Job strain and tobacco smoking: an individual-participant data meta-analysis of 166,130 adults in 15 European studies

Background

Tobacco smoking is a major contributor to the public health burden and healthcare costs worldwide, but the determinants of smoking behaviours are poorly understood. We conducted a large individual-participant meta-analysis to examine the extent to which work-related stress, operationalised as job strain, is associated with tobacco smoking in working adults.

Methodology and Principal Findings

We analysed cross-sectional data from 15 European studies comprising 166 130 participants. Longitudinal data from six studies were used. Job strain and smoking were self-reported. Smoking was harmonised into three categories never, ex- and current. We modelled the cross-sectional associations using logistic regression and the results pooled in random effects meta-analyses. Mixed effects logistic regression was used to examine longitudinal associations. Of the 166 130 participants, 17% reported job strain, 42% were never smokers, 33% ex-smokers and 25% current smokers. In the analyses of the cross-sectional data, current smokers had higher odds of job strain than never-smokers (age, sex and socioeconomic position-adjusted odds ratio: 1.11, 95% confidence interval: 1.03, 1.18). Current smokers with job strain smoked, on average, three cigarettes per week more than current smokers without job strain. In the analyses of longitudinal data (1 to 9 years of follow-up), there was no clear evidence for longitudinal associations between job strain and taking up or quitting smoking.

Conclusions

Our findings show that smokers are slightly more likely than non-smokers to report work-related stress. In addition, smokers who reported work stress smoked, on average, slightly more cigarettes than stress-free smokers.     

Genetics of microenvironmental sensitivity of body weight in rainbow trout (Oncorhynchus mykiss) selected for improved growth

Microenvironmental sensitivity of a genotype refers to the ability to buffer against non-specific environmental factors, and it can be quantified by the amount of residual variation in a trait expressed by the genotype's offspring within a (macro)environment. Due to the high degree of polymorphism in behavioral, growth and life-history traits, both farmed and wild salmonids are highly susceptible to microenvironmental variation, yet the heritable basis of this characteristic remains unknown. We estimated the genetic (co)variance of body weight and its residual variation in 2-year-old rainbow trout (Oncorhynchus mykiss) using a multigenerational data of 45,900 individuals from the Finnish national breeding programme. We also tested whether or not microenvironmental sensitivity has been changed as a correlated genetic response when genetic improvement for growth has been practiced over five generations. The animal model analysis revealed the presence of genetic heterogeneity both in body weight and its residual variation. Heritability of residual variation was remarkably lower (0.02) than that for body weight (0.35). However, genetic coefficient of variation was notable in both body weight (14%) and its residual variation (37%), suggesting a substantial potential for selection responses in both traits. Furthermore, a significant negative genetic correlation (-0.16) was found between body weight and its residual variation, i.e., rapidly growing genotypes are also more tolerant to perturbations in microenvironment. The genetic trends showed that fish growth was successfully increased by selective breeding (an average of 6% per generation), whereas no genetic change occurred in residual variation during the same period. The results imply that genetic improvement for body weight does not cause a concomitant increase in microenvironmental sensitivity. For commercial production, however, there may be high potential to simultaneously improve weight gain and increase its uniformity if both criteria are included in a selection index.     

The putative metal coordination motif in the endonuclease domain of human Parvovirus B19 NS1 is critical for NS1 induced S phase arrest and DNA damage

The non-structural proteins (NS) of the parvovirus family are highly conserved multi-functional molecules that have been extensively characterized and shown to be integral to viral replication. Along with NTP-dependent helicase activity, these proteins carry within their sequences domains that allow them to bind DNA and act as nucleases in order to resolve the concatameric intermediates developed during viral replication. The parvovirus B19 NS1 protein contains sequence domains highly similar to those previously implicated in the above-described functions of NS proteins from adeno-associated virus (AAV), minute virus of mice (MVM) and other non-human parvoviruses. Previous studies have shown that transient transfection of B19 NS1 into human liver carcinoma (HepG2) cells initiates the intrinsic apoptotic cascade, ultimately resulting in cell death. In an effort to elucidate the mechanism of mammalian cell demise in the presence of B19 NS1, we undertook a mutagenesis analysis of the protein's endonuclease domain. Our studies have shown that, unlike wild-type NS1, which induces an accumulation of DNA damage, S phase arrest and apoptosis in HepG2 cells, disruptions in the metal coordination motif of the B19 NS1 protein reduce its ability to induce DNA damage and to trigger S phase arrest and subsequent apoptosis. These studies support our hypothesis that, in the absence of replicating B19 genomes, NS1-induced host cell DNA damage is responsible for apoptotic cell death observed in parvoviral infection of non-permissive mammalian cells.     

Cutaneous B-cell lymphoma in a Perdido Key Beach mouse (Peromyscus poliontus trissyllepsis)

The Perdido Key beach mouse (Peromyscus poliontus trissyllepsis) is an endangered mammal indigenous to the panhandle beaches of Northwest Florida. A captive 3.5-y-old female mouse was evaluated because of severe pruritus, diffuse alopecia, skin reddening, and ulcerations over the dorsum of her body. Initial skin biopsy of the affected area suggested bacterial dermatitis but was inconclusive. Despite empiric antibiotic, anthelmintic, and antihistamine treatments, she continued to decline and developed severe ulcerations over the majority of her body. Postmortem histopathologic evaluation led to a tentative diagnosis of epitheliotropic lymphoma, suggestive of a mycosis fungoides T-cell-type cutaneous lymphoma. However, immunohistochemistry results challenged this diagnosis, indicating that the lesion was actually an epidermotropic B-cell lymphoma. Spontaneous cutaneous B-cell lymphomas are rare in rodents and had not previously been reported to occur in Perdido Key beach mice. This case report provides initial evidence that the Perdido Key beach mouse is susceptible to cutaneous B-cell lymphoma.     

Metal–metal interactions in linear tri-, penta-, hepta-, and nona-nuclear ruthenium string complexes

Density functional theory (DFT) methodology was used to examine the structural properties of linear metal string complexes: [Ru(3)(dpa)(4)X(2)] (X = Cl(-), CN(-), NCS(-), dpa = dipyridylamine(-)), [Ru(5)(tpda)(4)Cl(2)], and hypothetical, not yet synthesized complexes [Ru(7)(tpta)(4)Cl(2)] and [Ru(9)(ppta)(4)Cl(2)] (tpda = tri-α-pyridyldiamine(2-), tpta = tetra-α-pyridyltriamine(3-), ppta = penta-α-pyridyltetraamine(4-)). Our specific focus was on the two longest structures and on comparison of the string complexes and unsupported ruthenium backboned chain complexes, which have weaker ruthenium-ruthenium interactions. The electronic structures were studied with the aid of visualized frontier molecular orbitals, and Bader's quantum theory of atoms in molecules (QTAIM) was used to study the interactions between ruthenium atoms. The electron density was found to be highest and distributed most evenly between the ruthenium atoms in the hypothetical [Ru(7)(tpta)(4)Cl(2)] and [Ru(9)(ppta)(4)Cl(2)] string complexes.     

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci

Crohn''s disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻⁶). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻⁸; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻⁹; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻⁸; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻⁸; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻⁹; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.     

Angiopoietin-Like 4 Mediates PPAR Delta Effect on Lipoprotein Lipase-Dependent Fatty Acid Uptake but Not on Beta-Oxidation in Myotubes

Peroxisome proliferator-activated receptor (PPAR) delta is an important regulator of fatty acid (FA) metabolism. Angiopoietin-like 4 (Angptl4), a multifunctional protein, is one of the major targets of PPAR delta in skeletal muscle cells. Here we investigated the regulation of Angptl4 and its role in mediating PPAR delta functions using human, rat and mouse myotubes. Expression of Angptl4 was upregulated during myotubes differentiation and by oleic acid, insulin and PPAR delta agonist {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516. Treatment with {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 or Angptl4 overexpression inhibited both lipoprotein lipase (LPL) activity and LPL-dependent uptake of FAs whereas uptake of BSA-bound FAs was not affected by either treatment. Activation of retinoic X receptor (RXR), PPAR delta functional partner, using bexarotene upregulated Angptl4 expression and inhibited LPL activity in a PPAR delta dependent fashion. Silencing of Angptl4 blocked the effect of {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 and bexarotene on LPL activity. Treatment with {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 but not Angptl4 overexpression significantly increased palmitate oxidation. Furthermore, Angptl4 overexpression did not affect the capacity of {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 to increase palmitate oxidation. Basal and insulin stimulated glucose uptake, glycogen synthesis and glucose oxidation were not significantly modulated by Angptl4 overexpression. Our findings suggest that FAs-PPARdelta/RXR-Angptl4 axis controls the LPL-dependent uptake of FAs in myotubes, whereas the effect of PPAR delta activation on beta-oxidation is independent of Angptl4.     

D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1

This study investigated the role of catecholamine-related signaling pathways in the regulation of hepatic cytochrome P450 (CYP2E1). Central and peripheral catecholamine depletion with reserpine down-regulated CYP2E1. On the other hand, selective peripheral catecholamine depletion with guanethidine increased CYP2E1 apoprotein levels. Enrichment of peripheral catecholamines with adrenaline suppressed p-nitrophenol hydroxylase activity (PNP). PNP activity was also markedly suppressed by l-DOPA. Stimulation of D(2)-receptors with bromocriptine up-regulated CYP2E1, as assessed by enzyme activity and protein levels, whereas blockade of D(2)-dopaminergic receptors with sulpiride down-regulated this isozyme. These findings indicate that central and peripheral catecholamines have different effects on CYP2E1. Central catecholamines appear related to the up-regulation, whereas the role of peripheral catecholamines is clearly related to the type and location of adrenoceptors involved. D(2)-receptor-linked signaling pathways have an up-regulating effect on CYP2E1, while D(1)-receptor pathways may down-regulate this isozyme. It is worth noting that the widespread environmental pollutant benzo(alpha)pyrene (B(alpha)P) altered the modulating effect of catecholaminergic systems on CYP2E1 regulation. In particular, whereas stimulation or blockade of adrenoceptors had no effect on constitutive PNP activity, exposure to B(alpha)P modified the impact of central and peripheral catecholamines and alpha(2)-adrenoceptors on CYP2E1 expression. It appears that under the influence of B(alpha)P, alpha(2)-adrenergic receptor-linked signaling pathways increased CYP2E1 apoprotein levels. Given that a wide range of xenobiotics and clinically used drugs are activated by CYP2E1 to toxic metabolites, including the production of reactive oxygen species (ROS), it is possible that therapies challenging dopaminergic receptor- and/or alpha(2)-adrenoceptor-linked signaling pathways may alter the expression of CYP2E1, thus affecting the progress and development of several pathologies.     

Triacylglycerol fatty acid composition in diet-induced weight loss in subjects with abnormal glucose metabolism--the GENOBIN study

Background

The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention.

Methodology/Principal Findings

Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8±2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction.

Conclusions/Significance

Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00621205","term_id":"NCT00621205"}}NCT00621205