The human glucocorticoid receptor (hGR) is a ubiquitously expressed intracellular, ligand-dependent transcription factor, which mediates the action of glucocorticoids and influences physiologic functions essential for life. Alterations in the molecular mechanisms of hGR action modify glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms, and clinical aspects of primary generalized familial and sporadic glucocorticoid resistance (PGGR or Chrousos syndrome) and hypersensitivity (PGGH). The molecular basis of Chrousos syndrome and PGGH has been ascribed to mutations in the hGR gene, which alter tissue sensitivity to glucocorticoids. The stochastic nature of glucocorticoid signaling pathways in association with the variable effect that hGR gene mutations/polymorphisms might have on glucocorticoid signal transduction indicates that alterations in hGR action may have important implications for many critical biological processes, such as the behavioral and physiologic responses to stress, intermediary metabolism, the immune and inflammatory reaction, as well as growth, development, and reproduction.
Obesity, excessive daytime sleepiness (EDS), and self-reported short sleep duration appear to be on the rise, while there is evidence that obesity and these sleep disorders are strongly connected. In this paper, we review data that challenge the common belief that the sleep apnoea and sleep loss, frequently associated with obesity, are the primary determinants of obesity-related objective daytime sleepiness and subjective fatigue (tiredness without increased sleep propensity). Specifically, obesity is associated with objective and subjective EDS regardless of the presence of sleep apnoea. The association between obesity and EDS was confirmed in recent studies of large random samples of the general population or clinical samples, which showed that the primary determinants of subjective EDS were depression, metabolic disturbances, i.e. obesity/diabetes and insulin resistance, and lack of physical activity, and, secondarily, sleep apnoea or sleep loss. Paradoxically, within the obese, with or without sleep apnoea, those who slept objectively better at night are sleepier (objectively) during the day than those who slept worse. The distinguishing factor between those that slept better vs. those that slept worse appears to be level of emotional stress. Furthermore, many studies reported that obesity is associated with self-reported short sleep duration; however, it appears that short sleep duration is a marker of emotional stress rather than a reflection of true sleep loss. Based on these data, we propose that obesity-related deeper sleep and objective EDS are primarily related to metabolic disturbances, whereas obesity-related poorer sleep and subjective fatigue appear to be the result of psychological distress. Furthermore, based on data from studies in normal controls and patients with sleep disorders, it appears that the interaction of the hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines determines the level of sleep/arousal within the 24-hour cycle, i.e. "eucortisolemia" or "hypocortisolemia" plus hypercytokinemia is associated with high sleep efficiency and objective sleepiness, whereas "hypercortisolemia" plus hypercytokinemia is associated with low sleep efficiency and fatigue. In conclusion, we propose that the above-reviewed data provide the basis for a meaningful phenotypic and pathophysiologic sub-typing of obesity. One subtype is associated with emotional distress, poor sleep, fatigue, HPA axis "hyperactivity," and hypercytokinemia while the other is associated with non-distress, better sleep but more sleepiness, HPA axis "normo or hypoactivity," and hypercytokinemia. This proposed sub-typing may lead to novel, preventive and therapeutic strategies for obesity and its associated sleep disturbances.
The opinions of the authors do not necessarily reflect those of the affiliated Institutions. Every effort has been taken to verify the accuracy of statistical data presented; we apologize in advance for any errors or omissions. GPC served as vice-president and member of the Greek National Council of Research and Technology/Innovation (2010-2015).
Summary Strength‐reduction factors that reduce ordinates of floor spectra acceleration due to nonlinearity in the secondary system are investigated. In exchange for permitting some inelastic deformation to occur in the secondary system or its supports, these strength reduction factors allow to design the nonstructural elements or their supports for lateral forces that are smaller than those that would be required to maintain them elastically during earthquakes. This paper presents the results of a statistical analysis on component strength‐reduction factors that were computed considering floor motions recorded on instrumented buildings in California during various earthquakes. The effect of yielding in the component or its anchorage/bracing in offering protection against excessive component acceleration demands is investigated. It is shown that strength‐reduction factors computed from floor motions are significantly different from those computed from ground motions recorded on rock or on firm soils. In particular, they exhibit much larger reductions for periods tuned or nearly tuned to the dominant modal periods of the building response. This is due to the large differences in frequency content of ground motions and floor motions, with the former typically characterized by wide‐band spectra whereas the latter are characterized by narrow‐band spectra near periods of dominant modes in the response of the building. Finally, the study provides approximate equations to estimate component strength‐reduction factors computed through nonlinear regression analyses.
