohydrate and dihydrate , the overall differences between the densities of the stones was not statistically significant ( table 2 ) ( p = 0.05 ) and there was a cross over in densities among all studied stones ; a sharp demarcation among different types could not be found . \n hu of calcium and uric acid as well as for cystine and struvite stones to study the effect of stone volume on density , we divided the stones into 2 groups according to their median stone volume values : group 1 . \n 126 stones with stone size > 37.78 mm and volume > 4.3 mm group 2 . \n the smallest stone had a size of 0.5 mm and a volume of 0.9 mm . \n the largest stone had a size of 3620 mm and a volume of 19 mm . when the calculi were compared with each other , levene 's test was used . \n groups of uric acid and non ua according to stones volume we compared groups 1 and 2 with each other according to levene 's test . there was significant relationship between stone volume and ct attenuation only in stones with a volume 4.3 mm or more ( p < 0.05 ) ( figures 1 and 2 ) . in order to study this trend , we performed a logistic regression analysis for the prediction of the stone composition , which failed to show any significant differences between group 1 and 2 . figure 3 \n stones with volume > 4.3 mm on x axes and their hounsfield units on y axes . \n group 2 stones with volume < 4.3 mm on x axes and their hounsfield units on y annex . \n yagisawa showed that male patients had a significantly higher number of metabolic abnormalities than female patients , which is in agreement with our results which showed that urinary stone incidence has a male predominance ( 2.9 higher risk ) . \n the clinical management of urinary tract stones depends on the location , size , and number of calculi , as well as their chemical composition . \n the success rate with shock wave lithotripsy depends on these factors in addition to stones fragility . \n cystine , brushite , and calcium oxalate monohydrate stones are less fragile and may be better treated with shock wave lithotripsy . \n patients with uric acid stones may be treated medically by means of urine alkalization with or without shock wave lithotripsy . since the early 1990s , \n studies showed that helical ct can depict urinary stones more precisely than radiography , nephrotomography and excretory urography . the ability to predict the stone composition before treatment by ct helps in triaging patients . \n it enables the selection of patients with small ua containing stones who benefit from medical management rather than shock wave lithotripsy [ 1 , 11 ] . \n the usefulness of ct in making treatment decisions depends on the size , burden and location of the stone , as well as the degree of obstruction . due to the fact that uric acid stones are composed of only light chemical elements ( h , c , n \n , o ) , their x ray attenuation properties are different compared to those characteristic of non uric acid stone types such as calcium oxalate , and cystine . \n uric acid stones include heavy elements ( p , ca , s ) . consequently , uric acid stones have higher ct attenuations at higher kvp values than at lower kvp values , whereas non \n uric acid stones have higher ct attenuations at lower kvp values than at higher kvp values [ 3 , 4 ] . since the early 1980s \n , several studies were conducted in an attempt to determine the chemical composition of stones on the basis of x ray attenuation in vitro and in vivo . for our study \n , we used the largest number ( n = 253 ) of stones so far described , to the best of our knowledge . \n the in vitro studies , however , did not reproduce normal abdominal wall and fat , perinephric fat or the spine , causing uncertainty about standardization of the values obtained . \n for example , bellin used excised pig kidney placed in water , mostafavi and deveci placed stones in air , saw placed stones in water and grosjean used a jelly made of water , iodine and animal proteins surrounded with water . \n deveci used an air filled environment instead of phantoms containing water or fat . \n consequently , because the in vitro conditions were too far from the in vivo conditions , the results can not be considered a reference for in vivo determination of chemical composition . \n newhouse failed to distinguish each type of stone from all other types at 120 kv . \n attenuation values decline with smaller stones and wider collimation . saw et al . reported that a 1mm collimation width allowed for better identification of stones than a 3mm collimation . at a 10mm collimation , \n some uric acid stones with a diameter less than 4 mm could go undetected because of very low attenuation and partial volume effects . in the last 2 decades \n some authors reported promising results with the ability to identify all types of stones studied [ 11 , 18 ] . \n mostafavi studied 102 pure stones with ct scanning at both 80 and 120 kv and was able to differentiate the most common stone types ( struvite , cystine , and calcium oxalate ) using single energy scanning at 120 kv . \n found that using an absolute ct value at 120 kv , all types of renal calculi could be differentiated from each other . \n the pure stones from the least to the most dense were as follows : ua , struvite , cystine , calcium phosphate , and calcium oxalate . \n , they identified 82 calculi predominantly composed of calcium oxalate and 17 calculi predominantly composed of ua . \n when the hu values of calcium , ua , struvite , and cystine stones were compared , the overlap of ranges precluded accurate identification . by contrast , some authors reported limitations in identification of stone composition using ct . saw studied 127 stones at 1 , 3 and 10 mm collimation and could differentiate the stone types studied except for brushite from hydroxyapatite at 1 mm collimation . \n newhouse could not distinguish calcium based and struvite based stones from each other . \n grosjean showed that an overlap between different types of stones prohibited a reliable determination of chemical composition by two subsequent scans and this was explained by the movement of the kidneys as a result of respiration . \n hidas could not distinguish struvite stones and the subtypes of calcium stones ; this may be due to real chemical overlap between stone compositions and differences in absorption among patients of different sizes . \n numerous factors influence the measured ct attenuation values of a stone , mainly beam collimation width , stone size and x ray energy levels , ct attenuation values decline with smaller decline , smaller stones and wider collimation . \n , this may be the cause of not differentiating among stone types of < 4.3 mm . \n nakada reported that a more narrow collimation decreases the volume averaging artefact and improves the measurement of attenuation and size . \n our results are partially in agreement with the findings of primak et al . who could not identify small stones ( <3 mm ) . \n ascenti et al . identified all stones with a diameter of > 3 mm with a lower dose single energy ct . \n according to ascenti , characterization of stones <3 mm is often clinically less important because a high percentage of stone spontaneous passage . \n we failed to distinguish between ua and non ua stones because our analyzed stones were not pure stones , which are not uncommon in a clinical setting and most stones are not pure stones . \n contradictory results were documented by matlaga et al . who found no significant differences in stones size among ua and calcium oxalate groups . \n medical prophylaxis to prevent recurrence is still at the core of the treatment of urinary stone disease . \n stone analysis complements , but does not replace , urine and serum studies to assess for metabolic stone disease . \n however , stone analysis can present useful information , as it represents a biochemical patient history , documenting the urinary environment over time through type and conformation of crystal deposition . \n quality control studies conducted in europe from 1980 to 2001 demonstrated that the overall accuracy of stone analysis was improving with time and experience . \n ir and x ray diffraction methods were most reliable for artificial stone substances , but wet chemical methods produced an error rate from 6.594% . with existing technology , several steps could increase the reliability of stone analysis . \n due to incomplete sampling leading to errors , all stones obtained by the patient or the surgeon should be submitted for analysis ; this gives the analysis laboratory the best chance to detect all components that are present . according to singh , infrared spectroscopy is a sensitive , reliable , accurate , safe , and quick method of accurate stone analysis suitable for use in a clinical laboratory . \n measurements of specific absorption peaks of the spectrum of each sample , mean error rate being 22.5% . \n the quantitative stone analysis by infrared spectroscopy allows accurate separate zone wise analysis of the stone nucleus , external and internal layers not possible by other methods \n . limitations of our study : results should be interpreted with caution because the retrospective design of our study . \n we failed to show the effect of stone volume on its attenuations , and could not distinguish ua from non ua stones because most of our analyzed stones were not pure stones .", "role": "user" }, { "content": "introductionto investigate retrospectively the impact of urinary stone volume on computed tomography stone attenuations measured in hounsfield units in 253 patients with urolithiasis.material and methodsct scans were performed in 253 patients with suspected urinary stone disease from 2008 to 2010 using ct \n scanner siemens , somatom , sensation 64 . \n one experienced radiologist ( a.l ) who was blinded to the chemical composition of the stones retrospectively reviewed images and analyzed data to determine the composition of the stones . \n the results were compared with the biochemical analysis results obtained by infrared spectroscopy ( 100 ftir , perkinelmer).results253 consecutive patients from 2008 to 2010 were included into analysis : 189 males , and 64 females . \n mean age was 51.2 . \n according to stone volume , stones were divided into 2 groups : 126 stones with volume of 4.3 mm or more , 127 stones with volume less than 4.3 mm . \n there was a significant relationship between stone volume and its ct attenuation only in stones with a volume 4.3 mm or more ( p < 0.05).conclusionswe failed to show a significant relationship between stone volume and its attenuations in hounsfield units \n . we could not distinguish uric acid stones from non uric acid stones .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: recent studies have suggested simultaneous or metachronous lesions in multiorgans characterized by elevated serum levels of igg4 and abundant infiltration of igg4-positive plasma cells with various degrees of fibrosis , which lead us to propose the concept of a systemic disease [ 1 , 4 , 10 , 23 , 24 ] . \n however , there are many synonyms suggesting a systemic disease , such as igg4-related autoimmune disease , igg4-related sclerosing disease , igg4-related plasmacytic syndrome ( sips ) , igg4-related multiorgan lymphoproliferative syndrome ( igg4-molps ) , and systemic igg4-related disease , all of which may refer to the same conditions [ 24 , 25 ] ( table 1 ) . to simplify these conditions , members of two japanese research committees for igg4-related disease , one from view of fibrosclerosis ( chaired by prof . \n umehara h ) , both of which are supported by the research for intractable disease program from the ministry of health , labor , and welfare of japan , have agreed with unification of different nomenclatures as igg4-related disease ( igg4-rd ) and proposed the comprehensive diagnostic criteria ( cdc ) for igg4-rd . \n as it still remains unclear whether pathogenetic mechanisms in each involved organ - are same or not , the term igg4-rd was appointed as minimally reflecting these conditions to avoid misdiagnosis of malignancy as much as possible . \n the two japanese research committees independently analyzed the clinical features and conditions of igg4-rd and finally resulted in the following consensus with close collaboration [ 15 , 24 , 25 ] . \n ( 1 ) patients with igg4-rd show diffuse / focal organ enlargement , with mass - forming or nodular / thickened lesions in various organs , including the central nervous system , lachrymal / salivary glands [ 10 , 23 ] , thyroid gland [ 27 , 28 ] , lungs , pancreas [ 30 , 31 ] , biliary duct , liver , gastrointestinal tract [ 34 , 35 ] , kidneys , prostate gland , retroperitoneum , skin , lymph nodes [ 5 , 40 , 41 ] , and artery [ 42 , 43 ] . \n ( 2 ) these multiorgan lesions may occur synchronously or metachronously , with the prominent infiltration of lymphocytes and igg4-positive plasmacytes with fibrosis . \n ( 3 ) igg4-rd mainly affects middle - aged to elderly men except for igg4-related dacryoadenitis / sialadenitis . \n although clinical symptoms depending on involved organs are relatively mild , some patients develop serious complications such as obstructive jaundice due to hepatic , gallbladder , or pancreatic lesions ; hydronephrosis due to retroperitoneal fibrosis ; respiratory symptoms due to pulmonary lesions . \n ( 5 ) although the infiltration of igg4-positive cells and increased serum concentrations of igg4 characteristic of igg4-rd , the severity of fibrosis is dependent on the individual organs involved . for example , storiform fibrosis and obliterative phlebitis are characteristic of pancreatic , biliary tract , and retroperitoneal lesions but are rarely observed in lachrymal / salivary glands or lymph nodes . \n in addition to mif , there are many synonyms , such as igg4-related autoimmune disease , igg4-related sclerosing disease , igg4-related plasmacytic disease ( sips ) , and \n storiform fibrosis and obliterative phlebitis are characteristic of biliopancreatic , retroperitoneal , and renal lesions , but rarely observed in lachrymal / salivary glands and lymphnodes [ 24 , 25 ] . \n then , the nomenclature of igg4-related sclerosing disease is mainly based on the fibrous swollen organs , whereas those of igg4-sips and igg4-molps are based on lymphoplasmacytic proliferation and swollen lymph nodes without fibrosis [ 24 , 25 ] . \n although most patients have multiorgan lesions synchronously or metachronously , about 1020% of the patients show a solitary organ involved without confirming other organ involvement [ 24 , 25 ] . \n therefore , it is unclear whether the pathogenetic mechanism is same among individual organs or not . \n in addition to igg4-rd , igg4-associate conditions such as high serum levels of igg4 or abundant infiltration of igg4-positive cells were reported in some patients with malignancy ; pancreatic [ 6 , 45 ] , biliary and salivary cancer , gastrointestinal sarcoma , and ocular adnexal lymphoma [ 4951 ] . \n therefore , the term systemic may lead us to misdiagnosis of other organ lesions showing igg4-related conditions in cases of malignancy . \n based on these findings , the members of umehara and okazaki teams have agreed that the term \n the patients with igg-4-related disease show organ enlargement or nodular / hyperplastic lesions in organs in the entire body , synchronously or metachronously , due to the prominent infiltration and fibrosis of lymphocytes and plasmacytes ; however , the causes of the disease are still not clear . \n the organs known to be affected include the central nervous system , lacrimal / salivary glands , thyroid gland , lungs , pancreas , biliary duct , liver , gastrointestinal tracts , kidneys , prostate gland , retroperitoneum , skin , arteries , and lymph nodes . although it remains unclear whether this disease is the same as multifocal fibrosclerosis , that is a possibility . \n clinical symptoms vary depending on the organ in which the lesions are located , which suggests that it is hard to establish criteria covering all patients with igg4-rd . \n therefore , specific diagnostic criteria are required for each involved organ such igg4-related mikulicz 's disease ( igg4-related dacryoadenitis / sialadenitis ( table 2 ) , type 1 aip ( igg4-related pancreatitis ) ( table 3 ) , and igg4-related kidney disease [ 14 , 41 ] ( table 4 ) . however \n , these organ - specific criteria do not cover other organs or are not familiar to general clinicians and specialists . \n moreover , to avoid misdiagnosis of malignancy , all physicians have to know this emerging disease entity and can make a diagnosis of igg4-rd . \n therefore , the cdc for igg4-rd , containing three major criteria ( clinical , hematological and histopathological examinations ) , have been proposed for practical use of general physicians and nonspecialist ( table 5 ) . \n although sensitivity of the cdc for definitive igg4-rd is low in the organs to be difficult in taking biopsy specimens , it can detect possible cases of igg4-rd . in the probable or possible cases , \n ( 1 ) clinical examinationphysical examinations and imaging on us / ct / mri can show the characteristic diffuse / localized swelling , masses , or thickness in single or multiple organs ( figure 1 ) . \n physical examinations and imaging on us / ct / mri can show the characteristic diffuse / localized swelling , masses , or thickness in single or multiple organs ( figure 1 ) . \n ( 2 ) immunological examination \n ( a ) increase of serum levels of igg4the cutoff value for serum igg4 concentration , 135 mg / dl , was based on receiver operating characteristic ( roc ) curves , and its validity was confirmed in patients with autoimmune pancreatitis ( table 6 ) . in patients with single - organ involvement and serum igg4 concentration less than 135 mg / dl , the igg4/igg ratio may be helpful in making a diagnosis.however , elevated igg4 may be also observed in other diseases ( e.g. , atopic dermatitis , pemphigus , asthma , and multicentric castleman 's disease ) , especially in about 10% of malignancy , which suggests that high serum igg4 is not necessarily specific marker of igg4-rd . \n although a high cut - off value with > 270 mg / dl of igg4 increases specificity but decreased sensitivity of igg4-rd differing from pancreatic cancer . \n therefore , at present , the significance of elevated igg4 in the pathogenesis / pathophysiology of igg4-rd still remains unknown . \n ( b ) other immunological markersin addition to increased serum levels of igg4 , high serum levels of polyclonal -globulin , igg , and ige are often , and hypocomplementemia may occur . \n as these markers are less sensitive for igg4-rd , they are not included as a diagnostic criterion . \n ( a ) increase of serum levels of igg4the cutoff value for serum igg4 concentration , 135 mg / dl , was based on receiver operating characteristic ( roc ) curves , and its validity was confirmed in patients with autoimmune pancreatitis ( table 6 ) . in patients with single - organ involvement and serum igg4 concentration less than 135 mg / dl \n , the igg4/igg ratio may be helpful in making a diagnosis.however , elevated igg4 may be also observed in other diseases ( e.g. , atopic dermatitis , pemphigus , asthma , and multicentric castleman 's disease ) , especially in about 10% of malignancy , which suggests that high serum igg4 is not necessarily specific marker of igg4-rd . although a high cut - off value with > 270 mg / dl of igg4 increases specificity but decreased sensitivity of igg4-rd differing from pancreatic cancer . \n therefore , at present , the significance of elevated igg4 in the pathogenesis / pathophysiology of igg4-rd still remains unknown . \n ( b ) other immunological markersin addition to increased serum levels of igg4 , high serum levels of polyclonal -globulin , igg , and ige are often , and hypocomplementemia may occur . \n as these markers are less sensitive for igg4-rd , they are not included as a diagnostic criterion . \n the cutoff value for serum igg4 concentration , 135 mg / dl , was based on receiver operating characteristic ( roc ) curves , and its validity was confirmed in patients with autoimmune pancreatitis ( table 6 ) . in patients with single - organ involvement and serum igg4 concentration less than 135 mg / dl , the igg4/igg ratio may be helpful in making a diagnosis . \n however , elevated igg4 may be also observed in other diseases ( e.g. , atopic dermatitis , pemphigus , asthma , and multicentric castleman 's disease ) , especially in about 10% of malignancy , which suggests that high serum igg4 is not necessarily specific marker of igg4-rd . \n although a high cut - off value with > 270 mg / dl of igg4 increases specificity but decreased sensitivity of igg4-rd differing from pancreatic cancer . therefore , at present , the significance of elevated igg4 in the pathogenesis / pathophysiology of igg4-rd still remains unknown . \n in addition to increased serum levels of igg4 , high serum levels of polyclonal -globulin , igg , and ige are often , and hypocomplementemia may occur . \n as these markers are less sensitive for igg4-rd , they are not included as a diagnostic criterion . \n ( 3 ) histopathologic examinationalthough tissue biopsies are difficult to obtain from some organs , including the pancreas , retroperitoneum and ocular cavity , histopathological examination is important.(a ) marked lymphocyte and plasmacyte infiltration and fibrosis.storiform or swirling fibrosis or obliterative phlebitis is characteristic of igg4-rd and may be important in its diagnosis.(b ) infiltration of igg4-positive plasma cellsigg4/igg - positive cells more than 40% or 50% have been reported in lymphnodes of the patients with igg4-rd . on the other hand , \n more than 10 igg4-positive plasma cells are recommended that in diagnosis of type 1 aip . \n based on these findings , the cdc for igg4-rd recommend both the ratio of igg4/igg - positive cells > 40% and infiltration of > 10 igg4-positive plasma cells / hpf for the definitive diagnosis . \n it is noted that reactive infiltration of igg4-positive cells and fibrosis may be observed in various diseases and clinical conditions , such as rheumatoid synovitis , inflammatory oral and skin lesions , and around cancer . \n however , it is noted that some additional immune - mediated conditions with increased serum interleukin-6 ( il-6 ) such as multicentric castleman 's disease may show elevated serum igg4 and/or igg4+/igg+ plasma cell ratios > 40% . \n although tissue biopsies are difficult to obtain from some organs , including the pancreas , retroperitoneum and ocular cavity , histopathological examination is important.(a ) marked lymphocyte and plasmacyte infiltration and fibrosis.storiform or swirling fibrosis or obliterative phlebitis is characteristic of igg4-rd and may be important in its diagnosis.(b ) infiltration of igg4-positive plasma cellsigg4/igg - positive cells more than 40% or 50% have been reported in lymphnodes of the patients with igg4-rd . on the other hand , more than 10 igg4-positive plasma cells are recommended that in diagnosis of type 1 aip . \n based on these findings , the cdc for igg4-rd recommend both the ratio of igg4/igg - positive cells > 40% and infiltration of > 10 igg4-positive plasma cells / hpf for the definitive diagnosis . \n it is noted that reactive infiltration of igg4-positive cells and fibrosis may be observed in various diseases and clinical conditions , such as rheumatoid synovitis , inflammatory oral and skin lesions , and around cancer . \n however , it is noted that some additional immune - mediated conditions with increased serum interleukin-6 ( il-6 ) such as multicentric castleman 's disease may show elevated serum igg4 and/or igg4+/igg+ plasma cell ratios > 40% . \n storiform or swirling fibrosis or obliterative phlebitis is characteristic of igg4-rd and may be important in its diagnosis . \n igg4/igg - positive cells more than 40% or 50% have been reported in lymphnodes of the patients with igg4-rd . on the other hand , \n more than 10 igg4-positive plasma cells are recommended that in diagnosis of type 1 aip . based on these findings , \n the cdc for igg4-rd recommend both the ratio of igg4/igg - positive cells > 40% and infiltration of > 10 igg4-positive plasma cells / hpf for the definitive diagnosis . \n it is noted that reactive infiltration of igg4-positive cells and fibrosis may be observed in various diseases and clinical conditions , such as rheumatoid synovitis , inflammatory oral and skin lesions , and around cancer . \n however , it is noted that some additional immune - mediated conditions with increased serum interleukin-6 ( il-6 ) such as multicentric castleman 's disease may show elevated serum igg4 and/or igg4+/igg+ plasma cell ratios > 40% . \n ( 4 ) prohibition of facile steroid treatment in the cdc for igg4-rdpatients with malignant lymphoma or paraneoplastic lesions can sometimes be improved by steroid administration . therefore , steroid trials should be strictly avoided . \n however , patients having disease in organs difficult to biopsy , such as the pancreas , retroperitoneum , and pituitary , and respond to steroids may possibly have igg4-rd . in accordance with the guidelines for treatment of autoimmune pancreatitis , \n patients should be started on 0.5 - 0.6 mg / kg / day / prednisolone . \n if patients do not respond to the initial steroid therapy , the diagnosis should be reviewed again . \n however , patients having disease in organs difficult to biopsy , such as the pancreas , retroperitoneum , and pituitary , and respond to steroids may possibly have igg4-rd . in accordance with the guidelines for treatment of autoimmune pancreatitis \n , patients should be started on 0.5 - 0.6 mg / kg / day / prednisolone . \n if patients do not respond to the initial steroid therapy , the diagnosis should be reviewed again . \n ( 5 ) diseases to be excluded or differentiated \n ( a ) malignancies ( e.g. , cancer , lymphoma)in cases of malignancy in the involved organs , it is essential to determine whether malignant cells are present histopathologically . \n ( b ) similar diseasesother similar benign diseases including sjgren 's syndrome , primary sclerosing cholangitis , multicentric castleman 's disease , idiopathic retroperitoneal fibrosis , wegener 's granulomatosis , sarcoidosis , and churg - strauss syndrome should be differentially diagnosed using the diagnostic criteria for each disease . \n it is noted that multicentric castleman 's disease , one of hyper il-6 syndromes should be excluded from igg4-rd , even if the cdc for igg4-rd are fulfilled . \n ( a ) malignancies ( e.g. , cancer , lymphoma)in cases of malignancy in the involved organs , it is essential to determine whether malignant cells are present histopathologically . \n ( b ) similar diseasesother similar benign diseases including sjgren 's syndrome , primary sclerosing cholangitis , multicentric castleman 's disease , idiopathic retroperitoneal fibrosis , wegener 's granulomatosis , sarcoidosis , and churg - strauss syndrome should be differentially diagnosed using the diagnostic criteria for each disease . \n it is noted that multicentric castleman 's disease , one of hyper il-6 syndromes should be excluded from igg4-rd , even if the cdc for igg4-rd are fulfilled . \n in cases of malignancy in the involved organs , it is essential to determine whether malignant cells are present histopathologically . \n other similar benign diseases including sjgren 's syndrome , primary sclerosing cholangitis , multicentric castleman 's disease , idiopathic retroperitoneal fibrosis , wegener 's granulomatosis , sarcoidosis , and churg - strauss syndrome should be differentially diagnosed using the diagnostic criteria for each disease . \n it is noted that multicentric castleman 's disease , one of hyper il-6 syndromes should be excluded from igg4-rd , even if the cdc for igg4-rd are fulfilled . \n the sensitivity of cdc for definitive / probable igg4-rd is satisfactory in igg4-related md and igg4-related kd , but not in type 1 aip [ 6 , 13 ] . \n the major reason of low sensitivity in type 1 aip is that enough biopsy samples of the pancreas are not easily obtained in most of these patients . \n in addition , endoscopic ultrasonography ( eus ) , guide fine needle aspiration ( fna ) , is available in a few of institutes in japan , for examples only 16 of 226 ( 7% ) board member institutes in kink district of japan gastroenterological endoscopy society ( jges ) . on the other hand , \n the sensitivity of the cdc for possible igg4-rd is satisfactory in type 1 aip ( table 7 ) . \n in contrast , patients with type 1 aip could not be diagnosed by the comprehensive diagnostic criteria ( 0% ) for definite , because biopsies could not be obtained from most of these patients . \n therefore , combination of the cdc and organ - specific criteria should increase the sensitivity of diagnosis , even in the possible cases of igg4-rd . \n based on these findings , a diagnostic algorithm for igg4-rd in combination with the cdc and other organ - specific criteria has been proposed , although they have a limitation to the utility of the criteria proposed ( figure 2 ) . in patients with ( a ) organ enlargement , mass or nodular lesions , or organ dysfunction , performing of both ( b ) measurement of serum igg4 and ( c ) tissue biopsy is recommended . in the cases with > 135 mg / dl of igg4 , diagnostic histopathological findings of > 10 igg4 cells / hpf and an igg4/igg cell ratio \n > 40 can diagnose them as definitive aip . in possible or probable cases fulfilling criterion ( a ) with ( b ) , or ( c ) , organ - specific criteria for each disease should be applied . \n it is important to differentiate igg4-rd from malignant tumors of each organ ( e.g. , cancer , lymphoma ) and similar diseases ( e.g. , sjgren 's syndrome , primary sclerosing cholangitis , castleman 's disease , secondary retroperitoneal fibrosis , wegener 's granulomatosis , sarcoidosis , and churg - strauss syndrome ) by additional histopathological examination . \n future studies including other organ diseases similar to igg4-rd are needed to establish the diagnostic efficacy of cdc . \n all japan research team for igg4-rd unified the nomenclatures as igg4-related disease ( igg4-rd ) and proposed the comprehensive diagnostic criteria ( cdc ) for igg4-rd . \n the cdc for igg4-rd was made for the practical use and for general physicians to differentiate igg4-rd from malignancy or similar diseases as much as possible . \n although sensitivity of the cdc for definitive igg4-rd is low in the organs to be difficult in taking biopsy specimens , it can detect possible cases of igg4-rd . in the probable or possible cases ,", "role": "user" }, { "content": "recent studies suggest simultaneous or metachronous lesions in multiorgans characterized by elevated serum levels of igg4 and abundant infiltration of igg4-positive plasma cells with various degrees of fibrosis . \n two japanese research committees for igg4-rd , one from fibrosclerosis ( okazaki team ) and the other from lymph proliferation ( umehara team ) supported by the research program for intractable disease of the ministry of health , labor , and welfare of japan , have agreed with the unified nomenclature as igg4-rd and proposed the comprehensive diagnostic criteria ( cdc ) for igg4-rd . \n validation of the cdc demonstrated satisfactory sensitivity for the practical use of general physicians and nonspecialists but low sensitivity in the organs to be difficult in taking biopsy specimens such as type1 autoimmune pancreatitis ( igg4-related aip ) , compared with igg4-related sialadenitis / dacryoadenitis ( mikulicz 's disease ) and igg4-related kidney disease . \n although the diagnostic criteria covering all igg4-rd are hard to be established , combination with the cdc and organ - specific diagnostic criteria should improve sensitivity .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: an extracellular electrode placed in the brain measures the mean extracellular field potential , comprised of the aggregate electrical activity generated by various neural processes in a cell ensemble around the electrode tip ( figure 1a ) . for instance , the high frequency range ( from 0.61 to 3 khz ) of this signal has been estimated to carry a signature of the spiking activity of up to a few thousand cells located as far as 140300 m away ( e.g. gray et al . \n , 1995 ; henze et al . , 2000 ; logothetis , 2003 , 2008 ) . \n it is referred to as multi - unit ( mu ) activity and can be seen as reflecting the output of a local neural population . \n ( a ) an extracellular electrode placed in the brain measures the mean extracellular field potential , an aggregate signal originating from the population of neurons in the vicinity of the electrode tip . to obtain multi - unit spiking activity \n , the recorded voltage trace is high - pass filtered and individual action potentials are detected ( top ) . \n the local field potential ( lfp ) is comprised of the low frequency components of the extracellular field potential up to 200 hz ( bottom ) . its frequency composition varies over time . in the example shown here , \n prominent oscillations in the frequency band between 30 and 90 hz called the gamma - band are visible during the later part of the trace . \n ( b ) in primary visual cortex of awake primates , oscillations in the gamma - band of the local field potential are dominant during visual stimulation , as illustrated in the example . \n the raw signal ( black ) has been filtered in the gamma frequency range to obtain the gamma lfp ( grey ) . in contrast , low frequency voltage fluctuations ( < 200 hz ) mirror a different aspect of neural mass action : the so - called local field potentials ( lfp ) are commonly thought to be related to the input of a neural ensemble and dendritic processing within the network . in line with this reasoning , \n it is believed to measure primarily synchronized synaptic signals ( mitzdorf , 1985 , 1987 ) , subthreshold membrane oscillations ( kamondi et al . , 1998 ) and \n evidence supporting this hypothesis that the lfp reflects inputs and local processing comes from a study that showed that it is possible to predict the time course of the lfp in primary visual cortex from spikes in lgn but not vice versa ( calabrese et al . , under revision ) . while the lfp is used to study the neural processes underlying perception ( gail et al . \n , 2004 ; wilke et al . , 2006 ) , memory ( pesaran et al . , 2002 ) and attention ( fries et al . \n 2005 ) , the mechanism underlying its generation and its precise spatial resolution is not yet well known . \n a more detailed understanding of the relationship of the lfp to the spiking activity of neural populations is essential for many applications : first , oscillations in brain activity as measured by the lfp might reflect a specific mode of neural computation . in this spirit \n , the extracranial counterpart of the lfp the electroencephalogram ( eeg ) has been used in research and medical applications for decades ( swartz and goldensohn , 1998 ) and oscillations in the eeg have been used as a marker of diverse cognitive states . linking these high - level diagnostic markers to distinct modes of neural processing will require an in - depth understanding of the lfp , as a mesoscale signal bridging the gap between eeg and neural activity ( whittingstall and logothetis , 2008 ) . \n second , the lfp is correlated with the blood - oxygen - level dependent signal ( bold ) as measured by fmri ( goense and logothetis , 2008 ; logothetis et al . , 2001 ; \n lfp and mu activity , are correlated with bold for short stimulation paradigms , they dissociate in the case of prolonged stimulation with the sustained oscillations of the lfp better predicting the time course of the bold signal . \n thus , understanding which features of neural population activity are measured via the lfp will help to elucidate the source of the bold signal ( logothetis , 2008 ) . \n in addition , the lfp is comparably easy to obtain and has been used successfully to control motor prosthesis ( mehring et al . , 2003 ; andersen et al . , \n . a better understanding of the mechanisms generating the lfp might allow for the construction of better prosthetic devices . \n in different brain areas , the lfp comes in widely different flavours . in the hippocampus , for instance \n they are believed to be critical for temporal coding of information and synaptic plasticity in these circuits ( buzsaki , 2002 ) , as well as hippocampal cortical interactions ( siapas et al . \n in awake primates , sensorimotor regions of the cortex exhibit pronounced oscillations in the beta frequency band between 15 and 30 hz related to motor preparation and planning ( sanes and donoghue , 1993 ; scherberger et al . , 2005 ) . \n finally , in primary visual cortex of awake primates fast oscillations in the gamma - band between 30 and 90 hz are dominant during visual stimulation ( figure 1b , e.g. berens et al . , 2008 ; frien et al . , 2000 ) . in this review , we will focus exclusively on the latter and describe what the feature selectivity of lfp gamma - oscillations in primary visual cortex can teach us about the spatial extent of the network activity they resemble . \n in the absence of visual stimulation , the lfp in the primary visual cortex of awake macaques is dominated by slow fluctuations ( figure 2a ) , such that the power in low frequencies dominates the frequency spectrum ( figure 2b ; e.g. berens et al . , 2008 ; henrie and shapley , 2005 ; juergens et al . , 1999 ; young et al . , 1992 ) . \n this frequency dependence of the lfp power spectrum is not due to a frequency dependence of the impedance spectrum of the cortical tissue ( logothetis et al . , 2007 ) , although the morphology of neural dendrites might result in a low - pass filtering effect on neural signals ( pettersen and einevoll , 2008 ; see below ) . \n dominant fast oscillations in the gamma - band ( 3090 hz ) emerge during visual stimulation ( figure 2a ) and , accordingly , a pronounced increase of the power in this band can be observed ( figure 2c ) . \n interestingly , spikes of single neurons occur preferentially at the trough of these oscillations ( phase locking , berens et al . \n , 2006 ; ray et al . , 2008a ) and the gamma - power is the single most relevant feature for the prediction of spike density functions from the lfp ( rasch et al . \n a similar result has also been obtained in cat area 17 , where the coupling between spikes and lfp under visual stimulation as measured by the frequency dependent spike - field coherence is also highest in the gamma - band ( siegel , 2003 ) . \n lfp gamma - power thus might originate from processes that are intimately linked to the spiking of local populations of cortical neurons and , as gamma - oscillations occur predominantly during visual stimulation , they possibly reflect ongoing computations in these networks . \n ( a ) exemplar raw traces showing the lfp during a typical trial . before the onset of stimulation , \n ( c ) typical power spectra of the lfp during visual stimulation with two gratings of different orientation ( differing colours ) . a pronounced power increase in the gamma - band \n is observed . in particular , this increase depends in strength on the orientation of the visual stimulus . \n all displays in this figure were adapted from ( berens et al . , 2008 ) . while for spiking activity relatively precise estimates of the volume from which spikes are recorded are available ( gray et al . , 1995 ; henze et al . , 2000 \n ; logothetis , 2003 , 2008 ) , the exact spatial extent of the neural population contributing to the lfp as an aggregate signal is yet unknown and evidence remains somewhat inconclusive . \n estimates based on spectral coherence between simultaneously recorded sites ( goense and logothetis , 2008 ; juergens et al . , \n 1999 ) or current - source density analysis ( mitzdorf , 1987 ) range from 500 m up to 3 mm . \n recently , goense and logothetis ( 2008 ) have used reverse correlation with small circular gratings to determine the spatial summation properties of the lfp signal and found them to be very similar to those of the mu activity . \n a recent study has tried to predict the lfp time course from the spiking activity of mu activity and has found that taking sites from up to 1 mm away into account can significantly improve the reconstruction accuracy ( calabrese et al . \n the question of spatial resolution , however , is crucial : far reaching lfp coherence between sites , in particular in the gamma - band , has been interpreted as a hallmark of synchronization of distant cortical populations ( engel et al . , 2001 ) . to unambiguously attribute these findings to synchronization \n it is mandatory to have a precise estimate of the extent of the network contributing to the lfp gamma - band . \n while the complexity of network interactions prevents to study this question with current methodology directly , it can be approached indirectly by studying selectivity of the lfp to features of the visual stimulus and comparing it to the selectivity of mu activity ( berens et al . , 2008 ) . \n the feature selectivity of local groups of neurons such as measured by mu activity has been mapped extensively especially in primary visual cortex and for many features the spatial organization of mu preferences is well known ( e.g. bartfeld and grinvald , 1992 ; blasdel , 1992a , b ; hubel and wiesel , 1968 , 1974 ; lund et al . , 2003 ; ringach et al . , \n one extensively studied feature of neurons in visual cortical areas is their orientation tuning . in primary visual cortex , most mu sites respond with an elevated firing rate to bars or gratings of a certain orientation ( hubel and wiesel , 1968 ; ringach et al . , 2002 ) and show a gaussian - like tuning profile around this preferred orientation . \n it is natural to ask whether this important characteristic of neurons in v1 is also present in the gamma - band of the lfp recorded in this area . in our study ( berens et al . , 2008 ) , we find that indeed the lfp gamma - power increases in a stimulus specific manner during visual stimulation with an oriented grating ( figure 2c ) . furthermore , its selectivity for stimulus orientation was stronger for the gamma - band in comparison to any other frequency band of the lfp ( figure 3a , grey shaded region ) . \n nevertheless , even this most strongly tuned lfp band is less selective for orientation than mu activity measured simultaneously at the same site ( figure 3b ; berens et al . , 2008 ; frien et al . , 2000 ) . \n ( a ) mean orientation selectivity of the power in a frequency band of the local field potential of a population of recording sites ( open circles ) and a trial shuffled version for comparison ( open squares ) . \n the most prominent orientation selectivity is found in the gamma - band ( grey shading ) around 55 hz . \n ( b ) comparison of the mean orientation selectivity of the gamma - band of the lfp and mu activity recorded simultaneously from the same electrode . although the most selective lfp band was chosen , mu selectivity is on average still significantly higher , as indicated by the dark cross . \n distribution of differences in preferred orientation for simultaneously recorded lfp gamma - band and mu activity . \n while a large fraction of sites shows good agreement between the two , in a considerable amount of sites the preferred orientations of the two signals differ by more than 60. dark grey ( < 20 difference ) and light grey ( > 60 difference ) indicate sites used for figure 3e . \n the inset shows the orientation tuning functions of two exemplar sites , with lfp ( light grey ) and mu ( dark grey ) tuning functions overlaid . in the site shown on the left , both preferred orientations are close to each other while in the site shown on the right they are nearly 90 apart . \n the ocularity index measures how strongly the activity at a site is modulated by the eye of stimulation . \n ocularity indices of the mu activity are significantly stronger than those of the lfp gamma - band , but they are correlated well . \n ( e ) histogram of orientation selectivity index computed separately for sites with close ( dark grey ) and far away ( light grey ) preferred orientations [ sites as in ( c ) ] . \n arrows indicate the respective medians . on average , sites where the preferred orientation of the lfp gamma - band agrees well with that of the mu have higher orientation selectivity than the others . \n ( f ) average difference in gamma - power ( 25100 hz ) between the spectrum during stimulus presentation and baseline ( mean sem ) as a function of the diameter of the grating ( black line ) or the grating annulus ( grey line ) that was used for stimulation . for gratings , \n the gamma - power increases as a function of stimulus diameter . in the case of annuli , \n this alone was not sufficient to elicit pronounced gamma - oscillations . for experimental details regarding this panel , \n panels ( a e ) in this figure were adapted from berens et al . \n ( 2008 ) and data for panel ( f ) was provided by gieselmann and thiele ( 2008 ) . to further compare the feature selectivity of the two signals \n , we also mapped out orientation tuning curves of the average lfp power in the gamma - band and the corresponding mu spiking responses ( figure 3c , insets ) . \n interestingly , at some sites the preferred orientations of both signals agreed well while at others they did not , and differences in preferred orientation were widely distributed ( figure 3c ) . \n the overall correlation between preferred orientations obtained from the gamma - band of the lfp and the mu activity recorded simultaneously was surprisingly low ( 0.2 ; berens et al . , 2008 ) . \n ocular dominance columns are a second dominant organizational feature of primary visual cortex and typically cover slabs of about 500 m in diameter ( blasdel , 1992a ; hubel and wiesel , 1968 , 1977 ) . by selectively presenting stimuli to one eye \n only , we showed that the correlation between the ocular preferences of the mu activity and those of the lfp gamma - power are much better correlated ( figure 3d , 0.6 ; berens et al . , 2008 ) . why are the preferred orientations of mu activity and lfp gamma - band power only poorly correlated , while their ocular preferences are well correlated ? \n orientation tuning of spiking activity is organized at a very fine spatial scale in macaque v1 , where orientation columns span about 50 m ( hubel and wiesel , 1968 , 1974 , 1977 ) . \n ocular dominance columns on the other hand extend over about an order of magnitude more ( blasdel , 1992a ; hubel and wiesel , 1968 , 1977 ) . \n the fact that the preferred orientations of mu activity and the lfp gamma - band are not well correlated but ocular dominance properties are , suggests that the lfp gamma - band integrates signals over an area much larger than the size of orientation columns in v1 . \n we therefore conjecture that the gamma - band of the lfp reflects signals integrated from an area spanning at least 500800 m in diameter . according to our reasoning , the difference in correlation between the two signals for orientation and ocularity tuning is due to the scale of spatial integration . \n a critical test of this hypothesis is that the preferred orientation of the lfp should be close to that of the mu activity when the local neighbourhood of the recording location is comparably homogenous in preferred orientations , such as in linear zones , and differing from it in nonhomogenous parts of the orientation map . \n while our data did not allow us to test this hypothesis directly , we conjectured that if our reasoning was valid , homogenous zones should be characterized by higher lfp orientation selectivity than nonhomogenous zones ( nauhaus et al . , \n indeed , we found that the orientation selectivity of sites at which the preferred orientations of mu activity and lfp gamma - band power were close was higher than the selectivity of sites at which preferred orientations differed significantly ( figure 3e ) . \n in addition to differences in their orientation tuning , the gamma - band of the lfp and mu activity show different surround suppression characteristics ( gieselmann and thiele , 2008 ) . \n mu activity was typically maximal when the grating used for stimulation just covered its classical receptive field ( crf ) , and decreased when it was enlarged further . the gamma - power of the lfp , however , increased with grating size beyond the crf ( figure 3f , black line ) . \n the maximal oscillatory drive contributing to the lfp power occurred when stimuli covered approximately an area of 1 in diameter . converting this via the cortical magnification factor to cortical distance , \n gieselmann and thiele concluded that the gamma - band of the lfp integrates sources as far as 0.61.2 mm away from the electrode tip . \n interestingly , stimulation of the surround alone was not sufficient to evoke gamma - oscillations ( figure 3f , grey line ) . \n feature selectivity can , however , also inform hypotheses regarding other aspects of the underlying mechanisms generating the lfp . \n first , when we analysed how the correlation between the preferred orientations of mu activity and lfp power changed as a function of frequency band , we found that it increased from its initial low values in the gamma - band to saturate over 150 hz at 0.8 ( keep in mind , however , that less sites are tuned over all in these bands and mean selectivity is lower than in the gamma - band ; figure 3a ) , similar to findings from primary auditory cortex ( kayser et al . , 2007 ) , \n area mt ( liu and newsome , 2006 ) and somatosensory cortex ( ray et al . , 2008b ) . \n similarly , in a study using more naturalistic stimuli , such as movies , the high frequency regime at frequencies above 70 hz carried information about the stimulus which was very similar to mu activity , i.e. the two signals showed high signal correlations ( belitski et al . , 2008 ) . \n at lower frequencies , like those found to be most tuned to orientation in our study , this correlation was substantially weaker . \n similarly , for the prediction of spike times from the lfp features in the high gamma - band above 60 hz are most useful ( rasch et al . , 2008 ) . \n together , these findings point towards the hypothesis that the spatial extent of neural processes contributing to the lfp may be frequency dependent ( see below ) . \n second , it is yet unclear how different cell types contribute to the gamma - band power . \n the latter is increased by enhancing the contrast of the stimulus ( henrie and shapley , 2005 ) . \n in particular , while many neurons show pronounced saturation in their firing rate at high contrasts , the gamma - power can still increase beyond this saturation point . \n in addition , as mentioned above , enlarged stimulus size can enhance gamma - power even beyond a point where mu activity is starting to be inhibited ( figure 3f ; gieselmann and thiele , 2008 ) . \n enlarging the stimulus beyond the crf of the spiking responses or enhancing stimulus contrast activates interneuron networks more strongly ( angelucci et al . , 2002 ) , leading to the observed dissociations between spiking and lfp activity . \n these findings therefore hint towards an important role of inhibitory interneurons ( see below ) . \n the lfp is commonly thought to originate from a weighted average over potential changes in the vicinity of the electrode tip , generated by current sinks and sources in extracellular space ( as reviewed by goense and logothetis , 2008 ; logothetis , 2003 , 2008 ) . \n these are generated , for instance , when synchronous excitatory synaptic input activates the dendrites of a neuron , leading to a current sink at the dendrite and a source at the soma ( figure 4a ; mitzdorf , 1985 ) . \n the resulting dipole contributes to the measured lfp depending on the arrangement of the generating cell with respect to the local population . \n for example , pyramidal cells have large dendritic arbours facing in one direction opposing their somata and their dendrites are neatly aligned with each other ( a so - called \n open field arrangement ( johnston and wu , 1995 ; mitzdorf , 1985 ) . \n therefore , dendritic processes on pyramidal cells in the cortex are thought to contribute strongly to the lfp , as potential differences from the local network do not cancel each other due to their geometrical arrangement ( figure 4b ) . \n dipoles generated by the spiking activity itself are much faster , however , and therefore do not directly add to the lfp power . while it was originally thought that excitatory postsynaptic potentials form the most important source of lfp generating dipoles ( mitzdorf , 1985 , 1987 ) , more recently also other sources such as inhibitory synaptic input ( hasenstaub et al . , 2005 ) , subthreshold membrane oscillations ( kamondi et al . , 1998 ) and afterpotentials of somatodendritic action potentials ( buzsaki , 2002 ) have been found to contribute significantly to the lfp . \n ( a ) illustration of a pyramidal cell , where the dendritic tree is shown schematically on the left , the cell body and axon on the right . \n a synaptic potential creates a current sink on the dendritic tree and a current - source at the soma . \n ( b ) pyramidal cells are aligned in a very stereotype fashion , with large dendritic arbours facing one direction and somata facing to the other . in this so - called open field arrangement , \n synchronized synaptic input creates strong dipoles , since currents flow from individual cells do not cancel each other . \n ( c ) illustration of the excitatory - inhibitory cortical network involved in the generation of gamma - oscillations . \n thalamic inputs activate populations of infragranular ( inf ) and supragranular and granular ( sup ) glutamergic cells , as well as gabaergic cells . \n inhibitory synapses are indicated by a square ( symbol ) , excitatory synapses by a circle ( symbol ) . adapted from logothetis ( 2008 ) . \n the extracellular space acts like a volume conductor , which can , in principle , carry electrical signals over large distances and whose resistance depends on the geometry and layout of the neurons ( johnston and wu , 1995 ; logothetis et al . , 2007 ) . \n the impedance of the cortical tissue has been found to be isotropic and independent of frequency ( logothetis et al . , 2007 ; ranck jr . , 1963 ) . \n while recent modelling work suggests that even in purely resistive extracellular medium frequency dependent attenuation can be caused by the dendritic morphology of the neurons ( pettersen and einevoll , 2008 ) , the specific shape of the lfp spectrum as shown in figure 2b likely also reflects underlying neural processes . \n oscillators contributing to the lfp at different frequencies are possibly generated by processes on varying scale and strength ( buzsaki and draguhn , 2004 ; logothetis et al . \n low frequency oscillations , on the one hand , are thought to be formed by global neuromodulatory inputs ( steriade , 2006 ) giving rise to strong slow oscillators . \n gamma - rhythms , on the other hand , most likely originate locally within cortical microcircuits consisting of pyramidal cells and interneurons ( fries et al . , 2007 ; logothetis , 2008 ) . \n experimentally , this has been shown to be the source of the gamma - oscillations in the hippocampus of rats ( csicsvari et al . , 2003 ) \n where pyramidal cells and interneurons form networks with a distinct spatial layout much like in cortical tissue . \n similarly , we postulate that such circuits in cortex get activated by thalamic input , as surround stimulation alone was not sufficient to evoke gamma - oscillations ( gieselmann and thiele , 2008 ) . \n recurrent processing loops between pyramidal neurons of layer 4 and 2/3 and interneurons then generate the pronounced gamma - oscillations observed during visual stimulation ( figure 4c ) . \n thus , while pyramidal neurons may be the strongest mediator of dipoles contributing to the lfp due to their size and geometry , interneurons play an important role in generating the dipoles underlying gamma - oscillations : they act as rhythm generators via rhythmic inhibition of pyramidal neurons and synchronized inhibitory synaptic potentials contribute significantly to the membrane oscillations on pyramidal neurons ( bartos et al . , 2007 ; fries et al . , 2007 ; hasenstaub et al . , 2005 \n this is in good agreement with the idea that enhanced gamma activity during high contrast or surround stimulation reflects increased interneuron drive ( see above ) . for a more detailed discussion of interneuron networks and their role for cortical gamma - oscillations , \n mazzoni et al . ( 2008 ) used a model network consisting of sparsely connected pyramidal and interneurons and simulated the generation of the lfp from excitatory and inhibitory synaptic currents . \n interestingly , this simple model reproduced quantitatively accurate the dependence of lfp gamma - power on stimulus contrast as well as the dependence of information content in different lfp bands measured under naturalistic stimulation . \n how exactly these active network processes on different scales interact with passive low - pass filtering properties due to dendritic morphology ( pettersen and einevoll , 2008 ) to form the signal measured as lfp is yet to be determined . \n if the gamma - band of the lfp originates in local cortical circuits as also revealed by reverse correlation with very localized stimuli ( goense and logothetis , 2008 ) , why is the spatial resolution apparently so much poorer compared to mu activity ? \n we postulate that this results from the interplay of two factors : first , strong oscillations especially like those present under visual stimulation can spread in the extracellular medium for considerable distances , as this acts as an isotropic frequency independent resistor ( logothetis et al . \n note , however , that this effect becomes only noticeable when large stimuli that excite extended networks of neurons are used ( see discussion of berens et al . , 2008 ) . \n second , the spatial extent of microcircuits oscillating in phase and thus the size of the oscillating dipole is determined by the spread of thalamic axon fields , the size of the dendritic arbours of cortical neurons and intracortical horizontal connections ( angelucci et al . , 2002 ; lund et al . , 2003 ) . \n this will lead to contributions to the lfp signal by tissue at considerable distance from the electrode tip , as for instance thalamic axons in upper layer 4 fan out to cover an area of up to 1.2 mm . \n in addition , the lfp also integrates subthreshold oscillations , which do not lead to spiking activity . in the cat visual cortex , these synaptic response fields \n have been shown to extent significantly beyond the region in which spiking activity was evoked ( bringuier et al . , 1999 ) . \n while the above arguments provide a strong indication that the spatial resolution of the lfp gamma - band parallel to the cortical surface is on the scale of 6001000 m , specificity across different layers might be much higher . \n recent evidence from rodent somatosensory and prefrontal cortex , however , suggests that this is not the case ( sirota et al . , 2008 ) . using multiple silicon probes , sirota et al . \n ( 2008 ) showed that gamma oscillators typically engage cortical circuits spanning several hundred micrometers . \n the spatial resolution of the lfp is not only determined by the electric properties of the neural tissue and the spatial extent of the biophysical processes contributing to the lfp , but is also affected by properties of the recording apparatus such as electrode type , material and impedance as well as the exposed area at the electrode tip or the position of the reference electrode . \n the specific processes contributing to the different parts of the gamma - band spectrum , however , are yet unknown . \n our study ( berens et al . , 2008 ) shows that the feature selectivity of mu activity and the gamma - band of the lfp can differ substantially , as in the case of orientation tuning . for other features , such as ocular dominance , \n since these two features are organized on spatial scales differing by approximately one order of magnitude , the spatial resolution of the lfp can likely explain this discrepancy . \n in good agreement with other studies ( gieselmann and thiele , 2008 ) , we estimate the spatial resolution of the gamma - band of the lfp parallel to the cortical surface to be 6001000 m . \n gamma - oscillations in the lfp most likely arise in cortical networks of pyramidal and interneurons , when activated by thalamic stimulation , and are mediated by synchronized synaptic potentials impinging on pyramidal neurons . \n results on the feature selectivity of the lfp ( gieselmann and thiele , 2008 ; henrie and shapley , 2005 ) as well as direct measurement ( hasenstaub et al . , 2005 ) indicate an important contribution from interneurons as well . to precisely determine the aspects of neural mass action reflected in the gamma - band of the lfp will require an increased effort on many levels : important insight into the relevant subpopulation of neurons and receptors can be achieved through the adaptation of recently developed genetic tools that allow the selective manipulation of specific cell types and channels ( aronoff and petersen , 2008 ) \n . further , detailed reconstruction of neural circuits ( briggman and denk , 2006 ) in combination with biophysical modelling ( linden et al . \n , 2008 ; mazzoni et al . , 2008 ; pettersen and einevoll , 2008 ) might lead to a better understanding of which features of the anatomical layout are important for the generation and localization of lfp gamma - band oscillations . \n last , monitoring the activity on the dendrites and somata of many neurons in parallel using novel two - photon techniques might allow direct measurements of the voltage fluctuations recorded as the lfp ( reddy et al . , 2008 ) . \n the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .", "role": "user" }, { "content": "extracellular voltage fluctuations ( local field potentials , lfps ) reflecting neural mass action are ubiquitous across species and brain regions . \n numerous studies have characterized the properties of lfp signals in the cortex to study sensory and motor computations as well as cognitive processes like attention , perception and memory . \n in addition , its extracranial counterpart \n the electroencephalogram is widely used in clinical applications . \n however , the link between lfp signals and the underlying activity of local populations of neurons remains largely elusive . here , we review recent work elucidating the relationship between spiking activity of local neural populations and lfp signals . \n we focus on oscillations in the gamma - band ( 3090 hz ) of the lfp in the primary visual cortex ( v1 ) of the macaque that dominate during visual stimulation . given that in area v1 \n much is known about the properties of single neurons and the cortical architecture , it provides an excellent opportunity to study the mechanisms underlying the generation of the lfp .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: stress is a reaction to particular challenging or threatening events and is an essential part of our daily life . \n stress increases our focus and alertness in order to cope with these situations and to prepare for similar future occasions . \n a little stress is therefore beneficial , but too much chronic , low - level stress can have rather deleterious consequences and is a major risk factor for mental diseases such as depression ( e.g. brown et al . , 2004 ) . \n many studies have examined how stressful experiences modulate learning and memory ( jols et al . , 2006 ) . \n there is ample evidence that prolonged stress hampers learning and memory processes in humans and rodents ( lupien et al . , 2009 ) . \n numerous studies show that ( prolonged ) exposure to mild stressors reduces hippocampal long - term potentiation ( ltp ) and facilitates long - term depression ( ltd ) ( artola et al . , 2006 ; krugers et al . , 2006 ) , \n two forms of synaptic plasticity believed to underlie learning and memory . on the other hand \n there is profound evidence that stress can facilitate , and might even be essential for , good learning and memory performance in rodents ( oitzl and de kloet , 1992 ; sandi and rose , 1994 ; roozendaal and mcgaugh , 1996 ; sandi et al . , 1997 ; oitzl et al . , \n 2001 ) . such , memory enhancing effects of stress have also been reported in humans ( lupien et al . \n stress and stress hormones mainly facilitate learning and memory processes when stress is experienced in the context and around the time of the event that needs to be remembered ( jols et al . , 2006 ) . \n moreover , stress - hormones facilitate memory consolidation ( sandi and rose , 1994 ; oitzl et al . , 2001 ) , but suppress the retrieval of already stored information ( roozendaal et al . , 2009 ) . \n other factors that may play a role in the opposite effects of stress on memory are duration of stress ( prolonged versus acute ) as well as magnitude of stress ( alfarez et al . , 2006 ; jols et al . , \n 2006 ) . identifying the molecular and cellular mechanisms how stress enhances learning and memory and synaptic function \n recent studies have shown that hormones that are released during stress like norepinephrine and corticosteroids enhance hippocampal synaptic efficiency by differentially affecting ampa receptor function . \n norepinephrine and corticosterone rapidly but transiently affect ampa receptor trafficking ( hu et al . , 2007 ; \n in addition , glucocorticoids can also persistently modulate ampa receptor dynamics ( groc et al . \n in this perspectives article we discuss these recently identified mechanisms and propose a new model in which these hormones via their effects on ampa receptors promote synaptic efficiency and facilitate learning and memory processes . \n the influence of stress hormones on ampa receptor trafficking might reshape our thinking about the basic machinery regulation plasticity at synapses . \n in our daily lives we face many emotionally arousing experiences that can range from small displeasures to major life events such as accidents or loss of relatives . \n one important function of stress is to induce long - term adaptive responses . enhanced memory for stressful events is such a well - known highly adaptive phenomenon that helps to remember important information . \n exposure to stressful events activates multiple hormonal and neurotransmitter systems ( jols and baram , 2009 ) . \n many of these systems have been reported to modulate memory processes , such as the corticotropin - releasing factor ( crf ) ( blank et al . , 2003 ) . \n being aware of this , we focus in this perspectives article on the roles of norepinephrine and corticosteroid hormones . during exposure to emotionally arousing events , norepinephrine ( ne ) is rapidly released in the brain by neurons that originate from the locus coeruleus ( figure 1 ) . \n the major targets of these projections include the hippocampus , prefrontal cortex , and amygdala which are critical for learning and memory ( jols et al . , 2006 ) . \n exposure to arousing events also activates the hypothalamo - pituitary - adrenal ( hpa)-axis which results in a slower increased release of corticosterone ( in most rodents ) or cortisol ( humans ) from the adrenal glands ( figure 1 ) . \n these hormones enter the brain and bind to two subtypes of discretely localized receptors , the mineralocorticoid receptor ( mr ) and glucocorticoid receptor ( gr ) . \n mrs are occupied when hormone levels are low and exert their effects classically via the genome ( de kloet et al . , 2005 ) . \n recent evidence shows that corticosteroid hormones can also exert rapid non - genomic effects via mrs ( karst et al . , 2005 ) . \n in this way mrs could play a critical role during the initial phase of the stress response . \n grs have a 10-fold lower affinity for corticosterone , become activated when hormone levels rise after stress and slowly exert genomic actions in the hippocampus ( de kloet et al . , 2005 ; jols et al . , \n both mrs and grs are localized in regions that are critical for memory formation such as hippocampus , amygdala , and prefrontal cortex . \n exposure to a fearful event rapidly activates the autonomic nervous system and enhances norepinephrine levels in the brain . at the same time \n the hypothalamo pituitary - adrenal ( hpa ) axis is activated which causes a slow increase in plasma corticosterone levels . \n these hormones act via their receptors , which are present in regions that are critical for memory formation such as hippocampus , amygdala , and prefrontal cortex , to promote memory consolidation . for details see text . \n norepinephrine and corticosteroid hormones , via their receptors , play an important role in the memory enhancing effects of stress . \n ne enhances memory formation of emotional events via the brain -adrenergic receptors ( -ars ) both in humans and rodents : post - training application of norepinephrine or -ars agonists promotes memory consolidation in different memory tasks such as inhibitory avoidance task , fear conditioning and in morris water - maze learning ( hu et al . \n activation of -adrenergic receptors also enhances memory , presumably by enhancing the actions of -adrenergic actions ( ferry et al . \n corticosteroid hormones , via mrs have been implicated in the appraisal process and the onset of the stress response . via grs , these hormones promote long - term consolidation of information ( de kloet et al . , 1999 ; roozendaal et al . , \n accordingly , a point mutation in the mouse gr , which selectively prevents genomic actions , impairs spatial memory performance ( oitzl et al . , 2001 ) . \n importantly , recent literature suggests that both corticosteroids and norepinephrine work in concert for optimal memory performance both in humans and rodents ( de quervain et al . , 2009 ; \n thus , noradrenergic activation is essential for the memory enhancing effects and glucocorticoids play a permissive role in noradrenergic actions thereby promoting memory formation ( roozendaal et al . , 2009 ) . \n the basolateral complex of the amygdala ( bla ) is an important target for norepinephrine and corticosteroid hormones to facilitate memory for emotional events . \n several studies suggest that hormonal changes in bla - activity modulate memory consolidation by influencing plasticity in other brain regions that are critical for memory consolidation such as hippocampus and prefrontal cortex ( roozendaal et al . , 2009 ) . \n this way , stress - hormones via the bla can modulate different types ( e.g. spatial ) memory consolidation \n . however , norepinephrine and corticosteroid hormones can also influence hippocampal synaptic plasticity independent of bla - input ( karst and jols , 2005 ; wiegert et al . , 2006 ; hu et al . \n , 2007 ; martin et al . , 2009 ) . hormonal regulation of hippocampal - dependent learning and memory processes therefore likely occurs via direct or indirect ( via bla ) hormonal effects on hippocampal plasticity . \n the cellular mechanisms via which ne and corticosterone facilitate learning and memory processes remain largely unknown . via activation of -ars , ne can activate pka and camkii ( wang et al . , 2004 ; hu et al . , 2007 ) . in agreement with their memory enhancing effects , \n ne , via activation of -ars promotes the induction of hippocampal long - term potentiation ( ltp ) ( winder et al . \n corticosterone has been reported to rapidly increase hippocampal glutamate release probability ( karst et al . , 2005 ) and at the same time \n rapidly promotes the induction of hippocampal ltp ( wiegert et al . , 2006 ) . \n however , corticosterone is best known for it 's slowly and prolonged effects via the genomic pathway . upon activation , gr translocate to the nucleus and \n modify transcription of responsive genes , either through dna binding of homodimers or through protein \n protein interactions with other transcription factors ( de kloet et al . , 2005 ; jols et al . , \n , neurons induce slow but persistent changes in protein expression and facilitate cell physiology changes over the time course of hours ( morsink et al . , \n consistently , gr activation , via transcriptional regulation and the mitogen - activated protein kinase ( mapk ) signaling pathway appears to be critically involved in the memory enhancement of contextual information by corticosteroid hormones ( revest et al . , 2005 ) . despite these studies on second messenger systems that are modulated by stress hormones in parallel to their memory enhancing effects , \n our understanding of a molecular mechanism that can explain the memory enhancing effects of stress hormones is very limited . \n while glucocorticoids enhance the excitability of principal bla cells by increasing their intrinsic excitability and decreasing the impact of gaba(a ) inhibitory postsynaptic potentials ( ipsps ) ( duvarci and par , 2007 ) , recent findings indicate that hippocampal excitatory synapses are directly targeted by stress hormones ( karst and jols , 2005 ; hu et al . , 2007 ; \n we hypothesize that these stress - induced alterations in glutamatergic hippocampal synapses may explain at least in part how stress facilitates hippocampus - dependent learning and memory processes . \n synaptic plasticity at excitatory synapses is thought to be critical for information processing in the brain and to underlie many complex behaviors such as learning and memory . \n the best - studied forms of synaptic plasticity are long - term potentiation ( ltp ) and long - term depression ( ltd ) of excitatory synaptic transmission ( malinow and malenka , 2002 ; bredt and nicoll , 2003 ) . \n ltp involves the activity - dependent recruitment of ampa receptors to the postsynaptic membrane and a concurrent increase in ampa - mediated transmission whereas ltd reflects a decrease in synaptic ampa receptor function . \n the number and subunit compositions of synaptic ampa receptors are carefully regulated in order to modify synaptic strength during plasticity ( shepherd and huganir , 2007 ) . \n although concentrated at the postsynaptic membrane , ampa receptors are not static components of excitatory synapses . instead , \n surface ampa receptors are highly dynamic they are continuously delivered and removed in and out of synapses in response to neuronal activity . \n some synaptic membrane receptors can exchange with extrasynaptic receptors even in tens of milliseconds thereby underpinning the potential role of these receptors in tuning synaptic transmission ( heine et al . , \n ampa receptors are composed of four types of subunits , designated as glur1 ( glua1 ) , glur2 ( glua2 ) , glur3 ( glua3 ) , and glur4 ( glua4 ) , which combine to form tetramers . \n the subunit composition of ampa receptors has been proposed to dictate the mode of ampa receptor trafficking and their biophysical properties ( cull - candy et al . , 2006 ) . \n in the mature hippocampus , most ampa receptors are heterotetrameric , consisting of symmetric dimer of dimers of glur2 and either glur1 or glur3 ( song and huganir , 2002 ; mayer , 2005 ) . \n the leading model for constitutive and activity - dependent ampa receptor trafficking is that basal synaptic transmission is primarily mediated by glur2/3 heteromers , which undergo constitutive cycling into and out of synapses ( malinow and malenka , 2002 ) . \n however , a recent study suggests that 80% of synaptic ampa receptors in the hippocampus are glur1/2 heteromers , and most of the remaining receptors are glur2/3 heteromers ( lu et al . , 2009 ) . \n studies using overexpression of glur1 in ca1 pyramidal cells reveal that synaptic insertion of glur1 homomeric receptors is activity - dependent and can be elicited by ltp - inducing stimuli ( hayashi et al . , 2000 ) . \n likewise , heteromeric glur1/2 receptors are also synaptically inserted during plasticity ( shi et al . , 2001 ; kessels and malinow , 2009 ) . \n thus , activity dependent ( and ltp - induced ) delivery of ampa receptors is believed to depend on the glur1 subunit ( kessels and malinow , 2009 ) . \n whether ltp increases synaptic incorporation of endogenous ampa receptors that consist of homomeric glur1/1 receptors ( plant et al . , 2006 ) remains to be verified ( adesnik and nicoll , 2007 ) . \n once arrived at synapses , glur1/2 heteromers are believed to be gradually replaced by the cycling glur2/3 heteromers after ltp induction ( shi et al . \n multiple biochemical pathways can regulate the trafficking of synaptic receptors ( sheng and kim , 2002 ; kennedy et al . , 2005 ) . \n recent studies demonstrate that ampa receptor trafficking is regulated by both exocytotic and endocytotic processes and by their surface lateral diffusion in the plasma membrane ( choquet and triller , 2003 ; kennedy and ehlers , 2006 ; shepherd and huganir , 2007 ; newpher and ehlers , 2008 ) . \n both glur1/2 and glur2/3 containing ampa receptors are formed in the endoplasmic reticulum , move to the golgi compartment where they become glycosylated and traffic to the postsynaptic membrane were they are anchored by pdz - domain - containing scaffolding proteins ( kennedy and ehlers , 2006 ; sheng and hoogenraad , 2007 ) . \n although , the precise molecular mechanisms that govern synaptic ampa receptor incorporation remains unknown , recent findings shed new light on the underlying cellular processes . \n first , it was shown that endocytosis is important for the number of ampa receptors at the membrane surface and recycling endosomes supply ampa receptors for ltp ( park et al . , 2004 ) . \n recent evidence suggests that receptor recycling from postsynaptic endocytic zones which are adjacent to the postsynaptic density is crucial for maintaining a mobile population of surface ampa receptors that can be synaptically inserted to increase synaptic strength ( blanpied et al . , 2003 ; lu et al . \n second , although all ampa receptor subunits contain pdz - binding motifs , they interact with specific synaptic scaffold proteins ( bredt and nicoll , 2003 ; kim and sheng , 2004 ) . \n these synaptic scaffold proteins are thought to specifically regulate the synaptic clustering of different ampa - type receptor and participate in their specific dynamic exocytosis , endocytosis and surface trafficking routes ( kennedy et al . \n other synaptic proteins required for the trafficking of ampa receptors are stargazin and its related family of transmembrane ampa receptor regulatory proteins ( tarps ) ( nicoll et al . , 2006 ) and the recently identified mammalian cornichon homolog ( cnih ) family of small transmembrane proteins ( schwenk et al . , 2009 ) . \n third , several studies show that ltp - dependent trafficking of glur1 containing ampa receptors is strictly controlled by postsynaptic signaling pathways . \n phosphorylation of glur1 at serine 818 ( s818 ) by pkc is a critical event in the plasticity - driven synaptic incorporation of ampa receptors ( boehm et al . , 2006 ) , while phosphorylation of s831 by camkii and protein kinase c ( pkc ) and phosphorylation of s845 by camp - dependent protein kinase ( pka ) affects the open - channel probability of the receptor but may also regulate the synaptic incorporation of ampa receptor on the surface ( esteban et al . , 2003 ) . \n recently , it was found that pkc phosphorylation of the serine 816 ( s816 ) and s818 residues of glur1 enhanced binding of an actin - binding protein 4.1n to glur1 , facilitates extrasynaptic glur1 insertion and is critical for expression of ltp ( lin et al . , 2009 ) . \n importantly , genetically modified mice with knock - in mutations that block glur1 phosphorylation , show that s831 and s845 are critical for synaptic plasticity and memory ( lee et al . , 2003 ) . \n in agreement , mice lacking the glur1 subunit express deficits in short - term working memory ( reisel et al . , 2002 ) . \n glur2-containing ampar are almost impermeable for ca , caused by their editing ( sommer et al . , 1991 ; cull - candy et al . \n a number of studies suggest that this subunit dictates the removal of ampa receptors from the synapse during ltd ( bredt and nicoll , 2003 ) and controls recycling and degradation of ampa receptors after internalization ( lee et al . , 2004 ) . \n the clathrin adaptor ap2 which is critical for endocytosis may be relevant in this respect since it specifically binds to glur2 . \n recent work demonstrates a role for the extracellular domain of glur2 in promoting spine and synapse formation ( passafaro et al . \n . moreover , the glur2 subunit also has behaviorally relevance since spatial memory is hampered in mice with a forebrain specific loss of glur2 ( shimshek et al . , 2006 ) . \n evidence is accumulating that stress hormones like norepinephrine and glucocorticoids affect various aspects of ampa receptor function . \n the nature of these effects indicates that they include both rapid non - genomic effects and slow genomic and protein synthesis dependent actions . \n first , norepinephrine ( ne ) which is released during the initial phase of the stress response induces phosphorylation of glur1 at s845/s831 ( hu et al . , 2007 ) . \n these non - genomic effects are rapidly induced , reversible and occur via activation of -ars and involve a pka and camkii - dependent mechanism ( hu et al . , 2007 ) . \n moreover , phosphorylation of glur1 at the s845/s831 site lowers the threshold for ltp , and facilitates emotional memory formation ( hu et al . , 2007 ) . \n , these hormones rapidly and reversibly ( via non - genomic actions ) increase miniature excitatory postsynaptic currents ( mepscs ) frequency presumably reflecting increased presynaptic release of glutamate ( karst et al . , \n 2005 ) and increase lateral diffusion of predominantly glur2 containing ampa receptors ( groc et al . , 2008 ) . \n at the same time mr activation promotes activity dependent synaptic increase in glur2 containing ampa receptors ( groc et al . , 2008 ) . \n thus , a concept emerges showing that norepinephrine and mr activation rapidly but transiently via non - genomic actions promote synaptic glur1/2-containing ampa receptors ( figure 2 ) . \n this might contribute to a rapid non - genomic enhanced induction of ltp by both ne and corticosterone as reported before ( wiegert et al . \n , 2006 ; hu et al . , 2007 ) . moreover , the increase in ampa receptor mediated synaptic transmission might be relevant for the memory enhancing effects of these stress hormones . \n associative fearful learning has been reported to drive glur1-containing ampa receptors to the membrane , which also underlies this form of learning ( rumpel et al . , 2005 ) and \n ne induced phosphorylation of glur1 promotes contextual fear conditioning ( hu et al . , 2007 ) . \n these studies are in agreement with behavioral studies in mutant mice showing that glur1-containing ampa receptors are relevant for short - term , but not necessarily long - term memory processes ( zamanillo et al . , 1999 ; \n differential effects of stress hormones on ampa receptor trafficking . during the initial phase after stress exposure when norepinephrine ( ne ) \n are rapidly and reversible released activation of -ars and corticosteroid hormones via mrs modulate synaptic function ; release probability , lateral diffusion , synaptic incorporation of glur1/2 containing ampa receptors , and ( threshold for ) ltp is enhanced . \n second , corticosteroid levels slowly rise , return to baseline , but these hormones can have persistent genomic actions via gr activation . via gr activation \n these hormones increase synaptic incorporation of glur2/3 containing ampa receptors , increase lateral diffusion , and suppress ltp . after the initial phase of a stressor , ne levels return to baseline and \n they no longer affect phosphorylation of ampa receptors and induction of ltp ( hu et al . , 2007 ) . \n however , plasma corticosterone levels still rise , and via slow genomic action can persistently affect neuronal function . via grs \n these hormones slowly increase synaptic incorporation , lateral diffusion and mobility of glur2 containing ampa receptors ( groc et al . \n , 2008 ; martin et al . , 2009 ) along with slowly increasing ampa receptor synaptic transmission ( karst and jols , 2005 ; martin et al . , 2009 ) . \n immunofluorescent studies demonstrate that corticosterone , via gr activation and in a protein synthesis dependent manner \n increases surface labeling of glur2 containing ampa receptors ( rather than changing glur1 levels ) . \n this suggests that glucocorticoids slowly via genomic effects enhances synaptic levels of glur2/3-containing receptors ( figure 2 ) . \n first , the exchange of glur1/2 ampa receptors with glur2/3 containing ampa receptors has been implicated in maintaining synaptic strength and thereby provides a possible mechanism how these hormones persistently increase synaptic strength ( shi et al . , \n second , glur2 containing ampa receptors have been reported to promote spine formation which might provide a long - term structural adaptation to increase the capacity to store information ( passafaro et al . , 2002 ; saglietti et al . , 2007 ) . \n third , after exposure to emotionally arousing events , via a mechanism that requires gr activation , the ability to induce ltp is reduced ( kim and diamond , 2002 ; wiegert et al . , 2005 ) . \n the precise mechanism(s ) underlying this suppressive effect may involve occlusion of synaptic plasticity ( alfarez et al . \n . an important functional implication could be that impairing ltp induction prevents the ability to overwrite network information . at the longer term \n the slow increase in synaptic glur2/3 levels induced by stress hormones might therefore promote memory consolidation ( shimshek et al . , 2006 ) , e.g. by increasing the number of synapses or altering synaptic properties ( passafaro et al . \n , 2002 ; isaac et al . , 2007 ; saglietti et al . , 2007 ) . \n first , norepinephrine ( ne ) which is released during the initial phase of the stress response induces phosphorylation of glur1 at s845/s831 ( hu et al . , 2007 ) . \n these non - genomic effects are rapidly induced , reversible and occur via activation of -ars and involve a pka and camkii - dependent mechanism ( hu et al . , 2007 ) . \n moreover , phosphorylation of glur1 at the s845/s831 site lowers the threshold for ltp , and facilitates emotional memory formation ( hu et al . , 2007 ) . during this initial phase \n , these hormones rapidly and reversibly ( via non - genomic actions ) increase miniature excitatory postsynaptic currents ( mepscs ) frequency presumably reflecting increased presynaptic release of glutamate ( karst et al . , 2005 ) and \n increase lateral diffusion of predominantly glur2 containing ampa receptors ( groc et al . , 2008 ) . at the same time \n mr activation promotes activity dependent synaptic increase in glur2 containing ampa receptors ( groc et al . , 2008 ) . \n thus , a concept emerges showing that norepinephrine and mr activation rapidly but transiently via non - genomic actions promote synaptic glur1/2-containing ampa receptors ( figure 2 ) . \n this might contribute to a rapid non - genomic enhanced induction of ltp by both ne and corticosterone as reported before ( wiegert et al . \n , 2006 ; hu et al . , 2007 ) . moreover , the increase in ampa receptor mediated synaptic transmission might be relevant for the memory enhancing effects of these stress hormones . \n associative fearful learning has been reported to drive glur1-containing ampa receptors to the membrane , which also underlies this form of learning ( rumpel et al . , 2005 ) and \n ne induced phosphorylation of glur1 promotes contextual fear conditioning ( hu et al . , 2007 ) . \n these studies are in agreement with behavioral studies in mutant mice showing that glur1-containing ampa receptors are relevant for short - term , but not necessarily long - term memory processes ( zamanillo et al . \n differential effects of stress hormones on ampa receptor trafficking . during the initial phase after stress exposure when norepinephrine ( ne ) \n are rapidly and reversible released activation of -ars and corticosteroid hormones via mrs modulate synaptic function ; release probability , lateral diffusion , synaptic incorporation of glur1/2 containing ampa receptors , and ( threshold for ) ltp is enhanced . \n second , corticosteroid levels slowly rise , return to baseline , but these hormones can have persistent genomic actions via gr activation . via gr activation \n these hormones increase synaptic incorporation of glur2/3 containing ampa receptors , increase lateral diffusion , and suppress ltp . \n after the initial phase of a stressor , ne levels return to baseline and they no longer affect phosphorylation of ampa receptors and induction of ltp ( hu et al . , 2007 ) . however , plasma corticosterone levels still rise , and via slow genomic action can persistently affect neuronal function . via grs \n these hormones slowly increase synaptic incorporation , lateral diffusion and mobility of glur2 containing ampa receptors ( groc et al . , 2008 ; martin et al . , \n 2009 ) along with slowly increasing ampa receptor synaptic transmission ( karst and jols , 2005 ; martin et al . , 2009 ) . \n immunofluorescent studies demonstrate that corticosterone , via gr activation and in a protein synthesis dependent manner \n increases surface labeling of glur2 containing ampa receptors ( rather than changing glur1 levels ) . \n this suggests that glucocorticoids slowly via genomic effects enhances synaptic levels of glur2/3-containing receptors ( figure 2 ) . \n first , the exchange of glur1/2 ampa receptors with glur2/3 containing ampa receptors has been implicated in maintaining synaptic strength and thereby provides a possible mechanism how these hormones persistently increase synaptic strength ( shi et al . , \n second , glur2 containing ampa receptors have been reported to promote spine formation which might provide a long - term structural adaptation to increase the capacity to store information ( passafaro et al . \n third , after exposure to emotionally arousing events , via a mechanism that requires gr activation , the ability to induce ltp is reduced ( kim and diamond , 2002 ; wiegert et al . , 2005 ) . \n the precise mechanism(s ) underlying this suppressive effect may involve occlusion of synaptic plasticity ( alfarez et al . \n , 2006 ; groc et al . , 2008 ) . an important functional implication could be that impairing ltp induction prevents the ability to overwrite network information . at the longer term \n the slow increase in synaptic glur2/3 levels induced by stress hormones might therefore promote memory consolidation ( shimshek et al . , 2006 ) , \n e.g. by increasing the number of synapses or altering synaptic properties ( passafaro et al . \n , 2002 ; isaac et al . , 2007 ; saglietti et al . , 2007 ) . \n recent findings indicate that stress hormones like norepinephrine and corticosterone both rapidly and slowly increase ampa receptors mediated synaptic transmission . here , we hypothesize that differential effects on ampa receptor trafficking may provide a cellular mechanism that underlies the memory enhancing effects of these hormones . \n the fast effects of the norepinephrine and corticosterone mediated increase of surface ampa receptor levels are most likely due to increased ampa receptor trafficking ( hu et al . \n an important question that remains to be addressed is what are the underlying molecular mechanisms ? \n pka appears to be involved in norepinephrine - induced trafficking of ampa receptors ( hu et al \n . , 2007 ) and mr activation rapidly ( via a non - genomic pathway ) alters mepsc frequency via the erk pathway ( olijslagers et al . , 2008 ) . \n however it remains to be investigated how mr activation alters lateral diffusion of ampa receptors as well as the activity - dependent increase in synaptic ampa receptors . \n important candidates that mediate these rapid effects are the second messengers involved in rapid phosphorylation of ampa receptors like pka , camkii or pkc . \n in addition , it remains to be addressed how corticosterone slowly increases synaptic ampa receptor levels . \n the 3-h delay in onset of gr - induced glur2 surface expression and the dependence on protein synthesis suggests a mechanism involving transcriptional regulation of gr - affected genes . \n it is tempting to speculate that gr activation alters genes encoding proteins involved in regulating glur2/3 delivery and/or membrane anchoring . \n on one hand , there are multiple potential candidates that could directly influence ampa receptor trafficking , including auxiliary subunits of ampa receptors , such as cnih and tarps ( nicoll et al . , 2006 ; \n schwenk et al . , 2009 ) , scaffolding proteins , such as pick1 and grip ( terashima et al . , 2004 \n ; lu and ziff , 2005 ) and trafficking regulators nsf and ap2 ( lee et al . , 2002 ; kastning et al . , 2007 ) . \n however , no effect was seen in total ap2 levels in corticosterone treated hippocampal neurons ( martin et al . , 2009 ) . \n on the other hand , there are probably even more candidate proteins and regulatory mechanism that could more indirectly effect ampa trafficking . for example , an increase in surface glur2/3 receptors could be achieved by slowing down endocytosis or increasing the recycling of internalized receptors by affecting the general trafficking machinery or one of the multiple synaptic signaling pathways . moreover , \n ampa receptor surface mobility is known to be regulated by several ca - dependent processes such as depolarization , glutamate treatment , and tetanic stimulation ( tardin et al . , 2003 ; \n groc et al . , 2004 ; newpher and ehlers , 2008 ; heine et al . , \n it is very well possible that changes in ca signals contributes to the described increase in glur2 surface mobilization . \n norepinephrine and corticosterone could regulate ca influx by modulating glutamate receptors or voltage - sensitive ca channel activity or affect downstream kinases and phosphates signalling ( bloodgood and sabatini , 2007 ) . \n importantly , corticosteroid hormones have been shown to be potent regulators of calcium channels and currents ( van gemert et al . , 2009 ) . \n it is also possible that corticosterone affects the diffusion barrier that normally limits ampa receptor diffusion in the membrane ( martin et al . , 2009 ) . \n some answers about the molecular mechanism behind the slow gr - induced glur2 surface expression may come from the several hundred recently identified gr - affected target genes in a micro array survey using corticosterone - treated hippocampal slices of rats ( morsink et al . , 2006 ) . under basal conditions \n the corticosterone - invoked increase in freely mobile glur2 facilitates recruitment and increases synaptic efficacy ( martin et al . , 2009 ) . in this way \n furthermore , it has been described that enhanced ampa receptor levels a few hours after corticosterone application occlude ltp ( groc et al . , 2008 ) . \n interestingly , corticosterone also facilitates nmda receptor - invoked endocytosis of both synaptic and extra - synaptic glur2 under conditions that weaken synaptic transmission ( martin et al . , 2009 ) . \n an important functional implication of these effects could be that corticosterone on the longer term accentuates synaptic efficacy ( martin et al . , 2009 ) . \n a behaviorally very relevant question is therefore how and whether ampa receptors mediate the memory enhancing effects of stress hormones like corticosterone and norepinephrine . \n studies using mice carrying mutations in the glur1 phosphorylation sites indicate that norepinephrine - regulated phosphorylation of glur1 facilitates emotional memory ( hu et al . , 2007 ) . \n additional studies using ampa receptors with deletion of functional glur2 and/or glur3 subunits will be required to establish whether and which ampa receptors are essential for stress ( hormone ) induced facilitation of learning and memory . \n temporal erasure of functional ampa receptors may reveal whether regulation of ampa receptor function is critical for stress - induced facilitation of acquisition of information , consolidation of information or both . \n finally , there are several different compounds that are released upon exposure to stress such as neurotransmitters ( e.g. norepinephrine ) , neuropeptides and steroid hormones ( e.g. corticosteroid hormones ) ( jols and baram , 2009 ) . functionally , these individual mediators may act together for optimal memory performance ( de quervain et al . , 2009 ; \n . therefore it will be extremely relevant to precisely examine whether and how different stress - mediators together affect ampa receptor function and modulate learning and memory processes . \n the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .", "role": "user" }, { "content": "humans and rodents retain memories for stressful events very well . \n the facilitated retention of these memories is normally very useful . \n however , in susceptible individuals a variety of pathological conditions may develop in which memories related to stressful events remain inappropriately present , such as in post - traumatic stress disorder . \n the memory enhancing effects of stress are mediated by hormones , such as norepinephrine and glucocorticoids which are released during stressful experiences . here \n we review recently identified molecular mechanisms that underlie the effects of stress hormones on synaptic efficacy and learning and memory . \n we discuss ampa receptors as major target for stress hormones and describe a model in which norepinephrine and glucocorticoids are able to strengthen and prolong different phases of stressful memories .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: thirty - six subjects , with kellgren - lawrence scale16 level ii or greater oa , as diagnosed by their independent referring physician , were recruited to participate in a study that was approved by the university of connecticut , office of research compliance , for use of subjects in research . \n each provided written informed consent to participate after the risks and benefits of the study were explained to them . \n participants were recruited through presentations and posted announcements within a university community and four ( two rural and two urban ) community senior centers , from june 2008 to december 2009 . \n enrollment criteria were described and 36 subjects volunteered for the study . a small number ( < 10 individuals ) contacted the investigators via telephone or in person at a senior center to review their suitability for enrollment but did not qualify , most commonly because their knee had not been examined radiographically . \n thirty - four community dwelling subjects , average age of 62 14 years , median grade oa = iii ( 23 women , 64.87 10.67 years and median grade oa = iii , and 11 men , 54.6 19.91 years and median grade oa = iii ) completed the study ; the distribution of severity by gender is reported in table 1 . \n two subjects ( one woman , one man ) were lost due to non - study related medical complications ( illness precluding travel to weekly meetings and elective total hip arthrosplasty due to increasingly severe hip pain respectively ) during the course of the study . \n neither of these two participants completed more than 2 weeks of treatment for the study . \n any potential subject was excluded if they had received either hyaluronic acid or corticosteroid injections to either knee within the past 6 months , or had a history of an adverse reaction to cold application or diminished sensation to heat or cold in the area of the knee . \n furthermore , all subjects were advised to not increase the use of nonsteroidal anti - inflammatory medication at any point in time during the study . \n all subjects were medically cleared for participation by a physician ( personal physician or orthopedic surgeon ) knowledgeable of the participant s medical history , severity of symptoms from oa and current health status . \n the physician was asked to grade the severity of oa of the most involved knee on a form describing each level of the kellgren - lawrence scale.16 all subjects demonstrated the ability to self - apply the water - circulating device and complete the assigned treatments and questionnaires as instructed by members of the research team . \n subjects met with a member of the investigational team for an orientation session in a university laboratory room or a senior center where they regularly attended community activities . \n once consent was obtained subjects were instructed in how to complete the knee injury and osteoarthritis outcome score ( koos ) self - report questionnaire and 10 cm visual pain scale . \n details regarding the koos instrument as well as the process of scoring responses can be found at http://www.koos.nu/. subjects were then advised as to their first treatment assignment and instructed in the completion of that treatment . \n prior to meeting with any potential subjects , the order of treatments was balanced and randomized to eliminate any statistical order effects . \n forty different treatment orders were randomly selected from the 120 possible order combinations , and were numbered consecutively . \n when subjects enrolled , they were assigned to the order from a random draw of numbers corresponding to a treatment option . \n subjects were not informed of treatment order , and would learn of their assigned treatment at the beginning of each week of the study . \n each participant completed five treatment protocols including cold , warm , and contrast ( alternating cold and warm ) with the water circulating system ; superficial heat with an electric heating pad , or control ( no treatment ) of 1 week ( 7 days ) duration . the water - circulating device used for this study was the vitalwrap portable thermal and compression system ( vitalwear inc . \n this commercially available device offers a convenient means of applying superficial cold , heat , and an option for contrast through a garment wrapped around the knee . each treatment protocol consisted of twice - a - day ( morning and evening ) application of one of the treatment options for 5 consecutive days , followed by 2 days of nontreatment . \n each of the twice daily treatments was applied for 20 minutes except for the contrast treatment , which consisted of 4 minutes of warm followed by 2 minutes of cold ( the 4 minute by 2 minute cycle of heat , then cold , was repeated 3 times ) and concluded with 4 minutes of warm , in a total session of 22 minutes . during the control week of the study , participants sat quietly for 20 minutes each day in a self - determined position of maximal comfort . \n subjects completed the koos self - report questionnaire and visual analog pain scale at baseline ( at the beginning of the study , prior to any treatment application ) , and then twice on the 5th and 7th day of each treatment week . \n the koos was selected as the instrument of choice for measuring changes in the patients , since it is a validated exam for response to treatment in individuals with knee oa across a lifespan and regardless of level of activity.17 it is an easy - to - use , self - administered survey that provides for a comprehensive examination of five subscales ( pain , symptoms , functions , sports and recreational activities , fdl , and qol ) that are of importance to function and independence for many individuals with knee \n oa . following the completion of all five of the treatment protocols , subjects completed a preference for treatment scale and were asked about any adverse events and changes in weekly medication . \n no subject reported an adverse event and there was no report of a change in any anti - inflammatory or analgesic medications for any week of the study . to assess treatment preference , \n subjects were asked to rank the treatment options from most preferred through least preferred including the nontreatment control week . \n subjects were also encouraged to provide comments on their preferences and experiences with each treatment option used during this study . \n prior to the initiation of the study , we calculated the n size power based on a change of 15% in median score of the visual pain scale , and determined that there would need to be a population of 30 subjects to obtain the desired power of 0.80 . \n pain was selected for consideration since it is of primary concern and offered the best means of judging whether additional investigation might be warranted as a follow - up to learning more regarding treatment preference . \n after each week of treatment , subject data collected were tabulated from the day 5 and 7 koos questionnaire subscales of pain , symptoms , sports and recreation activities , fdl , and qol , and the visual analog pain for each treatment , along with baseline and control week scores . \n these data were used to investigate the relationships between treatment preference and changes in reported pain , and koos subscale responses . \n data were analyzed by a member of the research team who had no contact with subjects or the data collection process . \n differences in treatment response were analyzed separately for each of the subscales of interest ( as the koos was not developed to yield a composite score ) . \n responses to treatment for the day 5 measurements were assessed without regard to preference , and then by treatment of preference , via paired t - tests ( p 0.05 ) , with bonferroni correction . \n effect sizes for treatment were determined in reference to day 5 control values ( active control)/( active and control ) for active treatments . as a follow - up , koos and \n visual analog pain data were also analyzed to identify differences between treatment days 5 and 7 in each treatment option , via a within - subject repeated measure analysis of variance , ( p 0.05 ) . \n as shown in table 2 , participants reported a range of individual preferences for treatment setting . \n more participants preferred the warm treatment condition , but nearly one - half preferred either cold or the contrast treatment . most ( 32 of 34 ) preferred treatment with the water - circulating device compared to the use of a standard heating pad or no treatment . \n regardless of the preference , there were , on average , significant ( p < 0.05 ) improvements in pain , symptoms , fdl and qol koos subscale measures with the water circulating device treatment options , ( see tables 3 and 4 ) , when compared with baseline and control week measurements . \n twice daily rest ( control treatment ) resulted in improvements over baseline measures , and therefore the control week data served as our means for comparison with all active treatment options . \n the extent of improvement in pain and symptoms was often more pronounced when subjects utilized their preferred treatment versus their nonpreferred treatment ( tables 3 and 4 ) . \n data on the function , sport and recreational activities subscale were analyzed , as were data from the other subscales , but are not reported in table form . \n of the 34 subjects that completed the study , five female subjects , all who preferred the warm treatment ( three with oa level of iii and two with oa level of iv ) , reported a 0 of 100 on this subscale at all measurements , and two males who showed preference toward either warm or contrast treatments ( oa level ii ) reported a 100 out of 100 on the subscale at the baseline . \n analysis of variance within this remaining group indicated a nonsignificant change in the function , sport , and recreational activities subscale with all treatment options , ( p > 0.168 ) and change scores ranging from 0 to 67 points . \n responses similar to the koos data were noted in the visual analog pain assessment data , where greater relief was obtained when subjects used their preferred treatment ( table 5 ) . \n interestingly , the pattern of similarity between the koos pain and visual analog pain data did not extend to the responses of the group that preferred the warm treatment . in this group , \n the greatest average change in the visual analog scale was seen following the contrast treatment ( see table 5 ) . \n similar to the changes in the koos subscales , the effect size estimates ranging from 0.68 to 1.12 , was greatest when individuals used their preferred treatment versus all other treatment options . \n interestingly , nonsignificant differences were found between day 5 and day 7 reports . this nonsignificant difference ( \n p > 0.56 ) was found across all treatment options for all points of interest for all subjects . \n this finding suggests that changes in these measures may persist for a period of 48 hours after 5 days of continuous intervention . \n these findings demonstrate that participants with knee oa have individual preferences with regard to the use of heat , cold , or contrast to relieve pain and foster greater motor function . \n it is also apparent that the use of a wrap - around garment that allows temperature - controlled water to heat or cool is much preferred over a standard heating pad . \n the reasons for preferences to heat , cold , or contrast require additional investigation , but gender , age , and severity of oa are all likely to play some role . \n women most often preferred treatment providing warmth , while men were more likely to choose cold or contrast as their preferred choices of treatment . although more women were included in our study , the gender distribution was similar to that of the bjordal et al,5 zhang et al,6 and tubach et al19 reports , and reflects a gender difference in disease prevalence . on the whole , \n all of the active treatments resulted in improvement in all measures of interest ( see tables 3 and 4 ) . \n first , we recognize that it is not possible to blind patients to treatment when applying thermal modalities . \n moreover , the opportunity to use a novel treatment device may have influenced the responses provided by these patients . however , use of a water circulating device permitted us to learn what treatments ( heat , cold , or contrast ) these patients preferred using a single application method , and to begin examining the relationships between preference and self - report of pain and function in patients with clinically significant knee oa . \n we believe that the average magnitude of change reported on the koos and visual pain scale is sufficient to warrant further attention . \n tubach et al19 reported that a 32% relative change in pain represented a minimal clinically important improvement and corresponded to a \n fair response in patients with knee and hip oa treated with nonsteroidal anti - inflammatory drugs ( nsaids ) . when preferred treatments of cold and warm were used , the patients in this sample reported a mean pain reduction of 33% and 23% respectively . \n it is unknown what longer - term use might yield , but some patients can achieve meaningful relief through these interventions that persist for at least 2 days , with little risk . \n responses also fell within the range of clinically important difference as reported by roos,17 and correspond to the percent change in the pain ( see table 5 ) in individual studies of the response to nsaids4,5 and nonsurgical treatment options5 for individuals with knee oa . the effect size for change in pain with use of \n the preferred treatment was larger ( 44%48% ) than the nonpreferred treatment options ( 16%36% ) when the water - circulating device was used . \n bjordal et al5 reported the effect size for change in pain associated with the use of nsaids of 23% when nonresponders to medication were included in the analysis . \n we observed , especially in patients with more severe oa , that none of the treatments greatly changed the outcomes measures , however we do not believe this sample is sufficient for subgroup analysis of responders . while not the primary purpose of this project , the findings related to contrast treatment are quite interesting from a clinical perspective . when preferred , contrast treatment provided at least a two - fold difference to the next closest response to any of the other treatment options , in the percent change of the visual pain scale . \n while described in therapeutic modality texts,14,15 contrast treatment has not been extensively studied , especially in patient populations . \n hing et al13 completed a systematic review of contrast treatment and concluded that there is insufficient evidence to draw conclusions about this form of therapy . \n more importantly all of the randomized controlled clinical trials included in their report involved active athletes and college - aged patients , making generalizations to older and diseased populations problematic . \n moreover , the outcome measures reported were of little clinical interest , with the exception of measures of swelling following acute ankle sprain in college - aged patients.18 thus , our findings may be the first report to address measures of contrast therapy treatment outcomes that are truly meaningful to patients in a non - college aged or athletic populations . \n contrast treatment provided the greatest improvement in two of the four koos subscales , and was far superior for improving subjects pain rating via a visual pain scale . \n this finding is quite surprising given that the contrast treatment was not the most preferred treatment . \n however , some subjects noted that having to manually change from a warm setting to a cold setting at specific intervals of time as a prime reason for not preferring contrast . if the responses to contrast treatment we observed are substantiated through additional investigation , the use of an automatic timer to switch settings might change patient perception . despite the exploratory nature of this study , \n our findings have implications for clinicians as well as patients . rather than recommending that a patient specifically use heat or cold \n , we suggest that patients be advised to experiment with heat , cold , and if possible contrast , to identify their individual preference for treatment , and/or under which condition(s ) they experience the greatest relief of pain or symptoms . \n it is also possible that patients may find that their preference changes under differing circumstances . \n several subjects noted that their symptoms fluctuated with variations in activity , and in some cases , the weather . \n once again , individual experimentation may yield greater relief under specific circumstances in a safe and relatively cost - effective manner . \n in summary , we observed distinctly individual preferences for the use of heat , cold and contrast in patients with knee oa . a preference for treatment with a wrap - around garment over the use of a standard heating pad was also observed . in general , greater pain relief and functional improvements were found when subjects used their treatment of preference . \n these data support the recommendation that superficial heat or cold be included in the early efforts to manage patients with knee oa , and demonstrate that contrast be considered as a treatment option . \n we acknowledge that this is a preliminary investigation into the preferences of patients with knee oa to treatments . \n it is recommended that future avenues of research include the use of clinical assessments of functionality , eg , the 6-minute walk test , stand - and - walk test , or step test , along with a longer period of treatment to assess both the role of preference for self - directed , in - home care , and possible functional outcomes for patients . \n it is , we believe , apparent that patient preference must be considered in the development of future investigations .", "role": "user" }, { "content": "objective : this investigation assessed preferences for , and effects of , 5 days of twice daily superficial heat , cold , or contrast therapy applied with a commercially available system permitting the circulation of water through a wrap - around garment , use of an electric heating pad , or rest for patients with level ii iv osteoarthritis ( oa ) of the knee.methods:we employed a within subject , randomized order design to study 34 patients receiving each treatment in 1-week blocks . a knee injury and osteoarthritis outcome score ( koos ) questionnaire and visual analog pain scale was completed at baseline , and twice each week . \n treatment preferences were assessed in the last week of the study.results:treatment with the device set to warm was preferred by 48% of subjects . \n near equal preferences were observed for cold ( 24% ) and contrast ( 24% ) . \n pain reduction and improvements in koos subscale measures were demonstrated for each treatment but responses were ( p < 0.05 ) greater with preferred treatments . \n most patients preferred treatment with the water circulating garment system over a heating pad.conclusions:we recommend that when superficial heat or cold is considered in the management of knee oa that patients experiment to identify the intervention that offers them the greatest relief and that contrast is a treatment option .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: obesity prevalence has increased over the last 20 years . at the turn of the millennium , \n nearly two - thirds of americans were overweight or obese , and almost 5% were morbidly obese . \n obesity shortens life expectancy and will likely soon be the leading cause of preventable death in the united states . in the absence of reliable medical and behavioral therapies , and with the advent of minimally invasive technologies , \n more recent data suggest a leveling in procedure numbers despite the ongoing obesity epidemic , perhaps related to the evolution of center - of - excellence requirements [ 9 , 10 ] and linked reimbursement systems . \n systems which restrict cases to high - volume centers may ensure better outcomes and reduced costs in certain environments but may also risk stifle small programs by proscribed requirements and limit national bariatric surgery capacity . \n the current reimbursement environment has set a narrow margin for surgeons and healthcare systems intending to provide state - of - the - art bariatric services . \n therefore , programs have typically flourished in hospitals which focus on providing well - insured patients efficient customer - centric care . \n conversely , programs located in hospitals with prominent charitable and educational missions may struggle to preserve sufficient case volumes to maintain accreditation and profitability due to inherent inefficiencies . \n global efficiency initiatives for operating room processes have centered on improving case scheduling , data tracking , staff satisfaction , communications at all levels [ 1820 ] , and patient outflow . at the provider level , many areas of inefficiency have been improved by simple tracking and delineation of accountability ; however , certain patient - related variables , such as late arrival to hospital or difficult venous access , are more resistant to day - of - surgery systems improvement measures . \n when venous access efforts fail in the holding area , anesthesiologists often utilize valuable or time acquiring reliable peripheral or central intravenous lines . \n these services may not be compensated and often impact an anesthesiologist 's availability for other scheduled activity . as a result of the increased prevalence of hypercoagulable states seen in the morbidly obese , \n we have initiated an aggressive program for venous thromboembolism prophylaxis in our bariatric patients , which includes liberal use of inferior vena cava ( ivc ) filters for a proportion of our patients who are deemed high risk for pulmonary embolism . \n filters are placed in the outpatient setting in the interventional radiology suite < 24 hours prior to operation , with concomitant central venous line ( cvl ) insertion in all of these patients . \n therefore , since some of our bariatric surgery patients arrive on the day of surgery with reliable venous access and others do not , we have a simple means to assess the effect of reliable venous access on operating room efficiency . \n the study encompassed 268 consecutive patients who had laparoscopic gastric bypass between january 2001 and november 2006 . \n of these , 106 were referred to our interventional radiologists and had outpatient preoperative placement of a prophylactic ivc filter < 24 hours prior to operation . \n all patients present through standard same - day - surgery channels on the day of operation . \n routine preoperative protocols were applied by administrative , nursing , and physician staff . at university of north carolina hospitals , the precare nurses will attempt to achieve peripheral intravenous access if no access line is present . \n if venipuncture fails after two attempts , the anesthesiology team assumes responsibility for obtaining primary venous access . \n patients are often taken from the holding area to the operating room under the direction of the attending anesthesiologist , and decisions about venous access and monitoring are made at his or her discretion . \n we queried operating room databases to compare time between patient or entry and skin incision ( in - to - skin ) for patients with and without outpatient cvls . \n in addition , we searched billing databases for cvl collection rates . since or benchmarks for in - to - skin times are typically stratified by 15-minute increments , we graphically depicted the subject and control data in this fashion . \n statistical comparison utilized the raw continuous data was made by the nonpaired t - test , using p < 0.05 as a measure of statistical significance . \n the 106 patients who received preoperative cvls had demographics and average bmis similar to the 162 patients who did not receive preoperative cvls ( table 1 ) . patients with preoperative cvls had mean in - to - skin time of 35.6 12.5 minutes versus 42.5 13.9 minutes for those without preoperative cvls ( p < 0.0001 ) . when assessed in quarter - hour increments , the presence of a preoperative cvl \n was associated with 34.9% of subjects having skin incision by 30 minutes versus 16.36% of controls ( figure 1 ) . regarding reimbursement , interventional radiologists performing the outpatient cvls collected 28.2% of billings for cpt code 36556 . \n in contrast , those anesthesiologists who placed intraoperative cvls in the operating room collected less than 1% of dollars billed . among those 106 patients who received preoperative cvls , one catheter - related infection occurred in a patient with a long hospitalization from respiratory failure , and two self - limited catheter site infections \n while the number of american adults suffering from obesity continues to increase , the annual number of bariatric operations has been stable or decreasing in recent years . this trend may be attributable to the evolution of programs designed to direct patients to certified high - volume centers where the quality of care is believed to be best . with the arrival of a new administration in our nation 's capital , america has again focused awareness on prevention , management of chronic disease , and cost containment . \n bariatric surgery will likely come to increased attention as the only contemporary option to decrease the burden and overall utilization of healthcare resources related to america 's most costly disease . \n if governmental interventions crystallize candidacy criteria and eliminate bariatric surgery exclusions among healthcare insurers , the resultant resurgence in demand for procedures may tax the capacity of the system to increase patient throughput . \n increasing efficiency of systems is a strategy for increasing delivery of care without a concomitant and proportional increase in cost . in the highly regulated environment of bariatric surgery \n , efficiency initiatives will no doubt be integral in early efforts to maximally utilize existing systems , at least until the projected rising demand drives further program and infrastructure development . \n we have demonstrated that outpatient cvl placement in planned bariatric patients improves efficiency on the day of surgery . when the effect of a small incremental or time savings is considered on a broader scale , \n the potential to achieve significant monetary savings while perhaps even enhancing effective capacity emerges . with case volumes driving all systems for bariatric program certification \n , such efficiencies may bring many smaller centers to case levels that allow credentials to be obtained , with improved ability to compete for patients and contracts . \n in addition , improved reimbursement rates for cvl implantation noted in our study will further support the financial success of a program . \n although a higher level of difficulty for intravenous access in morbidly obese patients has not been established in comparative studies , there are a number of references to obesity as a contributing factor in difficult peripheral and central intravenous access [ 2531 ] . \n our data suggest that difficult venous access in bariatric surgery patients may contribute to or delays . \n with operating room cost per minute on the order of $ 1525 and with an average $ 66 per minute charged to patients , a savings of 15 minutes per case can have a significant financial impact at the hospital level , especially when a single attending anesthesiologist oversees two , three , or even four rooms at one time . \n moreover , each such delay avoided will prevent accumulating costs for subsequent patients ' scheduled in the same operating room . \n finally , the above estimates of cost do not account for lost efficiencies in terms of underutilized surgeons , operating room and recovery room personnel , and inpatient resources . \n since anesthesiologists are reimbursed less than 1% for cvls placed in the or , it is clear that these providers have no financial reason for resisting program initiatives to move cvl placement to the outpatient setting . \n in addition to improved or efficiency , we believe there are likely other intangible benefits to cvl placement prior to gastric bypass . a preexisting cvl reduces the number of tasks that must be performed prior to the induction of general anesthesia , which may decrease frustration levels when dealing with potentially difficult morbidly obese patients . \n the inpatient nursing and phlebotomy staff also benefit from secure venous access for delivery of medications and blood draws , which decreases their frustration and improves efficiency and customer service during the inpatient stay . finally , patients are happy to avoid multiple unsuccessful phlebotomy and peripheral venous line ( pvl ) placement attempts . there are risks associated with cvls , including those associated with placement such as arterial puncture , hematoma , and pneumothorax , and those which occur after placement such as catheter - related infections , catheter malfunction , and catheter - related thrombosis . \n since the cvl catheters described in this study were placed using ultrasound guidance by experienced vascular interventional radiologists , the insertion complication rate was low ( 0.62% ) , and since the majority of patients were immune competent , not critically ill , and had brief cvl dwell times , low rates of catheter - related infection were seen . \n in fact , similar risks have been associated with pvls , including arterial puncture , hematoma , infiltration , catheter malfunction , and catheter - related infections . while the rate of minor complications such as infiltration or phlebitis is high with pvls ( up to 21.7% ) , the rate of serious complications such as bacteremia is probably lower when compared to cvls . \n anecdotal reports of increased patient and anesthesiologist satisfaction with cvls are being assessed in subsequent studies . \n additional implementation of a plan for increased cvl utilization to enhance or efficiency will need to be balanced against the impact on interventional radiology unit capacity and professional satisfaction of the affected radiologists , as well as the impact on trainees in the operating rooms . \n useful data regarding or efficiency , related costs , potential savings , and complications could be obtained from a prospective randomized control trial comparing cvl placement prior to gastric bypass to cvl placement at the time of gastric bypass to peripheral intravenous access at the time of gastric bypass . \n outpatient placement of cvls prior to gastric bypass improves the efficiency of the operating room with earlier skin incision . for patients having ivc filter placement prior to bariatric surgery \n those patients not referred for ivc placement , we suggest surgeons and anesthesiologists evaluate for difficult intravenous access during the outpatient preoperative visit and consider referral for ultrasound - guided access during the 24 hours prior to scheduled surgery . \n such efforts will improve day - of - surgery efficiency and professional reimbursement for necessary procedures .", "role": "user" }, { "content": "background . \n bariatric surgery has increased across america . \n venous access is difficult in these patients . anesthesiologists often utilize valuable operating room ( or ) time acquiring reliable intravenous lines . \n our objective was to determine if outpatient central venous line ( cvl ) placement improves or efficiency and professional reimbursement for cvl insertion . \n methods . in our bariatric practice , selected surgery patients have outpatient cvls placed during prophylactic vena cava filter placement . in a cohort of 268 gastric bypass patients operated between 1/01 and 11/06 , we compared time - to - incision between 106 with pre - established cvls and 162 without . in addition , we determined professional compensation rates for cvls placed outpatient versus cvls inserted in the or . \n results . \n patients with preoperative ( outpatient ) cvls required 35.6 12.5 minutes to skin incision compared with 42.5 13.9 minutes for controls ( p < 0.0001 ) , and 34.9% had skin incision in < 30 minutes compared with 16.4% of controls . \n radiologists collected 28.2% of outpatient billings for cpt code 36556 , compared with anesthesiologists who collected < 1% when placing cvls in the or . \n conclusions . \n outpatient cvls prior to gastric bypass improve efficiency in the or with earlier skin incision . \n professional reimbursement is better for outpatient cvls than intraoperative inpatient cvls .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: right ventricular ( rv ) function is an important determinant of clinical status and prognosis of patients with various conditions , including pulmonary hypertension.1)2)3 ) there are many studies showing the functional analysis of rv and some of them revealed regional analysis of rv using strain analysis in patients undergoing long term exercise.4)5)6 ) however , little study is known to analyze rv function with 2-dimensional ( 2d ) strain echocardiography before and just after treadmill test . \n treadmill exercise is very similar with usual and non - specific activity most people can easily experience and we tried to evaluate importance of an acute cardiovascular adjustment of rv function to meet these needs which requires an integrated neural and hormonal responses that increase heart rate and stroke volume of rv . \n some researches showed the change of echocardiography just after exercise.7)8 ) the aim of this study is to show the change of regional rv function just after treadmill exercise with strain analysis . \n data from 38 consecutive patients who visited hospital for hypertension , chest pain or dyspnea between january 2007 and december 2010 were retrospectively analyzed . \n patients with heart failure , coronary artery occlusive disease , pulmonary thromboembolism , pulmonary hypertension of any cause , renal disorder or liver disease were excluded . \n symptom - limited graded treadmill exercise testing was performed with a standard bruce protocol in a fasting state , and a post - treatment treadmill exercise test was repeated at the same time of day as the baseline test.9 ) a 12-lead electrocardiogram was recorded at rest and 1-minute intervals until onset of limiting chest pain , leg fatigue or 0.2-mv st - segment depression . \n time to 0.1-mv st - segment depression was defined as the elapsed time from initiation of exercise to the occurrence of horizontal or down - sloping 0.1-mv st - segment depression measured at 80 ms after the j point . in this study , \n heart rate and systolic blood pressure at onset of 0.1-mv st - segment depression were measured to determine the ischemic threshold . \n all exercise tests and st - segment evaluations were performed by investigators blinded to results of coronary angiograms and treatment status . \n transthoracic echocardiography was performed at baseline and just after exercise test ( within 23 minutes ) . with the subject in the left lateral position , \n transthoracic examinations were conducted according to current guidelines.10)11)12 ) echocardiographic studies were performed in all subjects and all recordings were stored digitally and analyzed offline . \n measurements of left ventricular ( lv ) function included : lv outflow tract velocity time integral , lv end diastolic dimension , lv volume ( diastolic and systolic ) , ejection fraction . measurements of diastolic function , tricuspid regurgitation ( tr ) , rv outflow tract velocity time integral ( rvot vti ) , tissue doppler peak systolic velocity of tissue doppler imaging at the tricuspid annulus ( s ' ) velocity were performed . pulmonary vascular resistance ( pvr ) \n was calculated as per abbas et al.:13 ) pvr ( wood units ) = 10 ( tr velocity / rvot vti ) to estimate systolic function of rv , rv tissue doppler imaging ( s ' ) was measured in rv free wall . \n the 6 6 mm sample volume was placed directly underneath the mitral or tricuspid annulus in the basal myocardium in an apical fourchamber view . \n dynamic 2d ultrasound images of three cardiac cycles from apical two- , three- , and four chamber views were acquired using conventional ultrasound , with a frame rate of 57 to 72 frames per second . to measure strain and strain rate , \n the image analysis was performed offline using customized software within the echopac work station ( echopac , ge vingmed ultrasound , milwaukee , wi , usa ) . \n the endocardial boundary of the lv was delineated manually , after which the software automatically drew the epicardial boundary . \n the widths of the regions of interest were adjusted manually to match the actual endocardial and epicardial boundaries . \n automatic frame by frame tracking of speckle patterns during the cardiac cycle yielded a measure of strain and strain rate at any part of the myocardium . \n on 2d global longitudinal strain analysis , echocardiographic machine with a 3.5-mhz transducer and high frame rate ( 50 or more hz ) was used to image the rv in apical views . \n 2d global longitudinal strain of whole rv ( 6 segments ) and rv free wall only not including inter - ventricular septum ( 3 segments ) , were calculated using the echopac . \n the longitudinal strain and strain rate of the basal , middle , and apical portions of rv free wall and septum were obtained in apical four - chamber view . by averaging these segmental values , \n continuous variables were analyzed using one sample t tests and are expressed as mean sd . paired t \n all analyses were performed using spss version 20.0 ( ibm , armonk , ny , usa ) . \n p values < 0.05 were considered statistically significant , and all p values are two sided . \n data from 38 consecutive patients who visited hospital for hypertension , chest pain or dyspnea between january 2007 and december 2010 were retrospectively analyzed . \n patients with heart failure , coronary artery occlusive disease , pulmonary thromboembolism , pulmonary hypertension of any cause , renal disorder or liver disease were excluded . \n symptom - limited graded treadmill exercise testing was performed with a standard bruce protocol in a fasting state , and a post - treatment treadmill exercise test was repeated at the same time of day as the baseline test.9 ) a 12-lead electrocardiogram was recorded at rest and 1-minute intervals until onset of limiting chest pain , leg fatigue or 0.2-mv st - segment depression . \n time to 0.1-mv st - segment depression was defined as the elapsed time from initiation of exercise to the occurrence of horizontal or down - sloping 0.1-mv st - segment depression measured at 80 ms after the j point . in this study , \n heart rate and systolic blood pressure at onset of 0.1-mv st - segment depression were measured to determine the ischemic threshold . \n all exercise tests and st - segment evaluations were performed by investigators blinded to results of coronary angiograms and treatment status . \n transthoracic echocardiography was performed at baseline and just after exercise test ( within 23 minutes ) . with the subject in the left lateral position , \n transthoracic examinations were conducted according to current guidelines.10)11)12 ) echocardiographic studies were performed in all subjects and all recordings were stored digitally and analyzed offline . \n measurements of left ventricular ( lv ) function included : lv outflow tract velocity time integral , lv end diastolic dimension , lv volume ( diastolic and systolic ) , ejection fraction . \n measurements of diastolic function , tricuspid regurgitation ( tr ) , rv outflow tract velocity time integral ( rvot vti ) , tissue doppler peak systolic velocity of tissue doppler imaging at the tricuspid annulus ( s ' ) velocity were performed . pulmonary vascular resistance ( pvr ) \n was calculated as per abbas et al.:13 ) pvr ( wood units ) = 10 ( tr velocity / rvot vti ) to estimate systolic function of rv , rv tissue doppler imaging ( s ' ) was measured in rv free wall . \n the 6 6 mm sample volume was placed directly underneath the mitral or tricuspid annulus in the basal myocardium in an apical fourchamber view . \n dynamic 2d ultrasound images of three cardiac cycles from apical two- , three- , and four chamber views were acquired using conventional ultrasound , with a frame rate of 57 to 72 frames per second . to measure strain and strain rate , \n the image analysis was performed offline using customized software within the echopac work station ( echopac , ge vingmed ultrasound , milwaukee , wi , usa ) . \n the endocardial boundary of the lv was delineated manually , after which the software automatically drew the epicardial boundary . \n the widths of the regions of interest were adjusted manually to match the actual endocardial and epicardial boundaries . \n automatic frame by frame tracking of speckle patterns during the cardiac cycle yielded a measure of strain and strain rate at any part of the myocardium . \n on 2d global longitudinal strain analysis , echocardiographic machine with a 3.5-mhz transducer and high frame rate ( 50 or more hz ) was used to image the rv in apical views . \n 2d global longitudinal strain of whole rv ( 6 segments ) and rv free wall only not including inter - ventricular septum ( 3 segments ) , were calculated using the echopac . \n the longitudinal strain and strain rate of the basal , middle , and apical portions of rv free wall and septum were obtained in apical four - chamber view . by averaging these segmental values , \n continuous variables were analyzed using one sample t tests and are expressed as mean sd . paired t \n all analyses were performed using spss version 20.0 ( ibm , armonk , ny , usa ) . \n p values < 0.05 were considered statistically significant , and all p values are two sided . \n patients showed good exercise tolerance ( exercise duration , 737.0 132.2 sec ) and preserved systolic ejection fraction ( 65.0 8.0% ) . \n systolic blood pressure was 126.8 23.6 mm hg and diastolic blood pressure was 64.3 11.9 mm hg with mean heart rate was 74.8 19.7/min . left atrial volume index was 32.0 12.9 ml / m and tr peak velocity was 2.6 0.5 m / sec . \n early diastolic flow velocity / early diastolic annular velocity was 11.4 4.4 and s ' velocity was 6.7 4.9 cm / sec ( table 1 ) . \n there was no significant change of ejection fraction or chamber size except for rv tissue doppler imaging ( s ' ) . \n s ' velocity of tricuspid annulus was significantly increased after exercise ( pre vs. post , 7.5 2.4 cm / sec vs. 12.2 1.8 cm / sec , p = 0.006 ) ( table 2 ) . \n there was increasing tendency of absolute values in systolic velocity , strain and strain rate of rv base level ( table 3 ) . in follow - up data \n , there was significant change of systolic velocity at lateral apex of rv after exercise ( pre vs. post , 2.5 0.9 cm / sec vs. 3.9 1.4 cm / sec , p = 0.038 ) and significant change of systolic strain at mid portion of lateral wall ( pre vs. post , -14.1 6.7% vs. -22.6 6.8% , p = 0.022 ) and lateral apex ( pre vs. post , -18.2 7.6% vs. -22.3 5.8% , p = 0.010 ) after exercise . \n there was no significant change of systolic regional strain rate of rv after exercise ( table 4 , fig . 1 , 2 , and 3 ) . \n patients showed good exercise tolerance ( exercise duration , 737.0 132.2 sec ) and preserved systolic ejection fraction ( 65.0 8.0% ) . \n systolic blood pressure was 126.8 23.6 mm hg and diastolic blood pressure was 64.3 11.9 mm hg with mean heart rate was 74.8 19.7/min . left atrial volume index was 32.0 12.9 ml / m and tr peak velocity was 2.6 0.5 m / sec . \n early diastolic flow velocity / early diastolic annular velocity was 11.4 4.4 and s ' velocity was 6.7 4.9 cm / sec ( table 1 ) . \n there was no significant change of ejection fraction or chamber size except for rv tissue doppler imaging ( s ' ) . \n s ' velocity of tricuspid annulus was significantly increased after exercise ( pre vs. post , 7.5 2.4 cm / sec vs. 12.2 1.8 cm / sec , p = 0.006 ) ( table 2 ) . \n there was increasing tendency of absolute values in systolic velocity , strain and strain rate of rv base level ( table 3 ) . in follow - up data \n , there was significant change of systolic velocity at lateral apex of rv after exercise ( pre vs. post , 2.5 0.9 cm / sec vs. 3.9 1.4 cm / sec , p = 0.038 ) and significant change of systolic strain at mid portion of lateral wall ( pre vs. post , -14.1 6.7% vs. -22.6 6.8% , p = 0.022 ) and lateral apex ( pre vs. post , -18.2 7.6% vs. -22.3 5.8% , p = 0.010 ) after exercise . \n there was no significant change of systolic regional strain rate of rv after exercise ( table 4 , fig . 1 , 2 , and 3 ) . \n the anatomy and complex geometry of the rv confer significant limitations to 2d echocardiography.14)15 ) current studies use many novel technique including 3-dimensional or strain to analyze rv systolic function.16)17)18)19 ) speckle tracking echocardiography is a highly sensitive technique used to detect subtle myocardial dysfunction of systolic abnormalities.20)21)22 ) many studies revealed regional analysis of rv using strain analysis in patients undergoing long term exercise.4)5)6)23 ) anjak et al.23 ) demonstrated that tricuspid annular plane systolic excursion ( tapse ) and tricuspid annular systolic velocity are reliable and accurate measures of the rv response to exercise during a supine bicycle stress echocardiography protocol . in that study , authors showed activated rv contraction during exercise through significantly increased tapse , tissue doppler image velocity and peak rv strain compared with baseline ( -34 5% vs. -40 5% , baseline vs. 75 w ) . however , there is little study to show the regional analysis of rv with strain imaging before and just after treadmill exercise . \n here we analyzed the systolic rv function with strain both pre and post exercise in non - coronary artery disease population . in this study , there was significant change of systolic velocity and strain at lateral apex and mid portion of rv after treadmill exercise . \n more significant activation was noted in rv free wall apex and mid portion via strain analysis . \n compared with free wall , septal movement of rv is extremely dependent on lv movement , so septal wall motion is much more limited than the free wall of rv . \n the change of strain data at basal level of free wall between pre and post exercise is not significant . \n the absolute value of velocity and strain data of basal free wall is already larger even before exercise rather than mid or apex . \n for this reason , the difference between pre and post exercise may be relatively small . \n lord et al.24 ) revealed a similar study for rv function analysis within 30 minutes after ultra - endurance exercise , but it was performed to see the impact of ultra - marathon running on rv structure and function in highly trained runners . \n la gerche et al.4 ) showed a similar data for strain analysis immediate after endurance race ( 311 hours duration ) , the subjects were not a normal group but endurance athletes and the data was mean global strain data . in another report,25 ) \n improvement of rv strain was noted after chronic exercise training of 8 weeks , however we tried to evaluate regional rv function just after treadmill exercise . \n first , the number of patients enrolled was small , and our results should be confirmed in a larger population . \n second , we excluded patients in whom suitable views could not be obtained even by shifting or moving the echo probe from the standard 4 chamber view position . \n furthermore , the feasibility of 2d strain analysis software applied to rv has remained unclear , although this software has been applied to rv in several clinical studies . \n finally , the present study does not include long - term follow - up data . \n 2d strain imaging provides a precise tool to quantify regional rv function and reveals a characteristic regional pattern of rv after treadmill exercise . \n our study demonstrates for the first time the regional change of rv just after treadmill exercise . \n 2d strain imaging provides a precise tool to quantify regional rv function and reveals a characteristic regional pattern of rv after treadmill exercise . \n our study demonstrates for the first time the regional change of rv just after treadmill exercise .", "role": "user" }, { "content": "backgroundfunction of right ventricle ( rv ) influences on symptoms and prognosis in various diseases . \n however the regional rv function analyzed with 2-dimensional ( 2d ) strain echocardiography before and just after treadmill test has not been evaluated . \n the aim of this study was to show the change of regional rv function just after treadmill exercise with strain analysis.methodsa total of thirty eight patients who visited hospital for hypertension , chest pain or dyspnea between january 2007 and december 2010 were retrospectively analyzed ( men , 47.4% ; mean age , 54.9 7.2 years ) . \n treadmill exercise test and pre and post echocardiography were performed . \n 2d strain echocardiography was analyzed off line in rv free wall and septum.resultsmean exercise duration was 737 132 sec . \n tissue velocity in lateral tricuspid annulus is significantly increased in post exercise ( initial , 10.5 2.4 cm / sec vs. post exercise , 12.2 1.8 cm / sec , p = 0.006 ) . \n systolic strain of rv free wall apex and mid portion were significantly changed in post exercise stage ( free wall apex , -18.2 7.6% vs. -22.3 5.8% , p = 0.010 ; free wall mid , -14.1 6.7% vs. -22.6 6.8% , p = 0.022).conclusion2d strain imaging provides a precise tool to quantify regional rv function and reveals a characteristic regional pattern of rv after treadmill exercise .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: \n knee oa is one of the most common joint disorders and causes considerable pain and immobility . \n the initial treatment is nonoperative and consists of patient education , weight reduction , physical therapy , and , if needed , medication . drugs rarely relieve the symptoms entirely and mainly act as a palliative agent . \n other rehabilitative interventions are based on altering knee biomechanics , which may influence the development and progression of knee oa [ 4 , 23 ] . in selected patients with oa of the medial compartment , improvements in pain , function , and loading forces reportedly occur with valgus unloader knee braces . \n one randomized controlled trial ( rct ) suggested knee bracing resulted in better knee function compared with no brace in patients with oa with varus malalignment . \n many patients in that study , however , did not adhere to brace treatment , mainly because of skin irritation and bad fit . \n however , whether bracing corrects malalignment remains controversial [ 10 , 15 , 20 , 21 ] . \n like knee bracing , laterally wedged insoles may unload the diseased compartment , and two studies suggest wedges may correct varus malalignment [ 16 , 26 ] . one crossover study showed no effect of wedged soles in an elderly population with advanced stages of oa . \n however another study reported an improvement of symptoms in patients with mild to moderate oa treated with laterally wedged insoles . \n another study reported a similar effect while observing decreased nsaid intake when foot orthoses were used to treat knee oa . \n a cochrane review concluded there is some evidence that foot orthoses have additional beneficial effects in the treatment of symptomatic knee oa . \n laterally wedged soles may represent a substantial potential in the treatment of symptomatic knee oa because they are safe and generate fewer costs than knee bracing . \n furthermore , foot orthoses are easy to apply , and good adherence to the intervention has been reported [ 1 , 25 ] . \n we therefore asked whether laterally wedged insoles would result in reduction of pain and improvement in womac function scores compared with valgus bracing in patients with symptomatic medial compartmental knee \n . we also asked whether both treatments would correct knee malalignment in the frontal plane . \n we conducted a prospective open - label ( completely unblinded ) parallel rct in patients with symptomatic medial compartmental knee oa . \n all patients had been treated initially according to the practice guidelines by the dutch college of general practitioners ; including patient education , physical therapy and , if needed , analgesic use . \n we diagnosed the oa as medial when pain and tenderness in combination with osteoarthritic signs according to the kellgren - lawrence system of grade 1 or higher were located over the medial tibiofemoral compartment of the knee . \n the radiographic score was measured on digitalized standard short posteroanterior radiographs taken of the patient in the standing position . \n patients with symptoms not related to medial compartmental oa , younger than 35 years , an insufficient command of the dutch language , or no varus malalignment were excluded . \n the degree of knee alignment was assessed by the hip - knee - ankle ( hka ) angle and measured on a digitalized whole - leg radiograph taken with the patient in the standing position . \n earlier we reported high intraobserver ( icc = 0.98 ; 95% ci = 0.940.99 ) and interobserver ( icc = 0.97 ; 95% ci = 0.940.99 ) agreement for measurement of the hka angle using this technique . \n the hka angle was defined as the angle between two prolonged lines : one line of the center of the femur head to the top of the femoral notch and a second line from the center of the ankle to the center of the tibial spines . \n a positive value represented varus direction ; patients with an hka angle of 0 or less were excluded . \n the sample size calculation was based on the baseline mean visual analog scale ( vas ) score for pain of 6.0 and sd of 2.2 in the study of brouwer et al . who included patients according to similar criteria . \n we estimated a 1-point difference in vas between the two groups would represent a clinically relevant difference , being 15% of the baseline score . \n to detect such a difference with two - sided testing ( = 0.05 and power of 80% ) , we needed 40 patients in each group . with the assumption of 15% rate of loss of followup \n therefore between january 2006 and september 2007 , we recruited 92 patients meeting our criteria ; one investigator ( tmr ) enrolled all participants . \n one patient with medial compartment oa and clinical varus alignment was excluded because of valgus alignment assessed on the whole - leg radiograph , resulting in a total sample of 91 patients . \n there were 45 patients in the insole group and 46 in the bracing group ( table 1 ) ; four patients in the insole group and four in the bracing group were lost to followup . \n four patients in the insole group and six in the bracing group changed their initial treatment during the 6-month followup to other nonoperative or surgical treatment ( fig . 1 ) . \n the primary reason was no effect of treatment ( four of four patients in the insole group , and three of six patients in the brace group ) ; but other reasons included bad fit , reduction of symptoms , and increased crepitus at the knee.table 1baseline characteristics of the study population and for the two intervention groupscharacteristicstudy population ( n = 91)insole group ( n = 45)brace group ( n = 46)age ( years)*54.7 ( 7.0)54.4 ( 6.5)54.9 ( 7.4)gender ( % female)496535body mass index ( kg / m)29.2 ( 4.5)29.4 ( 4.9)29.0 ( 4.2)osteoarthritis medial grade ( % ) 1413248 2192315 3394237 4130osteoarthritis lateral grade ( % ) 0747672 1242226 2222analgesic use ( % ) none484552 when needed232422 daily293126pain severity ( vas , 010)*5.6 ( 2.6)5.7 ( 3.0)5.6 ( 2.2)function ( womac , 0100)*46.6 ( 18.4)46.5 ( 18.9)46.8 ( 18.2)hka angle ( )*6.9 ( 3.6)6.9 ( 3.6)7.0 ( 3.6 ) * values are expressed as means , with sds in parentheses ; positive angle represents varus alignment ; vas = visual analog scale ; hka = hip - knee - ankle angle.fig . \n baseline characteristics of the study population and for the two intervention groups * values are expressed as means , with sds in parentheses ; positive angle represents varus alignment ; vas = visual analog scale ; hka = hip - knee - ankle angle . \n participants were randomized according to a computer - generated procedure ( block randomization , with variable sizes of the blocks ) ; the randomization codes were held by an independent observer ( mr ) to ensure masked blocking . \n the participants were randomly allocated to their groups after informed consent had been obtained and all baseline measurements were completed . at baseline , we recorded age , gender , body mass index , severity of radiographic oa , varus alignment , analgesic use during the previous month , estimated average for pain severity during the previous week on a vas ( 010 , with a lower score representing less pain ) , and knee function using the womac score ( 0100 , with a higher score representing better outcome ) \n . participants were assigned either to an intervention group receiving a shoe - inserted leather sole with a lateral - wedge cork elevation of 10 mm along the entire length of the foot ( fig . \n the shoe - inserted sole was custom made and fitted by a specialized orthopaedic shoe technician . \n the valgus knee brace was commercially available for the right / left leg in four sizes ( mos genu ; bauerfeind ag , kempen , germany ) and consisted of a thigh shell and a calf shell connected by coated aluminum hinges on the medial and lateral sides ( fig . \n the degree of valgization depended on the degree of malalignment and the acceptance of the patient . \n participants were instructed to wear the insole or brace as much as tolerated , and they were asked to register the number of hours per week they wore the insole or brace.fig . \n 2an image of a left foot shows the leather sole and a laterally wedged cork elevation of 10 mm ( 6 wedge).fig . \n an image of a left foot shows the leather sole and a laterally wedged cork elevation of 10 mm ( 6 wedge ) . \n an image of a left knee shows the mos genu knee brace . at 6 months , one nonblinded investigator ( tmr ) , a trained orthopaedic surgeon , assessed the followup measurements including vas and womac scores , physical examination , analgesic use , and the mean number of hours per week \n secondary outcome measures were knee function using the womac subscale and varus alignment correction in the frontal plane using the hka angle . \n the difference in degrees between the hka angles assessed on a whole - leg radiograph with and without wearing the insole or brace was used . \n responders to the treatment were defined as having an improvement of 20% or more compared with the baseline score for pain ( vas ) and function ( womac function subscale score ) in accordance with the omeract - oarsi set of responder criteria . the optimal amount of time to wear an insole or brace during the day has not been determined , and compliance remains arbitrary . \n patients who were compliant were defined a priori as patients using the insole or brace more than 42 hours a week ( 7 days times 6 hours , which represents 75% of the working day ) . \n we established whether the variables had a normal distribution using the normality shapiro - wilk test . \n linear regression for continuous outcome measures ( vas pain , womac function , and hka angle ) and logistic regression for binary outcome measures ( responder yes or no ) were used to analyze the treatment effect . because we did not standardize medication use , we adjusted all analyses for medication use during the study . \n the last - value - carried - forward method was used for the missing data of patients lost to followup . \n the primary analysis was by intention to treat in that all participants properly randomized were included in the analysis even if they did not receive the treatment they were allocated to receive . \n a secondary analysis was limited to the 73 participants who received ( or were compliant with ) the treatment to which they were randomized ( per protocol analysis ) . \n subgroup analysis was performed for patients with medial knee oa lower than kellgren - lawrence grade 2 versus grade 2 or higher because it has been suggested laterally wedged insoles are more effective in early medial compartment knee oa . \n the effect size was calculated as the difference in mean outcomes of the insole group and brace group , divided by the sd of the outcome in the brace group . \n we used spss version 15.0 ( spss inc , chicago , il ) for statistical analysis . \n after 6 months , we observed no differences between the insole group and the brace group for vas pain scores ( mean , 0.06 ; 95% confidence interval [ ci ] , 1.05 , 0.93 ; effect size , 0.03 ) and womac function scores ( mean , 0.15 ; 95% ci , 7.95 , 7.65 , effect size , 0.008 ) . compared with baseline , the pain severity and womac function scores improved in both groups ( table 2 ) . the intention - to - treat and per - protocol analyses showed no differences in percentages of responders ( improvement of 20% compared with the baseline scores for vas pain and womac function ) between the insole and the brace groups ( 13% versus 20% and 14% versus 18% , respectively).table 2primary and secondary outcomes changes compared with baselineoutcomeinsole group ( n = 45)brace group ( n = 46)difference between groupseffect sizepain severity ( vas , 010)0.9 ( 2.4)1.0 ( 2.2)0.06 ( 1.05 , 0.93)0.03function ( womac , 0100)4.2 ( 16.9)4.0 ( 18.9)0.15 ( 7.95 , 7.65)0.008hka angle ( )0 ( 0.9)0.3 ( 1.0)0.22 ( 0.68 , 0.25)0.22 * values are expressed as means , with sds in parentheses ; four patients were lost to followup ; values are expressed as means , with 95% confidence intervals in parentheses , and are corrected for gender and use of pain medication at baseline and followup ; vas = visual analog scale ; hka = hip - knee - ankle angle . \n primary and secondary outcomes changes compared with baseline * values are expressed as means , with sds in parentheses ; four patients were lost to followup ; values are expressed as means , with 95% confidence intervals in parentheses , and are corrected for gender and use of pain medication at baseline and followup ; vas = visual analog scale ; hka = hip - knee - ankle angle . \n varus alignment correction when wearing the insole or brace was similar in the two groups ( 0.22 ; 95% ci , 0.68 , 0.25 ; effect size , 0.22 ) . \n the mean varus alignment ( hka angle ) for the insole group ( 6.9 ; sd , 3.6 ) was similar ( p = 0.8 ) at baseline compared with when wearing the wedge ( 6.9 ; sd , 4.1 ) . \n the mean hka angle for the bracing group was similar ( p = 0.3 ) with ( 7.0 ; sd , 3.6 ) and without the brace ( 6.7 ; sd , 3.2 ) . at 6 months , 71% of patients in the insole group complied with the treatment , which was greater ( p = 0.015 ) than 45% for the brace group . \n the laterally wedged insole was worn longer ( p = 0.006 ) during the week , with a mean of 57.8 hours ( sd , 28.8 hours ) in comparison to a mean of 38.8 hours ( sd , 32.2 hours ) for the knee brace . \n subgroup analysis stratified for patients with mild oa ( kellgren - lawrence grade 1 ) showed a slightly greater ( p = 0.068 ) percentage of responders in the insole group ( 46% ) than in the brace group ( 15% ) . \n skin irritation was the main complaint in the brace group ( n = 10 ) , and two patients had small blisters develop that had no clinical consequences . \n there is controversial evidence regarding whether foot orthoses or knee braces improve pain and function or correct malalignment in selected patients with oa of the medial knee compartment . \n insoles may represent a substantial treatment potential because they are safe and generate fewer costs than knee bracing . \n we asked whether laterally wedged insoles or valgus braces would reduce pain , enhance functional scores , and correct varus malalignment . \n first , the assessor was also the caregiver , and the one who informed the patient about the aims of the study . \n although the kind of interventions did not allow blinding of patients , the study would have been stronger by blinding the assessor for the functional outcome measurement ( clinical knee score ) , eg , by using an independent assessor . \n we used an exploratory approach but realize we did not determine our sample size to test for subgroup interactions . \n interaction tests have high false - negative risks , and results should be translated into practice with caution . \n third , our power permitted us to detect a 15% difference in pain reduction from baseline between the two groups . \n in hindsight , this may have been too optimistic because a recent crossover study failed to show changes greater than 10% between a neutral and a laterally wedged insole . \n these small effects for the insole and brace groups probably prevented us from observing differences between the two treatments . \n fourth , this study had a comparative effectiveness design , and the lack of a true control group may mean the changes observed in both groups are not real . \n fifth , the study was conducted in a tertiary referral university medical center that may affect the external validity of the study . however , the eligibility criteria were not highly selective and we believed the potential recruits were representative of patients in the local community . \n we found no differences in pain reduction and knee function improvement for laterally wedged insoles compared with valgus knee bracing for treatment of medial compartment knee oa after 6 months . according to the omeract - oarsi set of responder criteria for clinical trials in oa , 13% and 20% of our patients benefited from either the insole or brace treatment . \n the compliance in the insole group was greater compared with that for brace therapy , and the laterally wedged insole was worn longer during the day with a mean of 8 hours compared with 5.5 hours for the brace . \n subgroup analysis showed a better effect for the insole compared with the brace for patients with mild medial oa . \n described improvement on the womac pain scale of 9% in 41 patients treated with an unloader valgus brace , which was better than a nonbraced control group . \n brouwer et al . noted a better knee function score ( an improvement of 4 units of 100 ) after valgus bracing compared with nonbracing in a group of 95 patients with medial knee \n a recent crossover rct concluded wedged shoe insoles were not efficacious in patients with medial knee \n they compared laterally wedged insoles with neutral insoles , which may act as shock absorbers and relieve symptoms . \n we found a laterally wedged insole and a knee brace improved pain by a mean of 1 unit ( of 10 ) and function by a mean of 4 units ( of 100 ) from baseline . \n the omeract - oarsi defines a response to the treatment as having an improvement of 20% or greater for pain and function compared with baseline . \n we found no difference in percentage of responders ( 13% and 20% ; respectively ) between treatments after 6 months of followup . \n pham et al . also reported low percentages of responders for pain ( 27% ) and function ( 29% ) in patients treated with a laterally wedged insole after 12 months . \n it may be too ambitious to expect a 20% or greater improvement in function , especially when one bears in mind established operative treatments such as valgus - producing high tibial osteotomy in patients with adequate correction achieved only 12% improvement on a 100-point hospital for special surgery scale 1 year postoperatively . \n some authors have suggested lateral - wedge foot orthoses and braces unload the diseased medial compartment and improve symptoms by providing valgus stress [ 10 , 25 ] . \n we used a 10-mm cork elevation , which represents a 6 lateral wedge , because more elevation is uncomfortable to wear . \n a specialized orthopaedic technician applied the noncustom - made knee brace and adjusted valgus alignment as tolerated . \n our analysis showed no reduction in varus malalignment with the use of a laterally wedged insole or a knee brace . \n alignment only provides a static impression , and correction in the frontal plane may not affect clinical outcomes in the short term . \n reported that when knees with medial compartment oa are braced , neutral alignment performs as well as or better than valgus alignment . \n studies on the gait of a small number of patients suggest insoles and knee braces reduce the adduction moment about the knee [ 16 , 24 ] . \n the improvement in knee pain we observed in both groups may be attributed to unloading of the diseased compartment during gait . the optimal amount of time to wear an insole or brace during the day has not been determined . \n shoe inlays potentially may reduce knee stresses by acting as a shock absorber whereas proprioception may play a major role in the working mechanism of a brace . \n we defined compliance rather arbitrarily as occurring in patients wearing the insole or the brace 6 hours a day . \n although compliance was greater in the insole group than in the brace group , no differences in clinical outcomes could be detected after 6 months . \n reduction of muscle cocontractions may continue even after removing the insole or brace , which would result in a lasting effect . \n perhaps there is a threshold in time after which wearing the insole or brace does not contribute to the effectiveness . \n ogata et al . suggested laterally wedged insoles are most effective in patients with low - grade oa . based on explorative subgroup analysis \n , we found almost of our patients with medial oa ( < kellgren - lawrence grade 2 ) responded to the laterally wedged insole after 6 months . \n we found a 10-mm laterally wedged insole was well tolerated and provided a borderline better response than valgus bracing in patients with kellgren - lawrence grade 1 oa . especially for patients who do not want to undergo surgery \n , this may provide an alternative treatment option , which may be the focus of future research . \n few good clinical studies have been published on orthoses or bracing for treatment of medial compartment knee \n based on our data we conclude laterally wedged insoles may be an alternative to knee bracing for noninvasively treating the symptoms of medial knee oa .", "role": "user" }, { "content": "background there is controversial evidence regarding whether foot orthoses or knee braces improve pain and function or correct malalignment in selected patients with osteoarthritis ( oa ) of the medial knee compartment . \n however , insoles are safe and less costly than knee bracing if they relieve pain or improve function.questions/purposeswe therefore asked whether laterally wedged insoles or valgus braces would reduce pain , enhance functional scores , and correct varus malalignment comparable to knee braces.patients and methodswe prospectively enrolled 91 patients with symptomatic medial compartmental knee oa and randomized to treatment with either a 10-mm laterally wedged insole ( index group , n = 45 ) or a valgus brace ( control group , n = 46 ) . \n all patients were assessed at 6 months . \n the primary outcome measure was pain severity as measured on a visual analog scale . \n secondary outcome measures were knee function score using womac and correction of varus alignment on ap whole - leg radiographs taken with the patient in the standing position . additionally , we compared the percentage of responders according to the omeract - oarsi criteria for both groups.resultswe observed no differences in pain or womac scores between the two groups . \n neither device achieved correction of knee varus malalignment in the frontal plane . according to the omeract - oarsi criteria , 17% of our patients responded to the allocated intervention . \n patients in the insole group complied better with their intervention . \n although subgroup analysis results should be translated into practice cautiously , we observed a slightly higher percentage of responders for the insole compared with bracing for patients with mild medial oa.conclusionsour data suggest a laterally wedged insole may be an alternative to valgus bracing for noninvasively treating symptoms of medial knee oa.level of evidence level i , therapeutic study . \n see the guidelines for authors for a complete description of level of evidence .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: advances in genetic epidemiology have revealed that some genetic variants increase the risk for is . \n evidence suggests that genetic variation in the rennin angiotensin - aldosterone system ( raas ) contributes to the risk of ischemic stroke . among the various sequence variations in raas , \n the insertion / deletion ( i / d ) polymorphism in angiotensin i- converting enzyme ( ace ) is the most extensively studied . \n ace is a dipeptidyl carboxylase that converts angiotensin i into the antinatriuretic vasoactive angiotensin ii , an octapeptide involved in vasoconstriction , aldosterone production , and norepinephrine release from sympathetic nerve endings and inactivates bradykinin , a vasodilator and natriuretic substance . \n ace is encoded by a 21-kb 26 exons gene located on chromosome 17 at q23 . \n a deletion polymorphism in the ace gene consists of the absence of a 287-bp alu repetitive sequence in reverse orientation near the 3 end of intron 16 . \n mean ace activity concentration in dd carriers are around twice those found in ii carriers ( 1 , 2 ) . \n the purpose of this study was : a ) to report the distribution of ace genotypes and alleles in patients with ischemic stroke ( is ) , b ) to investigate the impact of ace polymorphism on serum lipid and apolipoprotein concentrations , as well as on ace activity and arterial blood pressure level . \n blood samples were obtained from 65 unrelated subjects with acute is ( mean age 41 ) . \n acute stroke patients were separated into two groups : one with large vessel disease ( 45 patients ) and the other with small vessel disease ( lacunar stroke ) ( 20 patients ) . \n they did not show any signs of cerebrovascular disease from their health questionnaires and clinical examinations . \n informed consent was obtained from each participant in the study ; and all procedures were in accordance with the helsinki declaration . \n dna was extracted by triton x-100 lysis , proteinase k digestion and phenol / chloroform extraction . \n the reaction pertaining to ace was performed with 20 pmol of the sense strand - specific primer sa66 , 7 pmol of the anti - sense strand - specific primer 167 , and 1.5 pmol of another i allele sense strand specific primer ace3 , as previously described ( 3 ) . \n amplification products pertaining to i / d polymorphism were separated by electrophoresis in 1.8 % ( w / v ) agarose gels . \n all gels were visualized and analyzed by gds8000 gel documentation system ( ultra violet products inc , upland ) . \n ace activity was determined in serum samples using commercial test ( trinity , biotech ) . \n results are presented as mean s.d . for continuous normally distributed variables , and as percent for categorical data . \n comparisons between normally distributed continuous variables were performed by the student s t - test and anova . \n if the distribution of quantitative variables was skewed , log - transformed values were used for the analysis . \n association between categorical variables was tested by the chi - square test for contingency tables . \n according demographic and clinical data of stroke patients and controls , we found that stroke patients were more often female , smokers , and hypertensive compared with controls . \n ace genotypes and allele distribution among cases and controls were also determined and presented in table 1 . \n there was no significant difference in the distribution of ace gene variant between cases and controls . \n table 2 shows the ace genotype and allele distribution among patients with large vessel stroke and small vessel ( lacunar ) stroke . \n patients with d allele had 9.21 ( 95% ci 1.6750.96 ) times higher risk for large vessel disease than lacunar stroke . \n patients with d allel had 4,68 ( 95% ci 1.1019.86 ) times higher risk for large vessel stroke than healthy persons d allele possessors . patients - carriers of dd genotypes had significantly higher ( p<0,05 ) tryglicerides , apolipoprotein b , higher ace catalitic activity , and significantly lower ( p<0,05 ) hdl - choleterol and apolipoprotein ai concentrations compared with control group . \n patients with is had higher levels of systolic blood pressure , diastolic blood pressure , mean arterial pressure and pulse pressure regardless of ace genotype they possess . \n there was no significant difference in serum lipids , apolipoproteins and blood pressure levels according ace genotype in stroke patients group . \n patients with dd genotype had significantly higher catalitic ace activity than patients with ii or i d genotype . \n this is the first study in serbia that has examined the effect of ace i / d gene polymorphism on is risk . \n no significant evidence was provided to support our hypothesis that ace gene polymorphism may represent a susceptibility mutation for is . \n previous reports on ace gene polymorphism and is produced conflicting results as to the importance of ace alleles in predisposition to is . \n we compiled results from 7 meta - analyses and 53 case - control studies ( table 4 ) . \n the first meta - analysis has evaluated the risk of stroke in 1196 subjects versus 722 controls from seven studies . \n it was concluded that the ace genotype conferred a small but modest effect , with an odds ratio of 1.31 ( 95% ci 1.061.62 ) , according to a dominant model of inheritance . \n a weaker association was seen under a recessive model ( 57 ) . in a meta - analysis of casas \n et al . ( 58 ) including 2990 predominantly white patients and 11 305 controls , the dd genotype was shown to confer a small but significant risk of ischemic stroke ( odds ratio 1.21 ; 95% ci 1.081.35 ) . from 2007 - 2009 five meta - analysis were published . \n ( 59 ) investigated the association of ace i / d in three ethnic groups of non - european descent ( a total of 3572 chinese individuals , 1601 japanese individuals , and 2750 korean individuals ) . the overall or for the nine studies in the chinese population was 1.90 ( 95% ci 1.232.93 ) and for six japanese studies the or was 1.74 ( 95% ci 0.883.42 ) . the overall or in the asian group ( chinese and japanese ) was 1.82 ( 95% ci 1.282.60 ) . \n ( 60 ) included six studies and did not detect a significant association with ace gene insertion / deletion polymorphism . \n xu et al . ( 61 ) identified statistically significant associations with is and ace i / d ( or = 1.87 , 95% ci = 1.452.42 ( 15 studies , 1935 patients/1485 controls ) . \n ( 62 ) analyzed 29 studies in chinese population ( 3654 patients/3058 controls ) and found that ace dd genotype is a risk factor cerebral infarction in chinese population ( or 1,91 ( 95% ci 1,562,34 ) , p<0,00001 ) . \n rao et al . ( 63 ) investigated the association of is subtypes of subjects with the ace i / d polymorphism published in 11 papers and gave ace / dd or 1.31 for small vessel stroke ( 95% ci 0.961.79 , p = 0.09 ) compared to large vessel stroke ( or 1.02 , 95% ci 0.821.26 , p = 0.88 ) showed a preferential association for the dd genotype with small compared to large vessel disease . \n twenty three out of 53 studies ( table 4 ) examined the association of ace gene polymorphism and ischemic stroke yielded a significant association with is . \n only a few studies have been done on the association of the ace i / d polymorphism with lacunar infarction . \n markus et al . ( 7 ) studied this polymorphism in a small series of lacunar infarction cases ( n=18 ) in which there was a positive association between d alele and lacunar infarction ; or associated with the dd genotype for lacunar stroke was 5.60 ( 95% ci , 2.00 to 15.71 ) . \n study on a japanese population found that , in hypertensive patients only , the ace d allele was associated with silent brain infarction ( 11 ) . \n however , this result was not replicated in another study using a larger population of lacunar infarction patients ( n=130 ) ( 9 ) . \n watanabe et al . ( 18 ) showed no association of the ace polymorphism with sbi in a smaller population ( n=36 ) . \n ( 64 ) failed to show an association with number of lacunae in 134 japanese patients . \n discrepancy in the obtained results can be explained by heterogeneity of study designs employed , differences in inclusion and exclusion criteria , ethnically different patient populations , small sample sizes , unmatched controls , combinations of ischemic and hemorrhagic strokes , different stroke subtypes and age of stroke onset , type of statistical evaluation , covariates , correction for multiple testing , and other factors that affect many publications . \n there is less literature data about the association of serum lipids and apolipoproteins with ace i / d polymorphism in patients with is . \n del ser et al . ( 65 ) showed that serym triglycerides concentration is elevated in stroke patients with dd ace genotype . \n ( 14 ) found significant association of triglycerides concentration and dd genotype ( dd > id = ii ) . \n it can be hypothesized that the increased serum triglycerides level in dd ace genotype could be a feature of an insulin resistence syndrome and determine atherogenic and thrombogenic risk ( 65 ) . \n agerholm - larsen et al . ( 66 ) determined the effect of ace genotype on serum ace activity in 900 women and men from the copenhagen city heart study and found that ace gene polymorphism explains 30 - 40% of variability in serum ace activity and this effect was codominant , with dd subjects having the highest , i d subjects intermediate , and ii subjects the lowest serum ace activity . \n the relatively small number of published studies with contradictory results examined the association between ace activity and ace i / d polymorphism in patients with is compared to the number of studies that examined only the association of ace i / d polymorphism polymorphism with is . \n our study showed expected trend in ace activity ( dd > id > ii ) in patient and control groups . \n patients with dd genotype had significantly higher ace activity ( p<0,05 ) compared with controls . \n this result is in accordance with croatian study ( patients with angiographicaly proved cerebral atherosclerosis ) ( 14 ) . \n ( 46 ) examined turkish acute stroke patients ( 185 ) although ace activity was high in dd genotype , no difference was determined to ace enzyme activity according to ace genotypes in patients and controls . \n some studies suggested that d allele of the ace gene is a marker of an elevated circulation ace level . \n catto et al . ( 9 ) reported plasma ace activity significantly lower in stroke patients ( cerebral infarction or cerebral hemorrhage ) than in controls , and levels of ace activity were significantly lower during the acute phase of stroke but were similar to level of control activity after 3 months . \n ( 7 ) found that patients with is and dd genotype has higher ace activity compared with carriers of ii genotype . \n we expect that subsequent genome - wide association studies in large and well - characterized groups of patients of different ethnic origin will contribute substantially in the near future to a better understanding of the pathophysiology underlying ischemic stroke and permit the identification of new therapeutic targets aimed at stroke prevention and neuroprotection from ischemic injury .", "role": "user" }, { "content": "the possible association of ace polymorphism with ischemic stroke ( is ) was evaluated in 65 patients with is and 330 age and bmi - matched controls . \n ace genotypes were determined by polymerase chain reaction ( pcr ) . \n there was no significant difference in ace genotype / allele frequencies between case and control group ( p>0.05 ) . \n patients with d allele had 4,7 times higher risk for large vessel is than healthy persons d allele possessors . persons with d allele had 9.2 times higher risk for large vessel disease than small vessel disease . \n these data suggest a possible association of ace gene polymorphism with pathogenesis of large vessel is .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: rapid growth in the area of medical genetics is providing a wealth of new options for dealing with genetic disease . these technologic advances often pose unique and significant ethical dilemmas which must be resolved by providers of genetic services and individuals who receive those services , as well as society in general . reproductive options such as artificial insemination by donor , genetic screening , in vitro fertilization , sex selection via prenatal testing , surrogate motherhood , foetal tissue transplantation , and gene therapy have generated considerable ethical concerns . as genetic counsellors relay important genetic and reproductive information to families at risk and to the public , they often play an important role in the way the relevant ethical issues are understood and acted upon . \n major ethical principles24 which govern the attitudes and actions of counsellors include ( i ) respect for patient autonomy , or the patient 's right to information and his / her right to make his / her own decisions , non - maleficence , which is defined by fletcher et al5 as one 's duty to minimize or prevent the infliction of harm on individuals and families ; ( ii ) beneficence , or taking action to help benefit others and prevent harm , both physical and mental , and ( iii ) justice , which requires that services be distributed fairly to those in need . \n other moral issues include veracity , the duty to disclose information or to be truthful , and respect for patient 's confidentiality . \n nondirective counselling , a hallmark of the genetics profession , is largely in accordance with the principle of respect for patient autonomy and incorporates the other ethical principles as well . \n information about the individual , family history , carrier status , risk of genetic disease to self or offspring can be stigmatising and hence needs to be kept confidential . \n most of the time the client is concerned about the future reproductive or personal health risks . \n the counsellor has to make an assessment by obtaining family history and by analysing the pedigree chart to provide information regarding the treatment options , preventive strategies including reproductive options and the financial and social implications . \n hence , a thorough assessment of the socio - cultural issues is essential along with large scale awareness programmes including comprehension of the information amongst young adults , patients and their relations and the medical professionals themselves with the help of religious , social leaders , social organisations , patient support groups and effective mass communication systems like radio , tv , films , periodicals , etc . to create public awareness \n ( i ) initial shock and denial ; ( ii ) subsequent anger and guilt ; ( iii ) followed by anxiety and depression ; and finally ( iv ) the phase of acceptance and adjustments . \n the counsellor needs to handle the clients carefully through the different phases to bring them out of each phase . \n the common indications for genetic counselling are occurrence of congenital malformations , mental retardation , neurogenetic disorders , myopathy , ambiguous genitalia , skeletal dysplasias , childhood deafness , down 's syndrome , haemoglobinopathies , haemophilia , wilson 's disease , mucopolysaccharidosis , familial cancers , consanguinous marriage , advanced maternal age , etc6 . \n genetic counselling is a multistep process involving clinical expertise and psycho - social impacts , hence specially trained clinicians can offer better counselling to such individuals and families . \n the steps involved include history taking along with drawing up the pedigree chart , clinical examination , diagnosis , management , advice on risk of recurrence and available preventive measures including prenatal diagnosis , wherever available . \n advances in the post - genome era have transformed the genetic counselling based on mendelian probabilities to the science of certainty based on antenatal diagnosis . \n a genetic counsellor needs to have excellent communication skills . a primary care physician or paediatrician or many times \n an obstetrician are the ideal clinicians who need to undergo training in genetic counselling as these specialists can provide a complete fullest comprehension of the disease to the families at risk and help them through their problems and facilitate their decision making for adjustments as well as reproductive choices . \n many a times specially trained individuals belonging to other specializations such as nursing or social sciences may take up the responsibility of genetic counsellor . \n such counsellors should have the required medical knowledge , necessary skills for providing efficient and effective counselling and also proper attitude , behaviour and appropriate training . \n there can not be a universal model for genetic counselling because counselling is an understanding of a set of facts according to the counsellors frame of reference , background in the science of genetics , and previous training and experience in effectively communicating with the consultee . in order to communicate effectively \n , the counsellor must consider the educational background of the consultee , what to disclose and how to limit the ways in which he or she can communicate . it has been found that the principal obstacles to the effective use of genetic counselling are emotional conflicts , and lack of knowledge of genetics and biology . an equally difficult assignment for the counsellor is presenting his / her knowledge in an unbiased manner5 . \n it is difficult for a counsellor to impart unbiased information because of the consultee 's personal and family history such as parental age , ethnic background , reproductive history , i.e. abortions , stillborn or dead siblings , and the age , sex and health of the living children . \n this may lead the counsellor to adopt a directive rather than a non - directive approach to genetic counselling . \n the major difference between directive and non - directive counselling is whether or not the counsellor actively participates or helps the consultees to make a decision . \n the non - directive approach involves presentation of the facts in an unbiased manner , leaving the entire responsibility of decision with the consultee . \n counsellors can be faced with dilemma in respect to certain inherited conditions because of improper measurements and observations and/or because of similar symptoms of many genetic diseases . \n however , the counsellor probably can not completely disassociate himself / herself from his / her own values and present the information in such a way that the recipient is not completely free to make his / her own judgement . \n the counsellor may not change the truth but the tone , manner of speech and other facial and body gestures can influence the information transfer . in a case where a counsellor feels that a pregnancy might be best for a family he / \n she could say to mr and mrs x , there is only one chance in four that your child would be affected . \n your chances for a healthy birth are very high , three chances out of four or 75 per cent. for family y with these same inherited defect , but a different social history , the counsellor may emphasize more on the problems that may arise because of the particular disorder . during counselling , \n the counsellor may come across other findings , that may put him in a situation of ethical dilemma7 . \n some of these are foetal sex , findings of questionable or potentially harmful significance , false paternity , etc . \n is there a need to disclose foetal sex to parents , if this finding is not related to any disease , except in x - linked disorders ? \n should physicians co - operate with the desire of the parents or individuals autonomy to know the foetal sex , especially when there may be reason to suspect that some parents will misuse the information and seek abortion elsewhere for undesired gender ? occasionally , disputes arise about the significance of laboratory findings especially about the true vs. pseudo - mosaicism or by possibility of contamination by maternal cells . when genuine doubt exists and it is too late to do a repeat procedure , what should the parents be told ? should conflict about findings and interpretations between professionals \n another example is when sonography suggests an irregularity of the foetal head but the amniotic fluid is normal for alpha - fetoprotein . \n the issue is whether the disclosure of a finding of probably small significance will result in severe parental anxiety leading to psychological problems . \n another difficult conflict involves males and females with normal phenotypes who are discovered to have xx or xy chromosomal complement , respectively . should they be told \n ? will a full biological explanation harm their self - esteem and damage them psychologically ? \n medical geneticists learn many family secrets , such as previous abortions , previous abnormal births , and occasional false paternity . \n the findings can be made after pnd ( prenatal diagnosis ) of a recessive disorder and testing the carrier parents or in the context of genetic screening after the birth of an affected child . \n the putative father believes that he must be a carrier , but tests are negative . \n should the family be protected from the disruption due to disclosure , with the risk of inappropriate decisions about future child bearing being based on false information ? should actual risk be revealed with no explanation ? should the mother be told the truth leaving the option to her to decide about further disclosure ? \n thalassaemia and sickle cell anaemia are the commonest haemoglobinopathies among the single gene disorders in india and their prevalence varies from 3 - 10 per cent in different populations . \n sickle cell disorders are much more frequent in specific population groups including some primitive tribes . \n high prevalence of these disorders , availability of good and sensitive carrier detection tests and prenatal diagnostic techniques make these conditions good candidates for population screening of carriers along with genetic counselling for primary prevention of the disease . \n screening of the extended family members of the affected child , high risk communities and general population screening are the different target groups for planning a haemoglobinopathy control programme as was done in countries like cyprus , greece and sardinia . \n what is being tested and why. counselling before the test should include complete information about the burden of the disease , and the implication of being detected as a thalassaemia carrier . \n it should be made clear to them that in majority of cases there are no health consequences to the carriers . \n the tests for carrier detection are available and it is possible to prevent the birth of an affected child if appropriate actions are taken at appropriate time by opting for prenatal diagnosis at the identified centres . the occurrence or recurrence in a family , the economic , social and psychological impacts , resources available to the family and the strategies for prevention have to be explained . \n the counsellor is expected to present all the information fairly and even - handedly without encouraging a particular course of action i.e. , a non - directive counselling and the client is encouraged to take autonomous decision on the future course of action after understanding the implications of the different strategies available . \n population screening is adapted as a national strategy in small countries to prevent genetic disorders specially haemoglobinopathies8 . in a country like india \n it is a major challenge and antenatal diagnosis of pregnant woman can be a possible , feasible strategy to prevent birth of a thalassaemic child . \n it is possible for the genetic counsellors to approach this target group in antenatal clinics under the national family welfare programme . \n diagnostic accuracy and safety for mother and foetus , abortion of the foetus diagnosed as homozygous for thalassaemia or sickle cell diseases , and access to prenatal diagnosis for those who can not afford it are the current ethical debate although more instances of persons coming forward for antenatal diagnosis are coming to light . \n the indian council of medical research conducted two multi - centric studies , one on community control of thalassaemia in six states9 and the other on sickle cell disorders amongst fourteen ethnically different primitive tribal population in four s0 tates over a period of five years10 from 2000 to 2005 for carrier detection , identifying index cases and screening of antenatal women for possibility of prenatal diagnosis along with genetic counselling . \n this was the first study in india reporting on the effects of genetic counselling in the primitive tribes . \n many of the marriageable youths counselled came forward for premarital screening indicating an effective counselling . similarly counselling high risk communities like sindhis , lohanas , banushallis , kutchis , etc . with targeted screening of these population groups for thalassaemia \n it is interesting to note that when the thalassaemia carrier screening was started in assam and west bengal the response was very poor . \n however , after intense awareness programme in the community and counselling on one to one basis the success in screening programme has increased tremendously in west bengal and assam . \n counselling extended families of the affected children is the most rewarding strategy adapted to reduce the burden of thalassaemia and other haemoglobinopathies although the fear of stigma and financial burden has prevented many eligible couples to come forward for carrier detection and prenatal diagnosis . \n unless all these groups are approached with sustained efforts by trained counsellors , no control programme can accomplish reduction in disease burden in the country . establishing testing centres alone without the necessary critical mass of trained counsellors and appropriate counselling strategies to understand and interpret \n the implication of the test results , will not be able to address the issues involved in genetic screening programmes . \n the need of the hour is to create a critical mass of trained genetic counsellors in the country which is grossly lacking at present . \n the only institution in the country at present to generate such human resource is sanjay gandhi postgraduate institute of medical sciences ( sgpgims ) , lucknow . \n more such centres need to be established in different regions of the country to face the challenge of controlling genetic disorders to reduce the morbidity . \n moral problems arise constantly in social life with the need to resolve conflicts between moral rules and principles to help , regulate and modify desires . when genetic risks are high , the desire to have a healthy child and to avoid danger to oneself , family and society are frequently in conflict . \n although more than 90 per cent of the counselling sessions end well with no or very little chances for the occurrence of the disease , the remaining people in the high risk category are left with three options : ( i ) prenatal diagnosis and abortion if required , ( ii ) artificial insemination , and ( iii ) gene therapy genetic counselling is a practical method of calculating risk figures , intended for information regarding the unborn , and we ought to use it in an efficient manner but in a direction , which our ethics and morality point to . \n the decision taken by the parents after the counselling session must leave them satisfied instead of placing them in a state of dilemma . application of science and scientific principles has two faces . to decide the correct use , man must deal with his conscious , individuals and social status and the ethics underlying the applications . \n rapid technological progress in the field of genetics demands the moral and ethical attention of each medical geneticist and genetic counsellor . \n these professionals are in an ideal position to understand and influence the ethical impact of new technology on the individuals and society . \n it is important that genetic counsellors continue being patient advocates while ethical guidelines for their use with appropriate counselling procedures are developed after ensuring adequate human resource in this area . \n there is an urgent national requirement to generate more trained genetic counsellors who can approach the problem with the understanding of the ethical issues and its appropriate handling with the sensitivity required for such conditions .", "role": "user" }, { "content": "genetic counselling is provided in places where genetic tests are carried out . \n the process involves pre - test counselling as well as post - test counselling to enable the individuals to face the situation and take appropriate decisions with the right frame of mind . \n major ethical principles which govern the attitudes and actions of counsellors include : respect for patient autonomy , non - maleficence , beneficence , or taking action to help benefit others and prevent harm , both physical and mental , and justice , which requires that services be distributed fairly to those in need . \n other moral issues include veracity , the duty to disclose information or to be truthful , and respect for patient confidentiality . \n nondirective counselling , a hallmark of this profession , is in accordance with the principle of individual autonomy \n . high prevalence of haemoglobinopathies with availability of good and sensitive carrier detection tests and prenatal diagnostic techniques makes these good candidates for population screening of carriers along with genetic counselling for primary prevention of the disease . \n screening of the extended family members of the affected child , high risk communities and general population screening including antenatal women are the main target groups for planning a haemoglobinopathy control programme \n . a critical mass of trained genetic counsellors who have understanding of the ethical issues and its appropriate handling with the required sensitivity is needed in india .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: hyperopic laser vision correction is considered challenging for refractive surgeons ( 1 , 2 ) . \n although lasik is considered by many refractive surgeons as the preferred technique , hyperopic correction presents additional challenges , starting from accurate detection of patient manifest refraction and integration of the cycloplegic refraction in this process followed by accurate centeration ( 19 ) . \n basically , the aim of excimer laser photo ablation in the case of hyperopic correction is to induce relative steepening in the central part of the cornea ; this target is achieved by an annular ablation profile , which induces more flattening in the corneal periphery ; thus , it is considered more challenging than the myopic ablation , which induces direct flattening in the corneal central area ( 1 , 3 ) . \n another difficulty is that hyperopic correction ablation time is longer than the equivalent dioptric correction for myopic refraction , which makes it more sensitive to patient eye movement and requires an accurate and fast eye - tracker in order to ensure that you place your laser ablation in the planned location ( 2 ) ; this problem may be further complicated by the fact that most of the patient who are seeking hyperopic refractive surgery are relatively old , so they may have a problem in fixation to a near target during ablation due to the presbyopic element , which may lead to de - centeration of the ablation . \n this problem is largely overcome by the newer , accurate eye - trackers combined with faster excimer laser systems ( 10 , 11 ) . another dilemma is where to center the ablation profile : the corneal vertex , the pupil center , or somewhere in between in order to estimate the true visual axis ; the problem is even exaggerated in these patients , as they usually have a wider - angle kappa ( 10 , 11 ) . \n higher incidence of epithelial ingrowth as the ablation occurs in the periphery adjacent to the flap edge so the epithelium might find a way under the flap to the deep ablated zone ( 12 ) . greater tendency of regression has been reported ( 5 , 13 ) , which may be explained by postoperative loss of accommodative spasm , mechanical instability of corneal tissue biomechanics , and/or irregular epithelial remodeling over the ablation zone ( 13 ) . \n several advancements in hyperopic lasik technique have been applied to overcome some of the previously mentioned problems , including a larger optical zone , which requires larger flap making , nomogram refinement , and proper centration ( 13 ) . in our study , we assessed the refractive outcomes of femtosecond assisted hyperopic lasik performed for the correction of low to moderate hyperopia . \n this retrospective study comprised 20 egyptian patients ( 12 females and eight males ) who had femtosecond laser - assisted hyperopic lasik using refractive surgery suite ( wavelight fs200 femtosecond laser and wavelight ex500 excimer laser ; alcon laboratories , ft worth , tx , usa ) , between january 2012 and september 2013 in the research institute of ophthalmology and international eye hospital , giza , egypt . \n the mean age of the patients was 47.23.84 ( ranging from 42 to 56 years ) ; all treatments were performed by the same surgeon ( t.n ) . \n inclusion criteria included a postoperative follow - up of at least 12 months and preoperative stable refraction for at least one year , normal corneal tomography with expected postoperative steep k reading not more than 48d , and postoperative residual stromal bed not less than 300 m . \n exclusion criteria included a preoperative cdva of worse than 20/30 , previous ocular surgeries , and corneal , uveal or retinal diseases . \n the preoperative examination included measuring uncorrected distance visual acuity ( udva ) , corrected distance visual acuity ( cdva ) , manifest and cycloplegic refractions ; full ophthalmological examination included slitlamp biomicroscopy , goldmann applanation tonometry , and full fundus evaluation . \n corneal tomography with placido - based topolyzer vario topography ( wavelight , erlangen , germany ) and scheimpflug - based imaging system ( pentacam , oculus optikgerte gmbh ) were also performed in all cases . \n postoperative follow - up examinations were conducted at 1 day , 1 week , 1 month , 3 months , 6 months , and 1 year . \n femtosecond flap creation with a wavelight fs200 femtosecond laser system was performed with intended flap diameter of 9.3 mm to allow a large ablation zone and transitional zone , an attempted flap thickness of 120 m with superior hinge and side angle cut of 120 degrees . \n excimer laser photo ablation was performed after lifting the femtosecond created flap using a wavelight ex500 excimer laser system with an optical zone of 7 mm . \n the treatment was centered on the corneal vertex when the difference between the pupil centroid and corneal vertex was less than 0.30 mm , which was measured by the topolyzer vario topography ( wavelight , erlangen , germany ) . \n this study was approved by the institutional review board and adhered to the tenets of the declaration of helsinki . statistical analysis and graphs \n were done with standard spreadsheet software program using microsoft excel 2013 ( microsoft corporation , seattle , wa , usa ) . \n this retrospective study comprised 20 egyptian patients ( 12 females and eight males ) who had femtosecond laser - assisted hyperopic lasik using refractive surgery suite ( wavelight fs200 femtosecond laser and wavelight ex500 excimer laser ; alcon laboratories , ft worth , tx , usa ) , between january 2012 and september 2013 in the research institute of ophthalmology and international eye hospital , giza , egypt . \n the mean age of the patients was 47.23.84 ( ranging from 42 to 56 years ) ; all treatments were performed by the same surgeon ( t.n ) . \n inclusion criteria included a postoperative follow - up of at least 12 months and preoperative stable refraction for at least one year , normal corneal tomography with expected postoperative steep k reading not more than 48d , and postoperative residual stromal bed not less than 300 m . \n exclusion criteria included a preoperative cdva of worse than 20/30 , previous ocular surgeries , and corneal , uveal or retinal diseases . \n the preoperative examination included measuring uncorrected distance visual acuity ( udva ) , corrected distance visual acuity ( cdva ) , manifest and cycloplegic refractions ; full ophthalmological examination included slitlamp biomicroscopy , goldmann applanation tonometry , and full fundus evaluation . \n corneal tomography with placido - based topolyzer vario topography ( wavelight , erlangen , germany ) and scheimpflug - based imaging system ( pentacam , oculus optikgerte gmbh ) were also performed in all cases . \n postoperative follow - up examinations were conducted at 1 day , 1 week , 1 month , 3 months , 6 months , and 1 year . \n femtosecond flap creation with a wavelight fs200 femtosecond laser system was performed with intended flap diameter of 9.3 mm to allow a large ablation zone and transitional zone , an attempted flap thickness of 120 m with superior hinge and side angle cut of 120 degrees . \n excimer laser photo ablation was performed after lifting the femtosecond created flap using a wavelight ex500 excimer laser system with an optical zone of 7 mm . \n the treatment was centered on the corneal vertex when the difference between the pupil centroid and corneal vertex was less than 0.30 mm , which was measured by the topolyzer vario topography ( wavelight , erlangen , germany ) . \n this study was approved by the institutional review board and adhered to the tenets of the declaration of helsinki . \n statistical analysis and graphs were done with standard spreadsheet software program using microsoft excel 2013 ( microsoft corporation , seattle , wa , usa ) . \n to assess the refractive outcome of the procedure , udva , cdva , mrse , manifest refractive cylinder , and stability were compared preoperatively and 1 week and 1 , 3 , 6 , and 12 months postoperatively . \n following the recommendation of waring et al . for standardized graphs and terms for refractive surgery results , \n the data were plotted in set of six standard graphs summarizing efficacy , predictability , safety , refractive astigmatism , and stability using microsoft excel templates ( microsoft corporation , seattle , wa , usa ) designed by london vision clinic ( london , w1 \n g 7la , uk ) . regarding the efficacy , as shown in figure 1 , the preoperative cdva compared with 12 months postoperative udva showed that all the 20 eyes ( 100% ) reached udva of 20/25 or better , and 17 eyes ( 85% ) reached 20/20 of udva , which reflected excellent efficacy of the procedure . in figure 2 \n preoperative and postoperative cdva were analyzed , and the visual acuity lines gain and loss were plotted showing that no eye lost any line of the cdva , which reflected excellent safety of the procedure ; on the other hand , one eye ( 5% ) gained one line and one eye ( 5% ) even gained two lines ; these results reflect potential extra benefits of the procedure and might be explained by the correction made on the corneal level , which is optically better than that on the glasses level and might be related to aberrations induced by the hyperopic magnifying plus lens used to correct hyperopia . predictability and refractive accuracy : \n predictability was directly associated with a lower standard deviation ( sd ) and standard error of the se deviation from the target at any point and a better tightness of fit of the attempted se versus the achieved se plot ( reflected by the correlation coefficient r2 = 0.947 ) . \n the scattergram comparing the achieved spherical equivalent refraction versus the attempted spherical equivalent refraction of every eye showed that all the eyes were within + /1.00 d postoperatively , and 95% ( 19 eyes ) were within + /0.50 d 12 months postoperatively . \n further assessment of the refractive accuracy was analyzed ; figure 4 shows the exact distribution of the 12 months postoperative udva in the whole series . \n figure 5 shows a comparison between the preoperative refractive astigmatism and 12 months postoperative refractive astigmatism , 85% of the eyes ( 17 eyes ) had less than or equal to 1d of astigmatism 12 months postoperatively , and 30% ( six eyes ) had less than or equal to 0.5 d astigmatism 12 months postoperatively . \n stability was defined as the repeatability of first week postoperative spherical equivalent refraction over the 12 months of follow - up . \n figure 6 shows the stability curve over the 12 months follow - up period which was excellent . \n as previous studies reported better refractive results with femtosecond laser flap creation than with mechanical microkeratome flap creation ( 14 , 15 ) , the purpose of this study was to evaluate the refractive outcome of femtosecond - assisted lasik for the correction of hyperopia using the alcon - wavelight fs200 femtosecond laser system and the allegreto ex500 as using a femtosecond laser in flap creation has potential benefits , as it creates a smoother stromal bed under the created flap , which is assumed to yield better refractive outcomes after laser refractive surgery ( 1425 ) . in this study , \n a flap creation as large as 9.3 mm was intended to allow accurate placement of the peripheral laser ablation inside the stromal bed and avoid hitting the peripheral epithelium , which eventually will regenerate with no refractive effect , leading to a more accurate and potentially more stable ablation . a planar flap results in less cutting of peripheral stromal fibers ( 1425 ) . \n in addition , the stroma bed is relatively dry after flap lifting , which may improve the efficacy of laser ablation , resulting in more optimal refractive outcome of hyperopia correction ( 14 , 15 , 24 ) . \n further , strong adhesion of the flap in the postoperative period may produce a stronger biomechanical flap stability ( 20 ) . \n several studies ( 39 , 13 , 15 , 2632 ) reported the outcome of excimer laser photoablation to correct hyperopia with different platforms with variable follow - up periods . \n these studies showed a high safety profile of the procedure with good efficacy and predictability except in high hyperopic correction ( 13 ) . \n it should be noted that evaluating refractive outcomes after hyperopic lasik can be challenging , as some patients may still have some sort of accommodation power , and some of them did not wear glasses for distance and acquired some sort of accommodative spasm , which takes time to relax . \n another important factor is that assessing refractive stability could be difficult because manifest refraction in hyperopic eyes can increase with age due to reduced ability to compensate for latent hyperopia , which could be falsely interpreted as regression of the procedure outcome . in our study \n , femtosecond - assisted lasik appears to be safe , predictable , and effective in correcting eyes with hyperopia in the first week , and the results remain almost stable within the follow - up period ( 12 months ) . \n the small sample size might be a limiting factor in our study , and longer follow - up is needed for a better conclusion regarding stability of the procedure .", "role": "user" }, { "content": "introductionlaser vision correction for hyperopia is challenging . \n the purpose of the study was to assess the refractive outcomes of femtosecond - assisted laser in situ keratomileusis ( lasik ) for hyperopic correction using wavefront - optimized ablation profiles.methodsthis retrospective case series study included 20 egyptian patients ( 40 eyes ) with hyperopia or hyperopic astigmatism with a mean manifest refraction spherical equivalent ( mrse ) of + 2.55d1.17 ( range from + 1.00 to + 6.00 ) who had uneventful femtosecond - a assisted lasik with wavefront - optimized aspheric ablation profile using refractive surgery suite ( wavelight fs200 femtosecond laser and wavelight ex500 excimer laser ) performed in the research institute of ophthalmology and international eye hospital , giza , egypt . \n statistical analysis was done using microsoft excel ( microsoft corporation , seattle , wa , usa).resultsthe procedure significantly reduced the mrse and cylinder post - operatively ( 95% were 0.50d and 100% 1.00 d ) , with stability of refraction and udva over the follow - up period ( up to 12 months ) after surgery . \n no eye lost any line of the cdva , which reflects the excellent safety profile of the procedure ; on the other hand , one eye ( 5% ) gained one line and one eye ( 5% ) even gained two lines . \n there were no significant complications during the procedure.conclusionsfemtosecond-assisted laser in situ keratomileusis for hyperopia showed predictable , effective , and safe refractive outcomes that were stable through 12 months . \n longer follow - up period is required to detect any further regression", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: enamel demineralization is a significant consequence of orthodontic treatment in patients with poor oral hygiene and its prevention is one of the greatest challenges faced by clinicians despite recent advances in caries management . \n fixed orthodontic appliances not only make conventional oral hygiene procedures difficult but also increase the number of plaque - retentive sites on the surfaces of teeth that are normally less susceptible to caries development.1 after such appliances are introduced into the oral cavity , the microbial flora of plaque exhibits a rapid shift toward acidogenic bacteria , most notably streptococcus mutans and lactobacilli.2,3 therefore , caries progression is faster in patients with fixed orthodontic appliances . in particular , \n the development of white spot lesions ( wsls ) around brackets is attributed to prolonged plaque accumulation.4,5,6,7,8 wsls become noticeable within 1 month of bracket placement , whereas caries development usually takes at least 6 months.9 these lesions are commonly seen on the buccal surfaces of teeth with brackets , especially in the gingival region.4,8,10 fluoridated toothpastes are considered the most effective agents for preventing enamel demineralization . \n the efficacy of the conventional toothpaste ( 1,000-ppm fluoride ) has been documented in many studies ; evidence suggests that toothpaste containing 5,000 ppm fluoride can further reduce demineralization and enhance remineralization.11,12 however , complete elimination of wsls is unlikely because of rapid remineralization of the enamel surface in the presence of high fluoride concentration , which restricts the passage of ions into the deeper , more affected layers . \n therefore , direct application of a high concentration of fluoride is not recommended.13 another preventive method is application of low levels of fluoride and calcium ions , which can penetrate deep into wsls , such as in the form of a casein phosphopeptide . \n cpp - acp maintains a supersaturated state of calcium and phosphate to enhance enamel remineralization.14 at present , cpp - acp is available in a variety of gels , creams , and mousses and can also be incorporated into chewing gum . \n some initial reports have shown that clinpro tooth creme ( 3 m espe , st . \n paul , mn , usa ) , a 0.21% ( w / w ) sodium fluoride ( 950-ppm fluoride ) anticavity toothpaste containing functionalized -tricalcium phosphate ( ftcp ) , is useful for reducing wsls . \n this process prevents undesirable interactions between calcium and fluoride , which could render both inactive . \n ftcp stabilizes fluoride in solution and maintains high concentrations concentrations of calcium phosphate and fluoride in wsls . \n quantitative light - induced fluorescence ( qlf ; inspektor research systems , amsterdam , netherlands ) is a validated instrument for assessing the mineral contents of smooth - surface lesions.15 the aim of this in vitro study was to examine the effects of fluoridated , cpp - acp - containing , and ftcp - containing toothpastes on remineralization of wsls by using qlf - d biluminator 2 ( inspektor research systems ) , which is a new qlf system used in combination with high - definition digital single - lens reflex ( dslr ) imaging . \n forty - eight premolars extracted for orthodontic reasons from 12 patients at wonkwang university dental hospital were used as the specimens . \n the teeth had no visible cracks , hypoplastic areas , and buccal - surface caries . \n the enamel surfaces of the specimens were cleaned with a rubber prophylaxis cup at slow speed by using a mixture of nonfluoridated pumice and water . \n afterward , the teeth were rinsed with distilled water and thoroughly dried . then , the root part of each tooth was embedded in self - curing acrylic resin ( orthocryl ; dentaurum , ispringen , germany ) . \n the enamel surfaces were painted with an acid - resistant nail varnish , except for a window of 2 3 mm at the center of the buccal surface , to prevent contact with the demineralizing and remineralizing agents . when the varnish dried , each tooth was soaked in demineralizing solution at 37 for 96 hours to create wsls . \n louis , mo , usa ) and 0.2% carbopol etd 2050 polymer ( lubrizol , wickliffe , oh , usa ) saturated with calcium and phosphorus . \n the solution was changed daily during this experiment . at the end of the demineralization phase , the relative fluorescence loss ( finitial ) \n light - induced fluorescent images were captured by using an intraoral fluorescence camera ( inspektor research systems bv ) , stored on a personal computer with image - capturing software ( c3 version 1.16 ; inspektor research systems ) , and examined with analyzing software ( qa2 version 1.16 ; inspektor research systems ) . for the treatment phase , \n the specimens were rubbed with deionized water by using cotton swabs twice daily for 2 weeks . at other times , they were immersed in a 1:1 mixture of artificial and human stimulated saliva ( saliva solution ) to reproduce the oral environment . \n taliva solution ( hanlim pharm , seoul , korea ) was used as the artificial saliva ; table 1 shows its composition . \n stimulated saliva was collected from men in their twenties with no medical history and was centrifuged . \n only the upper layer of the centrifuged saliva was used for the experiment . on each specimen , 1,000-ppm fluoride - containing toothpaste ( 2080 ; aekyung industrial , seoul , korea ) \n was applied for 3 minutes twice a day over 2 weeks by using a toothbrush . \n cpp-acp.containing toothpaste ( gc tooth mousse ; gc , tokyo , japan ) was applied for 3 min to each tooth twice a day for 2 weeks by using a fingertip . \n ftcp - containing toothpaste ( clinpro tooth creme ) was applied for 3 minutes to each tooth twice a day for 2 weeks by using a toothbrush . \n the fluorescence value of each specimen measured with qlf - d biluminator 2 after the 2 weeks of treatment ( post - treatment ) was recorded as ffinal . \n the difference between ffinal and finitial ( f ) was calculated to quantify the change in fluorescence of each specimen . \n the measurements of the treatment groups were compared by using the mann - whitney u - test . \n statistical analyses were performed by using spss program ( version 14.0 ; spss inc . , \n chicago , il , usa ) . the level of statistical significance was established as p < 0.05 . at the pretreatment and post - treatment time points , the measurement errors by dahlberg 's formula were 0.2177 and 0.2220 , respectively , and the intraclass correlation coefficients were 0.994 and 0.995 , respectively . \n forty - eight premolars extracted for orthodontic reasons from 12 patients at wonkwang university dental hospital were used as the specimens . \n the teeth had no visible cracks , hypoplastic areas , and buccal - surface caries . \n the enamel surfaces of the specimens were cleaned with a rubber prophylaxis cup at slow speed by using a mixture of nonfluoridated pumice and water . \n afterward , the teeth were rinsed with distilled water and thoroughly dried . then , the root part of each tooth was embedded in self - curing acrylic resin ( orthocryl ; dentaurum , ispringen , germany ) . \n the enamel surfaces were painted with an acid - resistant nail varnish , except for a window of 2 3 mm at the center of the buccal surface , to prevent contact with the demineralizing and remineralizing agents . when the varnish dried , each tooth was soaked in demineralizing solution at 37 for 96 hours to create wsls . \n louis , mo , usa ) and 0.2% carbopol etd 2050 polymer ( lubrizol , wickliffe , oh , usa ) saturated with calcium and phosphorus . \n the solution was changed daily during this experiment . at the end of the demineralization phase , the relative fluorescence loss ( finitial ) \n light - induced fluorescent images were captured by using an intraoral fluorescence camera ( inspektor research systems bv ) , stored on a personal computer with image - capturing software ( c3 version 1.16 ; inspektor research systems ) , and examined with analyzing software ( qa2 version 1.16 ; inspektor research systems ) . \n for the treatment phase , the specimens were randomly and equally divided into four groups . the specimens were rubbed with deionized water by using cotton swabs twice daily for 2 weeks . at other times , they were immersed in a 1:1 mixture of artificial and human stimulated saliva ( saliva solution ) to reproduce the oral environment . \n taliva solution ( hanlim pharm , seoul , korea ) was used as the artificial saliva ; table 1 shows its composition . \n stimulated saliva was collected from men in their twenties with no medical history and was centrifuged . \n only the upper layer of the centrifuged saliva was used for the experiment . on each specimen , 1,000-ppm fluoride - containing toothpaste ( 2080 ; aekyung industrial , seoul , korea ) \n was applied for 3 minutes twice a day over 2 weeks by using a toothbrush . \n cpp-acp.containing toothpaste ( gc tooth mousse ; gc , tokyo , japan ) was applied for 3 min to each tooth twice a day for 2 weeks by using a fingertip . \n ftcp - containing toothpaste ( clinpro tooth creme ) was applied for 3 minutes to each tooth twice a day for 2 weeks by using a toothbrush . \n the fluorescence value of each specimen measured with qlf - d biluminator 2 after the 2 weeks of treatment ( post - treatment ) was recorded as ffinal . \n the difference between ffinal and finitial ( f ) was calculated to quantify the change in fluorescence of each specimen . \n the specimens were rubbed with deionized water by using cotton swabs twice daily for 2 weeks . at other times , they were immersed in a 1:1 mixture of artificial and human stimulated saliva ( saliva solution ) to reproduce the oral environment . \n taliva solution ( hanlim pharm , seoul , korea ) was used as the artificial saliva ; table 1 shows its composition . \n stimulated saliva was collected from men in their twenties with no medical history and was centrifuged . \n on each specimen , 1,000-ppm fluoride - containing toothpaste ( 2080 ; aekyung industrial , seoul , korea ) was applied for 3 minutes twice a day over 2 weeks by using a toothbrush . \n cpp-acp.containing toothpaste ( gc tooth mousse ; gc , tokyo , japan ) was applied for 3 min to each tooth twice a day for 2 weeks by using a fingertip . \n ftcp - containing toothpaste ( clinpro tooth creme ) was applied for 3 minutes to each tooth twice a day for 2 weeks by using a toothbrush . \n the fluorescence value of each specimen measured with qlf - d biluminator 2 after the 2 weeks of treatment ( post - treatment ) was recorded as ffinal . \n the difference between ffinal and finitial ( f ) was calculated to quantify the change in fluorescence of each specimen . \n the measurements of the treatment groups were compared by using the mann - whitney u - test . \n statistical analyses were performed by using spss program ( version 14.0 ; spss inc . , \n the level of statistical significance was established as p < 0.05 . at the pretreatment and post - treatment time points , the measurement errors by dahlberg 's formula were 0.2177 and 0.2220 , respectively , and the intraclass correlation coefficients were 0.994 and 0.995 , respectively . \n however , mean f was higher in the ftcp and cpp - acp groups than in the fluoride and control groups . \n the fluoride group did not show a significant difference from the control group ( table 2 ) . \n the percent increase in fluorescence after the treatment was 0.480% , 0.500% , 0.940% , and 1.446% in the control , fluoride , cpp - acp , and ftcp groups , respectively . \n figures 1,2,3,4 show the pretreatment and post - treatment light - induced fluorescent images of one specimen from each group . \n wsls are not unique to orthodontic patients : they are observable in 3 - 82% of the children who have not received orthodontic treatment.16,17,18,19 in the orthodontic population , however , the prevalence rate of wsls ranges from 8.5% to 44% on the anterior teeth and 7.7% to 71% on the posterior teeth.20 the results of the present study indicate that application of ftcp- or cpp - acp - containing toothpaste may reduce wsls , compared with use of 1,000-ppm fluoride - containing toothpaste . in the present study , \n the application of cpp - acp - containing toothpaste resulted in a significant increase in fluorescence . \n the remineralization of wsls with cpp - acp has been previously studied with conflicting results . \n brchner et al.,21 in a prospective clinical trial , found that wsl regression was comparable between cpp - acp - containing and traditional toothpastes . \n they reported that application of cpp - acp - containing toothpaste after debonding of orthodontic appliances resulted in significantly increased fluorescence and reduced lesional area after 4 weeks of treatment , as assessed by qlf. the improvement was however not superior to \" natural \" regression occurring with daily use of fluoridated toothpaste . by using laser fluorescence \n , bhat et al.22 found that application of cpp - acp - containing cream with and without fluoride for 14 and 21 days , respectively , led to significant differences in remineralization of incipient enamel lesions . \n however , by using a ph - cycling model of early caries in bovine enamel , ogata et al.23 reported insufficient remineralization of enamel subsurface lesions with cpp - acp . polarized light \n photomicrographs and microradiographs did not reveal significant differences in mineral gain between cpp - acp - treated and control groups ; addition of low levels of fluoride was needed to observe lesional regression . \n the conflicting results of these studies may be related to the different methods of specimen preparation , treatment periods , and additional application of fluoride . in the ftcp group , \n we used 950-ppm sodium fluoride toothpaste containing ftcp , which , according to the manufacturer , is an innovative calcium - based additive that can help to remineralize enamel . by in vitro ph - cycling experiments designed to mimic remineralization of incipient enamel lesions , karlinsey and mackey24 reported that the combination of sodium fluoride with ftcp in a simple aqueous solution produces significantly greater surface and subsurface rehardening of wsls than use of fluoride alone . \n use of higher - concentration ( 1,500 - 5,000 ppm ) fluoride toothpastes and gels twice daily during orthodontic treatment has a demineralization - inhibiting tendency.25 however , such high doses of fluoride have negative effects , so the korea food and drug administration has recommended that the total fluoride content of toothpaste should be less than 1,000 ppm . \n further , although use of high doses of fluoride completely arrests the carious process , which is ideal for posterior carious lesions , wsls of orthodontic origin present a cosmetic challenge and regression is the therapeutic goal . \n if a high dose of fluoride is used locally , the arrested lesion will remain the same size and frequently becomes stained with organic debris . \n moreover , natural remineralization produces greater resistance to further dissolution because components are replaced with less - soluble substances having larger crystals during remineralization.26 this phenomenon has been reported as plugging of the diffusion pathways of enamel by hydroxyapatite crystals and as hyper - remineralization.6 to the best of our knowledge , this study is the first direct comparison of the remineralization effects of 1,000-ppm fluoride- , cpp - acp- , and ftcp - containing toothpastes on wsls , although quantitative assessment of fluoridated and cpp - acp - containing toothpastes has been reported . \n the better findings in the cpp - acp and ftcp groups than in the fluoride group may be attributable to the lack of rinsing in the former groups . \n further , the cpp - acp- and ftcp - containing toothpastes were applied for longer than the actual clinical usage and the saliva solution was changed once a day . \n this study improves our understanding of the preventive potential of the products , but it can not reproduce all the complexities of the living oral cariogenic environment . \n well - designed controlled clinical trials studies are required to examine the potential benefits of cpp - acp with fluoride and microabrasion with ftcp on remineralization . \n ftcp- and cpp - acp - containing toothpastes seem to be more effective in reducing wsls than 1,000-ppm fluoride - containing toothpastes .", "role": "user" }, { "content": "objectivethe purpose of this in vitro study was to examine the effects of fluoridated , casein phosphopeptide.amorphous calcium phosphate complex ( cpp - acp)-containing , and functionalized -tricalcium phosphate ( ftcp)-containing toothpastes on remineralization of white spot lesions ( wsls ) by using quantitative light - induced fluorescence ( qlf - d ) biluminator 2.methodsforty-eight premolars , extracted for orthodontic reasons from 12 patients , with artificially induced wsls were randomly and equally assigned to four treatment groups : fluoride ( 1,000 ppm ) , cpp - acp , ftcp ( with sodium fluoride ) , and control ( deionized water ) groups . \n specimens were treated twice daily for 2 weeks and stored in saliva solution ( 1:1 mixture of artificial and human stimulated saliva ) otherwise . \n qlf - d biluminator 2 was used to measure changes in fluorescence , indicating alterations in the mineral contents of the wsls , immediately before and after the 2 weeks of treatment.resultsfluorescence greatly increased in the ftcp and cpp - acp groups compared with the fluoride and control groups , which did not show significant differences.conclusionsftcp- and cpp - acp - containing toothpastes seem to be more effective in reducing wsls than 1,000-ppm fluoride - containing toothpastes .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: autism spectrum disorders ( asds ) describe a group of neurodevelopmental conditions in which the individuals face challenges with social engagement and age - appropriate play and fail to develop appropriate peer relationships according to their developmental level . \n although young people are frequently recommended to participate in leisure activities including play , sports , hobbies , and social activities , children with asd tend to spend time in passive play and maladaptive behaviors and they are less likely to spontaneously participate in organized leisure activities such as sports [ 2 , 3 ] . it could be attributed to their significant deficits in development of motor development and physical activity ( pa ) behavior [ 4 , 5 ] . \n social and behavioral impairments in asd can limit children opportunity to participate in physical activity and recreation programs that eventually end to their inactivity . \n physical inactivity predisposes children with asd to several comorbid conditions such as overweight and obesity [ 7 , 8 ] . to assess key correlates of physical activity \n , previous studies frequently addressed social variables as critical factors contribute to asd children physical activity . \n for example , pan showed that children with asd who had lower social engagement with adults displayed lower levels of physical activity than children had higher social involvement . indeed \n although children with asd receive rehabilitation services from an early age in order to improve daily performance and enhancement of active life , pa and leisure aspects of quality of life ( qol ) are underestimated in children with asd and their families [ 11 , 12 ] . to address the children needs , parents and caregivers have to spend many resources while making a balance between children needs and those of family or guardians is a difficult task . \n thus recently , studies examining qol in a wide range of individuals with asd indicated that adults with asd have lower scores in wellbeing measures [ 13 , 14 ] , and children also show a subideal outcome [ 15 , 16 ] . \n a recent study on asd demonstrated a positive connection between cheerfulness and participation in a quality leisure program ; authors also indicated that satisfaction is also correlated with leisure activities in individuals with asd . \n although some studies could not show any differences between the physical activity levels of children with and without asd , there is a general consensus that children with asd did not participate in enough pa necessary to meet the activity guidelines for wellbeing . \n most recent review of literature confirmed that children with asd fall short of the recommended physical activity levels and experience challenges in physical activity and physical education settings and thus recommended strategies to improve the physical activity statistics and quality of life among children with asd . \n limited research , to date , has looked at the barriers and facilitators of pa among children with asd . \n however , a number of barriers to physical activity from individual to social and environmental make pa participation of children with asd more difficult and may result in increasing their sedentary activities . \n a rare study examining parent - reported barriers to pa in children with asd reported significantly greater amount of barriers compared to td children . \n barriers reported by parents are too much supervision needed compared to td children , lack of skills , few friends , and exclusion by other children which are the most important barriers . \n however , children with asd themselves rated interpersonal ( such as screen activities ) , physical ( such as lack or unsafe equipment ) , and community ( such as lack of transportation to physical activity programs ) factors as the most frequent barriers . on the other hand , there are facilitators from personal ( individual versus team activities ) to collective ( such as social support ) that help children with asd to involve in a pa program . particularly the association between pa and social support has been established among children with asd . \n however a multiaspect approach is needed to assess the pa and leisure participation of children and adolescents with asd . \n of relevance to current study , it is important to examine whether the children with asd are provided with enough opportunities to participate in physical activities and what factors are playing a role in their physical activities . \n furthermore , identifying contributing factors into pa will be imperative to enhance the efficacy of interventions aimed to improve active life / wellbeing of children with asd . therefore , we aimed to assess the participation of a school based sample with asd in physical and daily activities . \n we further sought to examine individual ( e.g. , age and clinical symptoms ) and social ( e.g. , household structures ) factors contributing to the level of participation in leisure physical activities . \n a total sample of 83 children ( 53 boys and 31 girls ) with high functioning asd ( iq > 70 ) aged 6 to 15 years ( mean = 9.8 , sd = 1.8 ) were recruited from four autism specific schools in tehran . all of the subjects had received a clinical diagnosis of asd ( autism , asperger 's , or pervasive developmental disorder , not otherwise specified ) by a child psychiatrist or clinical psychologist and the diagnosis was confirmed using the revised autism diagnostic interview ( adi - r ) . \n this cross - sectional study was approved by the medical ethics committee of the tehran university of medical sciences . \n physical activity involvement during leisure time was examined using a modified checklist adapted from godin - shephard leisure time questionnaire ( glteq ) . \n we aimed to evaluate activities ( at least 15 minutes ) over a 7-day period asking two questions . \n the first question addresses the intensity of physical activities : strenuous ( e.g. , running , football ) , moderate ( e.g. , easy bicycling , easy swimming ) , and mild ( e.g. , yoga , easy walking ) . since children with asd were not acquainted to complete a self - report questionnaire , we modified the questions in order for parents / caregivers to reply . \n for instance how many times on the average do you do the following kinds of ? \n how many times on the average does your child do the following kinds of exercise ? we asked parents to consider physical activities all day long ( including school time ) when they answered the questions . \n also each child 's teacher was asked to help parent to include school time physical activities when asking the questions on how many times on the average does your child do the following kinds of exercise ? finally a composite score was calculated as activity score = ( 9 ( number of strenuous exercise episodes ) ) + ( 5 ( number of moderate exercise episodes ) ) + ( 3 ( number of mild exercise episodes ) ) . an additional question was presented as during a typical 7-day period ( a week ) how often does your child engage in any regular physical activity long enough to work up a sweat ( heart beats rapidly ) ? with three answer options as often , sometimes , and never / rarely . an overall total high score on both questions reflects a high level of physical activities . \n prior research showed an acceptable criterion validity and also reliability scores ( 0.74 and 0.80 ) ; our data on a subsample of participants ( 25 parents ) also showed a good test - retest reliability scores ( 0.79 and 0.81 ) . according to the activity guidelines \n , children were supposed to participate in exercise activities at least 60 minutes at a moderate to vigorous intensity on most ( five ) days of the week in order to be considered active ( glteq score = 5 5 days 4 ( 60/15 min ) 100 ) or they are considered inactive if their activity score was lower than the minimum recommendations ( glteq score < 100 ) . to assess the barriers to pa , parents were asked to specify the most frequent barriers to participation in leisure physical activity of their child . \n a list of barriers was provided including expense , lack of resources / opportunities , time limitation , motivation , and fear of injury and also an open item as other barriers . \n furthermore , parents were asked to complete a daily activity logbook for children , which was designed to obtain information about each child on their hourly engagement during a typical day . \n parents rated how much time , in average , children spent on solitary , social , home teaching , tv , feeding , school , and also sleep on daily basis . among those daily activities , social play ( i.e. , time spent on playing with peers ) and \n this questionnaire showed a good content validity and a satisfactory test - retest reliability ( intraclass correlation = 0.69 , p < 0.001 ) . \n moreover , we administered the autism treatment evaluation checklist ( atec ) to parents / caregivers to monitor the severity of autism symptoms . \n atec is a valid and helpful instrument to evaluate the severity asd symptoms in children with asd [ 25 , 26 ] . \n the checklist has four subscales , including language , sociability , sensory / cognitive awareness , health / physical / behavior , and the total score ( overall severity ) . \n finally , background demographic information of the participants was reviewed by the first author interviewing the families and using their medical profiles . in the next step , parental demographic variables including household structure ( single parent versus two parents ' family ) \n , household income , and the highest level of education obtained by parents were also recorded . \n parental education was examined by one question that asked participants to report the highest degree completed by either the father or the mother . for the current study , \n three education categories were created including low ( diploma and below ) , medium ( bachelor and below ) , and high ( master and above ) . \n participants were also asked to report total household income . for use in this paper , household income \n was categorized into four groups using the poverty income ratio ( based on poverty threshold from national central bank report ) . \n these categories ranged from below the poverty limit to incomes greater than three times the poverty limit . \n independent t - test was conducted to evaluate the statistical significance for the observed differences across gender ( boys and girls ) in outcome measurements ( physical activity score or daily activity measures ) . \n furthermore , in order to compare the time spent on solitary play and social play in total studied population , a paired t - test analysis was conducted . \n association between leisure scores or daily activities time and parental and child factors were assessed by correlation analysis . \n analyses were performed using the statistical package for the social sciences ( spss ) software version 17 for windows ( spss inc . , chicago , il , usa ) . \n however , it was very striking to find that only 10 ( 12% ) of children with asd were active and 73 ( 88% ) were inactive based upon activity guidelines and activity score measured by the glteq . \n addressing the frequency of activity participation , results showed that only 6% of children with asd often participated in physical activities , whereas 85.5% of them had \n never / rarely participated and 8.5% were sometimes involved in physical activities . \n furthermore , t - test analysis of glteq composite score showed that boys with asd participated in physical activities ( 58.8 22.1 ) more than girls with asd ( 35.5 14.5 ) ( t = 4.31 , 95% ci : 12.4833.13 , p < 0.001 ) . examining the correlates of children physical activities revealed that expectedly older children were less active than younger children ( r = 0.298 , p = 0.003 ) . \n there was no association between severity of disorder or parental education level and the activity score , but physical activity participation was positively correlated with the poverty income ratio ( r = 0.31 , p = 0.005 ) . \n t - test analysis showed that children in single - parent families had significantly lower activity scores than children in two parent 's families ( t = 3.91 , 95% ci : 9.3129.64 , p < 0.001 ) . \n based on the results obtained from independent t - test , girls were more involved in solitary play compared to boys ( t = 3.626 , 95% ci : 31.01106.22 , p < 0.001 ) . \n the results of paired t - test showed that children were predominantly more engaged in solitary play compared with social play activities ( t = 9.41 , 95% ci : 65.68100.80 , p < 0.001 ) . \n correlation analysis between daily activities and symptoms severity scores showed that social play participation was negatively correlated with language impairment ( r = 0.25 , p = 0.016 ) , sensory / cognitive awareness deficit ( r = 0.26 , p = 0.013 ) , and also overall severity score ( r = 0.29 , p = 0.005 ) . \n finally , parents reported that leading barriers of children adherence to physical activities were expense \n ( 31.7% ) and lack of resources and opportunities ( 30.1% ) followed by time ( 19.5% ) , motivation ( 17.1% ) , and fear of injury \n daily physical and play activities have an important role in the psychosocial development of children . \n in fact an appropriate activity profile prevents them from isolation in adulthood and significantly influences the wellbeing of children [ 17 , 28 ] . \n nevertheless , there was lack of studies assessing daily activities participation in children with asd and investigating the impact of individual and environmental factors on their physical activity parameters . \n results from the current study indicates that most of the children with asd do not have adequate physical activity participation since only few of our children met the minimum physical activity criteria . \n several studies have discovered that individuals with disabilities are more likely to be inactive and due to abundance of impediments they are less likely to participate in activities when they are compared with the general population [ 2932 ] . \n their findings show that asd and the severity of intellectual impairments place the people with disabilities at a higher risk for sedentariness [ 33 , 34 ] \n . a number of factors can limit the participation of children with asd in daily physical activities . \n those mainly include lack of positive experiences in exercises , frequent failures , emotional impairments , and low self - esteem . \n however , our data showed that such low participation was mostly due to the financial complaints and lack of resources or opportunities as reported by the parents . \n moreover , there were other factors ( e.g. , time constraints , lack of motivation , and fear of injury ) which can further limit the participation of autistic children in activities . \n interestingly , data from another developing country revealed similar barriers such as financial complaints , lack of knowledge , and perception of the situation in an asd sample . \n although there are differences in measurement of barriers across previous studies , almost similar patterns of barriers including time limits and financial constraints were reported as leading barriers to activity participation in children with disabilities particularly asd [ 15 , 36 , 37 ] . \n indeed this finding is not limited to asd and previous data from individuals with other disabilities revealed that disabled people face a number of barriers to pa participation even more than healthy population . \n expenditures of the child 's medical care impose a financial burden on families with an autistic child and therefore they require more financial resources . \n they also have to limit their productive working times in order to take care of their difficult children , which in turn will further challenge the possibility of secure a financial resource expansion . \n one of the important findings of the present study is that children from low - income families show lower level of pa than children from high - income families . \n children who grow up in a low - income family are more likely to live a sedentary lifestyle and experience more health problems related to physical inactivity compared to children from higher income families . \n there are a number of physical and social barriers to physical activity for low - income families including low access to parks and recreational services , traffic conditions and air pollution , lack of relevant alternatives of transportation , and lack of enough social support for physical activity . on the other hand , \n low - income families are often less able to overcome these barriers . due to financial constraints \n , there are fewer alternatives available for low - income people ; for example , they are not able to spend on a health club or recreation center membership . \n it can be expected that the problem is more complicated in families with an asd child . \n thus , the economically disadvantaged asd families may show a lower preference to participate in physical activities . \n furthermore , some parents have increasing concerns about their child 's health and possibility of an injury , which can explain their lack of interest toward activity participation of their autistic child . \n furthermore , they report lack of time and financial resources as the main impediments to participation in activities . \n our findings provide additional evidence regarding the effect of household structure on the leisure time activity involvement in children with asd . \n however , it is not clear if other variables such as presence of a sibling may influence the opportunities to engage in social play and daily social activities inside the family environment . \n expectedly children with asd showed a remarkably low social but high solitary play activity during a typical day . indeed \n a previous research has shown that the characteristics of asd as social , communicative , and motor impairments increase the likelihood of loneliness and decrease the opportunities for interactions in individuals with asd . \n previous studies suggested that a lower level of social play activities in addition to autistic character difficulties can have serious developmental and social consequences [ 4345 ] . examining the apparent role of autism symptom severity \n , we observed that the children with greater deficits ( e.g. , in communication ) had a lower engagement in social play activities . \n these results are in line with previous studies which indicated that there is an inverse correlation between severity of communication impairment and the level of life participation in individuals with disabilities . in fact \n , previous studies indicated that individuals with more severe motor or physical impairments or cognitive disabilities are at a higher risk of being excluded from daily activities [ 46 , 47 ] . \n our findings also indicated that there is a significant age and gender difference in level of physical activity and this is in line with studies of asd and general population . \n it can be explained that older children have low opportunities to participate in physical and recreation activities . \n furthermore , age may decrease the children motivation to participate in complex motor or physical activities . \n we also indicated that gender ( in favor of males ) influences the daily physical and play activities of children . \n gender differences in asd characteristics revealed that males with asd show more stereotypic and repetitive behaviors while there are more communication deficits in female counterparts . \n in addition , there is more achievements in motor skills and social competence in boys than girls with asd . \n one can argue that being a girl is associated with poor outcome in physical activity participation in asd . \n first , the cross - sectional design prevents an understanding of the exact nature of the daily activity participation , particularly with respect to its determinants . \n second , while a neurotypical control group was not included , it would be helpful to compare the scores of physical activity participation between neurotypical controls and children with asd . \n third , the measures solely relied on the parents ' ( or teachers ) self - report information ; thus , recall bias maybe a potential limitation . in conclusion , \n only a small part of children with asd are physically active according to activity guideline . \n financial concerns , lack of opportunities , and sociodemographic factors are indicated as major limitations of their physical activities .", "role": "user" }, { "content": "autism spectrum disorder ( asd ) indicates several neurodevelopmental impairments which may end in impairments in motor or physical activities . \n daily physical activity involvement was investigated in a total of 83 children ( 52 boys and 31 girls ) with asd aged 615 years . \n results indicated that only 10 ( 12% ) of children with asd were physically active . \n children were predominantly engaged in solitary play rather than social play activities . \n gender , family income , and household structure were found to be associated with activity scores . financial burden and lack of opportunities \n were noted as the leading barriers to physical activities . in conclusion \n , findings indicated a low rate of physical activity participation in children with asd that is closely associated with sociodemographic variables .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: even though adhesive technology has made a significant progress , numerous questions still remain unanswered . \n clinicians generally use high - speed diamond and carbide rotary instruments to prepare cavity designs for adhesive restorations . \n dentin bond strength were noted earlier with the use of these instruments.[14 ] therefore , information on the effects of cutting tooth with different rotary instruments on resin dentin bond strengths is essential . on the other hand , the thickness and the density of the smear layer created with bur or diamond abrasive \n have been reported to affect the bond strengths when total - etch and self - etch strategies were used.[58 ] hence , it is still unclear whether the cutting instrument or bonding technique is the crucial factor in resin \n the flow of fluid from the pulp to the dentino - enamel junction is the result of a slight but constant pulpal pressure . \n although the flow along individual tubules is very small , this is sufficient to oppose and greatly reduce the inward diffusion of the resin . \n hence , fluid movement in dentinal tubules plays a major role in determining the bonding . \n we aimed to evaluate the shear bond strength of composite to tooth by using different adhesive strategies and rotary instruments with simulated pulpal pressure in this study . \n sixty freshly extracted , noncarious human maxillary and mandibular molar teeth with divergent roots were collected . \n teeth free from caries , occlusal wear , sclerotic dentin and calcifications in the pulp chamber were selected for this study with the help of radiographs . \n all the specimens were cleaned to remove the adhering soft tissue or calculus and stored in distilled water which was periodically replaced . \n all the teeth were kept under positive hydrostatic intra - pulpal fluid pressure via pulp chambers filled with distilled water during tooth preparation and bonding procedures to simulate the clinical conditions . to create this mechanism , \n a hole of 4 mm in diameter was made in the furcation area of the teeth , between the roots . \n the roots were covered externally by one end of the rubber tube while the other end was connected to a plastic tube . \n the other end of this plastic tube was connected to a water - filled 2-ml plastic syringe . \n the junctions of the rubber tube and tooth , rubber tube and plastic tube , tube and syringe were sealed using cyanoacrylate glue and epoxy putty to maintain an air - tight seal of the water column . \n the teeth and the syringes were fixed to two thermocol pieces , which were in turn held in position by four burette holder stands . \n the column height of water was adjusted to 34 cm to provide approximately 25 mm hg of pressure , which is the average tissue pressure in a healthy pulp . \n group ia : total - etch bonding technique + diamond abrasive group ib : total - etch bonding technique + carbide bur group iia : self - etch bonding technique + diamond abrasive group iib : self - etch bonding technique + carbide bur this study evaluated the bond strength of composite to enamel and dentin . \n class ii proximal box - only cavities of standard dimensions , 4 mm bucccolingual , 4 mm occlusogingival and 2 mm mesiodistal , with facial and lingual walls straight and parallel to each other , were prepared [ figure 1 ] . \n in all the groups , the tooth surface was prepared under copious water spray with a high - speed air turbine ( 150,000 rpm ; nsk , nakanishi inc . \n teeth in group ia and group iia were prepared using diamond abrasives and teeth in group ib and group iib were prepared using carbide burs . \n schematic representation of the cavity preparation dimensions at proximal view the prepared enamel surface was etched with 36% phosphoric acid ( detrey conditioner 36 , dentsply , detrey , germany ) for 20 seconds . \n two coats of adhesive resin , xp bond universal total - etch adhesive ( dentsply , detrey , germany ) , were then applied with an applicator tip and then photopolymerized using a light intensity of 600 mw / cm for 10 seconds . \n the prepared surface was treated with two coats of the bonding agent , xeno v ( dentsply , detrey , germany ) and photopolymerized . in this study \n the proximal box was restored using a nanoceramic composite ( ceram x mono dentsply , detrey , germany ) , placed in 2-mm thick horizontal increments . \n each layer was photocured for at least 40 seconds from the occlusal side . as tooth preparations \n are commonly performed on dentin and enamel simultaneously in clinical situation , it is important to determine the effect of rotary instruments over adhesive bond strengths of enamel as well as of dentin . \n hence , in the current study , total bond strength values obtained by composite to both enamel and dentin surfaces were evaluated . \n specimens were removed from the assembly apparatus and mounted in plastic cylinders for loading at an angle of 45. this angle is important because the load applied at 45 angle stimulates high shearing stresses . \n the mounted specimens in the rings were stored in distilled water until testing was performed . bond strength between the restorative materials and tooth surface \n was measured in the shear mode with the universal testing machine ( lloyd- bangalore , india ) . \n the specimens were mounted in a jig , while a straight knife - edge rod ( 2-mm wide ) was applied at the tooth \n the total bonded surface area of the proximal box cavity preparation was 40 mm , and it was calculated as the sum of the surface area of the gingival wall ( 8 mm ) , facial wall ( 8 mm ) , lingual wall ( 8 mm ) and axial wall ( 16 mm ) . \n loads were converted to megapascals by dividing the loads in newtons by the total bonded surface area . \n n ( newtons ) = fracture load total bonded surface area = 8 + 8 + 8 + 16 = 40 mm results were subjected to statistical analysis using two - way analysis of variance ( anova ) and t - test at 95% level of confidence to know the effect of rotary instrument and adhesive technique ( independent variables ) on the bond strength ( dependent variable ) . in this study , \n sixty freshly extracted , noncarious human maxillary and mandibular molar teeth with divergent roots were collected . \n teeth free from caries , occlusal wear , sclerotic dentin and calcifications in the pulp chamber were selected for this study with the help of radiographs . \n all the specimens were cleaned to remove the adhering soft tissue or calculus and stored in distilled water which was periodically replaced . \n all the teeth were kept under positive hydrostatic intra - pulpal fluid pressure via pulp chambers filled with distilled water during tooth preparation and bonding procedures to simulate the clinical conditions . to create this mechanism , \n a hole of 4 mm in diameter was made in the furcation area of the teeth , between the roots . \n the roots were covered externally by one end of the rubber tube while the other end was connected to a plastic tube . \n the other end of this plastic tube was connected to a water - filled 2-ml plastic syringe . \n the junctions of the rubber tube and tooth , rubber tube and plastic tube , tube and syringe were sealed using cyanoacrylate glue and epoxy putty to maintain an air - tight seal of the water column . \n the teeth and the syringes were fixed to two thermocol pieces , which were in turn held in position by four burette holder stands . \n the column height of water was adjusted to 34 cm to provide approximately 25 mm hg of pressure , which is the average tissue pressure in a healthy pulp . \n group ia : total - etch bonding technique + diamond abrasive group ib : total - etch bonding technique + carbide bur group iia : self - etch bonding technique + diamond abrasive group iib : self - etch bonding technique + carbide bur \n class ii proximal box - only cavities of standard dimensions , 4 mm bucccolingual , 4 mm occlusogingival and 2 mm mesiodistal , with facial and lingual walls straight and parallel to each other , were prepared [ figure 1 ] . \n in all the groups , the tooth surface was prepared under copious water spray with a high - speed air turbine ( 150,000 rpm ; nsk , nakanishi inc . \n teeth in group ia and group iia were prepared using diamond abrasives and teeth in group ib and group iib were prepared using carbide burs . \n the prepared enamel surface was etched with 36% phosphoric acid ( detrey conditioner 36 , dentsply , detrey , germany ) for 20 seconds . \n two coats of adhesive resin , xp bond universal total - etch adhesive ( dentsply , detrey , germany ) , were then applied with an applicator tip and then photopolymerized using a light intensity of 600 mw / cm for 10 seconds . \n the prepared surface was treated with two coats of the bonding agent , xeno v ( dentsply , detrey , germany ) and photopolymerized . in this study \n the proximal box was restored using a nanoceramic composite ( ceram x mono dentsply , detrey , germany ) , placed in 2-mm thick horizontal increments . \n the prepared enamel surface was etched with 36% phosphoric acid ( detrey conditioner 36 , dentsply , detrey , germany ) for 20 seconds . \n two coats of adhesive resin , xp bond universal total - etch adhesive ( dentsply , detrey , germany ) , were then applied with an applicator tip and then photopolymerized using a light intensity of 600 mw / cm for 10 seconds . \n the prepared surface was treated with two coats of the bonding agent , xeno v ( dentsply , detrey , germany ) and photopolymerized . in this study \n the proximal box was restored using a nanoceramic composite ( ceram x mono dentsply , detrey , germany ) , placed in 2-mm thick horizontal increments . \n as tooth preparations are commonly performed on dentin and enamel simultaneously in clinical situation , it is important to determine the effect of rotary instruments over adhesive bond strengths of enamel as well as of dentin . \n hence , in the current study , total bond strength values obtained by composite to both enamel and dentin surfaces were evaluated . \n specimens were removed from the assembly apparatus and mounted in plastic cylinders for loading at an angle of 45. this angle is important because the load applied at 45 angle stimulates high shearing stresses . \n the mounted specimens in the rings were stored in distilled water until testing was performed . \n bond strength between the restorative materials and tooth surface was measured in the shear mode with the universal testing machine ( lloyd- bangalore , india ) . \n the specimens were mounted in a jig , while a straight knife - edge rod ( 2-mm wide ) was applied at the tooth \n the total bonded surface area of the proximal box cavity preparation was 40 mm , and it was calculated as the sum of the surface area of the gingival wall ( 8 mm ) , facial wall ( 8 mm ) , lingual wall ( 8 mm ) and axial wall ( 16 mm ) . \n loads were converted to megapascals by dividing the loads in newtons by the total bonded surface area . \n n ( newtons ) = fracture load total bonded surface area = 8 + 8 + 8 + 16 = 40 mm \n results were subjected to statistical analysis using two - way analysis of variance ( anova ) and t - test at 95% level of confidence to know the effect of rotary instrument and adhesive technique ( independent variables ) on the bond strength ( dependent variable ) . in this study , \n in the experiment , failure generally occurred as a combination of the following three modes : 1 ) fracture of the tooth structure , 2 ) fracture of restoration and 3 ) dislodgement of restoration . \n thus , failure was never purely adhesive or purely cohesive , but of mixed type . \n table 2 shows the statistical analysis ( anova ) of difference in shear bond strength in between groups . \n the mean shear bond strength and standard deviation values of different groups comparisons of the groups by two - way anova test table 1 shows that the mean shear bond strength values ranged from 4.30 to 6.24 mpa . \n diamond abrasive showed the greatest values of bond strength with the adhesive techniques and was statistically significant compared to carbide bur . \n total - etch group gave better bond strength over the self - etch group , but was not statistically significant . \n table 2 shows that adhesive technique is not a significant factor influencing the bond strength . \n there was no significant difference between total - etch and self - etch bonding agents ( p > 0.05 ) . \n statistically significant difference was observed between carbide and diamond rotary instruments ( p < 0.05 ) . \n the interaction ( joint effect ) of adhesive technique and rotary instrument on the bond strength is not statistically significant ( p > 0.05 ) . \n adhesives are routinely tested for bond strengths via in vitro tests , prior to the commercialization , as these methods provide immediate results . \n these laboratory studies are generally performed on flat tooth surfaces [ have most favorable configuration factor ( c - factor ) ] , prepared by using silicon carbide abrasive papers . unlike in clinical situations , \n another drawback of these bond strength studies was that they had been conducted without maintaining intra - pulpal pressure during bonding . \n hence , the experimental setup and methodology of the current study was designed to overcome these drawbacks and to mimic the clinical situation . in the current study , \n total shear bond strength values obtained by the composite to both enamel and dentin surfaces were evaluated simultaneously . \n the lower shear bond strength values recorded in this study can be explained by the following hypothesis : \n the c - factor is the ratio of bonded to unbonded walls of the preparation . \n c - factor for dental restorations typically ranges from 0.1 to 5.0 , with higher values ( > 1.5 ) indicating a greater likelihood of high interfacial stresses . \n box - like class i cavities would have a c - factor of 5 , whereas a flat surface , as in veneering , would have a c - factor of 1 . \n laboratory studies conducted at a c - factor of 1 tend to overestimate bonding performance compared with complex cavity preparations with high c - factors . \n the shrinkage forces in class ii cavities are high and result in debonding of one or more walls , when compared to flat surfaces with low c - factor . \n a study reported a 20% reduc - tion in bond strength of cavity bonding group as compared to flat surface bonding group.in vivo , dentin is penetrated by network of fluid - filled dentin tubules of 1.02.5 m diameter . \n the presence of fluid inside the dentinal tubules tends to dilute the dentin conditioner , decreases its potential for demineralization of the inter - tubular and peri - tubular dentin and eventually results in lower bond strength . \n moreover , water content and permeability of dentin is not identical for all regions because of variations in the number of tubules per millimeter . \n tubule density and peri - tubular dentinal area decrease and inter - tubular dentinal area increases , with distance from the pulp . \n for example , the permeability of occlusal dentin is higher over the pulp horns than at the center of the occlusal surface . \n similarly , proximal dentin is more permeable than occlusal dentin and coronal dentin is more permeable than root dentin . \n the problem of poor bonding to dentin near the pulp is due to the high content of water . \n hence , it is difficult to achieve uniform wetness simultaneously on the axial , pulpal and gingival walls , and between the superficial and deep dentin in class ii cavities \n lower values of bond strength have been reported in previous studies when the intra - pulpal fluid pressure was maintained.the bonded surface area is extremely important in determining the bond strength as fracture strength is measured per unit area . \n this may explain why the bond strength results in the present study were lower than the results obtained in studies where smaller dimension bonding surface had been used . \n the c - factor is the ratio of bonded to unbonded walls of the preparation . \n c - factor for dental restorations typically ranges from 0.1 to 5.0 , with higher values ( > 1.5 ) indicating a greater likelihood of high interfacial stresses . \n box - like class i cavities would have a c - factor of 5 , whereas a flat surface , as in veneering , would have a c - factor of 1 . \n laboratory studies conducted at a c - factor of 1 tend to overestimate bonding performance compared with complex cavity preparations with high c - factors \n . the shrinkage forces in class ii cavities are high and result in debonding of one or more walls , when compared to flat surfaces with low c - factor . \n a study reported a 20% reduc - tion in bond strength of cavity bonding group as compared to flat surface bonding group . \n in vivo , dentin is penetrated by network of fluid - filled dentin tubules of 1.02.5 m diameter . \n the presence of fluid inside the dentinal tubules tends to dilute the dentin conditioner , decreases its potential for demineralization of the inter - tubular and peri - tubular dentin and eventually results in lower bond strength . \n moreover , water content and permeability of dentin is not identical for all regions because of variations in the number of tubules per millimeter . \n tubule density and peri - tubular dentinal area decrease and inter - tubular dentinal area increases , with distance from the pulp . \n for example , the permeability of occlusal dentin is higher over the pulp horns than at the center of the occlusal surface . \n similarly , proximal dentin is more permeable than occlusal dentin and coronal dentin is more permeable than root dentin . \n the problem of poor bonding to dentin near the pulp is due to the high content of water . \n hence , it is difficult to achieve uniform wetness simultaneously on the axial , pulpal and gingival walls , and between the superficial and deep dentin in class ii cavities . \n lower values of bond strength have been reported in previous studies when the intra - pulpal fluid pressure was maintained . \n the bonded surface area is extremely important in determining the bond strength as fracture strength is measured per unit area . \n this may explain why the bond strength results in the present study were lower than the results obtained in studies where smaller dimension bonding surface had been used . \n the frictional stresses , along with plastic and elastic deformation of tooth , during mechanical tooth preparation result in formation of an amorphous layer of organic and inorganic debris called smear layer . \n this smear layer covers the dentin surface , adheres weakly to the underlying dentin and occludes the entrance of the dentinal tubules . as a part of restorative procedure in adhesive dentistry , the smear layer should be either removed with phosphoric acid ( total - etch technique ) or modified with acidic primers ( self - etch technique ) . \n after statistical evaluation , results concluded that the diamond rotary instrument gave a higher bond strength compared to the carbide rotary instrument with both the adhesive techniques . \n diamond abrasive cuts the surface by abrasion , while carbide bur cuts the surface by the cutting action of blades . \n earlier studies have concluded that the diamond abrasive creates a thicker smear layer and a rougher dentin surface with deeper and uniform grooves , when compared to those created by the carbide bur . \n hence , the rougher surface created by the diamond abrasives would have increased the surface area and facilitates better infiltration of the adhesive resins , resulting in better bond strength than carbide . \n based on the current adhesive techniques , there are two major approaches to produce an effective bond between resin and dentin . \n etch and rinse systems employ phosphoric acid to remove the smear layer , followed by primer / adhesive applications . on the other hand , \n non - rinsed self - etch systems utilize acidic monomers to modify the smear layer . \n the subsequent bonding process incorporates this modified smear layer within the resin dentin bond . \n earlier studies have reported that when total etch technique was used , bond strength of dentin was influenced by the rotary cutting instrument . \n they conclude that topography of the dentin surface after removal of the smear layer and demineralization of the dentin would reflect the coarseness of the abrasive and the coarser abrasives would increase the surface area . \n hence , it would be reasonable to assume that in the current study , the roughness created by the diamond abrasive must have influenced the bond strength with total - etch technique , resulting in higher bond strength . \n on the other hand , some studies have concluded that the bond strengths of the self - etch system are influenced by the thickness of the smear layer . \n they concluded that the self - etching primers produce less etching because of their relatively high ph ( > 2 ) . \n this leads to compromised smear layer removal , demineralization of the underlying dentin and further penetration of the adhesive resin , resulting in poor bond strength . \n on the contrary , this study showed higher bond strength of composite with diamond rotary instrument ( thicker smear layer ) than carbide bur ( thinner smear layer ) when bonded with self etch technique . \n his study concluded that carbide bur creates a fibrous smear layer composed of well - arranged and undisturbed collagen fibrils . \n this smear layer might not be as easily dissolved by acidic monomer when compared to thick smear layers created by diamond abrasives . \n however , further micro - morphological and chemical studies of resin dentin interfaces , as related to different surface preparation methods , are required to clarify this issue . apart from the initial bond strengths achieved in this study , unimpregnated collagen and \n smear debris of hybrid layer could affect the long - term bond strength and raise concern regarding the longevity of restorations . \n further research is required , as this study did not confirm the reliability of results based on scanning electron microscope ( sem ) analysis , which could have greatly helped in studying the fracture modes , micro - morphology of both smear layer and hybrid layer and surface topography of the substrate after tooth preparation . \n it may be difficult to compare the results of the current study to those of previous studies , as these studies were not done under same experimental conditions . \n innumerable studies have evaluated the bond strengths of adhesive material till date . but correlation between these in vitro bond strength studies and the clinical performance of adhesive materials has not yet been established . without such data , little confidence in adhesive behavior can be obtained . more importantly , without a thorough understanding of the performance of adhesives clinically , knowledge will never be gained relative to the adhesive mechanisms that are necessary for further research in this area . \n though such clinical data are delayed , in vitro studies with an experimental setup mimicking the clinical conditions should be conducted in the future for relevant results . within the limitations of the study \n , we conclude that : \n diamond abrasives resulted in better shear bond strength than carbide bur , with both the adhesive techniques androtary instrument was found to be a significant factor influencing bond strength . \n diamond abrasives resulted in better shear bond strength than carbide bur , with both the adhesive techniques and rotary instrument was found to be a significant factor influencing bond strength .", "role": "user" }, { "content": "aim : the aim of this study is to evaluate the shear bond strength of composite to tooth using different adhesive techniques and rotary instruments under simulated pulpal pressure.materials and methods : sixty extracted human molars were randomly divided into two groups of 30 samples each ( group i and ii ) , according to the adhesive technique followed ( i.e. total etch and self etch groups ) . \n each group was further divided into two sub - groups ( sub - groups a and b ) of 15 samples each according to the cutting instrument ( diamond abrasive or carbide burs ) used . \n class ii cavities were made with diamond abrasive or carbide burs , and restored with nano - composite under positive intra - pulpal pressure . \n shear bond strength of the specimens were recorded simultaneously.results:after statistical evaluation using two - way anova and t - test , the mean shear bond strength values of the groups are as follows : group ia- 4.69 mpa , group ib-6.15 mpa , group iia-4.3 mpa , and group iib-6.24 mpa . \n it was seen that group iib showed highest bond strength followed by group ib . \n group ii a showed the least bond strength.conclusions:within the limitations of the study , diamond abrasive gave better bond strength than carbide bur with both the adhesive techniques .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: a 21-year - old male patient with class ii subdivision presented with the chief complaint of missing teeth in his lower back tooth region . on clinical examination , \n impaction of 47 was noted with the distal cusps exposed among the alveolar mucosa in relation to 47 . \n he had a root canal treated 46 due to chronic pulpitis at the age of 10 years followed by a crown at the age of 16 years , which might be a significant cause to chief complaint of the patient . on clinical examination , 47 was missing and impacted with distal cusps exposed in the oral cavity without any signs of pericoronitis in the alveolar mucosa of 47 region . \n on radiographic examination , orthopantomogram revealed vertical impaction of 47 without any resorption or pathology associated with the teeth and periodontium . \n it was clearly noted that the potential for eruption was disrupted by the porcelain fused metalic ( pfm ) crown luted on endodontically treated 46 . \n precisely the distogingival margin of the pfm crown , which was over contoured in the distal aspect acted as an undercut preventing the eruption of 47 [ figure 1 ] . \n ( a ) preoperative mandibular occlusal view showing impacted 47 with the visible distal cusps , ( b ) right view , and ( c ) preoperative orthopantomogram the treatment protocol has been planned and executed by department of orthodontics and department of periodontics . the first step involved in the management of impacted permanent second molar is periodontal surgery over the gingival mucosa in relation to the impacted teeth , which was required to gain access to the buccal surface of 47 . \n the laser surgery was preferred since it had minimal bleeding thereby reducing bond failure on bonding . \n picasso soft tissue diode laser ( with 7 w , 810 nm ) was used in the surgery . a bondable attachment \n ( 0.22 slot mbt premolar bracket , oramco ) was placed in the exposed visible surface of impacted 47 . \n bondable bracket was preferred over buttons due to the advantage of wings and better bonding capacity . \n the attachment was exposed in the oral cavity during healing for connecting the appliance to the bonded attachment . \n a removable appliance was constructed for extrusion of 47 since it has higher anchorage control over the fixed appliance and easy to design for this purpose . \n removable appliance was the priority of choice due to the advantage of higher anchorage control and ease in design of the appliance . \n thus , a removable appliance was fabricated for mandibular arch with bilateral triangular clasp one in between 42 , 43 and other in between 33 , 34 . \n adams clasp one on the premolar on the fourth quadrant ( 45 ) and other on the molar in the third quadrant ( 36 ) . a custom made retraction spring with helix made with 17 25 titanium molybdenum alloy ( tma ) wire constructed with the acrylic material extending to the adams clasp of 46 . \n a horizontal arm made of tma wire with a posterior helix on the distal end tied using a ligature wire to the bracket on the impacted 47 and an anterior helix with two turns present at the buccal region of 46 , from the helix of the wire extends into the acrylic along with crossover arm of adams clasp ( on 45 ) to the lingual plate , finishing with a retention tag . the horizontal arm from the anterior helix to the posterior helix measures \n about 20 mm and the posterior helix with two full turns of 3 mm diameter is placed 1.5 cm above the bonded attachment thus , the force exerted when the posterior helix is tied to the attachment causes an extrusion force of 100 g / cm on the impacted 47 [ figures 24 ] . the extrusion appliance with the removable extrusion appliance engaged to the impacted teeth ( a ) preoperative , ( b ) 2 months after activation , ( c ) 4 months after activation , and ( d ) postoperative \n on clinical examination , 47 was missing and impacted with distal cusps exposed in the oral cavity without any signs of pericoronitis in the alveolar mucosa of 47 region . \n on radiographic examination , orthopantomogram revealed vertical impaction of 47 without any resorption or pathology associated with the teeth and periodontium . \n it was clearly noted that the potential for eruption was disrupted by the porcelain fused metalic ( pfm ) crown luted on endodontically treated 46 . \n precisely the distogingival margin of the pfm crown , which was over contoured in the distal aspect acted as an undercut preventing the eruption of 47 [ figure 1 ] . \n ( a ) preoperative mandibular occlusal view showing impacted 47 with the visible distal cusps , ( b ) right view , and ( c ) preoperative orthopantomogram \n the treatment protocol has been planned and executed by department of orthodontics and department of periodontics . \n the first step involved in the management of impacted permanent second molar is periodontal surgery over the gingival mucosa in relation to the impacted teeth , which was required to gain access to the buccal surface of 47 . \n the laser surgery was preferred since it had minimal bleeding thereby reducing bond failure on bonding . \n picasso soft tissue diode laser ( with 7 w , 810 nm ) was used in the surgery . a bondable attachment \n ( 0.22 slot mbt premolar bracket , oramco ) was placed in the exposed visible surface of impacted 47 . \n bondable bracket was preferred over buttons due to the advantage of wings and better bonding capacity . \n the attachment was exposed in the oral cavity during healing for connecting the appliance to the bonded attachment . \n a removable appliance was constructed for extrusion of 47 since it has higher anchorage control over the fixed appliance and easy to design for this purpose . \n removable appliance was the priority of choice due to the advantage of higher anchorage control and ease in design of the appliance . \n thus , a removable appliance was fabricated for mandibular arch with bilateral triangular clasp one in between 42 , 43 and other in between 33 , 34 . \n adams clasp one on the premolar on the fourth quadrant ( 45 ) and other on the molar in the third quadrant ( 36 ) . a custom made retraction spring with helix made with 17 25 titanium molybdenum alloy ( tma ) wire constructed with the acrylic material extending to the adams clasp of 46 . \n a horizontal arm made of tma wire with a posterior helix on the distal end tied using a ligature wire to the bracket on the impacted 47 and an anterior helix with two turns present at the buccal region of 46 , from the helix of the wire extends into the acrylic along with crossover arm of adams clasp ( on 45 ) to the lingual plate , finishing with a retention tag . the horizontal arm from the anterior helix to the posterior helix measures \n about 20 mm and the posterior helix with two full turns of 3 mm diameter is placed 1.5 cm above the bonded attachment thus , the force exerted when the posterior helix is tied to the attachment causes an extrusion force of 100 g / cm on the impacted 47 [ figures 24 ] . the extrusion appliance with the removable extrusion appliance engaged to the impacted teeth ( a ) preoperative , ( b ) 2 months after activation , ( c ) 4 months after activation , and ( d ) postoperative \n the construction and design of the appliance helped in achieving the treatment goals , which is extrusion of molar ( 47 ) and preserving the anchorage for its extrusion . \n the appliance 's merits are simple design , easy to fabricate , cost - effective , and anchorage control . \n likewise , there are demerits but of lesser significance than of merits , which are patient cooperation and initial speech disturbances . \n furthermore , the duration of this treatment was 7 months , which is considerably effective with monthly periodic visits and continuous force needed at the start of the treatment . \n the appliance scored higher in comparison with fixed appliance in the aspect of anchorage control as previously used removable appliance for maxillary canine impactions [ figure 5 ] . \n ( a ) postoperative mandibular occlusal view showing erupted 47 , ( b ) right view , ( c ) postoperative orthopantomogram showing a decrease in the distance between occlusal plane and 47 compared with preoperative \n the reduction of adversities such as de - arrangement of occlusion of the adjacent teeth , disturbance of bite is achieved by deriving anchorage from skeletal and soft tissue thereby avoiding impervious tooth movements . \n maintenance by the patient was achieved as expected when compared with fixed appliance used for extrusion of impacted tooth at a significant acceptable duration . \n further use of removable appliance for management of impacted teeth should be encouraged as the merits derived from the achieved in this treatment .", "role": "user" }, { "content": "the purpose of this article is to review the principles of case management of impacted mandibular molars and to illustrate their potential to respond well to treatment . \n although the scope of treatment may be influenced by the patient 's age , past dental history , severity of impaction , dentoalveolar development , and root form , the case reports demonstrate the inherent potential for good treatment outcome even in the most unfavorable circumstances .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: renal angiomyolipomas ( raml ) are uncommon benign renal tumours , composed of fat cells , smooth muscle cells and blood vessels . they are associated with a tendency to rupture resulting in sometimes - torrential retroperitoneal hemorrhage as the wunderlich syndrome or as severe potentially exsanguinating hematuria . these lesions may be sporadic in about 80% of cases or be associated with genetic disorders such as the tuberous sclerosis complex . \n when hemorrhage from raml occurs in pregnancy it presents a unique challenge requiring timely and systematic holistic definitive intervention with the goal of preventing fatality , preserving renal function as well as preventing fetal loss if possible . \n currently a gamut of management options are available including arterial embolization , radiofrequency ablation , cryoablation , mammalian target of rapamycin ( mtor ) inhibitors ; everolimus and partial or total nephrectomy . \n we report the management of severe bleeding from raml in pregnancy and highlight the need to adopt a management strategy that suits the practice environment and offers the patient standard and enduring care . \n \n a 26-year old trader , in her 16 week of pregnancy ( gravida 2 para 1 ) , presented on account of right flank pain and swelling with associated haematuria ( often in clots ) , weakness , vomiting and anorexia . physical examination revealed severe pallor , pulse ; 118 beats per min , blood pressure ; 90/60 mmhg respiratory rate ; 28/min , and a firm , tender right lumbar mass extending to the right upper quadrant . \n investigations revealed a pcv of 18% . she was admitted and resuscitated with blood transfusions , analgesics and bladder washouts via a 24 g 3 way foley catheter . when normotensive , tocolysis was commenced with oral nifedipine 20 mg with hourly monitoring of blood pressure . \n abdominal ultrasound findings showed a pulsatile well delineable oblong hypoechic fluid mass about 77.862 mm in size with its medial compartment in the mid pole . \n the fluid within the mass had a swirling character and on doppler insonation , this fluid had characteristics consistent with av fistulous aneurysmatic lesion or av malformation . \n liver harboured two hypoechoic solid focal lesions in the right lobe with features of haemangiomata . \n magnetic resonance imaging ( mri ) showed a large well defined complex mixed intensity mass involving the anterior and inferior aspects of the right kidney , 1512 cm in size and causes caliectasis of the supero - posterior remnant part of the kidney . \n the liver harboured poorly circumscribed multiple masses , which are hyperintense on t1 and t2 and post contrast . \n counseling was done , where the diagnosis and available treatment options ( surgical extirpation after stabilization ) were explained . \n she was also advised on the risk of perioperative fetal loss as well as the need for long term follow up for the clinically silent hepatic lesions . \n findings were those of a perirenal haematoma and large hemorrhagic renal mass involving the lower and mid poles and compressing the upper pole ; histopathology revealed renal angiomyolipoma ( figures 2 and 3 ) . \n angiomyolipoma ( aml ) is a benign mesenchymal tumor composed of variable proportions of adipose tissue , spindle and epithelioid smooth muscle cells and abnormal thickwalled blood vessels ; with the two organs most commonly involved being the kidney ( 77% ) and liver ( 14% ) . \n amls occur in two distinct ways , either sporadically or in association with tuberous sclerosis ( ts ) . and in this cohort the tumours are usually small , multiple and bilateral . \n although rare , amls can result in wunderlich s syndrome and or frank hematuria the prevalence of sporadic renal angiomyolipoma is 0.44% , with 0.60% in the female and 0.28% in the male subpopulations . \n though the causal mechanism is not clearly defined , it is thought that this is due to ubiquitous expression of oestrogen and progesterone receptors in amls . \n haemorrhage occurring in raml in pregnancy has been shown to be rare ; with only 22 cases reported in the last 35 years . \n the mean age of the mothers was 30.8 years with a mean gestation of 29.6 weeks . \n fetal survival till term in the patients treated by nephrectomy is also rare , to our knowledge , only reported in a 15 week pregnant patient with a raml of 7.510 cm . \n our patient who was 14.5 weeks pregnant , though with a larger tumor 1512 cm ( mri ) had a similar outcome ; she had caesarian section at 40 weeks with a healthy baby . concerning treatment options ranging from minimally invasive options such as embolization , radiofrequency ablation , cryoablation , novel therapies like everolimus to partial or total nephrectomy . \n earlier workers have shown that prevalence of major bleeding is high in sporadic amls with a diameter of > 6 cm . \n bleeding aml in pregnancy is a rare and complex vascular surgical emergency and should be managed in a multidisciplinary team . \n management is largely influenced by the haemodynamic stability of the mother , gestational age , presence or absence of foetal distress and the ready availability of facilities such as an angiography suite , operating theatre and neonatal intensive care . \n challenges experienced in her management include the absence of facilities for angiography and embolization and absence of in- house facilities for mri . \n this required careful consideration as to when patient could be moved to get the imaging done . \n we demonstrate that it is possible to manage severe bleeding from raml by resuscitation and well - timed radical nephrectomy at 14 weeks gestation with excellent maternal and fetal outcome .", "role": "user" }, { "content": "renal angiomyolipomas ( raml ) are uncommon benign renal tumours that are associated with a tendency to rupture resulting in sometimes - torrential retroperitoneal hemorrhage as the wunderlich syndrome or as severe potentially exsanguinating hematuria . \n when hemorrhage from raml occurs in pregnancy it presents a unique challenge requiring timely and appropriately adapted intervention with the goal of preventing fatality , preserving renal function as well as preventing fetal loss if possible . \n we report the management of severe bleeding from raml in pregnancy and highlight the need to adopt a management strategy that suits the practice environment and offers the patient standard and enduring care .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the study was conducted at the drug deaddiction and treatment center ( ddtc ) of the department of psychiatry at the postgraduate institute of medical education and research ( pgimer ) , chandigarh ; a tertiary - care hospital in north india that caters to more than 40 million people . \n most patients come by self or family referral , whereas others are referred from other hospitals or other departments of pgimer . \n the services of the center include outpatient , inpatient , laboratory , aftercare , and liaison with other governmental and nongovernmental agencies , and self - help groups . \n these services are provided by a team of psychiatrists , social workers , nurses , psychologists , and other support workers . \n the study covered women patients registered at the ddtc between september 1978 ( when the department of psychiatry started a dedicated substance abuse outpatient service ) and december 2011 . \n the diagnosis of substance dependence was made by a consultant psychiatrist after direct interview with the patient and the relatives . \n the diagnoses were made according to international classification of diseases ( icd)-9/-10 before / after december 1992 . \n detailed evaluation was followed by management including detoxification , symptomatic treatment , treatment of associated medical and psychiatric conditions , and psychosocial counseling of patients and their families . \n regular follow - ups were done by a psychiatrist , and if need be social workers , when patients drug use profile , social , and occupational functioning , and physical and psychological problems were monitored and documented . \n for all the 100 registered female subjects the available records were scanned and relevant information was retrieved according to a study specific predetermined coding plan . \n the information included sociodemographic profile , substance use pattern , physical and psychiatric comorbidities , impairment in different areas of functioning , and follow - up data . \n the clinical information was discerned from the recorded history , clinical evaluation , and follow - up notes . \n an earlier publication from our center has reported data on 35 patients registered between 1978 and 2003 . for the sake of reporting complete data over the almost entire period spanning the existence of the center ( 1978 - 2011 ) we decided to incorporate those 35 patients in our total sample . \n a semistructured proforma was used to record age , marital status , educational years , occupation , family type , religion , and locality . \n social support was measured on a 4-point scale measuring poor ( no support system ) , minimal ( support from only one source ; family , network , or society ) , fair ( support from two sources ) , or good social support ( support from multiple sources ) . \n this included details of substances , duration of dependence , and physical and psychiatric comorbidity . \n the information about the physical and psychiatric comorbidity was inferred from the history , clinical , and laboratory evaluation and monitoring of the patient throughout the contact period . \n four levels of drug - related complications were operationalized which covered the seven areas of functioning such as health , occupation , finance , family , marital , legal , and social areas . \n the severity of complications at the first presentation ( nil , mild , moderate , and severe ) was extracted from the case records . \n the duration of follow - up was calculated as number of months from first visit to the last visit to the hospital . \n simple binary logistic regression analysis with enter method was used to study the relationship among independent variables which were more frequently present in subjects who followed - up and who remained abstinent ( improved ) at follow - up . \n analysis was done by statistical package for social sciences ( spss ) version 14 for windows ( chicago , illinois , usa ) . \n a semistructured proforma was used to record age , marital status , educational years , occupation , family type , religion , and locality . \n social support was measured on a 4-point scale measuring poor ( no support system ) , minimal ( support from only one source ; family , network , or society ) , fair ( support from two sources ) , or good social support ( support from multiple sources ) . \n this included details of substances , duration of dependence , and physical and psychiatric comorbidity . \n the information about the physical and psychiatric comorbidity was inferred from the history , clinical , and laboratory evaluation and monitoring of the patient throughout the contact period . \n four levels of drug - related complications were operationalized which covered the seven areas of functioning such as health , occupation , finance , family , marital , legal , and social areas . \n the severity of complications at the first presentation ( nil , mild , moderate , and severe ) was extracted from the case records . \n the duration of follow - up was calculated as number of months from first visit to the last visit to the hospital . \n a semistructured proforma was used to record age , marital status , educational years , occupation , family type , religion , and locality . \n social support was measured on a 4-point scale measuring poor ( no support system ) , minimal ( support from only one source ; family , network , or society ) , fair ( support from two sources ) , or good social support ( support from multiple sources ) . \n this included details of substances , duration of dependence , and physical and psychiatric comorbidity . \n the information about the physical and psychiatric comorbidity was inferred from the history , clinical , and laboratory evaluation and monitoring of the patient throughout the contact period . \n four levels of drug - related complications were operationalized which covered the seven areas of functioning such as health , occupation , finance , family , marital , legal , and social areas . \n the severity of complications at the first presentation ( nil , mild , moderate , and severe ) was extracted from the case records . \n the duration of follow - up was calculated as number of months from first visit to the last visit to the hospital . \n simple binary logistic regression analysis with enter method was used to study the relationship among independent variables which were more frequently present in subjects who followed - up and who remained abstinent ( improved ) at follow - up . \n analysis was done by statistical package for social sciences ( spss ) version 14 for windows ( chicago , illinois , usa ) . \n the mean age of the sample was 36.33 years ( standard deviation ( sd ) : 11.87 years ; range : 12 - 63 years ) , with age of onset of substance intake of 27.30 years ( sd : 10.02 years ) , and age of onset of substance dependence of 29.21 years ( sd : 9.87 years ) . \n the mean duration of substance dependence was 7.10 years ( sd : 7.24 years ; median : 5 years ) . \n the mean years of education were 7.75 ( sd : 5.73 years ; range : 0 - 17 years ) . \n majority were married ( 65% ) , non - earning ( 72% ; includes 56% housewives ) , hindu by religion ( 63% ; 32% were sikh and 5% others ) , from urban locality ( 61% ) , and nuclear family ( 59% ) . \n majority was having fair / good social support ( 69% ) and family history of substance dependence was present in nearly half of the subjects ( 43% ) . \n the common substances were : tobacco ( 60% ) , opioids ( 27% ) , alcohol ( 15% ) , and sedatives ( 13% ) . \n tobacco was used by smoking , chewing , or both ( 28 , 27 , and 5% , respectively ) . \n the common opioids used were : injectable buprenorphine or pentazocine ( 14% ) , dextropropoxyphene ( 8% ) , heroine ( 4% ) , and opium or poppy husk ( 2% ) . \n the reasons for initiating substance use were : to alleviate frustration or stress ( 49% ) , curiosity ( 37% ) , and peer pressure ( 14% ) . \n comorbid psychiatric disorder ( other than substance dependence ) , present in 25% cases , included : depressive disorder ( moderate depression or dysthymia ; 12% ) , adjustment disorder ( 5% ) , somatoform disorder ( 3% ) , anxiety disorder and schizophrenia ( 2% each ) , and obsessive compulsive disorder and bipolar affective disorder ( 1% each ) . \n the common disorders were : migraine headache ( 4% ) , alcoholic liver disease and menorrhagia ( 3% each ) , hypertension and renal stone ( 2% each ) , and seizure disorder , human immunodeficiency virus ( hiv ) , cholecystitis , chronic obstructive pulmonary disorder , chronic suppurative otitis media , hydronephrosis , hypothyroidism , psoriasis , prolapse intervertebral disc , subarchnoid hemorrhage , and fibroid uterus ( 1% each ) . \n the most affected domains were of health ( 74% ) , family ( 57% ) , and social life ( 56% ) . \n other less affected domains were of financial ( 43% ) , occupational ( 42% ) , and marital life ( 33% ) . \n more than one - third subjects were detoxified with clonidine for opioids ( 24 cases ) or oral lorazepam / chlordiazepoxide for alcohol ( 13 cases ) . \n pharmacoprophylaxis was given to only five subjects : naltrexone ( three cases ) , and baclofen ( two cases ) . \n other additional psychotropics were given to 14 cases ( escitalopram - five cases ; imipramine - three cases ; and fluoxetine , duloxetine , mirtazapine , venlafaxine , olanzapine , and risperidone-1 case each ) . \n as 69 cases never followed - up , follow - up data were available only for 31 cases . \n the duration of follow - up ranged 0.5 - 72 months with a mean of 5.01 months ( median 2 months ) . \n the number of follow - ups ranged 1 - 30 with a mean of 3.96 ( median 3 ) follow - ups . \n improved. subjects who followed - up were more commonly non - hindus ( 43.2 vs 23.8% hindus , = 4.11 , p = 0.042 ) , dependent on opioids ( = 7.51 , p = 0.006 ) , with higher years of education ( 10.29 vs 6.60 years , t = 3.09 , p = 0.003 ) , and higher impairment score ( 4.80 vs 3.20 , t = 2.57 , p = 0.011 ) . \n the lowest follow - ups were in cases with tobacco dependence ( 13.33% , = 21.88 , p < 0.001 ) . \n subjects with improved / abstinent status at last follow - up were again more commonly non - hindus ( 32.4 vs 9.5% hindus , = 8.28 , p = 0.004 ) and with higher years of education ( 10.44 vs 7.15 years , t = 2.24 , p = 0.027 ) . as shown in table 1 , significant predictors for follow - up were being non hindu , opioid dependence , educational years , and impairment score ; the odds ratio was highest for opioid dependence . \n similarly significant predictors for abstinence at last follow - up were being non hindu , and educational years ; the odds ratio was highest for educational years . \n the mean age of the sample was 36.33 years ( standard deviation ( sd ) : 11.87 years ; range : 12 - 63 years ) , with age of onset of substance intake of 27.30 years ( sd : 10.02 years ) , and age of onset of substance dependence of 29.21 years ( sd : 9.87 years ) . \n the mean duration of substance dependence was 7.10 years ( sd : 7.24 years ; median : 5 years ) . \n the mean years of education were 7.75 ( sd : 5.73 years ; range : 0 - 17 years ) . \n majority were married ( 65% ) , non - earning ( 72% ; includes 56% housewives ) , hindu by religion ( 63% ; 32% were sikh and 5% others ) , from urban locality ( 61% ) , and nuclear family ( 59% ) . \n majority was having fair / good social support ( 69% ) and family history of substance dependence was present in nearly half of the subjects ( 43% ) . \n the common substances were : tobacco ( 60% ) , opioids ( 27% ) , alcohol ( 15% ) , and sedatives ( 13% ) . \n tobacco was used by smoking , chewing , or both ( 28 , 27 , and 5% , respectively ) . \n the common opioids used were : injectable buprenorphine or pentazocine ( 14% ) , dextropropoxyphene ( 8% ) , heroine ( 4% ) , and opium or poppy husk ( 2% ) . \n the reasons for initiating substance use were : to alleviate frustration or stress ( 49% ) , curiosity ( 37% ) , and peer pressure ( 14% ) . \n comorbid psychiatric disorder ( other than substance dependence ) , present in 25% cases , included : depressive disorder ( moderate depression or dysthymia ; 12% ) , adjustment disorder ( 5% ) , somatoform disorder ( 3% ) , anxiety disorder and schizophrenia ( 2% each ) , and obsessive compulsive disorder and bipolar affective disorder ( 1% each ) . \n the common disorders were : migraine headache ( 4% ) , alcoholic liver disease and menorrhagia ( 3% each ) , hypertension and renal stone ( 2% each ) , and seizure disorder , human immunodeficiency virus ( hiv ) , cholecystitis , chronic obstructive pulmonary disorder , chronic suppurative otitis media , hydronephrosis , hypothyroidism , psoriasis , prolapse intervertebral disc , subarchnoid hemorrhage , and fibroid uterus ( 1% each ) . \n the most affected domains were of health ( 74% ) , family ( 57% ) , and social life ( 56% ) . \n other less affected domains were of financial ( 43% ) , occupational ( 42% ) , and marital life ( 33% ) . \n more than one - third subjects were detoxified with clonidine for opioids ( 24 cases ) or oral lorazepam / chlordiazepoxide for alcohol ( 13 cases ) . \n pharmacoprophylaxis was given to only five subjects : naltrexone ( three cases ) , and baclofen ( two cases ) . \n other additional psychotropics were given to 14 cases ( escitalopram - five cases ; imipramine - three cases ; and fluoxetine , duloxetine , mirtazapine , venlafaxine , olanzapine , and risperidone-1 case each ) . \n as 69 cases never followed - up , follow - up data were available only for 31 cases . \n the duration of follow - up ranged 0.5 - 72 months with a mean of 5.01 months ( median 2 months ) . \n the number of follow - ups ranged 1 - 30 with a mean of 3.96 ( median 3 ) follow - ups . of those who did follow - up , 58.06% were recorded as \n improved. subjects who followed - up were more commonly non - hindus ( 43.2 vs 23.8% hindus , = 4.11 , p = 0.042 ) , dependent on opioids ( = 7.51 , p = 0.006 ) , with higher years of education ( 10.29 vs 6.60 years , t = 3.09 , p = 0.003 ) , and higher impairment score ( 4.80 vs 3.20 , t = 2.57 , p = 0.011 ) . \n the lowest follow - ups were in cases with tobacco dependence ( 13.33% , = 21.88 , p < 0.001 ) \n . subjects with improved / abstinent status at last follow - up were again more commonly non - hindus ( 32.4 vs 9.5% hindus , = 8.28 , p = 0.004 ) and with higher years of education ( 10.44 vs 7.15 years , t = 2.24 , p = 0.027 ) . \n as shown in table 1 , significant predictors for follow - up were being non hindu , opioid dependence , educational years , and impairment score ; the odds ratio was highest for opioid dependence . \n similarly significant predictors for abstinence at last follow - up were being non hindu , and educational years ; the odds ratio was highest for educational years . \n even then , compared to the west the problem of substance abuse among women is very low . \n however , it is being increasingly recognized among the related professionals and the media that the prevalence of substance abuse among women is showing a definite increase . \n as yet , this does not get reflected in official statistics for a variety of reasons : lack of funding and independent financial resources , societal stigma , and burden of childcare , problems in transportation , and the largely subordinate position of the women . \n the present research was a retrospective chart review with the aim of studying the profile of women seeking treatment at a deaddiction center at a tertiary care hospital . \n thus , it attempts to provide descriptive information about substances abuse among women in northern india . \n this profile of treatment seekers may help us to address more effectively a partly hidden problem . compared to an earlier study from our center , our sample was larger ( 100 vs 35 subjects ) , with higher drug abuse in family members ( 43 vs 20% ) and shorter duration of follow - up ( 5 vs 8 months ) . \n the commonest substance of abuse recorded was tobacco in our study compared to opioids in the earlier work . \n similar to that study more than half of our study subjects abstaining from the substances at last follow - up signify the importance of appropriate treatment and compliance in this subgroup . \n another study , also reported better outcome in women than men , despite differences in populations targeted , type of treatment , problem drug , and treatment setting . \n we found more follow - ups for non - hindu subjects , opioid dependence , higher education , and greater impairment and least follow - ups for nicotine dependence . similar to an earlier study our subjects with higher years of education were significantly more abstinent at the last follow - up . in our study , \n significant predictors of follow - up were non - hindu subject , opioid dependence , educational years , and impairment score , and predictors for remaining abstinent at last follow - up were non - hindu subject and educational years . majority of the 100 women in the present study being single , well - educated and in their 4 decade is similar to the finding of the rapid assessment survey . \n nearly half of our sample having initiated substance use to alleviate frustration or stress is in line with earlier report of humiliation , shame , anger , and marital conflict as major reasons to initiate drugs . \n the substances of abuse being mainly tobacco and opioids , and less commonly sedative - hypnotics and alcohol , is similar to earlier studies from other parts of india reporting no abuse of cannabis or inhalants among women . \n nearly half of our sample having a family history of substance dependence is supportive of earlier research establishing that family members , especially husband 's and father 's , substance abuse plays a contributory role in initiation of substance use in women . \n it is well - recognized that women have proportionately more fatty tissue , less body water , and lesser activity of gastric alcohol dehydrogenase enzyme than men , leading to higher drug concentration and related complications . in keeping with this , \n the physical and psychiatric comorbidity was quite prevalent in our sample as has also been reported by other studies from india and the west . \n also , our sample reporting health as the most affected area , alongside a longer duration of substance dependence and more impairment in family rather than financial or occupational domains is similar to the findings of another report from india . \n this finding is consistent with the literature from the west and india reporting a higher psychiatric comorbidity in women substance abusers . \n a more recent study reported older women to have relatively less severe substance abuse and better social networking and treatment outcome compared to younger women . \n some of the instruments , assessments , and definitions used ( e.g. , social support , impairment , and outcome ) were center - specific and have not been evaluated for their reliability . the sample comprised of women seeking deaddiction treatment at one center . \n hence , generalization of our findings to other deaddiction centers , and across the community and the country demands caution . \n a typical woman seeking treatment for substance abuse was a middle - aged , married , school drop - out , and house - wife from an urban nuclear family with substance abuse impacting their lives , especially their physical health . \n thus there is a need for measures to improve access to deaddiction services to women substance users in the community . \n this may well be a small part of the wider concerted social action in the context of empowerment , support , and attention to the special needs of women .", "role": "user" }, { "content": "background : in the recent decades increasing number of women have been seeking deaddiction services . despite \n that the report data is very limited from india.objectives:the present research aimed to study the demographic and clinical profile of women seeking deaddiction treatment at a tertiary care center in north india.materials and methods : retrospective structured chart review of 100 women substance abusers seeking treatment at a deaddiction center between september 1978 and december 2011.results:a typical case was of 36.3 years age , married ( 65% ) , urban ( 61% ) , nuclear family ( 59% ) based housewife ( 56% ) , with good to fair social support ( 69% ) . \n the commonest substance of abuse was tobacco ( 60% ) , followed by opioids ( 27% ) , alcohol ( 15% ) , and benzodiazepines ( 13% ) . \n the common reasons for initiation of substance use were to alleviate frustration or stress ( 49% ) and curiosity ( 37% ) . \n family history of drug dependence ( 43% ) , comorbidity ( 25% ) , and impairments in health ( 74% ) , family ( 57% ) , and social domains ( 56% ) were common . \n only a third of the sample paid one or more follow visit , and of those 58% were abstinent at the last follow - up . \n significant predictors identified were being non - hindu and higher educational years for abstinent status at follow-up.conclusion:the common substances of abuse were tobacco , opioids , and alcohol and benzodiazepines ; and family history of drug abuse and comorbidity were common . \n the follow - up and outcome were generally poor . \n this profile gives us some clues to address a hidden health problem of the community .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: avian influenza has received worldwide attention due to its rapid global spread via migratory birds and the growing number of human cases . the highly pathogenic avian influenza virus that the world health organization fears may cause \n a pandemic in humans comprises strains from the subtype h5n1 of influenza type a.(1 ) subtypes of influenza virus are named based on the observed combinations of two viral surface membrane glycoproteins , hemagglutinin ( ha)aaabbreviations : vs , virtual screening ; rcs , relaxed complex scheme ; rc , relaxed complex ; md , molecular dynamics ; ha , hemagglutinin ; na , neuraminidase ; cs - map , computational solvent mapping ; ncids , national cancer institute diversity set ; evsrcs , ensemble - based virtual screen with relaxed complex scheme ; dana , 2,3-didehydro-2-deoxy - n - acetyl neuraminic acid ; sa , sialic acid ; rmsd , root - mean - square deviation ; nbcr , national biomedical computational resource ; pragma , pacific rim application and grid middleware assembly ; csf4 , community scheduler framework ; apbs , adaptive poissonboltzmann solver ; nsc , national service center ; vmd , visual molecular dynamics ; namd , not another molecular dynamics ; sasa , solvent accessible surface area . \n and neuraminidase ( na ) , with 16 and 9 types known to date , respectively.(2 ) three historical pandemic flu viruses were caused by h1n1 ( 1918 ) , h2n2 ( 1957 ) , and h3n2 ( 1968 ) . \n abbreviations : vs , virtual screening ; rcs , relaxed complex scheme ; rc , relaxed complex ; md , molecular dynamics ; ha , hemagglutinin ; na , neuraminidase ; cs - map , computational solvent mapping ; ncids , national cancer institute diversity set ; evsrcs , ensemble - based virtual screen with relaxed complex scheme ; dana , 2,3-didehydro-2-deoxy - n - acetyl neuraminic acid ; sa , sialic acid ; rmsd , root - mean - square deviation ; nbcr , national biomedical computational resource ; pragma , pacific rim application and grid middleware assembly ; csf4 , community scheduler framework ; apbs , adaptive poissonboltzmann solver ; nsc , national service center ; vmd , visual molecular dynamics ; namd , not another molecular dynamics ; sasa , solvent accessible surface area . \n ha is involved in the attachment of viral particles to host cell surface glycoproteins , whereas na plays a role in the release of newly synthesized viral particles ( for a recent review , see ref ( 3 ) ) . \n na , a membrane - bound homotetrameric enzyme , releases viral paricles by cleaving terminal sialic acid ( sa ) residues on the host cell surface proteoglycans , bound by ha.(4 ) as the na active site is relatively well - conserved , it became a good target for structure - based antiviral drug development.(5 ) commercial inhibitors such as zanamivir and oseltamivir are stockpiled by various countries in case of a pandemic outbreak . while both drugs are successful in treating several human cases,(6 ) drug - resistant strains have quickly emerged due to antigenic drift . in 2006 , russell et al . reported the first crystal structures of a group-1 na ( n1 ) , which revealed the existence of a \n 150-cavity that , under various crystallization conditions , closed upon ligand binding to the active site through movement of the 150-loop.(9 ) to further probe the structure and dynamics of n1 , explicitly solvated molecular dynamics ( md ) simulations on the tetrameric n1 systems with ( holo ) or without ( apo ) oseltamivir bound were performed.(10 ) the simulations indicated that the flexibility of the 150-loop may be even greater than previously anticipated and that the dynamics of the neighboring 430-loop also influenced the topology of the binding site . \n more recently , representative conformations of the n1 binding site ( including the flexible 150- and 430-loop regions ) , extracted from a clustering analysis of the n1 md simulations , were used for computational solvent mapping ( cs - map ) , which assessed the binding affinity of small , solvent - sized probe molecules within these areas.(11 ) the mapping analyses revealed the presence of novel druggable hot spots in the 150- and 430-loop regions , providing further support for the feasibility of developing high - affinity inhibitors capable of binding these areas . \n such inhibitors may be applicable to the group-1 na s including n1 , n4 , n5 , and n8 , which have nearly identical active site regions,(9 ) but not necessarily group-2 enzymes ( n2 , n3 , n6 , n7 , and n9 ) , which appear to lack such well defined cavities . \n structure - based drug discovery has made significant progress in the past 30 years,(12 ) benefiting from recent advances in high performance and distributed grid computing.(13 ) however , the drawbacks are well documented ( reviewed in refs ( 14,17 ) ) , and only in the past decade have methods able to treat receptor flexibility been developed . \n a related challenge is the identification of drug leads out of large compound libraries through receptor - based virtual screening ( vs ) . \n vs is a widely used method that has been shown to be successful in a variety of studies , although it also has many shortcomings ( reviewed in refs ( 26 ) and ( 27 ) ) . \n the treatment of receptor flexibility within the scope of vs is still in its infancy and a very active area of research , as it is widely accepted that receptor flexibility plays an important role in molecular recognition . \n the use of multiple experimentally derived protein structures in vs has been shown to effectively improve enrichment factors and , most recently , aid in the discovery of novel compounds active against the p53 tumor repressor.(30 ) the relaxed complex scheme ( rcs ) , a hybrid computational method that combines the advantages of docking algorithms with dynamic structural information provided by md simulations , has been successfully applied to a number of systems . \n recently , raltegravir became the first fda approved drug targeting hiv integrase,(32 ) and the treatment of receptor flexibility with md simulations played a critical role in understanding the mechanism of action for this new class of inhibitors.(33 ) during md simulations of the integrase enzyme in complex with the known inhibitor 5citep , a new pocket adjacent to the binding site was revealed , and docking of ligands into this new area indicated favorable binding.(34 ) the development of compounds capable of binding to both the original binding site and the new cavity , so - called butterfly compounds , formed the basis for this new class of integrase inhibitors . in this work , we build upon these recent advances and present a novel , systematic , in silico lead identification strategy , with the goal of taking full receptor flexibility into account in the lead identification and scoring stages . \n vs experiments are carried out against the nci diversity set ( ncids ) on a set of eight n1 representative receptor structures,(31 ) consisting of two crystal structures and the three most dominant cluster - representative receptor structures as extracted from the explicitly solvated apo and holo md simulations.(10 ) the use of the most dominant md - generated structures systematically incorporates a broader range of receptor configurations into the hit identification process , in contrast to screening the crystal structures alone . \n we anticipate that for very flexible receptors , such as n1 , the incorporation of this variable structural information may identify new drug leads . indeed , \n comparison of the cluster representative structures suggests that the remarkable flexibility of the 150- and 430-loops results in correspondingly different 150- , 430- , and binding site cavities . \n this novel vs approach is further combined with the rcs , a lead validation and refinement technique in which the top n hits are redocked to the entire nonredundant receptor ensemble and rescored . ultimately , we report 27 experimentally available compounds that are predicted to have a binding affinity equal to or better than four known n1 antivirals . \n importantly , half of these compounds would have been neglected based on the crystal structure vs scores alone . \n examination of the interactions of these top hits within the na active site region reveals different classes of compounds with binding preference to the 150- , 430- , and catalytic cavities . \n several compounds are predicted to interact with key residues across two cavities and may provide novel bridging compound scaffolds . \n we anticipate that this ensemble - based virtual screen with relaxed complex scheme ( evsrcs ) approach may contribute to better structure - based drug design strategies for very flexible receptors . \n details of the simulation setup without any ligand bound are as previously described.(10)briefly , the apo system was built with the avian h5n1 na crystal structure 2hty.(9 ) protonation states for histidine residues were defined at an apparent ph 6.5 using the pdb2pqr web server.(35 ) all crystallographically resolved water oxygen positions were retained in the apo system , as well as ca ions , which are required for optimal na function.(36 ) to mimic experimental inhibition assay conditions , a 150 mm nacl salt bath was introduced . the simulated system contained 112311 atoms . \n details of the simulation setup with oseltamivir bound are as previously described.(10 ) briefly , the 2hu0 structure used for the holo system initially had a single oseltamivir molecule bound in the active site of chain b.(9 ) to introduce oseltamivir within each of the other chains , chain b was aligned to chain a , c , and d by superimposition of the backbone c atoms , and the resulting transformation matrix was applied to the oseltamivir molecule . \n amber9 was used to set up the oseltamivir - bound system using an identical protocol to the apo system , with the exception of the additional oseltamivir parameters . \n the composite tetrameric oseltamivir - bound system , comprising one oseltamivir molecule in each of the four active sites and calcium ions in 150 mm nacl salt bath , contained 112457 atoms . \n the apo and holo systems were energy minimized for 5 10 steps using namd version 2.6b1 ( http://www.ks.uiuc.edu/research/namd).(37 ) the md methods have been previously described in refs . \n free dynamics were subsequently performed using a 2 fs time step for a total of 40 ns for each system . \n trajectories were generated on the san diego supercomputing center s datastar machine ( benchmark time of 0.3 days / ns using 112 parallel processors ) . to generate a reduced , representative set of n1 structures , root - mean - square difference ( rmsd ) conformational clustering was performed as previously described in ref ( 11 ) with the gromos++ analysis software,(38 ) part of the gromos05 software for biomolecular simulation ( http://www.igc.ethz.ch/gromos ) . \n briefly , for the apo and holo simulations , each chain of the tetramer was extracted at 10 ps intervals over the 40 ns simulation . \n the resulting 1.6 10 trajectory structures for each simulation were superimposed using all c atoms to remove overall rotation and translation . \n the rmsd - clustering was performed on the subset of 62 residues that line the entire binding - site area , which we define here as the binding - site residues : 117119 , 133138 , 146152 , 156 , 179 , 180 , 196200 , 223228 , 243247 , 277 , 278 , 293 , 295 , 344347 , 368 , 401 , 402 , and 426441 . \n these residues were clustered into batches of similar configurations using the atom - positional rmsd of all atoms ( including side chains and hydrogens ) as the similarity criterion . \n a cutoff of 1.3 was chosen after evaluation of the dependence of cluster populations against the total number of clusters found for each simulation using a cutoff in the range 1.01.5 . \n the central member cluster structure , the structure within the cluster having the smallest rmsd to all other structures within the cluster ( i.e. , the centroid ) , was chosen as the cluster representative structure . \n fifty - one clusters were obtained for the apo system , and 27 clusters for the holo system , the three most dominant configurations represented about 21% , 20% , and 19% and 38% , 22% , and 14% of the apo and holo ensembles , respectively.(39 ) in figure 2 , we indicate the time points that correspond to each of the central member cluster structures . \n we do not mean to imply that all members of each cluster always form a continuous portion of the trajectory . \n in fact , although many structures near a similar time point can be found within any given cluster , multiple discontinuous time points are represented in the larger clusters . \n this indicates that areas of configurational space may be sampled multiple times within a single long trajectory . \n three cluster representative structures for the three most dominant clusters from the ( a ) apo and ( b ) holo simulations . \n the structures from the most dominant clusters are colored in pink ( apo-1 , holo-1 ) , the second most dominant in green ( apo-2 , holo-2 ) , and the third most dominant in orange ( apo-3 , holo-3 ) . \n the apo crystal structure ( open 150-loop ) is shown in silver , and the holo crystal structure ( closed 150-loop ) is shown in blue . \n ( a ) binding energy spectra of two known antivirals and the natural sialic acid substrate ( sa ) from the rc redocking against the 27 holo ensemble cluster representatives . \n the bar graph shows the percent ensemble population represented by each cluster , ordered by their corresponding md simulation time step . \n ( b ) binding energy statistics of the five control ligands from the rc redocking . \n the standard deviation of each rc weighted arithmetic mean of the binding energies is represented by an error bar . \n the three most dominant clusters from each of the apo and holo system and the two original crystal structures are used as receptors for virtual screening against the ncids library of compounds . \n autodocktools version 1.4.5(40 ) was used to add polar hydrogens and assign gasteiger charges(41 ) to each of the eight na structures . \n the pdb2pqr web server ( http://nbcr.net/pdb2pqr ) was used to simulate a biological assay ph of 6.5.(35 ) for each of the eight na structures , autogrid version 4.0 was used to create affinity grids centered on the active site . \n each grid enclosed an area of 64 by 72 by 66 with 0.375 spacing , and affinity grids were calculated for all of the following atom types : a ( aromatic carbon ) , c , f , i , n , na ( hydrogen - bond - accepting n ) cl , o , oa ( hydrogen - bond - accepting o ) , p , s , sa ( hydrogen - bond - accepting s ) , br , h , and e ( electrostatic ) . \n all na structures from simulations were aligned with the closed 150-loop crystal structure ( 2hu4 , chain b ) to maintain a consistent grid location . \n the ncids is a collection of approximately 2000 compounds that are structurally representative of a wide range of pharmacophores.(42 ) autodocktools version 1.4.5 was used to merge nonpolar hydrogens , add gasteiger charges to each ligand , and set up rotatable bonds through autotors . \n a number of ligands containing rare earth elements could not be processed and were excluded . \n five additional compounds experimentally known to bind avian influenza n1 were also included in the screen : sialic acid ( n - acetyl neuraminic acid , aka , nana or neu5ac , sa ) , 2,3-didehydro-2-deoxy - n - acetyl neuraminic acid ( dana ) , oseltamivir , zanamivir , and peramivir ( an experimental inhibitor in phase ii clinical trials(43 ) ) . \n autodock version 4.0.1 with the lamarckian genetic algorithm was used to simulate ligandreceptor docking.(44 ) docking parameters were optimized for the positive control docking of oseltamivir to the closed 150-loop conformation of na ( 2hu4 ) and were as follows : trials of 100 dockings , population size of 200 , random starting position and conformation , translation step ranges of 2.0 , rotation step ranges of 50 , elitism of 1 , mutation rate of 0.02 , crossover rate of 0.8 , local search rate of 0.06 , and 5 million energy evaluations . \n a total of 15104 docking jobs were run on the national biomedical computation resource ( nbcr , http://nbcr.net ) kryptonite cluster . \n docked conformations were clustered using a tolerance of 2.0 rmsd using the external clustering script provided with autodocktools version 1.4.5 . \n docking results were sorted by the lowest binding energy of the most populated cluster using autodocktools version 1.4.5 , and the top 30 hits from each of the eight systems were chosen for further analysis . \n the top hits from each screen were initially filtered for druglikeness by their adherence to lipinski s rule of fives.(45 ) it is recommended that compounds should conform to two or more of these rules,(46 ) and we only considered compounds conforming all rules in this study , i.e. , having no more than five hydrogen bond donors , no more than 10 hydrogen bond acceptors , a molecular weight under 500 g / mol , and a partition coefficient ( log p ) under 5.(45 ) compounds were filtered after rather than prior to docking to prevent premature exclusion of compounds that do not meet this criterion . \n a brief analysis of top binders , however , revealed that most compounds that failed the lipinski rules were unlikely drug candidates . \n although some compounds that failed the lipsinki rules also had good docking scores , this cutoff criterion was imposed to focus the scope of our search to the more promising compounds . \n the remaining hits were further filtered based on clustering criteria in autodock : we only consider a compound among the top hits if the most populated cluster included at least 25% of all docked conformations . \n receptorligand interactions , including hydrogen - bonding interactions and molecular surfaces , were calculated in autodocktools version 1.4.5 . a crucial metric for assessing the performance of high - throughput virtual screening is the extent to which a database of compounds could be enriched such that only a much smaller subset needs to be prepared and assayed to identify leads . the metric is often quantified by the enrichment factor ( ef):(19 ) \n where d is the total number of compound in the data set and s is a subset ( e.g. , < 2% ) of the data set . \n top hits were compared to a list of 263 known false positives.(49 ) these so - called promiscuous inhibitors are irregular compounds that inhibit nonspecifically by forming aggregates onto which the protein will adsorb and thus block activity . \n a similarity search was performed to identify false - positive aggregators within the 27 top hits , and none were found using the tanimoto index at 98% cutoff . to validate and refine the virtual screening results , \n redocking experiments were performed on the combined top 27 hits plus oseltamivir , zanamivir , peramivir , dana , and sa . \n each compound was redocked into the 27 central member cluster structures , which accounts for 100% of the ensemble variance from the holo simulation at 1.3 cutoffs . \n following the same docking procedure and parameter set described in the previous section , 756 redocking calculations were distributed to the pacific rim application and grid middleware assembly ( pragma , http://www.pragma-grid.net ) grid using the metascheduler community scheduler framework ( csf4 , http://sourceforge.net/projects/gcsf ) command line client and the output transferred back to the nbcr kryptonite cluster . \n the binding free energies were extracted with autodocktools 1.4.5 scripts , and the ligand binding spectra were plotted for further analysis . for the weight means and standard deviations calculations , the following formula was used . \n i is the index number of each holo ensemble cluster , whose percent distribution sums up to 100% . \n the selection criteria are identical to that used in the earlier virtual screening steps . in cases where the autodock cluster size does not meet the 25% cluster size cutoff , the lowest binding energy of the most populated cluster \n rc weighted harmonic mean is calculated by first converting the binding energies to inhibition constants ki as follows : \n\n where r is 1.98719 and t is 298.15 . \n the weighted harmonic mean ki value is then calculated from : \n\n at the end , ki is converted back to the rc harmonic weighted mean binding energy . \n electrostatic potentials were calculated using the adaptive poissonboltzmann solver ( apbs ) and mapped to the reduced molecular surface by python molecular viewer . to further quantify the changes in the binding site , \n the solvent accessible surface area was computed for each of the eight screened structures using vmd 1.8.6(52 ) with a probe radius of 1.4 . to maintain consistency in the comparisons to the crystal structures \n , 2hu4 ( holo crystal ) with the closed 150-loop , and the corresponding three most dominant representative cluster members from the md trajectories of the two structures are examined in parts a and b of figure 1 , respectively . \n the three most dominant clusters accounted for approximately 60% and 75% of the overall md ensembles , respectively . \n pairwise rmsd s are presented in table 1 for all structures over four carbon subsets : ( i ) all n1 atoms , ( ii ) the 62 residues lining the binding site , ( iii ) the 150-loop residues 146152 , and ( iv ) the 430-loop residues 430439 . as shown in table 1b and figure 1 , \n apo-1 exhibits the biggest differences in the 430-loop compared to the other structures except for apo-2 . on the other hand , \n the apo crystal is significantly different from apo-1 , apo-3 , holo-1 , and holo-3 but more similar to apo-2 and holo-1 in the 150-loop ; the holo crystal exhibits 3 rmsd to all other structures in terms of the 150-loop . \n overall , this analysis indicates the areas of greatest structural diversity and similarity among the different structures . \n distance matrices based on pairwise rmsd s calculated using ( a ) all n1 atoms ( lower triangle ) and the 62 residues lining the binding site ( upper triangle ) ; ( b ) the 150-loop residues ( lower triangle ) and the 430-loop residues ( upper triangle ) . in ( b ) , the rmsd values of the holo-1 cluster representative to the other structures are shown in grey , with the arrows illustrating the originating holo1 label for the 150-loop ( solid arrow ) and 430-loop ( broken arrow ) . \n bold numbers indicate the smallest rmsd value for a structure and italics indicate the largest value for a structure in comparison to all the other seven structures . \n the docking conditions for vs have been optimized using the oseltamivir - bound holo crystal structure ( ) . \n oseltamivir docks to the apo and holo crystal structures in a manner consistent with its crystallized conformation . \n the overall rmsd ( all - atoms ) of the predicted binding pose compared to the crystal structure pose is 1.8 for the holo crystal structure and 2.1 for the apo crystal structure ( ) . in the redocking of oseltamivir to the closed n1 structure , the differences between docked and crystal poses lie primarily in the orientation of the pentyl ether group , which interacts with the protein through variable hydrophobic interactions . \n the negatively charged carboxylate group is anchored through electrostatic interactions to the arginine trio ( r118 , r292 , and r371 ) and its position does not differ significantly between the docked and crystal poses . \n the successful redocking of oseltamivir confirms that autodock 4.0.1 is able to emulate experimental binding with an excellent degree of accuracy and precision , serving as a positive control to validate our virtual screening hits . to examine \n whether the screening conditions offer satisfactory discrimination of known na inhibitors and to provide positive controls for our larger scale vs analysis , we docked the set of five known inhibitors to the holo crystal ( with oseltamivir in the crystal structure removed ) as well as the 27 clusters obtained from the md trajectory clustering analysis ( figure 2 ) . \n both weighed harmonic mean and weighted arithmetic mean were used to calculate the binding affinity estimates , and both yield qualitatively similar results for the five control compounds ( figure 2b ) . in this work , we chose the weighed harmonic mean to rank the top hits because it tends to favor the lower binding energies , which should be given more weight in the evaluation of the overall binding affinity , and its better performance is supported by previous studies . \n for the control compounds , the binding energy difference fluctuates from 2.5 to 5 kcal / mol for dana and zanamivir , respectively . for zanamivir , \n the experimental ic50 is from 0.52.5 m,(55 ) the range we observed is from 0.05 m ( 10 kcal / mol ) to 215 m ( 5 kcal / mol ) . in agreement with what is known experimentally of the sialic - acid analogs \n , oseltamivir is predicted to be the best overall binder , followed by zanamivir and dana . \n however , peramivir is much more potent than dana , oseltamivir , and zanamivir , but its average binding profile is closer to that of dana ( figure 2 ) . as the cluster size represented by each structure used in the redocking varies , as shown in the lower half of the figure 2b , the weighted harmonic and arithmetic mean binding energies for each compound is calculated and the ranking is consistent with the visual examination described above . \n the vs results performed with the two crystal structures and 6 most dominant md ensemble representative structures are summarized in only hits that are in the top 30 and have at least 25% of the total population in their most populated cluster are selected from each set of vs results and indicated in bold . \n as is evident , the number of structure variants captured different compounds with binding energies ranging from 11.6 to 9.25 kcal / mol . \n note that at this cutoff of 9.25 kcal / mol , peramivir and dana are actually not selected , which will be discussed later . as some hits are ranked among the top 30 in more than one structure or cluster representative , a total of 27 top hits \n are reported in this work ( see table 3for a preview ) . given the size of the screening library employed here ( 1883 compounds ) , an enrichment factor of 20 is achieved for the top 2% ranked list and 40 for the top 1% ranked list . \n bold face identify those highlighted by the cs - map analysis.(39 ) underlined residues participate in interactions in more than one cavity across cavity boundaries . \n an asterisk indicates the residues that are found in the 150-cavity , but line the sa cavity when the 150-loop assumes a closed conformation . \n the top 27 recommended compounds ranked by their weighted harmonic mean energy ( kcal / mol ) from the rcs . \n the first column lists the final compound rank , which is also each compounds identification(42 ) ( comp i d ) . \n also listed are the predicted ki ( m ) as calculated from the weighted harmonic mean binding energy , the chemical structure , and the predicted binding sites . \n experimental ic50 values ( nm / l ) for oseltamivir , zanamivir , and peramivir are denoted with parenthesis.(55 ) for comparison , the last two columns indicate the compounds relative rank ( among all 1883 ncids compounds and the five control compounds screened ) in the crystal structure screenings . \n underlined hits are those identified from the ensemble screens but ranked very poorly in the crystal structure screens . \n the selected top hits are redocked into the 27 nonredundant structures representing the entire holo md ensemble . for each compound , the mean and minimum binding energies of a compound docked to the three most dominant clusters ( ensemble mean ) , \n all 27 holo - ensemble cluster representative structures ( rc mean ) , as well as the weighted harmonic mean of the binding energies to the full ensemble ( rc weighted harmonic mean ) , are plotted in figure 3 . for most of the compounds , \n the rc mean and the ensemble mean differ by less than 0.5 kcal / mol . only three compounds , 3 , 4 , and 15 , had binding energies differing by more than 1 kcal / mol . \n in addition , when the rc weighted harmonic mean method is used with compounds that may not have met the 25% cluster size cutoff , dana and peramivir are ranked higher than several of the top 27 hits . \n ensemble mean and ensemble minimum are the arithmetic mean and minimum of the binding energies obtained from screening against the three most dominant holo - ensemble structures . \n rc weighted harmonic nean , rc mean and rc minimum are the weighted harmonic mean , arithmetic mean , and minimum of the binding energies obtained from the rc redocking against the 27 holo ensemble cluster representatives . \n the percentages of the represented ensemble populations are shown in the bar graph scaled by the right axis . \n the active site of n1 may be best described in three cavities for convenience : ( i ) the sialic acid ( sa ) cavity and ( ii ) the 150-cavity , which have been previously named , and ( iii ) the 430-cavity , the presence and size of which is controlled by movement of the 430-loop . an examination of the top 27 hits and their interactions with the crystal structures and the cluster representatives clearly indicates that three cavities are areas of favorable binding ( figures 4 and 5 , and table 3 ) . \n the residues lining the three binding site cavities , which interact with the identified top hits and known inhibitors , are summarized in table 2 and are illustrated in for selected compounds . \n selected hits clustered in the ( a ) apo crystal , ( b ) apo-1 , ( c ) apo-2 , and ( d ) apo-3 structures . \n the electrostatic surface maps were generated using apbs and pmv using 85% opacity for the surface ( scale shown in panel d ) . \n selected hits clustered in the ( a ) holo crystal , ( b ) holo-1 , ( c ) holo-2 , and ( d ) holo-3 structures . \n the electrostatics surface map was generated using apbs and pmv using 85% opacity for the surface ( scale shown in panel d ) . \n the electrostatic surface maps for these ensemble structures are included to provide an additional perspective of the dynamic properties of these cavities . as shown in figures 4 and 5 \n , the sa cavity is largely negatively charged , whereas the 430-cavity is relatively positively charged and the 150-cavity remains relatively neutral in our docking conditions . \n the variations in the electrostatic surfaces are due to the changing surface topology ( e.g. , exposed residues ) between the different structures . \n to compare the changes in the binding site , the sasas were computed for the 62 residues lining the binding site and are as follows in decreasing order ( in ) : apo-1 , 6125 ; holo-3 , 5844 ; apo-2 , 5812 ; apo-3 , 5793 ; holo-2 , 5731 ; holo-1 , 5658 ; 2hty , 5467 ; 2hu4 , 5197 . \n the apo ensemble representative structures illustrate the large changes in the sasas during the apo simulation . in apo-1 , \n the 430-cavity is wide open ( figure 2b ) ; the 430-loop c rmsd is almost 4 from either of the crystal structures ( table 1 ) , and this is reflected in the largest exhibited sasa . \n apo-2 , however , with the 150-loop c rmsd at 1.14 from the apo crystal structure , has a much larger 3.88 rmsd from the holo crystal structure . \n apo-3 exhibits significant outward movement of both the 430-loop and the 150-loop , with the 150 loop \n c rmsd 1.17 from the apo crystal and 3.93 from the holo crystal . \n overall , the holo ensemble generated structures exhibit a tighter range of values for their respective sasas as compared to the apo ensemble . \n holo-1 , which represents 40% of the md snapshots , is most similar to apo-2 in the 150-loop c rmsd , and with a similar 150-cavity empty with no ligand bound . \n holo-2 shows significant movement of the 150-loop , with the 150 cavity smaller , yet allowing a bridging compound to interact in the cavity . \n holo-3 , which presents the largest sasa of the holo ensemble representative structures and shows significant changes in its electrostatic surface properties , is also capable of binding bridging compounds . \n the two top ranked hits , 1 and 2 , both contain a nitrogen - heavy six - membered ring . \n compound 2 has a pyrimidinecarbonitrile scaffold and is the parental compound for several existing compounds found in the patent database . \n it binds consistently in the sa cavity regardless of 150- or 430-loop motion ( ) . in its lowest energy pose docked to apo-3 , it forms hydrogen bonds to framework residues e119 and e227,(56 ) non - hydrogen bonding interactions with catalytic residues d151 , r152 , and y406 , and with framework residue w178.(56 ) compound 1 has a triazinane scaffold , derivatives of which are also found in the patent database with biological effects ( figure 6a ) . in the lowest energy conformation docked to the holo crystal structure , its diimino - triazinane functional group forms hydrogen bonds to framework residues e119 and s179 and the hydoxy(oxido)amino functional group forms hydrogen bonds to the catalytic arginine trio ( r118 , r292 , and r371 ) in the same manner as the carboxylate functional group of oseltamivir.(56 ) compound 1 also forms non - hydrogen - bonding interactions with known catalytic residues d151 , r224 , e276 , and y406 and framework residues r156 , w178 , e227 , and e277.(56 ) compound 1 was ranked high when the vs was conducted with the holo crystal alone . however , compound 2 dropped to no . \n ( a ) the apo crystal structure ( 2hty ) is shown above in silver with top hits 1 and 21 bound . \n these two compounds dock similarly in both crystal structures and their overlapping positions in both are pictured above . \n ( b ) a large number of hits docked to the wide - open 150-cavity in apo-1 , shown above in pink with compound 27 bound . a number of the compounds targeting the 150-cavity would not have been discovered or ranked extremely low ( table 3 ) based on the crystal structure screens alone . \n some of the highest affinity hits to the open and wide - open 150-cavity are steroids such as 5 , 23 , and 25 . \n these compounds interact with the 150-cavity primarily through hydrophobic interactions , specifically to hydrophobic residues v116 , i117 , l134 , t135 , s145 , t148 , v149 , p431 , i437 , w438 , and t439 . \n several other naphthalene - based compounds also bind with high affinity in the 150-cavity , interacting through hydrophobic interactions to the hydrophobic naphthalene group and through hydrogen - bonding interactions to polar functional groups on the naphthalene base ( table 3 ) . \n similar to the wide - open 150-cavity , the open 430-cavity is seen only in md simulations and not observed in the crystal structures . \n thirteen hits to the 430-cavity were identified among the top 27 hits ( table 3 ) . \n the 430-cavity also seems to favor naphthalene - based compounds , namely compounds 9 , 13 , 7 , and 10 . \n these compounds interact through hydrophobic interactions to hydrophobic residues p326 , y347 , s370 , w403 , s404 , y406 , i427 , g429 , p431 , i437 , w438 , and t439 in the 430-cavity . compound 7 is one example of a naphthalene - based compound that binds with high affinity to the open 430-cavity . \n other compounds with hydrophobic benzene rings , similar to naphthalene , also bind in the open 430-cavity with high affinity , for example , compounds 4 , 11 , 16 , 21 , 22 , and 26 . \n compound 21 is an interesting benzodiazepine that is highly ranked in the crystal structure screens but poorly ranked in the apo- and holo - ensemble screens and the rcs redocking ( table 3 ) . of the top 27 hits , seven hits dock \n four hits dock in the sa cavity and either the 150-cavity or the 430-cavity ( see for examples of the apo ensemble ) . \n these hits are of particular interest because they may be linked to known inhibitors to form a novel , bridged inhibitor that binds with higher affinity . \n three hits , compounds 3 , 15 , and 16 , dock primarily with hydrophobic interactions in the 430-cavity and extend a polar functional group into the sa cavity . \n the compound contains a diamino - triazine group that binds in the sa cavity and forms hydrogen bonds to catalytic residue r118 and to framework residues s179 and e277.(56 ) of these three residues , s179 and e277 are also predicted to mediate hydrogen - bonding by the cs - map analysis.(39 ) it also interacts through nonbonded interactions to catalytic residues d151 and y406 and framework residues e119 , r156 , w178 , and e227.(56 ) compound 18 binds simultaneously to the open 150-cavity through hydrophobic contacts to residues i117 , t135 , q136 and t439 , which are mediated by a methyl - chlorobenzene group on the ligand . unlike the other three hits that bind in the sa cavity , compound 18 need not be linked to sa . \n it is predicted to be a compound that will naturally bridge the catalytic residues in the sa cavity to the high - affinity open 150-cavity . \n the development of computational tools for computer - aided drug design depends on the critical compromise between accuracy and computational costs . \n ideally , the most reliable prediction of molecular affinity can be obtained through rigorous free energy calculations of the ligand - binding process ( ref ( 57 ) and references within ) . \n although the theory and methods are well established for calculating free energies , in practice , however , they are still prohibitively expensive to be employed in virtual screening of drug - like databases . to account for receptor flexibility in ligand binding \n , we have included representative snapshots from the md clustering analysis as part of the receptor ensemble , in addition to the crystal structures . in total , the four concatenated monomer trajectories ( extracted from the tetramer simulation ) are equivalent to 160 ns of md simulation . by choosing the three most dominant clusters from each simulation , the coverage of 60% of the apo simulation and 75% of the holo simulation accounts for a generous sampling of configurational space for n1 . \n still , the question remains whether the reduced set of cluster representative structures are biologically relevant . \n we have used the set of known inhibitors to investigate the behavior of the system . \n as shown in figure 2 , some configurations , e.g. , 3.41 , 29.68 ns , seem unfavorable to all the inhibitors , with as much as 5 kcal / mol difference observed for zanamivir . \n it is also evident that the three most dominant clusters , which correspond to 2.65 , 5.76 , and 22.02 ns , do not always have the lowest binding energy , which is often found in clusters with less than 0.01% of the total population of md snapshots . \n however , considering that the dominant configurations are most likely to be encountered by a ligand , we conjecture that the dominant clusters will be good candidates to represent the diversity of configurational space , within the sampling limitations of the md simulations . \n first , the oseltamivir - bound holo - ensemble accounts for ligand - induced effects on the binding site . \n second , any inhibitors may have to compete for the binding site with a favored natural substrate already bound . \n third , the holo ensemble contains oseltamivir , an analogue of the natural substrate sa . \n in fact , from this study , as shown in figure 2b , the apo-1 cluster representative has oseltamivir bound at the 150-cavity , albeit with a higher binding energy ( 7.22 kcal / mol ) this further suggests that the holo ensemble is more appropriate to use for rescoring the hits . \n last , the choice to use a holo - ensemble has also been shown to perform well in other works on the rc methodology(31 ) and the discovery of inhibitors against an rna editing ligase in trypanosoma brucei , the parasite responsible for african sleeping sickness.(58 ) the latter study used the qr - factorization method to extract a nonredundant ensemble of md snapshots and the rcs for rescoring of hits from a vs against a single crystal structure . \n a preliminary study using the known set of inhibitors indicated that the weighted harmonic mean method is able to rank the controls relative to one another for three out of the four inhibitors ( figure 3 ) . \n the natural substrate sa ranks closely to dana , with oseltamivir and zanamivir correctly ranked with higher affinity . \n the exception is peramivir , which is ranked lower than what is expected based on its experimental ic50 values . \n closer examination of the n8 with peramivir bound ( 2htu)(9 ) and the docking pose of peramivir in 2hty revealed no differences in the position and orientation of the ligand ( data not shown ) . \n it is possible that the current docking condition does not account for stabilizing interactions conferred by the solvent , water molecules , or other potential ligand induced conformational changes . on the other hand , the standard error ( 2 kcal / mol ) of autodock4 may be the limiting factor and the rescoring and reranking would be able to discriminate the true differences between some hits . \n this is consistent with the general observation that docking programs are good at separating the binders from nonbinders , but poor at ordering the hits based on their affinity.(59 ) however , by taking into account the different distributions of the cluster size , giving more weight to the clusters with more substantial populations in the calculation of the mean binding energy , the weighted harmonic mean method may be able to improve the rankings , and may offer an interesting area for future methodological development . \n for example , for each compound , we have examined the ensemble minimum binding energy , the lowest value from one of the three most dominant clusters , and the rc minimum binding energy , from the cluster with the lowest binding energy of all the 27 clusters ( figure 3 ) . \n eleven out of the 27 compounds had the ensemble minimum in the most abundant cluster , but only one of which , compound 10 , had a rc minimum also in an abundant cluster . \n overall , six out of 27 compounds had the ensemble minimum and rc minimum occurring in abundant clusters . \n the co - occurrence of ensemble minimum ( lowest binding energy of one of the top three clusters ) and the rc minimum ( lowest possible observed energy ) may indicate that a highly abundant configurational space ( i.e. , ensemble of substates ) is also favored by the ligand for most stable interaction . \n in fact , four out of the six co - occurrences occurred for compounds ranked within the top 10 hits , and all six ranked within the top 20 hits . in terms of binding energy , four out the six had identical binding energy between the ensemble minimum and rc minimum ; the other two had binding energy differing less than 1 kcal / mol . \n although the most populated structures may be most relevant to the initiation of binding events , it seems unlikely that they would be truly precatalytic states . \n some compounds that score poorly in the crystal - structure - only screen score well when md structures are used , demonstrating the advantages of using md structures to expand the description of the receptor s structure . \n conversely , other compounds that score well in the crystal - structure - only screen move down the list when the md structures are included ( e.g. , compound 21 ) ( figure 6 ) . \n this reordering happens for two reasons : first , because other compounds move up the list by producing better binding energies , and second , because some compounds produce a significantly worse binding energy when the md structures are included . \n for example , compound 21 appears to move down the list due to a combination of both reasons mentioned above . \n closer examination of compound 21 reveals that its position in the 430-cavity is compromised when the 430-loop opens during the md simulation ; as the loop opens , compound 21 loses contact with several stabilizing residues and thus the affinity is reduced . \n therefore , loop motion and the subsequent interactions gained and/or lost is the cause of many compounds movements up and/or down the reranked list . in \n , we noted that the cutoff of 9.25 kcal / mol meant that peramivir and dana would not have been selected . on the other hand , when these compounds were rescored together with the other top hits , taking into account all the lowest binding energies regardless of the size of the most populated cluster , peramivir and dana actually ranked better than some of the top hits . \n these data suggest that , given the current standard error of 2 kcal / mol for autodock4 , and the somewhat arbitrary nature of the 25% cutoff , the weighted harmonic mean or some improved knowledge - based heuristics may be applied to rescore an expanded list of hits and potentially recover some lost hits ( i.e. , false negatives ) . \n the md simulations offer representative conformations of the protein beyond what is provided by the static crystal structures alone , and they offer a possible description of the energy landscape where ligandreceptor interactions take place . \n the visual examination of the electrostatic surface maps for the different cavities , the various 150- and 430-loop configurations , and the sasa analyses indicate that at the monomer level , the n1 active site is highly dynamic . at the monomeric level , the dynamic opening and closing of the 150- and 430-cavities , with the corresponding change in the electrostatic field , may help target and orient the appropriate substrate to the catalytic site . in figure 2b , \n oseltamivir interacts in the 150-cavity of the apo-1 cluster representative structure , which represents a population size of about 20% . in figure 3 , \n it is possible that the open 150-cavity provides an initial binding site , helping to guide the substrate into contacts with the catalytic residues through further closing motion of the 150-loop . \n both crystallographic evidence and the md simulations indicate that this closed 150-loop is stabilized by oseltamivir in the active site , primarily through interactions with d151 and r152 . \n collectively , these observations may suggest that the closed substate is preferred when ligands are bound in the active site . \n interestingly , on the other side of the 430-cavity is an area known to be a second sa binding site in n9(60 ) and n2,(61 ) with hemadsorption activity . \n notably , sialic acid ( in the boat , chair , or twist conformation ) shows a preference to bind near this alternate site or the 430-cavity in 12 out of 18 docking experiments , albeit with lower energy and , often , lower clustering percentage than the sa cavity ( data not shown ) . \n moreover , the electrostatic surface potential maps indicate that this alternate sa binding site may exhibit a weak negative electrostatic potential . \n therefore it is possible that this alternate site acts to attract sa or to extend its interactions with the n1 binding site . \n the comparatively stronger electrostatic potential in the sa cavity may provide an electrostatic gradient to steer sa into the requisite catalytic location . \n the effect of electrostatics is well - known to play an influential role in controlling the diffusion of substrates into charged active site areas , as shown in the acetylcholinesterase system . \n previously , a cs - map analysis on the n1 cluster representative structures assessed the druggability of the newly defined areas identified in the md simulations.(11 ) using a complementary computational physics - based approach , cs - map identified suitable sites for potential ligand interactions , which were presented as probe clusters near the 150- and 430-loop regions . \n the consensus approach adopted in the cs - map analysis indicates that despite protein motion , the existence of hot spots over the binding site may persist , and that these areas may be relevant for drug discovery and design , as has also been shown through a variety of other methods . \n the work we present here provides support for the cs - map analysis through the docking of the ncids compound library to these novel hot spots ( table 2 ) . \n many of the ligands we present make contacts to the residues that were found to mediate a consistent probe contact , such as r152 , s153 , etc . \n , in the 150-cavity , and n369 , s370 in the 430-cavities , as illustrated in figure 6 and . \n the cs - map analysis also predicted that q136 and t439 are important mediators of nonbonded interactions and our docking studies support that claim.(39 ) we anticipate that ligands that make contact to these hot spots are more likely to be biologically relevant . \n the computationally derived potential hits as listed in table 3 are ranked using the rc weighted harmonic means , and their predicted site(s ) of interactions are indicated . \n the names of these compounds are shown in , along with the mean binding energy values shown in figure 3 . \n the differential preference of binding cavities by the top hits for the apo ensemble of receptors is illustrated in . \n the individual hits to each cavity may offer good starting points for hit to lead optimization , especially for those interested in using fragment - based approaches . \n compounds that are predicted to bridge two cavities simultaneously are especially interesting , particularly those that bridge either the 430- or 150-cavity to the sa cavity . in theory \n , these compounds should interfere with the binding of sa to the catalytic residues , represented in italics in table 2 , while providing additional selectivity for n1 through binding to the 150- or 430-cavities . \n clearly , these compounds will require further optimizations because their current binding energies and predicted ki s are not necessarily higher than those compounds that only interact with a single cavity . \n however , they provide an initial set of experimentally testable predictions regarding the capability of any compounds to bind to these newly identified , druggable areas . additional fragment - based approaches ( either computational or experimental ) to bridge known sa cavity binders with 150- and/or 430-cavity binding compounds can easily be envisioned . \n the influenza virus undergoes constant antigenic drift with a very high mutation rate yielding many different strains except for the essential catalytic residues that are conserved across species . \n therefore , it is important to consider known mutations and avoid compounds that interact with experimentally verified mutational hot spots . \n one set of the published mutations found in vivo or in vitro for h5n1 was h274y and n294s.(71)h274y results in resistance to oseltamivir , but not to zanamivir , whereas n294s results in low resistance to oseltamivir . \n compound 1 makes a nonbonded contact to n294 in holo-1 ; no other hits do . \n in addition , the e276d mutation has been shown to confer resistance without sacrificing the viability or genetic stability of the virus.(72 ) e276 is located directly in the sialic acid cavity and illustrates that even a subtle reduction in side chain length can be enough to confer resistance , further underscoring the need to develop new antivirals that target alternate areas such as the 150- and 430-cavities . \n other mutations have been identified in group-2 neuraminidases ( n2 , n9 ) and influenza type - b viruses , but it is often observed that mutant residues in one group are unrelated to those in another.(73 ) furthermore , when mutations from n2 are introduced into h5n1 , they result in significantly reduced viral viability.(74 ) another intriguing consideration is that the inhibitor does not necessarily need to make contact with the mutated residues in order for it to confer resistance . \n for example , oseltamivir does not make immediate contacts with h274 , but the mutation to tyrosine very likely causes tertiary changes in the protein that affect oseltamivir binding . \n additionally , it has been shown that changes in the ha glycosylation patterns can confer antiviral resistance in an na - independent manner . \n although our understanding of the complex interplay of interactions that confer resistance is incomplete , these factors can still be considered in the selection and design of n1 antivirals . \n through eight different virtual screens of the nci diversity set , which employed structures taken from crystallographic studies as well as representative structures from apo and holo md simulations , 27 drug - like ligands have been identified , which are predicted to bind with high affinity to avian influenza n1 . \n fourteen of these compounds are unique hits that would not have been found based on the crystal structure screens alone , and they include compounds that bind to flexible loop regions unseen in the crystal structures . \n importantly , the docking of thousands of compounds to the n1 binding site elucidated specific regions of high ligand - binding affinity in the flexible 150- and 430- cavities . \n these cavities and the residue contacts observed among the top hits strongly agree with the location of hot spots and residues predicted to mediate receptorligand interactions by a recent cs - map analysis . \n the top hits are validated and ranked through redocking experiments into a set of structures representing the holo ensemble within the rcs framework . \n this novel strategy for identifying na inhibitors may facilitate the design of better drugs in the fight against global pandemic influenza and be applicable in structure - based drug discovery initiatives .", "role": "user" }, { "content": "avian influenza virus subtype h5n1 is a potential pandemic threat with human - adapted strains resistant to antiviral drugs . \n although virtual screening ( vs ) against a crystal or relaxed receptor structure is an established method to identify potential inhibitors , the more dynamic changes within binding sites are neglected . to accommodate full receptor flexibility \n , we use autodock4 to screen the nci diversity set against representative receptor ensembles extracted from explicitly solvated molecular dynamics simulations of the neuraminidase system . \n the top hits are redocked to the entire nonredundant receptor ensemble and rescored using the relaxed complex scheme ( rcs ) . of the 27 top hits reported , half ranked very poorly if only crystal structures are used . \n these compounds target the catalytic cavity as well as the newly identified 150- and 430-cavities , which exhibit dynamic properties in electrostatic surface and geometric shape . \n this ensemble - based vs and rcs approach may offer improvement over existing strategies for structure - based drug discovery .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: rapid development has been achieved in the construction of discrete and extended molecular architectures by selfassembly processes.1 such derivatives can be classified as inorganicorganic supramolecular complexes as they are usually obtained from twocomponent reactions involving the coordination of organic ligands bearing n , o , or s donor atoms to lewisacidic inorganic metal cations.[1h ] , 2 due to the lack of p donating connectors and the usual use of simple transitionmetal cations , our group established an alternative approach by utilising organometallic polyphosphorus ( pn ) ligand complexes with flexible coordination modes as connectors between metal ions . by using this novel method , \n it was possible to synthesize one and twodimensional coordination polymers,3 vast fullerenelike supramolecular spherical aggregates,4 and organometallic nanosized capsules.5 more recently , this concept was extended to threecomponent reactions by using additional bipyridinebased organic linkers in combination with pn ligand complexes and metal ions . \n organometallicorganic hybrid polymers [ where pnbased organometallic fragments ( nodes ) are linked by organic spacers ] , which could not be obtained from classical twocomponent reactions . for example , the tetrahedrane complex [ cp2mo2(co)4(p2 ) ] ( cp = c5h5 ) ( 1 ) was treated with ag or cu salts in the presence of dipyridylethene to yield unprecedented one , two , and threedimensional organometallicorganic \n coordination polymers.6 these results motivated us to expand our research field raising the question as to whether it is possible to utilize some other n donor ligands in our reactions . \n one of those ligands is 2,2bipyrimidine bpym,[7a ] which is a special molecule , because it can act both as a di or tetradentate ligand . \n the supramolecular chemistry of this molecule has been extensively studied , and its coordination to transition metals afforded a rich library of zero and multidimensional complexes.8 now , however , we have shown that the reaction of the p2 ligand complex 1 with ag[bf4 ] ( 2 ) in the presence of 2,2bipyrimidine bpym ( 3 ) allows access to the two polymeric networks 4 and 5 , with the latter representing a unique organometallicinorganicorganic hybrid network . \n a variety of heterometallic metallacycles were synthesized by jin et al . by linking a simple organometallic moiety and a metal cation with organic linkers.[7b ] , [ 7c ] however , to the best of our knowledge , no extended hybrid networks with mixed \n complexed organometallic and inorganic nodes linked by organic spacers have been reported yet ( scheme 1 ) . \n reaction of 1 with ag[bf4 ] ( 2 ) and bpym ( 3 ) , synthesis of twodimensional hybrid polymers 4 and 5 , and schematic illustration of nodes and connectors . \n in a first step , attention was focused on the reaction of the p2 ligand complex 1 with the silver salt 2 and the bpym linker 3 in a 1:1:1 stoichiometric ratio in a mixture of ch2cl2/ch3cn at room temperature . \n this reaction afforded , after crystallization , two compounds 4 and 5 as orange crystals suitable for xray diffraction studies . \n the structures obtained from xray diffraction analysis performed on single crystals of 4 and 5 revealed that compound 4 is a novel twodimensional organometallicorganic hybrid polymer with ag2(1)2 organometallic nodes connected to each other by bpym linker molecules ( scheme 1 , figure 1 ) . \n furthermore , derivative 5 outlines a new class of twodimensional coordination polymers composed of inorganic agcontaining and organometallic ag2(1)2comprising nodes that are connected to each other by organic bpym linkers ( scheme 1 , figure 2 ) . \n cp and co ligands , hydrogen atoms and counterions are omitted for clarity . within the organometallic nodes of 4 , \n the two p2 ligands are coordinated to the silver ions by a frequently observed bridging : coordination mode . \n in addition , four bpym molecules are also coordinated to those silver ions , each by two n atoms . as a consequence , each silver ion in 4 possesses a distorted octahedral coordination sphere consisting of two p atoms and four n atoms ( figure 1 ) . \n p bond in derivative 4 [ 2.0925(11 ) ] is slightly elongated compared to that of the noncoordinated ligand 1 [ 2.079(6 ) ] . the ag \n p bonds [ 2.5795(8)2.6040(8 ) ] are slightly elongated compared to those of similar hybrid polymers previously reported.[6a ] the agag distance is long ( 5.480 ) revealing no argentophilic interactions.9 the ag2p4 sixmembered motifs in 4 are nearly planar ( folding angle 0.04 ) . the organometallic nodes in 4 form the vertices of a 2d network with cavities having circular \n meshes of a maximum diameter of 1.36 nm ( figure 1b ) . in derivative 5 , \n each repeating unit is composed of one ag2(1)2 organometallic fragment ( organometallic node ) and two ag ions ( inorganic nodes ) connected to each other by bpym spacers ( figure 2a ) . \n each organometallic node in 5 consists of two silver atoms to which two p2 ligands are coordinated in a very rare bridging : coordination mode ( figure 2b).10 in addition , two bpym molecules are also coordinated to the silver atoms , each by two of its n atoms . as a consequence , each silver ion within those organometallic nodes \n p bond in 5 [ 2.151(2 ) ] is slightly elongated compared to that of the noncoordinated ligand 1 [ 2.079(6 ) ] and ligand 1 in compound 4 . the ag \n p bond lengths [ 2.555(2)2.630(2 ) ] vary within a wider range compared to those of complex 4 . \n the agag distance is short [ 2.939(1 ) ] suggesting argentophilic interaction.9 the ag2p4 sixmembered motifs in the organometallic nodes of 5 are less planar than in 4 ( folding angle 6.60 ) . \n each organometallic node is connected to two 1d ribbonlike inorganicorganic fragments ( figure 2b ) . \n those 1d fragments are composed each of silver ions ( nodes ) linked by organic bpym connectors . \n each of those silver ions possesses a distorted octahedral coordination sphere with six coordinated n atoms of three bpym molecules . \n two of those bpym molecules are a part of the 1d fragments , while the third one links the 1d fragment to one ag2(1)2 organometallic node . \n in complex 5 , the inorganic ag nodes within the 1d fragments form the vertices of a 2d network with cavities having a hexagonal shape of a maximum diameter of 2.22 nm . \n it is worth noting that in the solid state packing of both 4 and 5 no solvent molecules are observed . \n in addition , all bf4 \n counteranions are located outside the selfassembled structures . regardless of several attempts , \n the new products 4 and 5 could not be separated from each other because of similar colour and solubility . \n both compounds are well soluble in donor solvents like ch3cn , but insoluble in other common organic solvents like ch2cl2 , thf and npentane . \n their roomtemperature p nmr spectrum in cd3cn shows a broad signal centered at = 79.1 ppm , which is upfield shifted compared to that of the free p2 ligand complex 1 ( = 43.2 ppm).11 their roomtemperature h and c nmr spectra present simple sets of signals revealing all expected signals corresponding to the protons andcarbon atoms of ligand 1 and the bpym linker 3 . \n the f nmr spectrum features two signals centered at 150.5 and 150.6 ppm , corresponding to the bf4 \n counteranions ( see the supporting information ) . in the mass spectrum , only fragments of ag2(1)2 together with a bpym linker are found , revealing like the nmr data the depolymerisation of the aggregates in donor solvents . \n the presented results contribute to a new direction in the area of metallosupramolecular chemistry in which the synthesis of coordination polymers composed by organometallic and inorganic \n those polymers are obtained by simply mixing ag[bf4 ] , bpym linker and a p2 ligand complex under ambient reaction conditions . \n the described synthesis opens the door to a novel class of coordination compounds for which compound 5 has been found as a first example . here \n , the combination of organometallic and inorganic nodes ( both containing transition metal coordination centers ) linked by organic molecules was found for the first time resulting in a 2d organometallicinorganicorganic hybrid network . \n it further shows the advantage of our approach using threecomponent reactions over the classical twocomponent reactions approach with metal ions and organic linkers . taking into consideration that supramolecular aggregation reactions are usually sensitive to reaction \n conditions,12 current studies involve similar threecomponent reactions with careful optimization of the reaction conditions for the selective synthesis of hybrid \n general : all experiments were performed under dry argon using standard schlenk techniques . the compounds 2,2bipyrimidine ( 3 ) and silver tetraflouroborate ( 2 ) were purchased from alfa aesar and sigmaaldrich , respectively , and used as received without further purification . \n the ligand complex [ cpmo2(co)4(p2 ) ] ( 1 ) was synthesized according to a literature procedure.13 solvents were freshly distilled under argon from cah2 ( ch2cl2 , ch3cn ) and from na / k alloy ( npentane ) . \n h , c , p and f nmr spectra were recorded with a bruker avance 300 spectrometer . \n h and c nmr chemical shifts are reported in parts per million ( ppm ) relative to me4si as external standard . \n p nmr chemical shifts are expressed in ppm relative to external 85 % h3po4 and were decoupled from the proton . \n f nmr chemical shifts are reported relative to cfcl3 . for the esi mass spectra a finnigan thermoquest \n synthesis and nmr characterization of complexes 4 and 5 : a solution of equimolar amounts of ag[bf4 ] ( 2 ; 0.040 g , 0.20 mmol ) , [ cp2mo2(co)4(p2 ) ] ( 1 ; 0.100 g , 0.20 mmol ) and bpym ( 3 ; 0.032 g , 0.20 mmol ) in a 1:1 mixture of ch2cl2 ( 10 ml)/ch3cn ( 10 ml ) was stirred at room temperature for 3 h. the reaction mixture was filtered using a teflon capillary to remove any suspended particles , and the obtained solution was layered with the same amount of npentane and kept at room temperature . after 1 week , orange crystals of 4 and 5 had formed . \n the crystals were isolated together by decantation of the overlaying solution , washed two times with npentane ( 2 ml ) , and subsequently dried at reduced pressure . \n h nmr ( 300 mhz , cd3cn , 25 c ) : = 5.36 ( s , 5 h , c5h5 ) , 7.70 ( t , \n j \n hh = 4.9 hz , 2 h , hbpym ) , 9.04 ( d , \n j \n hh = 4.9 hz , 4 h , 4 h , hbpym ) ppm . \n c{h } nmr ( 75.47 mhz , cd3cn , 25 c ) : = 88.1 ( s , c5h5 ) , 124.1 ( s , chbpym ) , 159.7 ( s , chbpym ) , 160.7 ( s , cbpym ) , 224.6 ( cco ) ppm . \n p{h } nmr ( 121.49 mhz , cd3cn , 25 c ) : = 79.1 ( s , \n 1/2 = 13.9 hz ) ppm . \n f{h } nmr ( 282.40 mhz , cd3cn , 25 c ) : = 150.6 ( s , bf4 ) , 150.5 ( s , bf4 ) ppm . \n esims ( ch3cn ) : m / z ( % ) = 1452.7 ( 1 ) [ ag2{cp2mo2(co)4p2}2(c8h6n4)(bf4 ) ] , 1100.6 ( 4 ) [ ag{cp2mo2(co)4p2 } ] , 760.9 ( 45 ) [ ag{cp2mo2(co)4p2}(c8h6n4 ) ] , 732.8 ( 12 ) [ ag{cp2mo2(co)4p2}(c8h6n4)co ] , 704.8 ( 20 ) [ ag{cp2mo2(co)4p2}(c8h6n4 ) 2 co ] , 676.8 ( 6 ) [ ag{cp2mo2(co)4p2}(c8h6n4 ) 3 co ] , 643.7 ( 10 ) [ ag{cp2mo2(co)4p2}(ch3cn ) ] , 422.9 ( 5 ) [ ag(c8n6n4)2 ] , 305.9 ( 100 ) [ ag(c8n6n4)(ch3cn ) ] , 264.9 ( 21 ) [ ag(c8n6n ) ] . \n singlecrystal xray crystallography : all diffraction experiments were performed at 123 k. the data sets were collected with a rigaku ( formerly : agilent technologies or oxford diffraction ) supernova diffractometer using cuk \n radiation . \n the structure solution and refinement were done with shelx.14 the h atoms were calculated geometrically , and a riding model was used during the refinement process . graphical material was created with olex2.15 \n ccdc 1483826 ( for 4 ) , and 1483827 ( for 5 ) contain the supplementary crystallographic data for this paper . \n these data can be obtained free of charge from the cambridge crystallographic data centre . \n supporting information ( see footnote on the first page of this article ) : crystallographic data ( table s1 ) . \n ", "role": "user" }, { "content": "the threecomponent reaction of the tetrahedral diphosphorus complex [ cp2mo2(co)4(2p2 ) ] ( 1 ) , with ag[bf4 ] ( 2 ) in the presence of 2,2bipyrimidine ( 3 ) leads to the formation of the two novel twodimensional networks 4 and 5 . \n compound 4 is a new twodimensional organometallicorganic hybrid polymer , while derivative 5 represents a unique twodimensional organometallicinorganicorganic hybrid polymer . \n these results show the possibility of synthesizing a new class of coordination polymers , which could not be obtained from twocomponent reactions with organic molecules in addition of metal ions .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: accurate risk stratification plays a very important role in the management of patients with acute and chronic coronary heart diseases ( chd ) . \n however , current prediction models that determine the potential adverse outcomes in patients with acute coronary syndromes do not take coronary artery lesions into account [ 13 ] . \n it is also well known that atherosclerosis is a systemic pathological process affecting multiple arteries ( coronary , extracranial , and arteries of the lower extremities ) . \n much of the current research in this area has focused on local manifestations of atherosclerosis in the affected area , leaving lesions of the associated vascular regions largely unnoticed due to the lack of proper diagnostic evaluation methods . \n stenosis of the coronary and cerebral arteries may manifest clinically as acute cardiovascular events or stroke , respectively , whereas other vascular lesions appear to be latent and may result in fatal complications under certain conditions . \n the choice of treatment method is of critical importance in patients with subclinical atherosclerosis in combination with chd because many of these conditions are characterised by an absence of haemodynamically significant lesions of noncoronary arteries . \n patients with polyvascular diseases ( pvd ) are at a high risk , requiring a special approach in treatment due to the characteristics of the arterial lesions . \n this study evaluates the clinical and prognostic role of haemodynamically insignificant stenosis of the extracranial and lower extremity arteries among patients with st - segment elevation myocardial infarction ( stemi ) . \n we attempted to develop a method for improving the predictive value of grace risk score by adding the additional risk factors . \n the study sample consisted of 423 russian patients with st - segment elevation myocardial infarction ( stemi ) consecutively admitted to the kemerovo cardiological centre in 2009 . \n in compliance with the recommendations of the european society of cardiology , the inclusion criterion for this study was a diagnosis of stemi up to 24 hours after its onset . \n age under 18 years and myocardial infarction after the percutaneous coronary intervention or coronary artery bypass surgery were the exclusion criteria . \n this study was approved by the local ethical committee , and all patients signed informed consent forms . \n complaints , previous medical history , results of clinical examination , electrocardiogram data , levels of cardiospecific enzymes , systemic haemodynamic values , and echocardiogram data were registered . \n colour duplex screening of the extracranial arteries ( eca ) and lower extremity arteries ( lea ) was performed on 57 days of hospitalization for all patients using the cardiovascular ultrasound system vivid 7 dimension ( general electric , usa ) with a 5.7 mhz linear array transducer ( for eca ) , a 2.53 mhz curved array transducer , and a 5 mhz linear array transducer ( for lea ) . \n the extent of arterial stenosis was assessed in b regimen and by dopplerography ( visualizing the local haemodynamics in the stenosis zone ) . \n common and internal carotid arteries and vertebral and subclavian arteries were visualized from both sides during the eca screening ; common and deep femoral arteries and popliteal , anterior , and posterior tibial arteries were visualized from both sides during the lea screening . the intima - media thickness ( imt ) of the common carotid artery was measured in automatic mode ( the value up to 1 mm was considered normal ) . \n creatinine clearance was calculated using the cockcroft - gault equation : ccr = ( ( 140 age ) mass ( in kilograms ) [ 0.85 if female])/(72 serum creatinine ( in mg / dl ) ) . \n haemoglobin , total cholesterol , glucose , and fibrinogen levels were also estimated immediately after hospital admission and before discharge . \n the preferable methods of myocardial reperfusion were defined in the shortest terms and included percutaneous coronary intervention ( pci ) and systemic thrombolytic therapy ( tlt ) . \n myocardial revascularization was not conducted when technical problems occurred or in patients with complex coronary anatomy or in those with contraindications to tlt or pci . \n all patients received the standard therapy of unfractionated heparin , aspirin , clopidogrel , angiotensin - converting enzyme inhibitors , beta - blockers , and statins . \n reperfusion was not carried out in 157 ( 37.12% ) cases ; additionally , 53 ( 12.53% ) patients received thrombolytic therapy , and 213 ( 50.35% ) underwent pci . \n statins , clopidogrel , aspirin , angiotensin - converting enzyme inhibitors , and beta - blockers were also prescribed after discharge . \n coronary artery bypass surgery was not carried out during the hospitalization . the disease outcome in a 12-month follow - up period \n was defined in 397 patients ( 95.43% of the initially discharged patients ) , and 39 fatal outcomes were registered ( 35 out of them were due to the cardiovascular causes ; in the rest of the cases , the cause was not specified ) . \n a statistical analysis was conducted using ibm spss statistic 19.0.0 ( ibm company , usa ) . \n we calculated the percentage ratio , mean , and the 95% confidence interval for the mean . \n the analysis of differences between the independent groups was carried out using pearson 's chi - square test . \n the cox proportional hazards survival regression was applied to identify the independent predictors of the fatal outcomes . \n the value of the chi - square test and the area under the roc - curve ( auc ) were taken into consideration ( c statistic ) . \n differences in the compared groups were considered to be statistically significant when the p value was less than 0.05 . \n the prevalence of pvd , as defined by the increased intima - media thickness ( imt ) or by the various degrees of stenosis , was quite high ( 94.80% ) . \n in addition , 29.55% of the patients were characterised by stenosis with an occlusion of more than 50% of the vessel lumen , 17.73% of the patients were characterised by stenosis with an occlusion of 30%50% of vessel lumen , and 44.52% of the patients were characterised by a stenosis with an occlusion of less than 30% of the vessel lumen or an increased imt . \n stratification of patients into groups revealed that the majority of patients ( 52.38% ) had lesions in all 3 arterial territories ( coronary arteries , eca , and lea ) , 46.37% of patients had chd together with the lesions in the eca , and only 1.25% of patients had manifestations of coronary artery atherosclerosis together with the lesions in the lea . \n severe stenosis in the large arteries was more frequent among older patients and was associated with an increased incidence of angina pectoris , congestive heart failure , and prior myocardial infarction and stroke in the medical history . \n iv ) , renal dysfunction , left ventricular systolic dysfunction , multivessel chd , and rare cases of hyperchylomicronaemia were registered in enrolled patients with pvd ( table 2 ) . \n thus , the presence of pvd among patients with stemi was found to be associated with a more severe clinical status . \n this fact also increases the value of determining the pathological mechanisms , which may help to assess prognosis . \n the grace score was calculated for all patients before discharge . on the basis of these scores , 167 subjects ( 39.48% ) \n were included in a low risk group ( score 2799 ) , 140 individuals ( 33.10% ) were categorised in the average risk group ( score 100127 ) , and 116 individuals ( 27.42% ) were regarded as high risk group ( score 128263 ) . \n the case fatality rates were 2.58% , 7.52% , and 22.94% , respectively , according to the distribution of grace score risk groups ( = 31.13 , p < 0.00001 ) . \n stenosis of more than 30% of the eca and lea lumina was significantly associated with a high incidence of fatal outcomes within the one - year follow - up period ( = 13.68 , p = 0.003 ) . \n in addition , patients without pvd ( n = 18 ) had no fatal outcomes , in contrast to the patients with the eca and lea stenosis with stenosis of less than 30% of the vessel lumen ( n = 193 , case fatality rate 5.70% ) . the individuals with stenosis with an occlusion of 30%50% of the vessel lumen \n ( n = 73 ) had 10.96% fatal outcomes in contrast to the patients with the stenosis of more than 50% of the vessel lumen \n there was no statistically significant difference in the incidence of fatal outcomes within the one - year follow - up period between patients who had lesions in all three vascular areas ( coronary arteries , eca , and lea ) and patients who had lesions only in two vascular areas ( coronary arteries , eca ) . \n the kaplan - meier curve , showing the 12-month survival depending on the severity of peripheral artery disease , is shown in figure 1 . according to these data , the risk of death in patients with noncoronary artery stenosis with an occlusion of more than 30% of the vessel lumen was higher than that of other groups and increased steadily until the 12th month of followup . \n we attempted to modify grace score model for the implementation of our results into the clinical practice . \n the cox proportional hazards survival regression analysis with stepwise selection of independent risk factors for death was carried out for the achievement of this aim . \n the traditional risk factors ( congestive heart failure , prior stroke , smoking status , and grace score ) and the new risk factor , pvd with a varying degree of severity , were selected among various parameters ( table 3 ) . \n our obtained model of risk stratification included all the factors indicated in table 3 and was named kemscore . \n a comparative analysis of prognostic values of the new model ( kemscore ) and the grace score model was conducted by comparing the auc ( figure 2 ) . \n the value of the auc for the grace score model was 0.71 ( 95% ci = 0.630.79 ) , whereas this value for the kemscore model was 0.83 ( 95% ci = 0.760.90 ) . \n thus , the addition of a new factor to the grace score model allows a more accurate risk stratification within one year after myocardial infarction . \n the previously described score system of risk factors was designed with the aim of convenient application in clinical practice ( table 4 ) . \n a point value was assigned to each of the factors based on their influence on the risk of death . \n the case fatality rate after myocardial infarction , according to the scores within one year , is presented in figure 3 . \n currently , there is no consensus on the incidence of multivessel atherosclerosis because of the different diagnostic approaches and study inclusion criteria . according to the literature , pvd incidence varies widely from 13.5% to 94% . \n several authors assessed only clinical manifestations of ischemic vascular events [ 8 , 9 ] , while other authors used angiographic methods of diagnostics [ 6 , 10 ] , and still others focused on the ankle - brachial index or ultrasound [ 7 , 12 ] assessment methods . \n in addition , a wide range of pvd incidences in patients with varying degrees of cardiovascular risk can be explained by analysing subjects regardless of their age , gender , and ischemic heart disease forms ( from stable angina to acute myocardial infarction with st - segment elevation ) . \n however , it is obvious that patients examined in outpatient settings will be characterised as having relatively low cardiovascular risk , and a determination of pvd incidence is substantially complicated compared to patients admitted to the hospital as a result of various cardiovascular events who , therefore , had higher cardiovascular risk . \n the detection of stenosis in the eca or lea and increased imt were the underlying criteria for the diagnosis of pvd in this study , and its prevalence was 95% . \n undoubtedly , a case that presents with pvd determines the high risk status of a patient . \n however , it is impossible to determine the exact contribution of this particular condition to the risk stratification schemes at the present time , due to the different approaches in the diagnosis of peripheral artery lesions . \n a number of published studies also suggested that pvd patients constitute a high risk group . \n have shown that patients with acute coronary syndrome associated with symptomatic peripheral arterial lesions had prior myocardial infarction , congestive heart failure , hypertension , hypercholesterolemia , diabetes mellitus , positive smoking status , and higher killip class , and multivessel atherosclerosis of the coronary arteries is more often compared to individuals without such lesions , as also confirmed by spencer et al . and van kuijk et al . . \n pvd was also associated with a higher frequency of adverse risk factors of presented coronary heart disease in this study . according to spencer et al . \n , a high case fatality rate was noted among patients with acute myocardial infarction and peripheral arterial disease ( pad ) within 12 months of followup . \n patients with pad were at a significantly increased risk of death at 1 year after hospital discharge ( adjusted or 2.00 , 95% ci = 1.582.52 ) in comparison with patients without prior pad . \n in the cafes - cave prospective study , 13,221 patients without clinical manifestations of cardiovascular diseases and with low risk of their development were involved . \n all patients were divided into four groups according to the results of ultrasonography of the extracranial arteries and lower extremity arteries . \n group 1 had no pathological changes in the arteries , group 2 had high imt , group 3 had plaques without luminal stenosis , and group 4 had plaques with luminal stenosis . \n the prevalence of adverse events over several years of followup was 0.1% , 8.6% , 39.3% , and 81.1% in these four groups , respectively . \n the authors supposed high imt to be associated with a low risk of cardiovascular events , the plaques without luminal stenosis to be associated with a moderate risk , and the plaques with luminal stenosis to be correlated with a high risk . in our study , patients with stemi , even with haemodynamically insignificant stenosis of noncoronary vascular origin , were shown to have significantly worse outcomes after 12 months of followup compared to patients with stemi without pvd . \n the past literature has shown evidence to support the idea that the grace score is equally effective in assessing prognosis at 6 and 12 months after acute coronary syndrome . de arajo gonalves et al . studied 460 consecutive patients admitted to the coronary care unit with an acs . \n the best predictive accuracy for death or mi at 1 year was obtained by the grace ( auc : 0.72 ( 95% ci = 0.670.76 ) ) . \n the values of the auc for the prognosis assessment ability of the grace score at the 6- and 12-month follow - up period were 0.73 ( 95% ci = 0.640.82 ) and 0.71 ( 95% ci = 0.630.79 ) , respectively . \n on 1183 spanish patients , the predictive value of the grace score was significantly higher , as the area under the curve ( auc ) was 0.90 ( 95% ci = 0.830.98 ) . \n however , in the study by lev et al . on 974 israeli patients , this value was much lower ( auc was 0.50 ( 95% ci = 0.470.54 ) ) . \n these examples show restrictions in the applicability of the current grace score model and the necessity to improve this model by adding new parameters . \n this study , therefore , proposed an improvement in the ability of the current model to predict prognosis by adding the severity of polyvascular diseases as an additional risk factor to the grace risk score . \n this factor is suggested to reflect not only a variety of other cardiovascular risk factors but also the severity of subclinical inflammation . \n it is important because such subclinical inflammation may lead to progression of atherosclerosis and the destabilisation of haemodynamically insignificant atherosclerotic plaques , causing development of new vascular events . \n firstly , the sample size was not large ; secondly , we have not assessed the reclassification and other endpoints such as nonfatal myocardial infarction , stroke , and so forth . \n polyvascular diseases with even insignificant stenosis of the peripheral arteries not only determine the presence of multiple risk factors for cardiovascular diseases in patients with myocardial infarction but also appear to be an independent predictor of adverse ( fatal ) cardiovascular outcome .", "role": "user" }, { "content": "hypothesis . to evaluate the clinical and prognostic role of haemodynamically insignificant stenosis of the extracranial arteries ( eca ) and lower extremity arteries ( lea ) among patients with st - segment elevation myocardial infarction ( stemi ) . \n patients and methods . \n the study sample consisted of 423 patients with stemi who were consecutively admitted to the kemerovo cardiological centre . \n results . \n the prevalence of polyvascular diseases ( pvd ) , as defined by an increased intima - media thickness ( imt ) of the common carotid artery or by stenosis of the eca or lea , was 95% . among patients with eca or lea , the case fatality rate of those with stenosis with occlusion of less than 30% of the vessel lumen was 5.7% , whereas the case fatality rate among patients with stenosis with occlusion of more than 30% of the vessel lumen was 15.1% ( 2 = 13.68 , p = 0.003 ) . using the grace score model , together with the determination of additional factors ( congestive heart failure , pvd , prior stroke , and smoking status ) \n , we developed an improved model ( kemscore ) for death risk stratification for a 12-month period . \n the value of the auc for our model ( kemscore ) was 0.83 ( 95% ci = 0.760.90 ) , which was significantly higher than the initial grace score value of 0.71 ( 95% ci = 0.630.79 ) .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: anti - mllerian hormone ( amh ) is secreted into the circulation by small growing follicles in the ovary , until they have reached the size at which they may be selected for dominance ( 68 mm ) . \n since the cohort of small growing follicles is in equilibrium with the total number primordial follicles , serum amh levels reflect the ovarian follicular pool . \n amh is therefore considered an accurate marker of ovarian reserve [ 3 , 4 ] . \n moreover amh levels vary less across different menstrual cycles as well as within one menstrual cycle as compared to other biomarkers of ovarian activity , such as fsh , which has a number of obvious clinical advantages [ 47 ] . indeed , according to different studies , \n the measurement of amh on a random basis throughout the menstrual cycle is associated with a very good accuracy when predicting ovarian response [ 810 ] . \n however while first studies reported a very low variability throughout the menstrual cycle [ 1114 ] , a number of more recent studies [ 1517 ] indicate a reduction of circulating amh in the luteal phase , hence raising the question if amh should better be measured on a fixed day of the menstrual cycles to foster standardization and to allow better cross comparison between individual assessments . in this review , we shed light on the partly controversial issue of amh variability , with particular attention on amh intracycle variability , that has been recently widely debated . \n moreover we evaluate the impact of ethnicity , bmi , and smoking behaviour on amh interindividual variability . \n finally we discussed changes in amh serum levels in two conditions of ovarian suppression , namely contraceptives use and pregnancy . \n when talking about hormonal stability , two different types of variability should be considered : the interindividual and the intraindividual variability . \n the interindividual variability of amh refers to variations in amh levels between different subjects and is first of all secondary to a very high variability in the number of growing follicles within groups of women of similar age [ 1820 ] . \n the high interindividual variability in amh is not surprising , given the wide variability of ovarian reserve in women . generally , high interindividual variability is a good characteristic for a hormone when used as discriminatory biomarker in a clinical setting ( figure 1 ) . \n indeed the high interindividual variability of amh makes it an ideal candidate biomarker with which to discriminate patients for diagnostic , prognostic , and other clinical purposes . \n in uni- and multi - variate analyses , black [ 21 , 22 ] and hispanic women exhibit serum amh levels 25% lower than those found in caucasian women of similar age . \n furthermore , an unexpectedly high number of black women has undetectable amh levels despite relatively young age and regular menstrual cycles , hence indicating a potential discrepancy between actual ovarian reserve and what is indicated by amh measurement in this population ( figure 2 ) . more research on the underlying biological phenomena and consequences of this finding \n however , this finding indicates that care should be taken when using amh reference values across different ethnicities . some papers , even if limited to small numbers of patients , indicated a negative relationship between bmi and serum amh levels [ 23 , 24 ] . \n in a recent large study performed in a healthy general female population , amh was negatively related to bmi , but the relationship was age dependent . \n in other words , in women , amh levels decreased and bmi increased with age ; hence , the relationship between amh and bmi was only secondary to the stronger relationship of the two variables with age . \n there is clear evidence that smoking may directly accelerate ovarian follicular depletion , thereby reducing the age at menopause [ 29 , 30 ] . \n moreover , smoking has been shown to alter metabolic path for several hormones including estradiol . \n however contradictory results have been reported on the relationship between smoking and amh , with some authors [ 3133 ] reporting reduced amh levels in smokers versus nonsmokers and others [ 18 , 27 , 3436 ] reporting similar values in both groups of women . in a more recent study , amh levels of 416 healthy women , including 99 smokers and 317 nonsmokers , were analyzed . \n as shown in figure 3 , at any age , the distribution of smokers was uniform in all quartiles of amh distribution ( figure 3 ) . \n in other words , in reference to a given age , a similar number of smoking women had high or low amh levels , respectively . \n accordingly , the debate on the impact of smoking on the follicular pool and the circulating amh levels has not yet been settled . in conclusion , according to the published studies , it seems that the variability in ovarian reserve and secondly ethnicity may largely explain the high degree of interindividual variability in amh levels . \n the intraindividual variability is indicative of variations in amh levels in one single subject and may be secondary to true biological variations in levels of circulating amh in women . \n we propose to distinguish among a long - term variability , a short - term variability and an ultra - short - term variability . \n the first refers to variations in amh levels that occur year after year and are indicative of the decline in the ovarian reserve of a single woman . \n the second depends on the monthly physiologic variability in ovarian function ; hence , the short - term variability may refer to intermenstrual cycle variability . \n the ultra - short - term variability indicates the day - by - day variability and refers to intramenstrual cycle variability . in a recent prospective longitudinal study \n , serum amh levels have been measured in healthy young prepubertal girls ( 6 to 13 years of age ) every 6 months for 3 years and the mean intraindividual coefficient of variation ( cv ) for amh was reported as 22% . \n this indicates that circulating amh shows on average only minor fluctuations within a limited time span ; thus , a random amh measurement is likely to be representative indeed for a given girl . \n the long , term variability in adult women has been mainly studied in cross - sectional studies , with some of them including as many as 1015 thousand patients [ 18 , 27 , 3841 ] . \n overall , the studies are in good agreement that amh declines with advancing age with a pattern that recalls the exponential decay of the primordial follicular pool [ 2 , 42 ] , which is best described by a quadratic equation . \n the intermenstrual cycle variability has been analyzed in two well conducted prospective studies [ 14 , 43 ] . \n both studies concluded that 89% of the variation in amh was due to between - subject variation , while only 11% of variability was secondary to individual fluctuation in amh levels ( figure 4 ) . \n furthermore , a recent prospective study reported a correlation of 0.88 between amh measurements performed on cycle day 2 or 3 in two subsequent cycles in women with regular spontaneous cycles . \n amh showed the highest between - cycle - correlation within an array of hormones assessed , including testosterone , fsh , e2 , inhibin b , and lh . a highly debated issue relates to whether amh significantly varies or not throughout the menstrual cycle . \n several studies have suggested that serum amh levels fluctuate little during the menstrual cycle , as would be expected from the evidence that amh is not secreted by the dominant follicle or corpus luteum [ 1114 ] ( figure 5 ) . \n amh is unique among the known hormones produced by antral follicles , because its secretion seems to be only marginally influenced by gonadotropins and it is dramatically reduced as follicles reach the full gonadotropin sensitivity . as a consequence , amh levels during the follicular phase do not reflect the activity of the developing large dominant follicle of the month , and conversely on any time point of the menstrual cycle amh levels provide information on the number of small antral follicle present in the ovary which are available for cyclic follicular recruitment . to study the intraindividual variability of amh , van disseldorp et al . \n the authors reported that the intraindividual variability of amh was only 13% and , most importantly , when dividing patients into quintiles according to basal amh levels , the intraindividual fluctuations were shown to fall in the same quintile in 72% of the cases and to cross two quintiles in only 1% of the cases . \n in contrast , some authors have noted significant fluctuations within one menstrual cycle [ 1517 ] . a very recent study found serum amh levels significantly lower in the luteal than follicular phase with a variation pattern similar to pituitary fsh , and the intraindividual variance of amh was as high as 80% . however the study was based on a very small group of subjects ( n = 12 ) , and some of them had as few as five blood samples throughout an entire menstrual cycle . \n moreover when analyzing values for single patients , the proposed decline of amh in the luteal phase was not evident in 25% of patients ( figure 6 ) , hence raising the questions if the observed reduction of amh in the luteal phase might be simply casual instead due to a biological reason indeed . in another prospective study \n including 20 women , serum amh levels were shown to fluctuate throughout the menstrual cycle . in this case , the observed fluctuations were absolutely random throughout the cycle and not associated to typical gonadotropin or ovarian steroid patterns . \n moreover , the amplitude was proportional to basal amh levels : women with low amh levels exhibited only minor fluctuations , whereas women with high basal amh levels showed relatively higher fluctuations . \n the author speculated to categorize amh pattern in the ageing ovary pattern and the younger ovary pattern . \n in spite of the good quality of the study , where blood samples were collected from each woman daily along a whole menstrual cycle , some criticisms have been put on roberts paper for the lack of the calculation of the intraindividual coefficient of variation , which is considered the optimal analysis for hormonal variability . however , at bottom line , sowers et al . \n 's study indicates in a clear and convincing way that serum amh levels vary throughout the menstrual cycle , that fluctuations may be relevant in those women with high basal levels , and most importantly that fluctuations are randomly distributed during the cycle . \n the random and noncyclic fluctuations in amh indicate that measuring the hormone on a fixed day of the menstrual cycle would not yield any advantage of a random assessment , for example , on any day of the menstrual cycle . in order to verify the effect of female age on the degree of amh fluctuations , a recent study re - evaluated for the third time the data previously described by hehenkamp et al . and van disseldorp et al . \n , the absolute intraindividual variation of amh ( deltaamh ) , that is , the difference between maximum and minimum serum level throughout one cycle , was found to be significantly and negatively associated with age . in other words , younger women had significantly larger fluctuations in amh levels than older women . \n it may be concluded that in patients with low ovarian reserve ( usually aged women ) , amh fluctuations have little clinical relevance , while in young patients with usually high ovarian reserve , fluctuations of amh might indeed impact on the discriminatory capability of diagnostic and predictive tests , respectively . \n the observed variability in amh levels may have a limiting effect on the main current application of amh as a predictive test in ivf practice . \n amh is widely used to predict the ovarian response and to individualize the treatment according to this prediction [ 5 , 9 , 46 , 47 ] . \n if amh values cross the cut - off values proposed for the ovarian response categories because of true biological variability in amh , this might lead to misclassification and erroneous treatment of patients . \n hence the impact of the documented amh variability needs to be tested in a clinical setting on a typical target population undergoing a clinically relevant predictive testing scenario . as reported in detail in several reviews and metanalysis [ 5 , 4850 ] \n , amh is the best hormonal marker for the prediction of ovarian response in ivf . \n when using a random amh measurement in order to prospectively predict ovarian response to exogenous fsh , correct categorization of 75% of patients in the three categories poor , normal , or hyper - responder can potentially be obtained . accordingly , although not as stable as thought before , amh still remains the most reliable ovarian hormone and the best hormonal predictor of ovarian response to stimulation in ivf , with the important advantage of being randomly measurable . \n since amh production by antral follicles has been considered to be largely gonadotropin independent , a logical consequence is that pituitary suppression , as occurring with oral contraceptives ( oc ) or physiologically during pregnancy , should not be associated with relevant changes in serum levels . \n a number of studies have been published on the effect of oc on amh levels [ 24 , 44 , 5157 ] and most of the available evaluations are not prospective . \n the very few prospective studies unfortunately limited the analysis to a few observational months ( 1 to 4 months ) of oc treatment and are thus potentially and insufficiently informative . \n oc use has been reported either to insignificantly influence amh concentration [ 44 , 51 , 52 , 54 , 55 ] or to reduce it significantly [ 53 , 5658 ] . \n a large cross - sectional study compared 180 and 76 twenty - year old oc users and nonusers , respectively , and found that long - term oc use was associated with a significant mean reduction in amh levels by 13% . recently \n a cohort study based on 863 healthy women ( 228 oc users and 504 nonusers ) reported that amh serum levels were 29.8% lower in oc users than those in nonusers . \n . however no dose - response relation was found between the dose of ethinyl estradiol and the impact on serum amh concentration . in a \n well - conducted prospective study , amh levels during oc pill intake in long - term oc users ( n = 25 ) and 2 months after stopping the oc were assessed . \n interestingly , a mean increase in amh levels by 30% after cessation of the oc was found ( from a mean of 2.0 ng / ml during oc to a mean of 2.6 ng / ml two months after the last pill , p = 0.001 ) . \n the study population consisted of 42 healthy women randomized to use for 9 weeks an oc in the form of either an oral pill ( n = 13 ) , a transdermal patch ( n = 15 ) , or a vaginal ring ( n = 14 ) . \n after 9 weeks of contraceptive use , serum amh levels decreased significantly by almost 50% as compared to baseline in all treatment groups ( figure 7 ) . \n this evidence is indicative of a suppressive effect of hormonal contraception on circulating amh levels , at least when considering long - term use . \n thus , serum amh concentration may not retain its accuracy as predictors of the ovarian reserve in women using hormonal contraceptives for long time . \n pregnancy is a physiological condition associated with ovarian suppression because of suppressed endogenous gonadotropin release . according to the concept that amh reflects the continuous fsh - independent noncyclic growth of small follicles in the ovary \n , it would be expected to find nonrelevant alteration in its levels during pregnancy . indeed , an early small cross - sectional study reported unmodified amh levels throughout pregnancy . \n subsequent studies reported contradictory results , with some confirming this finding [ 60 , 61 ] , while others describing a decrease in amh levels during pregnancy [ 62 , 63 ] . \n it has also been reported that the decline in amh during pregnancy is evident when using the beckman coulter but not the dsl assay . however , in the only longitudinal study available ( n = 60 ) , authors found a significant decrease in amh levels in the 2nd and 3rd trimesters compared to the 1st trimester and the mean reduction at the end of pregnancy was of about 50% . \n this study indicated that during pregnancy , there is a relative ovarian quiescence and reduced follicular maturation with a consequent decrease in the population of follicles secreting amh . at the same time , at least part of the observed reduction in amh levels during pregnancy could also be explained by the pregnancy - associated hemodilution and increased plasma - protein binding . \n in conclusion , on top of the age related decline in amh , significant fluctuations have been reported for a number of conditions and this has to be taken into account when interpreting values in clinical practice . \n this suggests that in clinical practice , amh can be measured independently of the cycle phase . \n prolonged ovarian suppression as induced by physiological or pharmacological interventions may reduce amh levels , since the long and profound pituitary gonadotropin suppression is associated with a reduced number of antral follicles . the exact role of patients ' characteristics , as ethnicity , and some habits , as smoking , on intra- and interindividual variability of amh need to be investigated further .", "role": "user" }, { "content": "anti - mullerian hormone ( amh ) is an ovarian hormone expressed in growing follicles that have undergone recruitment from the primordial follicle pool but have not yet been selected for dominance . \n it is considered an accurate marker of ovarian reserve , able to reflect the size of the ovarian follicular pool of a woman of reproductive age . in comparison to other hormonal biomarkers such as serum fsh , low intra- and intermenstrual cycle variability \n have been proposed for amh . \n this review summarizes the knowledge regarding within - subject variability , with particular attention on amh intracycle variability . \n moreover the impact of ethnicity , body mass index , and smoking behaviour on amh interindividual variability will be reviewed . \n finally changes in amh serum levels in two conditions of ovarian quiescence , namely contraceptives use and pregnancy , will be discussed . \n the present review aims at guiding researchers and clinicians in interpreting amh values and fluctuations in various research and clinical scenarios .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: androgenetic alopecia ( aga ) is the most common form of hair loss experienced in genetically predisposed individuals . \n it occurs due to the stimulation of genetically susceptible hair follicles by dihydrotestosterone ( dht ) . \n finasteride reduces dht level by inhibiting type ii 5 reductase , the enzyme responsible for conversion of testosterone to dht , thereby inhibiting miniaturization of hair follicles . \n oral intake of finasteride reduces dht levels in the blood and causes side effects such as decreased libido , erectile dysfunction , etc . , these side effects are temporary and normalize with continued use . \n once oral finasteride is stopped , the dht level rises and reverses its effects , thereby resulting in less dense hair . \n studies show that topical finasteride appears to have results equivalent to oral finasteride in aga , and has better tolerance . \n therefore , the we conducted a study to assess the efficacy of topical minoxidil fortified with finasteride in the maintenance of hair density post- treatment with oral finasteride . \n a retrospective assessment was done in 50 male patients with aga . the photographs and case sheets of aga patients with hamilton grading 5a and 6 ; and ludwigs pattern ii and iii falling in the age group of 20 - 40 years \n the patients had undergone treatment with oral finasteride and twice daily application of topical minoxidil 5% for a period of two years . after a considerable improvement in hair density was noticed , the patients were advised to discontinue oral finasteride and were shifted to topical minoxidil 5% fortified with 0.1% finasteride . \n forty - five of 50 patients had resumed the treatment with topical finasteride and minoxidil without interruption . \n five of 50 patients had discontinued the treatment for a period of 8 - 12 months resulting in a decrease in hair density to the initial level . \n these patients were then started only with topical minoxidil fortified with finasteride ; oral finasteride was not represcribed . \n the patients were followed up once every four months for a period of 12 months . at each follow up , \n photographs taken at baseline , i.e. when oral treatment was stopped , and the 4 month , 8 month , and 12 month of topical medication were assessed [ table 1 ] . \n the assessment of hair density maintenance after replacing oral finasteride with topical minoxidil and finasteride combination \n of the 45 patients ( on continuous treatment ) , 25 patients hair density was moderately maintained , as given in table 1 . \n these patients when shifted from oral to topical finasteride initially experienced some hair loss and then reached a plateau phase . \n they had no further hair loss and the hair density was well maintained [ figure 1a - d ] . \n seven patients had a slight decline in hair density when shifted from oral finasteride to topical treatment alone as seen in [ figure 2a - c ] and 13 patients did not experience a decline and even showed an improvement in the hair density . \n ( a ) initial stage before starting treatment , ( b ) improvement after oral finasteride treatment at eight months , ( c ) initial decline in hair density when oral finasteride was stopped , ( d ) plateauing of hair loss with well maintained hair density ( a ) initial phase before starting hair fall treatment , ( b ) improvement noticed after oral finasteride treatment , ( c ) decline in hair density after switching from oral to topical finasteride five of 50 patients had stopped all treatment for hair loss and showed a decrease in hair density over a period of 8 - 12 months [ figure 3a - c ] after stopping treatment . \n all these patients improved when started with topical minoxidil fortified with finasteride as seen in figure 3d . \n four of these patients had a good improvement in hair density after one year of follow up [ table 2 ] . \n ( a ) initial phase before starting treatment , ( b ) improvement noticed after oral finasteride treatment , ( c ) decline in hair density after stopping the treatment for a period of eight months , ( d ) good improvement in hair density after restarting topical medication the improvement of hair density in patients who had discontinued the treatment for a year and started with topical minoxidil and finasteride combination \n aga is an androgen mediated event and is the most common type of alopecia in men . it is genetically inherited and keeps progressing . \n the scalp dht level is higher in a bald scalp when compared to a hairy scalp . \n the food and drug administration approved treatment options for male aga are topical minoxidil and oral finasteride . \n 5 reductase causes conversion of testosterone to dht and finasteride is an inhibitor of type ii 5 reductase , thereby reducing the formation of dht molecules . \n hence , patients on oral finasteride have lower concentrations of dht in blood , thereby a reduced dht level is noticed in the scalp . \n this in turn reduces the follicular miniaturization and increases the anagen : telogen ratio . a study conducted by kaufman et al . \n , determined the effect of oral finasteride treatment for two years and the effect of withdrawal of treatment after one year . \n the results showed that the effect of oral finasteride was much better than the placebo group and there was reversal in the hair density after withdrawing the oral finasteride . \n a study to compare the efficacy of oral vs topical finasteride conducted by hajheydari et al . says that the efficacy of topical finasteride was at par with that of oral finasteride . \n therefore , minoxidil , a vasodilator and a potassium channel opener was used in combination with finasteride to aid in better absorption . a study conducted by tanglertsampan comparing the efficacy of 3% minoxidil alone and a combination of 3% minoxidil and 0.1% finasteride topically in the treatment of aga revealed minoxidil and finasteride combination to be better than minoxidil alone . in our study , 84.44% patients maintained the density well , showing the effectiveness of the combination in maintaining hair growth . in five patients who had discontinued the treatment , \n it was noted that 80% of patients had good improvement in a year upon restarting the treatment with topical finasteride in combination with minoxidil . \n this shows that the topical medication alone is beneficial in maintaining hair density as well as improving hair growth . \n oral finasteride is known to cause side effects such as erectile dysfunction and decreased libido due to decreased in blood dht . \n though this occurs in a minority of patients , we noticed that most of our patients were apprehensive about using oral finasteride on a long term basis . \n the case sheets of the five patients who had discontinued treatment , when reviewed , revealed that they were averse to taking oral finasteride because of its side effects , and hence had discontinued treatment . \n however , the limitation of this study is that the serum and scalp dht levels could not be obtained . \n a majority of patients in this study who discontinued oral finasteride and adopted topical minoxidil fortified with finasteride showed a minimal decline in hair density reaching a plateau phase , after which there was no further decline in the hair density . \n furthermore , it was well tolerated with no psychological fear of oral medication and good compliance . \n the five patients who had discontinued the treatment for a period of 8 - 12 months when resumed on topical minoxidil and finasteride combination showed good improvement in hair density . \n the combination of topical minoxidil and finasteride can thus be considered as a beneficial treatment strategy to maintain hair density after achieving initial improvement with oral finasteride , thereby obviating the use of oral finasteride indefinitely .", "role": "user" }, { "content": "background : finasteride acts by reducing dihydrotestosterone levels , thereby inhibiting miniaturization of hair follicles in patients with androgenetic alopecia ( aga ) . \n oral finasteride is associated with side effects such as decreased libido , sexual dysfunction , and gynecomastia.aim:the aim of the following study is to assess the efficacy of maintaining hair growth with 5% topical minoxidil fortified with 0.1% finasteride in patients with aga after initial treatment with 5% topical minoxidil and oral finasteride for two years.materials and methods : a retrospective assessment was done in 50 male patients aged 20 - 40 years with aga . \n all the patients had been initially treated with topical minoxidil and oral finasteride for a period of two years , after which the oral finasteride was replaced with topical minoxidil fortified with finasteride . \n five of 50 patients had discontinued the treatment for a period of 8 - 12 months and were then resumed with only topical minoxidil fortified with finasteride . the patients case sheets and photographs \n were reviewed by independent observers and the efficacy of minoxidil - finasteride combination was assessed.results:of the 45 patients who underwent a continuous treatment for aga , 84.44% maintained a good hair density with topical minoxidil - finasteride combinatio . \n of the five patients who discontinued oral finasteride for 8 - 12 months , four demonstrated good improvement in hair density when treatment was resumed with topical minoxidil - finasteride combination.conclusion:topical finasteride can be considered for hair density maintenance after initial improvement with oral finasteride , thereby obviating the indefinite use of oral finasteride .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: substance abuse is a common phenomenon in the world and has invaded the human society as the most important social damage . \n substance abuse is a nonadaptive model of drug use , which results in adverse problems and consequences , and includes a set of cognitive , behavioral , and psychological symptoms . \n iran also , due to its specific human and geographic features , has a relatively high degree of contamination . \n the world health organization 's report in 2005 shows that there are about 200 million opiate addicts in the world , reporting the highest prevalence in iran and the most frequency in the 2535 year - age group . \n the onset of drug use is often rooted in adolescence , and studies show that substance abuse is often related to cigarette and alcohol consumption in adolescence . \n results of studies indicate that age , being male , high - risk behavirs , and the existence of a cigarette smoker in the family or among friends , the experience of substance abuse , inclination and positive thoughts about smoking have relationship with adolescent cigarette smoking . \n studies also confirm that the chance of becoming a cigarette smoker among males and females is almost equal ( 11.2% ) ; however , the prevalence of regular alcohol consumption in males ( 22.4% ) is slightly higher than in females ( 19.3% ) . \n few studies have been conducted in iran on adolescents patterns of substance abuse , producing various data on the prevalence and the type of consumed drugs , but there is currently no known specific pattern of substance abuse in this age group ; therefore , this review study has studied drug consumption prevalence in the student population of the country by collecting various data . \n this article is a narrative review focusing on studies conducted in iran . in this research , \n all articles related to substance abuse and its patterns among high school students , which were conducted in iran and published in domestic and international journals , were investigated . \n the articles were acquired from academic medical journals , research periodicals and the scholar google , magiran , irandoc , and medlib . \n this study explored articles in the past 10 years ( 20012011 ) about iranian high school students . \n the full texts of the articles were often accessible in the scientific information database and magiran websites , but the full text of the article about gilan province was obtained after contacting the journal 's office . \n correspondence was made with the author of the article about mahriz city to obtain the article as it was not published in the toloee behdasht journal . \n these articles provide information about the consumed drug type , its prevalence in terms of the sex and age , and the experience of at - least - once consumption in the adolescent 's life . \n some articles had only pointed to drug consumption , which was also included in this research . some had attended to substance abuse in general terms without distinguishing different kinds of drugs , and in some articles only psychoactive drug use , was mentioned . \n the cases , in which the sample volume was not sufficient , or were not in the studied age groups , were excluded from the study . due to different categorizations in these articles regarding the long - term prevalence of substance abuse or the experience of at - least - once consumption , in this study the shared aspect of these articles , \n some articles had addressed the students predisposing factors for drug abuse , in addition to drug use prevalence , which were not included in this study for being scattered . \n an initial search into the data bases yielded 11 articles , two of which were related to years before the study time frame ( 1997 and 1998 ) . \n furthermore , two articles were ignored , one because of its different age group ( a lower age ) and the other because it had addressed a particular district in tehran with a small sample size . these results are based on 7 articles . \n all studies were about the 1419 years old group , and only three studies had distinguished between the sexes . \n a study was conducted in 2003 on 500 students , from 142 high schools and vocational schools in zahedan city , using a multi - stage cluster sampling method . in total , from the total of 259 females and 216 males who completed the questionnaire , the following results were obtained . \n the first experience of smoking was most often seen at the age of 14 ( 26.2% ) . \n a study was conducted in 2009 on 610 students of kerman 's male pre - university centers , in which the prevalence of each drug was reported , but the total consumption prevalence was not mentioned . a study in gilan province in 20042009 on 1927 high school students , including 46% females and 54% males , showed that the percentage of at - least - once use , including and excluding cigarette , was 23.7 and 12.8 , respectively . a study in karaj city in 20092010 on 447 high school students , including \n 239 females and 208 males , showed that 57% had at - least - once experience of drug use , including cigarette , of this number 56.1% were male and 43.9% were female . a study in nazarabad city in 2007 on 400 3 year high school students , including 204 females and 196 males with the mean age of 17.3 , showed that drug use prevalence , including and excluding cigarette , was 24.5% and 11.1% , respectively . \n a study was performed in lahijan city in 2004 on 2328 high school students , including 42.2% females and 57.8% males . \n a descriptive study was conducted in 2008 on a 285-member sample of male high school students . a research on kerman 's male pre - university students yielded the following results . \n the consumption prevalence of hookah was 15.5% , sedatives ( without medical prescription ) 40.7% , alcohol 37.7% , cigarette 34.6% , strong analgesics 10.2% , nas 9.7% , opium 8.7% , hashish 6.7% , ecstasy 6.6% , and heroin 4.9% . \n consumption prevalence for each drug type in gilan : the prevalence was 20% for cigarette , 10.5% for alcohol , 2.4% for opium , 1.2% for ecstasy , 2% for hashish , and 0.3% for heroin . in karaj city , \n the consumption prevalence was 53% for hookah , 24.8% for cigarette , 13.6% for alcohol , 2% for ecstasy , 2% for opium , 1.1% for hashish , 0.4% for crystal , and 0.2% for heroin . \n in nazarabad city , the consumption prevalence was found to be 23.1% for cigarette , 2% for opium , 1% for amphetamines and ecstasy , 0.5% for heroin , 0.3% for hashish and cocaine . \n the male and female drug consumption was 69.7% and 36.2% , respectively , representing a significant statistical difference ( p < 0.05 ) . \n a study in lahijan city showed that the consumption prevalence was 14.9% for cigarette , 2.4% for ecstasy , 4.1% for other drug types \n ( with the highest rate of consumption for opium and hashish ) . in the mahriz city of yazd , the consumption prevalence among the male 3 year high school students in 2008 was reported 6.8% for alcohol and 3% for psychoactive substances [ table 1 ] . \n the comparison of the prevalence of at - least - once drug use for each drug type in each studied region a study in zahedan also reported that at - least - once drug use prevalence was 1.6% and 8% , respectively , among females and males ; and at - least - once cigarette smoking prevalence was 7.8% and 25.2% , respectively , for females with the mean age of 15.8 and males with the mean age of 16 . in gilan , drug use , excluding cigarette , was reported 19.1% and 5.3% , respectively , for males and females , representing a significant statistical difference ( p < 0.05 ) . \n furthermore , cigarette and drug use prevalence was 31.3% and 14.8% in males and females , respectively , showing that this rate was significantly higher in males ( p < 0.05 ) . \n cigarette use prevalence was 25.9% and 3% , respectively , for male and female students . \n opium consumption was 3.3% and 1.5% among males and females , respectively , which was a significant statistical difference ( ) . \n drug consumption , excluding cigarette , was 19.1% and 5.3% , respectively , for males and females , pointing to a statistically significant difference ( p < 0.05 ) . \n ecstasy use prevalence was reported 3% and 1.1% , respectively , for males and females , pointing to a statistically significant difference ( p < 0.00081 ) ; 0.5% of males and 0.1% of females were heroin consumers , lacking any significant statistical difference ( p > 0.05 ) . in karaj city , \n drug consumption prevalence was studied for each sex and drug type [ table 2 ] . the comparison of the prevalence of at - least - once drug consumption for each sex in each studied region as the study conducted on students with the mean age of 16 in zahedan showed that the highest incidence of the first experience of cigarette smoking belonged to the age of 14 . a study in kerman on students with the mean age of 17.9 about the age at the first experience yielded the following results for each drug type : 14 for cigarette , 14.6 for alcohol , 13.9 for hookah , 13.1 for sedatives , 15.3 for analgesics , 17 for ecstasy , 16.7 for hashish , 16.7 for heroin , 16.7 for opium , and 15.3 for naswar . \n a study in gilan indicated that drug and cigarette consumption had significantly increased in males aged 19 and above ( 88.9% of males aged 19 and above ) ( p < 0.05 ) . according to a study in nazarabad , the highest drug use onset was at the age of 1516 . \n a study was conducted in 2003 on 500 students , from 142 high schools and vocational schools in zahedan city , using a multi - stage cluster sampling method . in total , from the total of 259 females and 216 males who completed the questionnaire , the following results were obtained . \n the first experience of smoking was most often seen at the age of 14 ( 26.2% ) . \n a study was conducted in 2009 on 610 students of kerman 's male pre - university centers , in which the prevalence of each drug was reported , but the total consumption prevalence was not mentioned . a study in gilan province in 20042009 on 1927 high school students , including 46% females and 54% males , showed that the percentage of at - least - once use , including and excluding cigarette , was 23.7 and 12.8 , respectively . a study in karaj city in 20092010 on 447 high school students , including \n 239 females and 208 males , showed that 57% had at - least - once experience of drug use , including cigarette , of this number 56.1% were male and 43.9% were female . a study in nazarabad city in 2007 on 400 3 year high school students , including 204 females and 196 males with the mean age of 17.3 , showed that drug use prevalence , including and excluding cigarette , was 24.5% and 11.1% , respectively . \n a study was performed in lahijan city in 2004 on 2328 high school students , including 42.2% females and 57.8% males . \n a descriptive study was conducted in 2008 on a 285-member sample of male high school students . \n the consumption prevalence of hookah was 15.5% , sedatives ( without medical prescription ) 40.7% , alcohol 37.7% , cigarette 34.6% , strong analgesics 10.2% , nas 9.7% , opium 8.7% , hashish 6.7% , ecstasy 6.6% , and heroin 4.9% . \n consumption prevalence for each drug type in gilan : the prevalence was 20% for cigarette , 10.5% for alcohol , 2.4% for opium , 1.2% for ecstasy , 2% for hashish , and 0.3% for heroin . in karaj city , \n the consumption prevalence was 53% for hookah , 24.8% for cigarette , 13.6% for alcohol , 2% for ecstasy , 2% for opium , 1.1% for hashish , 0.4% for crystal , and 0.2% for heroin . \n in nazarabad city , the consumption prevalence was found to be 23.1% for cigarette , 2% for opium , 1% for amphetamines and ecstasy , 0.5% for heroin , 0.3% for hashish and cocaine . \n the male and female drug consumption was 69.7% and 36.2% , respectively , representing a significant statistical difference ( p < 0.05 ) . \n a study in lahijan city showed that the consumption prevalence was 14.9% for cigarette , 2.4% for ecstasy , 4.1% for other drug types \n ( with the highest rate of consumption for opium and hashish ) . in the mahriz city of yazd , the consumption prevalence among the male 3 year high school students in 2008 was reported 6.8% for alcohol and 3% for psychoactive substances [ table 1 ] . \n the comparison of the prevalence of at - least - once drug use for each drug type in each studied region \n a study in zahedan also reported that at - least - once drug use prevalence was 1.6% and 8% , respectively , among females and males ; and at - least - once cigarette smoking prevalence was 7.8% and 25.2% , respectively , for females with the mean age of 15.8 and males with the mean age of 16 . \n in gilan , drug use , excluding cigarette , was reported 19.1% and 5.3% , respectively , for males and females , representing a significant statistical difference ( p < 0.05 ) . \n furthermore , cigarette and drug use prevalence was 31.3% and 14.8% in males and females , respectively , showing that this rate was significantly higher in males ( p < 0.05 ) . \n cigarette use prevalence was 25.9% and 3% , respectively , for male and female students . \n opium consumption was 3.3% and 1.5% among males and females , respectively , which was a significant statistical difference ( ) . \n drug consumption , excluding cigarette , was 19.1% and 5.3% , respectively , for males and females , pointing to a statistically significant difference ( p < 0.05 ) . \n ecstasy use prevalence was reported 3% and 1.1% , respectively , for males and females , pointing to a statistically significant difference ( p < 0.00081 ) ; 0.5% of males and 0.1% of females were heroin consumers , lacking any significant statistical difference ( p > 0.05 ) . in karaj city , \n drug consumption prevalence was studied for each sex and drug type [ table 2 ] . \n the comparison of the prevalence of at - least - once drug consumption for each sex in each studied region \n as the study conducted on students with the mean age of 16 in zahedan showed that the highest incidence of the first experience of cigarette smoking belonged to the age of 14 . a study in kerman on students with the mean age of 17.9 about the age at the first experience yielded the following results for each drug type : 14 for cigarette , 14.6 for alcohol , 13.9 for hookah , 13.1 for sedatives , 15.3 for analgesics , 17 for ecstasy , 16.7 for hashish , 16.7 for heroin , 16.7 for opium , and 15.3 for naswar \n a study in gilan indicated that drug and cigarette consumption had significantly increased in males aged 19 and above ( 88.9% of males aged 19 and above ) ( p < 0.05 ) . according to a study in nazarabad , the highest drug use onset was at the age of 1516 . \n exploring the mft performed in the usa on the 10 graders showed that drug use had increased from 11% to 34% during 19921996 . in 1998 , 12.10% of the 8 year and 12.5% of the 10 graders and 25.611 % had experienced illegal drug use in the previous month . it was shown that hashish , followed by opium and alcohol , is the most commonly used illicit drug . \n the immediate necessity of planning for reducing the consumption of these drugs among students , and consequently among university students , has become increasingly important . \n investigating addictive drugs prevalence among university students showed the prevalence in the following order : hookah ( 74.5% ) , cigarette ( 67.5% ) , opium ( 6.1% ) , alcohol ( 13.5% ) , psychoactive pills ( 5.26% ) , hashish and heroin . \n results of a meta - analysis showed that 7% of iranian adolescents regularly smoke , and 27% had experienced smoking . \n the increased cigarette use prevalence among iranian adolescents is a major public health concern . paying attention to healthy recreations for adolescents and \n the cross - sectional prevalence of drug use in 1997 among american 1217 years old adolescents was reported 11.4% , which was close to drug use prevalence , excluding cigarette . \n another study showed that 56% of male and 42% of female university students were drug users , which accords with the present research with regard to the higher number of the males . \n since , the addiction problem is an old problem in other countries , it might be better to use the solutions practiced by them to speed up our reaction in cases which adhere to our culture and customs . at - least - once alcohol use prevalence among \n the 8 year american students in 2005 and 2006 was 27% and 20% , respectively , increasing to 88% among the 12 year students . \n the history of hashish consumption among the 8 , the 10 , and the 12 year students was 10% , 23% , and 36% , respectively , representing a remarkable difference with our country 's students . about 0.5% of the 8 year and 10% of the 12 year students consumed cocaine , and the consumption of amphetamines by the 12 year students was 1.5% , being almost close to the consumption rate of iranian students . \n the open consumption of hashish is common in france by almost one - third of the population ( nearly 30% ) , compared with the average rate of 19% in european countries ; also the consumption of ecstasy and cocaine has increased over 20002005 , although it is 4% but yet remarkable . \n a study on students knowledge of narcotics in rafsanjan and yazd cities showed that 5.6% of yazdian and 10% of rafsanjanian students had at least one addicted person in their families . \n also , 2.23% of the yazdian and 7% of the rafsanjanian students held that narcotics could also be useful . \n the important issue here is the existence of an addicted relative and his or her leadership role in this regard ; therefore , this point suggests the further importance of the sensitivity of this age group with regard to their dependence on narcotics . \n it is noteworthy that kerman city , compared to other studied cities , has received higher rates of drug use , such that opium and heroin consumption in this city has been , respectively , almost 4 and 5 times that of other cities . \n these statistics also hold true clearly with regard to ecstasy and alcohol consumption , each being almost 3 times that of karaj and gilan . \n hashish consumption in the pre - university stage in this city is also higher than in other cities , which might be related to easier drug access in kerman . in the cities , in which sex - distinct studies were conducted , drug consumption by males had been , with no exception , far higher than by the females , which is , almost 4 times except for hookah and then cigarette . \n of course , it is not possible to judge firmly about drug use general prevalence as a result of the few studies in this field ; however , the important point is the relatively high drug use among the adolescent and effective group of the society , which deserves particular attention for education and intervention in this group . \n it has been observed that adolescent and young crystal users , compared to nonusers , show clinical symptoms , have less control and affection in their families , with excitable , aggressive and anxious personalities , and low accountability ; on the other hand , behavioral problems and friend influence are among the strongest risk factors of drug consumption among adolescent consumers . nevertheless , it is not clear to what extent the adolescent can manage the effect of behavioral problems and peer group interaction for refusing invitations for drug consumption . \n it has been stated that using software programs would assist in the prevention and increasing the youth 's skills for reducing drug use . \n it has been shown that adolescent inclination to and consumption of drugs decrease significantly in the 1 year of educational intervention . \n on the other hand , studies indicate that there is a relationship between the borderline personality disorder and the extent of drug abuse . therefore , prevention programs for harm reduction , treatment and consultation as the main objective of the intervention structure should apply to consumers . \n also , emphasis should be laid upon the relationship between schools and parental care as important protective factors for adolescents health . \n adolescence is a growth period which is associated with a relatively high rate of drug use and its related disorders . \n accordingly , recent progress in evaluating drug abuse among adolescents would continue for information sharing in the field of clinical and research services . \n therefore , attention to this group through coherent planning for damage prevention would still remain in priority . \n drug use is relatively high in the adolescent and effective group of the society , which requires particular attention and prompt and immediate intervention .", "role": "user" }, { "content": "background : as the first experience of substance abuse often starts in adolescence , and studies have shown that drug use is mainly related to cigarette and alcohol consumption , an initial exploration of substance abuse prevalence , including cigarette and alcohol , seems to be the first step in preventing and controlling drug consumption . \n this study aimed to explore studies on drug use among high school students by investigating articles published in the past decade in iran.methods:in this study , the databases inside the country were used to access articles related to substance abuse by students during 20012011 , among which 7 articles on 1419 years old high school students were studied.results:the seven studied articles showed that the highest drug use prevalence pertained to cigarette and hookah , followed by alcohol , opium , ecstasy , hashish and heroin . \n opium and heroin use in kerman city were , respectively , about 4 and 5 times of their use in other studied cities.conclusions:drug use is relatively high in the adolescent and effective group of the society , which requires particular attention and prompt and immediate intervention .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: congenital posterolateral diaphragmatic hernia ( cdh ) or bochdalek hernia ( bh ) is a life - threatening malformation characterized by an anomaly of the posterolateral foramina of bochdalek , through which the abdominal viscera migrate into the chest during fetal development.1 the incidence of cdh is 1 in 2,500 to 3,000 newborns.2 \n 3 vertebrates exhibit evolutionarily conserved asymmetries in the pattern of internal organ placement , which are essential for normal physiological function . \n alterations in the classic asymmetries ( situs solitus ) may occur as a complete mirror image reversal of all of the organs ( situs inversus totalis ) , or an incomplete reversal resulting in a wide spectrum of intermediate defects ( situs ambiguus ) , including heterotaxy ( reversal of individual organs along the left \n right axis ) and isomerism ( duplication or changes in normal symmetry ) . in situs \n inversus totalis , the heart is located on the right side of the chest , the left lung is trilobed and the right lung is bilobed , and the stomach and spleen occupy the right side , while the liver and gallbladder are present on the left side of the abdomen and the intestine is transposed.3 the situs inversus ( si ) condition has an estimated occurrence of 1 in 5,000 to 20,000 births and is either undiagnosed or is diagnosed incidentally during the investigation of another associated aliment.4 \n 5 one - fourth to one - fifth of patients with si have a genetically heterogeneous , autosomal - recessive disorder known as primary ciliary dyskinesia ( pcd ) , a dysfunction of the cilia that manifests during embryologic development.3 \n 6 normal functioning cilia are critical to the embryological development of proper organ laterality , and approximately 50% of pcd patients present with abnormalities of thoracoabdominal symmetry.6 these patients have kartagener syndrome ( ks ) , initially reported in the early 1900s , which is characterized by the triad of si , chronic sinusitis , and bronchiectasis.7 to the best of our knowledge , this is the first report documenting a case of a right - sided bh in a patient with ks . \n the report focuses on a 4.180-kg baby boy born by cesarian section from an epileptic mother , with the end of a gestation complicated by threatened abortion and polyhydramnios . \n physical examination revealed a distended thorax , intercostal retractions with decreased breathing sounds on the right side of the thorax , and a scaphoid abdomen . \n a chest radiograph revealed the presence of intestinal loops in the right pleural cavity with left displacement of the mediastinum ( fig . \n the baby was initially stabilized by emergency endotracheal intubation and ventilated with synchronized intermittent positive pressure ventilation with the following parameters : ti 0.3 , te 1 , peep 4 , and fio \n 2 35% . \n after 48 hours of stabilization , the baby underwent a laparotomy through the right abdomen . \n the right diaphragmatic defect was exposed and was sutured with interrupted nonabsorbable sutures . during laparotomy \n , the liver and the gallbladder appeared in the left and the spleen in the right hypochondrium . \n the baby was weaned from ventilation on the 7th postoperative day . a chest x - ray ( fig . \n 2 ) , echocardiography , and electrocardiograms revealed a right - sided heart ; the barium meal documented greater curvature of the right - oriented stomach and the barium enema showed a mirror image of intestinal tube , thereby confirming si . \n the baby was discharged on the 15th postoperative day with medical therapy for gastroesophageal reflux . during follow - up , the baby had several episodes of bronchitis and otitis . \n he underwent examinations to exclude cystic fibrosis , which included a sweat test and a genetic test that revealed the lack of relevant mutations . in vitro and electron microscopic ultrastructural analyses of nasal scraping respiratory cilia confirmed ks . \n a tympanogram revealed a flat curve , and parental history of si was negative . \n right - sided bh and ks are two rare disorders , with no reported association . \n embryogenesis of bh has been described as a failure in the closure of the pericardioperitoneal canal by the pleuroperitoneal membranes , which occurs during gestational week 8th.8 for this reason , it is hypothesized that an early return in the coelomic cavity of the foregut results in wide posterolateral spaces and dysfunctional pleuroperitoneal membranes . \n consequently , the abdominal viscera herniate into the thorax , which is thought to cause pulmonary hypoplasia by compression of the growing lung.8 the left bh is the most frequent cdh , and its preponderance with respect to the right side may be related to the early closure of the right pleuroperitoneal opening , although no theories have been postulated to explain this.9 cdh can be associated with different syndromes , such as fryns , donnai - barrow , beckwith - wiedemann , sympson - golabi - behmel , coffin - siris , and denys - drash syndromes . \n however , the association with ks has never been described.10 ks is characterized by the triad of si , chronic sinusitis , and bronchiectasis and is a subset of one of the most widely recognized ciliopathies , pcd , in which ciliary motility defects occur . particularly during embryogenesis \n , ks could alter normal left right axis formation , which determines the si . \n sutherland and ware have recently offered a detailed view of the five steps necessary to establish asymmetry in the vertebrate . \n si , caused by pcd , usually results from defects in signaling at the node involving cilia structure and function.10 three previous reports have described single laterality abnormalities in combination with a right - sided diaphragmatic defect ; only one has shown an abdominal si associated with a right - sided bh in which the karyotype was normal and the family history mentioned no other cases of laterality defects.3 retinoic acid has been implicated in both diaphragmatic development and situs anomalies . however , no evidence exists in the literature regarding the role of retinoic acid in ks . \n this is the first case of the association of right - sided bh and ks in a live patient . \n when dealing with an association of diaphragmatic hernia with situs inversus totalis , physicians should be mindful of the potential contribution of ciliary dyskinesia to chronic respiratory disease ( particularly bronchiectasis ) , which might otherwise be attributed to gastroesophageal reflux disease .", "role": "user" }, { "content": "we present a novel case of the association of right - sided bochdalek hernia , a diaphragmatic life - threatening malformation , and kartagener syndrome , which is characterized by congenital bronchiectasis , chronic sinusitis , and situs inversus . \n the developmental and clinical findings are discussed . \n when an association of diaphragmatic hernia with situs viscerum inversus is encountered , physicians should be mindful of the possibility of kartagener syndrome because this condition could significantly affect the morbidity of the patient .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: iatrogenic colonic perforation during colonoscopy is a well recognized though infrequent complication of the procedure . the rate of perforation for colonoscopy done for all indications , whether diagnostic or therapeutic , has been reported to be < 1% \n . risk factors for colonoscopic perforation include therapeutic interventions including polypectomy and biopsy particularly when done for larger lesions , pneumatic dilation and endoscopic coagulation [ 2 , 3 ] . here , we present a patient who sustained an injury to the cecum and terminal ileum following a polypectomy during routine screening colonoscopy . the patient presented with delayed symptoms of perforation . \n we therefore decided to perform an exploratory laparotomy which showed a significant defect across his ileocecal junction . \n the lesion was found to be an extramedullary plasmacytoma , a rare diagnosis in gastrointestinal pathology . \n we report a case of a 62-year - old man with a past medical history significant for hypertension and hypothyroidism who underwent diagnostic colonoscopy for melena at an outside facility at 9:00 a.m. on the day of the injury . \n the gastroenterologist identified a large nearly 4 cm pedunculated and ulcerated polyp at the medial border of the cecum in close proximity to the ileocecal junction ( fig . 1 ) . \n the lesion was removed endoscopically in its entirety through the use of a hot snare . \n the polyp measured nearly 4 cm and had an obvious ulceration on its surface as shown . \n the polyp measured nearly 4 cm and had an obvious ulceration on its surface as shown . \n the patient presented to the emergency department 5h post - procedure complaining of abdominal pain and had a firm abdomen . \n his computerized tomography ( ct ) scan showed a significant amount of pneumoperitoneum and inflammatory changes in the right lower quadrant in the region of the terminal ileum and cecum ( fig . 2 ) . \n as the patient was improving , we initially attempted a trial of non - operative management . in the interim , pathology from the endoscopic biopsy \n after 48 h the patient manifested signs of unsuccessful non - operative management characterized by increasing abdominal pain , tachycardia and rising leukocytosis . therefore , we decided to perform an exploratory laparotomy . \n ct scan of the abdomen revealing significant intra - abdominal free air ( left ) . on a lower portion of the scan \n , there are inflammatory changes evident in the right lower quadrant in the region of the ileum and cecum ( right ) . \n ct scan of the abdomen revealing significant intra - abdominal free air ( left ) . on a lower portion of the scan \n , there are inflammatory changes evident in the right lower quadrant in the region of the ileum and cecum ( right ) . \n these structures are difficult to discern in the presence of the inflammatory changes . in the operating room \n , we found two interloop abscesses in the mesentery of the distal ileum and cecum . \n after performing a right hemicolectomy including 10 cm of edematous distal ileum , we were able to identify the 2.5 cm defect extending across the ileocecal junction where the biopsy was performed ( fig . \n we performed a side - to - side stapled anastamosis from the terminal ileum to transverse colon , and diverted the gastrointestinal tract with a loop ileostomy . \n gross pathology of the iatrogenic colonoscopic injury to the ileocecal junction sustained during the snare polypectomy . \n gross pathology of the iatrogenic colonoscopic injury to the ileocecal junction sustained during the snare polypectomy . \n the top left insert shows hematoxylin and eosin ( h&e ) staining , whereas the upper and lower right inserts show special staining for the kappa or lambda type of the light chain , respectively . \n the left lower insert shows a higher power magnification showing multiple plasma cells with the presence of the characteristic cartwheel or clockface nuclei typical of plasma cells . as illustrated , the entirety of the polyp stains for the kappa light chain , indicating that the polyp comprised a monoclonal population of plasma cells and confirming that the lesion is a rare extramedullary plasmacytoma . \n these photos illustrate that the plasma cells were confined to the polyp itself , and that the polyp was pedunculated on a stalk of gastrointestinal tissue which can be appreciated at the mucosal border of the specimen . \n the pathology of the right colon and terminal ileum did not reveal any remaining areas of plasmacytoma at the site of perforation on either the colon or the terminal ileum . \n the top left shows h&e staining and the bottom left shows increased magnification , illustrating classic cartwheel nuclei . \n the top right and bottom right show special staining for either the kappa or lambda light chain , respectively . here \n the polyp specifically stains for the kappa light chain , indicating that it comprised a monoclonal population of plasma cells . \n the top left shows h&e staining and the bottom left shows increased magnification , illustrating classic cartwheel nuclei . \n the top right and bottom right show special staining for either the kappa or lambda light chain , respectively . here \n the polyp specifically stains for the kappa light chain , indicating that it comprised a monoclonal population of plasma cells . \n extramedullary plasmacytoma ( emp ) is a rare diagnosis with few cases presented in the literature . \n lopes da silva in a 2012 review of emp reported that there were 61 cases described in the literature searching as far back as 1947 . \n the true incidence of emp is unknown ; however , as many patients will be asymptomatic . of these 61 cases , \n 20 occurred in the duodenum , 24 in the jejunum and 17 in the ileum . \n the most common presentations were abdominal pain and other nonspecific symptoms including nausea , vomiting and weight loss . \n there is one case report of emp presenting as a small bowel intusseception in a patient with multiple myeloma . \n this may have been a similar circumstance with our patient whereby the large plasmacytoma was located in the distal ileum near the ileocecal valve . \n the lesion may have migrated into the cecum during the polypectomy as an intussceptum , which explains our finding of the perforation across both the cecum and terminal ileum . \n other cases in the literature have been described where emps are located in the distal ileum [ 6 , 7 ] . \n overall , the median age at presentation is 55 years and tends to be more frequent in men . \n imaging modalities including ct and positron emission tomography have been used in the work - up of plasmacytoma but tend to be nonspecific . \n treatment options classically have involved surgical resection . however , there are recent studies showing that these lesions may also be successfully treated endoscopically . as with any polyp \n removed endoscopically , the size of the lesion is related to the success of the removal as well as the rate of perforation . as endoscopic techniques continue to evolve , \n endoscopists have been able to treat larger and more invasive extramedullary gastrointestinal plasmacytomas in more aggressive but clinically safe and effective manners . \n [ 9 , 10 ] have shown successful endoscopic techniques in resection of colonic plasmacytomas which extend into the mucosa . in our case , \n the plasmacytoma was pedunculated and did not appear to invade the mucosa either grossly or on the histology as shown in fig . \n the injury sustained to the bowel wall was most likely iatrogenic from the application of the hot snare rather than an erosion of the lesion through the layers of the bowel wall .", "role": "user" }, { "content": "here we report the discovery of an extramedullary ileocecal plasmacytoma , a rare entity reported only 60 times in the literature . \n this finding occurred during management of a patient who had sustained an occult perforation during diagnostic colonoscopy . \n we explored the patient finding a large ileocecal perforation , and thus a right hemicolectomy was performed . \n interestingly , the pathology of the mass was consistent with an extramedullary plasmacytoma , which is a very rare gastrointestinal diagnosis . \n we end by summarizing the presentation and work - up of extramedullary plasmacytoma .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: 30 million people have diabetes and this is expected to increase to nearly 60 million by 2017 . given india 's limited resources , it is important for health policy makers to choose from the ever - widening list of health conditions that vie for attention , and it is a list to which diabetes must be added as an important public health problem . however , \n these dilemmas of choice are made even more difficult when policy makers have to prioritize on the basis of disease burden , cost - effectiveness , and equity . in this light , \n the landmark u.n general assembly in 2011 met to discuss the prevention and control of non - communicable diseases ( ncd ) . \n it was pointed out that non - communicable diseases are responsible for more deaths than all other causes . \n while the international community had traditionally focused on communicable diseases , the ncd -cardiovascular disease , diabetes , cancers , and other chronic respiratory diseases emerged , almost unnoticed , in the developing world . with this ever - increasing prevalence of obesity , diabetes , and coronary disease , \n it is likely that health policy - makers would assign an increasing proportion of funds to chronic diseases in the years to come . \n thus , the onus might be on optimizing the utilization of these funds for the best possible public health outcome . \n it is in this light , that we write this commentary on a simple , cost - effective strategy for preventing diabetes yoga therapy . \n the management of diabetes poses unique challenges in terms of modification of dietary practices , weight management , exercise , monitoring of body fluids ( blood , urine ) , footcare , use of drugs , and learning new technical skills such as blood glucose monitoring . \n health care systems need to be redesigned to deliver chronic care that is founded on existing primary care facilities , but supported by good referral systems . \n inaction will affect millions of lives - often the lives of those who have the least . to deal with the increasing morbidity and mortality \n , it is important to develop and evaluate low - cost strategies that build on available resources , and especially , interventions that can empower patients . \n the prevalence of diabetes mellitus in india is projected to increase by 60% and the economic burden by 50% over the same period . \n these numbers are overwhelming , and it may be pertinent to point out that highly successful , evaluated , prevention program have depended on highly resource - intensive behavior change techniques that would be extremely costly if rolled out universally and would bankrupt the wealthiest of nations . \n evidence from randomized controlled trials ( rct 's ) have already shown the usefulness , though expensive nature of carrying out lifestyle intervention programs . \n today , it is necessary to look at alternatives which are not resource - intensive and those which are nearer to the community that people live in . \n yoga therapy holds promise as a therapeutic intervention and health promotion measure , though studies are not conclusive . \n a recent randomized controlled study conducted in india also showed a significant improvement in the quality of life but a non - significant trend towards improvement in glycemic control in the intervention group . \n the advantages of yoga are that , it is a holistic philosophy , in which physical exercises are linked to a wider lifestyle and behavioral change that includes diet , relaxation , and stress management . \n it is also considered to be a potential therapeutic tool to achieve positive health and cure disease . \n , 80% of the expenditure on medical care for diabetes is made by the richest countries of the world . \n a study on determinants of medical outcomes showed that patient - related reasons were more responsible for variability in hba1c when compared with physician - related factors . \n controlling these patient - related factors hold the key to successful control . according to the american diabetes association guidelines regular \n , moderate intensity cardiovascular exercise training of at least 150 min / week , alone or in conjunction with resistance exercise training 3 times per week , has been shown to improve glucose control and glucose disposal , improve insulin sensitivity , contribute to weight loss . \n though regular exercise training is a cornerstone of complementary therapy , it is frequently underutilized as a treatment strategy for the prevention and treatment diabetes . in this context \n , the importance of yoga is related to the ease of use , safety , and multiple psychological benefits including stress reduction and mental health well being . \n there have been at least 22 rct studying the risk factors of developing type 2 diabetes with some evidence that the regular practice of yoga over 3 - 6 months can decrease the risk of developing diabetes and improve glucose control in healthy adults . \n the postulates on the efficacy of yogic practices in controlling diabetes is based on the exercise effect , changes in biochemical and hormonal profile , elimination of stress , and instilling a sense of discipline . \n if the patient - related reasons like discipline regarding food and exercise can be taken care of and added to this , if there is a positive effect on the biochemical and hormonal profile , it can help to modify the patient - related reasons and result in a better outcome for the patient with diabetes . \n thus , yoga - based programs may be a low - cost intervention strategy to improve physical as well as psychological well being . \n yoga provides slow rhythmic movements , which emphasize the stimulation of the organs and glands by easy bending and extension , which do not over - stimulate muscles but concentrate on focused stimulation . \n the insulin resistance syndrome or metabolic syndrome is a constellation of hyperglycemia , dyslipidemia , hypertension , and central obesity . \n increased sympathetic activity , enhanced cardiovascular reactivity , and reduced parasympathetic tone have been implicated in the pathogenesis of insulin resistance syndrome . \n recent research also shows that chronic psychological stress and negative affective states contribute to the pathogenesis and progression of insulin resistance , glucose intolerance , hypertension , and other irs - related conditions . \n studies have shown that yoga has a positive short - term effect on multiple diabetes - related outcomes , but its long - term effects are not clear . \n 7.5% had practiced yoga at some point and very interestingly , 90% of this population expressed the belief that yoga was helpful in improving , maintaining health or both . \n though yoga originated in india , extensive rct - based data are not available for our country . while there are many studies on yoga from india , the studies do have limitations : lack of control groups , reduced power because of a low number of study subjects , possible selection bias or influence of uncontrolled confounding , lack of appropriate statistical analyzes or presentation . \n additional studies using rigorous methodologies are necessary to examine the effects of yoga therapy on glycemic control , and quality of life of women with type 2 diabetes mellitus . \n a randomized study done in india found a significant improvement in fasting blood sugar , hba1c , and total cholesterol with yoga therapy . \n significant improvements in scores of psychological assessment ( satisfaction , impact , and worry ) were also seen . clinically significant reduction in the doses of hypoglycemic agents and insulin were observed after yoga lifestyle intervention . another study ( a more rigorous , inpatient yoga treatment accompanied by visceral cleansing procedures , in addition to asanas and pranayama ) was undergone by 149 patients for 40 days . \n this study showed that , for type 2 diabetes of less than 10 yrs duration and fasting glucose < 140 mg / dl , hyperglycemia can be controlled by yoga alone . \n however , patients with very severe hyperglycemia / glucose intolerance would need a combination of yoga and hypoglycemic drugs . \n , within a short period of study for 10 days was able to show a significant reduction in fasting glucose , total cholesterol , ldl , vldl , total cholesterol / hdl ratio with yoga therapy ; these were more marked in those with hypercholesterolemia and hyperglycemia . \n in addition to reporting a fall in fasting glucose and post - meal blood glucose , malhotra , et al . also reported a significant fall in waist - hip ratio and changes in insulin levels , suggesting a re - distribution of fat and glucose utilization . \n another study showed a significant decrease in bmi and anxiety and an increase in general well - being . \n a randomized trial conducted in uk found a significant improvement in the yoga group for hba1c , fasting glucose , ldl , and total cholesterol . \n they concluded that traditional i.e. , primarily yoga - based interventions may benefit patients with higher hba1c values . \n however , there are conflicting reports too- in an exploratory rct in uk , yoga did not show a dramatic benefit . in the intervention group , \n however , it was also suggested that some other factors like good background control in the targeted population ( mean hba1c-6.9 ) , small sample size , practical and motivational barriers to class attendance , physical and motivational barriers to engaging in exercise could be responsible for the marginal fall in hba1c . in a systematic review , \n innes , et al . suggested that yoga may be instrumental in improving core indices of the metabolic syndrome including glucose tolerance and insulin sensitivity , lipid profiles , anthropometric characteristics . \n patients in studies have shown improvement in glycemic control with reduction in dose requirement of oral hypoglycemics . among a small number of elderly , followed up for 7 years \n , there was good glycemic control and no long - term complications were reported in them . \n are there studies which have been carried out to ascertain the reasons for the benefit that yoga offers in the setting of type 2 diabetes / metabolic syndrome ? \n gordon , et al . conducted a prospective randomized study for 6 months on the effects of physical exercise and yoga therapy on oxidative stress indicators . \n fasting blood glucose decreased significantly , as did markers of oxidative stress ; anti - oxidant molecules showed a significant increase . in a controlled trial conducted in india on oxidative stress indicators like malonyl aldehyde , yoga practitioners achieved significant improvement in bmi , fasting glucose , post - meal glucose , malonyl aldehyde , glutathione , and vitamin c , and no adverse events \n thus , we suggest that yoga be considered as a candidate for community - based management programs in tackling the burden of type 2 diabetes . yoga is a potential intervention that is not resource - intensive . \n if studies prove the effectiveness of yoga , the future may see the emergence of a yoga movement by the people with diabetes to generate positive health . and finally , yoga , \n an innovation created in india , could find its way back to pre - eminence in this country , given its potential in the ever - increasing epidemic of diabetes and cardiovascular disease .", "role": "user" }, { "content": "the prevalence of diabetes is projected to increase to 80 million by 2030 , placing an immense burden on the health care resources of our country . \n thus , diabetes poses a challenge to health systems and the individual . \n hence , it is necessary to look at adjuncts to effective management of diabetes ; adjuncts which are not resource intensive and are nearer to the community that people live in . \n yoga holds promise as a therapeutic intervention and health promotion measure . \n this brief communication explores the studies done to date on the beneficial effects of yoga on diabetes .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: salmonella spp and campylobacter spp are important food - borne pathogens and the consumption of goat 's meat or unpasteurised goat 's milk and cheese have been associated with some outbreaks of infection in humans . \n both salmonella spp and campylobacter spp have been associated with disease in goats but they are also found in animals that show no signs of clinical illness . in dairy cows , \n the main source of contamination of bulk tank milk is faecal shedding of these pathogens by asymptomatic animals and this has led to the proposal of on - farm management interventions to enhance the safety of dairy products . as opposed to the situation for poultry , pigs , \n cattle and sheep , very few large - scale epidemiological studies have been undertaken on goats as potential faecal carriers of salmonella spp and campylobacter spp . to our knowledge , \n the objective of this investigation was to check for the presence of faecal carriers of salmonella spp and campylobacter spp among healthy murciano - granadina goats on 12 spanish farms . \n the study was conducted over a three - month period from may to july 2003 on 12 murciano - granadina goat herds reared on farms of the asociacin espaola de criadores de la cabra murciano - granadina ( acrimur ) , in the murcia ( southeastern ) region of spain . \n the herds ranged in size from 120 to 450 lactating goats , machine - milked once daily . in all herds , the milking parlour was separated from the housing area and the milk was conducted by milk pipeline to the receiver jar connected by milk delivery line to the refrigeration tank located in a separate room . \n milking routine did not include prior udder preparation or milking - unit sanitation between goats and post - dipping teat disinfection was carried out using iodine solution by dipper cup or teat sprayer . after milking , \n all the herds were classified free of brucellosis and tuberculosis and were under a mastitis control programme based on monitoring the somatic cell count and selective antibiotic dry therapy . \n the practice of artificial rearing , in which kids are withdrawn after parturition and fed pasteurised colostrum and milk replacer , was implemented in eight of the herds . \n nine of the 12 herds were allocated indoor space with free access to an open yard and were fed a balanced total mixed ration and alfalfa hay . \n the other three herds were given a similar diet but had access to pasture ( three hours per day ) . \n on the day of sampling , the farm owners declared that their herds had not had abortions nor were any of their animals currently suffering from digestive disorders . \n animals of up to four weeks of age were classified as goat kids ( n = 40 ) , those between one and nine months old were classified as replacement animals ( n = 81 ) and those older than nine months were classified as adults ( n = 101 ) . \n faeces were obtained directly from the rectum using swabs and transferred to tubes containing amies transport medium ( deltalab , barcelona , spain ) or cary blair transport medium ( deltalab ) . \n additionally , one sample of bulk tank milk was taken from each of the 11 herds . \n milk samples were collected into sterile containers ( 30 ml ) after agitation of the bulk tank milk at 5c . on the day of sampling \n , all samples were submitted to the laboratory by express mail in refrigerated containers and they were processed within 24 hours of reception . \n the procedures for the isolation of salmonella species included enrichment of swabs with amies transport medium and enrichment of milk samples in tetrathionate broth ( difco , becton dickinson , sparks , maryland , usa ) , supplemented with 40 mg / ml novobiocin ( sigma , sigma - aldrich , st . \n after 24 hours of incubation at 37c , samples were plated onto xld agar ( difco ) , and they were incubated for 24 hours at 37c . \n the procedures for the isolation of campylobacter species included enrichment of swabs with cary blair transport medium and enrichment of milk samples in bolton selective enrichment broth ( oxoid , basingstoke , uk ) . \n the broths were incubated at 37c for 48 hours in a microaerophilic atmosphere achieved using commercial gas - generating kits ( campygen , oxoid ) . following incubation \n , samples were plated on karmali selective medium ( oxoid ) and abeyta - hunt - bark agar and they were incubated in a microaerophilic atmosphere at 37c for 48 hours . \n neither salmonella nor campylobacter spp were recovered from the faeces samples or milk samples . in italy , cortesi et al . evaluated salmonella carriage in 40 healthy goat kids at slaughter , and recovered salmonella from the intestinal contents of only one animal . however , in nigeria , adesiyun et al . \n isolated salmonella spp from intestinal contents , bile and mesenteric lymph nodes in 19 ( 9.5% ) of 200 slaughtered goats , although these bacteria could be isolated from the intestinal contents of only five ( 2.5% ) of the animals studied . \n the carriage rates reported in those studies on intestinal contents of animals at slaughter contrast with the null rate in our survey ; perhaps , the difference in procedure for the collection of the samples may have been a significant contributory factor to that contrast . \n samples taken at slaughter can lead to overestimates of normal prevalence , since it has been shown that the stress of transportation and of food withdrawal experienced by animals before slaughter increases the number of shedders of salmonella spp among these animals . \n the overall impression from the three studies is that salmonella spp are rarely isolated from the intestinal contents or faeces of healthy goats . here \n , failure to find campylobacter spp in the faeces of any of the healthy goats is consistent with the results of an earlier study in norway in which neither campylobacter jejuni nor campylobacter coli was found in any of the rectal swabs and stool specimens of the goats examined . \n nevertheless , other investigators have reported the isolation of campylobacter spp from rectal swabs or faeces samples of healthy goats , although rates have been highly variable . in canada , \n prescott and bruin - mosch were able to identify c. jejuni in 2.7% of the animals studied . \n turkson et al . , in kenya , found campylobacter species in 6.3% of the goats sampled , and abrahams et al . in ghana \n detected c. jejuni , but not c. coli , in a high proportion ( 33.3% ) of the goats tested . \n these different carriage rates could be attributable to contact of goats with other animal species . thus , jiwa et al . \n explored the prevalence of campylobacter spp in healthy goats kept under various management systems in tanzania and observed that goats kept away from other farm animals , irrespective of whether the management system was good or poor , were negative for campylobacter spp . \n however , three out of 20 goats confined to a small area , but in contact with c. coli - positive pigs and chickens became infected with c. coli . \n the results of that study suggest that goats are not natural hosts of campylobacter spp and that pigs and poultry may be a source of infection . \n hence , the lack of faecal carriers of campylobacter spp reported here could be explained by the fact that the goats were not in contact with other animals , together with other factors such as the breed of goat and the environmental conditions . the failure to isolate salmonella spp or campylobacter spp from the bulk tank milk of the herds examined here does not provide evidence of contamination by faecal carriers , which are generally the main source of these pathogens in raw milk . \n this finding is in agreement with those obtained by other authors , who failed to detect these bacteria in unpasteurised milk from goats . in cow \n bulk tank milk samples , several studies have reported a frequency of isolation that ranged between 0.4% and 12.3% for c. jejuni and between 0.2% and 8.9% for salmonella . the results so far obtained for the milk of healthy goats suggest that goat 's milk is a safer product than cow 's milk \n . however , further studies are necessary to evaluate the risk of these pathogens contaminating milk in the bulk tank whenever there are clinical cases in the herd . in conclusion , \n the healthy murciano - granadina dairy goats examined were free of salmonella spp and campylobacter spp . \n this suggests that , under the management practices applied to this breed in spain , there is a very low risk that murciano - granadina goats will serve as a reservoir for these food - borne pathogens . \n this work was supported by a grant from the instituto de salud carlos iii ( grant fis g03/025 ) .", "role": "user" }, { "content": "this study was designed to investigate the occurrence of salmonella spp and campylobacter spp in faeces samples from 222 healthy murciano - granadina dairy goats reared on 12 farms in spain and in samples of bulk tank milk from 11 of those herds . \n neither salmonella spp nor campylobacter spp were isolated from any of the samples . \n our results suggest that , under the management practices applied to this breed in spain , murciano - granadina goats are not likely to be a significant reservoir for these food - borne pathogens .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: drug \n discovery involves a considerable effort in the selection \n and translation of in vitro leads into molecules \n with in vivo efficacy in an animal model of the disease . \n our collective memories are often short when it comes to decades of \n research in a single therapeutic area , let alone research of over \n more than a half - century , and yet the past may hold many insights \n to aid us in drug discovery efforts in both the present and future . \n as an example , from the 1940s to the 1960s , significant efforts led to first- and second - line drugs for mycobacterium tuberculosis ( mtb ) , \n which is the causative agent of tuberculosis ( tb ) . \n this disease has \n infected approximately 2 billion people and kills 1.3 million people \n annually . \n we critically need next - generation \n active small molecules as tools to query essential infection biology \n to drive novel therapies . \n next generation drugs must lack cross resistance to current \n therapeutics , shorten treatment , and address drug drug interactions \n with co - administered treatments . \n many molecules have been assessed as to their ability \n to modulate mtb infection in mice . \n these data reside \n in numerous journals and reports that are not readily accessible despite \n today s electronic media and databases . \n unfortunately , much \n of the early ( pre-1970s ) structure activity relationship ( sar ) \n data from both in vitro and in vivo models appears to have been neglected . typically , these data are \n only unearthed on a compound - by - compound basis when we rediscover an agent that was already known from decades ago . \n the field s interest in this historical data may have been \n unfortunately diminished due to the recent upsurge in whole - cell phenotypic \n high - throughput screens ( hts ) for novel antituberculars that have \n seen several million compounds tested . \n commercial vendor and in - house libraries have been assayed , leading to the clinical candidate \n sq-109 and a diarylquinoline hit that \n was optimized to the drug bedaquiline . \n however , these successful outcomes from screening represent anomalies \n as the road from hit to drug invokes words such as valley \n of death.mtb hts hit rates are usually below 1% , and most hits \n require a significant amount of chemical evolution in an effort to \n identify a probe let alone a drug discovery lead . to date \n we estimate \n about 1500 in vitro mtb hits of interest have been \n derived from one laboratory alone , while gsk has recently published another 177 promising in \n vitro actives . \n many laboratories \n have also described mtb hits ; so in total , there \n are likely close to 2000 compounds from recent efforts that may require \n triage before advancement of the most promising through the discovery \n pipeline . \n to significantly impact the tb field , these hits , \n or their evolved \n analogs , ideally must demonstrate in vivo activity \n in an animal model . rarely is the specific mtb target \n for these compounds known before in vivo testing . \n the mouse model of tb infection \n is considered important for comparative \n assessment of different treatments and optimization of tb drug dosing \n schedules . \n there has also been considerable \n development of the acute and chronic \n mouse models of mtb infection . \n given current resource limitations that are magnified for a neglected \n disease such as tb , we are faced with a dilemma : how do we efficiently \n select among the thousands of hits to decide which to carry forward \n for in vivo efficacy assessment ? \n this report \n details a novel approach to address this critical issue \n through the curation of 773 molecules that have been tested in the \n last 70 years in the mouse tb infection model . \n we present detailed analyses \n of the physiochemical and structural properties of both active and \n inactive molecules as well their chemical property space coverage \n in an effort to guide the future design of novel antitubercular chemical \n probes and drugs . \n furthermore , we leverage our experience with machine \n learning models for in vitro activity to construct and statistically \n validate these computational models to predict in vivo efficacy in the mtb - infected mouse model . \n the computational \n models are further validated through the correct prediction of 8 of \n 11 known in vivo actives absent from the training \n set . \n the models are also applied to score a set of 177 in \n vitro drug leads recently reported by glaxosmithkline ( gsk ) to aid in their prioritization for in \n vivo assessment . \n various search terms were \n used in pubmed to retrieve papers with \n compounds tested in murine acute and chronic mtb infection \n models . \n for example , tuberculosis and in vivo and mouse , \n tuberculosis and efficacy and mouse , and comparison \n and antituberculosis and mouse . \n the same search terms were \n also used in scifinder ( cas , columbus , oh ) and web of knowledge ( thomson \n reuters ) . \n individual journals were also searched online ( e.g. , tuberculosis , \n journal of medicinal chemistry , and plos journals ) . \n the in \n vivo data was manually curated , and structures were sketched \n using the mobile molecular datasheet ( mmds ) ios app , chemdraw ( perkin - elmer , waltham ma ) , or downloaded from \n chemspider ( www.chemspider.com ) and combined with pertinent \n data fields . \n the data has been made publically available in the cdd \n tb database ( collaborative drug discovery , inc . , \n molecules were classed as active / inactive , and \n this was generally based on the data in the publications . for example , \n a reduction of log cfu in lung greater or equal to 1 log was considered \n active . \n the initial assembled data set was shown to contain duplicates \n by utilizing the acd / chemfolder version 12 software program ( advanced \n chemistry development , http://www.acdlabs.com/products/km/ackm/chemfolder/ ) . utilizing the ability to check for duplicates and incorrect structures \n ( valence errors , pentavalent carbons , missing stereochemistry ) , identified \n structure issues were manually curated . \n a total of 18 compounds were \n either removed from the originally assembled data set or edited to \n deal with the identified errors . \n alogp , molecular weight , \n number of rotatable bonds , number of rings , number of aromatic rings , \n number of hydrogen bond acceptors , number of hydrogen bond donors , \n and molecular fractional polar surface area were calculated from input \n sd files using discovery studio 3.5 ( san diego , ca ) . \n we compared the 773 compounds with the \n previously described 745 compounds with known mtb targets collated from the literature and available in tb mobile ( version 1 ) that were utilized to generate a principal components analysis ( pca ) \n plot with the interpretable descriptors selected previously ( alogp , \n molecular weight , number of rotatable bonds , number of rings , number \n of aromatic rings , number of hydrogen bond acceptors , number of hydrogen \n bond donors , and molecular fractional polar surface area ) for machine \n learning . \n this pca model represents essentially the published target - chemistry \n property space for mtb . \n we also compared 1429 mtb hits ( active and nontoxic only , from the nih screens \n where ic90 < 10 g / ml or 10 m and a selectivity \n index ( si ) greater than 10 where the si is calculated from si = cc50/ic90 ) to show how they covered the target - chemistry \n property space . \n these analyses can be compared with those previously \n published which focused on in vitro mtb data . \n we have previously described the \n generation and validation of the \n laplacian - corrected bayesian classifier models developed from mtb growth inhibition screens of small molecule libraries using discovery studio 3.5 . \n this approach was utilized with the literature data curated in the \n course of this study . \n the following molecular descriptors were used \n and were calculated from input sd files : molecular function class \n fingerprints of maximum diameter 6 ( fcfp_6 ) , alogp , molecular weight , number of rotatable bonds , number of rings , \n number of aromatic rings , number of hydrogen bond acceptors , number \n of hydrogen bond donors , and molecular fractional polar surface area . \n models were validated using leave - one - out cross validation in which \n each sample was left out one at a time , a model was built using the \n remaining samples , and that model was utilized to predict the left - out \n sample . \n each model was internally validated , roc plots were generated , \n and the xv roc auc calculated . \n the bayesian model was additionally \n evaluated by leaving out 50% of the data and rebuilding the model \n 100 times using a custom protocol for validation to generate the roc \n auc , concordance , specificity , and selectivity as described previously . \n the internal roc value represents the training set value while the \n external roc represents the test set molecules left out . \n we also compared \n the resulting bayesian model with svm and rp forest and single tree \n models built with the same molecular descriptors in discovery studio . \n for svm models , we calculated interpretable descriptors in discovery \n studio and then used pipeline pilot to generate the fcfp_6 descriptors \n followed by integration with r. rp forest \n and rp single tree models used the standard protocol in discovery \n studio . in the case of rp forest models , \n a bootstrap sample of the original data is taken , and \n this sample is used to grow the tree . a bootstrap sample is a data \n set of the same size as the original one but in which the same data \n record can be included multiple times . \n rp single trees had a minimum \n of 10 samples per node and a maximum tree depth of 20 . in all cases , \n five - fold cross validation \n ( leave out 20% of the database five times ) \n was used to calculate the roc for the models generated . \n eleven compounds active in the mouse in vivo model were identified from a 1950s compilation . \n a further four active compounds resulted in 11 compounds that were predicted with the computational \n models developed ( table 4 ) . for each molecule , the closest distance to the training \n set \n was also calculated using the bayesian model in the calculated \n properties protocol method in discovery studio ( a value of zero represents \n a molecule in the training set , while larger values are further from \n the training set ) . \n 177 mtb leads were recently disclosed by gsk and represent a promising set of small molecules for further \n exploration \n as potential antitubercular drug candidates . \n the gsk set was scored \n with all of the in vivo models generated in this \n study . the mean closest distance to the training set \n was also calculated \n for the 177 compounds to provide an idea of similarity to the training \n set . \n these data were calculated from the outputs of each of the bayesian \n models . for each \n test set molecule a score for closest distance to \n training set was calculated using discovery studio ( described earlier ) . \n we averaged this number across the 177 molecules , where the closeness \n of a compound to the training set scales inversely with the value . \n the maximum tanimoto similarity for each molecule versus the training \n set was also calculated using mdl fingerprints . \n these compounds were then evaluated using tb mobile and clustering \n in discovery studio with the 745 compounds in this data set to infer \n potential targets . \n adme / tox properties \n for these compounds were generated using discovery studio admet predictors \n and custom bayesian models for pxr , herg , etc . \n scaffold analysis \n was performed using the sar table app ( for ios - based devices such as iphones and ipads ) , which provides \n a user interface for drawing scaffolds and substituents and specifying \n activity data . \n it also provides access to analysis functionality such \n as scaffold - substructure matching , structure activity model \n generation , data visualization , and manuscript figure creation . \n means for descriptor values for \n active and inactive compounds were compared by two tailed t - tests with jmp v. 8.0.1 ( sas institute , cary , nc ) . \n a total of 773 molecules were collated from the literature for \n the first time to our knowledge using various search terms in pubmed , \n scifinder , and web of knowledge ( see experimental \n section ) , for which there was data in acute or chronic mouse \n models of mtb infection ( table s1 , supporting information ) . following convention , an active \n compound minimally exhibited a 1 log10 reduction in mtb colony - forming units ( cfus ) in the lungs as compared \n to no - drug control . occasionally , other types of analyses required \n our best scientific judgment on the active / inactive boundary ; for \n example , the work of denny and co - workers used an activity ratio versus pa-824 . \n we considered a value > 0.4 \n as active given the demonstrated 2.53 log10 reduction \n in cfus in the lungs by pa-824 ( 2732 ) . \n older publications \n relied on extension of survival compared to negative and positive \n controls . \n fortuitously for machine learning \n model construction , the data set was divided almost equally between \n actives ( n = 362 ) and inactives ( n = 411 ) . through analysis of simple molecular descriptors ( see experimental section ) we sought to gain insight \n as to why active and inactive compounds behaved differently ( table \n s2 and figure s1 , supporting information ) . among the 773 compounds , statistically significant differences \n were found between the number of rings , their alogp , and fractional \n polar surface area ( table 1 ) . \n it should be \n noted that the standard deviations are large for the in vivo data and may stem from the heterogeneity of structures ( e.g. , between \n very small molecules , large macrolide antibiotics , and calixarenes ) \n and likely published experimental methods ( e.g. , different mice strains , \n dosing concentrations , dosing period , etc . ) . \n we would not advise using \n individual properties alone ( like calculated logp ) to differentiate in vivo active compounds as there were temporospatial effects \n for the descriptors , suggesting the addition of further compounds \n over time increases or decreases differences observed ( figure s1 , supporting information ) . \n mwt = molecular \n weight , hbd = \n hydrogen bond donor , hba = hydrogen bond acceptor , num rings = number \n of rings , num arom rings = number of aromatic rings , fpsa = fractional \n polar surface area , and rbn = rotatable bond number . \n fractional polar \n surface area ( fpsa ) = total partially positively charged molecular \n surface area divided by the total molecular surface area . \n pca can be used to understand multi - dimensional \n data represented \n by the multiple molecular descriptors representing the molecular properties \n of the training set and shows overlap in this property space between \n active and inactive compounds ( figure 1a ) . \n our analyses can also be compared to those previously performed with mtb in vitro data . \n this overlap \n would also suggest some complexity in using these individual molecular \n descriptors alone to distinguish in vivo active compounds . \n approved drugs for tb are distributed in this same chemical property \n space with much larger intravenous tb drugs ( representing generally \n larger molecules with different molecular properties ( less hydrophobic ) ) separated out of the main cluster ( figure 1b ) . \n coverage of mtb in vivo molecule property \n space : \n ( a ) n = 773 compounds showing how some actives ( yellow ) \n are outside the major cluster and represent more diverse molecules . \n ( b ) highlighting known first and second \n line tb drugs and others used against the disease ( bedaquiline , moxifloxacin , \n ofloxacin , sparfloxacin , imipenem , gatifloxacin , rifampin , pyrazinamide , \n rifalazil , rifapentine , rifabutin , levofloxacin , clarithromycin , amikacin , \n kanamycin , streptomycin , capreomycin ia , ethambutol , ethionamide , \n isoniazid , and meropenem ) . \n most mtb drugs ( yellow ) \n are hidden in the large blue cluster ; top left - hand cluster is amikacin , \n capreomycin ia , kanamycin , and streptomycin . \n pca using molecules known to inhibit specific mtb targets suggests that the in \n vivo compounds possess good coverage of known target chemistry \n property space and extend well outside of it ( figure 2a ) . \n however , it should be noted these targets do not broadly \n cover the chemistry property space of the mtb metabolome \n ( using molecules extracted from biocyc ) ( figure 2b ) , and the active in vivo compounds \n also only cover a fraction of the mtb metabolome \n pca plot ( figure 2c ) . coverage of mtb target molecule property space : \n ( a ) 745 tb mobile molecules ( blue ) with annotated targets and 773-member \n tb in vivo training set ( yellow ) pca ; 3pcs explain \n 88% of variance . \n ( b ) comparison of tb target molecule property space \n using data from tb mobile ( blue ) and 1770 mtb metabolites \n ( yellow ) using data from biocyc . \n ( c ) comparison of 1770 mtb metabolites ( blue ) and 773-member tb in vivo data \n set ( yellow ) ; 3pcs explain 87% of the variance . \n when the same in vivo compounds are compared \n to \n known mtb in vitro actives , they are also well distributed over the pca plot \n ( figure 3a ) \n . the majority of the in \n vivo actives overlap with the in vitro actives suggesting a good coverage of \n the chemistry property space ( and likely requirement for similar molecular \n features or descriptors ) , with a small number of the in vivo actives exploring property space distinct from that of the mtb in vitro actives from recently described screening efforts . \n this graphical tool can demonstrate differential coverage of chemical \n property space and may be utilized to explore how candidate molecules \n compare to molecules previously assayed in vivo . coverage \n of mtb in vitro growth inhibitor chemistry \n property space . \n ( a ) 1429 tb in vitro actives ( blue ) \n and 773 molecule tb in vivo data set ( yellow ) pca ; \n 3pcs explain 83.7% of variance . \n a significant component of the data set ( 51 of 773 molecules ; \n table \n s1 , supporting information ) contains the \n triazine central scaffold . \n these compounds were initially brought \n to our attention when we identified tcmdc-125802 ( ( e)-6-(2-((5-nitrofuran-2-yl)methylene)hydrazinyl)-n , n - diphenyl-1,3,5-triazine-2,4-diamine , \n figure 4a ; mic of 62.5 ng / ml against mtb ) through our machine learning \n models for in vitro antitubercular activity . \n a literature \n search highlighted one report of the antitubercular \n activity of tcmdc-125802 and related triazines from 1969 . \n figure 4 shows a matrix \n correlation plot of triazine substituents r versus r for this published data set based on mtb in vitro and in vivo data ( figure 4a ) . \n the data visualization quickly hones \n in on the features important at r and r ( i - propylamino , and n - propylamino groups ) \n in cells that are green ( figure 4b ) \n . this type \n of approach could be useful for interrogating other structure activity \n relationships within the complete in vivo data set . \n ( a ) triazine \n markush structure for analogs of tcmdc-125802 ( r = r = nhph ; r = h ) . \n ( b ) matrix correlation \n plot showing cells with mtb in vitro ( left ) and in vivo ( right ) data . \n ( c ) solid cells are used to show assayed \n compounds , and colored dots for activity estimates for hypothetical \n compounds using internally generated predictions . \n machine learning models are educated by example and provide an \n excellent opportunity to discern actives from inactives by both their \n physiochemical and structural properties . \n they have an additional benefit of enabling prediction of additional \n sets of small molecules with a significant degree of accuracy . \n previously , we have reported the validation of support vector machine \n ( svm ) , recursive partitioning ( rp ) single tree , and rp forest models \n to compare with bayesian models of in vitro antitubercular \n efficacy with acceptable ( selectivity index > 10 ) vero cell cytotoxicity . these types of models ( bayesian , svm , and rp ) \n are commonly used for drug discovery applications in virtual screening \n and balance fitting the training set data with external predictive \n capability outside of the training set s chemical property \n space . \n such approaches have been described by us in some detail previously , and the machine learning with the mtb in vivo data \n paralleled our practices with previous mtb in vitro data sets . \n we utilized fcfp_6 fingerprints and the following set of readily interpretable molecular descriptors : \n alogp , molecular weight , number of h - bond \n donors , number of h - bond acceptors , number of rings , number of aromatic \n rings , number of rotatable bonds , and molecular fractional polar surface \n area ( fpsa ) . \n the bayesian model statistics for 773 molecules , generated \n by leaving out 50% of the data and rebuilding the model 100 times \n using a custom protocol for validation to produce the cross - validated \n receiver operator curve area under the curve ( xv roc auc ) , concordance , \n specificity , and sensitivity as described previously , are shown in table 2 . \n the leave - out 50% \n 100 external roc score was 0.72 , while the concordance ( 66.91 ) , specificity \n ( 74.23 ) , and sensitivity ( 58.46 ) suggested a bias toward predicting \n inactive compounds . \n the 773 molecule bayesian model provides almost \n identical roc auc values with leave - one - out ( 0.77 ) , leave - out 50% \n 100 ( 0.72 ) , and the five - fold cross validation ( 0.73 , tables 2 and 3 ) . with five - fold cross \n validation \n ( leave out 20% 5 ) , the concordance ( 79.0% ) , specificity \n ( 90.3% ) , and sensitivity ( 66.3% ) also suggested a bias toward predicting \n inactive compounds ( table 3 ) , although all \n the values are higher compared to leave out 50% 100 fold . \n this \n result highlights the importance of testing different hold out groups \n and illustrates the model stability based on these values . using the \n fcfp-6 descriptors , \n the top 20 substructure descriptors consistent \n with both activity and relative lack of cytotoxicity all are derived \n from the riminophenazine core ( figure s2 , supporting \n information ) , while features of inactives are derived from \n the thioester , 2,6-disubstituted phenol , and guanidine chemotypes \n ( figure s3 , supporting information ) . \n this \n result is not surprising given that clofazimine and all 10 of its \n analogs were active . \n if we removed these 11 compounds , the effect \n on the five - fold cross validation statistics was minimal ( figures \n s4 and s5,supporting information ) but the \n clofazamine - related active features were replaced with others , such \n as o , s - disubstituted carbonothioate , \n 2,3-dihydro-7h - oxazino[2,3,4-ij]quinolin-7-one , and features derived from the fluoroquinolones ( figures \n s4 and s5 , supporting information ) . \n all \n machine learning methods showed comparable roc auc values ( 0.710.77 ) \n using five - fold internal validation for the mouse in vivo \n mtb data set ( table 3 ) . \n the svm model \n has the best statistics based on the five - fold cross validation with \n a roc value of 0.77 . in summary \n , these results suggest that statistically \n valid computational models can be derived that could be used for predicting \n new molecules . \n bayesian five - fold cross validation \n has sensitivity = 66.3% , specificity = 90.3% , and concordance = 79.0% . \n a compilation of 3500 compounds tested against mtb in the 1950s was identified \n after the initial data compilation for the training set . within this \n data set , 11 compounds were tested and were all active in the mouse in vivo model . of these , only \n seven were not in the 773 compounds we compiled . \n together these 11 compounds not in our training \n set ( figure s6 , supporting information ) \n were scored with all the computational models developed . \n the bayesian \n model correctly predicted 8 out of 11 actives and outperformed the \n other models ( table 4 ) . the 177 mtb leads ( actives in vitro ) recently disclosed by \n gsk were scored \n with the machine learning models . \n when pca is performed on these compounds \n and the in vivo data training set , the gsk compounds \n appear to be relatively localized in just a part of the in \n vivo data set chemistry property space ( figure s7a , supporting information ) . \n the predicted human \n intestinal absorption using alogp and psa suggests that the in vivo data set is quite divergent ( figure s8a , supporting information ) , while the gsk compounds \n are tightly clustered in a more drug - like area of property space for \n these two descriptors ( figure s8b , supporting \n information ) . \n the bayesian , svm , rp forest , and rp single tree \n models classed 85 , 133 , 41 , and 85 compounds as active in \n vivo , respectively ( table s3 , supporting \n information ) . \n there were statistically significant differences \n between predicted active and inactive compounds when one looked at \n the fpsa and hydrogen bond acceptor counts , as these had lower mean \n values in predicted active compounds ( table s4 , supporting information ) . \n twenty - four predicted actives were \n common across all four models ( table s5 , supporting \n information ) . \n these 24 compounds were analyzed separately along \n with the in vivo tb data set and appear to reside \n well within the chemistry property space of the in vivo tb data set molecules ( figure s7b , supporting \n information ) . \n the putative targets for these compounds were \n also assessed using tb mobile and clustered \n with the tb mobile data set . \n this result highlighted several compounds \n as likely mycolic acid transporter ( mmpl3 ) and ubiquinol cytochrome \n c reductase ( qcrb ) inhibitors as well as one as a potential dihydrofolate \n reductase ( dhfr ) inhibitor ( table s5 , supporting \n information ) . \n the mean closest distance to the training set \n was 0.49 ( range 0.090.74 , where larger numbers are more dissimilar , \n and a value of zero represents the molecule is in the training set ) . \n we are aware of a single report of in vivo data for \n these compounds , which is an assay of gsk 1589673a . \n a recent review has described \n a timeline for the introduction of \n the antitubercular drugs . \n several of \n these date back to the 1940s and 1950s and span up to the late 1960s . \n only recently ( 2012 ) has a new drug , namely , bedaquiline , been approved . \n although there are several drugs in clinical trials , the pipeline \n is relatively thin for a disease where drug resistance has a significant \n impact and extensively drug resistant mtb is present \n in nearly 60 countries . \n the last 1015 \n years have witnessed an upswing in high - throughput screening in an \n attempt to identify molecules that modulate perceived essential targets or from phenotypic screening in whole cells . \n the result has been the discovery of about 2000 in vitro \n mtb hits and perhaps 100s of promising leads . \n the next hurdle \n is likely the selection of appropriate compounds to test in the mouse in vivo model of infection . \n the history of this model itself \n dates back to the 1940s , and even though it has limitations in extrapolating \n to humans , it is the only animal model \n that has been validated with human subjects in guiding tb drug development . \n the mouse represents an expensive medium - throughput \n model and a bottleneck in screening when used for rank - ordering compounds . \n on the basis of a recent literature analysis of publications over \n a 12-year period \n , there was a five - fold increase in use of the tb \n mouse model from 1997 to 2009 . \n our own \n analysis looks at a much longer time period , collecting data from \n over 70 years and illustrates that between 1970 to 2000 there was \n a gap in the publication of mouse in vivo data ( figure \n s1 , supporting information ) , with just \n 55 compounds retrieved in this period out of the total 773 . \n we see \n no change in this previously reported increased utilization of the \n mouse model based on the large number of papers describing in vivo data for approximately 200 compounds from the last \n four years ( table s1 , supporting information ) , and it is therefore imperative that we question the current workflow \n and ask how greater cost- and time - efficiencies can be achieved . \n while we need to better understand how in vitro efficacy , absorption , metabolism , distribution and excretion ( adme ) , \n and in vivo pharmacokinetic profiles are linked to in vivo antitubercular activity , we also need to computationally \n learn from the collective experiences of the considerable number of \n generally small molecules ( 773 in this study alone ) that have been \n tested in the mouse model . \n these data serve as the training set for \n an educated computational model to prioritize hits \n for in vivo testing , minimizing the assessment of \n compounds likely to fail . \n several computational models are available \n to predict in vitro adme properties in addition to \n other physicochemical properties . \n while we and others have utilized machine learning models to predict mtb activity in vitro , the studies to date \n have not analyzed mtb in vivo data in mice . however , \n mathematical modeling of pathogen and host interactions pertinent \n to latent infection have been reported . in total , our utilization of machine learning methods with mtb has covered external model validation , hit discovery , \n lead optimization , data set fusion , and now in vivo data analysis . \n one reason for this previous lack of modeling mtb in vivo is perhaps because the achievement of in vivo efficacy is multi - factorial due to complex interactions \n between mtb , host , and drug . \n additionally , the data \n to conduct this in vivo modeling exercise had not \n been previously curated until now . \n the curation of this in vivo data , as with all \n literature data capture , must be conducted with attention paid to \n structure deposition errors . \n for example , after testing in mice , it \n was suggested that 27753-rp was a highly promising antituberculosis \n drug . \n subsequently , in the absence of \n supportive data , it was stated that griselimycin(e ) while effective in vitro against mtb was inactive in vivo . \n we were unable to find any further information \n on these compounds in the literature beyond their structures . in the \n process , we noted that the griselimycin structure does not define \n all of the stereocenters . finding 27753-rp proved another challenge , \n as it was characterized by the wrong molecular formula c67h11n10o11 ( \n the very low number of \n hydrogens was noted as compared with griselimycin c57h96n10o12 ) . \n searching chemspider for c67h116n10o11 retrieved the \n compound as the synonyms list contained 27753r.p . . \n the additional periods in the compound name rendered it invisible \n to previous searches for the literature name of \n this compound \n may deserve further characterization because it was active against \n a rifampicin - resistant strain of mtb , and it raises \n the concern that other important molecules active against mtb may be hidden in publications and databases while being \n obscured by synonyms or frank errors . our retrospective analysis \n of the data for small molecules ( monotherapy \n only ) in mtb - infected mice has been critical to the \n realization of what physicochemical properties and chemical features \n best describe the actives ( figure s2 , supporting \n information ) as well as inactives ( figure s3 , supporting information ) . \n this analysis is important because \n many promising in vitro active compounds do not show in vivo activity . \n the ring count was significantly \n higher in in vivo active compounds , and the alogp \n and fractional polar surface area were lower than in inactives . \n intriguingly , \n our analysis of mtb in vitro hts results has shown \n actives to have a higher calculated logp than inactives . \n the curated in vivo data was also \n analyzed using multiple interpretable descriptors and machine learning \n models in this study . \n all four of the methods we have described resulted \n in similar receiver operator curve ( roc ) values ( 0.710.77 ) , \n indicative of potentially useful models . \n these models can score small \n molecules ( absent in the training set ) to prioritize antitubercular \n hits and leads for crucial in vivo studies . \n we evaluated \n the models with 11 known in vivo actives and found \n the bayesian model outperformed the svm and tree methods ( table 4 ) . \n the bayesian model \n correctly identified 8 out of 11 small molecules , absent from the \n training set , as in vivo actives . \n compounds like \n the recently published indoleamide 3 ( table 4 , figure s6 , supporting information ) may have been poorly predicted due to the absence of features such \n as the cyclooctyl ring in the training set molecules , and the most \n similar compound ( missing this feature ) was classed as inactive . \n this \n points to the need for a structurally diverse training set and understanding \n the threshold similarity distance for making a prediction . \n scoring of a set of 177 in vitro active compounds from gsk with the \n different machine learning models showed some variation in the number \n predicted as likely active in vivo . \n twenty - four compounds \n were predicted as consensus actives ( table s5 , supporting information ) . \n this result represents a potential \n data set for testing the in vivo model predictions . \n their further prioritization for in vivo study could \n also rely on predicted adme / tox profiles and mtb targets \n ( table s6 , supporting information ) . additionally , \n with the attainment of more extensive sar for these chemical series \n , \n one could apply the scaffold analysis approach illustrated herein \n for the triazines . \n we have described \n a data curation and machine learning process \n that could be further expanded to capture the remaining public \n mtb in vivo data that we have been unable to find to date . \n as older articles prior to 1970 may not have an abstract in pubmed , \n we also used scifinder and web of knowledge to expand our possible \n range of journals covered to extract as many molecules as possible . \n ultimately , training and test set molecules were extracted from 119 \n references ( table s1 , supporting information ) . \n another consideration when curating data from old papers is that \n there are few clearly drawn structures , and it can be a very complex \n and tedious process even for experienced medicinal chemists to definitively \n identify structures . \n for this reason , some structures and data were \n excluded because of this uncertainty or structural ambiguity . while prospectively testing the models would be preferred , the \n high cost of in vivo experiments ( currently $5000 \n per compound ) renders this practically difficult , and much of this \n testing \n traditionally , \n the use of computational machine learning models in other areas for \n which testing is relatively expensive ( e.g. , adme / tox models like \n herg requiring patch clamping data ) has involved prospective \n testing on a long time scale ( 10 years ) as more data is generated \n by different groups and as more higher throughput techniques are developed . \n this also enables iterative model building and updating to expand \n the chemistry property space covered , while also expanding the scope \n of algorithms tested and compared with each other . in conclusion \n , \n we suggest that the machine learning methods described \n here utilized for modeling mtb in vivo data could \n also be applied to other diseases for which similar information from \n a pertinent animal model is available . \n currently , to our knowledge , \n there are no databases that cover or curate in vivo animal model data , and other sources like pubchem focus almost exclusively \n on in vitro hts data . \n several limitations of the \n current study include poor extrapolation from mouse ( or other animal \n models ) to human due to likely adme differences . \n in addition , we have not yet pursued modeling combination therapies \n and potential synergies and antagonisms of experimental antituberculars \n with known drug treatments . we have also not removed prodrugs from \n our data set , and we have combined data from several dosing routes , \n both of which may add to the noise in the models . \n it is important \n to note that the four computational models do not per se replace in vivo studies but instead they may enable \n prioritization of molecules that are likely to perform well in vivo . \n this approach has obvious benefits for decreasing \n costs and reducing animal testing as \n well as continuing to enrich and accelerate the tuberculosis drug \n discovery process by learning from prior data . \n it may also be a useful \n approach for design of antituberculars or at the very least prioritizing \n compounds for host - derived therapeutics for tb . \n this work also calls for more sharing of data so that we \n can avoid repeating the discoveries and failures of the past in the \n future .", "role": "user" }, { "content": "selecting and translating in vitro leads for a \n disease into molecules with in vivo activity in an \n animal model of the disease is a challenge that takes considerable \n time and money . as an example \n , recent years have seen whole - cell phenotypic \n screens of millions of compounds yielding over 1500 inhibitors of mycobacterium tuberculosis ( mtb ) . \n these must be prioritized for testing in the mouse in vivo assay for mtb infection , a validated model utilized \n to select compounds for further testing . \n we demonstrate learning from in vivo active and inactive compounds using machine learning \n classification models ( bayesian , support vector machines , and recursive \n partitioning ) consisting of 773 compounds . \n the bayesian model predicted \n 8 out of 11 additional in vivo actives not included \n in the model as an external test set . \n curation of 70 years of mtb data can therefore provide statistically robust computational \n models to focus resources on in vivo active small \n molecule antituberculars . \n this highlights a cost - effective predictor \n for in vivo testing elsewhere in other diseases .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: pilsicainide is a pure sodium channel blocker with slow recovery kinetics , and it is known to be effective in converting recent - onset atrial fibrillation to sinus rhythm.1)2 ) on the other hand , high plasma concentrations of class ic antiarrhythmic drugs , including pilsicainide , have been known to induce life - threatening tachyarrhythmias , such as ventricular tachycardia , torsades de pointes ( tdp ) and ventricular fibrillation.3 ) we report a case of sudden cardiac death ; the patient received only three low oral doses of pilsicainide ( 100 mg / day ) to convert paroxysmal atrial fibrillation to sinus rhythm and developed tdp only two days later during holter electrocardiogram ( ecg ) monitoring . \n this case may present a concern about the proarrhythmic effects of an oral pilsicainide for treatment of atrial fibrillation in octogenarian patients . \n an 84-year - old male visited our hospital due to palpitations and shortness of breath that began two days previously . \n he underwent physical examination , 12-lead ecg , chest x - ray , and blood tests . \n the patient 's heart rate was 150 beats / min , and his blood pressure was 126/76 mm hg . \n an ecg examination showed atrial fibrillation , which was considered to be of recent onset ( within 48 hours ) . \n although ecg showed a tendency for poor progression of r in v 1 - 3 , the patient had no chest pain and no history of coronary artery disease . \n in addition , an echocardiography , which was performed in a private clinic two months before the patient visited our hospital , showed normal left ventricular wall motion ; during the past two months , there were no significant differences of st - t changes in ecg . \n routine laboratory tests revealed serum sodium of 142 meq / l , potassium of 4.8 meq / l ( no hypokalemia and hyperkalemia ) and creatinine of 1.0 mg / dl , which were indicative of mild renal dysfunction . \n thus , oral low - dose pilsicainide at 50 mg twice daily was prescribed to convert atrial fibrillation to a sinus rhythm , and a holter ecg was ordered in the outpatient clinic . in addition , he started anticoagulant treatment with warfarin but did not receive any other drugs , including any other antiarrhythmic drugs . \n one day after receiving an oral administration of pilsicainide , he visited our hospital again , and a holter monitor was fitted to evaluate the efficacy of pilsicainide and initiated at 13:30 in the afternoon . at this time , he felt no palpitations and showed a sinus rhythm with normal qt and qtc intervals ( 320 msec and 400 msec , respectively ) in the cm5 lead of the holter ecg ( fig . \n 1 ) . however , the patient died during his sleep 18 hours after the holter ecg was started . \n the analysis of the holter ecg recording revealed that the cause of sudden death was an episode of tdp ( fig . \n the holter ecg showed that the patient developed atrial fibrillation followed by repetitive non - sustained and sustained tdp ( figs . 2 and 3 ) . \n 4 , the qtc interval in the holter ecg showed gradual elongation from 13:30 at the start until 6:00 the next day . at 7:00 the next day , tdp was observed , and it continued for approximately one hour ; at 8:00 , cardiac arrest was detected in the holter ecg . \n the segments with excessive noise , ectopic activity and atrial fibrillation were excluded from the analysis . \n the qtc interval was clearly prolonged compared with that of initial holter ecg . at the same time \n , the width of the qrs complexes was slightly prolonged compared with that of the initial holter ecg . \n pilsicainide , one of the class ic antiarrhythmic drugs , is very popular in japan and is also available in korea for terminating paroxysmal atrial fibrillation partially due to the favorable effects reported in the pilsicainide suppression trial on atrial fibrillation clinical study.2 ) an increase in the rate of sudden death in patients taking a class ic drug after myocardial infarction was reported in the cardiac arrhythmia suppression trial study;4 ) however , it is unknown whether pilsicainide also increases the rate of sudden death for patients with atrial fibrillation . \n pilsicainide is rapidly absorbed from the gastrointestinal tract , and most of it is excreted from the kidney ; therefore , the half - life of elimination is prolonged in patients with severe renal failure . \n in fact , previous studies reported arrhythmic events in patients after taking pilsicainide , and almost all these patients had renal function failure . in our case , the level of serum creatinine was in the normal range , but the patient was 84 years old , and his body weight was 65 kg . \n thus , the estimated creatinine clearance was 46 ml / min , and the estimated glomerular filtration rate was 54.4 ml / min/1.73 m , which were considered to represent mild renal dysfunction even though the serum creatinine was 1.0 mg / dl . although the terminal electrical events leading to sudden cardiac death are rarely recorded on holter ecg monitoring , in this case the patient happened to be wearing the holter ecg by chance during the cardiac event . \n the holter ecg monitor revealed a gradually prolonged qtc interval just before tdp , which was considered to indicate an elevated plasma concentration of pilsicainide , although the actual level was not measured . \n while orally administered pilsicainide is an effective drug for terminating atrial fibrillation , the dose should be adjusted cautiously in octogenarian patients even if their serum creatinine levels are within normal ranges . \n in addition , when pilsicainide is prescribed for the octogenarian , the patient should be admitted to the hospital for monitoring .", "role": "user" }, { "content": "an 84-year - old male received oral pilsicainide , a pure sodium channel blocker with slow recovery kinetics , to convert his paroxysmal atrial fibrillation to a sinus rhythm ; the patient developed sudden cardiac death two days later . \n the holter electrocardiogram , which was worn by chance , revealed torsade de pointes with gradually prolonged qt intervals . \n this drug is rapidly absorbed from the gastrointestinal tract , and most of it is excreted from the kidney . although the patient 's renal function was not highly impaired and the dose of pilsicainide was low , the plasma concentration of pilsicainide may have been high , which can produce torsades de pointes in the octogenarian . although the oral administration of class ic drugs , including pilsicainide , is effective to terminate atrial fibrillation , careful consideration must be taken before giving these drugs to octogenarians .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: investment in technological innovation is a public policy priority in europe and in many other regions of the world . \n large amounts of public money are spent on new and emerging technologies and on their product applications in order to create jobs , prosperity and wealth . \n for instance , since 1984 more than 18 billion of the eu framework research budgets has been spent on developing information and communication technologies ( icts ) . \n and the european commission announced in 2013 that the two science project winners of the eu s future and emerging technologies competition , on mapping the intricacies of the human brain , and on exploring the carbon - based material graphene , will each receive up to 1 billion over the next decade.1 there are already thousands of promising and rapidly spreading yet novel commercialised products that are based on the emerging chemicals and nano , bio , and information and communication ( nbic ) technologies . \n however , while technological innovations can bring many benefits , they can also cause much human suffering , environmental degradation and economic costs . in 2001 , the european environment agency ( eea ) published their first of two reports on late lessons from early warnings : the precautionary principle 18962000 documenting numerous cases such as pcbs , sulfur dioxide , benzene , asbestos , tributyltin ( tbt ) , and the pharmaceutical agent diethylstilbestrol ( des ) where failure to apply the precautionary principle resulted in much harm and delayed innovation.2 in 2013 , the european environment agency ( eea ) published a second report \n late lessons from early warnings : precaution , science , precaution , innovation.3 which analysed a further 20 case studies focusing , as in volume i , on the growth of knowledge about their hazards and related actions or inactions by decision makers . the cases analysed included lead in petrol , bisphenol a , neonicotinoid insecticides , minamata disease and perchloroethylene ( pce ) contamination , as well as some emerging technologies including genetically modified crops , nanotechnology and mobile phones . \n the second report also covered cross - cutting issues such as the economic consequences of inaction ; why businesses ignored robust early warnings ; the precautionary principle ; false positives ; and science for precautionary decision making . \n the report showed that precautionary environmental health regulation does not hamper innovation and concluded that there is a need to reduce delays between early warnings and actions , to rethink and enrich environment and health research , to improve the quality of risk assessments , and to foster greater public participation in choosing innovation pathways . \n the histories of the now well - known technologies and chemicals in the late lessons reports showed that a lack of anticipatory research into the early warning signs of their hazards contributed to the failure to take timely actions to prevent or minimise the serious , widespread and continuing harm to the public and environments caused by these technologies and products . \n late lessons specifically addressed the issue of anticipatory research by calling for adequate research into knowledge gaps and early warnings ; for more long - term monitoring ; and for the promotion of robust , diverse and adaptable technologies that would help to minimise the costs of surprises and maximise the benefits of innovation.2 is there evidence that these lessons have been reflected in choices about the nature and extent of anticipatory research into the potential environmental , health and safety ( ehs ) hazards of emerging chemicals and nbic technologies ? in preparation for volume 2 of late lessons two kinds of analyses were carried out in order to help answer this question . \n the first focused on the share of research between the historical and emerging chemicals that are , or have been , the basis for many consumer products . \n the second looked at the share of european funded research on developing new technologies and on anticipating their potential hazards . \n in an analysis of 78 environmental and health journals , grandjean4 revealed that since 2000 most research has focused on chemicals whose first early warnings about their hazards were identified some 20100 years ago , such as those reviewed in the first volume of \n late lessons from early warnings , namely polychlorinated biphenyl ( pcbs ) , sulfur dioxide , benzene , asbestos , tbt , methyl tert - butyl ether ( mbte ) and the pharmaceutical agent des.2 of the nearly 15 000 articles published on these substances since 1899 , grandjean et al found that some 40% had been published since 2000 . \n for other well established toxicants such as lead , mercury and dichlorodiphenyltrichloroethane ( ddt ) which were reviewed in the second volume of late lessons from early warnings , a similar pattern emerged : there were 15 000 articles published between 2000 and 2009 on lead , mercury and ddt alone . meanwhile , \n research on eight of the emerging , large production chemicals identified as priorities by the us environmental protection agency ( us epa),5 such as 1,3-dichlorobenzene , featured in only 352 of all the articles published in the 78 environment and health journals over the same period : five other chemicals on the us epa priority list did not feature in any of the articles . \n a similar picture emerged when the article analysis was extended to 2011.6 of course new scientific insights can emerge from more research into even well - known chemicals . \n we are not therefore suggesting the cessation of further research on relatively well - known chemicals but just a rebalancing of total research effort towards emerging priority chemicals . \n the focus of research on well - known rather than emerging priority chemicals , which grandjean calls \n scientific inertia , seems to be due to a number of factors : the traditional scientific requirement for high levels of proof via well - replicated studies ; the influence of senior academics who favour the chemicals they know most about ; the need to use costly laboratory infrastructure designed mainly for the \n old chemicals which can be most easily analysed ; the need to publish quickly ; and the conservative nature of many reviewers and research funders who are more likely to see results on time from studies of well - known chemicals than from the riskier proposals to study the less known.4 in addition , a history of corporate pushback against literature exposing risks associated with their products has also been well - documented , which might also add to scientific inertia.2 \n 3 scientific inertia increases the chance of hazards from new chemical products emerging as surprises. it also tends to stifle scientific innovation in those disciplines needed to identify emerging hazards such as epidemiology , exposure assessment , toxicology , endocrinology and development biology . \n we know from the well - known hazards , for example , benzene , asbestos , x - rays , lead , mercury , tobacco , vinyl chloride and des , that many of the early warnings were generated , strengthened , and then confirmed by epidemiological research . more research into the hazards of emerging chemicals and their less intrinsically hazardous alternatives , as well as more long - term health monitoring of consumers and environments , would encourage the use and development of scientific innovations in fields such as analytical and green chemistry , biomonitoring and epigenetics . \n of course long - term epidemiological monitoring of chemicals can not be very anticipatory compared with the much less time needed to get results from animal and other laboratory experiments . \n this is why public health needs to be protected by causal inferences based mainly on good laboratory evidence . \n this view is supported by the approach used by the international agency for research on cancer ( iarc ) for attributing carcinogenicity . \n the value of animal testing in predicting carcinogenicity is discussed by huff in the late lessons chapter on vinyl chloride.3 \n figures on the public funding of research on new technologies and on their potential hazards can be derived from the european commission reports on its framework programmes ( fps ) for research and technological development ( rtd ) . \n there have been seven fps spanning the last 20 years and in many cases , various commission reports have accessed the ehs - component of the funded research grants and projects in one manner or another . often , the ehs - component is unspecified and although we acknowledge that what defines as ehs - research can vary and that not all research grants and project might fall neatly into one category or the other , we rely on the european commission self - classification of ehs - research in this paper . for the fp46 , between 1996 and 2006 , \n the ehs - research corresponded to a mere 0.6% of the total rtd budget ( see table 1a ) . \n the latest fp7 programme , which ran from 2007 to 2013 , continues this focus on research and technological development rather than on anticipating and minimising potential hazards . \n for example , during the first three fp7 calls for proposals some 79 funded projects had an ( unspecified ) ehs component according to the european commission totalling 265 million.7 in comparison , the total budget of fp7 is more than 50 billion8 which gives a rtd / ehs - research ratio of 200 to 1 as just 0.5% of the total rtd budget went to ehs research . \n eu funding of rtd and ehs - research in nbic technologies and overall under the fp17 sum of the fp5 projects cemfec , guard , interphone , ramp 2001 and perform a. ehs , environmental , health and safety ; emf , electromagnetic field ; fp , framework programmes ; nbic , nano , bio , and information and communication ; rtd , research and technological development . \n when it comes to nbic technologies specifically , the ehs - research proportion is a little higher , although information is not available for all the fps . during fp7 , \n 3.5 billion has been provided for nanosciences , nanotechnologies , materials and new production technologies.8 in comparison , 25 projects have been given 82 million by 2011 to study the health and environmental impact of nanomaterials , which corresponds to 2.3%.13 these absolute amounts were more than twice the total spent on nanotechnology under fp6,10 \n 12 \n 13 but the rtd / ehs ratio was similar corresponding to 2.1% . on biotechnology , \n only one ehs - research relevant project has been funded on genetically modified organisms ( gmsafood worth 2.6 million ) after the first three calls of fp7.7 in contrast , 1.935 billion have been set aside under the theme food , agriculture and biotechnology in fp7,8 which yields a rtd / ehs - research ratio of about a 1000 : 1 . under fp6 , \n life sciences , genomics and biotechnology for health.17 in contrast , only some 200 million was spent on ehs - research,18 which corresponds to 8% for the total rtd budget of this theme . under fp5 and \n fp4 the themes on quality of life and management of living resources and on the \n biotechnology programme , received some 3 billion.14 \n 15 of which only some 70 million was spent on ehs research,16 corresponding to 2.3% . \n the total funding under fp17 came to 7.5 billion of which the ehs component came to 273 million , corresponding to 4% ( see table 1c ) . \n the rtd / ehs - research ratio for ict is much smaller than even the modest ratios for nano and biotechnologies . \n the fp7 programme provided 8.9 million for ehs projects during the first three calls for proposals7 compared with 9.1 billion that has been earmarked for ict,8 yielding a rtd / ehs - research ratio of about 1000 to 1 . under \n fp6 nothing seems to have been allocated to ehs - research on ict,21 but 8.8 million was spent on ehs under fp15.19 \n 20 in total the ehs research budget related to ict was a mere 0.09% of the budget that went into rtd of ict under fp17 ( see table 1d ) . \n the potential hazards of ict seem intrinsically less than for nano and biotechnologies and this may justify the much lower rtd / ehs - research ratio . however , the classification of the non - ionising radiations from mobile phones as a 2b ( possible ) carcinogen by the iarc in 2011 is a cause for serious concern that should generate follow - up research.22 the iarc classification has been controversial partly because it was based on just two large epidemiological studies which indicated possible brain cancer risks , according to most experts at the iarc meeting.23 \n 24 a lack of relevant animal data and divergent interpretations of the epidemiological data provide much scope for further research . \n the overall european public funding of research into the potential hazards of the nbic technologies during the fp17 programmes yields a rtd / ehs ratio of about 100 to 1.3 ( some 402 million compared with some 31 billion : see table 1 ) . \n the low rtd / ehs - research ratio on the european level may be offset by higher rtd / ehs - research ratios in the eu member states , but these figures are not readily available \n . however , it has been noted that between 2004 and 2009 some 220 million was spent on applications of nanotechnologies by the uk engineering and physical sciences research council compared with less than 20 million on the potential ehs hazards from nanotechnology by the medical research council and other government funded bodies.25 in contrast , the netherlands apparently has a public rtd / ehs - research ratio for nanotechnology of 85/15 ( personal communication ) . \n given the human suffering , environmental degradation and economic costs that have been associated with past wonder technologies , the question is how the overall rtd / ehs ratios that we have identified have come about and why are they so low ? are they \n the result of informed deliberation by research funders , or are they emergent properties of a complex and decentralised system of funding which nobody chooses and for which , therefore nobody is responsible ? could there be collective hubris about the low likelihood of potential harm from \n willful blindness which seems to be a common feature of life?26 the historical case studies in the \n late lessons reports provide many examples of authoritative but unsubstantiated assertions of safety about the then emerging technologies which helped justify very little research into potential hazards . \n for example , an expert asbestos witness told the uk parliamentary inquiry on asbestos in 1906 that one hears , generally speaking , that considerable trouble is now taken to prevent the inhalation of the dust so that the disease is not so likely to occur as heretofore27 and the general motors \n inventor of leaded petrol told the us surgeon general in 1925 that the average street will be so free from lead that it will be impossible to detect it or its absorption even though no actual experimental data has been taken.28 such largely unsubstantiated assertions of safety are to be found in current discussions about the nbic technologies as well . \n for example , it is sometimes asserted that there are no long - term health hazards from genetically modified crop in food despite the virtual absence of full - term animal studies to demonstrate this ; that there are no brain cancer hazards to children from mobile phones despite there being virtually no long - term studies in children covering the relevant latent period for brain cancers ; and that there are no chronic hazards from nanoparticles even though there are virtually no studies to demonstrate long - term safety . \n these assertions are based on the mistaken assumption that no evidence of harm is the same as evidence of no harm. low public rtd / ehs funding ratios could also be due to an aversion against looking for risks that could be \n inconvenient to find ; and a tendency to leave it to promoters and developers of a given technology to complete the ehs research which can \n for example , the leaded petrol industry controlled virtually all of the rather meagre ehs research into leaded petrol hazards from the 1920s to the 1960s28 ; and the six largest breeding and genetic engineering companies in the food sector control a research budget that is over eight times larger than that of the consultative group on international agricultural research , the world 's largest public sector agricultural food body.29 it is not known how much of this agricultural research by companies is spent on the potential ehs hazards of their biotechnologies . \n the technology companies contribution to ehs research on nanotechnology and ict is also difficult to identify . in 2010 , \n a uk house of lords report criticised the food industry for failing to be transparent about its research into the uses of nanotechnology and nanomaterials.25 it would be helpful if this information were to be disclosed for the food industries and for other industries as well . if history repeats itself the technology company expenditure on ehs research is likely to be low in comparison with their total rtd research budget . \n there is little incentive for companies to do research on the potential hazards of their own products , unless mandated by law , because most health and environmental harm from commercial technology and products is externalised onto societies and their taxpayers.30 \n 31 as a consequence there have been some proposals to incentivise technology producers to conduct more anticipatory ehs research , such as product taxes , for example on mobile phones , with the revenue being spent on ehs research24 ; and anticipatory assurance bonds that would be posted by large - scale novel technology producers which would eventually be returned to them , with interest , if potential hazards do not materialise.32 ehs research by technology producers also needs to overcome the funding bias and commercial pressures to downplay hazards , which have been extensively reported in the past.3335 it would therefore seem prudent to insulate company ehs - research from commercial pressures by erecting administrative barriers between their funding and its use by independent scientists , while balancing commercial secrecy with access to research materials and regulatory test data , as with genetically modified organisms ( gmos ) . for example \n , 24 leading corn insect scientists wrote to the us epa concerning the way gmo technology agreements explicitly prohibit research36 ( in order to access monsanto test data on the safety of a gm product , submitted to the european food safety agency , independent scientists had to use the german courts to access and verify the data37 ) and independent epidemiological research into mobile phones was delayed in the usa by legal action.38 meanwhile , as the public funding of rtd , including ehs research , is a subsidy to the private sector it may need to be repaid to taxpayers by appropriate royalty payments.39 \n what would be a prudent rtd / ehs - research ratio in light of the histories of asbestos , mercury , leaded petrol and other hazards analysed by the eea in \n ideally we should be able to identify comparable rtd / ehs - research ratios for historical technologies but we are not aware of such figures for the cases covered in the eea late lessons reports . \n however , it is clear from the historical narratives in the eea chapters that very little research was devoted to identifying hazards of , for example , asbestos , mercury , leaded petrol , dibromochloropropane ( dbcp ) , and x - rays at the time when such research would have been useful in minimising their future hazards . \n we have seen from the grandjean analysis that most of the ehs research into even the most well - established hazardous chemicals was conducted in the last 1015 years , which was many decades after their widespread use in consumer products began . despite some early warnings from epidemiological research about , for example , benzene in 1897,40 asbestos in 190641 and leaded petrol in 1926,28 \n it is reasonable to conclude from the historical technologies and products analysed by the eea that there was very little anticipatory research into their potential hazards and that the ehs - research remained very small until well after the hazards were manifest . \n the harmful consequences of ehs research , that was too little and too late has been extensive . \n the epidemiological and other research into well - known hazards that was eventually carried out has demonstrated that the nature and extent of harm expanded well beyond the hazards that were first identified . \n for example , asbestos has been found to cause an increasing range of diseases , with the main ones being asbestosis in 1929 , lung cancer in 1955 and mesothelioma in 1960 . \n these diseases have been found in an increasing variety of exposed groups , such as asbestos producers and users ; bystanders to users ; building occupants , families of asbestos workers , and neighbours , teachers , etc , and such diseases have also been shown to be capable of being caused by lower levels of exposure . \n a similar picture of expanding harm among an increasing variety of exposure groups caused by lower exposure levels than was previously thought possible has been eventually uncovered by research on lead , tobacco , pcbs , des , etc.2 \n 3 the health impacts on victims are incalculable but the financial costs to societies are also large . \n andersen and club30 have estimated that leaded petrol alone has caused losses of 46% of gross domestic product ( gdp ) in lost productivity from reduced iq . \n other harmful consequences of inaction on early warnings include damage to the commercial longevity of the products ; inequitable sharing of the costs of harm between the risk creators , risk victims and risk bearers ; skewed and information - poor impact assessments and cost / benefit analyses ; delays in the production of scientific knowledge and insights into the biological and ecological effects of the technologies ; delays in the creation of technological and benign by design innovations ; increased public distrust of industries and regulators who failed to anticipate hazards ; and increased regulatory and public pressure to regulate on the basis of hazard , and not risk , particularly when there is an absence of information about relevant exposures . \n identification of the prudent rtd / ehs - research ratio is not possible and any suggested ratio will inevitably seem somewhat arbitrary , but in order to avoid the costly consequences of inadequate anticipatory ehs research , we suggest that a prudent rtd / ehs ratio for nbic technologies would lie somewhere between 5% and 15% . \n the exact ratio depends on the intrinsic hazard potential , plausible exposure scenarios , and their novelty , persistence , bioaccumulation potential and spatial range . \n these are some of the features of emerging technologies that have been identified by the eea as justifying precautionary actions , including adequate anticipatory research.42 such research would also be part of \n responsible innovation , an idea that is gaining currency.43 there is evidence that there are sufficient knowledge gaps , uncertainties and areas of scientific ignorance in the nbic technologies that would justify such a substantial increase in ehs funding . \n for example , a recent report from who on nanomaterials notes that there are large knowledge gaps about potentially hazardous properties ; biological and ecological exposures ; and about biological and ecological fates and impacts of such exposures . \n it also notes deficiencies in current analytical techniques and monitoring methods for early warnings.44 similarly , the european commission 's scientific committee on newly identified health risks has regularly identified large knowledge gaps in its reports on radiofrequency ( rf ) from mobile phones.45 for example , research with some frequencies or modulations is very limited , and this is , particularly true regarding new and emerging technologies ; a number of areas were identified where the information regarding health effects is either absent or insufficient , or is too discordant to allow science - based assessment of the possibility of health effects ; a cohort or register - based case control study on magnetic field exposure and alzheimer 's disease incidence or mortality is recommended as a high priority ; and further studies of the effects of rf fields associated with mobile phone use and brain tumours in children are recommended as a high priority . \n there are also large gaps in knowledge and understanding as well as considerable areas of scientific ignorance about gmos in food . \n there is also a lack of research into such alternatives to gmos as agroecological farming methods which address soil and water quality as well as food productivity . \n this has been noted by the eu standing committee on agricultural research , which recently concluded that low input , high output systems that use nature 's capacities , should receive the highest priorities for funding.46 there are other complementary issues that increased ehs research could illuminate . \n these include analyses of the social needs that new technologies are intended to address47 ; alternative ways of meeting these needs ; the distribution of risks and benefits from new technologies across social groups and generations ; methods for enhanced public participation in helping to shape the strategic innovation pathways to , for example , sustainable food and energy production and the research agendas needed to adequately support such innovations.3 \n 48 \n 49 the sustainability challenges facing europe and other resource and energy intensive economies are considerable as big business , the organisation for economic co - operation and development ( oecd ) , and high - level advisory groups have illustrated.5053 meeting these challenges will need many innovative and sustainable technologies and products but without adequate and anticipatory research into their potential hazards , it is likely that much unforeseen and surprising harm and costs will accompany such innovations .", "role": "user" }, { "content": "history confirms that while technological innovations can bring many benefits , they can also cause much human suffering , environmental degradation and economic costs . but are we repeating history with new and emerging chemical and technological products ? in preparation for volume 2 of \n late lessons from early warnings ( european environment agency , 2013 ) , two analyses were carried out to help answer this question . a bibliometric analysis of research articles in 78 environmental , health and safety ( ehs ) journals revealed that most focused on well - known rather than on newly emerging chemicals . \n we suggest that this scientific inertia is due to the scientific requirement for high levels of proof via well replicated studies ; the need to publish quickly ; the use of existing intellectual and technological resources ; and the conservative approach of many reviewers and research funders . the second analysis found that since 1996 the funding of ehs research represented just 0.6% of the overall funding of research and technological development ( rtd ) . compared with rtd funding , ehs research funding for information and communication technologies , nanotechnology and biotechnology was 0.09% , 2.3% and 4% of total research , respectively . \n the low ehs research ratio seems to be an unintended consequence of disparate funding decisions ; technological optimism ; a priori assertions of safety ; collective hubris ; and myopia . in light of the history of past technological risks , where ehs research was too little and too late , we suggest that it would be prudent to devote some 515% of rtd on ehs research to anticipate and minimise potential hazards while maximising the commercial longevity of emerging technologies .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: boronic acids and boronic esters(1 ) are particularly important classes of compounds that have a wide range of uses and applications . \n for example , they are used in catalytic additions to ketones,(2 ) asymmetric conjugate additions,(3 ) enzyme inhibition , potent and selective serine protease inhibition , suzuki coupling reactions in organic synthesis , materials synthesis , and neutron capture therapy treatments for cancer patients . \n given the broad utility of boronic acids and esters , an understanding of the structural and electronic properties of these compounds is important . \n boron has two quadrupolar nmr - active isotopes , b ( i = 3 ; n.a . \n = 19.9% ; 10.744% ) and b ( i = 3/2 ; n.a . \n = 80.1% ; 32.084%).(24 ) both of these nuclides have small to moderate nuclear electric quadrupole moments , q ( q(b ) = 84.59 mb ; q(b ) = 40.59 mb).(25 ) the b nucleus is more receptive to nmr studies due to its higher natural abundance , smaller quadrupole moment , and availability of a central transition ( ct ) ( i.e. , mi = + 1/2 1/2 ) . \n when nmr experiments are conducted on solutions , rapid tumbling of the solute molecules leads to an averaging of molecular orientations . in many cases , \n this leads to sharp peaks , and isotropic chemical shift data may be obtained since the motion of the solute molecules is isotropic over the time scale of the nmr experiment . \n it is well - known that such nmr experiments can be applied to help elucidate and assign the structure of the compound being studied , provide data about the chemical environment of the nucleus being studied , provide information about dynamics such as reaction rates , or simply monitor a reaction in progress from initiation to completion . \n comprehensive b nmr studies have been conducted on boron compounds in solution and many isotropic chemical shifts ( iso ) have been recorded . \n the known boron chemical shift range for tricoordinate and tetracoordinate species covers approximately 210 ppm , with tetracoordinate species falling between iso = 20 and 120 ppm and tricoordinate species falling between iso = 90 and 20 ppm with respect to f3bo(c2h5)2 at 0 ppm . \n boronic acids and esters have chemical shifts in solution ranging from about 18 to 31 ppm.(26 ) the chemical shifts for b have been shown to correlate with the ligand electron - donating ability.(26 ) thus , the interpretation of b chemical shifts may provide insight into bonding . for tricoordinate boron compounds of the series br3 , bxr2 , bx2r , and bx3 ( x = electron - withdrawing ligand ; r = alkyl group ) , \n as one progresses from br3 to bx3 , the b isotropic chemical shifts decrease systematically , which has been interpreted as being associated with increased -electron backbonding from x to b.(26 ) in addition , a sterically congested environment tends to cause decreased -bonding ; hence , a positive shift may be observed with increasing steric bulk about the boron.(26 ) in powdered samples , the lack of rapid molecular tumbling corresponds to a static distribution of crystallite , and hence molecular , orientations . \n this leads to broadening of the nmr line shape . for b , solid - state nmr ( ssnmr ) spectra can provide information about both the quadrupolar interaction between the nucleus and the electric field gradient ( efg ) , as well as chemical shift anisotropy ( csa ) , \n an advantage of ssnmr experiments using quadrupolar nuclei is that additional parameters that reflect the orientation - dependence of the nmr interactions are available to describe the local geometry and bonding environment . \n we report the experimental characterization and interpretation of boron chemical shift ( cs ) and efg tensors in a series of solid boronic acids and esters ( figure 1 ) . \n boron-11 ssnmr experiments were performed under stationary and magic - angle spinning ( mas ) conditions at magnetic field strengths ( b0 ) of 9.40 and 21.1 t. at 21.1 t , the influence of the cs tensor on the observed ssnmr line shapes becomes extremely important as its line shape contribution ( in hz ) is proportional to b0 . \n in addition to improving sensitivity , ultrahigh - field ( > 18.8 t ) nmr spectrometers should therefore provide more precise measurements of the influence of the cs tensor on ssnmr spectra . in the case of quadrupolar nuclei , such as b , \n a high magnetic field usually produces narrower ct line shapes since the central transition signal broadening associated with the second - order quadrupolar coupling scales inversely with magnetic field . \n structures of the boronic acids ( 15 ) and boronic esters ( 610 ) used in this study . \n we also report on molecular orbital ( mo ) analyses performed to provide insight into the relationship between the molecular and electronic structure around the boron nucleus and the b nmr parameters . \n csa is often rationalized by considering contributions to the paramagnetic shielding term , as outlined in ramsey s theory of nuclear magnetic shielding . \n this theory posits that the nuclear magnetic shielding tensor can be broken down into two terms , a diamagnetic term ( dia ) and a paramagnetic term ( para ) . \n the theory may be applied in explaining the effects of orbital - mixing - induced paramagnetic shielding on csa . \n interpretation of experimental data alongside quantum chemical calculations has the potential to provide important information relating nmr parameters and molecular and electronic environments about the boron nucleus . \n the b ssnmr spectra presented here are affected by nuclear magnetic shielding ( ) and the quadrupolar interaction between q and the efg at the nucleus . \n the hamiltonian operator for b in a magnetic field may be expressed as : \n\n where the first term represents the zeeman interaction , the second represents the quadrupolar interaction , and the third represents the magnetic shielding interaction . \n magnetic shielding may be generally represented by a second - rank tensor , . diagonalization of the symmetric portion of yields the orientation of its principal axis system ( pas ) relative to an external axis system . in its pas , the three principal components ( i.e. , the diagonal matrix elements ) of the symmetric are ordered as follows : 11 22 33 . \n the experimentally observed iso may be defined in terms of magnetic shielding if a suitable shielding reference exists : \n\n where ii = 11 , 22 , 33 , iso . \n the three principal components of the cs tensor are ordered as follows : 11 22 33 . for both the and cs tensors , \n , the maryland convention will be used for reporting the and cs tensor parameters.(31 ) the span ( ) is defined as:(31 ) the skew ( ) is defined as:(31 ) as with the shielding and shift tensors , the efg tensor may be diagonalized to provide the principal elements of the tensor and the orientation of the pas . \n the principal components of the efg tensor are defined as follows : |v33| |v22| |v11| . the quadrupolar coupling constant ( cq ) \n may be expressed as : \n\n where e is the fundamental charge and h is planck s constant . \n the asymmetry parameter of the efg tensor is defined as : \n it is useful to discuss the breadth of the ct powder pattern due to second - order quadrupolar interactions , for a stationary sample , ignoring csa for the moment:(32 ) \n the breadth of the ct ( ct ) is inversely proportional to the larmor frequency ( l ) of the nucleus being studied . since l is directly proportional to b0 , this implies that ct is inversely proportional to b0 . \n the use of a larger b0 therefore results in a decrease in second - order quadrupolar broadening of the central transition in frequency units . boron-11 \n the paramagnetic shielding term may be defined as : \n\n where the terms in the numerator represent the degree of orbital mixing between the occupied and virtual orbitals contributing to a particular shielding component ( and are permuted over x , y , z ) , and the term in the denominator represents the energy gap between the two wave functions involved in the mixing . \n the five boronic acids [ 2-(tert - butyldimethylsilyloxy)naphthalene-6-boronic acid ( 1 ) , 2,6-dibromophenylboronic acid ( 2 ) , 2-chloropyridine-3-boronic acid ( 3 ) , 2-(hydroxymethyl)phenylboronic acid cyclic monoester ( 4 ) , and 2-acetyl-3-thiopheneboronic acid ( 5 ) ] , and five boronic esters [ 4-fluorophenylboronic acid neopentylglycol ester ( 6 ) , 4-nitrophenylboronic acid pinacol ester ( 7 ) , 1h - indazole-5-boronic acid pinacol ester ( 8) , 4-(2-propynylcarbamoyl)phenylboronic acid pinacol ester ( 9 ) , and 2,4,6-trimethoxyphenylboronic acid neopentyl glycol ester ( 10 ) ] in this study ( figure 1 ) were purchased from aldrich and were used without further purification . \n samples were powdered and packed in a glovebox under an inert atmosphere of nitrogen into 4 mm o.d . \n zro2 rotors , and nmr experiments were conducted using a bruker avanceiii nmr spectrometer ( b0 = 9.40 t , l(b ) = 128.38 mhz ) . \n a bruker 4.0 mm hxy triple - resonance mas probe tuned to b on the x channel was used . \n solid nabh4 has a chemical shift of 42.06 ppm relative to the primary standard , liquid f3bo(c2h5)2 ( where (b ) = 0.00 ppm).(33 ) for both mas and stationary samples , the hahn echo ( /2 1 \n typical /2 pulse lengths for solid nabh4 were 3.0 s . for the 10 samples under study , the \n pulse was used ( e.g. , 3.0 s/(i + 1/2 ) = 1.5 s , where i = 3/2 for b ) . \n signal averaging was carried out over a period of 4 min to 4 h for both static and mas samples . \n qcpmg experiments ( /2 1 2 acq( ) [ 3 4 acq(2)]n)(36 ) were also performed , where the number of full echoes acquired ( n ) depended on the transverse ( spinspin ) relaxation time constant t2 . in most cases , 96 full echoes were acquired . the value of 2 was varied from 450950 s , depending on the desired spikelet separation in the frequency domain , cpmg . \n modified qcpmg experiments were conducted , where the pulse in the echo train was replaced with a /2 pulse.(37 ) double - frequency sweep ( dfs ) shaped pulses were also used in conjunction with hahn echo and qcpmg experiments to enhance the ct signal intensity . \n the probes used at both fields exhibit a small , but manageable background b signal in the acquired spectra , as a result of boron nitride in the stators . \n the hahn echo pulse sequence was generally found to be effective at suppressing the background signal . \n samples were powdered and packed in a glovebox under a dry argon atmosphere into 2.5 mm o.d . \n zro2 rotors , and nmr experiments were conducted using a bruker avanceii nmr spectrometer ( b0 = 21.1 t , l(b ) = 288.80 mhz ) . \n spectra were acquired using topspin 1.3 software at the national ultrahigh - field nmr facility for solids in ottawa ( www.nmr900.ca ) . \n a bruker 2.5 mm hx mas vt probe tuned to b on the x channel was used . \n the referencing , calibration , and setup procedures were identical , and the pulse sequences , pulse widths , pulse delays , and experiment times were similar to those used at 9.40 t. the mas speed was 30 khz . \n all mas samples were cooled to room temperature using a vt unit to prevent sample decomposition caused by heat production at fast spinning speeds . \n fids were left - shifted to the echo maxima when necessary , apodized using a gaussian function of 525 hz for mas samples and 20200 hz for stationary samples , then fourier transformed . \n stack plots were produced with dmfit.(40 ) spectral simulations were performed using the wsolids1 program(41 ) which incorporates the space - tiling algorithm of alderman et al.(42 ) the error associated with spectral parameters was determined heuristically by analyzing the spectra ( mas and static echo , but not qcpmg ) obtained at both magnetic fields . in simulations , each nmr parameter was varied individually from the optimum value until a noticeable discrepancy with the experimental spectrum was observed . \n of the compounds studied , an x - ray crystal structure is available for compound 4(43 ) only ; this structure indicates a single crystallographically unique boron site . \n nmr spectra acquired presently strongly suggest that there is a single unique boron site for all other compounds studied as well . \n as such , all spectra were simulated using a single boron site for each compound . in some cases , boric acid or other decomposition products were included in simulations as an additional boron site . a model for each compound \n these structures were then subjected to geometry optimization using the b3lyp hybrid dft functional ( b3lyp)(44 ) and the 6 - 311+g * basis set for all atoms , while keeping the coordinates of the carbon and hydrogen atoms in the aromatic ring system frozen so as to not perturb the planarity of the aromatic system and to assist in convergence . on the resulting optimized structure , b3lyp \n was then used to perform an unrestrained second geometry optimization using the 6 - 311+g * basis set . \n dihedral angles ( ccbo ) of interest were altered simply by defining a new ccbo in gaussview for the optimized structure . \n although the crystal structure for phenylboronic acid has been reported,(45 ) geometry optimizations were performed in order to systematically vary ccbo . \n these computations were performed to isolate the impact of varying ccbo on the boron magnetic shielding tensor . \n efg and tensors were calculated using gaussian 03(46 ) running on an in - house 304 cpu system , and the amsterdam density functional package(47 ) ( adf ) running on the high performance computing virtual laboratory ( www.hpcvl.org ) cluster . \n dft calculations employing b3lyp(44 ) used the 6 - 311+g * basis set on all atoms . \n restricted hartreefock ( rhf ) calculations were also carried out using the same basis set . \n finally , magnetic shielding , efg , and mo analysis calculations using adf and employing the gga - revpbe dft method ( gga - revpbe ) were carried out using the tzp basis set on all atoms . \n boron-11 quadrupolar coupling constants were calculated from the largest principal component of the efg tensor , v33 , using eq 5 . \n calculated nmr parameters were parsed using efgshield.(48 ) the factor 9.7177 10 v m per atomic unit is used to convert v33 from atomic units to v m.(49 ) \n shown in table 1 are the boron efg and cs tensor values obtained via analytical simulations of the b nmr spectra of boronic acids and esters 110 . by simultaneously fitting data at both 9.40 and 21.1 t , the cq , q , and iso values were determined from mas nmr spectra . \n subsequently , stationary spectra were analyzed to determine the , , and euler angles relating the two tensor pass ( see figures 29 , s3 and s4 ) . \n experimental cq , q , iso , , , and euler angles for each boronic acid and ester compound studied . \n boric acid is included as the impurity present at 19.6 ppm in compounds 2 and 3 . \n the nmr parameters were included in the simulations of compounds 2 and 3 using 4 and 10% intensity relative to the main signal , respectively . a small range in cq(b ) \n is observed ( i.e. , from 2.66 mhz for compound 9 to 3.29 mhz for compound 1 ) . in general , the cq(b ) values for the boronic acids tend to be slightly larger than for the esters ; however , there is clearly overlap in the ranges for each class of compound ( see figure s2 ) . \n there is very little variation in the measured iso(b ) , which ranges from 26.0 ppm ( compound 5 ) to 31.0 ppm ( compound 4 ) , that is , only about 5% of the total known range for tricoordinate boron . \n because this range is so small , it is difficult to conclusively relate iso(b ) to any single structural or electronic feature , although there is a good correlation between the experimental isotropic chemical shift values and the calculated isotropic magnetic shielding values ( vide infra ) . in general , the directions of the eigenvectors corresponding to v33 and 33 are coincident within experimental error , as quantified by the euler angle . overall , we find that the span is the most sensitive nmr parameter to changes in the molecular and electronic structure from compound to compound , ranging from 10 ppm ( compound 9 ) to 40 ppm ( compound 2 ) ; that is , the variation in ( 30 ppm ) represents 75% of the maximum span value ( 40 ppm ) observed . \n because the span has the largest relative variation among the nmr parameters , it is our primary focus and its relationship with the local boron electronic and molecular structure is discussed in a subsequent section . shown in figure 2 are b ssnmr spectra of boronic ester 8 obtained at 9.40 and 21.1 t. as a representative example , we discuss in some detail these spectra and the extracted parameters . \n the cq(b ) value obtained for 8 is 2.76 0.20 mhz and q = 0.59 0.10 . \n csa is present and broadening is therefore observed in the spectrum due to both the quadrupolar interaction as well as csa ( = 14 2 ppm ) . \n the isotropic chemical shift of 30.3 1.0 ppm falls within the expected range for a boronic ester.(26 ) for the data obtained at both magnetic fields , simulated spectra fit very well with the experimental data ; hence , there are small experimental error values associated with the reported data ( table 1 ) . \n the b nmr spectra of both mas and stationary samples are less broad at 21.1 t. this narrowing is seen for all samples in the present work , as the broadening of the ct due to the second - order quadrupolar interaction decreases with increasing b0 and is always the case when broadening in the spectrum is dominated by the second - order quadrupolar interaction . \n qcpmg spectra were also obtained and each corresponding manifold of spikelets mimics the line shape of the stationary spectra . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . \n experimental qcpmg spectra of stationary powdered samples are shown in ( i ) b at 9.40 t and ( j ) b at 21.1 t. depicted in figures 39 are the b ssnmr spectra of compounds 14 , 7 , 9 , and 10 , respectively . upon examination of the spectra \n it is seen that the b line shapes associated with the boronic acids tend to be broader than the spectra of boronic esters . \n this observation is associated with the fact that the boronic acids tend to have larger cq(b ) and values . in table 1 , \n nmr parameters are also listed for boric acid , a known decomposition product of boronic acids.(1 ) this decomposition product is clearly identified in compounds 2 and 3 ( figures 4 and 5 ) as purchased and is responsible for the peak with iso = 19.6 ppm . \n in addition , spectra for compounds 1 , 2 , and 4 ( figures 3 , 4 , and 6 ) contain broad , low intensity features buried underneath the main signal . \n we speculate that these peaks are likely due to small amounts of an unknown impurity , decomposition product present in the sample , or possibly the result of less effective suppression of the signal due to boron nitride inside the stator . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . \n experimental qcpmg spectrum of a stationary powdered sample is shown in ( i ) b at 9.40 t. solid - state boron-11 nmr spectroscopy of 2 . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . \n the small peaks in spectra ( ad ) seen at 1 and 19 ppm are due to boric acid , and its spectral parameters may be found in table 1 . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . \n experimental qcpmg spectrum of a stationary powdered sample is shown in ( i ) b at 9.40 t. the small peaks in spectra ( ad ) seen at 1 and 19 ppm are due to boric acid , and its spectral parameters may be found in table 1 . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . \n experimental qcpmg spectrum of a stationary powdered sample is shown in ( j ) b at 21.1 t. solid - state boron-11 nmr spectroscopy of 9 . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . experimental qcpmg spectrum of a stationary powdered sample \n is shown in ( i ) b at 9.40 t. solid - state boron-11 nmr spectroscopy of 10 . \n experimental spectra of a powdered sample undergoing mas are shown in ( a ) b at 9.40 t and ( c ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( b ) and ( d ) ) using the parameters given in table 1 . \n experimental spectra of stationary powdered samples are shown in ( e ) b at 9.40 t and ( g ) b at 21.1 t. best - fit spectra were simulated using wsolids ( traces ( f ) and ( h ) ) using the parameters given in table 1 . \n experimental qcpmg spectrum of a stationary powdered sample is shown in ( i ) b at 9.40 t. figures s10s18 ( supporting information ) illustrate the b0 dependencies of the second - order quadrupolar interaction and csa observed in the magnetic resonance line shape for several of the boronic acids and esters . shown in these figures \n are the stationary spectra for each compound , the corresponding best - fit analytical simulation , and a simulation where the csa is ignored ( i.e. , = 0 ppm ) . comparing the traces where csa is included to those where \n it is not for the data acquired at 9.40 t , one clearly sees that the difference between the two traces is minimal . at 21.1 t \n figure 10 is a graphical representation of the measured values for different trigonal planar boron bonding environments.(50 ) as the central boron atom is bound to more oxygen atoms and fewer carbon atoms , the experimental values decrease dramatically . \n the oxygen atoms can donate electron density through lone pairs of electrons into the vacant p - orbital of the boron . \n as described in more detail later , the contributions to the paramagnetic portion of the total in the boron trigonal plane are reduced upon increasing oxygen coordination , which can explain the observed decrease in the measured .(50 ) the boronic acids and esters have values in the small / intermediate range relative to borates on the low end and boranes on the high end . \n even though the spans being examined are small , they are the most characteristic nmr parameters for each compound and can successfully be related to the immediate bonding environment ( figure 10 ) . \n graphical representation of experimental values for the compounds being studied ( table 1 ) and different borate and borane compounds.(50 ) data points indicate average values for a range of compounds ( boronic acids and esters ) or single experimental measurements ( borate and borane ) . \n the vertical bars for the boronic acid and ester data show the range of for each class of compound . in the case of borane and borate , \n the vertical bars represent the experimental measurement error for one compound ( trimesitylborane and triphenylborate).(50 ) as the central boron atom is bound to more oxygen atoms and fewer carbon atoms , the experimental values decrease dramatically . \n we briefly digress here to assess the effectiveness of modified - qcpmg(37 ) and dfs - modified - qcpmg signal enhancement techniques for boronic acids and esters . \n modified - qcpmg is similar to the conventional qcpmg pulse sequence , except that the pulses in the qcpmg echo train are replaced with /2 pulses.(37 ) the sequence suppresses homonuclear dipolar coupling ; hence , a longer effective t2 is observed , allowing more echoes to be acquired in the time - domain and resulting in sharper spikelets in the frequency - domain . \n we postulate that this sequence could be beneficial due to the large magnetogyric ratio and natural abundance of b. presently , the modified - qcpmg pulse sequence results in signal enhancement factors ranging from 1.04 in compound 9 to 1.42 in compound 5 , relative to the standard qcpmg pulse sequence . \n similarly , the dfs modified - qcpmg pulse sequence provides signal enhancement factors ranging from 1.80 in compound 8 to a high of 2.95 in compound 5 , relative to the standard qcpmg pulse sequence . \n as an example , shown in figure 11 are qcpmg , modified - qcpmg , and dfs modified - qcpmg nmr spectra for a representative boronic ester ( 9 ) , where signal enhancement factors of 1.04 and 2.16 are achieved . \n figure 11 also presents analogous data for a representative boronic acid ( 3 ) , where signal enhancement factors of 1.35 and 2.71 are obtained . \n further examples of signal enhancement for additional boronic acids and esters may be found in the supporting information ( figures s5 to s9 ) . \n although we were able to acquire high - quality b ssnmr spectra without the use of these signal enhancement techniques in the present study , it is worth noting that they were successful and that they might be useful for b ssnmr in more dilute systems . \n one specific example could involve achieving signal enhancement of the b ct of boronic acids present in dilute quantities in systems such as modified protease inhibitors.(10 ) solid - state boron nmr spectroscopy of 9 ( left ) and 3 ( right ) . \n experimental b spectra of stationary powdered samples at 9.40 t are shown in ( a ) and ( d ) using the qcpmg pulse sequence ; ( b ) and ( e ) using the modified - qcpmg pulse sequence with a signal enhancement factor of 1.04 and 1.35 , respectively ; and ( c ) and ( f ) using the dfs modified - qcpmg pulse sequence with a signal enhancement factor of 2.16 and 2.71 respectively , relative to qcpmg . \n are the boron efg and tensor results calculated using b3lyp , rhf , and gga - revpbe methods for compounds 110 ( see also tables s1 to s3 ) . \n the gga - revpbe calculated isotropic magnetic shielding constants are plotted against the experimental values of iso in figure 12 . \n a good correlation exists between the experimental and calculated data , as quantified by a correlation coefficient of r = 0.9000 ( excluding an outlier for boronic acid 2 ) . \n the experimental spans are also best reproduced by the gga - revpbe calculations , as quantified by a correlation coefficient of r = 0.9818 , once one outlier is excluded ( figure 12 ) . \n the outlier , corresponding to boronic acid 1 , may be tentatively rationalized by considering the relatively large experimental error associated with this particular measurement . \n correlation between the calculated ( adf / gga - revpbe ) and experimental span values ( a ) and calculated total isotropic shielding and experimental isotropic chemical shift values ( b ) measured in the solid state for each boronic acid and ester studied . \n data ( ( a ) , diamonds ) are described by a r value of 0.9818 and a trendline given by y = 1.0536x + 0.482 . \n one data point for boronic acid 1 ( ( a ) , square ) is not taken into account and is plotted separately . \n data in part ( b ) ( diamonds ) have a r value of 0.9000 with a trendline given by y = 1.0117x + 99.8 . \n one stray data point for boronic acid 2 ( ( b ) , square ) is not taken into account and is plotted separately . \n corresponds to boronic acid dimer . calculated values for boronic acid dimers which take into account hydrogen bonding interactions \n hybrid dft calculations were performed using the b3lyp functional and the 6 - 311+g * basis set on all elements . \n rhf calculations were performed using the 6 - 311+g * basis set on all elements . \n adf calculations were performed using the gga - revpbe functional and tzp basis set on all atoms . \n boric acid is included as the impurity present at 19.6 ppm in compounds 2 and 3 . \n the gga - revpbe - calculated values can be used to discuss the impact of hydrogen bonding , electronic substituents , and ccbo on the span . \n the two hydroxy groups present in boronic acids are capable of engaging in intermolecular hydrogen bonding . \n therefore , if hydrogen bonding interactions are present , the boronic acids being considered usually exist as dimers . \n only one crystal structure exists for the compounds being studied , that of compound 4 , which is a dimer.(43 ) boronic acids may also exist as oligomers in the solid state , as discussed , for example , by maly et al . \n we performed calculations on both boronic acid monomers and dimers to assess the impact of hydrogen bonding on the b nmr interaction tensors . \n we find that cq(b ) generally decreases slightly in the dimers , relative to the monomers . \n there is no consistent trend in the change of as a result of hydrogen bonding in the dimers . \n we attribute this observation to the fact that the value of ccbo ( as shown in figure 13 ) of the optimized structures changes differentially from compound to compound as a result of dimerization , in addition to the simple fact that the hydroxy groups are hydrogen bonded . \n correlation between the calculated values and ccbo for monomeric and dimeric forms of phenylboronic acid . shown \n are results for ( diamonds ) gaussian ( b3lyp ) monomer , ( squares ) gaussian ( b3lyp ) dimer , ( triangles ) adf ( gga - revpbe ) monomer , and ( circles ) adf ( gga - revpbe ) dimer . shown in red \n therefore , we next studied the impact of varying ccbo upon calculated values . shown in table 2 are the gga - revpbe optimized dihedral angles for each boronic acid and ester ( see also figure 13 ) , where the two carbon atoms are located in the aromatic ring , and the boron and oxygen atoms are part of the boronic acid or ester functionality . as noted earlier , ccbo is altered primarily by sterics , and depends on the bulkiness of nearby substituents on the aromatic ring . \n for example , for every boronic acid and ester possessing bulky substituents on the aromatic ring , particularly in the ortho position , the value of ccbo is always much greater relative to when there is a less bulky substituent . \n as this angle is systematically varied , the orientations of mos centered on boron , relative to the aromatic ring , change accordingly . \n an examination of the correlation between experimental and calculated spans ( figure 12 ) suggested a potential relationship between ccbo and both the experimental and calculated values . \n previous work by zhang et al . reported a dependence of the computed energy of boronic acids on this dihedral angle.(54 ) a plot of the value of as a function of the calculated value of ccbo for each compound reveals no clear and direct correlation , which is not surprising , as there are several variables changing simultaneously . \n for example , boronic acids have hydrogen bonding interactions taking place whereas the esters do not ; the aromatic substituents are different on the various compounds , and the dihedral angle changes primarily due to sterics . to determine \n if there is an underlying fundamental correlation between span and ccbo , phenylboronic acid was chosen as a model system . \n the value of ccbo was then systematically altered from 0 to 90 in 10 steps . \n for each ccbo , spans were calculated using both b3lyp and gga - revpbe density functional methods . \n two important conclusions may be drawn : ( i ) for all four data sets , there is a distinct positive correlation between and ccbo ; ( ii ) in all cases , the values are smaller for the phenylboronic acid monomer than for the dimer . \n it is clear that calculations predict that the presence of the hydrogen bonding interaction results in an increased span . \n the calculated variation of the span results from small changes ( on the order of 15 ppm ) in the values of the principal components of the magnetic shielding tensor as a result of hydrogen bonding . in no case \n do the calculations imply that the span varies because of the unilateral change of a single component ( see table s6 ) . \n it is the combination of these small changes , specifically in 11 and 33 , rather than a significant change in a single principal component , which leads to variation in the values . \n the 33 values become slightly larger , and the 11 values become smaller , resulting in an increased span overall . \n gga - revpbe calculations for the phenylboronic acid monomer were used to compile shielding tensor magnitude and orientation information at each ccbo . not surprisingly , the eigenvector corresponding to 33 remains nearly perpendicular to the boron bonding plane . for phenylboronic acid , 33 \n is calculated to intersect the boron bonding plane at an angle ranging from 76 to 90 , depending on the value of ccbo . \n in addition , for boronic acids and esters 110 , 33 remains perpendicular ( within 18 ) to the boron bonding plane . \n ( compound 4 is an exception to this rule with 22 being perpendicular , although compound 4 is also unique in the sense that it is a boronic acid monoester ) . to relate \n the mos to the observed and calculated values , the individual mo contributions to total shielding must first be examined . \n as previously mentioned , magnetic shielding may be partitioned into dia and para components . as conventionally partitioned , the paramagnetic shielding term is often the dominant term that contributes to shielding tensor anisotropy . \n if virtual rotation of this orbital by 90 produces a favorable overlap with a virtual p orbital of the boron atom , the situation results in paramagnetic contributions to the component along the axis of virtual rotation.(50 ) consider the action of the angular momentum operator ( eq 8) on a given mo wave function that can account for contributions to paramagnetic shielding due to orbital overlap between occupied and virtual states . \n the action that this angular momentum operator has on a p - character orbital , which is the case for the boron compounds being examined , can be visualized as a 90 rotation of the occupied orbital . \n if para is the dominant contributor to shielding anisotropy , we anticipate that there should be a relationship between the observed and the mos involved in mixing . to assist in visualization of this concept , consider the pair of mos which give the greatest contributions to para for compound 6 ( figure 14 ) . \n occupied orbital 33 ( homo-7 ) and virtual orbital 65 ( lumo+24 ) for compound 6 . \n these are the two orbitals involved in mixing which yield the largest contribution to total isotropic para . \n note the orbital overlap between a 90 virtual rotation of occupied orbital 33 out of the plane of the page and virtual orbital 65 . \n interestingly , however , when considering compounds 110 , there is no clear correlation between span and orbital energy gap between the occupied and virtual states that give the largest contribution to the total isotropic para . \n there is also no obvious correlation between the span and total isotropic para . from compound to compound , different effects need to be considered , including : hydrogen bonding , ccbo , and varying electronics of the different substituents on the aromatic ring . \n it is likely a composite of these different effects that clouds the relationship between and orbital energy gap or total isotropic para . \n when considering our model phenylboronic acid monomer system , there is a clear correlation between and total isotropic para . \n in addition , when the same pair of occupied and virtual mos are considered from compound to compound , as the orbital energy gap decreases , the span values increase , which is the expected correlation when the span is dominated by para . both the paramagnetic shielding tensor components as well as the total magnetic shielding components \n as ccbo increases from 0 to 90 , the separation between 11 and 33 increases , which equates to an increasing span ( eq 3 ) . in the plot \n where the contributions to paramagnetic shielding are plotted against ccbo , the paramagnetic contribution to 11 becomes increasingly negative with increasing dihedral while the paramagnetic contribution to 33 also decreases slightly . as a consequence of the paramagnetic contribution to 11 becoming increasingly negative , the total isotropic para will become more negative and the span will increase . \n however , a plot of total magnetic shielding against ccbo reveals that 11 shifts in the negative direction , while 33 becomes more positive as ccbo increases . \n consequently , we conclude that diamagnetic shielding contributions play a non - negligible role in determining the span values observed . \n numerical values are tabulated in the supporting information ( see tables s4 and s5 ) . \n plot of the adf / gga - revpbe calculated total magnetic shielding tensor components ( bottom ) and total isotropic para tensor components ( top ) versus ccbo for phenylboronic acid . \n the three data sets on each plot represent 11 ( diamonds ) , 22 ( squares ) , and 33 ( triangles ) . due to the demonstrated importance of diamagnetic \n shielding , a brief study was conducted to determine the effects of strong and mild electron - donating and withdrawing groups on the boron shielding tensor . \n phenylboronic acid was used as a control molecule , and a steric group ( bromine ) , a mild electron - donating group ( carboxylic acid ester ) , a strong electron - donating group ( amine ) , a mild electron - withdrawing group ( carboxyl ) , and a strong electron - withdrawing group ( nitro ) were each substituted in the ortho , meta , and para positions of the aromatic ring . \n while changes in the isotropic shielding constant are small for all substituents , we find that the presence of electron - withdrawing groups correlates with increases in the calculated values ( up to 13.5 ppm ) , whereas electron - donating groups have less of an effect on the calculated values . \n for both shifts in 11 in the negative direction which increase , and shifts in 11 in the positive direction which decrease , in general , it was 11 that had the largest change in magnitude as a result of substitution . \n these results are logical since tricoordinate boron compounds that feature boron atoms bound to multiple oxygen atoms have smaller observed values due to the lone pairs on the oxygen donating electron density to a virtual mo centered on the boron atom.(50 ) \n in this study , b cs and efg tensor information was successfully extracted from the b ssnmr spectra acquired for 10 boronic acids and esters . \n signal enhancement techniques were successfully applied and enhancement factors of up to 1.42 were achieved for modified - qcpmg , whereas factors of 1.802.95 were achieved for dfs modified - qcpmg , relative to the qcpmg sequence alone . \n the cq and values were found to be larger , on average , for boronic acids than for esters . \n for the five boronic acids , the span has an average value of 30.8 ppm , while for the five boronic esters , the average value is 17.8 ppm . in the case of b \n quadrupolar coupling constants , the average value is 3.0 mhz for the boronic acids and 2.8 mhz for the boronic esters . \n the ranges associated with cq and iso are small relative to their absolute magnitudes from compound to compound . \n however , the cs tensor span exhibits a significant relative range ( 75% ) and is the nmr parameter most characteristic of the molecular and electronic structure for the compounds studied . \n it has been advantageous to acquire data at high magnetic field strength as the effects of csa could be more precisely quantified . \n good correlation between experimental and gga - revpbe calculated spans as well as between the calculated isotropic shielding and experimental chemical shift values was observed . \n the span was shown to be positively correlated with ccbo in a model boronic acid over the range of 090 degrees . \n this is true regardless of whether hydrogen bonding is taking place , although does not increase as steeply with ccbo when hydrogen bonding is occurring . \n the hydrogen bonding interaction is correlated with a decrease in the total paramagnetic contribution to the isotropic magnetic shielding and a decrease in the span . \n contrary to the situation typically seen for larger spans , the diamagnetic part of the shielding tensor was shown to play a key role in explaining the observed trends in csa . finally , the presence of an electron - withdrawing group substituted on a model boronic acid resulted in an increase in the calculated . we have shown that the boron chemical shift tensor in boronic acids , and particularly the span of the cs tensor , is governed by a delicate interplay of several competing factors , including hydrogen bonding , dihedral angle , and the various electron - donating or withdrawing substituents bound to the aromatic ring . \n we speculate , therefore , that future b ssnmr experiments performed on similar materials will be most beneficial in comparative studies , where specific individual changes in structure may be probed and characterized .", "role": "user" }, { "content": "the results of a solid - state 11b nmr study of a series of 10 boronic acids and boronic esters with aromatic substituents are reported . \n boron-11 electric field gradient ( efg ) and chemical shift ( cs ) tensors obtained from analyses of spectra acquired in magnetic fields of 9.4 and 21.1 t are demonstrated to be useful for gaining insight into the molecular and electronic structure about the boron nucleus . \n data collected at 21.1 t clearly show the effects of chemical shift anisotropy ( csa ) , with tensor spans ( ) on the order of 1040 ppm . \n signal enhancements of up to 2.95 were achieved with a dfs - modified qcpmg pulse sequence . to understand the relationship between the measured tensors and the local structure better , calculations of the 11b efg and magnetic shielding tensors for these compounds were conducted . \n the best agreement was found between experimental results and those obtained from gga revpbe dft calculations . \n a positive correlation was found between and the dihedral angle ( ccbo ) , which describes the orientation of the boronic acid / ester functional group relative to an aromatic system bound to boron . \n the small boron csa is discussed in terms of paramagnetic shielding contributions as well as diamagnetic shielding contributions . \n although there is a region of overlap , both and the 11b quadrupolar coupling constants tend to be larger for boronic acids than for the esters . \n we conclude that the span is generally the most characteristic boron nmr parameter of the molecular and electronic environment for boronic acids and esters , and show that the values result from a delicate interplay of several competing factors , including hydrogen bonding , the value of ccbo , and the electron - donating or withdrawing substituents bound to the aromatic ring .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: nutrition imbalance and physical inactivity due to sedentary life style can lead to obesity , which is closely associated with an increased risk of metabolic syndrome ( booth et al . \n metabolic disorders including insulin resistance and overt type 2 diabetes ( t2d ) are highly related to secondary cardiovascular complications such as hypertension , myocardial infarction , and stroke ( abate , 2000 ; meshkani and adeli , 2009 ) . \n adiponectin is one of adipokines secreted from adipose tissue and involved in various biological processes such as energy homeostasis , immune actions , and vascular homeostasis ( cheng et al . , 2014 ; \n a number of clinical observations have demonstrated that circulating levels of adiponectin are markedly reduced in patients with obesity ( arita et al . , 1999 ) , t2d ( hotta et al . , 2000 ) , essential hypertension ( adamczak et al . , 2003 ) , and coronary artery disease ( cad ) ( kumada et al . , 2003 ; nakamura et al . , 2004 ) . \n based on above considerations , therapeutic interventions which can improve the action of adiponectin including elevation of circulating adiponectin concentration or up - regulation and/or activation of its receptors , could provide better understanding of strategies to ameliorate metabolic disorders and vascular disease . \n the focus of the present review is to summarize accumulating evidence showing the role of interventions such as pharmacological agents , exercise , calorie restriction ( cr ) , and gastric bypass surgery ( weight loss ) in the expression of adiponectin and adiponectin receptors . \n pharmacological / dietary interventions and lifestyle modifications such as exercise and cr to prevent and ameliorate cardiovascular disease and micro - vascular complications in t2d , have been shown to increase circulating levels of adiponectin in both experimental models and human studies ( simpson and singh , 2008 ; zhu et al . , 2008 ) . \n up - regulation of endogenous adiponectin and its receptors by interventions might have multiple beneficial effects on metabolic and cardiovascular diseases . \n peroxisome proliferator - activated receptors ( ppars ) are a group of nuclear receptor superfamily which functions as transcription factors regulating gene expression and play important roles in the regulation of cellular differentiation , development , and energy metabolism ( schoonjans et al . , \n the three types of ppar ( , , and / ) have been identified ( schoonjans et al . , 1996 ) . \n the ppar- agonists , thiazolidinediones ( tzds ) are widely used for anti - diabetic drugs that improve insulin sensitivity through enhancement of glucose disposal as well as reduction of gluconeogenesis in the target tissues of the body including skeletal muscle , liver , and adipose tissue ( furnsinn and waldhausl , 2002 ; kintscher and law , 2005 ) . \n a number of studies have shown that tzds such as rosiglitazone and pioglitazone increased circulating levels of adiponectin in both human and experimental rodent models ( choi et al . \n , 2005 ; iwaki et al . , 2003 ; kubota et al . , 2006 ; pajvani et al . , 2004 ) . \n in addition to ppar- , the ppar- agonist induced the increase in the circulating level of adiponectin associated with improvement in insulin sensitivity . \n for example , fenofibrate an agonist of nuclear receptor ppar- , increased serum levels of adiponectin in patients with primary hypertriglyceridemia ( koh et al . , \n therefore , it is tempting to speculate whether anti - hypertensive drugs such as candesartan and losartan ( angiotensin ii receptor antagonists ) increase adiponectin . \n these drugs , indeed , elevated circulating adiponectin without altering adiposity ( celik et al . , 2006 ; furuhashi et al . , 2003 ; koh et al . , 2004 ; koh et al . , 2006 ) . \n in addition , several other drugs for anti - diabetic ( glimepiride ) and anti - hypertension ( nebivolol , 1 receptor blocker ) have been shown to enhance plasma adiponectin concentrations in human subjects ( celik et al . , 2006 ; \n nagasaka et al . , 2003 ) . however , it is unclear whether elevated adiponectin is associated with improved cardiovascular outcomes . \n in addition to pharmacological agents , dietary fish oils ( fo ) and polyunsaturated fatty acids ( pufa ) have been shown to increase mrna expression of adiponectin in adipose tissue and circulating levels of adiponectin in several experimental models and human ( mostowik et al . \n , 2013 ; neschen et al . , 2006 ; rossi et al . , 2005 \n ) . furthermore , oolong tea , green tea extract and ( -)-catechin increased plasma adiponectin in humans and rodent models ( cho et al . , 2007 ; li et al . , 2006 ; shimada et al . , \n table 1 summarized the effects of pharmacological agents and dietary intervention on the expression of adiponectin . \n it is well documented that exercise or regular physical activity has beneficial effects on metabolic and cardiovascular disease . \n considering previous literatures , it is unclear whether exercise training ( physical activity ) increases adiponectin in circulation and its receptors in insulin - sensitive tissues such as adipose tissue , liver , and skeletal muscle . \n complicating interpretation of the existing data is dependent on multiple factors including species , the pathological condition , types ( endurance vs resistance exercise ) , intensity ( low , moderate , and intense ) , and duration of exercise ( acute vs chronic , short - term vs long - term ) , and sex . \n for example , in healthy , young subjects , it seemed that both acute and chronic aerobic exercise did not alter plasma level of adiponectin ( ferguson et al . \n , 2004 ; hulver et al . , 2002 ; jurimae et al . , 2006 ; punyadeera et al . , \n 2005 ) . however , chronic endurance training increased plasma adiponectin in obese adolescents ( balagopal et al . , 2005 ) , obese adults ( kondo et al . , 2006 ) , caucasian subjects with impaired glucose tolerance ( igt ) and t2d ( bluher et al . , 2006 ; oberbach et al . , \n 2006 ) . furthermore , endurance training increased mrna expression of adiponectin receptor ( adipor ) 1 and 2 in adipose tissue and skeletal muscle in normal glucose tolerance ( ngt ) , igt , and type 2 diabetic patients ( bluher et al . , 2006 ; bluher et al . , 2007 ; \n on the other hand , some studies by several other groups have shown that aerobic exercise did not change adiponectin expression in obese subject ( polak et al . , 2006 ) , insulin resistant female subjects ( marcell et al . , 2005 ) , and patients with t2d ( boudou et al . , 2003 ; yokoyama et al . , \n have demonstrated that only moderate - high intensity resistance training , not low intensity , increased plasma adiponectin in inactive subjects , suggesting that the intensity of exercise may be an important factor in the expression of adiponectin ( fatouros et al . , 2005 ) . \n table 2 shows a summary of studies examining effects of exercise training on adiponectin and adipors in both human and experimental models . \n calorie restriction ( cr ) refers to a dietary regimen low in calories without malnutrition and is known as an efficient lifestyle modification that delays the onset of metabolic and cardiovascular disease ( cava and fontana , 2013 ) . \n weight loss and/or cr have been shown to improve insulin resistance , t2d , and cardiovascular dysfunction in both human and rodent models ( weiss and fontana , 2011 ) . \n in addition , sustained weight loss by gastric bypass surgery ameliorated cardiovascular dysfunction ( brethauer et al . \n although it is not clear whether beneficial effects of these interventions are mediated by adiponectin signaling pathways , a number of studies have shown that cr and/or weight loss by gastric bypass surgery increased circulating levels of adiponectin . \n , 2010 ; schulte et al . , 2013 ) and obese subjects ( kobayashi et al . , 2004 ; \n however , some studies have shown that cr did not change plasma levels of adiponectin in patients with metabolic syndrome ( xydakis et al . , 2004 ) and t2d ( plum et al . , 2011 ) . \n interestingly , varady et al . ( 2009 ) have implicated that circulating adiponectin concentration increased 20% in the 510% weight loss group , not less than 5% weight loss group , suggesting a minimum degree of weight loss are required to improve adipokine profile in severely obese women . on the other hand , \n plum et al . suggested that roux - en - y gastric bypass surgery , not low calorie diet group , increased plasma adiponectin concentration in patients with t2d , although weight loss was comparable in both groups ( plum et al . , 2011 ) . this may suggest that roux - en - y gastric bypass surgery is more effective method than low calorie diet regimen in some kinds of obese diabetic patients . because metabolic and cardiovascular diseases are multi - factorial phenomena , we need to consider the effect of other metabolic disorders such as dyslipidemia , hypercholesterolemia , and hypertension on the expression of adiponectin . \n table 3 summarizes the effects of cr , weight loss and gastric bypass surgery on adiponectin . \n peroxisome proliferator - activated receptors ( ppars ) are a group of nuclear receptor superfamily which functions as transcription factors regulating gene expression and play important roles in the regulation of cellular differentiation , development , and energy metabolism ( schoonjans et al . , \n the three types of ppar ( , , and / ) have been identified ( schoonjans et al . , 1996 ) . \n the ppar- agonists , thiazolidinediones ( tzds ) are widely used for anti - diabetic drugs that improve insulin sensitivity through enhancement of glucose disposal as well as reduction of gluconeogenesis in the target tissues of the body including skeletal muscle , liver , and adipose tissue ( furnsinn and waldhausl , 2002 ; kintscher and law , 2005 ) . \n a number of studies have shown that tzds such as rosiglitazone and pioglitazone increased circulating levels of adiponectin in both human and experimental rodent models ( choi et al . , 2005 ; iwaki et al . , 2003 ; kubota et al . , 2006 ; pajvani et al . , 2004 ) . \n in addition to ppar- , the ppar- agonist induced the increase in the circulating level of adiponectin associated with improvement in insulin sensitivity . \n for example , fenofibrate an agonist of nuclear receptor ppar- , increased serum levels of adiponectin in patients with primary hypertriglyceridemia ( koh et al . , \n therefore , it is tempting to speculate whether anti - hypertensive drugs such as candesartan and losartan ( angiotensin ii receptor antagonists ) increase adiponectin . \n these drugs , indeed , elevated circulating adiponectin without altering adiposity ( celik et al . , 2006 ; furuhashi et al . , 2003 ; koh et al . , 2004 ; koh et al . , \n in addition , several other drugs for anti - diabetic ( glimepiride ) and anti - hypertension ( nebivolol , 1 receptor blocker ) have been shown to enhance plasma adiponectin concentrations in human subjects ( celik et al . , 2006 ; \n nagasaka et al . , 2003 ) . however , it is unclear whether elevated adiponectin is associated with improved cardiovascular outcomes . \n in addition to pharmacological agents , dietary fish oils ( fo ) and polyunsaturated fatty acids ( pufa ) have been shown to increase mrna expression of adiponectin in adipose tissue and circulating levels of adiponectin in several experimental models and human ( mostowik et al . , 2013 ; neschen et al . , 2006 ; rossi et al . , 2005 ) . furthermore , oolong tea , green tea extract and ( -)-catechin increased plasma adiponectin in humans and rodent models ( cho et al . , 2007 ; li et al . \n table 1 summarized the effects of pharmacological agents and dietary intervention on the expression of adiponectin . \n it is well documented that exercise or regular physical activity has beneficial effects on metabolic and cardiovascular disease . considering previous literatures , \n it is unclear whether exercise training ( physical activity ) increases adiponectin in circulation and its receptors in insulin - sensitive tissues such as adipose tissue , liver , and skeletal muscle . \n complicating interpretation of the existing data is dependent on multiple factors including species , the pathological condition , types ( endurance vs resistance exercise ) , intensity ( low , moderate , and intense ) , and duration of exercise ( acute vs chronic , short - term vs long - term ) , and sex . \n for example , in healthy , young subjects , it seemed that both acute and chronic aerobic exercise did not alter plasma level of adiponectin ( ferguson et al . \n , 2004 ; hulver et al . , 2002 ; jurimae et al . , 2006 ; punyadeera et al . , \n . however , chronic endurance training increased plasma adiponectin in obese adolescents ( balagopal et al . , 2005 ) , obese adults ( kondo et al . , 2006 ) , caucasian subjects with impaired glucose tolerance ( igt ) and t2d ( bluher et al . \n 2006 ) . furthermore , endurance training increased mrna expression of adiponectin receptor ( adipor ) 1 and 2 in adipose tissue and skeletal muscle in normal glucose tolerance ( ngt ) , igt , and type 2 diabetic patients ( bluher et al . , 2006 ; bluher et al . , 2007 ; \n , 2006 ) . on the other hand , some studies by several other groups have shown that aerobic exercise did not change adiponectin expression in obese subject ( polak et al . , 2006 ) , \n 2005 ) , and patients with t2d ( boudou et al . , 2003 ; yokoyama et al . , \n interestingly , fatouros et al . have demonstrated that only moderate - high intensity resistance training , not low intensity , increased plasma adiponectin in inactive subjects , suggesting that the intensity of exercise may be an important factor in the expression of adiponectin ( fatouros et al . , 2005 ) . \n table 2 shows a summary of studies examining effects of exercise training on adiponectin and adipors in both human and experimental models . \n calorie restriction ( cr ) refers to a dietary regimen low in calories without malnutrition and is known as an efficient lifestyle modification that delays the onset of metabolic and cardiovascular disease ( cava and fontana , 2013 ) . \n weight loss and/or cr have been shown to improve insulin resistance , t2d , and cardiovascular dysfunction in both human and rodent models ( weiss and fontana , 2011 ) . \n in addition , sustained weight loss by gastric bypass surgery ameliorated cardiovascular dysfunction ( brethauer et al . \n , 2011 ; zhang et al . , 2011 ) . although it is not clear whether beneficial effects of these interventions are mediated by adiponectin signaling pathways , a number of studies have shown that cr and/or weight loss by gastric bypass surgery increased circulating levels of adiponectin . \n , 2010 ; schulte et al . , 2013 ) and obese subjects ( kobayashi et al . , 2004 ; oberhauser et al . , 2012 ; \n however , some studies have shown that cr did not change plasma levels of adiponectin in patients with metabolic syndrome ( xydakis et al . , 2004 ) and t2d ( plum et al . , 2011 ) . \n 2009 ) have implicated that circulating adiponectin concentration increased 20% in the 510% weight loss group , not less than 5% weight loss group , suggesting a minimum degree of weight loss are required to improve adipokine profile in severely obese women . on the other hand , \n plum et al . suggested that roux - en - y gastric bypass surgery , not low calorie diet group , increased plasma adiponectin concentration in patients with t2d , although weight loss was comparable in both groups ( plum et al . , 2011 ) . \n this may suggest that roux - en - y gastric bypass surgery is more effective method than low calorie diet regimen in some kinds of obese diabetic patients . \n because metabolic and cardiovascular diseases are multi - factorial phenomena , we need to consider the effect of other metabolic disorders such as dyslipidemia , hypercholesterolemia , and hypertension on the expression of adiponectin . table 3 summarizes the effects of cr , weight loss and gastric bypass surgery on adiponectin . \n there is no doubt that pharmacological agents and lifestyle modifications affect metabolic and cardiovascular disease . in regard to the expression of adiponectin and its receptors with these interventions , it remains unclear whether these interventions ameliorate metabolic and cardiovascular dysfunction through adiponectin and its receptors - mediated signaling pathways . \n recent studies provide compelling evidence supporting the beneficial role of adiponectin in the metabolic and cardiovascular diseases . \n although significant progress has made in understanding the molecular mechanisms that underlie the beneficial actions of adiponectin , it should be noted that large discrepancies exist among those studies based on experimental design including species , type of intervention , and the pathological condition . \n further investigations in adiponectin signaling pathways will provide potential targets used for the therapeutic interventions in metabolic and cardiovascular disease .", "role": "user" }, { "content": "adiponectin secreted from adipose tissue binds to two distinct adiponectin receptors ( adipor1 and adipor2 ) identified and exerts its anti - diabetic effects in insulin - sensitive organs including liver , skeletal muscle and adipose tissue as well as amelioration of vascular dysfunction in the various vasculatures . \n a number of experimental and clinical observations have demonstrated that circulating levels of adiponectin are markedly reduced in obesity , type 2 diabetes , hypertension , and coronary artery disease . \n therapeutic interventions which can improve the action of adiponectin including elevation of circulating adiponectin concentration or up - regulation and/or activation of its receptors , could provide better understanding of strategies to ameliorate metabolic disorders and vascular disease . \n the focus of the present review is to summarize accumulating evidence showing the role of interventions such as pharmacological agents , exercise , and calorie restriction in the expression of adiponectin and adiponectin receptors .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: surgery for pancreatic cancer is probably the most demanding and risky operative procedure in abdominal surgery . \n remarkable progress has been achieved during the last three decades and pancreatic surgery can nowadays be performed safely with low morbidity and mortality in various specialized hospitals around the world . \n this is in part a result of regionalization of pancreatic surgery into high volume centers resulting in an increased resection rate in the presence of pancreatic carcinoma which is nowadays approximately 60% and to an extension of indications for resection . \n consequently , vascular resection , considered a contraindication for pancreatic resection a couple of years ago , is now implemented in the armamentarium of pancreatic surgeons to realize r0-resections when clearance of the portal or superior mesenteric vein can not be realized without vascular resection . \n the results following synchronous resection of liver metastasis together with resection of periampullary or pancreatic adenocarcinoma or pancreatic resection for m1 carcinoma are not equivocal . \n although these procedures can be performed safely , the median survival time ranges between 6 and 13 months [ 3 , 4 ] . \n therefore , synchronous metastasectomy of periampullary cancer is rarely performed when extended disease has already been found preoperatively . however , within daily clinical practice different scenarios occur which may require a decision for resection in an m1 situation . in a young patient with advanced disease , resection may provide a small but important increase of survival . \n in addition , metastatic disease may become overt when the point of no return has already been passed as it may be the case in the presence of positive interaortocaval lymphnodes , or metastatic disease will be detected during operation despite negative imaging results preoperatively . \n finally , a strong patient desire may force the surgeon to go further than consented guidelines may summarize existing evidence . since curative r0 resection is the most important prognostic factor for long - term survival even a small potential to achieve r0 resection may provide the legitimisation for extended resection despite the fact that overt systemic disease is already present . \n so far , there is little data available on the value of synchronous metastasectomy together with pancreatic resection in patients with pancreatic carcinoma . \n patients who undergo resection of metastases together with pancreatic resection seem to have a higher complication rate than patients with multivisceral liver resections . \n an extended lymphadenectomy is associated with an increased postoperative complication rate , but has no impact on long - term survival . \n the fact that despite r0 resection long - term survival does not exceed 25% even in the most experienced pancreatic centers may prove that carcinoma of the pancreas is a systemic disease . \n further improvement of survival can only be achieved by adjuvant treatment ( picozzi et al . , 2003 ) . \n it seems logical , that in the presence of metastatic disease a low tumor load may increase the success of adjuvant chemotherapy although the absolute increase in survival time may be very low . \n we therefore hypothesized that radical resection of m1-pancreatic carcinoma may be justified in well - selected patients as long as these operations can be performed with a low morbidity and mortality . \n thus , we aimed at reviewing our experiences with pancreatic resections in patients with m1 periampullary cancer of the pancreas after having launched a new pancreatic program in our hospital . \n there were 280 patients who underwent either pancreatoduodenectomy or left - sided pancreatic resection for histologically proven pancreatic adenocarcinoma or periampullary cancer . among this patient population \n we identified 20 ( 7,1% ) patients ( 9 men , 11 women ; mean age 60 years ) in our prospective database who underwent either a pancreaticoduodenectomy ( pd ) , or a left - sided distal pancreatectomy together with resection of metastasis for pancreatic adenocarcinoma . \n resection of metastatic disease was defined as the resection of any tumor deposit outside the regional lymph nodes or resection of infiltrated surrounding organs in order to achieve a r0 resection . \n magnetic resonance imaging , magnetic resonance cholangiography , or endoscopic retrograde cholangiopancreatography were performed when indicated . in patients who were found intraoperatively to harbour metastatic disease the decision for resection was based on the impression to reach a r0 situation with synchronous resection of metastasis and a good clinical performance status of asa iii or better . \n patients with suspected metastatic disease preoperatively were operated with potentially curative intention or with palliative intention . \n reasons for resection were good performance status and patient 's will to receive maximal treatment . \n all pathologic specimen were reviewed by a single pathologist ( at ) to confirm the diagnosis of pancreatic adenocarcinoma or cancer of the papilla vateri . \n a pancreatic fistula was defined as a prolonged drainage with amylase activity of more than 10.000 \n wound infection was defined as any wound requiring reopening for the drainage of pus together with a positive wound culture . \n mortality was defined as any death during postoperative hospitalization or within 30 days of surgery . \n follow - up information was obtained through direct contact with the patient and review of hospital charts and operative notes . \n the results of the study group were compared with a matched - pair control group of 20 patients with pancreatic adenocarcinoma , who were matched according to age and tumor location and who did undergo only pancreaticoduodenectomy or distal pancreatic resection for stadium iib or iii pancreatic adenocarcinoma . \n all statistical analyses were performed using spss - software ( version 15 ) . the distribution of age at operation , blood loss , and postoperative hospital stay were presented as median with range . \n comparisons between subgroups were performed with fisher 's exact test and differences between means were tested by the t - test . \n cases were matched with control group ( resection without multivisceral resection ) in a 1 : 1 fashion . \n specifically , cases and controls were matched on primary tumor characteristics and age of the patient . \n morbidity , mortality , and overall survival were compared between cases and control group . the nonparametric product limit method ( kaplan - meier estimations ) \n two - sided p values were always computed and an effect was considered statistically significant at p .05 . the primary tumor was located in the pancreatic head in 9 ( 45% ) patients , in the pancreatic tail in 9 ( 45% ) , and at the papilla vateri in 2 ( 10% ) . \n synchronous liver metastasis was present in 14 ( 70% ) patients , 4 ( 20% ) patients had peritoneal metastases , one patient had a metastasis in the transverse mesocolon , 2 ( 10% ) patients had a metastasis in the greater omentum , and 3 ( 15% ) patients had macroscopically lymph node metastases . \n six patients ( 30% ) had metastatic disease at more than one location . in 7 ( 35% ) \n metastatic disease was known before operation based on preoperative imaging in 5 of 20 patients ( 25% ) . \n of the 20 patients , 8 ( 40% ) underwent a pylorus - preserving duodenopancreatectomy and 2 ( 10% ) a classic whipple - procedure . in 8 ( 40% ) patients a distal pancreatic resection was performed and 2 ( 10% ) patients underwent a total pancreatectomy . \n details of the localisation of the tumor and the metastases , tnm - staging , r - status postoperatively , and type of surgery performed are listed in table 2 . \n an r0/r1-resection could be achieved in 11 patients ( 55% ) , whereas in the remaining patients only an r2 resection was performed due to remaining metastatic disease in liver . \n there was no perioperative mortality , and complications occurred in 9 ( 45% ) patients . \n the median intraoperative blood loss was 1000 ml ( range 3002500 ml ) and the median postoperative length of hospital stay was 20.7 d ( 1171 d ) . \n this was statistically not different to a matched - pair group of patients with ductal adenocarcinoma of the pancreas without metastatic disease ( tables 3 and 4 ) . \n all patients received postoperative adjuvant or palliative chemotherapy , two patients underwent neoadjuvant radiochemotherapy prior to surgery . \n the median postoperative survival was 10.7 months ( range 2.637.8 mo ) which was not significantly different to the control group who had a median survival time of 15.6 months ( p = .11 ; figure 1 ) . \n all deaths were caused by recurrent cancer.there was no difference in the median survival between patients with liver metastases ( median survival time 11 months ) compared to patients who had metastases at other locations ( median survival 14.1 months ; p = .62 ) . \n pancreatic cancer still carries a dismal prognosis and the potential to cure a patient can only be achieved when the primary tumor can be completely resected . \n however , this scenario can only be accomplished in about 5%25% of patients presenting with locally resectable cancer . \n patients with metastatic pancreatic cancer who receive palliative chemotherapy with gemcitabine have a median survival time of 5.6 months . various protocols with gemcitabine - based regimen or multidrug regimen tested in prospectively randomised phase \n iii clinical trials have not altered this situation substantially making metastatic pancreatic cancer one of the most frustrating malignancies to investigate and treat . \n therefore , when metastatic disease is recognized preoperatively , an operative procedure is usually avoided except for surgical palliation . \n in addition , according to the s-3 guidelines of the german cancer society pancreatic resections should be avoided in the presence of intraoperative metastatic disease . however \n , locally advanced disease may be resected as long as an r0 resection can be achieved . \n both statements have a grade of evidence of 3 which means that only systematic reviews and individual case control studies are available to scientifically support this statement . \n it seems reasonable , that postoperative chemotherapy may be more effective , when no gross tumor is left in situ . \n in addition , the high recurrence rate even after r0 resection is an indirect prove for early systemic spread which is not treatable by surgery but by chemotherapy . \n our study gives support to the hypothesis despite the relatively small number of patients that in the presence of metastasis of a pancreatic adenocarcinoma radical resection is possible and safe and that overall survival is comparable to patients who do not have metastatic disease . \n this relatively good result is in part consequence of restriction of the procedure to well suited patients who were expected to tolerate even a significantly expanded procedure . \n the mean age of our patients was 58 years , and all patients were either asa 1 or 2 ( data not given ) . \n therefore , it was expected that these patients would tolerate pancreatic resection with synchronous metastasectomy without significant increase in morbidity or mortality . \n nevertheless , the median survival of 10.6 months is low , but we believe that we could offer these patients additional life time , although quality of life was not evaluated . \n however , these procedures should be restricted to well - suited patients and only be performed at centers with significant expertise in pancreatic surgery . \n a shortcoming of the study may be the fact that patients had various presentation of the m1 category . \n most of our patients had liver metastasis , but there were also patients with peritoneal or lymph nodes metastases who were classified as m1 or the tumor involved surrounding organs . since there is no significant difference in survival \n according to the location of the metastasis of pancreatic carcinoma , we believe that an analysis of this group was appropriate . according to the results of at least 3 randomized trials extended \n lymphadenectomy has not been effective in improving survival of patients with pancreatic adenocarcinoma with 1 and 3 years survival between 51% and 77% and between 16 and 41% , respectively . \n therefore , in an nonmetastasized pancreatic adenocarcinoma a standard lymphadenectomy is adequate . when locally advanced cancer with suspected venous infiltration is present extensive surgery can be performed safely with morbidity and mortality rates comparable to conventional resections . in a recent analysis of 136 patients with locally advanced pancreatic cancer yekebas et al . could demonstrate that patients with concomitant vascular resections had the same median ( 15 versus 16 mo ; p = .86 ) and two year survival ( 34% versus 36% : p = .9 ) compared to patients who did not undergo vascular resection . even in multivariate analysis vascular infiltration was not considered a negative prognostic factor . \n even arterial encasement of the celiac trunk in the presence of a pancreatic corpus carcinoma is not considered a contraindication for surgery . \n recently published a series of 23 patients with pancreatic body cancer with infiltration of the celiac trunk . \n negative surgical margins were obtained in 91% of patients , postoperative mortality was 0% , and the median survival was 21 months . however , early hepatic recurrence in 6 patients was a hint that this procedure may be indicated for the treatment of less advanced disease . in a recently published study shrikhande et al \n . reported a series of 29 patients with m1 ductal adenocarcinoma of the pancreas who underwent pancreatic resection with synchronous resection of metastases . \n of these 11 patients had metastatic disease to the liver and 9 to the peritoneum . \n the authors concluded , that concomitant resection of primary pancreatic tumor and metastases can be performed safely . \n however , a risk benefit ratio should be carefully assessed since the overall increase in survival is moderate . in our study \n the survival time of patients with liver metastasis was 11 months compared to 14.1 months when metastases were located at other regions ( p = .62 ) . \n in a study of 22 patients who underwent pancreatic resection and synchronous liver resection for metastasised pancreatic adenocarcinoma , gleisner et al . found that the median survival was only 5.9 months , which was not statistically different from patients who underwent palliative bypass alone ( 5.6 months ; p = .46 ) . \n they concluded from the results of their study that simultaneous resection for patients who present with synchronous liver metastasis from pancreatic adenocarcinoma is not justified . in our study \n we found a median survival of 10.6 months for the complete group , while the 14 patients with liver metastases had a median survival of 11 months . despite this small increase \n we believe that in highly selected patients after careful counselling this aggressive therapy is still an option that should be offered to the patient . \n the fact that there was no significant difference in survival between the study and the matched - pair control group despite an objective difference in the median survival of 5 months is probably due to the limited number of patients . with an increased number of patients we would have expect this difference to reach statistical significance . compared to published results of patients receiving palliative chemotherapy who have a median survival time of approximately 5.48.4 months [ 13 , 14 ] \n , the increase in survival in patients with m1 ductal adenocarcinoma of the pancreas is about 2 - 5 months . \n we believe that patients who may benefit must be carefully selected and therapeutic options and expected survival should be discussed with the patients and their families . \n in the presence of pancreatic neuroendocrine carcinomas extended resections or even debulking operations seem to be associated with increased survival . \n reported on a series of 23 patients with pancreatic islet - cell carcinomas with synchronous hepatic metastases who underwent synchronous hepatic resections without perioperative mortality . \n this demonstrates , that extended resections in this subset of metastasized patients with primary pancreatic tumors are justified \n . the preoperative or intraoperative differentiation between a pancreatic adenocarcinoma and a neuroendocrine carcinoma may be difficult when typical carcinoma associated syndromes are missing preoperatively . \n however , intraoperatively the differentiation may be easier from the macroscopic point of view , and when histology has not been determined preoperatively , intraoperative frozen section may identify the tumor so operative strategy can be planned appropriately \n . currently , a monocentric prospective randomized trial on the value of pancreatic resection in the presence of liver metastasis is under way in germany ( nct00855634 , pamevitum ) . \n the results of this study may give further evidence whether pancreatic resection in this scenario is justified . \n the results of our study demonstrate , that resection of pancreatic adenocarcinoma with synchronous metastases can be performed safely . justification for combined resection should be made on an individual basis for each patient only . \n there is probably a small increase in survival compared to patients who undergo palliative chemotherapy and there was no statistically significant difference in survival compared to patients who underwent resection for stadium iib or iii tumors . \n the decision to resect a patient in an m1 situation should be carefully assessed and may be an option in highly selected cases .", "role": "user" }, { "content": "background . for m1 pancreatic adenocarcinomas pancreatic resection is usually not indicated . however , in highly selected patients synchronous metastasectomy may be appropriate together with pancreatic resection when operative morbidity is low . \n materials and methods . from january 1 , 2004 to december , 2007 a total of 20 patients with pancreatic malignancies were retrospectively evaluated who underwent pancreatic surgery with synchronous resection of hepatic , adjacent organ , or peritoneal metastases for proven uicc stage iv periampullary cancer of the pancreas . \n perioperative as well as clinicopathological parameters were evaluated . \n results . \n there were 20 patients ( 9 men , 11 women ; mean age 58 years ) identified . \n the primary tumor was located in the pancreatic head ( n = 9 , 45% ) , in pancreatic tail ( n = 9 , 45% ) , and in the papilla vateri ( n = 2 , 10% ) . \n metastases were located in the liver ( n = 14 , 70% ) , peritoneum ( n = 5 , 25% ) , and omentum majus ( n = 2 , 10% ) . \n lymphnode metastases were present in 16 patients ( 80% ) . \n all patients received resection of their tumors together with metastasectomy . \n pylorus preserving duodenopancreatectomy was performed in 8 patients , distal pancreatectomy in 8 , duodenopancreatectomy in 2 , and total pancreatectomy in 2 . \n morbidity was 45% and there was no perioperative mortality . \n median postoperative survival was 10.7 months ( 2.637.7 months ) which was not significantly different from a matched - pair group of patients who underwent pancreatic resection for uicc adenocarcinoma of the pancreas ( median survival 15.6 months ; p = .1 ) . conclusion . \n pancreatic resection for m1 periampullary cancer of the pancreas can be performed safely in well - selected patients . however , indication for surgery has to be made on an individual basis .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: syncope is a disabling condition , and patients with this problem frequently seek medical attention . in the framingham study \n the incidence of adults reporting at least one syncopal episode during their lifetime was estimated at 3% . \n the incidence of syncope is higher in females than in males , with a peak frequency at 15 to 19 years . \n abnormal reflex activity is caused by excessive vagal tone and sympathetic withdrawal , which leads to a critical decrease in cerebral blood flow . during the initial paraclinical evaluation for syncope , \n transmural , transseptal or apicobasal dispersion of repolarization creates voltage gradients that affect the j wave and t wave of the electrocardiogram . \n amplification of this repolarization underlies the development of life - threatening ventricular arrhythmias associated with various inherited or acquired ion channelopathies , which can give rise to the long qt , short qt , and brugada syndrome[38 ] . \n the sympathetic withdrawal and excessive vagal tone in syncope may cause repolarization abnormality in electrocardiogram . in this study we evaluated the t - peak - to - t - end interval and its dispersion in children with syncope to detect possible repolarization abnormalities in these patients . \n in a prospective study , between november 2009 and november 2010 we enrolled 54 children with possibility of syncope referred consecutively to motahari clinic affiliated with shiraz university of medical sciences in shiraz , iran for tilt table test . \n the patients receiving any medication or with any cardiac or seizure disorder were excluded from the study . \n the study was approved by ethic committee of shiraz university of medical sciences and informed consent was deemed unnecessary by the board because no intervention in any form was administered by the researchers . \n all participants were tilted on a tilt table to a 60-degree position for 45 min ( westminster protocol ) . at the onset of orthostatic weakness or syncope , \n the patients were immediately placed in the recumbent position and closely monitored until full recovery . for each participant with negative tilt table test , the tilt protocol was repeated after 10 min rest in the supine position and after the participant was given oral nitroglycerin to increase sensitivity of tilt table test ( 0.2 mg for < 10 year and 0.4 mg for > 10 year olds ) . \n all electrocardiograms were recorded with the participant in the supine position before starting the tilt test . \n recordings were made with a digital electrocardiogram machine ( alicia diagnostics , sanford , fl , usa ) . \n the digitally recorded electrocardiogram tracings were evaluated with a digital clipper in corel photo paint v.13 software ( ottawa , canada ) . \n t - peak - to - t - end interval and t - peak - to - t - end dispersion ( defined as the difference between the maximum and minimum t - peak - to - t - end interval in precordial leads v1 to v6 during a single beat ) were measured . \n the t - peak - to - t - end was measured in each precordial lead and obtained from the difference between qt interval and qt peak interval , measured from the beginning of the qrs until the peak of the t - wave ( fig . \n the t - peak - to - t - end was measured from the difference between qt interval ( line a ) and qt peak interval ( line b ) , measured from the beginning of the qrs until the peak of the t - wave the patients with positive tilt table test result were considered as case group and the patients with negative test as control group . \n t - peak - to - t - end interval and t - peak - to - t - end dispersion were compared in cases and controls . \n chicago , il , usa ) ( version 15 ) and medcalc 8.0 software ( mariakerke , belgium ) were used for data analysis . to examine the prognostic value of t- peak - to - t - end interval and t - peak - to - t - end dispersion and \n we used the mann - whitney test to compare the results between cases and controls . \n the intraobserver and interobserver variability were assessed in 10 patients with negative test for syncope using intraclass correlation and coefficients of variation , respectively . a value of p less than 0.05 was considered statistically significant . \n tilt table test was positive in 19 patients ( 7 boys , 12 girls ) and 35 patients had negative tilt test . \n mean age was 11.43.1 years in the patients with positive tilt test and 10.05.1 years in the patients with negative tilt test ( p=0.27 ) . according to the european task force on syncope classification , 18 patients had type 1 syncope ( mixed type ) , in which heart rate fell at the time of syncope but did not fall to less than 40 beats per minute for longer than 10 seconds with or without asystole for less than 3 seconds , in this type of syncope , blood pressure fell before heart rate did . \n this type asystole occurred for longer than 3 seconds and the fall in blood pressure coincided with or preceded the fall in heart rate . \n five patients developed syncope after using nitroglycerin , but there was no statistically significant difference in the frequency of t - peak - to - t - end between patients who received medication and those without medication ( p=0.68 ) . \n the t - peak - to - t - end interval in lead v1 was statistically longer in patients with a positive tilt test ( 0.360.062 vs 0.320.071 , p=0.007 ) . \n table 1 shows the t - peak - to - t - end dispersion in precordial leads . \n analysis of the receiver operating characteristic curve ( fig 2 ) showed that a t - peak - to - t - end interval larger than 0.32 in lead v1 had a sensitivity of 68.2% , a specificity of 78.1% and a positive likelihood ratio of 3.13 for the detection of syncope . \n t - peak - to - t - end dispersion was significantly larger in the case group ( 0.150.07 vs 0.110.04 ; p=0.003 ) . \n analysis of the roc curve ( fig 3 ) showed that a t - peak - to - t - end dispersion larger than 0.14 had a sensitivity of 47.4% , a specificity of 85.7% and a positive likelihood ratio of 3.32 for detecting patients with syncope . \n receiver operating characteristic curve shows the hot point of t - peak - to - t - end interval in lead v1 for detection of patients with and without syncope receiver operating characteristic curve shows the hot point of t - peak - to - t - end dispersion for detection of patients with and without syncope t - peak to t - end dispersion measured in the precordial leads in the patients with negative tilt tale test result ( 0 ) and patients with a positive tilt test ( 1 ) . \n sd : standard deviation ; the patients with negative tilt tale test result ( 0 ) and patients with a positive tilt test ( 1 ) there was good agreement between the two independent observers measurements for the duration of the qt interval , the time interval between the onset to peak of t wave ; and the t - peak - to - t - end was r = 0.94 , r = 0.93 , and r = 0.91 , respectively . \n interobserver variability for the time interval between the qt interval , the time interval between the onset and peak of t wave , and the t - peak - to - t - end was 53% , 43% , and 33% , respectively . \n reproducibility for the qt interval , the time interval between the onset and peak of t wave , and the t - peak - to - t - end were 74% , 53% , and 63% , respectively . \n the reproducibility of measurements was not affected by the heart rate ( range , 110160 ) . \n this study found a statistically significant increase in t - peak - to - t - end interval in lead v1 and t - peak - to - t - end dispersion in patients with a positive tilt test , compared to children with a negative tilt test . \n these findings reveal presence of repolarization abnormality in patient with syncope . currently , upright tilt testing is a widely accepted diagnostic test for evaluating patients with syncope[1014 ] . \n this test provides diagnostic evidence of the susceptibility to neurally - mediated syncope and it is considered the gold standard for establishing this diagnosis . in this study also 94% ( 18 from 19 ) patients had type 1 syncope ( mixed type ) . \n according to a new classification which has been proposed by the european task force on syncope , four types of syncope have now been described . \n heart rate falls at the time of syncope but does not fall to < 40 beats per minute for > 10 seconds with or without asystole for <3 seconds . \n heart rate falls to a ventricular rate < 40 beats per minute for > 10 seconds but asystole of > 3 seconds does not occur . \n heart rate does not fall > 10% from its peak at the time of syncope . \n the electrocardiogram is another important component in the work - up of patients with syncope ; this study establishes a definite diagnosis in approximately 5 percent of patients and is suggestive of the diagnosis in another 5 percent . \n some findings that may identify the probable cause of syncope include prolonged qt interval ( long qt syndrome ) , the presence of a delta wave ( wolff - parkinson - white syndrome ) , the presence of a right bundle branch block pattern with st segment elevation ( brugada syndrome ) , heart block , or the presence of t - wave inversion in the right precordial leads ( arrhythmogenic right ventricular dysplasia ) . however , most patients with syncope have normal electrocardiogram results . \n this fact suggests that cardiac anomalies are an unlikely cause of syncope , which accordingly is often associated with a good prognosis , particularly in young patients . in spite of the low diagnostic yield of electrocardiogram , it is inexpensive and risk - free . for these reasons , \n an electrocardiogram is considered a standard part of the evaluation for virtually all patients with syncope . \n the interval from the peak of the t wave to the end of the t wave in the electrocardiogram tracing has been referred to as the t - peak - to - t - end interval . \n this parameter is an indicator of transmural dispersion of surface electrocardiogram , which evaluates ventricular repolarization , and also is an indicator of the risk of arrhythmia . \n three electrophysiological types of cells -endocardial , epicardial , and m cells - , have been identified in the ventricular myocardium . \n differences in the course of repolarization of these three myocardial cell types contribute to the inscription of the t - wave on the electrocardiograph . \n the peak of the t - wave coincides with epicardial repolarization and the end of the t - wave with repolarization of the m cells , so that t - peak - to - t - end interval is an indicator of the transmural dispersion of repolarization . measuring t - peak - to - t - end dispersion provides an indicator of the maximum dispersion of repolarization : this indicator reflects variations of the transmural dispersion of repolarization among different regions of the ventricular myocardium . \n this interval can be a helpful predictor of the development of life - threatening arrhythmias[16 , 17 ] , as shown in studies that found it to be a risk factor for sudden cardiac death or ventricular arrhythmias in patients with brugada syndrome and hypertrophic cardiomyopathy[18 , 19 ] . \n however , other studies showed that prolonged t - peak - to - t - end interval was not associated with increased arrhythmic risk in patients with long qt syndrome , or in post - myocardial infarction patients treated with amiodarone[21 , 22 ] . \n takenaka et al showed that exercise can accentuate t - peak - to - t - end interval in patients with the form of congenital long - qt syndrome type 1 caused by a functional defect in the slow component of the delayed rectifier potassium current , but not in those with the type 2 form of congenital long - qt syndrome caused by a functional defects in the rapid component of the delayed rectifier potassium current . \n topilski et al found that qt , corrected qt and t - peak - to - t - end intervals were strong predictors of torsade de pointes . \n watanabe et al demonstrated that prolonged t - peak - to - t - end interval was associated with the development of ventricular tachycardia in high - risk patients with organic heart disease . \n a study also showed relationship between the t - peak to t - end interval , ventricular tachyarrhythmia , and death . \n current recommendations are to measure the t - peak - to - t - end interval in the precordial leads . \n if biphasic or triphasic t waves occur , the recommendation is to measure the interval from the first components nadir of the t wave to the end of the t wave[27 , 28 ] . to our knowledge \n , no studies have evaluated the relationship between t - peak - to - t - end and syncope , but a study by kula s et al showed that corrected qt dispersion measured in patients with neurally - mediated cardiac syncope showed circadian variations , with peak values in the late night and morning hours . \n they observed that corrected qt dispersion peaked in the morning hours , which coincides with the time of the peak number of episodes in these patients . \n a study by benatar and carbonez showed that the t - peak - to - t - end interval lengthened with increasing age as the heart rate decreased , and another report found no gender differences in t - peak - to - t - end interval between boys and girls . \n patients with catecholaminergic polymorphic ventricular tachycardia and the ryr2 mutation show increased t - peak - to - t - end interval at high heart rates , which improves with beta - blocker treatment . the t - peak - to - t - end interval can not be used to distinguish symptomatic from asymptomatic patients with congenital long qt syndrome . \n the t - peak - to - t - end to qt interval ratio has been shown to be an electrocardiographic indicator of arrhythmo - genesis for both congenital and acquired ion channel diseases that lead to ventricular arrhythmias . \n small sample size was the major limitation of our study which may preclude generalization of this study . \n our study of a sample of children with syncope shows that t - peak - to - t - end interval in lead v1 and t - peak - to - t - end dispersion were significantly larger in patients with a positive tilt test , and we suggest that this parameter may be useful in diagnosing pediatric patients with syncope . \n ", "role": "user" }, { "content": "objectivethe purpose of this study was to examine the relationship between t - peak - to - t - end interval and its dispersion in children with syncope to detect possible repolarization abnormalities in these patients.methodswe enrolled 19 patients with a positive tilt test for syncope ( 7 boys , 12 girls ) and 35 participants with normal results on the test.findingsmean age was 11.43.1 years in patients and 10.05.1 years in controls ( p = 0.27 ) . \n the t - peak - to - t - end interval in lead v1 was significantly longer in patients with a positive tilt test ( 0.360.062 vs. 0.320.071 , p=0.007 ) . \n t - peak - to - t - end interval dispersion was significantly greater in the group of patients ( 0.150.07 vs. 0.110.04 , p0.003).conclusionthe t - peak - to - t - end interval in lead v1 and t - peak - to - t - end dispersion were significantly larger in patients with a positive tilt test . \n our findings suggest a depolarization abnormality in children with syncope .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: among the several types of biocontrol \n agents , the pathogenic arthropod \n microorganisms such as the filamentous fungus metarhizium \n anisopliae deserve special attention \n . this fungus can infect \n a broad range of arachnid and insect hosts , from agricultural pests \n to vectors of human disease and recently the venomous spider loxosceles sp.m . \n anisopliae is also one of the \n most studied and applied biological control agents worldwide . \n this fungus has been successfully applied since \n the 1970s in brazil to control sugar cane pests , but the slow speed \n to kill some targets compared with chemical pesticides limits its \n commercial adoption . \n understanding the molecular mechanisms of the \n host / fungus interaction and identifying the proteins specifically \n expressed during the infection are crucial steps to improve biocontrol . \n the information can be applied to optimize commercial formulations \n or identify more efficient strains in nature or in fungal libraries . \n crop losses in brazil caused by arthropods can reach 75% for upland \n cotton and 35% for perennial cotton , of which about half is caused \n specifically by cotton stainer bugs ( dysdercus spp . \n , \n hemiptera : pyrrhocoridae).dysdercus peruvianus causes damage by eating cotton seed , staining the fibers , and transmitting \n phytopathogenic bacteria and fungi . \n the host - infection process of m. anisopliae begins \n with conidial adhesion to the host s exoskeleton surface ( unlike \n other biocontrol agents that require ingestion ) . \n after that , proteins \n are secreted for cuticle penetration and the enzyme activities that \n are secreted depend on the cuticle composition of the host . \n digestion of the cuticle is multifactorial and \n involves the mechanical pressure of the host tegument by apressorium \n combined with the participation of secreted hydrolytic and degradative \n enzymes , like proteases , chitinases , and lipases , that allow the penetration \n of the fungi through the host cuticle . during these events , \n classical aspects of the host immune system \n are activated , triggering countermeasures to the invading fungus . \n the dynamic interaction between fungus and insect \n the discovery \n of the insect - specific components may enable the development of improved \n formulations of biocontrol agents . \n the fungal proteins secreted \n during the interaction of m. anisopliae and d. peruvianus have not \n been analyzed in depth . \n two proteins ( gapdh and phosphatase ) have \n been implicated in the first step of infection and adhesion . \n the mechanism of m. anisopliae infection of the cotton stainer bug is unclear , \n and new studies are needed to better elucidate the mechanisms involved \n in invasion . in this work , we used insect cuticle to activate \n the fungal infection \n system and analyzed the secreted proteins \n by shotgun proteomics . \n differentially secreted \n proteins were also analyzed in silico , producing a network that revealed \n the potential interaction among proteins identified . \n the results \n present in this article are an important contribution to an understanding \n of this host pathogen system . \n anisopliae e6 ( its - based species identification \n genbank accession number ef051705 ) isolated from spittlebug ( deois flavopicta ) from the state of esprito santo , \n brazil was kept in cove s medium , and conidia were produced \n for liquid culture growth , as previously described . \n spores ( 10 ml ) were inoculated \n in 70 ml of basal medium ( bm ; 0.6% nano3 , 0.2% glucose , \n 0.2% peptone , 0.05% yeast extract ) containing 0.05% cholesteryl stearate \n and 0.7% d. peruvianus ( dp ) cuticle ( as infection \n condition ) or 1% glucose ( g ) for the control condition to mimic infection \n conditions . \n the flasks were incubated \n at 28 c with shaking ( 150 rpm ) for 48 or 96 h. the choice for \n this culture medium and culture times and conditions was made based \n on our previous work , where we detected \n infection enzymes , lipases , and proteases differentially in the presence \n of host cuticle components compared with different controls , where \n one of them was 1% glucose . \n also , in this previous work , we have proved \n that glucose had no influence on the secretion of these enzymes . \n therefore , \n glucose is not acting as a catabolite repressor and can be used to \n define the constitutive secretome , as previously used . \n a more detailed discussion about the use of glucose as control condition \n is presented as supporting information s1 . for cuticle preparation , \n adults of d. peruvianus were crushed by pressing and centrifuged 10 min , 8.000 g , to remove internal material . \n the cuticles were rinsed extensively \n five times with sterile , distilled water and sterilized by autoclaving \n and dried at 50 c before use in liquid cultures . \n triton x-100 was added and manually mixed \n to extract enzymes and proteins from the external surface , as previously \n described . \n these culture filtrates \n containing secreted proteins were used for experiments . after the \n filtration , 65 ml of each culture sample was immediately boiled for \n 15 min to inactivate m. anisopliae proteases , followed \n by freezing at 80 c and lyophilization . \n five ml of each \n replicate was directly frozen in 200 l aliquots and kept at \n 80 c for enzymatic assays . \n , colonies of d. peruvianus were maintained in transparent plastic flasks covered with a screen . \n insects were provided with cotton seeds ( gossypium hirsutum ) as a food source and sterile water . \n colonies of adult insects were maintained in a humid chamber ( > 90% \n rh ) at 28 c with a 16l:8d photoperiod . \n three \n groups of 20 adult insects were chosen \n randomly and used in each experiment . for exposure , \n anisopliae conidia ml for 15 s. after immersion , insects \n were separated into three groups of 20 ( 60 for each treatment ) and \n placed in glass flasks ( 63 cm 12 cm ) covered with \n a screen tissue and provided with cotton seeds and sterile water . \n all groups were maintained in a humidity chamber ( 90% rh ) at 28 c \n under a 16:8 l : d photoperiod . \n individual experiments were replicated three \n times . as a control , insects were treated in exactly the same way , \n but they were immersed in sterile water instead of the conidial suspension . \n protein measurements were carried out using the bicinchoninic acid \n ( bca ) protein assay ( pierce , rockford , il ) with bovine serum albumin \n as the standard . lyophilized supernatants \n were resuspended in small volumes of purified water ( jtbaker , usa ) \n and precipitated using methanol / chloroform . \n the protein concentration \n was determined using the bca assay ( thermo scientific , il ) . \n approximately \n 100 g m. anisopliae secreted proteins in dp \n cuticle or glucose ( 48 and 96h ) was suspended in digestion buffer \n ( 8 m urea , 100 mm tris - hcl ph 8.5 ) . \n proteins were reduced with 5 mm \n tris-2-carboxyethyl - phosphine ( tcep ) at room temperature for 20 min \n and alkylated with 10 mm iodoacetamide at room temperature in the \n dark for 15 min . after the addition of 1 mm cacl2 ( final \n concentration ) , \n the proteins were digested with 2 g of trypsin \n ( promega , madison , wi ) by incubation at 37 c during 16 h. proteolysis \n was stopped by adding formic acid to a final concentration of 5% . \n samples were centrifuged at 14 000 rpm for 20 min , and the \n supernatant was collected and stored at 80 c . \n three \n biological replicates and two technical replicates were analyzed for \n both m. anisopliae culture conditions ( 48 or 96 h \n in dp and g ) . \n capillary packed with 2.5 cm of 5 m luna \n strong cation exchanger ( scx ) ( whatman , clifton , nj ) followed by 2 \n cm of 3 m aqua c18 reversed -phase ( rp ) ( phenomenex , ventura , \n ca ) with a 1 m frit . \n the column was washed with buffer containing \n 95% water , 5% acetonitrile , and 0.1% formic acid . \n capillary with a 5 m pulled tip packed with \n 11 cm of 3 m aqua c18 resin ( phenomenex , ventura , ca ) was attached \n via a union . \n the entire split - column was placed in line with an agilent \n 1100 quaternary hplc ( palo alto , ca ) and analyzed using a modified \n 12-step separation , as previously described . \n the buffer solutions used were 5% acetonitrile/0.1% formic acid \n ( buffer a ) , 80% acetonitrile/0.1% formic acid ( buffer b ) , and 500 \n mm ammonium acetate , 5% acetonitrile , and 0.1% formic acid ( buffer \n c ) . \n step 1 consisted of a 70 min gradient from 0100% ( v / v ) \n buffer b. steps 210 had a similar profile with the following \n changes : 3 min in 100% ( v / v ) buffer a , 3 min in x% ( v / v ) buffer c , \n 4 min gradient from 0 to 10% ( v / v ) buffer b , and 101 min gradient \n from 10100% ( v / v ) buffer b. the 3 min buffer c percentages \n ( x ) were 10 , 20 , 30 , 40 , 50 , 60 , 70 , 80 , 90 , and 100% ( v / v ) . \n an additional \n step containing 3 min in 100% ( v / v ) buffer a , 3 min in 90% ( v / v ) buffer \n c and 10% ( v / v ) buffer b , and 110 min gradient from 10100% \n ( v / v ) buffer b were used . \n peptides \n eluted from \n the microcapillary column were electrosprayed directly into an ltq - xl \n mass spectrometer ( thermo finnigan , palo alto , ca ) with the application \n of a distal 2.4 kv spray voltage . \n a cycle of one full - scan mass spectrum \n ( 3002000 m / z ) followed by \n five data - dependent ms / ms spectra at a 35% normalized collision energy \n was repeated continuously throughout each step of the multidimensional \n separation . to prevent repetitive analysis , \n dynamic exclusion was \n enabled with a repeat count of 1 , a repeat duration of 30 s , and an \n exclusion list size of 200 . \n application of mass spectrometer scan \n functions and hplc solvent gradients was controlled by the xcalibur \n data system ( thermo , san jose , ca ) . \n protein \n identification and quantification analysis were done with integrated \n proteomics pipeline ( ip2 , integrated proteomics applications , inc . , www.integratedproteomics.com/ ) . \n tandem mass spectra were extracted \n into ms2 files from raw files using rawextract 1.9.9 and were searched using prolucid algorithm against the m. anisopliae arsef23 database \n from the national center for biotechnology information ( ncbi ) ( http://www.ncbi.nlm.nih.gov/genome/?term=metarhizium%20anisopliae%20arsef23 , downloaded on august 8 , 2012 ) . \n the peptide mass search tolerance \n was set to 3 da , and carboxymethylation ( + 57.02146 da ) of cysteine \n was considered to be a static modification . \n prolucid results were \n assembled and filtered using the dtaselect program using two sequest - defined \n parameters : the cross - correlation score ( xcorr ) and normalized difference \n in cross - correlation scores ( deltacn ) to achieve a false discovery \n rate of 1% . \n the following parameters were used to filter the peptide \n candidates : -p 1 -y 1 --trypstat --fpf 0.01 --dm -in . \n the software patternlab was used to identify \n differentially expressed proteins ( tfold module ) found in 48 and 96 h of m. anisopliae grown \n in dp cuticle . \n spectral counting ( as used by patternlab ) is \n a well - established semiquantitative method of determining relative \n protein abundance . \n the following parameters \n were used : proteins that were not detected in at least four out of \n six runs per condition were not considered , and bh q value of 0.05 ( 5% fdr ) was set . \n each individual protein was calculated \n according to the t test ( p value \n of 0.005 ) using an f stringency of 0.04 . also , an absolute fold change \n greater than two was used to select differently expressed proteins . \n patternlab s approximate area proportional venn diagram ( aapvd ) \n module was used for pinpointing exclusive proteins identified in a \n condition using a probability of 0.01 . \n the blast2go tool ( http://www.blast2go.org ) was used \n to categorize the proteins detected by gene ontology ( http://www.geneontology.org ) ( go ) annotation according to biological \n process and molecular function . \n other bioinformatic tools were \n used to investigate the characteristics \n of those proteins identified by mudpit . \n the targetp 1.0 ( cutoff > 0.9 ) , tmhmm 2.0 , and wolf psort ( http://wolfpsort.seq.cbrc.jp/ ) were used to \n evaluate the subcellular location , and signalp 4.1 and predgpi ( http://gpcr.biocomp.unibo.it/predgpi/index.htm ) were used for prediction of secreted proteins . \n targetp , tmhmm , \n and signalp programs are available in http://www.cbs.dtu.dk / services/. to avoid false - positives , we made the following analysis : ( 1 ) all \n proteins identified as secreted using targetp and signalp were extracted \n and then ran using tmhmm . \n then , all positive proteins yielded from steps ( 1 ) and \n ( 2 ) were used as input for wolfpsort to discard false - positives . \n one \n protein was considered secreted if it was positive in all of these \n programs : steps ( 1 ) plus ( 2 ) and wolfpsort . at the same time \n we also ran an analysis of the m. anisopliae secretome \n using the orthomcl program ( http://orthomcl.org/orthomcl/ ) to get valid assignments of our identified proteins to orthomcl - db \n groups , a set of proteins across one or more species that represent \n putative orthologs and in - paralogs . to construct a reference data \n set with the known interactions for the m. anisopliae , starting from the protein regulation data set originated from patternlab s \n aapv module , we downloaded from uniprot ( http://www.uniprot.org ) the database release uniprot_sprot_fungi 01_13 . \n we developed an \n in - house software tool to parse the protein list to extract the gene \n ontology terms . \n ontological \n distance was calculated considering the fraction of go terms \n shared over the sum of all distinct terms ; the resulting score is \n then bounded between 0 and 1 . \n we developed an in - house \n software tool to parse the protein ontological distance list into \n an interaction network . \n each interaction is not directional and is \n representative of the corresponding score in the ontological distance \n data set . \n each node in the interactions list is assigned a color based \n on its value in the protein regulation data set ranging in a gradient \n from blue , for down - regulated values , to red , for up - regulated ones . \n to visualize the network we used the open source medusa viewer . \n more detailed information about the interaction \n network is presented as supporting information \n s2 . for the protease assays , \n the reactions were initiated by adding dl - bapna ( benzoyl - dl - arginine-na ) or pr1-specific synthetic peptide substrate \n ( suc - ala - ala - pro - phe-na ) at 0.2 mm ( final concentration ) . \n kinetic \n assays were monitored at 37 c for 30 min in a spectramax spectrophotometer \n equipped with thermostat and shaking systems . one protease unit ( u ) \n was defined as the amount of enzyme that produces one mol of \n -nitroaniline per hour under the assay conditions described . \n catalase activity was \n estimated by the decrease in absorbance of h2o2 at 240 nm for 3 min . \n the decomposition of h2o2 was followed at 240 nm ( e = 39.4 mm cm ) . \n the assay for superoxide dismutase ( sod ) was conducted as \n previously \n described . a solution containing 0.05 \n m potassium phosphate buffer ph 7.8 , 13 mm l - methionine \n , \n 75 mm nbt ( nitrobluetetrazolium ) , 0.1 mm edta , and 0.025% triton x-100 \n was added to glass tubes . to start the reactions , we added the sample \n and 10 mm riboflavin at the same time that tubes were placed under \n fluorescent light for 15 min . \n sod unit was defined by nbt reduction per ml h. phosphatase activity was measured by the rate of -nitrophenol \n ( -np ) production . \n samples were \n incubated for 60 min at room temperature in 0.2 ml of reaction mixture \n containing 116.0 mm nacl , 5.4 mm kcl , 30.0 mm hepes - tris buffer ph \n 7.0 , and 5.0 mm -nitrophenylphosphate ( p - npp ) \n as substrate . \n the reaction was stopped by the addition of 0.2 ml of \n 20% trichloroacetic acid . \n subsequently , the reaction mixture was centrifuged \n at 1500 g for 15 min at 25 c . \n the absorbance \n was measured spectrophotometrically at 405 nm using a microplate reader \n spectramax ( molecular devices , usa ) . \n the concentration of released \n -nitrophenolate in the reaction was determined using a standard \n curve of -nitrophenolate for comparison . \n all enzymatic assays were performed \n in triplicate , with results obtained from at least three separate \n experiments . \n data were analyzed statistically using the student s t test and graphpad prism 5 software . \n to confirm the ability of m. anisopliae to infect \n and kill d. peruvianus , we performed \n bioassays . one hundred percent mortality of d. peruvianus was observed 6 days after exposure to m. anisopliae conidia formulation ( 10 conidia ml ) compared with 25% of the control ( figure s1 in the supporting information ) . \n changes in the secreted proteome \n induced by exposure to host cuticle , ( a model for infection condition ) \n were identified by comparing to a control condition ( glucose ) at 48 \n and 96 h. many more proteins were identified under the control condition , \n some overlapped , and others were unique to infection ( figure 1 ) . \n some important proteins related to cuticle degradation \n ( proteases ) and to defense and stress ( catalase and sod ) were identified \n exclusively in the secretome mimicking infection condition ( table 1 ) . \n distribution and overlap of proteins from m. anisopliae supernatant when grown in d. peruvianus cuticle \n medium after ( a ) 48 or ( b ) 96 h compared with glucose ( control medium ) . \n proteins were classified according \n to gene ontology . of the \n proteins seen under both conditions , \n 14 and 10 proteins \n were identified as differentially regulated at 48 and 96 h of growth \n in d. peruvianus cuticle , respectively ( table 2 ) . among these , eight were considered up- and six \n down - regulated in 48 h , and one up- and nine down - regulated for 96 \n h. the subtilisin protease pr1b was the only protein up - regulated \n at both time points . \n proteins were differentially expressed \n statistically using patternlab s tfold module , with an absolute \n fold change greater than 2.0 . \n negative numbers represent down - regulated proteins in supernatant \n when grown on insect cuticle , compared to control condition . \n we also analyzed the media before \n exposure to fungus to detect \n background contamination from the media components . according to the \n results \n , we can eliminate the media as a source of contamination ( supplemental \n table s1 in the supporting information ) . \n gene ontology ( go ) analyses provided a good view of m. \n anisopliae response to different conditions of growth . \n the \n go annotations of differentially regulated and exclusive proteins \n are shown in figure 2 . \n proteins containing \n hydrolase activity ( 34% ) ( including important virulence factors such \n as proteases ) , other functions ( 21% ) , and oxidoreductase activity \n ( 13% ) were most abundant in 48 h. the same molecular functions were \n also identified in 96 h : hydrolase activity ( 22% ) , other ( 23% ) , and \n oxidoreductase activity ( 13% ) . \n of the seven different proteins differentially \n regulated and annotated as hypothetical , we found four with conserved \n domains : tyrosinase ( oxidoreductase activity ) ; fungal lectine , related \n to immunomodulatory response , pyridoxamine 5-phosphate oxidase , \n related to fmn binding ; and endopeptidase ( table 3 ) . \n molecular functions are represented at \n multilevel for differentially expressed proteins obtained from m. anisopliae supernatant when grown in d. peruvianus cuticle medium for ( a ) 48 or ( b ) 96 h. according to blastp search . \n as others \n have , we addressed \n this issue by in silico scanning our identified proteins for secretion \n signals . \n table s2 in the supporting information shows the predicted localization and possible secretion of all proteins \n identified as differentially expressed under infection condition . \n the analysis was done using six different programs : targetp , signalp , \n tmhmm , predgpi , and wolfpsort following a pipeline , as already described , and secretool as alternative analysis . according \n to the results , \n 45% of proteins were inferred as secreted , extracellular , \n or containing peptide signal sequence . during the infection process \n of fungal pathogens , \n the amount \n of 45% of proteins inferred as secreted or containing peptide signal \n in our work is in accordance with the average of the majority of the \n fungal secretomes , but even with some of the proteins lacking in silico \n evidence of secretion , such as sod and ceramidase , they could be secreted \n by a nonclassical mechanism , such as through vesicles or by physiological \n wounding . \n it is possible also that some of these proteins could be \n products of mechanical wounding promoted by the mycelial agitation \n during culture or autolysis . \n however , as precisely pointed out in \n a botrytis cinerea secretome study , if cell lysis occurs , one would expect to observe many \n intracellular proteins that are known to have high abundance as internal \n mycelium proteins , and those specific proteins were not observed in \n our results . \n moreover , as recently reviewed for fungal secretomes , there are several lines of evidence indicating \n that various kinds of mechanistically distinct nonclassical export \n routes may exist and pathogenic fungi appear to have a particular \n feature lying in their ability to secrete proteins without canonical \n secretion signal . \n also , different proteins known to be only cytoplasmic \n are being commonly identified in fungal secretomes , and their presence \n does not seem to result from artifacts ( e.g. , cell lysis ) ; their functions \n in pathogenesis have not yet been identified . \n several proteins found \n in our work have matched with correspondent orthologs of other pathogenic \n fungi . among the fungi that presented correspondent matches with m. ansiopliae proteins \n , we could find different species \n being 50% matching to plant pathogens , around 10 and 37% to human \n pathogens and to other fungi considered nonpathogenic , respectively . \n interestingly , one of the proteins , the proteinase inhibitor i4 , has \n matched to a drosophila melanogaster protein . \n we also have made \n a comparison of our data to proteins identified \n in plant pathogens secretomes ( table 5 ) . because \n the infection processes of filamentous fungi entomopathogens and phytopathogens \n are very similar ( in molecular compounds , host and fungal structures , \n penetration process , and enzyme secretion ) , it is very interesting \n to identify common and specific proteins secreted induced by specific \n host components . \n several proteases , enzymes related to oxidative stress , \n phosphatases , and carbohydrate active enzymes were common to entomo- \n and phytopathogenic fungus . \n interestingly , \n some proteins \n identified in this paper were previously identified in other proteomic \n experiments related to insect infection ( table s3 in the supporting information ) . \n three proteases , pr1a , \n i , and j , were identified in a previous study of d. peruvianus . \n enzymatic assays for protease and \n for other enzymes were also applied to further validate the proteomic \n data . \n table 6 shows that the enzymatic activity \n results are in accordance with the proteomic results . for proteases \n we used two na substrates : general protease and the specific \n pr1 activity were higher when m. anisopliae was grown \n in culture media , mimicking the infection condition for both times \n analyzed . \n phosphatase \n activity in 48 h and catalase and sod activities were \n also higher under infection conditions thanunder control conditions . \n the identification and validation of known secretome components \n supports the use of the experimental design presented in this work \n to identify infection - related secreted proteins . to evaluate the network \n of those differentially regulated proteins identified exclusively \n under infection conditions ( cuticle secretome ) , we generated interaction \n networks . \n for the 48h time point , 24 proteins ( 58% ) were identified \n ( figure 3a ) . \n we observed that one protein represents \n the majority of connections : the serine protease pr1c . \n this protein \n was identified as up - regulated under infection conditions and was \n able to form 11 connections with several other proteases , including \n pr1a , b , i , and j ( figure 3b ) . \n it is therefore \n tempting to speculate that the physiological interaction between these \n proteins might contribute to the cooperation or coordination of their \n functions in the degradation of proteinaceous arthropod cuticle layer . \n evaluating the network by the highest score , \n that is , closest similarity \n in the ontological distance , we identified three groups . \n the first \n group related to protein degradation ( pr1a , i , and j ) , the second \n group with two proteins related to oxidation and fad binding , and \n the third group related to sugar degradation ( figure 3c ) . \n network analysis of differentially expressed proteins identified \n in 48h m. anisopliae supernatant when grown d. peruvianus cuticle medium . \n ( b ) cluster identifying proteins with higher connectivity : blue circle \n shown in panel a. ( c ) clusters showing higher score or strong interaction : \n red rectangles shown in panel a. spheres and triangles represent proteins ; \n lines connecting spheres indicate interactions between proteins . \n red \n spheres , proteins up - regulated in response to dp cuticle ; blue spheres , \n proteins down - regulated ; green triangles , exclusive proteins identified \n in dp cuticle . \n when the 96h network \n was analyzed , 40% of the proteins had predicted \n interactions ( figure 4 ) . \n when compared with \n the 48 h time point , it was not possible to identify any clusters \n of proteins with multiple connections . \n however , the highest score was observed \n for the same group that already appears in the 48 h time point , functions \n related to sugar degradation , suggesting the importance of these proteins \n in glucose uptake for fungal growth . \n network analysis of differentially expressed \n proteins identified \n in 96h m. anisopliae supernatant when grown d. peruvianus cuticle medium . \n spheres and triangles represent \n proteins ; lines connecting spheres indicate interactions between proteins . \n red spheres , proteins up - regulated in response to dp cuticle ; blue \n spheres , proteins down - regulated ; green triangles , exclusive proteins \n identified in dp cuticle . \n evaluating the secretion of proteins during \n the growth of microbial \n pathogens under artificial infection conditions could reveal strategies \n and the components responsible for the success of the host infection \n and colonization . \n the strategy of applying synthetic media to induce \n the activation of the infection systems has been applied with success , \n revealing genes and proteins involved in different stages of metarhizium anisopliae s infection process . \n most of the work in m. anisopliae has analyzed gene expression , which makes the identification of \n secreted proteins difficult . \n proteomics \n data is closer to the biologically active processes and should therefore \n be used to investigate biological phenomena and mechanisms , and it \n can be used to measure the presence of proteins in subcellular locations . \n only a few proteomic studies have been published \n on m. anisopliae and all applied low - throughput techniques . by applying shotgun proteomics , we were able to identify 71 proteins differentially expressed \n under infection conditions . \n most of these proteins were not detected \n in other proteomic experiments about insect infection . \n multiple molecular functions were assigned to these 71 proteins \n by go annotation , including several known to be involved in m. anisopliae infection ( hydrolase activity , enzyme inhibitor \n activity , oxidoreductase activity , superoxide dismutase activity , \n and protein and carbohydrate binding ) . \n the infection process occurs in three \n stages : ( 1 ) adhesion to the \n cuticle , ( 2 ) penetration of the cuticle , followed by ( 3 ) host colonization \n of the internal tissues . in this study \n , we addressed the secreted \n proteins induced by interactions with the host cuticle that are involved \n mainly in the second stage . \n for these stages , cuticle - degrading enzymes , \n virulence factors , and proteins related to nutrient acquisition were \n identified . \n in addition to many previously reported proteins that \n play key roles in host infection , here we report several additional \n new potential factors that could also play key roles in the important \n biological process of infection ; suggesting that the proteins may \n be attempting to manage the host response to infection . \n interestingly , \n we see this fungal action in the absence of an active host defense \n system . \n secretion of enzymes causing \n cuticle disruption enables penetration and gives a strong advantage \n to pathogens . \n lipolytic enzymes have been described \n as essential for m. anisopliae infection , mainly \n in early stages . \n consistent with this finding , we identified lactonohydrolase \n and neutral ceramidase only at 48 h. these enzymes are very specific , \n which is important considering the high complexity of lipids present \n in different host cuticles . \n moreover , ceramidase activity was reported to enhance phospholipase \n c activity in microbial pathogens . \n phospholipase \n c is a classic microbial virulence factor that has been detected in m. anisopliae . among the \n degradative enzymes of m. anisopliae , proteases are \n crucial for the infection because they are required to break through \n the protein containing cuticle and prepare the host proteins in the \n hemolymph for absorption as nutrients . \n five members of the subtilisin - like serine proteases family , pr1 , \n were differentially expressed . \n this enzyme class is the most extensively \n studied and best understood \n in entomopathogenicity and may also influence virulence or host specificity . \n pr1a was previously detected in other proteomics studies about m. anisopliae infection in different hosts , including callosobruchus maculatus , rhipicephalus microplus , and also dysdercus peruvianus . \n therefore , this protease is related to host \n infection but not to host specificity . \n we expected that pr1a would \n be the predominant protein produced during degradation of insect cuticles \n because ests for pr1a are 10 times more abundant \n than the second most highly expressed sequence ( pr1j ) . \n we found that pr1a was highly increased ; \n however , the increase in another serine protease , pr1b , was even greater . \n surprisingly , pr1j was not similarly up - regulated . \n it is crucial to \n remember that the levels of transcripts and translated proteins are \n sometimes imperfectly associated , and assumptions \n based at rna expression level can be very wrong because the real players \n in the infection systems are the proteins . \n proteases , such as pr1a \n and b , were also described as part of a general response to nutrient \n deprivation . \n other pr1 proteases previously \n identified in d. peruvianus infection were also identified \n in this work : pr1i and j. according to \n our results pr1j was the only serine protease down - regulated in 48 \n h , being secreted together with other 4 pr1 proteases ( pr1a , b , c , \n and i ) , which were up - regulated at the same time . \n this differential \n expression among different pr1 proteases could be related to host \n specificity and different cuticle composition during the infection . \n as previously discussed , degradation products \n function as specialized signals , allowing the fungus to sample \n this feedback also could explain the huge difference \n in the fold change of pr1b between 48 and 96 h. the dynamic interaction \n requires that different proteases in different amounts are employed \n at different moments during infection . \n other proteases , protease inhibitor \n i4 and leupeptin inactivating enzyme , were also identified and could \n be closely related to this complex proteolytic system . \n the proteomic \n data are in accordance with the enzymatic assays . the assays with \n the specific substrate for pr1 presented remarkably higher activity \n under infection condition compared with the control condition . \n on \n the basis of our results and data previously published , it is obvious that each protease could have different biological \n and functional roles . \n we believe the fungus is continuously sampling \n the environment and adjusts its secretions accordingly . \n we were \n interested in determining if the identified proteins act \n in complexes or networks . \n therefore , we \n developed an in silico approach to identify proteins with similar \n profiles . beyond the independent role of each protease / protein during \n the infection , \n our integrative interaction results provide new insight \n and a wider view into the m. anisopliae infection \n system . \n pr1c occupies a central position in the largest cluster of \n proteins at 48 h. because this protein presents the highest number \n of interaction nodes , its up - regulation could be secondary in relevance \n for the system compared with a possible regulatory and interactive \n role with several other important proteins . also , \n the proteins pr1a , \n i , and j show different expression levels , but they present the strongest \n interaction forces forming an internal cluster in the large proteolytic \n cluster at 48 h. in this way , the results can rank possible targets \n for future studies and also identify important proteins independently \n of their expression levels . in all previous studies , \n the main conclusions \n were always made from proteins / genes up - regulated , and obviously some \n regulatory players could be missed due to the limitations of this \n limited analysis over the complexity of the system . \n another set of interesting proteins \n are enzymes involved in protection \n against reactive oxygen species ( ros ) . \n catalases and superoxide dismutases \n ( sod ) , classical examples of these proteins , were identified in our \n proteomic results and validated in enzymatic assays and reported in \n previous studies . \n ( see table s3 in the supporting \n information . ) catalases and sods associated with m. \n anisopliae conidia have been shown to be involved in protection \n against uv radiation . because attempted \n penetration by filamentous pathogens is known to provoke ros production \n by the host , we did not expect to see \n these proteins in our artificial infection condition because the insect \n is dead and can not elicit a defensive response . \n there is growing evidence that ros are \n important for many aspects of fungal life , including infection , structure \n formation , cellular communication and signaling , and ecological process . among all differentially expressed proteins \n identified , several of them are classified in oxidoreductase activity \n molecular function according to go annotation . \n oxidoreductases are \n related to alteration of redox state of the host , which can perturb \n host gene expression in response to environmental stress such as fungal \n growth . \n it is possible that oxidoreductase \n activity combined with up - regulation of sod and catalase alters the \n regulation of the redox system of the host during the infection . \n this \n possible interaction was detected in our network results , where sod \n and fumarate reductase were both interacting with catalase . \n tyrosinase , \n another protein traditionally associated with uv resistance of conidia , \n was also up - regulated in infection . in beauveria bassiana , this protein is thought to have a role in virulence in later stages \n of infection . \n there is a growing body \n of evidence that in addition to the well - established roles for these \n proteins in stress tolerance and protection in the host these proteins \n appear to have a new role in fungal virulence . \n unfortunately , the molecular role of these proteins in this process \n is still unclear . \n for instance , ros play a major role in phytopathogens \n infection , a very similar system to entomopathogens , and even in this \n system the specific role of these molecules is not well understood . \n one possibility is that the differential expression \n of these proteins could manipulate the host redox system to alter \n host signaling mechanisms and defense response . \n g proteins are a family of \n proteins involved in transmitting signals from outside the cell to \n inside the cell . in m. anisopliae , this protein was previously characterized , playing roles in regulation \n of conidiation , virulence , and adhesion , modulating its ability to \n respond to environmental stimuli . \n interestingly , \n in this work , only the beta subunit was detected and probably is related \n to an unknown function outside the fungal cell . \n tyrosine phosphatase , \n up - regulated at 48 h and down - regulated at 96 h , together with other \n phosphatases , also plays critical roles in signaling and biotic stress . \n these enzymes were previously described as secreted microbial virulence \n factors targeting host - cell immune responses . \n specifically , m. anisopliae tyrosine phosphatase \n interferes with insect innate immune response to microbial infection , \n dephosphorylating phosphoproteins involved in protein transport in \n insect hemolymph . \n moreover , phosphatase \n activity was also shown to be one of the mediators of the adhesion \n process on the host surface , and possibly \n these enzymes are playing multiple roles during different times of \n the infection out and inside the host . \n extracellular effectors are defined as \n small molecules and proteins \n secreted by pathogens into the host where they alter host - cell structure \n and function . \n some of these proteins \n are well known and are previously characterized fungal effectors and \n or signaling interfering proteins that can act on host metabolites \n or proteins , possibly modifying responses to fungal infection in benefit \n to the pathogen . \n unrelated fungal pathogens secrete the same \n effectors for creating a more compatible host environment , including \n mechanisms to manipulate host - cell metabolism . \n the effector repertoire includes several proteins previously \n identified and described : glycosyl hydrolases , proteases , ros - related \n proteins , among others ( figure 5 ) . \n another \n classical effector , the cysteine - rich protein , was \n also identified . \n the combination of all proteins identified during \n the artificial activation of the infection system could reveal that m. anisopliae is not only degrading and consuming host components \n but also is actively modulating host physiology by the secretion of \n different proteins . also , \n as presented in table 4 , the proteins found in our study presented orthologs in several \n different fungal pathogens , which is possible evidence of correlation \n and conservation of different pathogenic systems linked to different \n hosts . according to this analysis of putative orthologs , \n the proteinase \n inhibitor i4 had the best match corresponding to a drosophila \n melanogaster protein , which reinforces the idea that the \n fungus is possibly actively interfering the host response \n . this inhibitor \n having the best match corresponding to an arthropod protein could \n probably be because it inhibits proteases expressed by the host , an \n arthropod , during the infection . \n proposed schematic model of fungal effectors \n and other proteins \n expressed by m. anisopliae during d. peruvianus infection , according to proteomic data . because the infection processes of filamentous fungi entomopathogens \n and phytopathogens are very similar ( in molecular compounds , host \n and fungal structures , penetration process , and enzyme secretion ) , \n it is very interesting to identify common and specific proteins secreted \n induced by specific host components . among the shared proteins are \n several proteases , enzymes related to oxidative stress , phosphatases , \n and carbohydrate active enzymes . also , according to the analysis made \n to check ortholog proteins , half of the proteins identified have the \n best match for correspondent orthologs in phytopathogens , which are \n 47.9% proteins from fusarium graminearum . with this \n result , \n the idea that these two similar pathogenic systems are evolutionarily \n conserved is in accordance . \n the fad binding domain protein is also \n shared , and although it contains a predicted secretion signal , its \n extracellular role is unexpected and currently unknown . however , fad \n binding domains are considered to be one of the most frequent pfam \n domains found throughout the secretome of two important filamentous \n fungi plant pathogens , fusarium graminearum and mycosphaerella graminicola , and are also detected in b. cinerea secretome , other important plant pathogen , reinforcing \n our result and the similarity of both pathogenic systems . some of the 30 proteins exclusively identified in m. anisopliae were already described in plant pathogens with a role in infection , \n as cystein - rich protein , for instance , but not yet detected in secretome \n studies . because secretome data for fungal entomopathogens are still \n limited , this difference to plant pathogens could be a very interesting \n approach to understand the specificity of both systems . \n it is \n important to highlight also that according to the result \n presented we found orthologs matching to human pathogens , most of \n the proteins matching to aspergillus fumigatus , and \n around 37% matching to other fungi considered nonpathogenic , like aspergillus nidulans and neurospora crassa . specifically , the proteins with the best match for nonpathogenic \n fungi proteins are also interesting targets for future studies due \n to this close similarity to nonpathogens \n . these proteins could be \n specific for the infection of m. anisopliae s \n host and expressed along with proteins also expressed by other pathogenic \n fungi , allowing the success of the infection . \n in this work , we presented a new view into m. anisopliae s infection system using , for the first time , shotgun proteomics \n and interaction network analysis . \n the differential expression of several \n proteins other than just a few degrading enzymes and other already \n expected and previously known proteins was accessed . using the insect \n model d. peruvianus and the induction of the infection \n system by a host cuticle , it is now possible to learn that fungus \n secretes different proteins that can act over different substrates \n within host environment , possibly altering host response and preparing \n an improved condition for fungal colonization . among these several \n proteins , \n for instance , \n the protein quantified with the highest spectral count in 48 and 96 \n h , the regulatory p domain protein , according to genome annotation , \n is actually a hypothetical protein according to blastp and probably \n has an important role in d. peruvianus infection ; \n by using network analysis techniques , we could integrate part of secreted \n proteome \n . this strategy could provide a way to target proteins for \n future studies , analyzing not only expression changes during infection \n but also its interaction with other secreted proteins . \n microbial infection \n is a complex process between the host and the pathogen , and further \n investigation of each protein identified and its specific role in \n this complex system is necessary . \n although each host can trigger different \n molecular responses , m. anisopliae s infection \n strategy against the insect d. peruvianus looks very \n similar to other unrelated pathogenic fungi because all fungi need \n to prepare the host for a successful infection . \n other proteins presenting \n orthologs in nonpathogenic fungi are also interesting targets for \n future studies because it could be the difference of the entompathogenic \n system compared with other infection systems . \n the results presented \n here are a relevant advance in the understanding of this particular \n host pathogen interaction process and may be applicable to \n the search for more efficient strains and to develop new formulations \n to control the cotton pest d. peruvianus .", "role": "user" }, { "content": "metarhizium anisopliae is an entomopathogenic \n fungus that has evolved specialized strategies to infect insect hosts . \n here we analyzed secreted proteins related to dysdercus peruvianus infection . using shotgun proteomics , abundance changes in 71 proteins \n were identified after exposure to host cuticle . among these proteins \n were classical fungal effectors secreted by pathogens to degrade physical \n barriers and alter host physiology . \n these include lipolytic enzymes , \n pr1a , b , c , i , and j proteases , ros - related proteins , oxidorreductases , \n and signaling proteins . \n protein interaction networks were generated \n postulating interesting candidates for further studies , including \n pr1c , based on possible functional interactions . \n on the basis of these \n results , we propose that m. anisopliae is degrading \n host components and actively secreting proteins to manage the physiology \n of the host . \n interestingly , the secretion of these factors occurs \n in the absence of a host response . \n the findings presented here are \n an important step in understanding the host pathogen interaction \n and developing more efficient biocontrol of d. peruvianus by m. anisopliae .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: surgery is an integral component of global health care , with an estimated 234 million operations being performed annualy worldwide.1 however , the operating room is imperiled by the threat of adverse events , many of which are related to communication . \n insufficient or ineffective communication is the most frequent cause of adverse events across all areas of health care , culminating in harms that range from delays in treatment to medication errors to wrong site surgery.24 a systematic review of adverse event studies revealed that 41% of all hospital adverse events occurred in the high - risk milieu of the operating room5 and a retrospective audit of patient medical records suggested that 50% of identified events were preventable.6 specifically , communication and teamwork failures in surgery were identified as a contributing factor in 38% of incidents in nonemergency procedures and could impact in up to 59% of incidents in emergency cases.3 while the imperative to avoid communication errors in the operating room is widely promulgated in patient safety discourse , progress has been slow.7,8 ambiguities , silences , or omissions in conveying clinical decisions to other members of the surgical team during the intraoperative period impact on team cohesion , hamper performance , and can contribute to procedural error . \n however , there is a paucity of research describing the information rendered in creating the dialog around clinical decisions among members of the surgical teams . \n the aim of this observational study was to describe the strategies used to communicate decisions during surgery and the ways in which this dialog creates or compromises shared situational awareness . \n the concept of situational awareness was first described in aviation to explain the perceptual skills needed for the success of fighter pilots.9 situational awareness refers to an individual s ability to maintain the big picture in a dynamically changing environment.10 endsley11 proposed three levels of situational awareness based on perception , comprehension and understanding , and projection . put simply , \n situational awareness is characterized by three questions , where have we come from ? , where are we now ? , and where are we going?.12 within the three levels of situational awareness , four key factors in endsleys11 model include : the role of goals in directing attention to determining the significance of perceived information ; the role of expectations informed by current perceptions of the situation ; different methods of information processing ( eg , analytic and intuitive decision - making ) to achieve situational awareness ; and the salience of feedback in maintaining situational awareness . as such \n , situational awareness relies on differentiating situations that may appear to be similar to determine the scope of the situation.13 each situation has its own associated set of possible futures , depending on the actions of the individual . \n situations are classified on a continuum ranging from clear , routine , and easily managed at one extreme , to confusing and dangerous , requiring particular skills and expertise.13 in surgery , teams of surgeons , anesthetists , nurses , and technicians work together on tasks towards a common end goal . \n while situational awareness is critical to the performance of individuals , it is also crucial to the performance of the team as a collective.14 shared situational awareness is when members have an appreciation of each other s activities and share common perspectives of events and goals.15 shared situational awareness suggests that during team activities , situational awareness overlaps and individuals need to perceive , comprehend , and project situational awareness components specific to their role in the team . \n successful performance consequently requires that team members have a good situational awareness of their specific components and also similar situational awareness for shared components.10,16 specifically , shared situational awareness requires team members to have an understanding of the type of information needed by others , knowledge of the devices used to distribute situational awareness ( eg , shared visual displays ) , shared team processes to facilitate sharing of relevant information ( eg , communication , coordination , cooperation ) , and shared mechanisms , ie , a shared mental model.10,14 a shared mental model enables team members to adapt swiftly and coordinate their actions based on their underlying knowledge and understanding of each other and of the present situation.16 in high performance teams , when a significant change in the situation is detected , a more focused assessment takes place , rendering a proactive rather than reactive response to expected and unexpected events.14 while there is a need for teams to cultivate shared situational awareness through effective communication , individual members often experience disconnections in situational awareness.14 disconnections in situational awareness can occur when information is not passed between members in a clear and concise manner . \n in addition , when the information is passed on to others , team members may interpret the information differently , based on dissimilar mental models.14,16 finally , even when team members share a similar comprehension of the current situation , they may have disparate projections of what is likely to happen . \n thus , the different mental models that team members possess have a bearing on the predictions they make.14 communicating consequential information during surgery ensures that members are on the same page and enhances coordination . \n previous human factors research has examined the broad domains of situational awareness.1013 however , there is limited research that describes the dialog of clinical decisions communicated to team members and how this enhances or compromises the team s shared situational awareness . \n studies of coordinating decision - making are rare , and have tended to focus on the technical aspects of surgical procedures,17 while others have explicitly focused on the role of the surgeon1719 or the scrub nurse,20 with little attention given to the surgical team as a collective . in the operating room , team members often have to make decisions under time pressure , increasing risk , and when unforeseen conditions and unanticipated problems emerge . \n this is not only pertinent to emergency surgery , because capricious situations requiring new decisions and/or a change of plan may also occur during elective surgery . \n this study is important because it identifies strategies that may help team members build shared situational awareness . \n the strategies used to support this dialog build situational awareness and allow members to recognize aspects of the situation that may pose a threat to safety and ensure that , if required , other team members are able to respond in a timely and appropriate way . \n a qualitative study design based on fieldwork methods using participant observations and semistructured interviews allowed us to describe the content and context of dialog around decisions , and the ways in which this enhances or hampers team members ability to build shared situational awareness . \n this study was conducted in the operating department of a large metropolitan teaching hospital that caters for all surgical specialties , except for gynecology , obstetrics , and pediatrics , in queensland , australia . at the time of this study , \n the operating suite had 22 commissioned operating rooms and performed over 18,000 operative procedures annually . \n the department was staffed by over 250 health care professionals who held surgical , medical , nursing , and ancillary roles and provided around - the - clock coverage . in this facility , \n the team consisted of surgical and anesthetic consultants and their trainees and residents , and registered and/or enrolled nurses practicing in scrub , scout , or anesthetic roles ( in this facility , registered and licensed practical nurses were employed to perform scrub [ instrument ] ) , scout [ circulating ] , and anesthesia assistance roles . \n participants were purposively selected,21 based on their ability to render useful insights on this subject , and consisted of members from surgery , anesthetics , and nursing . \n the choice of surgical procedures was purposive and participants were drawn from interdisciplinary groups who worked across 10 surgical specialties ( ie , vascular , cardiac , general , orthopedic , ophthalmology , otolaryngology , faciomaxillary , plastics , urology , and neurosurgery ) . \n maximum variation sampling21 was used to capture diverse characteristics in relation to different surgical specialties , divergent levels of clinical experience , and subspecialty roles . by comparing the responses and experiences of participants against each other , \n discrete but important differences were uncovered21 about teamwork and decision - making practices in surgery . \n methods included a reflective diary , participant observation , field notes , and focused interviews . \n the authenticity of a field study relies on the experience and expertise of the observer . \n the first - named author ( bg ) was trained in human factors research , had extensive experience as an operating room nurse , and performed all field work observations and interviews . \n bg kept a diary and journaled her perceptions prior to , during , and after field work to reduce the propensity to accept any internalized , taken - for - granted assumptions about context.22 during fieldwork , bg was located away from the operating table , with each team member and all entrances to the room in view . \n semistructured interviews were used to elicit participant perceptions23 of teamwork practices and decision - making in surgery . \n participants also validated information gathered through other sources , including observations and statements made by other team members . \n interviews lasted 2560 minutes , and were conducted at the discretion of the participant in a room away from the main work area . based on their personal preference \n , participants were either interviewed in groups or individually . a general interview guide was used and topics covered explored issues surrounding the contextual factors that fostered or threatened effective interdisciplinary teamwork . \n as the fieldwork progressed , questions varied and new questions were asked based on emergent findings . for example \n , the majority of medical participants described communications that occurred around clinical decision - making . \n therefore , additional questions , ie , how did you know to make the decision ? , what information did you need ? , and how was this information conveyed to other team members ? , were asked in subsequent interviews . \n data saturation was evident as the analysis progressed and precipitated an end point to data collection when no new information was revealed . prior to commencing the interviews , \n demographic data were collected in respect to participant age , years of experience , and professional role . \n ethics approval was given by the human research ethics committees of the hospital and the university . \n no members of staff were interviewed or observed without informed written consent being obtained . during the study period , \n consent was renegotiated and participants were informed about their right to withdraw at any time . \n the analysis was performed using the transcribed field notes and interviews in an iterative manner that involved open coding and categorizing to develop themes.23 codes were developed based on topics raised by participants in relation to teamwork practices and were subsequently categorized based on their similarities and differences . thematic analysis involved \n a process of breaking down , examining , comparing , and conceptualizing data to enable recognition of emerging patterns to identify major themes.24 theme identification reflected recurring events and dialog with similar content , both within and across the textual data . \n the themes extracted and their corresponding explanatory data were crosschecked among the research team to ensure consensus . in labeling the themes , a thick description was used to indicate the context from which they were drawn . during analysis \n , meetings were held with the coresearchers to discuss and reconsider emerging themes and subthemes . in establishing trustworthiness \n , the tenets of auditability , triangulation , and transferability were considered.25,26 all members of the research team were involved in data analysis in order to identify irregularities and establish consistency . \n once complete , the preliminary findings were taken back to participants for clarification and confirmation . \n memos connecting emerging findings to pieces of verbatim - supported emergent themes , and demonstrated an audit trail . \n triangulation was achieved through use of multiple data sources , which allowed a broad range of issues to be crosschecked , achieving convergent validity.26 there was purposive selection of a wide range of participants , based on maximum variation21 which enabled a comprehensive overview of the phenomena under study , so there may be conceptual transference to other similar settings . \n this study was conducted in the operating department of a large metropolitan teaching hospital that caters for all surgical specialties , except for gynecology , obstetrics , and pediatrics , in queensland , australia . at the time of this study , \n the operating suite had 22 commissioned operating rooms and performed over 18,000 operative procedures annually . \n the department was staffed by over 250 health care professionals who held surgical , medical , nursing , and ancillary roles and provided around - the - clock coverage . in this facility , \n the team consisted of surgical and anesthetic consultants and their trainees and residents , and registered and/or enrolled nurses practicing in scrub , scout , or anesthetic roles ( in this facility , registered and licensed practical nurses were employed to perform scrub [ instrument ] ) , scout [ circulating ] , and anesthesia assistance roles . \n participants were purposively selected,21 based on their ability to render useful insights on this subject , and consisted of members from surgery , anesthetics , and nursing . \n the choice of surgical procedures was purposive and participants were drawn from interdisciplinary groups who worked across 10 surgical specialties ( ie , vascular , cardiac , general , orthopedic , ophthalmology , otolaryngology , faciomaxillary , plastics , urology , and neurosurgery ) . \n maximum variation sampling21 was used to capture diverse characteristics in relation to different surgical specialties , divergent levels of clinical experience , and subspecialty roles . by comparing the responses and experiences of participants against each other , discrete but important differences were uncovered21 about teamwork and decision - making practices in surgery . \n methods included a reflective diary , participant observation , field notes , and focused interviews . \n the authenticity of a field study relies on the experience and expertise of the observer . \n the first - named author ( bg ) was trained in human factors research , had extensive experience as an operating room nurse , and performed all field work observations and interviews . \n bg kept a diary and journaled her perceptions prior to , during , and after field work to reduce the propensity to accept any internalized , taken - for - granted assumptions about context.22 during fieldwork , bg was located away from the operating table , with each team member and all entrances to the room in view . \n semistructured interviews were used to elicit participant perceptions23 of teamwork practices and decision - making in surgery . \n participants also validated information gathered through other sources , including observations and statements made by other team members . \n interviews lasted 2560 minutes , and were conducted at the discretion of the participant in a room away from the main work area . based on their personal preference , \n participants were either interviewed in groups or individually . a general interview guide was used and topics covered explored issues surrounding the contextual factors that fostered or threatened effective interdisciplinary teamwork . as the fieldwork progressed , questions varied and new questions were asked based on emergent findings . \n for example , the majority of medical participants described communications that occurred around clinical decision - making . \n therefore , additional questions , ie , how did you know to make the decision ? , what information did you need ? , and how was this information conveyed to other team members ? , were asked in subsequent interviews . \n data saturation was evident as the analysis progressed and precipitated an end point to data collection when no new information was revealed . prior to commencing the interviews , \n demographic data were collected in respect to participant age , years of experience , and professional role . \n ethics approval was given by the human research ethics committees of the hospital and the university . \n no members of staff were interviewed or observed without informed written consent being obtained . during the study period , \n consent was renegotiated and participants were informed about their right to withdraw at any time . \n the analysis was performed using the transcribed field notes and interviews in an iterative manner that involved open coding and categorizing to develop themes.23 codes were developed based on topics raised by participants in relation to teamwork practices and were subsequently categorized based on their similarities and differences . thematic analysis involved \n a process of breaking down , examining , comparing , and conceptualizing data to enable recognition of emerging patterns to identify major themes.24 theme identification reflected recurring events and dialog with similar content , both within and across the textual data . \n the themes extracted and their corresponding explanatory data were crosschecked among the research team to ensure consensus . in labeling the themes , a thick description was used to indicate the context from which they were drawn . during analysis \n , meetings were held with the coresearchers to discuss and reconsider emerging themes and subthemes . \n in establishing trustworthiness , the tenets of auditability , triangulation , and transferability were considered.25,26 all members of the research team were involved in data analysis in order to identify irregularities and establish consistency . \n once complete , the preliminary findings were taken back to participants for clarification and confirmation . \n memos connecting emerging findings to pieces of verbatim - supported emergent themes , and demonstrated an audit trail . \n triangulation was achieved through use of multiple data sources , which allowed a broad range of issues to be crosschecked , achieving convergent validity.26 there was purposive selection of a wide range of participants , based on maximum variation21 which enabled a comprehensive overview of the phenomena under study , so there may be conceptual transference to other similar settings . \n over 500 hours of observations were recorded involving 39 surgeons , 26 anesthetists , 63 nurses , and 15 ancillary staff across 10 surgical specialties . during the 6-month observational period , 160 surgical procedures were observed . in total , 16 individual and three group interviews were conducted with 24 participants ( table 1 ) . \n participant age ranged between 23 and 66 years , and their years of clinical experience from 12 months to 40 years . \n the domain of coordinating decision - making in surgery encompassed the complexity of the surgery , the condition of the patient , knowledge of the task , and the skills and abilities of other team members . \n coordination concerned the deliberate effort at managing the task through explicit distributed communication that allowed team members to build their situational awareness . \n clinical decision - making entailed identifying and considering options , selecting and communicating options , and re - evaluating and reviewing decisions based on these options . \n subsumed within this domain were three interlinking themes , ie , synchronizing actions and strategizing to adapt , sharing local knowledge , and planning contingency decisions based on priority . \n the theme of synchronizing actions and strategizing to adapt was underpinned by the capacity of team members to communicate decisions in the management and timing of individual and team tasks in an explicit manner . synchronizing and strategizing incorporated communicating a course of action based on team members level of situational awareness . \n the use of open explicit dialog around decisions facilitated distributed situational awareness , allowing participants to respond appropriately to the cues provided by others . however , there were also occasions when participants described the need to consciously focus on the task at hand , even if this at times culminated in loss of the peripheral information sources needed to inform such decisions . \n for instance , anesthetist participants particularly emphasized the use of algorithms as a decision - making strategy to deal with an anesthetic emergency : you have a series of algorithms which you go through but because you have a reasonable idea of what is going wrong , you step into the algorithm half way down it instead of starting at the top and then because you are wrong you get the wrong result you get fixated and finish up thinking you are quite sure you are getting evidence but then the lights go on and you go \n ( consultant anesthetist , interview 7 ) this anesthetist s failures in perception and comprehension of the situation resulted in an incomplete mental model . \n consequently , an over - reliance on a set of prescribed steps stymied this participant s ability to resolve the problem at hand because he was locked into an incorrect picture of the situation . \n it was only when an adverse event occurred that the anesthetist realized his comprehension of the situation was flawed . \n another participant revealed that when an error in judgment occurred , the ability to process information from other sources rapidly diminished : \n when you have a situation where something does go unexpectedly wrong or you do something that has a bad outcome and things are deteriorating quickly then you feel the anxiety rising , you focus , you tunnel , you really are trying to think clearly but because there is all this oh my god , oh my god what have i done? , when things go wrong unexpectedly because you have done something , you are so focused on that that you often forget about the peripherals . \n ( consultant anesthetist , interview 6 ) the distress of having an unfavorable outcome had a debilitating impact on this participant s situational awareness , causing her to shut down , thus limiting her capacity to convey decisions to others at the height of a crisis situation . \n i deliberately , consciously slow down , when i am doing a hepatectomy ; just near the end there is a rush , the organ is hanging on by a slither , you have a huge amount of liver coming out , your big hand hanging onto it and the temptation is to draw on it and accelerate the process which increases a vascular injury so it is at that point where i say publically to everyone i am going to slow down because i am getting to the critical last little step. i talk people through what i am doing and am talking myself through it \n i like to have as much correspondence as possible at that critical time . ( consultant surgeon , interview 16 ) the overt act of talking through the delicate concluding stages of the procedure enhanced team situational awareness because it served a dual purpose : it permitted the surgeon to keep abreast of the situation , achieve coherence and agreement with other team members on the goals of the task ; and also allowed the surgeon to be more accessible to the assistance , suggestions , advice or questions from others . \n in contrast , junior surgeons tended to fixate on the technical problem during critical periods of the operation , and reduced the exchange of information to a minimum during that time . only information related to perceptions of the status and dynamic components of the immediate situation , ie , level 1 situational awareness,11 \n was communicated to others under the assumption that they would reach similar projections as the operating surgeon . \n scrub nurses articulated the importance of organizing the layout of their sterile work area in a way that it allowed them to place their hand directly onto the instrument without looking away from the operative field . experienced scrub nurses focused on the operative field and listened for conversational exchanges between consultant surgeons and their trainees to learn of changes to the operative plan . \n these behaviors increased nurses levels of situational awareness and they were able to pre - empt the surgeon s needs and think ahead to ensure that the operation progressed smoothly . \n an experienced nurse stated that her decisions on the selection of instrument to pass to the surgeon at any given stage of the operation were essentially governed by her understanding and conception of what s happening now , and what can possibly go wrong . \n the second theme , ie , sharing local knowledge , encompassed context - specific understandings of individuals and the situation as a whole , as well as its many facets , and the ways such understandings contributed to the communication of decisions to build shared situational awareness . local knowledge referred to team members awareness of nuances and practices of individuals and their roles in the context of different surgical specialties . \n accordingly , team members awareness of individual capabilities , the ability of members to cohese as a collective , the condition of the patient , and the status of the procedure being performed , and the environment ( equipment , position of the patient , room layout ) , not only influenced the decisions made , but also how the dialog was constructed and conveyed . \n shared situational awareness in cardiac surgery was fostered by the deliberate use of closed - loop communication to convey that the steps taken in making a decision were purposeful , logical , and deliberate . in the cardiac room , tasks around perfusion and cardioplegia were managed by the perfusionist and cardiac surgeon through a series of sequenced actions and minicommunications with the aim of identifying the cause of the problem and returning the patient s system to a more normal , desirable state.27 in the context of this study , a perfusionist is an anesthesiologist who has received additional specialist training in cardiac perfusion and cardioplegia . \n coordination of actions was frequently heralded by a deliberate annunciation of steps taken by the perfusionist and surgeon , making explicit their expectations based on the current situation : in cardiac anesthesia and perfusion the rule is that when you are given an instruction or asked to do something , you confirm verbally that that is what you are doing \n cardiac is very regimented , there is one way of doing things and that is it . \n i anaesthetize and perfuse differently and behave differently in cardiac than i do in general theaters . \n ( consultant anesthetist , interview 12 ) in the cardiac room , attention to the orchestration of actions allowed both the surgeon and perfusionist to recognize urgency and use appropriate recovery methods to manage deviations from expected events . \n the dialog around decisions in the cardiac room was in stark contrast with the way decisions were communicated among team members in other surgical specialties . \n for example , conveying or confirming decisions about a change in case requirements ( eg , impending need for a microscope ) or changes in the order of patients listed for a morning or afternoon session based on procedural complexity and the availability of consultant surgical expertise , appeared to be made independently , without consultation with other key personnel in the room . in this instance , the disparate mental models that members possessed likely influenced their comprehension and the projections they made . \n although procedures may be booked as elective or routine , cardiovascular fluctuations during surgery , and variations in the acuity of the patient and their surgical anatomy , influenced clinical decisions concerning the approach and ongoing management of these cases : there will be lots of little subtleties that have gone on in raising a flap , transposing a flap , in doing a resection , whatever . \n those little changes that have occurred throughout the operation , it is still the same operation but it is different from the way you might have done it last week . if you havent seen all those things it might affect the way you communicate in the operation . \n ( trainee surgeon , interview 8) for this participant , prospectively communicating decisions based on changes in case needs and/or patient status alleviated the trepidation associated with potential or projected changes in tissue vascularity that frequently occurred during microsurgery . \n this behavior also served to inform other team members , thus building shared situational awareness . \n the observer witnessed instances when surgeons requested instruments and additional equipment to be taken onto the table in anticipation that they would be needed , albeit that they were not always used . giving this information well in advance permitted scrub nurses to prepare for probable challenges or changes . \n in contrast , delays , silences , or omissions in communicating imminent case needs to other team members based on a change in plan or approach culminated in members of the surgical subteam waiting at the operating table for an additional piece of equipment . \n as such , procedural disruptions occurred when the scout nurse left the room to retrieve a particular instrument or tray . clearly , disparate levels of access to vital information impacted on team members situational awareness , leading to different projections of what was likely to occur in the near future . nurse participants described behaviors that augmented their situational awareness . \n for instance , the importance of being focused throughout the operation in respect to careful listening and intent watching ; thus , knowing and understanding the normal sequences of the procedure was considered essential in gleaning useful information about the progress of surgery . in selected instances , \n the scrub nurse became the gatekeeper to the surgeon,28 vetting information flow based on their assessment of the status of the procedure : the scrub nurse is the best person to make the judgment as to when to ask for things because they know what part of the operation is the most critical or noncritical . ( registered nurse , interview 2 ) determining what information should be filtered through to the surgeon encompassed several factors , ie , experienced scrub nurses possessed good technical and scientific knowledge of the procedure being performed , an appreciation of its intricate and difficult stages , and had an understanding of any subtle changes in the demeanor of individual surgeons . \n both scrub and scout nurses were less likely to interrupt when the procedure was at a stage that required intense concentration by the surgeon , such as during the clipping of a cerebral aneurysm in neurosurgery . \n scout nurses also judged the urgency of incoming messages when answering cell phones or by questioning the approaching outsider regarding the details of the message . \n more experienced nurses intuitively discerned the surgeon s mood and used this knowledge to inform decisions about how they would interact with them , altering their approach as necessary . \n the final theme , ie , planning contingency decisions based on priority , illustrated the unpredictable nature of a myriad of clinical scenarios and the dilemmas confronting team members when making decisions about the urgency of events . contingency decisions referred to timely and explicit dialog based on a change of plan or priority , and thus fostered shared situational awareness . \n the majority of medical participants affirmed that judgment calls involved making decisions around priorities of care ; the essence of which was captured in this comment by one of the trainee surgeons : an emergency is by its nature very different than an elective case . \n yet decisions based on the priorities of patient care were not always mutually agreed upon , or discussed . from a basis of not having seen the patient , the surgeon has booked the case and they will give it a category 1 being the most urgent and 5 being almost elective , but they often incorrectly categorize their patients so they appear to be more urgent so they are done in hours or at a convenient time or will say this is an urgent case but we are not available until 5 pm. we end up saying that s rubbish you are not doing that or okay this case needs to go before that case. we often have to bump the orthopods out of theater to do an appendix or something . ( consultant anesthetist , interview 7 ) this scenario was common , ie , the triaging anesthetist s decisions were informed by the urgency of the procedure and how sick the patient was . \n floor coordinating nurses also made decisions around assigning priority when elective lists would over - run . \n the priority given to which listed cases would be cancelled was driven by time constraints and limited staffing to cover list over - runs . \n such decisions were also informed by the coordinating nurse s knowledge of the procedure , and how long it would take individual surgeons to complete the procedure within the remainder of the session . \n the coordinating nurse would enter the room and , in a low tone , speak quietly to the anesthetist , seeking agreement and support for the decision to cancel the case . \n once agreement had been reached , the decision was subsequently communicated to the attending surgeon . \n conversely , there were times when semielective or emergent cases could be booked or added to a surgical list ; accordingly , both the surgeon and the anesthetist in the room were approached simultaneously by the coordinating nurse . in assessing the situation and prioritizing actions \n , surgeons described threats in terms of the patient ( atypical anatomy , adhesions from previous surgery , unexpected findings , excessive blood loss ) , the task ( visibility or access problems , time pressure ) , and the team ( inexperience , unfamiliarity with the procedure ) . risk was considered in terms of potential harm to the patient , the surgeon , other team members , and the organization.19 the imperative to adapt or change in crisis situations and manage risk was patently illustrated when a surgeon participant abandoned his original operative plan because the patient s condition was obviously deteriorating . in articulating the need to change pace and shift strategies during surgery , he eloquently described decision - making that was based on a hypothesized outcome : \n i said to her ( scrub nurse ) , we need to get this patient closed ( patient s wound incision ) because we did switch our strategy . at a certain stage in the operation it switches from conventional surgery to what we call damage control where you stop all the bleeding , \n control the bowel contamination , but as soon as you have done that , you hurry up , pack the patient and send them quickly to icu . \n so i had to say we are changing the pace now. it is a really important change in strategy and this all comes from trauma protocols . ( consultant surgeon , interview 16 ) based on the surgeon s assessment of the current situation , he believed that there was little choice because of the tenuous balance of risk involved in unnecessarily prolonging this critical surgery . \n the priority was to prevent further deterioration and deal with life - threatening injuries rather than to restore function , reconstruct tissues , or improve perfusion . \n while other options may have been momentarily considered , the patient s deteriorating condition meant that the definitive course of action , with apparently little conscious deliberation , was conveyed to the scrub nurse . during decision - making , the experience of the surgeon and his or her ability to process information efficiently from other sources informed the decision . \n the delivery of explicit and timely dialog supplemented the mental model of other team members , building shared situational awareness , assisting members in preparing for a change of plan . in many instances , participants had to retrieve information regularly from multiple sources to make informed decisions , but often only had access to partial information that was relevant to a successful outcome . \n consequently , on occasions when bigger picture information was not volunteered , disparities in the perceived level of risk were further compounded : \n if you are going into a case , a situation where you do nt perceive there is great risk , the surgeon may perceive there is great risk but that hasnt been communicated . \n we go into a situation where we are dealing with someone who is a great risk but they are only operating on a toe nail once you have started if something is not quite right or if perhaps you are starting on a path the rest of the team might nt know . \n the theme of synchronizing actions and strategizing to adapt was underpinned by the capacity of team members to communicate decisions in the management and timing of individual and team tasks in an explicit manner . synchronizing and strategizing incorporated communicating a course of action based on team members level of situational awareness . \n the use of open explicit dialog around decisions facilitated distributed situational awareness , allowing participants to respond appropriately to the cues provided by others . however , there were also occasions when participants described the need to consciously focus on the task at hand , even if this at times culminated in loss of the peripheral information sources needed to inform such decisions . \n for instance , anesthetist participants particularly emphasized the use of algorithms as a decision - making strategy to deal with an anesthetic emergency : you have a series of algorithms which you go through but because you have a reasonable idea of what is going wrong , you step into the algorithm half way down it instead of starting at the top and then because you are wrong you get the wrong result you get fixated and finish up thinking you are quite sure you are getting evidence but then the lights go on and you go \n ( consultant anesthetist , interview 7 ) this anesthetist s failures in perception and comprehension of the situation resulted in an incomplete mental model . \n consequently , an over - reliance on a set of prescribed steps stymied this participant s ability to resolve the problem at hand because he was locked into an incorrect picture of the situation . \n it was only when an adverse event occurred that the anesthetist realized his comprehension of the situation was flawed . \n another participant revealed that when an error in judgment occurred , the ability to process information from other sources rapidly diminished : \n when you have a situation where something does go unexpectedly wrong or you do something that has a bad outcome and things are deteriorating quickly then you feel the anxiety rising , you focus , you tunnel , you really are trying to think clearly but because there is all this oh my god , oh my god what have i done? , when things go wrong unexpectedly because you have done something , you are so focused on that that you often forget about the peripherals . \n ( consultant anesthetist , interview 6 ) the distress of having an unfavorable outcome had a debilitating impact on this participant s situational awareness , causing her to shut down , thus limiting her capacity to convey decisions to others at the height of a crisis situation . \n i deliberately , consciously slow down , when i am doing a hepatectomy ; just near the end there is a rush , the organ is hanging on by a slither , you have a huge amount of liver coming out , your big hand hanging onto it and the temptation is to draw on it and accelerate the process which increases a vascular injury so it is at that point where i say publically to everyone i am going to slow down because i am getting to the critical last little step. i talk people through what i am doing and am talking myself through it \n ( consultant surgeon , interview 16 ) the overt act of talking through the delicate concluding stages of the procedure enhanced team situational awareness because it served a dual purpose : it permitted the surgeon to keep abreast of the situation , achieve coherence and agreement with other team members on the goals of the task ; and also allowed the surgeon to be more accessible to the assistance , suggestions , advice or questions from others . \n in contrast , junior surgeons tended to fixate on the technical problem during critical periods of the operation , and reduced the exchange of information to a minimum during that time . only information related to perceptions of the status and dynamic components of the immediate situation , ie , level 1 situational awareness,11 \n was communicated to others under the assumption that they would reach similar projections as the operating surgeon . \n scrub nurses articulated the importance of organizing the layout of their sterile work area in a way that it allowed them to place their hand directly onto the instrument without looking away from the operative field . \n experienced scrub nurses focused on the operative field and listened for conversational exchanges between consultant surgeons and their trainees to learn of changes to the operative plan . \n these behaviors increased nurses levels of situational awareness and they were able to pre - empt the surgeon s needs and think ahead to ensure that the operation progressed smoothly . \n an experienced nurse stated that her decisions on the selection of instrument to pass to the surgeon at any given stage of the operation were essentially governed by her understanding and conception of what s happening now , and what can possibly go wrong . \n the second theme , ie , sharing local knowledge , encompassed context - specific understandings of individuals and the situation as a whole , as well as its many facets , and the ways such understandings contributed to the communication of decisions to build shared situational awareness . local knowledge referred to team members awareness of nuances and practices of individuals and their roles in the context of different surgical specialties . \n accordingly , team members awareness of individual capabilities , the ability of members to cohese as a collective , the condition of the patient , and the status of the procedure being performed , and the environment ( equipment , position of the patient , room layout ) , not only influenced the decisions made , but also how the dialog was constructed and conveyed . \n shared situational awareness in cardiac surgery was fostered by the deliberate use of closed - loop communication to convey that the steps taken in making a decision were purposeful , logical , and deliberate . in the cardiac room , tasks around perfusion and cardioplegia were managed by the perfusionist and cardiac surgeon through a series of sequenced actions and minicommunications with the aim of identifying the cause of the problem and returning the patient s system to a more normal , desirable state.27 in the context of this study , a perfusionist is an anesthesiologist who has received additional specialist training in cardiac perfusion and cardioplegia . \n coordination of actions was frequently heralded by a deliberate annunciation of steps taken by the perfusionist and surgeon , making explicit their expectations based on the current situation : in cardiac anesthesia and perfusion the rule is that when you are given an instruction or asked to do something , you confirm verbally that that is what you are doing \n cardiac is very regimented , there is one way of doing things and that is it . \n i anaesthetize and perfuse differently and behave differently in cardiac than i do in general theaters . \n ( consultant anesthetist , interview 12 ) in the cardiac room , attention to the orchestration of actions allowed both the surgeon and perfusionist to recognize urgency and use appropriate recovery methods to manage deviations from expected events . \n the dialog around decisions in the cardiac room was in stark contrast with the way decisions were communicated among team members in other surgical specialties . \n for example , conveying or confirming decisions about a change in case requirements ( eg , impending need for a microscope ) or changes in the order of patients listed for a morning or afternoon session based on procedural complexity and the availability of consultant surgical expertise , appeared to be made independently , without consultation with other key personnel in the room . in this instance , the disparate mental models that members possessed likely influenced their comprehension and the projections they made . although procedures may be booked as elective or \n cardiovascular fluctuations during surgery , and variations in the acuity of the patient and their surgical anatomy , influenced clinical decisions concerning the approach and ongoing management of these cases : there will be lots of little subtleties that have gone on in raising a flap , transposing a flap , in doing a resection , whatever . \n those little changes that have occurred throughout the operation , it is still the same operation but it is different from the way you might have done it last week . if you havent seen all those things it might affect the way you communicate in the operation . ( trainee surgeon , interview 8) for this participant , prospectively communicating decisions based on changes in case needs and/or patient status alleviated the trepidation associated with potential or projected changes in tissue vascularity that frequently occurred during microsurgery . this behavior also served to inform other team members , thus building shared situational awareness . \n the observer witnessed instances when surgeons requested instruments and additional equipment to be taken onto the table in anticipation that they would be needed , albeit that they were not always used . giving this information well in advance permitted scrub nurses to prepare for probable challenges or changes . \n in contrast , delays , silences , or omissions in communicating imminent case needs to other team members based on a change in plan or approach culminated in members of the surgical subteam waiting at the operating table for an additional piece of equipment . as such \n , procedural disruptions occurred when the scout nurse left the room to retrieve a particular instrument or tray . clearly , disparate levels of access to vital information impacted on team members situational awareness , leading to different projections of what was likely to occur in the near future . \n for instance , the importance of being focused throughout the operation in respect to careful listening and intent watching ; thus , knowing and understanding the normal sequences of the procedure was considered essential in gleaning useful information about the progress of surgery . in selected instances , \n the scrub nurse became the gatekeeper to the surgeon,28 vetting information flow based on their assessment of the status of the procedure : the scrub nurse is the best person to make the judgment as to when to ask for things because they know what part of the operation is the most critical or noncritical . \n ( registered nurse , interview 2 ) determining what information should be filtered through to the surgeon encompassed several factors , ie , experienced scrub nurses possessed good technical and scientific knowledge of the procedure being performed , an appreciation of its intricate and difficult stages , and had an understanding of any subtle changes in the demeanor of individual surgeons . both scrub and \n scout nurses were less likely to interrupt when the procedure was at a stage that required intense concentration by the surgeon , such as during the clipping of a cerebral aneurysm in neurosurgery . \n scout nurses also judged the urgency of incoming messages when answering cell phones or by questioning the approaching outsider regarding the details of the message . \n more experienced nurses intuitively discerned the surgeon s mood and used this knowledge to inform decisions about how they would interact with them , altering their approach as necessary . \n the final theme , ie , planning contingency decisions based on priority , illustrated the unpredictable nature of a myriad of clinical scenarios and the dilemmas confronting team members when making decisions about the urgency of events . contingency decisions referred to timely and explicit dialog based on a change of plan or priority , and thus fostered shared situational awareness . \n judgment calls involved making decisions around priorities of care ; the essence of which was captured in this comment by one of the trainee surgeons : an emergency is by its nature very different than an elective case . \n yet decisions based on the priorities of patient care were not always mutually agreed upon , or discussed . from a basis of not having seen the patient , the surgeon has booked the case and they will give it a category 1 being the most urgent and 5 being almost elective , but they often incorrectly categorize their patients so they appear to be more urgent so they are done in hours or at a convenient time or will say this is an urgent case but we are not available until 5 pm. we end up saying that s rubbish you are not doing that or okay this case needs to go before that case. we often have to bump the orthopods out of theater to do an appendix or something . ( consultant anesthetist , interview 7 ) this scenario was common , ie , the triaging anesthetist s decisions were informed by the urgency of the procedure and how sick the patient was . \n floor coordinating nurses also made decisions around assigning priority when elective lists would over - run . \n the priority given to which listed cases would be cancelled was driven by time constraints and limited staffing to cover list over - runs . \n such decisions were also informed by the coordinating nurse s knowledge of the procedure , and how long it would take individual surgeons to complete the procedure within the remainder of the session . \n the coordinating nurse would enter the room and , in a low tone , speak quietly to the anesthetist , seeking agreement and support for the decision to cancel the case . \n once agreement had been reached , the decision was subsequently communicated to the attending surgeon . \n conversely , there were times when semielective or emergent cases could be booked or added to a surgical list ; accordingly , both the surgeon and the anesthetist in the room were approached simultaneously by the coordinating nurse . in assessing the situation and prioritizing actions \n , surgeons described threats in terms of the patient ( atypical anatomy , adhesions from previous surgery , unexpected findings , excessive blood loss ) , the task ( visibility or access problems , time pressure ) , and the team ( inexperience , unfamiliarity with the procedure ) . \n risk was considered in terms of potential harm to the patient , the surgeon , other team members , and the organization.19 the imperative to adapt or change in crisis situations and manage risk was patently illustrated when a surgeon participant abandoned his original operative plan because the patient s condition was obviously deteriorating . in articulating the need to change pace and shift strategies during surgery , he eloquently described decision - making that was based on a hypothesized outcome : \n i said to her ( scrub nurse ) , we need to get this patient closed ( patient s wound incision ) because we did switch our strategy . at a certain stage in the operation it switches from conventional surgery to what we call damage control where you stop all the bleeding , \n control the bowel contamination , but as soon as you have done that , you hurry up , pack the patient and send them quickly to icu . \n so i had to say we are changing the pace now. it is a really important change in strategy and this all comes from trauma protocols . \n ( consultant surgeon , interview 16 ) based on the surgeon s assessment of the current situation , he believed that there was little choice because of the tenuous balance of risk involved in unnecessarily prolonging this critical surgery . \n the priority was to prevent further deterioration and deal with life - threatening injuries rather than to restore function , reconstruct tissues , or improve perfusion . \n while other options may have been momentarily considered , the patient s deteriorating condition meant that the definitive course of action , with apparently little conscious deliberation , was conveyed to the scrub nurse . during decision - making , the experience of the surgeon and his or her ability to process information efficiently from other sources informed the decision . \n the delivery of explicit and timely dialog supplemented the mental model of other team members , building shared situational awareness , assisting members in preparing for a change of plan . in many instances , participants had to retrieve information regularly from multiple sources to make informed decisions , but often only had access to partial information that was relevant to a successful outcome . \n consequently , on occasions when bigger picture information was not volunteered , disparities in the perceived level of risk were further compounded : \n if you are going into a case , a situation where you do nt perceive there is great risk , the surgeon may perceive there is great risk but that hasnt been communicated . \n we go into a situation where we are dealing with someone who is a great risk but they are only operating on a toe nail once you have started if something is not quite right or if perhaps you are starting on a path the rest of the team might nt know . \n the findings herein suggest that coordinating decision - making in surgery encompassed synchronizing and strategizing actions , sharing local knowledge , and planning and prioritizing contingency decisions . \n explicit , distributed , and timely communication is crucial in facilitating the exchange of information for cohesive teamwork , as tasks and roles are deconstructed , performed and reconstructed in their entirety.29 in this study , efficient communication of clinical decisions heightened team members awareness of actual or potential problems , building shared situational awareness and assisting them to respond appropriately . \n the first theme , ie , synchronizing and strategizing actions , described behaviors associated with decisions around focusing on the immediate task , controlling the pace of surgery through self - talk , and thinking ahead by the surgeon . at critical junctures of the procedure , the effects of stress were evidenced in the ways that the communication patterns of surgeons and anesthetists changed in the absence of discussing crucial next step decisions . \n some junior doctors shut down and , instead , compensated by fixating on the technicalities of the task . alternatively \n , more experienced surgeons were able to sustain open dialog with others , thus explicitly coordinating tasks . \n the use of self - talk appeared to be pivotal in maintaining shared situational awareness , and also enabled surgeons to manage their stress levels . \n the ongoing dialog assists others to maintain vigilance , particularly during high tempo periods , because less information needs to be communicated relative to what is already mutually known and understood.30 scrub nurses behavior of overhearing conversations at the operating table heightened their situational awareness . \n where individuals or groups obtain direct , real - time updates for a particular decision - maker.31 a voice loop is a real - time auditory prompt that enables distributed translation of information among individuals in close physical proximity . \n voice loops , although uncommon in health care environments , are increasingly being recognized as an effective coordinating tool in high dependency settings.31 in our study , the act of listening in enabled scrub nurses to coordinate their activities , anticipate unexpected events , plan contingency responses , understand the rationale for nonroutine requests , and note fluctuations in voice tone that may signal an escalation in activity . \n nurses were thus able to participate actively in decision - making around coordination of personnel and equipment needs on selected occasions . \n our findings extend recent research which suggests that nurses have limited scope to make decisions in the operating room milieu.20 while nurses within surgical teams are not responsible for making \n life and death decisions in surgery , they are privy to many clinical decisions , and are thus tasked with communicating decisions about the synchronization of activities to others , and act as conduits of information . \n concordant with recent research,20 the nurses in this study used situational awareness to build a mental model by gathering cues presented in the environment and integrating information from an array of sources , much of which was based on their familiarity and experience with the surgeon and the procedure . \n the second theme , ie , sharing local knowledge , illustrated the importance of previous exposure to similar situations , understanding other team members capabilities , and the ways in which their roles and tasks intersected to meet shared team goals and expectations , and the use of closed - loop communication . \n complete shared situational awareness is often impossible , but using closed - loop communication guides effective coordination , and its absence diminishes team members ability to develop a shared mental model.32 in the cardiac room , the surgeon and the perfusionist have limited access to information that is relevant to a successful outcome.27 both the surgeon and perfusionist perform distinct tasks that demand unique expertise , yet these actions require careful orchestration if they are to meet the shared goals of surgery . \n situational awareness arises out of the process of using closed - loop communication in cardiac surgery because these structured minicommunications establish the current state of the patient s system and the sequencing of actions needed to perform tasks.27 nurse participants in our study tended to make intuitive decisions based on experiential knowledge , and this accords with previous research.33 nurses decisions centered on coordinating case requirements , booking and cancelling listed procedures , and choosing the most appropriate way to approach different surgeons according to their demeanor and situation . \n nurses filtered information that reached the surgeon , thus permitting surgeons to remain disconnected and separate from their broader environment , and allowing surgeons to concentrate on the act of surgery \n , which are notions identified in earlier critical discourse.28 gating information flow appeared to reduce the incidence of interruptions which have been previously identified as contributing to clinical error.34,35 however , vetting information may also have undesirable , unintended effects , ie , selectively communicating information to surgeons that nurses deemed as nonurgent may have contributed to an error elsewhere . essentially , in this situation , it is likely difficult for nurses to make distinctions between urgent and nonurgent messages because they do not necessarily know the context or the vital background information . \n the level to which participants were able to build situational awareness was determined by their ability to foresee , manage , and communicate their assessment of potential situational risks . \n most medical participants in our study considered clinical decision - making in terms of patient - related or task - related risks , and echoes findings elsewhere.18,19 senior surgeons illustrated situations where emergency decisions were underpinned by a judgment of likelihood or an estimation of risk , ie , decisions that are likely to be made on the basis of intuition and experience.19 however , it appeared that some participants had limited access to all relevant information regarding risk , limiting their ability to respond as expected . when decisions were enacted in emergency and time - pressured situations , distributed communication about the level of risk was , at times , constrained . \n in other cases , differing comprehensions of the current situation ( levels 1 and 2 situational awareness)32 secondary to disagreements about the patient s level of risk , may lead to an unfavorable outcome . \n situation assessment requires cognitive processing , and therefore contributes to workload.29 conceivably , situational awareness suffers because of competing demands , and even striking events can be missed because they are outside the individual s sphere of attention at that time . \n this study has a number of strengths , but we also recognize that several limitations exist . \n first , the single locale of the study setting limits the extent to which its findings may be generalized because the staff working in this hospital may be different in some way . despite this \n , there was representation across disciplines , permitting illumination of diverse professional perspectives and enhancing conceptual transferability.21 further , our findings are consistent with those of several other studies of communication and decision - making in surgery.1820 second , there are innate complexities in examining a context with which the observer has a high degree of familiarity . \n still , preconceived assumptions were challenged by diarizing field experiences and writing memos to enhance objectivity and professional judgment.22 as such , the effects of bias during data collection , interpretation , and description were minimized . finally , the differing methods used for some of the nurse participants may have given rise to different dynamics during interviews . \n this study has a number of strengths , but we also recognize that several limitations exist . first , the single locale of the study setting limits the extent to which its findings may be generalized because the staff working in this hospital may be different in some way . \n despite this , there was representation across disciplines , permitting illumination of diverse professional perspectives and enhancing conceptual transferability.21 further , our findings are consistent with those of several other studies of communication and decision - making in surgery.1820 second , there are innate complexities in examining a context with which the observer has a high degree of familiarity . \n still , preconceived assumptions were challenged by diarizing field experiences and writing memos to enhance objectivity and professional judgment.22 as such , the effects of bias during data collection , interpretation , and description were minimized . \n finally , the differing methods used for some of the nurse participants may have given rise to different dynamics during interviews . however , similar issues were explored and data saturation was achieved . \n behaviors such as the use of self - talk , closed - loop communication , and overhearing conversations help teams to build shared situational awareness . \n such behaviors allow team members to coordinate actions with others better , broadening the expertise and sphere of attention and reducing fixation . \n thus team members are enabled to perform their roles in parallel and strategize accordingly . any associated deficits in selectively attending to messages , transmitting information to the appropriate personnel , seeking additional information from key personnel , and eliciting a useful response , compounds the potential for adverse patient outcomes .", "role": "user" }, { "content": "backgroundfailure to convey time - critical information to team members during surgery diminishes members perception of the dynamic information relevant to their task , and compromises shared situational awareness . \n this research reports the dialog around clinical decisions made by team members in the time - pressured and high - risk context of surgery , and the impact of these communications on shared situational awareness.methodsfieldwork methods were used to capture the dynamic integration of individual and situational elements in surgery that provided the backdrop for clinical decisions . \n nineteen semistructured interviews were performed with 24 participants from anesthesia , surgery , and nursing in the operating rooms of a large metropolitan hospital in queensland , australia . \n thematic analysis was used.resultsthe domain coordinating decisions in surgery \n was generated from textual data . within this domain \n , three themes illustrated the dialog of clinical decisions , ie , synchronizing and strategizing actions , sharing local knowledge , and planning contingency decisions based on priority.conclusionstrategies used to convey decisions that enhanced shared situational awareness included the use of self - talk , closed - loop communications , and overhearing conversations that occurred at the operating table . \n behaviors that compromised a team s shared situational awareness included tunneling and fixating on one aspect of the situation .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the discovery of neural stem cells ( nscs ) at the beginning of the nineties led many people to consider definitively broken the dogma of the central nervous system ( cns ) as made up of nonrenewable elements [ 13 ] . \n this finding , along with the characterization of adult neurogenesis in the olfactory bulb and hippocampus [ 35 ] triggered new hopes for brain repair . yet , twenty years after , we realize that the dream of regenerative medicine applied to brain / spinal cord injuries and neurodegenerative diseases is still very far [ 6 , 7 ] . as a matter of fact , adult neurogenesis in mammals occurs mainly within two restricted areas known as neurogenic sites [ 3 , 8 ] : the forebrain subventricular zone ( svz ) , reviewed in ; and the hippocampal dentate gyrus ( subgranular zone , sgz ) , reviewed in . as a direct consequence of such topographical localization , \n most of the cns parenchyma out of the two classic neurogenic sites remains substantially a nonrenewable tissue . \n an indirect proof of this statement resides in the fact that most of the traumatic / vascular injuries and neurodegenerative diseases , which actually occur in \n regions , have still not found efficacious therapies capable of restoring cns structure and functions through cell replacement . \n thus , two decades after the discovery of nscs and the reaching of a satisfactory characterization of adult neurogenic sites , a gap remains between the occurrence of stem / progenitor cells in the cns of adult mammals and their effective capability to serve in brain repair . \n several aspects do converge in explaining this gap and , partly , in accounting for the heterogeneity of cns structural plasticity in mammals ( summarized in table 1 ) . during the last decade , new heterogeneity has been revealed by studies showing a substantial and widespread gliogenic [ 1216 ] , and to a lesser extent , neurogenic potential [ 1719 ] within the cns parenchyma , namely , in those areas previously considered as nonneurogenic . \n this new field of investigation revealed many unexpected potentialities for de novo cell genesis in the cns , although most aspects of parenchymal neurogliogenesis remain quite obscure and ill - defined . in particular , \n several unresolved aspects make parenchymal neurogenesis a difficult territory to be explored : ( i ) the contrast between a wide range of potentialities displayed by parenchymal progenitors isolated in vitro and far more restricted potentialities which can be observed in vivo [ 20 , 21 ] , ( ii ) the existence of studies reporting neurogenesis in parenchymal regions which have been denied or not confirmed by other researchers [ 2224 ] , and ( iii ) the real origin of progenitors which are induced to proliferate / migrate in different lesion models ( either mobilized from neurogenic sites or activated locally within the parenchyma ; see boxes 1 and 2 ) [ 2528 ] . in this paper \n the in vivo neurogenic / gliogenic potential of the mammalian brain parenchyma will be analyzed with particular reference to variables involved in its heterogeneity ( see figure 1 and table 1 ) . in order to avoid one of the most common misunderstandings , namely , the confusion between occurrence of de novo cell proliferation in the cns tissue and existence of true gliogenic / neurogenic processes ( see box 1 ) \n , the attention should be focused on the outcome(s ) of the newly generated progeny . before addressing in detail the heterogeneity of mammalian cns structural plasticity and cell genesis , a brief summary of comparative adult neurogenesis and progenitor cell developmental origin will be given . \n indeed , evolutionary explanations can provide an understanding of the logic followed ( or not ) by neurogenic processes through phylogeny , also accounting for the failure in cns repair / regeneration and scarce usefulness of adult neurogenesis as a possible solution for brain repair in mammals . in parallel , \n since developmental changes account for loss of cns reparative / regenerative capacities and neuro - glio - genic potential , it is also important to know the real origin of different types of progenitor cells . \n as a matter of fact , failure in mammalian brain repair after traumatic , vascular , and neurodegenerative injuries is due to ( i ) a substantial lack of cns reparative / regenerative capacity , ( ii ) a strong reduction in the extension of neurogenic regions within the whole cns , ( iii ) the fact that adult neurogenic sites serve specific physiological functions rather than brain repair ; for review , see [ 11 , 40 , 43 ] . \n it is important to note that if the occurrence of good neurogenic potentials would generally favor brain repair ( at least by making available stem / progenitor cells ) there is not a direct , linear relationship between occurrence of stem / progenitor cells and repair / regeneration , the latter processes strongly depending on the tissue environment and/or tissue reactions ( for selected examples of neurogenesis and regeneration see ) . \n comparative studies on adult neurogenesis in the animal world show that neurogenic processes are detectable in wide regions of the cns in invertebrates and nonmammalian vertebrates [ 29 , 44 , 45 ] . \n by contrast , in mammals neurogenic processes are restricted to two privileged areas ( neurogenic sites ) and the remaining cns is largely made up of nonrenewable tissue [ 32 , 46 , 47 ] . \n the state of substantial general plasticity and cell renewal existing in the oldest living metazoans , so that all cell types , including neurons , are balanced in their production and loss [ 48 , 49 ] , is progressively reduced in vertebrates , although fish and amphibians still maintain remarkable regenerative capacities [ 50 , 51 ] . \n then , in birds and mammals a transition between regeneration permissive and nonpermissive stages occurs soon after birth , and highly - restricted spots of adult neurogenesis serve homeostatic functions in specific neural circuits [ 52 , 53 ] . \n the decrease in neurogenic abilities occurs in parallel with topographical / numerical restriction of germinal layer - derived stem cell niches , whereas the decrease in regenerative abilities occur in parallel with other aspects : the impossibility to re - access to embryonic developmental programs during adulthood , the lack of differentiated cells capable of dedifferentiation , the development of a strong immune surveillance and the consequent tissue reactions which are detrimental ( reviewed in [ 11 , 41 ] ) . in some cases , \n the stem cells found in the cns of nonmammalian vertebrates are deployed for postnatal development of parts of the brain until the final structure is reached . in other cases \n , postnatal neurogenesis continues into adulthood leading to a net increase of the number of neurons with age ( reviewed in ) . \n an example is the cerebellar granular layer , which actually functions as a protracted development in postnatal mammals , whereas it becomes a persistent neurogenesis in adult teleosts , by continuously growing so that no definite adult cerebellar size is reached . \n in addition , when considering mammals , the failure in cns repair is a result of evolutionary constraints in which the injured tissue would not favor a strategy of regeneration but rather one of minimizing further damage ( e.g. , gliotic reaction ) . in conclusion , as a consequence of multiple converging aspects , cns regenerative capacity in mammals could have reached a point of nonreturn , in parallel with the persistence of some neurogenic processes which remain mainly focused on physiological functions ( e.g. , cell renewal / addition in selective neural circuits linked to learning / memory tasks [ 52 , 53 ] ) . \n an increased consciousness of the fact that scarce cns reparative capacity in mammals depends on multiple aspects should indicate that it is very unlikely that the finding of a single molecular factor or pharmacological treatment capable of eliciting repair / regeneration . \n comparative results from vertebrate species of different classes have demonstrated that adult neurogenesis is widespread among vertebrates but is employed by different species in different functional contexts [ 53 , 58 , 59 ] . \n in addition , a growing number of reports show remarkable heterogeneity even among mammals [ 1719 ] . \n this variability concerns both neurogenic sites and parenchymal neurogenesis ( reviewed in ; see below ) . \n this fact , along with a still incomplete knowledge of adult neurogenesis in humans ( especially within the parenchyma ) , partially hampers the reaching of well - established \n common rules which might be used in the translation of experimental preclinical data to human medicine . hence \n , dealing with mammalian cns structural plasticity , at least two levels of heterogeneity should be taken into account : that involving different types of neurogenic processes ( addressed in the next paragraph ) and that of interspecies differences ( mainly developed in the paragraph on parenchymal neurogenesis ) . \n detailed investigations carried out on the cellular , molecular , and functional outcomes of classic neurogenic sites revealed they are consistently present in all mammals studied , although with some differences . \n particularly when the outcome(s ) of the neurogenic process are involved , the differences could be remarkable . \n the occurrence of a rostral migratory stream which is active throughout life in rodents but temporally restricted to the postnatal period in humans is a prototypical example of variability among mammals . \n indeed , in humans this neurogenic process seems to fall in the category of delayed developmental processes rather than adult neurogenesis ( see below ) . \n in addition to differences in neurogenic sites , studies carried out during the last two decades revealed the presence of local , parenchymal progenitors which retain some proliferative capacity in most of the mature mammalian cns [ 12 , 14 , 15 , 1719 , 61 ] . \n this fact suggests that structural plasticity involving de novo cell genesis in the cns could be more widespread than previously thought , but also different when occurring in neurogenic sites or in the parenchyma ( table 2 ) . as a consequence of the increasing number of reports investigating adult neurogenesis in mammals , \n our perception of this biological process has gained new perspectives and nuances ( for deeper analysis see [ 29 , 3234 ] ) . \n what was previously thought as the genesis of new neurons in restricted brain areas endowed with nscs , can now be intended as a highly heterogeneous phenomenon ( summarized in figure 1 ) , whose heterogeneity depends on several variables ( see table 1 ) . \n the main elements of heterogeneity can be summarized as follows : ( i ) the location of progenitors : gathered within restricted neurogenic sites or widely spread out in the parenchyma ; ( ii ) the nature of the progenitors : bona fide nscs versus different types of progenitors ; ( iii ) the genetic and molecular features of the progenitors : cell lineage ( neuronal - like versus glial - like ) ; identification of differentiative stages ( dependent on the available markers ) ; ( iv ) the existence or not of well - characterized neurogenic niches : absence of niches or occurrence of atypical / non - identified niches in the parenchyma ; ( v ) the extension in time after birth : protracted , transient , persistent neurogenesis ; ( vi ) the ultimate fate of the progeny in terms of cell lineage : neuronal versus glial , astrocytic versus oligodendrocytic ; ( vii ) the ultimate fate of the progeny in terms of cell integration into circuits : complete versus incomplete neurogenesis ; ( viii ) the spontaneous occurrence of the process versus its injury - induced appearance ( briefly addressed in paragraphs 5 and 6 ) . \n this latter point could be considered a further step beyond the so - called constitutive neurogenesis , namely , the spontaneous , continuous genesis of new neurons as part of a physiologic , homeostatic process . due to multifaceted aspects of the above mentioned processes , some problems of terminology can also be raised ( summarized in box 1 ) . \n neurogenesis , which can be intended either as genesis of neurons or as genesis of neural cells , \n embryonic neurogenesis , namely , the process of building up the whole cns , involves both neuro- and gliogenesis , occurring in largely overlapping and strictly intermingled phases , whereas neurogenesis and gliogenesis can occur separately in the adult . \n the landscape is even more complex , since research on adult neurogenesis brought developmental neuroscience within the mature brain , and the intermix of structurally plastic changes involving cell genesis / differentiation with the fully assembled adult tissue is accompanied by a previously unexpected intermix of cell lineages ( e.g. , newly formed neuroblasts arising from astrocytic - like stem cells in vivo ) . for this reason , in this paper , when not speaking of well - characterized cell lineages , the notion of cell genesis instead of neurogenesis \n will be used , since in most neurogenic processes different cell types can be considered among the progenitors , and different progenies can be generated . \n hence , apart from detailed knowledge gathered around the activity of svz and sgz neurogenic sites , many aspects of parenchymal cell genesis remain obscure and/or unexplored , as a consequence of the heterogeneity depicted above . in the last few years , parenchymal neurogliogenesis was among the most studied yet less known issues , due to the widespread location of the progenitor cells and to the substantial lack of markers which specifically identify their real origin as well as the stage - specific steps of their differentiation . \n as a consequence , the presence / absence of neurogenic processes within different cns parenchymal regions in different mammalian species is still quite controversial and debatable . in most cases , \n furthermore , in some cases it is very difficult to show its final outcome(s ) , most of the parenchymal neurogenesis appearing incomplete as to the final differentiation / integration of the progeny ( figure 1 ) . \n finally , to correctly classify both germinal layer - derived and parenchymal neurogenesis some other aspects should be taken into account , such as the temporal extension of \n a further aspect is that of potential / lesion - induced neurogliogenesis , namely , the genesis of new cells as a consequence of different types of cns injury [ 25 , 26 , 28 , 63 ] or altered homeostasis . the latter issue will not be addressed in detail in this paper mainly focused on spontaneous / physiological states \n one of the features making possible the remarkable neurogenesis occurring in the neurogenic sites is their direct origin from embryonic , germinal layers which retain stem / progenitor cells along with the niche environment allowing their activity [ 10 , 65 ] . \n the svz and sgz actually are remnants of their embryonic counterpart , from which they maintain several cellular and molecular aspects in parallel with an adaptation to the changing anatomy of the postnatal and adult brain [ 66 , 67 ] . during development , the cns originates from the neuroepithelium , pseudostratified epithelial cells that maintain contact with both the ventricular and pial surfaces . as brain thickness increases , \n neuroepithelial cells transform into radial glia [ 65 , 68 ] . beside their classic role as scaffolding for migrating neurons during embryogenesis and their subsequent transformation into parenchymal astrocytes of the mature cns [ 69 , 70 ] \n , more recent studies have shown that radial glia cells behave as stem cells , leading to the genesis of astrocytes , neurons [ 71 , 72 ] , and , to a lesser extent , oligodendrocytes . \n thus radial glia cells not only serve as progenitors for many neurons and glial cells soon after birth , but also give rise to adult svz stem cells that continue to produce neurons throughout life . \n the origin of astrocytes that function as neural progenitors in the adult hippocampus has not been determined experimentally . \n a connection to radial glia cells has been suggested even in the hippocampal sgz [ 74 , 75 ] . \n the relationship of adult nscs to their developmental precursors offers clues to the unique characteristics that distinguish these germinal astrocytes from other astroglial cells in the brain parenchyma . indeed , parenchymal astrocytes lose very early their stem cell potential ( around postnatal day 10 in mice ) , although they can still proliferate in the severe gliosis induced after lesion , and resume multipotentiality in vitro . on the other hand , gliogenesis persists throughout the cns in the form of parenchymal cell genesis capable of creating new oligodendrocytes and , to a lesser extent , astrocytes , throughout life [ 12 , 15 ] . \n most of this gliogenic activity is attributed to synantocytes / polydendrocytes ( ng2 + cells ; see paragraph 6 ) which are widespread in the cns and whose origin is still partially obscure . \n oligodendrocytes originate from migratory and mitotic embryonic precursors which progressively mature into postmitotic myelin - producing cells . \n the sequential expression of developmental markers defines distinct phenotypic stages in the oligodendrocyte lineage , characterized by proliferative capacities , migratory abilities , and changes in morphology . \n the first oligodendrocyte - committed cell appears at embryonic day 12 ( e12 ) in two columns in the ventral ventricular zone of the motor neuron progenitor domain , which is defined by the expression of olig2 . \n the embryonic oligodendrocyte precursors are identified by their expression of platelet - derived growth factor alpha receptor ( pdgfr ) . \n the appearance of the oligodendrocyte lineage - associated markers olig2 ( essential for oligodendrocyte specification and differentiation ) and pdgfr ( which permits the expansion of the original precursor population ) is dependent on the concentrations of sonic hedgehog ( shh ) [ 81 , 82 ] . \n one or two days after their appearance , pdgfr+ cells exit the ventricular zone and expand by local proliferation and migration first in the ventral spinal cord region and then dorsally . \n finally , they occupy the entire parenchyma by the time of birth . a dorsal source of oligodendrocyte precursors was also shown to contribute to oligodendrogenesis in the spinal cord and hindbrain [ 84 , 85 ] . \n fate mapping experiments revealed a double source of oligodendrocyte precursors in the forebrain : cells expressing oligodendrocyte lineage markers , such as olig1 , olig2 , sox10 , and pdgfr , first appear ventrally , in the neuroepithelium of the medial ganglionic eminence , and then migrate laterally and dorsally into all parts of the developing forebrain by e16 to birth . \n however , several studies have provided evidence for a dorsal source of oligodendrocyte precursors in the lateral and/or caudal ganglionic eminence(s ) , which constitute a second wave of cells invading the cortex only by e18 [ 85 , 87 ] . \n nevertheless , adult oligodendrocytes derive only by dorsal precursors , since medial ganglionic eminence - derived precursors were demonstrated to completely disappear after birth . on the whole \n , it is thought that a unique oligodendrocyte population can derive from progenitor domains defined by different signaling molecules , in contrast to what has been established for neuronal specification during embryonic development , where different parts of the ventricular zone generate distinct types of neurons . in the rodent cns , \n once pdgfr+ cells have left the ventricular zone , they start to be termed oligodendrocyte progenitor cells ( opcs ) and acquire their most typical marker : an integral membrane chondroitin sulphate proteoglycan named ng2 ( nerve / glial antigen 2 ) . \n ng2 expression becomes detectable only at e14 , thus , from e17 to adulthood all pdgfr+ cells are ng2 + , and , conversely , all the parenchymal ( nonvascular ) ng2 + cells are pdgfr+ [ 88 , 89 ] . \n early embryonic ng2+/pdgfr+ opcs are small , undifferentiated , proliferative and motile cells . during embryogenesis , \n their morphology changes rapidly from a simple oval or polygonal cell body with few unbranched processes to a more differentiated and branched shape with a smaller cell soma [ 88 , 91 ] . coming back to comparative adult neurogenesis , nonmammalian vertebrates including fish , amphibians , and reptiles harbor a more widespread genesis of neurons in the parenchyma . \n such processes , due to their location , are apparently independent from the primitive germinal layers . nevertheless , recent studies which analysed in more detail the origin of adult neurogenesis in fish show that all neurogenic processes likely originate from remnants of the germinal layers ( reviewed in ) . \n teleost proliferation zones reflect a general proliferation pattern along the ventricular walls of the brain , distinctly localized in all its subdivisions along the rostrocaudal axis . between 12 and 16 distinct proliferation zones \n hence , across different animal classes , most stem cell populations retain contact to the ventricular system , and they appear as neuroepithelial cells , radial glia , or astroglial cell types \n . the different shapes of these progenitors have been suggested to be a secondary consequence of the architecture of the developing parenchyma overlying the ventricular stem cell zone of the embryo . this common pattern across animal species , along with data reported above on the origin of cycling glial progenitors in mammals , \n indirectly suggests that adult parenchymal neurogliogenesis ultimately derives from embryonic germinal layers , yet being able to persist independently in some cases . \n spontaneous ( constitutive ) parenchymal neurogenesis can be considered as a very rare phenomenon in mammals , and its regional location has been shown to be dependent on the animal species , age , and physiological / pathological states . \n different examples of neurogenesis occurring outside the two neurogenic sites have been described in rodents [ 19 , 61 ] , rabbits [ 17 , 18 ] , and monkeys [ 92 , 93 ] . \n remarkable differences can be observed between closely related orders ( e.g. , rodents and lagomorphs [ 17 , 18 ] ) , between species ( e.g. , rat and mouse [ 19 , 23 , 93 , 94 ] ) , and even different strains [ 95 , 96 ] . most parenchymal neurogenesis described in adult rodents seems to occur spontaneously at very low levels , rather being elicited / enhanced after specific physiological or pathological conditions [ 19 , 61 , 63 , 64 ] ( see below ) . \n dayer and colleagues showed the occurrence of new neurons in the deep layers of the rat cerebral cortex . by labelling newlyborn cells with multiple intraperitoneal injections of 5-bromo-2-deoxyuridine ( brdu ) and \n using markers of both immature and mature neurons to characterize the new cells through a detailed confocal analysis at different survival times , they demonstrated genesis of new gabaergic interneurons in both neocortex and striatum . at 4 - 5 weeks survival time , the 0.4 + / 0.13% of the brdu+ cells were mature neun+ neurons in the neocortex . \n interestingly , although several brdu+/dcx+/tuc4 + neuroblasts were identified close to the svz periventricular region , the great majority of cortical brdu+ cells were positive for ng2 \n . from these data the authors suggested that adult cortical newborn interneurons might originate from in situ progenitors . \n newly generated neurons are spontaneously produced in other regions of the adult brain starting from local , parenchymal progenitors . in the caudate nucleus , \n newly formed neuroblasts form longitudinally arranged doublecortin ( dcx ) and psa - ncam immunoreactive striatal chains similar to the svz chains . \n these neuroblasts are generated from clusters of proliferating cells which express the astroglial marker brain lipid binding protein ( blbp ) , and about 1/6 of surviving cells differentiate into calretinin striatal interneurons . \n always in rabbits , in sharp contrast with our common knowledge concerning the cns of other mammals studied so far , a remarkable genesis of cells is detectable in the peripuberal , and to a lesser extent , adult cerebellar cortex . \n systemically administered brdu detected at different postinjection survival times ( up to two months ) reveals newly generated psa - ncam+/dcx+/pax2 + interneurons of neuroepithelial origin homogeneously distributed in the cerebellar cortex . \n thus , in the striatal and cerebellar parenchyma of lagomorphs new neurons are generated independently from the remnants of germinal layers , yet their final outcome and their role in the adult neural circuits remains obscure ; reviewed in . \n the heterogeneity in parenchymal neurogenesis adds to that described for neurogenic processes occurring in adult neurogenic sites , which have been related to adaptation to ecological pressures . at present , this is one of the most satisfactory functional explanations for adult neurogenesis in the entire phylogenetic tree , along with multiple , genetically determined variables spanning from the brain anatomy / developmental history to the animal lifespan . \n this range of possibilities can also be increased by nongenetic variables , such as experience - dependent cues [ 58 , 59 ] . among the unsolved issues of parenchymal neurogenesis \n are the numerous reports which have not been confirmed by further studies or by other laboratories [ 22 , 23 , 26 , 98100 ] , along with a series of data which have been denied in studies trying to reproduce the same results [ 24 , 36 , 101 , 102 ] . without entering in the scientific and technical discussion about these controversies , \n it is evident that we still did not grasp the real limits of parenchymal neurogenesis and that further studies are required before finally accepting , or denying the existence of some neurogenic processes . on the other hand , \n what appears clear is that some stem / progenitor cells in the parenchyma are able to give rise to new neurons in experimental and/or pathological conditions [ 28 , 63 , 64 ] . various examples of reactive \n beside neurogenesis induced from adjacent neurogenic sites [ 25 , 27 ] , some neurogenic / gliogenic processes are also thought to start from local , parenchymal progenitors [ 28 , 63 , 103 , 104 ] . \n for instance , local progenitors in layer i of the rat cerebral cortex , which in normal conditions seem to be rather quiescent , are activated after ischemia giving rise to new cortical interneurons . also in a slow and progressive model of striatal neuronal degeneration , besides activation of svz progenitors , genesis of neuroblasts has been found to occur also from local progenitors in mice . \n this suggests that certain pathological states can stimulate either migration of progenitors from the adult svz or activation of local neuronal progenitors . yet , one of the issues which remain poorly investigated is whether the adult brain parenchyma belonging to spontaneously nonneurogenic areas could be endowed with quiescent progenitor cells which can be stimulated to awake under specific environmental conditions , independently from the contribution of germinal layers . in other words , \n what remains irresolute is whether spontaneous and lesion - induced neurogenesis follow the same pathways and/or involve the same progenitors . \n then , another intriguing possibility to be explored is that lesion - induced neuroblasts occurring in multiple forms of brain injury are committed to transient neuronal types , which contribute to restorative rather than replacement mechanisms . \n a case placed in between the spontaneous and experimentally - induced neurogenesis is that of the hypothalamus . \n several publications based on experiments carried out on rodents have been reporting data on this brain region as a new site for adult constitutive neurogenesis in mammals ( for review see ) . under physiological conditions , both in rats and mice [ 108 , 109 ] \n , proliferative activity does occur in the ependymal layer of the third ventricle and within the surrounding parenchyma . in rats , xu and collaborators using electron microscopy and \n immunohistochemistry showed that tanycytes lining the third ventricle proliferate and express molecules usually found in glial , stem - like progenitor cells , such as blbp and nestin . \n the presence of putative neural progenitors was further supported by the isolation of cells able to give rise to neurospheres from the hypothalamus . \n one month after brdu injection , proliferating cells , some of which expressing hu protein , were detected in the surrounding parenchyma . \n similar results were obtained in mice , yet in both rodent species no clear evidence has supported constitutive and complete hypothalamic adult neurogenesis under physiological conditions . a significant increase in hypothalamic proliferating cells \n delivery of brdu ( 350% more positive nuclei , in comparison to i.p . treated animals ) , nevertheless , in spite of such cell proliferation the level of neurogenesis in the intact hypothalamus seems to be arrested at a very premature stage . on the other hand , growth factor infusion [ 61 , 107 , 110 ] or certain experimental conditions / models , such as prolonged heat exposure and the agrp - tfam mutant mice ( with agouti - related peptide neuronal degeneration ) investigated by pierce and xu , seem to increase neurogenesis in the hypothalamus . \n intracerebroventricular infusion of insulin growth factor i in rats triggered an intense proliferation along the third periventricular area and in the parenchyma of the caudal hypothalamus . \n treatment with bfgf in rats and cntf in mice , it was shown that proliferation induced by growth factors can be followed by genesis of newborn neurons . \n detailed morphological and molecular analyses of the third periventricular region of these animals showed interesting architectural similarities with the svz neurogenic niche ( e.g. , proliferating astroglial cells contacting the ventricle by an apical process bearing a single cilium ) , with tanycytes as primary proliferating elements lining the third ventricle . yet \n , additional studies are necessary to clearly demonstrate / confirm whether hypothalamic newborn neurons generated after physiological / pathological stimulation actually become part of the preexisting circuits playing a role in energy - balance mechanisms . \n taking into account the multifaceted aspects dealing with parenchymal neurogenesis , difficulties encountered in such type of research are not only technical . \n they are also linked to the occurrence of processes placed in the middle between two well - characterized extremes of structural plasticity , such as synaptic plasticity and complete adult neurogenesis . \n in a recent review article five levels have been dissected in the neurogenic processes in order to critically evaluate / compare different parenchymal neurogenic events ( a graphic representation of the five levels is given in figure 1 ) . \n the subsequent steps span from cell division to possible integration of specified / differentiated elements into the cns tissue , and according to this view , only when any of the five steps are filled the neurogenic process should be classified as \n as a result , all the parenchymal neurogenic processes described until now can actually be considered as incomplete . \n this could explain why many claims of neurogenic processes were subsequently refuted because not sustained by experimental evidence . \n the piriform cortex is one of those regions in which results reported by different researchers are quite controversial ; see , for example , references [ 92 , 112114 ] . \n since long time , this cortical region is known to harbor a population of neurons immunoreactive for psa - ncam and dcx [ 114116 ] , which are two markers highly expressed in newly generated neurons but also present in nonnewly generated cells . \n indeed , deeper investigations have shown that the piriform cortex contains a population of immature , nonnewly generated neurons which display very few ( or no ) synapses and are frequently sheathed by glial lamellae . \n these cells , by remaining in an immature state for indeterminate time , can represent a \n reservoir of neurons that could possibly be recruited into the preexisting neural circuits although not generated ex novo . \n in conclusion , alternative and multiple forms of plasticity involving neurons can overlap within the so - called nonneurogenic tissue , affecting preexisting cells / circuits and increasing the complexity of the whole picture of brain structural remodeling . \n in the past , neurogenesis and gliogenesis had always been kept separate , the latter being considered less important than the former . in recent years \n , adult gliogenesis has been reevaluated as many populations of progenitor cells with glial - like features and proliferative capacity have been shown to exist in the mature mammalian cns [ 13 , 15 ] . as a matter of fact \n , parenchymal cell genesis in the so - called nonneurogenic regions is mainly gliogenic . in most regions of the cns , \n parenchymal progenitors assure a slow process of constitutive gliogenesis leading to renewal of oligodendrocytes and , to a lesser extent , astrocytes [ 12 , 15 , 118 ] . in rodents , the major population of cycling progenitors located outside \n the germinal niches are ng2 + cells morphologically , antigenically , functionally distinct from mature astrocytes , oligodendrocytes , and microglia [ 12 , 14 , 15 ] . these cells are also called polydendrocytes to highlight their stellate morphology and lineal relationship to oligodendrocytes , synantocytes for their contiguity to neurons , or \n oligodendrocyte progenitor cells ( opcs ) because they were found able of generating myelinating oligodendrocytes [ 12 , 119 , 120 ] . \n nevertheless , many polydendrocytes remain as a resident cell population of ng2-expressing cells in the mature white and grey matter after oligodendrocytes are generated . \n thus it is widely accepted they represent the fourth cns major glial population , representing 29% of total cells . in the last decade , ng2 + cells have generated a lot of interest among neuroscientists , because they show a series of features quite unusual in opcs . \n these include ( i ) an almost uniform distribution in both grey and white matter ; ( ii ) a stellate morphology ; ( iii ) an intimate association with neurons from which they receive synapses [ 13 , 14 ] ; ( iv ) proliferative capacity in the adult brain [ 13 , 121 , 122 ] ( v ) a potential for giving rise to astrocytes and neurons that may be recruited to areas of lesion in the context of brain injury or pathology . at present \n , it is generally accepted that polydendrocytes are opcs , even if the demonstration that polydendrocytes differentiate into mature myelinating oligodendrocytes in vivo is challenging , because ng2 expression is lost before the terminal differentiation of these cells and the appearance of mature oligodendrocyte antigens . \n for instance , they coexpress the pdgfr , and during the first postnatal week , in the corpus callosum and cortex , they start expressing the immature oligodendrocyte antigen o4 . \n polydendrocytes also express the basic helix - loop - helix ( bhlh ) transcription factors olig1 and olig2 , which are required for oligodendrocyte specification and differentiation as well as sox9 and sox10 transcription factors [ 122 , 124 ] . \n moreover , pulse - chase labeling of proliferating cells using brdu revealed that the number of brdu+ng2 + cells decreases while that of brdu+ oligodendrocytes increases over time [ 12 , 125 ] . \n cell - grafting experiments have shown that polydendrocytes give rise to myelinating cells when they are transplanted into an environment free of endogenous myelinating cells . recently \n , more direct evidence for the oligodendroglial fate of polydendrocytes was obtained from cell fate - mapping experiments using transgenic mice that express cre recombinase ( cre ) in ng2-expressing cells or that express inducible cre ( creer ) , under the regulation of the cspg4 , pdgfr , or olig2 genes , which enable determination of the fate of polydendrocytes at a given time during development [ 99 , 127 ] . \n early cell - culture studies showed that opcs purified from rat optic nerves differentiate not only into oligodendrocytes but also into process - bearing type-2 astrocytes in the presence of serum factors , which led to the concept of bipotential oligodendrocyte type-2-astrocyte ( o-2a ) progenitor cells . \n there are now controversial observations suggesting that bipotentiality of polydendrocytes might be real or an in vitro artifact [ 126 , 128 , 129 ] , and most likely these cells are inherently capable of differentiating into astrocytes but are prevented from fulfilling their astroglial fate in the normal in vivo environment . on the whole , while all of these studies consistently support the oligodendrocyte lineage of the ng2 + cells , the genesis of astrocytes from ng2 + cells is confirmed only during postnatal ages . \n all these different and sometimes controversial results may be explained by some methodological / technical differences , but may also reflect heterogeneity in progenitor cell populations / subpopulations ( mostly not yet identified ) , which is far to be elucidated . in this context , we have recently identified a population of multipolar glial cells immunoreactive for the microtubule associated protein 5 ( map5 ) , which share features but also differences with ng2 + progenitor cells . \n these multipolar , map5 + cells are newly generated , parenchymal elements of the oligodendroglial lineage , which represent a stage - specific population of polydendrocytes ( crociara et al . \n another issue which remains unresolved not only for adult glial progenitors but also for parenchymal neurogenic progenitors , is their way of cell division . in other words , \n what it is still not clear is the real nature of adult cns cycling cells in terms of stem or progenitor elements . \n using lineage tracing by retroviral infection , brdu labeling in vivo , and transgenic mice expressing tamoxifen - inducible ng2creer and fluorescent cre reporter alleles to study the fate of single ng2 + cells has revealed that age and neuroanatomical location determine whether these cells can either self - renew , generate mature oligodendrocytes , or both [ 101 , 131 , 132 ] . \n adult ng2 + progenitors have a very long cell cycle and many of them can divide at least twice , only a limited proportion of the progeny differentiating into mature oligodendrocytes . \n after stab wound injury , many of these progenitors reenter the cell cycle very fast , whereas voluntary physical exercise shows the opposite effect with increased exit of the cell cycle followed by an enhanced and fast differentiation into mature oligodendrocytes . \n the authors of this study observed that proteoglycan ng2 segregates asymmetrically during mitosis to generate opc cells of distinct fate , and a decrease in such asymmetry coincides with premalignant , abnormal self - renewal rather than differentiation . on the whole , \n the data available on proliferative dynamics of parenchymal progenitors still need further investigation but strongly suggest that adult cns parenchymal cell populations are subject to profound modulation by environmental stimuli and can be involved in pathology . \n a better knowledge of adult neurogenesis and gliogenesis and of its relative underlying mechanisms is considered fundamental in order to figure out new efficacious therapies for brain repair . under pressure of this statement , studies on this topic have increased exponentially during the last two decades , sometimes leading to excessive emphasis about theoretical correlations between neuro - glio - genic processes and brain repair . \n focusing on the real neurogenic / gliogenic potential of the mammalian cns should avoid to turn an exciting biological discovery into a therapeutic illusion . the existence of nscs opened the intriguing perspective of cell replacement - aimed therapeutic strategies for neurodegenerative diseases , yet , twenty years later , this approach is still hampered by overwhelming problems concerning the final integration of both transplanted and endogenously induced cells . at the basis of this failure \n are evolutionary constraints and the fact that cell renewal occurring in adult neurogenic sites is primarily involved in tissue homeostasis , being hardly useful in response to external injury and neurodegenerative brain damage affecting the parenchyma [ 11 , 40 ] . in this context \n , the discovery of parenchymal cell genesis represents a new plastic potential to be explored within wide regions of the cns , including those areas affected by different neurodegenerative diseases and traumatic injuries . \n nevertheless , a vast number of reports currently published in the domain of parenchymal cell genesis ( references in ) , although accurate and carried out with multiple technical approaches , do suggest that in most cases newly formed elements barely survive and do not fully integrate . \n in addition , the extreme heterogeneity of parenchymal neurogliogenesis makes the mammalian cns parenchyma a harsh territory for neuroscience studies and for brain repair , in which new unanswered questions are continuously opened ( see box 2 ) .", "role": "user" }, { "content": "during the last two decades basic research in neuroscience has remarkably expanded due to the discovery of neural stem cells ( nscs ) and adult neurogenesis in the mammalian central nervous system ( cns ) . \n the existence of such unexpected plasticity triggered hopes for alternative approaches to brain repair , yet deeper investigation showed that constitutive mammalian neurogenesis is restricted to two small neurogenic sites hosting nscs as remnants of embryonic germinal layers and subserving homeostatic roles in specific neural systems . \n the fact that in other classes of vertebrates adult neurogenesis is widespread in the cns and useful for brain repair sometimes creates misunderstandings about the real reparative potential in mammals . nevertheless , in the mammalian cns parenchyma , which is commonly considered as \n nonneurogenic , some processes of gliogenesis and , to a lesser extent , neurogenesis also occur . \n this \n parenchymal \n cell genesis is highly heterogeneous as to the position , identity , and fate of the progenitors . \n in addition , even the regional outcomes are different . in this paper the heterogeneity of mammalian parenchymal neurogliogenesis will be addressed , also discussing the most common pitfalls and misunderstandings of this growing and promising research field .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: in this prospective clinical trial , 400 patients older than 30 years old ( in class 1 , 2 , and 3 of american society of anesthesiologists classification ) who were scheduled for elective operative fixation of fractured hip , enrolled ; all of them were admitted in al - zahra and kashani hospitals in isfahan and all of them signed informed consent from . \n patients were included if they had no dementia or cognitive dysfunctions and no history of opioid or psychotic drugs use . patients with hypersensitivity to blood transfusion , sever reaction to cement implantation , sever bleeding , hypotension needed interventions , prolonged operation changed surgical plan which impressed the study goals , were excluded . \n an anesthesiologist visited all the patients a night before surgery and any known history of hematologic , endocrine , cardiovascular , pulmonary , and central nervous system diseases were noted . also , systolic , diastolic , and mean arterial pressures were recorded . \n patients were randomly assigned into two groups using random - number table : ga ( general anesthesia ) and na ( neuraxial anesthesia ) . \n all patients were infused ringer 's lactate solution ( 4 ml / kg ) on arrival in the operating room and also received low dose of heparin as a dvt prophylaxis . \n systolic , diastolic , and mean arterial pressures were recorded before induction of anesthesia by anesthesiologist . in the ga group , patients were given ringer 's lactate solution ( 10 ml / kg ) to oppose the vasodilatation and hypotension resulting from intravenous anesthetics during induction of anesthesia . \n they received a standardized general anesthesia involving pre - oxygenation and induction with fentanyl ( 2 g / kg ) followed by thiopental ( 5 mg / kg ) until loss of consciousness ; then lidocaine ( 1.5 mg / kg ) and pancuronium ( 0.1 mg / kg ) were administered . \n anesthesia was maintained using halothane ( 0.5 - 1.5% ) in oxygen and nitrous oxide ( ratio 1:1 ) . \n mechanical ventilation with a constant tidal volume of 10 ml / kg and respiratory rate of 12 per minute was maintained throughout the study . at the end of the operation , \n the volatile anesthetic agents were discontinued and residual neuro - muscular block was antagonized with intravenous prostigmin ( 0.04 mg / kg ) and atropine ( 0.02 mg / kg ) . \n extubation was performed when the patient was judged to be awake . in the na group \n , patients were given ringer 's lactate solution ( 15 ml / kg ) prior to the induction of anesthesia and received either spinal or epidural anesthesia . \n after sterile preparation and draping , in spinal anesthesia group , plain bupivacaine 0.5% ( 3 ml ) was injected over 10 seconds into the subarachnoid space at the l3-l4 interspace via 23-g withacre needle placed midline approach . in the epidural group \n , anesthesia was performed using an 18-g - touhy needle at the l3-l4 interspace and after an initial test dose of plain bupivacaine 0.5% ( 5 ml ) with epinephrine ( 1:200000 ) was injected followed 5 minutes later by a further 20 ml . \n all patients were monitored by non - invasive electrocardiogram , blood pressure , and pulse oxymetry . additionally , end - tidal carbon dioxide ( etco2 ) was monitored and maintained within 35 - 40 mmhg during operation in the ga group . in both groups , \n preloading with ringer 's lactate solution prevented sever reduction in blood pressure and kept mean of arterial pressure above 70% of baseline levels in hypertensive patients and above 65 mmhg in normotensive patients.3 blood pressure was measured every 15 minutes and if it fell to below these limits , halothane was reduced gradually in the ga group and an additional 10 ml / kg ringer 's lactate solution was infused in a period of 10 minutes in the na group to reestablish the acceptable blood pressure.11 if the blood pressure did not respond after these interventions , 5 - 10 mg bolus of intravenous ephedrine , according to the degree of hypotension , was administered . \n the second dose was repeated after 5 minutes if the blood pressure was not normalized . \n five minutes after the second dose of ephedrine , if the mean arterial pressure was still less than 70% of its baseline value , further ephedrine boluses were administered , and the case regarded as a failure in the study . \n hemoglobin level was measured before surgery ( baseline ) , 6 hours , and 2 , 3 , and 5 days after the end of it . \n the total estimated intraoperative blood loss was recorded at the end of each surgery with bloody gauze counting and measuring volume of suction bottles ; also , the amount of postoperative hemorrhage was measured according to its volume in hemovac drain . \n the time interval between the induction of anesthesia ( ga or na ) and dressing of the site of operation was recorded as the duration of surgery . \n postoperative pain severity was evaluated using a visual analogue scale ( vas ) ranging from 0 ( no pain ) to 10 ( worst possible pain ) . \n the vas was evaluated by a nurse at the time of discharge from recovery room and by a second nurse on the ward at the 2 , 3 , and 5 day after surgery . \n intravenous morphine ( 5 mg ) was administered to the patients re - quested analgesia and its total amounts were recorded till 5 days after the end of surgery . \n cognitive dysfunctions were noted before discharge from recovery room , and at 24 and 48 hours after the end of the surgery based on time , person , and place disorientation . \n postoperative complications such as deep veins thrombosis , congestive heart failure , myocardial infarction , atelectasis , pulmonary infection , and cerebrovascular accidents are diagnosed by the consultant specialist . \n the number of patients who died over one month period in the hospital or after discharge from it was recorded . \n the data were analyzed using spss statistical package ( version 12 , spss inc . , \n frequencies were compared by mann - whitney and chi - square tests , as appropriate , and t - test was used to compare the averages . \n during the study period , 400 consecutive patients with the required surgical indication were included . \n three patients of the ga group and 10 of the na group were excluded because of change in anesthetic or surgical plan . \n one hundred and ninety - seven ( 50.9% ) patients were allocated to the ga group , whereas 190 ( 49.1% ) patients constituted the na group . \n of 190 neuraxial anesthesia patients , 164 ( 42.4% ) , 1 ( 4% ) and 22 ( 5.7% ) received spinal , epidural and continuous epidural anesthesia , respectively . \n patients and surgical characteristics , baseline hemoglobin and length of stay in hospital before surgery are listed in table 1 . \n patient characteristics , preoperative hemoglobin values , duration of hospitalization , and some intraoperative data in the general anesthesia group ( ga ) and neuroaxial group ( na ) the mean of intraoperative blood loss , mean of vas scores in recovery and on the 3 postoperative day , and also the length of stay in hospital after surgery in the na group were significantly less than the ga group . \n both groups showed a significant decrease in hemoglobin values on the 2 and 3 postoperative days comparing to the baseline values ( p < 0.001 ) ( table 2 ) . \n the mean intra- and post - operative blood loss , hemoglobin changes , pain scores and the duration of hospitalization in both groups there was no significant difference between two groups regarding the abundance of cardiovascular and respiratory complications ( table 3 ) . \n no patients in either group suffered from cardiac insufficiency , deep vein thrombosis , or cerebral events . in the na group , \n frequency of postoperative complications and mortality rate in both groups the number of patients who developed cognitive dysfunction in recovery room was signifycantly higher in the ga group compared with the na group . \n although the number of patients who died was more in the na group , but no significant difference was found between the two groups for in - hospital and out - hospital mortality . \n on the 2 postoperative day , there was a greater incidence of cardiac ischemic events and respiratory complications in both groups . \n also , myocardial infarction was reported more on the 3 postoperative day , although this difference was not statistically significant . \n the mean of ephedrine doses ( 0.8 4.4 vs. 3.2 8.1 mg administered to the ga and na groups respectively ) was statistically significant ( p < 0.001 ) . also , the mean of morphine consumption in the ga group ( 5.0 6.3 mg ) was higher than the na group ( 3.4 7.4 mg ) ( p = 0.004 ) . \n this study showed that the mean of blood loss during operation was significantly more in patients receiving general anesthesia than neuraxial anesthesia . in two previous separate meta - analysis assessing the patients undergoing different surgical procedures12 and the candidates of hip and spinal column surgeries , the researchers demonstrated that general anesthesia is accompanied by more hemorrhage compared with neuraxial anesthesia.1213 in a review article , macfarlane et al reported that in four out of ten studies , patients receiving ga had significantly more bleeding , and in the other six there was no significant difference between groups considering blood loss.14 they reported that the mean of reduction of blood loss was different from 118 ml to 595 ml , but in our study this value was 238 ml . in a prospective controlled study , \n patients undergoing hip surgery under spinal anesthesia had less blood loss than patients receiving general anesthesia.15 neuraxial anesthesia blocks alpha and beta adrenergic receptors , leads to reduction of heart rates , vascular tone , and blood pressure . \n the decreased blood pressure acts like controlled hypotension which results in less blood loss.16 in this study , the amount of intraoperative ephedrine consumption to oppose hypotension was significantly more in neuraxial method than in general anesthesia . thus the established intraoperative hypotension is in an accepted limitation , it can explain the less blood loss in neuraxial anesthesia patients . \n the other justifying reason can be an increase in venous blood pressure in patients receiving general anesthesia especially with mechanical ventilation.17 in this study there was no difference between the groups regarding postoperative blood loss amount and the hemoglobin changes until the 5 postoperative day ; but in both groups the mean of hemoglobin changes was statistically lower on the 2 and 3 postoperative days compared to preoperative values . in our study , the mean of duration of hospitalization was significantly more in patients receiving general anesthesia . \n miniche et al surveyed 42 volunteers of hip surgery undergoing general or continuous epidural anesthesia and found that the duration of hospitalization was similar in both groups.18 the difference may be attributed to their smaller studied population and applying only one method of neuraxial anesthesia which was continuous epidural anesthesia . \n sutcliffe and parker in a retrospective study found no difference in factors of hospitalization in 1333 patients receiving either general or neuraxial anesthesia for hip surgery.19 this contradiction can be due to the different kind of studies . \n vaida et al declared that the beneficial effects of neuraxial analgesia are reduction of stress hormones , inhibition of central hyper sensitization and ultimately shortening the duration of hospitalization . \n they believed that increase in pain severity and cognitive dysfunction in patients receiving general anesthesia resulted in longer hospitalization.20 our findings demonstrated that the pain severity , especially at recovery room and on the 3 aostoperative day was lower in neuraxial group . \n moreover , gonano et al studied 40 volunteers of hip and knee surgeries and reported that spinal anesthesia accompanied by less postoperative pain compared to general anesthesia.21 furthermore , a meta - analysis on 1362 patients reported that neuraxial anesthesia or peripheral nerve block leads to less postoperative pain.22 additionally , a review article reported that in ten of eleven studies , patients receiving epidural anesthesia significantly suffered less pain than general anesthesia groups.14 the reduction in pain severity at recovery room can be attributed to the residual effects of sensory block of neuraxial anesthesia . \n also , the lower pain on postoperative days may be due to the beneficial effects of preemptive analgesia in neuraxial anesthesia application . in our study , \n the frequency of postoperative events , including cardiovascular and respiratory complications , were similar in both groups . \n in fact , there was no statistically deference in the incidence of myocardial ischemia , myocardial infarction , atelectasia , and pulmonary infection between groups . \n our results were different from the results of urwin et al study1 ; in their study , incidence of dvt and myocardial infarction in patients undergoing correction of fractured hip surgery under neuraxial anesthesia was lower than general anesthesia patients . \n meanwhile , the incidence of cerebrovascular accidents and intraoperative hypotension were lower in patients receiving general anesthesia.1 the reasons for differences in findings might be due to the difference in sample size and the kind of the study . in other words \n , they evaluated 2161 patients retrospectively while we studied 387 patients prospectively . in a meta - analysis , \n a lower incidence of dvt and pulmonary emboli in patients receiving neuraxial anesthesia for hip surgery was showed.15 however , ohara et al reported no significant difference in incidence of postoperative myocardial infarction , congestive heart failure ( chf ) , and mental dysfunction between both groups receiving either general or neuraxial anesthesia in a retrospective study.9 this finding was similar to the present study . \n we also found no statistical difference in mental dysfunction on the 2 and 3 postoperative days between the groups . \n this was in similarity to the findings of some previous studies.923 our results revealed that patients receiving general anesthesia had more mental dysfunction in recovery room . \n this difference might be due to the remaining effect of anesthetic drugs at recovery room . in our study \n , there was no difference in the abundance of death during hospital stay and out of hospital till 30 days after surgery . in one study on 425 patients in a primary investigation \n , they reported that the anesthetic technique has a role in morbidity and mortality of patients . \n but , after controlling the differences of the studied groups , they revealed that there is no difference in morbidity and mortality rate between the groups.16 thus , the authors concluded that the major reasons for morbidity and mortality of these patients are their coexisting disease ( e.g. diabetes , cardiovascular disease , etc ) , elderly , and undesirable physical condition and not an anesthetic technique . in limited studies , \n the difference in the incidence of mortality and morbidity after neuraxial and general anesthesia was reported . \n for example , in one study , 53 high risk patients were evaluated and the results showed a lower incidence of morbidity and mortality after epidural anesthesia compared to general anesthesia.24 in another clinical trial , the effect of anesthetic techniques was not proved.25 but in another study , the effect of neuraxial anesthesia on short term mortality was drawn but it had not differ from general anesthesia considering long term mortality.26 in fact , in a majority of the studies , we may not be able to rely on the results due to the small sample size and a low study power . \n as in our study , the sample size was calculated according to the major postoperative complications , the absence of significant difference in mortality might be attributed to small sample size . \n this would be possibly considered as a weakness of this study . moreover , due to the limitation in performance of some specific diagnostic tests or the mildness of some clinical signs of diseases , there is a possibility that some postoperative complications might be undiagnosed . \n also , one of the limitations of our study was lack of some predictors such as sickness at admission scale or acute physiologic score from the appache i and asa ; so we can not conclude that mortality is due to anesthetic techniques or coexisting diseases . \n in conclusion , this clinical investigation demonstrated that general and neuraxial anesthesia have a similar incidence of postoperative complications and mortality in candidates of hip surgery . \n we believe that because of the less intraoperative hemorrhage , shorter hospital stay , and lower postoperative pain in patients undergoing neuraxial anesthesia for hip surgery , this technique is superior as compared to general anesthesia . in a summary , the results suggest that more controlled studies with larger sample size and more precise diagnostic tests , in multiple centers are needed to eliminate the limitations of our study . \n hs was one of the members of reaserch team and also helped to write the manuscript . \n sjh was one of the members of reaserch team , also helped to write the manuscript , and corrected the manuscript according to reviewers comments . \n rt was one of the members of reaserch team and also helped to write the manuscript .", "role": "user" }, { "content": "background : surgery for hip fractures can be done under general or neuraxial anesthesia . \n this study aimed to compare these two methods concerning their postoperative complications , duration of operation , hospitalization and the mortality rate within a period of one month after surgery.methods:400 patients aged more than 30 years old and scheduled for elective operative fixation of fractured hip , randomly enrolled in two equal groups of general ( ga ) and neuraxial ( na ) anesthesia . \n hemoglobin level was measured before and 6 hours , 2 , 3 and 5 days after the surgery . \n the intra and postoperative blood loss , duration of surgery , the severity of pain at the time of discharge from recovery and at the 2nd , 3rd and 5th postoperative days were recorded . \n statistical analysis was performed using spss version 12.0 by mann - whitney , chi - square , and t tests . \n p < 0.05 was considered significant.results:both groups were similar regarding age , weight , and gender ratio . \n there was no significant difference in baseline hemoglobin , duration of surgery , length of hospitalization before surgery and the type of surgery . \n the mean of intraoperative blood loss and visual analogue score ( vas ) in recovery and at the 3rd postoperative day , and also the length of hospitalization after surgery were significantly less in neuraxial anesthesia group . \n both groups showed a significant decrease in hemoglobin values on the 2nd and 3rd postoperative days comparing to the baseline ( p < 0.001).conclusions : the morbidity and mortality rates of patients undergoing hip surgery were similar in both methods of anesthesia , but postoperative pain , blood loss , and duration of hospitalization were more in patients undergoing general anesthesia .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: incidence of infective endocarditis ( ie ) has remained somewhat constant since the past era despite improvement in the diagnosis and treatment . \n acute ie by staphylococcus aureus ( including infrequently reported community - acquired methicillin - resistant staphylococcus aureus [ mrsa ] ) has a rising trend and may present with rapid progression and systemic sequelae . \n several studies have reported mrsa infections in populations lacking the previous contact with health - care facilities . \n we hereby present a case of acute mrsa endocarditis ; with rapidly progressive digital gangrene and hence masquerading as peripheral vascular disease ( pvd ) . a high index of suspicion , subsequent investigations , identification of the etiologic agent , and antibiotic sensitivity testing assured appropriate pharmacotherapy and eventually stopped further progression and resulted in cure of the infection . \n a 21-year - male patient presenting with pain and bluish discoloration of the left upper limb for 2 days and high fever for 1 week was referred to the department of cardiology for peripheral angiography for suspected pvd . \n there was no history of joint pain , rash , convulsion , myocardial infarction , any hypercoagulable state , recent or past hospital stay , central venous cannulation , and intravenous drug abuse . \n clinical examination revealed ischemic changes in left upper limb with early gangrenous changes of left hand distal to the metatarsophalangeal joints . \n pulse was absent in left upper limb from axillary artery downward , high volume collapsing pulse was found in other limbs . \n peripheral signs of aortic regurgitation ( ar ) were present , and hill 's sign was positive at 50 mmhg . \n jugular venous pressure was normal , and apex was at left 5 intercostal space just outside the midclavicular line . \n working clinical diagnosis was that of peripheral embolism in a case of ie of the aortic valve with severe aortic incompetence . \n routine blood examination revealed hb - 9.8gm% , tlc - 18900/mm , and neutrophil - 87% . \n serum ana ( hep2 ) , anti - ds dna , p - anca , c - anca , homocysteine , antiphospholipid antibody , anticardiolipin antibody , b2 glycoprotein1 , and markers for hypercoagulable states : all were negative . \n on transthoracic echocardiography , oscillating vegetation was seen attached to the right and noncoronary cusp of aortic valve along with coaptation failure of the aortic valve with severe ar [ figures 1 and 2 ] . \n left ventricle was mildly dilated ( left ventricular internal diameter diastolic = 59 mm , left ventricular ejection fraction - 58% , and no regional wall motion abnormality ) . \n two consecutive blood cultures ( more than 12 h apart ) were sent before administration of antibiotics . \n doppler ultrasonography ( usg ) study showed sluggish flow across left brachial , ulnar , and radial artery . \n vegetations in the right and noncoronary cusps of aortic valve in two - dimensional echocardiography . \n balloon embolectomy by fogarty 's catheter was performed , and pulse in the left upper limb improved slightly . however , fever continued . \n doppler usg followed by exploration of the swelling revealed pseudoaneurysm ( 3.5 cm 2.5 cm 3 cm ) of subclavian artery [ figure 3 ] , with collection of pus and slightly enlarged surrounding lymph nodes . \n the pseudoaneurysm was excised , and aspirated pus was sent for culture and sensitivity . on obtaining pus and blood culture reports of mrsa and concurrent antibiograms , antibiotic therapy was rescheduled with vancomycin for 6 weeks and gentamicin for 4 weeks along with monitoring of renal parameters . \n we inferred the final diagnosis as mrsa - mediated acute ie of aortic valve ( probably with preexisting rheumatic heart disease ) , complicated with mycotic embolic phenomenon and iatrogenic mycotic pseudoaneurysm . \n despite the decreasing incidence of rheumatic heart disease and increased frequency of degenerative valve disease , annual incidence of ie ( 410/100,000 population ) and associated mortality ( 1/100,000 per year ) have remained constant . \n valvular leaflets are quickly destroyed by bacteria multiplying rapidly within the ever - growing friable vegetations . \n early complications ( within a week ) include dyspnea and fatigue of severe congestive heart failure and a wide spectrum of neuropsychiatric complications resulting from central nervous system involvement . \n the diagnosis is worth consideration in any patient who has unexplained fever , has organ involvement that may be attributed to embolic phenomenon , or appears to have a multisystem disease . \n the incidence of peripheral embolization is highest with s. aureus endocarditis although digital gangrene is rarely reported . \n the systemic involvement owing to embolic phenomenon in the decreasing order of frequency is splenic , cerebral , pulmonary , renal , and coronary followed by the extremities . \n pseudoaneurysm is defined as a localized , irreversible dilatation of an artery by at least 1.5 times its normal diameter , and the disruption of the vascular wall caused by an infection of a previously normal artery or more rarely as a result of secondary infection of a preexisting aneurysm . when associated with acute endocarditis \n , the pathogenesis is related to the release of septic emboli of cardiac focus through the bloodstream , lodgment in atherosclerotic plaques , or vasa vasorum causing inflammation of the vessel wall , with consequent damage and dilatation of the arterial wall . \n rarely , pseudoaneurysm may complicate embolectomy ( 6% ) because of intimal linear or full - thickness tears or disruption of the vessel wall . here \n , the cause might be either destruction of arterial wall with catheter - related intervention and/or colonization of the bacteria and very rapid destruction of the wall by bacterial exotoxin . \n rapid peripheral embolization and later on mycotic pseudoaneurysm formation justify high virulence of the concerned infective agent . \n community - associated mrsa isolates often possess a novel type iv sccmec , as well as the pvl gene , which encodes a virulent exotoxin . \n brachial artery and peroneal artery pseudoaneurysm following fogarty 's balloon embolectomy have been reported in the past , but not subclavian artery pseudoaneurysm . \n our case illustrates an unusual presentation of ie and highlights the complication of interventional management . \n the approach should be based on the assessment of clinical course , imaging studies , laboratory results for confirmation of etiology , and guided administration of appropriate antibiotic therapy . \n \n ", "role": "user" }, { "content": "a young male patient presented at a tertiary care hospital with cold and bluish left upper limb accompanied with digital gangrene arousing suspicion of peripheral vascular disease . \n history did not reveal any high - risk behavior . \n clinical examination and subsequent investigations lead to the diagnosis of acute infective endocarditis of native aortic valve along with peripheral embolism caused by methicillin - resistant staphylococcus aureus . \n fogarty 's balloon embolectomy was done following which patient developed pseudoaneurysm of the left subclavian artery . \n these iatrogenic sequelae were managed with the resection of the pseudoaneurysm and prolonged antibiotic therapy as per the culture and sensitivity report .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: pseudoaneurysms of the extracranial carotid artery ( ecca ) are uncommon , and many of these vascular lesions can be managed with medical therapy alone . however , large or symptomatic ecca pseudoaneurysms require intervention . although ecca lesions have traditionally been treated with surgery , the evolution and dissemination of endovascular techniques and technologies have shifted the management of ecca pseudoaneurysms toward minimally invasive approaches . \n giant pseudoaneurysms resulting in compression and luminal narrowing of the parent vessel are difficult to treat with endovascular intervention since mass effect from the pseudoaneurysm can cause in - stent stenosis . \n the aim of this case report is to describe the use of a telescoping dual covered stent graft construct for the endovascular treatment of a giant ecca pseudoaneurysm which was imposing a significant local mass effect on the common carotid artery ( cca ) bifurcation . \n a 56-year - old male presented with an enlarging left - sided neck mass over a period of 2 months . on initial examination \n , the patient had left cranial nerve x and xii palsies , as well as local oropharyngeal medialization and edema , which resulted in rightward displacement of the glottis and airway compromise . \n neck computed tomography ( ct ) showed a very large left - sided neck mass extending from the level of the c2 transverse process superiorly to the supraclavicular fossa inferiorly , and measuring 8.5 and 13 cm in maximum transverse and craniocaudal dimensions , respectively [ figure 1a - c ] . \n the mass resulted in considerable displacements of the larynx toward the right side , with mild airway narrowing . \n neck computed tomography , ( a ) axial , ( b ) coronal , and ( c ) sagittal views , shows an 8.5 cm 13 cm mass filling the majority of the left side of the neck . \n after a failed surgical biopsy of the mass resulted in significant intraoperative bleeding , neck computed tomography angiography , ( d ) axial , ( e ) coronal , and ( f ) sagittal views , shows an enlarging mass arising from the left common carotid artery bifurcation with a central , uniformly enhancing component measuring 5.2 cm 5 cm 5 cm , consistent with a partially thrombosed , giant extracranial carotid artery pseudoaneurysm the initial diagnosis was suspected to be a necrotic , metastatic squamous cell cancer . \n the patient underwent an open biopsy , which revealed a large amount of organized hematoma . on further dissection , \n a large quantity of active hemorrhage was encountered , and therefore , establishing the diagnosis of a pseudoaneurysm . \n the intraoperative bleeding was controlled with pressure , the wound was closed , and the patient was transported to radiology , where neck ct angiography ( cta ) demonstrated a giant , partially thrombosed ecca pseudoaneurysm arising from the left cca bifurcation [ figure 1d - f ] . \n mass effect from the pseudoaneurysm resulted in narrowing of the cca just proximal to the carotid bulb as well as stenosis of the proximal internal carotid artery ( ica ) . after reviewing the findings of the neck cta , \n arterial access was established with a 7-french right femoral cook shuttle sheath ( cook medical , bloomington , indiana , usa ) . \n angiography showed a giant ecca pseudoaneurysm , with a neck spanning the distal cca , external carotid artery ( eca ) , and carotid sinus [ figure 2a and b ] . \n a headway 21 microcatheter ( microvention , tustin , california , usa ) was navigated over a synchro-14 microguidewire ( stryker neurovascular , fremont , california , usa ) across the neck of the pseudoaneurysm into the left ica . \n a rosen exchange guidewire ( cook medical ) was then positioned high in the left ica . \n a 7 mm 50 mm viabahn endoprosthesis heparin - bonded covered stent graft ( w. l. gore and associates , flagstaff , arizona , usa ) was deployed from the lower cervical ica to the distal cca . \n next , an 8 mm 38 mm atrium advanta v12 balloon - expandable covered stent graft ( maquet , rastatt , germany ) was deployed , within the first covered stent , from the carotid sinus to the cca . \n cerebral angiography , ( a ) anteroposterior and ( b ) lateral views of a left common carotid artery injection , shows a giant extracranial carotid artery pseudoaneurysm , with a neck spanning the distal common carotid artery , external carotid artery , and carotid sinus . \n mass effect from the pseudoaneurysm is resulting in compression and luminal narrowing of the proximal internal carotid artery . \n the extracranial carotid artery pseudoaneurysm was treated with an 8 mm 38 mm atrium advanta v12 covered stent telescoped within a 7 mm 50 mm viabahn endoprosthesis covered stent . \n poststenting control angiography , ( c ) anteroposterior and ( d ) lateral views of a left common carotid artery injection , shows occlusion of the pseudoaneurysm and improved caliber of the internal carotid artery final control angiography demonstrated obliteration of the pseudoaneurysm and improved caliber of the previously stenotic proximal ica , without any evidence of intracranial complications [ figure 2c and d ] . \n the patient was prescribed dual antiplatelet therapy ( aspirin 100 mg and clopidogrel 75 mg daily ) for 6 weeks postoperatively , followed by monotherapy with aspirin indefinitely . \n carotid doppler ultrasonography on postoperative day 2 showed patency of the dual stent graft construct spanning the left distal cca and proximal ica as well as occlusion of the pseudoaneurysm . due to the patient 's multiple medical comorbidities , he remained hospitalized for a month after the stenting procedure but was eventually discharged home without postoperative neurological complications . \n the goal of endovascular therapy for ecca pseudoaneurysms is occlusion of the pseudoaneurysm while preserving flow through the affect portions of the cca and ica . \n although unilateral eca occlusion is universally well tolerated due to extensive collateral supply , ica occlusion can result in devastating thromboembolic and ischemic cerebral infarctions . \n therefore , reconstructive approaches ( i.e. , stenting ) are generally preferred over destructive approaches ( e.g. , ica occlusion or ligation ) . in a cohort of 116 ecca pseudoaneurysms , fankhauser et al . reported that the mean diameter of symptomatic pseudoaneurysms was 1.7 cm . \n the pseudoaneurysm in our case was substantially larger , with a maximum diameter of 13 cm . \n these giant lesions present unique challenges to both surgical and endovascular treatment , particularly when mass effect from the pseudoaneurysm is compressing the parent artery . \n the use of covered stents has been previously reported for the treatment of ecca pseudoaneurysms . however , due to the size and extensive mass effect from pseudoaneurysm in our patient , we did not believe a single stent would provide sufficient radial force to maintain the patency of the compressed ica . \n therefore , we used a telescoping dual covered stent graft construct , in which a balloon - mounted covered stent was deployed within another heparin - bonded covered stent , to simultaneously achieve twin goals : ( 1 ) exclusion of the ecca pseudoaneurysm and ( 2 ) luminal restoration of the ica . \n a technique utilizing telescoping covered stents can be employed for the endovascular treatment of appropriately selected patients with large or giant ecca pseudoaneurysms \n . however , further studies assessing the long - term patency of telescoping dual covered stent constructs are necessary . \n \n ", "role": "user" }, { "content": "large pseudoaneurysms which compress the parent vessel are challenging lesions to successfully treat with endovascular therapy . \n we describe the endovascular treatment of a giant extracranial carotid artery ( ecca ) pseudoaneurysm resulting in substantial mass effect on the common carotid artery ( cca ) bifurcation using a telescoping dual covered stent graft construct . \n a 56-year - old male was diagnosed with an 8.5 cm 13 cm pseudoaneurysm arising from the left cca bifurcation , which was causing luminal narrowing of the cca and proximal internal carotid artery ( ica ) . \n the patient underwent endovascular intervention , during which a balloon - expandable covered stent was deployed within a heparin - bonded covered stent , such that the overall construct spanned from the cca to the lower cervical ica . \n the employment of a telescoping dual covered stent technique can successfully treat appropriately selected patients with large or giant ecca pseudoaneurysms , with the concomitant goals of excluding the pseudoaneurysm and restoring the luminal caliber of the parent artery .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: recombinant protein drugs approved by the fda over the past 25 years have become a cornerstone of medical and especially endocrine practice ( table 1 ) . as the first wave of biopharmaceuticals has expired or is about to approach expiry , the opportunity for the development of subsequent biosimilar or follow - on protein product ( fopp ) versions of these products has emerged . however , second entry biopharmaceuticals differ significantly from traditional chemical generics ( table 2 ) . in the standard pharmaceutical sector , \n competition from cost - effective generic medicines is encouraged for many years now to stimulate innovation and to free up health care budget resources . \n biosimilars , unlike conventional generic drugs , require more quality data and therefore must demonstrate full comparability ( including immunogenicity data ) , to the reference product . \n this of course begs the question : what is the incentive to develop a biosimilar ? unlike with traditional generic products , there is the potential in europe to extrapolate to all indications of the reference product ( in this case humatrope or genotropin ) , which may go part of the way answering this question . \n one way this is achieved is by providing an abridged registration procedure which allows an applicant to apply for marketing authorization of a patent - free medicine to replace full clinical trials with noninferiority bioequivalence studies . \n the manufacturer must prove the quality of the generic product and , since the safety and efficacy of the active substance are already well known , the generic has to demonstrate its therapeutic equivalence with the original product through what are called bioequivalence studies . \n due to the complexity of biotechnology - derived products and the sensitive manufacturing process involved , the standard generic approach is not appropriate for biopharmaceuticals , and a specific legal pathway for the registration of these products was needed . in the eu , the current provisions of european medical evaluation agency ( emea ) for approval of what have come to be called \n similar biological medicinal products or biosimilars have been in force since october 2005 ( guideline on similar biological medicinal products ) ) . therefore \n biosimilar does not designate second - entry versions of biopharmaceuticals whose patent protection has expired , but rather a high quality product just as in new drug applications ( ndas ) . \n authorization of biosimilars is granted on the basis of the strict guidelines of european drug law , which requires in - depth proof that the second - entry product is similar to the original product in terms of quality , safety , and efficacy . \n an important prerequisite for the development of biosimilars or fopps has been the advances in analytics seen over the past two decades . \n twenty years ago , available analytical technologies were not refined enough to allow an in - depth physicochemical comparison of complex protein molecules and protein drugs were therefore not amenable to direct laboratory comparisons . \n today 's analytical techniques enable in - depth investigation of all the relevant properties of a recombinant protein or glycoprotein regarding its primary , secondary , tertiary and quaternary structures , allowing direct and thorough comparison of the quality and characteristics of biopharmaceuticals . in the us \n citizen 's petition was filed by both pfizer and genentech to disallow the approval of biosimilars by the fda . \n sandoz patiently only sought approval for omnitrope , a recombinant human growth hormone that is structurally identical to pfizer 's genotropin , which itself was approved under a 1995 new - drug application ( nda ) . \n as part of its application , sandoz submitted chemical data , bioassays in hypophysectomized rats , safety studies in rats and rabbits , human pharmacokinetic and pharmacodynamic ( pk / pd ) studies and results of phase iii studies ( see , below for details ) . \n after a year of deliberations the fda decided that it was unable to reach a decision on the approvability of the application because of unresolved scientific and legal issues . \n sandoz sued and after protracted legal wrangling from 2003 to 2007 omnitrope and valtropin , another fopps from korea manufactured by lg life sciences in collaboration with biopartners from switzerland were finally approved in 2007 after a district court instructed the fda to end its marathon round of keep - away and make a decision about the product [ 1 , 5 ] . \n it is true that in 2007 bills were introduced in the us congress with the goal of creating a viable abbreviated approval scheme for fopps . \n although there was some well meaning talk that one of the bills would be included in the recently passed fda amendment act , unfortunately none reached a floor vote and the us approval process continues to lag seriously behind europe , which recently also approved biosimilar erythropoetin as well granulocyte colony stimulating factor ( gcsf ) ( sandoz , press release 2008 ) . when the fda ultimately approved omnitrope and valtropin , it allowed an abbreviated pathway with at least 6-month clinical data from a phase iii study . \n it did so only because hgh had been historically regulated under the federal food drug and cosmetic act ( ffdca ) and not under public health service act ( phsa ) from 1944 which regulates most protein - based products in the us , for example , interferon . \n fortunately , a few select recombinant products such as insulin , glucagons , hgh , and thyrotropin alpha are governed under the ffdca from 1938 and are approved in the us under new - drug applications . in its approval \n the fda finally acknowledged that a comparison of end products of different manufacturing processes was possible in select cases because of improvements in the availability of analytical techniques . \n omnitrope , and implicitly also valtropin , were approvable because it had a well characterized protein structure , a known mechanism of action , a lack of glycosylation and a long and well documented history of clinical use with a safety and efficacy profile thoroughly described in the literature . \n the fda should also be able to rely on studies and analyses done to secure emea , canadian , or australian approval . \n even though the emea [ 68 ] and us approval process requires phase iii studies , for example , hgh it did have a marked effect on lowering costs , contrary to expectations in the us senate . some scientific issues which have led well - meaning critics to doubt the clinical utility and safety of fopps do remain unresolved .most notably the potential for complex quaternary structure , pd , and immunogenicity , is owing to changes in manufacturer , inert ingredients and packaging . \n for example , in the case of eprex , a dna recombinant erythropoietin , not a biosimilar , serious problems arose when a stabilizer in the manufacturing process was changed from albumin to sorbitol antierythropoietin ; antibodies were formed and potentially lethal pure red call aplasia developed as a most serious side effect [ 1315 ] . \n thus postmarketing pharmacovigilance studies will probably be required for all except the simplest fopps for the foreseeable future . \n these provisions regarding phase iv studies are also in place for omnitrope in the us and europe and will also be carried out for valtropin once it is being marketed . in summary \n two biosimilar somatropins omnitrope ( sandoz ) and valtropin ( lg life sciences , biopartners ) have recently in 2007 been approved by the us food and drug administration and previously by emea [ 68 ] as a follow on protein product . \n omnitrope is being marketed in the us since 2007 for ghd in children and adults . \n it is only reasonable to study metabolic effects of a fopp in a very sensitive population , that is , growth hormone deficiency . \n once efficacy is demonstrated in that model it is extremely unlikely that the drug will behave suddenly differently in a less sensitive model ( e.g. , sga or turner syndrome ) . in the fda ruling neither drug \n was rated as therapeutically equivalent and therefore substitutable for any of the other approved growth hormone products . \n there are currently in the us two possible pathways for approval for follow on protein product , either are found in section 505 of the food , drug and cosmetic ( fdc ) act applicable to drugs or under section 351 of the phs act applicable to biological products . \n omnitrope was approved under section 505(b ) 2 of the fdc act which is usually applied to generic drugs and allows for an abbreviated approval pathway . in the previous years \n the fda approved also other follow - on products under section 505 of the fdca . \n these include glucagen ( glucagons recombinant for injection ) , hylenex ( hyaluronidase recombinant human ) , and fortical ( calcitonin salmon recombinant ) nasal spray . \n following guidelines published first by emea in 2006 [ 79 ] both valtropin and omnitrope have chosen the most sensitive model ( prepubertal children with gh deficiency ) with stable thyroid hormone and/or glucocorticoid replacement therapies if indicated , to show comparative efficacy and safety to the reference biological medicinal product . \n omnitrope contains human gh produced by recombinant technology using e. coli as expression system . during the clinical development program various formulations of gh \n the effect of omnitrope ( covance ) was compared in 89 naive children with ghd to genotropin ( pfizer ) . \n efficacy was similar , the covance formulation however led to a high titer of gh antibodies ( abs ) ( 60% ) without adverse effects on growth velocity . \n their occurrence was most likely related to the presence of an increased level of host cell protein . \n after introduction of additional purification steps ab frequency dropped to the accepted range . in subsequent omnitrope formulations \n no patient developed antibodies against gh and 1 patient developed anti - hcp antibodies during the 12 months study ( data on file with sandoz ) . \n these studies are still ongoing in the same cohort and a phase iii study is now in its 7th year with centrally measured igf-1 , carbohydrate metabolism parameters , and antibodies against gh and host cell protein ( hcp ) . \n the registration trial was powered with 98 gh deficient children in the valtropin arm compared to 49 children in the humatrope arm . \n after the initial 12-months period , all enrolled patients were treated for an additional 12 month period . \n these studies were powered according to strict fda guidelines to detect noninferiority at a 1.8 cm growth velocity difference . \n in addition , one uncontrolled 12 supportive study in 30 treatment - nave girls aged 29 years with short stature due to turner syndrome was performed . \n height velocity increased significantly in this observational study from baseline values of 3.75 + 1.76 cm / year rose to 9.73 + 1.55 cm / year . \n there were no relevant differences in the development of anti - gh ab between valtropin ( 23% ) and the reference product ( 3% ) . \n the observed frequency of anti s. cerevisiae ab ( 2% ) did not raise concern as these ab do not appear to have adjuvant properties , which could amplify the immune response ( 4.16 ) . \n pd data ( rise in igf-1 and igfbp-3 ) are for both omnitrope and valtropin similarly reassuring when compared to genotropin and humatrope table 4 [ 4 , 11 , 12 ] ( for valtropin data see table 4 and [ 11 , 18 ] for omnitrope ) . \n it is unclear at present whether regulatory agencies will eventually allow commercial use of approved biosimilar somatropins in non - gh deficient states . in the current giudelines [ 68 , 19 ] it is considered that the demonstration of similar efficacy and safety in gh deficient children can be extrapolated to other indications of the reference somatropins ( genotropin and humatrope ) . \n current guidelines both in europe and in the us [ 68 , 19 ] propose study durations of 612 months for a comparative efficacy and safety assessment in children . \n all carried out studies for significantly longer periods of time ( in the case of omnitrope for 7 years thus far and in the case of valtropin for more than 3 years [ 18 , 20 ] ) . \n a common misconception about biosimilars is that there is the potential for reduced quality standards . \n this is definitely not the case , as all aspects of the comparability exercise have to be fulfilled in fully characterizing the product and demonstrating similarity or noninferiority . \n both products will be monitored in phase iv pharmacovigilance programs just like most of the other previously nda approved somatropins . \n these risk - management programs take into account that long - term information is necessary for biosimilars as far as carbohydrate metabolism , ab formation , and the development of igf-1 receptor expressing cancers.this approach has been in place for previously approved growth hormones and it is therefore reasonable to put a similar program in place for the class of fopp or biosimilars medicinal gh products . given the low frequency of adverse effects in all gh products only a long - term large pharmacopidemiological study will have a chance to detect adverse effects . \n the existing databases are insufficient to answer the question of tumor - growth promoting potential of gh effects . \n therefore these potential serious adverse side effects have to be explored for all growth hormones including biosimilars ( b. weise , personal comment ) . \n the high ab titers in the initial omnitrope product formulation manufactured by covance are no longer found in patients receiving the currently marketed formulation . \n in fact anti - gh ab and anti - hcp ab titers are not different from the comparator genotropin . \n gh is administered in an unphysiologic fashion , that is , by subcutaneous injection , there will therefore always be low level ab formation . neutralizing or blocking ab titers were never seen with any biosimilar or fopp product . \n regarding the issue of switching patients receiving a growth hormone preparation to a biosimilar medicinal product , it is of interest that in a recent position paper by the arzneimittelkommission ( drug review board ) of the german medical association voices no concern . \n the board does not see any reason not to switch patients receiving a biopharmaceutical to a biosimilar medicinal product if so desired or requested because of lower cost . \n in other countries , including the us , third party payers increasingly demand similar changes as a cost - saving measure . \n it has been argued that the safety of biosimilars is not on a par with the knowledge gained through the previous approval processes for gh . \n the previous growth hormones study data that were submitted after 12 months data from phase iii studies were available and both emea and fda require 612 months data for submission of biosimilars or fopps . both lgls / biopartners and sandoz submitted 12 months data . in the cases of sandoz and lgls / biopartners now seven- and , respectively , three - year safety data from phase iii studies have been presented in abstract from[18 , 20 ] , providing a degree of scientific scrutiny absent from phase iv postmarketing studies . \n ideally the final choice of product to be prescribed must be made by the informed physician . \n unfortunately this process is being dismantled in the us where payors increasingly prescribe which gh preparations can be used .", "role": "user" }, { "content": "as the first wave of biopharmaceuticals is set to expire , biosimilars or follow - on protein products ( fopps ) have emerged . \n the regulatory foundation for these products is more advanced and better codified in europe than in the us . \n recent approval of biosimilar somatropin ( growth hormone ) in europe and the us prompted this paper . \n the scientific viability of biosimilar growth hormone is reviewed . \n efficacy and safety data ( growth rates , igf-1 generation ) for up to 7 years for pediatric indications measure up favorably to previously approved growth hormones as reference comparators . while the approval in the us is currently only for treatment of growth hormone deficiency ( ghd ) in children and adults , the commercial use of approved biosimilar growth hormones will allow in the future for in - depth estimation of their efficacy and safety in \n non - gh deficient states as well .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: walking is one of the most fundamental actions required for human life , and feet play a \n particularly important role in supporting the human body and maintaining balance during \n walking1 . \n because of this , incorrect \n walking habits primarily appear as an imbalance between the two feet . \n in particular , \n flatfoot is characterized by a medial longitudinal arch that is lowered in a chronic or \n abnormal way , resulting in hyperextension of the plantar fascia , spring ligament , and tendon \n of the tibialis posterior2 . as the ability \n to receive and disperse weight decreases due to the abnormality of the sole structure , \n excessive compensation by the outer muscles occurs and causes foot imbalance3 . \n hence , flatfoot walking induces excessive \n pronation of the feet , which delivers the weight load to the tibia , causing pain in the \n tibia and knee . this can result in damage to the lower limb4 . in a study using functional foot orthotics ( ffos ) to solve the problem of foot deformity , \n pratt5 examined the prevention or \n correction of deformity , formation of sufficient supporting ground , promotion of standing or \n walking exercise , and improvement of walking efficiency . \n feet play an important role in the \n lower kinetic chain ; they distribute the weight load generated during exercise and disperse \n it in the stance period during walking . \n moreover , an appropriate shoe liner and orthotic can decrease muscle \n activity and provide comfort , while increasing exercise performance ability7 , 8 . \n as \n the ffo supports a balanced weight distribution in the plantar area and arch , it aids in \n efficient shock absorption , including the ground reaction generated during walking or \n running , which reduces pain and unstable joint motion9 . as such , \n although there are a number of studies analyzing the ankle and knee , research studying the \n pelvis , which is used as a center point of the body , during walking is scarce . \n hence , this \n study examined the impact of wearing ffos on the pelvic angle among young adults who have \n flatfoot , using a vicon motion system device . \n the subjects of this study consisted of 15 college students enrolled in university k , \n located in cheonan city , korea , from september 1 to 20 in 2015 . \n the study included \n participants with no musculoskeletal disease who were diagnosed with flatfoot and have a \n calcaneal pitch angle less than 15 , indicated by radiological measurements . \n this study \n acquired approval from the clinical test screening committee at korea nazarene university \n and was reviewed according to the declaration of helsinki . \n the general characteristics of \n the research subjects who participated in this study are summarized in table 1table 1.general participant characteristicssubjects ( n=15)gender ( m / f)8/7age ( yrs)21.1 3.4height ( cm)162.1 6.1weight ( kg)63.1 7.1calcaneal pitch angle ( )13.5 1.2values are presented as the mean sd . \n values are presented as the mean sd the ffos worn by the subjects in this study were customized for each individual s foot \n shape and created with thermoplastic materials . \n a high - density resistance elastic pad , cup \n sole for the plantar arch , low - elasticity pad for shock absorption in the heel , and \n ethylenevinylacetate ( eva ) were used to create the ffos . when designing the foot orthotic \n for a subject , the researcher positioned the heel bone vertical to the ground and let the \n subtalar joint maintain its natural position . while preventing pronation of the subject s \n feet and excluding excessive foot movement , measurements were taken and an evaluation was \n performed while weight was loaded under the realigned condition of the foot . \n specifically , the experimenter measured and evaluated the subjects feet and molded both \n foot shapes using pedilen foam . with a prepared positive plaster model , plaster correction \n was performed ( checking pressure points or sensitive parts of the feet ) , followed by shell \n production and modeling with thermoplastic . \n next , posting and grinding ( trimming and \n alignment adjustment ) were performed and the production of the foot orthotic was finalized \n with a covering material10 , 11 . \n the study equipment consisted of six mx - f40 cameras ( vicon , hansung , korea ) , two or6 - 7 \n force plates ( amti , usa ) , and nexus software . \n each mx camera forms the two - dimensional \n images obtained from optical markers into three - dimensional images , so that in addition to \n the location data of the markers , measurements for each segment of the body can be obtained . \n the force plates express the ground reaction \n force of both feet during walking as vectors . \n moreover , an ultranet system synchronized the \n motor mechanic data from the camera and the kinematic data from the force plate into the \n same frame12 , 13 . to compute the pelvic joint angle , a plug - in gait model , based on the newington - helen hayes \n gait model , was used . \n this was measured by the three - dimensional motion capture device from \n the vicon motion system . \n the local coordinate system of each segment was created using the \n three - dimensional spatial coordinates of each measured marker point , and a euler algorithm \n was derived . \n each gait cycle was differentiated using the heel strike as a standard , and one \n gait cycle of walking from each subject was extracted for time normalization12 . in this experiment , only the results from \n the mid - swing and mid - stance periods of the gait cycle were extracted , which provides the \n highest and lowest points , respectively . in this study , to measure the change in the pelvic angle , walking on a previously \n fabricated walkway before and after wearing the customized ffos was analyzed using \n high - quality 3d cameras and the vicon motion system ( vicon , oxford , uk ) . to measure the \n pelvic angle in the stance period during walking , markers were placed on the anterior \n superior iliac spine ( asis ) and anterior inferior iliac spine ( aiis ) bilaterally . \n moreover , \n the dynamic change was quantified to compute the difference in the pelvic angle on the left \n and right sides . \n all subjects performed a preliminary motion five times to become familiar \n with the test . \n data for three walking trials were processed for quantitative computation and \n their average values were analyzed . \n the changes before and after wearing the orthotic were analyzed using paired t - tests . \n examining the change in the pelvic angle in the experimental group before and after wearing \n the ffo revealed large changes in the pelvic angle on both the left and right sides during \n the pre - stance and mid - stance and pre - swing and mid - swing periods of the gait cycle before \n wearing the orthotic . \n however , no significant differences were observed in the pelvic angle changes \n of the left versus right side after wearing the orthotic ( p>0.05 ; table 2table 2.comparison of the pelvic angle before and after wearing the foot orthoticpre - stance ( )mid - stance ( )pre - swing ( ) mid - swing ( )pretestposttestpretestposttestpretestpretestpretestpretestright4.2 0.22.6 0.6*6.5 0.64.4 0.2 * 3.5 0.21.9 0.5 * 7.5 0.54.8 0.2*left4.4 0.72.2 0.3*6.2 0.54.2 0.4 * 3.0 \n 0.32.1 0.7 * 7.0 0.75.0 0.4*values are presented as the mean se . \n values are presented as the mean se . * significant difference from the pre - test value , p<0.05 \n this study examined the change in the pelvic angle at the mid - stance and mid - swing phases \n of walking before and after wearing ffos , in a sample of young adults who have flatfoot , \n with the expectation that wearing ffos will affect the pelvic angle during the gait cycle \n among those with flatfoot . examining the change in the pelvic angle during the stance period \n before and after wearing \n the ffo revealed that the angle significantly decreased on the left \n and right sides in the pre - stance and mid - stance and pre - swing and mid - swing periods after \n wearing the ffo . \n although the angle decreased after wearing the ffo , compared to before , the \n decrease was not significant . \n this implies that wearing a custom - fit ffo ameliorates tension \n in the sole muscle and fascia and prevents the decrease of the plantar arch during the \n mid - stance and mid - swing periods in flatfoot walking , resulting in a decrease in the pelvic \n angle . \n an ffo can reduce the height change of the foot arch , which eventually prevents its \n collapse during dynamic movement . \n moreover , ffos support effective energy consumption during \n walking by reducing fatigue in the foot muscles , which is frequently observed among flatfoot \n patients13 . \n they also help reverse \n abnormal changes in the joints and revert the joint positions back to their natural \n locations . \n hence , a change was observed that restricted movement to the side of the pelvis \n joint in the sagittal plane of the pelvis after wearing ffos . \n wu14 reported that foot orthotics are used for foot alignment \n and support , prevention and correction of foot deformity , and improvement of foot function . \n if individuals with flatfoot develop disorders of the joints and feet , ffos can alter the \n walking mechanism , which consequently affects the other lower limb joints15 . \n moreover , they help evenly disperse shock \n on the sole by compensating for functional insufficiencies in the flat foot in each phase of \n walking16 . as such \n , the improved \n results in the lower limb and foot accomplished by wearing an ffo that are reported in \n previous literature were likely accomplished through organic changes in the pelvic angle via \n the functional changes observed in this study . \n future studies based on these results that \n examine complex organic changes in all joints of the lower limb after wearing ffos will \n contribute to further advancement in orthotics .", "role": "user" }, { "content": "[ purpose ] this study examined the impact of wearing a functional foot orthotic on the \n pelvic angle of young adults who have flatfoot . [ subjects and methods ] a total of 15 \n college students diagnosed with flatfoot were included in the study . \n changes in the pelvic \n angle in the stance period during walking before and after orthotic use were measured \n using a vicon motion system ( vicon , hansung , korea ) . \n the data were analyzed using spss \n 12.0 for windows . \n [ results ] in the experimental group , the pelvic angle during the \n mid - stance and mid - swing periods of the gait cycle significantly decreased on the left and \n right sides after wearing the orthotic , compared to the measurements taken before orthotic \n usage . \n the pelvic angle change on the left and right sides also decreased after wearing \n the orthotic , though this difference was not significant . \n [ conclusion ] the pelvic angle of \n college students with flatfoot decreased after they wore orthotics . \n this implies that \n wearing orthotic shoes can greatly benefit individuals during normal walking by promoting \n passive changes that decrease the pelvic angle .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: speech is essential to human activity as it is an important function of the stomatognathic system , which uses the oral cavity as a part of the vocal apparatus . \n the voice is produced in the larynx with the aid of the vocal cords vibrating due to the expiratory airflow . \n the frequency of the fundamental laryngeal tone is dependent on the vocal cord tension , which then modulated in the resonance cavities and their shape conditioning the vowel formants [ 1 , 2 ] . \n the speech articulatory organs include the tongue , palate , alveolar processes , gums , teeth , and lips . \n the teeth , alveolus , and palate are static components of speech articulation whereas tongue , lip , and velum are dynamic components . \n therefore , phonetics must be considered with mechanics and esthetics as the cardinal factors contributing to the success of the dental prosthesis [ 2 , 3 ] . \n complete loss of teeth can cause persistent speech disorders by altering dental articulation areas that will severely reduce the quality of speech ; particularly the alteration of frontal maxillary morphology leads to impairment of speech production . \n however , they disturb speech production themselves as they restrict the flexibility of the tongue , narrow the oral cavity , and alter the articulation areas of the palate and teeth [ 5 , 6 ] . \n dentures should be made to enable the patient to produce voice and speech without deficiencies . \n about 25% of patients in clinical dentistry are considered to suffer from temporary or permanent changes in articulation due to the application of removable dentures . \n articulatory errors may be due to denture factors like altered vertical dimension , size , and position of the teeth , thickness , and contour of the denture base [ 1 , 2 ] . \n accurate approximation of palatal contours of a maxillary complete denture to a patient 's tongue can improve speech intelligibility , if other factors such as tooth position , occlusal plane , and occlusal vertical dimension are satisfactory . \n pound , in 1950 , stated that anterior palatal region plays an important role in pronunciation of consonants . \n he termed it as playground of tongue because 90% of tongue 's rapid manipulation while talking was restricted to this area and area lingual to lower anterior teeth . \n so the palatal vaults of maxillary dentures should be shaped like natural ones to facilitate correct pronunciation and the quality of speech sound production improved within the first week after insertion of new dentures . \n the most important instruments for the investigation of speech sound production are the trained hearing of a speech and language professional , spectral analysis , and palatographics [ 4 , 10 , 11 ] . \n spectral analysis has been used to examine the effects of dental prostheses on speech sound production . with the use of spectral analysis \n , a sound event can be split into three dimensions : frequency , amplitude , and chronologic sequence . \n the data obtained can be visualized in 2-dimensional cartesian coordinates with the color or grey shade as the third dimension . \n although less common , a 3-dimensional profile representation can be used instead [ 4 , 5 , 11 , 12 ] . studies on speech sound production may have a clinical impact because many patients attach great importance to undisturbed speech sound production after dental treatment and heyink et al \n . found that 28 ( 21% ) of 131 denture wearing individuals from an elderly population had speech problems . \n the aim of this study was to investigate the influence of reproduction of different palatal rugae materials and thickness on complete dentures speech using spectrogram . \n three completely edentulous male patients , aged 5060 , were selected from the outpatient clinic of prosthodontics department , faculty of dental medicine , al - azhar university ( ethical approval number 589/2012 ) . \n the selected patients must be free from any systemic diseases or any dental problems and must be able to read in a regular manner for reading the paragraph . \n twelve complete upper dentures were incorporated in this study ; four upper complete dentures with different palatal rogue changes for each patient were constructed . \n the patients ' speech records in this study were divided into five groups , group i : patients without denture , group ii : patients with upper acrylic denture having polished anterior palatal surface without rugae reproduction in usual thickness ( 22.5 mm ) , group iii : patients with conventional upper acrylic denture with rugae reproduction on its polishing surfaces in usual thickness ( 22.5 mm ) , group iv : patients with metallic upper denture base of minimal thickness ( 0.51 mm ) and direct ragged metallic palatal surface at rugae area , and group v : patients with upper denture having palatal rugae constructed from resilient acrylic resin material with thickness less than conventional denture ( 1.52 mm ) . \n the dentures in groups iii , iv , and v were made by duplicating the denture previously constructed to group ii to preserve the same tooth position , occlusal plane , vertical dimension , and denture base thickness for each patient . after that \n , the duplicated denture was used as trial denture as the rugae reproduction was performed . \n the first impression was poured with stone to be used as a palatal rugae replica . \n the second impression was performed as the area of rugae in the impression was poured with softened wax to make a palatal rugae template . \n the wax was removed from the impression and sealed on the polishing surface of the trial duplicated denture base at the area of rugae . \n the trial denture was processed in the usual manner , finally finishing and polishing the final denture with its rugae . \n the patient adaptation period must be about two weeks to avoid any mistake of new denture problems . according to inukai et al . \n the speech adaptation to new complete denture normally takes place within 2 to 4 weeks after insertion . \n speech samples were recorded after insertion of each denture for groups using computerized speech lab ( csl ) ( spectrogram ) ( csl kay elemetrics model 4300 , usa ) in phoneatric unit , ent department , specialized ain - shams hospital . after the period of adaptation , the sound recordings were performed in a special room phonically isolated with the patient speaking in a sensible microphone . \n a microphone produces a time - varying electrical voltage that is proportional to the increase or decrease in local pressure that constitutes sound . \n the patients were asked to sit in upright position to allow reading of a passage in comfortable amplitude and pitch . \n distance from microphone is about 10 cm to avoid a lot of stochastic noise . \n the set unit csl consists of external module with high speed dual channel , the plug - in board with 2 high speed digital signal processing integrated circuits , high quality microphone , and software version 3.1 and all patients were subjected to analysis of their signal after it is captured using sampling rate of 20 khz and bandwidth is 300 . \n the continuous electric signal can be converted to a digital representation suitable for manipulation by a computer . \n computers equipped with the proper hardware can convert the analog voltage variations into digital sound waveforms by a process called analog - to - digital conversion . \n the higher the sampling rate , the better the sound quality , but the more the bits required . \n there is a direct relationship between the accuracy of quantization and the number of bits required [ 4 , 15 ] . \n the tested sounds selected were /s/ unvoiced linguodental fricative ; /sh/ unvoiced linguoalveolar fricative ; /z/ voiced linguoalveolar fricative ; /t/ unvoiced linguoalveolar stop ; /d/ voiced linguoalveolar stop ; /l/ voiced linguoalveolar stop . \n these sounds were selected in a paragraph to avoid the patient trials to adjust himself for optimum utterance . \n the spectral analysis was not done on the whole word of the paragraph but only on word fragments that permit perception of these alterations as /s \n / sh / z / t / d/ and /l/ sounds . breaking the words into sounds \n was performed for each patient in order to achieve more profound study of individual phonetic characteristics and a higher quality of studied phenomena . \n the spectral analysis of the taken signal was measured by the maximum energy ( frequency , hz ) for /s/ , /sh/ , and /z/ sounds . however , for /t / d/ and /l/ sounds , it was measured by time interval ( m / sec . ) because they have less voice onset time for adaptive patient speak . \n data were statistically analyzed by one - way anova followed by tukey 's post hoc test at the significance level of = 0.05 . \n data of the tested groups was presented as mean and standard deviation ( sd ) values ( table 1 ) . \n the collected data for /s/ sound in five groups showed that the highest mean value was observed with groups iv and ii , and the lowest mean value was with group i. for the /z/ sound , the highest mean value was with groups iv and v and the lowest mean value was with group i. for /sh/ sound , the highest mean value was with groups iv and v and the lowest mean value was with group ii ( figure 1 ) . for /t/ sound , \n the highest mean value was with groups iv and iii and the lowest mean value was with group ii . for /d/ sound , groups i and iv showed the highest mean value , and group ii showed the lowest mean value . for /l/ \n sound , groups v and i showed the highest mean value and group iii showed the lowest mean value ( figure 2 ) . \n the reproduction of rugae area in acrylic denture ( group iii ) produced highly significant difference with /t/ sound and significant difference with /sh \n / z/ and /d/ sounds and lowest significant difference with /l/ sound ( p < 0.05 ) . in the denture with metallic base , group iv produces highly significant difference with /s \n / z / sh / t/ and /d/ sounds and significant differences with /l/ sound ( p < 0.05 ) . in group \n / t/ sound ( p < 0.05 ) . moreover , speaking without denture or with conventional denture without rugae produced the lowest significance with all tested /s \n / z / sh / t / d/ sounds except /l/ sound ( p < 0.05 ) . \n the present study discusses the changes of the denture factors such as proper rugae shaping and base thickness for adequate tongue space and articulation . if it is determined that the tongue is a possible source of the speech problem , a structural change in the denture should be considered . \n speech problems are frequently reported after complete denture placement mainly expressed as problems with consonants , especially lingopalatal sounds . \n analyzed spectrograms are different by frequency ( low or high ) of emitted sounds related to the denture changes and oral resonance cavity . \n specific letters were selected because not all the letters can be verified . according to sinescu et al . , some sounds such as /z / s / t/ and /sh/ are more sensible and more often compromised due to the changes of oral structures and because of the demand for more precise articulation movements . \n it was suggested that the tongue needs surfaces with greater tactile stimulation in analogy to the anatomic structures . \n the importance of palatal rugae in complete denture construction for proper sound production was revealed by this study . \n this comes with the agreement of the study , which advocated developing a normal /s/ and /sh/ sounds , and it may be necessary to thicken the incisive papilla region to prevent the jet of air emitted by the median sulcus of the tongue from escaping toward the vault . \n bulking of the tongue palatal contact area and the area of the incisive papilla will facilitate proper enunciation and eliminate much of the postinsertion practice period [ 7 , 19 ] . \n the metallic dentures selected to provide minimal cross section enhance maximum space for sound production . the essential factor in production of correct \n as the depth of this groove decreased , /s/ is pronounced toward /sh/ as a lisp . \n therefore , as in this study , when using metallic denture base , a minimal thickness faced the tongue permitting its proper grooving . \n investigate the speech of two edentulous subjects fitted with a complete maxillary prosthesis made of three different palatal materials : aluminium , resin , and stellite . \n these recordings were tested from the auditory point of view by a series of six listeners ( four men and two women ) in an anechoic room . \n the results show that the group fitted with a metal prosthesis ( aluminum , stellite ) was more intelligible regarding the way they were perceived by others . \n reports of acoustic analysis revealed that pronunciation of s , sh , \n t , and d was clearer with rugae incorporated denture than conventional denture . \n intelligibility reports showed many substitutional errors with conventional denture . with customized rugae denture speech was clearer . \n allen stated that the most widely used procedure to improve denture phonetics is the random thinning of the entire maxillary lingual surface to create more space for the tongue . \n such arbitrary removal of acrylic resin from the palatal surface ignores the critical importance of correct palatal contours in the proper formation of sounds . \n this finding disagrees with the result obtained from this study , because this opinion may be correct in case of lower denture to restore critical tongue space and thinning of acrylic denture may cause fracture . \n the results of this study coincide with the result reported by ravishankar and singh as they reported that the lingopalatal ( anterior ) sounds /c/ ( soft ) , /d \n / t / n / s / z/ , and /r/ are formed by the contact of the tip of the tongue with the most anterior part of the palate called the alveolus or the lingual side of anterior teeth . \n if the denture base in the rugae area is too thick , the /t/ in tend sounds like /d/ and the /d/ sounds like /t/ . the patient emotional behavior in relation to a prosthetic treatment can also influence the speech patterns . \n patients , who psychologically accepted their dentures , shortly after they started wearing them , also had fewer speech difficulties than those who did not accept the dentures and for this reason , the adaptation period was used in this study . \n therefore , in the adaptation period , a series of speech defects may be noted as hypernasality . \n as the patient uses his custom - made prosthesis with accurate biomechanical and physiological properties , these complaints decrease and elimination of these problems can be noted over time . \n the character of speech sounds is difficult to be analyzed and interpreted but it is detected with accuracy by the hearing sense , which is a more sensitive analysis device than well - known handmade devices . \n this result is not in agreement with the study , as the computerized device is more accurate than hearing sense . \n important investigations of speech sounds are based on the fourier spectrum and on the short - time fourier spectrum ( spectrogram ) . \n the most accurate measurements methods were , as this study suggested , by jindra et al . \n , kobayashi et al . , and gtcen - toller who chose speech sounds analysis by using standard signal processing methods . \n its evaluation of the studied phenomena is both qualitatively and quantitatively valuable making the reproducibility of the analysis applicable . \n so the sample size of three instead of five was used . the fourier method for the phonetic evaluation \n the phonetic alterations are considered classic for the human voice and could also be represented even for the higher spectrum . in the present study , \n it is recommended to reproduce the rugae area in complete denture because the phonetic quality of complete denture with rugae was superior to the conventional denture . \n if the denture was too thick in the anterior region , the result would be a faulty /sh / d / z / t / l/ sound . \n / sh / t / d/ and /z/ sounds . the use of resilient acrylic to reproduce the rugae in complete denture can enhance /z", "role": "user" }, { "content": "objective . to investigate the influence of reproduction of different thickness and palatal rugae materials on complete dentures speech using computerized speech lab ( csl ) ( spectrogram ) . \n materials and methods . \n three completely edentulous male patients ( aged 5060 years ) were selected for reading a paragraph . \n twelve upper dentures were constructed , four for each patient . \n the patients ' speech groups were divided into five groups , group i : patients without dentures ; group ii : patients rehabilitated with conventional acrylic dentures ; group iii : patients with conventional acrylic dentures with rugae reproduction ; group iv : patients with dentures with metallic framework of minimal thickness and direct ragged metallic palatal surface at rugae area ; group v : patients with dentures with palatal rugae constructed from resilient acrylic resin material with thickness less than conventional denture . \n speech samples were recorded after insertion of each denture for groups using computerized speech lab ( csl ) ( spectrogram ) . \n the sounds selected were lingopalatal /s \n / z / sh / t / d/ and /l/. results . \n group iii produced high mean significant difference with /sh \n / t/ sound . for group iv , the difference was noticed with /s \n / z / sh / t/ and /d/ sounds , while for group v the difference was shown with /z \n / l/ sound ( p < 0.05 ) . conclusion . \n it is recommended to reproduce the rugae area in complete denture because the phonetic quality of complete denture with rugae is superior to the conventional denture .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: nephrogenic systemic fibrosis ( nsf ) , initially named nephrogenic fibrosing dermopathy , was first reported in 2001 by cowper et al . . \n since then , more than 360 cases have been tracked by the yale international nsf registry and over 500 cases have been reported to the us food and drug administration medwatch database . \n nsf occurs most often in middle - aged adults ( mean age of 52 years ) with either chronic kidney disease or acute kidney injury but has also been observed in children and older patients . \n nsf usually manifests approximately 2 - 10 weeks ( median 5 weeks ) after exposure to gadolinium - based contrast agents ( gbcas ) . \n there is no gender or racial predisposition . of nsf cases reported to the yale registry , \n it has become clear that nsf is also associated with fibrotic damage to internal viscera such as the esophagus , lungs , heart , skeletal muscle , and kidneys ( prompting a change in name from nephrogenic fibrosing dermopathy to nephrogenic systemic fibrosis ) . in some cases \n , it became apparent that the common factor in most patients was the prior use of gbcas during magnetic resonance imaging , however , in many cases ( e.g. , when imaging brain tumors ) , the use of gbcas are critical for enhancing the imaging of blood vessels \n . the basic clinical features of nsf include acute to subacute onset of limb edema ( more so in the lower limbs ) accompanied by cutaneous erythematous to violaceous papules and plaques overlying dermal and subcutaneous fat fibrosis . \n when fully developed , clinical nsf is characterized by limb pain , contractures , and loss of mobility . \n the clinical syndrome strongly mimics scleroderma and eosinophilic fasciitis , and may be rapidly progressive . \n nsf has specific clinical and histopathologic characteristics that should be used to make a definitive diagnosis . \n histologic features include a haphazard arrangement of thickened collagen bundles , mucin deposition , and an increase in fibroblast - like cells that stain positively for cd34 and procollagen i , the same immunohistochemical profile as that of circulating fibrocytes ( which play an important role in disease development ) . \n this abnormal pathology extends into the fibrous septa between fat lobules , contributing to the typical clinical manifestation of woody induration and a \n it has been hypothesized that this pathology is the effect of the bone marrow - derived circulating fibrocytes ( normally recruited to repair injured tissue ) behaving in an exuberantly abnormal fashion in the dermis and fibrous septa of the subcutaneous fat . \n to date , the yale registry indicates that at the time of disease onset , 79% of patients with nsf were receiving renal dialysis and 17% had some degree of renal insufficiency but were not being dialyzed ( those with acute kidney injury , unspecified renal insufficiency , or chronic kidney disease stage iv or v ) . \n the remaining patients were in the immediate post - renal - transplant period ( cowper , unpublished data ) . \n experimental data suggests that when gadolinium , a rare earth element that is naturally highly toxic to animals and humans , is bound to proprietary chelating agents , it is essentially biologically inert in the circulation of a patient with normal kidney function ( in whom the half - life would be roughly 90 minutes ) . \n since gbcas are cleared from the body virtually exclusively by the kidneys , the current hypothesis is that individuals with reduced renal clearance are exposed to these agents longer than those with normal renal function , which can lead to nsf in the vulnerable , however , the exact pathogenic mechanisms remain unknown . \n because gadolinium is not normally ingested by humans , radiologic examinations where gbcas are administered are the only significant source of human exposure . \n several pharmaceutical companies produce a variety of gbcas , which are distinguishable by their varying proprietary chelating agents ( ligands ) . \n the ligands are classified as structurally linear or macrocyclic and exhibit both ionic and non - ionic forms . \n the macrocyclic gadolinium - ligand complexes are less prone to dechelation ( which would render the gbca potentially toxic ) and are therefore more stable than the linear non - ionic agents . \n this is thought to be the underlying reason why macrocyclic agents are only rarely associated with nsf . \n interestingly , even among the linear agents there may be differences in propensity to trigger nsf between ionic and non - ionic varieties . in the event of dechelation , ionic gadolinium ( gd ) quickly binds to ubiquitous phosphate , forming insoluble gadolinium phosphate and leading to prolonged exposure to biologically active gadolinium . with \n complicating the situation is that , over the years , various gbcas have been used interchangeably and patients charts typically do not necessarily reflect which brands were administered , making it very difficult to retrospectively pinpoint the precise agents used . \n the risk of nsf is estimated to be between 2% and 6% in patients with chronic kidney disease ( stage iv and v ) and acute kidney injury , with the most risk associated with higher degrees of impairment and less effective modes of clearance ( i.e. , peritoneal dialysis ) . \n a recent change in fda labeling of gbcas suggests the linear non - ionic agents ( optimark and omniscan ) as well as the most widely - used linear ionic agent ( magnevist ) be specifically contraindicated in the setting of renal disease . \n the warning requires that screening ( medical history and/or laboratory tests ) be conducted for renal dysfunction prior to the administration of gbcas . \n these recent labeling changes are in line with recommendations already made by the european medicines agency and the american college of radiology . since the fda black box warnings were first issued in 2007 , the incidence of new cases has dropped from 36.5 cases per 100,000 to 4 cases per 100,000 . \n in general , treatment of nsf using topical steroids , immunosuppressive therapy , and plasmapheresis has been ineffective . \n several studies have described anecdotal treatments that may improve nsf , including ultraviolet - a exposure , pentoxifylline , sodium thiosulfate , photopheresis , and rapamycin , however , these studies suffered from small numbers , no controls , and sometimes a lack of peer review . \n recent data presented by jonathan kay at the fourth annual symposium on nephrogenic systemic fibrosis and gadolinium - based contrast agents demonstrated that imatinib mesylate improved skin tethering and thickening as judged by the rodnan skin score . \n however , all of the patients in the study relapsed after the drug was discontinued and it has not yet been determined whether the noted beneficial effects were related to a reduction in interstitial edema or a partial reversal of the fibrosis . \n the second - generation drugs dasatinib and nilotinib are currently in the queue to be evaluated . \n used energy dispersive spectroscopy , x - ray microscopy , and inductively coupled plasma mass spectroscopy to detect gadolinium in skin and other tissues from patients with nsf . \n however , based on their studies , a high tissue level of gadolinium is not necessarily sufficient to produce nsf by itself . \n they also showed that gadolinium could be displaced ( dechelated ) from its ligand in the presence of another metal such as iron or zinc . \n this transmetallation would result in free ionic gadolinium ( which , as noted above , would be very likely to form insoluble gadolinium phosphate ) and a ligand complex with iron , zinc , or another displacing metal . \n factors which facilitate transmetallation are high or low blood ph levels , endothelial injury , inflammation , and high phosphate levels , all of which are present in the tissue milieu of patients with renal insufficiency . \n high et al . also showed that the tissues with the highest levels of gadolinium are associated with the most severe fibrosis in the skin and other organs such as the heart , lungs , lymph nodes , eye tissues , muscle , and liver . \n synchrotron x - ray fluoroscopy also has been used successfully to detect gadolinium in tissues . \n nsf is the only fibrosing disorder where the trigger is essentially known but the pathogenic mechanisms have yet to be fully clarified . \n nsf can also serve as a model to gain an understanding of the pathways responsible for idiopathic fibrosing disorders in other organ systems . \n current investigation into nsf has revealed that in vitro gbcas stimulate fibroblasts from patients with nsf ( and those from normal controls ) to secrete increased amounts of extracellular matrix , hyaluronic acid , and collagen . \n however , serum from patients with nsf also stimulates fibroblasts to secrete increased amounts of these same substances . \n serum from dialysis patients behaves similarly but not to the same magnitude . in rats , \n some linear gbcas stimulate fibroblasts to proliferate and caused normal fibroblasts to transform into myofibroblast - like cells with a phenotype similar to that of differentiated fibroblasts present in nsf lesions . chelating agents alone ( sans gadolinium ) \n fibrocytes , circulating bone marrow - derived mesenchymal stem cells , also accumulate in nsf lesions , where they further differentiate into fibroblasts and myofibroblasts . increased sensitivity of nsf fibrocytes to gadolinium \n it is clear that the stability of the gbca complex is the most important factor , thereby implicating free gadolinium as the culprit in inducing the disease and absolving the chelating agents . in studies of renally insufficient rats , \n linear non - ionic gbcas produced the most gadolinium deposition in the skin , which was further promoted by high tissue levels of phosphate . \n the first is osteopontin , a multifunctional protein first identified in bone but present in virtually all tissues . \n a major modulator of processes involving fibrosis and wound repair , osteopontin was found to be elevated in an experimental gadolinium - induced rat model of nsf . \n additonally , cox created a gadolinium - induced rat model of nsf in which an experimental anti - platelet - derived growth factor receptor compound , as well as the cancer drug imatinib , were both effective in preventing and reversing fibrosis . \n nsf is the only fibrosing disorder where the trigger is essentially known but the pathogenic mechanisms have yet to be fully clarified . \n nsf can also serve as a model to gain an understanding of the pathways responsible for idiopathic fibrosing disorders in other organ systems . \n current investigation into nsf has revealed that in vitro gbcas stimulate fibroblasts from patients with nsf ( and those from normal controls ) to secrete increased amounts of extracellular matrix , hyaluronic acid , and collagen \n . however , serum from patients with nsf also stimulates fibroblasts to secrete increased amounts of these same substances . \n serum from dialysis patients behaves similarly but not to the same magnitude . in rats , \n some linear gbcas stimulate fibroblasts to proliferate and caused normal fibroblasts to transform into myofibroblast - like cells with a phenotype similar to that of differentiated fibroblasts present in nsf lesions . chelating agents alone ( sans gadolinium ) \n fibrocytes , circulating bone marrow - derived mesenchymal stem cells , also accumulate in nsf lesions , where they further differentiate into fibroblasts and myofibroblasts . increased sensitivity of nsf fibrocytes to gadolinium has been shown in various experiments . in another rat model , \n it is clear that the stability of the gbca complex is the most important factor , thereby implicating free gadolinium as the culprit in inducing the disease and absolving the chelating agents . in studies of renally insufficient rats , \n linear non - ionic gbcas produced the most gadolinium deposition in the skin , which was further promoted by high tissue levels of phosphate . \n the first is osteopontin , a multifunctional protein first identified in bone but present in virtually all tissues . \n a major modulator of processes involving fibrosis and wound repair , osteopontin was found to be elevated in an experimental gadolinium - induced rat model of nsf . \n additonally , cox created a gadolinium - induced rat model of nsf in which an experimental anti - platelet - derived growth factor receptor compound , as well as the cancer drug imatinib , were both effective in preventing and reversing fibrosis . \n recent reports have indicated that patients at the highest risk for nsf have chronic kidney disease stages iv or v and that no cases have been observed in patients in earlier stages thus far . \n therefore , careful screening of patients for underlying kidney disease or severe injury using measurements of serum creatinine and other appropriate tests of renal function ( the choice of which depends on medical history and physical examination ) should decrease the risk of nsf in patients receiving gbcas . keeping a careful history of previous exposure to a gbca , both in time and dose , \n post - imaging dialysis has also been proposed as a way to mitigate the development of nsf in certain high - risk patients by removing circulating gbca in a more timely manner . currently , this is recommended only in cases in which the patient is already receiving hemodialysis . for \n those not being dialyzed , or those on peritoneal dialysis , no specific recommendations exist . \n ", "role": "user" }, { "content": "nephrogenic systemic fibrosis , initially called nephrogenic fibrosing dermopathy , has been strongly linked to exposure to gadolinium - based contrast media used in magnetic resonance imaging in patients with renal insufficiency . \n this review discusses recent advances in our understanding of the pathophysiology and clinical approach to patients with chronic kidney disease who require diagnostic imaging with gadolinium - based contrast media .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: artemisinin - based combination therapies ( acts ) which are currently the world health organization ( who ) recommended first - line treatment for uncomplicated malaria in endemic areas are under serious threat of resistance due to several reasons . \n the relatively high cost of these antimalarials has made their manufacture a lucrative venture for pharmaceutical industries ; a situation that has led to the proliferation of diverse brands on the market . \n this has led some unscrupulous people to indulge in the manufacture of substandard and falsified brands [ 114 ] . the who acknowledges the difficulty that this situation presents to the quality assurance of antimalarials on the market , especially in developing countries where enforcement of laws regarding manufacture , importation , and distribution of medicines is relatively lax . \n ghana and togo have already adopted artemether / lumefantrine and artesunate / amodiaquine as their first - line treatment for plasmodium falciparum malaria but according to the world malaria report 2013 these countries still present high endemicity with 100 percent of their populations living in high transmission areas . \n p. falciparum resistance has been confirmed in several parts of south east asia , where the problem of counterfeit medicines is well - organised [ 13 , 6 , 7 ] . \n the manufacture , distribution , and use of poor quality medicines ( degraded , substandard , and counterfeit ) are major factors in the development of resistance . \n there has been considerable global controversy and tensions among public health stakeholders regarding the definitions of categories of poor quality medicines . the 1992 operational definition of counterfeit medicines adopted by the who and later revised by impact in 2008 have been criticised for incorporating intellectual property and legal considerations , thus diverting attention from the core issues of safety , quality , and efficacy of medicines [ 1620 ] . \n the problem led to the who 2010 proposal thatuntil consensus was reached , medical products produced or distributed with the intent of fraud could be described as \n substandard / spurious / falsely labelled / falsified / counterfeit medical products ( ssffc ) . however , this lumping of all poor quality medicines together has been described as creating a misleading impression that they all have similar deficiencies . \n new proposals suggest that substandard medicines should be separated from counterfeit products and that the term counterfeit should be excluded from the definitions for the purpose of international cooperation [ 18 , 19 ] . \n thus substandard medicines are defined as pharmaceutical products produced by legitimate manufacturers ( originator and generic ) which do not meet their quality standards and specifications [ 2224 ] . \n falsified medicines , like substandard ones , also do not meet quality specifications ; the distinction is that there is a deliberate intent to breach regulatory requirements [ 18 , 19 , 25 ] . \n since the acts remain the most effective treatment for uncomplicated and p. falciparum malaria , it is extremely important to monitor the quality of our acts , as part of the measures to contain the spread of act - resistant parasites to the malaria - endemic african region . \n ghana has benefitted more than togo from several who - sponsored and other studies carried out to evaluate the quality of acts distributed in the malaria - endemic regions of africa [ 8 , 11 , 26 , 27 ] . \n notable among these is the 2011 report of a who survey of the quality of selected antimalarial medicines circulating in six countries of sub - saharan africa which showed that products from nigeria had the highest failure rate ( 64% ) followed by ghana ( 39% ) and then cameroon ( 37% ) . among act samples tested in ghana \n , failures resulted from insufficient api , related substances test and tablet mass uniformity test , indicating inconsistencies in the implementation of gmp in both domestic and imported products . \n although there was also a substantial amount of unregistered products especially among the acts , the nature of failure rates for registered and unregistered medicines was similar . \n generally , the results of the survey were not considered representative enough to conclude on the quality of medicines in ghana and further investigations were proposed . \n nonetheless , it was recommended that the food and drugs authority ( fda ) should strengthen its regulatory and surveillance systems to minimize the presence of unregistered medicines . \n the relatively high number of manufacturers supplying either registered or unregistered products was considered a challenge to quality assurance of antimalarials in ghana . \n the global report on antimalarial medicine efficacy and medicine resistance ( 20002010 ) includes studies carried out in both ghana and togo . whereas , in 2006 , the treatment failure rate in ghana was greater than the 10% threshold at which the who recommends an initiation of a change in medicines in national treatment policies , similar studies carried out in togo around the same period gave treatment failure rates of 4.4% for artemether / lumefantrine and 6% for artesunate / amodiaquine . \n these findings suggest that regular monitoring to assess the quality of antimalarial medicines circulating in ghana and other countries in the subregion is crucial . \n our recent study which involved the validation and application of quality assurance methods to antimalarial medicines distributed in accra , ghana , identified substandard samples , with insufficient api . in the current study , \n the sampling area extended outside accra to cover other major cities and towns , with special interests in the border areas , since porous borders have the potential of serving as conduits of poor quality antimalarial medicines circulating within the subregion and beyond . \n since togo has not been included in many of the medicine quality surveys , this was a good opportunity to undertake a comprehensive quality evaluation of acts distributed in togo . \n the major objective of the present study was to determine the quality of artemisinin - based antimalarial medicines available to the consumers in the two countries with respect to the international pharmacopoeia ( ph . int . ) \n in both countries , the sampling design was mainly by convenience sampling since it did not follow a complete list of outlets in defined areas . however , sampling sites were chosen based on the level of economic activity ( both high and low ) and proximity to border towns . \n all brands of locally manufactured as well as imported artemisinin - based antimalarial medicines available to the consumer were collected . since consumers usually buy from retail outlets ( pharmacies and licensed chemical shops ) more than from wholesalers , majority of the samples \n another reason for purchasing most of the samples from retailers instead of wholesalers was to cut down on cost . \n for example , if three packets of a medicine containing ten tablets each were enough for chemical analysis , it was cheaper to purchase these three individual packets from a retailer than buy a whole box of the same medicine containing about twenty packets from a wholesaler . \n this strategy enabled us to buy more samples that belonged to different batches of the same medicine . \n the samplers constituted members of the research team and they posed as normal shoppers buying medication . \n when different and large quantities of antimalarials were being bought from the same seller it was sometimes necessary to explain that they were for research purposes . in such cases , some sellers sold out freely , possibly because they were doing good business , while others did so with some reservation . \n togo has 5 economic zones , namely , maritime , plateaux , central , kara , and savanes regions ( figure 1 ) . \n the antimalarial medicines were collected between december 2010 and march 2011 from four sampling sites in three of the designated zones as follows : maritime region - lom ( zone 1 ) and anho ( zone 2 ) ; plateaux region - atakpame ( zone 3 ) and savanes region - dapaong ( zone 4 ) . \n they were purchased from both regular pharmacies and nonaccredited medicine stores in the market from lom area . \n it is important to mention that antimalarial medicines sold in regular pharmacies in the country come from 4 large commercial suppliers all located in lom : uniphart ( union des pharmaciens du togo ) , cameg ( centrale d'achat des mdicaments essentiels et gnriques ) , sotomed ( socit togolaise des mdicaments ) and gt - pharm ( groupement togolais des pharmaciens ) . in ghana , \n 6 sampling sites located in the coastal , the middle , and the savannah belts of the country were selected . a previous study on the quality of antimalarial medicines in ghana focused on acts distributed in accra ( zone 1 ) ; therefore the present study excluded accra . \n takoradi ( zone 3 ) in the coastal belt and kumasi ( zone 6 ) in the middle belt were chosen due to the high level of economic activity in these cities . \n kumasi is the second largest city in ghana while takoradi is the third largest , but it also has the country 's second largest seaport which handles most of the country 's cocoa and rubber exports . \n in addition , it is the largest city in the country 's oil producing region and also handles exports of minerals such as manganese and bauxite . \n winneba and awutu , two relatively small rural towns , were selected as zone 2 . \n bolgatanga / sandema ( zone 4 ) in the savannah belt , aflao ( zone 5 ) , and half - assini ( zone 7 ) , also in the coastal belt , were selected based on their situation near the borders of the country . \n they are border towns with burkina faso , togo , and la cote d'ivoire , respectively ( figure 1 ) . \n all the samples were purchased between september 2010 and april 2011 and together with the togo collection were analysed within the period of their shelf lives . \n a total of 132 antimalarial medicines were collected from the two countries , 58 ( 43.9% ) from ghana and 74 ( 56.1% ) from togo . \n they comprised 90 ( 68.2% ) artemisinin - based coformulated and artemisinin - based coblistered medicines ( acts ) and 42 ( 31.8% ) artemisinin - based monotherapy formulations . \n thirty nine of the samples contained artesunate , 14 of which were all oral monotherapy . \n a more in - depth survey may confirm the dearth or otherwise of these vital treatments in both countries . \n there were 81 samples containing artemether , out of which 22 were monotherapy formulations ( injections and suppositories ) . \n table 1 gives a breakdown of the antimalarial medicines obtained from both countries per the product type , outlet , and the zone of collection while table 2 shows a further breakdown of the product type . \n the countries of origin of the samples show a huge reliance of the two countries on importation of medicines ( 80.3% ) . \n the majority of the samples ( 50.8% ) were stated as manufactured in india , followed by 12.9% in ghana . \n nine ( 6.8% ) samples were stated as originating from togo while the rest were stated as manufactured in nine other countries : morocco , senegal , china , england , germany , france , the united states , vietnam , and spain . who international chemical reference substance ( icrs ) for all samples analysed was obtained from the european directorate for the quality of medicines and healthcare ( edqm ) , strasbourg , france . \n prior to the more rigorous chemical assays , visual inspection of packaging and dosage form was employed as a quick means of checking the quality or otherwise of the samples . \n the packaging was checked for correct and legible labelling of active ingredients and strength , expiration date , batch number , manufacturer , and country of origin . \n the study did not go as far as forensic examination of trademarks , product designs , or holograms . \n the appearance of the samples was also examined for discolouration , chippings , or excessive powder . \n basic ( colorimetric ) tests , also known as simplified tests , provide simple and readily applicable methods for confirmation of the identity of active pharmaceutical ingredients ( apis ) . to ensure that all the samples contained the requisite api , each of them was evaluated using methods described in the who basic tests for pharmaceutical dosage forms together with various who restricted documents that are prepared for incorporation into the international pharmacopoeia . \n the previously described sq - tlc protocol was employed as a rapid , simple , and affordable quality monitoring tool to estimate the api content of the samples . \n figure 2 shows a chromatogram of an artemether - lumefantrine coformulated medicine assayed for artemether api content . applied to the plate \n were 2.0 l of a 1 mg / ml solution of the medicine sample and varying volumes of 1 mg / ml solution of the rs ( 1.02.4 l ) . \n when the chromatogram was scanned and saved onto a computer , application of microsoft office picture manager in varying the intensity of the spots gave the following observations : the artemether api of the sample at 2.0 l started to fade from the tlc plate around the same time as the artemether rs spot at 1.6 l but faded completely before the artemether rs spot at 1.8 l . since these volumes are equivalent to the corresponding quantities of the api in g , this observation implies that the actual amount of api contained in the sample is between 1.6 g and 1.8 g of pure api and not the expected 2.0 g . \n since the label claim of the dosage form is 20 mg of artemether , the lower percentage limit is , 1.6/2.0 100 = 80% , equivalent to 16 mg per tablet of artemether , while the upper limit is 90% , equivalent to 18 mg per tablet of artemether . \n a range of 8090% of artemether api is not compliant with the who international pharmacopoeia requirement which stipulates that each tablet must contain not less than 90% and not more than 110% of the amount of artemether stated on the label . \n the sq - tlc assay of the sample therefore suggests that this sample is noncompliant with respect to api content . to further confirm and validate the results of the sq - tlc \n , all the medicine dosage forms were assayed using hplc as a more accurate method of quantitative analysis . \n the experimental details for preparation of solutions of the apis in the dosage forms were previously indicated . \n the area under the curve ( auc ) for each of them was calculated from their respective chromatograms obtained from the assay . \n the average auc was then calculated and their concentrations determined from the calibration curves . \n . describes separate methods for the assay of artesunate and amodiaquine , there appears to be no pharmacopoeia method for the simultaneous assay of artesunate - amodiaquine coformulated medicines [ 3133 ] . \n thus slight modifications to the experimental conditions described by gandhi et al . were applied in the current study . \n figure 3 shows a chromatogram of a preparation containing 0.6 mg / ml artesunate and 1.8 mg / ml amodiaquine . \n artemether single component , lumefantrine single component , and artemether - lumefantrine coformulated medicines . in view of the large number of samples \n gradient method , ( artemether : 19 minutes ; lumefantrine : 34 minutes ) , a modified method resulting in a shorter retention time was developed and used in the present study . \n extraction of api from the medicine dosage forms was done with acetic acid followed by acetonitrile . while lumefantrine ionizes in acetic acid causing it to dissolve , artemether \n therefore , acetic acid would dissolve lumefantrine while acetonitrile would dissolve artemether , causing both apis to be soluble in the solvent mixture . to overcome the issue of low concentrations of artemether in the coformulated medicine ( 16.7% ) coupled with its low molar absorptivity , higher concentrations of the medicines \n were prepared to enable the detection of artemether while at the same time being mindful of unnecessarily overloading the column with lumefantrine . \n the linearity of this intervention , when tested with the calibration curve , gave r values of 0.995 for lumefantrine and 0.999 for artemether . \n figure 4 shows a chromatogram of a preparation containing about 0.4 mg / ml artemether and 2.4 mg / ml lumefantrine . \n a modified version of the method described in the ph . int . was used in the hplc assay of dihydroartemisinin dosage forms . \n the findings of the study have been submitted to the funding body , west africa health organisation ( waho ) , and are also available in the students ' thesis reports which are now in the public domain . \n no official report has , however , been made to our nmras , the companies , or the who rapid alert system . \n visual inspection did not reveal any false - labelling ; however , one oral artesunate monotherapy among the ghana samples appeared slightly chipped and powdery . \n overall , about 46% of the collected samples were not registered by either country 's respective medicine regulatory authority \n . a greater proportion of the ghanaian collection ( 79.3% ) was unregistered while togo had only 21.6% unregistered samples , suggesting a possible more rigorous enforcement of regulatory laws in togo than in ghana . \n results of the basic tests indicated that with the exception of the slightly chipped and powdery oral artesunate monotherapy sample in the ghana collection , which totally lacked the api , all the antimalarial medicines analysed contained the requisite apis . \n due to the large data generated from both assays , a selection of the results is presented in table 3 . \n three categories of antimalarial medicines were identified based on the percentage or quantity of the api present . \n requirements ( not less than 90% and not more than 110% of the amount of api stated by the label ) . this category was labeled compliant ( c ) . \n requirements because the quantities of their apis were either below or above the pharmacopoeia limits . \n however , some samples were identified to have recorded percentages that were marginally compliant with the upper and lower ph . \n thus another category was created for them and labeled border - line compliant ( blc ) . for the sq - tlc assay , \n samples which fell within 5% of the upper and lower limits ( i.e. , 85% to 115% ) were considered blc while a margin of 2% was set for the more accurate hplc assay . \n failure of a sample was based on the pharmacopoeia noncompliance of the api component of the medicine formulation . for the acts , \n a sample was considered to have failed if either both or one of the apis did not meet pharmacopoeia specifications . \n the sq - tlc results obtained using the two different solvent systems described previously were comparable and therefore complemented each other . \n the results of the basic tests were largely corroborated by the sq - tlc in that the visualizing agents used in developing the chromatograms gave characteristic colours indicative of the nature of a specific api present . \n cobaltous nitrate saturated with sodium chloride was used for the first time as the visualizing agent in the sq - tlc determination of amodiaquine and was found to be a better detection reagent than the i2/ki solution normally used for amodiaquine . the only sample ( 3n7 , table 3 ) which failed the visual inspection of dosage form as well as the basic test was not detected by both sq - tlc and hplc , corroborating the previous observations . \n however , one artesunate monotherapy medicine from the togolese collection which gave a positive basic test appeared differently on tlc in both the colour of the spot and rf with respect to the rs . \n there were 39 artesunate - containing samples , 14 of which were all oral monotherapy . \n thirty - seven of the artesunate - containing samples were tested and the results showed a 100% failure rate for the artesunate component by both sq - tlc and hplc analyses . \n apart from two artesunate monotherapy formulations , one from each country , which did not contain any active ingredient , all the other samples contained insufficient quantities of the active ingredient as indicated by the manufacturers . \n anova at 95% confident interval for artesunate - containing samples collected from both ghana [ f(2,39 ) = 0.028 , p > 0.05 ] and togo [ f(2,46 ) = 0.431 , p > 0.05 ] did not reveal a statistically reliable difference between the means of artesunate recovery using tlc solvent system one , tlc solvent system two , and the hplc method . \n analysis of the amodiaquine component of the medicines , however , indicated that 13 out of 14 of the ghana collection met ph . \n requirements using both methods , while one sample failed by both sq - tlc and hplc analyses [ f(2,42 ) = 0.016 , p > 0.05 ] . \n all the 11 amodiaquine - containing medicines obtained from togo passed the content requirement tests using both methods [ f(2,42 ) = 0.001 , p > 0.05 ] . \n thirty - two samples were collected in ghana : one artemether injection and 31 artemether - lumefantrine acts . \n the injection passed both assays while , of the 30 out of the 31 acts analysed for artemether content , 22 samples ( 73.3% ) and 25 samples ( 83.3% ) failed using hplc and sq - tlc assays , respectively . \n anova did not reveal a statistically reliable difference between the means of artemether recovery using tlc solvent system one , tlc solvent system two , and the hplc method . \n , only one sample out of the 31acts failed the content requirements for lumefantrine by both sq - tlc and hplc analyses [ f(2,90 ) = 0.275 , p > 0.05 ] . \n incidentally , the artemether component of this medicine passed hplc analysis . considering the quantities of both components , however , only 9 out of the 31 samples were fully compliant , comprising 8 coformulated medicines and the only artemether injection . \n the togo samples comprised 4 artemether suppogels , 17 artemether injections , and 28 artemether - lumefantrine coformulated tablets . \n the assay for artemether content gave the following results : 14 artemether out of the 17 injections failed the sq - tlc assay while the remaining 3 were border - line compliant ; only 5 out of the 17 injections failed the hplc assay-7 were fully compliant while 5 were border - line compliant . in the 28 acts , \n artemether content failed by 100% and 85.7% in sq - tlc and hplc assays , respectively . \n anova , however , failed to reveal a statistically reliable difference between the means of artemether recovery using tlc solvent one system , tlc solvent two system , and the hplc method . \n the assay for lumefantrine in the 28 artemether - lumefantrine coformulated tablets gave the following results : 100% failure by sq - tlc ; 21.4% failure , 28.6% marginally compliant , and 50% fully compliant by hplc . \n anova revealed a statistical reliable difference between the means of lumefantrine recovery using tlc solvent one system , tlc solvent two system , and the hplc method [ f(2,48 ) = 4.123 , p < 0.05 ] . \n twelve dihydroartemisinin - containing samples ( 6 acts and 6 monotherapy formulations ) were collected from both countries . the ghana collection comprised four dihydroartemisinin / piperaquine acts and five dihydroartemisinin monotherapy formulations while the togo collection comprised two acts ( dihydroartemisinin / piperaquine and dihydroartemisinin / sulfadoxine / pyrimethamine ) and one monotherapy formulation . in each collection , the failure rates for the two dosage forms were similar and the sq - tlc assay results were largely confirmed by the hplc results . \n anova showed no statistical difference between the means of sample recovery using tlc solvent one system , tlc solvent two system and the hplc method . \n f(2,24 ) = 2.146 , p > 0.05 . for the togo samples , while the co - formulated sample with sulfadoxine / pyrimethamine could not be assayed by hplc due to interference by the sulfadoxine component , the sq - tlc showed that the dihydroartemisinin api component was more than the manufacturer 's label claim ( 110120% ) and hence noncompliant . \n generally , the results of the sq - tlc assay of the antimalarials were validated by the corresponding hplc results . with exception of an artesunate single component copackaged amodiaquine , in which the amodiaquine component failed by sq - tlc assay but passed the hplc assay , sq - tlc assay of all the artesunate - containing samples collected from both countries was confirmed by the hplc results . \n however , in the assay of artemether and lumefantrine , estimation of api content by sq - tlc gave some results that were on the lower limit as compared with hplc results ( tables 4 and 5 ) . \n this has been attributed to failure to exhaustively extract the api in such situations prior to sq - tlc analyses . \n lumefantrine api assayed by sq - tlc was noncompliant for all samples collected from togo while only 5 samples failed in the hplc assay . \n thirteen samples were fully compliant while 8 were marginally compliant . this discrepancy has been traced to nonexhaustive extraction of the lumefantrine api by acetonitrile for sq - tlc assay . \n it was also used in the extraction of the ghana samples for both the sq - tlc and hplc assays and the results were comparable . in the case of the artemether injections which recorded better quality with respect to the hplc assay , the liquid formulation may have favoured analysis by hplc more than sq - tlc . \n substandard medicines are defined as pharmaceutical products produced by legitimate manufacturers which do not meet their quality standards and specifications [ 2224 ] . \n falsified medicines like substandard ones also do meet quality specifications ; the distinction is that there is a deliberate intent to breach regulatory requirements [ 18 , 19 , 25 ] . none of the sample packages was identified to be wrongly or falsely labelled and even for the two oral artesunate monotherapies whose api was not detected , it is difficult to determine this as an intentional breach of regulatory requirement . \n the increasing incidence of production and distribution of substandard medicines by genuine manufacturers operating legally in many developing countries poses a major health hazard and this places greater responsibility on national drug regulatory agencies to ensure the production of quality drugs for use in their countries . \n the high failure rate especially of the acts was mostly due to insufficient quantities of the artemisinin component in the dosage forms . \n for instance all the artesunate / amodiaquine acts from both countries failed due to insufficient artesunate api . \n a possible implication of this is that , for artesunate / amodiaquine acts or monotherapy , it appears that manufacturers may be deliberately putting in smaller amounts of the more expensive artesunate component while the right amounts of the less expensive nonartemisinin components are kept at a minimum . \n hence cures may be obtained even when the medicine used does not meet pharmacopoeia standards . \n it has been observed that treatment of malaria with artesunate / amodiaquine combination therapy has dramatically improved efficacy over amodiaquine alone [ 3638 ] . \n addition of artesunate to amodiaquine is also reported to reduce gametocytemia compared to amodiaquine monotherapy , thereby theoretically reducing transmission [ 37 , 38 ] . \n the presence of insufficient quantities of artesunate api is therefore a cause for concern because administration of suboptimal doses of medicines to parasites even though in many cases reduces symptomatic episodes of the disease in patients leaves many uncleared parasites in the body of individuals . \n this has been a major intermediate in the development of resistance because upon reinfection , these parasites which have been exposed to subtherapeutic doses of the medicines have been shown to undergo mutations that make them tolerant to the medicines [ 39 , 40 ] . \n artemether and artemether / lumefantrine antimalarial medicines formed the bulk of the samples analysed ( 77 , 18 of which were parenteral monotherapy ) . \n this is a clear indication of the widespread use of artemether / lumefantrine as the preferred therapeutic agent due to its tolerability . \n the results obtained by both sq - tlc and hplc analyses of the ghana collection were not different from the trend observed in the analysis of the artesunate / amodiaquine samples . in most cases , while the artemether component was insufficient , the lumefantrine component was compliant . \n failure in dihydroartemisinin api content was a result of the presence of either insufficient or overdose quantities . \n the problem with overdosing is that it puts patients at the risk of toxicity which is equally dangerous . \n since the two countries rely heavily on importation of antimalarial medicines ( 80.3% ) from different countries , and ghana especially had significant quantities of unregistered medicines ( 76.3% unregistered for ghana and 21.6% unregistered for togo ) , a quality assessment of medicines from domestic and foreign sources as well as for registered and unregistered medicines was carried out . \n it was observed that the overall failure rates of the samples assayed were comparable irrespective of manufacturing source with 77.3% of domestic samples and 77.5% of imported samples failing . \n a country by country analysis , however , showed almost twice the failure rate in locally manufactured medicines in ghana ( 92.3% ) compared to togo ( 55.6% ) . \n failure rates in the imported samples were similar : 76.2% for ghana and 78.3% for togo . in the case of registration status , \n a greater percentage of registered medicines ( 83.8% ) than unregistered medicines ( 79.1% ) failed in ghana . \n the overall figures of 70.8% failure for registered medicines and 84.7% for unregistered medicines suggest that the registration status of a medicine does not necessarily translate into quality . \n these findings further suggest that the quality of the antimalarial medicines may have been compromised at the manufacturing stage rather than through the distribution chain since no decomposition products were observed during the assay by sq - tlc and/or hplc . \n the porous nature of the west african borders makes cross - border exchange of goods including medicines relatively difficult to control . in order to determine possible cross - border transfer of antimalarials , and whether this had any significant impact on quality , collection and analysis of medicines from areas at and close to the borders of the two countries \n the variation observed in the quality of the antimalarial medicines collected from border areas and inland cities was insignificant . the more significant observation confirming possible cross - border exchanges or distribution by the same importers was the occurrence of medicine samples of the same batch from the same manufacturer being found in the two countries . \n there were two sets of artemether - lumefantrine coformulated tablets from the two countries with the same batch number . \n there was no evidence of registration of these batches with the regulatory authorities in either country . \n in set one , both component apis were compliant in the ghana collection ( 5p3 ) , whereas insufficient quantities of artemether was found in the togo collection ( 1pm2 ) . in the second \n set , both api components in the togo collection ( 2pm2 ) as well as artemether api in the ghana collection ( 6p4 ) were noncompliant . \n samples 5p3 and 1pm2 could easily have been exchanged in cross - border activity because they were collected in the border town of aflao ( ghana ) and lome ( togo ) , respectively . on the other hand , \n samples 2pm2 and 6p4 were collected at aneho ( eastern border of togo ) and half assini ( western border of ghana ) , respectively . a dihydroartemisinin sample ( 1qm6 ) , collected from lome , togo , also belonged to the same batch as a ghana ( half assini ) collection coded 6q1 . \n while sample 1qm6 gave an sq - tlc range of 110115% making it border - line compliant , the hplc showed it was compliant , with a value of 106.77% of the manufacturer 's label claim . on the other hand , \n sample 6q1 failed both sq - tlc ( 7075% ) and hplc ( 80.75% ) analyses , revealing the variation in composition of api even within same batches of the same medicine . \n these findings suggest the possible existence of extensive cross - border distribution of medicines between the two countries even though the direction of flow is not apparent , neither is it known whether the exchange is legitimate . \n nonetheless , it confirms the point that the circulation of falsified or substandard medicines could have serious public health implications for all the countries involved . to obtain better representative results in the two countries \n , it is recommended that subsequent quality evaluation surveys employ the more rigorous random sampling plan and also extend beyond the current sampling sites . due to the potential rapid development of parasite resistance , \n the use of monotherapy artemisinin - based antimalarial medicines has been discouraged , while coformulated acts usage has been positively encouraged . \n as already highlighted in previous sections , collections made during this study revealed a significant circulation of monotherapy formulations of dihydroartemisinin , artesunate , and artemether still being openly distributed and sold , especially in togo . \n it is important to note , however , that the more vital parenteral artesunate recommended for severe malaria was not available in any of the sampling sites . \n the results obtained in this study are in consonance with other results published in recent times . \n , in a study on antimalarials distributed in the accra metropolis , found that out of 23 artesunate containing samples analysed , only 3 artesunate single - dose and 1 artesunate - amodiaquine co - formulations were compliant with ph . \n none of the six ( 6 ) artemether containing medicines passed , while one of the two dihydroartemisinin assayed by hplc passed . \n overall , the passing rate was 4 out of 31 samples analysed by hplc , with two other samples being borderline compliant . in another study , ofori - kwakye et al . . \n also reported that the artesunate content of tablets sampled in kumasi varied between 47.9% and 99.9% of the manufacturer 's label claim and only 3 ( 17.6% ) of the samples met the european pharmacopoeial requirements for content of active ingredients . \n a more recent survey of the quality of selected antimalarial medicines circulating in six countries of sub - saharan africa ( cameroon , ethiopia , ghana , kenya , nigeria and the united republic of tanzania ) carried out by the who found that although there was also a substantial amount of unregistered products especially among the acts , the nature of failure rates for registered and unregistered medicines was similar . \n the failure rate in terms of country comparison showed that products from nigeria had the highest ( 64% ) , followed by ghana ( 39.5% ) and then cameroon ( 37% ) . \n the findings of the study suggest the existence of substandard artemisinin - based antimalarial medicines in both ghana and togo . \n the presence of insufficient active pharmaceutical ingredient was identified as the main cause of the poor quality . in most cases , \n the lacking component was the artemisinin - type medicine while the cheaper nonartemisinin component was present in sufficient quantities . \n the study has revealed that the registration status of antimalarial medicines on the ghanaian market has not improved since the 2011 publication of the who qamsa report on the quality of antimalarials in selected african countries including ghana . \n togo has a better registration status and cross - border activity between the two countries may not be a common phenomenon . the results also show that the registration status as well as the manufacturing source of the antimalarial medicines sampled did not have any significant impact on their quality since failure rates were comparable . \n this suggests that there exist inconsistencies in implementation of gmps in both domestic and foreign products . \n we realise the enormity of the task and recommend that relevant departments within our universities are strengthened and accredited to assist the nmras undertake regular quality assurance and pharmacovigilance . \n we also recommend a greater enforcement of adherence to medicine registration procedures by regulators to improve the implementation of gmps by domestic manufacturers and ensure that imported medicines are tested in who prequalified laboratories . in this regard , any medicine donations must be accepted only if they comply with established guidelines . \n furthermore , better cooperation among all stakeholders - manufacturers , importers / exporters , distributors , regulators , and indeed the consumer must be promoted through frequent education and training . \n results obtained from the sq - tlc assays were generally confirmed by the hplc assays , affording another opportunity to apply and verify the suitability of the semiquantitative tlc assay as a rapid analytical tool for antimalarial medicines . \n one major objective achieved in the present study which the previous work did not address due to technical reasons was to develop suitable hplc methods for concurrent assay of both components of the single tablet coformulated acts in the determination of their quality . in the previous study , failure or otherwise of the samples \n was based on only the pharmacopoeia compliance of the artemisinin component of the medicine formulation , even for acts which were presented or marketed as coblistered formulations . \n the who , in its global plan for artemisinin resistance containment , has indicated that the effort at containing resistance to the acts should include among other activities the withdrawal of orally administered artemisinin - based monotherapies , substandard , and falsified medicines . \n the artemisinins are the chief components of the acts and every effort has to be made to prolong their useful therapeutic lives together with those of their partner drugs .", "role": "user" }, { "content": "this study , conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines , reports on the quality of 132 artemisinin - based antimalarial medicines distributed in ghana and togo . \n three methods were employed in the quality evaluation \n basic ( colorimetric ) tests for establishing the identity of the requisite active pharmaceutical ingredients ( apis ) , semi - quantitative tlc assay for the identification and estimation of api content , and hplc assay for a more accurate quantification of api content . from the basic tests , only one sample totally lacked api . the hplc assay , however , showed that 83.7% of the acts and 57.9% of the artemisinin - based monotherapies failed to comply with international pharmacopoeia requirements due to insufficient api content . in most of the acts , \n the artemisinin component was usually the insufficient api . \n generally , there was a good correlation between the hplc and sq - tlc assays . \n the overall failure rates for both locally manufactured ( 77.3% ) and imported medicines ( 77.5% ) were comparable . \n similarly the unregistered medicines recorded a slightly higher overall failure rate ( 84.7% ) than registered medicines ( 70.8% ) . \n only two instances of possible cross - border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the us healthcare costs are assuming an increasing level of importance . medicare expenditures for inpatient care are expected to increase from us$129.1 billion in 2008 to us$234.9 billion in 2019 . \n approximately 19.6% of medicare recipients are rehospitalized within 30 days following discharge from an acute care setting . in 2010 , \n the patient protection and affordable care act ( ppaca ; p.l.-11 - 148 ) was signed into law in the united states . \n hospital readmission is a complex problem with multiple etiologies , and there are no simple strategies to reduce their incidence . despite the complexity , readmission is seen as an important performance and accountability measure for hospitals . \n hospital readmission following hip fracture is a frequent and serious sentinel event that may be avoidable and may indicate a gap in care . \n hip fracture is the leading orthopedic discharge diagnosis associated with 30-day readmission in terms of numbers . \n because readmission to the hospital following a hip fracture is so common , it adds considerably to the costs on an already overburdened health care system . \n readmission rates following hip fracture have increased slightly from 14.3% in 2004 to 14.5% in 2009 . \n hip fracture has been shown to be the third most costly diagnosis in medicare recipients aged 65 and older accounting for 4.6% share of total spending . \n most hip fractures occur in patients aged 65 years and older , which is the most rapidly growing segment of the population in the united states . \n the number of hip fractures is predicted to increase by 51% by 2025 . with increasing number of patients treated and discharged , the associated economic impact of hospital readmission is also growing . \n this manuscript will analyze the costs of the initial inpatient admission , readmission , and 30-day hospital readmission rates of 1081 patients with a native nonpathologic , low - energy hip fracture treated at a single level 3 trauma center over a 65-month period . \n the causes of readmission and the outcomes of the readmitted patients will also be examined . \n the objective of this study is to evaluate the costs , frequencies , and reasons for readmission after hip fracture . \n a secondary purpose of the study would be to compare the costs of readmission to the costs of the original admission . \n all patients aged 65 and older admitted to a 261-bed university - affiliated level 3 trauma center between april 30 , 2005 , and september 30 , 2010 , with a unilateral , native , nonpathologic low - energy proximal femur fracture were identified from a fracture registry and included for analysis . \n patients with periprosthetic fractures , pathologic fractures , bilateral injuries , and high - energy mechanisms were excluded . \n all patients had retrospective chart reviews completed by a member of the research team as part of a hospital quality management initiative . \n data were collected by a study nurse from patients directly and from their medical records and included demographic information , comorbidities , surgical management , in - hospital complications as well as any readmission within 30 days of original discharge . \n readmissions within the original health care system , which includes 2 hospitals , were confirmed with the hospital s admission tracking computer system . \n these patients were contacted by telephone for information regarding their readmission . because data on costs of care could not be obtained , these patients were excluded from financial analysis . \n we also analyzed charges for care rather than actual costs because charges are typically reported by governmental reports . \n statistical analyses were performed on spss v20 software with statistical significance being reached on the 2-tailed student t test when p < .05 . \n all patients aged 65 and older admitted to a 261-bed university - affiliated level 3 trauma center between april 30 , 2005 , and september 30 , 2010 , with a unilateral , native , nonpathologic low - energy proximal femur fracture were identified from a fracture registry and included for analysis . \n patients with periprosthetic fractures , pathologic fractures , bilateral injuries , and high - energy mechanisms were excluded . \n all patients had retrospective chart reviews completed by a member of the research team as part of a hospital quality management initiative . \n data were collected by a study nurse from patients directly and from their medical records and included demographic information , comorbidities , surgical management , in - hospital complications as well as any readmission within 30 days of original discharge . \n readmissions within the original health care system , which includes 2 hospitals , were confirmed with the hospital s admission tracking computer system . \n these patients were contacted by telephone for information regarding their readmission . because data on costs of care could not be obtained , these patients were excluded from financial analysis . \n we also analyzed charges for care rather than actual costs because charges are typically reported by governmental reports . \n statistical analyses were performed on spss v20 software with statistical significance being reached on the 2-tailed student t test when p < .05 . \n the average time to surgery after admission for these patients was 25.5 hours , with a hospital length of stay ( los ) of 4.2 1.9 days . \n of these patients , 129 ( 11.9% ) were readmitted to an acute care facility within 30 days of their initial discharge date . \n the average hospital los for readmissions was 8.7 18.8 days , which was significantly longer than the initial stay ( 4.6 2.3 days ) for these patients after presenting with a native hip fracture ( p = .03 ) . \n full data were available on 123 of these patients ; 6 patients were readmitted to regional hospitals from which financial data could not be obtained . \n the primary causes of readmission were medical complications or other reasons in 108 ( 83.7% ) of 129 patients and surgical complications in 21 ( 16.3% ) of 129 patients . there were a total of 24 other medical diagnoses associated with these 108 medical readmissions . \n table 1.basic group characteristics.patient characteristicsn = 1081gender male24.0% female76.0%age ( mean sd)85.1 8.4race , % caucasian94.8 hispanic1.3 black1.2 asian2.1 native american0.2 other0.3prefracture residence , % community48.9 skilled nursing facility37.6 assisted living13.5charlson score , mean sd3.1 2.1dementia,%47.4parker mobility , mean sd3.8 3.2readmission rate , % 11.9reoperation rate , % 0.74length of stay for readmitted patients , days \n initial hospitalization4.6 2.3 readmission8.7 18.8 p value.0312-month mortality rate patients not readmitted21.8% readmitted patients56.2% \n p value.0001hospital charges for readmitted patients initial admissionus$16 308 us$6400 readmissionus$14 191 us$25 035 p value.36abbreviation : sd , standard deviation . \n basic group characteristics . abbreviation : sd , standard deviation . of the surgical readmissions , \n 12 ( 9.3% ) involved an injury that was caused by falling after hospital discharge . \n of these 12 patients , 3 patients sustained a periprosthetic femoral fracture , 3 had a contralateral hip fracture , 2 dislocated their hemiarthroplasties , and 4 sustained nonhip fractures . \n there were 3 patients with failed fixation1 sliding hip screw cutout , 1 failed fixation of a femoral neck fracture ( with cannulated screws ) , and 1 failed hemiarthroplasty that required reoperation . \n pneumonia represented the most common medical reason for readmission ( 27 patients , 20.9% ) . \n the next most common reasons were congestive heart failure ( chf ) and atrial fibrillation ( 7 patients each , 5.4% ) . mental status changes , renal complications ( dehydration , acute renal failure , and hyponatremia ) , and other cardiac conditions ( myocardial infarction ) were other diagnoses associated with readmission . \n additional diagnoses included 6 ( 4.6% ) intestinal obstructions ( small bowel obstruction and fecal impaction ) , 5 gastrointestinal bleeds , 6 ( 4.6% ) patients with clostridium difficile infections , 3 patients with stage iii or greater pressure sores , 2 patients with adult failure to thrive , and 5 each with cerebral vascular accidents , urinary infection , and other diagnoses . see table 2 for detailed causes of readmission . \n table 2.causes of readmission.organ system \n subtotaltotal ( n = 129)diedpercentage of 129pulmonary \n\n\n\n\n\n pneumonia27351127.3 \n respiratory failure6 \n 1 \n\n chronic obstructive disease2 \n\n\n gastrointestinal \n\n\n\n\n\n gastrointestinal bleed521 \n 16.4 \n small bowel obstruction3 \n\n\n\n fecal impaction \n 3 \n 1 \n\n\n c. difficile infection \n 6 \n 1 \n\n illeus2 \n\n\n\n failure to thrive2 \n 2 \n neurologic \n\n\n\n\n\n stroke510 \n 7.8 \n delirium2 \n 1 \n\n seizure2 \n\n\n\n intracranial hemorrhage1 \n\n\n cardiovascular \n\n\n\n\n\n congestive heart failure \n 716312.5 \n atrial fibrillation7 \n\n\n\n myocardial infarction2 \n\n\n musculoskeletal \n\n\n\n\n\n refracture324 \n 18.8 \n failure of fixation3 \n\n\n\n new site fracture7 \n\n\n\n deep wound infection3 \n 2 \n\n superficial wound infection2 \n\n\n\n dislocation of joint2 \n\n\n\n pressure ulcer \n 3 \n 1 \n\n hematoma1 \n\n\n genitourinary \n\n\n\n\n\n urinary infection \n 513 \n 10.2 \n urosepsis2 \n 1 \n\n urinary retention1 \n\n\n\n acute renal failure3 \n\n\n\n electrolyte abnormality2 \n\n\n hematologic \n\n 5 \n 3.9 \n anemia2 \n\n\n\n pulmonary emboli or deep vein thrombosis3 \n\n\n other \n 55 \n 3.9 \n deemed potentially avoidable readmissions \n nineteen percent ( 24 patients ) died during their readmission versus 2.8% during the index admission ( see table 2 for causes of death ) . when analyzing the 1-year mortality those patients readmitted within 30 days had a 1-year mortality rate of 56.2% versus 21.8% for those patients not readmitted ( p < .0001 ) . \n patient factors analyzed for association with readmission are presented in table 3 ( univariate ) and table 4 ( multivariate logistic regression ) . in multivariate analysis , \n the odds of readmission were significantly increased with age greater than 85 , at least partial disability in katz activities of daily living score , in - hospital delirium , preoperative arrhythmia , presence of pacemaker , diabetes , and dementia . \n there were strong associations that did not meet statistical significance on multivariate analysis between readmission and male sex ( p = .05 ) , time to surgery over 24 hours ( p = .05 ) , medium parker mobility scores ( p = .06 ) , 4 or higher charlson score ( p = .05 ) , and presence of gastroesophageal reflux disease ( p = .05 ) . \n total , n = 1081readmitted , n = 129rate , 11.9% \n p valueage 60 - 696334.7%.005 70 - 79183158.1% \n 80 - 894675110.9% \n 903686016.3% \n gender male2524015,9%.035 female8298910.7% \n residence community5295510.3%.21 assisted living1472214.9% \n skilled nursing3845113.2% \n preoperative parker mobility score high ( 9)191168.9%.16 medium ( 5 - 8)2683814.2% \n low ( 0 - 4)6227512.1% \n preoperative function independent4794609.6%.094 partial dependence4216014.3% \n dependent1812312.7% \n charlson score \n\n\n\n low ( 0 - 1)281248.5%.106 medium ( 2 - 3)4015012.5% \n high ( 4 or more)3995513.8% \n dementia \n\n\n\n yes5166913.4%.10 no5656010.6% \n\n p values represent univariate analysis . the parker mobility score is a functional assessment that rates the patient s ability to get about the house , to get out of the house , and to go shopping , with no difficulty ( 3 ) , with an aid ( 2 ) , with help from another person ( 1 ) , and not at all ( 0 ) . \n table 4.multivariate analysis for independent predictors of readmission.factorodds95% confidence interval \n p valueage > 851.581.02 - 2.26.02 \n male1.491.00 - 2.24.05assisted living1.520.82 - 2.59.12skilled nursing1.240.84 -1.85.29time to surgery > 24 hours1.461.00 - 2.15.05parker mobility score medium ( 5 - 8)1.810.98 - 3.35.06 low ( 0 - 4)1.500.85 - 2.64.16activities of daily living partial or complete disability1.511.03 - 2.25.03 \n charlson score \n\n\n medium ( 2 - 3)1.530.97 - 2.55.11 high ( 4 or more)1.651.00 - 2.74.05in - hospital complications ( initial hospitalization for index fracture ) delirium1.661.14 - 2.41.01 \n hematoma7.510.47 - 121.16 urinary tract infection1.840.39 - 8.84.44 preoperative arrhythmia1.621.09 - 2.39.02 \n past medical history pacemaker1.751.11 - 2.76.02 \n gerd1.440.99 - 2.10.05 diabetes1.911.22 - 2.99.005 \n dementia1.611.12 - 2.22.01 \n cardiac disease1.020.66 - 1.59.92 alcoholism1.120.46 - 2.68.81 tobacco use0.990.56 - 1.73.54abbreviation : gerd , gastroesophageal reflux disease . \n the parker mobility score is a functional assessment that rates the patient s ability to get about the house , to get out of the house , and to go shopping , with no difficulty ( 3 ) , with an aid ( 2 ) , with help from another person ( 1 ) , and not at all ( 0 ) . \n denotes statistical significance ( p < .05 ) hospital charges were available for 123 of the 129 readmitted patients . \n these patients accumulated an average hospital charge of us$16 308 us$6400 during their initial hospitalization for their native hip fractures . \n the average charges accumulated during their readmission within 30 days was us$$14 191 us$25 035 ( p = .36 ) . \n us$4200.81congestive heart failureus$14 526.71 us$3921.52myocardial infarctionus$15 131.50 us$1720.39 \n clostridium difficile infectionus$16 016.40 us$2193.88obstipationus$15 693.00 us$4922.85gastrointestinal bleedus$15 418.00 us$6153.86small bowel obstructionus$18 322.50 us$5438.36ileusus$17 017.67 us$2570.99thromboembolic eventus$10 508.33 us$10 453.86decubitus ulcerus$16 343.00 us$6398.96deep infectionus$15 842.75 us$3233.37superficial infectionus$10 029.50 us$1207.03hip dislocationus$22 262.00 us$1711.20failure of fixationus$11 976.00 us$3710.90second fractureus$18 676.29 us$4840.90strokeus$14 836.00 us$5456.59deliriumus$11 314.33 us$1049.60seizureus$15 \n 439.50 us$5479.37copd exacerbationus$20 908.67 us$5972.60pneumoniaus$16 145.20 us$4765.17acute kidney injuryus$13 119.67 us$8624.22fluid / electrolyte disturbanceus$16 003.67 us$4703.08urinary tract infectionus$16 796.00 us$11 724.00abbreviation : copd , chronic obstructive pulmonary disease ; sd , standard deviation . \n average age ( number of patients)1 - 7 days8 - 14 days15 - 21 days22 - 30 dayspulmonary \n\n\n\n\n\n\n pneumonia89 5 ( n = 27)13932 \n respiratory failure88 5 ( n = 6)4101 \n chronic obstructive disease82 7 ( n = 2)0101gastrointestinal \n\n\n\n\n\n\n gastrointestinal bleed87 6 ( n = 5)1301 \n small bowel obstruction90 6 ( n = 3)2100 \n fecal impaction92 13 \n ( n = 3)0102 \n\n clostridium difficile infection93 2.5 ( n = 6)2301 \n illeus72 8 ( n = 2)2000 \n failure to thrive88 4 ( n = 2)2000neurologic \n\n\n\n\n\n\n stroke83 11 ( n = 5)2201 \n delirium86 6 ( n = 2)1001 \n seizure77 8 ( n = 2)1010 \n intracranial hemorrhage87 ( n = 1)0010cardiovascular \n\n\n\n\n\n\n congestive heart failure92 8 ( n = 7)1015 \n atrial fibrillation85 6 ( n = 7)5002 \n myocardial infarction94 \n 1(n = 2)1001musculoskeletal \n\n\n\n\n\n\n refracture78 9 ( n = 3)2001 \n failure of fixation92 3 ( n = 3)1110 \n new site fracture87 4 ( n = 7)4021 \n deep wound infection85 10 ( n = 3)0300 \n superficial wound infection79 6 ( n = 2)0110 \n dislocation of joint74 16 ( n = 2)0020 \n pressure ulcer89 6 ( n = 3)0012 \n hematoma89 ( n = 1)1000genitourinary \n\n\n\n\n\n\n urinary infection90 7 ( n = 5)1220 \n urosepsis87 5 ( n = 2)1100 \n urinary retention98 ( n = 1)1000 \n acute renal failure83 10 ( n = 3)1101 \n electrolyte abnormality96 1 ( n = 2)1100hematologic \n\n\n\n\n\n\n anemia82.5 1 ( n = 2)2000 \n pulmonary emboli or deep vein thrombosis78 6 ( n = 3)2010other \n 90 3 ( n = 5)2201 \n number of patients readmitted in each time period . \n this is the first study looking at patient - level clinical and financial data on patients with hip fracture from the united states . \n readmission is often associated with serious medical and surgical complications of the original hospitalization , and this was true in this study . \n . however , here we identified some reasons for readmissions that are indicators or poor quality and are potentially preventable ( table 2 ) . in this study , \n these preventable causes can serve as targets for future quality improvement efforts . under ppaca , \n the centers for medicare and medicaid services ( cms ) will begin to hold hospitals accountable for their medical readmission rates starting with 4 specific diagnoses . \n this will be accomplished with public reporting of individual hospital readmission rates and decreased hospital reimbursement from cms . \n it is clear that government policy is capable of altering practice habits of clinicians through financial incentives or penalties . \n reducing payments and ultimately reducing monetary resource allocation toward the most costly medical conditions does not necessarily result in similar outcomes . \n patients with hip fracture may increase financial burden on the health care system before they have sustained a fracture . \n kilgore et al recently studied 60 354 medicare patients with hip fractures and found 88% of increased health care expenditure is directly associated with the fracture . \n furthermore , in the months leading up to their fracture , these patients consumed significantly more health care resources than matched controls . \n expenditures on every body system studied ( ie , cardiovascular , pulmonary , endocrine , neurologic , genitourinary , etc ) increased significantly after their hip fracture . \n this suggests that the patient who sustains a hip fracture is experiencing a general decline in health prior to his or her fracture . \n more critical research into this topic may yield models that could potentially predict a patient s risk of hip fracture , which may allow for preventive measures to be developed . \n one study of 606 patients for 180 days after hip fracture found an readmission rate of 8.3% . \n the rate varied by discharge destination with inpatient rehabilitation ( 4.5% ) and home ( 5.1% ) having the lowest rates . \n multivariate analysis in this study further supported that inpatient rehabilitation decreased readmission rates , while patients with longer loss had higher odds of readmission . \n buecking et al reviewed 402 patients with hip fracture ( 80% living at home alone or with family ) and found a 12% readmission rate . \n the majority ( 79% ) were not related to their fracture , with respiratory failure ( 25% ) , cardiovascular morbidity ( 15% ) , and infectious disease ( 10% ) being the most common reasons for readmission , all similar to our data in this study . \n multivariate analysis suggested that males and specifically femoral neck fractures had an increased risk of readmission . \n discharge to inpatient rehabilitation , especially those with more comorbidities , may be a potential route for improving readmission rates . \n french et al described a 30-day readmission rate of 18.3% using claims data from 41 331 us veterans aged 65 years with a hip fracture . \n the readmitted patients in that study had a 1-year mortality rate of 48.5% compared with a 24.9% mortality rate in veterans who were not readmitted . \n bookvar et al described a prospective analysis of 562 patients with hip fracture aged 50 years . \n of these readmissions , 11% were readmitted for surgical causes and 89% were readmitted for medical reasons . \n readmitted patients in their series were found to have an increased risk of mortality , impaired gait , and placement in a nursing home 6 months following fracture . \n jencks et al published a 30-day readmission rate of 17.9% after major hip or femur surgery and cited pneumonia and chf as being the 2 most frequent causes of readmission . \n the recently published dartmouth atlas report on readmissions highlights the considerable variation seen in readmission rates seen among both community and academic medical centers . \n the specific causes for this variation are not clear . there has been no improvement in readmission rates over the past decade , 14.3% in 2004 and 14.5% in 2009 . for new york state hospitals , \n many causes for readmission have been described including communication issues , problems with medication reconciliation , lack of satisfactory follow - up care , and defects in the original inpatient care . \n other causes for readmissions may include shorter loss , increased age of the patients , and increased burden of comorbidity carried by these patients . \n typically , the inpatient care team only addresses the inpatient care phase with no interventions extending past the inpatient stay . \n the authors believe that some of our readmissions are likely of a preventable nature including some cases of constipation , cutout of implants , and congestive failure . there are likely some cases that could be avoided with improved communication with receiving providers at the time of the discharge handoff . \n there have been several successful methods published for reduction in readmissions following medical hospitalization including early follow - up care with the primary care physician , the coleman discharge coaching model , and the naylor model . \n additional efforts at improving the discharge process , communication , and postdischarge follow - up may improve the readmission rates \n this is a single - center study conducted in a hip fracture program with a strong history for quality improvement , comanaged care , and utilizing standardized protocols . \n the sample size of 1081 with 129 readmissions is certainly not large enough to generalize these results . \n larger , multicenter studies may be useful to determine whether these results can be generalized to other centers . \n another limitation is the retrospective nature of the data collection which may not fully capture all readmissions or adverse events . as a countermeasure , \n we have tried to capture all the 30-day readmissions by reviewing medical records and calling the patients , families , or caregivers following discharge . \n the patients included in this study may not accurately represent the populations seen at many centers . \n half of our patient population were admitted from a nursing home or assisted ( residential care ) living home , whereas most published studies describe 80% to 90% of patients with hip fracture admitted from a home living setting . \n we were also unable to access a detailed data sample for 6 of the patients readmitted to regional hospitals . \n this is a limitation inherent to the us health care system where medical and economic data are typically not shared between regional hospitals . \n this is a single - center study conducted in a hip fracture program with a strong history for quality improvement , comanaged care , and utilizing standardized protocols . \n the sample size of 1081 with 129 readmissions is certainly not large enough to generalize these results . \n larger , multicenter studies may be useful to determine whether these results can be generalized to other centers . \n another limitation is the retrospective nature of the data collection which may not fully capture all readmissions or adverse events . as a countermeasure , \n we have tried to capture all the 30-day readmissions by reviewing medical records and calling the patients , families , or caregivers following discharge . \n the patients included in this study may not accurately represent the populations seen at many centers . \n half of our patient population were admitted from a nursing home or assisted ( residential care ) living home , whereas most published studies describe 80% to 90% of patients with hip fracture admitted from a home living setting . \n we were also unable to access a detailed data sample for 6 of the patients readmitted to regional hospitals . \n this is a limitation inherent to the us health care system where medical and economic data are typically not shared between regional hospitals . \n the most common reasons for readmission include pneumonia , chf , new fractures , intestinal obstructions , and infections . of the patients , \n readmitted patients generated similar average hospital charges during readmission ( us$14 191 ) compared to their initial hospitalization ( us$16 308 ) .", "role": "user" }, { "content": "introduction : hip fracture is the leading orthopedic discharge diagnosis associated with 30-day readmission in terms of numbers . because readmission to the hospital following a hip fracture is so common , it adds considerably to the costs on an already overburdened health care system.methods:patients aged 65 and older admitted to a 261-bed university - affiliated level 3 trauma center between april 30 , 2005 , and september 30 , 2010 , with a unilateral , native , nonpathologic low - energy proximal femur fracture were identified from a fracture registry and included for analysis . \n readmissions within 30 days of hospital discharge , costs , and outcomes were collected and studied.results:of 1081 patients , 129 ( 11.9% ) were readmitted within 30 days . \n the average hospital length of stay for readmissions was 8.7 18.8 days , which was significantly longer than the initial stay ( 4.6 2.3 days ) ( p = .03 ) . \n nineteen percent ( 24 patients 19% ) died during readmission versus 2.8% during the index admission . \n these patients accumulated an average hospital charge of us$16 308 us$6400 during their initial hospitalization for compared with charges for their readmissions of us$14 191 us$25 035 ( p = .36).discussion : readmission was usually associated with serious medical or surgical complications of the original hospitalization.conclusions:readmission after hip fracture is costly and harmful . \n charges were similar between the original fracture admission and the readmission . \n patients were readmitted most frequently for medical diagnoses following their original hospital stay . some of these readmissions may have been avoidable .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: in spite of increasing the prevalence of overweight worldwide , underweight remains a major public health problem in the developing countries ( 1 ) . \n underweight is associated with nutritional deficiencies , negative body image , fatigue , menstrual irregularity , eating disorders and may also predict an increased risk of osteoporosis and reduced fertility as an adult ( 35 ) . \n in addition , 81% of non - western societies prefer plump or moderately fat women ( 6 ) . \n therefore , in these societies underweight has been linked to body image dissatisfaction which induces a tendency to achieve desirable body weight and shape by self - diet management or consulting the dietitian . \n measurement of resting metabolic rate ( rmr ) , as a major component of energy expenditure , plays a critical role in the development of nutrition support therapy to estimate total energy requirements ( 79 ) . \n indirect calorimetry is the reference standard for measurement of rmr in research studies ( 10 , 11 ) . \n however due to complexity , high cost of application , lack of skilled staff , hard feasibility and time consuming , is not always possible to be used in clinical settings ( 12 , 13 ) . \n various studies have been undertaken to develop some predictive equations for estimating rmr such as harris - benedict , mifflin , who / fao / unu , muller , owen , schofield and liu formulas ( 1420 ) . \n these equations are based upon regressive analysis of body weight , height , sex , age , fat free mass , fat mass , body surface area as independent variables . \n besides , it has been reported that ethnicity is an effective factor in rmr prediction ( 20 ) \n . therefore determination of the most appropriate equations that can accurately predict rmr for different ethnic groups has been suggested ( 20 , 21 ) . \n franken - field and colleagues identified that there are disparities in knowledge regarding the applicability of current metabolic rate prediction equation in different populations and suggested validation studies in different racial / ethnic populations ( 10 ) . \n more recently , several authors have validated rmr predictive equations in healthy subjects with different weights and races / ethnicities . \n they have indicated that several commonly used equations such as harris - benedict , fao / who / unu , mifflin and owen et al formulas may not be appropriate for metabolic rate prediction in certain different weights and racial / ethnic groups ( 17 , 2123 ) . \n in addition , most of the commonly used predictive equations were developed from studies in normal , overweight and obese subjects and such equations were less accurate for underweight subjects ( 16 ) . \n therefore , they developed different formulas for different ranges of body mass index , including one for bmi < 18.5 kg / m . in order to determine the most appropriate predictive equation for the iranian underweight females , this study aimed to compare the accuracy of the commonly used rmr predictive equations with rmr measured by indirect calorimetry \n in this cross - sectional study conducted in 2013 , 104 volunteer female students were recruited from tabriz universities via flyers and announcements . \n inclusion criteria were included : being apparently healthy had no chronic disease ( e.g. cancer , type 2 diabetes , etc . ) , age range of 1830 years old and had bmi<18.5 kg / m . \n exclusion criteria were included : pregnancy , lactation , being athlete and current using of medications known to affect rmr ( e.g. diuretics , corticosteroids , anti - psychotic and thyroid drugs ) . \n the protocol of this study was approved by the ethics committee of tabriz university of medical sciences and . before study \n weight was measured to the nearest 0.1 kg using the in - built bia as a weight scale ; participants were weighed in light clothing without shoes . \n height was measured to the nearest 0.1 cm using a wall - mounted stadiometer while subjects were standing without shoes with shoulders in a standard position . \n body mass index ( bmi ) was calculated as the weight in kilograms divided by the height in square meters ( kg / m ) . \n waist circumference was measured between the inferior margin of the last rib and the iliac crest . \n the greatest circumference of hip was considered as the hip circumference and the waist to hip ratio ( whr ) was calculated . \n this method is widely used because it is relatively cheap , quick , and non - invasive and requires limited operator training ( 24 ) . \n tanita bc-418 ma eight electrode , hand to foot system ( tanita co. , tokyo , japan ) was used for measurements of impedance ( 1 ) , estimation of body fat ( 0.1% ) , fm ( 0.1 kg ) and ffm ( 0.1 kg ) , at a frequency of 50 khz . \n the subjects age , gender , and height of each subject were entered in to the machine , and a standard 2 kg was entered as an adjustment for clothing weight in all participants . \n subjects were then asked to stand barefoot on the metal foot - plates of the machine while holding the handles for 30 sec . \n the fitmate was developed by cosmed ( roma , italy ) is a new portable metabolic analyzer designed to measure oxygen consumption and resting metabolic rate . \n this instrument uses a turbine flow meter that is located at the end of a disposable face mask for measuring minute volume and galvanic full cell oxygen sensor for analyzing the feo2 . using a fixed rq ( respiratory quotient ) of 0.85 , calculation of rmr is allowed . in a previous study , fitmate gave reproducible and accurate oxygen consumption and rmr measurements when compared to the douglas bag method and no significant differences were reported between two techniques for oxygen consumption and rmr in a wide range of bmi ( 25 ) . in this study \n , participants underwent to evaluation between 8:00 to 10 am in the morning after 1012 h fasting and were advised to avoid strenuous exercise from 24h before rmr measurement and refrain from caffeinated beverages and medications . \n subjects sat quietly for 20 minutes prior to rmr measurement , then they were asked to put fitmate mask on their nose and mouth at sitting and supine position in a quiet room with temperature around 25 c . using the fit mate metabolic system for 15 minutes \n calibration was done automatically for every measurement ( 25 ) for each subject , rmr was estimated using the selected equations , as listed in table 1 and compared to measure rmr . \n equations used to predict resting metabolic rate ( kcal / day ) weight based formula . weight and height based formula all data were reported as means standard deviation . paired t - test was used to evaluate the difference between the measured rmr values and those estimated by predictive equations . \n accuracy of predictive formulas at the individual level was defined as percentage of the subjects who s predicted rmr was within 10% of measured rmr ( 12 , 26 ) . \n a prediction < 90% of measured rmr was considered as under - prediction , and a prediction > 110% of measured rmr was considered as over - prediction . \n group level accuracy was considered as the mean percentage difference ( bias ) between measured and predicted rmr . \n the root mean squared prediction error ( rmse ) was used to indicate how well the model predicted in our data set ( 12 ) . \n bland - altman analysis was used to determine the extent of error for predictive equations compared to measure rmr ( 27 , 28 ) . \n in this cross - sectional study conducted in 2013 , 104 volunteer female students were recruited from tabriz universities via flyers and announcements . \n inclusion criteria were included : being apparently healthy had no chronic disease ( e.g. cancer , type 2 diabetes , etc . ) , age range of 1830 years old and had bmi<18.5 kg / m . \n exclusion criteria were included : pregnancy , lactation , being athlete and current using of medications known to affect rmr ( e.g. diuretics , corticosteroids , anti - psychotic and thyroid drugs ) . \n the protocol of this study was approved by the ethics committee of tabriz university of medical sciences and . before study \n weight was measured to the nearest 0.1 kg using the in - built bia as a weight scale ; participants were weighed in light clothing without shoes . \n height was measured to the nearest 0.1 cm using a wall - mounted stadiometer while subjects were standing without shoes with shoulders in a standard position . \n body mass index ( bmi ) was calculated as the weight in kilograms divided by the height in square meters ( kg / m ) . \n waist circumference was measured between the inferior margin of the last rib and the iliac crest . \n the greatest circumference of hip was considered as the hip circumference and the waist to hip ratio ( whr ) was calculated . \n this method is widely used because it is relatively cheap , quick , and non - invasive and requires limited operator training ( 24 ) . \n tanita bc-418 ma eight electrode , hand to foot system ( tanita co. , tokyo , japan ) was used for measurements of impedance ( 1 ) , estimation of body fat ( 0.1% ) , fm ( 0.1 kg ) and ffm ( 0.1 kg ) , at a frequency of 50 khz . \n the subjects age , gender , and height of each subject were entered in to the machine , and a standard 2 kg was entered as an adjustment for clothing weight in all participants . \n subjects were then asked to stand barefoot on the metal foot - plates of the machine while holding the handles for 30 sec . \n the fitmate was developed by cosmed ( roma , italy ) is a new portable metabolic analyzer designed to measure oxygen consumption and resting metabolic rate . \n this instrument uses a turbine flow meter that is located at the end of a disposable face mask for measuring minute volume and galvanic full cell oxygen sensor for analyzing the feo2 . using a fixed rq ( respiratory quotient ) of 0.85 , calculation of rmr is allowed . in a previous study , fitmate gave reproducible and accurate oxygen consumption and rmr measurements when compared to the douglas bag method and no significant differences were reported between two techniques for oxygen consumption and rmr in a wide range of bmi ( 25 ) . in this study \n , participants underwent to evaluation between 8:00 to 10 am in the morning after 1012 h fasting and were advised to avoid strenuous exercise from 24h before rmr measurement and refrain from caffeinated beverages and medications . \n subjects sat quietly for 20 minutes prior to rmr measurement , then they were asked to put fitmate mask on their nose and mouth at sitting and supine position in a quiet room with temperature around 25 c . using the fit mate metabolic system for 15 minutes , the resting energy expenditure was measured . \n calibration was done automatically for every measurement ( 25 ) for each subject , rmr was estimated using the selected equations , as listed in table 1 and compared to measure rmr . \n equations used to predict resting metabolic rate ( kcal / day ) weight based formula . weight and height based formula \n paired t - test was used to evaluate the difference between the measured rmr values and those estimated by predictive equations . \n accuracy of predictive formulas at the individual level was defined as percentage of the subjects who s predicted rmr was within 10% of measured rmr ( 12 , 26 ) . a prediction \n < 90% of measured rmr was considered as under - prediction , and a prediction > 110% of measured rmr was considered as over - prediction . \n group level accuracy was considered as the mean percentage difference ( bias ) between measured and predicted rmr . \n the root mean squared prediction error ( rmse ) was used to indicate how well the model predicted in our data set ( 12 ) . \n bland - altman analysis was used to determine the extent of error for predictive equations compared to measure rmr ( 27 , 28 ) . \n all subjects were between 18 and 30 years old . the mean body mass index ( bmi ) was 17.31.3 kg / m ( 13.419.2 ) . \n comparison of measured rmr with predicted rmr are presented in table 3 , the mean measured rmr derived from the fitmate was 1084.7175 kcal / day ( 7361490 ) . \n there were no significant differences between measured rmr and rmr calculated by muller and abbreviation equations . \n baseline characteristics of underweight female subjects ( n=104 ) whr , waist to hip ratio rmr , resting metabolic rate comparison of measured rmr with predicted rmr in underweight females weight based formula/ weight and height based formula p values are obtained by paired t - test analysis . \n bland - altman plots displaying bias and agreement of 3 selected predicted equations are presented in fig . \n the lowest mean difference between measured rmr and estimated rmr was found in the muller prediction equation with mean difference of 2.8 kcal / day and the 95% limits of agreement from 316.9 to 322.5 kcal / day . \n dashed lines indicate the limit of agreement compared to measured rmr values , the abbreviation and muller equations slightly under - predicted rmr , while other equations significantly over - predicted it . \n table 4 shows the accuracy rates , percentage bias and the rmse values ( in kcal / d ) of different predicted equations in studied subjects . as indicated in table 4 , the range of accuracy varied between equations from 23.1% to 54.8% . the percentage bias for equations varied from 0.63% to 24.6% , and the rmse varied from 162 to 278 kcal / d . among ten equations , \n the highest accuracy rate was produced by the muller equation , with 54.8% accurate prediction ( 22.1% under - prediction and 23.1% over prediction ) and a small percentage bias of 1.8% and rmse of 162 kcal / d . \n the lowest percentage bias was found in the abbreviation equation ( 0.63 ) ; however the accuracy rate was 43.3% and rmse was 173 kcal / d . \n the owen equation provided 47.1% accurate prediction ( with 16.3% under - prediction and 36.5% over - prediction ) , with a bias of 6.8% and rmse of 171 kcal / d . \n the accuracy rates of rmr predicted by different equations in underweight female subjects ( n=104 ) weight and height based formula the percentage of subjects predicted by this predictive equation within 10% of the measured value . the percentage of subjects predicted by this predictive equation within < 10% of the measured value . \n the percentage of subjects predicted by this predictive equation within > 10% of the measured value . mean percentage error between predictive equation and measured value . \n the largest under - prediction that was found with this predictive equation as a percentage of the measured value . \n the largest over - prediction that was found with this predictive equation as a percentage of the measured value . \n the commonly used predictive equations were not appropriate for underweight subjects and created a new predictive equation for this specific population ( 17 ) . in this study , we evaluated accuracy of muller and different previously developed rmr predictive equations against measured rmr in 104 iranian healthy underweight female students . \n we found that among 10 rmr predictive equations that were used in this study , muller et al . \n equation gave a fairly acceptable rmr prediction , while most of the commonly used rmr predictive equations did not accurately predict rmr at both group and individual levels . \n our data also showed that all of the equations except muller and abbreviation equations significantly overestimated rmr in underweight young females , with mean differences ranging from 42.2 to 224kcal / day . \n overestimations may be due to : first , it has been reported that energy requirements of people from developing countries are low and using standard equations might lead to greater bias and overestimation of energy requirements ( 29 ) . \n second , in underweight people adaptation to under - eating and underweight may result in hypometabolic status ( 30 ) . \n third , underweight subjects such as anorexia nervosa patients who are considered to be physically healthy , seem to be characterized by elevated rq larger than 0.8 . \n since fitmate calculates rmr from oxygen consumption using a fixed rq of 0.85 , if rq is between 0.85 and 1 , underestimation is possible ( 3133 ) . since who equations have been derived from researches in subjects with a wide range of bmi , \n however in our study there were significant differences in rmr predicted by who equations and measured rmr with accuracy rates of 35.6% for weight - base and 25% for weight - based and height - base equations . since who equations have been developed from research in europeans and considering the impact of ethnicity on rmr , the who equations may not be appropriate for asians , especially for iranian underweight females . \n in addition , who weight - base predictive equation overestimates rmr at low body mass index ( 10 ) . \n it was reputed that owen equation can be used for all weight group classifications ( 18 ) . in this study , in spite of 47.1% accuracy rate , owen equation had statistically significant difference with those measured by indirect calorimetry in group means . \n although , owen equation was developed from a sample of 44 women aged 18 to 65 years old , only one of them was underweight . \n therefore , it appears that the owen equation is not suitable for prediction of rmr in underweight individuals . \n these discrepancies could be due in part to the differences in the body composition and physical activity level between subjects in the previous and current studies ( 34 ) . \n it has been reported that the fat free mass play an important role in rmr value ( 7 , 9 ) and the physical activity training also can influence rmr by increasing lean tissue mass and influencing residual metabolism rate ( 35 ) . \n furthermore , most of the equations have been developed from researches in western caucasian people ; it is likely that a greater proportion of body weight in western women is made up of muscle and viscera with higher energy expenditure , as compared to their asian counterparts ( 34 , 36 ) . \n harris - benedict and who equations overestimated the rmr in asian women ( 22 ) . \n they indicated that measured rmr was significantly lower than predictive rmr using harris - benedict and who equations by 8.5% ( p<.001 ) and 5.4% ( p<.01 ) , respectively ( 22 ) . \n the differences between measured and predicted rmr values may be partially explained by methodological problems . \n since there are no reference databases for methodological approaches , the accuracy of studies can be affected by the different criteria of measurements such as measurement condition , time and etc . \n . limitations of this study include : first , the research was restricted to women with narrow age range ( 1830 years old ) . \n secondly , the absence of control group which would have helped to clarify potential bmi differences . \n thirdly , we measured each subject only once thereby we could not estimate the intra - individual variation in rmr . \n however , for better management of nutritional plans in this specific range of bmi , further studies are needed to develop and validate more suitable new equations . \n ethical issues ( including plagiarism , informed consent , misconduct , data fabrication and/or falsification , double publication and/or submission , redundancy , etc . ) have been completely observed by the authors .", "role": "user" }, { "content": "background : underweight as a public health problem in young women is associated with nutritional deficiencies , menstrual irregularity , eating disorders , reduced fertility , etc . since resting metabolic rate ( rmr ) \n is a necessary component in the development of nutrition support therapy , therefore we determined the accuracy of commonly used predictive equations against rmr measured by indirect calorimetry among healthy young underweight females.methods:this cross - sectional study was conducted on 104 underweight females aged 1830 years old with body mass index ( bmi ) < 18.5 kg / m2 in 2013 . after collecting anthropometric data , body composition was measured by bioelectric impedance analysis ( bia ) . \n rmr was measured by using indirect calorimetry ( fitmate ) and was estimated by 10 commonly used predictive equations . \n comparisons were conducted using paired t - test . \n the accuracy of the rmr equations was evaluated on the basis of the percentage of subjects predicted rmr within 10% of measured rmr.results:the mean bmi of subjects was 17.31.3 kg / m2 . \n the measured rmr ranged 7361490 kcal / day ( mean 1084.7175 kcal / day ) . \n findings indicated that except muller and abbreviation , other equations significantly over estimated rmr , compared to measured value ( p<0.05 ) . \n as an individual prediction accuracy , these predictive equations showed poor performance with the highest accuracy rate of 54.8% for muller equation ( 22.1% under and 23.1% over - prediction ) and 43.3% for abbreviation equation ( 31.7% under and 25% over - prediction ) , the percentage bias was 1.8% and 0.63% and rmse was 162 and 173 kcal / d , respectively.conclusion:although muller equation gave fairly acceptable prediction , more suitable new equations are needed to be developed to help better management of nutritional plans in young underweight people .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: adrenoleukodystrophy ( x - linked ald ) is a disorder of peroxisomal fatty acid beta - oxidation , and this brings about the accumulation of very - long chain fatty acids ( vlcfa ) in tissues throughout the body . \n nearly one - third will present with the childhood cerebral form of the disease , between ages 4 and 10 . \n anaesthetic management of children with x - linked ald has been previously reported . in view of the rarity of these cases , anaesthetic management of these patients \n this is probably the first reported case in the literature of an x - linked ald child who received total intravenous anaesthesia ( tiva ) and discuss the anaesthetic implications to ensure the best possible result for these patients . \n our patient was a 9-year - old indian male with x - linked cerebral ald who required general anaesthesia for a permanent catheter insertion via left internal jugular vein for plasmapheresis . \n the patient was diagnosed in june 2011 at 6 years of age when he presented with partial seizures . \n he underwent an unrelated donor umbilical cord blood transplant ( minor b->o incompatibility ) and maintained stable donor chimerism . \n post - operative recovery was uneventful and he led a relatively normal seizure free life . \n investigations determined that he was suffering from severe autoimmune haemolytic anaemia , liver dysfunction and steroid related side effects . \n physical examination revealed a 46 kg male with pallor , yellow sclera and cushingoid facies . \n his pre - operative investigations showed a haemoglobin concentration of 3 g / dl , which eventually improved to 6.9 g / dl after several cycles of plasmapheresis and blood transfusion , and a raised total bilirubin of 97 mol / l . \n the patient was tilted 30 degrees head - up , pre - oxygenated and cricoid pressure was applied . \n however , ventilation could not be achieved , and decision was made to release cricoid pressure . \n anaesthesia was induced with a target propofol concentration of 4 g / ml and remifentanil infusion rate of 4 ng / ml . muscle relaxation was provided with rocuronium 0.7 mg / kg . \n maintenance of anaesthesia was achieved with a target propofol concentration of 2.5 g / ml and remifentanil infusion rate of 3 ng / ml . post - operative analgesia was obtained with 10 ml of lignocaine 1% infiltrated over the surgical site . following the procedure that lasted 105 minutes , \n after the patient demonstrated airway protective reflexes , spontaneous eye opening and a regular respiratory pattern , the trachea was extubated . \n the myelin in the central nervous system , the adrenal cortex and the leydig cells in the testes are generally the main tissues involved . \n the anaesthesiologist must consider several factors in his management including mental retardation , seizure disorder , hypotonia , liver dysfunction , gastro - oesophageal reflux and abnormal adrenocortical function . \n proper drug history is crucial as our patient is on an immunosuppressive regime and chronic steroid replacement , which may affect his ability to compensate for the stress of surgery . \n anaesthetic drug dosages may need correction due to hepatic enzyme adjustment secondary to his anti - convulsant therapy . \n mental retardation can be presented in the form of a difficult and uncooperative patient , especially in a child . \n pre - operative sedation should be avoided because of the risk of worsening airway obstruction due to hypotonic pharyngeal muscles . \n post - operatively , the patient may be observed for longer period in the recovery room because airway obstruction may be worsened by residual anaesthesia or traumatic oedema . \n anti - convulsants are continued up to the day of surgery , and potentially epileptogenic anaesthetic agents such as ketamine or enflurane are avoided . \n administration of a histamine-2 antagonist and rapid sequence induction with cricoid pressure are recommended . in our case , \n the patient was intubated using a rapid onset muscle relaxant without cricoid pressure but with a head up position of 30 degrees . \n there was no visualization of gastric contents on direct laryngoscopy later or clinical evidence of aspiration . \n the present patient was on chronic steroid therapy and confined to a wheelchair , thus was susceptible to bone mineral density loss and iatrogenic fracture during transfer . \n induction agents previously used were thiopentone , propofol and sevoflurane while anaesthesia was maintained with isoflurane , and sevoflurane . \n commercial propofol is formulated in 10% soybean oil emulsion and does not contain very long chain fatty acid ( vlcfa ) . \n unlike thiopetone , propofol does not worsen the patient 's deranged liver function tests and still provide rapid recovery . \n propofol may cause epileptiform movements , but the latest studies have indicated no real evidence of epilepsy on electroencephalography . \n we did not contemplate use of etomidate as an induction agent although our patient was on chronic steroid replacement and peri - operative steroids were administered . \n this is because we preferred to minimize the number of drugs used , and a different agent would have been necessary for the maintenance of anaesthesia . \n remifentanil was selected for its rapid onset and short half - life , which is unaffected by the duration of infusion . \n although no studies have evaluated the effects of opioids in these patients , they may have an exaggerated sensitivity to the respiratory depressant effects of these drugs and should be avoided . \n we used the non - depolarizing agent rocuronium , at a dose of 0.7 mg / kg to 1 mg / kg , due to its rapid onset of action inspite of its longer duration of action . \n however , the risk of hyperkalaemia in these patients is unknown with one report of hyperkalaemia after succinylcholine was used in a patient with multiple sclerosis . \n the other option of intubation with a remifentanil bolus was dismissed , as this will not improve the grade of intubation . \n moreover , studies have reported an increased incidence of difficult intubation when neuromuscular blocking agents were avoided . although inhalational anaesthesia has been the basis of paediatric anaesthesia for many years , we believe that tiva is expanding its role in paediatrics with new advances in technology . \n one of the benefits of tiva is the enhanced quality of emergence from anaesthesia . in our case \n , we also wanted to ensure a smooth , peaceful recovery for the child and subsequently a less traumatic experience for the parents . \n it is a known fact that post - operative agitation is common in preschool children after inhalational anaesthesia and can cause a lot of distress to both the patient and the parents . \n inhalational agents which are the main culprits are avoided and furthermore , propofol itself has anti - emetic properties . \n vomiting frequently ensues in children older than 2 or 3 years and can be a source of great agony as well as misery for them . in our patient who has a higher risk of gastro - oesophageal reflux and pulmonary aspiration \n lastly , we believe that the intravenous agents used in tiva would ensure the safest outcome for the patient based on the reasons discussed above . it is essential to tailor our anaesthesia management to our patient , and in our case , we deem that tiva with propofol and remifentanil to be advantageous over the other anaesthetic methods . \n in summary , the optimal anaesthetic management for these patients has yet to be established . \n we have described the successful management of a child with x - linked adrenoleukodystrophy with use of total intravenous anaesthesia using propofol and remifentanil with a favourable outcome .", "role": "user" }, { "content": "we present a 9-year - old boy with x - linked cerebral adrenoleukodystrophy ( x - linked ald ) and previous umbilical cord transplant who required general anaesthesia . \n an anaesthetic plan for each individual should be tailored to ensure the best possible anaesthetic care for these patients . \n the anaesthetic considerations include mental retardation , seizure disorder , hypotonia , liver function abnormalities , gastro - oesophageal reflux , impaired adrenocortical function and immunosuppression . \n pre - operative sedation should be avoided because of hypotonia of the pharyngeal muscles . \n anti - convulsants are continued , and potentially epileptogenic anaesthetic agents are avoided . \n the patient was intubated using a modified rapid sequence induction with a head up position of 30 degrees . \n four other cases have been reported in literature . \n nevertheless , there is still no established anaesthetic management for these patients , and total intravenous anaesthesia can be considered as a safe and alternative method of anaesthesia . to the best of our knowledge , \n this is the first reported use of total intravenous anaesthesia with propofol and remifentanil in a case of cerebral adrenoleukodystrophy , and with a favourable outcome .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: \n 2 dry pelvic bones and 1 sacrum from same cadaver was reconstructed to be the pelvic ring . \n 10 , 20 and 30 mm vertical displacement of right pelvic bone was performed at levels of sacroiliac joint and pubic symphysis for representing right vprd . \n then , the pelvis was set sacral inclination at 60 from x - ray table for outlet and anteroposterior pelvic radiographs . \n right vprd was measured by referring to superior most pelvic articular surface of both sacroiliac joints and sacral long axis . \n radiographic vprd and actual displacement were analyzed by pearson correlation coefficient at more than 0.90 for the strong correlation and strongly significant simple regression analysis was set at p < 0.01 . \n radiographic vprd from outlet and anteroposterior pelvic views at 10 mm actual displacement were 20.12 1.98 and 4.08 3.76 mm , at 20 mm were 40.31 1.97 and 9.94 7.27 mm and at 30 mm were 58.56 2.53 and 11.29 2.89 mm . \n statistical analyses showed that radiographic vprd from pelvic outlet view is 1.95 times of actual displacement with strong correlation at 0.992 coefficient and strongly significant regression analysis ( p < 0.001 ) with 0.984 of r value . whereas , the measurement from anteroposterior pelvic radiograph was not strongly significant . \n \n vertical pelvic bone displacement creates unstable pelvic ring injury that is a serious trauma and life - threatening.123 pelvic radiographs include anteroposterior , inlet and outlet views are routinely taken in order to measure pelvic displacement for considering proper management.34 hence , measurement of vertical displacement of the pelvic ring injury from pelvic radiographs were studied . \n five cadaveric dry bones of normal complete pelvic ring comprising 2 pelvic bones and 1 sacrum from the same cadaver were enrolled . \n the specimens were obtained from three males and two females , age ranged from 25 to 75 years old , no history of pelvic fracture , hip arthroplasty and metabolic bone diseases . both pelvic bones and 1 sacrum were anatomically reconstructed to be a pelvic ring . left pelvic bone \n was anatomically joined to sacrum in order to construct left sacroiliac joint by fixing pelvic and sacral articular surfaces of sacroiliac joint with two surface adhesive tape and secured the stability of the sacroiliac joint by plastic tape between left first sacral foramen and iliac wing . \n 10 , 20 , and 30 mm vertical displacement of right pelvic bone along the sacroiliac joint were performed in order to represent vertical displacement of right pelvic ring injury . \n then , middle of superior aspect of right sacroiliac joint was marked at pelvic and sacral sites at a and b respectively [ figure 1 , left ] . \n after that right pelvic bone was removed and viewed pelvic articular surface of right sacroiliac joint . \n ac line was drawn from a along the articular surface perpendicularly to superior articular surface of sacroiliac joint at a and ended at inferior articular surface at c. 10 , 20 , and 30 mm were marked on the ac line for sequentially performing vertical displacement of right pelvic bone by referring to the marker b at sacral site of sacroiliac joint b [ figure 1 , middle and right ] . \n the vertical displacement of right pelvic bone without pelvic anterior or posterior rotation was controlled by the same distance of displacement of pubic symphysis . during the displacement , width of the pubic symphysis \n the displacement of right pelvic bone was fixed by plastic tape between right and left obturator foramens for stabilizing pubic symphysis and two surface adhesive tape between articular surfaces of right sacroiliac joint as well as augmented by plastic tape between right first sacral foramen and iliac wing for stabilizing the sacroiliac joint [ figure 1 ] . for inlet pelvic radiograph , \n therefore , the inlet pelvic radiograph can not be used for assessing vertical displacement of the pelvic ring . \n the specimen was laid on 3 cm thickness foam board and adjusted anterior surface of first and second sacrum inclination to be 60 from x - ray table as normal sacral inclination of the patient laid on the x - ray table.5 outlet and anteroposterior pelvic radiographs were taken . \n x - ray tube was 40 inches from the specimen and 45 cephalad for the pelvic outlet view and 90 x - ray tube for anteroposterior pelvic view . using picture archiving and communication system and measurement tools , vertical displacement of right pelvic bone in millimeter was measured . long axis of sacrum was drawn referring to sacral spinous processes ( xy ) . \n superior most pelvic articular surface of right and left sacroiliac joints were identified and marked at d and e respectively . \n df and eg lines were drawn from d and e perpendicularly to xy at f and g. gf distance was measured as radiographic vertical displacement of right pelvic bone [ figure 2 ] . the data with more than 0.80 inter and intra - observer reliability were used for statistical analysis . correlation between radiographic and actual vertical displacement of the pelvic bone were analyzed by pearson correlation coefficient and considered more than 0.90 as strong correlation . \n the data was further analyzed by simple regression analysis and considered as strongly significant alpha level at p < 0.01 . \n the pelvic ring was anatomically reconstructed by using 2 pelvic bones and 1 sacrum from the same cadaver . \n middle superior right sacroiliac joint was marked at pelvic and sacral sites at a and b respectively ( left figure ) . \n ac line was drawn from a along pelvic articular surface of sacroiliac joint perpendicularly to superior aspect of sacroiliac joint and ended at inferior articular surface at c. 10 , 20 , and 30 mm were marked along ac line ( middle figure ) . \n 20 mm of vertical right pelvic bone displacement was performed for representing vertical displacement of pelvic ring injury ( right figure ) radiographic vertical displacement of right pelvic bone was measured from pelvic outlet view by using superior pelvic articular surface of both sacroiliac joints and long sacral axis as references \n radiographic vertical right pelvic bone displacement from the outlet and anteroposterior pelvic views at 10 mm actual vertical displacement of the pelvic bone were 20.12 1.98 ( 95% confidence interval [ ci ] : 17.66 , 22.59 ) and 4.08 3.76 ( 95% ci : 0 , 8.75 ) mm , at 20 mm were 40.31 1.97 ( 95% ci : 37.87 , 42.76 ) , 9.94 7.27 ( 95% ci : 0.92 , 18.97 ) mm and at 30 mm were 58.56 2.53 ( 95% ci : 55.41 , 61.70 ) , 11.29 2.89 ( 95% ci : 7.71 , 14.88 ) mm respectively . \n inter and intra observer reliability of the measurements from pelvic outlet radiograph was 0.86 and from anteroposterior pelvic radiograph was 0.82 . \n the statistical analysis of radiographic vertical displacement of the pelvic bone from pelvic outlet view and actual displacement showed a strong correlation with 0.992 of pearson correlation coefficient and simple regression analysis was also strongly significant ( p < 0.001 ) . \n in addition , simple regression equation showed that radiographic vertical displacement of the pelvic bone from pelvic outlet view was 1.95 times of actual displacement with 0.984 of r value [ table 1 and figure 3 ] . \n whereas , analysis of measurement of vertical displacement of the pelvic bone from anteroposterior pelvic radiograph and actual displacement showed no strong correlation with 0.539 of the correlation coefficient as well as no strongly significant simple regression analysis ( p = 0.038 ) . \n moreover , r value for simple regression equation is only 0.290 [ table 1 ] . \n regression analysis graph showing relationship between radiographic vertical pelvic bone displacement from outlet pelvic view and actual displacement was about 2 times data of radiographic and actual vertical pelvic bone displacements , correlation and simple regression analysis \n vertical displacement of pelvic ring injury is a serious condition.12 the injury occurs as dislocation or fracture dislocation of sacroiliac joint and pubic symphysis.34 the injury creates unstable pelvic ring.123467 pelvic radiographs provide information about pelvic displacement in term of widening pelvic symphysis and vertical displacement of pelvic ring injury . \n however , the study showed the measurement of vertical displacement of pelvic bone from anteroposterior pelvic radiograph was inconsistent and did not strongly correlate to the actual displacement ( r showed low value ) . whereas , the measurement of vertical pelvic bone displacement from pelvic outlet radiograph showed strongly significant and consistent correlation about 2 times of actual displacement with high r value . \n this might be the result of different degrees of x - ray beam related to pelvic position between the outlet and anteroposterior pelvic radiographs . \n vertical displacement of the pelvic bone in the study was performed along the plane of sacroiliac joint . \n the displacement of the pelvic bone at level of sacroiliac joint was equal to displacement of pubic symphysis . \n this resulted the measurement of vertical displacement of pelvic bone with neither anterior nor posterior rotation of the pelvic ring . \n moreover , the pelvic inclination was set 60 at anterior surface of first and second sacrum . \n this represented pelvic inclination of lying patient.5 in the study , vertical displacement of the pelvic bone was measured by using superior most of pelvic articular surface of both sacroiliac joints and long axis of the sacrum as references . \n both radiographic references were clearly viewed and identified especially in pelvic outlet radiograph . moreover , the measurement of vertical pelvic bone displacement was directly performed at sacroiliac joint in term of upward displacement of articular surfaces . \n this measurement technique of vertical displacement of pelvic ring injury can be performed although the pelvic ring injury associated with fracture of ala sacrum . in conclusion , the results of study showed that pelvic outlet radiograph provides efficient measurement of vertical displacement of pelvic bone with 2 times of actual displacement . \n hence , we recommended that vertical displacement of pelvic ring injury in term of pelvic bone displacement should be measured by using pelvic outlet radiograph and consider a half of the measurement as actual displacement of the pelvic ring injury .", "role": "user" }, { "content": "background : vertical pelvic ring displacement ( vprd ) is a serious injury and needs assessment . \n pelvic outlet radiographs are routinely taken . however \n , relationship of radiographic and actual vprd is still in question . \n thus , measurement of vprd from pelvic radiographs was studied.materials and methods:2 dry pelvic bones and 1 sacrum from same cadaver was reconstructed to be the pelvic ring . \n five specimens were enrolled . \n 10 , 20 and 30 mm vertical displacement of right pelvic bone was performed at levels of sacroiliac joint and pubic symphysis for representing right vprd . \n then , the pelvis was set sacral inclination at 60 from x - ray table for outlet and anteroposterior pelvic radiographs . \n right vprd was measured by referring to superior most pelvic articular surface of both sacroiliac joints and sacral long axis . \n radiographic vprd and actual displacement were analyzed by pearson correlation coefficient at more than 0.90 for the strong correlation and strongly significant simple regression analysis was set at p < 0.01.results:radiographic vprd from outlet and anteroposterior pelvic views at 10 mm actual displacement were 20.12 1.98 and 4.08 3.76 mm , at 20 mm were 40.31 1.97 and 9.94 7.27 mm and at 30 mm were 58.56 2.53 and 11.29 2.89 mm . \n statistical analyses showed that radiographic vprd from pelvic outlet view is 1.95 times of actual displacement with strong correlation at 0.992 coefficient and strongly significant regression analysis ( p < 0.001 ) with 0.984 of r2 value . \n whereas , the measurement from anteroposterior pelvic radiograph was not strongly significant.conclusion:pelvic outlet radiograph provides efficient measurement of vprd with 2 times of actual displacement .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: despite the increasingly large number of antidepressants available to treat depressive disorders , patients continue to experience relatively modest response and remission rates.1,2 in addition , patients treated with antidepressants may experience adverse side effects that not only hinder compliance and adherence to treatment but also , in some cases , may contribute to increasing disability , patient suffering , and morbidity.3 this evidence has recently prompted clinicians to become interested in nonpharmaceutical - grade supplements to counteract depression symptoms.4 from a strategic point of view , these supplements could be used mainly as a complementary therapy in order to enhance the efficacy of standard antidepressants without further worsening their tolerability or as initial monotherapy in those patients with moderate symptoms of disease . \n one of the supplements that has been more exhaustively and deeply studied is s - adenosyl - l - methionine ( same ) , a naturally occurring methyl group donor present in the human body.5 many controlled trials , some of them also double - blinded , have found same to be more effective than placebo and comparable with tricyclic antidepressants to treat depressive states.6 this seems to be particularly evident when same is administered either intravenously or intramuscularly . \n although some trials also demonstrated its efficacy following oral administration , this seems to be true only when same is administered in high doses.7 one could argue that some doubts still remain about its safety , at least in terms of the possible production of toxic methylated compounds like homocysteine , s - adenosylhomocysteine , methanol , formaldehyde , and formic acid.8 in consideration of this , a number of same - based supplements have recently been formulated with the addition of such active ingredients as folate and/or vitamin b6 and/or vitamin b12 all of which are known to be able to enter the homocysteine circuit to possibly avoid the risk of creating dangerous toxic methylated compounds and to be strictly linked to support same synthesis.9 betaine , like folate , vitamin b6 , and vitamin b12 , is an active ingredient involved as a cofactor in the homocysteine circuit , and is known to be able to reduce plasma homocysteine levels when administered orally.10 betaine is also known to generate a sparing effect for same and increase its plasma levels ; for example , when used in alzheimer s disease.11 on this basis , we have recently tested , as add - on therapy , the association of same and betaine in improving the antidepressant effect of enteric - coated same in patients with mild / moderate depression . \n results of this clinical trial , currently under new investigation on a larger number of patients , have shown that both treatments act similarly in improving symptoms such as anxiety , psychomotor agitation , feelings of helplessness and worthlessness , physical efficiency , and somatization . since the association of same plus betaine determined better statistically significant results following 90-day therapy,12 we decided to evaluate its efficacy and tolerability as monotherapy by comparing it with amitriptyline , chosen as a control substance due to its wide use in depression , in a 12-month pilot , open - label , randomized , observational trial in individuals with a recent diagnosis of mild depression . \n this 12-month , open - label , randomized , observational , controlled trial was conducted in the setting of routine practice , in accordance with the principles stated in the declaration of helsinki and consistent with good clinical practice , as defined by the international conference on harmonization and in accordance with the ethical principles underlying european union directive 2001/20/ec and the united states code of federal regulations , title 21 , part 50 ( 21cfr50).13 the protocol , individuals consent , and privacy forms were approved by the local review board . \n all the patients provided their written informed consent to participate in this study after a full explanation of the study had been given . \n the study was conducted in a single outpatients clinic in italy ( bari ) between february 2012 and september 2013 on 64 patients enrolled on the basis of a diagnosis of moderate depression as evaluated according to the zung self - rating depression scale.14 sixty patients completed the study and were evaluated from a statistical point of view . \n inclusion criteria were age between 18 and 75 years ; participants signing of the informed consent ; zung self - rating depression scale score between 30 and 60 ; and use , if needed , of antihypertensive drugs , cardiovascular aspirin , ticlopidine , warfarin , anti - inflammatory drugs , analgesics , antipyretics , antibiotics , and antifungal drugs . \n exclusion criteria were age below 18 or over 75 years ; failure to sign the informed consent ; being treated with any antidepressant drugs in the last 12 months ; zung self - rating depression scale score over 60 ; suicidal ideation ; neurological disease ; epilepsy ; pregnancy ; breastfeeding ; and diagnosis of liver cirrhosis , severe heart failure , hepatic , and/or renal impairment . \n all the individuals started taking either amitriptyline or same plus betaine for the whole length of the study ( 12 months ) . \n zung self - rating depression scale measurements were taken at t=0 ( enrollment ) and after 3 , 6 , and 12 months . for a further evaluation of treatment tolerability \n patients also had the possibility of contact with clinicians at any time by phone . before starting the study \n , all patients underwent an initial screening assessment that included medical history , physical examination , vital sign measurement ( blood pressure and heart rate ) , a 12-lead electrocardiogram ( ecg ) , aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) blood analysis , and evaluation of body weight . at the end of the study , or at drop - off \n , all the enrolled subjects again underwent blood pressure and heart rate examinations , ecg , ast and alt blood analysis , and measurement of body weight . \n the patients were treated with 75 mg / day ( 25 mg three times a day at 8 am , 2 pm , and 10 pm ) of amitriptyline formulated as tablets ( laroxyl ; teofarma , valle salimbene , italy ) or with an enteric - coated supplement ( ddm metile ; omeopiacenza , piacenza , italy ) containing 250 mg same per tablet ( gnosis , desio , italy ) plus 125 mg of betaine ( procemsa , nichelino , italy ) . \n ddm metile was administered twice a day at 8 am and 8 pm on an empty stomach . \n laroxyl is a nonreimbursable drug ( c - type ) with the following marketing authorization number : 019906015 . \n ddm metile ; in agreement with italian law , was registered as a food supplement with the ministry of health in 2010 ( registration number : 52171 ) . both active ingredients ( same and betaine ) of ddm metile \n are accepted ingredients , as far as quality and quantity are concerned , for nutraceutical formulas ; all excipients used to formulate ddm metile are also food - grade ingredients . \n the primary efficacy end points of the study were assessed through the scores resulting from the zung depression self - rating scale . \n the secondary end points included the occurrence of side effects , tolerability , and compliance . \n tolerability and compliance were scored as very poor , poor , fairly good , good , or excellent . \n primary and secondary end points were evaluated at 3 , 6 , and 12 months after enrolling . \n the individuals could contact the physicians in charge of the study at any time if needed . to check individuals \n adherence to therapy , each patient had to report the number of tablets used per day , giving back the empty boxes of the drugs as soon as tablets were finished . \n the wilcoxon signed - rank test was used to analyze any differences from baseline scores in the same treatment group . the mann \n whitney u test and fisher exact test were used to analyze any score differences between the two groups . \n this 12-month , open - label , randomized , observational , controlled trial was conducted in the setting of routine practice , in accordance with the principles stated in the declaration of helsinki and consistent with good clinical practice , as defined by the international conference on harmonization and in accordance with the ethical principles underlying european union directive 2001/20/ec and the united states code of federal regulations , title 21 , part 50 ( 21cfr50).13 the protocol , individuals consent , and privacy forms were approved by the local review board . \n all the patients provided their written informed consent to participate in this study after a full explanation of the study had been given . \n the study was conducted in a single outpatients clinic in italy ( bari ) between february 2012 and september 2013 on 64 patients enrolled on the basis of a diagnosis of moderate depression as evaluated according to the zung self - rating depression scale.14 sixty patients completed the study and were evaluated from a statistical point of view . \n inclusion criteria were age between 18 and 75 years ; participants signing of the informed consent ; zung self - rating depression scale score between 30 and 60 ; and use , if needed , of antihypertensive drugs , cardiovascular aspirin , ticlopidine , warfarin , anti - inflammatory drugs , analgesics , antipyretics , antibiotics , and antifungal drugs . \n exclusion criteria were age below 18 or over 75 years ; failure to sign the informed consent ; being treated with any antidepressant drugs in the last 12 months ; zung self - rating depression scale score over 60 ; suicidal ideation ; neurological disease ; epilepsy ; pregnancy ; breastfeeding ; and diagnosis of liver cirrhosis , severe heart failure , hepatic , and/or renal impairment . \n the study scheme is presented in figure 1 . after enrolling and randomizing , all the individuals started taking either amitriptyline or same plus betaine for the whole length of the study ( 12 months ) . \n zung self - rating depression scale measurements were taken at t=0 ( enrollment ) and after 3 , 6 , and 12 months . for a further evaluation of treatment tolerability \n before starting the study , all patients underwent an initial screening assessment that included medical history , physical examination , vital sign measurement ( blood pressure and heart rate ) , a 12-lead electrocardiogram ( ecg ) , aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) blood analysis , and evaluation of body weight . at the end of the study , or at drop - off \n , all the enrolled subjects again underwent blood pressure and heart rate examinations , ecg , ast and alt blood analysis , and measurement of body weight . \n the patients were treated with 75 mg / day ( 25 mg three times a day at 8 am , 2 pm , and 10 pm ) of amitriptyline formulated as tablets ( laroxyl ; teofarma , valle salimbene , italy ) or with an enteric - coated supplement ( ddm metile ; omeopiacenza , piacenza , italy ) containing 250 mg same per tablet ( gnosis , desio , italy ) plus 125 mg of betaine ( procemsa , nichelino , italy ) . \n ddm metile was administered twice a day at 8 am and 8 pm on an empty stomach . \n laroxyl is a nonreimbursable drug ( c - type ) with the following marketing authorization number : 019906015 . \n ddm metile ; in agreement with italian law , was registered as a food supplement with the ministry of health in 2010 ( registration number : 52171 ) . both active ingredients ( same and betaine ) of ddm metile \n are accepted ingredients , as far as quality and quantity are concerned , for nutraceutical formulas ; all excipients used to formulate ddm metile are also food - grade ingredients . \n the primary efficacy end points of the study were assessed through the scores resulting from the zung depression self - rating scale . \n the secondary end points included the occurrence of side effects , tolerability , and compliance . \n tolerability and compliance were scored as very poor , poor , fairly good , good , or excellent . \n primary and secondary end points were evaluated at 3 , 6 , and 12 months after enrolling . \n the individuals could contact the physicians in charge of the study at any time if needed . to check individuals \n adherence to therapy , each patient had to report the number of tablets used per day , giving back the empty boxes of the drugs as soon as tablets were finished . \n the wilcoxon signed - rank test was used to analyze any differences from baseline scores in the same treatment group . the mann \n whitney u test and fisher exact test were used to analyze any score differences between the two groups . \n a total of 64 individuals with a diagnosis of mild depression according to the zung depression self - rating scale were enrolled in the trial . of these \n a total of 32 were randomized to receive amitriptyline and 32 were randomized to receive same plus betaine . \n the characteristics of the randomized groups are shown in table 1 , where no significant differences between the two groups are observable . \n on the basis of the scores calculated at t=0 and at t=3 months , the two groups do not show any statistically significant difference . at t=6 months and at t=12 months , \n both treatments demonstrate effectiveness . however , the statistical analysis performed to establish a direct comparison between the two treatments demonstrates better performance of the same / betaine therapy in comparison with the results obtained with amitriptyline ( table 2 ) . while the percentage of the score reduction was similar in both groups at t=3 months ( 4.4% and 6.7% ) , at t=6 months , and at t=12 months , the score reduction was about 22% and 17% for the amitriptyline group and about 34% and 37% for the same / betaine group . \n in addition , treatment with same plus betaine seems to determine more important results than amitriptyline in terms of the number of people considered depression free . respectively , at t=6 months and t=12 months , only four and one out of 30 patients treated with amitriptyline exhibited a global score below 30 , while the depression - free individuals of the same / betaine group were , at the same time , 15 and 19 out of 30 ( table 3 ) . as for tolerability ( table 4 ) , both treatments seem to be well tolerated , even if during the study two ( males ) individuals of the amitriptyline group did not complete the study because of side effects ( gastric pain and sexual disorders ) . \n also in the same / betaine group , two individuals ( a male and a female ) did not complete the study , but in this case the reason for their early withdrawal was protocol violation . in terms of compliance , the two treatments resulted to be overlapping ( table 5 ) . at the end of the study , or at time of drop - off , no significant difference versus t=0 was observed in terms of blood pressure heart rate examinations , ecg , ast , alt , and body weight ( data not shown ) . \n amitriptyline is a tricyclic antidepressant introduced in the 1960s for the treatment of major depressive disorders . to date \n , this is the only us - approved indication , although amitriptyline has already been used for a number of other symptoms , including migraine prophylaxis , neuropathic pain disorders and fibromyalgia , nocturnal enuresis , and irritable bowel syndrome . \n anti - inflammatory and antimicrobial properties of the drug have been reported as well.15 amitriptyline can not be considered excellent in terms of safety , and in a recent paper it was found to be the least safe among the treatments included in a study that assessed six antidepressants.16 nevertheless , amitriptyline is largely used to counteract depressive disorders . \n same is an endogenous molecule endowed with methyl donor properties and is involved in the pathway for synthesis of hormones , neurotransmitters , nucleic acids , proteins , and phospholipids . \n the antidepressant role played by same is mainly due to its role as intermediate in the synthesis of norepinephrine , dopamine , and serotonin . \n moreover , low same levels have been found in the cerebrospinal fluid of depressed individuals , and higher plasma same levels have been associated with improvement in depressive symptoms . on the other hand , because of the much debated topic of the possibility that it increases the plasma levels of methylated compounds such as homocysteine , same is also believed to be able to increase cardiovascular risk . \n co - administration of betaine a cofactor involved in reducing plasma homocysteine level should reduce such a risk and should be able to determine a sparing effect on endogenous same . \n due to these assumptions , administration of same plus betaine could be considered a possible and valid optional treatment in place of same alone . as described in \n , in a recent trial , our group has indeed observed a better clinical performance of the association of same plus betaine versus same alone , both as add - on therapy , in patients with mild / moderate depression.12 in the light of this finding , we decided to evaluate the antidepressant role played by the administration of same plus betaine as monotherapy in individuals with a recent diagnosis of mild depression , comparing its effectiveness and tolerability with amitriptyline . \n the results seem to demonstrate that same / betaine treatment is a valid therapeutic option that is more effective and safer than the control treatment with amitriptyline . \n the effectiveness seems to become statistically appreciable at t=6 months , lasting until the end of the trial ( t=12 months ) . in our experience , and according to literature , the treatment of depression with same in responsive individuals normally occurs quickly , even in a few weeks of treatment.17 unfortunately , we have no tools to understand the delay observed in our trial . \n it may be due to the type of enrolled individuals ( with a recent diagnosis of depression and never treated with antidepressant ) , to the same dose used ( for patients with zung self - rating depression scale score between 45 and 60 , the administered dose could be too low ) , or to the presence of betaine . \n enrolled patients were also taking other drugs ( see materials and methods ) . \n therefore , in the absence of multivariate analysis to determine whether taking other drugs might affect the results , the delay of activity seems to be difficult to interpret . in our trial , co - administration of same plus betaine did not determine important side effects , and in our opinion the association can be considered safe . \n limits of the trial are 1 ) , it not being double - blind and 2 ) , the low number of people involved . to overcome these two important possible biases \n , our group is trying to organize a larger double - blind , placebo - controlled study to confirm the antidepressant role of the association of same plus betaine versus antidepressant different from same . \n the study , by plasma analysis , will also provide us with an idea of the possible toxic methylated compounds that could be generated by the long - term administration of an same - based formula and whether the presence of betaine can effectively reduce them . \n on the basis of our study results , it may be assumed that the administration of same plus betaine is a valid and safe monotherapeutic option to treat individuals with a recent diagnosis of mild depression .", "role": "user" }, { "content": "backgrounds - adenosyl - l - methionine ( same ) , a safe , endogenous , pleiotropic methyl donor well known for its antidepressant role , has been assumed to have a possible role in increasing plasma levels of compounds known to be able to raise cardiovascular risk . \n although the issue is still being debated , betaine ( trimethylglycine ) , a specific methyl donor involved in the homocysteine circuit , may be able to reduce such a risk and/or , by determining a sparing effect on endogenous same , may be able to improve the clinical efficiency of same itself . indeed , preliminary results have shown clinical improvement determined by an add - on therapy with betaine administered along with same , versus same alone , to patients affected by mild / moderate depression.aimto evaluate the safety and antidepressant role played by the association of same plus betaine versus amitriptyline administered in untreated individuals with a recent diagnosis of mild depression.methodsthis small , open - label , randomized , observational study enrolled 64 individuals with a diagnosis of mild depression according to the zung self - rating depression scale . \n after randomization , they were treated with either laroxyl ( amitriptyline , 75 mg / day ) or ddm metile ( enteric - coated same , 500 mg / day , plus betaine , 250 mg / day ) for 12 months . \n assessment of clinical scores and tolerability was performed at t=0 and after 3 , 6 , and 12 months.resultsafter 3 months , both treatments showed a small and not statistically significant improvement . \n after 6 and 12 months , both treated groups demonstrated a more noticeable improved response , although the group treated with same plus betaine showed better results in terms of score , number of individuals in remission , and side effects . \n compliance was overlapping in both treatments.conclusionthe association of same plus betaine seems to be a safe and effective tool to counteract mild depression and also when used as monotherapy in subjects with a recent diagnosis .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the efficacy and safety of budesonide / formoterol administered via dry powder inhaler ( dpi ) are well established . \n however , pressurised metered - dose inhalers ( pmdis ) , the most commonly used inhalation devices in many countries worldwide , are currently being developed with hydrofluoroalkane ( hfa)-based propellants to avoid the well - known ozone - depleting effects of chlorofluorocarbon propellants . \n accordingly , budesonide / formoterol has also been reformulated as an hfa pmdi ( symbicort rapihaler ) . \n the present study demonstrates that budesonide / formoterol administered via the novel hfa pmdi is an effective and well - tolerated treatment for adults and adolescents , and is therapeutically equivalent to budesonide / formoterol delivered via a dpi . \n these data provide further understanding of the use of the different budesonide / formoterol devices , and ultimately , will help provide clinicians and patients with greater freedom to select a delivery system that meets their needs and preferences . \n inhaled corticosteroid ( ics)/long - acting bgr 2-agonist ( laba ) therapies are the recommended maintenance treatment option for adults with persistent asthma ( 1 ) . \n one such therapy is budesonide / formoterol in one dry - powder inhaler ( dpi ) ( symbicort turbuhaler , astrazeneca r&d , lund , sweden ) , a combination that has been shown in numerous trials to be an effective and well - tolerated treatment for asthma ( 27 ) \n . the pharmacological properties of budesonide / formoterol mean that this combination is suitable for use in different settings . \n the formoterol component is associated with a rapid onset of bronchodilatory effect , similar to that of standard , short - acting bgr 2-agonist ( saba ) reliever medications , such as salbutamol ( 8) , as well as an extended duration of action , which is comparable with that of salmeterol ( 9 ) . \n budesonide , on the other hand , has a prolonged dwell time in the airway tissues , resulting in a long duration of anti - inflammatory effect ( 1012 ) . \n these properties mean that budesonide / formoterol is effective when given once daily ( 2 ) and when used in the acute setting ( 13 ) . \n in addition , the nature of the dose response curves of both budesonide and formoterol ( 1416 ) means that temporarily increasing the dose of budesonide / formoterol in response to decreasing asthma control can provide patients with additional clinical benefits without increasing the risk of adverse systemic effects . as such , budesonide / \n formoterol is uniquely suitable for adjustable maintenance dosing ( 3 , 4 , 17 , 18 ) and for use as maintenance and reliever therapy [ symbicort maintenance and reliever therapy ( smart ) ] ( 57 , 19 ) . \n although the use of dpis , such as turbuhaler , is well established , pressurised metered - dose inhalers ( pmdis ) are the most commonly used inhalation devices in many countries worldwide ( 20 ) . \n the majority of available pmdi devices contain chlorofluorocarbon ( cfc ) propellants , which have well - documented adverse effects on the atmospheric ozone layer . over the past few years \n , research has led to the development and approval of hydrofluoroalkane ( hfa)-based aerosols which do not have ozone - depleting properties as alternatives to cfc propellants ( 21 ) . \n accordingly , budesonide / formoterol has also been reformulated as an hfa pmdi ( symbicort rapihaler ) to provide clinicians and patients with greater freedom to select a delivery system that meets their needs and preferences . \n the aim of this study was to compare the efficacy and safety of the new pmdi formulation of budesonide / formoterol with that of budesonide / formoterol dpi and budesonide ( pulmicort , astrazeneca r&d , lund , sweden ) pmdi in adults and adolescents with asthma . \n adult and adolescent outpatients ( aged 12 years ) with asthma ( 22 ) for 6 months , who were inadequately controlled on ics alone , were enrolled . for inclusion , patients had to have a forced expiratory volume in 1 s ( fev1 ) 50% and 90% of predicted normal ( prebronchodilator ) , reversibility of 12% fev1 after inhalation of terbutaline 1 mg ( bricanyl turbuhaler , astrazeneca ) and a history of daily ics use ( stable dose of 5001600 mu g / day within 30 days prior to enrolment ) for 3 months . before randomisation , \n all patients had to have a total asthma symptom score 1 on 4 of the last 7 days of run - in ( scale : 0 = no symptoms , 1 = aware of symptoms but can tolerate them easily , 2 = asthma causing enough discomfort to interfere with normal activities or sleep and 3 = unable to perform normal activities or sleep because of asthma ; day- and nighttime scores summed ) . \n the first patient was enrolled on 30th april 2002 and the last patient completed the study on 6th february 2003 . \n this was a 12-week , phase iii , randomised , double - blind , double - dummy , parallel - group study conducted in 62 centres across eight countries ( brazil , bulgaria , canada , hungary , mexico , the philippines , thailand and the uk ) . \n the study complied with good clinical practice guidelines and the ethical principles of the declaration of helsinki . \n an independent ethics committee or institutional review board approved the study protocol and patient consent form at each centre . \n patients were instructed to stop taking their laba therapy for 3 days prior to the beginning of the run - in period ( visit 1 ) . \n also , those using an ics / laba combination were requested to stop treatment with the combination 3 days before visit 1 and to continue with the same ics alone . \n saba use was restricted at 6 h prior to visit 1 . during the study period [ \n run - in and treatment period ( visits 15 ) ] any bgr 2-agonists other than study reliever and reversibility test medication were not permitted . following a 10- to 14-day run - in , during which patients continued their prestudy ics medication ( stable dose ) , patients were randomised to treatment ( two inhalations twice daily ) with one of the following : budesonide pmdi 200 mu g ( pulmicort pmdi ) ; budesonide / formoterol dpi 160/4.5 mu g ( symbicort turbuhaler ) ; or budesonide / formoterol pmdi 160/4.5 mu g ( symbicort rapihaler ) . \n the doses of budesonide in each group were comparable ; differences are explained by labelling changes for new inhaled drugs that require the delivered dose to be reported rather than the metered dose . \n patients were randomised sequentially in blocks of six using a computer - generated randomisation schedule . \n the randomisation schedule was computer generated at astrazeneca research and development , charnwood , uk . to maintain blinding , \n each patient received only two of the three devices : one active and one placebo device . \n an inhaled saba ( terbutaline 0.5 mg per inhalation or equivalent ) was available for all patients for symptom relief . \n the primary efficacy end - point was the change in morning peak expiratory flow ( pef ) from baseline ( mean of the last 10 days of run - in ) to the mean value over the 12-week treatment period . \n secondary efficacy end - points included : change from baseline ( mean of the last 10 days of run - in ) to the mean value over the treatment period in evening pef ; reliever medication use ; reliever medication - free days ; nighttime awakenings caused by asthma ; asthma symptom score ; symptom - free days ( a night and day without asthma symptoms and no nighttime awakenings caused by asthma ) ; and asthma - control days ( a night and day without asthma symptoms or reliever medication use and no nighttime awakenings caused by asthma ) . \n all pef measurements [ taken prior to inhalation of study medication using a mini - wright peak flow meter ( clement clarke , harlow , uk ) ] , reliever medication use , nighttime awakenings caused by asthma and asthma symptom scores were recorded by patients in a daily diary . change from baseline ( week 0 ) to the mean of the treatment period ( weeks 212 ) in fev1 and change from baseline ( week 0 ) to the end of treatment ( week 12 ) in asthma quality of life questionnaire ( standardised version ) [ aqlq(s ) ] scores ( 23 ) were also predefined secondary end - points . \n fev1 was assessed during clinic visits at enrolment and randomisation and at 2 , 6 and 12 weeks postrandomisation , according to european respiratory society recommendations ( 24 , 25 ) . \n the 32-item aqlq(s ) was administered during clinic visits at randomisation and at weeks 2 and 12 ( seven - point scale : 1 = greatest possible impairment and 7 = least impairment ) ( 23 ) . a change in aqlq(s ) \n score of 0.5 units was defined as a clinically relevant change ( 26 ) . \n safety assessments included adverse events ( assessed throughout ) , vital signs ( assessed at enrolment , randomisation , weeks 2 and 12 ) and clinical laboratory parameters ( haematology , clinical chemistry and urinalysis ; assessed at randomisation , weeks 2 and 12 ) . \n all patients received instruction on how to use the pmdi and dpi devices and the peak flow metre before the start of the study at visit 1 . \n each participating study site was provided with a turbuhaler / pmdi to be used with disposable mouthpieces / actuators , allowing patients to practise the inhalation technique . \n the intent - to - treat ( itt ) population ( i.e. all randomised patients with postrandomisation data ) was used for the main efficacy analyses . \n the primary objective of the study was to show that budesonide / formoterol pmdi was more efficacious than budesonide pmdi . \n the study was powered on this primary objective and approximately 600 evaluable patients ( 200 in each arm ) were required for a 90% probability of detecting a true difference between budesonide / formoterol pmdi and budesonide pmdi of 13 l / min in mean change in morning pef , assuming a standard deviation of 40 l / min ( two - group t - test with a 5% two - sided significance level ) . \n a secondary objective was to compare the efficacy of budesonide / formoterol pmdi with that of budesonide / formoterol dpi . \n therapeutic equivalence between budesonide / formoterol pmdi and budesonide / formoterol dpi was considered to be established if the 95% confidence interval ( ci ) for the mean difference in morning pef was within the prespecified equivalence limits of 15 and + 15 l / min , as described previously ( 27 ) . assuming a standard deviation of 40 l / min , there was 90% probability of this ci being contained within these limits given that the actual difference was < 1.5 l / min . \n results of the secondary analysis were not adjusted for multiplicity but a per - protocol ( stability ) analysis ( excluding patients who violated the inclusion / exclusion or randomisation criteria ) was performed to confirm the therapeutic equivalence data . \n diary - card end - points , averaged over available data , were analysed using a validated analysis of variance ( anova ) model with treatment and country as fixed factors and the run - in mean ( last 10 days ) as a covariate . \n fev1 and aqlq(s ) were also analysed using an anova model with treatment and country as fixed factors and the randomisation value as a covariate . \n adult and adolescent outpatients ( aged 12 years ) with asthma ( 22 ) for 6 months , who were inadequately controlled on ics alone , were enrolled . for inclusion , patients had to have a forced expiratory volume in 1 s ( fev1 ) 50% and 90% of predicted normal ( prebronchodilator ) , reversibility of 12% fev1 after inhalation of terbutaline 1 mg ( bricanyl turbuhaler , astrazeneca ) and a history of daily ics use ( stable dose of 5001600 mu g / day within 30 days prior to enrolment ) for 3 months . before randomisation , \n all patients had to have a total asthma symptom score 1 on 4 of the last 7 days of run - in ( scale : 0 = no symptoms , 1 = aware of symptoms but can tolerate them easily , 2 = asthma causing enough discomfort to interfere with normal activities or sleep and 3 = unable to perform normal activities or sleep because of asthma ; day- and nighttime scores summed ) . \n the first patient was enrolled on 30th april 2002 and the last patient completed the study on 6th february 2003 . \n this was a 12-week , phase iii , randomised , double - blind , double - dummy , parallel - group study conducted in 62 centres across eight countries ( brazil , bulgaria , canada , hungary , mexico , the philippines , thailand and the uk ) . \n the study complied with good clinical practice guidelines and the ethical principles of the declaration of helsinki . \n an independent ethics committee or institutional review board approved the study protocol and patient consent form at each centre . \n patients were instructed to stop taking their laba therapy for 3 days prior to the beginning of the run - in period ( visit 1 ) . also , those using an ics / laba combination were requested to stop treatment with the combination 3 days before visit 1 and to continue with the same ics alone . \n saba use was restricted at 6 h prior to visit 1 . during the study period [ \n run - in and treatment period ( visits 15 ) ] any bgr 2-agonists other than study reliever and reversibility test medication were not permitted . following a 10- to 14-day run - in , during which patients continued their prestudy ics medication ( stable dose ) , patients were randomised to treatment ( two inhalations twice daily ) with one of the following : \n budesonide pmdi 200 mu g ( pulmicort pmdi ) ; budesonide / formoterol dpi 160/4.5 mu g ( symbicort turbuhaler ) ; or budesonide / formoterol pmdi 160/4.5 mu g ( symbicort rapihaler ) . \n the doses of budesonide in each group were comparable ; differences are explained by labelling changes for new inhaled drugs that require the delivered dose to be reported rather than the metered dose . \n patients were randomised sequentially in blocks of six using a computer - generated randomisation schedule . \n the randomisation schedule was computer generated at astrazeneca research and development , charnwood , uk . to maintain blinding , \n each patient received only two of the three devices : one active and one placebo device . \n an inhaled saba ( terbutaline 0.5 mg per inhalation or equivalent ) was available for all patients for symptom relief . \n the primary efficacy end - point was the change in morning peak expiratory flow ( pef ) from baseline ( mean of the last 10 days of run - in ) to the mean value over the 12-week treatment period . \n secondary efficacy end - points included : change from baseline ( mean of the last 10 days of run - in ) to the mean value over the treatment period in evening pef ; reliever medication use ; reliever medication - free days ; nighttime awakenings caused by asthma ; asthma symptom score ; symptom - free days ( a night and day without asthma symptoms and no nighttime awakenings caused by asthma ) ; and asthma - control days ( a night and day without asthma symptoms or reliever medication use and no nighttime awakenings caused by asthma ) . \n all pef measurements [ taken prior to inhalation of study medication using a mini - wright peak flow meter ( clement clarke , harlow , uk ) ] , reliever medication use , nighttime awakenings caused by asthma and asthma symptom scores were recorded by patients in a daily diary . \n change from baseline ( week 0 ) to the mean of the treatment period ( weeks 212 ) in fev1 and change from baseline ( week 0 ) to the end of treatment ( week 12 ) in asthma quality of life questionnaire ( standardised version ) [ aqlq(s ) ] scores ( 23 ) were also predefined secondary end - points . \n fev1 was assessed during clinic visits at enrolment and randomisation and at 2 , 6 and 12 weeks postrandomisation , according to european respiratory society recommendations ( 24 , 25 ) . \n the 32-item aqlq(s ) was administered during clinic visits at randomisation and at weeks 2 and 12 ( seven - point scale : 1 = greatest possible impairment and 7 = least impairment ) ( 23 ) . a change in aqlq(s ) \n score of 0.5 units was defined as a clinically relevant change ( 26 ) . \n safety assessments included adverse events ( assessed throughout ) , vital signs ( assessed at enrolment , randomisation , weeks 2 and 12 ) and clinical laboratory parameters ( haematology , clinical chemistry and urinalysis ; assessed at randomisation , weeks 2 and 12 ) . \n all patients received instruction on how to use the pmdi and dpi devices and the peak flow metre before the start of the study at visit 1 . \n each participating study site was provided with a turbuhaler / pmdi to be used with disposable mouthpieces / actuators , allowing patients to practise the inhalation technique . \n the intent - to - treat ( itt ) population ( i.e. all randomised patients with postrandomisation data ) was used for the main efficacy analyses . \n the primary objective of the study was to show that budesonide / formoterol pmdi was more efficacious than budesonide pmdi . \n the study was powered on this primary objective and approximately 600 evaluable patients ( 200 in each arm ) were required for a 90% probability of detecting a true difference between budesonide / formoterol pmdi and budesonide pmdi of 13 l / min in mean change in morning pef , assuming a standard deviation of 40 l / min ( two - group t - test with a 5% two - sided significance level ) . \n a secondary objective was to compare the efficacy of budesonide / formoterol pmdi with that of budesonide / formoterol dpi . \n therapeutic equivalence between budesonide / formoterol pmdi and budesonide / formoterol dpi was considered to be established if the 95% confidence interval ( ci ) for the mean difference in morning pef was within the prespecified equivalence limits of 15 and + 15 l / min , as described previously ( 27 ) . assuming a standard deviation of 40 l / min , there was 90% probability of this ci being contained within these limits given that the actual difference was < 1.5 l / min . \n results of the secondary analysis were not adjusted for multiplicity but a per - protocol ( stability ) analysis ( excluding patients who violated the inclusion / exclusion or randomisation criteria ) was performed to confirm the therapeutic equivalence data . \n diary - card end - points , averaged over available data , were analysed using a validated analysis of variance ( anova ) model with treatment and country as fixed factors and the run - in mean ( last 10 days ) as a covariate . \n fev1 and aqlq(s ) were also analysed using an anova model with treatment and country as fixed factors and the randomisation value as a covariate . \n a total of 892 patients were enrolled and 680 were subsequently randomised to study treatment ( 217 to budesonide pmdi , 229 to budesonide / formoterol dpi and 234 to budesonide / formoterol pmdi ) . \n the itt and safety populations comprised 679 patients ( one patient in the budesonide / formoterol pmdi group was lost to follow - up ) . for the primary analysis , 216 , 223 and 229 patients in the budesonide pmdi , budesonide / formoterol dpi and budesonide / formoterol pmdi groups , respectively , had morning pef data from both the run - in and the treatment period . \n six hundred patients completed the study ; discontinuations were comparable between the three treatment groups ( 29 , 23 and 27 for budesonide pmdi , budesonide / formoterol dpi and budesonide / formoterol pmdi , respectively ) . \n patients demographics and baseline characteristics were well balanced across the three treatment groups ( table 1 ) . in total , 109 ( 16% ) \n patients were aged 1217 years , 520 ( 76% ) were aged 1864 years and 51 ( 8% ) were aged 65 years ; the distribution of adolescent and elderly patients was even across the three groups . \n self - reported adherence to study medication ( percentage of diary - logged days on which study medication was used ) was equally high across all the three treatment groups ( > 98% ) . \n patient demographics and baseline characteristics one patient was 11 years and 354 days old at the enrolment visit . \n deviations from inclusion criteria not considered sufficiently significant to justify exclusion of data from the full analysis . \n aqlq(s ) , asthma quality of life questionnaire ( standardised version ) ; dpi , dry - powder inhaler ; fev1 , forced expiratory volume in 1 s ; ics , inhaled corticosteroid ; laba , long - acting 2-agonist ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler . \n budesonide / formoterol dpi and budesonide / formoterol pmdi improved morning pef compared with budesonide pmdi ( p < 0.001 for both ) ( figure 1 ) . following treatment , \n the adjusted mean change in morning pef was 31.4 and 28.6 l / min higher in the budesonide / formoterol dpi and budesonide / formoterol pmdi groups , respectively , than in the budesonide pmdi group . \n analysis of improvements from baseline in morning pef with budesonide / formoterol dpi and budesonide / formoterol pmdi established that the two treatments were therapeutically equivalent ( table 2 ) . \n a stability analysis of improvements from baseline in morning pef in the per - protocol population confirmed the therapeutic equivalence of the two budesonide / formoterol inhalation devices ; the adjusted mean difference between budesonide / formoterol pmdi and budesonide / formoterol dpi was 4.9 l / min ( 95% ci : 12.8 to 3.0 ; p = 0.22 ) . therapeutic equivalence of budesonide / formoterol dpi and budesonide / formoterol pmdi therapeutic equivalence was defined as a 95% ci for the difference in morning pef between budesonide / formoterol pmdi and budesonide / formoterol dpi within the range 15 to + 15 l / min . \n ci , confidence interval ; dpi , dry - powder inhaler ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler . \n change in morning pef following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n dpi , dry - powder inhaler ; ns , not significant ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler all secondary diary end - points were improved to a greater extent with budesonide / formoterol dpi and budesonide / formoterol pmdi than with budesonide pmdi ( table 3 ; figure 2 ) . for most end - points , \n the improvements seen with budesonide / formoterol pmdi were similar to those observed with budesonide / formoterol dpi , with the exception of symptom - free and asthma - control days , which were increased by a slightly greater degree with budesonide / formoterol dpi ( table 3 ) . \n consistent with improvements in diary end - points , both budesonide / formoterol dpi and budesonide / formoterol pmdi also improved fev1 compared with budesonide pmdi ( figure 3 ) , with no significant difference between the two budesonide / formoterol devices . \n changes in secondary diary end - points following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi p < 0.01 vs. budesonide pmdi p < 0.05 budesonide / formoterol dpi vs. budesonide / formoterol pmdi . \n dpi , dry - powder inhaler ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler . \n change in fev1 following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n dpi , dry - powder inhaler ; e , enrolment ; fev1 , forced expiratory volume in 1 s ; pmdi , pressurised metered - dose inhaler ; r , randomisation ; w , week change in ( a ) total asthma symptoms and ( b ) reliever medication - free days following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n dpi , dry - powder inhaler ; pmdi , pressurised metered - dose inhaler budesonide / formoterol dpi and budesonide / formoterol pmdi provided similar clinically relevant improvements in health - related quality of life ( figure 4 ) . these improvements with budesonide / formoterol dpi and budesonide / formoterol \n pmdi were statistically greater than those provided by budesonide pmdi [ adjusted mean change in aqlq(s ) overall score : + 0.76 ( p < 0.001 vs. budesonide pmdi ) , + 0.65 ( p = 0.002 vs. budesonide pmdi ) and + 0.37 , respectively ] . \n for the overall aqlq(s ) score , 52% and 56% of budesonide / formoterol pmdi - treated and budesonide / formoterol dpi - treated patients , respectively , had a clinically relevant increase of 0.5 units compared with 35% of patients in the budesonide pmdi group . change in aqlq(s ) following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n aqlq(s ) , asthma quality of life questionnaire ( standardised version ) ; dpi , dry - powder inhaler ; pmdi , pressurised metered - dose inhaler . \n * * * p < 0.001 , * * p < 0.01 , * p < 0.05 vs. budesonide pmdi there were no clinically important differences between treatment groups with regard to adverse events [ overall ( table 4 ) and ics- and bgr 2-agonist - related events ( table 5 ) ] , vital signs or laboratory parameters . \n only 32% of patients experienced one or more adverse events , the majority of which were mild or moderate in severity . \n four patients reported serious adverse events : two in the budesonide pmdi group ( joint dislocation / accident / fracture , asthma aggravated ) and two in the budesonide / formoterol pmdi group ( menorrhagia , increase in liver enzyme activity ) ; none were considered ( after follow - up ) to be related to study treatment . \n most frequently reported adverse events only adverse events reported for 10 patients in total are included . \n incidence of adverse events related to treatment with bgr 2-agonists or ics dpi , dry - powder inhaler ; ics , inhaled corticosteroid ; pmdi , pressurised metered - dose inhaler . \n thirty patients ( 15 in the budesonide pmdi group , four in the budesonide / formoterol dpi group and 11 in the budesonide / formoterol pmdi group ) discontinued the study because of adverse events . \n the most frequently reported adverse event causing discontinuation was asthma aggravated [ seven , two and one patient(s ) in the budesonide pmdi , budesonide / formoterol dpi and budesonide / formoterol pmdi groups , respectively ] . \n other adverse events leading to discontinuation included nausea , tremor , palpitations and lower respiratory tract infection . \n a total of 892 patients were enrolled and 680 were subsequently randomised to study treatment ( 217 to budesonide pmdi , 229 to budesonide / formoterol dpi and 234 to budesonide / formoterol pmdi ) . \n the itt and safety populations comprised 679 patients ( one patient in the budesonide / formoterol pmdi group was lost to follow - up ) . for the primary analysis , 216 , 223 and 229 patients in the budesonide pmdi , budesonide / formoterol dpi and budesonide / formoterol pmdi groups , respectively , had morning pef data from both the run - in and the treatment period . \n six hundred patients completed the study ; discontinuations were comparable between the three treatment groups ( 29 , 23 and 27 for budesonide pmdi , budesonide / formoterol dpi and budesonide / formoterol pmdi , respectively ) . \n patients demographics and baseline characteristics were well balanced across the three treatment groups ( table 1 ) . in total , 109 ( 16% ) \n patients were aged 1217 years , 520 ( 76% ) were aged 1864 years and 51 ( 8% ) were aged 65 years ; the distribution of adolescent and elderly patients was even across the three groups . \n self - reported adherence to study medication ( percentage of diary - logged days on which study medication was used ) was equally high across all the three treatment groups ( > 98% ) . \n patient demographics and baseline characteristics one patient was 11 years and 354 days old at the enrolment visit . \n deviations from inclusion criteria not considered sufficiently significant to justify exclusion of data from the full analysis . \n aqlq(s ) , asthma quality of life questionnaire ( standardised version ) ; dpi , dry - powder inhaler ; fev1 , forced expiratory volume in 1 s ; ics , inhaled corticosteroid ; laba , long - acting 2-agonist ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler . \n budesonide / formoterol dpi and budesonide / formoterol pmdi improved morning pef compared with budesonide pmdi ( p < 0.001 for both ) ( figure 1 ) . following treatment , \n the adjusted mean change in morning pef was 31.4 and 28.6 l / min higher in the budesonide / formoterol dpi and budesonide / formoterol pmdi groups , respectively , than in the budesonide pmdi group . \n analysis of improvements from baseline in morning pef with budesonide / formoterol dpi and budesonide / formoterol pmdi established that the two treatments were therapeutically equivalent ( table 2 ) . \n a stability analysis of improvements from baseline in morning pef in the per - protocol population confirmed the therapeutic equivalence of the two budesonide / formoterol inhalation devices ; the adjusted mean difference between budesonide / formoterol pmdi and budesonide / formoterol dpi was 4.9 l / min ( 95% ci : 12.8 to 3.0 ; p = 0.22 ) . therapeutic equivalence of budesonide / formoterol dpi and budesonide / formoterol pmdi therapeutic equivalence was defined as a 95% ci for the difference in morning pef between budesonide / formoterol pmdi and budesonide / formoterol dpi within the range 15 to + 15 l / min . \n ci , confidence interval ; dpi , dry - powder inhaler ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler . \n change in morning pef following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n dpi , dry - powder inhaler ; ns , not significant ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler all secondary diary end - points were improved to a greater extent with budesonide / formoterol dpi and budesonide / formoterol pmdi than with budesonide pmdi ( table 3 ; figure 2 ) . for most end - points , the improvements seen with budesonide / formoterol pmdi were similar to those observed with budesonide / formoterol dpi , with the exception of symptom - free and asthma - control days , which were increased by a slightly greater degree with budesonide / formoterol dpi ( table 3 ) . \n consistent with improvements in diary end - points , both budesonide / formoterol dpi and budesonide / formoterol pmdi also improved fev1 compared with budesonide pmdi ( figure 3 ) , with no significant difference between the two budesonide / formoterol devices . \n changes in secondary diary end - points following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi p < 0.01 vs. budesonide pmdi p < 0.05 budesonide / formoterol dpi vs. budesonide / formoterol pmdi . \n dpi , dry - powder inhaler ; pef , peak expiratory flow ; pmdi , pressurised metered - dose inhaler . \n change in fev1 following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n dpi , dry - powder inhaler ; e , enrolment ; fev1 , forced expiratory volume in 1 s ; pmdi , pressurised metered - dose inhaler ; r , randomisation ; w , week change in ( a ) total asthma symptoms and ( b ) reliever medication - free days following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n budesonide / formoterol dpi and budesonide / formoterol pmdi provided similar clinically relevant improvements in health - related quality of life ( figure 4 ) . these improvements with budesonide / formoterol dpi and budesonide / formoterol \n pmdi were statistically greater than those provided by budesonide pmdi [ adjusted mean change in aqlq(s ) overall score : + 0.76 ( p < 0.001 vs. budesonide pmdi ) , + 0.65 ( p = 0.002 vs. budesonide pmdi ) and + 0.37 , respectively ] . \n for the overall aqlq(s ) score , 52% and 56% of budesonide / formoterol pmdi - treated and budesonide / formoterol dpi - treated patients , respectively , had a clinically relevant increase of 0.5 units compared with 35% of patients in the budesonide pmdi group . change in aqlq(s ) following treatment with budesonide pmdi , budesonide / formoterol dpi or budesonide / formoterol pmdi . \n aqlq(s ) , asthma quality of life questionnaire ( standardised version ) ; dpi , dry - powder inhaler ; pmdi , pressurised metered - dose inhaler . * \n * * p < 0.001 , * * p < 0.01 , * p < 0.05 vs. budesonide pmdi \n there were no clinically important differences between treatment groups with regard to adverse events [ overall ( table 4 ) and ics- and bgr 2-agonist - related events ( table 5 ) ] , vital signs or laboratory parameters . \n only 32% of patients experienced one or more adverse events , the majority of which were mild or moderate in severity . \n four patients reported serious adverse events : two in the budesonide pmdi group ( joint dislocation / accident / fracture , asthma aggravated ) and two in the budesonide / formoterol pmdi group ( menorrhagia , increase in liver enzyme activity ) ; none were considered ( after follow - up ) to be related to study treatment . \n most frequently reported adverse events only adverse events reported for 10 patients in total are included . \n incidence of adverse events related to treatment with bgr 2-agonists or ics dpi , dry - powder inhaler ; ics , inhaled corticosteroid ; pmdi , pressurised metered - dose inhaler . \n thirty patients ( 15 in the budesonide pmdi group , four in the budesonide / formoterol dpi group and 11 in the budesonide / formoterol pmdi group ) discontinued the study because of adverse events . \n the most frequently reported adverse event causing discontinuation was asthma aggravated [ seven , two and one patient(s ) in the budesonide pmdi , budesonide / formoterol dpi and budesonide / formoterol pmdi groups , respectively ] . \n other adverse events leading to discontinuation included nausea , tremor , palpitations and lower respiratory tract infection . \n budesonide / formoterol , which is available as a dpi , has been reformulated as an hfa pmdi to enable delivery of this effective and well - tolerated therapy via two different devices that meet the needs and requirements of both patients and clinicians alike without detriment to the environment . \n this large - scale , international , double - blind , double - dummy study set out to compare the efficacy and safety of this novel pmdi formulation of budesonide / formoterol with that of the established dpi , budesonide / formoterol turbuhaler , and budesonide pmdi in adults and adolescents with inadequately controlled asthma . \n morning pef demonstrated that both budesonide / formoterol therapies are more effective than budesonide pmdi . \n the magnitude of improvement in morning pef with both budesonide / formoterol therapies was within the range of that reported previously for budesonide / formoterol dpi ( 2 , 17 , 28 , 29 ) , thus verifying the results of the present study . \n furthermore , the analysis of the secondary objective demonstrated that , for improvements in morning pef , budesonide / formoterol pmdi is therapeutically equivalent to budesonide / formoterol dpi . analysis of other efficacy end - points relating to lung function , asthma symptoms , disease control and health - related quality of life supports the comparable efficacy of budesonide / formoterol pmdi with budesonide / formoterol dpi and the superiority of both formulations over budesonide pmdi . \n the only statistical differences between the two devices which favoured budesonide / formoterol dpi were in the composite end - points : symptom - free days and asthma - control days . in both cases , \n differences were driven by the additional improvement in daytime total asthma symptom score ( data not shown ) . \n previous studies report that the degree of lung deposition for the dpi device is approximately 23 times that of the corresponding pmdi device ( 3032 ) and hence it is possible that this may have contributed to the significant differences in symptom - free days and asthma - control days observed in this study . \n however , there is no existing literature regarding the relative degree of lung deposition for budesonide / formoterol dpi or pmdi and as the degree of lung deposition varies for different dpis and pmdis it can not be assumed that turbuhaler dpi will deliver 23 times more drug to the lungs when compared with a pmdi ( 33 ) . \n instead it is more likely that any improvements in asthma symptoms associated with dpi are due to random variation and a much larger study would be required to detect a clear difference in outcome for these variables . \n furthermore , as there were no differences between the two devices in end - points such as nighttime awakenings , 24-h total asthma symptom scores and reliever medication use ( markers of asthma control ) , and in the number of adverse events reported as asthma aggravated ( an indicator of more severe events ) , it is unlikely that the difference in daytime symptom variables is clinically important . \n interestingly , the improvements in lung function and symptom - related end - points with both budesonide / formoterol therapies appeared to be progressive , with the evidence of continuing improvement between weeks 2 and 6 ( figures 13 ) . \n conversely , but perhaps not unexpectedly , there appeared to be little evidence of progressive improvement with budesonide pmdi in this patient population . \n as previously reported in comparative studies of budesonide / formoterol dpi vs. budesonide dpi ( 2 , 18 , 34 , 35 ) , and as would be expected for an ics ( 1 ) , budesonide pmdi improved asthma symptoms , measures of asthma control and health - related quality of life , but these improvements were smaller than those seen with the budesonide / formoterol therapies . in the clinical setting , \n choice of inhaler device is less likely to depend on efficacy and tolerability and is more likely to be influenced by other factors , for example cost , the patient 's ability to use the selected device correctly and personal preference ( 36 ) . \n dpi devices are generally more expensive than pmdis and the therapeutic equivalence observed between the delivery devices suggests that either would be suitable for use in normal clinical practice . besides cost , differences in ease of use and technique between pmdi and the dpi are likely to have a large influence on choice of inhaler for individual patients and clinicians . although both devices are relatively easy to use , each has technical limitations which can limit effectiveness ( 37 ) . in this study patients \n each participating study site was provided with a dpi / pmdi to be used with disposable mouthpieces / actuators , allowing patients to practise the inhalation technique . \n furthermore , results report that compliance ( study drug use measured by self - reported diary recording of daily treatment intake ) was similar across all treatment groups . \n thus , it is unlikely that patients randomised to receive the pmdi inhaler had any disadvantages compared with those using the dpi with regard to inhaler technique . in the clinical setting , \n providing each individual with the most appropriate inhaler has the potential to result in more effective patient care ( 37 ) . in terms of safety , \n budesonide / formoterol pmdi , budesonide / formoterol dpi and budesonide pmdi were well tolerated , with a low overall incidence of adverse events across the three treatment groups . \n adverse events were slightly more common in the budesonide pmdi group although this was not thought to be clinically relevant and the majority of patients who reported aggravated asthma as an adverse event were in this treatment group . \n importantly , the tolerability profiles of both budesonide / formoterol therapies were similar to that reported previously for budesonide / formoterol dpi ( 29 ) . in conclusion \n , this study demonstrates that budesonide / formoterol , administered via the hfa pmdi or dpi , is an effective and well - tolerated treatment for adult and adolescent patients with asthma , with both devices being therapeutically equivalent . \n the availability of both devices will give clinicians greater freedom to select a cost - effective therapy that suits the needs and preferences of individual patients and clinicians themselves .", "role": "user" }, { "content": "backgroundbudesonide / formoterol is an effective treatment for both asthma and chronic obstructive pulmonary disease . \n this study compared the efficacy and safety of a novel hydrofluoroalkane ( hfa ) pressurised metered - dose inhaler ( pmdi ) formulation of budesonide / formoterol with that of budesonide pmdi and budesonide / formoterol dry - powder inhaler ( dpi ; turbuhaler).methodsthis was a 12-week , multinational , randomised , double - blind , double - dummy study involving patients aged 12 years with asthma . \n all patients had a forced expiratory volume in 1 s of 5090% predicted normal and were inadequately controlled on inhaled corticosteroids ( 5001600 mu g / day ) alone . following a 2-week run - in , during which they received their usual medication , \n patients were randomised ( two inhalations twice daily ) to budesonide pmdi 200 mu g , budesonide / formoterol dpi 160/4.5 mu g or budesonide / formoterol pmdi 160/4.5 mu g. the primary efficacy end - point was change from baseline in morning peak expiratory flow ( pef).resultsin total , 680 patients were randomised , of whom 668 were included in the primary analysis . therapeutically equivalent increases in morning pef \n were observed with budesonide / formoterol pmdi ( 29.3 l / min ) and budesonide / formoterol dpi ( 32.0 l / min ) ( 95% confidence interval : 10.4 to 4.9 ; p = 0.48 ) . \n the increase in morning pef with budesonide / formoterol pmdi was significantly higher than with budesonide pmdi ( + 28.7 l / min ; p < 0.001 ) . similar improvements with budesonide / formoterol pmdi vs. budesonide pmdi were seen for all secondary efficacy end - points . \n both combination treatments were similarly well tolerated.conclusionsbudesonide/formoterol , administered via the hfa pmdi or dpi , is an effective and well - tolerated treatment for adult and adolescent patients with asthma , with both devices being therapeutically equivalent .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: \n \n competitive swimming has long been associated with shoulder pain , as 90% of the propulsion comes from the upper extremity . \n in addition , competitive swimmers usually train 6 to 7 days per week , 2 workouts per day , with yardage around 12,00016,000 yards daily . \n it has been estimated that a swimmer training 10,000 yards per day takes around 400,000 strokes in a season . \n the different strokes used in swimming freestyle , backstroke , butterfly , and breaststroke may also present as another factor . \n the biomechanics of the shoulder in butterfly , backstroke , and freestyle are very similar . \n the major difference is that freestyle and backstroke use a body roll during recovery and pull - through , whereas butterfly uses body lift . \n in fact , proper timing in the stroke has shown butterfly to have a wave characteristic to it , and that finding an optimum frequency , amplitude , and phase characteristic could improve performance . \n other published data show different muscle firing patterns in painful shoulders and non - painful shoulders . \n this study aims to prove a link between competitive swimmers who specialize in the butterfly stroke and have a higher risk of shoulder injury . \n if a statistically significant increase in the rate of shoulder injury among butterfly specialists could be proven to exist , it could be deduced that the stroke itself is responsible for injury , independent of other risks like the distance trained or technique used . \n it would suggest that high use of the butterfly stroke has an inherent risk to the shoulders . \n the survey included questions pertaining to the incidence of swimmer 's injuries , if any . \n the study was similar to that performed by grote et al . ; however , the shoulder was studied as opposed to the hip adductors . to eliminate gender differences that may bias the results , only men 's teams were surveyed . \n the survey contained general questions about the athlete , such as age , height , weight , best stroke , age of entry into swimming , age of specialization into best stroke , and highest level of swimming attained . by surveying the top 25 teams , this study focused on those athletes who are among the country 's most elite swimmers , and were on a similar level . however , there was still variation , from olympic champions to conference team swimmers . \n the survey also included questions about training in the water and out of the water . \n in addition , questions included distance per week , number of workouts per week , percentage of practice that was butterfly / best stroke , percentage of practice that used hand paddles , and participation in weight training , stretching , or other dry land exercises . finally , the survey asked for information about injuries . \n questions included number of days of shoulder pain , severity of shoulder pain , number of days of training and competition missed , medical assistance sought , and types of treatment applied . the types of treatment included those that had been previously published with successful pain relief in competitive swimming . \n this study was granted exemption from review status from the irb based on 45 cfr 46.101(b)(2 ) . \n the teams were selected from the final duel meet rankings of the 2004 - 2005 swimming season , as reported by the college swimming coaches association of america , cscaa , the official rankings of college swimming . \n all members of the swimming team were eligible and encouraged to participate in the study ; however , we asked that members of the diving team not complete the questionnaire . \n the final team rankings were announced on march 10 , 2005 , and the top 25 teams ( with rank and conference affiliation ) were determined [ table 1 ] . teams ranking in the top 25 in the final poll of the 2004 - 2005 season with their conference affiliation the coaching staff of all teams was contacted either by phone or e - mail . \n teams that agreed to participate were mailed packets containing the survey , pens , and a return envelope . \n enough surveys were sent so that every member of the swimming team , but not the diving team , was able to participate . \n participation was entirely voluntary , and participants were again reminded of the confidentiality of their answers . of the 25 teams , 11 teams agreed to participate , two teams declined participation , and 12 teams did not respond . \n there were a total of 296 surveys sent to the teams , based on the number of swimmers listed on their men 's team roster , obtained from each team 's website . \n the institutional biostatistics department completed the analysis of the data using anova , chi squared , and fisher 's exact test . \n the survey included questions pertaining to the incidence of swimmer 's injuries , if any . \n the study was similar to that performed by grote et al . ; however , the shoulder was studied as opposed to the hip adductors . to eliminate gender differences that may bias the results , only men 's teams were surveyed . \n the survey contained general questions about the athlete , such as age , height , weight , best stroke , age of entry into swimming , age of specialization into best stroke , and highest level of swimming attained . by surveying the top 25 teams , this study focused on those athletes who are among the country 's most elite swimmers , and were on a similar level . however , there was still variation , from olympic champions to conference team swimmers . \n the survey also included questions about training in the water and out of the water . \n in addition , questions included distance per week , number of workouts per week , percentage of practice that was butterfly / best stroke , percentage of practice that used hand paddles , and participation in weight training , stretching , or other dry land exercises . finally , the survey asked for information about injuries . \n questions included number of days of shoulder pain , severity of shoulder pain , number of days of training and competition missed , medical assistance sought , and types of treatment applied . the types of treatment included those that had been previously published with successful pain relief in competitive swimming . \n this study was granted exemption from review status from the irb based on 45 cfr 46.101(b)(2 ) . \n the teams were selected from the final duel meet rankings of the 2004 - 2005 swimming season , as reported by the college swimming coaches association of america , cscaa , the official rankings of college swimming . \n all members of the swimming team were eligible and encouraged to participate in the study ; however , we asked that members of the diving team not complete the questionnaire . \n the final team rankings were announced on march 10 , 2005 , and the top 25 teams ( with rank and conference affiliation ) were determined [ table 1 ] . \n teams ranking in the top 25 in the final poll of the 2004 - 2005 season with their conference affiliation the coaching staff of all teams was contacted either by phone or e - mail . \n teams that agreed to participate were mailed packets containing the survey , pens , and a return envelope . \n enough surveys were sent so that every member of the swimming team , but not the diving team , was able to participate . \n participation was entirely voluntary , and participants were again reminded of the confidentiality of their answers . of the 25 teams , 11 teams agreed to participate , two teams declined participation , and 12 teams did not respond . \n there were a total of 296 surveys sent to the teams , based on the number of swimmers listed on their men 's team roster , obtained from each team 's website . \n the institutional biostatistics department completed the analysis of the data using anova , chi squared , and fisher 's exact test . \n the primary outcome , days per week of shoulder pain , showed no significant difference between strokes [ figure 1 ] . \n the results showed that 43% of butterfly specialists reported no shoulder pain , and 73% reported shoulder pain 2 days per week or less . \n this is consistent with the other strokes43% of breaststroke specialists , 42% of freestyle specialists , and 41% of backstroke specialists reported zero days of shoulder pain . \n this table shows the percentage of athletes reporting the number of days of shoulder pain per week . \n as the figures show , the different strokes have a similar percentage of self reported injuries additionally , the intensity of shoulder pain was not significantly different [ figure 2 ] . using a scale of 1 - 5 , with 5 being maximal shoulder pain , butterfly swimmers reported a similar intensity to other strokes . \n this level and frequency of pain had very little impact on practice and competition participation . among butterfly specialists , \n 92% of athletes were not limited in butterfly training , and 8% were limited in 1 - 2 practices per week . \n the majority of swimmers specializing in other strokes also reported zero days of training limited by shoulder pain . \n those reporting zero days of pain individual medley ( 89% ) , freestyle ( 82% ) , backstroke ( 93% ) , and breaststroke ( 72%)is similar to butterfly swimmers . \n all butterfliers reported that they had missed 0 - 3 competitions because of shoulder pain . \n all swimmers secializing in the individual medley , backstroke , and breaststroke also reported 0 - 3 competitions missed because of shoulder pain . \n freestyle swimmers had 97% with 0 - 3 competitions missed , 2% with 4 - 6 competitions missed , and 2% missed greater than 12 competitions . \n training was also found to be similar among the different strokes , specifically the distance trained . \n swimmers reported training between 50,000 and 75,000 yards per weeks , with 88% of butterfliers , 83% of individual medley specialists , 58% of freestylers , 66% of backstrokers , and 70% of breaststrokers reporting this distance . \n the maximal amount of shoulder pain reported is similar in percentage between the different strokes . \n this is consistent across each stroke hand paddles are used in approximately equal amounts for training among the different strokes . \n the most common response , using hand paddles between 20% and 40% of training , was selected by 54% of butterfliers , 61% of individual medley specialists , 42% of freestylers , 48% of backstrokers , and 41% of breaststrokers . \n additional information was obtained regarding out of water training , including weight training , and stretching . \n the majority of athletes report participating in 2 - 3 weight training sessions per week . by stroke , this was reported as 65% of butterfliers , 89% of individual medley specialists , 76% of freestylers , 79% of backstrokers , and 80% of breaststrokers . \n , the majority reported that 40 to 60% of the workouts focused on upper body conditioning . by stroke , this was reported as 78% of butterfliers , 50% of individual medley specialists , 61% of freestylers , 66% of backstrokers , and 52% of breaststrokers . \n this was answered by 17% of butterfliers , 67% of individual medley specialists , 39% of freestylers , 38% of backstrokers , and 33% of breaststrokers . \n the most common response among butterfliers was 4 - 5 sessions per week , which was chosen by 26% of the participants . \n athletes also had no difference among the different strokes in seeking medical treatment for their injuries . \n fifty - eight percent of butterfliers consulted medical professionals , while individual medley swimmers ( 61% ) , freestylers ( 37% ) , backstrokers ( 59% ) , and breaststrokers ( 54% ) were all similar ( p = 0.125 ) . \n ice and rest were the most commonly selected forms of treatment , while only 5 of the 187 athletes required surgery . \n common injuries reported were consistent with repetitive motion and overuse type injuries , including tendonitis and bursitis . \n the primary outcome of the study shows that no single stroke has a higher incidence of shoulder pain . \n this is contrary to the hypothesis for the study , which is that the butterfly stroke , based both on personal experience and biomechanical evidence previously published , is a risk for shoulder pain . \n this is further confirmed by the similarities among training patterns with this group of high level athletes . \n it is important to note that these different risk factors did not influence the results . \n because the distance trained in each stroke is so similar , it is reasonable to assume that it is an independent risk factor for all swimmers , not a risk associated with ones best stroke a recent study performed by wolf et al \n . followed a single division i university for five years , and showed a higher rate of injury in non - freestyle swimmers , with a relative risk of 1.33 . \n this can correct for injury rates that are due to the training protocol at a single university , also discussed by the authors . \n although this study followed both men 's and women 's teams , and did not prove a statistical difference in injuries by gender , there is still a chance gender could alter the rate of injury by stroke . \n because these were not clustered around a specific stroke , it would be reasonable to conclude that the high volume of training for competitive swimming is responsible for the overuse injuries . \n this supports the link between competitive swimming and painful shoulders , which has been previously published . \n because the information is self - reported , athletes may be unlikely to self - report injury . \n some swimmers may not consider their pain to be out of the ordinary , just a normal feeling associated with training , and thus not report having days of shoulder pain . \n one coach refused participation because he was afraid of suggesting shoulder injuries to his team . \n the swimming season typically consists of long - distance training in the fall and winter , and shorter , speed - oriented workouts in the spring . \n if , for example , the surveys were sent early in the year , before the heaviest training has taken place , the rate of shoulder pain may be less , whereas after the heaviest training part of the season , the rate may be higher . \n because participation was voluntary , athletes with injuries may have been hesitant to complete the survey . \n also , because the project was completed at practice , athletes with injuries severe enough to prevent participation would not have been present . \n this would mean that the study selected for healthy athletes . additionally , the surveys were administered in the spring following the ncaa championships . \n at this point in the season , the majority of graduating seniors have retired and would not be attending practices . \n this may give a falsely low participation rate of 61.8% , and it is likely that a higher percentage of athletes who actually were given a survey completed and returned their survey . \n also , the teams were not selected at random , and one of the authors was previously an athlete on one of the invited teams . \n although this should not have any effect on the results reported , it is important to note that coaches known personally may be more likely to follow instructions carefully and work to obtain a higher rate of participation . it would also be important to involve causes of shoulder pain not related to swimming . \n previous injuries from non - swimming , or even non - athletic sources a car accident , for example may be responsible for the shoulder pain reported . additionally , the shoulder pain could come from non - swimming training methods , such as weight lifting , which is worsened by swimming training . \n other medical conditions can cause shoulder pain which are not swimming or even musculoskeletal in origin . these can include autoimmune arthritis , infectious arthritis , and thoracic outlet syndrome , among others . \n non - swimming causes of shoulder pain were not addressed in the survey and should be included for future studies . as with any survey study , this also has the inherent limitation of recall bias , specifically with injury diagnosis . \n ideally , all the participating athletes could be examined for diagnosis of their shoulder pain . \n one possible way this could be accomplished would be to distribute the survey at a competition , where a physical examination could also be performed . \n although this study did not produce results showing any increased rate of shoulder pain among any single stroke , future research can be conducted to further clarify this issue . as suggested , different times of the season \n a study to compare the same groups of athletes at the beginning , middle , and end of the season may show different rates of shoulder pain between the different strokes at the different points in the season . \n there was no difference in the rate of self - reported shoulder pain among collegiate male swimmers based on their primary stroke .", "role": "user" }, { "content": "purpose : to established an association between shoulder pain and the stroke specialization among ncaa men swimmers.materials and methods : all members of the top 25 ncaa men 's swim teams were invited to complete the survey . \n eleven teams with a total of 187 participants completed the study survey . \n the teams were mailed surveys that included multiple choice questions regarding their primary stroke and their incidence of shoulder pain . additionally , the survey included questions about risk factors including distance trained , type of equipment , weight training , and stretching.results:the analysis showed that there was no significant difference in the rates of shoulder pain among the four strokes and individual medley specialists . \n the other risk factors did not show a significant correlation with shoulder pain.conclusions:this study found no significant correlation between stroke specialty and shoulder pain in male collegiate swimmers.level of evidence : level 3.clinical relevance : descriptive epidemiology study .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: in its 2010 science report unesco noted the growing concern about conflict of interest ( coi ) in scientific journals . \n unesco cited a call for scientific journals to adopt a common standard regarding the complex and growing financial arrangements that have developed in recent years between vested interests and independent scientists . \n an analysis by vom saal and welshons for example , showed that 11 out of 11 industry - funded studies found bisphenol a ( bpa ) had no significant action , while 109 of 119 studies that had no industry funding ( 92 % ) did find effects of bpa . \n the international committee of medical journal editors ( icmje ) has produced a standard disclosure of conflicts of interest form which icmje member journals require authors to use . \n the world association of medical editors ( wame ) has highlighted the need for journals to take action regarding the issue of coi : if coi is not managed effectively it can cause authors , reviewers , and editors to make decisions that , consciously or unconsciously , tend to serve their competing interests at the expense of their responsibilities in the publication process , thereby distorting the scientific enterprise . \n this consequence of coi is especially dangerous when it is not immediately apparent to others . \n in addition , the appearance of coi , even where none actually exists , can also erode trust in a journal by damaging its reputation and credibility . in \n 2010 the 2nd world conference on research integrity approved a position statement , responsible research publication : international standards for authors . \n the committee on publication ethics ( cope ) described these as the first universal global guidelines for authors from all areas of scholarly publishing . \n cope urged all editors to incorporate these standards into their editorial policies and instructions for authors . in december 2013 , as a joint endeavour to promote a common standard regarding coi disclosure , wame , cope , the directory of open access journals , and the open access scholarly publishers association published the principles of transparency and best practice in scholarly publishing . \n cope has adopted a code of conduct for journal editors with which it requires in theory , its 7,000 member journals to comply . \n cope recommends that , if a conflict of interest comes to light after publication of an article , the journal should publish a correction disclosing the conflict of interest . \n if a cope member is not willing to comply with its code of conduct , cope will aim to discuss that with the member , and will ask them to consider their membership of the organization . \n it appears that progress has been made . in the cases below , however , involving five cope member journals , these policies were disregarded . \n even when cope concluded that a complaint regarding undisclosed conflict of interest was substantiated and recommended that the journal involved publish a correction in compliance with cope s policy , cope categorically notified the journal that it was free to disregard cope s recommendation and continue as a cope member without any consequences . \n cope has never used its enforcement ability and has never asked a journal to withdraw its membership of cope . furthermore apart from cope , \n the annals of occupational hygiene ( aoh ) published two papers on research , financed by georgia pacific corporation ( gp ) regarding asbestos - containing joint compound that the company had sold in the past [ 11 , 12 ] . \n the company was facing court cases involving nearly $ 1 billion in liability related to this product . \n three of the five authors of the two articles worked for exponent and one was an employee who gp deliberately transferred for the purpose of carrying out the research , to be under the control of gp s litigation department . \n david michaels has described exponent as one of the premier firms in the product defense business . \n these firms profit by helping corporations minimize public health and environmental protection and fight claims of injury and illness . \n ( ) this is science for hire period , and it is extremely lucrative , states michaels . in june 2013 \n a new york court ruled that the two papers , and six additional similar articles financed by gp , constituted potential crime - fraud . \n the court stated that gp had commissioned the research with the intent of casting doubt on the capability of chrysotile asbestos to cause cancer , planned to use the articles to assist its litigation efforts , that gp s lawyers had significant input in the content , reporting of the results and prepublication review process of the articles , and that the articles failed to disclose the participation of the company lawyers . \n article 2.1 of cope s code of conduct requires that readers be informed whether the funder of the research had any role in the research and its publication and if so , what this was . \n they do not disclose that the company s litigation department had control over the work nor that one of the authors had been transferred so as to be under the direction of gp s litigation department . \n the aoh should have withdrawn the articles or at the very least , required publication of an erratum in compliance with cope s article 2.1 , to disclose that the study was not a normal study , but controlled by gp s litigation department , with the research data thus rendered inaccessible under lawyer - client privilege . \n instead the article remains on the aoh website with no conflict of interest statement from the authors disclosing their own and their consulting companies financial ties to georgia pacific . \n the reader thus assumes that the article complies with cope s code of ethics , which it does not . \n the chief editor of the aoh noah seixas , published a commentary , protecting our science , stating that through reviewing the gp decision , it had become clear that the aoh should strengthen its procedures regarding coi . \n the aoh will monitor the results of the litigation involving the gp research , seixas wrote , and if the court finds evidence of fraud in the production of the research reported in our pages , we will act on these findings in accord with the cope guidelines for ethical publication . \n of course the aoh should take action in accord with the cope guidelines in the face of evidence of research fraud . \n and it is commendable that the aoh is discussing these issues and plans to adopt stronger coi disclosure standards . \n seixas avoids the question however , as to why the aoh took no action to address the non - compliance with the cope code of conduct - a code the aoh says it follows . in july 2014 the journal current opinion in pulmonary medicine ( copm ) published an article by david bernstein , health risks of chrysotile asbestos , which stated : there are no conflicts of interest . \n bernstein did not comply with this requirement and indicated that he had no such activities . \n his work has been funded by asbestos industry organisations such as the chrysotile institute and the international chrysotile association . over the past several years \n , bernstein has been continuously financed by the asbestos industry to write articles and make presentations promoting use of chrysotile asbestos in brazil , china , colombia , india , indonesia , korea , mexico , quebec , russia , south africa , thailand , vietnam , malaysia , the philippines , ukraine and zimbabwe . in copm bernstein stated that he received no funding for his article . \n the article , however , relied on and cited bernstein s asbestos industry financed articles , which bernstein self - praised as being of outstanding importance . \n copm thus acted as a conduit for undeclared asbestos industry financed work which promoted the industry s interests . \n a complaint was submitted to the editors and publisher that bernstein had contravened the journal s coi disclosure requirements by failing to disclose his intimate long - standing and continuing financial ties to the asbestos industry . in response to the complaint , the publisher stated : we will publish an erratum that states he ( bernstein ) is a paid consultant to the chrysotile asbestos industry and name the commercial organisations he has been paid by in the last 36 months . \n the journal then published the following erratum:the health risk of chrysotile asbestos : erratumduring the editing process of the recent article by bernstein the conflicts of interest statement was wrongly amended from no conflicts of interest relevant to this article to there are no conflicts of interest. the publisher apologises for this error.dr bernstein would like to take this opportunity to clarify that he works as a scientific consultant to the chrysotile asbestos industry and gives presentations worldwide on the science of chrysotile asbestos . in the last three years \n he has received payment for his consultancy services from : honeywell international , chrysotile association and zimbabwe national chrysotile taskforce.dr bernstein received no payment compensation or funding for the current article . \n the health risk of chrysotile asbestos : erratum during the editing process of the recent article by bernstein the conflicts of interest statement was wrongly amended from no conflicts of interest relevant to this article to there are no conflicts of interest. the publisher apologises for this error . \n dr bernstein would like to take this opportunity to clarify that he works as a scientific consultant to the chrysotile asbestos industry and gives presentations worldwide on the science of chrysotile asbestos . in the last three years \n he has received payment for his consultancy services from : honeywell international , chrysotile association and zimbabwe national chrysotile taskforce . \n the article is solely his work and the opinions stated therein are his own . \n the implied interpretation put forward by the publisher , that only payments made for work conducted for the single particular article constitute coi , guts any meaningful coi disclosure ; it violates the journal s coi disclosure form , which requires authors to disclose financial activities outside the submitted work ; and it flaunts the icmje s coi standard that authors must disclose interactions with any entity that could be considered broadly relevant to the work . . in 2013 , \n bernstein and co - author jacques dunnigan published a review article , health risks of chrysotile revisited , in critical reviews in toxicology ( crt ) . \n they stated that the preparation of the review was funded by a grant from two asbestos industry organisations , the international chrysotile association ( ica ) and the chrysotile institute . \n the president of the ica , bob pigg , stated that no grant existed . instead , court documents show that bernstein submitted invoices of approximately us $ 2,800 per - diem to the ica for services rendered in writing the manuscript . in total , the ica paid us $ 179,306.51 , almost all of which was paid to bernstein , with a small amount going to dunnigan , for the writing of the article . \n the declaration of interests stated that bernstein had appeared as an expert witness in litigation concerned with \n alleged health effects of exposure to chrysotile and dunnigan had served as an expert witness on the health effects of chrysotile before the workers compensation board of qubec . \n the authors did not disclose the extensive financing they receive as consultants to the asbestos industry . \n the publisher of the journal , informa pharmaceutical science , requires full disclosure of all financial , consulting , and personal relationships that could be viewed as presenting a potential conflict of interest . furthermore , informa states that if any potential conflicts of interest are found to have been withheld following publication , the journal will proceed according to cope guidance . \n several scientists submitted a complaint to the editor of the journal , pointing out that the authors had violated the journal s coi requirements . \n clearly , the coi policy of critical reviews in toxicology is excellent on paper . in practice , however , it was disregarded . in 2013 , \n the international journal of environmental research and public health ( ijerpu ) published an article , domestic asbestos exposure : a review of epidemiologic and exposure data . \n the fourth , david dahlstrom , a former exponent employee , now has his own consulting company . between 2001 and 2009 , three auto companies ( chrysler , ford and gm ) paid exponent over 26 million dollars to help them defeat claims by mechanics and family members regarding asbestos - related disease . in the article in the ijerpu , the authors stated under conflicts of interest : no funding was obtained to prepare this manuscript . \n two of the authors ( david l. dahlstrom and fionna mowat ) have been designated as experts in litigation matters related to asbestos , and all authors have been retained as consultants in asbestos - related litigation matters . thus , apparently , the authors carried out this work pro bono . \n the article was conspicuously tailored to meet the exact needs of auto companies facing litigation on this issue and its conclusions were beneficial to these companies litigation activities : these results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation . under its potential coi requirements , the ijerpu states that financial support for the study must be fully disclosed . the publication fee for the article to be published in this open access journal was $ 1,750 . \n when asked , dahlstrom , said that he did not know who paid the fee for his article to be published , but felt confident that exponent had paid . \n a request was made to dahlstrom that , in the interest of transparency , he and his co - authors publish a correction in the ijerpu to disclose who paid the fee for publishing their manuscript and whether the payer had any coi . \n requests to the corresponding author of the article , emily goswami , and to the editor - in - chief of the journal , paul b. tchounwou , were met with silence . \n the publisher of the journal , mdpi ag in switzerland , responded saying : we are a member of cope and refer to their guidelines and advice when cases that are not clear - cut come up . \n payment of article processing fees would be considered as financial support for the research , so any conflict of interest between the funder and the research topic should be declared . when requested to disclose who paid the publication fee for the article and whether the payer had any coi , mdpi ag refused , however , to do so . \n authors need only acknowledge external funding sources , said mdpi ag . funding by the authors themselves or their employer does not need acknowledgment , as it does nt add an additional stakeholder . \n readers are not informed whether exponent paid its employees to write the article , and whether exponent paid the publication fee . \n they are not informed that exponent has received multi - million dollar contracts from auto companies that derived a benefit from the article . in its may 2012 issue , the european journal of cancer prevention ( ejcp ) published an article by carlo la vecchia and paolo boffetta , role of stopping exposure and recent exposure to asbestos in the risk of mesothelioma . \n authors must state all possible conflicts of interest in the manuscript , including financial , consultant , institutional and other relationships that might lead to bias or a conflict of interest . \n the authors stated they had no conflict of interest , when they had , in fact , been paid by companies facing criminal charges for asbestos - related deaths of workers from mesothelioma . in march 2011 and july 2011 they advanced in courts , as expert witnesses for the defence , the same arguments they put forward in the article they submitted to the ejcp in september 2011 . \n as soon as the print proofs of the ejcp paper became available in november 2011 , the company lawyers submitted them as evidence for the defence . \n these arguments enabled the current company managers to have impunity for the deaths of the workers . \n the authors stated that the italian cancer research association ( airc ) had funded the article . \n the editor - in - chief of the journal , jaak janssens , rejected the complaint , saying that the authors had reaffirmed that they had no coi . \n i still do nt see the conflict of interest , especially reading the content of the paper again . in march 2014 , \n a complaint was submitted to cope , pointing out that the journal had contravened specific provisions of cope s code of conduct by failing to disclose coi ; that the editor - in - chief had no known expertise on the asbestos issue but had approved the article in four days , which constituted an improper peer review process ; that no policies were in place for handling submissions from an associate editor to ensure unbiased review ; that the journal had not corrected the inaccurate funding information ; that the journal did not have a system for managing board members conflicts of interest and did not publish a list of board members relevant financial and other interests . on october 6 , 2014 , \n cope informed the journal that the information indicated that the authors had a coi , which should have been declared . \n on october 14 , phil daly , senior publisher , medical journals , at wolters kluwer , informed cope and the complainants : we are following your recommendation and we are preparing a note for publication that addresses these issues . in december 2014 , the ejcp published the following erratum : role of stopping exposure and recent exposure to asbestos in the risk of mesothelioma : erratumeuropean journal of cancer prevention 2015 , 24:68the authors would like to bring the reader s attention the conflicts of interest for their review paper ( la vecchia and boffetta , 2012 ) , and subsequent correspondence ( la vecchia and boffetta , 2014 ) . \n la vecchia has acted as expert witness for the defendants or the judge in criminal trials involving occasional exposure to asbestos , on behalf of enel ( rome , italy ) , edison ( milan , italy ) , pirelli tyres ( milan , italy ) and the ordinary tribunal of turin ( italy ) . \n boffetta has acted as expert witness for the defendants in a criminal trial involving exposure to asbestos in the manufacture of synthetic polymers and risk of mesothelioma ( edison , milan , italy).this work was not conducted with the contribution of the italian association for cancer research as stated on page 229 and the authors withdraw this statement on the acknowledgement of funding . \n role of stopping exposure and recent exposure to asbestos in the risk of mesothelioma : erratum european journal of cancer prevention 2015 , 24:68 the authors would like to bring the reader s attention the conflicts of interest for their review paper ( la vecchia and boffetta , 2012 ) , and subsequent correspondence ( la vecchia and boffetta , 2014 ) . \n la vecchia has acted as expert witness for the defendants or the judge in criminal trials involving occasional exposure to asbestos , on behalf of enel ( rome , italy ) , edison ( milan , italy ) , pirelli tyres ( milan , italy ) and the ordinary tribunal of turin ( italy ) . \n boffetta has acted as expert witness for the defendants in a criminal trial involving exposure to asbestos in the manufacture of synthetic polymers and risk of mesothelioma ( edison , milan , italy ) . \n this work was not conducted with the contribution of the italian association for cancer research as stated on page 229 and the authors withdraw this statement on the acknowledgement of funding . \n when asked what action will be taken with regard to the other issues raised in the complaint , daly stated : during our review , \n in addition to those points mentioned previously , we have raised the awareness on conflicts of interest . \n we have met some of the editors and have other communication and educational recommendations ( e.g. cope s elearning modules ) planned , and that we will follow these up on a regular basis . \n it is a positive outcome that , as a result of the complaint filed with cope , the ejcp finally published the erratum and is undertaking educational activities for the journal s editors re coi , education that is clearly much needed . \n the publisher deserves credit for taking action to comply with cope s standards , for publishing an erratum that addresses the coi issue clearly and for requiring the authors to accept responsibility for correcting their undeclared coi . relying on individuals to devote a year of continuous effort to persuade a cope member journal to comply with \n furthermore , cope stated it would take no action whatsoever , if the ejcp rejected cope s recommendation . \n the mounting evidence of systematic attempts by commercial interests to corrupt the literature can not be ignored , states the british medical journal ( bmj ) . \n the problem is so serious that the bmj has adopted a policy of zero tolerance on education articles with financial links to industry . \n yet , as the above examples show , when authors or journals violate coi requirements , no accountability mechanism is in place . without accountability , \n when cope receives complaints of violations of its code of conduct , cope acts as a neutral third party , with the overall aim that airing of these concerns will lead to an improvement in the understanding and practice of publication ethics more widely . \n cope also protects its member journals with anonymity , when it reports the cases on its website . \n in addition to using an internal , voluntary approach , comparable to corporate codes of conduct , cope underlines its lack of resources to handle complaints : complainants , journals and publishers should understand that cope is run by a voluntary council , and complaints are just one of a large number of activities undertaken by the council . . \n thus , a handful of cope volunteers deal with complaints of ethical violations on the edges of their spare time . \n the evidence clearly demonstrates that ensuring ethical publishing standards is not a priority of the scientific community . \n cope describes its role as being a forum for editors and publishers of peer - reviewed journals to discuss all aspects of publication ethics . \n neither the scientific community nor the publishing community has established an effective mechanism to deal with the coi issue . while hundreds of millions of dollars are spent on scholarly studies , virtually no funds are dedicated to upholding ethical standards and keeping the field honest . yet , as the bmj and unesco point out , this is a key public policy challenge of our times and poses a significant threat to human and environmental health . these are not abstract issues . \n countless lives have been destroyed because scientists , with undisclosed industry ties , have abetted endless industry subterfuge by creating doubt over the evidence . \n the strategy invented by the asbestos and tobacco industries has been appropriated by numerous other industries . \n in addition to the human tragedy , the economic costs caused by distorted scientific research of this kind are huge . a recent editorial in nature noted : transparency is the best defense against the purchase of undue influence by those with the most financial clout . in areas where tough standards are needed to protect public health , and powerful and wealthy interests have a financial incentive to water down these standards , such transparency is more than desirable \n margaret chan , director - general of the world health organization ( who ) , states that : research , evidence , and information are the foundation for sound health policies , for monitoring the impact , and for ensuring accountability . \n she then points out that even the very best scientific evidence can have less persuasive power than corporate lobbies . \n a major global problem , notes chan , is the fact that industries fund research geared to create doubt and prevent needed action to protect public health . \n industry suppression of scientific data creates misinformation and skews priorities for research and public health interventions , says the who , which has called for action to stop this abuse . \n the failure of the scientific community to take effective action to address conflict of interest has serious repercussions for public health policy . \n faced with this void , government scientists , who have less freedom to act than other scientists , are challenging the censorship and distortion of research that conflicts with agribusiness industry interests . \n public employees for environmental responsibility , for example , representing local , state and federal researchers in the u.s . , have filed a legal petition to require the u.s . \n department of agriculture to adopt policies to prevent political suppression or alteration of studies and to lay out clear procedures for investigating allegations of scientific misconduct . faced with the same problems of suppression and distortion of scientific research \n the professional institute of the public service of canada , representing 15,000 federal government scientists , engineers and researchers has tabled a proposal that would obligate the government to negotiate scientific integrity policies . \n the scientific community has created self - educational , professional mechanisms , such as cope and wame . \n what is urgently needed is that the scientific community create a practical mechanism whose purpose is to provide transparency , oversight and accountability to help stop the contamination of the scientific literature by undisclosed coi.leaders in the scientific community with an impeccable track record of commitment to ethical standards should launch an initiative to set up an independent , effective and credible mechanism , such as a center for monitoring and implementing publication ethics . \n it would take responsibility to investigate complaints , call for appropriate action and report publicly . \n even a small center , set up by respected scientists , would make a difference in creating transparency and accountability.a center that monitored and publicly reported contraventions would impact a journal s and a scientist s credibility . \n amnesty international does not have enforcement powers ; but its monitoring and public reporting role has great impact.the impact factor of journals should include contraventions of coi disclosure requirements reported by the center . even journals with loose ethical standards would take this consequence seriously.cope , icmje , wame and other organisations and agencies should provide funds ( perhaps 5 % of their budget ) to the center , since it will be playing a critical role to implement the fundamental goals to which these organisations are committed . if necessary , a special publication ethics implementation fee could be charged to members . if the scientific community is not willing to put resources into ethical quality control , then they will send a clear message that they have no serious commitment to ethical standards.the leadership committee should examine previous initiatives such as the integrity in science project , operated by the center for science in the public interest , which monitored the scientific literature for failure to disclose coi and maintained an open database of scientists ties to industry.institutions , such as the national library of medicine , that appear to confer credibility via listing studies , as well as government committees and agencies , such as the environmental protection agency and the occupational safety and health administration , universities and professional societies , must adopt a strict policy requiring public coi disclosure and specifying consequences for violations , such as exclusion from future participation or placement on a list of unsatisfactory coi disclosure conduct.the proposed ethics centre should play a leadership role in monitoring and reporting how well , or how badly , government agencies , professional societies , universities and journals are requiring and enforcing ethical standards . \n it could be a much needed , credible voice calling for practical and effective changes , where systemic and repeated problems exist.opportunities to develop practical solutions should be seized , such as funding currently offered by the office of research integrity , us department of health and human services , for conferences or workshops to produce tangible outcomes towards research integrity compliance .a campaign could be launched calling for 1 % of all research funding to be dedicated to ethical quality control carried out by the proposed ethics centre . as well as monitoring and reporting , the centre would thus be able to fund independent , public interest research to document significant ethical failures in the current system , such as fraudulent peer review mechanisms , and propose practical solutions . \n presently , these egregious problems are dealt with in an ad hoc , random manner.the centre would be able to address other instances of conflicting interests , such as the fact that scientists career opportunities may be affected by their ability to bring in grants or research contracts to their university .the leadership committee should draw on the expertise of individuals and organisations who have successfully implemented effective , credible accountability mechanisms to protect the public interest . \n various models could be examined - research integrity offices set up by universities ; ombudsman offices set up by governments . \n however , reliable knowledge and practical models exist as to how to make them effective . \n leaders in the scientific community with an impeccable track record of commitment to ethical standards should launch an initiative to set up an independent , effective and credible mechanism , such as a center for monitoring and implementing publication ethics . \n it would take responsibility to investigate complaints , call for appropriate action and report publicly . \n even a small center , set up by respected scientists , would make a difference in creating transparency and accountability . a center that monitored and \n amnesty international does not have enforcement powers ; but its monitoring and public reporting role has great impact . \n the impact factor of journals should include contraventions of coi disclosure requirements reported by the center . \n cope , icmje , wame and other organisations and agencies should provide funds ( perhaps 5 % of their budget ) to the center , since it will be playing a critical role to implement the fundamental goals to which these organisations are committed . \n if necessary , a special publication ethics implementation fee could be charged to members . \n if the scientific community is not willing to put resources into ethical quality control , then they will send a clear message that they have no serious commitment to ethical standards . \n the leadership committee should examine previous initiatives such as the integrity in science project , operated by the center for science in the public interest , which monitored the scientific literature for failure to disclose coi and maintained an open database of scientists ties to industry . \n institutions , such as the national library of medicine , that appear to confer credibility via listing studies , as well as government committees and agencies , such as the environmental protection agency and the occupational safety and health administration , universities and professional societies , must adopt a strict policy requiring public coi disclosure and specifying consequences for violations , such as exclusion from future participation or placement on a list of unsatisfactory coi disclosure conduct . \n the proposed ethics centre should play a leadership role in monitoring and reporting how well , or how badly , government agencies , professional societies , universities and journals are requiring and enforcing ethical standards . \n it could be a much needed , credible voice calling for practical and effective changes , where systemic and repeated problems exist . \n opportunities to develop practical solutions should be seized , such as funding currently offered by the office of research integrity , us department of health and human services , for conferences or workshops to produce tangible outcomes towards research integrity compliance . \n a campaign could be launched calling for 1 % of all research funding to be dedicated to ethical quality control carried out by the proposed ethics centre . as well as monitoring and reporting \n , the centre would thus be able to fund independent , public interest research to document significant ethical failures in the current system , such as fraudulent peer review mechanisms , and propose practical solutions . \n presently , these egregious problems are dealt with in an ad hoc , random manner . \n the centre would be able to address other instances of conflicting interests , such as the fact that scientists career opportunities may be affected by their ability to bring in grants or research contracts to their university . \n the leadership committee should draw on the expertise of individuals and organisations who have successfully implemented effective , credible accountability mechanisms to protect the public interest . \n various models could be examined - research integrity offices set up by universities ; ombudsman offices set up by governments . \n however , reliable knowledge and practical models exist as to how to make them effective . \n in 2011 and 2012 the annals of occupational hygiene ( aoh ) published two papers on research , financed by georgia pacific corporation ( gp ) regarding asbestos - containing joint compound that the company had sold in the past [ 11 , 12 ] . \n the company was facing court cases involving nearly $ 1 billion in liability related to this product . \n three of the five authors of the two articles worked for exponent and one was an employee who gp deliberately transferred for the purpose of carrying out the research , to be under the control of gp s litigation department . \n david michaels has described exponent as one of the premier firms in the product defense business . \n these firms profit by helping corporations minimize public health and environmental protection and fight claims of injury and illness . \n ( ) this is science for hire period , and it is extremely lucrative , states michaels . in june 2013 \n a new york court ruled that the two papers , and six additional similar articles financed by gp , constituted potential crime - fraud . \n the court stated that gp had commissioned the research with the intent of casting doubt on the capability of chrysotile asbestos to cause cancer , planned to use the articles to assist its litigation efforts , that gp s lawyers had significant input in the content , reporting of the results and prepublication review process of the articles , and that the articles failed to disclose the participation of the company lawyers . \n article 2.1 of cope s code of conduct requires that readers be informed whether the funder of the research had any role in the research and its publication and if so , what this was . \n they do not disclose that the company s litigation department had control over the work nor that one of the authors had been transferred so as to be under the direction of gp s litigation department . \n the role of a litigation department is not to be impartial or independent . its purpose is to do everything possible to defend the company s interests . \n the aoh should have withdrawn the articles or at the very least , required publication of an erratum in compliance with cope s article 2.1 , to disclose that the study was not a normal study , but controlled by gp s litigation department , with the research data thus rendered inaccessible under lawyer - client privilege . \n instead the article remains on the aoh website with no conflict of interest statement from the authors disclosing their own and their consulting companies financial ties to georgia pacific . \n the reader thus assumes that the article complies with cope s code of ethics , which it does not . \n the chief editor of the aoh noah seixas , published a commentary , protecting our science , stating that through reviewing the gp decision , it had become clear that the aoh should strengthen its procedures regarding coi . \n the aoh will monitor the results of the litigation involving the gp research , seixas wrote , and if the court finds evidence of fraud in the production of the research reported in our pages , we will act on these findings in accord with the cope guidelines for ethical publication . \n of course the aoh should take action in accord with the cope guidelines in the face of evidence of research fraud . \n and it is commendable that the aoh is discussing these issues and plans to adopt stronger coi disclosure standards . \n seixas avoids the question however , as to why the aoh took no action to address the non - compliance with the cope code of conduct - a code the aoh says it follows . \n in july 2014 the journal current opinion in pulmonary medicine ( copm ) published an article by david bernstein , health risks of chrysotile asbestos , which stated : \n bernstein did not comply with this requirement and indicated that he had no such activities . \n his work has been funded by asbestos industry organisations such as the chrysotile institute and the international chrysotile association . over the past several years \n , bernstein has been continuously financed by the asbestos industry to write articles and make presentations promoting use of chrysotile asbestos in brazil , china , colombia , india , indonesia , korea , mexico , quebec , russia , south africa , thailand , vietnam , malaysia , the philippines , ukraine and zimbabwe . in copm bernstein stated that he received no funding for his article . \n the article , however , relied on and cited bernstein s asbestos industry financed articles , which bernstein self - praised as being of outstanding importance . \n copm thus acted as a conduit for undeclared asbestos industry financed work which promoted the industry s interests . \n a complaint was submitted to the editors and publisher that bernstein had contravened the journal s coi disclosure requirements by failing to disclose his intimate long - standing and continuing financial ties to the asbestos industry . in response to the complaint , the publisher stated : we will publish an erratum that states he ( bernstein ) is a paid consultant to the chrysotile asbestos industry and name the commercial organisations he has been paid by in the last 36 months . \n the journal then published the following erratum:the health risk of chrysotile asbestos : erratumduring the editing process of the recent article by bernstein the conflicts of interest statement was wrongly amended from no conflicts of interest relevant to this article to there are no conflicts of interest. the publisher apologises for this error.dr bernstein would like to take this opportunity to clarify that he works as a scientific consultant to the chrysotile asbestos industry and gives presentations worldwide on the science of chrysotile asbestos . in the last three years \n he has received payment for his consultancy services from : honeywell international , chrysotile association and zimbabwe national chrysotile taskforce.dr bernstein received no payment compensation or funding for the current article . \n the health risk of chrysotile asbestos : erratum during the editing process of the recent article by bernstein the conflicts of interest statement was wrongly amended from no conflicts of interest relevant to this article to there are no conflicts of interest. the publisher apologises for this error . \n dr bernstein would like to take this opportunity to clarify that he works as a scientific consultant to the chrysotile asbestos industry and gives presentations worldwide on the science of chrysotile asbestos . in the last three years \n he has received payment for his consultancy services from : honeywell international , chrysotile association and zimbabwe national chrysotile taskforce . \n the article is solely his work and the opinions stated therein are his own . \n 2014 ; 20:366370 . the implied interpretation put forward by the publisher , that only payments made for work conducted for the single particular article constitute coi , guts any meaningful coi disclosure \n ; it violates the journal s coi disclosure form , which requires authors to disclose financial activities outside the submitted work ; and it flaunts the icmje s coi standard that authors must disclose interactions with any entity that could be considered broadly relevant to the work . . \n in 2013 , bernstein and co - author jacques dunnigan published a review article , health risks of chrysotile revisited , in critical reviews in toxicology ( crt ) . \n they stated that the preparation of the review was funded by a grant from two asbestos industry organisations , the international chrysotile association ( ica ) and the chrysotile institute . \n instead , court documents show that bernstein submitted invoices of approximately us $ 2,800 per - diem to the ica for services rendered in writing the manuscript . in total \n , the ica paid us $ 179,306.51 , almost all of which was paid to bernstein , with a small amount going to dunnigan , for the writing of the article . \n the declaration of interests stated that bernstein had appeared as an expert witness in litigation concerned with \n alleged health effects of exposure to chrysotile and dunnigan had served as an expert witness on the health effects of chrysotile before the workers compensation board of qubec . \n the authors did not disclose the extensive financing they receive as consultants to the asbestos industry . \n the publisher of the journal , informa pharmaceutical science , requires full disclosure of all financial , consulting , and personal relationships that could be viewed as presenting a potential conflict of interest . furthermore , informa states that if any potential conflicts of interest are found to have been withheld following publication , the journal will proceed according to cope guidance . \n several scientists submitted a complaint to the editor of the journal , pointing out that the authors had violated the journal s coi requirements . \n clearly , the coi policy of critical reviews in toxicology is excellent on paper . in practice , however , it was disregarded . \n in 2013 , the international journal of environmental research and public health ( ijerpu ) published an article , domestic asbestos exposure : a review of epidemiologic and exposure data . \n the fourth , david dahlstrom , a former exponent employee , now has his own consulting company . between 2001 and 2009 , three auto companies ( chrysler , ford and gm ) paid exponent over 26 million dollars to help them defeat claims by mechanics and family members regarding asbestos - related disease . in the article in the ijerpu , the authors stated under conflicts of interest : no funding was obtained to prepare this manuscript . \n two of the authors ( david l. dahlstrom and fionna mowat ) have been designated as experts in litigation matters related to asbestos , and all authors have been retained as consultants in asbestos - related litigation matters . \n the article was conspicuously tailored to meet the exact needs of auto companies facing litigation on this issue and its conclusions were beneficial to these companies litigation activities : these results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation . under its potential coi requirements , \n the ijerpu states that financial support for the study must be fully disclosed . \n the publication fee for the article to be published in this open access journal was $ 1,750 . \n when asked , dahlstrom , said that he did not know who paid the fee for his article to be published , but felt confident that exponent had paid . \n a request was made to dahlstrom that , in the interest of transparency , he and his co - authors publish a correction in the ijerpu to disclose who paid the fee for publishing their manuscript and whether the payer had any coi . \n requests to the corresponding author of the article , emily goswami , and to the editor - in - chief of the journal , paul b. tchounwou , were met with silence . \n the publisher of the journal , mdpi ag in switzerland , responded saying : we are a member of cope and refer to their guidelines and advice when cases that are not clear - cut come up . \n payment of article processing fees would be considered as financial support for the research , so any conflict of interest between the funder and the research topic should be declared . when requested to disclose who paid the publication fee for the article and whether the payer had any coi , mdpi ag refused , however , to do so . \n funding by the authors themselves or their employer does not need acknowledgment , as it does nt add an additional stakeholder . \n readers are not informed whether exponent paid its employees to write the article , and whether exponent paid the publication fee . \n they are not informed that exponent has received multi - million dollar contracts from auto companies that derived a benefit from the article . \n in its may 2012 issue , the european journal of cancer prevention ( ejcp ) published an article by carlo la vecchia and paolo boffetta , role of stopping exposure and recent exposure to asbestos in the risk of mesothelioma . \n authors must state all possible conflicts of interest in the manuscript , including financial , consultant , institutional and other relationships that might lead to bias or a conflict of interest . the authors stated they had no conflict of interest , when they had , in fact , been paid by companies facing criminal charges for asbestos - related deaths of workers from mesothelioma . in march 2011 and july 2011 \n they advanced in courts , as expert witnesses for the defence , the same arguments they put forward in the article they submitted to the ejcp in september 2011 . \n as soon as the print proofs of the ejcp paper became available in november 2011 , the company lawyers submitted them as evidence for the defence . \n these arguments enabled the current company managers to have impunity for the deaths of the workers . \n the authors stated that the italian cancer research association ( airc ) had funded the article . \n the editor - in - chief of the journal , jaak janssens , rejected the complaint , saying that the authors had reaffirmed that they had no coi . \n i still do nt see the conflict of interest , especially reading the content of the paper again . in march 2014 , \n a complaint was submitted to cope , pointing out that the journal had contravened specific provisions of cope s code of conduct by failing to disclose coi ; that the editor - in - chief had no known expertise on the asbestos issue but had approved the article in four days , which constituted an improper peer review process ; that no policies were in place for handling submissions from an associate editor to ensure unbiased review ; that the journal had not corrected the inaccurate funding information ; that the journal did not have a system for managing board members conflicts of interest and did not publish a list of board members relevant financial and other interests . on october 6 , 2014 , \n cope informed the journal that the information indicated that the authors had a coi , which should have been declared . \n on october 14 , phil daly , senior publisher , medical journals , at wolters kluwer , informed cope and the complainants : we are following your recommendation and we are preparing a note for publication that addresses these issues . in december 2014 , the ejcp published the following erratum : role of stopping exposure and recent exposure to asbestos in the risk of mesothelioma : erratumeuropean journal of cancer prevention 2015 , 24:68the authors would like to bring the reader s attention the conflicts of interest for their review paper ( la vecchia and boffetta , 2012 ) , and subsequent correspondence ( la vecchia and boffetta , 2014 ) . \n la vecchia has acted as expert witness for the defendants or the judge in criminal trials involving occasional exposure to asbestos , on behalf of enel ( rome , italy ) , edison ( milan , italy ) , pirelli tyres ( milan , italy ) and the ordinary tribunal of turin ( italy ) . \n boffetta has acted as expert witness for the defendants in a criminal trial involving exposure to asbestos in the manufacture of synthetic polymers and risk of mesothelioma ( edison , milan , italy).this work was not conducted with the contribution of the italian association for cancer research as stated on page 229 and the authors withdraw this statement on the acknowledgement of funding . \n role of stopping exposure and recent exposure to asbestos in the risk of mesothelioma : erratum european journal of cancer prevention 2015 , 24:68 the authors would like to bring the reader s attention the conflicts of interest for their review paper ( la vecchia and boffetta , 2012 ) , and subsequent correspondence ( la vecchia and boffetta , 2014 ) . \n la vecchia has acted as expert witness for the defendants or the judge in criminal trials involving occasional exposure to asbestos , on behalf of enel ( rome , italy ) , edison ( milan , italy ) , pirelli tyres ( milan , italy ) and the ordinary tribunal of turin ( italy ) . \n boffetta has acted as expert witness for the defendants in a criminal trial involving exposure to asbestos in the manufacture of synthetic polymers and risk of mesothelioma ( edison , milan , italy ) . \n this work was not conducted with the contribution of the italian association for cancer research as stated on page 229 and the authors withdraw this statement on the acknowledgement of funding . \n when asked what action will be taken with regard to the other issues raised in the complaint , daly stated : during our review , \n in addition to those points mentioned previously , we have raised the awareness on conflicts of interest . \n we have met some of the editors and have other communication and educational recommendations ( e.g. cope s elearning modules ) planned , and that we will follow these up on a regular basis . it is a positive outcome that , as a result of the complaint filed with cope , the ejcp finally published the erratum and is undertaking educational activities for the journal s editors re coi , education that is clearly much needed . \n the publisher deserves credit for taking action to comply with cope s standards , for publishing an erratum that addresses the coi issue clearly and for requiring the authors to accept responsibility for correcting their undeclared coi . relying on individuals to devote a year of continuous effort to persuade a cope member journal to comply with \n furthermore , cope stated it would take no action whatsoever , if the ejcp rejected cope s recommendation . \n the mounting evidence of systematic attempts by commercial interests to corrupt the literature can not be ignored , states the british medical journal ( bmj ) . \n the problem is so serious that the bmj has adopted a policy of zero tolerance on education articles with financial links to industry . yet , as the above examples show , when authors or journals violate coi requirements , no accountability mechanism is in place . without accountability , \n when cope receives complaints of violations of its code of conduct , cope acts as a neutral third party , with the overall aim that airing of these concerns will lead to an improvement in the understanding and practice of publication ethics more widely . \n cope also protects its member journals with anonymity , when it reports the cases on its website . \n in addition to using an internal , voluntary approach , comparable to corporate codes of conduct , cope underlines its lack of resources to handle complaints : complainants , journals and publishers should understand that cope is run by a voluntary council , and complaints are just one of a large number of activities undertaken by the council . . \n thus , a handful of cope volunteers deal with complaints of ethical violations on the edges of their spare time . \n the evidence clearly demonstrates that ensuring ethical publishing standards is not a priority of the scientific community . \n cope describes its role as being a forum for editors and publishers of peer - reviewed journals to discuss all aspects of publication ethics . \n neither the scientific community nor the publishing community has established an effective mechanism to deal with the coi issue . while hundreds of millions of dollars are spent on scholarly studies , virtually no funds are dedicated to upholding ethical standards and keeping the field honest . yet , as the bmj and unesco point out , this is a key public policy challenge of our times and poses a significant threat to human and environmental health . these are not abstract issues . \n countless lives have been destroyed because scientists , with undisclosed industry ties , have abetted endless industry subterfuge by creating doubt over the evidence . \n the strategy invented by the asbestos and tobacco industries has been appropriated by numerous other industries . \n in addition to the human tragedy , the economic costs caused by distorted scientific research of this kind are huge . a recent editorial in nature noted : transparency is the best defense against the purchase of undue influence by those with the most financial clout . in areas where tough standards are needed to protect public health , and powerful and wealthy interests have a financial incentive to water down these standards , such transparency is more than desirable \n margaret chan , director - general of the world health organization ( who ) , states that : \n research , evidence , and information are the foundation for sound health policies , for monitoring the impact , and for ensuring accountability . \n she then points out that even the very best scientific evidence can have less persuasive power than corporate lobbies . \n a major global problem , notes chan , is the fact that industries fund research geared to create doubt and prevent needed action to protect public health . \n industry suppression of scientific data creates misinformation and skews priorities for research and public health interventions , says the who , which has called for action to stop this abuse . \n the failure of the scientific community to take effective action to address conflict of interest has serious repercussions for public health policy . \n faced with this void , government scientists , who have less freedom to act than other scientists , are challenging the censorship and distortion of research that conflicts with agribusiness industry interests . \n public employees for environmental responsibility , for example , representing local , state and federal researchers in the u.s . , have filed a legal petition to require the u.s . \n department of agriculture to adopt policies to prevent political suppression or alteration of studies and to lay out clear procedures for investigating allegations of scientific misconduct . faced with the same problems of suppression and distortion of scientific research \n the professional institute of the public service of canada , representing 15,000 federal government scientists , engineers and researchers has tabled a proposal that would obligate the government to negotiate scientific integrity policies . \n the scientific community has created self - educational , professional mechanisms , such as cope and wame . \n what is urgently needed is that the scientific community create a practical mechanism whose purpose is to provide transparency , oversight and accountability to help stop the contamination of the scientific literature by undisclosed coi.leaders in the scientific community with an impeccable track record of commitment to ethical standards should launch an initiative to set up an independent , effective and credible mechanism , such as a center for monitoring and implementing publication ethics . \n it would take responsibility to investigate complaints , call for appropriate action and report publicly . \n even a small center , set up by respected scientists , would make a difference in creating transparency and accountability.a center that monitored and publicly reported contraventions would impact a journal s and a scientist s credibility . \n amnesty international does not have enforcement powers ; but its monitoring and public reporting role has great impact.the impact factor of journals should include contraventions of coi disclosure requirements reported by the center . even journals with loose ethical standards would take this consequence seriously.cope , icmje , wame and other organisations and agencies should provide funds ( perhaps 5 % of their budget ) to the center , since it will be playing a critical role to implement the fundamental goals to which these organisations are committed . if necessary , a special publication ethics implementation fee could be charged to members . if the scientific community is not willing to put resources into ethical quality control , then they will send a clear message that they have no serious commitment to ethical standards.the leadership committee should examine previous initiatives such as the integrity in science project , operated by the center for science in the public interest , which monitored the scientific literature for failure to disclose coi and maintained an open database of scientists ties to industry.institutions , such as the national library of medicine , that appear to confer credibility via listing studies , as well as government committees and agencies , such as the environmental protection agency and the occupational safety and health administration , universities and professional societies , must adopt a strict policy requiring public coi disclosure and specifying consequences for violations , such as exclusion from future participation or placement on a list of unsatisfactory coi disclosure conduct.the proposed ethics centre should play a leadership role in monitoring and reporting how well , or how badly , government agencies , professional societies , universities and journals are requiring and enforcing ethical standards . \n it could be a much needed , credible voice calling for practical and effective changes , where systemic and repeated problems exist.opportunities to develop practical solutions should be seized , such as funding currently offered by the office of research integrity , us department of health and human services , for conferences or workshops to produce tangible outcomes towards research integrity compliance .a campaign could be launched calling for 1 % of all research funding to be dedicated to ethical quality control carried out by the proposed ethics centre . as well as monitoring and reporting \n , the centre would thus be able to fund independent , public interest research to document significant ethical failures in the current system , such as fraudulent peer review mechanisms , and propose practical solutions . \n presently , these egregious problems are dealt with in an ad hoc , random manner.the centre would be able to address other instances of conflicting interests , such as the fact that scientists career opportunities may be affected by their ability to bring in grants or research contracts to their university .the leadership committee should draw on the expertise of individuals and organisations who have successfully implemented effective , credible accountability mechanisms to protect the public interest . \n various models could be examined - research integrity offices set up by universities ; ombudsman offices set up by governments . \n however , reliable knowledge and practical models exist as to how to make them effective . \n leaders in the scientific community with an impeccable track record of commitment to ethical standards should launch an initiative to set up an independent , effective and credible mechanism , such as a center for monitoring and implementing publication ethics . \n it would take responsibility to investigate complaints , call for appropriate action and report publicly . \n even a small center , set up by respected scientists , would make a difference in creating transparency and accountability . a center that monitored and \n amnesty international does not have enforcement powers ; but its monitoring and public reporting role has great impact . \n the impact factor of journals should include contraventions of coi disclosure requirements reported by the center . \n cope , icmje , wame and other organisations and agencies should provide funds ( perhaps 5 % of their budget ) to the center , since it will be playing a critical role to implement the fundamental goals to which these organisations are committed . if necessary , a special publication ethics implementation fee could be charged to members . \n if the scientific community is not willing to put resources into ethical quality control , then they will send a clear message that they have no serious commitment to ethical standards . \n the leadership committee should examine previous initiatives such as the integrity in science project , operated by the center for science in the public interest , which monitored the scientific literature for failure to disclose coi and maintained an open database of scientists ties to industry . \n institutions , such as the national library of medicine , that appear to confer credibility via listing studies , as well as government committees and agencies , such as the environmental protection agency and the occupational safety and health administration , universities and professional societies , must adopt a strict policy requiring public coi disclosure and specifying consequences for violations , such as exclusion from future participation or placement on a list of unsatisfactory coi disclosure conduct . \n the proposed ethics centre should play a leadership role in monitoring and reporting how well , or how badly , government agencies , professional societies , universities and journals are requiring and enforcing ethical standards . \n it could be a much needed , credible voice calling for practical and effective changes , where systemic and repeated problems exist . \n opportunities to develop practical solutions should be seized , such as funding currently offered by the office of research integrity , us department of health and human services , for conferences or workshops to produce tangible outcomes towards research integrity compliance . \n a campaign could be launched calling for 1 % of all research funding to be dedicated to ethical quality control carried out by the proposed ethics centre . as well as monitoring and reporting \n , the centre would thus be able to fund independent , public interest research to document significant ethical failures in the current system , such as fraudulent peer review mechanisms , and propose practical solutions . \n presently , these egregious problems are dealt with in an ad hoc , random manner . \n the centre would be able to address other instances of conflicting interests , such as the fact that scientists career opportunities may be affected by their ability to bring in grants or research contracts to their university . \n the leadership committee should draw on the expertise of individuals and organisations who have successfully implemented effective , credible accountability mechanisms to protect the public interest . \n various models could be examined - research integrity offices set up by universities ; ombudsman offices set up by governments . \n however , reliable knowledge and practical models exist as to how to make them effective . \n it is not beyond the capability of the scientific community to take practical action on the problem of coi . above", "role": "user" }, { "content": "the article addresses the failure of the scientific community to create an effective mechanism to protect the integrity of the scientific literature from improper influence by vested interests . \n the seriousness of this threat is increasingly recognized . \n scientists willing to distort scientific research to serve vested interests receive millions of dollars for their services . \n organizations such as the international committee of medical journal editors , the world association of medical editors and the committee on publication ethics ( cope ) have launched initiatives to establish international standards for conflict of interest ( coi ) disclosure . cope requires its 7,000 member journals to comply with its code of conduct for journal editors . while these initiatives are encouraging , they are internal educational endeavours only . \n five examples are given showing failure of cope member journals to comply with cope s code of conduct . \n while cope offers a complaint process , it involves only discussion and voluntary compliance . \n cope neither polices nor enforces its code . instead of the current feeble , un - resourced process , which delivers neither transparency nor accountability , \n the article proposes the creation of a mechanism that will employ specific , effective measures to address contraventions of coi disclosure requirements .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: pterostilbene is a phenol that is chemically related to resveratrol , a possible contributor to the french paradox which associates red wine consumption and lower coronary heart disease [ 1 , 2 ] . \n naturally found in blueberries and grapes , pterostilbene is a phytoalexin , a class of compounds naturally synthesized by plants during pathogen infection . \n the primary structural difference between pterostilbene and resveratrol is that pterostilbene contains two methoxy groups and one hydroxyl group while resveratrol has three hydroxyl groups . \n the two methoxy groups cause pterostilbene to be more lipophilic , which increases oral absorption and gives pterostilbene a higher potential for cellular uptake . \n pterostilbene has a longer half - life ( 105 minutes versus 14 minutes ) and higher oral bioavailability ( 80% versus 20% ) compared to resveratrol [ 47 ] . \n pterostilbene also has low total body clearance and subsequent vss which suggests extensive tissue distribution . \n animal studies have demonstrated efficacy in cardiometabolics ( e.g. , cholesterol and blood glucose ) , as well as cancer and cognition mediators [ 810 ] . \n substances that are generally recognized as safe ( gras ) are exempt from premarket food and drug administration ( fda ) review and may be intentionally added to food . \n the criteria for gras status are described in sections 201(s ) and 409 of the food additives amendment to the federal food , drug , and cosmetic act in 1958 . \n after 1958 , any food substance must be scientifically evaluated by experts and deemed safe for human consumption to attain the gras recognition . a short - term \n , open - label trial conducted in 13 healthy volunteers evaluated the in vivo activity of a pterostilbene - rich extract ( pterocarpus marsupium ) . \n this healthy volunteer trial did not examine synthesized or pure pterostilbene with a blinded control and did not investigate long - term safety in a target patient population . \n our trial is the first controlled trial performed in humans evaluating the safety of pterostilbene . \n this trial was a prospective , randomized , double - blind placebo - controlled intervention trial . \n the target population was patients with hypercholesterolemia , defined as a baseline total cholesterol 200 mg / dl and/or , baseline low - density lipoprotein cholesterol 100 mg / dl . \n patients were included if they were 18 years of age and on either no cholesterol therapy or cholesterol medication at a stable dose for at least 2 months prior to baseline laboratory . \n patients were excluded if they had significant hepatic , renal , or gastrointestinal tract disease , were receiving thiazolidinediones or fibric acid derivatives , had current overt cardiovascular disease , were women of reproductive potential not receiving birth control , or were pregnant / nursing women . \n subjects were divided equally into one of four groups : pterostilbene 50 mg twice daily ( low dose ) , pterostilbene 125 mg twice daily ( high dose ) , pterostilbene 50 mg / grape extract 100 mg twice daily ( low dose + grape extract ) , or matching placebo twice daily for 68 weeks . \n pterostilbene has demonstrated similar ppar- activation at approximately equimolar concentrations in animal models . since a standard human dose of ciprofibrate is 100 mg / \n day , this dose was selected for the lowest effective pterostilbene dose in monotherapy and combination . \n the higher daily dose was evaluated to assess for potential dose - related efficacy or adverse effect . \n all patients received identical counseling on lifestyle intervention and compliance with currently prescribed medication regimens . \n the manufacturer of the pterostilbene and placebo products was deemed in compliance by the fda current good manufacturing practices prior to the initiation of this trial . \n the safety markers included biochemical and subjective measures collected at two visits ( baseline and final ) . \n primary safety measures included alanine aminotransferase ( alt ) , aspartate aminotransferase ( ast ) , serum creatinine , and blood glucose . \n other safety markers include blood electrolytes and symptomatic subjective adverse drug reactions ( adrs ) collected during patient interviews at baseline and final visits . \n blood pressure , cholesterol , and weight were collected and reported separately as efficacy endpoints . \n linear mixed models were used to estimate primary safety measure treatment effects in order to account for intra subject associations arising from the repeated measures before and after longitudinal design . \n various models were fit to examine potential baseline effects including as appropriate the following:3-way interaction models of final outcome treatment group baseline value;2-way interaction models including all 2-way terms from ( 1 ) but excluding the 3-way term;models assuming baseline value affected change similarly across treatment groups;models assuming change in outcome were independent of baseline value . \n 3-way interaction models of final outcome treatment group baseline value ; 2-way interaction models including all 2-way terms from ( 1 ) but excluding the 3-way term ; models assuming baseline value affected change similarly across treatment groups ; models assuming change in outcome were independent of baseline value . each model was examined in unadjusted and adjusted form ( adjusting for age , gender and race ) . \n final reported treatment effects were obtained from the simplest appropriate adjusted model for each outcome . for secondary measures compared to baseline and/or placebo , \n a t - test was performed for continuous data and a fisher 's exact test was performed for dichotomous data . \n ( n = 60 ) , 2 patients were lost to follow up and 2 patients withdrew from the trial . \n one withdrawal was due to a lost trial medication bottle and the other withdrawal was due to worsening of cholesterol from an outside laboratory . \n there was no biochemical adrs on liver , kidney , or glucose markers ( see figure 1 ) . \n there were no statistically significant self - reported adrs versus placebo ( see table 2 ) . \n there were no major adrs ( e.g. , hospitalization , new - onset disease , infection , or death ) . \n there was a significant 3.6% reduction in bicarbonate in the high - dose group versus placebo ( p = 0.02 ) with a similar trend in both low - dose groups . the combination of grape extract and low - dose pterostilbene decreased bun by 7.1% from baseline ( p = 0.01 ) , but this reduction was not significant when compared to placebo ( p = 0.20 ) . \n additionally , we performed a single - blinded quality assessment of 2 samples from 3 randomly selected bottles in each trial arm . \n the average amount of pterostilbene was 95% or higher of the listed active ingredient amount in all samples evaluated . \n this is the first well - designed comparison of pterostilbene in a dose - ranging controlled human trial . \n there appears to be no direct effect of pterostilbene on measures of hepatic or renal function . \n currently available fda - approved ppar- agonists ( e.g. , fenofibrate or pioglitazone ) have both renal and hepatic dose adjustments required . \n fenofibrate has reported increases in serum creatinine from baseline by 12% as an adr . despite a high prevalence of a combination with statin \n there does not appear to be a need for such precautions with pterostilbene in doses up to 250 mg / day . \n myopathy was reported in patients not taking statins in both low - dose groups on 3 occasions . \n the lack of myopathy in the high - dose group and in statin users decreases the likelihood of this adr in relation to pterostilbene . \n though a drug - drug interaction with statins appears unlikely , possible drug - drug interactions with other medication classes warrant further investigation . \n there is unlikely an association of pterostilbene with gastrointestinal adr ( with or without food ) or itching as both reported adrs occurred to a low extent in only the placebo and high dose groups . while < 20% of completers reported any dietary changes during the trial , increased appetite \n although detailed changes in weight will be reported separately , there was no overall trend towards an increase in body weight . \n participants reporting this adr ( n = 4 ) all gained weight ( average 1.7 pounds ) . \n this unique response in a small subgroup of patients warrants periodic weight monitoring and further investigation . \n the slight decrease in bicarbonate could indicate a minor acidic effect of pterostilbene in the blood . \n this is an expected outcome due to the general acidic nature of phenols , such as pterostilbene . \n this finding does indicate that the encapsulated method of delivery used in this trial appears to be sufficient for blood absorption in humans . \n some limitations include a small trial population in one region of the united states over approximately 7 weeks . \n also , the total daily dose was restricted to 250 mg and no patient reported overuse . while there are no obvious signs of toxicity at this maximum dose , the potential for toxicity can not be excluded at higher doses . \n results of a previous short - term healthy volunteer trial demonstrated no baseline changes in blood count when evaluating a pterostilbene - rich extract . \n the risk of hematological or urinary adrs was not demonstrated in animal models or a common adr with currently available ppar- agonists . \n . additional evaluation of ecg monitoring is warranted considering that the target patient population is at - risk for cardiovascular disease and previous dietary supplements have demonstrated qtc prolongation ( i.e. , ephedra ) . in the united states , \n unfortunately , some dietary supplements may contain varying and even absent amounts of listed active ingredients . in this trial \n pterostilbene is generally safe for use in humans at doses up to 250 mg per day .", "role": "user" }, { "content": "objectives . the purpose of this trial was to evaluate the safety of long - term pterostilbene administration in humans . methodology . \n the trial was a prospective , randomized , double - blind placebo - controlled intervention trial enrolling patients with hypercholesterolemia ( defined as a baseline total cholesterol 200 mg / dl and/or baseline low - density lipoprotein cholesterol 100 mg / dl ) . \n eighty subjects were divided equally into one of four groups : ( 1 ) pterostilbene 125 mg twice daily , ( 2 ) pterostilbene 50 mg twice daily , ( 3 ) pterostilbene 50 mg + grape extract ( ge ) 100 mg twice daily , and ( 4 ) matching placebo twice daily for 68 weeks . \n safety markers included biochemical and subjective measures . \n linear mixed models were used to estimate primary safety measure treatment effects . \n results . \n the majority of patients completed the trial ( 91.3% ) . \n the average age was 54 years . \n the majority of patients were females ( 71% ) and caucasians ( 70% ) . \n there were no adverse drug reactions ( adrs ) on hepatic , renal , or glucose markers based on biochemical analysis . \n there were no statistically significant self - reported or major adrs . \n conclusion . \n pterostilbene is generally safe for use in humans up to 250 mg / day .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: one of the important risks is the existence of high levels of gasoline vapors including benzene that during work shifts employees are exposed to . \n employees in functional units are more vulnerable population because of their continuous contact with harmful substances such as benzene . \n based on usepa ( united state environmental protection agency ) and iarc ( international agency for research cancer ) reports , benzene has been classified to be a group a and class 1 human ( 1 ) . \n adverse health effects of benzene appear in two different type ; short - term and long - term . \n short - term effects are associated with high concentration and may involve headaches , dizziness , distraction and defects temporary memory and tremors . whereas , exposure to benzene in a long - term is connected to intricate adverse health effects such as immunological , hemato - toxicity , geno - toxicity , adverse effects on reproductive organs , and as well as various cancers ( 1 , 2 ) . \n therefore , a powerful method is required to predict existent exposure to harmful substances besides to evaluate probable adverse effects ( 3 ) . \n although several mathematical models have been carried out so far , there is high complexity related to chemical exposure in terms of human health . due to the lack of information about chemical impacts on human particularly in long - term impacts , \n some unpredictable factors that called uncertainties can affect health risk assessment ( 4 , 5 ) . \n health risk assessment through inhalation concerning benzene emission from equipment at the unit of benzene production was accomplished . \n this project is an example of using a hybrid approach that can incorporate uncertainties to assessment s process . \n major variables affecting the absorption of chemicals moreover key parameters in the dispersion of chemicals can be reflected in a hybrid system which combining fuzzy logic and neural networks ( 5 , 6 ) . in this research \n however , breathing rates are affected by many individual characteristics , including age , sex , weight , health , and level of physical activity ( running , jogging , etc . ) \n ( 5 , 9 ) . perhaps the first and distinguished use of fuzzy sets in health risk assessment was on the application of fuzzy logic in the environmental risk assessment ( 10 ) . \n one more example which connected to human health risk assessment is the application of fuzzy sets in human health risk assessment . \n fuzzy sets were employed to estimate carcinogenic risk caused by air pollution in ten russian cities ( 11 ) . \n the study area was in the northern part of the persian gulf with a distance of 10 miles from the coast . \n the plant mainly produced about one million tons annually of benzene , paraxylene , orto - xylene used to produce ethylbenzene , styrene , cyclohexane , and nitrobenzene . \n benzene from refinery streams was typically produced from catalytic reformats pyrolysis , gasoline , and toluene de - alkylation . \n this study focused on tasks and activities those are exposed to potential contact with benzene during refinery . \n main workplaces related to workers exposed to benzene such as loading of tankers were listed in table 1 . \n each workplace maybe had a different group of job and activities . in order to increase the information about jobs , activities , tasks , and \n main work places for workers the sampling procedure was based on absorption of benzene in an active charcoal tube ( active sampling ) ( 12 ) . \n skc model 222 pumps have been utilized for gas sampling . the glass tubes with a 6 mm external diameter , 4 mm internal diameter and 70 mm height , containing activated charcoal holder with a restrictive orifice ( separated by a 2-mm part of urethane foam ) were installed . \n the pump was adjusted to work for 30 min at a flow rate of 100 ml / min ( 12 ) . \n four measuring procedures were performed lasting one week in the middle of each season ( 12 , 13 ) . \n consequently , by the end of the week 70 samples were taken and during 15/2/2012 to 21/09/2013 totally 280 samples were collected . for detailed information stickers attached on each tube to tag sampling number , the time of end duration of sampling , the pump number , the humidity , the wet and dry temperature , and the date of sampling ( 13 ) . the human lifetime average daily dose ( ladd ) \n equation for a single chemical exposure proposed by u.s.epa ( 2011 ) that related to cancer risk model ( presuming that the inhalation is the only route of intake ) is , as shown in \n eq . \n ( 14 ) : \n ladd = ca.ir.ef.ed / bw.at \n the cancer risk ( cr ) is calculated for exposure to benzene using eq . \n ( 15 ) : \n cancer risk = ladd ( g / kg / day)sf ( g / kg / day)1 for equation 1 , ca is the concentration of a chemical in an exposure medium ( g / m ) , ir represents the inhalation rate ( m / h ) , ef is the exposure frequency ( number of working days per year ) , ed is the exposure duration ( working years ) , bw is the body weight ( kg ) , at is averaging time ( at=70 yr 365 d / year for carcinogens ) , ladd shows lifetime average daily dose ( g / kg / day ) and sf in equation 2 , is the cancer slope factor of benzene ( linear low - dose cancer potency factor ) ( 15 ) . \n the quality of data in equation 1 is uncertain even if definite exposure - related measurements are available for variables ( 16 ) . to explain more , some unpredictable parameters can change the results . as an illustration , movement of contaminants among environmental media changes \n remarkably the quality of data , therefore , uncertainty plays a crucial role involved in each variable as well as affected by physical and chemical factors ( 11 , 16 ) . \n these variables ; wind speed , ambient temperature , humidity and rainfall cause fluctuation in concentration of air pollutants ( 17 ) . \n furthermore , the inhalation rate is also influenced by multiple individual aspects including age , body weight , and amounts of physical activity ( 5 , 11 ) . \n owing to these numerous variables , the trustworthy approach is required to make a better risk evaluation . therefore , to overcome the problems of uncertainties the hybrid method was prepared ( 5 , 18 ) . \n in this figure , each tablet represents a sub - system combined ; they determine the chemical absorption rate through inhalation . \n the receptor description ( inhalation rate ) and dose estimation sections use a set of fuzzy rules and obtain the average daily inhalation dose , based on fuzzy inference . \n the exposure prediction section consists of a designed neural network using a new back - propagation algorithm . \n this section created in order to calculate of real ambient concentration . in the following sections , details about the subdivisions will be explained ( 5,18 ) . \n integrated system of risk assessment ( 5 ) a. artificial neural network b. life lifetime average daily inhalation dose standard quantities technique in health issues has been often vague and unclear adjectives such as a little , too much ; so at the start it is necessary to quantify these adjectives and change them into fuzzy sets ( 19 , 20 ) . in this section \n age , body weight , and activity tend to be the significant reasons of daily energy expenditure in healthy people for as long as is also in energy balance ( 20 , 21 ) . \n variables must be delineated with linguistic values rather than numerical values ( 5 , 21 ) . \n 2 shows one of the prepared fuzzy sets ( fuzzy numbers ) that related to age with three linguistic values . \n the horizontal vector indicates the size of the parameter and the vertical vector represents the degree of membership ( degree of dependence ) of each value ( 5 ) . \n membership functions of the variable age ( 5 ) the membership function for age was set to range from 18 to 80 yr ( 22 ) . \n using census and demographic details , age ( in years ) was divided into three fuzzy linguistic sets : low , ranging from 18 to 30 ; medium , ranging from 25 to 64 ; and high , ranging from 59 to 80 ( 5 , 22 ) . according to brainard and burmaster ( 23 ) , body weight ( 45110 kg ) \n it has been divided into three linguistic sets : low ( from 45 to 68 kg ) , medium ( from 56 to102 kg ) , and high ( from 90 to110 kg ) . \n fuzzy set was made for physical activity by means of four linguistic values and follows skewed ( normal ) distribution ( 5 ) . as for long - term physical activity levels ( pals ) , it is ranging from 1.2 to 2.5 times the bmr ( basal metabolic rate ) , where 1.2 represents the minimal intensity of activity and 2.5 shows a very physically active lifestyle . aging is a parameter that can remarkably decline high - intensity activity ( 21 ) . \n moreover , seven linguistic values ranging from 525 m / day with normal distribution have been provided to show inhalation rate , which is compatible with the human capability ( 14 ) . \n anns are working based on specified transfer function and made by artificial neurons ( 17 ) . \n using particular function anns can adjust the value of different weights properly . in order to neural network learning \n hence , the data set for this project were randomly divided into a ratio of 3:1 between training and testing sets , respectively ( 7 , 10 , 17 ) . as a result , available data ( 280 samples ) arbitrarily fragmented into two subsets . \n one of those was training groups and included 75% of data . by developing the model this group predicted the concentration of benzene for the second group that contained the 25% of data ( 10 , 17 ) . \n parameters ; wind speed , temperature , relative humidity , rainfall and measured concentration was chosen as model input data . the predicted benzene concentration was the output parameter . \n the third layer involved just one neuron which is output parameter and shows actual benzene concentration . \n a typical three - layer neural network is shown in fig . 3 ( 17 ) . \n selected three layer neural network ( 17 ) details of the meteorological monitoring devices before conducting the network preparation procedure , a training group ( 75% of the data ) consisting of 210 cases had to be prepared from the environmental data done by the back propagation paradigm . \n training group itself became divided into training set and testing set that this process conducted randomly . \n first one is the training set consisted of 90% of the data or 189 cases used to train the model . \n the second or final 10% contains 21 cases were left out as a test set ( 7 , 17 , 24 ) . \n output variables from the artificial neural network stage and fuzzy logic section contributed to the last part of the hybrid model and produced a chronic daily intake dose ( 18 ) . \n the predicted benzene concentrations lie between 0 and 67 ( g / m ) considered very high . \n ( 25 ) , the peak concentrations in the study area are high and the membership function for output and some fuzzy rules must be adjusted to range 0 and 67 ( g / m ) . \n the process of adjustment was easily done that indicates a powerful feature of the dose assessment modeling system as well as the adaptability to different scenarios . in different circumstances , \n the user can change fuzzy rules according to the different situations ( 6 , 9 ) . \n the outputs from the benzene prediction divided into six linguistic variables based on the frequency distribution of the data . \n the membership function of variable concentration is shown in fig . 4 ( 18 ) . \n the output from the receptor block was divided by the body weight to derive m / d / kg then contributed as input to the dose estimation section ( 5 , 18 ) . \n the daily intake rate for the dose estimation is expressed by four linguistic fuzzy sets and is expressed in m / d / kg ( 18 ) . finally , the life average daily intake dose defined as seven fuzzy linguistic values and ranging from 0 to 6 g / kg / d . \n input variable predicted concentration ( g / m ) a sample fuzzy inference calculation for the dose estimation block is shown in fig . \n 5 . where ir denotes inhalation rate normalized for body weight ( m / day / kg ) \n ; cc indicates chemical concentration ( g / m ) ; ladid = lifetime average daily inhalation dose ( g / kg / d ) . as an illustration , if the inhalation rate were considered 0.35 \n m / kg / d , the ambient benzene concentration is 15 g / m , lifetime average daily inhalation dose would be 1.63 g / kg / day . \n fuzzy inference for estimation of ladid ( matlab software ; fuzzy toolbox ) comparison of observed and predicted concentration ( source : author 's calculations ) the output from this last module gives the overall dose through inhalation for each individual around the site , taking into account both the exposure factors and the receptor factors in a quantitative way , based on neural network and fuzzy inference . \n when the exposure is quantified , combined with integrated risk information system ( iris ) toxicity factors , then as a final point the related risk can be estimated . \n the study area was in the northern part of the persian gulf with a distance of 10 miles from the coast . \n the plant mainly produced about one million tons annually of benzene , paraxylene , orto - xylene used to produce ethylbenzene , styrene , cyclohexane , and nitrobenzene . \n benzene from refinery streams was typically produced from catalytic reformats pyrolysis , gasoline , and toluene de - alkylation . \n this study focused on tasks and activities those are exposed to potential contact with benzene during refinery . \n main workplaces related to workers exposed to benzene such as loading of tankers were listed in table 1 . \n each workplace maybe had a different group of job and activities . in order to increase the information about jobs , activities , tasks , and \n the sampling procedure was based on absorption of benzene in an active charcoal tube ( active sampling ) ( 12 ) . \n skc model 222 pumps have been utilized for gas sampling . the glass tubes with a 6 mm external diameter , 4 mm internal diameter and 70 mm height , containing activated charcoal holder with a restrictive orifice ( separated by a 2-mm part of urethane foam ) were installed . \n the pump was adjusted to work for 30 min at a flow rate of 100 ml / min ( 12 ) . \n four measuring procedures were performed lasting one week in the middle of each season ( 12 , 13 ) . \n consequently , by the end of the week 70 samples were taken and during 15/2/2012 to 21/09/2013 totally 280 samples were collected . for detailed information stickers attached on each tube to tag sampling number , the time of end duration of sampling , the pump number , the humidity , the wet and dry temperature , and the date of sampling ( 13 ) . \n the human lifetime average daily dose ( ladd ) equation for a single chemical exposure proposed by u.s.epa ( 2011 ) that related to cancer risk model ( presuming that the inhalation is the only route of intake ) is , as shown in \n eq . \n ( 14 ) : \n ladd = ca.ir.ef.ed / bw.at \n the cancer risk ( cr ) is calculated for exposure to benzene using eq . \n ( 15 ) : \n cancer risk = ladd ( g / kg / day)sf ( g / kg / day)1 for equation 1 , ca is the concentration of a chemical in an exposure medium ( g / m ) , ir represents the inhalation rate ( m / h ) , ef is the exposure frequency ( number of working days per year ) , ed is the exposure duration ( working years ) , bw is the body weight ( kg ) , at is averaging time ( at=70 yr 365 d / year for carcinogens ) , ladd shows lifetime average daily dose ( g / kg / day ) and sf in equation 2 , is the cancer slope factor of benzene ( linear low - dose cancer potency factor ) ( 15 ) . the quality of data in equation 1 is uncertain even if definite exposure - related measurements are available for variables ( 16 ) . to explain more , some unpredictable parameters can change the results . as an illustration , movement of contaminants among environmental media changes \n remarkably the quality of data , therefore , uncertainty plays a crucial role involved in each variable as well as affected by physical and chemical factors ( 11 , 16 ) . \n these variables ; wind speed , ambient temperature , humidity and rainfall cause fluctuation in concentration of air pollutants ( 17 ) . \n furthermore , the inhalation rate is also influenced by multiple individual aspects including age , body weight , and amounts of physical activity ( 5 , 11 ) . \n owing to these numerous variables , the trustworthy approach is required to make a better risk evaluation . \n therefore , to overcome the problems of uncertainties the hybrid method was prepared ( 5 , 18 ) . the construction of the system is displayed in fig . 1 ( 5 ) . \n in this figure , each tablet represents a sub - system combined ; they determine the chemical absorption rate through inhalation . \n the receptor description ( inhalation rate ) and dose estimation sections use a set of fuzzy rules and obtain the average daily inhalation dose , based on fuzzy inference . \n the exposure prediction section consists of a designed neural network using a new back - propagation algorithm . \n this section created in order to calculate of real ambient concentration . in the following sections , details about the subdivisions will be explained ( 5,18 ) . \n integrated system of risk assessment ( 5 ) a. artificial neural network b. life lifetime average daily inhalation dose \n standard quantities technique in health issues has been often vague and unclear adjectives such as a little , too much ; so at the start it is necessary to quantify these adjectives and change them into fuzzy sets ( 19 , 20 ) . in this section \n age , body weight , and activity tend to be the significant reasons of daily energy expenditure in healthy people for as long as is also in energy balance ( 20 , 21 ) . \n variables must be delineated with linguistic values rather than numerical values ( 5 , 21 ) . \n 2 shows one of the prepared fuzzy sets ( fuzzy numbers ) that related to age with three linguistic values . \n the horizontal vector indicates the size of the parameter and the vertical vector represents the degree of membership ( degree of dependence ) of each value ( 5 ) . \n membership functions of the variable age ( 5 ) the membership function for age was set to range from 18 to 80 yr ( 22 ) . using census and demographic details , age ( in years ) \n was divided into three fuzzy linguistic sets : low , ranging from 18 to 30 ; medium , ranging from 25 to 64 ; and high , ranging from 59 to 80 ( 5 , 22 ) . according to brainard and burmaster ( 23 ) , body weight ( 45110 kg ) \n it has been divided into three linguistic sets : low ( from 45 to 68 kg ) , medium ( from 56 to102 kg ) , and high ( from 90 to110 kg ) . \n fuzzy set was made for physical activity by means of four linguistic values and follows skewed ( normal ) distribution ( 5 ) . \n as for long - term physical activity levels ( pals ) , it is ranging from 1.2 to 2.5 times the bmr ( basal metabolic rate ) , where 1.2 represents the minimal intensity of activity and 2.5 shows a very physically active lifestyle . aging is a parameter that can remarkably decline high - intensity activity ( 21 ) . \n moreover , seven linguistic values ranging from 525 m / day with normal distribution have been provided to show inhalation rate , which is compatible with the human capability ( 14 ) . \n anns are working based on specified transfer function and made by artificial neurons ( 17 ) . \n using particular function anns can adjust the value of different weights properly . in order to neural network learning \n hence , the data set for this project were randomly divided into a ratio of 3:1 between training and testing sets , respectively ( 7 , 10 , 17 ) . as a result , available data ( 280 samples ) arbitrarily fragmented into two subsets . \n one of those was training groups and included 75% of data . by developing the model this group predicted the concentration of benzene for the second group that contained the 25% of data ( 10 , 17 ) . parameters \n ; wind speed , temperature , relative humidity , rainfall and measured concentration was chosen as model input data . \n the third layer involved just one neuron which is output parameter and shows actual benzene concentration . \n a typical three - layer neural network is shown in fig . 3 ( 17 ) . \n selected three layer neural network ( 17 ) details of the meteorological monitoring devices before conducting the network preparation procedure , a training group ( 75% of the data ) consisting of 210 cases had to be prepared from the environmental data done by the back propagation paradigm . \n training group itself became divided into training set and testing set that this process conducted randomly . \n first one is the training set consisted of 90% of the data or 189 cases used to train the model . \n the second or final 10% contains 21 cases were left out as a test set ( 7 , 17 , 24 ) . \n output variables from the artificial neural network stage and fuzzy logic section contributed to the last part of the hybrid model and produced a chronic daily intake dose ( 18 ) . \n the predicted benzene concentrations lie between 0 and 67 ( g / m ) considered very high . \n ( 25 ) , the peak concentrations in the study area are high and the membership function for output and some fuzzy rules must be adjusted to range 0 and 67 ( g / m ) . \n the process of adjustment was easily done that indicates a powerful feature of the dose assessment modeling system as well as the adaptability to different scenarios . in different circumstances , \n the user can change fuzzy rules according to the different situations ( 6 , 9 ) . \n the outputs from the benzene prediction divided into six linguistic variables based on the frequency distribution of the data . \n the membership function of variable concentration is shown in fig . 4 ( 18 ) . \n the output from the receptor block was divided by the body weight to derive m / d / kg then contributed as input to the dose estimation section ( 5 , 18 ) . \n the daily intake rate for the dose estimation is expressed by four linguistic fuzzy sets and is expressed in m / d / kg ( 18 ) . finally , the life average daily intake dose defined as seven fuzzy linguistic values and ranging from 0 to 6 g / kg / d . \n input variable predicted concentration ( g / m ) a sample fuzzy inference calculation for the dose estimation block is shown in fig . \n 5 . where ir denotes inhalation rate normalized for body weight ( m / day / kg ) ; cc indicates chemical concentration ( g / m ) ; ladid = lifetime average daily inhalation dose ( g / kg / d ) . as an illustration , \n m / kg / d , the ambient benzene concentration is 15 g / m , lifetime average daily inhalation dose would be 1.63 g / kg / day . \n fuzzy inference for estimation of ladid ( matlab software ; fuzzy toolbox ) comparison of observed and predicted concentration ( source : author 's calculations ) the output from this last module gives the overall dose through inhalation for each individual around the site , taking into account both the exposure factors and the receptor factors in a quantitative way , based on neural network and fuzzy inference . \n when the exposure is quantified , combined with integrated risk information system ( iris ) toxicity factors , then as a final point the related risk can be estimated . \n in this section , leave - one - out cross - validation ( loocv ) was followed with the aim of training and testing the ann model . frequently , one sample is kept for testing while the rest is used for training up to all samples are finally tested ( 26 ) . \n before the proposed model is applied to the particular application , it must be trained using all available samples ( 27 ) . \n the training of network continued until maximum correlation within the measured and predicted output was achieved ( table 3 ) . \n correlation expressed by r - squared that r is coefficient of multiple determinations and relative root mean square error ( rmse ) ( 26 ) . \n correlation results are perfect when an r - squared value of 1 , a very good fit is next to 1 and a very poor fit less than 0 . on the other side , \n how much the value of rrmse is smaller ; the performance of the model is better . \n ambient air temperature affects significantly the exposure levels , as a result , the high temperatures in the summer and spring explains the increased benzene concentrations in exposure values . \n when temperatures are very low ( winter - time ) , the exposure levels are less than usual for an equivalent quantity of close benzene level ( fig . 8) . \n the presence of wind reduces exposure levels , especially to employees who are performing outdoor activities . \n no strong correlation found between wind speed and exposure levels of employees working in laboratory and control room . \n annually average concentration ( source : author 's calculation ) seasonal comparison of ambient concentration of benzene ( source : author 's calculations ) the measured benzene concentrations and the related exposure levels are not considered as an acute health risk ; meanwhile , this is the possibility of leukemia existence after chronic occupational contact with benzene due to measured concentration . \n long - term individual risk will be calculated by combining usepa integrated risk information system ( iris ) toxicity features with results from exposure assessment section ( 18 ) . \n the individual excess cr was calculated for exposure to benzene through inhalation is presented in table 4 . \n the best estimate for the variable distribution of risk in a population implied 33% of people exposed less than 110 . \n based on epa clean air act risk range , 110 risk range is considered as the most health protective end of the range ( 27 , 28 ) . whereas 110 is the midpoint of risk range and 67% of the population is ranging from 110 to 9.810 cancer risk probability ( 27 , 28 ) . \n individual health risk assessment ( based on average exposure obtained by passive sampling ) the average estimated risk for all work areas considering exposure to benzene is equal to 2.410 , ranging from 1.510 to 6.910 . \n the results counsel potential cancer risk for period exposure to benzene within the numerous areas but at different levels ( fig . \n these differences result from differences in the employee 's type of activity , age , weight , and breathing rate that in common methods of risk assessment they did not pay attention to them \n in this section , leave - one - out cross - validation ( loocv ) was followed with the aim of training and testing the ann model . frequently , one sample is kept for testing while the rest is used for training up to all samples are finally tested ( 26 ) . \n before the proposed model is applied to the particular application , it must be trained using all available samples ( 27 ) . \n the training of network continued until maximum correlation within the measured and predicted output was achieved ( table 3 ) . \n correlation expressed by r - squared that r is coefficient of multiple determinations and relative root mean square error ( rmse ) ( 26 ) . \n correlation results are perfect when an r - squared value of 1 , a very good fit is next to 1 and a very poor fit less than 0 . on the other side , \n how much the value of rrmse is smaller ; the performance of the model is better . \n ambient air temperature affects significantly the exposure levels , as a result , the high temperatures in the summer and spring explains the increased benzene concentrations in exposure values . \n when temperatures are very low ( winter - time ) , the exposure levels are less than usual for an equivalent quantity of close benzene level ( fig . 8) . \n the presence of wind reduces exposure levels , especially to employees who are performing outdoor activities . \n no strong correlation found between wind speed and exposure levels of employees working in laboratory and control room . \n annually average concentration ( source : author 's calculation ) seasonal comparison of ambient concentration of benzene ( source : author 's calculations ) \n the measured benzene concentrations and the related exposure levels are not considered as an acute health risk ; meanwhile , this is the possibility of leukemia existence after chronic occupational contact with benzene due to measured concentration . \n long - term individual risk will be calculated by combining usepa integrated risk information system ( iris ) toxicity features with results from exposure assessment section ( 18 ) . \n the individual excess cr was calculated for exposure to benzene through inhalation is presented in table 4 . \n the best estimate for the variable distribution of risk in a population implied 33% of people exposed less than 110 . \n based on epa clean air act risk range , 110 risk range is considered as the most health protective end of the range ( 27 , 28 ) . whereas 110 is the midpoint of risk range and 67% of the population is ranging from 110 to 9.810 cancer risk probability ( 27 , 28 ) . \n individual health risk assessment ( based on average exposure obtained by passive sampling ) the average estimated risk for all work areas considering exposure to benzene is equal to 2.410 , ranging from 1.510 to 6.910 . \n the results counsel potential cancer risk for period exposure to benzene within the numerous areas but at different levels ( fig . \n these differences result from differences in the employee 's type of activity , age , weight , and breathing rate that in common methods of risk assessment they did not pay attention to them . potential cancer risk \n the complete conception in establishing an integrated product is a dynamic model for risk estimation , able to evaluate probable interactions among the levels of benzene exposure through different task designs , those lead to different levels of benzene metabolic rate and subsequently to discount risk estimations ( 29 , 30 ) . in this model , \n risk factors that can influence inhalation rate were age , body weight , and physical activity of persons . \n these parameters considered as the input variable of fuzzy logic in order to estimate exposure level for the various situation of employees . \n the hybrid system also used artificial neural network approach to predict actual atmospheric benzene concentration . \n major variables affecting pollutant concentration were wind speed , ambient temperature , humidity , and rainfall . \n expert viewpoint is used as fuzzy rules and the rules can be changed according to the needs of the user . \n the produced composite model shows promise as a new tool for chemical exposure and health risk assessment , which it allows multiple uncertainties incorporate into health risk assessment . \n in this project , the new hybrid dose model has been able to replicate a measured exposure prospering believed to be more representative of actual intake dose than data from previously accepted methods . \n overall , according to aforementioned reasons this system can produce risk assessment data that appear realistic . \n ethical issues ( including plagiarism , informed consent , misconduct , data fabrication and/or falsification , double publication and/or submission , redundancy , etc . ) have been completely observed by the author .", "role": "user" }, { "content": "background : reliable methods are crucial to cope with uncertainties in the risk analysis process . \n the aim of this study is to develop an integrated approach to assessing risks of benzene in the petrochemical plant that produces benzene . \n we offer an integrated system to contribute imprecise variables into the health risk calculation.methods:the project was conducted in asaluyeh , southern iran during the years from 2013 to 2014 . \n integrated method includes fuzzy logic and artificial neural networks . \n each technique had specific computational properties . \n fuzzy logic was used for estimation of absorption rate . \n artificial neural networks can decrease the noise of the data so applied for prediction of benzene concentration . \n first , the actual exposure was calculated then it combined with integrated risk information system ( iris ) toxicity factors to assess real health risks.results:high correlation between the measured and predicted benzene concentration was achieved ( r2= 0.941 ) . as for variable distribution , the best estimation of risk in a population implied \n 33% of workers exposed less than 1105 and 67% inserted between 1.0105 to 9.8105 risk levels . \n the average estimated risk of exposure to benzene for entire work zones is equal to 2.4105 , ranging from 1.5106 to 6.9105.conclusion:the integrated model is highly flexible as well as the rules possibly will be changed according to the necessities of the user in a different circumstance . \n the measured exposures can be duplicated well through proposed model and realistic risk assessment data will be produced .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: congenital heart defects ( chd ) , especially with left - to - right shunts , are the cause of reduced physical performance . \n the presence of congenital abnormalities in the heart of grown - up patients , as well as structural changes due to the surgical treatment in the childhood contributes to excessive hypokinesia . in most cases \n the reason of low exercise tolerance is not an active disease itself but the fear of health worsening due to excessive training . \n there is still no clear answer to the major , while repeatedly asked question , whether chd is a definitive contraindication to competitive sports , especially extreme sports . \n general guidelines for physical activity in the grown - up patients with chd ( grown - up patients with congenital heart disease \n guch ) recommend an individual approach to participation in sports . a suitable strategy of intensity of trainings and preparation for more excessive challenges \n the form of an individualized comprehensive cardiac rehabilitation program ( ccr - guch ) is preferred . \n mountain climbing is associated with physical efforts in terms of rapid atmospheric pressure changes , low oxygen concentration in the air , and permanently reduced ambient temperature . \n therefore , high mountain activities result in a heavy cardiovascular load as well . in high altitudes symptoms of acute mountain sickness ( ams ) can appear despite certain preparing , and they include headache , sleep disturbances , loss of appetite , peripheral edema ( usually face edema , mainly the eyelids ) , strong palpitations , nausea and/or vomiting , and dyspnea after a relatively little effort . the purpose of the study was to present endurance parameters and a personalized comprehensive cardiac rehabilitation program before extreme mountain climbing of a 27-year - old patient with an uncorrected ventricular septal defect ( vsd ) . \n a 26-year - old female patient with an uncorrected congenital perimembranous ventricular septal defect ( vsd ) , a member of a professional mountaineering alpine club , was admitted to the department of cardiac rehabilitation before the planned high - mountain expedition . \n her past sporting achievements were limited to successful climbing up to the level of 2500 m above sea level . professional preparation and assessment of actual exercise capacity \n was recommended by the cardiologist , who was afraid of the limitations arising from chd before scheduled extreme climbing mont blanc ( 4000 m above sea level ) for the first time in her sport career . \n the heart defect was diagnosed after birth , the patient was regularly controlled in the outpatient clinic for pediatric and congenital heart defects . \n the heart defect was regarded as borderline with a small left - to - right shunt ( qp : qs - ratio below 1.5 : 1 ) , with no signs of pulmonary overflow or pulmonary hypertension . \n the girl was not referred for surgical treatment due to a stable clinical course and mild hemodynamic consequences , with good physical capacity . \n her life - passion was mountain climbing , and there were no established medical limitations for mountaineering up to the altitude of 2000 m. current echocardiographic examination showed a normal ventricular size and systolic function , regular anatomy and the function of the valves , with a restrictive left - to - right shunt via the small ( 4 mm ) perimembranous vsd . \n doppler examination revealed a high interventricular gradient ( 93 mmhg ) and no features of pulmonary hypertension . \n electrocardiography ( ecg ) recorded a regular sinus rhythm 98 beats / min , clockwise rotation and incomplete right axis deviation . \n laboratory blood tests remained entirely normal . before to the exercise capacity assessment and the beginning of individualized endurance training , the patient was presented to the consultant cardiothoracic surgeon . after meticulous analysis of her current clinical status and echocardiographic data , the history of the disease and finally the lack of free consent to any operation declared by the patient , she was disqualified from surgery or percutaneous intervention . in view of the strong plans of high - mountain climbing with a summer mont blanc expedition , \n the patient was admitted for a three - week 's long personalized comprehensive ccr - guch program . \n her training heart rate zone was kept in the range 130 - 146 beats per minute . \n ccr - guch was based on an endurance cardiac program , with activation of respiratory muscles and elements of strength training . \n an important education how to behave in extreme physical loads with self - monitoring techniques , and learning of effective breathing with a heart rate control were conducted . in order to fully assess the cardiopulmonary reserve and exercise capacity before and after the climbing , \n cardiac imaging was supplemented by a functional assessment , including cardiopulmonary exercise testing ( cpx ) . \n we used a classic bicycle ergometer following the ramp protocol with an initial load of 5 w and the increase of load at 10 w/1 min . \n this test was terminated with a load of 129 w , peak oxygen uptake ( vo2 peak ) 26 ml / kg / min , hr 172/min , peak respiratory exchange ratio ( rer peak ) 1.13 , vo2 ( at ) 18 ml / kg / min , ve ( vco2 ) slope 27 . the second cpx was conducted after her returning from the expedition . \n both tests were terminated due to maximal fatigue of the patient ( 18 points of borg scale ) . \n the anthropometric parameters and results of both exercise tests are shown in table i. parameters obtained during the stress test before departing and after returning from the expedition cpx 1 initial cardiopulmonary exercise test before the expedition , cpx 2 cardiopulmonary exercise test after the expedition , bmi body mass index , peakvo2 peak oxygen consumption , vo2at oxygen consumption at the anaerobic threshold , ve / vco2 slope \n work load , hrmax maximal heart rate , hr at rest heart rate at the rest , bf breathing frequency , ve at rest lung ventilation at rest , vemax lung ventilation at peak of exercise while climbing the mont blanc ( 4810 m above sea level ) the patient was asked to check and register her pulse regularly , and to observe accompanying clinical symptoms . \n those recordings were conducted in each intermediate station in the mountains . while climbing the following values of heart rates were obtained : station nidd aigle 2372 m above sea level : hr 68/min ; station refuge des houches rognesles 2768 m above sea level : hr 108/min ; station aig du gouter 3817 m above sea level : hr 116/min . after entering the station vallot 4363 m above sea level at air temperature of minus 8c : hr 116/min . \n the first symptoms of ams in the form of worse - being and perceived needs of longer rest already appeared above the height of 3000 m above sea level . due to the severity of the symptoms of ams in the form of persistent headaches , shortness of breath , dry cough and general weakness , the patient decided to stop climbing after 14 days of the expedition , reaching a height of 4400 m above sea level . \n the problems of adolescent patients with congenital heart diseases ( guch ) are becoming more noticeable due to the increasing number of such cases in the population . in this group \n there are also patients awaiting an unlimited participation in life activities , including extreme sports . \n proper selection of forms of activity and exercise preparation for extreme sports is an important issue , which may anticipate not only successes in competitions , but first of all , the safety of the constraints imposed by congenital heart disease . exercise capacity of patients with chd in the polish population , with those after correction of the most typical cardiac septal defects , is reduced , and worse when compared to healthy population [ 35 ] . an effective way to improve exercise tolerance is participation in comprehensive cardiac rehabilitation programs dedicated to guch patients [ 68 ] . \n following literature data and institutional experience , authors undertook a task of preparation of an adolescent patient with uncorrected vsd for high mountain climbing . \n this extreme sport naturally appeared to be reserved for a highly selected group of completely healthy enthusiasts , in whom any deterioration of health preclude further climbing . \n the issue of a potentially negative impact of competitive sports on a completely healthy heart can not be ignored either . \n the exposure of patients with chd to changes in atmospheric pressure at high altitude was the subject of detailed studies in patients flying in planes . \n the final arguments for controversial qualification of women for ccr - guch before extreme climbing were excluded pulmonary hypertension and reverse right - to - left shunts . for the preparation for the expenditure , \n the preparation process was carried out for a month , including initial interval endurance exercise training , with a continuous increase until the work load of 100 watts . \n learning of effective breathing was very valuable in the patient 's treatment . despite the natural value of breathing control in extreme circumstances , it helped to gain the ability to acquire the respiratory compensation in rarefied mountain air . following the effective breathing instructions at the time of climbing she was able to increase the volume of breath and reduce the energy associated with frequent shallow breaths . \n we want to emphasize that in her opinion these practical skills were very helpful to facilitate extreme effort in high altitudes , against the threat of ams . \n this is confirmed by the observed slight decrease in ventilation at rest and during maximum exercise efforts , accompanied by a subjective sense to improve heart performance in subsequent cpx studies . \n the program was carried out using standard equipment used for ccr [ 8 , 11 , 12 ] . \n the process of preparation of the individual with an uncorrected chd following general principles of endurance training appears to be an original solution of a rare problem , although we can not exclude the use of our experience also in other guch patients declaring their intention to participate in extreme sports . \n directly after the completion of individualized ccr - guch training , the patient underwent a cpx to check and prove the ability to undertake difficulties of the expedition . \n both tests were performed on the same bicycle ergometer according to a ramp protocol with the initial load of 5 w and a constant 10 watt / min load increment . \n the anaerobic threshold was determined by the v - slope method and verified by respiratory equivalents , according to generally accepted principles for the assessment of patients with cardiovascular problems [ 11 , 13 ] . during subsequent exercise tests ( before and after climbing ) \n , no significant endurance parameter changes were observed , while there was a significant decrease in resting and maximum hr . \n these changes are typical of patients undergoing regular endurance training [ 9 , 14 ] . in our opinion , \n participation in extreme mountaineering of the patient with an uncorrected chd must not be considered in terms of competition , it is just a personal success by itself . \n meticulous medical examination and specialized preparation allowed for safe overcome of hardships of the mont blanc expedition . \n the ability to have self - conscious control of the cardiovascular and pulmonary indicators like hr , bp and breathing parameters , proved to be decisive for the safety of our patient . \n regardless of comprehensive preparation , the symptoms of foreseeable ams appeared , while were properly identified by the woman . \n the intense course of ams could be caused by insufficiently short acclimatization time at each altitude ( rest periods ) , adapted to healthy members of the expedition . since research on small groups and descriptions of clinical cases are treated in accordance with the principles of ebm as not very strong evidence , it is desirable to extend the research on the impact of ccr and high mountain expeditions on population of young adults with hemodynamically insignificant chd . \n physical activity associated with a heavy load in people with an uncorrected chd who have not developed pulmonary hypertension and reverse right - to - left flow seems to be safe.participation of guch patients in extreme mountain climbing requires special preparation , individually designed endurance training and education program , conducted by the team of professionals in specialist centers . \n physical activity associated with a heavy load in people with an uncorrected chd who have not developed pulmonary hypertension and reverse right - to - left flow seems to be safe . \n participation of guch patients in extreme mountain climbing requires special preparation , individually designed endurance training and education program , conducted by the team of professionals in specialist centers . \n ", "role": "user" }, { "content": "congenital heart defects ( chd ) are the cause of reduced physical performance . \n the presence of congenital abnormalities in the heart of grown - up patients contributes to excessive hypo - kinesia . \n we present endurance parameters and a personalized comprehensive cardiac rehabilitation program before an extreme mountain climbing of a 27-year - old patient with an uncorrected ventricular septal defect ( vsd ) . \n a 26-year - old female patient with an uncorrected congenital vsd was admitted to the department of cardiac rehabilitation before the planned high - mountain expedition . professional preparation and assessment of actual exercise capacity \n was performed before scheduled extreme climbing . \n we conclude that physical activity associated with a heavy load in people with uncorrected chd who have not developed pulmonary hypertension and reverse right - to - left flow seems to be safe , while participation of grown - up patients with congenital heart disease ( guch ) in extreme mountain climbing requires special preparation , individually designed endurance training and education program , conducted by the team of professionals in specialist centers .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: this is a retrospective analysis of a prospective study that was approved by our institutional review board and is compliant with the health insurance and portability and accountability act ( hipaa ) . \n all patients or their legal representative(s ) provided written informed consent for participation in one of two specific studies and for inclusion in our institutional research database . \n we evaluated safety data obtained from our database of ferumoxytolenhanced mri ( femri ) exams performed between june 2013 and march 2016 . briefly , study data were collected and managed using redcap20 electronic data capture tools hosted at our institution . \n redcap ( research electronic data capture ) is a secure , webbased application designed to support data capture for research studies by providing 1 ) an intuitive user interface for validated data entry ; 2 ) audit trails for tracking data manipulation and export procedures ; 3 ) automated export procedures for data downloads to common statistical packages ; and 4 ) procedures for importing data from external sources . \n preliminary phenotypic data fields currently include general demographics , clinical indication , laboratory data , imaging sequence type , contrast type and administration , hemodynamic measurements , and limited outcome parameters . \n data summarized in the current study consists of internal , singlecenter data from the authors ' institution . clinical eligibility criteria for femri \n included patients of all ages , gender , ethnicity , and renal function without a history of allergic reaction to iron agents or laboratory work concerning iron disorders . \n those with routine clinical contraindications for mri ( metallic foreign objects , deep brain stimulators , shrapnel , aneurysm clips , cochlear implants , dental implants ) were not eligible . \n those with implanted cardiac devices were included ; device and institutionalspecific safety protocols were followed according to previously published work.21 all consecutive femri exams logged in our database were included . to compare the effects of ferumoxytol on objective measures of blood pressure , heart rate , oxygen saturation , and endtidal co2 to those of gadofosveset \n , we identified an age and gendermatched group of patients who had undergone gadofosveset enhanced ( ge ) and fe cardiovascular mri exams and whose detailed physiologic documentation were available for review . \n gadofosveset was chosen as a comparator because , as an fdaapproved gbca , it has the longest intravascular halflife and its relaxivity properties most closely resemble those of ferumoxytol . \n aes and their severity were defined according to the common terminology criteria for adverse events v4.0 ( ctcae ) developed by the national cancer institute22 : aes are any unfavorable and unintended signs , symptoms , or disease temporally associated with the administration of ferumoxytol or gadofosveset . \n note that this definition does not require that the ae be causally related to the agent , only to its temporal administration . \n an attending physician assessed the patient 's baseline condition and was present throughout the mri exams . \n aes were graded as : mild ( grade 1 ) , moderate ( grade 2 ) , severe ( grade 3 ) , lifethreatening ( grade 4 ) , or fatal ( grade 5 ) ( table 1a ) . \n the causal relationship of aes to ferumoxytol administration was also rated by the attending physician as definitely , probably , possibly , or unrelated ( table 1b ) and confirmed by consensus discussion with referring physicians . \n all mri scans were performed in facilities where resuscitation equipment was readily available and with close proximity to an emergency room or acute care facility . \n classification of adverse events and their relationship to ferumoxytol administration based on the common terminology criteria for adverse events ( ctcae ) v4.0 developed by the national cancer institute(22 ) . \n adverse events ( ae ) are defined as any unfavorable and unintended signs , symptoms , or disease temporally associated ' with the administration of ferumoxytol regardless of the causal relationship . \n definitions are as defined in ctcae v4.0 : instrumental adls refer to preparing meals , shopping for groceries or clothes , using the telephone , managing money , etc . \n selfcare adls refer to bathing , dressing and undressing , feeding self , using the toilet , taking medications , and not bedridden . for those examined under general \n anesthesia , cardiovascular anesthesiologists performed continuous monitoring of vital signs including extremity pulse oximetry waveforms and ventilatory parameters.23 hemodynamic and respiratory parameters including heart rate , blood pressure ( noninvasive and/or direct arterial ) , pulse oximetry , and endtidal co2 were recorded in the electronic medical record and encompassed a 30minute time window following ferumoxytol or gadofosveset administration . \n although the stability of physiologic parameters and the absence or presence of aes were documented in the electronic medical records for all patients in our study , detailed data on the specifics of physiological parameters ( heart rate , blood pressure , pulse oximetry ) were entered into the imaging database only for those patients who underwent imaging under anesthesia . \n our hemodynamic and respiratory monitoring and recording procedures were independent of whether ferumoxytol was administered as a bolus or slow infusion . \n technical details for femri have been previously described.4 , 8 , 9 , 24 images were acquired at both 1.5 t ( n = 19 ) and 3.0 t ( n = 198 ) . \n each stock 17ml ferumoxytol vial containing 510 mg elemental iron ( 30 mg fe / ml ) and was diluted 810 based on the patient 's size . while the adult therapeutic dose calls for two 510mg injections given 38 days apart , the dose for diagnostic purposes is generally 4 mg / kg ( 280 mg for an average adult ) . prior to march 2015 , we administered ferumoxytol as an iv bolus up to 2 mg / kg for firstpass imaging and steadystate images were subsequently acquired ( at a total dose of 4 mg fe / kg ) . following the fda 's warning of rare hypersensitivity reactions and recommendation for slow iv infusion , we administered dilute ferumoxytol only as a slow infusion over 10 minutes and only steadystate imaging was performed . for gadofosveset enhanced mri ( gemri ) , \n gadofosveset trisodium was administered at 0.06 mmol / kg as a single bolus and technical details have also been previously described.23 \n statistical analyses were performed using medcalc 12.0.1.0 ( mariakerke , belgium ) . \n data were tested for normality using the d'agostinopearson test and are reported as mean standard deviation or median and interquartile range ( iqr ) . \n analysis of variance ( anova ) was used to compare between group ( femri vs. gemri ) and withingroup variations in physiologic indices immediately preinjection , immediately postinjection , and 30 minutes postinjection . \n bonferroni correction was used to adjust for multiple comparisons . a twosided pvalue < 0.05 was considered statistically significant . \n aes and their severity were defined according to the common terminology criteria for adverse events v4.0 ( ctcae ) developed by the national cancer institute22 : aes are any unfavorable and unintended signs , symptoms , or disease temporally associated with the administration of ferumoxytol or gadofosveset . \n note that this definition does not require that the ae be causally related to the agent , only to its temporal administration . \n an attending physician assessed the patient 's baseline condition and was present throughout the mri exams . \n aes were graded as : mild ( grade 1 ) , moderate ( grade 2 ) , severe ( grade 3 ) , lifethreatening ( grade 4 ) , or fatal ( grade 5 ) ( table 1a ) . \n the causal relationship of aes to ferumoxytol administration was also rated by the attending physician as definitely , probably , possibly , or unrelated ( table 1b ) and confirmed by consensus discussion with referring physicians . \n all mri scans were performed in facilities where resuscitation equipment was readily available and with close proximity to an emergency room or acute care facility . \n classification of adverse events and their relationship to ferumoxytol administration based on the common terminology criteria for adverse events ( ctcae ) v4.0 developed by the national cancer institute(22 ) . \n adverse events ( ae ) are defined as any unfavorable and unintended signs , symptoms , or disease temporally associated ' with the administration of ferumoxytol regardless of the causal relationship . \n definitions are as defined in ctcae v4.0 : instrumental adls refer to preparing meals , shopping for groceries or clothes , using the telephone , managing money , etc . \n selfcare adls refer to bathing , dressing and undressing , feeding self , using the toilet , taking medications , and not bedridden . \n for those examined under general anesthesia , cardiovascular anesthesiologists performed continuous monitoring of vital signs including extremity pulse oximetry waveforms and ventilatory parameters.23 hemodynamic and respiratory parameters including heart rate , blood pressure ( noninvasive and/or direct arterial ) , pulse oximetry , and endtidal co2 were recorded in the electronic medical record and encompassed a 30minute time window following ferumoxytol or gadofosveset administration . \n although the stability of physiologic parameters and the absence or presence of aes were documented in the electronic medical records for all patients in our study , detailed data on the specifics of physiological parameters ( heart rate , blood pressure , pulse oximetry ) were entered into the imaging database only for those patients who underwent imaging under anesthesia . \n our hemodynamic and respiratory monitoring and recording procedures were independent of whether ferumoxytol was administered as a bolus or slow infusion . \n technical details for femri have been previously described.4 , 8 , 9 , 24 images were acquired at both 1.5 t ( n = 19 ) and 3.0 t ( n = 198 ) . \n each stock 17ml ferumoxytol vial containing 510 mg elemental iron ( 30 mg fe / ml ) and was diluted 810 based on the patient 's size . while the adult therapeutic dose calls for two 510mg injections given 38 days apart , the dose for diagnostic purposes is generally 4 mg / kg ( 280 mg for an average adult ) . prior to march 2015 , we administered ferumoxytol as an iv bolus up to 2 mg / kg for firstpass imaging and steadystate images were subsequently acquired ( at a total dose of 4 mg fe / kg ) . following the fda 's warning of rare hypersensitivity reactions and recommendation for slow iv infusion , we administered dilute ferumoxytol only as a slow infusion over 10 minutes and only steadystate imaging was performed . for gadofosveset enhanced mri ( gemri ) , gadofosveset trisodium was administered at 0.06 mmol / kg as a single bolus and technical details have also been previously described.23 \n data were tested for normality using the d'agostinopearson test and are reported as mean standard deviation or median and interquartile range ( iqr ) . \n analysis of variance ( anova ) was used to compare between group ( femri vs. gemri ) and withingroup variations in physiologic indices immediately preinjection , immediately postinjection , and 30 minutes postinjection . \n a total of 217 unique consecutive patients ( n = 91 pediatric ; n = 126 adults ) , ages 3 days to 94 years , had 237 injections for femri over a 2.75year period at our institution . \n ninetyfour patients underwent femri under anesthesia , of whom 71 had detailed hemodynamic and physiologic data available in our database . \n the pregnancies were all considered highrisk and femri examinations were performed to exclude placenta accreta ( n = 4 ) and renal vein thrombosis ( n = 1 ) in the setting of acute renal failure . there was a total of 237 ferumoxytol injections : 124 injections without anesthesia , 108 injections under anesthesia , and five injections under mild oral sedation . in all , 104 patients received bolus injections , while 113 received slow infusions of ferumoxytol . \n a group of 23 patients with congenital heart disease ( ages 2 days to 12.5 years , 43% female , weighing 11 [ 3.617.8 ] kg , creatinine 26.5 [ 24.844.2 ] \n mol / l , estimated glomerular filtration rate [ egfr ] 21 to > 60 ml / min/1.73 m ) , had gemri under general anesthesia . \n age spectrum of unique patients ( n = 217 , 91 pediatric , 126 adults ) who had femri \n . patients of a wide age range including those with immature ( pediatrics ) or impaired renal function ( elderly ) underwent femri . \n age definitions : neonates 1 month ; infants > 1 month to 2 years ; children > 2 years to 12 years ; adolescents > 12 years to 16 years ; young adults > 16 years to 39 years ; middleaged adults > 39 years to 65 years ; older adults > 65 years \n . characteristics of patients undergoing ferumoxytolenhanced mri data are reported as median ( interquartile range ) . for adults ( age 18 years ) , \n the egfr was derived from the mdrd ( modification of diet in renal disease ) equation ( levey as et al . \n , the bedside schwartz equation was used to calculate egfr ( schwartz gj et al . \n no severe , lifethreatening , or fatal aes occurred acutely or at followup for either femri or gemri . \n average followup time was 14.9 8.4 months for femri and 45.3 5.7 months for gemri . \n patient 1 was a 20yearold female with ckd and an upper extremity thrombus who underwent femri to exclude thrombi in the central veins . prior to undergoing the femri , she felt nauseated and claustrophobic , but decided to proceed with femri and had a recurrent bout of nausea immediately after a 0.8ml timing test injection of ferumoxytol . \n the following day , ferumoxytol was administered while the patient was in her room ; she was transported to the mri suite and had successful imaging under anesthesia . \n her nausea was possibly related to ferumoxytol injection , but may have been coincidental , since she was felt to have uremic gastritis . \n patient 2 was a 19yearold male with oxalosis and ckd on dialysis who underwent femri without anesthesia to exclude the presence of a thrombus at the tip of the dialysis catheter . \n the patient was on opioid medications for chronic pain and was in mild distress prior to the mri exam . \n within several minutes of ferumoxytol injection , he felt nauseated , but did not vomit . \n his nausea was felt definitely related to ferumoxytol injection , possibly with potentiation by opiates . \n two other mild aes were noted ( one case of nausea and vomiting and one case with hypoglycemic symptoms ) , but these were felt to be secondary to the patients ' comorbidities and unrelated to ferumoxytol administration . \n tryptase levels ( marker of mast cell release ) were not obtained . on review of medical records at followup \n , there were 10 deaths , all of which were secondary to progression of underlying disease and unrelated to ferumoxytol injection . \n distribution and transient temporal variations of physiologic indices for patients undergoing femri and gemri under general anesthesia are presented in fig . \n , there were no statistically significant changes in the physiological parameters between preinjection and up to 30 minutes postinjection ( p = 0.12 , 95% confidence interval [ ci ] 93106 bpm for heart rate , p = 0.92 , 95% ci 4957 for mean arterial blood pressure , p = 0.68 , 95% ci 9598 mmhg for oxygen saturation , and p = 0.86 , 95% ci 3235 mmhg for endtidal co2 ) . \n betweengroup ( femri vs. gemri ) variations among age and gendermatched groups also showed no statistical difference in heart rate ( p = 0.69 , 95% ci 96113 bpm ) , mean arterial blood pressure ( p = 0.74 , 95% ci 4452 mmhg ) , oxygen saturation ( p = 0.76 , 95% ci 9498% ) , and endtidal co2 ( p = 0.73 , 95% ci 3137 mmhg ) . comparison of hemodynamic parameters between those who received bolus injections vs. slow infusions of ferumoxytol also showed no significant difference in mean arterial blood pressure ( p = 0.12 , 95% ci 5058 mmhg ) or heart rate ( p = 0.25 , 95% ci = 91105 bpm ) . \n data reflect values immediately preinjection ( preinj ) , immediately postinjection ( postinj ) , and 30minute postinjection of ferumoxytol or gadofosveset . \n the bottom and top of the box represent the first and third quartile , while the band within the box represents the median . a : the hr ( bpm ) , mean arterial blood pressure ( map , mmhg ) , and pulse oximetry ( % ) distribution of all patients ( n = 94 , ages 3 days to 86 years , 36% female ) undergoing femri . variations in hr ( p = 0.12 , \n 95% ci 93106 bpm ) , map ( p = 0.92 , 95% ci 4957 mmhg ) , and pulse oximetry ( p = 0.68 , 95% ci 9598% ) were not statistically significant . \n b : the hr , map , and pulse oximetry distribution between a comparable group of patients undergoing femri ( n = 23 , ages 3 days to 13 years , 43% female ) and gemri ( n = 23 , ages 2 days to 12.6 years , 43% female ) under general anesthesia . \n betweengroup variations were not statistically significant ( hr [ p = 0.69 , 95% ci 96113 bpm ] , map [ p = 0.74 , 95% ci 4452 mmhg ] , pulse oximetry [ p = 0.76 , 95% ci 9498% ] ) . \n bpm , beats per minute ; hr , heart rate ; map , mean arterial blood pressure . \n a total of 217 unique consecutive patients ( n = 91 pediatric ; n = 126 adults ) , ages 3 days to 94 years , had 237 injections for femri over a 2.75year period at our institution . \n ninetyfour patients underwent femri under anesthesia , of whom 71 had detailed hemodynamic and physiologic data available in our database . \n the pregnancies were all considered highrisk and femri examinations were performed to exclude placenta accreta ( n = 4 ) and renal vein thrombosis ( n = 1 ) in the setting of acute renal failure . there was a total of 237 ferumoxytol injections : 124 injections without anesthesia , 108 injections under anesthesia , and five injections under mild oral sedation . in all , 104 patients received bolus injections , while 113 received slow infusions of ferumoxytol . \n a group of 23 patients with congenital heart disease ( ages 2 days to 12.5 years , 43% female , weighing 11 [ 3.617.8 ] kg , creatinine 26.5 [ 24.844.2 ] \n mol / l , estimated glomerular filtration rate [ egfr ] 21 to > 60 ml / min/1.73 m ) , had gemri under general anesthesia . \n age spectrum of unique patients ( n = 217 , 91 pediatric , 126 adults ) who had femri \n . patients of a wide age range including those with immature ( pediatrics ) or impaired renal function ( elderly ) underwent femri . \n age definitions : neonates 1 month ; infants > 1 month to 2 years ; children > 2 years to 12 years ; adolescents > 12 years to 16 years ; young adults > 16 years to 39 years ; middleaged adults > 39 years to 65 years ; older adults > 65 years \n . characteristics of patients undergoing ferumoxytolenhanced mri data are reported as median ( interquartile range ) . for adults ( age 18 years ) , \n the egfr was derived from the mdrd ( modification of diet in renal disease ) equation ( levey as et al . \n , the bedside schwartz equation was used to calculate egfr ( schwartz gj et al . \n no severe , lifethreatening , or fatal aes occurred acutely or at followup for either femri or gemri . \n average followup time was 14.9 8.4 months for femri and 45.3 5.7 months for gemri . \n patient 1 was a 20yearold female with ckd and an upper extremity thrombus who underwent femri to exclude thrombi in the central veins . prior to undergoing the femri , she felt nauseated and claustrophobic , but decided to proceed with femri and had a recurrent bout of nausea immediately after a 0.8ml timing test injection of ferumoxytol . \n the study was terminated and she returned to her room with stable vital signs . the following day , \n ferumoxytol was administered while the patient was in her room ; she was transported to the mri suite and had successful imaging under anesthesia . \n her nausea was possibly related to ferumoxytol injection , but may have been coincidental , since she was felt to have uremic gastritis . \n patient 2 was a 19yearold male with oxalosis and ckd on dialysis who underwent femri without anesthesia to exclude the presence of a thrombus at the tip of the dialysis catheter . \n the patient was on opioid medications for chronic pain and was in mild distress prior to the mri exam . \n within several minutes of ferumoxytol injection , he felt nauseated , but did not vomit . \n his nausea was felt definitely related to ferumoxytol injection , possibly with potentiation by opiates . \n two other mild aes were noted ( one case of nausea and vomiting and one case with hypoglycemic symptoms ) , but these were felt to be secondary to the patients ' comorbidities and unrelated to ferumoxytol administration . \n tryptase levels ( marker of mast cell release ) were not obtained . on review of medical records at followup \n , there were 10 deaths , all of which were secondary to progression of underlying disease and unrelated to ferumoxytol injection . \n distribution and transient temporal variations of physiologic indices for patients undergoing femri and gemri under general anesthesia are presented in fig . \n , there were no statistically significant changes in the physiological parameters between preinjection and up to 30 minutes postinjection ( p = 0.12 , 95% confidence interval [ ci ] 93106 bpm for heart rate , p = 0.92 , 95% ci 4957 for mean arterial blood pressure , p = 0.68 , 95% ci 9598 mmhg for oxygen saturation , and p = 0.86 , 95% ci 3235 mmhg for endtidal co2 ) . \n betweengroup ( femri vs. gemri ) variations among age and gendermatched groups also showed no statistical difference in heart rate ( p = 0.69 , 95% ci 96113 bpm ) , mean arterial blood pressure ( p = 0.74 , 95% ci 4452 mmhg ) , oxygen saturation ( p = 0.76 , 95% ci 9498% ) , and endtidal co2 ( p = 0.73 , 95% ci 3137 mmhg ) . \n comparison of hemodynamic parameters between those who received bolus injections vs. slow infusions of ferumoxytol also showed no significant difference in mean arterial blood pressure ( p = 0.12 , 95% ci 5058 mmhg ) or heart rate ( p = 0.25 , 95% ci = 91105 bpm ) . \n data reflect values immediately preinjection ( preinj ) , immediately postinjection ( postinj ) , and 30minute postinjection of ferumoxytol or gadofosveset . \n the bottom and top of the box represent the first and third quartile , while the band within the box represents the median . a : the hr ( bpm ) , mean arterial blood pressure ( map , mmhg ) , and pulse oximetry ( % ) distribution of all patients ( n = 94 , ages 3 days to 86 years , 36% female ) undergoing femri . \n variations in hr ( p = 0.12 , 95% ci 93106 bpm ) , map ( p = 0.92 , 95% ci 4957 mmhg ) , and pulse oximetry ( p = 0.68 , 95% ci 9598% ) were not statistically significant . \n b : the hr , map , and pulse oximetry distribution between a comparable group of patients undergoing femri ( n = 23 , ages 3 days to 13 years , 43% female ) and gemri ( n = 23 , ages 2 days to 12.6 years , 43% female ) under general anesthesia . \n betweengroup variations were not statistically significant ( hr [ p = 0.69 , 95% ci 96113 bpm ] , map [ p = 0.74 , 95% ci 4452 mmhg ] , pulse oximetry [ p = 0.76 , 95% ci 9498% ] ) . \n bpm , beats per minute ; hr , heart rate ; map , mean arterial blood pressure . \n the results of our study showed no severe , lifethreatening , or fatal aes caused by 237 ferumoxytol injections in 217 unique patients across a wide range of ages , renal function , and clinical indications . \n based on defined criteria set forth in ctcae v4.0 , there were two mild aes , which were related or possibly related to ferumoxytol injection . \n no aes occurred in any patients examined under anesthesia in either the femri group or the gemri group . \n betweengroup ( femri vs. gemri ) and withingroup variations in heart rate , blood pressure , pulse oximetry , and endtidal co2 were not statistically different . \n blood pressure and heart rate changes between those receiving bolus ferumoxytol injections vs. slow infusions were also not statistically significant . compared to other iv iron supplements , ferumoxytol was developed to have lower freeiron release,25 decreased immunologic allergic reaction , and improved safety profile.25 , 26 the safety of ferumoxytol as a therapeutic agent was assessed in three randomized , openlabel , controlled , premarketing clinical trials ( n = 1726).27 overall , the general consensus was that true hypersensitivity reactions associated with newer iv iron products are rare and that the therapeutic benefits outweigh the risks.28 \n however , based on 79 aes during the postmarketing surveillance period , the fda issued a black box warning regarding the rare , but potential for fatal hypersensitivity reactions . to date , \n although an immunemediated anaphylaxis mechanism has been demonstrated for older , highmolecular weight iron dextran formulations,30 an igemediated pathway for new iv iron products has not been elucidated.31 while all iv iron products are associated with hypersensitivity reactions , the risk of serious aes ( anaphylaxis ) is rare.28 , 32 the fda 's boxed warning in march 2015 reiterated a serious hypersensitivity risk of 0.2% ( 3/1726 ) in those with kidney disease and a risk of 2.6% ( 16/1014 ) in those without kidney disease.29 a pooled analysis of postmarketing safety trials33 , 34 , 35 , 36 , 37 related to therapeutic use of ferumoxytol support an aggregate hypersensitivity risk of 0.03% ( 3/9820 ) , with a range of 0.021.3% ( 2/8666 to 1/80 , respectively)35 , 36 of serious aes . in two recent observational , \n headtohead studies comparing outcomes and aes relating to the therapeutic use of iv iron formulations including ferumoxytol,32 , 38 no increased cardiovascular mortality was identified in dialysisdependent patients receiving ferumoxytol ( n = 3752 , mean age 65 [ iqr 5475 years ] , hr 0.99 ; 95% ci 0.831.19).38 the anaphylaxis rate for ferumoxytol was 0.03% ( 28/82117).32 although low , these rates are higher than the reported rate of anaphylaxis for all gbcas ( 0.002%39 to 0.008%40 . regarding gadofosveset use in children and young adults , however , the risk of severe aes has been reported as 0.28% ( 2 of 711 injections ) postmarketing,41 which is comparable to the serious hypersensitivity risk of ferumoxytol in patients with impaired renal function as cited by the fda . \n the second concern raised for ferumoxytol is hypotension , which was reported in the march 2015 fda communication as having a risk of 1.7%.29 the mechanism may be related to release of labile free iron,42 potentially leading to hypotension and cardiorespiratory compromise.32 free iron is known to be reactive and effects have been observed with other iv iron formulations.43 , 44 as a result , the fda has recommended dilution and slow administration . in our study , \n fluctuations in blood pressure and heart rate were not statistically significant in betweengroup ( femri vs. gemri ) or withingroup comparisons . \n when we compared the variations in blood pressure and heart rate between those receiving bolus vs. slow infusions , we also did not find a statistically significant difference . whereas it is possible that our more moderate diagnostic bolus infusion rates impose a lower labile iron challenge than the therapy infusion rate , our sample size is insufficient to draw any conclusion about mechanism . in our study \n , at all levels of blood pressure and heart rate fluctuations , blood oxygen saturation and the extremity perfusion waveforms remained completely stable , suggesting that peripheral perfusion , and therefore whole body perfusion , was unaffected . \n other hypersensitivity reactions such as pruritus , rash , urticaria , back pain , chest pain , nausea , and vomiting have also been postulated to be related to free iron release.42 these manifestations are felt to be nonimmunologic reactions either due to free iron or mediated by complement activation and mast cell release,45 but can be misinterpreted as anaphylaxis and result in the inappropriate escalation of care . in our study , the two cases of nausea were selflimiting and required no therapy . \n those who use ferumoxytol as a therapeutic agent have advocated for a period of watchful waiting \n when mild reactions do occur.46 while premedication with diphenhydramine and h1 blockers have previously been used in the context of hypersensitivity reactions , it has recently been suggested that their effect may in fact be deleterious . \n further , the sedative component can confound the patient 's mental status and potentiate hemodynamic fluctuations such as tachycardia and hypotension.45 \n to date , two published studies47 , 48 have specifically evaluated the safety of femri in children and young adults . \n one study47 reported a transient 610 mmhg fluctuation in blood pressure for a cohort of 86 subjects ( age 1 day to 34 years ) . \n the second study48 was performed under an fdaapproved investigational new drug ( ind ) protocol . \n vital signs and laboratory data in 68 patients , ages 5 to 25 years , were assessed and no significant changes in vital signs or relevant laboratory values occurred . \n there were four mild aes ( two cases of transient hypotension , one case of nausea , one case of erythema and warmth at the injection site ) , which were all selflimited . in all studies that have specifically assessed the safety of ferumoxytol as an mri contrast agent to date , no severe , lifethreatening , or fatal aes \n further , while transient variations in blood pressure have been observed in both femri and gemri groups in our study , definitive conclusions are challenging , particularly when there is wide variability in blood pressure for both adults49 , 50 and children.51 , 52 regardless , standard procedures should be in place to manage complications should they arise . \n compared to prior safety reports of ferumoxytol as an mri contrast agent , our work was performed in a larger patient cohort of all ages , renal function , and wider range of clinical indications . \n we also provide a comparison using a current fdaapproved intravascular mri contrast agent ( gadofosveset trisodium ) . \n while not conducted under an fdaapproved ind protocol , our findings are consistent with and expand on already published experiences47 , 48 with ferumoxytol . \n more important , the safety experience reported in this study reflects postmarketing safety findings in a clinical population . \n since completing this analysis , we have obtained an fdaapproved ind protocol to use ferumoxytol as an mri contrast agent in children with congenital heart disease ( ind # 129441 ; clinicaltrials.gov identifier nct02752191 ) . \n while the american college of radiology , the canadian association of radiologists , and the european medicine agency caution the use of gbcas in the setting of acute renal failure and/or an egfr < 30 ml / min/1.73 m , it is instructive to note , however , that 79% ( 55/70 survey respondents ) of pediatric imaging specialists ( radiologists and cardiologists ) in an international survey currently use gbcas in neonates , a population where the physiologic egfr is impaired ( 26 ml / min/1.73 m ) due to immature renal function.53 while the standard of care may vary from one institution to another and occasionally deviate from guidelines , the risktobenefit ratio is always considered in daily clinical practice . in this context , where other agents or tests may be suboptimal in the setting of renal dysfunction or immature renal function , the risktobenefit ratio of ferumoxytol as an mri contrast agent should also be weighed . \n our study has several limitations . first , selection bias relating to the retrospective nature of the study design , the clinical patient population , and followup duration limit the overall generalizability of the study . because the study was not designed as a randomized clinical trial , patients referred for ferumoxytol mri frequently had complex medical conditions , were acutely sick , and had limited alternative cardiovascular imaging options . while there is frequent and regular contact between imaging investigators and referring physicians , specific followup timepoints were not prospectively determined , which may have been an additional source of bias . \n second , because of the low frequency of serious hypersensitivity reactions , our study is not sufficiently powered to reach definitive conclusions regarding the rate of adverse reactions associated with diagnostic use of ferumoxytol or to detect differences in the ae rates between ferumoxytol and conventional gbca . \n our report should be viewed as a singlecenter interim safety experience of ferumoxytol as an offlabel mri contrast agent in a spectrum of patients with varying age and clinical indications . in conclusion , based on our experience \n , the diagnostic offlabel use of ferumoxytol for mri is welltolerated with few aes . given \n ferumoxytol 's dual potential as a therapeutic drug and an mri contrast agent , prospective and systematic investigations will be helpful to better define the mechanisms involved in the mediation of aes and the diagnostic effectiveness of femri . \n a multicenter safety registry and related clinical research trials are needed to help maximize the benefit and mitigate risks associated with the use of ferumoxytol as an mri contrast agent . \n ", "role": "user" }, { "content": "purposeto summarize our singlecenter safety experience with the offlabel use of ferumoxytol for magnetic resonance imaging ( mri ) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium.materials and methodsconsecutive patients who underwent ferumoxytolenhanced ( fe ) mri exams were included . \n adverse events ( aes ) were classified according to the common terminology criteria for adverse events v4.0 . in a subgroup of patients examined under general anesthesia , recording of blood pressure , \n heart rate , oxygen saturation , and endtidal co2 was performed . \n a comparable group of 23 patients who underwent gadofosvesetenhanced ( ge ) mri under anesthesia with similar monitoring was also analyzed.resultsin all , 217 unique patients , ages 3 days to 94 years , underwent femri . \n no ferumoxytolrelated severe , lifethreatening , or fatal aes occurred acutely or at followup . \n two patients developed ferumoxytolrelated nausea . \n betweengroup ( fe vs. gemri ) comparisons showed no statistical difference in heart rate ( p = 0.69 , 95% confidence interval [ ci ] 96113 bpm ) , mean arterial blood pressure ( map ) ( p = 0.74 , 95% ci 4452 mmhg ) , oxygen saturation ( p = 0.76 , 95% ci 9498% ) , and endtidal co2 ( p = 0.73 , 95% ci 3137 mmhg ) . \n no significant change in map ( p = 0.12 , 95% ci 5058 mmhg ) or heart rate ( p = 0.25 , 95% ci 91105 bpm ) was noted between slow infusion of ferumoxytol ( n = 113 ) vs. bolus injection ( n = 104).conclusionin our singlecenter experience , no serious aes occurred with the diagnostic use of ferumoxytol across a wide spectrum of age , renal function , and indications . \n because of the limited sample size , firm conclusions can not be drawn about the generalizability of our results . \n thus , vigilance and monitoring are recommended to mitigate potential rare adverse reactions . \n level of evidence : 2j . \n magn . \n reson . \n imaging 2017;45:804812 .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the putative health benefits of dietary fibre ( df ) have been investigated over a number of years and have been shown to be many and varied ( brownlee , 2011 ; european food safety , 2010 ; gunness & gidley , 2010 ) . by definition df is not digested in the upper gi tract therefore early investigations into health benefits focused on the colon and the use of df as a nutrient source for intestinal microbiota ( gibson & roberfroid , 1995 ) . \n however , more recently attention has also focused on interactions in the upper gi tract . in particular , \n the ability of df to increase both gastric and intestinal viscosity has been investigated by a number of groups but a key early work showed that dietary fibre could be used to increase the viscosity of digesta and reduce the rate of absorption of glucose ( jenkins et al . , 1978 ) . \n more recent studies have confirmed the health benefits of a wide range of dietary fibre ( anderson et al . , 2009 ; frassetto , schloetter , mietus - synder , morris , & sebastian , 2009 ; nilsson , ostman , holst , & bjorck , 2008 ) . \n these include decreasing risk factors for cvd , lowering energy intake and glycaemic index , which have an impact on risk factors for type 2 diabetes . \n however , the mechanisms by which such health benefits are gained is still poorly understood ( lattimer & haub , 2010 ) . the df sodium alginate has also been shown to reduce energy intake . in a study where participants consumed a preload sodium alginate formulation , daily preprandial ingestion of the sodium alginate formulation produced a significant 134.8 kcal ( 7% ) reduction in mean daily energy intake ( paxman , richardson , dettmar , & corfe , 2008 ) . \n they are used extensively in the food and chemical industries as thickening and stabilising agents . \n alginate ( e401 ) is a linear polysaccharide polymer with homopolymeric blocks of ( 1 - 4)-linked -d - mannuronate ( m ) and -l - guluronate ( g ) residues covalently linked together in different blocks . \n the monomers can appear in homopolymeric g - blocks , consecutive m - blocks or alternating mg - blocks . \n the ratio of m to g has a marked effect on the properties of the polymer . in a study by jensen et al . \n ( jensen , knudsen , viereck , kristensen , & astrup , 2012 ) alginate solutions with a low m : g ratio ( 0.8 ) exhibited higher gel strength than solutions with higher m : g ratios ( 1.3 and 2.5 ) . \n the gelation of alginate ( sol / gel transition ) is almost independent of temperature but is induced by the presence of divalent cations such as ca , which is associated with the g - blocks . \n indeed there is a strong link between the strength of calcium alginate gels and the average length of the g - blocks ( smidsrod & draget , 1997 ) . \n digestion in the upper gi tract releases nutrients , which then diffuse through the unstirred mucus layer to the intestinal enterocytes where they are absorbed \n . however , many nutrients such as lipids and some vitamins are not water soluble and so spontaneously form self - assembled structures such as micelles and liposomes ( mu & hoy , 2004 ) before diffusing away from the intestinal lumen . \n both small particles and soluble hydrocolloids are free to diffuse from the lumen but have the potential to be trapped by the intestinal mucus layer . \n the ability of dietary fibre to increase luminal viscosity is known to be an important factor affecting both transit times and rates of hydrolysis . \n thus fibre may trap the products of digestion such as mixed micelles and consequently slow absorption . \n it has also been suggested that soluble dietary fibre may be trapped on the surface of the mucus and that this in turn prevents the diffusion of other hydrocolloids or mixed micelles ( gunness & gidley , 2010 ; theuwissen & mensink , 2008 ) . \n such a mechanism has been used as a possible explanation of the cholesterol lowering ability of df ( othman , moghadasian , & jones , 2011 ) as it would also interrupt the recycling of bile salts leading to the conversion of cholesterol into bile in the liver . in the absence of an attractive interaction between the df and \n mucus the trapping of the df by the mucus is dependent on the relative sizes of the df polymers and the pores in the mucus network . \n recent work has shown that the pore size of the mucus varies quite widely from 25 to 200 nm ( round et al . , 2012 ) . \n this compares to the size of a typical df such as -glucan , molecular weight 1001000 kda ( 150250 nm ) ( shelat , vilaplana , nicholson , gidley , & gilbert , 2011 ) or alginate of 190 kda and 100 nm in diameter ( strand , boe , dalberg , sikkeland , & smidsrod , 1982 ) . \n examples of alginate / mucin interaction with biological relevance have been shown previously ( taylor , pearson , draget , dettmar , & smidsrod , 2005 ) . \n indeed , the authors of the article have a patent for using oligo - guluronates alone ( polyguluronic acid ) to disrupt airway mucus in cystic fibrosis patients ( taylor , draget , & smidsrod , 2009 ) . \n in addition to the function of the oligo - guluronates , the mixed block polymers have been suggested to be mucin secretagogs ( shimotoyodome , meguro , hase , tokimitsu , & sakata , 2001 ) . \n this appears to be a general affect for high viscosity fibre ( ito et al . , 2009 ) and this is partly supported by the fact that the use of low molecular weight sodium alginate in rats showed no activity after feeding for 10 days ( hino et al . , \n thus it appears that while g - block alginate polymers disrupt mucus structure , other alginates enhance the mucus layer . in the work described here \n we have studied the ability of two different types of alginate with differing m : g ratios to diffuse into intestinal mucus and subsequently change its permeability to a range of particles . \n we have used 500 nm carboxylated latex beads as a probe particle in order to determine the micro - viscosity of the mucus alginate mixture and fluorescently labelled chyme resulting from simulated digestion of a fat containing meal in order to determine changes in mucus permeability to the self - assembled products of lipid digestion . \n porcine mucus was prepared as described previously ( macierzanka et al . , 2011 ) . \n briefly , fresh porcine small intestine was obtained from a local abattoir and stored on crushed ice for transport to the laboratory . \n the gut was rinsed through with ice cold phosphate buffer ( 10 mm phosphate ph 6.5 , 5 mm edta ) followed by a further rinse with the same buffer containing a protease inhibitor ( 0.5 mm pefabloc ( aebsf ) ) . \n the gut was then opened out flat and mucus was collected by gently scraping the jejunal surface . \n muc2 mucin was prepared for dpi measurements using the methods described elsewhere ( macierzanka et al . , 2011 ) . \n alginates with a range of mannuronic / guluronic ( m / g ) ratios were kindly donated by danisco . \n their composition , molecular weight and the viscosity of a 1% ( w / w ) solution are as follows : sample d1 had an m / g ratio of 60/40 , a molecular weight of 350 kda . \n the d4 sample had an m / g ratio of 35/65 , a quoted molecular weight of 315 kda . \n subsequent measurement of the molecular weight yielded a weight average of 280 kda and the size distribution given in fig . \n 1 . samples of both forms of alginate were fluorescently labelled using dtaf ( 5-(4,6-dichlorotriazinyl ) aminofluorescein ) ( life technologies ltd , paisley , uk ) . \n polysaccharide was dissolved at 10 mg / ml in 50 mm sodium bicarbonate adjusted to ph 9.0 with 1.0 m naoh . \n this was mixed overnight at 1:0.4 v / v with a solution of dtaf ( 10 mg / ml in dmso ) at room temperature . \n the reaction mixture was dialysed in 10 kda cut - off dialysis tubing against pbs until no residual dtaf could be detected in the dialysate by uv absorbance at 490 nm . \n the labelling density of the resulting alginate was an average of 2.5 fluorophore molecules per alginate molecule . \n although the labelling involved prolonged exposure of the alginate to ph 9 , this is unlikely to have degraded the alginate by -elimination and certainly no evidence of this was seen . \n a very low concentration ( 0.03 mg / ml ) and high ionic strength solvent ( 0.3 m nacl ) were used so as to render negligible the effects of non - ideality . \n a high ionic strength was chosen to minimise non - ideality effects an optima xl - i ( beckman instruments , palo alto , usa ) equipped with rayleigh interference optics was used . \n sample solution ( 400 l ) and reference buffer ( 400 l ) were injected into the respective channels of double sector 12 mm optical path length cells . \n the rayleigh interference optical system was used to record changes in the concentration versus radial displacement profiles with time . \n an initial low rotor speed of 3000 rpm was used to check for the presence of any large sedimenting species and then adjusted to a rotor speed of 40,000 rpm . \n scans were taken at 2 min intervals for a run time of 24 h. the data was analysed using the least squares ( ls - g(s ) ) procedure of sedfit ( dam & schuck , 2004 ) , which solves the lamm equation describing the change of concentration distribution with radial position with time in terms of a distribution of sedimentation coefficients , g(s ) vs s , where s is the sedimentation coefficient . \n the standard conditions of density and viscosity of water at 20.0 c were used for adjustment of the sedimentation coefficients s to s20,w values . \n knowledge of the weighted average molecular weight ( molar mass ) , mw from sec mals and the corresponding weighted average sedimentation coefficient from sedimentation velocity measured by analytical ultracentrifugation allows the sedimentation coefficient g(s ) vs s to be transformed into an estimate for the distribution of molecular weight , f(m ) vs m using the extended fujita method of harding et al . , and built into the sedfit routine . assuming a value for the conformation parameter for alginate 0.33 ( harding et al . , 2011 ) , and \n taking mw = 280,000 and the corresponding s value at 0.03 mg / ml = 4.3 s this yields a value for s = 0.0685 . \n 1 . the measurements of bulk viscosity were measure using a ta instrument g2 rheometer ( ta instruments , crawley , west sussex , uk ) equipped with a cone and plate geometry ( aluminium cone ; 6/40 mm cone angle / diameter , truncation gap 12 m ) . \n the temperature was held at 37 c and samples were allowed to equilibrate in the instrument for 30 min prior to measurement . \n a viscosity ramp test was performed over a shear rate range from 0.01 to 500 s over 15 min . \n the ability of the alginate polymers ( d1 and d4 ) to penetrate into porcine mucus was determined using time - lapse microscopy . \n ex vivo porcine mucus and fluorescein - labelled alginate were layered in a 9 mm diameter by 0.9 mm depth perfusion well ( coverwell , sigma , poole . \n laser scanning confocal microscopy was used to follow the diffusion of the alginate into the mucus for 90 min using a leica sp1 with a 20x objective ( leica microsystems , mannheim , germany ) . \n linear fluorescent intensity profiles were generated from the time - lapse images using imagepro - plus 7.0 ( media cybernetics inc . \n the diffusion coefficient was calculated from the fluorescence profiles using the following equation , f(x , t)=aerfc(x4dt ) , where the fluorescence f is described as a function of distance from the starting boundary x and time t. here , a is an arbitrary scalar , erfc is the complimentary error function and d is the diffusion coefficient of the fluorescent alginate . \n diffusion of alginate in mucus was assessed using fluorescence recovery after photo - bleaching ( frap ) . \n briefly , fluorescein - labelled alginate d4 was mixed into mucus samples at concentrations between 0 and 0.1% . \n samples were gently mixed and loaded onto glass slides using 9 mm 120 m secureseal spacers ( sigma , poole , uk ) . \n the frap was conducted using a leica sp5 ( ii ) laser scanning confocal microscope with an 8 khz resonance scanner . a bleach spot of 50 \n m diameter was used with an initial post bleach of 3.7 s at 37 ms / frame , followed by 25 s at 250 ms / frame . \n diffusion coefficients were calculated from the fluorescence recovery data using nonlinear least - square fitting as described by ( ladha et al . , 1996 ) , using the following equation , f(t)=f(0)+f()(t/d)1+(t/d ) , where f(t ) is the observed fluorescence as a function of time , f(0 ) is the fluorescence immediately after bleaching , f( ) is the fluorescence at infinite time after bleaching , is the depth of bleach and d is the diffusion time . the lateral diffusion coefficient , d is then given by d = /4d , where is the radius of the bleach region . \n solutions of muc2 mucin were prepared using 10 mm phosphate , 137 mm nacl , 3.7 mm kcl , ph 6.5 buffer . \n mucin concentrations used were 20 , 100 and 500 g / ml . alginate solution at 0.6 mg / ml was prepared from a high guluronic acid alginate ( d4 ) . \n calcium chloride solution to test for calcium - mediated alginate crosslinking was at concentration of 3 mm . \n details of the dual polarisation interferometer are given in the accompanying paper ( westwood , noel , & parker , 2010 ) . \n standard silicon oxynitride chip was used , typically described as being essentially a silicon dioxide surface . after establishing a baseline with the standard buffer increasing concentrations of mucin \n were run over the chip surface at a flow rate of 10 l / min for 10 min each followed by a 15 l / min 10 min rinsing step . after the four mucin concentrations \n the stokes viscosity was calculated from ensemble data from multiple particle tracking of 500 nm latex beads . the mean square displacement ( msd ) of 500 nm carboxylated latex beads \n was determined at 22 c over 50 frames at 2 frames / s using multiple particle tracking as outlined in more detail previously ( macierzanka et al . , 2011 ) . \n the diffusion coefficient was calculated from the msd as d = msd/4 t , where t is the timescale over which the displacement has occurred . from the measured diffusion coefficient of 500 nm latex beads , we calculated the local viscosity using the stokes \n a 3.0 mg / ml sodium caseinate solution in 150 mm nacl ph 6.5 stabilised emulsion containing 18% triglyceride ( sunflower oil ) was prepared by passing a premix of oil and na - cas for a total of 6 times at 20,000 psi through a microfluidiser ( microfluidics , massachusetts , usa ) . \n the emulsion was digested using the standardised in vitro digestion protocol recommended by the infogest cost action ( minekus et al . , 2014 ) , involving 2 h gastric followed by 2 h of small intestinal simulation . \n the mean size ( d3,2 ) of the original emulsion was 1.0 m . the ability of digested emulsion to diffuse through mucus was assessed at the beginning of the duodenal phase ( 5 min ) and after 2 h ( 120 min ) and with or without alginate at 0.1% . \n the lipid in the emulsion was visualised using nile red at a final concentration of 50 m ( sigma , poole , uk ) . \n the frap experiments were conducted as described for alginate diffusion using bleach spot of 36 m diameter with an initial post bleach of 7.36 s at 74 ms / frame , followed by 50 s at 500 ms / frame . \n in this manuscript we have shown that the dietary fibre sodium alginate can combine with intestinal mucus to decrease the diffusion of lipid digestion products . \n however , measurements of alginate diffusion used the combined data from fluorescently labelled d1 and d4 alginates as no differences were seen between the two . \n even though it is not a direct indicator of the properties of a gel network seen by object diffusing at the molecular scale , it is nevertheless important as a measure of molecular interactions . \n previous experiments on porcine ex vivo mucus removed from the small intestine yielded a mean viscosity of 10 pa at a shear rate of 0.2 s and at 37 c and the stokes viscosity determined by particle tracking was 3.7 mpa at 37 c for 500 nm beads ( macierzanka et al . , 2011 ) . \n using the same conditions , the ex vivo mucus samples used in this study yielded similar values for the bulk viscosity as shown by the control sample in fig . 2 . \n having established the shear thinning behaviour of the mucus , we studied the effect of adding d4 alginate in increasing concentrations up to 0.05% . \n no significant effect of alginate addition was seen even for the highest concentration . despite having seen no change in the viscosity of mucus after the addition of alginate , it is still important to know whether the alginate alone exhibited significant viscosity under conditions simulating those in the small intestine . \n 3 shows the viscosity of d4 alginate as a function of shear rate over the same range of concentrations used in fig . 2 . \n the rheology was measured in the ionic environment recommended by the infogest protocol ( minekus et al . , \n thus , the ph was 7.0 , the calcium concentration was 0.6 mm , the ionic strength was 184 \n it is clear from fig . 3 that the low concentrations of alginate that we used in these experiments ( 0.0150.05% ) cause only a very minor increase in viscosity over that of water and thus are likely to have a minimal effect on the rate of digestion and the diffusion of digestion products in vivo in the intestinal lumen . only by increasing the concentration of the alginate to 0.1% was a significant increase in viscosity achieved . \n the ability of the alginate and mucus to mix is likely to be of importance if the permeability is to be affected . \n thus , we were also interested to see whether the alginate could itself diffuse freely into the intestinal mucus . \n both polymers carry significant negative charge and results from the rheology suggest that there was no significant interaction between the two . experiments were conducted using fluorescently labelled alginate as described above . \n 4a shows the profile of fluorescence intensity and thus alginate concentration normal to the surface of the ex vivo mucus . \n the peak in intensity at the boundary of the mucus layer indicates that either entrapment or possibly binding of the alginate to the mucus increased the local concentration . \n the diffusion of the alginate into the mucus is shown by the increase in fluorescence some 250 m from the surface . \n it was immediately clear from the change in fluorescence as a function of time that the alginate was able to diffuse into the mucus layer with a relatively high diffusion coefficient ( 1010 m / s ) . \n it was also clear that the apparent diffusion tended to decrease as a function of time . \n 4b shows the decrease in diffusion coefficient of the fluorescent alginate from 10 min to 90 min after the start of penetration into the mucus . \n the data is shown as the ratio of diffusion coefficients and indicates that there was consistently a drop to about 30% of the initial diffusion coefficient after 90 min and although there was a correlation between the size of the drop in diffusion and the alginate concentration , it was not statistically significant . \n there was also no difference observed between the different types of alginate and so the data was pooled . despite the lack of significant concentration dependence , the trend suggests that at higher alginate concentrations the drop in diffusion was faster leading to a smaller decrease from 10 to 90 min after penetration . \n in addition to measuring the diffusion of alginate over 90 min as it slowly diffused into a layer of mucus , we also studied the local diffusion over a few seconds using frap . \n 4c ) show that in buffer alone the diffusion coefficient of the alginate was 3.2 10 m / s , which yields a hydrodynamic radius of 7 nm if we assume that the conditions for the stokes einstein equation hold . \n this low figure highlights the fact that the smallest polymers diffuse the fastest , heavily biasing the outcome to the lowest molecular weight fraction in fig . 1 . \n diffusion through the mucus was slightly affected by the concentration of the alginate but at the highest concentration measured ( 0.1% ) was only reduced by a factor of two from diffusion in the buffer . \n all of these measurements suggest that there were no interactions between the polymer and the mucus and that the alginate was free to diffuse into the intestinal mucus . \n in addition to assessing the ability of the alginate to diffuse into intestinal mucus , we also used dpi to determine whether there was any specific interaction between the two polymers . the data in fig . \n 5 shows the initial adsorption of mucin onto the silicon dioxide surface of the dpi chip at three increasing concentrations from 0.004 to 0.5 mg / ml . there was negligible adsorption at the lowest mucin concentration . at the second and third concentrations \n there was progressively more adsorption and a low density indicating an open structure with loops and tails stretching from the surface . \n after the final adsorption step the density of the residual adsorbed material jumped to a value of 0.45 g / ml and , the thickness dropped from 2530 nm to 78 nm ( data not shown ) implying the mucin was relatively flat on the surface . subsequently exposing this mucin surface to alginate , calcium and more \n alginate showed no changes in the adsorbed layer and no interaction , suggesting that for these polymers to interact they need to interpenetrate in bulk solution rather than at an interface . \n having established that sodium alginate was able to diffuse into the mucus with a diffusion coefficient similar to that in water or slightly lower , we investigated the ability of the increasing concentrations of d4 alginate to increase the micro - viscosity of the mucus . \n the stokes viscosity was calculated from the diffusion of 500 nm latex beads through the mucus / alginate polymer mixture and is shown in fig . \n interestingly , even though the measurement of these samples showed no increase in bulk viscosity of the mucus after introducing the alginate , the micro - viscosity increased , even for the lowest concentration of alginate . \n the stokes viscosity increased as a linear function of alginate concentration indicating that the effect of the two polymers was additive . \n although the diffusion of 500 nm latex beads was decreased by the addition of alginate to intestinal mucus at relatively low concentrations , this does not mean that the diffusion of digestion products from the intestinal lumen to the site of absorption would be decreased . \n it is likely that the majority of the self - assembled products of lipid digestion will be much smaller in size than 500 nm . \n therefore , we fluorescently labelled the lipid from digesta generated as outlined in the methods section . \n the surface area mean size of the lipid droplets in the original emulsion was 1.0 m . the mean size of the lipid structures undergoing brownian motion in the digesta from the 5 and 120 min samples was much more difficult to determine because of the presence of a wide range of particulates . \n these were partly from the pancreatin used in the simulation of intestinal digestion but also from the self - assembly of the products of lipid hydrolysis . \n the size distributions of the three samples are given in the supplementary information ( figure s1 ) . \n the ability of the digestion products to penetrate the mucus in the presence of various concentrations of alginate is shown in fig . \n the 5 min sample was still largely in the form of 1 m lipid droplets that were slow to diffuse whereas the 120 min digesta was more than twice as mobile . \n the addition of 0.1% alginate had no effect on the 5 min sample but decreased the diffusion of the 120 min sample by almost a factor of two . \n in this article we have investigated the ability of the dietary fibre sodium alginate to decrease the diffusion of the products of lipid digestion through porcine intestinal mucus . \n the concentrations of alginate we have used are equivalent to those that might be encountered after consumption of a food containing alginate as a stabiliser . \n thus , if this food is consumed we can assume a dilution of around a factor of 10 by the time it reaches the mid small intestine . \n this is based on the same assumptions as the in vitro digestion where each of the three phases of digestion ( oral , gastric , small intestinal ) represents a 50% dilution ( minekus et al . , \n it is clear from the rheological measurements shown in figs . 2 and 3 that such low concentrations are likely to have little effect on the bulk viscosity of the chyme in the intestinal lumen or the mucus layer of the intestinal wall . \n whilst bulk rheological and tribological properties may be important for lubrication of the gi tract , the barrier function involves much smaller length - scales . \n the porcine intestinal mucus used in this study comprises primarily muc2 mucin and was characterised with a mean molecular weight of 4.6 10 da . \n this is considerably larger than the 2.8 10 da of the alginate . in recent work \n we showed that the pore size of the muc2 mucin varied from 25 to 200 nm ( round et al . , 2012 ) , which is rather smaller than the muc2 mucin structure proposed by ambort et al . \n ( ambort et al . , 2012 ) in which the pore size is in excess of 1 m . in the former case , the alginate would be able to diffuse through all the pores but not the 500 nm latex beads . in the case of the ambort model \n this model nominally describes the properties of the muc2 mucus network in the large intestine . \n however , the mucus layer in the small intestine is much more heterogeneous with only the denser regions having these properties ( johansson , larsson , & hansson , 2011 ) . nonetheless , according to the ambort model both the alginate and \n the 500 nm latex should be able to diffuse through all regions of the small intestine mucus . \n the fact that the apparent diffusion of the alginate decreased as a function of time suggests that the pores at the surface of the mucus became clogged with the alginate . \n this was confirmed by an increase in fluorescence in the boundary region of the mucus over that seen in the pool of alginate introduced into the luminal space as shown in fig . \n the lack of any attractive interaction between the alginate and mucin in the dpi experiments illustrated in fig . 5 \n , strongly suggests that the mucus was indeed only able to trap the alginate in this way . \n however , despite this apparent entrapment , the bulk rheology of the mixed mucus , alginate systems is in agreement with previous measurements on alginate and porcine gastric mucin ( pgm ) ( taylor - nordgard & draget , 2011 ) . \n the results suggest that potentially any high molecular weight non - interacting fibre might have the same general effect . the limited levels of entrapment and the small increases in bulk rheology discussed above , suggest that the addition of alginate to intestinal mucus would have only a limited effect on the local microrheology . \n 6 that the viscosity encountered by 500 nm particles was increased after alginate addition even at the lowest concentrations used and that the effect was purely additive . \n the data here contrasts with previous measurements on pgm showing limited diffusion of 200 nm latex beads ( taylor - nordgard , nonstad , olderoy , espevik , & draget , 2014 ) . \n the data suggest that even though the beads were able to diffuse through the mucus , the pores did not need much alginate to limit the diffusion significantly . \n finally the addition of the range of particles present in digesta to mucus in order to assess their ability to diffuse through it in the presence or absence of alginate gave slightly conflicting results . \n the mean particle size of the original emulsion was 1.0 m but the addition of the emulsion to gastric and then small intestinal simulation altered this significantly . \n after 5 min of simulated duodenal digestion of a protein stabilised emulsion , there were a large number of particles present ranging in size from less than 100 nm to more than 100 m . \n consequently , the degree of penetration was low as was the mean diffusion coefficient and the presence of 0.1% alginate made little difference to the diffusion coefficients obtained . \n it is not clear however , what the mean size of the diffusing particles was under those circumstances . \n after 120 min simulated digestion , the particle size distribution was still very broad , although one might expect the droplet size to have decreased as a result of hydrolysis of the oil . \n the addition of 0.1% alginate decreased the diffusion to about half of the original value . \n the data here confirm our original hypothesis and may be sufficient to limit the type of fast lipid absorption that leads to hyperlipidaemia , which has been seen as a potential health issue . \n however , a 50% decrease in the rate of lipid diffusion may not be enough to have an impact on lipid absorption in vivo or bile salt recycling . in conclusion \n , we have investigated the ability of sodium alginate to decrease the permeability of small intestinal mucus . \n we have shown there are no interactions between sodium alginate and the small intestinal mucus at the molecular level . as a result the bulk rheological properties of intestinal mucus were little altered by the addition of low concentrations of alginate . \n the alginate was able to freely diffuse into the mucus where it had a significant effect on the diffusion of 500 nm latex beads , indicating an additive effect on the microviscosity and suggesting that the mucus pore size was close to 500 nm . \n however , while the permeability to 500 nm latex beads was significantly affected , the permeability to lipid digestion products was only decreased to a limited extent . \n while the low concentrations of alginate may have limited effect on lipid absorption in vivo , further research investigating the role of alginates and other dietary fibres on reducing rates of lipid absorption in the small intestine could lead to strategies to combat health issues such as hyperlipidaemia , obesity and type-2 diabetes .", "role": "user" }, { "content": "in the small intestine the nature of the environment leads to a highly heterogeneous mucus layer primarily composed of the muc2 mucin . \n we set out to investigate whether the soluble dietary fibre sodium alginate could alter the permeability of the mucus layer . \n the alginate was shown to freely diffuse into the mucus and to have minimal effect on the bulk rheology when added at concentrations below 0.1% . despite this lack of interaction between the mucin and alginate , \n the addition of alginate had a marked effect on the diffusion of 500 nm probe particles , which decreased as a function of increasing alginate concentration . \n finally , we passed a protein stabilised emulsion through a simulation of oral , gastric and small intestinal digestion . \n we subsequently showed that the addition of 0.1% alginate to porcine intestinal mucus decreased the diffusion of fluorescently labelled lipid present in the emulsion digesta . \n this reduction may be sufficient to reduce problems associated with high rates of lipid absorption such as hyperlipidaemia .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: some clinicians consider treatment to be early if it is started in the primary or early mixed ( permanent first molars and incisors present ) dentition stage . \n others define treatment as early if it is started in the late mixed dentition stage ( before the eruption of second bicuspids and permanent upper canines ) . \n part of the controversy is centered around whether to initiate treatment in the deciduous or early mixed dentition stage as a two - phase treatment or to start treatment in the late mixed dentition or permanent dentition stage as a one - phase treatment . \n some orthodontists advocate early orthodontic treatment in particular types of malocclusion , such as functional crossbite , dental habits , severe crowding with increased overjet , and class iii malocclusion with maxillary deficiency . \n others prefer to start orthodontic treatment of some malocclusions , such as class ii , at the late mixed dentition stage as a one - phase of treatment . \n those orthodontists advocating early treatment believe that the early correction of specific dental and skeletal discrepancies at the deciduous or early mixed dentition stages has several benefits . \n first , this treatment method takes advantage of normal growth to modify skeletal growth and corrects the malocclusion ; it reduces the time needed for phase ii treatment and the severity of the malocclusion ; it has better and more stable results ; it improves patient self - esteem and parental satisfaction ; it reduces the potential for iatrogenic tooth damage , such as trauma to susceptible incisors , root resorption , and decalcification ; and finally , it is associated with greater patient compliance among preadolescent children , as they tend to be more adherent to treatment instructions . \n orthodontists who prefer late treatment have argued that early treatment at deciduous or early mixed dentition has no long - term benefits , whereas the advantages of one - phase orthodontic treatment have been shown . \n one - phase treatment takes advantage of the sufficient remaining growth , avoids patient / parent burnout due to lengthy two - phase treatment , avoids unpredictable growth dynamics that can occur at the preadolescent ages , and finally , one - phase is lower cost than two - phase treatment . \n many orthodontists recommend that occlusion assessment be carried out before 7 years of age to determine whether to start the treatment early or later . \n 2008 recommended intervention in the early mixed dentition stage in cases of crossbite , increased overjet , deepbite with palatal impingement and severe crowding . \n the differences in the preferred timing of treatment for specific malocclusion have been reported among orthodontists in different countries as noted by kiyak et al . \n he studied orthodontists views on the timing of treatment for different skeletal and dental deviations in three countries : italy , turkey , and united states ( us ) . \n found that orthodontists in italy preferred two - phase treatment for increased overjets and severe crowding , as opposed to those in the us and turkey , who recommended one - phase treatment . \n most of the orthodontists in these three countries agreed that it was preferable to treat particular malocclusions , such as an anterior crossbite and severe arch constriction , during the primary or early mixed dentition stage . \n researchers have not established the preferred timing of treatment for class ii malocclusions , and it remains an issue of controversy . \n many orthodontists reported that class ii malocclusion with or without crowding can be treated successfully in only one phase during the late mixed dentition stage at puberty . \n in contrast , class ii malocclusion is considered the most common indication for starting early orthodontic treatment in finland . \n when early orthodontic treatment is contemplated , every orthodontist should ask several questions : do the benefits of early intervention justify the extra cost , time , and energy involved in two - phase treatment , and does early treatment eliminate or reduce the need for another orthodontic treatment at a later stage ? \n the purpose of the present study was to analyze the perspective of orthodontists practicing in saudi arabia regarding the ideal time to initiate treatment . \n this research also sought to assess the relationship between orthodontists views and their genders , types of practice , and years of experience . \n a cross - sectional survey was conducted by sending questionnaires electronically to 165 practicing orthodontists in different regions of saudi arabia . \n the names of the orthodontists were obtained from the directory of the saudi dental society and the saudi orthodontic society . \n the first section recorded demographic details , including gender , length of time in practice , location of orthodontic training program attended , and the type of practice . \n in addition , the respondents were asked to report the proportion of patients of different ages treated ( i.e. 6 - 8 , 8 - 11 , 12 - 18 , and older than 18 years ) and the proportion of conventional versus surgical orthodontic treatments rendered in their practices . \n the second section of the questionnaire comprised a list of 29 types of occlusal deviations , functional problems , and temporomandibular disorders ( tmds ) [ appendix ] , which were selected from the previous questionnaire that was distributed to orthodontists throughout the us . \n the original questionnaire included a list of the most common malocclusions , which were obtained from the existing literature and textbooks . \n the list was revised and refined by three faculty members in the department of orthodontics at the university of washington dental school and four orthodontists in private practices around the country . \n the final list included 41 types of malocclusions ; some of these distinguished between male and female patients and others specified the extent of deviation ( e.g. different overjet ) or described side - effects of the deviation ( e.g. occurrence of attrition or periodontal concerns ) . in the present study , the orthodontists were asked to consider at what stage they would most likely initiate orthodontic treatment for a child who had one of the types of occlusal deviations , functional problems , and tmds listed in the questionnaire as their main orthodontic problem . \n they were also asked to rate their responses on a scale of x ( no treatment needed ) to 5 ( treatment in the adult dentition ) [ appendix ] . \n ethical approval of the study was obtained from the ethical committee of college of dentistry research center at king saud university . \n the survey was sent in may 2013 and the last response was received in august 2013 . \n data processing and analysis were carried out using the statistical package software system ( version 21 , spss inc . , \n frequency distributions and descriptive statistics for gender , length of time in practice , type of practice , patient age range treated in the practice , and the treatment type was generated . \n in addition , the frequency of treatment for each occlusal deviation , functional problem , and tmds at each specific stage was determined . \n group comparisons ( for gender , practice experience , and patient age range treated in the practice ) were performed with chi - square tests of association for each occlusal deviation , functional problem , and tmds . \n the data were tabulated and crosschecked . data processing and analysis were carried out using the statistical package software system ( version 21 , spss inc . , chicago , il , usa ) . \n frequency distributions and descriptive statistics for gender , length of time in practice , type of practice , patient age range treated in the practice , and the treatment type was generated . \n in addition , the frequency of treatment for each occlusal deviation , functional problem , and tmds at each specific stage was determined . group comparisons ( for gender , practice experience , and patient age range treated in the practice ) were performed with chi - square tests of association for each occlusal deviation , functional problem , and tmds . \n thirty - three of the respondents were males ( 63.5% ) working in group or partnership practices ( 74.6% ) rather than solo practices ( 25.4% ) , and who were treating patients with conventional orthodontics ( 94.2% ) rather than surgical orthodontics or both ( 5.8% ) . \n the percentage of orthodontists treating their patients in the adolescent age range ( 12 - 18-year - old ) was higher ( 44.2% ) than other age ranges , followed by children aged 8 - 11 ( 30.8% ) and adults older than 18 years ( 21.2% ) . \n the lowest percentage was young children aged 6 - 8 ( 3.8% ) [ table 1 ] . \n the mean years of experience among the respondents was 15.7 ( 9 ) , with a range of 2 - 33 years [ table 1 ] . \n the respondents represented different orthodontic programs throughout the us , europe , and saudi arabia . \n frequency distributions and descriptive statistics for gender , length of time in practice , type of practice , patient age range treated in the practice , and the treatment type the majority of respondents ( 90% ) reported that they would treat most of the occlusal deviations in the mixed dentition stage . \n they preferred treatments of 13 conditions in the early mixed dentition stage , eight conditions in the late mixed dentition stage , and three conditions in either stage . \n four conditions were rated as best treated in either the late mixed or the permanent dentition stage . these were overjet > 6 mm with interdental spacing ( 44.2% in each stage ) ; maxillary midline diastema > 2 mm ( 36.5% and 57.7% , respectively ) ; deepbite > 5 mm without palatal impingement ( 54.2% and 36.2% , respectively ) ; and congenitally missing permanent teeth ( 57.7 and 34.6% , respectively ) . \n of the 29 occlusal deviations , the majority of orthodontists agreed that only one condition , that is , mandibular prognathism , was best treated during the adult dentition stage ( 55.8% ) . \n [ tables 2 and 3 ] respectively summarize the occlusal deviations rated as best treated in the early and late mixed dentition stages . \n the most frequent occlusal deviations to be treated in the early mixed dentition stage ( n=52 ) the most frequent occlusal deviations to be treated in the late mixed dentition stage ( n=52 ) the condition of moderate mandibular retrognathia among males and females orthodontists was considered best treated during the late mixed dentition stage ( 73.1% and 76.9% , respectively ) . the majority of respondents stated that anterior crossbite ( without obvious signs of attrition or periodontal abnormalities , with and without functional shift ) was the most frequent indication for treatment during the early mixed dentition stage ( 75% , 71.2% and 75% , respectively ) . \n the conditions of posterior crossbite , obvious skeletal openbite > 1 mm , and severe crowding in maxillary or mandibular arch with significant esthetic concerns were most likely to be treated in either the early or late mixed dentition stage ( 46.2% and 50% , 48.1% in each stage ; 51.9% and 48.1% , respectively ) . \n more than half of the respondents preferred to treat deepbite with dental wear and ectopic development and eruption of incisors in the early mixed dentition stage ( 55.8% and 73.1% , respectively ) . \n the majority of respondents preferred to treat most of the functional problems in the deciduous or early mixed dentition stage ( 86.6% ) . \n seventy - five percentage of orthodontists said they would treat thumb - sucking problems in the early mixed dentition stage whereas 23.1% would treat this condition in the deciduous dentition stage . \n furthermore , any malocclusion leading to speech disorder would be treated in the early mixed dentition stage ( 55.8% ) followed by the deciduous dentition stage ( 30.8% ) . \n more than half of the respondents selected to refer most tmd cases to specialists ( 53.8% ) . \n however , the remaining respondents preferred to treat tmds problems in the permanent dentition stage ( 40.4% ) . \n chi - square analysis was performed to test the association of treatment timing with the participants genders , lengths of time in practice , and range of patients age treated in their respective practices . \n the results showed that there was a significant difference in the years of practice between male and female orthodontists where 60.6% of males had practiced more than 15 years compared with 26.3% of females \n chi - square test to compare between orthodontists gender and years of practice the result also indicated that , no significant difference between the years of practice among males and females and the proportion of patients of different ages treated in their practices ( df = 3 = 4.1 ; p = 0.25 ) . \n in addition , there was no significant difference between the types of practices ( solo or group practice ) and the proportions of patients of different ages treated in the practices ( df = 6 = 9.8 ; p = 0.13 ) . \n chi - square tests also showed that orthodontists with more than 15 years of experience preferred to treat obvious skeletal openbite > 1 mm and severe crowding in maxillary or mandibular arch with significant esthetic concerns in the late mixed dentition stage , whereas less experienced orthodontists preferred to treat these two conditions in the early mixed dentition stage ( = 40 and = 52 , respectively ; p 0.001 ) [ table 5 ] . \n moreover , male orthodontists were more likely to initiate treatment of maxillary midline diastema > 2 mm and congenitally missing permanent teeth in the late mixed dentition , whereas female orthodontists preferred to treat these conditions in the permanent dentition stage ( = 36.2 and = 47.9 , respectively , p < 0.001 ) [ table 6 ] . \n chi - square test of association for treatment timing of different occlusal deviations and orthodontists years of practice chi - square test of association for treatment timing of different occlusal deviations and orthodontists gender in cases with mandibular prognathism , the orthodontists with greater numbers of younger patients were more likely to treat this condition in the early mixed dentition stage . \n on the other hand , orthodontists with more adolescent patients preferred to initiate orthodontic treatment in the late mixed or permanent dentition stage ( df = 6 = 45 , p < 0.001 ) . \n finally , orthodontists with < 15 years of experience tended to refer patients with tmds to specialists and on the other hand , orthodontists with more than 15 years of experience preferred to treat patients with deviations in opening ( df = 3 = 48 , p < 0.001 ) or spontaneous pain in the temporomandibular joint area ( df = 6 = 39.3 , p < 0.001 ) . \n there is scarce information regarding the ideal timing to start orthodontic treatment among saudi professionals . \n the present study has shed important information about the opinion of orthodontist on when to initiate orthodontic treatment in saudi arabia . in orthodontics , \n the decision of early or late treatment is most frequently based on professional choices for each child according to his or her needs rather than on evidence from sound clinical research . \n furthermore , orthodontists should consider several factors when making their clinical decision for either early or late orthodontic intervention . \n the ideal orthodontic treatment should achieve the best outcome in the shortest time with the lowest cost . \n the orthodontists who responded to this survey worked in several sectors , including public health facilities , hospitals , universities , and private practices . \n in addition , some of the respondents had received their orthodontic training in saudi arabia , whereas others had studied abroad in the us , uk , and norway . \n a wide variety of workplaces and training programs in the present study could have increased the variation in the timing of treatment . in this study , the majority of the respondents recommended early treatment for most of the occlusal deviations . \n all types of anterior crossbite disorders described in the questionnaire were most likely to be treated during early mixed dentition . \n mandibular retrognathia and increased overjet with interdental spacing were most appropriately treated in the late mixed dentition . \n this could be related to the fact that the treatment of such conditions at this age could enhance the growth of a retrognathic mandible , allow for utilization of the leeway space , and shorten the treatment time . however , true mandibular prognathism was frequently selected during the adult dentition as most appropriately treated surgically after the completion of growth . in the present study \n , orthodontists generally favored early treatment for most of the functional habits , such as thumb sucking , mouth breathing , and tongue thrusting , which can contribute to unfavorable growth of the jaws and protruded upper anterior teeth , possibly leading to trauma and speech problems . \n the preference of early intervention in cases with functional problems could be due to the benefits of early treatment , which include improved facial profile , smile , speech , and self - esteem . \n early treatment also reduces or eliminates the time required for the second phase of treatment . \n the results showed that the orthodontists with more younger - age patients tended to recommend early intervention more often than did orthodontists with a greater number of adolescent patients ; these respondents preferred late intervention . \n moreover , more experienced orthodontists preferred to treat patients with tmds , whereas those with fewer years of experience tended not to initiate orthodontic treatment for most patients with tmds and prefer to refer them to tmd specialists . \n this difference might be explained by the greater clinical experience obtained among the former group of orthodontists . \n the results of the present study must be interpreted cautiously due to the small sample size and the study 's survey data - collection method . \n further , future research should also investigate factors other than the length of time in practice , training program completed , and type of practice that could affect the treatment timing decision . \n furthermore , a longitudinal study is required to test the impact of the orthodontists decisions to initiate early or late treatments based on outcomes and cost - effectiveness . \n the majority of respondents preferred to treat most of the occlusal deviations in the mixed dentition stageanterior crossbite was the most frequent indication for treatment during the early mixed dentition stagethe majority of respondents favored treating most of the functional problems in the deciduous or early mixed dentition stageorthodontists with more years of experience preferred to treat obvious skeletal openbite and severe crowding in both arches with significant esthetic concerns in the late mixed dentition , whereas less experienced orthodontists favored treatment of the two conditions in the early mixed dentition stagemore experienced orthodontists preferred to treat patients with tmds , whereas those with fewer years of experience tended not to initiate orthodontic treatment for most patients with tmds or prefer to refer them to tmd specialists . \n the majority of respondents preferred to treat most of the occlusal deviations in the mixed dentition stage anterior crossbite was the most frequent indication for treatment during the early mixed dentition stage the majority of respondents favored treating most of the functional problems in the deciduous or early mixed dentition stage orthodontists with more years of experience preferred to treat obvious skeletal openbite and severe crowding in both arches with significant esthetic concerns in the late mixed dentition , whereas less experienced orthodontists favored treatment of the two conditions in the early mixed dentition stage more experienced orthodontists preferred to treat patients with tmds , whereas those with fewer years of experience tended not to initiate orthodontic treatment for most patients with tmds or prefer to refer them to tmd specialists .", "role": "user" }, { "content": "objectives : this study aimed to outline orthodontists perspectives at what stage they would initiate orthodontic treatment and also sought to assess the relationship between orthodontists views and their genders , types of practice , and experience levels.materials and methods : a questionnaire was sent electronically to 165 practicing orthodontists at different regions in saudi arabia . the orthodontists were asked to consider at what stage they would initiate orthodontic treatment for a child with one of 29 different types of occlusal deviations , functional problems , and temporomandibular disorders ( tmds ) listed in the questionnaire as their main orthodontic problem . \n frequency distributions of all the variables were derived , and comparisons were made using the chi - square tests.results:fifty-two electronically completed questionnaires were returned ( 31.5% response rate ) . \n the majority of the respondents were males ( 63.5% ) . \n the majority of respondents ( 90% ) reported that they would treat most of the occlusal deviations in the mixed dentition stage . \n anterior cross - bite was the most frequent indication for treatment during the early mixed dentition stage ( 73.7% ) . \n conditions rated as best treated during the late mixed , or the permanent dentition stages were ; overjet > 6 mm with interdental spacing , maxillary midline diastema > 2 mm and deep bite > 5 mm without palatal impingement . \n the majority of respondents ( 86.6% ) preferred to treat most of the functional problems in the deciduous or early mixed dentition stage . \n orthodontists with more than 15 years of experience preferred to treat patients with tmds , whereas those with < 15 years of experience opted to refer such patients to tmd specialists.conclusions:the findings of the present study suggest that orthodontists should consider many factors , such as the risks , benefits , duration , and costs of early and late intervention , when deciding the best timing to begin orthodontic treatment .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: bovine babesiosis is economically the most important tick - borne disease of cattle worldwide including areas of australia , africa , south and central america ( bock et al . \n in addition , the united states is continuously under threat of reintroduction of the vector and the disease ( bock et al . \n 2004 ) . under natural conditions , babesia bovis transmitted by the tick rhipicephalus microplus , \n they multiply by merogony in erythrocytes while in ticks by sporogony ( susan and asa 1999 ) . \n the disease is the most prevalent in tropical and subtropical countries , affecting cattle industries causing a major economic impact worldwide ( bse et al . \n costs due to babesiosis are the results of high mortality , ill - thrift , abortions , loss of milk / meat production and draft power and from control measures such as acaricide treatments , purchase of vaccines and therapeutics ( bock et al . 2004 ) . \n it was estimated that losses and control of babesiosis and anaplasmosis in kenya , zimbabwe , tanzania , south africa , china , india , indonesia and philippines cost 5.1 , 5.4 , 6.8 , 21.6 , 19.4 , 57.2 , 3.1 and 0.6 million us dollars annually , respectively ( bock et al . \n kaufmann ( 1996 ) reported that the mortality rates in cattle infected by b. bovis without treatment could reach 7080% . \n the diagnosis of ruminant babesiosis is generally based upon the microscopic examination of giemsa - stained blood smears and clinical signs in acute cases . \n previous studies provide information on the relative susceptibility of various breeds of cattle to babesia infection ( bock et al . 1997 ) . in egypt , bovine babesiosis \n is caused mainly by b. bigemina and b. bovis and considered as the most important and endemic parasitic disease affecting cattle ( nagati 1947 , adham et al . \n bovine babesiosis has a significant impact on meat and milk production and consequently , on livestock management ( adham et al . \n the rapidly changing patterns of demand for cattle and its products point to cattle production being an important and increasing component of the egyptian agriculture economy which required improving cattle health . \n egyptians farmers cross between the holstein - friesian breed and a native local breed known as baladi cattle breed ( bos taurus ) to improve production and disease resistance . \n water buffaloes ( bubalus bubalis ) represent an important source of various human needs , such as meat , horns , hides , milk and milk products , leather , land plowing , and transportation of people and crops ( somparn et al . \n 2004 ) . due to the fact that water buffaloes are raised together with cattle , \n among which bovine babesiosis is highly prevalent ( iseki et al . 2010 ) , they might be potential carriers for babesia parasites . \n babesia bovis infection was experimentally investigated in splenectomised buffaloes ( mahmoud and abou - zeina 2008 ) . \n yao et al . ( 1997 ) reported the clinical findings on buffaloes after experimental infection with cryopreserved b. bovis parasites . \n however , efforts to furnish information about natural infection with b. bovis in water buffaloes as well as crossbred cattle are necessary for better understanding of disease pattern under uncontrolled field conditions and subsequently , implementation the suitable policy for treatment and control . \n the objective of the present study was to investigate the natural b. bovis infection in water buffaloes in comparison to crossbred cattle under field conditions in egypt . \n blood samples were collected from the jugular vein into edta - containing tubes from 35 animals ( 23 cattle and 12 buffaloes ) of both sexes and aged 25 years , and were originating from different villages : el - aslogy , shobk basta and tel basta around zagazig city , sharkia province . \n these animals were divided into 2 groups , the field - exposed ( diseased ) group comprised of 20 cattle and 9 water buffaloes which was examined at the veterinary teaching hospital , faculty of veterinary medicine , zagazig university , during the period from march to june 2008 and resulted to have persistent fever , anemia and anorexia . \n the control group ( 3 cows and 3 buffaloes ) was carefully examined clinically and parasitologically and found healthy and free from external , internal , and hemoparasites . \n the common available foods for animals under the present study were mainly consisted of barseem ( trifolium alexandrinum ) , rice or wheat straw and concentrate mixture ( 12 kg / head / day ) . \n crossbred cattle were resulted from crossbreeding between the imported holstein - friesian breed cattle and egyptian baladi cattle breed ( bos taurus ) . \n samples collection , handling and examination of cattle and buffaloes under the current study were done after approval of animals owners . \n animals were subjected to clinical and hematological examinations at veterinary teaching hospital , faculty of veterinary medicine , zagazig university . \n the filed - exposed group showed various degrees of bovine babesiosis such as high fever ( > 40 c ) , anorexia , hemoglobinuria ( bloody urine ) , anemia , and jaundice . \n the control group was examined thoroughly for presence of any abnormal clinical changes and external parasites , and was thoroughly examined by different laboratory techniques such as direct smear , flotation , sedimentation and barmen s techniques and blood film to confirm the absence of any internal parasites and/or hemoparasites ( rosenberger 1990 ) . \n thin blood films were prepared immediately after taking the blood samples directly from the ear vein in the field to allow these smears to dry by air then fixed by using methanol for about 35min , allow them to dry by air after fixation step then stained with giemsa stain diluted at 8% with distilled water for about 3045min . \n they were dried by air and examined on olympus microscope using oil immersion lens at x1000 magnification ( kelly 1984 ) . \n blood film was examined for b. bovis at 1/41/2 inch from the end of the film by visually scanning from one side of the film to other ( cross sectional method ) to give constant and representative examination . each blood film and at least twenty microscopic fields of each slide were examined twice before being considered negative . \n approximately 5ml of blood was taken from the jugular vein of all animals with a syringe containing edta . \n the blood samples were subjected to hematological parameters analysis ( schalm et al . 1975 , coles 1986 ) , that is , red blood cell ( rbc ) and white blood cell ( wbc ) counts were made with improved neubauer hacmocytometers , hemoglobin concentration ( hb ) by sahli s haemoglobinometer and packed cell volume ( pcv% ) by microhematocrit tubes . \n the obtained data were statistical analyzed by mean of computer based statistical program , spss ( borenstein et al . \n data were analyzed using student s t - test to compare the mean data between groups . \n blood samples were collected from the jugular vein into edta - containing tubes from 35 animals ( 23 cattle and 12 buffaloes ) of both sexes and aged 25 years , and were originating from different villages : el - aslogy , shobk basta and tel basta around zagazig city , sharkia province . \n these animals were divided into 2 groups , the field - exposed ( diseased ) group comprised of 20 cattle and 9 water buffaloes which was examined at the veterinary teaching hospital , faculty of veterinary medicine , zagazig university , during the period from march to june 2008 and resulted to have persistent fever , anemia and anorexia . \n the control group ( 3 cows and 3 buffaloes ) was carefully examined clinically and parasitologically and found healthy and free from external , internal , and hemoparasites . \n the common available foods for animals under the present study were mainly consisted of barseem ( trifolium alexandrinum ) , rice or wheat straw and concentrate mixture ( 12 kg / head / day ) . \n crossbred cattle were resulted from crossbreeding between the imported holstein - friesian breed cattle and egyptian baladi cattle breed ( bos taurus ) . \n samples collection , handling and examination of cattle and buffaloes under the current study were done after approval of animals owners . \n animals were subjected to clinical and hematological examinations at veterinary teaching hospital , faculty of veterinary medicine , zagazig university . \n the filed - exposed group showed various degrees of bovine babesiosis such as high fever ( > 40 c ) , anorexia , hemoglobinuria ( bloody urine ) , anemia , and jaundice . \n the control group was examined thoroughly for presence of any abnormal clinical changes and external parasites , and was thoroughly examined by different laboratory techniques such as direct smear , flotation , sedimentation and barmen s techniques and blood film to confirm the absence of any internal parasites and/or hemoparasites ( rosenberger 1990 ) . \n thin blood films were prepared immediately after taking the blood samples directly from the ear vein in the field to allow these smears to dry by air then fixed by using methanol for about 35min , allow them to dry by air after fixation step then stained with giemsa stain diluted at 8% with distilled water for about 3045min . \n they were dried by air and examined on olympus microscope using oil immersion lens at x1000 magnification ( kelly 1984 ) . \n blood film was examined for b. bovis at 1/41/2 inch from the end of the film by visually scanning from one side of the film to other ( cross sectional method ) to give constant and representative examination . each blood film and at least twenty microscopic fields of each slide were examined twice before being considered negative . \n approximately 5ml of blood was taken from the jugular vein of all animals with a syringe containing edta . \n 1975 , coles 1986 ) , that is , red blood cell ( rbc ) and white blood cell ( wbc ) counts were made with improved neubauer hacmocytometers , hemoglobin concentration ( hb ) by sahli s haemoglobinometer and packed cell volume ( pcv% ) by microhematocrit tubes . \n the obtained data were statistical analyzed by mean of computer based statistical program , spss ( borenstein et al . 1997 ) . \n data were analyzed using student s t - test to compare the mean data between groups . \n cattle infected with b. bovis showed typical clinical signs of babesiosis , table 1 . briefly , highly rise in body temperature ( 4041.5 c ) , conjunctival and vaginal mucous membranes were anemic and the clinical severity was ranged from paleness in mild cases to severe yellow discoloration ( icterus ) in more progressive cases , dark brown to dark red ( coffee - color ) urine , hemoglobinuria was common sign in cattle with severe clinical manifestation and accelerated heart and respiratory rates . \n various degrees of tick infestations were present around groins , horns , inter - mandibular space , and ears . \n water buffaloes infected with b. bovis showed a milder form ( less severe ) of clinical signs of infection in comparison to the clinical signs appeared on b. bovis - infected cattle . \n these clinical signs were in the form of highly rise in body temperature ( 4041.5 c ) , and conjunctival and vaginal mucous membranes were mainly anemic and pale in color and loss of body condition . \n icterus , hemoglobinuria and nervous manifestations were not detected / observed in the affected buffaloes . \n giemsa - stained blood smears from b. bovis infected animals showed intra - erythrocytic piroplasms of b. bovis that were in the form of pyriform or pear - shaped , fig . \n blood smears from b. bovis progressive cases of cattle showed severe hemolytic anemia with abnormalities in cell size ( anisocytosis ) and cell shape ( poikilocytosis ) of erythrocytes , fig . \n 2 . giemsa - stained blood smears from b. bovis uninfected cattle and buffaloes showed no parasites or erythrocytic changes . \n the control group resulted to be healthy on clinical and laboratory examination and free from external , internal and hemoparasites . \n the mean values of rbcs , hemoglobin amount , pcv % , wbcs , and differential leucocytic count are listed in table 2 . \n briefly , the important findings can be summarized as follows ; there is a clear significant difference in the haematological parameters between b. bovis - infected buffaloes and b. bovis - infected cattle in comparison to control group at p - value ( 0.01 ) and ( 0.001 ) , respectively . \n haematological changes for b. bovis - infected buffaloes were less significant than their changes for b. bovis - infected cattle . \n cattle infected with b. bovis showed typical clinical signs of babesiosis , table 1 . briefly , highly rise in body temperature ( 4041.5 c ) , conjunctival and vaginal mucous membranes were anemic and the clinical severity was ranged from paleness in mild cases to severe yellow discoloration ( icterus ) in more progressive cases , dark brown to dark red ( coffee - color ) urine , hemoglobinuria was common sign in cattle with severe clinical manifestation and accelerated heart and respiratory rates . \n various degrees of tick infestations were present around groins , horns , inter - mandibular space , and ears . \n water buffaloes infected with b. bovis showed a milder form ( less severe ) of clinical signs of infection in comparison to the clinical signs appeared on b. bovis - infected cattle . \n these clinical signs were in the form of highly rise in body temperature ( 4041.5 c ) , and conjunctival and vaginal mucous membranes were mainly anemic and pale in color and loss of body condition . \n icterus , hemoglobinuria and nervous manifestations were not detected / observed in the affected buffaloes . \n giemsa - stained blood smears from b. bovis infected animals showed intra - erythrocytic piroplasms of b. bovis that were in the form of pyriform or pear - shaped , fig . \n blood smears from b. bovis progressive cases of cattle showed severe hemolytic anemia with abnormalities in cell size ( anisocytosis ) and cell shape ( poikilocytosis ) of erythrocytes , fig . \n 2 . giemsa - stained blood smears from b. bovis uninfected cattle and buffaloes showed no parasites or erythrocytic changes . \n the control group resulted to be healthy on clinical and laboratory examination and free from external , internal and hemoparasites . \n the mean values of rbcs , hemoglobin amount , pcv % , wbcs , and differential leucocytic count are listed in table 2 . \n briefly , the important findings can be summarized as follows ; there is a clear significant difference in the haematological parameters between b. bovis - infected buffaloes and b. bovis - infected cattle in comparison to control group at p - value ( 0.01 ) and ( 0.001 ) , respectively . \n haematological changes for b. bovis - infected buffaloes were less significant than their changes for b. bovis - infected cattle . \n babesia bovis is one of the most important blood parasites affecting cattle and buffaloes and in its acute forms , it lowers the productive performance of the affected animals ( talkhan et al . \n most of the previous studies described the clinical findings of b. bovis infection in cattle of different breeds . to the best of our knowledge , \n this is the first study which investigating thoroughly the clinical and hematological pictures of natural b. bovis infection in water buffaloes under uncontrolled field conditions . \n the reported clinical findings of b. bovis infection in cattle come in agreement with what was previously described by brown and torres ( 2008 ) , georgi et al . \n the demonstrated high fever could be attributed as response to the effect of unspecific toxic substances produced during the metabolism of babesia on thermoregulatory ( radostits et al . \n it was notable that water buffaloes identified as b. bovis - infected showed a milder form ( less severe ) of clinical signs of b. bovis infection in comparison to the clinical signs appeared on b. bovis - infected cattle . \n this variation was represented in appearance of icterus , hemoglobinuria and nervous manifestations in clinically infected cattle while they were not reported in infected buffaloes . \n this finding may propose that buffaloes may have more tolerance to clinical infection with b. bovis than cattle . \n tolerance means that the host is infected by the pathogen , but suffers little adverse effect ( fao 2007 ) . \n it could be argued that buffaloes may have acquired natural immunity / tolerance to some extent against b. bovis infection . \n genetic variations within the host between cattle and buffaloes may explain the variation in their susceptibility . \n ( 1997 ) who found that b. bovis produces acute , often fatal , infections in buffaloes . \n the proportion of buffaloes identified as b. bovis - infected was ( 31.1% ) while the proportion of cattle identified as b. bovis - infected was ( 68.9% ) within the same period of the study . \n this finding could suggest that water buffalos have more tendencies to be carriers ( apparently healthy ) than showing clinical manifestations . \n ( 2008 ) who noticed that water buffaloes seem to be unapparent carriers of the parasite . the marked anemia and hemoglobinuria in cattle \n could be attributed to the severe haemolytic process associated the presence of babesia piroplams inside the erythrocytes and destruction of large numbers of these erythrocytes by the parasite resulting in hemoglobinaemia and consequently hemoglobinuria ( georgi et al . \n 1990 , fujinaga 1981 ) , the physical effect of parasite multiplication ( wright 1981 ) , the increase of phagocytosis of erythrocytes by activated macrophages ( shoda et al . \n 2000 , court et al . 2001 ) , the production of an anti - erythrocyte antibody ( goe s et al . \n 2007 ) and the increase in the erythrocytic membrane permeability ( alkhalil et al . 2007 ) . \n hematological findings showed a significant decrease in the rbcs , wbcs counts , hb concentrations and pcv% in the b. bovis - infected animals in comparison to the control group , these observations were similar to what were reported by col and uslu ( 2007 ) and durrani et al . \n hematological changes resulted from b. bovis infection in buffaloes are less significant than the hematological changes of b. bovis infection in cattle , table 2 . \n this finding reflected clinically on b. bovis - infected buffaloes which showed a milder form of clinical picture of b. bovis infection than b. bovis - infected cattle . \n the hemolytic anemia due to the breakdown of erythrocytes membranes leading to release of hemoglobin and manifested by the presence of free hemoglobin resulting in the discoloration of the plasma ( sowemimo - coker 2002 ) . \n extensive lipid peroxidation in biological membranes causes disturbances of its structural integrity , loss of fluidity , decrease in membrane potential , and increased permeability to ions ( gutteridge 1995 ) . \n these changes lead to rupture of the membrane and release of cell contents ( halliwell and chirico 1993 ) . \n babesia parasite ( alkhalil et al . 2007 ) , and b. bovis ( aikawa et al . 1985 ) dramatically alters the permeability of its host erythrocytes to various organic solutes . \n b. bovis infection is associated with impairment of blood parameters and subsequently , hematological examination may be a useful tool for confirmation the clinical diagnosis of bovine babesiosis . \n water buffaloes showed a milder form of b. bovis infection than cattle suggesting that buffaloes may be more tolerant to the clinical infection with b. bovis than cattle . \n hematological changes as a result of b. bovis infection in buffaloes are less significant than hematological changes of b. bovis infection in cattle . \n b. bovis infection might be associated with severe clinical and hematological changes especially in cattle , which might be of bad prognosis . with respect to the study population \n , future studies should consider a larger sample size for cattle and buffaloes for the robustness of the findings . \n recent molecular techniques such as pcr showed many advantages with regard to the sensitivity and specificity for detection and surveillance of hemoparasites ( nayel et al . \n hence , it would be advisable for future studies to use such techniques for investigating the b. bovis infection in buffaloes .", "role": "user" }, { "content": "backgroundthere is a little or no data available on the natural babesia bovis ( b. bovis ) infection in water buffaloes ( bubalus bubalis ) comparing to the available one for cattle . \n this study was conducted to investigate the natural b. bovis infection in water buffaloes in comparison to crossbred cattle under field conditions in egypt.methods:a total of 35 buffaloes and cattle were clinically and laboratory investigated from march to june 2008 . \n twenty - nine buffaloes and cattle out of 35 were naturally infected with b. bovis and showed signs of bovine babesiosis . \n three cows and three buffaloes showed no clinical signs and were free from external , internal , and blood parasites served as control group.results:babesia bovis - infected cattle showed typical signs of bovine babesiosis while b. bovis - infected buffaloes showed a milder form ( less severe ) of the clinical signs . \n advanced cases of cattle showed dark brown to dark red ( coffee - color ) urine , hemoglobinuria and nervous manifestations while these manifestations were not detected in the infected buffaloes . \n hematological changes in both species however , these changes were less significant in buffaloes than those reported in cattle.conclusion:this paper documents the first description of natural b. bovis infection in water buffaloes which were found to be more likely to be tolerant than cattle to the natural clinical infection with b. bovis and its subsequent haematological changes . \n our finding may lead to a better understanding of the disease pattern of b. bovis infection under field conditions in buffaloes .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: hodgkin lymphoma ( hl ) is unique among malignancies in that the cancerous cell is rare ( as few as one in 100 cells ) and instigates the creation of a tumor mass by attracting a stroma of reactive non - clonal lymphocytes , eosinophils and fibroblasts . \n the pathologic hallmark and malignant cell of classical hl is the multinucleated , giant reed - sternberg ( rs ) cell . \n rs cells are derived from b lymphocytes of germinal center origin and arise due to a disturbance in cytokinesis by mononuclear hodkgin cells . \n regulatory and signal transducing proteins in the nuclear factor kappa b ( nfb ) pathway are often mutated , resulting in constitutive activation of nfb . altered signaling through jak / stat proteins , in particular gain - of - function in jak2 , is strongly implicated as well in the pathogenesis of the rs cell . \n epstein - barr virus ( ebv ) plays a significant role and is implicated in 40 percent of hl cases . \n the role of the rs cell as a recruiter of non - clonal cells to form a tumor mass is unique . \n beyond avoidance of apoptosis , nfb and ebv contribute to hl pathogenesis by inducing rs cells to elaborate cytokines and chemokines such as il-8 , il-12 , ccr4 and tgf- that drive the aggregation of the surrounding inflammatory infiltrate . \n rs cells activation of nfb and tumor necrosis factor receptor family members leads to expression of th2 cytokines that recruit eosinophils , th2 cells and fibroblasts . \n a key feature of hl , strongly linked to the multinucleated nature of the rs cell , is the presence of chromosomal aberrations . \n case series show strong evidence of chromosomal instability and aberrations in most cases of hl ; tetraploidy or near - tetraploidy are frequently observed . \n it has been speculated that rs cells or their immediate precursors are derived from a karyotypically aberrant lineage . \n although chromosomal instability is strongly implicated in rs cell formation and hl pathogenesis , the mechanisms behind chromosomal instability in hl and the evolution of the rs cell are incompletely known . \n klhdc8b is a mitotically - expressed kelch - domain protein whose deficiency has recently been linked to hl pathogenesis , due to a familial hl pedigree in which a chromosomal translocation disrupted klhdc8b . \n the pedigree and the disruption of klhdc8b provided a rare opportunity for insight into the origins of the rs cell . \n we have performed detailed investigation of the role of klhdc8b in maintaining mitotic integrity and faithful segregation of chromosomes . \n we recently reported in the journal of biological chemistry that interfering with the function of klhdc8b leads to significant increases in multinucleation , mitotic errors , abscission failure , centrosomal amplification and aneuploidy . \n our ability to recapitulate key features of the rs cell demonstrated the essential roles of mitotic integrity and faithful chromosomal segregation in protecting against hl and shed key light on the molecular mechanisms behind aneuploidy , an essential but poorly - explained component of hl pathology and pathogenesis . \n we achieved stable knockdown of klhdc8b by rna interference in hela cells , b lymphoblasts and fibroblasts . in hela cells \n , we also stably expressed a klhdc8b - gfp fusion protein , which functioned in a dominant - negative role . \n we observed significant increases in multinucleation , aberrant mitoses , delayed or failed abscission , centrosomal amplification , production of micronuclei and aneuploidy ( table 1 ) . \n disruption of klhdc8b also led to asymmetric segregation of daughter nuclei , formation of anucleated daughter cells and multipolar mitotic figures . \n thus , we recapitulated the major pathologic features of the rs cell and showed that klhdc8b helps maintain chromosomal stability . to the best of our knowledge , \n our study was the first to report the association of a particular gene with centrosomal amplification and aneuploidy in hl . \n supernumerary centrosomes are known to cause multipolar mitoses and chromosome missegregation , suggesting a direct link between centrosomal amplification and chromosomal instability . \n we observed increased numbers of multipolar mitoses and metaphases by live cell imaging and fluorescence immunohistochemistry in cells expressing the klhdc8b - gfp fusion protein , though inadequate numbers were available for statistical analyses . \n supernumerary centrosomes , which can yield multipolar mitoses at metaphase ( fig . 1 ) \n , may directly lead to missegregation of chromosomes by forming extra microtubule attachments that interfere with bidirectional mitotic segregation . \n a tripolar metaphase is seen in a mitotic hela cell stably expressing the klhdc8b - gfp fusion protein . \n tripolar mitoses , which lead to chromosomal missegregation , are one manifestation of interfering with klhdc8b s normal function . \n chromosomes are stained with dapi ( blue ) , and spindles are stained with antibodies against -tubulin ( red ) . \n a z - stack of images was obtained with a nikon a1r confocal laser scanning microscope , using nis elements acquisition software ( nikon ) . \n our data suggest a mechanism for chromosomal instability in hl , by which defects in midbody function lead to centrosomal amplification . \n centrosomal amplification may be a direct effect of midbody protein dysfunction or may arise due to the accumulation of centrosomes from failed mitoses . \n supernumerary centrosomes cause missegregation of chromosomes , in some cases due to multipolar mitoses , leading to cells that have lost or gained chromosomes ; the missegregated chromosomes may contain tumor suppressor genes or genes that regulate inflammation , favoring the inflammatory functional profile of the rs cell . \n telomere shortening and loss in hl cell lines l-428 and l-1236 may lead to breakage - bridge fusion ( bbf ) cycles , in which sister chromatids without telomeres fuse to each other and subsequently form internuclear dna bridges during anaphase . the bridges are subsequently broken by forces of tension , leading to uncapped chromatids that are free to repeat the cycle again , resulting in translocations and aneuploid nuclei . \n bbf cycles may account for unequal and disrupted distribution of chromosomes between nuclei , resulting in rs cell nuclei that may be chromosome - poor , or aneuploid . \n . they may be less informative about the initial steps leading to chromosomal instability than they are indicative of the damage that can be inflicted by chromosomal instability processes in rs cells . \n interfering with klhdc8b s function resulted in an increased incidence of micronuclei , which originate from chromosome fragments that arise due to dna damage or missegregated chromosomes . \n the whole or partial chromosomes are sequestered into structures similar to but much smaller than normal nuclei ( fig . 2 ) . \n given that we observed increased rates of aneuploidy , it is more likely that the micronuclei observed in our study are composed of whole chromosomes . \n several micronuclei ( arrows ) are observed in a multinuclear hela cell expressing the klhdc8b - gfp fusion protein . \n the inset demonstrates the dic image of the cell , including the green and blue channels . \n a z - stack of images was obtained with a nikon a1r confocal laser scanning microscope , using nis elements acquisition software ( nikon ) . \n pulverization or shattering into pieces in greek ) , the phenomenon of a single chromosome pieced together from tens to hundreds of rearranged fragments , gives insight into how chromosomal instability can trigger carcinogenesis over a brief mutational time span . \n bbf cycles and impaired double - strand break repair may contribute to chromothripsis , but the most promising model for the generation of chromothriptic chromosomes is based on micronuclei . it is hypothesized that the dna of chromosomes or chromosome fragments in micronuclei does not appropriately condense at the g2/m cell cycle checkpoint , and the chromosomes are then pulverized during mitosis . \n the dna is subsequently reassembled into patchwork chromosomes that are ultimately reincorporated into the main cellular nucleus . \n additionally , micronuclei suffer from inadequate acquisition of dna repair and synthesis machinery , further contributing to double - strand breaks , pulverization and thus the rapid accumulation of mutations . \n klhdc8b protects against micronucleus formation and thus possibly chromothripsis , which appears to be a promising candidate mechanism by which the aneuploid rs cell acquires the multiple mutations necessary to allow evasion of apoptosis and establishment of an inflammatory microenvironment . \n the concept of a micronuclear environment that is deficient in dna damage repair and dna synthesis mechanisms suggests a link between the functions of faithful chromosomal segregation and dna damage repair . \n similar connections exist within the identities of the many proteins performing these two seemingly separate tumor suppressor functions . \n brca1 and brca2 are well - known for their roles in signaling dna damage and directly participating in dna repair , respectively , but both proteins also localize to the midbody and protect against aneuploidy . \n the nucleic - acid binding proteins of the nf90/nf45 complex help repair double - strand breaks by non - homologous end joining , yet they also protect against cytokinesis failure and multinucleation . \n these findings raise the intriguing possibility that klhdc8b plays a tumor suppressor role extending beyond guarding against mitotic errors and aneuploidy , perhaps in dna damage repair . \n we plan to investigate the possible roles of this midbody protein , a relative newcomer to the field of cancer biology , with subsequent cellular and animal models of klhdc8b dysfunction .", "role": "user" }, { "content": "the reed - sternberg ( rs ) cell is the driving force behind hodgkin lymphoma ( hl ) , a unique malignancy in which the rare rs cell creates an inflammatory microenvironment that recruits a reactive tumor infiltrate . \n well - known oncogenic factors such as nuclear factor kappa b ( nfb ) signaling and epstein - barr virus infection are linked to hl pathogenesis but do not adequately explain the rs cell s key pathologic features of multi - nucleation , abnormalities of centrosome function and number and aneuploidy . \n chromosomal instability is also considered a key pathway in the origin of the rs cell , though the molecular mechanisms have largely been a black box . we demonstrated that the midbody kelch domain protein klhdc8b protects against mitotic errors , centrosomal amplification and chromosomal instability . here we discuss how the new findings linking klhdc8b to mitotic integrity and faithful chromosomal segregation are providing mechanistic explanations for the origin of the rs cell and the molecular pathogenesis of chromosomal instability in hl .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: several histopathologic features of periampullary adenocarcinoma tumors correlate with survival following resection , including lymph node ( ln ) status , perineural infiltration , lymphovascular invasion , and lymph node ratio ( lnr ) . \n both perineural infiltration and lymphovascular invasion in pancreaticoduodenectomy specimens were found to be associated with a decreased 5-year survival . \n perineural invasion alone has also been shown to be a strong predictor of survival in patients with periampullary , duodenal , and ampullary adenocarcinomas [ 24 ] . \n identified a higher resectability rate and better prognosis in patients with ampulla of vater tumors and emphasized that the ln status likely influenced survival outcomes . \n more recently , the utility of the lnr , defined here as the number of positive ln divided by the total number of ln assessed in a surgical specimen , has been highlighted as a potential factor in predicting mortality [ 6 , 7 ] . \n for nonperiampullary tumors , the lnr has also been correlated with prognosis , including gastric cancer , esophageal squamous cell carcinoma , small bowel adenocarcinoma , colorectal cancer , breast cancer , and melanoma . \n notably , the lnr was an independent prognostic indicator for overall survival in patients undergoing curative gastrectomy for gastric cancer , but it did not prove to be superior to standard pn staging . \n in contrast , the lnr in patients with node - positive breast cancer was able to further subdivide patients across all pn groups , suggesting that the lnr may add prognostic value to the traditional tnm classification . \n furthermore , the lnr may be a more precise predictor of survival than traditional pn staging in some patients with colon cancer [ 16 , 17 ] . in patients with cholangiocarcinoma \n , ln metastasis serves as a major prognostic factor , while the number of ln resected and the lnr also yield high prognostic value [ 18 , 19 ] . considering this , the lnr has been proposed as a superior prognostic variable for numerous types of tumors . as such , the association between the lnr and periampullary tumors has also been investigated . following curative resection for ampulla of vater carcinoma , \n the lnr and a minimum of 16 evaluated nodes were identified as robust prognostic factors for disease - specific survival . \n in contrast , retrospective evaluations of pancreatic cancer and ampullary carcinoma demonstrated that the number of metastatic nodes , but not lnr , was one of the most important prognostic factors [ 21 , 22 ] . \n however , a significant association between the lnr and survival for patients with pancreatic cancer was identified in separate studies [ 6 , 2325 ] . \n furthermore , using data from patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma , the lnr has been shown to be one of the most powerful predictors of short- and long - term survival and has been suggested as a new tool for stratifying patients in future trials . \n thus , beyond the qualitative ln status ( positive or negative nodes ) , the lnr may provide a quantitative tool that improves the current classification system for periampullary tumors [ 7 , 26 ] . \n although most of the aforementioned studies evaluated the association between various histopathologic features and prognosis , they were unable to instigate significant changes in the staging classification for periampullary tumors . \n this outcome was likely attributable to the fact that their focus was often seeking only one variable as the best predictor of their outcome , as opposed to utilizing several criteria similar to the current tnm staging to better classify periampullary tumors . \n therefore , we aim to evaluate the association between mortality and several histopathologic features of periampullary adenocarcinoma tumors , including the lnr , at multiple time points in order to better predict patient prognosis . \n we performed a retrospective review to assess the correlation between several histopathologic features of periampullary adenocarcinoma tumors and mortality following surgical intervention . \n we identified 207 patients with periampullary adenocarcinoma tumors who underwent attempted curative resection ( pancreaticoduodenectomy , r0 or r1 resection completed ) between january 1 , 2001 and december 31 , 2009 . \n patients with concurrent malignancies , a history of periampullary adenocarcinoma ( or other pancreatic cancers ) , or perioperative mortalities ( i.e. , patients dying within 30 days of surgery ) were excluded . \n the social security death index was utilized to determine current living status ( last updated at april 27 , 2012 ) . \n clinical and histopathologic features were assessed from the medical record , and overall survival at 1 year , 3 years , and to date was determined . \n although pathology and operative reports were available for all patients , more detailed records were not routinely uploaded into our electronic medical record until 2006 , which limited the collection and utilization of some clinical parameters . \n disease - free survival was unable to be calculated due to the limited follow - up at our institution . \n statistical analyses were conducted using stata 10.0 ( statacorp , college station , tx ) . \n categorical variables were analyzed using chi - squared ( \n ) tests , and continuous variables were analyzed using mann - whitney u tests . \n univariate and multivariable logistic regression were performed to assess clinicopathologic characteristics associated with 1- and 3-year mortality following surgical resection ( odds ratios and 95% confidence intervals reported ) . \n the selection of variables for the multivariate analyses was based upon the results of the univariate analyses . \n similarly , univariate and multivariate cox proportional hazard model analyses were performed to evaluate the relationship of these features with all mortality to date ( hazard ratios and 95% confidence intervals reported ) . \n classification and regression trees ( cart 6.0 ; salford systems , san diego , ca ) were used to analyze the interactions between 11 different risk factors and the outcomes of interest and 1- and 3-year mortality . \n the risk factors included age , gender , subtype of periampullary tumor , tumor size , pathologic margin status , ln status , total number of ln removed , number of positive ln , lnr ( number of positive ln / total number of ln removed ) , perineural infiltration , and lymphovascular invasion . \n cart analysis was used to grow a decision tree using the gini splitting criteria with a minimum number of 10 parent node cases and a minimum number of cases for the child nodes of 1 . given the limited size of the data set ( n = 207 ) , the tree 's classification accuracy was determined by way of a cross - validation method . to do this , \n one segment was successfully held out while the remaining segments were used to grow a tree , and the classification accuracy of the holdout segment was recorded . \n the overall cross - validation accuracy was determined by summing the results across all of the jackknifed segments . \n of the 207 patients identified , there were 106 males and 101 females with a median age of 69 years ( range 2887 years ) . \n there were 1728 surgeries performed annually ( median 23 surgeries ) between 2001 and 2009 . \n most tumors were pancreatic in origin ( 56% versus 23% ampullary , 12% duodenum , and 9% distal common bile duct ) . \n similar proportions were noted in a cohort of patients from the seer cancer registry who underwent pancreaticoduodenectomy between 1993 and 2003 : 62.5% pancreatic , 18.9% ampullary , 7% duodenal , and 11.6% distal bile duct . \n the median tumor size was 2.75 cm , and an r0 resection was achieved in 70.5% of patients ( \n ( n = 106 ) , and perineural infiltration was reported in 66% ( n = 137 ) . \n at least one ln was positive in 64% of patients ( n = 133 ) , and the median number of positive ln was one . \n while 207 patients were followed up for at least 1 year , only 187 had been followed up for at least 3 years at the time of analysis . at 1-year follow - up , \n significant differences between survivors and nonsurvivors were noted for 8 clinicopathologic features ( age , tumor size , margin status , lymphovascular invasion , perineural invasion , overall ln status , number of positive ln , and lnr ; table 1 ) . excluding age , \n similar differences were observed between the two groups at 3-year follow - up ( table 1 ) . \n the median overall follow - up was 1.9 years , while it was 5.6 years for survivors alone and 1.7 years for nonsurvivors alone . \n the crude overall survival was 31% at the end of the follow - up period . \n overall survival at 1 year was 73% and dropped to 40% by 3 years after surgery . \n using univariate logistic regression , 1-year mortality was independently associated with 7 clinicopathologic characteristics : age , tumor size , margin status , lymphovascular invasion , perineural infiltration , ln status , and lnr ( data not shown ) . more specifically , perineural invasion had the strongest association with 1-year mortality ( or 3.03 , ci 1.426.47 ) , although ln status ( or 2.93 , ci 1.416.1 ) and margin status ( or 2.87 , ci 1.55.49 ) were quite similar . additionally , an increase in the lnr by 1% increased the odds of mortality by 1.03-fold . \n however , the average number of ln removed was 20 ; thus , a change by 1 ln would equate with a 5% change in the lnr and thus a 1.16-fold increase in the odds of mortality . \n multivariate analysis also revealed a significant association between 1-year mortality and the lnr ( or 1.02 , ci 11.04 ; table 2 ) . \n notably , the model adjusting for the lnr ( model e ) accounts for 13.3% of the variability ( adjusted r \n ) in 1-year mortality , while the other models account for 10.812.9% ( table 2 ) . for 3-year mortality , univariate logistic regression analyses revealed independent associations with 6 clinicopathologic characteristics : tumor size , margin status , lymphovascular invasion , perineural infiltration , ln status , and lnr ( data not shown ) . \n in contrast to 1-year mortality where perineural invasion was strongest , at 3 years the overall ln status ( positive or negative ) had the strongest association ( or 6.42 , ci 3.3212.41 ) . however , perineural invasion remained a strong predictor ( or 5.44 , ci 2.8110.52 ) . \n similar to 1-year mortality , an increase in the lnr by 1% increased the odds of mortality by 1.08-fold . \n thus , a change by 1 ln would equate with a 5% change in the lnr ( assuming 20 ln were assessed ) and consequently a 1.47-fold increase in the odds of mortality . \n therefore , qualitative ln status and perineural invasion appear to be stronger predictors than lnr in predicting 3-year mortality . \n this is further supported by multivariate analyses where the model adjusting for overall ln status ( model d ) accounts for 22.5% of the variability in 3-year mortality ( adjusted r \n ) , while the other models account for 12.920.6% ( table 2 ) . \n similar findings were noted using univariate cox proportional hazards , where perineural infiltration ( hr 2.61 , ci 1.773.85 ) and overall ln status ( hr 2.69 , ci 1.843.95 ) had strong associations with overall mortality ( data not shown ) . in multivariate cox analyses , \n all clinicopathologic characteristics included were significant independent predictors ( p < 0.05 ) in all models ( table 3 ) . \n more specifically , the presence of positive ln appeared to have the strongest crude association with overall mortality . \n to create the cart decision trees , 11 risk factors were entered into the software to classify survivor and nonsurvivor patients at 1- and 3-year follow - up . \n variables included age ( continuous ) , gender ( male or female ) , tumor size ( continuous ) , margin status ( positive or negative ) , tumor subtype ( pancreatic , distal common bile duct , ampullary , or duodenal ) , lymphovascular invasion ( positive or negative ) , perineural invasion ( positive or negative ) , ln status ( positive or negative ) , number of positive ln ( continuous ) , total number of ln removed ( continuous ) , and lnr ( continuous ) . for 1-year mortality , \n the cart tree grown with the training data set contained 7 levels ( figure 1 ) . \n the most important factor was the lnr as 84% with a lnr 0.1 were alive at 1 year ( n = 102 of 122 ) . of patients with a lnr \n > 0.1 , the next most important risk factor was tumor size , where 100% of patients with tumors 2.05 were alive at 1 year ( n = 13 ) and 100% of those with tumors > 2.05 but 2.3 died ( n = 4 ) . \n further splits were developed , and the decision tree had an overall classification accuracy of 82% for the training data set . to validate these findings , \n a subset of the data was used to test the model , yielding a score of 74% overall accuracy ( table 4 ) . for 3-year mortality , \n the cart tree grown with the training data set contained only one level ( figure 2 ) . \n the most important factor was again the lnr as 78% with a lnr > 0.04 were deceased at 3 years ( n = 88 of 113 ) and 66% of those with a lnr 0.04 were alive ( n = 49 of 74 ) . \n this decision tree had an overall classification accuracy of 73% for the training data set , which was similar for the testing data set ( overall accuracy 72% ; table 4 ) . \n based on a similar cohort of patients undergoing pancreaticoduodenectomies from 1998 to 2007 at our institution , we previously demonstrated an inverse relationship between the lnr and survival , which was strongest for pancreatic and ampullary tumors . here \n , we again demonstrate that a higher lnr is likely a significant risk factor for patients undergoing attempted curative resection of a periampullary adenocarcinoma tumor . using multiple analytic methods \n , it proved to be a significant variable in univariate and multivariate regression analyses , as well as being identified as the best initial stratification variable in recursive partitioning analysis . \n more specifically , the cart analyses suggest that the two most important risk factors for determining 1-year mortality were the lnr and tumor size , while only the lnr was able to risk - stratify patients at 3 years . a focused , separate analysis of 246 patients with specifically pancreatic adenocarcinoma reported a significant prognostic value of the lnr for both short- and long - term survival after pd . \n this was similarly confirmed in a recent study of 551 patients who underwent resection for periampullary tumors , and a lnr > 0.2 was identified as an independent prognostic factor for overall survival . while our analyses included the lnr as a continuous variable , one of the original studies evaluating the association between the lnr and pancreatic cancer found a statistically significant difference only for patients with a ratio of 15% to 19% , which has subsequently been used as the categorical cutoff for other follow - up studies [ 7 , 28 ] . \n the slight difference in cutoff values between the earlier report and the current investigation may be related to the inclusion of all periampullary tumors here . in this study , we wished to determine whether lnr by itself or other risk factors influenced survival in all four periampullary adenocarcinoma tumors over a longer period of time . \n we demonstrated that several other histopathologic features appeared to be significantly associated with prognosis , including tumor size , margin status , qualitative ln status , perineural infiltration , and lymphovascular invasion . \n data on tumor grade and adjuvant therapies were incomplete and , thus , not included in our analyses . excluding the lnr \n , perineural invasion appeared to be most significantly associated with 1-year mortality , while overall ln status yielded a stronger correlation at 3-year follow - up , although both variables were significant at both time points . in a similar study of 346 patients undergoing resection for periampullary cancers , only nodal metastasis and neural invasion significantly predicated overall survival in multivariate analysis \n nevertheless , as noted in a recent study of 1,147 patients over three decades , long - term survival has not significantly improved for patients undergoing resection for pancreatic cancer , which highlights the importance of creating novel stratification systems to help develop targeted and more appropriate treatment regimens . \n it has been proposed that the subtype of periampullary tumor also contributes to prognosis [ 32 , 33 ] . therefore , \n identification of biomarkers that aid in distinguishing the various subtypes may consequently correlate with survival . \n for example , recent investigations have demonstrated that hepatocyte nuclear factor 4-alpha ( hnf4 ) is an effective tool for identifying different ampullary cancer subtypes and is an independent predictor of a favorable prognosis . \n although limited by a relatively small sample size , subdividing our patient population by tumor subtype did not appear to influence patient stratification in our recursive partitioning analysis . \n others have suggested that a minimum number of ln need to be assessed in the surgical specimen in order to optimize prognostic accuracy and prevent stage migration errors . using a cohort of 5,465 patients from the seer cancer registry that underwent pancreaticoduodenectomy between 1993 and 2003 , gutierrez et al . demonstrated that a minimum of 10 ln should be examined in order to determine ln status . here , the mean number of ln assessed was 19.8 , but there was one patient with only 1 ln identified in the surgical specimen ( per report ) and 17 patients with fewer than 10 ln reported . \n of this patient subset , 1-year survival was 53% versus 74.7% for patients with 10 ln assessed ( p = 0.053 ) . by 3-year follow - up , this initially notable difference disappeared ( 3-year survival 41.2% for those with < 10 ln versus 39.4% for those with 10 ln ) . \n furthermore , there was no significant difference overall between 1- or 3-year survivors and nonsurvivors based on the total number of ln assessed ( table 1 ) . \n these findings suggest that the total number of ln evaluated may be an early risk factor but likely becomes less important as time progresses . \n one of this study 's strengths and weaknesses is the inclusion of patients over a 9-year period . during this time , the analysis of the pathologic specimens likely evolved with the emerging data related to margin status . \n was one of the first to evaluate the implementation of a standardized protocol for assessing resection margins in pancreatic head adenocarcinomas and found a significantly higher r1 rate with the newer protocol ( r1 rate 85% with the standardized protocol versus 53% with the nonstandardized protocol ) . \n the r1 rates , however , were not significantly altered by the implementation of the standardized protocol for ampullary or distal bile duct cancers . \n the r1 rates for all periampullary adenocarcinoma tumors in this study varied from 7% in 2008 to 56.5% in 2005 , while the most recent rate in 2009 was 23% and the overall was 29% . \n furthermore , the resection margin status was significantly associated with mortality in our regression analyses . \n although it is clear that specimen dissection technique and standardization of the pathologic examination are crucial [ 36 , 37 ] , the advancements in imaging over recent years have also influenced the selection of patients appropriate for attempted surgical resection and , thus , the overall margin status and ability to achieve an r0 resection . \n in addition to the more traditional histopathologic features assessed in surgical specimens , current research is investigating other potential biomarkers that may better correlate with prognosis and/or potentially aid in early diagnosis . \n cancer antigens ca19 - 9 and ca125 were some of the earlier biomarkers to be evaluated , but they lack sensitivity and specificity to be used for predicting prognosis . currently , serum ca19 - 9 levels are used primarily for diagnosis and/or following patients with active or a history of pancreatic cancer [ 39 , 40 ] . in an attempt to find novel biomarkers of the disease \n , one study found that cd56 and certain mucins were associated with vascular and perineural invasion and together may serve as markers of prognosis in patients with periampullary tumors . \n cyclin d1 was also found to be independently associated with prognosis in some periampullary tumors [ 42 , 43 ] , while p16 protein has shown some correlation with perineural invasion and , thus , potentially prognosis . \n although some of these biomarkers show great promise , their exact utility in prognosticating outcomes has yet to be validated in routine clinical practice . \n in contrast , the information needed to calculate the lnr of a surgical specimen is often readily available in most pathology reports . \n furthermore , it has the potential to serve as an adjunct to traditional tnm staging and may have additive risk stratification capability , which may be particularly important early in the disease course when survival declines most rapidly . \n our study systematically evaluated this and several other histopathologic features at multiple time points in order to adequately assess the ability of these variables to risk - stratify these tumors . \n in addition , our findings are supported by a unique and thorough analysis , which not only included traditional multivariate regression analyses , but also were further verified by another underutilized technique called recursive partitioning . \n the benefits of the latter method are its capacity to consider numerous variables simultaneously ( even more than that typically recommended for multivariate analyses ) , its ability to consider one variable in the context of other variables , and the mathematical calculations performed to determine the best stratification variable for the specified outcome within a particular data set . while regression methods may be more useful when seeking to quantify the relative contribution of the explanatory variables , recursive partitioning often provides insight into the data structure and relationships between variables . \n this analytical method has been used previously for similar questions [ 45 , 46 ] , but our study is one of the first to apply this technique as a tool for risk - stratifying patients with periampullary tumors . as suggested by cook and goldman , \n this simple and intuitive type of analysis for classifying subjects has the potential to help identify novel and synergistic interactions among multiple variables and potentially aids in developing more practical risk stratification tools . \n overall mortality appears to be more closely related to the lnr within the first year following surgery . \n longer follow - up periods , however , demonstrated a stronger association between overall mortality and the qualitative ln status and perineural invasion . \n evidence suggests that the current staging paradigm for periampullary adenocarcinoma tumors may need to be updated to include the lnr . \n however , further investigations are required to fully evaluate the utility of the lnr as either a replacement or an adjunct to the standard pn staging . \n in addition , patients living beyond a certain time frame following curative resection may require reanalysis for determining their continued prognosis .", "role": "user" }, { "content": "introduction . several histopathologic features of periampullary tumors \n have been shown to be correlated with prognosis . \n we evaluated their association with mortality at multiple time points . methods . \n a retrospective chart review identified 207 patients with periampullary adenocarcinomas who underwent pancreaticoduodenectomy between january 1 , 2001 and december 31 , 2009 . \n clinicopathologic features were assessed , and the data were analyzed using univariate and multivariate methods . \n results . in univariate analysis , \n perineural invasion had a strong association with 1-year mortality ( or 3.03 , ci 1.426.47 ) , and one lymph node ( ln ) increase in the ln ratio ( lnr ) equated with a 5-fold increase in mortality . \n in contrast , ln status ( or 6.42 , ci 3.3212.41 ) and perineural invasion ( or 5.44 , ci 2.8110.52 ) had the strongest associations with mortality at 3 years . using cox proportional hazards , perineural invasion ( hr 2.61 , ci 1.773.85 ) and ln status ( hr 2.69 , ci 1.843.95 ) had robust associations with overall mortality . \n recursive partitioning analysis identified lnr as the most important risk factor for mortality at 1 and 3 years . \n conclusions . \n overall mortality was closely related to the lnr within the first year , while longer follow - up periods demonstrated a stronger association with perineural invasion and overall ln status . \n therefore , the current staging for periampullary tumors may need to be updated to include the lnr .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: the evolution of artificial codes depends upon human intelligence ( 1 ) , whereas the genetic code is believed to evolve through very lengthy and very ancient selection processes that began in the rna world ( 2 ) and subsequently optimized and maturated in the modern world after dna finally replaced one of rna s major roles bearing and passing on the genetic information in a robust way . \n the birth of life as its primordial form rna was proposed to take place about 3.5 billion years ago around a time window of a few hundred million years 3 . , 4 . , 5 .. although it is impossible to reconstruct real cellular processes of the two early yet brilliant transitions of life : from the rna life first to the rna protein life and then to the rna protein dna life ( 6 ) , \n a description of plausible scenarios for the processes is of importance in understanding stepwise creations of many molecular mechanisms and their basic machineries . in this short paper \n , we attempt to propose a theoretical framework for such transitions to better understand their impact on the maturity of the genetic code . \n this proposition is certainly not free of loopholes but should be able to stimulate further contemplation and imagination . whether a model becomes popular or not relies entirely on its predicting power and its insights into molecular details yet to be revealed . \n the evolution of the genetic code began in the early phase of the rna world where rna molecules started to be built as simple nucleotide repeats or polymers . \n these de novo - synthesized polymers had to survive somehow for millions and millions of years in order to allow life to get started with structurally and functionally divergent rna molecules that provide complexity and perform sufficient functions . \n although template - directed synthesis might not be initially necessary since protocells certainly had to fight for life s seed components among themselves , these rna molecules could either be cut and pasted at the molecular level or be chemically modified to turn into other similar structures at the building - block level for structural and functional diversities . \n rna editing was obviously a molecular mechanism as part of the rna polymerization machinery aside from splicing . \n once engulfing wars among the protocells started going , rna molecules and their complexes had to be consistently synthesized , chemically modified , spliced , and assembled into two essential classes , operational and informational . up to a point , template - directed synthesis of rnas might have exhibited advantages over simple undirected polymerization . \n the operational rnas or ribozymes resembled the modern proteinaceous molecules and their complexes , whereas the informational rnas or riboscripts were functionally equivalent to messenger rnas in the contemporary biological world ( cb world ) . in the cb world , the latter is called rna splicing , which is either catalyzed by a \n ( usually a complex formed by proteins and rna as well as dna sometimes ; table 1)the spliceosome or self - spliced . \n of course , we have made here a bold assumption that life may start as a prototype of eukaryotic organism rather than prokaryote - like before recruitment of dna , and eukaryotes are known to have preserved some of the critical molecular mechanisms such as rna splicing through the spliceosomal pathway and complex organelles generated from intermediates of engulfing each other . \n the primitive genetic code would not be considered necessary until early versions of the rna - built translatosome were invented , which made primitive life forms leap into the late phase ( phase ii ) of the rna world the rna \n once requisite polypeptides were synthesized according to a ciphertext , genetic codes came into the play . \n if we assume that the early life forms and their shared genetic code did not use cytidine ( c ) before the involvement of dna , since it seems not stable enough to join primitive organisms 7 . , 8 . \n , the first set of codons was simple and purine - sensitive at the third codon position ( cp3 ) 9 . \n , 10 .. the codons were mostly made of adenosine ( a ) and uridine ( u ) , formed by a binary code that only distinguished purine from pyrimidine ( figure 1a ) . \n if we assume that the modern code became universal in life s early history or inherited the rna code with faith , it encoded possibly seven amino acids ( here we assume isoleucine and methionine are exchangeable and functionally equivalent ; both are capable of starting peptide synthesis ) as well as possessed both start and stop signals . \n these amino acids have rather impressive physicochemically diversified side chains , albeit relatively devoid of small and acidic amino acids ( figure 1b ) . \n since primitive translatosomes were made to be simple , there was a possibility that the first aminoacyl - trna synthetases ( aarss ) might have started as a permanent part of this protein - manufacturing machinery and fell off from it , together with trnas , as the genetic code forged ahead for creating peptide complexity . \n the first batch of rna - encoded proteins was mostly protective for integrity of primordial cells and their cellular components , and undoubtedly included those for rna binding and membrane stability , constituted by basic , aromatic , and hydrophobic amino acids . \n the first division of aarss was predicted to ensure protein diversity so that they must distinguish the two polar amino acids , asparagine and tyrosine , as well as the two aromatic amino acids , phenylalanine and tyrosine . \n in contrast , it might not be necessary to tell leucine , isoleucine , and methionine apart . \n there are at least two possible scenarios : one concerns the limited recruitment of guanine ( g ) and the other assumes editing mechanisms that convert adenosine ( a ) to inosine ( i ) . \n both scenarios should be able to provide significant structural diversity and coding capacity for ribozymes and riboscripts , respectively . \n base or nucleoside conversions between the two purine - containing nucleosides a and i as well as between the two pyrimidine - containing nucleosides u and c , have been carried over to the cb world . \n inosine is capable of forming double hydrogen bonds with u , g , and c. although the two scenarios may not be mutually exclusive , that is , they might have evolved independently or co - existed , we discuss them separately just for simplicity . in one scenario , we assume that g was recruited by riboscripts in a limited way in addition to serving as a divergent building block and processing signals for ribozymes ( figure 2a ) . although a ribozyme without g and c was proven functional ( 11 ) , structural and functional diversities provide advantages for life forms to compete for survival . \n since dinucleotides ag and gu are designated as signals for splice sites , the expansion of the codons in this scenario might be limited to tryptophane , glutamic acid , aspartic acid , cysteine , and glycine . \n these five new recruits are very impressive : the largest ( tryptophane ) , the negatively charged ( glutamic acid and aspartic acid ) , the disulfide - bond - forming ( cysteine ) , and the smallest ( glycine ) amino acids . in the other scenario , we assume that a was selectively and constantly edited into i in riboscripts in a context of a and i co - existence , so codons were extended to match more aa - trnas . \n the result of this extension became identical to the first scenario ( figure 2b ) . \n this scenario is strongly supported by the distribution of aars classes ( figure 3 ) as the expansion of amino acids and their corresponding aarss follow the class rule largely ( 12 ) . \n in addition , similar roles of nucleotide modifications have been inherited by all the extant life forms , such as wobble pairing between anticodons of trna molecules and codons of mrna ( 13 ) . \n for instance , aay ( n ) and its sibling codons , iay ( d ) , aiy ( s ) , and iiy ( g ) , share the same class of aarss . the k group ( aar , air , iar , and iir ) has a little complication , as there are two lys - rss belonging to classes i and ii . \n correspondingly , lysine s sibling codons can certainly go with class i ( glu - rs and arg - rs ) except glycine that was defined by its y - ending codons . \n an alternative explanation is that gly - rs may have an unusual history since its active form is a unique tetramer . \n the consensus of the two scenarios suggests an early - expanded genetic code that encodes twelve amino acids other than start and stop codons . \n the second recruitment of the early genetic code has to be arginine , serine , and valine after dinucleotides gu and ag were finally freed from serving as sequences of splice sites since spliceosomes became more sophisticated . \n the new addition that makes a set of fifteen amino acids was a subtle extension of the existing amino acids considering both the physicochemical property and the secondary structure : arginine was an alternative of lysine ; serine was a smaller version of tyrosine ; and valine added another variation to the hydrophobic amino acids \n leucine , isoleucine , methionine , and phenylalanine 14 . , 15 . , 16 . \n , 17 .. the most puzzling feature of the code is its unusual redundancy where only three amino acids , arginine , leucine , and serine , are encoded with six codons ; they by now have all been recruited and later expanded to acquire their quadruplets when cytosine joined the genetic code . \n let us first make a few observations on leucine in comparison to the other two amino acids . \n first , although they are all among the most abundant amino acids in the extant genomes , leucine is always the most abundant in all three kingdoms of modern life forms . \n serine comes to the second among eukaryotic genomes , such as in the human and arabidopsis genomes . \n arginine is the least abundant among the three , which barely makes it to the top ten among some of the bacterial genomes . \n second , leucine has the easiest codon conversion between the doublet and the quadruplet among all three amino acids : a simple base transition between u and c results in a change from uur to cur . \n this suggests that leucine is capable of playing essential structural roles for most proteins and maintains their integrity when gc content increases . \n similarly , to keep arginine and serine unchanged , transversions have to be introduced ; a single transversion has to take place to change agr to cgr for arginine , and double transversions , agy to ucy for serine , are indispensable . \n third , leucine has dimensions most similar to four other amino acids with side chains that have rather diverse physicochemical properties from it : isoleucine , histidine , methionine , and lysine 14 . \n , 15 .. all three observations support the notion that leucine should be the most abundant amino acids for all major life forms . by the same token \n serine differs from leucine and arginine in forming protein secondary structures ; it prefers turns as compared to leucine that favors alpha - helix and arginine that is rather neutral to all three major secondary structures . \n the only amino acid that is indiscriminately honored by alpha - helix , beta - sheet , and turn . \n these observations lead to a hypothesis that the additional codons for these three amino acids were tailored to balance the abundant amino acids when dna nucleotide composition changes , such as gc content or ag ( purine ) content increases . \n the corresponding codons are organized in such a way that they balance between pro - diversity and pro - robustness halves of the genetic code 9 . \n , 10 .. the result of such a balancing power is the stability of amino acid composition and its subtle effect on protein conformations when mutations bombard the coding sequence over evolutionary time scales . by now \n , the genetic code is good enough for directing protein synthesis , and the sophistication of proteinaceous cellular machineries have made life more diverged , robust , and complex . the final or the third recruitment of the code had to happen when dna replaced rna as the informational molecule for better precision and stability . \n reverse - transcription that made this a reality , and the template - directed dna replication marked the beginning of the new world . \n the evolution of many new cellular mechanisms , such as dna replication , repair , and dna - directed transcription , made the new world having achieved its perfection almost immediately ( figure 4 ) . \n the contemporary genetic code was born and fixed after cytosine and its deoxyl derivative joined in as one of the four building blocks for rna and dna , respectively . \n the code had to be filled up with new recruits as the coding capacity increased . \n histamine and glutamine filled in instantly due to their contributions to catalytic properties and similarities to the two existing basic amino acids , respectively . \n , 15 .. this new recruit plays a very crucial role in protein structure and function diversity : swapping between a hydroxyl group with hydrophilic property and hydrophobic side chain if the size change is tolerable for essential functions of a protein . \n , it distorts the protein backbone in a unique way that no other amino acid does ; on the other hand , it fits in with its hydrophobicity and modest size , resulting minimal changes when replacing other amino acids , such as aspartic acid , glutamine , and threonine . \n the corresponding expansion pattern in aars classes also supports the simple extension hypothesis . aside from the six - fold degenerate codons , there are six sets of codons involved in the final expansion , which encode six amino acids . \n they are all in the same class of aarss as those of the closest ( or neighboring ) g - containing or i - pairing codons . \n for instance , aarss for two doublet - encoding amino acids , histidine ( car ) and glutamine ( cay ) , are the same as those for glutamic acid ( gar ) and aspartic acid ( gay ) , respectively . \n first , it shaped up the code through a long creation and optimization process so that the code finally adapted to a format that minimized the damage power of nucleotide changes on rna in the rna world or on both dna and rna in the cb world . \n second , the code has organized in such a way that changes in dna composition alter protein composition in a very distinct direction from the au - rich quarter to the gc - rich quarter , a shift emphasizing amino acids in favorite of either the catalytic moiety or the structural moiety , respectively . \n third , while minimizing damage through a well - organized code , evolution also took the advantage of sequence variation at the third codon position ; variations of the transversion type ( between r and y ) at this position alter the encoded amino acids . there are 15 amino acids ( 75% ) in the pro - diversity half of the canonical genetic code , which are sensitive to transversional changes . \n finally , the relic of the changing code has still been observed in yeast and some organellar genomes , involving especially amino acids with six - fold degenerate codes arginine , leucine , and serine ( 18 ) \n must have been the first molecular mechanism invented in the rna world . since replication as a biological term \n is dedicated to describe the process of making copies of a dna molecule , we have to invent another word for making rna copies , namely editosome , which is capable of both replicating a rna molecule and editing it to change its minor content individually . \n the second major molecular mechanism in the rna world has to be the spliceosome that cut and paste rna fragments . \n the third one is the translatosome that manufactures proteins directly ; it marks the transition of a primitive rna world to a mature rna world where a transition to the modern world or the cb world started . \n the key contribution of proteins to this transition is the accuracy of physicochemical activities of active proteins such as enzymes and receptors . \n rna complex , so did the cb world thereafter by the invention of replisome , repairosome , and transcriptosome ; all of them are dna - dependent . \n if we say the translatosome marked the ending of the rna world , the reverse - transcriptosome declared the birth of the cb world where new inventions continued until the rest of the -somes were made to work ( table 1 ) . \n evolution works on genes and their variants that are borne by individuals within a species . \n this is largely true for multicellular organisms but not true for most of the unicellular organisms , especially prokaryotes where horizontal gene transfer is a major cellular process for exchanging genes and their variants . \n individuals carry gene variations distinct from the rest of the same species and survive within a breeding population . \n selection will only work on the variations of genes and dna elements in germlines for multicellular organisms where they may result in advantage in survival for the variation - bearing individuals . \n therefore , evolution starts from alterations of dna sequences , filtered through the genetic code , reaches protein sequences , and the result is tested by fitness and survival at the individual level . \n whether a theoretical model becomes popular or not depends on its predicting power and subsequent validation of its predictions . \n although it is extremely hard for a model that attempts to predict the almost unpredictable what had happened in the rna world , we can still make some of the most obvious predictions . \n first , the codon expansion model predicts that some of the protein domains may be created with the early codons and their corresponding amino acids so they are transversion - sensitive at cp3 . \n the idea can be extended to expect that most of the protein domains in dna - related machineries may be built by the fully expanded codons so they were able to recruit the full set of amino acids for functional intricacies . \n however , it is very difficult to re - establish the initial composition of the assumed codon - biased domains since evolution has been taking its toll of altering them constantly for billions of years . \n second , the model predicts that the splicing and editing machineries are invented earlier for building a viable ancestral life form so that the prokaryotes might have lost most of them , if not all . since heavy compartmentalization , such as building organelles and nucleus , had to come after proteins replaced most of the operational rnas , we believe that a true eukaryote might have been born from an eukaryote - like precursor rather than its function - striped forms prokaryotes or prokaryote - like organisms . \n the final example is the prediction that certain groups of prokaryotes may keep significantly low gc content for maintaining a biased purine content , and these organisms should use more ancient protein domains in their proteomes dominated by purine - sensitive amino acids 19 . , 20 . \n , 21 .. we did try to validate some of our predictions by examining some ancient proteins that are believed to be created in the rna world . \n for instance , some of the rna - binding proteins must be among the first to be invented for the protection of functional rna molecules , including single - strand or double - strand binding proteins as well as their binding domains : the single - stranded rna - binding domain ( ssrbd ) and double - stranded rna - binding domain ( dsrbd ) . \n since evolution has done its job to check the essentiality of every amino acid for a given protein domain , we need only to align the sequences over a diverged panel and look for the decisive or highly conserved amino acids in the domain . taking the dsrbd of ribonuclease 3 as an example \n , we demonstrate a two - parameter method to identify the most essential amino acids for the domain based on the physicochemical properties of amino acid side chains . \n the single parameters are simple physicochemical property measures , such as polarity , surface area , size , charge , hydrophobicity , and disulfide - linkage . \n the double parameters are various combinations of the single parameters , such as size polarity and surface area hydrophobicity . in the alignment of dsrbd with four subdomains from various ribonuclease 3 proteins \n , we can easily recognize a few amino acids that are either strictly conserved or less strictly conserved across wide taxonomic groups ( figure 5 ) . \n lysine is firmly restricted in both size and charge for rna binding through electronic interaction . \n in contrast , aspartic acids ( asparagine ) and leucine ( phenylalanine ) in the subdomains are less conserved , perhaps only polarity and hydrophobicity are important for their rna - binding functions , respectively , that is , they are restricted only by a single parameter . \n tyrosine is another strictly conserved amino acid among the four subdomains ; it is constraint by both shape and hydrophobicity , which are important factors for rna binding through the interaction ( specific to aromatic amino acids ) . \n the highly conserved lysine and tyrosine in ribonuclease 3 rna - binding domains suggest an early invention . \n the evolution of the genetic code began in the early phase of the rna world where rna molecules started to be built as simple nucleotide repeats or polymers . \n these de novo - synthesized polymers had to survive somehow for millions and millions of years in order to allow life to get started with structurally and functionally divergent rna molecules that provide complexity and perform sufficient functions . \n although template - directed synthesis might not be initially necessary since protocells certainly had to fight for life s seed components among themselves , these rna molecules could either be cut and pasted at the molecular level or be chemically modified to turn into other similar structures at the building - block level for structural and functional diversities . \n rna editing was obviously a molecular mechanism as part of the rna polymerization machinery aside from splicing . \n once engulfing wars among the protocells started going , rna molecules and their complexes had to be consistently synthesized , chemically modified , spliced , and assembled into two essential classes , operational and informational . up to a point , template - directed synthesis of rnas might have exhibited advantages over simple undirected polymerization . \n the operational rnas or ribozymes resembled the modern proteinaceous molecules and their complexes , whereas the informational rnas or riboscripts were functionally equivalent to messenger rnas in the contemporary biological world ( cb world ) . in the cb world , the latter is called rna splicing , which is either catalyzed by a \n ( usually a complex formed by proteins and rna as well as dna sometimes ; table 1)the spliceosome or self - spliced . \n of course , we have made here a bold assumption that life may start as a prototype of eukaryotic organism rather than prokaryote - like before recruitment of dna , and eukaryotes are known to have preserved some of the critical molecular mechanisms such as rna splicing through the spliceosomal pathway and complex organelles generated from intermediates of engulfing each other . \n the primitive genetic code would not be considered necessary until early versions of the rna - built translatosome were invented , which made primitive life forms leap into the late phase ( phase ii ) of the rna world the rna \n once requisite polypeptides were synthesized according to a ciphertext , genetic codes came into the play . \n if we assume that the early life forms and their shared genetic code did not use cytidine ( c ) before the involvement of dna , since it seems not stable enough to join primitive organisms 7 . , 8 . \n , the first set of codons was simple and purine - sensitive at the third codon position ( cp3 ) 9 . \n , 10 .. the codons were mostly made of adenosine ( a ) and uridine ( u ) , formed by a binary code that only distinguished purine from pyrimidine ( figure 1a ) . \n if we assume that the modern code became universal in life s early history or inherited the rna code with faith , it encoded possibly seven amino acids ( here we assume isoleucine and methionine are exchangeable and functionally equivalent ; both are capable of starting peptide synthesis ) as well as possessed both start and stop signals . \n these amino acids have rather impressive physicochemically diversified side chains , albeit relatively devoid of small and acidic amino acids ( figure 1b ) . \n since primitive translatosomes were made to be simple , there was a possibility that the first aminoacyl - trna synthetases ( aarss ) might have started as a permanent part of this protein - manufacturing machinery and fell off from it , together with trnas , as the genetic code forged ahead for creating peptide complexity . \n the first batch of rna - encoded proteins was mostly protective for integrity of primordial cells and their cellular components , and undoubtedly included those for rna binding and membrane stability , constituted by basic , aromatic , and hydrophobic amino acids . \n the first division of aarss was predicted to ensure protein diversity so that they must distinguish the two polar amino acids , asparagine and tyrosine , as well as the two aromatic amino acids , phenylalanine and tyrosine . \n in contrast , it might not be necessary to tell leucine , isoleucine , and methionine apart . \n there are at least two possible scenarios : one concerns the limited recruitment of guanine ( g ) and the other assumes editing mechanisms that convert adenosine ( a ) to inosine ( i ) . \n both scenarios should be able to provide significant structural diversity and coding capacity for ribozymes and riboscripts , respectively . \n base or nucleoside conversions between the two purine - containing nucleosides a and i as well as between the two pyrimidine - containing nucleosides u and c , have been carried over to the cb world . \n inosine is capable of forming double hydrogen bonds with u , g , and c. although the two scenarios may not be mutually exclusive , that is , they might have evolved independently or co - existed , we discuss them separately just for simplicity . in one scenario , we assume that g was recruited by riboscripts in a limited way in addition to serving as a divergent building block and processing signals for ribozymes ( figure 2a ) . \n although a ribozyme without g and c was proven functional ( 11 ) , structural and functional diversities provide advantages for life forms to compete for survival . \n since dinucleotides ag and gu are designated as signals for splice sites , the expansion of the codons in this scenario might be limited to tryptophane , glutamic acid , aspartic acid , cysteine , and glycine . \n these five new recruits are very impressive : the largest ( tryptophane ) , the negatively charged ( glutamic acid and aspartic acid ) , the disulfide - bond - forming ( cysteine ) , and the smallest ( glycine ) amino acids . in the other scenario , we assume that a was selectively and constantly edited into i in riboscripts in a context of a and i co - existence , so codons were extended to match more aa - trnas . \n the result of this extension became identical to the first scenario ( figure 2b ) . \n this scenario is strongly supported by the distribution of aars classes ( figure 3 ) as the expansion of amino acids and their corresponding aarss follow the class rule largely ( 12 ) . \n in addition , similar roles of nucleotide modifications have been inherited by all the extant life forms , such as wobble pairing between anticodons of trna molecules and codons of mrna ( 13 ) . \n for instance , aay ( n ) and its sibling codons , iay ( d ) , aiy ( s ) , and iiy ( g ) , share the same class of aarss . the k group ( aar , air , iar , and iir ) has a little complication , as there are two lys - rss belonging to classes i and ii . \n correspondingly , lysine s sibling codons can certainly go with class i ( glu - rs and arg - rs ) except glycine that was defined by its y - ending codons . \n an alternative explanation is that gly - rs may have an unusual history since its active form is a unique tetramer . \n the consensus of the two scenarios suggests an early - expanded genetic code that encodes twelve amino acids other than start and stop codons . \n the second recruitment of the early genetic code has to be arginine , serine , and valine after dinucleotides gu and ag were finally freed from serving as sequences of splice sites since spliceosomes became more sophisticated . \n the new addition that makes a set of fifteen amino acids was a subtle extension of the existing amino acids considering both the physicochemical property and the secondary structure : arginine was an alternative of lysine ; serine was a smaller version of tyrosine ; and valine added another variation to the hydrophobic amino acids \n leucine , isoleucine , methionine , and phenylalanine 14 . , 15 . , 16 . \n , 17 .. the most puzzling feature of the code is its unusual redundancy where only three amino acids , arginine , leucine , and serine , are encoded with six codons ; they by now have all been recruited and later expanded to acquire their quadruplets when cytosine joined the genetic code . \n let us first make a few observations on leucine in comparison to the other two amino acids . \n first , although they are all among the most abundant amino acids in the extant genomes , leucine is always the most abundant in all three kingdoms of modern life forms . \n serine comes to the second among eukaryotic genomes , such as in the human and arabidopsis genomes . \n arginine is the least abundant among the three , which barely makes it to the top ten among some of the bacterial genomes . \n second , leucine has the easiest codon conversion between the doublet and the quadruplet among all three amino acids : a simple base transition between u and c results in a change from uur to cur . \n this suggests that leucine is capable of playing essential structural roles for most proteins and maintains their integrity when gc content increases . \n similarly , to keep arginine and serine unchanged , transversions have to be introduced ; a single transversion has to take place to change agr to cgr for arginine , and double transversions , agy to ucy for serine , are indispensable . \n third , leucine has dimensions most similar to four other amino acids with side chains that have rather diverse physicochemical properties from it : isoleucine , histidine , methionine , and lysine 14 . \n , 15 .. all three observations support the notion that leucine should be the most abundant amino acids for all major life forms . by the same token \n serine differs from leucine and arginine in forming protein secondary structures ; it prefers turns as compared to leucine that favors alpha - helix and arginine that is rather neutral to all three major secondary structures . \n the only amino acid that is indiscriminately honored by alpha - helix , beta - sheet , and turn . \n these observations lead to a hypothesis that the additional codons for these three amino acids were tailored to balance the abundant amino acids when dna nucleotide composition changes , such as gc content or ag ( purine ) content increases . \n the corresponding codons are organized in such a way that they balance between pro - diversity and pro - robustness halves of the genetic code 9 . \n , 10 .. the result of such a balancing power is the stability of amino acid composition and its subtle effect on protein conformations when mutations bombard the coding sequence over evolutionary time scales . by now \n , the genetic code is good enough for directing protein synthesis , and the sophistication of proteinaceous cellular machineries have made life more diverged , robust , and complex . \n the final or the third recruitment of the code had to happen when dna replaced rna as the informational molecule for better precision and stability . \n reverse - transcription that made this a reality , and the template - directed dna replication marked the beginning of the new world . \n the evolution of many new cellular mechanisms , such as dna replication , repair , and dna - directed transcription , made the new world having achieved its perfection almost immediately ( figure 4 ) . \n the contemporary genetic code was born and fixed after cytosine and its deoxyl derivative joined in as one of the four building blocks for rna and dna , respectively . \n the code had to be filled up with new recruits as the coding capacity increased . \n histamine and glutamine filled in instantly due to their contributions to catalytic properties and similarities to the two existing basic amino acids , respectively . \n , 15 .. this new recruit plays a very crucial role in protein structure and function diversity : swapping between a hydroxyl group with hydrophilic property and hydrophobic side chain if the size change is tolerable for essential functions of a protein . \n on the one hand , it distorts the protein backbone in a unique way that no other amino acid does ; on the other hand , it fits in with its hydrophobicity and modest size , resulting minimal changes when replacing other amino acids , such as aspartic acid , glutamine , and threonine . \n the corresponding expansion pattern in aars classes also supports the simple extension hypothesis . aside from the six - fold degenerate codons , there are six sets of codons involved in the final expansion , which encode six amino acids . \n they are all in the same class of aarss as those of the closest ( or neighboring ) g - containing or i - pairing codons . \n for instance , aarss for two doublet - encoding amino acids , histidine ( car ) and glutamine ( cay ) , are the same as those for glutamic acid ( gar ) and aspartic acid ( gay ) , respectively . \n first , it shaped up the code through a long creation and optimization process so that the code finally adapted to a format that minimized the damage power of nucleotide changes on rna in the rna world or on both dna and rna in the cb world . \n second , the code has organized in such a way that changes in dna composition alter protein composition in a very distinct direction from the au - rich quarter to the gc - rich quarter , a shift emphasizing amino acids in favorite of either the catalytic moiety or the structural moiety , respectively . \n third , while minimizing damage through a well - organized code , evolution also took the advantage of sequence variation at the third codon position ; variations of the transversion type ( between r and y ) at this position alter the encoded amino acids . \n there are 15 amino acids ( 75% ) in the pro - diversity half of the canonical genetic code , which are sensitive to transversional changes . \n finally , the relic of the changing code has still been observed in yeast and some organellar genomes , involving especially amino acids with six - fold degenerate codes arginine , leucine , and serine ( 18 ) . \n must have been the first molecular mechanism invented in the rna world . since replication as a biological term \n is dedicated to describe the process of making copies of a dna molecule , we have to invent another word for making rna copies , namely editosome , which is capable of both replicating a rna molecule and editing it to change its minor content individually . \n the second major molecular mechanism in the rna world has to be the spliceosome that cut and paste rna fragments . \n the third one is the translatosome that manufactures proteins directly ; it marks the transition of a primitive rna world to a mature rna world where a transition to the modern world or the cb world started . \n the key contribution of proteins to this transition is the accuracy of physicochemical activities of active proteins such as enzymes and receptors . \n rna complex , so did the cb world thereafter by the invention of replisome , repairosome , and transcriptosome ; all of them are dna - dependent . \n if we say the translatosome marked the ending of the rna world , the reverse - transcriptosome declared the birth of the cb world where new inventions continued until the rest of the -somes were made to work ( table 1 ) . \n evolution works on genes and their variants that are borne by individuals within a species . \n this is largely true for multicellular organisms but not true for most of the unicellular organisms , especially prokaryotes where horizontal gene transfer is a major cellular process for exchanging genes and their variants . \n individuals carry gene variations distinct from the rest of the same species and survive within a breeding population . \n selection will only work on the variations of genes and dna elements in germlines for multicellular organisms where they may result in advantage in survival for the variation - bearing individuals . \n therefore , evolution starts from alterations of dna sequences , filtered through the genetic code , reaches protein sequences , and the result is tested by fitness and survival at the individual level . \n whether a theoretical model becomes popular or not depends on its predicting power and subsequent validation of its predictions . \n although it is extremely hard for a model that attempts to predict the almost unpredictable what had happened in the rna world , we can still make some of the most obvious predictions . \n first , the codon expansion model predicts that some of the protein domains may be created with the early codons and their corresponding amino acids so they are transversion - sensitive at cp3 . \n the idea can be extended to expect that most of the protein domains in dna - related machineries may be built by the fully expanded codons so they were able to recruit the full set of amino acids for functional intricacies . \n however , it is very difficult to re - establish the initial composition of the assumed codon - biased domains since evolution has been taking its toll of altering them constantly for billions of years . \n second , the model predicts that the splicing and editing machineries are invented earlier for building a viable ancestral life form so that the prokaryotes might have lost most of them , if not all . since heavy compartmentalization , such as building organelles and nucleus , had to come after proteins replaced most of the operational rnas , we believe that a true eukaryote might have been born from an eukaryote - like precursor rather than its function - striped forms prokaryotes or prokaryote - like organisms . \n the final example is the prediction that certain groups of prokaryotes may keep significantly low gc content for maintaining a biased purine content , and these organisms should use more ancient protein domains in their proteomes dominated by purine - sensitive amino acids 19 . , 20 . \n , 21 .. we did try to validate some of our predictions by examining some ancient proteins that are believed to be created in the rna world . \n for instance , some of the rna - binding proteins must be among the first to be invented for the protection of functional rna molecules , including single - strand or double - strand binding proteins as well as their binding domains : the single - stranded rna - binding domain ( ssrbd ) and double - stranded rna - binding domain ( dsrbd ) . \n since evolution has done its job to check the essentiality of every amino acid for a given protein domain , we need only to align the sequences over a diverged panel and look for the decisive or highly conserved amino acids in the domain . taking the dsrbd of ribonuclease 3 as an example , we demonstrate a two - parameter method to identify the most essential amino acids for the domain based on the physicochemical properties of amino acid side chains . \n the single parameters are simple physicochemical property measures , such as polarity , surface area , size , charge , hydrophobicity , and disulfide - linkage . \n the double parameters are various combinations of the single parameters , such as size polarity and surface area hydrophobicity . in the alignment of dsrbd with four subdomains from various ribonuclease 3 proteins \n , we can easily recognize a few amino acids that are either strictly conserved or less strictly conserved across wide taxonomic groups ( figure 5 ) . \n lysine is firmly restricted in both size and charge for rna binding through electronic interaction . \n in contrast , aspartic acids ( asparagine ) and leucine ( phenylalanine ) in the subdomains are less conserved , perhaps only polarity and hydrophobicity are important for their rna - binding functions , respectively , that is , they are restricted only by a single parameter . \n tyrosine is another strictly conserved amino acid among the four subdomains ; it is constraint by both shape and hydrophobicity , which are important factors for rna binding through the interaction ( specific to aromatic amino acids ) . \n the highly conserved lysine and tyrosine in ribonuclease 3 rna - binding domains suggest an early invention . \n a primordial code was composed of a and u rather than all four nucleotides a , u , g , and c. early in the rna world , g served as one of the three essential building blocks of the operational rna molecules but not part of the genetic code . \n if interactions among molecules started easy , these interactions should be less intimate , which leads to our second assumption for the first set of amino acids : they might be the larger and more diversified in physicochemical properties . \n each of the new additions was added stepwisely with justification on subtle to significant alterations with minimal functional damage for proteins . \n as the molecular mechanisms evolved , the genetic code eventually became mature and fixed to a large extent in the cb world . \n we may never be able to prove the history and maturation process of the genetic code , but a meaningful scenario will stimulate our thoughts and give us a logical way to understand the possible arrangement of the genetic code . \n new ideas will come soon , agree or disagree with us , leading to an active forum for fruitful discussions on other scenarios on the origin of the genetic code .", "role": "user" }, { "content": "it is believed that in the rna world the operational ( ribozymes ) and the informational ( riboscripts ) rna molecules were created with only three ( adenosine , uridine , and guanosine ) and two ( adenosine and uridine ) nucleosides , respectively , so that the genetic code started uncomplicated . \n ribozymes subsequently evolved to be able to cut and paste themselves and riboscripts were acceptive to rigorous editing ( adenosine to inosine ) ; the intensive diversification of rna molecules shaped novel cellular machineries that are capable of polymerizing amino acids a new type of cellular building materials for life . \n initially , the genetic code , encoding seven amino acids , was created only to distinguish purine and pyrimidine ; it was later expanded in a stepwise way to encode 12 , 15 , and 20 amino acids through the relief of guanine from its roles as operational signals and through the recruitment of cytosine . \n therefore , the maturation of the genetic code also coincided with ( 1 ) the departure of aminoacyl - trna synthetases ( aarss ) from the primordial translation machinery , ( 2 ) the replacement of informational rna by dna , and ( 3 ) the co - evolution of aarss and their cognate trnas . \n this model predicts gradual replacements of rna - made molecular mechanisms , cellular processes by proteins , and informational exploitation by dna .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: education of patients about prescribed drugs is becoming an increasingly important aspect of public health care system throughout the world . in a country like india where quacks outnumber the qualified physicians , patients suffer due to lack of knowledge about drugs prescribed to them . \n there is often a discrepancy between what the patient has been advised and how the patient complies with the given instructions . during recent years lot of attention \n has been paid to rational use of medicine , but still there are lacunae in educating patients about the prescribed drugs . \n non - compliance rates of 30 - 80% are consistently reported in the literature even in developed countries . \n one of the important cause of non - compliance is failure of communication between the health care provider and the patient . \n the patient is supposed to attain the information regarding the prescribed drugs at various levels like at the time of consultation with the doctor , when the patient visits the pharmacist to get the medicine and even after the patient has actually started taking drug . at the first level \n i.e. , at the time of patient 's interaction with the doctor , patient should be informed about the disease , progression of the disease , the drugs patient is supposed to take , lag period required for the benefits of prescribed drug to appear , possible side effects , how to recognize those side effects , how serious these are and what measures should be taken by the patient regarding the disease and side effects . at the second level comes the interaction of the patient with the pharmacist . here again , patient should be re - enforced about the dosage regimen prescribed by the doctor and if possible , pharmacist should fit it into the patient 's daily routine so that the compliance can be improved . \n in addition , the patient should be informed about the proper storage method of the drug . \n the third and the last stage is when patient starts taking the medication , where the patient actually needs the practical application of the above information . at this point of time , patient may not be able to recall many things . here the written information , if given , by the doctor / pharmacist can be of great help . \n a lot of information to the patient at this stage can be attained by the patient package insert ( ppi ) or by searching the internet . \n this study was planned to know the knowledge of the patients about the drug information they posses regarding drugs they are going to consume . \n a cross - sectional survey was conducted in the city of north india in september 2011 . \n the patients visiting four chemist shops ( in different locations of the city ) were given a preformed questionnaire ( in english as well as in vernacular ) and answers were sorted . since most of the patients procure drugs from the chemists in indian set up , so chemist shop was selected as a source point for patients enrollment in the study . \n the questionnaire was adopted from the who guide to good prescribing a practical manual . \n section 1 dealt with therapeutic effects of drugs , section 2 dealt with side effects of drugs , section 3 had questions regarding instructions given to the patient , section 4 was regarding warnings and precautions to be taken by the patient while taking the drugs and section 5 was having questions regarding the information required by the doctor during the next visit . \n in addition to this name , age / sex , diagnosis and address of the patient were recorded . the name and qualifications of the prescriber \n the consent of the patients was taken and nature and scope of the study was explained to them in vernacular language . \n the questions were read to the patients by the investigator and answers were recorded on the performa . \n the patients having prescription from the doctors having recognized degree in allopathic system of medicine were included in the study . \n the questions were answered only by the patients , the relatives and attendants were not allowed to participate in the study . \n all the answers were recorded as right or wrong and any further detail was not taken into account . \n total two hundred sixty four patients having valid prescription from the allopathic doctor were given questionnaire performa . \n of these one hundred fifty eight ( 59.84% ) patients were male and one hundred six ( 40.16% ) were female . \n fifty eight ( 21.97% ) were graduates or above , one hundred eighteen ( 44.69% ) were above matric but below graduation , fifty six ( 21.21% ) were below matriculate and thirty ( 11.36% ) had never gone to school . \n of the two hundred sixty four patients , one hundred sixty two patients ( 61.36% ) knew why they needed the drug but when it came to what symptoms the drug will take care of , only ninety eight patients ( 37.12% ) responded correctly . \n only eighty nine patients ( 33.71% ) knew when the effect of drug was expected to start . \n seventy one respondents ( 26.89% ) knew what can happen and what to do if the dose is missed . \n only thirty five patients ( 13.26% ) knew about the ses produced by the concerned drug , and only fifteen of them ( 5.68% ) knew how to recognize them . of these , only 10 patients ( 3.79% ) knew for how long those ses can continue . \n sixteen patients ( 6.06% ) knew about the seriousness of the ses , eleven patients ( 4.17% ) knew what should be done if ses occur [ table 1 ] . \n response of the participants to the study questions of two hundred sixty four patients , two hundred forty respondents ( 90.91% ) knew about the correct method of consuming the drug and two hundred forty four patients ( 92.42% ) knew about the time when it should be taken . \n one hundred eighty eight patients ( 71.21% ) knew about the duration of the therapy . \n only fifty eight patients ( 21.97% ) had correct knowledge regarding the storage of the drug . \n thirty of the enrolled patients ( 11.36% ) knew about the conditions in which the drug should not be taken . \n only 8 patients ( 3.03% ) knew about the maximum dose which can be taken safely . \n one hundred thirty eight respondents ( 52.27% ) knew about the importance of completing the full treatment course . in response to a question about when to report back to doctor or not to report , one hundred ninety respondents ( 71.97% ) responded correctly . \n only forty five respondents ( 17.05% ) knew about the circumstances in which they should report earlier to the doctor . in response to the query about the information which will be required by the doctor at the next visit , \n it is a well known fact that communication matters , especially in situations involving public dealings , yet this concept is routinely ignored in the education of clinicians . \n we are in the situation of breakdown in communication between patients and doctors , increasing patient dissatisfaction , rising number of complaints and claims for malpractice and abandonment of conventional medicine for alternatives that are often unproved . \n the present study was planned with the objective to assess the level of communication between the doctor and the patient . \n it should be noted that this study was done in an urban area , where 31.81% of patients were graduate or above , and that the patients responses were simply recorded as right or wrong and were not verified further . \n the results of the study showed mixed responses of the patients information regarding various aspects of drug usage . \n the awareness of the patients regarding the therapeutic effects of the drugs was relatively better as compared to their knowledge regarding side effects thus highlighting the fact that doctors are not open to talk about the side effects of the drug with the patients . \n though it is not a formal obligation on part of doctors to warn the patients of all possible side effects of the treatment / drug but it is their moral duty to give sufficient information ( not too little and not too much which can cause confusion ) to patients so that their interests are protected . \n it seemed that the patients were well aware about how and when to take the drug , though relatively few patients were aware of how to store the drug ( 21.97% ) and this may possibly be due to the lack of trained pharmacists in most of the private health care settings . \n significantly , fewer patients knew about the drug related warnings and the information required by doctors at the future consultations . \n the lack of information on the part of the patient may result from poor doctor - patient ratio which in turn leads to larger number of patients examined by a doctor resulting in lesser time spent per patient . \n several studies have shown that doctors and patients have different opinions on what makes good and effective communication . \n these differences greatly influence the level of interaction between doctors and patients which in turn affects patient compliance and health outcomes . \n having good communication is the key skill for doctors to establish good doctor patient relationship . \n studies have shown positive correlation between doctor 's skill to communicate and satisfaction of the patient . in a study by roter et al . , the improvement in doctors communication skills was shown to be associated with a reduction in emotional distress to the patient . \n there is great deal of evidence that changing doctors behavior and communication skills can be achieved quite easily with proper teaching and it lasts for considerable time . \n the toronto consensus statement published in 1991 clearly showed that communication problems in clinical practice are important and common . \n it also outlined that quality of communication is related to health outcome for the patients , but that traditional medical education is ineffective at teaching communication skills . \n not surprisingly , many undergraduate and post - graduate medical education and training programs have made the attainment of good communication skill a essential requirement . \n the medical trainees are required to be sensitized about the patients perspective and emotional needs . \n medical educators should use knowledge of patient 's perception of care to focus teaching on areas that will help trainees to meet patient 's expectations . \n although requirement for better communication skill is well recognized , the training of this aspect is still neglected in medical courses in india . it is recommended that exercises emphasizing communication skills with patients in simulated clinical environment may be included at appropriate levels of medical training . \n this will help the students acquiring better communication skills in the formative years of their carrier and thus improve the scenario in the coming years . \n on the surface , skill to communicate appears to be a simple concept within health care but it is a skill difficult to acquire and implement . \n the lack of communication limits the quality of service that a patient can get . in the present study also \n the key areas that need to be stressed upon are , informing the patients about the side effects , warnings and future consultations . \n the good communication skill can result in better health outcomes , higher compliance rates and of course , greater satisfaction of the patient .", "role": "user" }, { "content": "background : communication skills play an important role in establishing doctor - patient relationship is widely recognized throughout the world . \n the information passed on to the patients affects the treatment outcomes.objectives:the present study was undertaken to evaluate the level of awareness among opd patients about prescribed drugs.materials and methods : a total of two hundred sixty four patients having a valid prescription from a doctor practicing in allopathic system , visiting 4 different chemist shops in a north indian city were enrolled in the study . \n all the enrolled patients were given a preformed questionnaire to be answered on the spot.results:it was found that though a considerable number of patients were aware about the therapeutic effects of the drugs and the manner of administration of the medicines ; they lacked information regarding the side effects , warnings and the information their doctor may require at the next consultation.conclusion:the study highlighted the fact that doctors need to spend more time with the patients to make them active participants in the drug therapy .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: driven by technological advances , especially in the last decade , mobile - health ( m - health ) systems and services have refined access to specialized healthcare delivery [ 15 ] . \n advances in wireless and sensor networks , mobile and cloud computing , compression technologies , mobile devices and nanotechnologies , and associated standards and algorithms for efficient communication , interoperability , and ease of integration have fostered the evolution of such systems and services . toward this end , \n social media colossal acceptance linked with an overwhelming number of smartphone medical - oriented applications is expected to bring further growth , initiating a decisive subject involvement . while economic benefit is still debatable based on current deployment , it is indisputable that widespread adoption in daily clinical practice will provide significant financial savings . \n medical video communication systems aim to meet the demand for emergency telematics , within ambulance care , remote diagnosis and care for frail elderly people and people with mobility problems , mass population screening , especially in developing countries and in disaster incidents and battlefields , and for medical education purposes and second opinion provision ( see figure 1 ) . \n medical video communication m - health systems have been primarily based on impressive data rates increase and extended coverage of wireless infrastructure , linked with new compression technologies and high - efficiency low - complexity codec equipment . moreover , active involvement of medical experts in the design allowed the development of clinically resilient telemedicine frameworks , increasing system 's robustness and objective of providing adequate quality video diagnostics . \n the most prevailing research trends in the design of m - health telemedicine systems are summarized next : ( a ) medical video modality - aware ( m - aware ) systems , where individual properties of different video modalities guide the encoding , transmission , and evaluation process ( e.g. , diagnostically relevant encoding paired with unequal error protection of regions of diagnostic interest ) [ 1115 ] , ( b ) multilayer and cross - layer optimization systems , which minimize a cost function constructed of different layer parameters such as packet loss rate ( plr ) , end - to - end - delay and delay jitter , frame objective ratings ( e.g. , peak signal - to - noise - ration ( psnr ) , structure similarity ( ssim ) index ) , video resolution , frame rate , and so forth , for optimum performance [ 1619 ] , and finally ( c ) studies which focus on clinical quality assessment protocols and recommendations [ 1012 , 20 ] . in this study , \n the aim is to develop a low - cost telemedicine platform for the wireless communication of adequate diagnostic quality video using open - source technologies . \n the aim is to depict that open - source software tools can deliver the acceptable performance required for demanding medical video communications , using commercially available infrastructure . \n in fact , we aim to bridge the gap between theory and practice , by providing a proof - of - concept study which can accelerate the wider deployment of m - health systems in daily clinical practice . despite the widespread belief by the research community that such systems and services can provide significant time advantages that can prove vital for the patients ' health , the adoption in daily practice is rather limited . \n this is partly due to the relatively limited studies depicting real - life implementation of medical video streaming systems , attributed to the absence of wireless channels that could support video communications at the in - hospital video resolution . \n the latter was documented for earlier studies in the literature , where limited upload data rates of 3 g channels bounded the successfully communicated medical video to quarter video graphics array ( qvga-320 240 ) resolution [ 2124 ] . here , \n we employ top performing open - source software , investigate medical video communications at scalable resolutions , for the most common encoding structures found in the literature today , and evaluate their clinical performance for an overwhelming number of cases . \n we examine two widely available wireless channels , namely , wireless local area network ( wlan ) as the benchmark case and 3.5 g high - speed packet access ( hspa ) as the default utilization scenario . \n the objective is to demonstrate that high - resolution medical video communication is possible , approaching the clinical standards of in - hospital examination . to accomplish this task , we summarize the primary objectives of this paper in three different areas.open-source platform for wireless medical video communication : the primary focus of this paper is the development of an open - source platform that will provide for adequate diagnostic quality medical video communications . \n such a system will benefit from low - cost development and ease of deployment especially for telemedicine services in developing countries . \n moreover , it will serve as a research tool that will accelerate research in m - health video communication systems and facilitate medical education purposes.coding efficiency : we examine different video resolution transmission for the most widely used coding structures today , employing the most efficient h.264/avc encoder , namely , x264 . \n the use of higher video resolution such as 560 416 resolution suggests that medical video communication at the in - hospital - acquired resolution is possible using open - source technologies . \n video communications over hspa networks : we investigate currently available 3.5 g mobile cellular networks performance in cyprus using quality of service ( qos ) metrics ( such as packet loss rate , delay , and delay jitter ) . the utilization of variable frame delay ( vfd ) algorithm as a calibration step before computing psnr aims to bridge the gap between objective and subjective ratings , by removing temporal mismatch between transmitted and received videos . open - source platform for wireless medical video communication : the primary focus of this paper is the development of an open - source platform that will provide for adequate diagnostic quality medical video communications . such a system will benefit from low - cost development and ease of deployment especially for telemedicine services in developing countries . moreover , it will serve as a research tool that will accelerate research in m - health video communication systems and facilitate medical education purposes . coding efficiency : we examine different video resolution transmission for the most widely used coding structures today , employing the most efficient h.264/avc encoder , namely , x264 . \n the use of higher video resolution such as 560 416 resolution suggests that medical video communication at the in - hospital - acquired resolution is possible using open - source technologies . \n video communications over hspa networks : we investigate currently available 3.5 g mobile cellular networks performance in cyprus using quality of service ( qos ) metrics ( such as packet loss rate , delay , and delay jitter ) . the utilization of variable frame delay ( vfd ) algorithm as a calibration step before computing psnr aims to bridge the gap between objective and subjective ratings , by removing temporal mismatch between transmitted and received videos . the rest of the paper is organized as follows : section 2 provides an overview of the developed open - source platform and outlines individual components characteristics that relate to video transmission . section 3 describes the undertaken methodology , while section 4 provides the experimental evaluation . \n open - source software is quickly becoming the designated tool for development and evaluation in research and academia , as well as pilots , for potentially commercial applications . \n this is mainly attributed to the lower costs involved in developing and maintaining open - source applications , source - code availability which enhances reusability and enables customization , and an ever - increasing community which supports and expands available features . here \n , the choice of open - source tools aims to develop , evaluate , and disseminate a low - cost telemedicine system , easily deployable , which will provide reliable communication of real - time medical video for remote diagnosis purposes . \n such a system can serve as a research tool for the design and development of new m - health systems and services , be used as a medical education tool , and can serve as a telemedicine platform , especially in developing countries . \n it is worth noting here that the particular interface is the developer 's interface . for integration into standard clinical practice , \n next , we provide a step - by - step analysis of the system 's utilization and the associated open - source components . following video acquisition , the video is encoded using the ffmpeg software and more specifically the x264 libraries , which implement the h.264/avc standard . it is worth noting that x264 has been ranked as the most efficient codec in comparative evaluations of widely available h.264/avc codecs . as illustrated in figure 2(a ) , the main encoding features can be selected using the encoding menu , while additional advanced parameters may be inserted using the command line interface . using vlc player , of the videolan project , the resulting real - time transport protocol ( rtp ) \n packets are streamed over the underlying wireless network to the medical expert 's remote end . \n this procedure is performed using the sender 's video communication interface appearing in figure 2(b ) . \n the user is asked to define the receiver 's ip address and communication port , in addition to the transmitting frame rate and packet size ( if different from the encoding parameters ) . \n simultaneously , wireshark network protocol analyzer is triggered at the receiver 's side for packet monitoring and qos measurements . \n the receiver also uses vlc to render the transmitted video , which is decoded using ffmpeg . at the receiver 's side \n , only the incoming port needs to be defined ( see figure 2(c ) ) . for video quality assessment purposes , \n the latter enables full reference ( fr ) objective video quality assessment ( vqa ) algorithms such as psnr to validate the capacity of the proposed system to accommodate adequate diagnostic quality medical video communications . \n the variable frame delay ( vfd ) algorithm has been recently introduced by the national telecommunication and information association ( ntia ) . \n vfd aims to alleviate the temporal mismatch between transmitted and received video frames , likely to be introduced by video pauses during video transmission . \n such pauses can occur due to varying network state , resulting from signal attenuation , mobility , handover , and so forth . to compensate for these changes , adaptive streaming algorithms may employ temporal downsampling of the streaming content , which is a common practice in scalable video streaming and cross - layer design systems , or even choose to drop frames . \n moreover , frame freezing ( displaying the previous frame in the absence of the current frame ) is a widespread error concealment method found in many codecs . as a result \n , full reference vqa metrics often fail to deliver ratings that do correlate with perceptual quality . \n vfd , acting as a calibration step before fr quality assessment , removes temporal mismatch and allows objective fr algorithms to provide reliable quality measurements . \n variable frame delay algorithm computes the mean square error ( mse ) between the normalized processed ( received ) frame and a predefined window of normalized original frames , for a given region of interest . in this manner , \n when it comes to computing the objective vqa metric , the algorithm uses for comparison the original frame that minimizes the mse with the relevant processed frame . \n provided that all computations are performed using only the luminance information ( or the y channel ) , video sequences for the following formulas will be denoted as y(i , j , t ) , where t = 0 , 1 , 2 , , n 1 , n is the total number of frames parting the video , and i and j correspond to the image 's row and column , respectively . \n a subscript p denotes a processed video ( i.e. , transmitted video ) , while a subscript o stands for the original , uncompressed video sequence . the procedure for normalizing processed video frames to have zero mean and unit variance appears in ( 1 ) : \n ( 1 ) yp(i , j , tp)=(yp(i , j , tp)mp)p,(i , j)sroi , tp=0,1,2, ,n1 . \n this is a user - defined parameter which aims to restrict frame alignment computations within the most significant video region as well as eliminate boundary pixel values . \n similarly , the original video is normalized using \n ( 2)yo(i , j , to)=(yo(i , j , to)mo)o , ( i , j)sroi , to = firstalign+firstalign+1 , firstalign+2, ,firstalign+n1 . \n compared to the processed video sequence , the video time durations used for mean and standard deviation computation for the original video sequence use the term firstalign , which corresponds to the best match guess between processed and original frames . \n next , having normalized both sequences , the mse between processed and original videos for a ( user ) predefined window of frames is estimated using ( 3 ) . \n when not all frames are available ( e.g. , beginning or end of each sequence ) , only the available frames are used for computing the mse : \n ( 3)mse(to , tp)=meanover i , j{[yo(i , j , to)yp(i , j , tp)]2},tp=0,1,2, \n ,n1,to = firstaligntuncert+tp, ,firstalign , + tp, ,firstalign+tuncert+tp . to reduce alignment errors the algorithm imposes an additional causality constraint , based on heuristic methods \n . however , the techniques used during these steps of the vfd algorithm are outside the scope of this paper . \n vfd algorithm can be used both as a calibration step before employing a fr vqa algorithm and for estimating the impact of temporal mismatch caused during real - time video streaming . \n five atherosclerotic plaque ultrasound videos , with spatial video resolution of 560 416 acquired at 40 frames per second ( fps ) , compose the dataset used during the experimental evaluation . \n the investigated encoding setup includes scalable video resolutions that reflect the most common resolutions used in atherosclerotic plaque ultrasound video transmission , different bitrates according to the wireless channel 's capacity , and different encoding schemes and profiles for improved efficiency . \n table 1 summarizes the encoding parameters that were used in this study . for the lower qcif resolution ( 176 144 ) , the videos were encoded at the following bitrates : ( a ) 128 kbps , ( b ) 256 kbps , and ( c ) 324 kbps . \n these bitrates are well within the typical upload data rates of 3.5 g high - speed downlink packet access ( hsdpa , rel . \n ( 352 288 ) , in addition to the aforementioned bitrates , ultrasound videos were also encoded at 512 kbps , to ensure adequate diagnostic quality . finally , videos at the acquired \n , 560 416 resolution were encoded at bitrates of 512 kbps and 768 kbps . \n 6 ) mobile cellular networks can accommodate upload transmission rates of the latter two resolutions . to investigate the most efficient encoding structure , we examined the most common encoding formats used in real - time video transmission found in the literature today . \n the main h.264/avc profile was used for all schemes besides the ipppp case , which was encoded using the baseline profile . \n the values of the remaining encoding parameters were selected using coarse - to - fine parameter optimization for the parameters appearing in the literature . \n the maximum slice size is set to 500 bytes , as this value was found to minimize latency and provided for better objective ratings compared to higher values . \n the packet size was selected accordingly , so that when a packet is lost or corrupted , the error would be limited within slice boundaries . \n gop size and intra - update interval is set to fifteen frames . in this manner and in conjunction with a frame rate of 15 \n this is very important for medical video communications , as it maximizes the probability of error - free cardiac cycles , hence clinical quality . \n the first scenario examines medical video communications within a wireless local area network ( wlan ) . \n anticipated integration of such systems in daily clinical practice is expected to reduce in - hospital delays , potentially unsafe for the patient 's health movements for routine exams , as well as medical expert 's visits to outpatient clinics . \n the second scenario investigates wireless communications based on commercially available high speed packet access ( hspa ) network in cyprus . despite a theoretical upload speed of 5.8 mbps advertised by the provider , \n the typical measured upload speed is around 1 mbps , with an average delay of 135 ms . \n the sender is connected to the 3.5 g network , while the receiver is connected to a wifi local network . \n similarly to the first scenario , the measurements took place in different time periods for a realistic approximation of actual conditions . \n this scenario simulates medical video transmission in emergency situations to the hospital and/or from remote areas and generally areas where internet access is only available via a cellular network . \n likewise , it can be used for mass population screening purposes and most importantly as a gateway of access to specialized care in developing countries with limited resources . to validate the performance of the proposed system , objective and subjective vqa \n was employed , while quality of service ( qos ) measurements assessed network 's stability . \n for that reason , and as documented in section 3 , vfd algorithm was applied as a calibration step before psnr computations . for the computation of the qos metrics , like the packet loss rates ( plr ) and the end - to - end delay , wireshark network protocol analyzer was employed . \n subjective ( clinical ) ratings were based on the clinically established protocol described in . using a rating scale of 1 to 5 , \n a rating of 5 signified a diagnostically lossless video , while a rating of 4 an acceptable loss of minor details . at the lowest end , \n the medical expert was asked to provide individual ratings for ( a ) plaque presence , ( b ) degree of stenosis , and ( c ) plaque type and morphology . \n as documented in [ 911 , 20 ] , encoding parameters like video resolution , frame rate , and compression ratio greatly impact the clinical capacity of the transmitted video ( see table 3 ) . more specifically , cif resolution allows sufficient clinical information for categorizing plaque type , as opposed to qcif resolution . \n similarly , higher 4cif resolution enables the medical expert to assess plaque morphology , which is not always feasible with lower cif resolution . \n in this section we discuss the experimental evaluation of the proposed medical ultrasound video transmission platform . \n we present results in terms of investigated coding structures efficiency , performance of real - time medical video transmission over wlan and hspa channels , and clinical capacity of the communicated ultrasound videos . \n results were obtained using two lenovo thinkpad t500 laptops , intel core 2 @ 2.53 ghz , 4 g ram , and 32-bit windows 7 operating system . for the purposes of this study , \n figure 3 shows coding structures compression performance at different bitrates and video resolutions , for a typical ultrasound video . \n the trend is the same for all videos parting the dataset as depicted in the left - most box plots of figures 4(a)4(g ) . \n coding structures employing bidirectional prediction depict comparable performance , with ipbbp and ipbbbbp attaining the best result , and ipbbbbbbbbp following closely . on the other hand \n however , ippp encoding benefits from lower motion estimation times and increased error resilience in noisy environments [ 9 , 34 ] . \n denoted by the red - dashed line , is the clinically acceptable threshold for ultrasound video communication described in . for qcif resolution , \n all but the lowest investigated bitrates achieve psnr ratings higher than the designated threshold . for higher cif resolution , as depicted in figure 3(b ) , ippp coding structure at 256 kbps is marginally above the desired threshold . \n therefore , using a higher bitrate of 324 kbps would be more appropriate when streaming clinically important content . \n similarly , for the higher 560 416 video resolution , single - directional prediction encoding falls below the designated threshold at 324 kbps , while higher investigated bitrates attain diagnostically acceptable ratings . here \n , it is important to note that clinical capacity is directly affected by video dimensions ( see section 4 and table 3 ) . \n video packets do not traverse outside the controlled wireless environment , which is not extended beyond the hospital premises . as a result , \n packet end - to - end delay and packet loss rates are minimal , in the order of 50 ms and 1% , respectively , resulting in high diagnostic quality ultrasound video rendering . as evident in the scenario 1 \n denoted box plots of figures 4(a)4(g ) , for all videos in the examined dataset , objective ratings following wireless transmission are well above the desired threshold for diagnostically lossless communications , approaching the ratings of the compressed video prior to transmission . \n the latter is also shown in table 5 , where average psnr ratings of all investigated cases are documented . \n it is worth noting here that widespread earlier wlan ieee 802.11 standards such as a , b , g , and n have not been designed to facilitate video streaming content . \n however , due the high data rates and strong signal coverage in the vicinity of a building area , they have accommodated such applications , especially in the absence of severe background traffic ( avoiding collision and resources overload ) , as in the presented scenario . the new generation of wlans , however , and more specifically the ieee 802.11aa standard termed robust streaming of audio video transport streams , is expected to mitigate this phenomenon and provide for demanding video streaming content such as medical video . \n the transmitting end is situated kilometers away from the hospital premises , while varying network conditions affect the quality of the transmitted stream . \n figures 4(a)4(g ) depict the box plots of psnr ratings of the received video ( denoted as scenario 2 ) . \n the objective quality drops abruptly ( see also table 5 ) , failing to match the clinically acceptable threshold . \n however , neither the end - to - end delay of 135 ms nor the plr values between 1 - 2% are high enough to justify such a dramatic decrease in ultrasound video quality . \n the latter observation was verified by the clinical evaluation ( see below ) , which provided clinically accepted ratings for the hspa communicated videos . as the medical expert noted , a temporal freeze in the received video could not compromise the diagnostic capacity of the examined videos , as the clinical information available in prior and subsequent cardiac cycles was sufficient for a confident diagnosis . driven by the previously finding and bearing in mind that psnr often fails to correlate with perceived video quality , led us in considering means of objectively evaluating the instantaneous temporal freeze effect present in the received video . \n variable frame delay algorithm was specifically designed to address video pauses during live streaming events , dictated by the high likelihood of such occurrences and the need to evaluate their perceptual impact . as demonstrated in table 4 , \n low psnr ratings are attributed to specific video pauses which cause a temporal mismatch between the transmitted and the received video sequences . table 4 highlights a typical temporal misalignment between the transmitted video ( stored at the receiver side ) and the original video , used for full reference vqa ratings . \n , there is a one frame skip in the transmitted video , which results either from a lost frame or a delayed frame . in the absence of vfd calibration , \n fr vqa would propagate this error to subsequent frames as well , resulting in miscomputation of psnr ratings . \n , we observe a temporal freeze with a three - frame duration ( frames 31 and 32 are the same with frame 30 ) . \n again , vfd calibration prevents psnr measurements to be computed between frames with a temporal mismatch of the three frames . \n it is worth noting here that temporal mismatch experienced is amplified when using bidirectional prediction , while it is relatively moderate for single - directional prediction ( see also clinical evaluation section ) . \n applying vfd calibration for removing temporal disparity enables psrn metric to compare the most relative frames and hence deliver ratings which correspond to the ultrasound video 's actual clinical capacity . \n the right - most box plots of figures 4(a)4(g ) show that the psnr ratings following vfd calibration are significantly higher than those prior to vfd calibration and close to those of the transmitted ultrasound video . despite the fact that these ratings are in accordance with the clinical evaluation as detailed later , further tuning is required to accommodate a fair objective evaluation . in the presented results , received frames \n were compared to the most relative transmitted frames indicated by the vfd algorithm , without addressing erroneous and delayed frames causing the temporal mismatch . as a result , \n the depicted psnr ratings are based on fewer frames than the total sequence frames resulting in slightly higher psnr values . \n table 7 demonstrates the results of kruskal - wallis ( kw ) nonparametric analysis of variance ( anova ) test , which statistically compares the objective results of the investigated transmission scenarios illustrated in figure 4 and table 5 , for 560 416 resolution video . \n as depicted in table 7 , and in accordance with the aforedescribed scenarios discussion , results obtained using wlan transmission and hspa wireless network following vfd calibration are close to the compressed psnr values prior transmission . as a result , there is no significant difference when statistically comparing these scenarios . on the other hand , \n hspa wireless transmission psnr values prior to vfd calibration are significantly different from the compressed videos psnr values prior to transmission , as well as the rival wireless transmission schemes , as evident in table 7 . \n the presented results for the higher 560 416 video resolution also hold for the lower qcif and cif resolutions . in the context of the clinical evaluation of this work , \n the physician evaluated a representative sample of the different encoding methods , image analysis , and quality ( bitrate ) . \n the medical expert was able to access the original video before each evaluation session and provided individual ratings for plaque presence , artery stenosis , and plaque - type and morphology . \n as expected , clinical ratings for the first scenario , depicted in table 6(a ) , suggest diagnostically lossless communication . \n more specifically , the clinical information in the transmitted video is equivalent to that of the original video , for detecting atherosclerotic plaque formation on artery walls and estimating the corresponding degree of the artery stenosis . for the most demanding task of plaque type characterization , clinically acceptable ratings ( over 4 ) were assigned in all cases . \n cif resolution encoded at 512 kbps and 560 416 resolution encoded at 768 kbps attained higher scores than cif resolution encoded at 324 kbps and 560 416 resolution encoded at 512 kbps , respectively . \n clinical evaluation of the hspa communicated videos appears in table 6(b ) . despite video pauses experienced in the received video , the medical expert is able to provide a confident diagnosis , as evident by the diagnostically acceptable ratings ( besides plaque - type assessment for cif resolution at 324 kbps ) . \n contrary to scenario 1 , however , it is not clear that higher resolution and bitrates facilitate higher clinical ratings . \n while the aforementioned statement is true for cif resolution , for 560 416 resolution the ratings are the same for the investigated bitrates . \n this is due to the fact that clinical ratings are primarily affected by the frequency of the temporal misalignments . \n a very important observation commented by the medical expert is that single - directional prediction is more resilient to temporal mismatch , while ipbbbbbbbbp coding structure is more vulnerable to video pauses , among bidirectional prediction investigated schemes . \n this is attributed to the increased gap between anchor p - frames and the absence of hierarchical coding . \n the key finding here is that diagnostically acceptable medical video communications at the clinically acquired resolution can be facilitated for the data transfer rates found in hspa wireless networks ( see figure 5 ) . \n the latter is not possible for 3 g and hsdpa communications , which are restricted by the upload data transfer speeds . \n cif resolution medical video communication stands as the boundary scenario for these two wireless networks . \n this paper demonstrates the capacity of the proposed open - source - based telemedicine platform to accommodate reliable wireless communication of medical video . \n comprehensive experimentation showed that adequate diagnostic quality ultrasound video at the clinically acquired resolution can be realized using both wlan and commercially available hspa wireless networks . \n the former wireless channel can provide for medical education purposes and remote diagnosis within the hospital premises . \n the latter can be broadly used for remote access to specialized physicians , in emergency incidents , and for mass population screening . \n low - cost implementation and ease of deployment can turn out to be a valuable tool for providing m - health solutions in developing countries , as well as for research purposes . \n both objective and subjective video quality assessment methods were employed to validate the clinical capacity of the transmitted video . \n bidirectional prediction utilization provided for higher objective ratings than single - directional prediction . using the vfd algorithm to remove the temporal mismatch present in hspa communicated video , as a calibration step before fr vqa metrics , enabled computing objective scores that correlate with medical experts ratings . \n ongoing research includes enhancing the current platform with modality - aware encoding features , investigating mobility aspects in wireless communication for emergency care and extending experiments over long - term evolution ( lte ) and lte - advanced wireless channels . \n moreover , mobile devices with limited resources like smart phones and tablets , based on android and ios operating systems are currently considered as end - user equipment . \n additionally , we also want to investigate how the new high - efficiency video coding ( hevc ) standard can lead to more efficient , diagnostically resilient encoding . \n the proposed framework is currently validated for use in other medical video modalities including trauma , abdominal aortic aneurysm ( aaa ) , and fluoroscopy medical videos .", "role": "user" }, { "content": "an m - health system for real - time wireless communication of medical video based on open - source software is presented . \n the objective is to deliver a low - cost telemedicine platform which will allow for reliable remote diagnosis m - health applications such as emergency incidents , mass population screening , and medical education purposes . \n the performance of the proposed system is demonstrated using five atherosclerotic plaque ultrasound videos . \n the videos are encoded at the clinically acquired resolution , in addition to lower , qcif , and cif resolutions , at different bitrates , and four different encoding structures . commercially available \n wireless local area network ( wlan ) and 3.5 g high - speed packet access ( hspa ) wireless channels are used to validate the developed platform . \n objective video quality assessment is based on psnr ratings , following calibration using the variable frame delay ( vfd ) algorithm that removes temporal mismatch between original and received videos . \n clinical evaluation is based on atherosclerotic plaque ultrasound video assessment protocol . \n experimental results show that adequate diagnostic quality wireless medical video communications are realized using the designed telemedicine platform . \n hspa cellular networks provide for ultrasound video transmission at the acquired resolution , while vfd algorithm utilization bridges objective and subjective ratings .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: vitamin c is known as an essential anti - oxidant ( 1,2 ) and enzymatic co - factor for physiological reactions such as hormone production , collagen synthesis ( 3 ) and immune potentiation ( 4 - 6 ) . \n naturally , an insufficiency of vitamin c leads to severe injuries to multiple organs , especially to the heart and brain , since they are both highly aerobic organs that produce more oxygen radicals . \n in fact , studies of in vivo effect on vitamin c are difficult since most animals , except human and some primate , are capable of synthesizing vitamin c endogenously ( 7 ) . \n however , gulo ( -/- ) mice were recently developed by the l - gulono--lactone oxidase ( gulo ) gene deletion like human , thus they should be supplied with dietary vitamin c ( 8) . it already has been reported that vitamin c concentration was decreased by 10~15% in plasma of the gulo ( -/- ) mice without supplementation of vitamin c for 2 weeks ( 8) . \n we also reported that vitamin c level was remarkably decreased in the most organs in the gulo ( -/- ) mice without supplementation of vitamin c for 3 weeks ( 9 ) . \n in addition , we found that numbers of t cell was decreased in the spleen of vitamin c - insufficient gulo ( -/- ) mice ( 10 ) . even though it is thought that vitamin c shows its anti - viral or anti - tumor effects through the up - regulation of the activity of natural killer ( nk ) cells and tumor specific cytolytic t lymphocytes ( ctls ) , its related evidences in vivo are still unclear . \n the reason why it is impossible to investigate in vivo effect of vitamin c is that all of animals could synthesize vitamin c from glucose thorough the action of l - glunolactone--oxidase ( gulo ) , as described above ( 7 ) . \n however , we confirmed that vitamin c up - regulates nk cell activity through the regulation of activating / inhibitory receptors on the surface of nk cell ( our unpublished data ) . since it is commonly known that vitamin c and nk cells are closely related to the prevention of common cold and the flu ( 11 - 13 ) , we evaluated in vivo anti - viral effect of vitamin c and its related mechanism in gulo ( -/- ) mice against influenza virus ( h3n2/honkong/1/68 ) . \n first , wild type , vitamin c - sufficient gulo ( -/- ) mice and vitamin c - insufficient gulo ( -/- ) mice were subjected to intranasal inoculation of 20 hemagglutination units ( hau ) of influenza virus , and then their survival was monitored . \n interestingly , we observed that vitamin c - insufficient gulo ( -/- ) mice expired within 1 week , but all of wild type and vitamin c - sufficient gulo ( -/- ) mice survived ( fig . \n however , the supplementation of vitamin c on a day after virus inoculation could not prevent the death of vitamin c - insufficient gulo ( -/- ) mice ( fig . \n it suggests that a sufficient amount of vitamin c is needed to prevent in vivo pathogenesis of influenza virus . also , considering that h3n2 influenza virus shows a good circulation in humans and pigs as well as a slow antigenic drift in swine ( 14 ) , we believe that the antigenic divergence between human and swine influenza virus might be increased . \n 1 suggest that vitamin c may effectively prevent severe or fatal damages in humans by the infection of influenza virus as well . to clarify the underlying mechanisms on the survival by the presence of the sufficient amounts vitamin c in the mice \n 2 , viral titer in the lung from vitamin c - insufficient gulo ( -/- ) mice was 10 to 15-fold increased , when it was compared with viral titer in wild type and vitamin c - sufficient gulo ( -/- ) mice . however , when gulo ( -/- ) mice were supplemented with vitamin c after virus inoculation , we could not observe a definite suppression of viral replication . \n this provides the importance of the vitamin c concentration at the initial stage of influenza virus infection . \n that is to say , damages through the replication of influenza viruses can be effectively prevented , when vitamin c concentration is sufficiently high at the initial stage of viral infection . \n if it is insufficient , however , the pathogenesis of influenza virus could not be prevented . \n it is known that type i interferons ( ifns ) , ifn- and - , play an important role in prevention of viral pathogenesis as their amounts increase within 1 or 2 days after virus infection ( 15,16 ) . \n we then measured the amounts of ifn- and - in bronchoalveolar ( bal ) fluid and plasma in each mice after intranasal inoculation of influenza virus . \n as we expected , the levels of ifn- and - in bal fluid and plasma from vitamin c - insufficient gulo ( -/- ) mice were quiet lower than those in wild type and vitamin c - sufficient gulo ( -/- ) mice ( fig . \n this result proves that vitamin c is an essential factor for the production of anti - vital immune response during the early phase of virus infection through the production of type i ifns . \n the phosphorylation of signal transducers and activators of transcription ( stats ) is the critical signaling process after the dimerization of its receptors , when type i ifns are increased ( 17,18 ) . \n even though it is not presented this reports , we found the defects on the phosphorylation of stat3 in t cells from gulo ( -/- ) mice upon vitamin c insufficiency ( 10 ) . \n therefore , the activation of stats in vitamin c - sufficient gulo ( -/- ) mice upon virus infection should be further investigated . \n the defects on the production of type i ifns followed by the activation of stats are closely related to the inflammatory responses due to the failure of controlling virus replication at the initial stage of its infection ( 19 ) . \n to investigate the inflammatory response in vitamin c - sufficient gulo ( -/- ) mice by influenza virus infection , we compared the levels of pro - inflammatory cytokines , il-1/ and tnf- in the bal fluids from wild type , vitamin c - sufficient gulo ( -/- ) mice and vitamin c - insufficient gulo ( -/- ) mice after virus infection . as a result , the production of il - il-1/ and tnf- was definitely increased in vitamin c - insufficient gulo ( -/- ) mice ( fig . \n at the same time , the infiltration of inflammatory cells into the lung is increased approximately 2.5-fold in vitamin c - insufficient gulo ( -/- ) mice than in others ( fig . \n 4d ) . in our previous report regarding the preventive role of vitamin c on the pathogenesis of acute liver inflammation \n , we have observed that the increase of the infiltration of immune cells into the liver and slight increase of tnf- production in vitamin c - insufficient gulo ( -/- ) mice ( 10 ) . \n and then the excessive inflammatory responses were occurred by the in vivo challenge of concanamycin a ( 10 ) . taken together , it seems that in vivo vitamin c insufficient status induces hyper - reactive immune responses against virus / bacterial infection or chemicals . \n it is generally known that plasma concentration of vitamin c in the mice is approximately 80~100 m . when the amount of vitamin c is present less than 20 m in the plasma , we called it as vitamin c insufficiency or \" sub - scurvy \" ( 9 ) . considering that systemic concentration of vitamin c in gulo ( -/- ) mice at 3 weeks \n after vitamin c withdrawal was 10~20 m , we presented the effect of vitamin c insufficiency , not vitamin c deficiency . in conclusion , \n vitamin c plays a critical role in vivo anti - viral immune responses against influenza virus through the increase of ifn - il-1/ production . \n therefore , it might be possible that the maintaining sufficient levels of vitamin c in the plasma by the continuous uptake through the diet or supplement could effectively prevent in vivo pathogenesis of influenza virus at the initial stage of viral infection . \n the gulo ( -/- ) mice were obtained from the mutant mouse regional resource center ( university of california , davis , usa ) . c57bl/6j wild - type and the gulo ( -/- ) mice were maintained in a specific pathogen - free condition at an animal facility in the seoul national university college of medicine . \n male gulo ( -/- ) mice ( 4~5 weeks old ) were maintained for about 3 weeks with or without vitamin c supplementation ( sodium l - ascorbate , 3.3 g / l , sigma , st . \n the influenza a virus ( iav ) strain was kindly provided by huan h nguyen ( international vaccine institute , seoul , korea ) . \n iav ( hongkong/1/68 , h3n2 ) was grown for 7~10 days in embryonated hens eggs , and then titrated by hemagglutination inhibition assay ( 20 ) . \n mice were anesthetized and intranasally administered 30l pbs containing 20 hau iav ( hongkong/1/68 , h3n2 ) . the illness and mortality of mice \n after 1 day of iav , blood was collected from the intra - orbital plexus with a heparinized capillary tube . \n the levels of ifn-/ ( pbl interferon source , piscataway , nj , usa ) , il-1/ and tnf- ( r&d system , minneapolis , mn , usa ) were measured using elisa , according to the manufacturer 's instructions . \n bal fluids were collected by lavaging the trachea and lungs with a total of 2 ml pbs containing 1% bovine serum albumin and 0.1% nan 3 ( blocking solution ) . \n total rnas of naive or iav - infected mice were isolated using trizol reagent ( invitrogen , carlsbad , ca , usa ) and were reverse - transcribed into cdna using oligo ( dt ) primers and amv reverse transcriptase ( intron , daejeon , korea ) . \n the real - time rt - pcr was processed with sybr green pcr master mix ( mbi fermentas , st . \n leon - rot , germany ) and performed using an exicycler ( bioneer , daejeon , korea ) . \n the specific primers for iav m2 gene ( 5'-aagaccaatcctgtcacctctga-3 ' and 5'-caaagcgtctacgc tgcag tcc-3 ' ) and mouse 2 m gene ( 5'-tgtctcactgaccggcctgt-3 ' and 5'-gttcagtatgttcggcttcc-3 ' ) . \n the difference between expression of iav m2 and 2 m was calculated using the 2 method . \n unpaired two - tailed t test was used to compare the two groups ( wt vs. gulo ( -/- ) or gulo ( -/- ) vs. gulo ( -/-)+vitamin c ) . \n statistical tests were carried out using graphpad instat version 5.01 ( graphpad software , le jolla , ca ) . \n the gulo ( -/- ) mice were obtained from the mutant mouse regional resource center ( university of california , davis , usa ) . c57bl/6j wild - type and the gulo ( -/- ) mice were maintained in a specific pathogen - free condition at an animal facility in the seoul national university college of medicine . \n male gulo ( -/- ) mice ( 4~5 weeks old ) were maintained for about 3 weeks with or without vitamin c supplementation ( sodium l - ascorbate , 3.3 g / l , sigma , st . \n the influenza a virus ( iav ) strain was kindly provided by huan h nguyen ( international vaccine institute , seoul , korea ) . \n iav ( hongkong/1/68 , h3n2 ) was grown for 7~10 days in embryonated hens eggs , and then titrated by hemagglutination inhibition assay ( 20 ) . \n mice were anesthetized and intranasally administered 30l pbs containing 20 hau iav ( hongkong/1/68 , h3n2 ) . the illness and mortality of mice \n after 1 day of iav , blood was collected from the intra - orbital plexus with a heparinized capillary tube . \n the levels of ifn-/ ( pbl interferon source , piscataway , nj , usa ) , il-1/ and tnf- ( r&d system , minneapolis , mn , usa ) were measured using elisa , according to the manufacturer 's instructions . \n bal fluids were collected by lavaging the trachea and lungs with a total of 2 ml pbs containing 1% bovine serum albumin and 0.1% nan 3 ( blocking solution ) . \n total rnas of naive or iav - infected mice were isolated using trizol reagent ( invitrogen , carlsbad , ca , usa ) and were reverse - transcribed into cdna using oligo ( dt ) primers and amv reverse transcriptase ( intron , daejeon , korea ) . \n the real - time rt - pcr was processed with sybr green pcr master mix ( mbi fermentas , st . \n leon - rot , germany ) and performed using an exicycler ( bioneer , daejeon , korea ) . \n the specific primers for iav m2 gene ( 5'-aagaccaatcctgtcacctctga-3 ' and 5'-caaagcgtctacgc tgcag tcc-3 ' ) and mouse 2 m gene ( 5'-tgtctcactgaccggcctgt-3 ' and 5'-gttcagtatgttcggcttcc-3 ' ) . \n the difference between expression of iav m2 and 2 m was calculated using the 2 method . \n unpaired two - tailed t test was used to compare the two groups ( wt vs. gulo ( -/- ) or gulo ( -/- ) vs. gulo ( -/-)+vitamin c ) . \n statistical tests were carried out using graphpad instat version 5.01 ( graphpad software , le jolla , ca ) .", "role": "user" }, { "content": "l - ascorbic acid ( vitamin c ) is one of the well - known anti - viral agents , especially to influenza virus . \n since the in vivo anti - viral effect is still controversial , we investigated whether vitamin c could regulate influenza virus infection in vivo by using gulo ( -/- ) mice , which can not synthesize vitamin c like humans . \n first , we found that vitamin c - insufficient gulo ( -/- ) mice expired within 1 week after intranasal inoculation of influenza virus ( h3n2/hongkong ) . \n viral titers in the lung of vitamin c - insufficient gulo ( -/- ) mice were definitely increased but production of anti - viral cytokine , interferon ( ifn)-/ , was decreased . on the contrary , the infiltration of inflammatory cells into the lung and production of pro - inflammatory cytokines , \n tumor necrosis factor ( tnf)- and interleukin ( il)-/ , were increased in the lung . taken together \n , vitamin c shows in vivo anti - viral immune responses at the early time of infection , especially against influenza virus , through increased production of ifn-/.", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: human inherited diseases , for example , are detectable by observing certain chromosomes of the existing 46 chromosomes in human body . \n karyotype , a systemized array of the chromosomes of a single cell prepared either by drawing or by photography , is often used for this purpose . to make a karyotype it is necessary to identify each one of the 46 chromosomes ( 22 pair of autosomal and a pair of sex chromosomes ) . \n karyotyping consists of the identification , classification , and presentation of the 23 pairs of the chromosomes in a single picture . \n this process , which is usually done manually by a human expert , is a difficult and time - consuming task . in conventional karyotyping , \n giemsa - banded cells are photographed under a light microscope ( an example picture is shown in figure 1a ) during the metaphase stage . \n the result of the karyotyping process for figure 1a , which is done manually by a cytogeneticist , is shown in figure 1b . \n karyotyping , ( a ) g - banded chromosomes as seen under a light microscope , and ( b ) corresponding karyotype ( a male ) it is certainly of interest to have accurate techniques in doing karyotyping . inaccuracy may lead to disastrous consequences , for example , when dealing with disease identification . \n it may cause a misleading observation on one 's set of chromosomes that may lead to false diagnosis on the patient 's condition . \n of course , one would rather have traditional methods , yet somewhat still accurate , to diagnose the disease he has , than become paralyzed or dead due to unintentional medical malpractice . \n features used in chromosome classification generally fall into two main categories of the geometrical features and the band pattern - based features . \n the length of the chromosome and the centromeric index ( ci ) are the most important geometrical features . \n ci is the ratio of the length of the short arm of the chromosome to its long arm . \n these two arms are separated from each other in a point called centromere . based on the location of the centromere along the chromosomes , there are three classes defined for them . in some chromosomes , which are called metacentric , \n the centromere is located in the middle of the long axis of the chromosome and the two arms are almost of the same length ( therefore ci 1 ) . \n chromosomes number 1 , 3 , 16 , 19 , and 20 are metacentric . a chromosome is called acrocentric when the centromere divides the chromosome into two arms of unequal length . \n chromosomes number 13 , 14 , 15 , 21 , and 22 belong to this class . in the last class of the chromosomes named telocentric \n the short arm is very small and the centromere is located near to one of the two ends of the chromosome . from these explanations , it is clear that ci is an important feature for classification of the chromosomes \n . automatic classification of chromosomes has been a well - studied problem in the last four decades.[611 ] natural complexity of the problem is caused by various unpredictable appearances of the chromosomes due to nonrigid nature of them . \n the proposed algorithm is based on the calculation and analyzing the vertical and horizontal projection vectors of the binary image of the chromosome . \n this algorithm can not apply on the rotated or highly bent chromosomes . to remove this restriction , \n the projections are performed on the medial axis or skeleton of the chromosome in the algorithms . in other words , \n the using feature in these algorithms is the length of the line segment that connects two boundary pixels and is perpendicular to the skeleton . \n this feature is raised from this sentence : the centromere is located in the narrowest part of the chromosome along its longitudinal direction . \n the block diagram of the proposed algorithm for centromere localization is shown in figure 2 . \n input of this block diagram is an image of one chromosome which is cropped manually . \n the first step in the proposed algorithm is to segment the input image which a simple thresholding algorithm . a sample result of this thresholding algorithm is shown in figure 3 . \n the centerline of the chromosome region is computed and a polynomial curve is fitted to it . on the other hand , \n the proposed feature ( concavity degree ) is computed for the pixels of the chromosome 's boundary . \n then , the concavity degrees are projected to the centerline and the corresponding pixel to the maximum concavity is chosen as the centromere location . \n block diagram of the proposed algorithm for centromere localization segmentation of the chromosome , ( a ) original image , ( b ) segmented image by the method , and ( c ) the chromosome 's boundary the remainder of this paper is structured as follows . \n the proposed feature , concavity degree , and the method of its computation are presented in the concavity degree calculation section . \n therefore , the search for the centromere location can not be performed on a straight line ( i.e. , vertical or horizontal ) . \n so , the centerline of the chromosome region may be used to search for the centromere location . \n skeleton of the figure 3b is plotted in the figure 4a . as can be seen , \n the raw skeleton consists of some undesirable branches and its search is very hard . to overcome this problem , \n computation of the chromosome 's centromere , ( a ) initial skeleton , ( b ) obtained centerline by the method , and ( c ) plot of the fitted curve to the centerline on the original image in our proposed method of search the centerline pixels , the perpendicular line to each pixel is required . \n thus , to reduce the noise effect and to obtain an equation for the slope of the centerline 's pixels , two polynomial curves of degree 4 are fitted to the x- and y - coordinates of the centerline . if the polynomial coefficients of the x- and y - coordinates store to p1 and p2 vectors , respectively , ( 1 ) and ( 2 ) are the corresponding equations of the fitted curves : xt = p14t+p13t+p12t+p11t+p10 ( 1 ) yt = p24t+p23t+p22t+p21t+p20 ( 2 ) where t = 1 , 2 , , n and n is the number of centerline pixels . \n this fitted curve of figure 4b is shown on the original chromosome image in figure 4c . \n , it is observed that the centromere line has the shortest length among all the perpendicular lines . \n two endpoints of the centromere line are concave points another important feature of the chromosome line is the concavity of its endpoints [ figure 5 ] . \n therefore , the focus of this paper is on this novel feature and development of an algorithm to centromere localization based on this feature . \n angles and curvature are probably the most widely used features for concavity calculation . however , both angle and curvature are vulnerable to noise , especially when the segmentation step can not produce a neat and clean contour due to the noise . in this paper , \n the property of convex regions [ figure 6 ] is used to define a new concavity calculation method . \n demonstration of convex and nonconvex regions , ( a ) in a convex region , for every pair of points within the region , every point on the straight line segment that joins them is also within the region , ( b ) in a nonconvex region , previous condition is not valid for some pair of points based on the above discussion , for the concave points , the straight line segment between two near boundary points is outside of the region . \n illustration of concave and convex points to compute the concavity degree of each boundary pixel , its corresponding boundary points by distance h are considered as the two endpoints of its line segment . then , this line is plotted and its points that are not on the region are enumerated . \n the concavity degree is defined as the ratio of outside points of the line segment to the total number of the line segment points ( 3 ) : where r is the region of the chromosome and r is its complement . \n also , li is the region of the line segment and ci is the concavity degree corresponding to the ith boundary pixel . \n thus , the value of li is equal to 2h-1 ( two endpoints are not considered as the line segment points ) . \n figure 8 shows the proposed method on an image . in this figure , pixel 1 is a fully concave point and by considering its corresponding line segment , its ci is 1 . on the other hand , \n pixel 2 is a fully convex point and by considering its corresponding line segment , its ci is 0 . \n demonstration of the proposed method to computation of concavity degrees of two pixels . for pixel 1 , which is a concave point , the corresponding line ( that connects two pixels by h distance before and after it ) has no intersection by the region . on the other hand , for pixel 2 , which is a convex point , \n all of the corresponding line overlies on the region concavity degrees for the chromosome 's boundary of figure 3c are depicted in figure 9 . in this figure \n as can be comprehended visually , for the more concave pixels , the value of ci is larger . \n concavity degrees of the boundary pixels ( brighter colors correspond to the larger concavity degrees ) thus , the boundary pixels that have larger ci are candidates for the endpoints of the centromere line . in the next section , \n the proposed algorithm for the centromere line detection based on the concavity degrees is presented . \n the search for the centromere location is performed on the centerline curve . on the other hand , \n the concavity feature is defined on the boundary pixels . therefore , the boundary pixels that are corresponded to the centerline pixels should be found . to find these boundary pixels , the perpendicular line for any centerline pixel is obtained and intercrossed by the boundary pixels . for any pixel on the centerline of the chromosome , the perpendicular slope to it may compute by ( 4 ) the equation of the line that passes through the current pixel with slope s is ( 5 ) y = st(x xt)+yt . \n two pixels in the two sides of the chromosome boundary that this line passes through can be found ( lt and rt ) . \n the score of this pixel on the centerline is the sum of the concavity degrees for two boundary pixels as in ( 6 ) : three samples of the perpendicular lines to the centerline pixels and their corresponding boundary pixels st = clt + crt . \n ( 6 ) so any pixel on the centerline that has larger st may be the location of the centromere and the corresponding line may be the centromere line . \n the maximum value is corresponded to the centromere location estimated centromere line for a sample chromosome \n this figure may depict the high quality of the proposed method . estimated centromere lines for some sample chromosomes to quantify the accuracy , for 50 images of chromosomes the centromere location are marked manually . \n then , the proposed algorithm is applied on them and distance between the results of algorithm and the markers are computed as the error of the algorithm . \n eight samples of the manually marks ( yellow square ) and the results of the proposed algorithm ( green triangle ) are shown in figure 14 . \n manually marks are depicted by the yellow square and the results of the proposed algorithm are depicted by the green triangle average error of the proposed algorithm is listed in table 1 . \n the width of test images is about 100 and their height is about 200 pixels . \n moreover , the average error using the shortest line and combination of the shortest line and larger concavity are listed in table 1 . from this table \n , it can be observed that the average error using concavity degree is smaller than the average error using the line segment length . \n moreover , the combination of these two features results in a smaller average error . comparing the average and variance of the errors of the proposed method using three features : \n larger concavity , shortest line , and their combination figure 15 is an example of the higher performance of the concavity degree from the line segment length . \n parts ( a ) and ( b ) in this figure are corresponded to the concavity degree and line segment length features , respectively . \n so , for this example the performance of concavity degree is higher ( from table 1 , average error of this feature also is smaller ) . \n this higher performance corresponds to the robustness of concavity degree to the noise and other nonideal conditions . \n an example of the higher performance of the concavity degree from the line distance , ( a ) result of the proposed method using concavity degree , and ( b ) using the lie distance \n an accurate algorithm for locating the centromere in a microscopic image of a human chromosome was presented . \n centromere locating is important for feature extraction and classification of the chromosomes , which is a necessary step toward automatic karyotyping . \n the algorithm is based on the calculation of the concavity degree for boundary pixels of the chromosome region and projecting them to the centerline . \n the mean error ( euclidean distance between the reference and automatically extracted centromere locations ) is about 2.25 pixels , which is small and the accuracy may be satisfactory . the combination of the concavity degree and line segment length results in smaller error . in this paper , \n thus , the method of their combination and definition of new features can be studied in the future works . \n in addition , the input of the proposed algorithm was an image of one chromosome which was cropped manually . \n mohammad reza mohammadi was born in qom in iran , on july 25 , 1987 . \n he received undergraduate and msc degrees from amirkabir university of technology in 2009 and 2011 , respectively . \n he is currently a phd student of sharif university of technology and researches in biomedical signal and image processing lab ( bisipl ) . \n his interests and research include biomedical image processing , machine vision , and machine learning .", "role": "user" }, { "content": "analyzing the features of the chromosomes can be very useful for diagnosis of many genetic disorders or prediction of possible abnormalities that may occur in the future generations . for this purpose , \n karyotype is often used , for which to be made , it is necessary to identify each one of the 24 chromosomes from the microscopic images . \n definition and extraction of the morphological and band pattern - based features for each chromosome is the first step to identify them . \n centromere location is an important morphological feature . in this paper , \n a novel algorithm for centromere localization is presented . \n the procedure is based on the calculation and analyzing the concavity degree of the chromosome 's boundary pixels . in this method , \n the centerline of the chromosome is computed and the score of each pixel on the centerline is considered as the sum of the concavity degree of two pixels on the chromosome 's boundary that are perpendicular to it . finally , location of the centromere is estimated as one pixel on the centerline which is corresponding to the maximum score . when applied the proposed algorithm on 50 images , an average error of 2.25 pixels for centromere localization is achieved .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: heterotaxy syndrome ( hs ) or situs ambiguous is defined as the abnormal arrangement of organs and vessels as opposed to the orderly arrangement typical of situs solitus and situs inversus . \n we present an interesting case of malrotation with volvulus where the diagnosis was delayed because of the association with hs . \n a 2-year - old boy presented with recurrent episodes of abdominal pain with distension , bilious vomiting and fever for 3 weeks . he weighed 8 kg and had a history of failure to thrive since early infancy . \n he was a known case of ventricular septal defect ( vsd ) and was on digoxin . \n the abdominal radiograph showed a prominent gas shadow in the upper half of the abdomen that was initially mistaken for a dilated colonic shadow by the treating physician . \n he had a hemoglobin of 14.1 gm% and total leucocyte count of 9800/mm with blood urea 89 mg / dl and serum creatinine of 1.3 mg / dl . \n the 2d - echo revealed situs solitus with levocardia and a small 3 mm peri membranous vsd . \n the child was kept nil per oral and the fluid and electrolyte imbalance corrected . due to persistent bilious aspirates , \n an upper gastrointestinal ( gi ) contrast study was performed that suggested malrotation with volvulus and situs inversus [ figure 2 ] . \n the stomach and duodenum were in mirror image position with gross distension up to the third part of the duodenum . \n the entire small bowel was healthy but enclosed in a thin transparent sac containing jelly - like material in the left half of the abdomen [ figure 3 ] . the ascending and transverse colon were posterior to the duodenum . \n multiple splenunculi ( five in number ) of variable sizes , were seen in the right upper quadrant related to the greater curvature of the stomach [ figure 4 ] . \n the bowel was derotated after excising thick ladd 's bands , sac excised and inversion appendectomy performed . \n the superior mesenteric vessels were seen to lie more toward the posterior aspect of the mesentery after the procedure . \n prominent gas shadow in the upper half of the abdomen upper gastrointestinal contrast study showing dilated stomach in the upper - right quadrant of the abdomen , duodenojejunal flexure to the left of the midline and cork screw appearance suggestive of volvulus laparotomy findings of distended duodenum , ladd 's bands and small bowel enclosed in a transparent cocoon polysplenia located in the upper - right quadrant along the greater curvature of the stomach \n heterotaxy syndrome ( hs ) is associated with an abnormal arrangement of organs and vessels . based on the spleen , it has three major subtypes : ( a ) asplenia ; ( b ) polysplenia , that is , cluster of small splenunculi , a multilobed spleen or a large spleen accompanied with several smaller splenules ; and ( c ) normal spleen located in the right upper quadrant of the abdomen . \n ( 1 ) hs with asplenia ( right atrial isomerism ) is characterized by bilateral right - sidedness including bilateral right lungs with epiarterial bronchi , bilateral \n hs with polysplenia also called as left atrial isomerism is characterized by a tendency toward bilateral left sidedness that may include bilateral left ( bilobed ) lungs with hyparterial bronchi , bilateral left \n this is a rare complex disorder with an incidence of approximately 4 per 1 million live births . \n apart from congenital cardiac anomalies ( 5090% ) , hs is also associated with abnormal symmetry of liver ( 5067% ) , preduodenal portal vein ( 1750% ) , biliary atresia with hypoplasia of portal vein , abnormally short or truncated pancreas ( 50% ) , interruption of inferior vena cava with continuation via a dilated azygos or hemiazygos vein into superior vena cava ( 58100% ) and malrotation ( 70100% ) with or without midgut volvulus . \n patients with heterotaxy may have different degrees of intestinal rotation varying from classic malrotation predisposing to volvulus to nonrotation , where due to a broader mesentery such a risk is reduced . due to this variability \n symptomatic patients , as in our case , with suspicion of midgut volvulus should undergo exploratory laparotomy promptly . \n as barium studies may not predict that patients will be at risk for midgut volvulus , the ladd 's procedure should perhaps be performed in all patients with malrotation . moreover , elective intervention is always better tolerated than an emergency surgery . with continuing advances in cardiovascular care , there is improved survival beyond infancy and therefore the presence of an associated cardiac anomaly should not be a contraindication for surgical management of malrotation in children with heterotaxy . in our patient who had only a small vsd , the failure to thrive was most likely due to recurrent attacks of volvulus which had been neglected until then . \n the presence of a thin transparent membranous sac enclosing the small bowel was also unusual in this case and has not been reported in the literature before . \n the sac could very well represent the amniotic membrane during physiological hernia in utero and gives us a likely embryological period at which the defects occurred . \n an appropriate contrast study should be performed in patients with unusual abdominal radiograph findings to avoid delay in diagnosis . \n diagnosis of malrotation volvulus in a child with heterotaxy is a challenge both for the clinician and radiologist .", "role": "user" }, { "content": "a 2-year - old boy with heterotaxy syndrome with associated polysplenia , ventricular septal defect , and malrotation of gut with volvulus is presented . \n there was delay in diagnosis due to the unusual plain abdominal radiography findings . at laparotomy \n , the midgut was also found to be enclosed in a thin transparent cocoon .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: metabolic syndrome ( ms ) is a risk factor for the development of diabetes mellitus ( dm ) and cardiovascular disease ( cvd ) complications and the development to overt diabetes passes through subclinical prediabetic states that most times coexist with one or more metabolic disorders such as hypertension , dyslipidemia , and/or obesity . \n ms involves related and connected factors that increase the risk of coronary heart disease ( chd ) , cvds , and dm type 2 ( dmt2 ) . \n the principal features include dyslipidemia ( elevated triglycerides and apolipoprotein b ( apob)-containing lipoproteins and low high - density lipoproteins ( hdl ) , hypertension , and dysregulated glucose hemostasis . abdominal obesity and/or insulin resistance ( ir ) are also core manifestations of the syndrome . \n the definition is growing to include chronic proinflammatory and prothrombic states , nonalcoholic fatty liver disease , and sleep apnea . \n perhaps , this explains the various criteria used and the need to define the criteria used in studying or diagnosing this syndrome . \n the 2009 atlas report of the international diabetes federation ( idf ) on the prevalence rates of diabetes showed that diabetes prevalence is much more prominent in the developing regions of the world and more than 438 million people will be living with diabetes by the year 2030 citing idf 2004 , 2006 and who 2000 reported noted that 70% of world diabetes cases are resident in the developing countries . \n a prevalence of 13 - 30% in developing countries and approximately 30 - 35% in developed countries for ms has been reported . \n an area that needs studying is the prevalence of chronic disorders in young adult populations in rural areas with limited health services . \n thus , the prediabetes and cardiovascular complications study ( paccs ) , including this preliminary study , focuses on the ndokwa local government area of nigeria . \n health disparity issues between the poor and the rich , the urban and rural dwellers , and ethnic / racial minority and majority groups are factors that influence the prevalence of chronic diseases . \n knowledge , attitude , and practice ( kap ) gaps of individuals in these communities also predispose to the risk of developing diabetes and cvds . \n it has been shown that self - care among individuals with type 2 diabetes improved glycemic control and reduced complications . therefore , health education and counseling is an indispensable component of the management strategies of cvd and dm risk factors . \n assessment of prediabetes and ms is a useful tenet to determine the level of prevalence of these risk factors and this can be achieved through screening and identifying the knowledge and perceptions of the communities towards these risk factors . \n part of the objectives of this pilot data is to gather data on prevalence of ms and prediabetes in the ndokwa region with a view to develop program for prevention . \n ethics approval was obtained from human research ethics committee of novena university and the local government ministry of health at kwale , delta state nigeria . \n the mixed secondary / high ( abbi grammar school ) institution was contacted through the principal for a public lecture and recruitment of participants among the staff and students . \n public lectures were followed by provision of information sheets as well as consent forms and questionnaires . \n seventy - four volunteers , of equal number ( 37 ) of each gender , complied / responded , and were included in the pilot screening . \n exclusion criteria were age less than 18years or greater than 60 years , if the subject had previous diagnosis of diabetes , and the inability to provide contacts for future follow - up should screening for ms and prediabetes be positive . \n cardiochek point of care testing ( poct ) equipment was used to measure blood glucose level and lipid profile according to manufacturer 's instructions . \n cholesterol and hdl - cholesterol ( in very low - density lipoprotein ( vldl ) and ldl depleted plasma ) by the cholesterol esterase and oxidase / peroxidase reactions , while triglycerides was by the lipoprotein lipase / glycerol kinase / glycerophosphate and oxidase / peroxidase reactions . \n two participants initially presented with high blood glucose level that was interpreted as diabetes and on the consideration of concerns and merits of poct , the participants were invited for repeat screening and are scheduled for follow - up . \n anthropometric measures included height and waste circumference ( wc ) , which were measured by tape and weight by precision scale . \n the waist was defined as the midway between iliac crest and coastal margin ( lower rib ) ; while the hip circumference was defined as being the widest circumference over the buttocks and below the iliac crest . \n ms in this study is defined according to three criteria as indicated in table 1 . \n given that european criteria is recommended pending availability of specific criteria , ethnic specific waist circumference ( wc ) as other considered factor in idf 2005 criteria was presumed from the mean values to be obtained . \n screening of the participants from abbi grammar school occurred in the school , while those recruited through the churches took place at the privately owned st mathias hospital , abbi . \n the study population has , on average , a healthy body mass index ( bmi ) of 24 kg / m , wc of 82 cm , blood pressure of 131/76 mmhg , blood glucose level of 96 mg / dl , and total cholesterol ( tc)/hdl ratio of 4.0 . \n descriptive statistics evaluation of data shows that more females are worse in almost all indices than males , except in blood pressure and hdl [ figure 1 ] . \n multivariate statistical comparison of the female versus male group show a statistically significant difference ( multivariate analysis of variance ( manova ) : p < 0.001 ) . the prevalence of ms according to the three different criteria \n show some disparity in outcome between the who 1999 system compared to the other two definitions [ figure 2 ] . \n prevalence ( % ) of individual risk factors of metabolic syndrome . * who , * * atpiii and idf , atpiii , idf european , idf ethnic . atp iii = third adult treatment panel , idf = international diabetes federation , who = world health organization , bp = blood pressure , bgl = blood glucose level , tg = triglyceride , hdl = high - density lipoprotein , bmi = body mass index , wc = waist circumference prevalence of metabolic syndrome according to the three different criteria . * * * bmi > 25 kg / m it should be noted that idf in figure 2 include evaluation based on the idf european standard . \n what is new in this pilot result is the attempt to develop the wc cut point for sub - saharan african community . \n we acknowledge that the best approach to develop reference values is by running a population study to establish mean 2 standard deviation ( sd) range . in this circumstance \n , we want to establish reference range of wc in the community ; in order to authoritatively substitute for > 102 cm in men and 88 cm in women of europeans . \n a poct was chosen in this study because the machine is portable ; specimen collection is relatively not traumatic to participants , and fast turnaround time of results . \n such factors make poct ideal for screening , especially in rural communities . using the three criteria , the results from this pilot study show that abnormal levels of the individual parameters of ms such as blood glucose , triglyceride levels , and wc ; as well as high blood pressure ( who definition ) , are more prevalent in females compared to males . \n therefore , when these particular indices are considered separately ; more females than males seem to be at risk of cvd . however , the prevalence of abnormal hdl cholesterol as well as high blood pressure ( atp iii and idf definitions ) is less in females than in males [ figure 1 ] . \n the observation from this preliminary study indicate that the who 1999 criteria identified the least , but equal prevalence ( 3% ) in females and males . \n the atpiii 2001 and idf 2005 criteria identified more ms in males than in females [ figure 2 ] . \n our study shows prevalence of 8% in females and 11% in males ( atpiii 2001 criteria ) , 5% in females and 8% in males ( idf2005 european criteria ) , and 14% females and 17% males ( idf 2005 ethnic criteria ) , and 14% males and 17% females ( idf 2005 ethnic criteria ) . \n these figures are comparatively lower than for instance in seychelles , another low - mid income country from african region where higher prevalence levels ( 25 - 30% ) of ms at the age of 25 - 64 years ; and using the atp , who , and idf definitions the prevalence of 24 , 25 , and 25.1% in men and 32.2 , 24.6 , and 35.4% in women , respectively , were reported . \n the study on spanish adult workers using idf and atp iii diagnostic criteria reports that in adult spanish males and females , the presence of ms with adjusted global prevalence was 12.4% using atp iii criteria and 16.5% using the idf criteria ; and prevalence in males was always higher than in females . \n the european standard of idf identified more ms than the atpiii , as the ethnic specific standard of idf in this study did . \n results from the spanish study are comparable to ours , but we are mindful of the differences in settings and these include urban in the spanish study , while our study was rural based . the influences of other factors such as physical and socioeconomic factors , which are different , are not established . \n a study in a rural african population , ghana , reports the overall prevalence of ms by the idf and atp iii criteria were 35.9 and 15.0% , respectively . \n the study further noted alarming female preponderance by both criteria and that the triad of central obesity , high blood pressure , and low hdl cholesterol were most responsible for the syndrome in this rural population . in evaluating the various criteria for ms \n , it has been noted that the idf is closest to atpiii in that it includes the same variables , but it differs in that central obesity is an essential component . \n also the waist measurement is set at a lower level than in atp iii and it is ethnic - specific . in a study of adults over 20 years , in chennai , a city in southern india , ms was in 23.2% by the who criteria , 18.3% by atp iii criteria , and 25.8% by the idf criteria . \n the who criteria marked out a much higher population for coronary artery disease ( cad ) risk compared to atp iii and idf criteria in males but not in females . \n although the prevalence of ms varies according to the definition used , the study identified a greater number in males , which further corroborate with our observation presented in figure 2 . \n our data [ figure 2 ] show that atpiii criteria pick up ms that is otherwise missed by who classification . while this may be argued as due to our acknowledged study limitation , it is noteworthy that nowadays , following the general consensus , the two most widely used definitions of ms are those of the atpiii and the idf . using these criteria , a prevalence of 13 - 30% of ms in developing countries and approximately 30 - 35% in developed countries is usually found . \n it has been noted that the who definition is better suited as a research tool , whereas the national cholesterol education program ( ncep ) atp iii definition was more useful for clinical practice . \n clinicians prefer simple tools to assess patients and improve their management and it is generally agreed that the ncep atpiii definition is simpler for practice . \n it requires only a fasting assessment of blood glucose , whereas the who definition can require an oral glucose tolerance test . \n further the who definition can also require assessment of ir and this is a relatively complicated test . \n there is no single test that can directly diagnose ir in clinical practice ; and it is irrational to recommend such test where basic laboratory services are either inaccessible or unaffordable . \n the prevalence of 6% in females and 3% in males for prediabetes in our study was lower than 10% of people in the age group 25 years and above reported in pakistan are suffering from prediabetes and in the same article they noted that prevalence of prediabetes was 23.4% among south asians . \n the findings of the present study are still lower than the observation of sabir et al . \n , who found that in the adult fulanis of northern nigeria there was a high prevalence of prediabetes using impaired fasting glucose ( ifg ) or impaired glucose tolerance ( igt ) as indices . \n they found prevalence rates of igt and ifg were 8 and 6.9% , respectively , and noted that the relative high prevalence of igt was similar to idf estimates of about 8% prevalence for igt in nigeria . \n these higher prevalence reports indicate that larger sample sized cross - sectional study is required to confirm our observation regarding the prediabetes in ndokwa community of nigeria . \n this pilot study is paccs first preliminary investigation in the rural community of nigeria ; and it is envisaged to expand the study longitudinal with more samples population and vertical with follow - ups . \n poct may be best suited in a rural setting in a developing community to screen for diabetes and ms . \n this study is mindful that other parameters that contribute to diabetes or ms were not studied , but the observations are significant . \n the results show that prevalence of prediabetes ms may be low in the ndokwa region of nigeria by comparison with rural communities elsewhere \n . however , it appears females are at greater risk than males to develop diabetes ; whereas males seem more at risk of ms perhaps due to hdl cholesterol and stricter definition of blood pressure . \n relative to atpiii 2001 criteria , either the idf2005 european standard may underestimate ms , or the idf ethnic specific could overestimate the prevalence .", "role": "user" }, { "content": "background : global prevalence of metabolic syndrome ( ms ) and diabetes is increasing , but the reference ranges for ms indices have yet to be established for sub - saharan african countries . as part of the international research collaboration agenda for prediabetes and cardiovascular complications study ( paccs ) , a pilot study was conducted in one of the ndokwa communities of nigeria in 2013.aim:the study was to obtain preliminary indication of prevalence and reference values of ms in the rural communities of a low - mid income country.materials and methods : seventy - four volunteer participants were recruited , after public lectures in high schools and churches in the community . body mass index ( bmi ) , blood pressure and waist circumference ( wc ) , blood glucoselevel , and lipid profile were measured . \n percentage prevalence ms was determined using commonest three criteria ( third adult treatment panel ( atp iii ) 2001 , international diabetes federation ( idf ) 2005 , and world health organization ( who ) 1999).results : when individual indices of ms are considered separately ; the males seem healthier than females . however , the prevalence of high - density lipoprotein ( hdl ) cholesterol was higher in males than in females . \n equal 3% prevalence of ms was seen in both genders using the who standard . \n other criteria show prevalence of 8% females and 11% males ( atp iii ) , 5% females and 8% males ( idf 2005 european ) , and 14% females and 17% males ( idf 2005 ethnic).conclusion : the prevalence of ms is higher in males than females ; and relative to atp iii 2001 criteria , either the idf 2005 european may underestimate ms , or the ethnic specific could overestimate the prevalence . \n hence , it is important to define the criteria to be used .", "role": "assistant" } ]

[ { "content": "You are a medical writer. Summarize the following article: kaiser permanente medical care program ( kaiser permanente ) is a fully integrated , nonprofit , group practice health plan that provides comprehensive medical services to over 2.5 million members ( january 1995 ) throughout northern california ( including the san francisco bay and sacramento metropolitan areas ) or 2530% of the surrounding population . \n the kaiser permanente membership closely approximates the general population ethnically and socioeconomically except for the extreme tails of the income distribution ( 11 ) . in 1993 , kaiser permanente established the kaiser permanente northern california diabetes registry . \n the registry is updated annually by identifying all health plan members with diabetes from automated databases for pharmacy , laboratory , hospitalization records , and outpatient diagnoses ( 1214 ) . \n the registry sensitivity is estimated to be 96% based on chart review ( 15 ) . during 19941996 , all \n noninstitutionalized registry members 19 years or older identified as having diabetes prior to 1 january 1996 ( n = 90,302 ) were selected for participation in a health survey ( self - administered questionnaire ) or a computer - assisted telephone interview in english or spanish . \n eighty - three percent of eligible members participated in the survey . after removing those denying having diabetes or discontinuing membership , 70,748 respondents with diabetes remained . \n the survey collected information on , among other things , ethnicity , information needed to classify diabetes type ( see karter et al . for algorithm ) , family history of diabetes , education , and behavioral risk factors . \n survey respondents were ethnically diverse : 14% black , 12% asian , 10% latino , and 64% non - latino white . \n 44% were filipino , 24% were chinese , 12% were japanese , and 19% were korean , other asian , or mixed race . \n we compared the demographic composition ( age , sex , socioeconomic status ) of diabetes survey responders to nonresponders in a previous study ( 14 ) and found no evidence to suggest responder bias . \n in addition to survey - derived data , we obtained measures of neighborhood - level socioeconomic status by linking each member s address to the 1990 census block group - level average annual 1989 per capita income . \n we used a survey follow - up study design to evaluate the incidence density of lea and its predictors , restricting analysis to the 28,701 survey respondents who had triglyceride data within 1 year of baseline . \n baseline was defined as 1 january 1995 for all members surveyed in 1994 and the survey date ( january 1995 to march 1997 ) for those surveyed after that date . \n the duration of follow - up ( person - time ) was tabulated through membership records and ended with an event censoring due to dropping of kaiser permanente membership for any period greater than 2 months , death , or the end of the study ( 31 december 2006 ) . \n we excluded those with a history of prior lea events noted in hospital discharge records during the 5 years prior to baseline . \n prognostic , confounding , and stratifying variables ( see below ) were ascertained at or prior to baseline from automated records , the diabetes survey , and the 1990 census . \n in two separate validations of amputation procedures ( a. karter , personal communication , n = 109 ; and j.v . selby and d. zhang , n = 209 ) , 99% of electronic hospital discharge records were confirmed by chart review . using direct standardization with the entire diabetes cohort as the population standard \n , we calculated age - adjusted sex- and ethnicity - specific rates for lea . proportional hazards regression ( cox ) models were then used to calculate adjusted hazard ratios ( hrs ) as an estimate of the relative risk of elevated triglycerides ( < 150 , 150199 , 200499 , and > 500 mg / dl ) associated with lea . after detecting no violations of the proportionality assumption \n , we specified a series of cox regression models , including a base demographic model ( age- , race- , and sex - adjusted plus an indicator for elevated triglycerides , ldl , and hdl ) and specified saturated models that added socioeconomic variables ( race , individual - level education , average census block level income , and proportion in working class occupations ) , health behaviors ( smoking status , alcohol intake , self - reported treatments for diabetes including diet and exercise , and frequency of self - monitoring of blood glucose ) , and clinical factors including type of diabetes , diabetes duration , type of diabetic medications , first - degree family history of diabetes , bmi ( underweight , normal , overweight , obese ) ( 18 ) , height quartiles ( 19,20 ) , hypertension ( self - reported and pharmacy records of antihypertensive medication dispensing ) , peripheral neuropathy ( self - report ) ( 17,21 ) , a1c ( < 7 , 78 , 810 , > 10 \n g / dl ) , ldl ( < 100 , 100129 , 130159 , > 160 mg / dl ) , hdl ( < 40 , 4059 , > 60 mg / dl ) , and use of statin or other lipid - lowering agents . \n we included patients with any amputation of the lower extremity . in two separate validations of amputation procedures ( a. karter , personal communication , n = 109 ; and j.v . \n selby and d. zhang , n = 209 ) , 99% of electronic hospital discharge records were confirmed by chart review . \n using direct standardization with the entire diabetes cohort as the population standard , we calculated age - adjusted sex- and ethnicity - specific rates for lea . proportional hazards regression ( cox ) models were then used to calculate adjusted hazard ratios ( hrs ) as an estimate of the relative risk of elevated triglycerides ( < 150 , 150199 , 200499 , and > 500 mg / dl ) associated with lea . after detecting no violations of the proportionality assumption , we specified a series of cox regression models , including a base demographic model ( age- , race- , and sex - adjusted plus an indicator for elevated triglycerides , ldl , and hdl ) and specified saturated models that added socioeconomic variables ( race , individual - level education , average census block level income , and proportion in working class occupations ) , health behaviors ( smoking status , alcohol intake , self - reported treatments for diabetes including diet and exercise , and frequency of self - monitoring of blood glucose ) , and clinical factors including type of diabetes , diabetes duration , type of diabetic medications , first - degree family history of diabetes , bmi ( underweight , normal , overweight , obese ) ( 18 ) , height quartiles ( 19,20 ) , hypertension ( self - reported and pharmacy records of antihypertensive medication dispensing ) , peripheral neuropathy ( self - report ) ( 17,21 ) , a1c ( < 7 , 78 , 810 , > 10 g / dl ) , ldl ( < 100 , 100129 , 130159 , > 160 mg / dl ) , hdl ( < 40 , 4059 , > 60 mg / dl ) , and use of statin or other lipid - lowering agents . \n using direct standardization with the entire diabetes cohort as the population standard , we calculated age - adjusted sex- and ethnicity - specific rates for lea . proportional hazards regression ( cox ) models were then used to calculate adjusted hazard ratios ( hrs ) as an estimate of the relative risk of elevated triglycerides ( < 150 , 150199 , 200499 , and > 500 mg / dl ) associated with lea . after detecting no violations of the proportionality assumption , we specified a series of cox regression models , including a base demographic model ( age- , race- , and sex - adjusted plus an indicator for elevated triglycerides , ldl , and hdl ) and specified saturated models that added socioeconomic variables ( race , individual - level education , average census block level income , and proportion in working class occupations ) , health behaviors ( smoking status , alcohol intake , self - reported treatments for diabetes including diet and exercise , and frequency of self - monitoring of blood glucose ) , and clinical factors including type of diabetes , diabetes duration , type of diabetic medications , first - degree family history of diabetes , bmi ( underweight , normal , overweight , obese ) ( 18 ) , height quartiles ( 19,20 ) , hypertension ( self - reported and pharmacy records of antihypertensive medication dispensing ) , peripheral neuropathy ( self - report ) ( 17,21 ) , a1c ( < 7 , 78 , 810 , > 10 g / dl ) , ldl ( < 100 , 100129 , 130159 , > 160 mg / dl ) , hdl ( < 40 , 4059 , > 60 mg / dl ) , and use of statin or other lipid - lowering agents . \n patients who sustained an lea were older ( 61 years [ sd 11.2 ] vs. 59 years [ 11.2 ] ) , had a longer duration of diabetes ( 14 years [ 9.7 ] vs. 9 years [ 9.5 ] ) , and had a higher hemoglobin a1c ( 9.05 g / dl [ 2.12 ] vs. 8.36 g / dl [ 1.94 ] ) compared with those who did not sustain an lea ( table 1 ) . \n the age- and sex - adjusted nontraumatic lea incidence rate ( 95% ci ) was 2.3 ( 1.53.1 ) per 1,000 person - years ( table 2 ) . \n the sex - specific , age - adjusted rates ( 95% ci ) were 1.4 ( 1.21.7 ) per 1,000 person - years for women and 3.2 ( 1.64.8 ) for men . \n the age- and sex - adjusted incidence rates ( 95% ci ) for white , black , hispanic , and asians were 2.7 ( 1.54.0 ) , 2.0 ( 1.62.5 ) , 1.4 ( 1.11.8 ) , and 0.9 ( 0.51.3 ) , respectively . \n baseline characteristics for 28,701 members with diabetes experiencing incident nontraumatic leas compared with those without incident lea oha , oral hypoglycemic agent . \n incidence rates per 1,000 person - years ( 95% cis ) for lea procedures crude hrs for triglyceride , ldl , and hdl levels revealed a significant , stepwise relationship with triglycerides : 150199 mg / dl , hr 1.10 ( 95% ci 0.921.32 ) ; 200499 mg / dl , 1.27 ( 1.101.47 ) ; and > 500 mg / dl , 1.65 ( 1.302.10 ) ( reference < 150 mg / dl ) . \n minimally adjusted cox proportional hazards models including triglyceride , ldl , and hdl levels continued to demonstrate a stepwise association between triglycerides and lea risk : 150199 mg / dl , hr 1.07 ( 95% ci 0.891.29 ) ; 200499 mg / dl , 1.20 ( 1.031.40 ) ; and > 500 mg / dl , 1.39 ( 1.031.88 ) ( reference < 150 mg / dl ) . \n ldl was again not significantly associated with amputation risk , whereas hdl showed a protective effect between 4059 mg / dl ( hr 0.74 [ 95% ci 0.640.87 ] ) but not at > 60 mg / dl ( 1.21 [ 0.921.60 ] ) ( reference hdl < 40 mg / dl ) . \n a further - adjusted cox proportional hazards model ( model 1 in table 3 ) including triglycerides , ldl , hdl , age , sex , and race also revealed a stepwise association of triglycerides and lea risk . \n cox proportional hazards models with hrs ( 95% cis ) for nontraumatic lea model 1 : triglycerides , ldl , hdl , age , sex , and race . \n model 2 : model 1 + education , income , whether lives in working class neighborhood , smoking , alcohol use , bmi , height , adherence to guidelines for self - monitoring of blood glucose , exercise , statin medication , fibrate / niacin medication , family history of diabetes , duration of diabetes , a1c , type of diabetes and therapy , history of hypertension , neuropathy , retinopathy , esrd , stroke , and heart attack . \n the stepwise association between triglycerides and lea persisted despite further adjustment for socioeconomic ( individual - level education , average census block level income , and proportion in working class occupations ) , health behavioral ( smoking , bmi , drinking , adherence to guidelines for self - monitoring of blood glucose , and exercise ) , and clinical variables ( statin medication , fibrates / niacin medication , family history of diabetes , height , duration of diabetes , a1c , type of diabetes and therapy , hypertension , neuropathy , retinopathy , stroke , heart attack , and end - stage renal disease [ esrd ] ) ( model 2 in table 3 ) . as expected , duration of diabetes , a1c , height , hypertension , neuropathy , retinopathy , esrd , stroke , and heart attack were also associated with amputation . \n interestingly , statin medication use and fibrates / niacin medication use did not have statistically significant hrs . \n ldl > 160 mg / dl and hdl > 60 mg / dl were the only levels of these tests associated with an increased risk of amputation ; it appeared to be a threshold effect for ldl , but there was no consistent or stepwise relationship for hdl . \n additionally , the rates of elevated triglycerides did differ substantially by race ( 21 , 40 , 46 , and 46% among african americans , asians , whites , and hispanics , respectively ; p < 0.001 ) . however , we failed to detect a significant interaction between triglyceride level and race ( p = 0.83 ) , suggesting that the relationship between triglycerides and amputation risk did not differ by race . \n furthermore , similar results were seen with triglyceride level and amputation risk using the entire diabetes cohort and utilizing a missing indicator for those who did not have triglyceride levels at baseline . \n we also found that , as expected , there was a significant , inverse correlation between triglyceride and hdl levels ( correlation = 0.24 , p < 0.0001 ) . \n however , this modest collinearity was not considered sufficient to distort our triglyceride effect estimates from the cox regression models . \n in this large , multiethnic cohort of diabetic patients , we found that elevated triglyceride levels are associated with lea even after adjusting for a host of potential confounders . \n the consistency of the relationship between triglycerides and lea across ethnic groups was further supportive . \n this is in contrast to low hdl , which was not associated with increased amputation risk . \n the threshold of ldl levels above 160 mg / dl was also associated with increased risk of amputation . \n dyslipidemia has been proposed as a potential risk factor in the development of diabetes complications such as retinopathy and neuropathy based on results utilizing the dcct / edic cohort and the eurodiab study ( 7,22 ) . \n our results suggest that high triglyceride levels , independent of the other major lipid components , may put patients at risk for one major diabetes complication lea . \n these results add to the finding in prior studies that elevated triglyceride levels may be a risk factor for complications of diabetes ( 5,7,8 ) , including lea ( 9,10 ) . \n however , the current study involved a larger population and found the association to be statistically significant even after adjusting the models for a multitude of variables that were not assessed in the prior studies . given the current state of the literature , the guidelines on triglyceride management do not advocate aggressive treatment . \n the national cholesterol education program recommends diet and exercise for patients with triglyceride levels between 150199 mg / dl , to consider treatment in high - risk patients with levels 200499 mg / dl , and to use pharmacologic treatment when levels are 500 mg / dl or greater to prevent pancreatitis , but not necessarily to prevent microvascular and macrovascular complications ( 23 ) . clearly , further studies are needed to ascertain the role of hypertriglyceridemia in these diabetic sequelae . \n our study gives further support to the notion that triglycerides may be one of the key modifiable risk factors in the development of amputations . \n if this association holds in clinical trials , then clinicians may have a target with the potential to improve important patient outcomes . \n one of the main limitations of this study is that a large proportion of our population did not have data on triglyceride , hdl , and ldl levels during the year prior to baseline ; at the time , these assessments were not done nearly as frequently or routinely as is common today . however , our sensitivity analysis using missing triglycerides as an indicator and evaluating the entire diabetes cohort suggests that missing data did not substantially bias our findings . \n also , observational cohort studies , particularly cross - sectional designs , can make erroneous assumptions between cause and effect when suggestive variables correlate . in our study , \n the longitudinal study design and exclusion of patients with prevalent amputations at baseline precludes time - ordering violations ( i.e. , lea preceding the triglyceride ascertainment ) . \n another limitation is that observational studies are vulnerable to residual confounding ; however , we were able to adjust for a wide array of confounders , which should greatly reduce this concern . \n the major strengths of this study are its longitudinal cohort design , validated and complete capture of lea events , and large sample size with rich array of clinical and behavioral data . \n additionally , our diabetes registry captures patients who are not treated with diabetes medications ( medical nutritional therapy ) through laboratory findings and outpatient diagnosis records , providing a more representative diabetic sample than pharmacy - based registries that only capture patients receiving prescriptions or studies from diabetes specialty clinics that typically include patients with more severe disease . in summary , \n elevated triglyceride level was associated with subsequent lea independently of the other lipid components and a wide range of potential confounders in this large , well - characterized diabetic cohort . though specific guidelines exist for cholesterol ( ldl and hdl levels ) management in this patient population , only vague guidelines exist for triglyceride management ( 23 ) . \n this observational study suggests that triglyceride levels are predictive of amputation risk in a stepwise fashion . despite standards of glycemic , blood pressure , and cholesterol control , \n patients continue to develop microvascular and macrovascular complications ( combination of neuropathy and macroangiopathy is thought to cause leas ) , and triglyceride control may be an important additional primary prevention effort . more research is necessary to define a causal role of triglyceride levels on amputation risk in diabetic patients . based on this current robust cohort study , such research should be a priority .", "role": "user" }, { "content": "objectiveto determine the association between triglyceride levels and lower - extremity amputation ( lea ) risk in a large diabetic cohort.research design and methodsthis is a 10-year survey follow - up study ( from 19952006 ) of 28,701 diabetic patients with a baseline triglyceride measure . \n all patients were fully insured members of the kaiser permanente medical care program and responded to a survey at baseline that included information on ethnicity , socioeconomic status , education , behavioral factors , and information required to determine type of diabetes . the relationship between triglycerides and time to incident nontraumatic lea , defined by primary hospitalization discharge or procedures , was evaluated using cox proportional hazards models.resultstriglyceride level was an independent , stepwise risk factor for nontraumatic leas within this large diabetic cohort : triglycerides 150199 mg / dl , hazard ratio ( hr ) 1.10 ( 95% ci 0.921.32 ) ; 200499 mg / dl , 1.27 ( 1.101.47 ) ; > 500 mg / dl , 1.65 ( 1.302.10 ) ( reference < 150 mg / dl).conclusionshypertriglyceridemia is a significant risk factor for lea in diabetic patients even after controlling for known socioeconomic , health behavioral , and clinical factors . \n this previously unrecognized clinical risk needs to be further investigated to determine if treatment of triglycerides can reduce amputation risk .", "role": "assistant" } ]