Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-α (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKα/β phosphorylation and subsequent NF-κB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects

Dependence of impurity binding energy on nitrogen and indium concentrations for shallow donors in a GaInNAs/GaAs quantum well under intense laser field

Within the framework of the effective-mass approximation, using a variational method, we have calculated the effect of intense laser radiation on the binding energy of the shallow-donor impurities in a Ga1-xInxNyAs1-y/GaAs single quantum well for different nitrogen and indium mole concentrations. Our numerical results show that the binding energy strongly depends on the laser intensity and frequency (via the laser dressing parameter) and it also depends on the nitrogen and indium concentrations. Impurity binding energy under intense laser fields can be tuned by changing the nitrogen and indium mole fraction

Worldwide trends in blood pressure from 1975 to 2015 : a pooled analysis of 1479 population-based measurement studies with 19.1 million participants

Background Raised blood pressure is an important risk factor for cardiovascular diseases and chronic kidney disease. We estimated worldwide trends in mean systolic and mean diastolic blood pressure, and the prevalence of, and number of people with, raised blood pressure, defined as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher. Methods For this analysis, we pooled national, subnational, or community population-based studies that had measured blood pressure in adults aged 18 years and older. We used a Bayesian hierarchical model to estimate trends from 1975 to 2015 in mean systolic and mean diastolic blood pressure, and the prevalence of raised blood pressure for 200 countries. We calculated the contributions of changes in prevalence versus population growth and ageing to the increase in the number of adults with raised blood pressure. Findings We pooled 1479 studies that had measured the blood pressures of 19.1 million adults. Global age-standardised mean systolic blood pressure in 2015 was 127.0 mm Hg (95% credible interval 125.7-128.3) in men and 122.3 mm Hg (121.0-123.6) in women; age-standardised mean diastolic blood pressure was 78.7 mm Hg (77.9-79.5) for men and 76.7 mm Hg (75.9-77.6) for women. Global age-standardised prevalence of raised blood pressure was 24.1% (21.4-27.1) in men and 20.1% (17.8-22.5) in women in 2015. Mean systolic and mean diastolic blood pressure decreased substantially from 1975 to 2015 in high-income western and Asia Pacific countries, moving these countries from having some of the highest worldwide blood pressure in 1975 to the lowest in 2015. Mean blood pressure also decreased in women in central and eastern Europe, Latin America and the Caribbean, and, more recently, central Asia, Middle East, and north Africa, but the estimated trends in these super-regions had larger uncertainty than in high-income super-regions. By contrast, mean blood pressure might have increased in east and southeast Asia, south Asia, Oceania, and sub-Saharan Africa. In 2015, central and eastern Europe, sub-Saharan Africa, and south Asia had the highest blood pressure levels. Prevalence of raised blood pressure decreased in high-income and some middle-income countries; it remained unchanged elsewhere. The number of adults with raised blood pressure increased from 594 million in 1975 to 1.13 billion in 2015, with the increase largely in low-income and middle-income countries. The global increase in the number of adults with raised blood pressure is a net effect of increase due to population growth and ageing, and decrease due to declining age-specific prevalence. Interpretation During the past four decades, the highest worldwide blood pressure levels have shifted from high-income countries to low-income countries in south Asia and sub-Saharan Africa due to opposite trends, while blood pressure has been persistently high in central and eastern Europe. Funding Wellcome Trust. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license.Peer reviewe

How palatable food disrupts appetite regulation.

Appetite regulation is part of a feedback system that controls the energy balance, involving a complex interplay of hunger and satiety signals, produced in the hypothalamus as well as in peripheral organs. Hunger signals may be generated in peripheral organs (e.g. ghrelin) but most of them are expressed in the hypothalamus (neuropeptide Y, orexins, agouti-related peptide, melanin concentrating hormone, endogenous opiates and dopamine) and are expressed during situations of energy deficiency. Some satiety signals, such as cholecystokinin, glucagon-like peptide 1, peptide YY and enterostatin are released from the digestive tract in response to food intake. Others, such as leptin and insulin, are mobilized in response to perturbations in the nutritional state. Still others are generated in neurones of the hypothalamus (alpha-melanocyte-stimulating hormone and serotonin). Satiety signals act by inhibiting the expression of hunger signals and/or by blunting their effect. Palatable food, i.e. food rich in fat and sugar, up-regulates the expression of hunger signals and satiety signals, at the same time blunting the response to satiety signals and activating the reward system. Hence, palatable food offsets normal appetite regulation, which may explain the increasing problem of obesity worldwide