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p are used. A significant proportion of patients with PHPT would have also required genetic studies if the guidelines were followed.Children are the planet’s most valuable resource. Mortality rates and longevity in children are improving; however, morbidity related to early-life exposures is increasing and with it health spending. A focus on identifying and addressing environmental components related to not only chronic childhood illnesses but also major adult mortalities would help contain current healthcare budgets. selleck chemicals Child Health and the Environment (CHE) is an emerging discipline dedicated to managing early-life exposures (prenatal and childhood) on health outcomes throughout life. In Canada, as well as around the world, recognition of this area is growing, but progress has been slow and training of physicians is lacking. The WHO works closely with the Children’s Environmental Health Clinic in Canada as well as collaborating centres around the world to build awareness of environmental health issues and promote improved care of children. Core competencies in CHE for physicians would provide an important step forward.

Unhealthy lifestyles caused a huge disease burden. Adopting healthy lifestyles is the most cost-effective strategy for preventing non-communicable diseases. The aim was to perform a systematic review and meta-analysis to quantify the relationship of combined lifestyle factors (eg, cigarette smoking, alcohol consumption, physical activity, diet and overweight/obesity) with the risk of all-cause mortality, cardiovascular mortality and incident cardiovascular disease (CVD).

PubMed and EMBASE were searched from inception to April 2019. Cohort studies investigating the association between the combination of at least three lifestyle factors and all-cause mortality, cardiovascular mortality or incidence of CVD were filtered by consensus among reviewers. Pairs of reviewers independently extracted data and evaluated study quality. Random-effects models were used to pool HRs. Heterogeneity and publication bias were tested.

In total, 142 studies were included. Compared with the participants with the least-healthy lifestyles, those with the healthiest lifestyles had lower risks of all-cause mortality (HR=0.45, 95% CI 0.41 to 0.48, 74 studies with 2 584 766 participants), cardiovascular mortality (HR=0.42, 95% CI 0.37 to 0.46, 41 studies with 1 743 530 participants), incident CVD (HR=0.38, 95% CI 0.29 to 0.51, 22 studies with 754 894 participants) and multiple subtypes of CVDs (HRs ranging from 0.29 to 0.45). The associations were largely significant and consistent among individuals from different continents, racial groups and socioeconomic backgrounds.

Given the great health benefits, comprehensively tackling multiple lifestyle risk factors should be the cornerstone for reducing the global disease burden.

Given the great health benefits, comprehensively tackling multiple lifestyle risk factors should be the cornerstone for reducing the global disease burden.Long-term administration of some antiepileptic drugs often increases blood lipid levels. In this study, we investigated its molecular mechanism by focusing on the nuclear receptors constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are key transcription factors for enzyme induction and lipid metabolism, respectively, in the liver. Treatment of mice with the CAR activator phenobarbital, an antiepileptic drug, increased plasma triglyceride levels and decreased the hepatic expression of PPARα target genes related to lipid metabolism. The increase in PPARα target gene expression induced by fenofibrate, a PPARα ligand, was inhibited by cotreatment with phenobarbital. CAR suppressed PPARα-dependent gene transcription in HepG2 cells but not in COS-1 cells. The mRNA level of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a coactivator for both CAR and PPARα, in COS-1 cells was much lower than in HepG2 cells. In reporter assays with COS-1 cells overexpressing PGC1α, CAR suppressed PPARα-dependent gene transcription, depending on the coactivator-binding motif. In mammalian two-hybrid assays, CAR attenuated the interaction between PGC1α and PPARα Chemical inhibition of PGC1α prevented phenobarbital-dependent increases in plasma triglyceride levels and the inhibition of PPARα target gene expression. These results suggest that CAR inhibits the interaction between PPARα and PGC1α, attenuating PPARα-dependent lipid metabolism. This might explain the antiepileptic drug-induced elevation of blood triglyceride levels. SIGNIFICANCE STATEMENT Constitutive active/androstane receptor activated by antiepileptic drugs inhibits the peroxisome proliferator-activated receptor α-dependent transcription of genes related to lipid metabolism and upregulates blood triglyceride levels. The molecular mechanism of this inhibition involves competition between these nuclear receptors for coactivator peroxisome proliferator-activated receptor γ coactivator-1α binding.The eastern woodchuck (Marmota monax) is a hibernating species extensively used as an in vivo efficacy model for chronic human hepatitis B virus infection. Under laboratory conditions, woodchucks develop a pseudohibernation condition; thus, the pharmacokinetics (PK) of small-molecule therapeutics may be affected by the seasonal change. The seasonal PK of four probe compounds were characterized over 12 months in seven male and nine female laboratory-maintained woodchucks. These compounds were selected to study changes in oxidative metabolism [antipyrine (AP)], glucuronidation [raltegravir (RTG)], renal clearance [lamivudine (3TC)], and hepatic function [indocyanine green (ICG)]. Seasonal changes in physiologic parameters and PK were determined. Seasonal body weight increases were ≥30%. Seasonal changes in body temperature and heart rate were less then 10%. The mean AP exposure remained unchanged from April to August 2017, followed by a significant increase (≥1.0-fold) from August to December and subsequent deiation in drug PK and/or toxicity. This information is also valuable to drug metabolism and veterinary scientists in understanding woodchuck’s seasonal metabolism and behavior under the pseudohibernation condition.