Correlation as a determinant of configurational entropy in supramolecular and protein systems.

For biomolecules in solution, changes in configurational entropy are thought to contribute substantially to the free energies of processes like binding and conformational change. In principle, the configurational entropy can be strongly affected by pairwise and higher-order correlations among conformational degrees of freedom. However, the literature offers mixed perspectives regarding the contributions that changes in correlations make to changes in configurational entropy for such processes. Here we take advantage of powerful techniques for simulation and entropy analysis to carry out rigorous in silico studies of correlation in binding and conformational changes. In particular, we apply information-theoretic expansions of the configurational entropy to well-sampled molecular dynamics simulations of a model host-guest system and the protein bovine pancreatic trypsin inhibitor. The results bear on the interpretation of NMR data, as they indicate that changes in correlation are important determinants of entropy changes for biologically relevant processes and that changes in correlation may either balance or reinforce changes in first-order entropy. The results also highlight the importance of main-chain torsions as contributors to changes in protein configurational entropy. As simulation techniques grow in power, the mathematical techniques used here will offer new opportunities to answer challenging questions about complex molecular systems.

The cortisol response in policemen: intraindividual variation, not concentration level, predicts truncal obesity.

OBJECTIVES: Chronic stress, characteristic of police work, affects the hypothalamic-pituitary-adrenal axis' control of cortisol production. Capacity to vary cortisol may be the appropriate measurement to interpret associations with chronic diseases, including obesity, best measured by variability within a person, not central tendency. METHODS: On each of 217 policemen, 18 saliva specimens were obtained for cortisol. Statistical models examined the associations of within-subjects (W-S) cortisol standard deviation (SD) and W-S cortisol mean with waist circumference and four body composition indexes: BMI, and three derived from DEXA: fat-mass, and trunk and extremities lean-mass. Explained variance and the functional nature of associations are reported. RESULTS: Associations of anthropometrics with W-S cortisol mean were not statistically significant at P < 0.05; all associations with W-S cortisol SD were significant. The association of trunk lean mass index (LMIt ) with W-S cortisol SD dominated all models. Associations of W-S cortisol SD with other indexes vanished when models contained LMIt ; when any other index was included in models predicting LMIt , associations with W-S cortisol SD remained significant. The functional association between LMIt and W-S cortisol SD is progressively "hockey stick," monotonic increasing, and flattens at joint high values. CONCLUSIONS: Results support inferences that LMIt measures visceral adiposity and W-S cortisol variability appears to be an appropriate construct to measure in association with visceral adiposity. The "hockey stick" character of the association is consistent with other investigations suggesting obesity is associated with less W-S cortisol variation; however, the monotonic increase and flattening of association at increasing W-ScortisolSD values suggests a more complex association, potentially interpretable by allostasis models of causation.

Adiposity, muscle, and physical activity: predictors of perturbations in heart rate variability.

OBJECTIVES: This study examines cross-sectional associations of indices of adiposity, lean body mass, and physical activity, with heart rate variability (HRV), a marker for parasympathetic cardiac vagal control. METHODS: The study population consists of 360 officers from the Buffalo New York Police Department. Indices of adiposity include body mass index, waist circumference, and a fat-mass index taken from dual-energy X-ray absorptiometry (DEXA) measurements. Lean body mass indices were derived from DEXA measurements of trunk mass and extremity lean mass. Physical activity was measured using a 7-day self-report questionnaire. HRV was obtained from 5-min electrocardiogram measurements by means of parametric spectral analysis resulting in estimates for high-frequency (HF) and low-frequency (LF) HRV. RESULTS: Both HF and LF HRV were significantly associated with markers for adiposity, two components of lean mass and physical activity with all associations being in the expected direction except that for trunk lean mass. This unexpected result is explained by the possibility that trunk mass is a marker for visceral adiposity rather than lean mass. Body mass index did not explain any additional variance in HRV above and beyond waist circumference and the DEXA indices. CONCLUSIONS: Higher levels of physical activity, lower levels of markers for central adiposity and higher lean mass in the extremities predict higher levels of HRV in this population of police officers. This association between modifiable risk factors and markers for autonomic function suggest possible interventions that may improve health and performance.

Body mass index versus dual energy x-ray absorptiometry-derived indexes: predictors of cardiovascular and diabetic disease risk factors.

OBJECTIVES: The body mass index (BMI), a ratio of weight/height(2) , dominates estimation of adiposity in population studies. BMI, however, does not distinguish among fat, muscle, or bone mass. Accordingly, its usage to assess and manage obesity in the population is limited. This study compares the use of BMI with direct measures of fat- and lean-mass to predict established cardiovascular and diabetes risk factors: blood pressure, lipids, and glucose. METHODS: The entire Buffalo Police Department was the object of recruitment to a baseline study of physiological and psychological stress. Four hundred nine officers constitute the sample for this analysis. Regression methods focusing on explained variance in blood pressure, high density lipoprotein (HDL) cholesterol, and blood glucose compare the use of BMI to that of fat- and lean-mass indexes derived from dual energy X-ray absorptiometry (DEXA). RESULTS: DEXA indexes explain 1.6%-3.3% (P < 0.05, all risk factors) more variance than BMI. Fat mass drives the association for blood pressure, trunk lean mass for HDL cholesterol, and both for blood glucose. High degrees of multicollinearity complicate interpretation of predictive models jointly containing BMI and DEXA indexes. CONCLUSIONS: In police officers, DEXA indexes are better predictors of cardiovascular disease and diabetes risk factors. However, populations with different distributions of fitness, diet, and health conditions may demonstrate differentfeatures. In contrast to BMI, DEXA-derived measurements suggest avenues to explore metabolic processes, which relate to an index's underlying association with risk and may suggest more effective intervention strategies.

Natan 'Nikolai' Abramovich Vigdorchik (1874-1954): social activism and public health in early 20th-century Russia.

Virtually unknown in the West, the physician Nikolai Vigdorchik is recognized in Russian-Soviet history for his role in introducing social security into Russia. He rose from Jewish working-class origins to a career that combined activism in labour rights and public health with extensive and path-breaking publications in social security, occupational safety and public health. He contributed more than 30 years of leadership to Soviet research and educational institutions devoted to occupational safety and health. Vigdorchik's 1935 publication on lead and hypertension is illustrative of his contribution to modern epidemiological methods, describing a statistical bias in the study of hospitalized patients. It predates by 11 years Joseph Berkson's paper, after whom the bias is named. Vigdorchik's life illustrates a modern-day conundrum: social activism comes with political cost -- by virtue of its evidence-based orientation, public health science is safer but both are necessary to move a culture towards health and stability.

The Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) pilot study: methods and participant characteristics.

PURPOSE: The Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) study is one of the first population-based studies to integrate psychological, physiological, and subclinical measures of stress, disease, and mental dysfunction. This pilot study was undertaken to establish a methodology and descriptive results for a larger police study. METHODS: A stratified sample of 100 officers was randomly selected from the Buffalo, NY Police Department. Salivary cortisol served as a stress biomarker. Flow mediated dilation (FMD) and carotid intima-media thickness (IMT) were performed with ultrasound. Dual Energy X-Ray Absorptiometry (DEXA) and anthropometric measures assessed body composition. Self-report measures of depression and posttraumatic stress disorder (PTSD) were obtained. RESULTS: Recruitment attained for the study was 100%. Seventy-five percent showed a cortisol increase upon awakening, 90% a negative diurnal slope, and 77% an increased cortisol response after a high protein lunch challenge. Dexamethasone suppression was evident. FMD showed an increase in mean brachial artery diameter of 3.2% in men and 3.9% in women, and mean IMT was lower (male=0.67 mm; female=0.62 mm) compared to populations of similar age. For males, the mean body-mass index (BMI) was 29.8 kg/m2 and total body fat 23.4%. For females, the mean BMI was 26.7 kg/m2 and total body fat 31.5%. For all officers, 16% met criteria for depression; 36% reported elevated PTSD symptoms. CONCLUSIONS: Compared to populations of similar age, police officers had slightly lower FMD, lower carotid IMT, elevated BMI, and higher reported rates of depression and PTSD. Standardized physiological and psychological data collection and descriptive results confirmed that the methodology of the study is feasible in a working police population.

Associations of cortical astrogliosis with cognitive performance and dementia status.

We examined 204 decedents of the autopsy component of the Honolulu-Asia Aging Study, a longitudinal cohort study, who had been clinically assessed for dementia. A sensitive ELISA technique was used to quantify glial fibrillary acidic protein (GFAP), a marker for astrogliosis, in four specific cortical brain regions and assess associations between GFAP and 1) a measure of cognitive function, 2) several clinical dementia conditions, and 3) neuritic plaque (NP) and neurofibrillary tangle (NFT) formation. Cognitive function was inversely associated with GFAP in the occipital, parietal and temporal lobes, but not in the frontal lobe. This relationship remained significant when the contribution of NP and NFT counts was removed. Further, compared to brain samples from non-demented individuals, significantly greater GFAP levels were found in samples from individuals diagnosed with Alzheimer's disease, mixed dementia, and vascular mediated dementia. Because elevated levels of GFAP reflect astroglial responses to even subtle forms of neural damage, our data indicate that increments in GFAP may provide independent, supporting evidence for the damage underlying dementia, even in the absence of other evidence of neuropathology such as the presence of NPs or NFTs. Our findings underscore the need to look beyond standard neuropathological measures putatively linked to specific neuropathological conditions in efforts to identify common cellular and molecular processes that contribute to dementia.

Environmental, life-style, and physical precursors of clinical Parkinson's disease: recent findings from the Honolulu-Asia Aging Study.

BACKGROUND: Increased westernization with Japanese migration to the U. S. in the early 20(th) century is thought to have altered the risk of cardiovascular disease. Whether similar effects include changes in the risk of Parkinson's disease (PD) is not clear. This report describes the relations between environmental, life-style, and physical attributes and the incidence of PD that have been observed in the Honolulu-Asia Aging Study. METHODS: Beginning in 1965, environmental, life-style, and physical attributes were recorded at selected examinations in a cohort of 8,006 Japanese-American men. Subjects were followed for clinical PD. FINDINGS: During 30 years of follow- up, PD was observed in 137 men. Overall incidence (7.1/10,000 person-years) was generally higher than in Asia and similar to rates observed in Europe and the U. S. Precursors of PD included constipation, adiposity, years worked on a sugar or pineapple plantation, years of exposure to pesticides, and exposure to sugar cane processing. Factors showing an inverse association with PD included coffee intake and cigarette smoking. Among dietary factors, carbohydrates increased the risk of PD while the intake of polyunsaturated fats appeared protective. Total caloric intake, saturated and monounsaturated fats, protein, niacin, riboflavin, beta-carotene, vitamins A, B, and C, dietary cholesterol, cobalamin, alpha-tocopherol, and pantothenic acid showed no clear relation with clinical PD. INTERPRETATION: Findings suggest that several environmental, life-style, and physical attributes appear to be precursors of PD. Whether patterns of precursors can be used to identify individuals at high risk of future PD or can broaden the scope of early interventions or recruitment into neuroprotective trials warrants further study.

Plantation work and risk of Parkinson disease in a population-based longitudinal study.

CONTEXT: Parkinson disease (PD) has an unknown cause; however, convincing evidence is emerging that indicates pesticides can selectively injure the dopaminergic system in laboratory animals. Retrospective studies in humans demonstrate a link between exposure to agricultural lifestyle factors and PD. OBJECTIVE: To determine whether working on a plantation in Hawaii and exposure to pesticides are associated with an increased risk of PD decades later. DESIGN AND SETTING: Prospective cohort study based on the island of Oahu, Hawaii, with 30 years of follow-up. Years of work on a plantation were assessed by questionnaire at study enrollment in 1965. Self-reported information on pesticide exposure was collected at a separate examination 6 years later. PARTICIPANTS: Participants were 7986 Japanese American men born between 1900 and 1919 who were enrolled in the longitudinal Honolulu Heart Program. MAIN OUTCOME MEASURES: Incident PD was determined by medical record review or by an examination conducted by a study neurologist at a later date. RESULTS: During follow-up, 116 men developed PD. Age-adjusted incidence increased significantly among men who worked more than 10 years on a plantation. The relative risk of PD was 1.0 (95% confidence interval, 0.6-1.6), 1.7 (95% confidence interval, 0.8-3.7), and 1.9 (95% confidence interval, 1.0-3.5) for men who worked on a plantation 1 to 10 years, 11 to 20 years, and more than 20 years compared with men who never did plantation work (P =.006, test for trend). Age-adjusted incidence of PD was higher in men exposed to pesticides than in men not exposed to pesticides although this was not statistically significant (P =.10, test for trend). CONCLUSION: These longitudinal observations regarding plantation work in Hawaii support case-control studies suggesting that exposure to pesticides increases the risk of PD.

Significance of genetic information in risk assessment and individual classification using silicosis as a case model.

Over the last decade the role of genetic data in epidemiological research has expanded considerably. We recently published a case-control study that evaluated the interaction between silica exposure and minor variants in the genes coding for interleukin-1alpha (IL-1alpha), interleukin-1 receptor antagonist (IL-1RA) and tumor necrosis factor alpha (TNFalpha) as risk factors associated with silicosis, a fibrotic lung disease. In contrast, this report uses data generated from these studies to illustrate the utility of genetic information for the purposes of risk assessment and clinical prediction. Specifically, this study will address how, given a known exposure, genetic information affects the characterization of risk groups. Relative operating characteristic (ROC) curves were then used to determine the impact of genetic information on individual classification. Logistic regression modeling procedures were used to estimate the predicted probability of developing silicosis. This probability was then used to construct predicted risk deciles, first for a model with occupational exposure only and then for a model containing occupational exposure and genetic main effects and interactions. Results indicate that the exposure-only model effectively captures an increasing relationship between predicted risk deciles and prevalence of observed silicosis cases. Individuals comprising the highest risk decile were almost four times as likely to have silicosis as opposed to the lowest risk decile. The addition of genetic data, however, substantially improved characterization of risk categories; the proportion of cases in the highest risk decile was almost eight times that in the lowest risk decile. However, the ROC curve and classification analysis demonstrated that the addition of genetic main effects and interactions did not significantly impact on prediction of the individual's case status. These results indicate that genetic information plays a valuable role in effectively characterizing risk groups and mechanisms of disease operating in a substantial proportion of the population. However, in the case of fibrotic lung disease caused by silica exposure, information about the presence or absence of the minor variants of IL-1alpha, IL-1RA and TNFalpha is unlikely to be a useful tool for individual classification.