Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms

Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling.

There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell–cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation

Early antenatal prediction of gestational diabetes in obese women: development of prediction tools for targeted intervention

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0–18+6 weeks’ gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68–0.74). This increased to 0.77 (95%CI 0.73–0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74–0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most

Home country advantage? The influence of Italian, German and Austrian employee representatives in the UniCredit European Works Council

This article examines the first European Works Council (EWC) to be established in the Italian banking sector, at UniCredit. It focuses on the interaction between Italian, German and Austrian delegations of employee representatives and on the perspectives and practices that reflect their different cultural and institutional backgrounds in industrial relations. Much of the literature suggests that employee representatives from the home country of a multinational company are likely to mould EWC structures in accordance with their own national backgrounds and have greater confidence in dealing with central management in EWC meetings. Our findings partly substantiate this argument, but also suggest that minority delegations, when they have the benefit of strong national institutional arrangements and less fragmented union patterns, are more likely to be cohesive and experienced and therefore able to challenge management and sometimes win significant arguments over strategy

Observations of V838 Mon in the CO rotational lines

We investigate the structure of a field around the position of V838 Mon as seen in the lowest CO rotational transitions. We also measure and analyse emission in the same lines at the position of V838 Mon.Observations have primarily been done in the CO J = 2-1 and J = 3-2 lines using the KOSMA telescope. A field of 3.4 squared degrees has been mapped in the on-the-fly mode in these transitions. Longer integration spectra in the on-off mode have been obtained to study the emission at the position of V838 Mon. Selected positions in the field have also been observed in the CO J = 1-0 transition using the Delingha telescope.In the observed field we have identified many molecular clouds. They can be divided into two groups from the point of view of their observed radial velocities. One, having V(LSR) in the range 18-32 km/s, can be identified with the Perseus Galactic arm. The other one, having V(LSR) between 44-57 km/s, probably belongs to the Norma-Cygnus arm. The radial velocity of V838 Mon is within the second range but the object does not seem to be related to any of the observed clouds. We did not find any molecular buble of a 1 degree dimension around the position of V838 Mon claimed in van Loon et al. An emission has been detected at the position of the object in the CO J = 2-1 and J = 3-2 transitions. The emission is very narrow (FWHM ~ 1.2 km/s) and at V(LSR) = 53.3 km/s. Our analysis of the data suggests that the emission is probably extended.Comment: paper accepted in A&

Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study

<p><b>Background:</b> Antioxidant vitamins are often described as having “independent” associations with risk of cancer, cardiovascular disease (CVD) and mortality. We aimed to compare to what extent a range of antioxidant vitamins and carotenoids are associated with adulthood and childhood markers of socioeconomic deprivation and to adverse lifestyle factors.</p> <p><b>Methods and Findings:</b> Socioeconomic and lifestyle measures were available in 1040 men and 1298 women from the MIDSPAN Family Study (30–59 years at baseline) together with circulating levels of vitamins A, C, E, and carotenoids (α-carotene, β-carotene, lutein and lycopene). Markers of socioeconomic deprivation in adulthood were consistently as strongly associated with lower vitamin C and carotenoid levels as markers of adverse lifestyle; the inverse association with overcrowding was particularly consistent (vitamin C and carotenoids range from 19.1% [95% CI 30.3–6.0] to 38.8% [49.9–25.3] lower among those in overcrowded residencies). These associations were consistent after adjusting for month, classical CVD risk factors, body mass index, physical activity, vitamin supplements, dietary fat and fibre intake. Similar, but weaker, associations were seen for childhood markers of deprivation. The association of vitamin A or E were strikingly different; several adult adverse lifestyle factors associated with higher levels of vitamin A and E, including high alcohol intake for vitamin A (9.5% [5.7–13.5]) and waist hip ratio for vitamin E (9.5% [4.8–14.4]), with the latter associations partially explained by classical risk factors, particularly cholesterol levels.</p> <p><b>Conclusions:</b> Plasma vitamin C and carotenoids have strong inverse associations with adulthood markers of social deprivation, whereas vitamin A and E appear positively related to specific adverse lifestyle factors. These findings should help researchers better contextualize blood antioxidant vitamin levels by illustrating the potential limitations associated with making causal inferences without consideration of social deprivation.</p&gt

High-resolution optical spectroscopy of V838 Monocerotis in 2009

V838 Mon erupted at the beginning of 2002. In the course of the outburst the object evolved to low effective temperatures and declined as a very late M-type supergiant. Among various scenarios proposed to explain the nature of the outburst, the most promising is a stellar merger event. We aim at studying the structure and evolution of the object in the decline from the 2002 eruption. We obtained spectroscopic observations of V838 Mon in January--March 2009 with UVES/VLT. The results are analysed and compared with similar observations obtained in October 2005 with HIRES/Keck. The most striking difference between 2009 and 2005 is a complete absence of the B3V component and of the [FeII] emission lines in 2009. The present spectrum displays only the spectrum of the 2002 eruption remnant. It resembles that of an M6 giant, although the molecular bands in V838 Mon are deeper than those in standard stellar spectra of a similar spectral class. Several atomic lines, which displayed P-Cyg profiles in 2005, are now dominated by pure absorptions. Some of these lines, however, show a narrow emission component, which, as we argue, measures the radial velocity of V838 Mon. The resulting heliocentric velocity is 71 km/s, which very well agrees with the velocity obtained from SiO maser observations. The atomic lines and the molecular bands show very complex kinematics. In some atomic lines and high-excitation molecular bands we observe matter infalling in the object atmosphere. The infall components were already observed in 2005, but were less pronounced and present in fewer lines than in 2009. We argue that the most negative radial velocity components seen in the resonance atomic lines and in the low-excitation molecular bands were formed in the ejecta of the 2002 eruption. The B3V companion most probably became engulfed in an opaque dusty matter of the 2002 V838 Mon ejecta.Comment: A&A, in pres

Exploring the Developmental Overnutrition Hypothesis Using Parental–Offspring Associations and FTO as an Instrumental Variable

Using parental-offspring associations and theFTO gene as an instrumental variable for maternal adiposity, Debbie Lawlor and colleagues found that greater maternal BMI during offspring development does not appear to have a marked effect on offspring fat mass at age 9-11

The importance of both setting and intensity of physical activity in relation to non-clinical anxiety and depression

Physical activity is associated with good physical and mental health. Current recommendations suggest that people should achieve 30 minutes of moderate-intensity activity most days of the week to gain health benefits. This activity may be accumulated in leisure time, in active commuting, at work or in the home. Here we look at the cross-sectional relationship between physical activity and mental health as measured by the HADS anxiety and depression scores in a sample of 1,742 participants from a Scottish general population survey. The participants were men and women in three age cohorts aged around 24, 44 and 64 years who, in 1995, were interviewed face to face and also self-completed the HADS depression and anxiety scale. Respondents reported their levels of physical activity at work, in the home and in leisure time; the intensities of activity were also determined. Physical activity was related to depression scores but not to anxiety scores. There was no relationship between work physical activity and depression score. Among women, depression score increased with each additional episode of vigorous home activity. In both sexes, depression score decreased with each additional episode of vigorous leisure activity, but among men the decrease in depression score with moderate leisure activity was reversed if a lot of moderate activity was undertaken. We have found a variable relationship between depression scores and various settings for physical activity. Researchers, policymakers and practitioners who are interested in the relationship between physical activity and mental health should take into account the setting for activity as well as frequency, duration and intensity of activity