Nutrient-stimulated insulin secretion is dependent upon the generation of metabolic coupling factors in the mitochondria of the pancreatic B cell.

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

and cell morphology. Fluorescent images of fura 2-10aded neutrophils attached to albumin-coated glass were recorded with a high sensitivity CCD camera while [Ca2+]~ was assessed with a dual excitation microfluorimetry. The majority of the initially round cells studied showed changes in shape which started either before or at the same time as the onset of the [Ca2+]~ transients.These data suggested that a rise in [Ca2+]i is not a prerequisite for shape change. This conclusion was confirmed by observation of movement and spreading in cells whose [Ca2÷]i transients were abolished by chelation of extraceUular Ca 2÷. Instead, our data suggest that spreading or adhesion itself initiates the [Ca2+]t activity. In keeping with this hypothesis, cytochalasin B, which prevents both cell movement and adhesion, completely inhibited generation of Using a rapid monitoring system We have described spontaneous and chemoattractant-triggered, multiple [Ca2+]~ elevations in neutrophils adherent both to albumin or fibronectin-coated surfaces (11). More recently Marks and Maxfield (19) have shown that such [Ca2÷]i transients appear to be linked to neutrophil movement during chemotaxis on poly-D-lysine-coated glass in the presence of serum. Neutrophils that extended pseudopods and assumed a polarized morphology were always observed to exhibit [Ca2÷]i transients even in the absence of chemoattractants. While [Ca2+]i transients are associated with cell spreading and locomotion, it is not clear whether transients in some way cause the movement, or if they are the result of cell movement.Spreading and locomotion are mediated by receptors that bridge the cell to the substrate. The numerically and functionally dominant adhesion receptor of neutrophils is the integrin CR3 (also known as Mac-l, Mol, CDllb/CD18, and am~2) (36). Blockade of this receptor with mAbs prevents spreading and/or chemotaxis on a variety of substrates including albumin (6), fibrinogen (38), complement protein C3bi (39), as well as on endothelial cells in vitro (9, 17) and in vivo (4,26,33). CR3 is likely to make a major contribution to cell locomotion since the chemoattractant stimuli C5a (17), tumor necrosis factor (TNF)a (17), interleukin (IL)-8 (7), and PMA (35) cause dramatic enhancement of the ca-

No abstract

Low levels of vitamin D are common among Swiss adults, in particular during winter months and outside the Italian-speaking region.

Exocytosis from Weibel-Palade bodies, the secretory granules of vascular endothelial cells, causes the rapid release of von Willebrand factor (vWF), an adhesive glycoprotein involved in primary hemostasis, and cell surface expression of P-selectin, a membrane protein involved in neutrophil binding. Thus, exocytosis may represent a link between hemostasis and inflammation. We investigated the effect of reactive oxygen intermediates (ROIs) on vWF secretion. Incubation of cultured endothelial cells with xanthine oxidase (XO), which generates superoxide anions (O2-), induces a potent, rapid secretory response. However, vWF release was not observed in response to H2O2. Extracellular, subendothelial vWF deposits typically seen after exocytosis from Weibel-Palade bodies were observed after exposure to XO. XO caused a rapid, sustained increase in intracellular free calcium concentration ([Ca2+]i). vWF secretion was markedly inhibited by BAPTA-AM, a cell-permeant calcium chelator. Removal of extracellular calcium did not inhibit vWF release, although the sustained phase of the [Ca2+]i increase was suppressed. These results suggest that XO-induced vWF release is mediated by the initial increase in [Ca2+]i which is caused by calcium mobilization from intracellular stores rather than by calcium influx. Exocytosis from Weibel-Palade bodies may contribute to the pathogenic effect of ROIs in atherosclerosis and inflammation.

Frailty prevalence in older adults has been reported but is largely unknown in middle-aged adults. We determined the prevalence of frailty indicators among middle-aged and older adults from a general Swiss population characterized by universal health insurance coverage and assessed the determinants of frailty with a special focus on socioeconomic status. Participants aged 50 and more from the population-based 2006–2010 Bus Santé study were included (N = 2,930). Four frailty indicators (weakness, shrinking, exhaustion, and low activity) were measured according to standard definitions. Multivariate logistic regressions were used to determine associations. Overall, 63.5%, 28.7%, and 7.8% participants presented no frailty indicators, one frailty indicator, and two or more frailty indicators, respectively. Among middle-aged participants (50–65 years), 75.1%, 22.2%, and 2.7% presented 0, 1, and 2 or more frailty indicators. The number of frailty indicators was positively associated with age, hypertension, and current smoking and negatively associated with male gender, body mass index, waist-to-hip ratio, and serum total cholesterol level. Lower income level but not education was associated with higher number of frailty indicators. Frailty indicators are frequently encountered in both older and middle-aged adults from the Swiss general population. Despite universal health insurance coverage, household income is independently associated with frailty.

Daily energy expenditure is significantly lower in RA patients compared with matched controls, mainly due to less moderate-intensity PAs performed. Disease activity and fatigue are important contributing factors. These points need to be addressed if promoting PA in RA patients is a health goal. Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov, NCT01228812.