Abstract. Vgontzas AN, Bixler EO, Chrousos GP (Penn State College of Medicine, Hershey, PA; National Institutes of Health, Bethesda, MD, USA). Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance (Minisymposium). J Intern Med 2003; 254: –. Obstructive sleep apnoea (OSA) is a very prevalent disorder particularly amongst middle‐aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a ‘local abnormality’ of the respiratory track rather than as a ‘systemic illness’. In 1997, we first reported that the pro‐inflammatory cytokines interleukin (IL)‐6 and tumour necrosis factor‐ α (TNF α ) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL‐6 or TNF α plasma levels and the body mass index (BMI). In subsequent studies, we showed that IL‐6, TNF α , leptin and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnoea. The association of OSA with insulin resistance and diabetes type 2 has been confirmed since then in several epidemiological and clinical studies. Furthermore, our findings that women with polycystic ovary syndrome (PCOS, a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness support the pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnoea and sleepiness may be manifestations of a serious metabolic disorder, namely the Metabolic or Visceral Obesity Syndrome, include: obesity without sleep apnoea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity and age; and increased prevalence of sleep apnoea in postmenopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA. In conclusion, accumulating evidence provides support to our model of the bi‐directional, feedforward, pernicious association between sleep apnoea, sleepiness, inflammation and insulin resistance, all promoting atherosclerosis and cardiovascular disease.
The human glucocorticoid receptor (hGR) beta, a splicing variant of the classic receptor hGRalpha, functions as a dominant-negative inhibitor of hGRalpha. We explored the mechanism(s) underlying this effect of hGRbeta by evaluating the interactions of this isoform with known steroid receptor coactivators. We found that hGRbeta suppressed the transcriptional activity of both activation function (AF)-1 and AF-2 of hGRalpha, indicating that hGRbeta may exert its dominant-negative effect by affecting the function of coactivators that are attracted to these transactivation domains. hGRbeta bound to one of the p160 coactivators, the glucocorticoid receptor-interacting protein 1 (GRIP1) via its preserved AF-1 but not via its defective AF-2 in vitro. In a chromatin immunoprecipitation assay, hGRbeta prevented coprecipitation of GRIP1 with hGRalpha tethered to glucocorticoid response elements of the endogenous tyrosine aminotransferase promoter, whereas deletion of the AF-1 of hGRbeta abolished this effect. In further experiments, overexpression of GRIP1 attenuated the suppressive effect of hGRbeta on hGRalpha-mediated transactivation of the mouse mammary tumor virus promoter. Competition for binding to glucocorticoid response elements or heterodimerization with hGRalpha via the D loop dimerization interface occurred, but they were not necessary for the suppressive effect of hGRbeta on the transcriptional activity of hGRalpha. Our findings suggest that hGRbeta suppresses the transcriptional activity of hGRalpha by competing with hGRalpha for binding to GRIP1, and possibly other p160 coactivators, through its preserved AF-1. These findings suggest that participation of hGRbeta in the formation of a coactivator complex renders this complex ineffective.
No abstract is provided for this article.
Sustainability in construction is related to the use of industrial by-products, such as fly ash (FA). FA varies in chemical/mineralogical composition, depending on the raw materials burnt during its production. While FA produced from coal-fired power stations is extensively used in cementitious composites, heavy oil FA produced from the firing of heavy fuels (e.g., mazut or diesel) remains largely unused. This paper focuses on the novel use of heavy fuel fly ash (HFFA), as a replacement of Class F FA, in high-volume fly ash self-compacting composites. Two different grain size distributions of HFFA were used in quantities 5–15% w/w of cement and Class F FA for the production of the composites. The assessment of the physico-mechanical properties and microstructure of the end-products at different curing ages suggests that HFFA may be used at quantities ≤10% w/w, without any negative effects. In fact, depending on the quantity and grain size distribution of the HFFA, this may even improve some of the properties of the end-products in the long term, provided that a careful mix design is adopted. The findings show the potential of sustainable reuse of HFFA and are beneficial for its incorporation into design codes.
A seismic fragility assessment procedure is developed for atmospheric steel liquid storage tanks. Appropriate system and component-level damage states are defined by identifying the failure modes that may occur during a strong ground motion. Special attention is paid to the elephant’s foot buckling failure mode, where the estimation of the associated capacity and demand requires thorough consideration within a probabilistic framework. A novel damage state is introduced to existing procedures with respect to the uncontrollable loss of containment scenario. Fragility curves are estimated by introducing both aleatory and epistemic sources of uncertainty, thus providing a comprehensive methodology for the seismic risk assessment of liquid storage tanks. The importance of dynamic buckling is acknowledged and the issue of non-sequential damage states is finally revealed.
