Heritability of daytime cortisol levels in children

INTRODUCTION Cortisol is a steroid hormone secreted by the outer cortex of the adrenal gland. Its secretion is stimulated by ACTH (adrenocorticotrophic hormone), produced in the pituitary in response to corticotropin-releasing hormone (CRH), a product from neurons in the paraventricular nucleus of the hypothalamus.After its release, the major part of cortisol binds to the plasma proteins corticosteroid binding globulin (CBG, or transcortin) and albumin, which prevents the hormone from penetrating the membranes of their target cells. About 3--5% of the total cortisol is the unbound, biologically active fraction. This active fraction has permissive, suppressive, stimulatory, and preparative action effects in the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology (Sapolsky, Romero, and Munck, 2000). Although cortisol is mainly known for its pivotal role in generating an adequate response to phy

The recent intellectual structure of geography

An active learning project in an introductory graduate course used multidimensional scaling of the name index in Geography in America at the Dawn of the 21st Century, by Gary Gaile and Cort Willmott, to reveal some features of the discipline\u27s recent intellectual structure relevant to the relationship between human and physical geography. Previous analyses, dating to the 1980s, used citation indices or Association of American Geographers spe- cialty-group rosters to conclude that either the regional or the methods and environmental subdisciplines bridge human and physical geography. The name index has advantages over those databases, and its analysis reveals that the minimal connectivity that occurs between human and physical geography has recently operated more through environmental than through either methods or regional subdisciplines

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Airway obstruction, serum vitamin D and mortality in a 33-year follow-up study

Background and objective: Chronic obstructive pulmonary disease and low vitamin D status predict mortality, but their combined effect on mortality remains inconclusive. We aimed to investigate a joint effect of airway obstruction and vitamin D status on mortality in a nationally representative cohort. Methods: We analysed data of 6676 Finnish adults participating between 1978 and 1980 in a national health examination survey, undergoing spirometry and having all necessary data collected. We followed them up in national registers through record linkage until 31 December 2011. We categorised the subjects with obstruction using the lower limit of normal (LLN) and the measured serum 25-hydroxyvitamin-D (s-25(OH)D) into tertiles. Results: Both obstruction and low s-25(OH) D independently predicted mortality in a multivariate model adjusted also for age, sex, smoking, education, leisure physical activity, body mass index, asthma and serum C-reactive protein. However, a statistically significant (p = 0.007) interaction emerged: the adjusted mortality HRs (95% CI's) for s-25(OH)D in tertiles among the subjects without and with obstruction were 1.00 (lowest), 0.96 (0.87-1.05) and 0.89 (0.81-0.98); and 1.00, 0.96 (0.71-1.31) and 0.57 (0.40-0.80), respectively. Conclusions: In conclusion, obstruction and low s-25(OH)D predict mortality independently of each other. Our findings suggest that low vitamin D status might be particularly detrimental among subjects with obstruction.Peer reviewe

Effect of Monthly, High‐Dose, Long‐Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy

Background: The effects of monthly, high‐dose, long‐term (≥1‐year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. Methods and Results: A total of 517 adults (58% male, aged 50–84 years) were recruited into a double‐blinded, placebo‐controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9–1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000‐IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow‐up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25‐hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow‐up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (<50 nmol/L) at baseline. In this subgroup, mean changes in the vitamin D group (n=71) versus placebo group (n=79) were −5.3 mm Hg (95% confidence interval [CI], −11.8 to 1.3) for brachial systolic BP (P=0.11), −2.8 mm Hg (95% CI, −6.2 to 0.7) for brachial diastolic BP (P=0.12), −7.5 mm Hg (95% CI, −14.4 to −0.6) for aortic systolic BP (P=0.03), −5.7 mm Hg (95% CI, −10.8 to −0.6) for augmentation index (P=0.03), −0.3 m/s (95% CI, −0.6 to −0.1) for pulse wave velocity (P=0.02), −8.6 mm Hg (95% CI, −15.4 to −1.9) for peak reservoir pressure (P=0.01), and −3.6 mm Hg (95% CI, −6.3 to −0.8) for backward pressure amplitude (P=0.01). Conclusions: Monthly, high‐dose, 1‐year vitamin D supplementation lowered central BP parameters among adults with vitamin D deficiency but not in the total sample. Clinical Trial Registration URL: http://www.anzctr.org.au. Unique identifier: ACTRN12611000402943

P2 purinergic receptor modulation of cytokine production

Cytokines serve important functions in controlling host immunity. Cells involved in the synthesis of these polypeptide mediators have evolved highly regulated processes to ensure that production is carefully balanced. In inflammatory and immune disorders, however, mis-regulation of the production and/or activity of cytokines is recognized as a major contributor to the disease process, and therapeutics that target individual cytokines are providing very effective treatment options in the clinic. Leukocytes are the principle producers of a number of key cytokines, and these cells also express numerous members of the purinergic P2 receptor family. Studies in several cellular systems have provided evidence that P2 receptor modulation can affect cytokine production, and mechanistic features of this regulation have emerged. This review highlights three separate examples corresponding to (1) P2Y6 receptor mediated impact on interleukin (IL)-8 production, (2) P2Y11 receptor-mediated affects on IL-12/23 output, and (3) P2X7 receptor mediated IL-1β posttranslational processing. These examples demonstrate important roles of purinergic receptors in the modulation of cytokine production. Extension of these cellular observations to in vivo situations may lead to new therapeutic strategies for treating cytokine-mediated diseases

Ethnic Differences in Body Composition and Obesity Related Risk Factors: Study in Chinese and White Males Living in China

The purpose of this cross-sectional observational study was to identify ethnic differences in body composition and obesity-related risk factors between Chinese and white males living in China. 115 Chinese and 114 white male pilots aged 28–63 years were recruited. Fasting body weight, height and blood pressure were measured following standard procedures. Whole-body and segmental body composition were measured using an 8-contact electrode bioimpedance analysis (BIA) system. Fasting serum glucose, fasting plasma total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides (TG) were assessed using automatic biochemistry analyzer. After adjusting for age and body mass index (BMI), Chinese males had significantly higher percentage of body fat (PBF) both with respect to whole body (Chinese: 23.7%±0.2% vs. Whites: 22.4%±0.2%) and the trunk area (Chinese: 25.0%±0.3% vs. Whites: 23.2%±0.3%) compared to their white counterparts. At all BMIs, Chinese males had significantly higher fasting glucose levels (Chinese: 5.7±1.0 mmol/L vs. Whites: 5.2±1.0 mmol/L) but lower high-density lipoprotein levels (Chinese: 0.8±1.0 mmol/L vs. Whites: 1.0±1.0 mmol/L) than white males. In addition, a marginally significantly higher diastolic blood pressure was found among Chinese men than that among white men (Chinese: 80±1.0 mmHg vs. Whites: 77±1.0 mmHg). Chinese males had more body fat and a greater degree of central fat deposition pattern than that seen in white males in the present study. Furthermore, data on blood pressure, fasting glucose and blood lipids suggest that Chinese men may be more prone to obesity-related risk factors than white men