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[ "anxiety affects quality of life in those living with parkinson 's disease ( pd ) more so than overall cognitive status , motor deficits , apathy , and depression [ 13 ] .", "although anxiety and depression are often related and coexist in pd patients , recent research suggests that anxiety rather than depression is the most prominent and prevalent mood disorder in pd [ 5 , 6 ] . yet ,", "our current understanding of anxiety and its impact on cognition in pd , as well as its neural basis and best treatment practices , remains meager and lags far behind that of depression .", "overall , neuropsychiatric symptoms in pd have been shown to be negatively associated with cognitive performance .", "for example , higher depression scores have been correlated with lower scores on the mini - mental state exam ( mmse ) [ 8 , 9 ] as well as tests of memory and executive functions ( e.g. , attention ) [ 1014 ] .", "likewise , apathy and anhedonia in pd patients have been associated with executive dysfunction [ 10 , 1523 ] .", "however , few studies have specifically investigated the relationship between anxiety and cognition in pd .", "one study showed a strong negative relationship between anxiety ( both state and trait ) and overall cognitive performance ( measured by the total of the repeatable battery for the assessment of neuropsychological status index ) within a sample of 27 pd patients .", "furthermore , trait anxiety was negatively associated with each of the cognitive domains assessed by the rbans ( i.e. , immediate memory , visuospatial construction , language , attention , and delayed memory ) .", "two further studies have examined whether anxiety differentially affects cognition in patients with left - sided dominant pd ( lpd ) versus right - sided dominant pd ( rpd ) ; however , their findings were inconsistent .", "the first study found that working memory performance was worse in lpd patients with anxiety compared to rpd patients with anxiety , whereas the second study reported that , in lpd , apathy but not anxiety was associated with performance on nonverbally mediated executive functions and visuospatial tasks ( e.g. , tmt - b , wms - iii spatial span ) , while in rpd , anxiety but not apathy significantly correlated with performance on verbally mediated tasks ( e.g. , clock reading test and boston naming test ) .", "furthermore , anxiety was significantly correlated with neuropsychological measures of attention and executive and visuospatial functions . taken together ,", "it is evident that there are limited and inconsistent findings describing the relationship between anxiety and cognition in pd and more specifically how anxiety might influence particular domains of cognition such as attention and memory and executive functioning .", "it is also striking that , to date , no study has examined the influence of anxiety on cognition in pd by directly comparing groups of pd patients with and without anxiety while excluding depression .", "given that research on healthy young adults suggests that anxiety reduces processing capacity and impairs processing efficiency , especially in the central executive and attentional systems of working memory [ 26 , 27 ] , we hypothesized that pd patients with anxiety would show impairments in attentional set - shifting and working memory compared to pd patients without anxiety .", "furthermore , since previous work , albeit limited , has focused on the influence of symptom laterality on anxiety and cognition , we also explored this relationship .", "seventeen pd patients with anxiety and thirty - three pd patients without anxiety were included in this study ( see table 1 ) .", "the cross - sectional data from these participants was taken from a patient database that has been compiled over the past 8 years ( since 2008 ) at the parkinson 's disease research clinic at the brain and mind centre , university of sydney .", "inclusion criteria involved a diagnosis of idiopathic pd according to the united kingdom parkinson 's disease society brain bank criteria and were confirmed by a neurologist ( sjgl ) .", "patients also had to have an adequate proficiency in english and have completed a full neuropsychological assessment .", "ten patients in this study ( 5 pd with anxiety ; 5 pd without anxiety ) were taking psychotropic drugs ( i.e. , benzodiazepine or selective serotonin reuptake inhibitor ) .", "patients were also excluded if they had other neurological disorders , psychiatric disorders other than affective disorders ( such as anxiety ) , or if they reported a score greater than six on the depression subscale of the hospital anxiety and depression scale ( hads ) .", "thus , all participants who scored within a depressed ( hads - d > 6 ) range were excluded from this study , in attempt to examine a refined sample of pd patients with and without anxiety in order to determine the independent effect of anxiety on cognition .", "this research was approved by the human research ethics committee of the university of sydney , and written informed consent was obtained from all participants .", "self - reported hads was used to assess anxiety in pd and has been previously shown to be a useful measure of clinical anxiety in pd .", "a cut - off score of > 8 on the anxiety subscale of the hads ( hads - a ) was used to identify pd cases with anxiety ( pda+ ) , while a cut - off score of < 6 on the hads - a was used to identify pd cases without anxiety ( pda ) .", "this criterion was more stringent than usual ( > 7 cut - off score ) , in effort to create distinct patient groups .", "the neurological evaluation rated participants according to hoehn and yahr ( h&y ) stages and assessed their motor symptoms using part iii of the revised mds task force unified parkinson 's disease rating scale ( updrs ) . in a similar way", "this was determined by calculating a total left and right score from rigidity items 3035 , voluntary movement items 3643 , and tremor items 5057 from the mds - updrs part iii ( see table 1 ) .", "processing speed was assessed using the trail making test , part a ( tmt - a , z - score ) .", "attentional set - shifting was measured using the trail making test , part b ( tmt - b , z - score ) .", "working memory was assessed using the digit span forward and backward subtest of the wechsler memory scale - iii ( raw scores ) .", "language was assessed with semantic and phonemic verbal fluency via the controlled oral word associated test ( cowat animals and letters , z - score ) .", "the ability to retain learned verbal memory was assessed using the logical memory subtest from the wechsler memory scale - iii ( lm - i z - score , lm - ii z - score , % lm retention z - score ) . the mini - mental state examination ( mmse )", "demographic , clinical , and neuropsychological variables were compared between the two groups with the independent t - test or mann whitney u test , depending on whether the variable met parametric assumptions .", "chi - square tests were used to examine gender and symptom laterality differences between groups .", "all analyses employed an alpha level of p < 0.05 and were two - tailed .", "spearman correlations were performed separately in each group to examine associations between anxiety and/or depression ratings and cognitive functions .", "as expected , the pda+ group reported significant greater levels of anxiety on the hads - a ( u = 0 , p < 0.001 ) and higher total score on the hads ( u = 1 , p < 0.001 ) compared to the pda group ( table 1 ) .", "groups were matched in age ( t(48 ) = 1.31 , p = 0.20 ) , disease duration ( u = 259 , p = 0.66 ) , updrs - iii score ( u = 250.5 , p = 0.65 ) , h&y ( u = 245 , p = 0.43 ) , ledd ( u = 159.5 , p = 0.80 ) , and depression ( hads - d ) ( u = 190.5 , p = 0.06 ) .", "additionally , all groups were matched in the distribution of gender ( = 0.098 , p = 0.75 ) and side - affected ( = 0.765 , p = 0.38 ) .", "there were no group differences for tmt - a performance ( u = 256 , p = 0.62 ) ( table 2 ) ; however , the pda+ group had worse performance on the trail making test part b ( t(46 ) = 2.03 , p = 0.048 ) compared to the pda group ( figure 1 ) .", "the pda+ group also demonstrated significantly worse performance on the digit span forward subtest ( t(48 ) = 2.22 , p = 0.031 ) and backward subtest ( u = 190.5 , p = 0.016 ) compared to the pda group ( figures 2(a ) and 2(b ) ) .", "neither semantic verbal fluency ( t(47 ) = 0.70 , p = 0.49 ) nor phonemic verbal fluency ( t(47 ) = 0.39 , p = 0.70 ) differed between groups .", "logical memory i immediate recall test ( u = 176 , p = 0.059 ) showed a trend that the pda+ group had worse new verbal learning and immediate recall abilities than the pda group . however , logical memory ii test performance ( u = 219 , p = 0.204 ) and logical memory % retention ( u = 242.5 , p = 0.434 ) did not differ between groups .", "there were also no differences between groups in global cognition ( mmse ) ( u = 222.5 , p = 0.23 ) .", "participants were split into lpd and rpd , and then further group differences were examined between pda+ and pda. importantly , the groups remained matched in age , disease duration , updrs - iii , dde , h&y stage , and depression but remained significantly different on self - reported anxiety .", "lpda+ demonstrated worse performance on the digit span forward test ( t(19 ) = 2.29 , p = 0.033 ) compared to lpda , whereas rpda+ demonstrated worse performance on the digit span backward test ( u = 36.5 , p = 0.006 ) , lm - i immediate recall ( u = 37.5 , p = 0.008 ) , and lm - ii ( u = 45.0 , p = 0.021 ) but not lm % retention ( u = 75.5 , p = 0.39 ) compared to rpda.", "this study is the first to directly compare cognition between pd patients with and without anxiety .", "the findings confirmed our hypothesis that anxiety negatively influences attentional set - shifting and working memory in pd .", "more specifically , we found that pd patients with anxiety were more impaired on the trail making test part b which assessed attentional set - shifting , on both digit span tests which assessed working memory and attention , and to a lesser extent on the logical memory test which assessed memory and new verbal learning compared to pd patients without anxiety . taken together ,", "these findings suggest that anxiety in pd may reduce processing capacity and impair processing efficiency , especially in the central executive and attentional systems of working memory in a similar way as seen in young healthy adults [ 26 , 27 ] .", "although the neurobiology of anxiety in pd remains unknown , many researchers have postulated that anxiety disorders are related to neurochemical changes that occur during the early , premotor stages of pd - related degeneration [ 37 , 38 ] such as nigrostriatal dopamine depletion , as well as cell loss within serotonergic and noradrenergic brainstem nuclei ( i.e. , raphe nuclei and locus coeruleus , resp . , which provide massive inputs to corticolimbic regions ) . over time", ", chronic dysregulation of adrenocortical and catecholamine functions can lead to hippocampal damage as well as dysfunctional prefrontal neural circuitries [ 39 , 40 ] , which play a key role in memory and attention .", "recent functional neuroimaging work has suggested that enhanced hippocampal activation during executive functioning and working memory tasks may represent compensatory processes for impaired frontostriatal functions in pd patients compared to controls . therefore , chronic stress from anxiety ,", "for example , may disrupt compensatory processes in pd patients and explain the cognitive impairments specifically in working memory and attention seen in pd patients with anxiety .", "it has also been suggested that hyperactivation within the putamen may reflect a compensatory striatal mechanism to maintain normal working memory performance in pd patients ; however , losing this compensatory activation has been shown to contribute to poor working memory performance .", "anxiety in mild pd has been linked to reduced putamen dopamine uptake which becomes more extensive as the disease progresses .", "this further supports the notion that anxiety may disrupt compensatory striatal mechanisms as well , providing another possible explanation for the cognitive impairments observed in pd patients with anxiety in this study .", "noradrenergic and serotonergic systems should also be considered when trying to explain the mechanisms by which anxiety may influence cognition in pd . although these neurotransmitter systems are relatively understudied in pd cognition , treating the noradrenergic and serotonergic systems has shown beneficial effects on cognition in pd .", "selective serotonin reuptake inhibitor , citalopram , was shown to improve response inhibition deficits in pd , while noradrenaline reuptake blocker , atomoxetine , has been recently reported to have promising effects on cognition in pd [ 45 , 46 ] .", "overall , very few neuroimaging studies have been conducted in pd in order to understand the neural correlates of pd anxiety and its underlying neural pathology .", "future research should focus on relating anatomical changes and neurochemical changes to neural activation in order to gain a clearer understanding on how these pathologies affect anxiety in pd . to further understand how anxiety and cognitive dysfunction are related ,", "future research should focus on using advanced structural and function imaging techniques to explain both cognitive and neural breakdowns that are associated with anxiety in pd patients .", "research has indicated that those with amnestic mild cognitive impairment who have more neuropsychiatric symptoms have a greater risk of developing dementia compared to those with fewer neuropsychiatric symptoms .", "future studies should also examine whether treating neuropsychiatric symptoms might impact the progression of cognitive decline and improve cognitive impairments in pd patients .", "previous studies have used pd symptom laterality as a window to infer asymmetrical dysfunction of neural circuits .", "for example , lpd patients have greater inferred right hemisphere pathology , whereas rpd patients have greater inferred left hemisphere pathology .", "thus , cognitive domains predominantly subserved by the left hemisphere ( e.g. , verbally mediated tasks of executive function and verbal memory ) might be hypothesized to be more affected in rpd than lpd ; however , this remains controversial .", "it has also been suggested that since anxiety is a common feature of left hemisphere involvement [ 48 , 49 ] , cognitive domains subserved by the left hemisphere may also be more strongly related to anxiety .", "results from this study showed selective verbal memory deficits in rpd patients with anxiety compared to rpd without anxiety , whereas lpd patients with anxiety had greater attentional / working memory deficits compared to lpd without anxiety .", "although these results align with previous research , interpretations of these findings should be made with caution due to the small sample size in the lpd comparison specifically .", "recent work has suggested that the hads questionnaire may underestimate the burden of anxiety related symptomology and therefore be a less sensitive measure of anxiety in pd [ 30 , 50 ] . in addition , our small sample size also limited the statistical power for detecting significant findings .", "based on these limitations , our findings are likely conservative and underrepresent the true impact anxiety has on cognition in pd . additionally , the current study employed a very brief neuropsychological assessment including one or two tests for each cognitive domain .", "future studies are encouraged to collect a more complex and comprehensive battery from a larger sample of pd participants in order to better understand the role anxiety plays on cognition in pd .", "another limitation of this study was the absence of diagnostic interviews to characterize participants ' psychiatric symptoms and specify the type of anxiety disorders included in this study .", "future studies should perform diagnostic interviews with participants ( e.g. , using dsm - v criteria ) rather than relying on self - reported measures to group participants , in order to better understand whether the type of anxiety disorder ( e.g. , social anxiety , phobias , panic disorders , and generalized anxiety ) influences cognitive performance differently in pd .", "one advantage the hads questionnaire provided over other anxiety scales was that it assessed both anxiety and depression simultaneously and allowed us to control for coexisting depression .", "although there was a trend that the pda+ group self - reported higher levels of depression than the pda group , all participants included in the study scored < 6 on the depression subscale of the hads .", "controlling for depression while assessing anxiety has been identified as a key shortcoming in the majority of recent work .", "considering many previous studies have investigated the influence of depression on cognition in pd without accounting for the presence of anxiety and the inconsistent findings reported to date , we recommend that future research should try to disentangle the influence of anxiety versus depression on cognitive impairments in pd . considering the growing number of clinical trials for treating depression , there are few if any for the treatment of anxiety in pd .", "anxiety is a key contributor to decreased quality of life in pd and greatly requires better treatment options .", "moreover , anxiety has been suggested to play a key role in freezing of gait ( fog ) , which is also related to attentional set - shifting [ 52 , 53 ] .", "future research should examine the link between anxiety , set - shifting , and fog , in order to determine whether treating anxiety might be a potential therapy for improving fog ." ]

[ "<S> research on the implications of anxiety in parkinson 's disease ( pd ) has been neglected despite its prevalence in nearly 50% of patients and its negative impact on quality of life . </S>", "<S> previous reports have noted that neuropsychiatric symptoms impair cognitive performance in pd patients ; however , to date , no study has directly compared pd patients with and without anxiety to examine the impact of anxiety on cognitive impairments in pd . </S>", "<S> this study compared cognitive performance across 50 pd participants with and without anxiety ( 17 pda+ ; 33 pda ) , who underwent neurological and neuropsychological assessment . </S>", "<S> group performance was compared across the following cognitive domains : simple attention / visuomotor processing speed , executive function ( e.g. , set - shifting ) , working memory , language , and memory / new verbal learning . </S>", "<S> results showed that pda+ performed significantly worse on the digit span forward and backward test and part b of the trail making task ( tmt - b ) compared to the pda group . </S>", "<S> there were no group differences in verbal fluency , logical memory , or tmt - a performance . in conclusion , </S>", "<S> anxiety in pd has a measurable impact on working memory and attentional set - shifting . </S>" ]

[ "1. Introduction", "2. Methods", "3. Results", "4. Discussion" ]

[ [ "anxiety affects quality of life in those living with parkinson 's disease ( pd ) more so than overall cognitive status , motor deficits , apathy , and depression [ 13 ] .", "although anxiety and depression are often related and coexist in pd patients , recent research suggests that anxiety rather than depression is the most prominent and prevalent mood disorder in pd [ 5 , 6 ] . yet ,", "our current understanding of anxiety and its impact on cognition in pd , as well as its neural basis and best treatment practices , remains meager and lags far behind that of depression .", "overall , neuropsychiatric symptoms in pd have been shown to be negatively associated with cognitive performance .", "for example , higher depression scores have been correlated with lower scores on the mini - mental state exam ( mmse ) [ 8 , 9 ] as well as tests of memory and executive functions ( e.g. , attention ) [ 1014 ] .", "likewise , apathy and anhedonia in pd patients have been associated with executive dysfunction [ 10 , 1523 ] .", "however , few studies have specifically investigated the relationship between anxiety and cognition in pd .", "one study showed a strong negative relationship between anxiety ( both state and trait ) and overall cognitive performance ( measured by the total of the repeatable battery for the assessment of neuropsychological status index ) within a sample of 27 pd patients .", "furthermore , trait anxiety was negatively associated with each of the cognitive domains assessed by the rbans ( i.e. , immediate memory , visuospatial construction , language , attention , and delayed memory ) .", "two further studies have examined whether anxiety differentially affects cognition in patients with left - sided dominant pd ( lpd ) versus right - sided dominant pd ( rpd ) ; however , their findings were inconsistent .", "the first study found that working memory performance was worse in lpd patients with anxiety compared to rpd patients with anxiety , whereas the second study reported that , in lpd , apathy but not anxiety was associated with performance on nonverbally mediated executive functions and visuospatial tasks ( e.g. , tmt - b , wms - iii spatial span ) , while in rpd , anxiety but not apathy significantly correlated with performance on verbally mediated tasks ( e.g. , clock reading test and boston naming test ) .", "furthermore , anxiety was significantly correlated with neuropsychological measures of attention and executive and visuospatial functions . taken together ,", "it is evident that there are limited and inconsistent findings describing the relationship between anxiety and cognition in pd and more specifically how anxiety might influence particular domains of cognition such as attention and memory and executive functioning .", "it is also striking that , to date , no study has examined the influence of anxiety on cognition in pd by directly comparing groups of pd patients with and without anxiety while excluding depression .", "given that research on healthy young adults suggests that anxiety reduces processing capacity and impairs processing efficiency , especially in the central executive and attentional systems of working memory [ 26 , 27 ] , we hypothesized that pd patients with anxiety would show impairments in attentional set - shifting and working memory compared to pd patients without anxiety .", "furthermore , since previous work , albeit limited , has focused on the influence of symptom laterality on anxiety and cognition , we also explored this relationship ." ], [ "seventeen pd patients with anxiety and thirty - three pd patients without anxiety were included in this study ( see table 1 ) .", "the cross - sectional data from these participants was taken from a patient database that has been compiled over the past 8 years ( since 2008 ) at the parkinson 's disease research clinic at the brain and mind centre , university of sydney .", "inclusion criteria involved a diagnosis of idiopathic pd according to the united kingdom parkinson 's disease society brain bank criteria and were confirmed by a neurologist ( sjgl ) .", "patients also had to have an adequate proficiency in english and have completed a full neuropsychological assessment .", "ten patients in this study ( 5 pd with anxiety ; 5 pd without anxiety ) were taking psychotropic drugs ( i.e. , benzodiazepine or selective serotonin reuptake inhibitor ) .", "patients were also excluded if they had other neurological disorders , psychiatric disorders other than affective disorders ( such as anxiety ) , or if they reported a score greater than six on the depression subscale of the hospital anxiety and depression scale ( hads ) .", "thus , all participants who scored within a depressed ( hads - d > 6 ) range were excluded from this study , in attempt to examine a refined sample of pd patients with and without anxiety in order to determine the independent effect of anxiety on cognition .", "this research was approved by the human research ethics committee of the university of sydney , and written informed consent was obtained from all participants .", "self - reported hads was used to assess anxiety in pd and has been previously shown to be a useful measure of clinical anxiety in pd .", "a cut - off score of > 8 on the anxiety subscale of the hads ( hads - a ) was used to identify pd cases with anxiety ( pda+ ) , while a cut - off score of < 6 on the hads - a was used to identify pd cases without anxiety ( pda ) .", "this criterion was more stringent than usual ( > 7 cut - off score ) , in effort to create distinct patient groups .", "the neurological evaluation rated participants according to hoehn and yahr ( h&y ) stages and assessed their motor symptoms using part iii of the revised mds task force unified parkinson 's disease rating scale ( updrs ) . in a similar way", "this was determined by calculating a total left and right score from rigidity items 3035 , voluntary movement items 3643 , and tremor items 5057 from the mds - updrs part iii ( see table 1 ) .", "processing speed was assessed using the trail making test , part a ( tmt - a , z - score ) .", "attentional set - shifting was measured using the trail making test , part b ( tmt - b , z - score ) .", "working memory was assessed using the digit span forward and backward subtest of the wechsler memory scale - iii ( raw scores ) .", "language was assessed with semantic and phonemic verbal fluency via the controlled oral word associated test ( cowat animals and letters , z - score ) .", "the ability to retain learned verbal memory was assessed using the logical memory subtest from the wechsler memory scale - iii ( lm - i z - score , lm - ii z - score , % lm retention z - score ) . the mini - mental state examination ( mmse )", "demographic , clinical , and neuropsychological variables were compared between the two groups with the independent t - test or mann whitney u test , depending on whether the variable met parametric assumptions .", "chi - square tests were used to examine gender and symptom laterality differences between groups .", "all analyses employed an alpha level of p < 0.05 and were two - tailed .", "spearman correlations were performed separately in each group to examine associations between anxiety and/or depression ratings and cognitive functions ." ], [ "as expected , the pda+ group reported significant greater levels of anxiety on the hads - a ( u = 0 , p < 0.001 ) and higher total score on the hads ( u = 1 , p < 0.001 ) compared to the pda group ( table 1 ) .", "groups were matched in age ( t(48 ) = 1.31 , p = 0.20 ) , disease duration ( u = 259 , p = 0.66 ) , updrs - iii score ( u = 250.5 , p = 0.65 ) , h&y ( u = 245 , p = 0.43 ) , ledd ( u = 159.5 , p = 0.80 ) , and depression ( hads - d ) ( u = 190.5 , p = 0.06 ) .", "additionally , all groups were matched in the distribution of gender ( = 0.098 , p = 0.75 ) and side - affected ( = 0.765 , p = 0.38 ) .", "there were no group differences for tmt - a performance ( u = 256 , p = 0.62 ) ( table 2 ) ; however , the pda+ group had worse performance on the trail making test part b ( t(46 ) = 2.03 , p = 0.048 ) compared to the pda group ( figure 1 ) .", "the pda+ group also demonstrated significantly worse performance on the digit span forward subtest ( t(48 ) = 2.22 , p = 0.031 ) and backward subtest ( u = 190.5 , p = 0.016 ) compared to the pda group ( figures 2(a ) and 2(b ) ) .", "neither semantic verbal fluency ( t(47 ) = 0.70 , p = 0.49 ) nor phonemic verbal fluency ( t(47 ) = 0.39 , p = 0.70 ) differed between groups .", "logical memory i immediate recall test ( u = 176 , p = 0.059 ) showed a trend that the pda+ group had worse new verbal learning and immediate recall abilities than the pda group . however , logical memory ii test performance ( u = 219 , p = 0.204 ) and logical memory % retention ( u = 242.5 , p = 0.434 ) did not differ between groups .", "there were also no differences between groups in global cognition ( mmse ) ( u = 222.5 , p = 0.23 ) .", "participants were split into lpd and rpd , and then further group differences were examined between pda+ and pda. importantly , the groups remained matched in age , disease duration , updrs - iii , dde , h&y stage , and depression but remained significantly different on self - reported anxiety .", "lpda+ demonstrated worse performance on the digit span forward test ( t(19 ) = 2.29 , p = 0.033 ) compared to lpda , whereas rpda+ demonstrated worse performance on the digit span backward test ( u = 36.5 , p = 0.006 ) , lm - i immediate recall ( u = 37.5 , p = 0.008 ) , and lm - ii ( u = 45.0 , p = 0.021 ) but not lm % retention ( u = 75.5 , p = 0.39 ) compared to rpda." ], [ "this study is the first to directly compare cognition between pd patients with and without anxiety .", "the findings confirmed our hypothesis that anxiety negatively influences attentional set - shifting and working memory in pd .", "more specifically , we found that pd patients with anxiety were more impaired on the trail making test part b which assessed attentional set - shifting , on both digit span tests which assessed working memory and attention , and to a lesser extent on the logical memory test which assessed memory and new verbal learning compared to pd patients without anxiety . taken together ,", "these findings suggest that anxiety in pd may reduce processing capacity and impair processing efficiency , especially in the central executive and attentional systems of working memory in a similar way as seen in young healthy adults [ 26 , 27 ] .", "although the neurobiology of anxiety in pd remains unknown , many researchers have postulated that anxiety disorders are related to neurochemical changes that occur during the early , premotor stages of pd - related degeneration [ 37 , 38 ] such as nigrostriatal dopamine depletion , as well as cell loss within serotonergic and noradrenergic brainstem nuclei ( i.e. , raphe nuclei and locus coeruleus , resp . , which provide massive inputs to corticolimbic regions ) . over time", ", chronic dysregulation of adrenocortical and catecholamine functions can lead to hippocampal damage as well as dysfunctional prefrontal neural circuitries [ 39 , 40 ] , which play a key role in memory and attention .", "recent functional neuroimaging work has suggested that enhanced hippocampal activation during executive functioning and working memory tasks may represent compensatory processes for impaired frontostriatal functions in pd patients compared to controls . therefore , chronic stress from anxiety ,", "for example , may disrupt compensatory processes in pd patients and explain the cognitive impairments specifically in working memory and attention seen in pd patients with anxiety .", "it has also been suggested that hyperactivation within the putamen may reflect a compensatory striatal mechanism to maintain normal working memory performance in pd patients ; however , losing this compensatory activation has been shown to contribute to poor working memory performance .", "anxiety in mild pd has been linked to reduced putamen dopamine uptake which becomes more extensive as the disease progresses .", "this further supports the notion that anxiety may disrupt compensatory striatal mechanisms as well , providing another possible explanation for the cognitive impairments observed in pd patients with anxiety in this study .", "noradrenergic and serotonergic systems should also be considered when trying to explain the mechanisms by which anxiety may influence cognition in pd . although these neurotransmitter systems are relatively understudied in pd cognition , treating the noradrenergic and serotonergic systems has shown beneficial effects on cognition in pd .", "selective serotonin reuptake inhibitor , citalopram , was shown to improve response inhibition deficits in pd , while noradrenaline reuptake blocker , atomoxetine , has been recently reported to have promising effects on cognition in pd [ 45 , 46 ] .", "overall , very few neuroimaging studies have been conducted in pd in order to understand the neural correlates of pd anxiety and its underlying neural pathology .", "future research should focus on relating anatomical changes and neurochemical changes to neural activation in order to gain a clearer understanding on how these pathologies affect anxiety in pd . to further understand how anxiety and cognitive dysfunction are related ,", "future research should focus on using advanced structural and function imaging techniques to explain both cognitive and neural breakdowns that are associated with anxiety in pd patients .", "research has indicated that those with amnestic mild cognitive impairment who have more neuropsychiatric symptoms have a greater risk of developing dementia compared to those with fewer neuropsychiatric symptoms .", "future studies should also examine whether treating neuropsychiatric symptoms might impact the progression of cognitive decline and improve cognitive impairments in pd patients .", "previous studies have used pd symptom laterality as a window to infer asymmetrical dysfunction of neural circuits .", "for example , lpd patients have greater inferred right hemisphere pathology , whereas rpd patients have greater inferred left hemisphere pathology .", "thus , cognitive domains predominantly subserved by the left hemisphere ( e.g. , verbally mediated tasks of executive function and verbal memory ) might be hypothesized to be more affected in rpd than lpd ; however , this remains controversial .", "it has also been suggested that since anxiety is a common feature of left hemisphere involvement [ 48 , 49 ] , cognitive domains subserved by the left hemisphere may also be more strongly related to anxiety .", "results from this study showed selective verbal memory deficits in rpd patients with anxiety compared to rpd without anxiety , whereas lpd patients with anxiety had greater attentional / working memory deficits compared to lpd without anxiety .", "although these results align with previous research , interpretations of these findings should be made with caution due to the small sample size in the lpd comparison specifically .", "recent work has suggested that the hads questionnaire may underestimate the burden of anxiety related symptomology and therefore be a less sensitive measure of anxiety in pd [ 30 , 50 ] . in addition , our small sample size also limited the statistical power for detecting significant findings .", "based on these limitations , our findings are likely conservative and underrepresent the true impact anxiety has on cognition in pd . additionally , the current study employed a very brief neuropsychological assessment including one or two tests for each cognitive domain .", "future studies are encouraged to collect a more complex and comprehensive battery from a larger sample of pd participants in order to better understand the role anxiety plays on cognition in pd .", "another limitation of this study was the absence of diagnostic interviews to characterize participants ' psychiatric symptoms and specify the type of anxiety disorders included in this study .", "future studies should perform diagnostic interviews with participants ( e.g. , using dsm - v criteria ) rather than relying on self - reported measures to group participants , in order to better understand whether the type of anxiety disorder ( e.g. , social anxiety , phobias , panic disorders , and generalized anxiety ) influences cognitive performance differently in pd .", "one advantage the hads questionnaire provided over other anxiety scales was that it assessed both anxiety and depression simultaneously and allowed us to control for coexisting depression .", "although there was a trend that the pda+ group self - reported higher levels of depression than the pda group , all participants included in the study scored < 6 on the depression subscale of the hads .", "controlling for depression while assessing anxiety has been identified as a key shortcoming in the majority of recent work .", "considering many previous studies have investigated the influence of depression on cognition in pd without accounting for the presence of anxiety and the inconsistent findings reported to date , we recommend that future research should try to disentangle the influence of anxiety versus depression on cognitive impairments in pd . considering the growing number of clinical trials for treating depression , there are few if any for the treatment of anxiety in pd .", "anxiety is a key contributor to decreased quality of life in pd and greatly requires better treatment options .", "moreover , anxiety has been suggested to play a key role in freezing of gait ( fog ) , which is also related to attentional set - shifting [ 52 , 53 ] .", "future research should examine the link between anxiety , set - shifting , and fog , in order to determine whether treating anxiety might be a potential therapy for improving fog ." ] ]

[ "small non - coding rnas are transcribed into mrna but remain untranslated in eukaryotic cells .", "they include sirna ( small interfering rna ) , mirna ( microrna ) , pirna ( piwi - interacting rna ) and snorna ( small nucleolar rna ) .", "mirnas are a class of multifunctional singled - stranded small rna which are ~20 nt in length and regulate the stability or translational efficiency of targeted messenger rna depending on the base - pairing complementarity between the mirna and its target mrna [ 1 , 2 ] . although over 1,000 mirna sequences have been identified from the tissues or cells of human origin and other species , as many as 1,000 to 10,000 mirnas per genome have been predicted [ 3 , 4 ] .", "mirnas regulate a broad range of biological processes including timing of development , cell cycle progression , stem cell self - renewal , differentiation , cancer initiation , cancer cell proliferation , metastasis and apoptosis [ 511 ] .", "cancer is caused by multiple processes including uncontrolled cellular proliferation and inappropriate survival of apoptotic cells .", "many regulatory factors switch on or off genes that govern cell division and direct cellular proliferation .", "mirnas regulate gene expression and play important roles in the onset and progression of tumorigenesis .", "emerging evidence demonstrates the involvement of mirna in mammary gland tumorigenesis , functioning either as tumor suppressors or oncogenes .", "although the current treatment of radiation therapy , chemotherapy and hormone therapy slow mammary gland tumor growth , prolong survival and improve the quality of patients life , metastatic breast cancer still remains incurable due to our limited understanding of the molecular mechanisms through which tumorigenesis and metastasis occur .", "as small non - coding rnas regulate gene expression and tumorigenesis , they may represent a novel cancer therapy .", "unlike mrna , mirnas are transcribed but never translated . some mirnas are transcribed from non - coding regions between genes , deriving from independent transcription unit .", "other mirnas are transcribed together with coding mrnas from the coding region of the genome , deriving from the introns of gene transcripts [ 13 , 14 ] .", "mirna gene copy number gain / loss and mirna gene mutation have been observed in breast cancer resulting in the aberrant expression of mirna .", "the first study about the altered expression of mirnas in human breast cancer patients and human breast cancer cell lines was reported in 2005 by lorio et al . ,", "in which 29 mirnas were identified with aberrant expression based on microarray and northern blot analysis of 76 breast tumor samples and 14 human breast cell lines .", "zhang and colleagues analyzed 283 human mirna genes on 55 human breast primary tumors and 18 human breast cancer cell lines using array - based comparative genomic hybridization .", "the results demonstrated a high frequency ( ~72.8% ) of gene copy number abnormality in mirna - containing regions in human breast cancer .", "wang et al . collected 68 patients with newly diagnosed breast cancer and examined the expression of selected mirnas in tumor and adjacent non - tumor tissues .", "mir-21 , mir-106a and mir-155 were significantly over - expressed in the tumor specimens compared with normal controls , whereas mir-126 , mir-199a and mir-335 were significantly decreased in expression in the tumor samples .", "our studies of the mir-17 - 92 cluster demonstrated decreased expression of mir-17/20 in human breast cancer specimens compared with matching normal breast tissue from the same patient .", "subsequent analysis identified reduced mir-17/20 expression in node - positive compared with node - negative breast cancers and demonstrated that mir-17/20 inhibited breast cancer cell migration and invasion via a heterotypic signaling .", "although the tendency for a global decrease of mirna expression in human cancers originally suggested a general tumor suppressor function of mirnas , subsequent studies showing the aberrant expression of specific mirnas in breast cancer suggest mirna - specific roles in breast cancer onset and progression .", "many distinct mirnas have been shown to regulate breast cancer cell proliferation , apoptosis , cancer stem cell expansion , and tumorigenesis .", "mirna may function as either tumor suppressors or oncogenes depending on the cell type , culture conditions , target genes and pathway .", "the involvement of mirna in mammary gland tumorigenesis has been reviewed recently [ 21 , 22 ] .", "le et al . described the expression pattern and regulatory network of key mirnas in breast cancer , including let-7 , mir-34 , mir-125 , mir-200 family , mir-205 , mir-21 , mir-10 and the mir-17 - 92 cluster .", "adams et al . reviewed the mirna regulation of estrogen signaling pathway and erbb2/her signaling pathway in breast cancer .", "the understanding of how mirnas are involved in breast cancer through regulating the cell cycle remains rudimentary .", "herein we summarize the recent literature and research progress on the mechanism by which mirnas regulate the breast cancer cell cycle and cellular proliferation ( fig . ", "1mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint cyclin d1 is either overexpressed or amplified in ~50% of breast cancer .", "the abundance of cyclin d1 is rate - limiting in breast cancer cellular proliferation and g1-s phase transition [ 23 , 24 ] .", "in addition , cyclin d1 is a critical downstream target of erbb2- , ras- and -catenin- induced breast cancers , and is sufficient for the induction of mammary tumors when targeted to the mammary gland of mice .", "antisense inhibition of cyclin d1 expression in vivo suppressed the growth of neut - transformed mammary adenocarcinoma cells in nude mice .", "conserved sequences of the cyclin d1 3utr contain potential binding sites for multiple mirnas including mir-17/20/106 , mir-15/16 , mir-23 and let-7 .", "mir-17/20 binds the cyclin d1 3utr , inhibiting the expression of cyclin d1 , resulting in cell cycle arrest at the g1 phase and suppression of mcf-7 cell proliferation [ 18 , 26 ] .", "the regulation of cyclin d1 expression by mir-17 - 92 , as well as mir-15/16 , was confirmed by deshpande et al . .", "the let-7 family functions as a tumor suppressor in a variety of cancers including lung , colon , ovarian and breast cancer .", "schultz et al . demonstrated the downregulation of cyclin d1 by mirna let-7 in control of cancer cell growth .", "the regulation of cyclin d1 by mirna is likely of broad importance as cyclin d1 encodes the regulatory subunit of a kinase that phosphorylates and inactivates the prb family proteins to inhibit dna synthesis , and phosphorylates nuclear respiratory factor 1 ( nrf-1 ) to inhibit mitochondria biogenesis [ 32 , 33 ] .", "furthermore , cyclin d1 promotes breast epithelial cell angiogenesis and migration , and promotes chromosomal instability which in turn contributes to tumorigenesis .", "the mir-221/222 cluster regulates the cell cycle , cell growth and epithelial - to - mesenchymal transition ( emt ) in breast cancer .", "mir-221/222 inhibited p27 and p57 abundance , facilitating g1-s phase transition , thereby promoting cancer cell proliferation [ 36 , 37 ] .", "moreover , mir-221/222 may contribute to the aggressive clinical behavior of basal - like breast cancers .", "the breast cancer basal - like subtype - specific mirnas , mir-221 and mir-222 , promote emt in breast cancer by targeting trps1 ( trichorhinophalangeal syndrome type 1 ) which inhibits emt by repressing zeb2 expression .", "mir-221 and/or mir-222 expression in mcf-7 and t47d breast cancer cells decreased er expression associated with tamoxifen resistance .", "the onco - mirna mir-21 is overexpressed in a wide variety of cancers including breast cancer [ 40 , 41 ] .", "mir-21 induced cellular proliferation , migration , invasion , emt , cancer stem cell characteristics and chemotherapy resistance in human breast cancer [ 42 , 43 ] .", "high mir-21 level is associated with poor prognosis , advanced stage , positive lymph node status and reduced survival time in breast cancer .", "mir-21 promotes mcf-7 cellular proliferation in part through inhibiting the expression of a tumor suppressor gene programmed cell death 4 ( pdcd4 ) . in colon cancer ,", "mir-21 participates in a dna damage - induced g2-m checkpoint through suppressing the cell cycle regulator cdc25a .", "a recent report demonstrated the mir-21 regulates the cell cycle through targeting cdc25a in mcf-7 breast cancer cells . with a potential anti - cancer chemical 3,3-diindolylmethane treatment ,", "mir-27a expression is upregulated in human breast cancer cell lines . in mda - mb-231 cells ,", "mir-27a negatively regulated the zinc finger zbtb10 gene and myt-1 , thereby promoting breast cancer cell proliferation .", "mir-27a suppressed myt-1 , increased cdc2/cyclin b activity and promoted the g2-m checkpoint in mda - mb-231 cells . thus , distinct mirnas affect key genetic targets that govern distinct cell - cycle checkpoints including cyclins , cdks , cdk inhibitors and the g2-m regulation apparatus .", "in addition to cell - cycle control , breast tumor onset and progression and breast tumor stem cells are also regulated by distinct mirnas .", "cancer stem cells ( cscs ) are characterized by their self - renewal capacity , an ability to differentiate into non - tumorigenic cell progeny , and their ability to seed tumors when transplanted into animal hosts .", "cell surface markers such as cd44 , cd24 , cd133 , epithelial - specific antigen and aldehyde dehydrogenase-1 are frequently used to isolate and enrich cscs .", "the involvement of mirnas in regulating tumor formation by cscs or tumor - initiating cells ( t - ic ) has been widely investigated .", "let-7 expression is very low to undetectable level in embryonic stem cells ( es cells ) and increases with differentiation .", "a comparison of mirna expression between breast t - ic and non - t - ic demonstrated reduced let-7 expression in t - ic and increased abundance with differentiation .", "transduction of breast cscs with let-7 reduced the proportion of undifferentiated cells , inhibited cell proliferation , mammosphere formation , and tumor formation in vivo .", "clarke and colleagues identified 37 mirnas which were differentially expressed between human breast cscs ( cd44cd24lineage ) and lineage nontumorigenic breast cancer cells .", "the mir-200 family members were downregulated in human breast cscs and normal mammary stem / progenitor cells .", "expression of mir-200 inhibited breast cancer stem cell expansion in vitro , and suppressed the tumor formation ability of human breast cancer stem cell in vivo .", "ectopic mir-34c expression reduced breast t - ics self - renewal , inhibited emt and suppressed tumor cell invasiveness via silencing notch4 .", "zhu et al . found the reduced mir-128 expression in human breast t - ic was accompanied by bmi-1 and abcc5 overexpression , and associated with chemotherapeutic resistance and poor survival .", "enforced mir-128 expression increased the sensitivity of breast cancer cells to doxorubicin - induced apoptosis and dna damage .", "emerging evidence has demonstrated the importance of cscs in cancer initiation , cancer metastasis and drug resistance .", "cscs are believed to be one of the most promising targets for cure of cancer .", "the discovery that non - coding rnas regulate cscs widens our understanding of cscs , and may provide potential novel strategies for breast cancer therapy .", "deletion of chromosome 6q , including region 6q14-q16 , is frequently observed in breast cancer .", "the small non - coding snorna u50 is a candidate tumor suppressor gene in the 6q14 - 16 region , playing a role in the development and/or progression of breast cancer .", "genomic deletion and transcriptional downregulation of snorna u50 was detected in breast cancer cell lines .", "re - expression of snorna u50 inhibited colony formation of the human breast cancer cells hs578 t and mda - mb-231 .", "pirnas are small non - coding rna that form rna - protein complexes through interactions with piwi proteins .", "pirna was initially discovered in germ line cells , and considered as germ line - specific small rnas .", "emerging evidence indicates that pirna expression occurs in somatic cells [ 57 , 58 ] and piwil2 expression has been identified in human breast cancer cells .", "high - throughput deep sequencing identified a group of small rnas matching pirna sequences in human breast cancer tissues and breast cancer cell lines .", "the study of these non - coding small rnas in human cancer is just starting .", "the identification of the expression signature of these non - coding small rnas in breast cancer subtypes , and an understanding of their functional significance to oncogene expression , tumor initiation and tumor cell metastasis may shed important new perspectives on the role of these non - coding small rnas in breast cancer .", "small non - coding rna - based diagnostic and therapeutic applications for human cancer are expected in the near future . although tumor - targeted delivery and local administration are still major challenges to the practical application of gene therapy for cancer , mirna - based cancer therapeutic approaches are being established and tested in animal models .", "synthetic mirna mimics or mirna expression vectors have been successfully applied to restore or overexpress mirna in vitro . chemically modified lna anti - sense mirna inhibitor and other approaches have been used to block mirna function in cells .", "kim et al . recently reported significant anti - tumor effect of virus - mediated delivery of mir-145 combined with 5-fu to treat breast cancer .", "intranasal delivery of let-7 and intravenous delivery of mir-34a mimics for non - small - cell lung cancer treatment and a virus - mediated delivery of mir-26a for liver cancer treatment in mouse model demonstrate the promise of mirna for treatment of cancer .", "dysregulated expression of mirnas has implicated components of the non - coding genome as either oncogenes or tumor suppressors of breast cancer .", "experimental evidence has shown specific mirnas regulating the initiation , progression , metastasis and drug resistance of breast cancer via control of the cell cycle , altering cellular proliferation , altering cellular apoptosis and/or controlling the population of tumor stem cells . dysregulated", "mirna expression has also been observed in cancer associated fibroblasts ( caf ) and in the systemic circulation [ 65 , 66 ] .", "the circulating mirnas have the potential to serve as novel diagnostic and prognostic biomarkers for breast cancer .", "a specific subset of dysregulated mirnas in breast cancer cells may serve as targets for gene therapy either alone or as an adjuvant treatment to current clinical protocols for breast cancer patients ." ]

[ "<S> small non - coding rnas include sirna , mirna , pirna and snorna . </S>", "<S> the involvement of mirnas in the regulation of mammary gland tumorigenesis has been widely studied while the role for other small non - coding rnas remains unclear . here </S>", "<S> we summarize the involvement of mirna in breast cancer onset and progression through regulating the cell cycle and cellular proliferation . </S>", "<S> the regulation of breast cancer stem cells and tumor regeneration by mirna is reviewed . </S>", "<S> in addition , the emerging evidence demonstrating the involvement of pirna and snorna in breast cancer is briefly described . </S>" ]

[ "Introduction", "Aberrant Expression of miRNA in Breast Cancer", "miRNA Regulation of Cell Cycle and Mammary Gland Tumorigenesis", "miRNA Regulation of Breast Cancer Stem Cells", "Other Non-coding Small RNAs in Breast Cancer", "Therapeutic Application of miRNA", "Concluding Remarks" ]

[ [ "small non - coding rnas are transcribed into mrna but remain untranslated in eukaryotic cells .", "they include sirna ( small interfering rna ) , mirna ( microrna ) , pirna ( piwi - interacting rna ) and snorna ( small nucleolar rna ) .", "mirnas are a class of multifunctional singled - stranded small rna which are ~20 nt in length and regulate the stability or translational efficiency of targeted messenger rna depending on the base - pairing complementarity between the mirna and its target mrna [ 1 , 2 ] . although over 1,000 mirna sequences have been identified from the tissues or cells of human origin and other species , as many as 1,000 to 10,000 mirnas per genome have been predicted [ 3 , 4 ] .", "mirnas regulate a broad range of biological processes including timing of development , cell cycle progression , stem cell self - renewal , differentiation , cancer initiation , cancer cell proliferation , metastasis and apoptosis [ 511 ] .", "cancer is caused by multiple processes including uncontrolled cellular proliferation and inappropriate survival of apoptotic cells .", "many regulatory factors switch on or off genes that govern cell division and direct cellular proliferation .", "mirnas regulate gene expression and play important roles in the onset and progression of tumorigenesis .", "emerging evidence demonstrates the involvement of mirna in mammary gland tumorigenesis , functioning either as tumor suppressors or oncogenes .", "although the current treatment of radiation therapy , chemotherapy and hormone therapy slow mammary gland tumor growth , prolong survival and improve the quality of patients life , metastatic breast cancer still remains incurable due to our limited understanding of the molecular mechanisms through which tumorigenesis and metastasis occur .", "as small non - coding rnas regulate gene expression and tumorigenesis , they may represent a novel cancer therapy ." ], [ "unlike mrna , mirnas are transcribed but never translated . some mirnas are transcribed from non - coding regions between genes , deriving from independent transcription unit .", "other mirnas are transcribed together with coding mrnas from the coding region of the genome , deriving from the introns of gene transcripts [ 13 , 14 ] .", "mirna gene copy number gain / loss and mirna gene mutation have been observed in breast cancer resulting in the aberrant expression of mirna .", "the first study about the altered expression of mirnas in human breast cancer patients and human breast cancer cell lines was reported in 2005 by lorio et al . ,", "in which 29 mirnas were identified with aberrant expression based on microarray and northern blot analysis of 76 breast tumor samples and 14 human breast cell lines .", "zhang and colleagues analyzed 283 human mirna genes on 55 human breast primary tumors and 18 human breast cancer cell lines using array - based comparative genomic hybridization .", "the results demonstrated a high frequency ( ~72.8% ) of gene copy number abnormality in mirna - containing regions in human breast cancer .", "wang et al . collected 68 patients with newly diagnosed breast cancer and examined the expression of selected mirnas in tumor and adjacent non - tumor tissues .", "mir-21 , mir-106a and mir-155 were significantly over - expressed in the tumor specimens compared with normal controls , whereas mir-126 , mir-199a and mir-335 were significantly decreased in expression in the tumor samples .", "our studies of the mir-17 - 92 cluster demonstrated decreased expression of mir-17/20 in human breast cancer specimens compared with matching normal breast tissue from the same patient .", "subsequent analysis identified reduced mir-17/20 expression in node - positive compared with node - negative breast cancers and demonstrated that mir-17/20 inhibited breast cancer cell migration and invasion via a heterotypic signaling .", "although the tendency for a global decrease of mirna expression in human cancers originally suggested a general tumor suppressor function of mirnas , subsequent studies showing the aberrant expression of specific mirnas in breast cancer suggest mirna - specific roles in breast cancer onset and progression ." ], [ "many distinct mirnas have been shown to regulate breast cancer cell proliferation , apoptosis , cancer stem cell expansion , and tumorigenesis .", "mirna may function as either tumor suppressors or oncogenes depending on the cell type , culture conditions , target genes and pathway .", "the involvement of mirna in mammary gland tumorigenesis has been reviewed recently [ 21 , 22 ] .", "le et al . described the expression pattern and regulatory network of key mirnas in breast cancer , including let-7 , mir-34 , mir-125 , mir-200 family , mir-205 , mir-21 , mir-10 and the mir-17 - 92 cluster .", "adams et al . reviewed the mirna regulation of estrogen signaling pathway and erbb2/her signaling pathway in breast cancer .", "the understanding of how mirnas are involved in breast cancer through regulating the cell cycle remains rudimentary .", "herein we summarize the recent literature and research progress on the mechanism by which mirnas regulate the breast cancer cell cycle and cellular proliferation ( fig . ", "1mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint mirna regulation of mammary gland tumorigenesis in control of the cell cycle . through targeting different genes and different cyclin / cdk complexes , mir-17/20 and", "let-7 regulate the g1-s transition ; mir-21 and mir-27a regulate the g2-m checkpoint cyclin d1 is either overexpressed or amplified in ~50% of breast cancer .", "the abundance of cyclin d1 is rate - limiting in breast cancer cellular proliferation and g1-s phase transition [ 23 , 24 ] .", "in addition , cyclin d1 is a critical downstream target of erbb2- , ras- and -catenin- induced breast cancers , and is sufficient for the induction of mammary tumors when targeted to the mammary gland of mice .", "antisense inhibition of cyclin d1 expression in vivo suppressed the growth of neut - transformed mammary adenocarcinoma cells in nude mice .", "conserved sequences of the cyclin d1 3utr contain potential binding sites for multiple mirnas including mir-17/20/106 , mir-15/16 , mir-23 and let-7 .", "mir-17/20 binds the cyclin d1 3utr , inhibiting the expression of cyclin d1 , resulting in cell cycle arrest at the g1 phase and suppression of mcf-7 cell proliferation [ 18 , 26 ] .", "the regulation of cyclin d1 expression by mir-17 - 92 , as well as mir-15/16 , was confirmed by deshpande et al . .", "the let-7 family functions as a tumor suppressor in a variety of cancers including lung , colon , ovarian and breast cancer .", "schultz et al . demonstrated the downregulation of cyclin d1 by mirna let-7 in control of cancer cell growth .", "the regulation of cyclin d1 by mirna is likely of broad importance as cyclin d1 encodes the regulatory subunit of a kinase that phosphorylates and inactivates the prb family proteins to inhibit dna synthesis , and phosphorylates nuclear respiratory factor 1 ( nrf-1 ) to inhibit mitochondria biogenesis [ 32 , 33 ] .", "furthermore , cyclin d1 promotes breast epithelial cell angiogenesis and migration , and promotes chromosomal instability which in turn contributes to tumorigenesis .", "the mir-221/222 cluster regulates the cell cycle , cell growth and epithelial - to - mesenchymal transition ( emt ) in breast cancer .", "mir-221/222 inhibited p27 and p57 abundance , facilitating g1-s phase transition , thereby promoting cancer cell proliferation [ 36 , 37 ] .", "moreover , mir-221/222 may contribute to the aggressive clinical behavior of basal - like breast cancers .", "the breast cancer basal - like subtype - specific mirnas , mir-221 and mir-222 , promote emt in breast cancer by targeting trps1 ( trichorhinophalangeal syndrome type 1 ) which inhibits emt by repressing zeb2 expression .", "mir-221 and/or mir-222 expression in mcf-7 and t47d breast cancer cells decreased er expression associated with tamoxifen resistance .", "the onco - mirna mir-21 is overexpressed in a wide variety of cancers including breast cancer [ 40 , 41 ] .", "mir-21 induced cellular proliferation , migration , invasion , emt , cancer stem cell characteristics and chemotherapy resistance in human breast cancer [ 42 , 43 ] .", "high mir-21 level is associated with poor prognosis , advanced stage , positive lymph node status and reduced survival time in breast cancer .", "mir-21 promotes mcf-7 cellular proliferation in part through inhibiting the expression of a tumor suppressor gene programmed cell death 4 ( pdcd4 ) . in colon cancer ,", "mir-21 participates in a dna damage - induced g2-m checkpoint through suppressing the cell cycle regulator cdc25a .", "a recent report demonstrated the mir-21 regulates the cell cycle through targeting cdc25a in mcf-7 breast cancer cells . with a potential anti - cancer chemical 3,3-diindolylmethane treatment ,", "mir-27a expression is upregulated in human breast cancer cell lines . in mda - mb-231 cells ,", "mir-27a negatively regulated the zinc finger zbtb10 gene and myt-1 , thereby promoting breast cancer cell proliferation .", "mir-27a suppressed myt-1 , increased cdc2/cyclin b activity and promoted the g2-m checkpoint in mda - mb-231 cells . thus , distinct mirnas affect key genetic targets that govern distinct cell - cycle checkpoints including cyclins , cdks , cdk inhibitors and the g2-m regulation apparatus .", "in addition to cell - cycle control , breast tumor onset and progression and breast tumor stem cells are also regulated by distinct mirnas ." ], [ "cancer stem cells ( cscs ) are characterized by their self - renewal capacity , an ability to differentiate into non - tumorigenic cell progeny , and their ability to seed tumors when transplanted into animal hosts .", "cell surface markers such as cd44 , cd24 , cd133 , epithelial - specific antigen and aldehyde dehydrogenase-1 are frequently used to isolate and enrich cscs .", "the involvement of mirnas in regulating tumor formation by cscs or tumor - initiating cells ( t - ic ) has been widely investigated .", "let-7 expression is very low to undetectable level in embryonic stem cells ( es cells ) and increases with differentiation .", "a comparison of mirna expression between breast t - ic and non - t - ic demonstrated reduced let-7 expression in t - ic and increased abundance with differentiation .", "transduction of breast cscs with let-7 reduced the proportion of undifferentiated cells , inhibited cell proliferation , mammosphere formation , and tumor formation in vivo .", "clarke and colleagues identified 37 mirnas which were differentially expressed between human breast cscs ( cd44cd24lineage ) and lineage nontumorigenic breast cancer cells .", "the mir-200 family members were downregulated in human breast cscs and normal mammary stem / progenitor cells .", "expression of mir-200 inhibited breast cancer stem cell expansion in vitro , and suppressed the tumor formation ability of human breast cancer stem cell in vivo .", "ectopic mir-34c expression reduced breast t - ics self - renewal , inhibited emt and suppressed tumor cell invasiveness via silencing notch4 .", "zhu et al . found the reduced mir-128 expression in human breast t - ic was accompanied by bmi-1 and abcc5 overexpression , and associated with chemotherapeutic resistance and poor survival .", "enforced mir-128 expression increased the sensitivity of breast cancer cells to doxorubicin - induced apoptosis and dna damage .", "emerging evidence has demonstrated the importance of cscs in cancer initiation , cancer metastasis and drug resistance .", "cscs are believed to be one of the most promising targets for cure of cancer .", "the discovery that non - coding rnas regulate cscs widens our understanding of cscs , and may provide potential novel strategies for breast cancer therapy ." ], [ "deletion of chromosome 6q , including region 6q14-q16 , is frequently observed in breast cancer .", "the small non - coding snorna u50 is a candidate tumor suppressor gene in the 6q14 - 16 region , playing a role in the development and/or progression of breast cancer .", "genomic deletion and transcriptional downregulation of snorna u50 was detected in breast cancer cell lines .", "re - expression of snorna u50 inhibited colony formation of the human breast cancer cells hs578 t and mda - mb-231 .", "pirnas are small non - coding rna that form rna - protein complexes through interactions with piwi proteins .", "pirna was initially discovered in germ line cells , and considered as germ line - specific small rnas .", "emerging evidence indicates that pirna expression occurs in somatic cells [ 57 , 58 ] and piwil2 expression has been identified in human breast cancer cells .", "high - throughput deep sequencing identified a group of small rnas matching pirna sequences in human breast cancer tissues and breast cancer cell lines .", "the study of these non - coding small rnas in human cancer is just starting .", "the identification of the expression signature of these non - coding small rnas in breast cancer subtypes , and an understanding of their functional significance to oncogene expression , tumor initiation and tumor cell metastasis may shed important new perspectives on the role of these non - coding small rnas in breast cancer ." ], [ "small non - coding rna - based diagnostic and therapeutic applications for human cancer are expected in the near future . although tumor - targeted delivery and local administration are still major challenges to the practical application of gene therapy for cancer , mirna - based cancer therapeutic approaches are being established and tested in animal models .", "synthetic mirna mimics or mirna expression vectors have been successfully applied to restore or overexpress mirna in vitro . chemically modified lna anti - sense mirna inhibitor and other approaches have been used to block mirna function in cells .", "kim et al . recently reported significant anti - tumor effect of virus - mediated delivery of mir-145 combined with 5-fu to treat breast cancer .", "intranasal delivery of let-7 and intravenous delivery of mir-34a mimics for non - small - cell lung cancer treatment and a virus - mediated delivery of mir-26a for liver cancer treatment in mouse model demonstrate the promise of mirna for treatment of cancer ." ], [ "dysregulated expression of mirnas has implicated components of the non - coding genome as either oncogenes or tumor suppressors of breast cancer .", "experimental evidence has shown specific mirnas regulating the initiation , progression , metastasis and drug resistance of breast cancer via control of the cell cycle , altering cellular proliferation , altering cellular apoptosis and/or controlling the population of tumor stem cells . dysregulated", "mirna expression has also been observed in cancer associated fibroblasts ( caf ) and in the systemic circulation [ 65 , 66 ] .", "the circulating mirnas have the potential to serve as novel diagnostic and prognostic biomarkers for breast cancer .", "a specific subset of dysregulated mirnas in breast cancer cells may serve as targets for gene therapy either alone or as an adjuvant treatment to current clinical protocols for breast cancer patients ." ] ]

[ "ohss is a serious complication of ovulation induction , occurring in 1 - 10% of in vitro fertilization patients ( rizk and aboulghar , 1991 ; brinsden et al . , 1995 ) .", "this iatrogenic condition has a spectrum of clinical and laboratory manifestations ranging from mild to severe , even life - threatening conditions ( rizk et al . , 1990 ) . among the serious manifestations of ohss are ascites and pleural effusion ( rizk and smitz , 1992 ) .", "vascular endothelial growth factor has emerged as one of the factors most likely involved in the pathophysiology of ohss ( geva and jaffe , 2000 ; rizk and aboulghar , 2010 ) .", "vascular endothelial growth factor is an angiogenic cytokine that is a potent stimulator of the vascular endothelium and appears to play an integral role in follicular growth , corpus luteum function and ovarian angiogenesis ( rizk et al . , 1997 ) .", "vascular endothelial growth factor causes increased capillary permeability with its sequelae of ascites and possible pleural effusion ( rizk et al . , 1997 ; gomez et al . , 2002 ) .", "human chorionic gonadotrophin is thought to play a crucial role in the development of ohss ( rizk et al .", "two distinct forms of severe ohss have been described : early and late forms ( papanikolaou et al . , 2005 ; mathur et al . , 2000 ) .", "early ohss is caused by the administration of exogenous human chorionic gonadotrophin ( hcg ) and it starts before the 10th day after oocyte retrieval , while the late form is the result of endogenous human chorionic gonadotrophin release in the event of pregnancy , and it starts after the 10th day following oocyte aspiration ( papanikolaou et al . , 2005 ;", "such strategies included the use of low dose gonadotropins and frequent monitoring during controlled ovarian stimulation , cycle cancellation , coasting , freeze all embryos and the use of gonadotropin releasing hormone ( gnrh ) agonist as an oocyte trigger in gnrh antagonist cycles ( rizk et al .", "the use of antagonist in the luteal phase with total freeze of embryos to prevent severe ohss has also been suggested ( lainas et al . , 2012 ) .", "such strategies should be used especially in patients at high risk for developing severe ohss , including those who are young , have low body weight , have polycystic ovary syndrome , those who experience high estradiol levels , rapidly increasing estradiol levels , high number of follicles during controlled ovarian stimulation and those with high number of oocytes retrieved ( rizk and aboulghar , 1999 ; delvigne , 2009 ) .", "dopamine agonists have been proposed for the prevention of ohss in women at high risk . however , the study by lvarez et al . ", "( 2007 ) suggested that it was only effective in reducing the incidence of moderate ohss , but not in its severe form ( alvarez et al . , 2007 ) .", "low - dose aspirin therapy and doxycycline have also been suggested to inhibit angiogenesis ( fainaru et al . , 2009 ) .", "( 2011 ) believes that the concept of an ohss - free clinic has become a reality .", "the authors suggest that this approach should include pituitary down - regulation using a gnrh antagonist , ovulation triggering with a gnrh agonist and vitrification of oocytes or embryos ( devroey et al . , 2011 ) .", "severe and critical forms of ohss are associated with significant ascites ( golan et al . , 1989 ; rizk et al . ,", "ascites results in an increased abdominal pressure compromising venous return , cardiac output and renal perfusion ( navot et al .", "paracentesis is frequently needed , as prompt drainage of fluid produces a significant clinical and biochemical improvement , including spontaneous diuresis and hastening the resolution process ( rizk et al .", ", multiple paracenteses may be required to relieve symptoms and avoid serious sequelae of hemoconcentration , hypotension , decreased renal perfusion and severe respiratory compromise . instead of multiple interventions ,", "the placement of a catheter temporarily for a few days will permit complete drainage through one procedure ( rizk and aboulghar , 1999 ) .", "pigtail catheters have been used for drainage in various clinical situations . in a previous study we described the use of percutaneous placement of a pigtail catheter for drainage of ascites caused by severe / critical ohss ( abuzeid et al . , 2003 ) .", "in this study we established the efficacy and safety of pigtail catheter drainage in the management of severe / critical ohss in patients who underwent in vitro fertilization and embryo transfer at our centre between 1999 and 2001 on both inpatient and outpatient basis .", "the aim of the current study was to evaluate the role of the pigtail catheter drainage in outpatient management of patients with early onset severe ohss .", "this is a retrospective study that included all patients who underwent in vitro fertilization and developed severe or critical ohss by the golan classification ( golan et al . , 1989 ) in the period between 2004 and 2009 .", "all patients underwent an ultrasound evaluation which documented the presence of severe ascites and bilateral ovarian enlargement .", "all patients presented with shortness of breath , marked abdominal distension , nausea , weight gain and lower abdominal pain .", "thirteen patients complained of vomiting , and 3 patients reported decreased urine output ( less than 720 cc per 24 hours ) and had haemoglobin 15 g / dl .", "all 33 patients were offered treatment using pigtail catheter insertion as an alternative to trans - vaginal paracentesis .", "blood studies including a complete blood count , creatinine , electrolytes , serum albumin and total protein , and coagulation panel were ordered prior to the procedure .", "all 33 patients were rehydrated with intravenous crystalloid solutions ( 0.9% normal saline ) .", "care was taken to give the patient the same amount of fluid as the amount that was drained from the peritoneal cavity . ", "all pigtail catheter placements were performed in the operating room at our surgical centre . the catheter ( 6 - 0 french , 2.0 mm , boston scientific , quincy , ma , usa ) was introduced utilizing a non - disposable metal gamete intra - fallopian treatment ( gift ) trocar and cannula ( embryon gift catheter , ivf online , gilford , ct , usa ) which was introduced into the largest accessible ascitic fluid pocket in the upper outer quadrant of the abdominal wall under local anaesthesia and trans - abdominal ultrasound guidance . the trocar was then removed and a glide wire ( boston scientific corp . , watertown , ma , usa ) was threaded through the gift canula . the canula was removed with care so as to keep the glide wire in the peritoneal cavity .", "the pigtail catheter was guided into the peritoneal cavity by the wire after removal of the stylet of the pigtail catheter .", "the catheter was anchored to the skin using 2 - 0 silk suture and it was supported by gauze , which was covered by a tegaderm .", "the catheter was connected to a three - way stop cock which was connected to a drainage bag .", "initial amount of drained fluid was calculated and subsequently the patients were trained to drain 1000 cc per day ( 500 cc in the morning and 500 cc in the evening ) .", "one liter normal saline and 500 cc of 6% hydroxyethyle starch solution ( hespan ) was administered to the patient on the same day of pigtail catheter placement .", "any patient with critical ohss according to the golan classification , or those in whom the presenting symptoms and signs did not completely subside after drainage of ascitic fluid and iv fluid replacement , were admitted to the hospital for observation and further management .", "all other patients were sent home . once there was minimal or no drainage from the catheter , the patient returned to the office for removal of the catheter .", "the patients were encouraged to drink plenty of fluids and to increase their protein intake .", "all patients kept a diary for body weight , abdominal girth , and urine output before and after the procedure .", "patients were seen in the office as needed for evaluation and hydration with normal saline .", "demographic data including mean age ( years ) , duration of infertility ( years ) , bmi ( kg / m2 ) and aetiology of infertility are illustrated in table i. ovarian stimulation data including number of treatment days , total dose of recombinant follicle stimulating hormone , hormone serum levels , endometrial thickness , number of follicles and number of patients receiving only 5000 iu of human chorionic gonadotrophin is illustrated in table ii .", "our data include the number of patients requiring early versus late placement of pigtail catheter , mean amount of ascitic fluid drained immediately after pigtail placement , number of days of pigtail catheter drainage and the number of days between oocyte retrieval and the onset of severe ohss symptoms requiring pigtail placement .", "table iii also illustrates the number of patients who underwent coasting , number of patients who received prophylactic hespan on day of egg retrieval .", "values are expressed as mean + standard deviation values are expressed as mean + standard deviation : rfsh = recombinant fsh ; hmg = human menopausal gonadotropins ; hcg = human chorionic gonadotropin ; e2 = estradiol values are expressed as mean + standard deviation three patients ( 9% ) required an early placement of a pigtail catheter while 30 patients ( 91% ) had late placement of the catheter ( table iii ) .", "twenty - nine patients ( 88% ) were managed on an outpatient basis without any complications .", "four patients ( 12% ) required hospital admission for 1 - 7 days ( 3 + 2.7 ) , three for associated severe pleural effusion requiring thoracentesis .", "these three patients were admitted to the hospital immediately after insertion of the pigtail catheter for management of severe pleural effusion and careful observation .", "one patient was admitted 48 hours after insertion of the pigtail catheter for work up for chest pain , all tests were negative .", "navot et al . , 1992 ; rizk and aboulghar , 1999 ) , but perhaps the most accepted classification of ohss is the one described by golan et al as mild , moderate and severe ( golan et al . , 1989 ) .", "however , clinicians should be aware that ohss is a dynamic condition and moderate ohss may progress to severe ohss within hours ( rizk and aboulghar , 1999 ; rizk , 2009 ) .", "therefore , the practice committee of the american society for reproductive medicine ( asrm ) proposed a classification for ohss of mild , worsening and serious ( the practice committee of the american society for reproductive medicine , 2008 ) . recognizing the patients at high - risk , prevention and early recognition are the most important steps in the management of ohss ( rizk , 2006 ) .", "however , severe forms of ohss , especially late onset type that occurs when patients are pregnant , most likely will continue to happen , albeit at much lower rate , unless one reverts to a total freeze of all embryos after the use of gnrh agonist as a trigger shot in a gnrh antagonist cycle ( donoso and devroey , 2013 ; devroey et al . , 2011 ) .", "traditional treatment consists mainly of supportive management until spontaneous resolution occurs ( rizk , 1994 ) .", "although moderate ohss does not usually require intervention , outpatient monitoring is essential to identify progression to a severe form ( rizk , 2006 ) .", "patients with moderate ohss can be managed on an outpatient basis by adequate hydration and close daily monitoring of weight gain and abdominal girth to detect progression to severe ohss , and to provide intervention , if required ( rizk , 2010 ) .", "patients presenting with severe forms of ohss are usually managed on inpatient basis and most patients with critical ohss are admitted to intensive care units for aggressive supportive measures to avoid maternal morbidity and mortality ( the practice committee of the american society for reproductive medicine , 2008 ) .", "correction of hypovolemia , electrolyte imbalance and hypoalbuminemia are the basic principles during the treatment of severe ohss ( rizk , 1994 , 2006 ; myrianthefs et al . , 2000 ) .", "( 1992 ) suggested that paracentesis is the single most important treatment modality in life - threatening ohss not controlled by medical therapy .", "paracentesis and removal of ascites result in relieving the pressure on the inferior vena cava and improvement in venous return , cardiac output and renal perfusion ( padilla et al . , 1990 ) .", "therefore , prompt drainage of fluid produces significant clinical and biochemical improvement , including spontaneous diuresis and hastening the resolution process ( abuzeid et al .", ", 2003 ; the practice committee of the american society for reproductive medicine , 2008 ) .", "it is also possible that removal of ascites decreases the amount of vegf and its effects on vascular permeability .", "therefore ultrasound guided drainage of the ascitic fluid should be performed in severe cases of ohss with respiratory distress , oliguria or severe abdominal pain ( padilla et al . , 1990 ) .", "this can be done either trans - vaginally ( aboulghar et al . , 1990 ) or trans - abdominally ( padilla et al . ,", "1990 ) . however , recurrence of ascites is common in severe cases of ohss .", "placement of a pigtail catheter has been proposed by some investigators to allow drainage of ascitic fluid whenever it accumulates without the need for further surgical procedures ( abuzeid et al . , 2003 ) .", "in a previous study we reported the use of percutaneous pigtail catheter for drainage of ascites in severe ohss as an alternative to repeated paracentesis ( abuzeid et al . , 2003 ) .", "this procedure is relatively simple and requires a short period of time as compared to the time needed to gradually aspirate any fluid accumulation transvaginally .", "immediate relief of symptoms and signs of severe ohss after pigtail catheter insertion was an important finding .", "in addition , the ease by which any accumulated ascitic fluid was drained resulted in a faster resolution of ohss ( abuzeid et al . ,", "no infection was reported ( abuzeid et al . , 2003 ) . in that study the first 13 patients", "they were discharged home with the pigtail catheter in place and managed on an outpatient basis until ohss subsided ; thereafter the catheter was removed .", "the last 13 patients were managed on an outpatient basis without any problem ( abuzeid mi , et al . , 2003 ) .", "our previous study confirmed the safety and effectiveness of the pigtail catheter for the management of severe ohss .", "therefore , we embarked on the current study to evaluate the role of pigtail catheter drainage in outpatient management of patients with severe ohss syndrome . in the current study we demonstrated that patients who were diagnosed very early with severe ohss can be managed safely and effectively on outpatient basis using pigtail catheter drainage , iv fluid replacement and careful monitoring .", "although all 33 patients presented with shortness of breath , marked abdominal distension , nausea , weight gain and lower abdominal pain , and 13 of them complained of vomiting , ( all are criteria for hospital admission according to the practice committee of the american society for reproductive medicine on ohss ) , 30 patients were sent home as their presenting symptoms were relieved .", "early diagnosis and intervention resulted in rapid elimination of the symptoms of severe ohss and normalization of vital signs , which allow us to manage the patients on outpatient basis .", "the pigtail catheter placements were performed without complications and patients were discharged home after a few hours of observation .", "the patients who needed hospital admission were those with associated severe pleural effusion requiring thoracentesis .", "another patient was admitted to the hospital for 1 day for work up for chest pain and possible diagnosis of pulmonary embolism .", "once pulmonary embolism was ruled out , she was discharged home with a pigtail catheter in place and she was managed on outpatient basis .", "outpatient management of ohss has no place in those who fail to have complete resolutions of their symptoms , or those with severe hyperproteinuria or electrolyte imbalance .", "certainly it has no place in patients with critical ohss such as those with severe pleural effusion , diminished urine output , severe hemoconcentration and those at increased risk of thromboembolic risks ( rizk , 2010 ) .", "it is imperative to stress that such a protocol can only be used in patients who are motivated , reliable and have the necessary support at home to allow them to return to the clinic or go to the emergency room if the need arises .", "it also requires dedicated in vitro fertilization nurses to educate and follow up the patient on a daily basis .", "contrary to other reports that state that access to intravenous albumin is a critical part of outpatient management for severe ohss , we did not use any albumin replacement ( lincoln et al . , 2002 ) .", "the reason behind the use of intravenous albumin is to increase intravascular oncotic pressure , thereby curtailing the exodus of free water from the intravascular space . in our study", "we used hespan instead of albumin , as some investigators have shown that it is beneficial in reducing the incidence of severe ohss ( youssef et al . , 2011 ) . by increasing the intravascular oncotic pressure", "in addition , the majority of our patients had late onset ohss as a result of pregnancy .", "hespan should be used with caution in patients with late onset ohss only when benefits outweigh risks.it is a fact that outpatient management of early severe ohss is a common practice among infertility specialists after trans - vaginal aspiration of ascitic fluid and iv fluid hydration .", "outpatient management by repeated abdominal or trans - vaginal paracentesis has been reported to be safe , effective and cost effective ( lincoln et al .", ", 2002 ; shrivastav et al . , 1994 ; fluker et al . , 2000", "( 1994 ) were the first to suggest that day care management in patients with severe ohss with abdominal paracentesis and iv hydration was simple , safe and effective compared with traditional treatment with in - patient hospitalization and supportive measures .", "( 2002 ) concluded that the need for hospitalization for hyperstimulated patients can be minimized by outpatient management of severe ohss with trans - vaginal culdocentesis and rehydration with crystalloids and albumin .", "( 2000 ) advocated in a pilot study an active management strategy for moderate ohss , which involved early paracentesis designed to minimize the progression from moderate to severe ohss , instead of late paracentesis aimed at speeding up recovery in severely ill patients .", "( 2010 ) concluded that early outpatient paracentesis for moderate to severe ohss is the most cost effective management plan when compared with traditional conservative inpatient therapy .", "( 2009 ) reported a large series of patients with severe ohss in whom the vast majority were successfully managed as outpatients with use of aggressive trans - vaginal paracentesis ( smith et al . , 2009 ) . despite the findings in our study", "it is important to emphasize that ohss remains a serious disorder with the potential for rapid deterioration , requiring hospitalization and intensive treatment of a critically ill patient .", "the life - threatening complications of ohss are secondary to thromboembolism or compromised pulmonary or cardiovascular function and multi - organ failure", ". there have been isolated reports of women dying from the complications associated with ohss .", "the mortality rate related to ohss is very low and was estimated by brinsden et al . ", "more recently , reports regarding maternal mortality rates due to ohss in the netherlands and united kingdom demonstrate an incidence of approximately 3 deaths per 100,000 in ivf cycles ( braat et al .", ", 2006 ; lewis , 2007 ) . eleven lethal complications of assisted reproductive technology have been documented and summarized by braat et al . ", "several investigators reported sporadic fatality as a result of ohss due to adult respiratory distress syndrome , massive pulmonary oedema , myocardial infarction , and carotid artery occlusion resulting in cerebral infarction . in this study", "we describe a modified technique of what interventional radiologists usually use for pigtail catheter placement .", "we observed that in the obese patients the metal introducer provided in the pigtail catheter kit is difficult to use ; instead we used the non disposable gamete intra - fallopian treatment trocar and cannula to facilitate the introduction of the catheter through the abdominal wall of such patients .", "this technique helps to manage the patients in the office without the need for sending her to the hospital for an interventional radiologist to place the catheter .", "however , the patients in this study were identified from our in vitro fertilization database ; the study included every patient who developed severe / critical ohss .", "in addition , the lack of a control group that was managed without pigtail catheter placement limits the conclusions that can be drawn from our study . in summary ,", "drainage of ascitic fluid in patients with severe / critical ohss is an important step in the management of this condition ( rizk , 2010 ) .", "the placement of a pigtail catheter resulted in a safe and effective outpatient management of the majority of patients with severe ohss .", "however , outpatient management of this potentially fatal condition requires clear understanding that rapid deterioration may occur , which may necessitate hospitalization and intensive treatment of a critically ill patient ( rizk , 2006 , 2010 ) .", "patients with critical ohss and those with persistence of symptoms of severe ohss despite insertion of a pigtail catheter and drainage of ascitic fluid should be admitted to the hospital for inpatient management ." ]

[ "<S> objective : to evaluate the efficacy and safety of outpatient management of severe ovarian hyperstimulation syndrome ( ohss ) requiring placement of a pigtail catheter.methods : retrospective analysis of thirty - three consecutive patients who underwent in - vitro fertilization ( 2003 - 2009 ) and developed severe / critical ohss requiring placement of a pigtail catheter . </S>", "<S> patients who were managed on outpatient basis were monitored by frequent office visits , daily phone calls , and received iv normal saline for hydration when required.results : in 3 patients ( 9.1% ) ohss started early , requiring placement of a pigtail catheter 4.3 + 0.6 days after retrieval . in 30 patients ( 90.9% ) </S>", "<S> ohss started late ( 14 4 days after retrieval ) . </S>", "<S> the mean amount of ascitic fluid drained immediately after placement of the catheter was 2085 1018 cc . </S>", "<S> the pigtail catheter was removed after 7.8 5.3 days . </S>", "<S> of the 31 patients who had embryo transfer ( two had total freeze ) , 84% conceived . </S>", "<S> twenty - nine patients ( 88% ) were managed on outpatient basis without any complications . </S>", "<S> four patients required hospital admission for 1 - 7 days ( 3.0 2.7 ) . </S>", "<S> one patient with severe ohss was admitted for work up for chest pain . </S>", "<S> three patients with critical ohss with severe pleural effusion requiring thoracentesis were admitted for supportive measures.conclusion : the placement of a pigtail catheter resulted in safe and effective outpatient management for the majority of patients with severe ohss . </S>" ]

[ "Introduction", "Materials and Methods", "Results", "Discussion" ]

[ [ "ohss is a serious complication of ovulation induction , occurring in 1 - 10% of in vitro fertilization patients ( rizk and aboulghar , 1991 ; brinsden et al . , 1995 ) .", "this iatrogenic condition has a spectrum of clinical and laboratory manifestations ranging from mild to severe , even life - threatening conditions ( rizk et al . , 1990 ) . among the serious manifestations of ohss are ascites and pleural effusion ( rizk and smitz , 1992 ) .", "vascular endothelial growth factor has emerged as one of the factors most likely involved in the pathophysiology of ohss ( geva and jaffe , 2000 ; rizk and aboulghar , 2010 ) .", "vascular endothelial growth factor is an angiogenic cytokine that is a potent stimulator of the vascular endothelium and appears to play an integral role in follicular growth , corpus luteum function and ovarian angiogenesis ( rizk et al . , 1997 ) .", "vascular endothelial growth factor causes increased capillary permeability with its sequelae of ascites and possible pleural effusion ( rizk et al . , 1997 ; gomez et al . , 2002 ) .", "human chorionic gonadotrophin is thought to play a crucial role in the development of ohss ( rizk et al .", "two distinct forms of severe ohss have been described : early and late forms ( papanikolaou et al . , 2005 ; mathur et al . , 2000 ) .", "early ohss is caused by the administration of exogenous human chorionic gonadotrophin ( hcg ) and it starts before the 10th day after oocyte retrieval , while the late form is the result of endogenous human chorionic gonadotrophin release in the event of pregnancy , and it starts after the 10th day following oocyte aspiration ( papanikolaou et al . , 2005 ;", "such strategies included the use of low dose gonadotropins and frequent monitoring during controlled ovarian stimulation , cycle cancellation , coasting , freeze all embryos and the use of gonadotropin releasing hormone ( gnrh ) agonist as an oocyte trigger in gnrh antagonist cycles ( rizk et al .", "the use of antagonist in the luteal phase with total freeze of embryos to prevent severe ohss has also been suggested ( lainas et al . , 2012 ) .", "such strategies should be used especially in patients at high risk for developing severe ohss , including those who are young , have low body weight , have polycystic ovary syndrome , those who experience high estradiol levels , rapidly increasing estradiol levels , high number of follicles during controlled ovarian stimulation and those with high number of oocytes retrieved ( rizk and aboulghar , 1999 ; delvigne , 2009 ) .", "dopamine agonists have been proposed for the prevention of ohss in women at high risk . however , the study by lvarez et al . ", "( 2007 ) suggested that it was only effective in reducing the incidence of moderate ohss , but not in its severe form ( alvarez et al . , 2007 ) .", "low - dose aspirin therapy and doxycycline have also been suggested to inhibit angiogenesis ( fainaru et al . , 2009 ) .", "( 2011 ) believes that the concept of an ohss - free clinic has become a reality .", "the authors suggest that this approach should include pituitary down - regulation using a gnrh antagonist , ovulation triggering with a gnrh agonist and vitrification of oocytes or embryos ( devroey et al . , 2011 ) .", "severe and critical forms of ohss are associated with significant ascites ( golan et al . , 1989 ; rizk et al . ,", "ascites results in an increased abdominal pressure compromising venous return , cardiac output and renal perfusion ( navot et al .", "paracentesis is frequently needed , as prompt drainage of fluid produces a significant clinical and biochemical improvement , including spontaneous diuresis and hastening the resolution process ( rizk et al .", ", multiple paracenteses may be required to relieve symptoms and avoid serious sequelae of hemoconcentration , hypotension , decreased renal perfusion and severe respiratory compromise . instead of multiple interventions ,", "the placement of a catheter temporarily for a few days will permit complete drainage through one procedure ( rizk and aboulghar , 1999 ) .", "pigtail catheters have been used for drainage in various clinical situations . in a previous study we described the use of percutaneous placement of a pigtail catheter for drainage of ascites caused by severe / critical ohss ( abuzeid et al . , 2003 ) .", "in this study we established the efficacy and safety of pigtail catheter drainage in the management of severe / critical ohss in patients who underwent in vitro fertilization and embryo transfer at our centre between 1999 and 2001 on both inpatient and outpatient basis .", "the aim of the current study was to evaluate the role of the pigtail catheter drainage in outpatient management of patients with early onset severe ohss ." ], [ "this is a retrospective study that included all patients who underwent in vitro fertilization and developed severe or critical ohss by the golan classification ( golan et al . , 1989 ) in the period between 2004 and 2009 .", "all patients underwent an ultrasound evaluation which documented the presence of severe ascites and bilateral ovarian enlargement .", "all patients presented with shortness of breath , marked abdominal distension , nausea , weight gain and lower abdominal pain .", "thirteen patients complained of vomiting , and 3 patients reported decreased urine output ( less than 720 cc per 24 hours ) and had haemoglobin 15 g / dl .", "all 33 patients were offered treatment using pigtail catheter insertion as an alternative to trans - vaginal paracentesis .", "blood studies including a complete blood count , creatinine , electrolytes , serum albumin and total protein , and coagulation panel were ordered prior to the procedure .", "all 33 patients were rehydrated with intravenous crystalloid solutions ( 0.9% normal saline ) .", "care was taken to give the patient the same amount of fluid as the amount that was drained from the peritoneal cavity . ", "all pigtail catheter placements were performed in the operating room at our surgical centre . the catheter ( 6 - 0 french , 2.0 mm , boston scientific , quincy , ma , usa ) was introduced utilizing a non - disposable metal gamete intra - fallopian treatment ( gift ) trocar and cannula ( embryon gift catheter , ivf online , gilford , ct , usa ) which was introduced into the largest accessible ascitic fluid pocket in the upper outer quadrant of the abdominal wall under local anaesthesia and trans - abdominal ultrasound guidance . the trocar was then removed and a glide wire ( boston scientific corp . , watertown , ma , usa ) was threaded through the gift canula . the canula was removed with care so as to keep the glide wire in the peritoneal cavity .", "the pigtail catheter was guided into the peritoneal cavity by the wire after removal of the stylet of the pigtail catheter .", "the catheter was anchored to the skin using 2 - 0 silk suture and it was supported by gauze , which was covered by a tegaderm .", "the catheter was connected to a three - way stop cock which was connected to a drainage bag .", "initial amount of drained fluid was calculated and subsequently the patients were trained to drain 1000 cc per day ( 500 cc in the morning and 500 cc in the evening ) .", "one liter normal saline and 500 cc of 6% hydroxyethyle starch solution ( hespan ) was administered to the patient on the same day of pigtail catheter placement .", "any patient with critical ohss according to the golan classification , or those in whom the presenting symptoms and signs did not completely subside after drainage of ascitic fluid and iv fluid replacement , were admitted to the hospital for observation and further management .", "all other patients were sent home . once there was minimal or no drainage from the catheter , the patient returned to the office for removal of the catheter .", "the patients were encouraged to drink plenty of fluids and to increase their protein intake .", "all patients kept a diary for body weight , abdominal girth , and urine output before and after the procedure .", "patients were seen in the office as needed for evaluation and hydration with normal saline ." ], [ "demographic data including mean age ( years ) , duration of infertility ( years ) , bmi ( kg / m2 ) and aetiology of infertility are illustrated in table i. ovarian stimulation data including number of treatment days , total dose of recombinant follicle stimulating hormone , hormone serum levels , endometrial thickness , number of follicles and number of patients receiving only 5000 iu of human chorionic gonadotrophin is illustrated in table ii .", "our data include the number of patients requiring early versus late placement of pigtail catheter , mean amount of ascitic fluid drained immediately after pigtail placement , number of days of pigtail catheter drainage and the number of days between oocyte retrieval and the onset of severe ohss symptoms requiring pigtail placement .", "table iii also illustrates the number of patients who underwent coasting , number of patients who received prophylactic hespan on day of egg retrieval .", "values are expressed as mean + standard deviation values are expressed as mean + standard deviation : rfsh = recombinant fsh ; hmg = human menopausal gonadotropins ; hcg = human chorionic gonadotropin ; e2 = estradiol values are expressed as mean + standard deviation three patients ( 9% ) required an early placement of a pigtail catheter while 30 patients ( 91% ) had late placement of the catheter ( table iii ) .", "twenty - nine patients ( 88% ) were managed on an outpatient basis without any complications .", "four patients ( 12% ) required hospital admission for 1 - 7 days ( 3 + 2.7 ) , three for associated severe pleural effusion requiring thoracentesis .", "these three patients were admitted to the hospital immediately after insertion of the pigtail catheter for management of severe pleural effusion and careful observation .", "one patient was admitted 48 hours after insertion of the pigtail catheter for work up for chest pain , all tests were negative ." ], [ "navot et al . , 1992 ; rizk and aboulghar , 1999 ) , but perhaps the most accepted classification of ohss is the one described by golan et al as mild , moderate and severe ( golan et al . , 1989 ) .", "however , clinicians should be aware that ohss is a dynamic condition and moderate ohss may progress to severe ohss within hours ( rizk and aboulghar , 1999 ; rizk , 2009 ) .", "therefore , the practice committee of the american society for reproductive medicine ( asrm ) proposed a classification for ohss of mild , worsening and serious ( the practice committee of the american society for reproductive medicine , 2008 ) . recognizing the patients at high - risk , prevention and early recognition are the most important steps in the management of ohss ( rizk , 2006 ) .", "however , severe forms of ohss , especially late onset type that occurs when patients are pregnant , most likely will continue to happen , albeit at much lower rate , unless one reverts to a total freeze of all embryos after the use of gnrh agonist as a trigger shot in a gnrh antagonist cycle ( donoso and devroey , 2013 ; devroey et al . , 2011 ) .", "traditional treatment consists mainly of supportive management until spontaneous resolution occurs ( rizk , 1994 ) .", "although moderate ohss does not usually require intervention , outpatient monitoring is essential to identify progression to a severe form ( rizk , 2006 ) .", "patients with moderate ohss can be managed on an outpatient basis by adequate hydration and close daily monitoring of weight gain and abdominal girth to detect progression to severe ohss , and to provide intervention , if required ( rizk , 2010 ) .", "patients presenting with severe forms of ohss are usually managed on inpatient basis and most patients with critical ohss are admitted to intensive care units for aggressive supportive measures to avoid maternal morbidity and mortality ( the practice committee of the american society for reproductive medicine , 2008 ) .", "correction of hypovolemia , electrolyte imbalance and hypoalbuminemia are the basic principles during the treatment of severe ohss ( rizk , 1994 , 2006 ; myrianthefs et al . , 2000 ) .", "( 1992 ) suggested that paracentesis is the single most important treatment modality in life - threatening ohss not controlled by medical therapy .", "paracentesis and removal of ascites result in relieving the pressure on the inferior vena cava and improvement in venous return , cardiac output and renal perfusion ( padilla et al . , 1990 ) .", "therefore , prompt drainage of fluid produces significant clinical and biochemical improvement , including spontaneous diuresis and hastening the resolution process ( abuzeid et al .", ", 2003 ; the practice committee of the american society for reproductive medicine , 2008 ) .", "it is also possible that removal of ascites decreases the amount of vegf and its effects on vascular permeability .", "therefore ultrasound guided drainage of the ascitic fluid should be performed in severe cases of ohss with respiratory distress , oliguria or severe abdominal pain ( padilla et al . , 1990 ) .", "this can be done either trans - vaginally ( aboulghar et al . , 1990 ) or trans - abdominally ( padilla et al . ,", "1990 ) . however , recurrence of ascites is common in severe cases of ohss .", "placement of a pigtail catheter has been proposed by some investigators to allow drainage of ascitic fluid whenever it accumulates without the need for further surgical procedures ( abuzeid et al . , 2003 ) .", "in a previous study we reported the use of percutaneous pigtail catheter for drainage of ascites in severe ohss as an alternative to repeated paracentesis ( abuzeid et al . , 2003 ) .", "this procedure is relatively simple and requires a short period of time as compared to the time needed to gradually aspirate any fluid accumulation transvaginally .", "immediate relief of symptoms and signs of severe ohss after pigtail catheter insertion was an important finding .", "in addition , the ease by which any accumulated ascitic fluid was drained resulted in a faster resolution of ohss ( abuzeid et al . ,", "no infection was reported ( abuzeid et al . , 2003 ) . in that study the first 13 patients", "they were discharged home with the pigtail catheter in place and managed on an outpatient basis until ohss subsided ; thereafter the catheter was removed .", "the last 13 patients were managed on an outpatient basis without any problem ( abuzeid mi , et al . , 2003 ) .", "our previous study confirmed the safety and effectiveness of the pigtail catheter for the management of severe ohss .", "therefore , we embarked on the current study to evaluate the role of pigtail catheter drainage in outpatient management of patients with severe ohss syndrome . in the current study we demonstrated that patients who were diagnosed very early with severe ohss can be managed safely and effectively on outpatient basis using pigtail catheter drainage , iv fluid replacement and careful monitoring .", "although all 33 patients presented with shortness of breath , marked abdominal distension , nausea , weight gain and lower abdominal pain , and 13 of them complained of vomiting , ( all are criteria for hospital admission according to the practice committee of the american society for reproductive medicine on ohss ) , 30 patients were sent home as their presenting symptoms were relieved .", "early diagnosis and intervention resulted in rapid elimination of the symptoms of severe ohss and normalization of vital signs , which allow us to manage the patients on outpatient basis .", "the pigtail catheter placements were performed without complications and patients were discharged home after a few hours of observation .", "the patients who needed hospital admission were those with associated severe pleural effusion requiring thoracentesis .", "another patient was admitted to the hospital for 1 day for work up for chest pain and possible diagnosis of pulmonary embolism .", "once pulmonary embolism was ruled out , she was discharged home with a pigtail catheter in place and she was managed on outpatient basis .", "outpatient management of ohss has no place in those who fail to have complete resolutions of their symptoms , or those with severe hyperproteinuria or electrolyte imbalance .", "certainly it has no place in patients with critical ohss such as those with severe pleural effusion , diminished urine output , severe hemoconcentration and those at increased risk of thromboembolic risks ( rizk , 2010 ) .", "it is imperative to stress that such a protocol can only be used in patients who are motivated , reliable and have the necessary support at home to allow them to return to the clinic or go to the emergency room if the need arises .", "it also requires dedicated in vitro fertilization nurses to educate and follow up the patient on a daily basis .", "contrary to other reports that state that access to intravenous albumin is a critical part of outpatient management for severe ohss , we did not use any albumin replacement ( lincoln et al . , 2002 ) .", "the reason behind the use of intravenous albumin is to increase intravascular oncotic pressure , thereby curtailing the exodus of free water from the intravascular space . in our study", "we used hespan instead of albumin , as some investigators have shown that it is beneficial in reducing the incidence of severe ohss ( youssef et al . , 2011 ) . by increasing the intravascular oncotic pressure", "in addition , the majority of our patients had late onset ohss as a result of pregnancy .", "hespan should be used with caution in patients with late onset ohss only when benefits outweigh risks.it is a fact that outpatient management of early severe ohss is a common practice among infertility specialists after trans - vaginal aspiration of ascitic fluid and iv fluid hydration .", "outpatient management by repeated abdominal or trans - vaginal paracentesis has been reported to be safe , effective and cost effective ( lincoln et al .", ", 2002 ; shrivastav et al . , 1994 ; fluker et al . , 2000", "( 1994 ) were the first to suggest that day care management in patients with severe ohss with abdominal paracentesis and iv hydration was simple , safe and effective compared with traditional treatment with in - patient hospitalization and supportive measures .", "( 2002 ) concluded that the need for hospitalization for hyperstimulated patients can be minimized by outpatient management of severe ohss with trans - vaginal culdocentesis and rehydration with crystalloids and albumin .", "( 2000 ) advocated in a pilot study an active management strategy for moderate ohss , which involved early paracentesis designed to minimize the progression from moderate to severe ohss , instead of late paracentesis aimed at speeding up recovery in severely ill patients .", "( 2010 ) concluded that early outpatient paracentesis for moderate to severe ohss is the most cost effective management plan when compared with traditional conservative inpatient therapy .", "( 2009 ) reported a large series of patients with severe ohss in whom the vast majority were successfully managed as outpatients with use of aggressive trans - vaginal paracentesis ( smith et al . , 2009 ) . despite the findings in our study", "it is important to emphasize that ohss remains a serious disorder with the potential for rapid deterioration , requiring hospitalization and intensive treatment of a critically ill patient .", "the life - threatening complications of ohss are secondary to thromboembolism or compromised pulmonary or cardiovascular function and multi - organ failure", ". there have been isolated reports of women dying from the complications associated with ohss .", "the mortality rate related to ohss is very low and was estimated by brinsden et al . ", "more recently , reports regarding maternal mortality rates due to ohss in the netherlands and united kingdom demonstrate an incidence of approximately 3 deaths per 100,000 in ivf cycles ( braat et al .", ", 2006 ; lewis , 2007 ) . eleven lethal complications of assisted reproductive technology have been documented and summarized by braat et al . ", "several investigators reported sporadic fatality as a result of ohss due to adult respiratory distress syndrome , massive pulmonary oedema , myocardial infarction , and carotid artery occlusion resulting in cerebral infarction . in this study", "we describe a modified technique of what interventional radiologists usually use for pigtail catheter placement .", "we observed that in the obese patients the metal introducer provided in the pigtail catheter kit is difficult to use ; instead we used the non disposable gamete intra - fallopian treatment trocar and cannula to facilitate the introduction of the catheter through the abdominal wall of such patients .", "this technique helps to manage the patients in the office without the need for sending her to the hospital for an interventional radiologist to place the catheter .", "however , the patients in this study were identified from our in vitro fertilization database ; the study included every patient who developed severe / critical ohss .", "in addition , the lack of a control group that was managed without pigtail catheter placement limits the conclusions that can be drawn from our study . in summary ,", "drainage of ascitic fluid in patients with severe / critical ohss is an important step in the management of this condition ( rizk , 2010 ) .", "the placement of a pigtail catheter resulted in a safe and effective outpatient management of the majority of patients with severe ohss .", "however , outpatient management of this potentially fatal condition requires clear understanding that rapid deterioration may occur , which may necessitate hospitalization and intensive treatment of a critically ill patient ( rizk , 2006 , 2010 ) .", "patients with critical ohss and those with persistence of symptoms of severe ohss despite insertion of a pigtail catheter and drainage of ascitic fluid should be admitted to the hospital for inpatient management ." ] ]

[ "congenital adrenal hyperplasia ( cah ) refers to a group of autosomal recessive disorders caused by an enzyme deficiency which leads to defects in biosynthesis of steroid precursors .", "depending on the severity and degree of 21 hydroxylase deficiency , the clinical spectrum may vary from mild form of non classical cah to classic cah .", "however , the non classical cah variant is more common with a prevalence rate of 1 in 1000 .", "it also helps in maintaining normal levels of precursors by suppressing adreno cortico trophic hormone ( acth ) . during childhood", ", the management is largely focused on achieving normal growth and attaining appropriate final adult height .", "johns medical college hospital , bangalore by the department of endocrinology on patients diagnosed to have cah and seen in the outpatient clinic between january 2012 and october 2012 . during this period", "data regarding demography , clinical presentation at time of diagnosis , treatment details , height sds and bmi were collected .", "all patients underwent biochemical testing for 17 hydroxy progesterone ( 17 ohp ) levels for assessment of adequacy of therapy . bone age assessment with left hand and wrist", "bmi was calculated for all patients and obesity was defined using who charts as values above 95th percentile .", "17 ohp levels between 1 ng / ml and 12 ng / ml were considered appropriate ; values below 1 ng / ml suggested suppression and over treatment and values above 12 ng / ml suggested under treatment .", "29 patients were included in the study of which 22 were females ( 76% ) and 7 were males ( 24% ) . based on the cross sectional data collected , 11 patients were adults ( age > 18 ) and 18 patients were children ( 62% ) . among the males ,", "one child was identified at birth via a neonatal screening program , one child presented with early pubarche , the other 5 infants presented between their 3rd and 6th week of life with features suggestive of adrenal crisis - poor feeding , vomiting and failure to gain weight .", "one of the male patients incidentally also had a penoscrotal hypospadias which was surgically corrected . among the females ,", "9 infants were identified at birth due to presence of genital ambiguity ( 40% ) , 1 presented with symptoms of adrenal crisis at 4 weeks of life , 4 patients presented in the pre pubertal period due to early onset adrenarche ( 18% ) , 5 patients presented in the late adolescent period with marked virilization ( 23% ) and 3 patients presented with features of poly cystic ovarian disease ( pcos ) .", "all the five patients who presented in the late adolescent period had obvious genital ambiguity from birth , however , they sought medical attention only much later due to marked virilization and failure to attain menarche .", "one among them had actually been evaluated and even underwent a clitoroplasty at a young age , but unfortunately , the diagnosis of cah was missed as she was mistakenly categorized as probable ovo testicular dsd due to presence of mullerian structures with a phallic length of around 6 cm .", "all these 5 women had a masculine built at presentation with poor breast development , severe hirsutism , muscular body habitus , temporal balding and varying degrees of deepening of voice .", "the non classical cah ( nccah ) patients presented in adulthood with complaints of irregular cycles and hirsutism ; they had no features of virilisation .", "simple virilizing was the most common sub class seen among the women ( 81% ) whereas the salt wasting type was predominant among boys ( 85% ) .", "around 35% of patients had short stature as defined by height sds < -2.0 ; 2 patients who presented with adrenarche had increase in height sds , however , their bone age was also correspondingly advanced .", "all the children were treated with hydrocortisone ; almost all adult patients were on dexamethasone .", "none of the nccah patients were treated with glucocorticoids ; they were on anti - androgen therapy along with oral contraceptive pills .", "most adult classic cah patients with complaints of hirsutism were treated with either spironolactone or finasteride .", "pubertal induction with ethinyl estradiol was initiated for three of the adult patients who sought medical care late .", "analysis of 17 ohp levels revealed that 32% were suppressed with levels less than 1ng / ml ; appropriate in 47% and inadequate in 21% of patients .", "we report the phenotypic features of a cohort of patients with cah being evaluated and managed in a tertiary centre in southern india . in this series ,", "the typical presentation of male babies were with adrenal crisis between the 3 and 6 week of life . around 20% of female patients with classic cah", "were identified and appropriately treated only after late adolescence even when genital ambiguity was present since birth .", "short stature was seen in one third of patients on therapy and the average final adult height among patients with classic cah was 142.37 , which was significantly lower than the mean adult height for females in our population .", "the mean final adult height of 157.5 cm for those with nccah was better than their classic cah counterpart .", "obesity and hypertension were not found to be significantly higher in this cohort of cah patients .", "one third of patients had suppressed 17 ohp levels suggestive of over replacement therapy which may also contribute to the reduction in the final adult stature ." ]

[ "<S> congenital adrenal hyperplasia is a group of autosomal recessive disorders caused by enzyme deficiency which leads to defects in biosynthesis of steroid precursors . </S>", "<S> most common is 21 hydroxylase deficiency . </S>", "<S> clinical spectrum varies from non - classical cah to classic cah , and it may be simple virilising form or salt - wastinfg type . </S>", "<S> 29 patients were included in our study from january 2012 to october 2012 . </S>", "<S> 76% were females . </S>", "<S> male babies typically presented with adrenal crisis between 3rd to 6th week of life . around 20% of females </S>", "<S> were identified and appropriately treated only after late adolescence . </S>", "<S> short stature was seen in 1/3rd of patients . </S>", "<S> 1/3rd of patients had suppressed 17 ohp levels suggestive of over - replacement therapy which may contribute to final reduction in adult height . </S>" ]

[ "I", "M", "R", "D" ]

[ [ "congenital adrenal hyperplasia ( cah ) refers to a group of autosomal recessive disorders caused by an enzyme deficiency which leads to defects in biosynthesis of steroid precursors .", "depending on the severity and degree of 21 hydroxylase deficiency , the clinical spectrum may vary from mild form of non classical cah to classic cah .", "however , the non classical cah variant is more common with a prevalence rate of 1 in 1000 .", "it also helps in maintaining normal levels of precursors by suppressing adreno cortico trophic hormone ( acth ) . during childhood", ", the management is largely focused on achieving normal growth and attaining appropriate final adult height ." ], [ "johns medical college hospital , bangalore by the department of endocrinology on patients diagnosed to have cah and seen in the outpatient clinic between january 2012 and october 2012 . during this period", "data regarding demography , clinical presentation at time of diagnosis , treatment details , height sds and bmi were collected .", "all patients underwent biochemical testing for 17 hydroxy progesterone ( 17 ohp ) levels for assessment of adequacy of therapy . bone age assessment with left hand and wrist", "bmi was calculated for all patients and obesity was defined using who charts as values above 95th percentile .", "17 ohp levels between 1 ng / ml and 12 ng / ml were considered appropriate ; values below 1 ng / ml suggested suppression and over treatment and values above 12 ng / ml suggested under treatment ." ], [ "29 patients were included in the study of which 22 were females ( 76% ) and 7 were males ( 24% ) . based on the cross sectional data collected , 11 patients were adults ( age > 18 ) and 18 patients were children ( 62% ) . among the males ,", "one child was identified at birth via a neonatal screening program , one child presented with early pubarche , the other 5 infants presented between their 3rd and 6th week of life with features suggestive of adrenal crisis - poor feeding , vomiting and failure to gain weight .", "one of the male patients incidentally also had a penoscrotal hypospadias which was surgically corrected . among the females ,", "9 infants were identified at birth due to presence of genital ambiguity ( 40% ) , 1 presented with symptoms of adrenal crisis at 4 weeks of life , 4 patients presented in the pre pubertal period due to early onset adrenarche ( 18% ) , 5 patients presented in the late adolescent period with marked virilization ( 23% ) and 3 patients presented with features of poly cystic ovarian disease ( pcos ) .", "all the five patients who presented in the late adolescent period had obvious genital ambiguity from birth , however , they sought medical attention only much later due to marked virilization and failure to attain menarche .", "one among them had actually been evaluated and even underwent a clitoroplasty at a young age , but unfortunately , the diagnosis of cah was missed as she was mistakenly categorized as probable ovo testicular dsd due to presence of mullerian structures with a phallic length of around 6 cm .", "all these 5 women had a masculine built at presentation with poor breast development , severe hirsutism , muscular body habitus , temporal balding and varying degrees of deepening of voice .", "the non classical cah ( nccah ) patients presented in adulthood with complaints of irregular cycles and hirsutism ; they had no features of virilisation .", "simple virilizing was the most common sub class seen among the women ( 81% ) whereas the salt wasting type was predominant among boys ( 85% ) .", "around 35% of patients had short stature as defined by height sds < -2.0 ; 2 patients who presented with adrenarche had increase in height sds , however , their bone age was also correspondingly advanced .", "all the children were treated with hydrocortisone ; almost all adult patients were on dexamethasone .", "none of the nccah patients were treated with glucocorticoids ; they were on anti - androgen therapy along with oral contraceptive pills .", "most adult classic cah patients with complaints of hirsutism were treated with either spironolactone or finasteride .", "pubertal induction with ethinyl estradiol was initiated for three of the adult patients who sought medical care late .", "analysis of 17 ohp levels revealed that 32% were suppressed with levels less than 1ng / ml ; appropriate in 47% and inadequate in 21% of patients ." ], [ "we report the phenotypic features of a cohort of patients with cah being evaluated and managed in a tertiary centre in southern india . in this series ,", "the typical presentation of male babies were with adrenal crisis between the 3 and 6 week of life . around 20% of female patients with classic cah", "were identified and appropriately treated only after late adolescence even when genital ambiguity was present since birth .", "short stature was seen in one third of patients on therapy and the average final adult height among patients with classic cah was 142.37 , which was significantly lower than the mean adult height for females in our population .", "the mean final adult height of 157.5 cm for those with nccah was better than their classic cah counterpart .", "obesity and hypertension were not found to be significantly higher in this cohort of cah patients .", "one third of patients had suppressed 17 ohp levels suggestive of over replacement therapy which may also contribute to the reduction in the final adult stature ." ] ]

[ "type 1 diabetes ( t1d ) results from the destruction of insulin producing pancreatic cells by a cell specific autoimmune process ( 1 ) . chronic pancreatic inflammation ( insulitis ) and destruction of islet -cells in type 1 diabetes", "is mediated by the immune cells , particularly autoreactive cd4 and cd8 t lymphocytes , b cells , macrophages and dendritic cells ( 2 ) . in order to obtain insight into type 1 diabetes pathogenic mechanisms in humans and to test novel therapeutic approaches for its treatment , different preclinical models of the disease such as spontaneous and accelerated diabetes in the non - obese diabetic ( nod ) mice ,", "biobreeding rats , or diabetes induced in susceptible rodent strains by multiple low doses of streptozotocin ( mlds ) are now available ( 3 ) . in the pathogenesis of t1d , several proinflamma - tory cytokines including ifn - , tnf- , il-1 , as well as il-17 ( 4 - 6 ) , have been implicated .", "it is also thought that the production of anti - inflammatory cytokines such as il-4 , il-10 and tgf- correlates with protection from t1d ( 6 ) .", "it has been shown that some drugs such as pentoxifylline ( ptx ) have immunomodulatory and anti - inflammatory activity , which might represent a potential preventive therapy for autoimmune diseases .", "ptx is a methyl xanthine - derived general phosphodiesterase ( pde ) inhibitor that has been available for many years to treat vascular disorder ( 7 ) .", "phosphodiesterases ( pdes ) are a family of enzymes that regulate intracellular levels of the cyclic nucleotides cyclic adenosine monophosphate ( camp ) and cyclic guanosine monophosphate ( cgmp ) by catalyzing their breakdown to inactive metabolites .", "drugs that increase the levels of camp , tend to reduce the production of proinflammatory mediators and increase the production of anti - inflammatory mediators by immune cells ( 8) . in recent years , the potential of ptx as an immunomodulatory and anti - inflammatory agent gained interest as it has been shown to effectively suppress the synthesis of tnf- and other pro inflammatory cytokines such as ifn - and il-12 in vitro and in vivo ( 9 - 10 ) .", "ptx has been successfully used for the treatment of experimental autoimmune diseases including experimental autoimmune myocarditis ( eam ) ( 11 ) , experimental autoimmune encephalomyelitis ( 12 ) , and adjuvant arthritis ( 13 ) . in the present study", ", we hypothesized that pentoxifylline , due to its anti - inflammatory and immunosuppressive activity , may affect autoimmune diabetes .", "consequently , we decided to investigate whether pentoxifylline treatment could prevent the development of mlds - induced diabetes in mice .", "streptozotocin ( stz ) , citrate buffer , pentoxifylline ( ptx ) , rpmi 1640 , l - glutamine , dimethylsul- foxide ( dmso ) , concanavalin a , mtt ( ( 3-(4,5-dimethyl - thiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) and fetal calf serum fetal were purchased from sigma - aldrich ( st.louis , mo ) .", "male c57bl/6 mice , weighing 20 to 25 g , were housed in a room with a 12-hr light / dark cycle .", "diabetes was induced by multiple low - dose of streptozotocin ( mlds ) injection in male c57bl/6 mice .", "stz was dissolved in 0.1 m citrate buffer ( ph 4.5 ) and injected intraperitoneally ( ip ) , within 10 min of preparation , at a dose of 40 mg / kg / day for 5 consecutive days .", "the blood samples were obtained from the tail vein of non - fasted mice , and glucose was measured using a glucometer ( accu - chech active ) .", "mice were considered diabetic when their non - fasting blood glucose level was > 250 mg / dl ( 14 ) .", "subsequently , the mice were allocated to three therapeutic groups ( n=7 per group ) ( normal control group , mlds group ( diabetic control group ) and treatment group ) . treatment with ptx ( 100 mg / kg / day for 21 days , ip )", "plasma , separated from blood by centrifugation , was stored at -80c until insulin assay .", "mice were euthanized and their splenic tissues were removed on day 21 for cytokine assay and mtt test .", "non - fasting blood sugar level was measured in 0 , 7 , 14 and 21 days after streptozotocin induced diabetes by using a glucometer ( accu - chech active).the blood samples were obtained from the tail vein of non - fasted mice ( 14 ) . before mice were euthanized , blood was collected from each mouse on day 21 in heparinized tubes .", "mice were euthanized and their spleens were removed on day 21 for cytokine production assay .", "after aseptic removal , spleens were placed in cold hanks solution and teased apart with a pair of forceps and a needle .", "a single cell suspension was obtained by passing it through a 200-mesh net and hemolyzed by the buffer solution containing 1 mmol / l tris hcl and 1% nh4cl ( ph 7.2 ) .", "subsequently , the macrophage cell content was depleted by incubation of the cell suspension in tissue culture dishes at 37c ( air+5% co2 ) to allow these cells to adhere to the bottom of the culture dishes .", "remaining free floating cells were seeded on culture dishes at a density of 510cells / ml in rpmi 1640 with 10% fetal calf serum , and 2", "the splenocytes ( 510cells / ml ) were treated with 2 g / ml concanavalin a for 72 hr , and cell supernatants were collected , then the levels of il-10 , il17 and ifn - were measured by elisa kits according to the manufacturers instructions .", "mouse splenic lymphocytes ( 110cells / ml ) were incubated in the absence or presence of concanavalin a ( 1.25 g / ml ) in a 96-well flat - bottom microculture plat in triplicate for 72 hr . thirty microliters of 5 mg / ml mtt ( ( 3-(4,5-dimethylthiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) in pbs was added to each well , and the plate was incubated at 37c for 4 hr .", "after incubation at 37c for 5 min , absorbance was measured spectro - photometrically at 490 nm . the stimulation index si ) was calculated according to the following formula : si= od concanavalin a ( con a ) stimulated lymphocyte proliferation / od spontaneous lymphocyte proliferation without con a. one - way analysis of variance ( anova ) followed by tukey s test were used for multiple comparisons between groups .", "streptozotocin ( stz ) , citrate buffer , pentoxifylline ( ptx ) , rpmi 1640 , l - glutamine , dimethylsul- foxide ( dmso ) , concanavalin a , mtt ( ( 3-(4,5-dimethyl - thiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) and fetal calf serum fetal were purchased from sigma - aldrich ( st.louis , mo ) .", "male c57bl/6 mice , weighing 20 to 25 g , were housed in a room with a 12-hr light / dark cycle .", "diabetes was induced by multiple low - dose of streptozotocin ( mlds ) injection in male c57bl/6 mice .", "stz was dissolved in 0.1 m citrate buffer ( ph 4.5 ) and injected intraperitoneally ( ip ) , within 10 min of preparation , at a dose of 40 mg / kg / day for 5 consecutive days .", "the blood samples were obtained from the tail vein of non - fasted mice , and glucose was measured using a glucometer ( accu - chech active ) .", "mice were considered diabetic when their non - fasting blood glucose level was > 250 mg / dl ( 14 ) .", "subsequently , the mice were allocated to three therapeutic groups ( n=7 per group ) ( normal control group , mlds group ( diabetic control group ) and treatment group ) . treatment with ptx ( 100 mg / kg / day for 21 days , ip ) was initiated in treatment group when they were considered diabetic . at the same time , the control groups received saline vehicle alone with the same schedule .", "plasma , separated from blood by centrifugation , was stored at -80c until insulin assay .", "mice were euthanized and their splenic tissues were removed on day 21 for cytokine assay and mtt test .", "non - fasting blood sugar level was measured in 0 , 7 , 14 and 21 days after streptozotocin induced diabetes by using a glucometer ( accu - chech active).the blood samples were obtained from the tail vein of non - fasted mice ( 14 ) .", "before mice were euthanized , blood was collected from each mouse on day 21 in heparinized tubes .", "mice were euthanized and their spleens were removed on day 21 for cytokine production assay .", "after aseptic removal , spleens were placed in cold hanks solution and teased apart with a pair of forceps and a needle .", "a single cell suspension was obtained by passing it through a 200-mesh net and hemolyzed by the buffer solution containing 1 mmol / l tris hcl and 1% nh4cl ( ph 7.2 ) .", "subsequently , the macrophage cell content was depleted by incubation of the cell suspension in tissue culture dishes at 37c ( air+5% co2 ) to allow these cells to adhere to the bottom of the culture dishes .", "remaining free floating cells were seeded on culture dishes at a density of 510cells / ml in rpmi 1640 with 10% fetal calf serum , and 2 mmol / l l - glutamine .", "the splenocytes ( 510cells / ml ) were treated with 2 g / ml concanavalin a for 72 hr , and cell supernatants were collected , then the levels of il-10 , il17 and ifn - were measured by elisa kits according to the manufacturers instructions .", "mouse splenic lymphocytes ( 110cells / ml ) were incubated in the absence or presence of concanavalin a ( 1.25 g / ml ) in a 96-well flat - bottom microculture plat in triplicate for 72 hr . thirty microliters of 5 mg / ml mtt ( ( 3-(4,5-dimethylthiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) in pbs was added to each well , and the plate was incubated at 37c for 4 hr . the plate was then centrifuged and followed by removal of medium .", "after incubation at 37c for 5 min , absorbance was measured spectro - photometrically at 490 nm . the stimulation index si ) was calculated according to the following formula : si= od concanavalin a ( con a ) stimulated lymphocyte proliferation / od spontaneous lymphocyte proliferation without con a.", "one - way analysis of variance ( anova ) followed by tukey s test were used for multiple comparisons between groups .", "all stz - induced diabetic mice with ptx treatment remained hyperglycemic on day 14 , and no significant difference in blood glucose levels was demonstrated between ptx and mlds(diabetic control group ) group .", "however , the levels of glucose in diabetic mice were significantly reduced after treatment with ptx ( p<0.05 ) , for 21day , when compared to the values of diabetic control mice ( figure 1 ) .", "effect of pentoxifylline treatment on blood glucose levels ( * p<0.05 ) to evaluate -cell function in terms of insulin release , we measured the plasma insulin levels on day 21 ( figure 2 ) .", "ptx prevented the mlds - induced reduction in plasma insulin , indicating a possible protective effect of ptx against -cell damage .", "effect of pentoxifylline treatment on plasma levels of insulin ( * p<0.05 ) treatment of mice with ptx significantly decreased mlds - induced production of ifn- and il-17 , while increased il-10 as compared with those in mlds group ( diabetic control group ) ( p<0.05)(figure 3 ) .", "effect of pentoxifylline on productions of ifn il-10 and il-17 of diabetic murine splenocytes induced by con a ex vivo ( * p<0.05 versus diabetic control group ) the stimulation index ( si ) in treatment group with ptx showed a significant decrease as compared with that in mlds group ( diabetic control group ) ( p<0.05)(figure 4 ) .", "effects of pentoxifylline on the proliferation of splenic lymphocytes induced by con a after 72 hr ( * p<0.05 )", "all stz - induced diabetic mice with ptx treatment remained hyperglycemic on day 14 , and no significant difference in blood glucose levels was demonstrated between ptx and mlds(diabetic control group ) group .", "however , the levels of glucose in diabetic mice were significantly reduced after treatment with ptx ( p<0.05 ) , for 21day , when compared to the values of diabetic control mice ( figure 1 ) .", "effect of pentoxifylline treatment on blood glucose levels ( * p<0.05 ) to evaluate -cell function in terms of insulin release , we measured the plasma insulin levels on day 21 ( figure 2 ) .", "ptx prevented the mlds - induced reduction in plasma insulin , indicating a possible protective effect of ptx against -cell damage .", "treatment of mice with ptx significantly decreased mlds - induced production of ifn- and il-17 , while increased il-10 as compared with those in mlds group ( diabetic control group ) ( p<0.05)(figure 3 ) .", "effect of pentoxifylline on productions of ifn il-10 and il-17 of diabetic murine splenocytes induced by con a ex vivo ( * p<0.05 versus diabetic control group )", "the stimulation index ( si ) in treatment group with ptx showed a significant decrease as compared with that in mlds group ( diabetic control group ) ( p<0.05)(figure 4 ) .", "effects of pentoxifylline on the proliferation of splenic lymphocytes induced by con a after 72 hr ( * p<0.05 )", "in rodents , experimental insulin - dependent diabetes can be induced by multiple low doses of streptozotocin ( mlds ) ( 15 ) .", "this model is a commonly used animal model that has many histological and clinical features similar to those of human type 1 diabetes and involves the participation of macrophages and t cells .", "streptozotocin ( stz ) is a pancreatic cell toxin that induces inflammation of the islets by immune cells when it is given in multiple low doses ( 16 ) .", "this model of diabetes offers some advantages , such as simultaneous appearance of diabetes mellitus in all animals and not having immune abnormalities that may complicate studies in spontaneous diabetes in non - obese diabetic ( nod ) mice or bio breeding ( bb ) rats .", "therefore , this model as a good model has been applied extensively to investigate the type 1 diabetes mellitus , especially study the immune pathways and modulations of autoimmune insulitis and cell death ( 17 - 18 ) .", "c57bl/6 mice , also called c57 black 6 or simply black 6 has the advantage of strain stability and easy breeding .", "the most common application of c57bl/6 mice is to serve as physiological or pathological models for in vivo experiments ( 19 ) . as such", ", mlds induced c57bl/6j mice were chosen to evaluate the anti - hyperglycemic activity of ptx and investigate the immunotherapeutic molecular mechanisms of how ptx attenuated the development of t1d .", "ptx is commonly used for the treatment of microcirculatory disorders and yields only minimal side effects in patients .", "in addition , due to its varied immunomodulatory effects , ptx has been used in several autoimmune diseases including rheumatoid arthritis ( 20 ) , multiple sclerosis ( 21 ) , and systemic lupus erythematosus ( 22 ) .", "drugs that increase the level of camp , including pde inhibitors , are known to prevent or attenuate inflammatory cell responses ( 20 ) .", "previous studies have also shown that ptx lowers blood glucose levels in diabetic animals ( 23 ) , and the results from the present studies also indicated that ptx possessed an anti - hyperglycemic property .", "more importantly , the present data demonstrated that ptx could increase serum insulin concentrations in type 1 diabetic mice .", "it has been shown that ptx could reduce ( but not abrogate ) the insulin requirements or lengthen the honeymoon ( non - insulin - requiring ) period in a study of 21 children with new - onset type 1diabetes ( 24 ) .", "t helper 1 cells produce proinflammatory cytokines ( tnf- , ifn - , il-1 , il-6 , and il-12 ) , which activate macrophages and cytotoxic t cells to destroy -cells , whereas anti - inflammatory cytokines ( il-4 and il-10 ) that are produced by activated t helper 2 cells , prevent -cell destructive insulitis ( 25 ) .", "il-10 has been shown to prevent the onset of diabetes in mice ( 26 ) . in response to cytokine stimulation , -cells generate reactive oxygen species ( ross ) and reactive nitrogen species such as nitric oxide ( no ) , which facilitate their destruction ( 27 ) .", "no is also synthesized within cytokine - activated macrophages by inducible nitric oxide synthase ( inos ) ( 28 ) .", "more recently , the role of il-17-producing t cells have been demonstrated in the development of several autoimmune diseases , including multiple sclerosis , rheumatoid arthritis and type 1 diabetes .", "il-17 is a proinflammatory cytokine that is detrimental to pancreatic islet cells ( 29 ) .", "il-17 promotes infiltration of neutrophils and macrophages , stimulates the production of other proinflammatory cytokines , including tnf- , il-1 , il-6 and il-12 , by activated macrophages and induces nitric oxide release from cells that interferes with their function and cause -cell destruction ( 30 , 5 ) .", "it has been assumed that ptx similar to camp elevating agents , selectively suppresses the production of t helper type 1(il-2 , ifn - ) , but not t helper type 2(il-4 , il-6 , il-10 ) cytokines ( 31 ) .", "however , it has also been demonstrated that the effect of ptx on cytokine production is cell - specific ( 32 ) .", "the present study shows that ptx is not only able to inhibit the release of proinflammatory cytokines ( ifn - and il-17 ) , but can also increase the production of anti - inflammatory cytokines ( il-10 ) . since ptx has been found to be able to inhibit the release of proinflammatory cytokines ( 33 ) , and favor th2 response ( 34 ) , it may indirectly interfere with the induction of inos .", "it has been shown that pde inhibitors elevate camp , prevent or attenuate inflammatory cell responses ( 35 ) and suppress proliferation of lymphocytes ( 36 ) .", "our findings are consistent with previous studies , showing that ptx treatment prevented lymphocyte proliferation .", "in summary , results of the present work demonstrated that the suppressive effect of the ptx treatment on t1d was accompanied by decreased blood glucose level , increased plasma insulin level , suppression of t cell proliferation , down - regulation of th1 and th17 cytokines ( ifn - and il-17 ) and increase in the production of il-10 in supernatant of splenic culture of the treated mice .", "it seems that pentoxifylline treatment has a therapeutic effect against mlds - induced diabetes in mice ." ]

[ "<S> objective(s):pentoxifylline is an immunomodulatory and anti - inflammatory agent and is used in vascular disorders . </S>", "<S> it has been shown that pentoxifylline inhibits proinflammatory cytokines production . </S>", "<S> the purpose of this study was to investigate the therapeutic effects of pentoxifylline on the treatment of autoimmune diabetes in mice.materials and methods : diabetes was induced by multiple low dose of streptozotocin ( mlds ) injection ( 40 mg / kg / day for 5 consecutive days ) in male c57bl/6 mice . </S>", "<S> after induction of diabetes , mice were treated with pentoxifylline ( 100 mg / kg / day ip ) for 21 days . </S>", "<S> blood glucose levels and plasma levels of insulin were measured . </S>", "<S> splenocytes were tested for proliferation by mtt test and cytokine production by elisa.results:pentoxifylline treatment prevented hyperglycemia and increased plasma insulin levels in the diabetic mice . aside from reducing lymphocyte proliferation , pentoxifylline significantly inhibited the production of proinflammatory interleukin 17 ( il-17 ) as well as interferon gamma ( ifn- ) , while increased anti - inflammatory cytokine il-10 as compared with those in mlds group ( diabetic control group).conclusion : these findings indicate that pentoxifylline may have therapeutic effect against the autoimmune destruction of the pancreatic beta - cells during the development of mlds - induced type 1 diabetes in mice . </S>" ]

[ "Introduction", "Materials and Methods", "Drug and Reagent", "Animals and materials", "Animal treatments", "Quantification of glucose in the blood", "Plasma insulin determination", "Splenocyte culture and cytokine determination", "MTT proliferation assay", "Statistical analysis", "Results", "Effects of pentoxifylline on MLDS-induced hyperglycemia and plasma insulin level", "Effects of pentoxifylline on cytokine production in type 1 diabetic murine splenocytes", "Effects of pentoxifylline on the proliferation of splenic lymphocytes", "Discussion", "Conclusion" ]

[ [ "type 1 diabetes ( t1d ) results from the destruction of insulin producing pancreatic cells by a cell specific autoimmune process ( 1 ) . chronic pancreatic inflammation ( insulitis ) and destruction of islet -cells in type 1 diabetes", "is mediated by the immune cells , particularly autoreactive cd4 and cd8 t lymphocytes , b cells , macrophages and dendritic cells ( 2 ) . in order to obtain insight into type 1 diabetes pathogenic mechanisms in humans and to test novel therapeutic approaches for its treatment , different preclinical models of the disease such as spontaneous and accelerated diabetes in the non - obese diabetic ( nod ) mice ,", "biobreeding rats , or diabetes induced in susceptible rodent strains by multiple low doses of streptozotocin ( mlds ) are now available ( 3 ) . in the pathogenesis of t1d , several proinflamma - tory cytokines including ifn - , tnf- , il-1 , as well as il-17 ( 4 - 6 ) , have been implicated .", "it is also thought that the production of anti - inflammatory cytokines such as il-4 , il-10 and tgf- correlates with protection from t1d ( 6 ) .", "it has been shown that some drugs such as pentoxifylline ( ptx ) have immunomodulatory and anti - inflammatory activity , which might represent a potential preventive therapy for autoimmune diseases .", "ptx is a methyl xanthine - derived general phosphodiesterase ( pde ) inhibitor that has been available for many years to treat vascular disorder ( 7 ) .", "phosphodiesterases ( pdes ) are a family of enzymes that regulate intracellular levels of the cyclic nucleotides cyclic adenosine monophosphate ( camp ) and cyclic guanosine monophosphate ( cgmp ) by catalyzing their breakdown to inactive metabolites .", "drugs that increase the levels of camp , tend to reduce the production of proinflammatory mediators and increase the production of anti - inflammatory mediators by immune cells ( 8) . in recent years , the potential of ptx as an immunomodulatory and anti - inflammatory agent gained interest as it has been shown to effectively suppress the synthesis of tnf- and other pro inflammatory cytokines such as ifn - and il-12 in vitro and in vivo ( 9 - 10 ) .", "ptx has been successfully used for the treatment of experimental autoimmune diseases including experimental autoimmune myocarditis ( eam ) ( 11 ) , experimental autoimmune encephalomyelitis ( 12 ) , and adjuvant arthritis ( 13 ) . in the present study", ", we hypothesized that pentoxifylline , due to its anti - inflammatory and immunosuppressive activity , may affect autoimmune diabetes .", "consequently , we decided to investigate whether pentoxifylline treatment could prevent the development of mlds - induced diabetes in mice ." ], [ "streptozotocin ( stz ) , citrate buffer , pentoxifylline ( ptx ) , rpmi 1640 , l - glutamine , dimethylsul- foxide ( dmso ) , concanavalin a , mtt ( ( 3-(4,5-dimethyl - thiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) and fetal calf serum fetal were purchased from sigma - aldrich ( st.louis , mo ) .", "male c57bl/6 mice , weighing 20 to 25 g , were housed in a room with a 12-hr light / dark cycle .", "diabetes was induced by multiple low - dose of streptozotocin ( mlds ) injection in male c57bl/6 mice .", "stz was dissolved in 0.1 m citrate buffer ( ph 4.5 ) and injected intraperitoneally ( ip ) , within 10 min of preparation , at a dose of 40 mg / kg / day for 5 consecutive days .", "the blood samples were obtained from the tail vein of non - fasted mice , and glucose was measured using a glucometer ( accu - chech active ) .", "mice were considered diabetic when their non - fasting blood glucose level was > 250 mg / dl ( 14 ) .", "subsequently , the mice were allocated to three therapeutic groups ( n=7 per group ) ( normal control group , mlds group ( diabetic control group ) and treatment group ) . treatment with ptx ( 100 mg / kg / day for 21 days , ip )", "plasma , separated from blood by centrifugation , was stored at -80c until insulin assay .", "mice were euthanized and their splenic tissues were removed on day 21 for cytokine assay and mtt test .", "non - fasting blood sugar level was measured in 0 , 7 , 14 and 21 days after streptozotocin induced diabetes by using a glucometer ( accu - chech active).the blood samples were obtained from the tail vein of non - fasted mice ( 14 ) . before mice were euthanized , blood was collected from each mouse on day 21 in heparinized tubes .", "mice were euthanized and their spleens were removed on day 21 for cytokine production assay .", "after aseptic removal , spleens were placed in cold hanks solution and teased apart with a pair of forceps and a needle .", "a single cell suspension was obtained by passing it through a 200-mesh net and hemolyzed by the buffer solution containing 1 mmol / l tris hcl and 1% nh4cl ( ph 7.2 ) .", "subsequently , the macrophage cell content was depleted by incubation of the cell suspension in tissue culture dishes at 37c ( air+5% co2 ) to allow these cells to adhere to the bottom of the culture dishes .", "remaining free floating cells were seeded on culture dishes at a density of 510cells / ml in rpmi 1640 with 10% fetal calf serum , and 2", "the splenocytes ( 510cells / ml ) were treated with 2 g / ml concanavalin a for 72 hr , and cell supernatants were collected , then the levels of il-10 , il17 and ifn - were measured by elisa kits according to the manufacturers instructions .", "mouse splenic lymphocytes ( 110cells / ml ) were incubated in the absence or presence of concanavalin a ( 1.25 g / ml ) in a 96-well flat - bottom microculture plat in triplicate for 72 hr . thirty microliters of 5 mg / ml mtt ( ( 3-(4,5-dimethylthiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) in pbs was added to each well , and the plate was incubated at 37c for 4 hr .", "after incubation at 37c for 5 min , absorbance was measured spectro - photometrically at 490 nm . the stimulation index si ) was calculated according to the following formula : si= od concanavalin a ( con a ) stimulated lymphocyte proliferation / od spontaneous lymphocyte proliferation without con a. one - way analysis of variance ( anova ) followed by tukey s test were used for multiple comparisons between groups ." ], [ "streptozotocin ( stz ) , citrate buffer , pentoxifylline ( ptx ) , rpmi 1640 , l - glutamine , dimethylsul- foxide ( dmso ) , concanavalin a , mtt ( ( 3-(4,5-dimethyl - thiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) and fetal calf serum fetal were purchased from sigma - aldrich ( st.louis , mo ) ." ], [ "male c57bl/6 mice , weighing 20 to 25 g , were housed in a room with a 12-hr light / dark cycle ." ], [ "diabetes was induced by multiple low - dose of streptozotocin ( mlds ) injection in male c57bl/6 mice .", "stz was dissolved in 0.1 m citrate buffer ( ph 4.5 ) and injected intraperitoneally ( ip ) , within 10 min of preparation , at a dose of 40 mg / kg / day for 5 consecutive days .", "the blood samples were obtained from the tail vein of non - fasted mice , and glucose was measured using a glucometer ( accu - chech active ) .", "mice were considered diabetic when their non - fasting blood glucose level was > 250 mg / dl ( 14 ) .", "subsequently , the mice were allocated to three therapeutic groups ( n=7 per group ) ( normal control group , mlds group ( diabetic control group ) and treatment group ) . treatment with ptx ( 100 mg / kg / day for 21 days , ip ) was initiated in treatment group when they were considered diabetic . at the same time , the control groups received saline vehicle alone with the same schedule .", "plasma , separated from blood by centrifugation , was stored at -80c until insulin assay .", "mice were euthanized and their splenic tissues were removed on day 21 for cytokine assay and mtt test ." ], [ "non - fasting blood sugar level was measured in 0 , 7 , 14 and 21 days after streptozotocin induced diabetes by using a glucometer ( accu - chech active).the blood samples were obtained from the tail vein of non - fasted mice ( 14 ) ." ], [ "before mice were euthanized , blood was collected from each mouse on day 21 in heparinized tubes ." ], [ "mice were euthanized and their spleens were removed on day 21 for cytokine production assay .", "after aseptic removal , spleens were placed in cold hanks solution and teased apart with a pair of forceps and a needle .", "a single cell suspension was obtained by passing it through a 200-mesh net and hemolyzed by the buffer solution containing 1 mmol / l tris hcl and 1% nh4cl ( ph 7.2 ) .", "subsequently , the macrophage cell content was depleted by incubation of the cell suspension in tissue culture dishes at 37c ( air+5% co2 ) to allow these cells to adhere to the bottom of the culture dishes .", "remaining free floating cells were seeded on culture dishes at a density of 510cells / ml in rpmi 1640 with 10% fetal calf serum , and 2 mmol / l l - glutamine .", "the splenocytes ( 510cells / ml ) were treated with 2 g / ml concanavalin a for 72 hr , and cell supernatants were collected , then the levels of il-10 , il17 and ifn - were measured by elisa kits according to the manufacturers instructions ." ], [ "mouse splenic lymphocytes ( 110cells / ml ) were incubated in the absence or presence of concanavalin a ( 1.25 g / ml ) in a 96-well flat - bottom microculture plat in triplicate for 72 hr . thirty microliters of 5 mg / ml mtt ( ( 3-(4,5-dimethylthiazolyl)-2,5-diphenyl - tetrazolium bromide ) ) in pbs was added to each well , and the plate was incubated at 37c for 4 hr . the plate was then centrifuged and followed by removal of medium .", "after incubation at 37c for 5 min , absorbance was measured spectro - photometrically at 490 nm . the stimulation index si ) was calculated according to the following formula : si= od concanavalin a ( con a ) stimulated lymphocyte proliferation / od spontaneous lymphocyte proliferation without con a." ], [ "one - way analysis of variance ( anova ) followed by tukey s test were used for multiple comparisons between groups ." ], [ "all stz - induced diabetic mice with ptx treatment remained hyperglycemic on day 14 , and no significant difference in blood glucose levels was demonstrated between ptx and mlds(diabetic control group ) group .", "however , the levels of glucose in diabetic mice were significantly reduced after treatment with ptx ( p<0.05 ) , for 21day , when compared to the values of diabetic control mice ( figure 1 ) .", "effect of pentoxifylline treatment on blood glucose levels ( * p<0.05 ) to evaluate -cell function in terms of insulin release , we measured the plasma insulin levels on day 21 ( figure 2 ) .", "ptx prevented the mlds - induced reduction in plasma insulin , indicating a possible protective effect of ptx against -cell damage .", "effect of pentoxifylline treatment on plasma levels of insulin ( * p<0.05 ) treatment of mice with ptx significantly decreased mlds - induced production of ifn- and il-17 , while increased il-10 as compared with those in mlds group ( diabetic control group ) ( p<0.05)(figure 3 ) .", "effect of pentoxifylline on productions of ifn il-10 and il-17 of diabetic murine splenocytes induced by con a ex vivo ( * p<0.05 versus diabetic control group ) the stimulation index ( si ) in treatment group with ptx showed a significant decrease as compared with that in mlds group ( diabetic control group ) ( p<0.05)(figure 4 ) .", "effects of pentoxifylline on the proliferation of splenic lymphocytes induced by con a after 72 hr ( * p<0.05 )" ], [ "all stz - induced diabetic mice with ptx treatment remained hyperglycemic on day 14 , and no significant difference in blood glucose levels was demonstrated between ptx and mlds(diabetic control group ) group .", "however , the levels of glucose in diabetic mice were significantly reduced after treatment with ptx ( p<0.05 ) , for 21day , when compared to the values of diabetic control mice ( figure 1 ) .", "effect of pentoxifylline treatment on blood glucose levels ( * p<0.05 ) to evaluate -cell function in terms of insulin release , we measured the plasma insulin levels on day 21 ( figure 2 ) .", "ptx prevented the mlds - induced reduction in plasma insulin , indicating a possible protective effect of ptx against -cell damage ." ], [ "treatment of mice with ptx significantly decreased mlds - induced production of ifn- and il-17 , while increased il-10 as compared with those in mlds group ( diabetic control group ) ( p<0.05)(figure 3 ) .", "effect of pentoxifylline on productions of ifn il-10 and il-17 of diabetic murine splenocytes induced by con a ex vivo ( * p<0.05 versus diabetic control group )" ], [ "the stimulation index ( si ) in treatment group with ptx showed a significant decrease as compared with that in mlds group ( diabetic control group ) ( p<0.05)(figure 4 ) .", "effects of pentoxifylline on the proliferation of splenic lymphocytes induced by con a after 72 hr ( * p<0.05 )" ], [ "in rodents , experimental insulin - dependent diabetes can be induced by multiple low doses of streptozotocin ( mlds ) ( 15 ) .", "this model is a commonly used animal model that has many histological and clinical features similar to those of human type 1 diabetes and involves the participation of macrophages and t cells .", "streptozotocin ( stz ) is a pancreatic cell toxin that induces inflammation of the islets by immune cells when it is given in multiple low doses ( 16 ) .", "this model of diabetes offers some advantages , such as simultaneous appearance of diabetes mellitus in all animals and not having immune abnormalities that may complicate studies in spontaneous diabetes in non - obese diabetic ( nod ) mice or bio breeding ( bb ) rats .", "therefore , this model as a good model has been applied extensively to investigate the type 1 diabetes mellitus , especially study the immune pathways and modulations of autoimmune insulitis and cell death ( 17 - 18 ) .", "c57bl/6 mice , also called c57 black 6 or simply black 6 has the advantage of strain stability and easy breeding .", "the most common application of c57bl/6 mice is to serve as physiological or pathological models for in vivo experiments ( 19 ) . as such", ", mlds induced c57bl/6j mice were chosen to evaluate the anti - hyperglycemic activity of ptx and investigate the immunotherapeutic molecular mechanisms of how ptx attenuated the development of t1d .", "ptx is commonly used for the treatment of microcirculatory disorders and yields only minimal side effects in patients .", "in addition , due to its varied immunomodulatory effects , ptx has been used in several autoimmune diseases including rheumatoid arthritis ( 20 ) , multiple sclerosis ( 21 ) , and systemic lupus erythematosus ( 22 ) .", "drugs that increase the level of camp , including pde inhibitors , are known to prevent or attenuate inflammatory cell responses ( 20 ) .", "previous studies have also shown that ptx lowers blood glucose levels in diabetic animals ( 23 ) , and the results from the present studies also indicated that ptx possessed an anti - hyperglycemic property .", "more importantly , the present data demonstrated that ptx could increase serum insulin concentrations in type 1 diabetic mice .", "it has been shown that ptx could reduce ( but not abrogate ) the insulin requirements or lengthen the honeymoon ( non - insulin - requiring ) period in a study of 21 children with new - onset type 1diabetes ( 24 ) .", "t helper 1 cells produce proinflammatory cytokines ( tnf- , ifn - , il-1 , il-6 , and il-12 ) , which activate macrophages and cytotoxic t cells to destroy -cells , whereas anti - inflammatory cytokines ( il-4 and il-10 ) that are produced by activated t helper 2 cells , prevent -cell destructive insulitis ( 25 ) .", "il-10 has been shown to prevent the onset of diabetes in mice ( 26 ) . in response to cytokine stimulation , -cells generate reactive oxygen species ( ross ) and reactive nitrogen species such as nitric oxide ( no ) , which facilitate their destruction ( 27 ) .", "no is also synthesized within cytokine - activated macrophages by inducible nitric oxide synthase ( inos ) ( 28 ) .", "more recently , the role of il-17-producing t cells have been demonstrated in the development of several autoimmune diseases , including multiple sclerosis , rheumatoid arthritis and type 1 diabetes .", "il-17 is a proinflammatory cytokine that is detrimental to pancreatic islet cells ( 29 ) .", "il-17 promotes infiltration of neutrophils and macrophages , stimulates the production of other proinflammatory cytokines , including tnf- , il-1 , il-6 and il-12 , by activated macrophages and induces nitric oxide release from cells that interferes with their function and cause -cell destruction ( 30 , 5 ) .", "it has been assumed that ptx similar to camp elevating agents , selectively suppresses the production of t helper type 1(il-2 , ifn - ) , but not t helper type 2(il-4 , il-6 , il-10 ) cytokines ( 31 ) .", "however , it has also been demonstrated that the effect of ptx on cytokine production is cell - specific ( 32 ) .", "the present study shows that ptx is not only able to inhibit the release of proinflammatory cytokines ( ifn - and il-17 ) , but can also increase the production of anti - inflammatory cytokines ( il-10 ) . since ptx has been found to be able to inhibit the release of proinflammatory cytokines ( 33 ) , and favor th2 response ( 34 ) , it may indirectly interfere with the induction of inos .", "it has been shown that pde inhibitors elevate camp , prevent or attenuate inflammatory cell responses ( 35 ) and suppress proliferation of lymphocytes ( 36 ) .", "our findings are consistent with previous studies , showing that ptx treatment prevented lymphocyte proliferation ." ], [ "in summary , results of the present work demonstrated that the suppressive effect of the ptx treatment on t1d was accompanied by decreased blood glucose level , increased plasma insulin level , suppression of t cell proliferation , down - regulation of th1 and th17 cytokines ( ifn - and il-17 ) and increase in the production of il-10 in supernatant of splenic culture of the treated mice .", "it seems that pentoxifylline treatment has a therapeutic effect against mlds - induced diabetes in mice ." ] ]

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["Objetivo:","Mtodos:","Resultados:","Concluses:","INTRODUCTION","METHODS"," Patients "," Procedures(...TRUNCATED)

[["determinar a presena de anticorpos ige especficos para superantgenos estafiloccicos e o grau de s(...TRUNCATED)

["the family is the cornerstone of human social support network and its presence is essential in eve(...TRUNCATED)

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[ "I", "M", "F", "D", "C" ]

[["the family is the cornerstone of human social support network and its presence is essential in ev(...TRUNCATED)

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["<S> background and objective : anxiety and depression are among the psychological disorders in h(...TRUNCATED)

["INTRODUCTION ","METHODS ","ETHICAL CONSIDERATIONS","RESULTS ","DISCUSSION ","CONFLICT OF INTEREST"(...TRUNCATED)

[["development of human societies and industrialization as well as changes in stress sources has cha(...TRUNCATED)

["sixty - four patients in nepal that met us department of defense enrollment criteria ( 9 ) for inf(...TRUNCATED)

["<S> worldwide emergence of variant viruses has prompted a change in the 20052006 h3n2 influenza a (...TRUNCATED)

["Materials and Methods","Sample Collection and Antigenic Analysis","Molecular Analysis","Results","(...TRUNCATED)

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["rising levels of obesity are becoming a worldwide phenomenon and are increasingly identified as a (...TRUNCATED)

["<S> excess weight has generally been associated with adverse health outcomes ; however , the link (...TRUNCATED)

[ "1. Introduction", "2. Methods", "3. Results", "4. Discussion" ]

[["rising levels of obesity are becoming a worldwide phenomenon and are increasingly identified as a(...TRUNCATED)