Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability

BACKGROUND: The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. RESULTS: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS). CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis

Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study

<p>Abstract</p> <p>Background</p> <p>Complaints of unrefreshing sleep are a prominent component of chronic fatigue syndrome (CFS); yet, polysomnographic studies have not consistently documented sleep abnormalities in CFS patients. We conducted this study to determine whether alterations in objective sleep characteristics are associated with subjective measures of poor sleep quality in persons with CFS.</p> <p>Methods</p> <p>We examined the relationship between perceived sleep quality and polysomnographic measures of nighttime and daytime sleep in 35 people with CFS and 40 non-fatigued control subjects, identified from the general population of Wichita, Kansas and defined by empiric criteria. Perceived sleep quality and daytime sleepiness were assessed using clinical sleep questionnaires. Objective sleep characteristics were assessed by nocturnal polysomnography and daytime multiple sleep latency testing.</p> <p>Results</p> <p>Participants with CFS reported unrefreshing sleep and problems sleeping during the preceding month significantly more often than did non-fatigued controls. Participants with CFS also rated their quality of sleep during the overnight sleep study as significantly worse than did control subjects. Control subjects reported significantly longer sleep onset latency than latency to fall asleep as measured by PSG and MSLT. There were no significant differences in sleep pathology or architecture between subjects with CFS and control subjects.</p> <p>Conclusion</p> <p>People with CFS reported sleep problems significantly more often than control subjects. Yet, when measured these parameters and sleep architecture did not differ between the two subject groups. A unique finding requiring further study is that control, but not CFS subjects, significantly over reported sleep latency suggesting CFS subjects may have an increased appreciation of sleep behaviour that may contribute to their perception of sleep problems.</p

Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study

BACKGROUND: The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria. METHODS: This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms). RESULTS: One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm. CONCLUSION: The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians

Entropies of Negative Incomes, Pareto-Distributed Loss, and Financial Crises

Health monitoring of world economy is an important issue, especially in a time of profound economic difficulty world-wide. The most important aspect of health monitoring is to accurately predict economic downturns. To gain insights into how economic crises develop, we present two metrics, positive and negative income entropy and distribution analysis, to analyze the collective “spatial” and temporal dynamics of companies in nine sectors of the world economy over a 19 year period from 1990–2008. These metrics provide accurate predictive skill with a very low false-positive rate in predicting downturns. The new metrics also provide evidence of phase transition-like behavior prior to the onset of recessions. Such a transition occurs when negative pretax incomes prior to or during economic recessions transition from a thin-tailed exponential distribution to the higher entropy Pareto distribution, and develop even heavier tails than those of the positive pretax incomes. These features propagate from the crisis initiating sector of the economy to other sectors

Using machine learning and an ensemble of methods to predict kidney transplant survival.

We used an ensemble of statistical methods to build a model that predicts kidney transplant survival and identifies important predictive variables. The proposed model achieved better performance, measured by Harrell's concordance index, than the Estimated Post Transplant Survival model used in the kidney allocation system in the U.S., and other models published recently in the literature. The model has a five-year concordance index of 0.724 (in comparison, the concordance index is 0.697 for the Estimated Post Transplant Survival model, the state of the art currently in use). It combines predictions from random survival forests with a Cox proportional hazards model. The rankings of importance for the model's variables differ by transplant recipient age. Better survival predictions could eventually lead to more efficient allocation of kidneys and improve patient outcomes

Randomization Modeling to Ascertain Clustering Patterns of Human Papillomavirus Types Detected in Cervicovaginal Samples in the United States

<div><p>Detection of multiple human papillomavirus (HPV) types in the genital tract is common. Associations among HPV types may impact HPV vaccination modeling and type replacement. The objectives were to determine the distribution of concurrent HPV type infections in cervicovaginal samples and examine type-specific associations. We analyzed HPV genotyping results from 32,245 cervicovaginal specimens collected from women aged 11 to 83 years in the United States from 2001 through 2011. Statistical power was enhanced by combining 6 separate studies. Expected concurrent infection frequencies from a series of permutation models, each with increasing fidelity to the real data, were compared with the observed data. Statistics were computed based on the distributional properties of the randomized data. Concurrent detection occurred more than expected with 0 or ≥3 HPV types and less than expected with 1 and 2 types. Some women bear a disproportionate burden of the HPV type prevalence. Type associations were observed that exceeded multiple hypothesis corrected significance. Multiple HPV types were detected more frequently than expected by chance and associations among particular HPV types were detected. However vaccine-targeted types were not specifically affected, supporting the expectation that current bivalent/quadrivalent HPV vaccination will not result in type replacement with other high-risk types.</p></div

Significant combinations for k = two, three and four HPV types.

<p>The graphs depict the non-strata (<b>A</b>) and study-k (<b>B</b>) permutation models. Boundary lines (dots) show p-value significance at 10⁻⁴ and 10⁻⁸. The mean expected counts on the x-axis represents the average number of observations from 1,000 randomized matrices; the y-axis shows the actual observed counts for the type combinations. Single observations of 4 HPV type combinations are excluded.</p

Summary of the studies in the aggregate analysis.

<p>Summary of the studies in the aggregate analysis.</p