Theoretical analysis of the mechanisms of a gender differentiation in the propensity for orthostatic intolerance after spaceflight

<p>Abstract</p> <p>Background</p> <p>A tendency to develop reentry orthostasis after a prolonged exposure to microgravity is a common problem among astronauts. The problem is 5 times more prevalent in female astronauts as compared to their male counterparts. The mechanisms responsible for this gender differentiation are poorly understood despite many detailed and complex investigations directed toward an analysis of the physiologic control systems involved.</p> <p>Methods</p> <p>In this study, a series of computer simulation studies using a mathematical model of cardiovascular functioning were performed to examine the proposed hypothesis that this phenomenon could be explained by basic physical forces acting through the simple common anatomic differences between men and women. In the computer simulations, the circulatory components and hydrostatic gradients of the model were allowed to adapt to the physical constraints of microgravity. After a simulated period of one month, the model was returned to the conditions of earth's gravity and the standard postflight tilt test protocol was performed while the model output depicting the typical vital signs was monitored.</p> <p>Conclusions</p> <p>The analysis demonstrated that a 15% lowering of the longitudinal center of gravity in the anatomic structure of the model was all that was necessary to prevent the physiologic compensatory mechanisms from overcoming the propensity for reentry orthostasis leading to syncope.</p

Regulation of Heterochromatin Assembly on Unpaired Chromosomes during Caenorhabditis elegans Meiosis by Components of a Small RNA-Mediated Pathway

Many organisms have a mechanism for down regulating the expression of non-synapsed chromosomes and chromosomal regions during meiosis. This phenomenon is thought to function in genome defense. During early meiosis in Caenorhabditis elegans, unpaired chromosomes (e.g., the male X chromosome) become enriched for a modification associated with heterochromatin and transcriptional repression, dimethylation of histone H3 on lysine 9 (H3K9me2). This enrichment requires activity of the cellular RNA-directed RNA polymerase, EGO-1. Here we use genetic mutation, RNA interference, immunofluorescence microscopy, fluorescence in situ hybridization, and molecular cloning methods to identify and analyze three additional regulators of meiotic H3K9me2 distribution: CSR-1 (a Piwi/PAZ/Argonaute protein), EKL-1 (a Tudor domain protein), and DRH-3 (a DEAH/D-box helicase). In csr-1, ekl-1, and drh-3 mutant males, we observed a reduction in H3K9me2 accumulation on the unpaired X chromosome and an increase in H3K9me2 accumulation on paired autosomes relative to controls. We observed a similar shift in H3K9me2 pattern in hermaphrodites that carry unpaired chromosomes. Based on several assays, we conclude that ectopic H3K9me2 accumulates on paired and synapsed chromosomes in these mutants. We propose alternative models for how a small RNA-mediated pathway may regulate H3K9me2 accumulation during meiosis. We also describe the germline phenotypes of csr-1, ekl-1, and drh-3 mutants. Our genetic data suggest that these factors, together with EGO-1, participate in a regulatory network to promote diverse aspects of development

Association Between Depression and Peripheral Artery Disease: Insights From the Heart and Soul Study

BACKGROUND: Depression is known to increase the risk of coronary artery disease, but few studies have evaluated the association between depression and peripheral artery disease (PAD). We examined the association of depression with PAD and evaluated potential mediators of this association. METHODS AND RESULTS: We used data from the Heart and Soul Study, a prospective cohort of 1024 men and women with coronary artery disease recruited in 2000–2002 and followed for a mean of 7.2±2.6 years. Depressive symptoms were assessed with the validated 9-item Patient Health Questionnaire. Prevalent PAD at baseline was determined by self-report. Prospective PAD events were adjudicated on the basis of review of medical records. We used logistic regression and Cox proportional-hazards models to estimate the independent associations of depressive symptoms with prevalent PAD and subsequent PAD events. At baseline, 199 patients (19%) had depressive symptoms (Patient Health Questionnaire ≥10). Prevalent PAD was reported by 12% of patients with depression and 7% of those without depression (base model adjusted for age and sex: odds ratio 1.79, 95% confidence interval 1.06–3.04, P=0.03; full model adjusted for comorbidities, medications, PAD risk factors, inflammation, and health behaviors: odds ratio 1.59, 95% confidence interval 0.90–2.83, P=0.11). During follow-up, PAD events occurred in 7% of patients with depression and 5% of those without depression (base model adjusted for age and sex: hazard ratio 2.09, 95% confidence interval 1.09–4.00, P=0.03; full model adjusted for comorbidities, medications, PAD risk factors, inflammation, and health behaviors: hazard ratio 1.33, 95% confidence interval 0.65–2.71, P=0.44). Factors explaining >5% of the association between depression and incident PAD events included race/ethnicity, diabetes, congestive heart failure, high-density lipoprotein, triglyceride levels, serum creatinine, inflammation, smoking, and levels of physical activity. CONCLUSIONS: Depressive symptoms were associated with a greater risk of PAD. Because the association was explained partly by modifiable risk factors, our findings suggest that more aggressive treatment of these risk factors could reduce the excess risk of PAD associated with depression. (J Am Heart Assoc. 2012;1:e002667 doi: 10.1161/JAHA.112.002667.

Association Between Depression and Peripheral Artery Disease: Insights From the Heart and Soul Study

BACKGROUND: Depression is known to increase the risk of coronary artery disease, but few studies have evaluated the association between depression and peripheral artery disease (PAD). We examined the association of depression with PAD and evaluated potential mediators of this association. METHODS AND RESULTS: We used data from the Heart and Soul Study, a prospective cohort of 1024 men and women with coronary artery disease recruited in 2000–2002 and followed for a mean of 7.2±2.6 years. Depressive symptoms were assessed with the validated 9-item Patient Health Questionnaire. Prevalent PAD at baseline was determined by self-report. Prospective PAD events were adjudicated on the basis of review of medical records. We used logistic regression and Cox proportional-hazards models to estimate the independent associations of depressive symptoms with prevalent PAD and subsequent PAD events. At baseline, 199 patients (19%) had depressive symptoms (Patient Health Questionnaire ≥10). Prevalent PAD was reported by 12% of patients with depression and 7% of those without depression (base model adjusted for age and sex: odds ratio 1.79, 95% confidence interval 1.06–3.04, P=0.03; full model adjusted for comorbidities, medications, PAD risk factors, inflammation, and health behaviors: odds ratio 1.59, 95% confidence interval 0.90–2.83, P=0.11). During follow-up, PAD events occurred in 7% of patients with depression and 5% of those without depression (base model adjusted for age and sex: hazard ratio 2.09, 95% confidence interval 1.09–4.00, P=0.03; full model adjusted for comorbidities, medications, PAD risk factors, inflammation, and health behaviors: hazard ratio 1.33, 95% confidence interval 0.65–2.71, P=0.44). Factors explaining >5% of the association between depression and incident PAD events included race/ethnicity, diabetes, congestive heart failure, high-density lipoprotein, triglyceride levels, serum creatinine, inflammation, smoking, and levels of physical activity. CONCLUSIONS: Depressive symptoms were associated with a greater risk of PAD. Because the association was explained partly by modifiable risk factors, our findings suggest that more aggressive treatment of these risk factors could reduce the excess risk of PAD associated with depression. (J Am Heart Assoc. 2012;1:e002667 doi: 10.1161/JAHA.112.002667.

Posttraumatic Stress Disorder Is Associated With Worse Endothelial Function Among Veterans

BACKGROUND: Current research in behavioral cardiology reveals a significant association between posttraumatic stress disorder (PTSD) and increased risk for cardiovascular disease and mortality; however, the underlying mechanisms remain poorly understood. We hypothesized that patients with PTSD would exhibit endothelial dysfunction, a potential mechanism involved in the development and progression of cardiovascular disease. METHODS AND RESULTS: A total of 214 outpatients treated at the San Francisco Veterans Affairs Medical Center underwent tests of endothelial function and evaluation for PTSD. Flow‐mediated vasodilation of the brachial artery was performed to assess endothelial function, and current PTSD status was defined by the PTSD Checklist, based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), with a score ≥40. Multivariable linear regression models were used to estimate the association between PTSD status and endothelial function. Patients with PTSD (n=67) were more likely to be male (99% versus 91%, P=0.04) and to have depression (58% versus 8%, P<0.0001) and were less likely to be on an angiotensin‐converting enzyme inhibitor (17% versus 36%, P=0.007) or β‐blocker treatment (25% versus 41%, P=0.03). Univariate analysis demonstrated that patients with PTSD had significantly lower flow‐mediated vasodilation (5.8±3.4% versus 7.5±3.7%; P=0.003); furthermore, lower flow‐mediated vasodilation was associated with increasing age (P=0.008), decreasing estimated glomerular filtration rate (P=0.003), hypertension (P=0.002), aspirin (P=0.03), and β‐blocker treatments (P=0.01). In multivariable analysis, PTSD remained independently associated with lower flow‐mediated vasodilation (P=0.0005). CONCLUSIONS: After adjusting for demographic, comorbidity, and treatment characteristics, PTSD remained associated with worse endothelial function in an outpatient population. Whether poor endothelial function contributes to the higher risk of cardiovascular disease in patients with PTSD deserves further study

Posttraumatic Stress Disorder Is Associated With Worse Endothelial Function Among Veterans

BACKGROUND: Current research in behavioral cardiology reveals a significant association between posttraumatic stress disorder (PTSD) and increased risk for cardiovascular disease and mortality; however, the underlying mechanisms remain poorly understood. We hypothesized that patients with PTSD would exhibit endothelial dysfunction, a potential mechanism involved in the development and progression of cardiovascular disease. METHODS AND RESULTS: A total of 214 outpatients treated at the San Francisco Veterans Affairs Medical Center underwent tests of endothelial function and evaluation for PTSD. Flow‐mediated vasodilation of the brachial artery was performed to assess endothelial function, and current PTSD status was defined by the PTSD Checklist, based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), with a score ≥40. Multivariable linear regression models were used to estimate the association between PTSD status and endothelial function. Patients with PTSD (n=67) were more likely to be male (99% versus 91%, P=0.04) and to have depression (58% versus 8%, P<0.0001) and were less likely to be on an angiotensin‐converting enzyme inhibitor (17% versus 36%, P=0.007) or β‐blocker treatment (25% versus 41%, P=0.03). Univariate analysis demonstrated that patients with PTSD had significantly lower flow‐mediated vasodilation (5.8±3.4% versus 7.5±3.7%; P=0.003); furthermore, lower flow‐mediated vasodilation was associated with increasing age (P=0.008), decreasing estimated glomerular filtration rate (P=0.003), hypertension (P=0.002), aspirin (P=0.03), and β‐blocker treatments (P=0.01). In multivariable analysis, PTSD remained independently associated with lower flow‐mediated vasodilation (P=0.0005). CONCLUSIONS: After adjusting for demographic, comorbidity, and treatment characteristics, PTSD remained associated with worse endothelial function in an outpatient population. Whether poor endothelial function contributes to the higher risk of cardiovascular disease in patients with PTSD deserves further study

Effects of gravitational mechanical unloading in endothelial cells: association between caveolins, inflammation and adhesion molecules.

Mechanical forces including gravity affect endothelial cell (ECs) function, and have been implicated in vascular disease as well as physiologic changes associated with low gravity environments. The goal of this study was to investigate the impact of gravi