p22phox C242T SNP inhibits inflammatory oxidative damage to endothelial cells and vessels

Background— T NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism (SNP) C242T of the p22phox subunit of NADPH oxidase has been reported to be negatively associated with coronary heart disease (CHD) and may predict disease prevalence. However, the underlying mechanisms remain unknown. Methods and Results— Using computer molecular modelling we discovered that C242T SNP causes significant structural changes in the extracellular loop of p22phox and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22phox reduced significantly Nox2 expression but had no significant effect on basal endothelial O2.- production or the expression of Nox1 and Nox4. When cells were stimulated with TNFα (or high glucose), C242T p22phox inhibited significantly TNFα-induced Nox2 maturation, O2.- production, MAPK and NFκB activation and inflammation (all p<0.05). These C242T effects were further confirmed using p22phox shRNA engineered HeLa cells and Nox2-/- coronary microvascular endothelial cells. Clinical significance was investigated using saphenous vein segments from non CHD subjects after phlebectomies. TT (C242T) allele was common (prevalence of ~22%) and compared to CC, veins bearing TT allele had significantly lower levels of Nox2 expression and O2.- generation in response to high glucose challenge. Conclusions— C242T SNP causes p22phox structural changes that inhibit endothelial Nox2 activation and oxidative response to TNFα or high glucose stimulation. C242T SNP may represent a natural protective mechanism against inflammatory cardiovascular diseases.

Long-term positive effects of repeating a year in school: Six-year longitudinal study of self-beliefs, anxiety, social relations, school grades, and test scores

Consistently with a priori predictions, school retention (repeating a year in school) had largely positive effects for a diverse range of 10 outcomes (e.g., math self-concept, self-efficacy, anxiety, relations with teachers, parents and peers, school grades, and standardized achievement test scores). The design, based on a large, representative sample of German students (N = 1,325, M age = 11.75 years) measured each year during the first five years of secondary school, was particularly strong. It featured four independent retention groups (different groups of students, each repeating one of the four first years of secondary school, total N = 103), with multiple post-test waves to evaluate short- and long-term effects, controlling for covariates (gender, age, SES, primary school grades, IQ) and one or more sets of 10 outcomes realised prior to retention. Tests of developmental invariance demonstrated that the effects of retention (controlling for covariates and pre-retention outcomes) were highly consistent across this potentially volatile early-to-middle adolescent period; largely positive effects in the first year following retention were maintained in subsequent school years following retention. Particularly considering that these results are contrary to at least some of the accepted wisdom about school retention, the findings have important implications for educational researchers, policymakers and parents.