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major depressive disorder ( mdd ) and posttraumatic stress disorder ( ptsd ) have been associated with higher incidence of cardiovascular disease [ 14 ] and diabetes [ 5 , 6 ] .
one mechanism that may contribute to the comorbidity between psychopathology and adverse health outcomes is chronic inflammation , whose role in atherosclerosis is well established [ 7 , 8 ] .
c - reactive protein ( crp ) is a marker of systemic inflammation and provides a useful indicator of chronic inflammation . increased circulating concentrations of crp are associated with mdd [ 7 , 911 ] . increased circulating concentrations of crp have also been described in ptsd [ 1214 ] ; however , the relationship is not as clear as other data are equivocal [ 1517 ] . because inflammation may be a key factor in understanding the significant comorbidity between psychiatric disorders and physical diseases , establishing other psychological factors that help explain the relationship between inflammation and psychiatric disorders and how problems with inflammation may develop is critical .
ample evidence indicates that early life stress is associated with chronic inflammation in adulthood [ 18 , 19 ] , and this may be particularly true among african americans .
for example , a recent meta - analysis on the role of childhood maltreatment ( i.e. , childhood sexual , physical , and emotional abuse and physical and emotional neglect ) in inflammation in adulthood demonstrated a significant positive association between exposure to childhood trauma and higher circulating concentrations of crp .
childhood maltreatment exposure may be particularly detrimental to the immune system via problematic alterations in the function of the hypothalamic pituitary adrenal ( hpa ) axis , a major component of the body 's stress response system and a system that both modulates and is modulated by inflammatory processes [ 22 , 23 ] .
based on this evidence , some posit that chronic inflammation may be one mediator in the relationship between early trauma exposure and the later development of psychiatric disorders .
it is important to note that the results of the meta - analysis on childhood trauma and inflammation suggested a relatively subtle ( although significant ) effect of trauma exposure on inflammatory activation suggesting that there may be other important components to this pathway that should be considered .
emotion dysregulation , or deficits in awareness and management of intense negative emotional states , is a transdiagnostic risk factor for the development and maintenance of many psychological disorders , including depression and ptsd [ 23 , 24 ] , and may be another psychological factor that impacts chronic inflammation .
importantly , emotional development begins early in life and developmental research has shown a strong relationship between exposure to childhood maltreatment and the development of emotion regulation deficits in adolescence and adulthood [ 2527 ] .
this may occur in part because emotion regulation strategies are learned by caregivers and when family environments are harmful or unsupportive , children are less likely to be exposed to appropriate regulatory behavior and more likely to experience emotional invalidation where emotional expression is ignored , rejected , or punished .
therefore , emotion dysregulation may be an important mechanism by which early life adversity confers lifetime risk for psychological disorders [ 25 , 26 ] . based on the strong link between childhood maltreatment and emotion dysregulation
recent research in fact suggests that emotion functioning is related to inflammation . a longitudinal study examining emotional functioning in 7-year - old children showed that inappropriate self - regulation and distress proneness during childhood predicted higher circulating concentrations of crp in adulthood .
other cross - sectional research on adults looked specifically at emotion regulation and showed that reappraisal ( an adaptive emotion regulation skill ) was associated with lower circulating concentrations of crp while suppression ( a maladaptive emotion regulation skill ) was associated with elevated circulating concentrations of crp . taken together , these studies indicate that emotion dysregulation could be important in predicting chronic inflammation , although no studies to our knowledge have examined the specific association between emotion dysregulation and circulating concentrations of crp among traumatized adults with high rates of depression and ptsd .
one population at particular risk for elevated systemic inflammation is individuals with type 2 diabetes mellitus ( t2 dm ) .
multiple recent longitudinal studies show that elevated circulating concentrations of crp put individuals at greater risk of developing t2 dm [ 31 , 32 ] . understanding psychological factors that may be associated with increased inflammation levels in individuals with t2 dm could be useful when considering how to improve treatments .
therefore , the goal of the present study was to examine the differential associations between trauma exposure , emotion dysregulation , current mdd , current ptsd , and crp concentrations in a highly traumatized urban , minority sample of women with t2 dm . we hypothesized that emotion dysregulation would be associated with higher concentrations of crp independent of the effects of trauma exposure and current psychiatric diagnoses ( i.e. , ptsd and mdd ) .
participants were drawn from astudy of risk factors for the development of ptsd in a low socioeconomic , urban minority population .
participants were recruited from waiting rooms in the diabetic , gynecology , and primary care medical clinics at a publically funded hospital in atlanta , georgia .
we did not narrow recruitment to specific criteria but approachedany individual in the waiting room . to be eligible for participation , subjects had to be between the ages of 18 and 65 and able to give informed consent ( see for full details regarding study procedures ) .
the investigation was carried out in accordance with the latest version of the declaration of helsinki and informed consent of the participants was obtained after the nature of the procedures had been fully explained .
after signing the informed consent approved by the emory institutional review board and the research oversight committee of grady memorial hospital , an interview was administered with questionnaires regarding trauma history and psychological variables .
a subgroup of female participants with t2 dm was chosen for a separate associated study .
exclusion criteria included current bipolar or psychotic disorder diagnosis , alcohol or substance dependence , treatment for an autoimmune disorder , treatment with nonsteroidal anti - inflammatory , glucocorticoid , or anticonvulsant , and current treatment with an antipsychotic , benzodiazepine , or antidepressant .
on the morning of the interview , height and weight were measured for calculation of body mass index ( bmi ) and fasting blood samples were collected for later batch assessment of crp concentrations ( approximately 2 weeks after initial assessment ) .
the current study included 40 diabetic african - american women with a mean age of 51.88 years ( sd = 7.57 years , range = 3265 ) .
education levels were as follows : 18.8% reported less than high school education , 21.9% reported having a high school diploma or ged , 37.5% reported having some college or technical school education , and 21.9% reported graduating from technical school or college .
only 25.0% of participants were employed and 84.4% had a household monthly income of $ 1999 or less .
the ders is a 36-item psychometrically validated self - report measure of emotion regulation difficulties .
it measures several aspects of emotion regulation , including awareness and understanding of one 's emotions , acceptance of negative emotions , the ability to successfully engage in goal - directed behavior and control impulsive behavior when experiencing negative emotions , and the ability to use situationally appropriate emotion regulation strategies .
for the present study the overall scale , as well as six subscales , of emotion regulation was examined .
the internal consistency of the ders total scale was high ( = 0.92 ) .
it was administered to detail frequency and type of trauma(s ) experienced ; consistent with prior research , total level of trauma exposure was measured by a sum score reflecting the total frequency of different types of trauma ( e.g. , car accident , sexual assault ) a participant had been exposed to over the course of their life . for this study ,
the number of traumatic experiences reflects the total number of different types of events that an individual experienced or witnessed . in order to separate lifetime trauma exposure and childhood abuse
, we excluded the childhood abuse items from the tei ( i.e. , exposure to sexual abuse , physical abuse , and emotional abuse ) .
the ctq is a 25-item , reliable , and valid self - report instrument assessing sexual , physical , emotional abuse , and neglect in childhood ( = 0.92 in current study ) .
bernstein and fink established scores for none , mild , moderate , and severe for each type of abuse . for descriptive purposes , the data from the ctq were used to create a categorical variable to account for the presence or absence of moderate - to - severe reported exposure to emotional ( score 13 ) , physical ( score 10 ) , and sexual ( score 8) abuse in childhood ( 0 = none or mild abuse ; 1 = the presence of moderate or severe abuse scores for at least one of the three types of abuse ) . a continuous measure of overall severity of childhood abuse exposure was also calculated and used as the measure of child abuse severity in all analyses .
the caps is an interviewer - administered psychometrically validated diagnostic instrument measuring ptsd [ 37 , 38 ] .
it includes items that rate social and occupational functioning , global ptsd symptom severity , and the validity of participant 's responses .
the caps assesses current ptsd and was used to determine presence / absence of a ptsd diagnosis . mini is a structured diagnostic interview that assesses mood , anxiety , substance use , and psychotic disorders based on dsm - iv - tr criteria .
mini has shown good reliability and validity across different samples [ 39 , 40 ] .
for the present study , only the current major depression section was used to assess presence / absence of current mdd .
body mass index is calculated as bmi = body mass ( kg)/(height ( m ) ) .
mean bmi for this sample was 36.53 ( sd = 7.30 , range = 2153.80 ) .
serum samples were stored at 80c until the time of highly sensitive crp ( hscrp ) assay .
serum hscrp concentrations were determined using an immunoturbidimetric assay from sekisui diagnostics ( lexington , ma ) on the beckman au480 chemistry analyzer , with an interassay coefficient of variation ( cv ) of 5.2% and an intra - assay cv of 3.1% .
individuals with circulating concentrations of hscrp > 20 mg / l were excluded from analysis because hscrp > 20 mg / l suggests the presence of an active infection or other illnesses that could seriously confound study findings ( two individuals were excluded from analyses ( hscrp = 26.25 and 61.69 ) ) .
circulating concentrations of hscrp averaged 5.70 mg / l ( sd = 4.81 , range = 0.2318.43 ) .
glucose is measured by enzymatic methods on the beckman au480 using reagents from beckman coulter ( fullerton , ca ) .
average glucose level for this sample was 125.05 ( sd = 38.31 , range = 35.70208.15 ) .
hba1c was measured using high performance liquid chromatography by arup laboratories ( salt lake city , utah ) .
average hba1c for this sample was 7.61 ( sd = 1.71 , range = 4.9013.60 ) .
the overall analytic approach was to examine the predictive utility of trauma , current ptsd , current mdd , and emotion dysregulation on hscrp concentrations .
hscrp concentrations , trauma exposure , and emotion dysregulation variables were positively skewed . however , the level of skewness ( range : 0.321.96 ) in this sample fell within acceptable parameters for the sample size on all variables except child abuse severity and the difficulty with emotion regulation strategies dimension of emotion dysregulation .
each had one outlier which affected the level of kurtosis , but results remained the same with or without these outliers included and so they remained in the models presented .
differences in trauma level , emotion dysregulation , and bmi were also examined by both mdd and ptsd diagnoses using analysis of variance ( table 1 ) . for variables of interest , bivariate correlations ( continuous variables ) and a univariate analysis of variance ( categorical variables )
then , based on the results of the correlational analyses , a series of linear regression models was fit to examine the unique predictive value of child abuse , current mdd , and emotion dysregulation on hscrp .
potential covariates for regression analysis were first identified based on previous research suggesting associations with circulating concentrations of hscrp : age , income , bmi , hemoglobin a1c , and baseline blood glucose level [ 9 , 4245 ] . due to the small sample size and risk for low power in detecting significant effects ,
associations between hscrp and these potential covariates were first assessed to determine if their inclusion in the regression model was warranted .
no significant differences emerged between any of the variables and hscrp except for bmi ( r = 0.40 , p = 0.01 ) and therefore only bmi was included as a covariate in the regression analysis .
all analyses were conducted with spss 23.0 software package ( twelve primary analyses were conducted resulting in a bonferroni correction value of p < 0.004 ) .
this was a highly traumatized sample , with all participants reporting the experience of at least one type of trauma in their lifetime ( excluding child abuse ; m = 4.31 , sd = 2.28 ) .
many participants were also exposed to childhood abuse ( i.e. sexual , physical , or emotional abuse ) , with 35.0% of the sample reporting exposure to moderate - to - severe child abuse .
rates of depression and ptsd were also high in this sample , with 32.5% ( n = 13 ) meeting criteria for current mdd and 32.5% ( n = 13 ) meeting criteria for current ptsd . the majority of those individuals that met diagnostic criteria for at least one diagnosis in fact met diagnostic criteria for both mdd and ptsd ( 22.5% of overall sample , n = 9 ) .
as shown in table 1 , individuals with depression and ptsd were more likely to report higher levels of child abuse ( p < 0.01 and p < 0.001 , resp . ) and emotion dysregulation ( p <
0.01 and p < 0.05 , resp . ) . rates of other trauma exposure and bmi were not significantly different across groups . to determine the extent of association between trauma exposure , emotion dysregulation , and hscrp , we first calculated pearson correlation coefficients among our variables of interest ( see table 2 ) .
bmi was also included in these analyses to evaluate independent associations with the variables of interest .
overall emotion dysregulation was significantly positively correlated with hscrp concentrations ( p < 0.001 ) . when looking at the six dimensions of emotion dysregulation , all six were significantly positively correlated with difficulty controlling impulses and lack of emotion regulation strategies showing the strongest correlations ( p < 0.001 ) .
all significant associations except for lack of awareness of emotions would survive correction for multiple comparisons .
the association between child abuse severity and hscrp trended toward significance ( p = 0.067 ) .
however , overall trauma exposure ( excluding child abuse ) was not significantly correlated with hscrp . regarding associations between trauma exposure and emotion dysregulation ,
child abuse severity was associated with overall emotion dysregulation ( p < 0.05 ) as well as nonacceptance of emotions ( p = 0.01 ) and difficulty with goal - directed behavior in the presence of strong emotions ( p = 0.05 ) .
overall trauma exposure ( excluding child abuse ) was not associated with emotion dysregulation . however
, child abuse severity and overall trauma exposure ( excluding abuse ) were significantly correlated with each other ( p < 0.05 ) . regarding bmi , only one emotion dysregulation dimension
lack of awareness of emotions was significantly associated with bmi ( p < 0.05 ) .
univariate analysis of variance was then used to examine mean differences in hscrp by ptsd and mdd diagnosis .
as shown in figure 1 , univariate analysis of variance results showed that there was a significant increase in mean hscrp across current mdd diagnosis ( f = 19.12 , p < 0.001 ) but not current ptsd diagnosis ( f = 2.87 , p = 0.10 ) .
next , a series of linear regression models was run to test the differential associations of child abuse , current mdd , and emotion dysregulation with hscrp .
then , child abuse severity was entered into the second step of the regression model .
as shown in table 3 , when bmi was included in step 1 , higher bmi was significantly related to higher hscrp levels ( p < 0.05 ) .
when child abuse severity was included in step 2 , it was not significant in predicting hscrp .
in step 3 , when current mdd was entered into the regression model , mdd was significantly predictive of hscrp ( p < 0.01 ) , accounting for 13% of the variance in hscrp independent of bmi and child abuse severity .
when overall emotion dysregulation was included in the model in step 4 , emotion dysregulation was significantly predictive of hscrp ( p < 0.001 ) above and beyond bmi , child abuse severity , and current mdd , surviving correction for multiple comparisons and accounting for 25% of unique variance in predicting higher hscrp concentrations .
including ptsd in the model did not change the results ; a model was also run with continuous measures of depression ( mini ) and ptsd ( caps ) and significant results did not change .
to our knowledge , the current study is the first to evaluate the differential relationship between emotion dysregulation , trauma exposure , psychiatric disorders , and circulating crp concentrations in a traumatized sample of women . in support of our hypothesis , within this sample of african - american females with t2 dm , we found that emotion dysregulation was significantly associated with higher peripheral concentrations of crp .
this result is consistent with recent research which has shown that emotional functioning in childhood predicts elevated crp in adulthood and expands previous findings to demonstrate that emotion dysregulation was significantly predictive of elevated crp above and beyond already known risk factors , including bmi , trauma , and current mdd .
although all dimensions of emotion dysregulation measured were significantly related to higher crp , difficulty engaging in goal - directed behavior in the presence of strong emotions and a lack of strategies for managing strong negative emotions showed the strongest associations with elevated concentrations of crp .
these results indicate that heightened inflammation in those with high emotion dysregulation in the current study may be due to chronic activation of neuroendocrine and immune systems in response to chronic stress exposure as a result of a lack of effective strategies for managing negative emotions . indeed , exposure to repeating and unrelenting psychosocial stressors results in the dysregulation of the feedback mechanisms that regulate the activity of the hpa axis and the inflammatory system [ 21 , 22 ] . under normal conditions ,
glucocorticoids are released in response to stressors that act to inhibit the activity of the immune system .
however , overactivation of the hpa axis in response to chronic stress exposure leads to dysfunction of the hpa axis and glucocorticoid responsiveness that leads to an attenuation of glucocorticoid - induced inhibition of the inflammatory response .
thus , it is possible that an inability to manage negative emotions in response to psychosocial stressor exposure with adaptive strategies facilitates increased inflammation .
although the direction of causality can not be established from an association study , improving emotion regulation strategies and individuals ' ability to tolerate strong emotions and not act on them may be a useful area to focus on in treatment with individuals who have comorbid psychopathology and chronic inflammation .
future studies with a controlled experimental design are needed to assess whether improvements in emotional regulation can lead to reductions in inflammation .
it is also critical that more research be conducted to dissect the associations between the various dimensions of emotion dysregulation and chronic inflammation to inform treatment decisions .
consistent with previous research , we also found that current depression was associated with a proinflammatory state .
indeed , individuals with mdd have been shown in meta - analyses to have elevated crp [ 7 , 911 ] , as well as increased levels of interleukin-6 ( il-6 ) and tumor necrosis factor- ( tnf- ) [ 9 , 47 ] .
causal pathways between depression and inflammation have been debated and much of the evidence has focused on the role of proinflammatory cytokines in the development of depressive symptoms and sickness behavior ( e.g. , anhedonia , sleep , and appetite changes [ 4851 ] ) . however , not all individuals with depression show a heightened inflammatory state , and it is likely that in fact the positive association between depression and inflammation is a result of a complex and bidirectional process in which components of the central nervous system ( e.g. , hpa axis , autonomic nervous system ) alter inflammation and depression which in turn impact one another . our finding that current depression is associated with higher crp in females is helpful since some recent population - based studies found sex differences in associations between depression and crp , such that the relationship was only found for men [ 10 , 11 ] .
however , other studies looking specifically at women have found strong associations between mdd and higher levels of crp in women [ 52 , 53 ] , and our finding indicates further support for this relationship among women .
it will be important to continue evaluating sex differences in the association between inflammation and psychopathology as the type of population studied clearly impacts the interpretation and generalizability of the association .
while depression was significantly associated with crp , current ptsd was not , which contradicts some previous findings [ 1214 ] .
however , the literature on this association is mixed , with studies also showing a negative association between ptsd and crp or no association at all [ 16 , 17 ] .
it is likely that the specificity of our sample ( highly traumatized african - american females with t2 dm ) contributed to these results and therefore limits the generalizability of these results to other populations .
there may be other pathways associated with the stress response system and emotion dysregulation that may be more relevant to ptsd than inflammation , such as enhanced glucocorticoid negative feedback of the hpa axis and heightened activity of the sympathetic nervous system .
ongoing studies in our lab are beginning to examine how immune , neuroendocrine , and autonomic function all relate to ptsd and mdd in the context of acute stress .
it is possible that this is in part due to the fact that all women included in the study had been exposed to traumatic events ( mean = 4.23 types of events ) .
however , although not significant in this sample , we did see a trend toward a positive association between child abuse and peripheral concentrations of crp .
our small sample size made us underpowered to detect small effects , and it is likely that with more women included , this effect would be statistically significant .
this result would fit with previous research finding a relationship between child abuse exposure and inflammation in adulthood . of note
, emotion dysregulation and child abuse were significantly related , and based on the strong effect found between emotion dysregulation and crp , it is possible that emotion dysregulation is the mechanism by which early trauma contributes to chronic inflammation , although this could not be explored in this cross - sectional study .
more research is needed to determine potential risk pathways of trauma exposure and emotion regulation problems on the development of inflammation and should be examined in both traumatized and nontraumatized populations .
the current study has some limitations that should be kept in mind when interpreting the results .
first , the study was cross - sectional in nature , which does not allow for the determination of causality .
it is certainly possible that chronic inflammation leads to higher levels of emotion dysregulation , as some research has shown that inflammation can lead to mood and emotional changes .
however , the strong evidence that emotion dysregulation develops throughout childhood and is impacted by early life trauma [ 2527 , 5759 ] , along with initial evidence that the emotional functioning in childhood predicts adult crp concentrations , provides support for emotion dysregulation as an underlying mechanism that might lead to chronic inflammation and later health problems such as cardiovascular disease and diabetes . in addition
this means that participants needed to have insight into their emotion regulation difficulties in order to report them .
a lack of insight could have underestimated the severity of emotion dysregulation within this group of women .
however , the ders has shown good construct validity in its strong relationship with psychiatric symptoms and outcomes ( e.g. , ptsd symptoms , self - harm behavior [ 34 , 6062 ] ) .
recent research has also shown associations between the poor impulse control dimension of the ders and lower activation of the rostral anterior cingulate cortex during an impulse control task , suggesting that this self - report measure of emotion dysregulation is related to already known neural mechanisms associated with adaptive emotion regulation , thus further supporting its validity .
another limitation is that the homogeneity of the study population means that the results may not be generalizable to other samples .
this sample included all african - american women with t2 dm and high levels of trauma exposure , thus exceeding the rates of psychiatric disorders generally found in community samples .
however , the homogeneous sample is a strength as african - american women with t2 dm are clearly an at - risk sample that would benefit from improved interventions .
past research has shown increased inflammatory biomarkers in low - socioeconomic - status african - american communities [ 63 , 64 ] which is consistent with our sample of traumatized t2 dm women , as overall peripheral concentrations of crp in this sample were very high ( mean = 5.70 mg / l , sd = 4.80 ) .
finally , the small sample size of this study means that we may not have had enough power to detect small , yet clinically important associations between the variables examined .
this was evident in the association between child abuse severity and higher concentrations of crp ( r = 0.29 , p = 0.067 ) that was trending toward significance .
this is the first study to examine the complex relationships between trauma , psychiatric disorders , self - reported emotion dysregulation , and crp and therefore more research with larger sample sizes is needed to replicate these findings .
within at - risk groups it may be particularly beneficial to target psychological treatment interventions that may also then impact inflammation .
crp is easily measured and is a significant predictor of risk for serious physical conditions like cardiovascular disease .
future research should examine how psychological interventions for depression and/or ptsd might differentially affect emotion dysregulation and crp concentrations and whether changes in one might then influence the status of the other .
there is already some evidence that reductions in chronic inflammation can result from treating depression and that reducing inflammation decreases affective symptoms .
emotion dysregulation may be an even more useful treatment target since it cuts across psychiatric disorders and can be implemented in the context of various treatment modalities ( e.g. , cognitive - behavioral , acceptance and commitment , and dialectical behavior therapies ) and may be more easily integrated into nonpsychiatric settings ( e.g. , primary care and diabetes clinics ) where brief skills training is more feasible than long - term psychotherapy . | c - reactive protein ( crp ) , a marker of systemic inflammation , has been associated with major depressive disorder ( mdd ) and posttraumatic stress disorder ( ptsd ) .
emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state .
the objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus ( t2 dm ) .
we examined associations between trauma exposure , mdd , ptsd , emotion dysregulation , and crp among 40 african - american women with t2 dm recruited from an urban hospital .
emotion dysregulation was measured using the difficulties in emotion regulation scale .
ptsd and mdd were measured with structured clinical interviews .
child abuse and lifetime trauma load were also assessed .
analyses showed that both emotion dysregulation and current mdd were significantly associated with higher levels of crp ( p < 0.01 ) .
current ptsd was not significantly related to crp . in a regression model , emotion dysregulation was significantly associated with higher crp ( p < 0.001 ) independent of body mass index , trauma exposure , and mdd diagnosis .
these findings suggest that emotion dysregulation may be an important risk factor for chronic inflammation beyond already known risk factors among women with t2 dm , though a causal relationship can not be determined from this study . | <s>[INST]major depressive disorder ( mdd ) and posttraumatic stress disorder ( ptsd ) have been associated with higher incidence of cardiovascular disease [ 14 ] and diabetes [ 5 , 6 ] .
one mechanism that may contribute to the comorbidity between psychopathology and adverse health outcomes is chronic inflammation , whose role in atherosclerosis is well established [ 7 , 8 ] .
c - reactive protein ( crp ) is a marker of systemic inflammation and provides a useful indicator of chronic inflammation . increased circulating concentrations of crp are associated with mdd [ 7 , 911 ] . increased circulating concentrations of crp have also been described in ptsd [ 1214 ] ; however , the relationship is not as clear as other data are equivocal [ 1517 ] . because inflammation may be a key factor in understanding the significant comorbidity between psychiatric disorders and physical diseases , establishing other psychological factors that help explain the relationship between inflammation and psychiatric disorders and how problems with inflammation may develop is critical .
ample evidence indicates that early life stress is associated with chronic inflammation in adulthood [ 18 , 19 ] , and this may be particularly true among african americans .
for example , a recent meta - analysis on the role of childhood maltreatment ( i.e. , childhood sexual , physical , and emotional abuse and physical and emotional neglect ) in inflammation in adulthood demonstrated a significant positive association between exposure to childhood trauma and higher circulating concentrations of crp .
childhood maltreatment exposure may be particularly detrimental to the immune system via problematic alterations in the function of the hypothalamic pituitary adrenal ( hpa ) axis , a major component of the body 's stress response system and a system that both modulates and is modulated by inflammatory processes [ 22 , 23 ] .
based on this evidence , some posit that chronic inflammation may be one mediator in the relationship between early trauma exposure and the later development of psychiatric disorders .
it is important to note that the results of the meta - analysis on childhood trauma and inflammation suggested a relatively subtle ( although significant ) effect of trauma exposure on inflammatory activation suggesting that there may be other important components to this pathway that should be considered .
emotion dysregulation , or deficits in awareness and management of intense negative emotional states , is a transdiagnostic risk factor for the development and maintenance of many psychological disorders , including depression and ptsd [ 23 , 24 ] , and may be another psychological factor that impacts chronic inflammation .
importantly , emotional development begins early in life and developmental research has shown a strong relationship between exposure to childhood maltreatment and the development of emotion regulation deficits in adolescence and adulthood [ 2527 ] .
this may occur in part because emotion regulation strategies are learned by caregivers and when family environments are harmful or unsupportive , children are less likely to be exposed to appropriate regulatory behavior and more likely to experience emotional invalidation where emotional expression is ignored , rejected , or punished .
therefore , emotion dysregulation may be an important mechanism by which early life adversity confers lifetime risk for psychological disorders [ 25 , 26 ] . based on the strong link between childhood maltreatment and emotion dysregulation
recent research in fact suggests that emotion functioning is related to inflammation . a longitudinal study examining emotional functioning in 7-year - old children showed that inappropriate self - regulation and distress proneness during childhood predicted higher circulating concentrations of crp in adulthood .
other cross - sectional research on adults looked specifically at emotion regulation and showed that reappraisal ( an adaptive emotion regulation skill ) was associated with lower circulating concentrations of crp while suppression ( a maladaptive emotion regulation skill ) was associated with elevated circulating concentrations of crp . taken together , these studies indicate that emotion dysregulation could be important in predicting chronic inflammation , although no studies to our knowledge have examined the specific association between emotion dysregulation and circulating concentrations of crp among traumatized adults with high rates of depression and ptsd .
one population at particular risk for elevated systemic inflammation is individuals with type 2 diabetes mellitus ( t2 dm ) .
multiple recent longitudinal studies show that elevated circulating concentrations of crp put individuals at greater risk of developing t2 dm [ 31 , 32 ] . understanding psychological factors that may be associated with increased inflammation levels in individuals with t2 dm could be useful when considering how to improve treatments .
therefore , the goal of the present study was to examine the differential associations between trauma exposure , emotion dysregulation , current mdd , current ptsd , and crp concentrations in a highly traumatized urban , minority sample of women with t2 dm . we hypothesized that emotion dysregulation would be associated with higher concentrations of crp independent of the effects of trauma exposure and current psychiatric diagnoses ( i.e. , ptsd and mdd ) .
participants were drawn from astudy of risk factors for the development of ptsd in a low socioeconomic , urban minority population .
participants were recruited from waiting rooms in the diabetic , gynecology , and primary care medical clinics at a publically funded hospital in atlanta , georgia .
we did not narrow recruitment to specific criteria but approachedany individual in the waiting room . to be eligible for participation , subjects had to be between the ages of 18 and 65 and able to give informed consent ( see for full details regarding study procedures ) .
the investigation was carried out in accordance with the latest version of the declaration of helsinki and informed consent of the participants was obtained after the nature of the procedures had been fully explained .
after signing the informed consent approved by the emory institutional review board and the research oversight committee of grady memorial hospital , an interview was administered with questionnaires regarding trauma history and psychological variables .
a subgroup of female participants with t2 dm was chosen for a separate associated study .
exclusion criteria included current bipolar or psychotic disorder diagnosis , alcohol or substance dependence , treatment for an autoimmune disorder , treatment with nonsteroidal anti - inflammatory , glucocorticoid , or anticonvulsant , and current treatment with an antipsychotic , benzodiazepine , or antidepressant .
on the morning of the interview , height and weight were measured for calculation of body mass index ( bmi ) and fasting blood samples were collected for later batch assessment of crp concentrations ( approximately 2 weeks after initial assessment ) .
the current study included 40 diabetic african - american women with a mean age of 51.88 years ( sd = 7.57 years , range = 3265 ) .
education levels were as follows : 18.8% reported less than high school education , 21.9% reported having a high school diploma or ged , 37.5% reported having some college or technical school education , and 21.9% reported graduating from technical school or college .
only 25.0% of participants were employed and 84.4% had a household monthly income of $ 1999 or less .
the ders is a 36-item psychometrically validated self - report measure of emotion regulation difficulties .
it measures several aspects of emotion regulation , including awareness and understanding of one 's emotions , acceptance of negative emotions , the ability to successfully engage in goal - directed behavior and control impulsive behavior when experiencing negative emotions , and the ability to use situationally appropriate emotion regulation strategies .
for the present study the overall scale , as well as six subscales , of emotion regulation was examined .
the internal consistency of the ders total scale was high ( = 0.92 ) .
it was administered to detail frequency and type of trauma(s ) experienced ; consistent with prior research , total level of trauma exposure was measured by a sum score reflecting the total frequency of different types of trauma ( e.g. , car accident , sexual assault ) a participant had been exposed to over the course of their life . for this study ,
the number of traumatic experiences reflects the total number of different types of events that an individual experienced or witnessed . in order to separate lifetime trauma exposure and childhood abuse
, we excluded the childhood abuse items from the tei ( i.e. , exposure to sexual abuse , physical abuse , and emotional abuse ) .
the ctq is a 25-item , reliable , and valid self - report instrument assessing sexual , physical , emotional abuse , and neglect in childhood ( = 0.92 in current study ) .
bernstein and fink established scores for none , mild , moderate , and severe for each type of abuse . for descriptive purposes , the data from the ctq were used to create a categorical variable to account for the presence or absence of moderate - to - severe reported exposure to emotional ( score 13 ) , physical ( score 10 ) , and sexual ( score 8) abuse in childhood ( 0 = none or mild abuse ; 1 = the presence of moderate or severe abuse scores for at least one of the three types of abuse ) . a continuous measure of overall severity of childhood abuse exposure was also calculated and used as the measure of child abuse severity in all analyses .
the caps is an interviewer - administered psychometrically validated diagnostic instrument measuring ptsd [ 37 , 38 ] .
it includes items that rate social and occupational functioning , global ptsd symptom severity , and the validity of participant 's responses .
the caps assesses current ptsd and was used to determine presence / absence of a ptsd diagnosis . mini is a structured diagnostic interview that assesses mood , anxiety , substance use , and psychotic disorders based on dsm - iv - tr criteria .
mini has shown good reliability and validity across different samples [ 39 , 40 ] .
for the present study , only the current major depression section was used to assess presence / absence of current mdd .
body mass index is calculated as bmi = body mass ( kg)/(height ( m ) ) .
mean bmi for this sample was 36.53 ( sd = 7.30 , range = 2153.80 ) .
serum samples were stored at 80c until the time of highly sensitive crp ( hscrp ) assay .
serum hscrp concentrations were determined using an immunoturbidimetric assay from sekisui diagnostics ( lexington , ma ) on the beckman au480 chemistry analyzer , with an interassay coefficient of variation ( cv ) of 5.2% and an intra - assay cv of 3.1% .
individuals with circulating concentrations of hscrp > 20 mg / l were excluded from analysis because hscrp > 20 mg / l suggests the presence of an active infection or other illnesses that could seriously confound study findings ( two individuals were excluded from analyses ( hscrp = 26.25 and 61.69 ) ) .
circulating concentrations of hscrp averaged 5.70 mg / l ( sd = 4.81 , range = 0.2318.43 ) .
glucose is measured by enzymatic methods on the beckman au480 using reagents from beckman coulter ( fullerton , ca ) .
average glucose level for this sample was 125.05 ( sd = 38.31 , range = 35.70208.15 ) .
hba1c was measured using high performance liquid chromatography by arup laboratories ( salt lake city , utah ) .
average hba1c for this sample was 7.61 ( sd = 1.71 , range = 4.9013.60 ) .
the overall analytic approach was to examine the predictive utility of trauma , current ptsd , current mdd , and emotion dysregulation on hscrp concentrations .
hscrp concentrations , trauma exposure , and emotion dysregulation variables were positively skewed . however , the level of skewness ( range : 0.321.96 ) in this sample fell within acceptable parameters for the sample size on all variables except child abuse severity and the difficulty with emotion regulation strategies dimension of emotion dysregulation .
each had one outlier which affected the level of kurtosis , but results remained the same with or without these outliers included and so they remained in the models presented .
differences in trauma level , emotion dysregulation , and bmi were also examined by both mdd and ptsd diagnoses using analysis of variance ( table 1 ) . for variables of interest , bivariate correlations ( continuous variables ) and a univariate analysis of variance ( categorical variables )
then , based on the results of the correlational analyses , a series of linear regression models was fit to examine the unique predictive value of child abuse , current mdd , and emotion dysregulation on hscrp .
potential covariates for regression analysis were first identified based on previous research suggesting associations with circulating concentrations of hscrp : age , income , bmi , hemoglobin a1c , and baseline blood glucose level [ 9 , 4245 ] . due to the small sample size and risk for low power in detecting significant effects ,
associations between hscrp and these potential covariates were first assessed to determine if their inclusion in the regression model was warranted .
no significant differences emerged between any of the variables and hscrp except for bmi ( r = 0.40 , p = 0.01 ) and therefore only bmi was included as a covariate in the regression analysis .
all analyses were conducted with spss 23.0 software package ( twelve primary analyses were conducted resulting in a bonferroni correction value of p < 0.004 ) .
this was a highly traumatized sample , with all participants reporting the experience of at least one type of trauma in their lifetime ( excluding child abuse ; m = 4.31 , sd = 2.28 ) .
many participants were also exposed to childhood abuse ( i.e. sexual , physical , or emotional abuse ) , with 35.0% of the sample reporting exposure to moderate - to - severe child abuse .
rates of depression and ptsd were also high in this sample , with 32.5% ( n = 13 ) meeting criteria for current mdd and 32.5% ( n = 13 ) meeting criteria for current ptsd . the majority of those individuals that met diagnostic criteria for at least one diagnosis in fact met diagnostic criteria for both mdd and ptsd ( 22.5% of overall sample , n = 9 ) .
as shown in table 1 , individuals with depression and ptsd were more likely to report higher levels of child abuse ( p < 0.01 and p < 0.001 , resp . ) and emotion dysregulation ( p <
0.01 and p < 0.05 , resp . ) . rates of other trauma exposure and bmi were not significantly different across groups . to determine the extent of association between trauma exposure , emotion dysregulation , and hscrp , we first calculated pearson correlation coefficients among our variables of interest ( see table 2 ) .
bmi was also included in these analyses to evaluate independent associations with the variables of interest .
overall emotion dysregulation was significantly positively correlated with hscrp concentrations ( p < 0.001 ) . when looking at the six dimensions of emotion dysregulation , all six were significantly positively correlated with difficulty controlling impulses and lack of emotion regulation strategies showing the strongest correlations ( p < 0.001 ) .
all significant associations except for lack of awareness of emotions would survive correction for multiple comparisons .
the association between child abuse severity and hscrp trended toward significance ( p = 0.067 ) .
however , overall trauma exposure ( excluding child abuse ) was not significantly correlated with hscrp . regarding associations between trauma exposure and emotion dysregulation ,
child abuse severity was associated with overall emotion dysregulation ( p < 0.05 ) as well as nonacceptance of emotions ( p = 0.01 ) and difficulty with goal - directed behavior in the presence of strong emotions ( p = 0.05 ) .
overall trauma exposure ( excluding child abuse ) was not associated with emotion dysregulation . however
, child abuse severity and overall trauma exposure ( excluding abuse ) were significantly correlated with each other ( p < 0.05 ) . regarding bmi , only one emotion dysregulation dimension
lack of awareness of emotions was significantly associated with bmi ( p < 0.05 ) .
univariate analysis of variance was then used to examine mean differences in hscrp by ptsd and mdd diagnosis .
as shown in figure 1 , univariate analysis of variance results showed that there was a significant increase in mean hscrp across current mdd diagnosis ( f = 19.12 , p < 0.001 ) but not current ptsd diagnosis ( f = 2.87 , p = 0.10 ) .
next , a series of linear regression models was run to test the differential associations of child abuse , current mdd , and emotion dysregulation with hscrp .
then , child abuse severity was entered into the second step of the regression model .
as shown in table 3 , when bmi was included in step 1 , higher bmi was significantly related to higher hscrp levels ( p < 0.05 ) .
when child abuse severity was included in step 2 , it was not significant in predicting hscrp .
in step 3 , when current mdd was entered into the regression model , mdd was significantly predictive of hscrp ( p < 0.01 ) , accounting for 13% of the variance in hscrp independent of bmi and child abuse severity .
when overall emotion dysregulation was included in the model in step 4 , emotion dysregulation was significantly predictive of hscrp ( p < 0.001 ) above and beyond bmi , child abuse severity , and current mdd , surviving correction for multiple comparisons and accounting for 25% of unique variance in predicting higher hscrp concentrations .
including ptsd in the model did not change the results ; a model was also run with continuous measures of depression ( mini ) and ptsd ( caps ) and significant results did not change .
to our knowledge , the current study is the first to evaluate the differential relationship between emotion dysregulation , trauma exposure , psychiatric disorders , and circulating crp concentrations in a traumatized sample of women . in support of our hypothesis , within this sample of african - american females with t2 dm , we found that emotion dysregulation was significantly associated with higher peripheral concentrations of crp .
this result is consistent with recent research which has shown that emotional functioning in childhood predicts elevated crp in adulthood and expands previous findings to demonstrate that emotion dysregulation was significantly predictive of elevated crp above and beyond already known risk factors , including bmi , trauma , and current mdd .
although all dimensions of emotion dysregulation measured were significantly related to higher crp , difficulty engaging in goal - directed behavior in the presence of strong emotions and a lack of strategies for managing strong negative emotions showed the strongest associations with elevated concentrations of crp .
these results indicate that heightened inflammation in those with high emotion dysregulation in the current study may be due to chronic activation of neuroendocrine and immune systems in response to chronic stress exposure as a result of a lack of effective strategies for managing negative emotions . indeed , exposure to repeating and unrelenting psychosocial stressors results in the dysregulation of the feedback mechanisms that regulate the activity of the hpa axis and the inflammatory system [ 21 , 22 ] . under normal conditions ,
glucocorticoids are released in response to stressors that act to inhibit the activity of the immune system .
however , overactivation of the hpa axis in response to chronic stress exposure leads to dysfunction of the hpa axis and glucocorticoid responsiveness that leads to an attenuation of glucocorticoid - induced inhibition of the inflammatory response .
thus , it is possible that an inability to manage negative emotions in response to psychosocial stressor exposure with adaptive strategies facilitates increased inflammation .
although the direction of causality can not be established from an association study , improving emotion regulation strategies and individuals ' ability to tolerate strong emotions and not act on them may be a useful area to focus on in treatment with individuals who have comorbid psychopathology and chronic inflammation .
future studies with a controlled experimental design are needed to assess whether improvements in emotional regulation can lead to reductions in inflammation .
it is also critical that more research be conducted to dissect the associations between the various dimensions of emotion dysregulation and chronic inflammation to inform treatment decisions .
consistent with previous research , we also found that current depression was associated with a proinflammatory state .
indeed , individuals with mdd have been shown in meta - analyses to have elevated crp [ 7 , 911 ] , as well as increased levels of interleukin-6 ( il-6 ) and tumor necrosis factor- ( tnf- ) [ 9 , 47 ] .
causal pathways between depression and inflammation have been debated and much of the evidence has focused on the role of proinflammatory cytokines in the development of depressive symptoms and sickness behavior ( e.g. , anhedonia , sleep , and appetite changes [ 4851 ] ) . however , not all individuals with depression show a heightened inflammatory state , and it is likely that in fact the positive association between depression and inflammation is a result of a complex and bidirectional process in which components of the central nervous system ( e.g. , hpa axis , autonomic nervous system ) alter inflammation and depression which in turn impact one another . our finding that current depression is associated with higher crp in females is helpful since some recent population - based studies found sex differences in associations between depression and crp , such that the relationship was only found for men [ 10 , 11 ] .
however , other studies looking specifically at women have found strong associations between mdd and higher levels of crp in women [ 52 , 53 ] , and our finding indicates further support for this relationship among women .
it will be important to continue evaluating sex differences in the association between inflammation and psychopathology as the type of population studied clearly impacts the interpretation and generalizability of the association .
while depression was significantly associated with crp , current ptsd was not , which contradicts some previous findings [ 1214 ] .
however , the literature on this association is mixed , with studies also showing a negative association between ptsd and crp or no association at all [ 16 , 17 ] .
it is likely that the specificity of our sample ( highly traumatized african - american females with t2 dm ) contributed to these results and therefore limits the generalizability of these results to other populations .
there may be other pathways associated with the stress response system and emotion dysregulation that may be more relevant to ptsd than inflammation , such as enhanced glucocorticoid negative feedback of the hpa axis and heightened activity of the sympathetic nervous system .
ongoing studies in our lab are beginning to examine how immune , neuroendocrine , and autonomic function all relate to ptsd and mdd in the context of acute stress .
it is possible that this is in part due to the fact that all women included in the study had been exposed to traumatic events ( mean = 4.23 types of events ) .
however , although not significant in this sample , we did see a trend toward a positive association between child abuse and peripheral concentrations of crp .
our small sample size made us underpowered to detect small effects , and it is likely that with more women included , this effect would be statistically significant .
this result would fit with previous research finding a relationship between child abuse exposure and inflammation in adulthood . of note
, emotion dysregulation and child abuse were significantly related , and based on the strong effect found between emotion dysregulation and crp , it is possible that emotion dysregulation is the mechanism by which early trauma contributes to chronic inflammation , although this could not be explored in this cross - sectional study .
more research is needed to determine potential risk pathways of trauma exposure and emotion regulation problems on the development of inflammation and should be examined in both traumatized and nontraumatized populations .
the current study has some limitations that should be kept in mind when interpreting the results .
first , the study was cross - sectional in nature , which does not allow for the determination of causality .
it is certainly possible that chronic inflammation leads to higher levels of emotion dysregulation , as some research has shown that inflammation can lead to mood and emotional changes .
however , the strong evidence that emotion dysregulation develops throughout childhood and is impacted by early life trauma [ 2527 , 5759 ] , along with initial evidence that the emotional functioning in childhood predicts adult crp concentrations , provides support for emotion dysregulation as an underlying mechanism that might lead to chronic inflammation and later health problems such as cardiovascular disease and diabetes . in addition
this means that participants needed to have insight into their emotion regulation difficulties in order to report them .
a lack of insight could have underestimated the severity of emotion dysregulation within this group of women .
however , the ders has shown good construct validity in its strong relationship with psychiatric symptoms and outcomes ( e.g. , ptsd symptoms , self - harm behavior [ 34 , 6062 ] ) .
recent research has also shown associations between the poor impulse control dimension of the ders and lower activation of the rostral anterior cingulate cortex during an impulse control task , suggesting that this self - report measure of emotion dysregulation is related to already known neural mechanisms associated with adaptive emotion regulation , thus further supporting its validity .
another limitation is that the homogeneity of the study population means that the results may not be generalizable to other samples .
this sample included all african - american women with t2 dm and high levels of trauma exposure , thus exceeding the rates of psychiatric disorders generally found in community samples .
however , the homogeneous sample is a strength as african - american women with t2 dm are clearly an at - risk sample that would benefit from improved interventions .
past research has shown increased inflammatory biomarkers in low - socioeconomic - status african - american communities [ 63 , 64 ] which is consistent with our sample of traumatized t2 dm women , as overall peripheral concentrations of crp in this sample were very high ( mean = 5.70 mg / l , sd = 4.80 ) .
finally , the small sample size of this study means that we may not have had enough power to detect small , yet clinically important associations between the variables examined .
this was evident in the association between child abuse severity and higher concentrations of crp ( r = 0.29 , p = 0.067 ) that was trending toward significance .
this is the first study to examine the complex relationships between trauma , psychiatric disorders , self - reported emotion dysregulation , and crp and therefore more research with larger sample sizes is needed to replicate these findings .
within at - risk groups it may be particularly beneficial to target psychological treatment interventions that may also then impact inflammation .
crp is easily measured and is a significant predictor of risk for serious physical conditions like cardiovascular disease .
future research should examine how psychological interventions for depression and/or ptsd might differentially affect emotion dysregulation and crp concentrations and whether changes in one might then influence the status of the other .
there is already some evidence that reductions in chronic inflammation can result from treating depression and that reducing inflammation decreases affective symptoms .
emotion dysregulation may be an even more useful treatment target since it cuts across psychiatric disorders and can be implemented in the context of various treatment modalities ( e.g. , cognitive - behavioral , acceptance and commitment , and dialectical behavior therapies ) and may be more easily integrated into nonpsychiatric settings ( e.g. , primary care and diabetes clinics ) where brief skills training is more feasible than long - term psychotherapy .[/INST]c - reactive protein ( crp ) , a marker of systemic inflammation , has been associated with major depressive disorder ( mdd ) and posttraumatic stress disorder ( ptsd ) .
emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state .
the objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus ( t2 dm ) .
we examined associations between trauma exposure , mdd , ptsd , emotion dysregulation , and crp among 40 african - american women with t2 dm recruited from an urban hospital .
emotion dysregulation was measured using the difficulties in emotion regulation scale .
ptsd and mdd were measured with structured clinical interviews .
child abuse and lifetime trauma load were also assessed .
analyses showed that both emotion dysregulation and current mdd were significantly associated with higher levels of crp ( p < 0.01 ) .
current ptsd was not significantly related to crp . in a regression model , emotion dysregulation was significantly associated with higher crp ( p < 0.001 ) independent of body mass index , trauma exposure , and mdd diagnosis .
these findings suggest that emotion dysregulation may be an important risk factor for chronic inflammation beyond already known risk factors among women with t2 dm , though a causal relationship can not be determined from this study .</s> |
full - length human cxcr1 ( residues 1 to 350 ) was expressed with an n - terminal gst partner and a c - terminal his6 tag in e. coli bl21 cells .
isotopically labeled samples were obtained by growing bacteria in m9 media containing n labeled ammonium sulfate and c6-glucose or 2-c - glycerol ( cambridge isotope laboratories ) . a sample of selectively c / n - phe labeled cxcr1 was also prepared .
after cell lysis , the gst - cxcr1-his6 fusion protein was bound to ni - nta resin .
cxcr1 was separated from gst by incubation with thrombin and then purified and refolded in dmpc proteoliposomes by detergent dialysis .
the resulting proteoliposomes were suspended in buffer , isolated by ultra - centrifugation , and packed as a hydrated pellet into the mas rotor .
, cxcr1 proteoliposomes were incubated with varying concentrations of i - labeled and unlabeled il-8 , and bound il-8 was determined by measuring radioactivity in a scintillation counter after removing any free il-8 ligand ( supplementary fig .
cxcr1 proteoliposomes were reconstituted with gi / o protein trimer , and used to measure s - gtps binding as a function of agonist il-8 concentration ( supplementary fig .
refolded cxcr1 binds il-8 ( kd ~ 15 nm ) and activates g - protein in a ligand - dependent manner ( ec50 ~ 1 nm ) , with affinities similar to those reported in the literature .
nmr experiments , experimental parameters and measurements of restraints are described in supplementary information , including supplementary table 2 .
c chemical shifts were externally referenced to dss by setting the adamantane methylene carbons to a c chemical shift frequency of 40.48 ppm ; n chemical shifts were externally referenced to liquid ammonia by setting the ammonium sulfate nitrogen to 26.8 ppm .
fast rotational diffusion ( > 10 hz ) of the protein was verified by analysis of co powder pattern line shapes .
resonances from residues 20 - 325 of cxcr1 were all assigned , except for those corresponding to seven pro residues ( p22 , p93 , p170 , p180 , p185 , p214 and p257 ) and one arg ( r285 ) .
two disulfide bonds ( c30-c277 , c110-c187 ) were determined from the characteristic cb and ca chemical shifts that reflect the oxidation states of cys sites .
backbone dihedral angle ( , ) restraints were derived from the experimentally measured isotropic chemical shifts using cs - rosetta and talos .
values of the experimental h - n dc and h - ca dc used in the structure calculations were measured from the perpendicular edge frequencies of the respective rotationally averaged powder patterns . for each dc , the perpendicular edge frequency
was multiplied by 4 to obtain the frequency of dipolar splitting between the parallel edges of the pake doublet . in most measurements , the sign of the h - n dc could be determined unambiguously . in cases where this was not possible , and for all of the h - ca dc data ,
structure calculations were performed in three stages using the programs : cs - rosetta ; rosetta ( including both the coarse - grained and all - atom potentials as well as the implicit membrane potential available in rosetta version 3.2 ) ; and xplor - nih . in the first stage , we used cs - rosetta together with the amino acid sequence of cxcr1 and the assigned isotropic chemical shifts from ca , cb , co , and n protein sites , to generate a molecular fragment database , containing 67,784 9-residue fragments and 69,204 3-residue fragments . in the second stage , we used the resulting molecular fragment database , together with the experimental dc restraints and the structure of rhodopsin ( pdb i d : 1f88 ) as topology template , to fold 20,000 structural models with the coarse - grained and implicit membrane potentials of rosetta .
these coarse - grained structural models were evaluated according to their rosetta energy and backbone ca rmsd to the lowest energy structure .
the 1,000 lowest energy models were selected for further refinement using the all - atom energy function and implicit membrane environment of rosetta , together with the experimental dc restraints , and the experimentally determined disulfide bond restraints .
the rosetta all - atom relax protocol was implemented for 10 cycles with an increasing h - n dc restraint weighting factor ramped from 1 to 3 kcalmolhz .
structure refinement was performed using a simulated annealing protocol with xplor - nih internal variable molecular dynamics and all the experimental nmr restraints . during simulated annealing
, the temperature was lowered from 500 k to 50 k. experimentally determined disulfide bonds were included by explicit definition in the molecular structure file of cxcr1 .
backbone dihedral angles were imposed with a range of 2 for helices and 30 for loops , and a fixed force constant ( 1,000 kcalmolrad ) .
h - n dc restraints were imposed with a range of 2 khz and a ramped force constant ( 0.1 - 2.5 kcalmolkhz ) .
h - ca dc restraints were imposed with a range of 4 khz and a ramped force constant ( 0.05 - 1.25 kcalmolkhz ) .
the protocol also included a potential for knowledge - based torsion angles implemented with a dimensionless force constant ( 0.2 ) , a potential for the radius of gyration implemented for residues 28 to 325 with a fixed force constant ( 10 kcalmol ) , plus energy terms to enforce covalent geometry and prevent atomic overlap .
the magnitude and symmetry of the molecular alignment tensor were fixed , with values of the axial alignment ( da ) and rhombicity ( rh ) parameters set to 10.52 khz and 0 , respectively , as expected for a membrane protein in phospholipid bilayers with an order parameter of 1.0 and an amide nh bond length of 1.05 .
the h - ca dc alignment tensor was normalized to the maximum value of the h - n dc .
a total of 100 structures were calculated and the 10 lowest energy structures were selected as the structural ensemble for analysis ( fig . 1e , supplementary table 1 ) .
rmsds and r factors , reflecting correlations between experimentally observed values of the restraints and values calculated from the refined structure , were estimated as described .
full - length human cxcr1 ( residues 1 to 350 ) was expressed with an n - terminal gst partner and a c - terminal his6 tag in e. coli bl21 cells .
isotopically labeled samples were obtained by growing bacteria in m9 media containing n labeled ammonium sulfate and c6-glucose or 2-c - glycerol ( cambridge isotope laboratories ) . a sample of selectively c / n - phe labeled cxcr1 was also prepared .
after cell lysis , the gst - cxcr1-his6 fusion protein was bound to ni - nta resin .
cxcr1 was separated from gst by incubation with thrombin and then purified and refolded in dmpc proteoliposomes by detergent dialysis .
the resulting proteoliposomes were suspended in buffer , isolated by ultra - centrifugation , and packed as a hydrated pellet into the mas rotor .
to assay il-8 ligand binding , cxcr1 proteoliposomes were incubated with varying concentrations of i - labeled and unlabeled il-8 , and bound il-8 was determined by measuring radioactivity in a scintillation counter after removing any free il-8 ligand ( supplementary fig .
cxcr1 proteoliposomes were reconstituted with gi / o protein trimer , and used to measure s - gtps binding as a function of agonist il-8 concentration ( supplementary fig .
refolded cxcr1 binds il-8 ( kd ~ 15 nm ) and activates g - protein in a ligand - dependent manner ( ec50 ~ 1 nm ) , with affinities similar to those reported in the literature .
nmr experiments , experimental parameters and measurements of restraints are described in supplementary information , including supplementary table 2 .
c chemical shifts were externally referenced to dss by setting the adamantane methylene carbons to a c chemical shift frequency of 40.48 ppm ; n chemical shifts were externally referenced to liquid ammonia by setting the ammonium sulfate nitrogen to 26.8 ppm .
fast rotational diffusion ( > 10 hz ) of the protein was verified by analysis of co powder pattern line shapes .
resonances from residues 20 - 325 of cxcr1 were all assigned , except for those corresponding to seven pro residues ( p22 , p93 , p170 , p180 , p185 , p214 and p257 ) and one arg ( r285 ) .
two disulfide bonds ( c30-c277 , c110-c187 ) were determined from the characteristic cb and ca chemical shifts that reflect the oxidation states of cys sites .
backbone dihedral angle ( , ) restraints were derived from the experimentally measured isotropic chemical shifts using cs - rosetta and talos .
values of the experimental h - n dc and h - ca dc used in the structure calculations were measured from the perpendicular edge frequencies of the respective rotationally averaged powder patterns . for each dc , the perpendicular edge frequency
was multiplied by 4 to obtain the frequency of dipolar splitting between the parallel edges of the pake doublet . in most measurements , the sign of the h - n dc could be determined unambiguously . in cases where this was not possible , and for all of the h - ca dc data
structure calculations were performed in three stages using the programs : cs - rosetta ; rosetta ( including both the coarse - grained and all - atom potentials as well as the implicit membrane potential available in rosetta version 3.2 ) ; and xplor - nih . in the first stage , we used cs - rosetta together with the amino acid sequence of cxcr1 and the assigned isotropic chemical shifts from ca , cb , co , and n protein sites , to generate a molecular fragment database , containing 67,784 9-residue fragments and 69,204 3-residue fragments . in the second stage , we used the resulting molecular fragment database , together with the experimental dc restraints and the structure of rhodopsin ( pdb i d : 1f88 ) as topology template , to fold 20,000 structural models with the coarse - grained and implicit membrane potentials of rosetta .
these coarse - grained structural models were evaluated according to their rosetta energy and backbone ca rmsd to the lowest energy structure .
the 1,000 lowest energy models were selected for further refinement using the all - atom energy function and implicit membrane environment of rosetta , together with the experimental dc restraints , and the experimentally determined disulfide bond restraints .
the rosetta all - atom relax protocol was implemented for 10 cycles with an increasing h - n dc restraint weighting factor ramped from 1 to 3 kcalmolhz .
, structure refinement was performed using a simulated annealing protocol with xplor - nih internal variable molecular dynamics and all the experimental nmr restraints . during simulated annealing
, the temperature was lowered from 500 k to 50 k. experimentally determined disulfide bonds were included by explicit definition in the molecular structure file of cxcr1 .
backbone dihedral angles were imposed with a range of 2 for helices and 30 for loops , and a fixed force constant ( 1,000 kcalmolrad ) .
h - n dc restraints were imposed with a range of 2 khz and a ramped force constant ( 0.1 - 2.5 kcalmolkhz ) .
h - ca dc restraints were imposed with a range of 4 khz and a ramped force constant ( 0.05 - 1.25 kcalmolkhz ) .
the protocol also included a potential for knowledge - based torsion angles implemented with a dimensionless force constant ( 0.2 ) , a potential for the radius of gyration implemented for residues 28 to 325 with a fixed force constant ( 10 kcalmol ) , plus energy terms to enforce covalent geometry and prevent atomic overlap .
the magnitude and symmetry of the molecular alignment tensor were fixed , with values of the axial alignment ( da ) and rhombicity ( rh ) parameters set to 10.52 khz and 0 , respectively , as expected for a membrane protein in phospholipid bilayers with an order parameter of 1.0 and an amide nh bond length of 1.05 .
the h - ca dc alignment tensor was normalized to the maximum value of the h - n dc .
a total of 100 structures were calculated and the 10 lowest energy structures were selected as the structural ensemble for analysis ( fig . 1e , supplementary table 1 ) .
rmsds and r factors , reflecting correlations between experimentally observed values of the restraints and values calculated from the refined structure , were estimated as described .
| cxcr1 is one of two high - affinity receptors for the cxc chemokine interleukin-8 ( il-8 ) , a major mediator of immune and inflammatory responses implicated in many disorders , including tumor growth1 - 3 .
il-8 , released in response to inflammatory stimuli , binds to the extracellular side of cxcr1 .
the ligand - activated intracellular signaling pathways result in neutrophil migration to the site of inflammation2 .
cxcr1 is a class - a , rhodopsin - like g - protein - coupled receptor ( gpcr ) , the largest class of integral membrane proteins responsible for cellular signal transduction and targeted as drug receptors4 - 7 . despite its importance , its molecular mechanism is poorly understood due to the limited structural information available .
recently , structure determination of gpcrs has advanced by tailoring the receptors with stabilizing mutations , insertion of the protein t4 lysozyme and truncations of their amino acid sequences8 , as well as addition of stabilizing antibodies and small molecules9 that facilitate crystallization in cubic phase monoolein mixtures10 .
the intracellular loops of gpcrs are critical for g - protein interactions11 and activation of cxcr1 involves both n - terminal residues and extracellular loops2,12,13 .
our previous nmr studies indicate that il-8 binding to the n - terminal residues is mediated by the membrane , underscoring the importance of the phospholipid bilayer for physiological activity14 . here
we report the three - dimensional structure of human cxcr1 determined by nmr spectroscopy .
the receptor is in liquid crystalline phospholipid bilayers , without modification of its amino acid sequence and under physiological conditions
. features important for intracellular g - protein activation and signal transduction are revealed . | <s>[INST]full - length human cxcr1 ( residues 1 to 350 ) was expressed with an n - terminal gst partner and a c - terminal his6 tag in e. coli bl21 cells .
isotopically labeled samples were obtained by growing bacteria in m9 media containing n labeled ammonium sulfate and c6-glucose or 2-c - glycerol ( cambridge isotope laboratories ) . a sample of selectively c / n - phe labeled cxcr1 was also prepared .
after cell lysis , the gst - cxcr1-his6 fusion protein was bound to ni - nta resin .
cxcr1 was separated from gst by incubation with thrombin and then purified and refolded in dmpc proteoliposomes by detergent dialysis .
the resulting proteoliposomes were suspended in buffer , isolated by ultra - centrifugation , and packed as a hydrated pellet into the mas rotor .
, cxcr1 proteoliposomes were incubated with varying concentrations of i - labeled and unlabeled il-8 , and bound il-8 was determined by measuring radioactivity in a scintillation counter after removing any free il-8 ligand ( supplementary fig .
cxcr1 proteoliposomes were reconstituted with gi / o protein trimer , and used to measure s - gtps binding as a function of agonist il-8 concentration ( supplementary fig .
refolded cxcr1 binds il-8 ( kd ~ 15 nm ) and activates g - protein in a ligand - dependent manner ( ec50 ~ 1 nm ) , with affinities similar to those reported in the literature .
nmr experiments , experimental parameters and measurements of restraints are described in supplementary information , including supplementary table 2 .
c chemical shifts were externally referenced to dss by setting the adamantane methylene carbons to a c chemical shift frequency of 40.48 ppm ; n chemical shifts were externally referenced to liquid ammonia by setting the ammonium sulfate nitrogen to 26.8 ppm .
fast rotational diffusion ( > 10 hz ) of the protein was verified by analysis of co powder pattern line shapes .
resonances from residues 20 - 325 of cxcr1 were all assigned , except for those corresponding to seven pro residues ( p22 , p93 , p170 , p180 , p185 , p214 and p257 ) and one arg ( r285 ) .
two disulfide bonds ( c30-c277 , c110-c187 ) were determined from the characteristic cb and ca chemical shifts that reflect the oxidation states of cys sites .
backbone dihedral angle ( , ) restraints were derived from the experimentally measured isotropic chemical shifts using cs - rosetta and talos .
values of the experimental h - n dc and h - ca dc used in the structure calculations were measured from the perpendicular edge frequencies of the respective rotationally averaged powder patterns . for each dc , the perpendicular edge frequency
was multiplied by 4 to obtain the frequency of dipolar splitting between the parallel edges of the pake doublet . in most measurements , the sign of the h - n dc could be determined unambiguously . in cases where this was not possible , and for all of the h - ca dc data ,
structure calculations were performed in three stages using the programs : cs - rosetta ; rosetta ( including both the coarse - grained and all - atom potentials as well as the implicit membrane potential available in rosetta version 3.2 ) ; and xplor - nih . in the first stage , we used cs - rosetta together with the amino acid sequence of cxcr1 and the assigned isotropic chemical shifts from ca , cb , co , and n protein sites , to generate a molecular fragment database , containing 67,784 9-residue fragments and 69,204 3-residue fragments . in the second stage , we used the resulting molecular fragment database , together with the experimental dc restraints and the structure of rhodopsin ( pdb i d : 1f88 ) as topology template , to fold 20,000 structural models with the coarse - grained and implicit membrane potentials of rosetta .
these coarse - grained structural models were evaluated according to their rosetta energy and backbone ca rmsd to the lowest energy structure .
the 1,000 lowest energy models were selected for further refinement using the all - atom energy function and implicit membrane environment of rosetta , together with the experimental dc restraints , and the experimentally determined disulfide bond restraints .
the rosetta all - atom relax protocol was implemented for 10 cycles with an increasing h - n dc restraint weighting factor ramped from 1 to 3 kcalmolhz .
structure refinement was performed using a simulated annealing protocol with xplor - nih internal variable molecular dynamics and all the experimental nmr restraints . during simulated annealing
, the temperature was lowered from 500 k to 50 k. experimentally determined disulfide bonds were included by explicit definition in the molecular structure file of cxcr1 .
backbone dihedral angles were imposed with a range of 2 for helices and 30 for loops , and a fixed force constant ( 1,000 kcalmolrad ) .
h - n dc restraints were imposed with a range of 2 khz and a ramped force constant ( 0.1 - 2.5 kcalmolkhz ) .
h - ca dc restraints were imposed with a range of 4 khz and a ramped force constant ( 0.05 - 1.25 kcalmolkhz ) .
the protocol also included a potential for knowledge - based torsion angles implemented with a dimensionless force constant ( 0.2 ) , a potential for the radius of gyration implemented for residues 28 to 325 with a fixed force constant ( 10 kcalmol ) , plus energy terms to enforce covalent geometry and prevent atomic overlap .
the magnitude and symmetry of the molecular alignment tensor were fixed , with values of the axial alignment ( da ) and rhombicity ( rh ) parameters set to 10.52 khz and 0 , respectively , as expected for a membrane protein in phospholipid bilayers with an order parameter of 1.0 and an amide nh bond length of 1.05 .
the h - ca dc alignment tensor was normalized to the maximum value of the h - n dc .
a total of 100 structures were calculated and the 10 lowest energy structures were selected as the structural ensemble for analysis ( fig . 1e , supplementary table 1 ) .
rmsds and r factors , reflecting correlations between experimentally observed values of the restraints and values calculated from the refined structure , were estimated as described .
full - length human cxcr1 ( residues 1 to 350 ) was expressed with an n - terminal gst partner and a c - terminal his6 tag in e. coli bl21 cells .
isotopically labeled samples were obtained by growing bacteria in m9 media containing n labeled ammonium sulfate and c6-glucose or 2-c - glycerol ( cambridge isotope laboratories ) . a sample of selectively c / n - phe labeled cxcr1 was also prepared .
after cell lysis , the gst - cxcr1-his6 fusion protein was bound to ni - nta resin .
cxcr1 was separated from gst by incubation with thrombin and then purified and refolded in dmpc proteoliposomes by detergent dialysis .
the resulting proteoliposomes were suspended in buffer , isolated by ultra - centrifugation , and packed as a hydrated pellet into the mas rotor .
to assay il-8 ligand binding , cxcr1 proteoliposomes were incubated with varying concentrations of i - labeled and unlabeled il-8 , and bound il-8 was determined by measuring radioactivity in a scintillation counter after removing any free il-8 ligand ( supplementary fig .
cxcr1 proteoliposomes were reconstituted with gi / o protein trimer , and used to measure s - gtps binding as a function of agonist il-8 concentration ( supplementary fig .
refolded cxcr1 binds il-8 ( kd ~ 15 nm ) and activates g - protein in a ligand - dependent manner ( ec50 ~ 1 nm ) , with affinities similar to those reported in the literature .
nmr experiments , experimental parameters and measurements of restraints are described in supplementary information , including supplementary table 2 .
c chemical shifts were externally referenced to dss by setting the adamantane methylene carbons to a c chemical shift frequency of 40.48 ppm ; n chemical shifts were externally referenced to liquid ammonia by setting the ammonium sulfate nitrogen to 26.8 ppm .
fast rotational diffusion ( > 10 hz ) of the protein was verified by analysis of co powder pattern line shapes .
resonances from residues 20 - 325 of cxcr1 were all assigned , except for those corresponding to seven pro residues ( p22 , p93 , p170 , p180 , p185 , p214 and p257 ) and one arg ( r285 ) .
two disulfide bonds ( c30-c277 , c110-c187 ) were determined from the characteristic cb and ca chemical shifts that reflect the oxidation states of cys sites .
backbone dihedral angle ( , ) restraints were derived from the experimentally measured isotropic chemical shifts using cs - rosetta and talos .
values of the experimental h - n dc and h - ca dc used in the structure calculations were measured from the perpendicular edge frequencies of the respective rotationally averaged powder patterns . for each dc , the perpendicular edge frequency
was multiplied by 4 to obtain the frequency of dipolar splitting between the parallel edges of the pake doublet . in most measurements , the sign of the h - n dc could be determined unambiguously . in cases where this was not possible , and for all of the h - ca dc data
structure calculations were performed in three stages using the programs : cs - rosetta ; rosetta ( including both the coarse - grained and all - atom potentials as well as the implicit membrane potential available in rosetta version 3.2 ) ; and xplor - nih . in the first stage , we used cs - rosetta together with the amino acid sequence of cxcr1 and the assigned isotropic chemical shifts from ca , cb , co , and n protein sites , to generate a molecular fragment database , containing 67,784 9-residue fragments and 69,204 3-residue fragments . in the second stage , we used the resulting molecular fragment database , together with the experimental dc restraints and the structure of rhodopsin ( pdb i d : 1f88 ) as topology template , to fold 20,000 structural models with the coarse - grained and implicit membrane potentials of rosetta .
these coarse - grained structural models were evaluated according to their rosetta energy and backbone ca rmsd to the lowest energy structure .
the 1,000 lowest energy models were selected for further refinement using the all - atom energy function and implicit membrane environment of rosetta , together with the experimental dc restraints , and the experimentally determined disulfide bond restraints .
the rosetta all - atom relax protocol was implemented for 10 cycles with an increasing h - n dc restraint weighting factor ramped from 1 to 3 kcalmolhz .
, structure refinement was performed using a simulated annealing protocol with xplor - nih internal variable molecular dynamics and all the experimental nmr restraints . during simulated annealing
, the temperature was lowered from 500 k to 50 k. experimentally determined disulfide bonds were included by explicit definition in the molecular structure file of cxcr1 .
backbone dihedral angles were imposed with a range of 2 for helices and 30 for loops , and a fixed force constant ( 1,000 kcalmolrad ) .
h - n dc restraints were imposed with a range of 2 khz and a ramped force constant ( 0.1 - 2.5 kcalmolkhz ) .
h - ca dc restraints were imposed with a range of 4 khz and a ramped force constant ( 0.05 - 1.25 kcalmolkhz ) .
the protocol also included a potential for knowledge - based torsion angles implemented with a dimensionless force constant ( 0.2 ) , a potential for the radius of gyration implemented for residues 28 to 325 with a fixed force constant ( 10 kcalmol ) , plus energy terms to enforce covalent geometry and prevent atomic overlap .
the magnitude and symmetry of the molecular alignment tensor were fixed , with values of the axial alignment ( da ) and rhombicity ( rh ) parameters set to 10.52 khz and 0 , respectively , as expected for a membrane protein in phospholipid bilayers with an order parameter of 1.0 and an amide nh bond length of 1.05 .
the h - ca dc alignment tensor was normalized to the maximum value of the h - n dc .
a total of 100 structures were calculated and the 10 lowest energy structures were selected as the structural ensemble for analysis ( fig . 1e , supplementary table 1 ) .
rmsds and r factors , reflecting correlations between experimentally observed values of the restraints and values calculated from the refined structure , were estimated as described .
[/INST]cxcr1 is one of two high - affinity receptors for the cxc chemokine interleukin-8 ( il-8 ) , a major mediator of immune and inflammatory responses implicated in many disorders , including tumor growth1 - 3 .
il-8 , released in response to inflammatory stimuli , binds to the extracellular side of cxcr1 .
the ligand - activated intracellular signaling pathways result in neutrophil migration to the site of inflammation2 .
cxcr1 is a class - a , rhodopsin - like g - protein - coupled receptor ( gpcr ) , the largest class of integral membrane proteins responsible for cellular signal transduction and targeted as drug receptors4 - 7 . despite its importance , its molecular mechanism is poorly understood due to the limited structural information available .
recently , structure determination of gpcrs has advanced by tailoring the receptors with stabilizing mutations , insertion of the protein t4 lysozyme and truncations of their amino acid sequences8 , as well as addition of stabilizing antibodies and small molecules9 that facilitate crystallization in cubic phase monoolein mixtures10 .
the intracellular loops of gpcrs are critical for g - protein interactions11 and activation of cxcr1 involves both n - terminal residues and extracellular loops2,12,13 .
our previous nmr studies indicate that il-8 binding to the n - terminal residues is mediated by the membrane , underscoring the importance of the phospholipid bilayer for physiological activity14 . here
we report the three - dimensional structure of human cxcr1 determined by nmr spectroscopy .
the receptor is in liquid crystalline phospholipid bilayers , without modification of its amino acid sequence and under physiological conditions
. features important for intracellular g - protein activation and signal transduction are revealed .</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``Fisheries Restoration and Irrigation
Mitigation Act of 2007''.
SEC. 2. PRIORITY PROJECTS.
Section 3(c)(3) of the Fisheries Restoration and Irrigation
Mitigation Act of 2000 (16 U.S.C. 777 note; Public Law 106-502) is
amended by striking ``$5,000,000'' and inserting ``$2,500,000''.
SEC. 3. COST SHARING.
Section 7(c) of Fisheries Restoration and Irrigation Mitigation Act
of 2000 (16 U.S.C. 777 note; Public Law 106-502) is amended--
(1) by striking ``The value'' and inserting the following:
``(1) In general.--The value''; and
(2) by adding at the end the following:
``(2) Bonneville power administration.--
``(A) In general.--The Secretary may, without
further appropriation and without fiscal year
limitation, accept any amounts provided to the
Secretary by the Administrator of the Bonneville Power
Administration.
``(B) Non-federal share.--Any amounts provided by
the Bonneville Power Administration directly or through
a grant to another entity for a project carried under
the Program shall be credited toward the non-Federal
share of the costs of the project.''.
SEC. 4. REPORT.
Section 9 of the Fisheries Restoration and Irrigation Mitigation
Act of 2000 (16 U.S.C. 777 note; Public Law 106-502) is amended--
(1) by inserting ``any'' before ``amounts are made''; and
(2) by inserting after ``Secretary shall'' the following:
``, after partnering with local governmental entities and the
States in the Pacific Ocean drainage area,''.
SEC. 5. AUTHORIZATION OF APPROPRIATIONS.
Section 10 of the Fisheries Restoration and Irrigation Mitigation
Act of 2000 (16 U.S.C. 777 note; Public Law 106-502) is amended--
(1) in subsection (a), by striking ``2001 through 2005''
and inserting ``2008 through 2014''; and
(2) in subsection (b), by striking paragraph (2) and
inserting the following:
``(2) Administrative expenses.--
``(A) Definition of administrative expense.--In
this paragraph, the term `administrative expense'
means, except as provided in subparagraph (B)(iii)(II),
any expenditure relating to--
``(i) staffing and overhead, such as the
rental of office space and the acquisition of
office equipment; and
``(ii) the review, processing, and
provision of applications for funding under the
Program.
``(B) Limitation.--
``(i) In general.--Not more than 6 percent
of amounts made available to carry out this Act
for each fiscal year may be used for Federal
and State administrative expenses of carrying
out this Act.
``(ii) Federal and state shares.--To the
maximum extent practicable, of the amounts made
available for administrative expenses under
clause (i)--
``(I) 50 percent shall be provided
to the State agencies provided
assistance under the Program; and
``(II) an amount equal to the cost
of 1 full-time equivalent Federal
employee, as determined by the
Secretary, shall be provided to the
Federal agency carrying out the
Program.
``(iii) State expenses.--Amounts made
available to States for administrative expenses
under clause (i)--
``(I) shall be divided evenly among
all States provided assistance under
the Program; and
``(II) may be used by a State to
provide technical assistance relating
to the program, including any staffing
expenditures (including staff travel
expenses) associated with--
``(aa) arranging meetings
to promote the Program to
potential applicants;
``(bb) assisting applicants
with the preparation of
applications for funding under
the Program; and
``(cc) visiting
construction sites to provide
technical assistance, if
requested by the applicant.''. | Fisheries Restoration and Irrigation Mitigation Act of 2007 - Amends the Fisheries Restoration and Irrigation Mitigation Act of 2000 to direct the Secretary of the Interior, acting through the Director of the U.S. Fish and Wildlife Service, to give priority to any project that has a total cost of less than $2.5 million (currently, $5 million).
Authorizes the Secretary, without further appropriation and without fiscal year limitation, to accept any amounts provided to the Secretary by the Administrator of the Bonneville Power Administration.
Requires: (1) any amounts provided by the Bonneville Power Administration directly or through a grant to another entity for a project carried out under the Program to be credited toward the non-federal share of project costs; and (2) the Secretary's report on projects under such Act to be made after partnering with local governmental entities and the states in the Pacific Ocean drainage area (Oregon, Washington, Montana, and Idaho).
Authorizes appropriations for the Act through FY2014. Sets forth limits and requirements on the amount that may be used each fiscal year for federal and state administrative expenses of carrying out this Act. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``Fisheries Restoration and Irrigation
Mitigation Act of 2007''.
SEC. 2. PRIORITY PROJECTS.
Section 3(c)(3) of the Fisheries Restoration and Irrigation
Mitigation Act of 2000 (16 U.S.C. 777 note; Public Law 106-502) is
amended by striking ``$5,000,000'' and inserting ``$2,500,000''.
SEC. 3. COST SHARING.
Section 7(c) of Fisheries Restoration and Irrigation Mitigation Act
of 2000 (16 U.S.C. 777 note; Public Law 106-502) is amended--
(1) by striking ``The value'' and inserting the following:
``(1) In general.--The value''; and
(2) by adding at the end the following:
``(2) Bonneville power administration.--
``(A) In general.--The Secretary may, without
further appropriation and without fiscal year
limitation, accept any amounts provided to the
Secretary by the Administrator of the Bonneville Power
Administration.
``(B) Non-federal share.--Any amounts provided by
the Bonneville Power Administration directly or through
a grant to another entity for a project carried under
the Program shall be credited toward the non-Federal
share of the costs of the project.''.
SEC. 4. REPORT.
Section 9 of the Fisheries Restoration and Irrigation Mitigation
Act of 2000 (16 U.S.C. 777 note; Public Law 106-502) is amended--
(1) by inserting ``any'' before ``amounts are made''; and
(2) by inserting after ``Secretary shall'' the following:
``, after partnering with local governmental entities and the
States in the Pacific Ocean drainage area,''.
SEC. 5. AUTHORIZATION OF APPROPRIATIONS.
Section 10 of the Fisheries Restoration and Irrigation Mitigation
Act of 2000 (16 U.S.C. 777 note; Public Law 106-502) is amended--
(1) in subsection (a), by striking ``2001 through 2005''
and inserting ``2008 through 2014''; and
(2) in subsection (b), by striking paragraph (2) and
inserting the following:
``(2) Administrative expenses.--
``(A) Definition of administrative expense.--In
this paragraph, the term `administrative expense'
means, except as provided in subparagraph (B)(iii)(II),
any expenditure relating to--
``(i) staffing and overhead, such as the
rental of office space and the acquisition of
office equipment; and
``(ii) the review, processing, and
provision of applications for funding under the
Program.
``(B) Limitation.--
``(i) In general.--Not more than 6 percent
of amounts made available to carry out this Act
for each fiscal year may be used for Federal
and State administrative expenses of carrying
out this Act.
``(ii) Federal and state shares.--To the
maximum extent practicable, of the amounts made
available for administrative expenses under
clause (i)--
``(I) 50 percent shall be provided
to the State agencies provided
assistance under the Program; and
``(II) an amount equal to the cost
of 1 full-time equivalent Federal
employee, as determined by the
Secretary, shall be provided to the
Federal agency carrying out the
Program.
``(iii) State expenses.--Amounts made
available to States for administrative expenses
under clause (i)--
``(I) shall be divided evenly among
all States provided assistance under
the Program; and
``(II) may be used by a State to
provide technical assistance relating
to the program, including any staffing
expenditures (including staff travel
expenses) associated with--
``(aa) arranging meetings
to promote the Program to
potential applicants;
``(bb) assisting applicants
with the preparation of
applications for funding under
the Program; and
``(cc) visiting
construction sites to provide
technical assistance, if
requested by the applicant.''.[/INST]Fisheries Restoration and Irrigation Mitigation Act of 2007 - Amends the Fisheries Restoration and Irrigation Mitigation Act of 2000 to direct the Secretary of the Interior, acting through the Director of the U.S. Fish and Wildlife Service, to give priority to any project that has a total cost of less than $2.5 million (currently, $5 million).
Authorizes the Secretary, without further appropriation and without fiscal year limitation, to accept any amounts provided to the Secretary by the Administrator of the Bonneville Power Administration.
Requires: (1) any amounts provided by the Bonneville Power Administration directly or through a grant to another entity for a project carried out under the Program to be credited toward the non-federal share of project costs; and (2) the Secretary's report on projects under such Act to be made after partnering with local governmental entities and the states in the Pacific Ocean drainage area (Oregon, Washington, Montana, and Idaho).
Authorizes appropriations for the Act through FY2014. Sets forth limits and requirements on the amount that may be used each fiscal year for federal and state administrative expenses of carrying out this Act.</s> |
the 1g cosyntropin test has some advantages over the 250g test as a test of adrenal function .
one of the concerns regarding the 1 g test includes stability of the cosyntropin when reconstituted and stored . classically the 5 percentile responses to cosyntropin in normal individuals have been used to define a normal response .
we performed a 1g cosyntropin test using reconstituted and refrigerated ( 4 - 8 c ) cosyntropin in saline solution in 49 non pregnant adults who were apparently healthy and had no exposure to exogenous glucocorticoids .
we analysed the data for any association between duration of cosyntropin solution storage and the cortisol responses to cosyntropin administration .
the mean sd cortisol level at baseline , 30 and 60 min were-12.19 3 g / dl , 20.72 2.63 g / dl , 16.86 3.33 g / dl .
the 5 percentile cortisol response at 30 min was 16.5 g / dl ( 16.33 g / dl rounded off ) .
the correlation coefficients between number of days of cosyntropin solution storage and the cortisol responses at 30 and 60 min were ( spear mans rho = 0.06,-0.24 respectively ) ( p = 0.69 and 0.41 ) .
there were no differences in cortisol values whether the storage was for less than 30 days or more than 30 days ( mean difference 0.25 g / dl p = 0.44 ) .
the 5 percentile normative values determined for our assay is lower than what is currently being used clinically and in research publications .
prolonged refrigerated storage of cosyntropin solution does not affect the validity of the 1 g cosyntropin test .
the 250 g cosyntropin test has been conventionally used as a test for impaired adrenal reserve .
the cosyntropin that is commercially available is a 250 g preparation ; it contains the 1 - 24 amino acids of adrenocorticotropic hormone ( acth ) .
earliest studies with cosyntropin showed that responses to cosyntropin were similar to surgical stress or trauma . in a study comparing 250 g , 0.5 g , 1 g cosyntropin with insulin tolerance test ( itt ) in healthy volunteers , the 1 g test was found to produce plasma 1 - 24acth levels of 120 pmol / l , approximately twice as high than that of the itt but of the same order of magnitude .
the cortisol responses at 30 minute were comparable to that of the 250 g synacthen test .
pmol / l nearly 220 times that produced during insulin tolerance test ( itt ) or 1 g synacthen .
moreover 1 g synacthen test has been used in studies looking into milder degrees of hpa axis suppression , such as patients with asthma using inhaled corticosteroids ( ics ) .
receiver operator curve analyses which are classically used to assess the utility of clinical screening tests suggest that 1 g test is superior to 250 g test
. there has been some criticism of the 1 g test because the stability of reconstituted cosyntropin has been questioned and there has been one publication involving 8 normal individuals that suggests that cosyntropin if administered in small quantities produces false positive results presumably because it tends to adhere to plastic tubing used to administer the drug .
conflicting this report there is evidence in literature for the stability of reconstituted cosyntropin in saline for up to four months .
not withstanding these controversies 1 g cosyntropin test has been used widely in research protocols to identify impaired adrenal reserve both internationally and in india .
the cut offs for a clear pass response for the 1 and 250 g tests have been classically derived as a response above the 5 percentile response in a group of normal individuals for each test .
studies have pointed out the need for determining normative responses for the cortisol assay because of variability between different assay methods .
previous metanalyses have suggested a cut - off of 16 g / dl for the 30 min value while using the 1 g test when the test is used in patients with suspected adrenal insufficiency . despite this
we performed a pilot study using the 1 g cosyntropin test in 49 normal individuals in order to obtain the 5 percentile response for the test using an immuno chemiluminometric assay .
we also simultaneously tested the hypothesis that storage of synacthen in saline solution for up to 60 days does not affect cortisol responses .
forty nine non - pregnant volunteer normal adults were tested after institutional ethical review board clearance and informed consent .
following were the exctlusion criteria :
use of any oral / topical / inhaled glucocorticoid in the past 3 years for any durationhistory of hypothalamo pituitaryadrenal diseasehistory of head injury in the pasthistory of snake bitehistory of disseminated intravascular coagulation in the pastany history of diseases known to cause adrenal insufficiency.reconstitution and storage : synthetic acth124 1ml of solution 250 g / ml ( synacthen , novartis , manufactured by alliance pharmaceutical ltd chippenham , wiltshire u.k ) was diluted in 499 ml of 0.9% saline in plastic intravenous fluid container .
after reconstitution the solution was stored in refrigerator 2 - 8 for up to 60 days .
use of any oral / topical / inhaled glucocorticoid in the past 3 years for any duration history of hypothalamo pituitaryadrenal disease history of head injury in the past history of snake bite history of disseminated intravascular coagulation in the past any history of diseases known to cause adrenal insufficiency .
performance of the test : an i.v access with 21 gauge scalp vein set was obtained .
blood was taken at 08:00 hrs for basal cortisol , two ml of the reconstituted solution containing 1 g co - syntropin was administered intravenously through the same cannula .
the scalp vein set was flushed with 10 ml of normal saline following administration of cosyntropin .
an interim analysis showed that the 60 min value was significantly lower than the 30 min value .
since our aim was to identify the peak response we did not perform the 60 min cortisol test in remaining patients , to optimize use of resources available to us .
a note was made regarding the duration of storage of reconstituted co - syntropin at the time of the test .
cortisol assay was done using the automated immuno chemiluminometric access2 assay system ( beckmann- coulter gallaway , ireland ) .
cumulative coefficient of variation was 3.68% at 16.9 g / dl and 9.77% at 2.77 g / dl . internal quality control ( iqc ) material lypocheck immuno assay plus control lot no .
40240 from biorad laboratories with known cortisol concentrations were analyzed on the days of sample run .
the 1 g cosyntropin test was performed in 49 subjects , 38 male ( 77.6% ) .
the mean age of the subjects was 37.2 years , range ( 19 - 84 years ) .
majority of the subjects were young with 59.2% being 36 years or younger , 14.3% of subjects were 55 years or older[figure 1 ] .
the age distribution of studied subjects the mean cortisol values at three time points are depicted in table 1 .
the cortisol values at 30 min were significantly higher than the 0 min and 60 min value p < 0.001 for both .
the lowest and highest cortisol values at each time point and the fifth percentile cortisol value at each time point are depicted in table 1 .
the lowest four responses at 30 min were 13.86 g / dl , 16.07 g / dl , 16.60 g / dl and 17.47 g / dl .
the 5 percentile response was 16.33 g / dl - rounded off to 16.5 g / dl .
cortisol values at different time points for the group all values in g / dl mean and 95% ci values of coristol at baseline,30 min and 60 min the incremental cortisol response was 8.53 2.56 g / dl ( mean sd ) . ranging from 2.61 - 16.92 g / dl .
there was excellent correlation between the 30 min cortisol value and the incremental cortisol response pearsons r = 0.405 p = 0.004 .
the cortisol values at 30 and 60 min had no relationship with number of days of refrigerated storage of the prepared cosyntropin solution .
spear mans rho = 0.06,-0.24 and p = 0.69 , 0.41 for 30 min and 60 min cortisol respectively ( data not shown ) .
we divided the studied normal individuals into two groups one where the duration of reconstituted cosyntropin was stored < 30 days and another where duration of storage 30 days .
there was no difference in the mean 30 min cortisol response using the paired t test ( mean difference 0.25 g / dl p = 0.44 ) table 2 .
in our study we found that the 30 min cortisol response was higher than the 60 min cortisol response .
the value of cortisol corresponding to 5 percentile cortisol response in our study population was 16.5 g / dl . we also found that there was no association between duration of refrigeration of reconstituted synacthen and cortisol response for up to 60 days .
classical comparative studies showed similar 30 min responses to cosyntropin for the 1 and 250 g tests in the same individuals . in the 1 g test the cortisol values quickly reduce and the 60 min value is always lower than the 30 min value . the obvious clinical implication for this
will be that while using the 1 g ldsst test one needs to ensure that the 30 min sampling not be delayed by a few minutes as one can obtain a falsely low value for the cortisol response .
offs for adrenal insufficiency have been derived by investigators as a 5 percentile response in normal individuals . but this method has been disputed by some investigators who feel that the cut point for cortisol value in a stimulation test has to be derived by comparison with a gold standard usually the itt and doing a roc analysis . unfortunately in the most common clinical situation where stimulation testing is necessary- basal cortisol levels are equivocal with no clinical evidence of adrenal insufficiency and itt is not feasible- there is no gold standard for diagnosis of adrenal insufficiency . also in many cases
some centers follow the protocol of using a response above the 5 percentile of normal response as a cut - off to rule out hpa axis suppression , they also use the 2.5 to 5 percentile values as abnormal requiring steroid supplementation as required .
the practice of using 5 percentile responses and using them clinically is continuing with the understanding that the cut points so derived are only a guide to clinical decision making .
in a recent study klose et al . , showed that the 2.5 percentile response varied from 17.2 g / dl ( 475 nmol / l ) to 18.9 g / dl ( 523 nmol / l ) in three different contemporary assays and the stimulated cortisol values varied up to 110 nmol / l ( 3.98 g / dl ) in the same sample when assayed by different methods .
the tendency for a downward shift in cortisol values has been attributed to higher specificity for cortisol and lesser cross reactivity with intermediaries of cortisol metabolism . the use of 550 nmol / l ( 20 g / dl ) or 500 nmol / l ( 18 g / dl ) as a cut off would lead to substantial number of false positives .
our study we found that the 5 percentile cut - off was 16.5 g / dl this value is substantially lower than 18 g / dl being used clinically .
this figure is similar to 16 g / dl identified by roc curve analysis of patient level data of different published studies while using the 1 g cosyntropin test .
the contribution of our study is that we have demonstrated that stimulated cortisol cut - offs lower than the currently used cut point is probably warranted with our assay . in order to arrive at a clinically useful cut off we need to study cortisol values at 30 min in patients with clinically suspected cortisol insufficiency with a longitudinal follow - up .
we suggest that any cortisol value below 16.5 g / dl at 30 min while using the 1 g cosyntropin test will be suspicious of adrenal insufficiency based on our data alone .
one of the main criticisms against the 1 g cosyntropin test is that storage of prepared cosyntropin solution is not possible and it has to be used immediately upon reconstitution .
a previous study has shown stability of cosyntropin after storage for four months at 4c .
our study also had similar findings when we used the 30 min cortisol value as an indirect bioassay of the 1 - 24 acth levels , we found no difference in cortisol levels on storage up to 30 days or even longer .
this finding is of importance in a resource constrained country like ours where reconstituted cosyntropin can be used stored for up to two months and used in multiple patients .
measurement of 1 - 24 cosyntropin in the reconstituted solution and/or retesting in the same individuals after duration of storage could have better supported our hypothesis and these are shortcomings in our study . | background : the 1g cosyntropin test has some advantages over the 250g test as a test of adrenal function .
one of the concerns regarding the 1 g test includes stability of the cosyntropin when reconstituted and stored .
classically the 5th percentile responses to cosyntropin in normal individuals have been used to define a normal response .
recent studies have shown that these normative values should be determined for individual assays.materials and methods : we performed a 1g cosyntropin test using reconstituted and refrigerated ( 4 - 8 c ) cosyntropin in saline solution in 49 non pregnant adults who were apparently healthy and had no exposure to exogenous glucocorticoids .
the cosyntropin solution was stored for up to 60 days following reconstitution .
we analysed the data for any association between duration of cosyntropin solution storage and the cortisol responses to cosyntropin administration.results:the mean sd cortisol level at baseline , 30 and 60 min were-12.19 3 g / dl , 20.72 2.63 g / dl , 16.86 3.33 g / dl .
the 5th percentile cortisol response at 30 min was 16.5 g / dl ( 16.33 g / dl rounded off ) .
the correlation coefficients between number of days of cosyntropin solution storage and the cortisol responses at 30 and 60 min were ( spear mans rho = 0.06,-0.24 respectively ) ( p = 0.69 and 0.41 ) .
there were no differences in cortisol values whether the storage was for less than 30 days or more than 30 days ( mean difference 0.25 g / dl p = 0.44).conclusion : the 5th percentile normative values determined for our assay is lower than what is currently being used clinically and in research publications .
prolonged refrigerated storage of cosyntropin solution does not affect the validity of the 1 g cosyntropin test . | <s>[INST]the 1g cosyntropin test has some advantages over the 250g test as a test of adrenal function .
one of the concerns regarding the 1 g test includes stability of the cosyntropin when reconstituted and stored . classically the 5 percentile responses to cosyntropin in normal individuals have been used to define a normal response .
we performed a 1g cosyntropin test using reconstituted and refrigerated ( 4 - 8 c ) cosyntropin in saline solution in 49 non pregnant adults who were apparently healthy and had no exposure to exogenous glucocorticoids .
we analysed the data for any association between duration of cosyntropin solution storage and the cortisol responses to cosyntropin administration .
the mean sd cortisol level at baseline , 30 and 60 min were-12.19 3 g / dl , 20.72 2.63 g / dl , 16.86 3.33 g / dl .
the 5 percentile cortisol response at 30 min was 16.5 g / dl ( 16.33 g / dl rounded off ) .
the correlation coefficients between number of days of cosyntropin solution storage and the cortisol responses at 30 and 60 min were ( spear mans rho = 0.06,-0.24 respectively ) ( p = 0.69 and 0.41 ) .
there were no differences in cortisol values whether the storage was for less than 30 days or more than 30 days ( mean difference 0.25 g / dl p = 0.44 ) .
the 5 percentile normative values determined for our assay is lower than what is currently being used clinically and in research publications .
prolonged refrigerated storage of cosyntropin solution does not affect the validity of the 1 g cosyntropin test .
the 250 g cosyntropin test has been conventionally used as a test for impaired adrenal reserve .
the cosyntropin that is commercially available is a 250 g preparation ; it contains the 1 - 24 amino acids of adrenocorticotropic hormone ( acth ) .
earliest studies with cosyntropin showed that responses to cosyntropin were similar to surgical stress or trauma . in a study comparing 250 g , 0.5 g , 1 g cosyntropin with insulin tolerance test ( itt ) in healthy volunteers , the 1 g test was found to produce plasma 1 - 24acth levels of 120 pmol / l , approximately twice as high than that of the itt but of the same order of magnitude .
the cortisol responses at 30 minute were comparable to that of the 250 g synacthen test .
pmol / l nearly 220 times that produced during insulin tolerance test ( itt ) or 1 g synacthen .
moreover 1 g synacthen test has been used in studies looking into milder degrees of hpa axis suppression , such as patients with asthma using inhaled corticosteroids ( ics ) .
receiver operator curve analyses which are classically used to assess the utility of clinical screening tests suggest that 1 g test is superior to 250 g test
. there has been some criticism of the 1 g test because the stability of reconstituted cosyntropin has been questioned and there has been one publication involving 8 normal individuals that suggests that cosyntropin if administered in small quantities produces false positive results presumably because it tends to adhere to plastic tubing used to administer the drug .
conflicting this report there is evidence in literature for the stability of reconstituted cosyntropin in saline for up to four months .
not withstanding these controversies 1 g cosyntropin test has been used widely in research protocols to identify impaired adrenal reserve both internationally and in india .
the cut offs for a clear pass response for the 1 and 250 g tests have been classically derived as a response above the 5 percentile response in a group of normal individuals for each test .
studies have pointed out the need for determining normative responses for the cortisol assay because of variability between different assay methods .
previous metanalyses have suggested a cut - off of 16 g / dl for the 30 min value while using the 1 g test when the test is used in patients with suspected adrenal insufficiency . despite this
we performed a pilot study using the 1 g cosyntropin test in 49 normal individuals in order to obtain the 5 percentile response for the test using an immuno chemiluminometric assay .
we also simultaneously tested the hypothesis that storage of synacthen in saline solution for up to 60 days does not affect cortisol responses .
forty nine non - pregnant volunteer normal adults were tested after institutional ethical review board clearance and informed consent .
following were the exctlusion criteria :
use of any oral / topical / inhaled glucocorticoid in the past 3 years for any durationhistory of hypothalamo pituitaryadrenal diseasehistory of head injury in the pasthistory of snake bitehistory of disseminated intravascular coagulation in the pastany history of diseases known to cause adrenal insufficiency.reconstitution and storage : synthetic acth124 1ml of solution 250 g / ml ( synacthen , novartis , manufactured by alliance pharmaceutical ltd chippenham , wiltshire u.k ) was diluted in 499 ml of 0.9% saline in plastic intravenous fluid container .
after reconstitution the solution was stored in refrigerator 2 - 8 for up to 60 days .
use of any oral / topical / inhaled glucocorticoid in the past 3 years for any duration history of hypothalamo pituitaryadrenal disease history of head injury in the past history of snake bite history of disseminated intravascular coagulation in the past any history of diseases known to cause adrenal insufficiency .
performance of the test : an i.v access with 21 gauge scalp vein set was obtained .
blood was taken at 08:00 hrs for basal cortisol , two ml of the reconstituted solution containing 1 g co - syntropin was administered intravenously through the same cannula .
the scalp vein set was flushed with 10 ml of normal saline following administration of cosyntropin .
an interim analysis showed that the 60 min value was significantly lower than the 30 min value .
since our aim was to identify the peak response we did not perform the 60 min cortisol test in remaining patients , to optimize use of resources available to us .
a note was made regarding the duration of storage of reconstituted co - syntropin at the time of the test .
cortisol assay was done using the automated immuno chemiluminometric access2 assay system ( beckmann- coulter gallaway , ireland ) .
cumulative coefficient of variation was 3.68% at 16.9 g / dl and 9.77% at 2.77 g / dl . internal quality control ( iqc ) material lypocheck immuno assay plus control lot no .
40240 from biorad laboratories with known cortisol concentrations were analyzed on the days of sample run .
the 1 g cosyntropin test was performed in 49 subjects , 38 male ( 77.6% ) .
the mean age of the subjects was 37.2 years , range ( 19 - 84 years ) .
majority of the subjects were young with 59.2% being 36 years or younger , 14.3% of subjects were 55 years or older[figure 1 ] .
the age distribution of studied subjects the mean cortisol values at three time points are depicted in table 1 .
the cortisol values at 30 min were significantly higher than the 0 min and 60 min value p < 0.001 for both .
the lowest and highest cortisol values at each time point and the fifth percentile cortisol value at each time point are depicted in table 1 .
the lowest four responses at 30 min were 13.86 g / dl , 16.07 g / dl , 16.60 g / dl and 17.47 g / dl .
the 5 percentile response was 16.33 g / dl - rounded off to 16.5 g / dl .
cortisol values at different time points for the group all values in g / dl mean and 95% ci values of coristol at baseline,30 min and 60 min the incremental cortisol response was 8.53 2.56 g / dl ( mean sd ) . ranging from 2.61 - 16.92 g / dl .
there was excellent correlation between the 30 min cortisol value and the incremental cortisol response pearsons r = 0.405 p = 0.004 .
the cortisol values at 30 and 60 min had no relationship with number of days of refrigerated storage of the prepared cosyntropin solution .
spear mans rho = 0.06,-0.24 and p = 0.69 , 0.41 for 30 min and 60 min cortisol respectively ( data not shown ) .
we divided the studied normal individuals into two groups one where the duration of reconstituted cosyntropin was stored < 30 days and another where duration of storage 30 days .
there was no difference in the mean 30 min cortisol response using the paired t test ( mean difference 0.25 g / dl p = 0.44 ) table 2 .
in our study we found that the 30 min cortisol response was higher than the 60 min cortisol response .
the value of cortisol corresponding to 5 percentile cortisol response in our study population was 16.5 g / dl . we also found that there was no association between duration of refrigeration of reconstituted synacthen and cortisol response for up to 60 days .
classical comparative studies showed similar 30 min responses to cosyntropin for the 1 and 250 g tests in the same individuals . in the 1 g test the cortisol values quickly reduce and the 60 min value is always lower than the 30 min value . the obvious clinical implication for this
will be that while using the 1 g ldsst test one needs to ensure that the 30 min sampling not be delayed by a few minutes as one can obtain a falsely low value for the cortisol response .
offs for adrenal insufficiency have been derived by investigators as a 5 percentile response in normal individuals . but this method has been disputed by some investigators who feel that the cut point for cortisol value in a stimulation test has to be derived by comparison with a gold standard usually the itt and doing a roc analysis . unfortunately in the most common clinical situation where stimulation testing is necessary- basal cortisol levels are equivocal with no clinical evidence of adrenal insufficiency and itt is not feasible- there is no gold standard for diagnosis of adrenal insufficiency . also in many cases
some centers follow the protocol of using a response above the 5 percentile of normal response as a cut - off to rule out hpa axis suppression , they also use the 2.5 to 5 percentile values as abnormal requiring steroid supplementation as required .
the practice of using 5 percentile responses and using them clinically is continuing with the understanding that the cut points so derived are only a guide to clinical decision making .
in a recent study klose et al . , showed that the 2.5 percentile response varied from 17.2 g / dl ( 475 nmol / l ) to 18.9 g / dl ( 523 nmol / l ) in three different contemporary assays and the stimulated cortisol values varied up to 110 nmol / l ( 3.98 g / dl ) in the same sample when assayed by different methods .
the tendency for a downward shift in cortisol values has been attributed to higher specificity for cortisol and lesser cross reactivity with intermediaries of cortisol metabolism . the use of 550 nmol / l ( 20 g / dl ) or 500 nmol / l ( 18 g / dl ) as a cut off would lead to substantial number of false positives .
our study we found that the 5 percentile cut - off was 16.5 g / dl this value is substantially lower than 18 g / dl being used clinically .
this figure is similar to 16 g / dl identified by roc curve analysis of patient level data of different published studies while using the 1 g cosyntropin test .
the contribution of our study is that we have demonstrated that stimulated cortisol cut - offs lower than the currently used cut point is probably warranted with our assay . in order to arrive at a clinically useful cut off we need to study cortisol values at 30 min in patients with clinically suspected cortisol insufficiency with a longitudinal follow - up .
we suggest that any cortisol value below 16.5 g / dl at 30 min while using the 1 g cosyntropin test will be suspicious of adrenal insufficiency based on our data alone .
one of the main criticisms against the 1 g cosyntropin test is that storage of prepared cosyntropin solution is not possible and it has to be used immediately upon reconstitution .
a previous study has shown stability of cosyntropin after storage for four months at 4c .
our study also had similar findings when we used the 30 min cortisol value as an indirect bioassay of the 1 - 24 acth levels , we found no difference in cortisol levels on storage up to 30 days or even longer .
this finding is of importance in a resource constrained country like ours where reconstituted cosyntropin can be used stored for up to two months and used in multiple patients .
measurement of 1 - 24 cosyntropin in the reconstituted solution and/or retesting in the same individuals after duration of storage could have better supported our hypothesis and these are shortcomings in our study .[/INST]background : the 1g cosyntropin test has some advantages over the 250g test as a test of adrenal function .
one of the concerns regarding the 1 g test includes stability of the cosyntropin when reconstituted and stored .
classically the 5th percentile responses to cosyntropin in normal individuals have been used to define a normal response .
recent studies have shown that these normative values should be determined for individual assays.materials and methods : we performed a 1g cosyntropin test using reconstituted and refrigerated ( 4 - 8 c ) cosyntropin in saline solution in 49 non pregnant adults who were apparently healthy and had no exposure to exogenous glucocorticoids .
the cosyntropin solution was stored for up to 60 days following reconstitution .
we analysed the data for any association between duration of cosyntropin solution storage and the cortisol responses to cosyntropin administration.results:the mean sd cortisol level at baseline , 30 and 60 min were-12.19 3 g / dl , 20.72 2.63 g / dl , 16.86 3.33 g / dl .
the 5th percentile cortisol response at 30 min was 16.5 g / dl ( 16.33 g / dl rounded off ) .
the correlation coefficients between number of days of cosyntropin solution storage and the cortisol responses at 30 and 60 min were ( spear mans rho = 0.06,-0.24 respectively ) ( p = 0.69 and 0.41 ) .
there were no differences in cortisol values whether the storage was for less than 30 days or more than 30 days ( mean difference 0.25 g / dl p = 0.44).conclusion : the 5th percentile normative values determined for our assay is lower than what is currently being used clinically and in research publications .
prolonged refrigerated storage of cosyntropin solution does not affect the validity of the 1 g cosyntropin test .</s> |
SECTION 1. SHORT TITLE.
This Act may be cited as the ``American Land Sovereignty Protection
Act''.
SEC. 2. FINDINGS AND PURPOSES.
(a) Findings.--Congress finds that--
(1) the power to dispose of and make all necessary rules
governing property belonging to the United States is vested in
Congress under section 3 of article IV of the Constitution;
(2) some Federal property designations under international
agreements concern land use policies and regulations for
property belonging to the United States that, under section 3
of article IV of the Constitution, can be implemented only by
an Act of Congress;
(3) some international property designations, such as those
under the United States Biosphere Reserve Program and the Man
and Biosphere Program of the United Nations Scientific,
Educational, and Cultural Organization, operate under
independent national committees, such as the United States
National Man and Biosphere Committee, that have no legislative
directive or authorization from Congress;
(4) actions by the United States in making such
designations may affect the use and value of nearby non-Federal
property;
(5) the sovereignty of the States is a critical component
of our Federal system of government and a bulwark against the
unwise concentration of power;
(6) private property rights are essential for the
protection of freedom;
(7) actions by the United States to designate property
belonging to the United States under international agreements
in some cases conflict with congressional constitutional
responsibilities and the sovereign powers of the States; and
(8) actions by the President in applying certain
international agreements to property owned by the United States
diminish the authority of Congress to make rules respecting the
property.
(b) Purposes.--The purposes of this Act are--
(1) to reaffirm the power of Congress under section 3 of
article IV of the Constitution over international agreements
that concern disposal, management, and use of property
belonging to the United States;
(2) to protect State powers not reserved to the Federal
Government under the Constitution from Federal actions
designating property under international agreements;
(3) to ensure that no United States citizen suffers any
diminishment or loss of individual rights as a result of
Federal action designating property under an international
agreement for the purpose of imposing restrictions on use of
the property;
(4) to protect private interests in property from
diminishment as a result of Federal action designating property
under international agreements; and
(5) to provide a process under which the United States may,
when it is desirable to do so, designate property under an
international agreement.
SEC. 3. CLARIFICATION OF CONGRESSIONAL ROLE IN WORLD HERITAGE SITE
LISTING.
Section 401 of the National Historic Preservation Act Amendments of
1980 (16 U.S.C. 470a-1) is amended--
(1) by striking ``Sec. 401. (a)'' and inserting the
following:
``SEC. 401. PARTICIPATION BY THE UNITED STATES.
``(a) In General.--'';
(2) in the first sentence of subsection (a)--
(A) by striking ``The Secretary of the Interior''
and inserting ``Subject to subsections (b), (c), (d),
and (e), the Secretary of the Interior (referred to in
this section as the `Secretary')''; and
(B) by inserting ``(referred to in this section as
the `Convention')'' after ``1973'';
(3) in subsection (b)--
(A) by striking ``(b) The Secretary of the
Interior'' and inserting ``(b) Nomination of Property
to World Heritage Committee.--The Secretary''; and
(B) in the fourth sentence--
(i) by striking ``Representatives and'' and
inserting ``Representatives,''; and
(ii) by inserting before the final period
``, and the appropriate State and local
governments'';
(4) in subsection (c), by striking ``(c) No non-Federal
property may be nominated by the Secretary of the Interior''
and inserting ``(c) Nomination of Non-Federal Property to World
Heritage Committee.--No non-Federal property may be nominated
by the Secretary''; and
(5) by adding at the end the following:
``(d) Requirements for Nomination of Properties.--The Secretary
shall not nominate a property under subsection (b) unless--
``(1) the Secretary publishes a proposed nomination in the
Federal Register and conducts a proceeding under sections 555,
556, and 557, of title 5, United States Code;
``(2) the Secretary, in carrying out the proceeding
described in paragraph (1)--
``(A) considers--
``(i) natural resources associated with the
property proposed to be nominated and other
property located within 10 miles of the
property to be nominated; and
``(ii) the impact that inclusion of the
property proposed to be nominated on the World
Heritage List would have on existing and future
uses of the property proposed to be nominated
or other property located within 10 miles of
the property to be nominated; and
``(B) determines that commercially viable uses (in
existence on the date of the nomination) of the
property proposed to be nominated and of other property
located within 10 miles of the property proposed to be
nominated will not be adversely affected by inclusion
of the property on the World Heritage List; and
``(3) the Secretary submits to Congress a report that--
``(A) contains the information described in
subparagraphs (A) and (B);
``(B) describes the necessity for including the
property on the list; and
``(C) proposes legislation authorizing nomination
of the property; and
``(4) the nomination is specifically authorized by an Act
of Congress enacted after the date of the report.
``(e) Objection to Inclusion of Property.--The Secretary shall
object to the inclusion of property in the United States on the list of
World Heritage in Danger established under Article 11.4 of the
Convention, unless--
``(1) the Secretary submits to Congress the report required
under subsection (d)(1)(C); and
``(2) the Secretary is specifically authorized to assent to
the inclusion of the property on the list by an Act of Congress
enacted after the date of submission of the report under
paragraph (1).
``(f) Decisionmaking.--Notwithstanding any provision of the
Convention, all land management decisions with respect to any Federal
or State land shall remain the responsibility of the land management
agency that administers the land.''.
SEC. 4. PROHIBITION AND TERMINATION OF UNAUTHORIZED UNITED NATIONS
BIOSPHERE RESERVES.
Title IV of the National Historic Preservation Act Amendments of
1980 (16 U.S.C. 470a-1 et seq.) is amended by adding at the end the
following:
``SEC. 403. PROHIBITION AND TERMINATION OF UNAUTHORIZED UNITED NATIONS
BIOSPHERE RESERVES.
``(a) In General.--No Federal official may nominate property in the
United States for designation as a Biosphere Reserve under the Man and
Biosphere Program of the United Nations Educational, Scientific, and
Cultural Organization unless--
``(1) the Secretary of State publishes a proposed
nomination in the Federal Register and conducts a proceeding
under sections 555, 556, and 557, of title 5, United States
Code;
``(2) the Secretary of State, in carrying out the
proceeding described in paragraph (1)--
``(A) considers--
``(i) natural resources associated with the
property proposed to be nominated and other
property located within 10 miles of the
property to be nominated; and
``(ii) the impact that inclusion of the
property proposed to be designated as a
Biosphere would have on existing and future
uses of the property proposed to be nominated
or other property located within 10 miles of
the property to be nominated;
``(B) determines that commercially viable uses (in
existence on the date of the nomination) of the
property proposed to be nominated and of other property
located within 10 miles of the property proposed to be
nominated will not be adversely affected by designation
of the property as a Biosphere; and
``(3) the Secretary of State submits to Congress a report
that--
``(A) contains the information described in
subparagraphs (A) and (B);
``(B) describes the necessity for including the
property in the program; and
``(C) proposes legislation authorizing nomination
of the property; and
``(4) the nomination is specifically authorized by an Act
of Congress enacted after the date of the report.
``(b) Objection to Inclusion of Property.--The Secretary of State
shall object to the designation of property in the United States as a
Biosphere Reserve under the Man and Biosphere Program of the United
Nations Educational, Scientific, and Cultural Organization, unless--
``(1) the Secretary of State submits Congress the report
required under subsection (a)(1)(C); and
``(2) the Secretary of State is specifically authorized to
assent to the inclusion of the property on the list by an Act
of Congress enacted after the date of submission of the report
under paragraph (1).
``(c) Properties Designated Before Date of Enactment.--Any
designation of property in the United States as a Biosphere Reserve
under the Man and Biosphere Program of the United Nations Educational,
Scientific, and Cultural Organization made before the date of enactment
of this section shall terminate on December 31, 2003, unless the
Biosphere Reserve--
``(1) is specifically authorized by a law enacted after the
date of enactment of this section and before December 31, 2003;
``(2) consists solely of property that on the date of
enactment of this section is owned by the United States; and
``(3) is subject to a management plan that specifically
ensures that the use of nearby non-Federal property is not
limited or restricted as a result of the designation.
``(d) Decisionmaking.--Notwithstanding any provision of the
Convention, all land management decisions with respect to any Federal
or State land shall remain the responsibility of the land management
agency that administers the land.''.
SEC. 5. TECHNICAL AMENDMENTS.
Title IV of the National Historic Preservation Act Amendments of
1980 (16 U.S.C. 470a-1 et seq.) is amended--
(1) in the last sentence of section 401(b), by striking
``Committee on Natural Resources'' and inserting ``Committee on
Resources''; and
(2) in section 402, by striking ``Sec. 402. Prior to the
approval'' and inserting the following:
``SEC. 402. MITIGATION OF ADVERSE EFFECTS OF FEDERAL UNDERTAKINGS
OUTSIDE THE UNITED STATES.
``Prior to the approval''. | American Land Sovereignty Protection Act - Amends the National Historic Preservation Act Amendments of 1980 to prohibit the Secretary of the Interior from nominating any non-federal property for inclusion on the World Heritage List unless the Secretary: (1) publishes a proposed nomination in the Federal Register and conducts required hearings; (2) considers natural resources in the area, as well as the impact that inclusion would have on existing and future property uses; (3) determines that commercially viable uses of the property and adjacent property within ten miles will not be adversely affected by inclusion; and (4) submits a report to Congress describing the necessity of such inclusion and proposing legislation authorizing such nomination.Requires the Secretary to object to inclusion of property on the World Heritage in Danger list unless the Secretary: (1) submits such report to Congress; and (2) is specifically authorized to assent to such inclusion by an Act of Congress.Prohibits any Federal official from nominating property for designation as a Biosphere Reserve unless the Secretary of State: (1) publishes such proposed nomination and conducts required hearings; (2) makes the same considerations and submits the same type of report as required of the Secretary for inclusion on the World Heritage List and the nomination is specifically authorized by an Act of Congress. Requires such Secretary to object to such a designation unless such report is submitted and such Secretary is specifically authorized to assent to such inclusion by an Act of Congress. Provides transitional provisions for property so designated before the enactment of this Act. | <s>[INST]SECTION 1. SHORT TITLE.
This Act may be cited as the ``American Land Sovereignty Protection
Act''.
SEC. 2. FINDINGS AND PURPOSES.
(a) Findings.--Congress finds that--
(1) the power to dispose of and make all necessary rules
governing property belonging to the United States is vested in
Congress under section 3 of article IV of the Constitution;
(2) some Federal property designations under international
agreements concern land use policies and regulations for
property belonging to the United States that, under section 3
of article IV of the Constitution, can be implemented only by
an Act of Congress;
(3) some international property designations, such as those
under the United States Biosphere Reserve Program and the Man
and Biosphere Program of the United Nations Scientific,
Educational, and Cultural Organization, operate under
independent national committees, such as the United States
National Man and Biosphere Committee, that have no legislative
directive or authorization from Congress;
(4) actions by the United States in making such
designations may affect the use and value of nearby non-Federal
property;
(5) the sovereignty of the States is a critical component
of our Federal system of government and a bulwark against the
unwise concentration of power;
(6) private property rights are essential for the
protection of freedom;
(7) actions by the United States to designate property
belonging to the United States under international agreements
in some cases conflict with congressional constitutional
responsibilities and the sovereign powers of the States; and
(8) actions by the President in applying certain
international agreements to property owned by the United States
diminish the authority of Congress to make rules respecting the
property.
(b) Purposes.--The purposes of this Act are--
(1) to reaffirm the power of Congress under section 3 of
article IV of the Constitution over international agreements
that concern disposal, management, and use of property
belonging to the United States;
(2) to protect State powers not reserved to the Federal
Government under the Constitution from Federal actions
designating property under international agreements;
(3) to ensure that no United States citizen suffers any
diminishment or loss of individual rights as a result of
Federal action designating property under an international
agreement for the purpose of imposing restrictions on use of
the property;
(4) to protect private interests in property from
diminishment as a result of Federal action designating property
under international agreements; and
(5) to provide a process under which the United States may,
when it is desirable to do so, designate property under an
international agreement.
SEC. 3. CLARIFICATION OF CONGRESSIONAL ROLE IN WORLD HERITAGE SITE
LISTING.
Section 401 of the National Historic Preservation Act Amendments of
1980 (16 U.S.C. 470a-1) is amended--
(1) by striking ``Sec. 401. (a)'' and inserting the
following:
``SEC. 401. PARTICIPATION BY THE UNITED STATES.
``(a) In General.--'';
(2) in the first sentence of subsection (a)--
(A) by striking ``The Secretary of the Interior''
and inserting ``Subject to subsections (b), (c), (d),
and (e), the Secretary of the Interior (referred to in
this section as the `Secretary')''; and
(B) by inserting ``(referred to in this section as
the `Convention')'' after ``1973'';
(3) in subsection (b)--
(A) by striking ``(b) The Secretary of the
Interior'' and inserting ``(b) Nomination of Property
to World Heritage Committee.--The Secretary''; and
(B) in the fourth sentence--
(i) by striking ``Representatives and'' and
inserting ``Representatives,''; and
(ii) by inserting before the final period
``, and the appropriate State and local
governments'';
(4) in subsection (c), by striking ``(c) No non-Federal
property may be nominated by the Secretary of the Interior''
and inserting ``(c) Nomination of Non-Federal Property to World
Heritage Committee.--No non-Federal property may be nominated
by the Secretary''; and
(5) by adding at the end the following:
``(d) Requirements for Nomination of Properties.--The Secretary
shall not nominate a property under subsection (b) unless--
``(1) the Secretary publishes a proposed nomination in the
Federal Register and conducts a proceeding under sections 555,
556, and 557, of title 5, United States Code;
``(2) the Secretary, in carrying out the proceeding
described in paragraph (1)--
``(A) considers--
``(i) natural resources associated with the
property proposed to be nominated and other
property located within 10 miles of the
property to be nominated; and
``(ii) the impact that inclusion of the
property proposed to be nominated on the World
Heritage List would have on existing and future
uses of the property proposed to be nominated
or other property located within 10 miles of
the property to be nominated; and
``(B) determines that commercially viable uses (in
existence on the date of the nomination) of the
property proposed to be nominated and of other property
located within 10 miles of the property proposed to be
nominated will not be adversely affected by inclusion
of the property on the World Heritage List; and
``(3) the Secretary submits to Congress a report that--
``(A) contains the information described in
subparagraphs (A) and (B);
``(B) describes the necessity for including the
property on the list; and
``(C) proposes legislation authorizing nomination
of the property; and
``(4) the nomination is specifically authorized by an Act
of Congress enacted after the date of the report.
``(e) Objection to Inclusion of Property.--The Secretary shall
object to the inclusion of property in the United States on the list of
World Heritage in Danger established under Article 11.4 of the
Convention, unless--
``(1) the Secretary submits to Congress the report required
under subsection (d)(1)(C); and
``(2) the Secretary is specifically authorized to assent to
the inclusion of the property on the list by an Act of Congress
enacted after the date of submission of the report under
paragraph (1).
``(f) Decisionmaking.--Notwithstanding any provision of the
Convention, all land management decisions with respect to any Federal
or State land shall remain the responsibility of the land management
agency that administers the land.''.
SEC. 4. PROHIBITION AND TERMINATION OF UNAUTHORIZED UNITED NATIONS
BIOSPHERE RESERVES.
Title IV of the National Historic Preservation Act Amendments of
1980 (16 U.S.C. 470a-1 et seq.) is amended by adding at the end the
following:
``SEC. 403. PROHIBITION AND TERMINATION OF UNAUTHORIZED UNITED NATIONS
BIOSPHERE RESERVES.
``(a) In General.--No Federal official may nominate property in the
United States for designation as a Biosphere Reserve under the Man and
Biosphere Program of the United Nations Educational, Scientific, and
Cultural Organization unless--
``(1) the Secretary of State publishes a proposed
nomination in the Federal Register and conducts a proceeding
under sections 555, 556, and 557, of title 5, United States
Code;
``(2) the Secretary of State, in carrying out the
proceeding described in paragraph (1)--
``(A) considers--
``(i) natural resources associated with the
property proposed to be nominated and other
property located within 10 miles of the
property to be nominated; and
``(ii) the impact that inclusion of the
property proposed to be designated as a
Biosphere would have on existing and future
uses of the property proposed to be nominated
or other property located within 10 miles of
the property to be nominated;
``(B) determines that commercially viable uses (in
existence on the date of the nomination) of the
property proposed to be nominated and of other property
located within 10 miles of the property proposed to be
nominated will not be adversely affected by designation
of the property as a Biosphere; and
``(3) the Secretary of State submits to Congress a report
that--
``(A) contains the information described in
subparagraphs (A) and (B);
``(B) describes the necessity for including the
property in the program; and
``(C) proposes legislation authorizing nomination
of the property; and
``(4) the nomination is specifically authorized by an Act
of Congress enacted after the date of the report.
``(b) Objection to Inclusion of Property.--The Secretary of State
shall object to the designation of property in the United States as a
Biosphere Reserve under the Man and Biosphere Program of the United
Nations Educational, Scientific, and Cultural Organization, unless--
``(1) the Secretary of State submits Congress the report
required under subsection (a)(1)(C); and
``(2) the Secretary of State is specifically authorized to
assent to the inclusion of the property on the list by an Act
of Congress enacted after the date of submission of the report
under paragraph (1).
``(c) Properties Designated Before Date of Enactment.--Any
designation of property in the United States as a Biosphere Reserve
under the Man and Biosphere Program of the United Nations Educational,
Scientific, and Cultural Organization made before the date of enactment
of this section shall terminate on December 31, 2003, unless the
Biosphere Reserve--
``(1) is specifically authorized by a law enacted after the
date of enactment of this section and before December 31, 2003;
``(2) consists solely of property that on the date of
enactment of this section is owned by the United States; and
``(3) is subject to a management plan that specifically
ensures that the use of nearby non-Federal property is not
limited or restricted as a result of the designation.
``(d) Decisionmaking.--Notwithstanding any provision of the
Convention, all land management decisions with respect to any Federal
or State land shall remain the responsibility of the land management
agency that administers the land.''.
SEC. 5. TECHNICAL AMENDMENTS.
Title IV of the National Historic Preservation Act Amendments of
1980 (16 U.S.C. 470a-1 et seq.) is amended--
(1) in the last sentence of section 401(b), by striking
``Committee on Natural Resources'' and inserting ``Committee on
Resources''; and
(2) in section 402, by striking ``Sec. 402. Prior to the
approval'' and inserting the following:
``SEC. 402. MITIGATION OF ADVERSE EFFECTS OF FEDERAL UNDERTAKINGS
OUTSIDE THE UNITED STATES.
``Prior to the approval''.[/INST]American Land Sovereignty Protection Act - Amends the National Historic Preservation Act Amendments of 1980 to prohibit the Secretary of the Interior from nominating any non-federal property for inclusion on the World Heritage List unless the Secretary: (1) publishes a proposed nomination in the Federal Register and conducts required hearings; (2) considers natural resources in the area, as well as the impact that inclusion would have on existing and future property uses; (3) determines that commercially viable uses of the property and adjacent property within ten miles will not be adversely affected by inclusion; and (4) submits a report to Congress describing the necessity of such inclusion and proposing legislation authorizing such nomination.Requires the Secretary to object to inclusion of property on the World Heritage in Danger list unless the Secretary: (1) submits such report to Congress; and (2) is specifically authorized to assent to such inclusion by an Act of Congress.Prohibits any Federal official from nominating property for designation as a Biosphere Reserve unless the Secretary of State: (1) publishes such proposed nomination and conducts required hearings; (2) makes the same considerations and submits the same type of report as required of the Secretary for inclusion on the World Heritage List and the nomination is specifically authorized by an Act of Congress. Requires such Secretary to object to such a designation unless such report is submitted and such Secretary is specifically authorized to assent to such inclusion by an Act of Congress. Provides transitional provisions for property so designated before the enactment of this Act.</s> |
Organizers of an effort to oust Wisconsin's Republican Gov. Scott Walker say they are submitting 1 million petition signatures, almost double the number needed to force a recall election.
Their effort was spurred by anger over Walker's efforts last year to reduce the bargaining power of public sector unions.
The Wisconsin elections board now must verify that there are enough valid signatures, a process expected to take several months.
In a recall election, voters can remove an elected official before the end of his or her term. In Wisconsin, those forcing the recall generally put up a candidate to face the official in a special eleciton.
An election may not happen until June or later.
Organizers also turned in on Tuesday about 305,000 more signatures than needed to force a recall election of Walker's lieutenant governor. ||||| • The Government Accountability Board has transported the boxes of recall petitions to a state-owned building in Madison. The location will not be made public until all the petitions have been scanned to digital files. Scanning is expected to take several days.
• The GAB has 31 days to validate the signatures, but officials have said they will be in court asking for an extension that could stretch well beyond 60 days. The GAB also will ask a judge that all of the recalls be held on the same day.
• Those wishing to challenge signatures have 10 days from when they receive copies of the recall signatures to file with the GAB. Republican Party spokesman Ben Sparks said the party has 5,000 volunteers ready to examine petitions.
• When election workers are finished verifying signatures and analyzing challenges, they will deliver a report to GAB board members.
• The board will then rule on the validity of the recalls. If it rules in favor, an election date will be set six weeks from that point. There is a high possibility of legal challenges, which could push the election date back even farther. | – Looks like Wisconsin Gov. Scott Walker will be facing a recall re-election. Leaders of the Democratic effort say they collected 1 million signatures for today's filing, about double the necessary amount. The figure represents about the same number of votes Walker received in the November 2010 election, notes the Wisconsin State Journal. The signatures will need to be verified by the state elections board, which could take months, reports AP. Earlier, the group trying to recall Senate Majority Leader Scott Fitzgerald said it would easily make its quota as well. The same applies to the lieutenant governor and three other state senators, all of them Republicans. The recall efforts stem from Walker's move last year to essentially eliminate the collective bargaining rights of public workers. | <s>[INST]Organizers of an effort to oust Wisconsin's Republican Gov. Scott Walker say they are submitting 1 million petition signatures, almost double the number needed to force a recall election.
Their effort was spurred by anger over Walker's efforts last year to reduce the bargaining power of public sector unions.
The Wisconsin elections board now must verify that there are enough valid signatures, a process expected to take several months.
In a recall election, voters can remove an elected official before the end of his or her term. In Wisconsin, those forcing the recall generally put up a candidate to face the official in a special eleciton.
An election may not happen until June or later.
Organizers also turned in on Tuesday about 305,000 more signatures than needed to force a recall election of Walker's lieutenant governor. ||||| • The Government Accountability Board has transported the boxes of recall petitions to a state-owned building in Madison. The location will not be made public until all the petitions have been scanned to digital files. Scanning is expected to take several days.
• The GAB has 31 days to validate the signatures, but officials have said they will be in court asking for an extension that could stretch well beyond 60 days. The GAB also will ask a judge that all of the recalls be held on the same day.
• Those wishing to challenge signatures have 10 days from when they receive copies of the recall signatures to file with the GAB. Republican Party spokesman Ben Sparks said the party has 5,000 volunteers ready to examine petitions.
• When election workers are finished verifying signatures and analyzing challenges, they will deliver a report to GAB board members.
• The board will then rule on the validity of the recalls. If it rules in favor, an election date will be set six weeks from that point. There is a high possibility of legal challenges, which could push the election date back even farther.[/INST]– Looks like Wisconsin Gov. Scott Walker will be facing a recall re-election. Leaders of the Democratic effort say they collected 1 million signatures for today's filing, about double the necessary amount. The figure represents about the same number of votes Walker received in the November 2010 election, notes the Wisconsin State Journal. The signatures will need to be verified by the state elections board, which could take months, reports AP. Earlier, the group trying to recall Senate Majority Leader Scott Fitzgerald said it would easily make its quota as well. The same applies to the lieutenant governor and three other state senators, all of them Republicans. The recall efforts stem from Walker's move last year to essentially eliminate the collective bargaining rights of public workers.</s> |
walter dandy was the first research to describe radicular pain as an extradural mass associated syndrome in 19293 ) .
mixter and barr , however , reported in 1934 that extruded disc materials cause sciatic pain and described the surgical approach11 ) .
intervertebral disc degeneration18 ) , smoking , occupational
and sports - related physical activity , microtrauma , such as obesity ,
environmental factors covered by the different forms of
life12 ) , genetic factors1 ) , congenital defects of vertebral formation16 )
are involved in the etiology of lumbar disc herniation .
the disc herniation depending on vertebral corpus developmental
anomaly is available only one case in english literature .
a thirty - year - old female patient was admitted to our clinic with complaints of low back and right leg pain after a fall 3 weeks ago .
physical examination was evaluated as normal and there were not any features identified in family history .
the neurological examination was described as right straight leg raising test positive at 45 degrees , full muscle strength , norm active tendon reflexes , right s1 dermatome hypoesthesia .
lumbar computed tomography ( ct ) was planned because s1 lumbar vertebra fracture was suspected in the lumbosacral graph ap / l ( fig .
1 ) based on history of trauma . lumbar magnetic resonance imaging ( mri ) was performed as fusion anomaly was detected but s1 vertebral corpus was not broken on the lumbar ct ( fig .
l5-s1 right paramedian disc herniation was detected with the precipitation of trauma on the lumbar mri ( fig .
development of the spinal canal due to congenital defects in the lumbar mr imaging was normal ( fig .
the patient did not consent to surgical treatment and was referred to physical therapy clinic for conservative treatment .
disc herniation occurs as a result of displacement of lumbar intervertebral disc annulus fibrosis and nucleus polyposis fibrosis in the vertebral canal7 ) .
lumbar disc herniation can be symptomatic as a result of compression on the spinal nerves or roots .
radicular symptoms occur due to generation of nerve root ischemia because of the direct mechanical effect of the herniated disc material , or with an inflammatory response and the effect of secondary edema and compression of vascular structures9 ) . in the etiology of the disease ,
cumulative microtrauma was held responsible and it is reported to be more frequently encountered in those driving motor vehicles , those with sedentary life style and in smokers12 ) .
these anomalies are classified as disorders of formation , segmentation disorders and the composition of the two complex disorders5 ) .
although the pathophysiology of spina bifida can be described , the embryological pathogenesis of vertebral corpus fusion anomaly is not fully known .
mesoderm structure emerges after the second week of embryological development of the vertebrae that make up the spine .
skeletal system develops from the para - axial mesoderm and the lateral plates ( somatic layer ) , and crista neuralis .
paraaxial mesoderm creates a series of segmented tissue block known as the somite towards caudal from both sides of the neural tube , somatomeres and occipital region .
the position of the sclerotome cells changes to surround the notochord and the spinal column in the fourth week of development .
this positional change occurs with the differentiation of surrounding structures and not the active migration of those sclerotome cells13 ) .
thus , the resulting mesenchymal column retains segmental traces by leaving less - dense areas containing intersegmental arteries of sclerotomies blocks .
the caudal part of each sclerotome segment is heavily divided and collected in the ongoing stages of development .
this division is so intense that it moves towards the environment intersegmental tissue and thus , a caudal part of the sclerotome is connected to cephalic part of another sclerotome .
thus , vertebral body becomes intersegmental with the connection of intersegmental tissue and the pre - cartilaginous vertebra body10 ) . among sclerotomes that are poor in cell count in cranial and rich in cell count in caudal forms , the one that contains the poo r area forms the intervertebral disc , while the one that contains the rich area constitutes a section of vertebral body10 ) .
these formation defects occurring in the embryological period cause anomalies regarding the vertebra and the disc10 ) . among congenital vertebral anomalies ,
double facet joint formation8 ) , the absence of pedicle17 ) , and absence of lumbar articular processes are reported ; however , vertebral corpus fusion defect as in our case was reported before only one time2 ) .
butterfly vertebra is an uncommon congenital disorder characterized by a symmetrical fusion defect resulting in a sagittal cleft vertebra2 ) .
intervertebral disc was filled due to the lack of development of annulus fibrosis in cavity associated with the defect of embryological development of the vertebral corpus and trauma as a result of weakness in our case and it caused the patient to develop lumbar disc hernia .
therefore disc herniation could occur more easily in patients with vertebral body defect than in patients with normal vertebral body .
congenital vertebra corpus fusion anomalies are typically asymptomatic . however , these anomalies incidentally detected during routine radiographic investigations and post - traumatic radiological evaluations6 ) .
the specific radiological examinations usually include direct roentgenogram , ct and mri15 ) . in our case ,
vertebral fusion defects were determined with lumbar radiograph performed due to back pain after trauma .
we thought that the defect occurred during the development in the embryological period of the vertebral body .
however , that intervertebral disc was the weakest link as sufficient circular annulus fibrosis had not developed here .
there were no other osseous pathologies such as spina bifida occulta , facet abnormalities , and/or pedicle anomaly in our case .
disc herniation in patients with congenital bone deformities associated with congenital developmental defects are considered related problems in the spinal canal . on the level of the patient 's filum terminale , whether tethered cord syndrome should be investigated14 ) .
there was not a congenital defect of development of the spinal canal in our case ( fig .
5 ) . presenting with similar symptoms , such as back and leg pain , especially adult clinical presentation patients with lumbar disc herniation group tethered cords can be confused with tethered cord . and
these types of cases after trauma can be misevaluated and overlooked as congenital malformation without treatment .
especially , patients with congenital malformations and an unusual clinic should be examined carefully with advanced radiological imaging techniques . | lumbar disc herniation is characterized with low back and leg pain resulting from the degenerated lumbar disc compressing the spinal nerve root .
the etiology of degenerative spine is related to age , smoking , microtrauma , obesity , disorders of familial collagen structure , occupational and sports - related physical activity .
however , disc herniations induced by congenital lumbar vertebral anomalies are rarely seen .
vertebral fusion defect is one of the causes of congenital anomalies .
the pathogenesis of embryological corpus vertebral fusion anomaly is not fully known . in this paper , a 30-year - old patient who had the complaints of low back and right leg pain after falling from a height
is presented .
she had right l5-s1 disc herniation that had developed on the basis of s1 vertebra corpus fusion anomaly in lumbar computed tomography .
this case has been discussed in the light of literature based on evaluations of lumbar computed tomography ( ct ) and magnetic resonance imaging ( mri ) .
this case is unique in that it is the first case with development of lumbar disc herniation associated with s1 vertebral corpus fusion anomaly .
congenital malformations with unusual clinical presentation after trauma should be evaluated through advanced radiological imaging techniques . | <s>[INST]walter dandy was the first research to describe radicular pain as an extradural mass associated syndrome in 19293 ) .
mixter and barr , however , reported in 1934 that extruded disc materials cause sciatic pain and described the surgical approach11 ) .
intervertebral disc degeneration18 ) , smoking , occupational
and sports - related physical activity , microtrauma , such as obesity ,
environmental factors covered by the different forms of
life12 ) , genetic factors1 ) , congenital defects of vertebral formation16 )
are involved in the etiology of lumbar disc herniation .
the disc herniation depending on vertebral corpus developmental
anomaly is available only one case in english literature .
a thirty - year - old female patient was admitted to our clinic with complaints of low back and right leg pain after a fall 3 weeks ago .
physical examination was evaluated as normal and there were not any features identified in family history .
the neurological examination was described as right straight leg raising test positive at 45 degrees , full muscle strength , norm active tendon reflexes , right s1 dermatome hypoesthesia .
lumbar computed tomography ( ct ) was planned because s1 lumbar vertebra fracture was suspected in the lumbosacral graph ap / l ( fig .
1 ) based on history of trauma . lumbar magnetic resonance imaging ( mri ) was performed as fusion anomaly was detected but s1 vertebral corpus was not broken on the lumbar ct ( fig .
l5-s1 right paramedian disc herniation was detected with the precipitation of trauma on the lumbar mri ( fig .
development of the spinal canal due to congenital defects in the lumbar mr imaging was normal ( fig .
the patient did not consent to surgical treatment and was referred to physical therapy clinic for conservative treatment .
disc herniation occurs as a result of displacement of lumbar intervertebral disc annulus fibrosis and nucleus polyposis fibrosis in the vertebral canal7 ) .
lumbar disc herniation can be symptomatic as a result of compression on the spinal nerves or roots .
radicular symptoms occur due to generation of nerve root ischemia because of the direct mechanical effect of the herniated disc material , or with an inflammatory response and the effect of secondary edema and compression of vascular structures9 ) . in the etiology of the disease ,
cumulative microtrauma was held responsible and it is reported to be more frequently encountered in those driving motor vehicles , those with sedentary life style and in smokers12 ) .
these anomalies are classified as disorders of formation , segmentation disorders and the composition of the two complex disorders5 ) .
although the pathophysiology of spina bifida can be described , the embryological pathogenesis of vertebral corpus fusion anomaly is not fully known .
mesoderm structure emerges after the second week of embryological development of the vertebrae that make up the spine .
skeletal system develops from the para - axial mesoderm and the lateral plates ( somatic layer ) , and crista neuralis .
paraaxial mesoderm creates a series of segmented tissue block known as the somite towards caudal from both sides of the neural tube , somatomeres and occipital region .
the position of the sclerotome cells changes to surround the notochord and the spinal column in the fourth week of development .
this positional change occurs with the differentiation of surrounding structures and not the active migration of those sclerotome cells13 ) .
thus , the resulting mesenchymal column retains segmental traces by leaving less - dense areas containing intersegmental arteries of sclerotomies blocks .
the caudal part of each sclerotome segment is heavily divided and collected in the ongoing stages of development .
this division is so intense that it moves towards the environment intersegmental tissue and thus , a caudal part of the sclerotome is connected to cephalic part of another sclerotome .
thus , vertebral body becomes intersegmental with the connection of intersegmental tissue and the pre - cartilaginous vertebra body10 ) . among sclerotomes that are poor in cell count in cranial and rich in cell count in caudal forms , the one that contains the poo r area forms the intervertebral disc , while the one that contains the rich area constitutes a section of vertebral body10 ) .
these formation defects occurring in the embryological period cause anomalies regarding the vertebra and the disc10 ) . among congenital vertebral anomalies ,
double facet joint formation8 ) , the absence of pedicle17 ) , and absence of lumbar articular processes are reported ; however , vertebral corpus fusion defect as in our case was reported before only one time2 ) .
butterfly vertebra is an uncommon congenital disorder characterized by a symmetrical fusion defect resulting in a sagittal cleft vertebra2 ) .
intervertebral disc was filled due to the lack of development of annulus fibrosis in cavity associated with the defect of embryological development of the vertebral corpus and trauma as a result of weakness in our case and it caused the patient to develop lumbar disc hernia .
therefore disc herniation could occur more easily in patients with vertebral body defect than in patients with normal vertebral body .
congenital vertebra corpus fusion anomalies are typically asymptomatic . however , these anomalies incidentally detected during routine radiographic investigations and post - traumatic radiological evaluations6 ) .
the specific radiological examinations usually include direct roentgenogram , ct and mri15 ) . in our case ,
vertebral fusion defects were determined with lumbar radiograph performed due to back pain after trauma .
we thought that the defect occurred during the development in the embryological period of the vertebral body .
however , that intervertebral disc was the weakest link as sufficient circular annulus fibrosis had not developed here .
there were no other osseous pathologies such as spina bifida occulta , facet abnormalities , and/or pedicle anomaly in our case .
disc herniation in patients with congenital bone deformities associated with congenital developmental defects are considered related problems in the spinal canal . on the level of the patient 's filum terminale , whether tethered cord syndrome should be investigated14 ) .
there was not a congenital defect of development of the spinal canal in our case ( fig .
5 ) . presenting with similar symptoms , such as back and leg pain , especially adult clinical presentation patients with lumbar disc herniation group tethered cords can be confused with tethered cord . and
these types of cases after trauma can be misevaluated and overlooked as congenital malformation without treatment .
especially , patients with congenital malformations and an unusual clinic should be examined carefully with advanced radiological imaging techniques .[/INST]lumbar disc herniation is characterized with low back and leg pain resulting from the degenerated lumbar disc compressing the spinal nerve root .
the etiology of degenerative spine is related to age , smoking , microtrauma , obesity , disorders of familial collagen structure , occupational and sports - related physical activity .
however , disc herniations induced by congenital lumbar vertebral anomalies are rarely seen .
vertebral fusion defect is one of the causes of congenital anomalies .
the pathogenesis of embryological corpus vertebral fusion anomaly is not fully known . in this paper , a 30-year - old patient who had the complaints of low back and right leg pain after falling from a height
is presented .
she had right l5-s1 disc herniation that had developed on the basis of s1 vertebra corpus fusion anomaly in lumbar computed tomography .
this case has been discussed in the light of literature based on evaluations of lumbar computed tomography ( ct ) and magnetic resonance imaging ( mri ) .
this case is unique in that it is the first case with development of lumbar disc herniation associated with s1 vertebral corpus fusion anomaly .
congenital malformations with unusual clinical presentation after trauma should be evaluated through advanced radiological imaging techniques .</s> |
"in most current free space optical ( fso ) communication systems , for reasons of simplicity , inte(...TRUNCATED) | " to detect @xmath0-ary pulse amplitude modulation signals reliably in an fso communication system ,(...TRUNCATED) | "<s>[INST]in most current free space optical ( fso ) communication systems , for reasons of simplici(...TRUNCATED) |
"Starving koalas secretly culled at Cape Otway, 'overpopulation issues' blamed for ill health \n \n (...TRUNCATED) | "– Koalas' numbers on one part of Australia are too big for their own good, and some are starving(...TRUNCATED) | "<s>[INST]Starving koalas secretly culled at Cape Otway, 'overpopulation issues' blamed for ill heal(...TRUNCATED) |
"the observation of neutrinoless double-@xmath0 @xmath5 decays would demonstrate the majorana nature(...TRUNCATED) | " we present a framework to combine data from the latest neutrinoless double-@xmath0 decay experimen(...TRUNCATED) | "<s>[INST]the observation of neutrinoless double-@xmath0 @xmath5 decays would demonstrate the majora(...TRUNCATED) |
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