Vitamin E supplementation and atherosclerosis : epidemiological studies in elderly and smokers

The antioxidant vitamin E may have beneficial effects on several indicators of human health. We studied the impact on atherosclerosis, immune response and total mortality in smokers and elderly people, who are at risk for increased oxidative stress. Vitamin E may exert its effect on atherosclerosis by protecting low density lipoprotein (LDL) against lipid peroxidation. Moreover, lipid peroxidation may also negatively influence the immune response. In addition to its antioxidant function, vitamin E may be beneficial through effects on cellular function, e.g., by preserving endothelium-dependent vaso-relaxation or decreasing cytokine production.Observational studies . In a cross-sectional study among 158 male lifelong smokers aged 50 to 75 years, adjusted vitamin E intake and plasma levels were not associated with intima media wall thickness (IMT) of the common carotid artery. IMT ,which is a marker for atherosclerosis, was measured non-invasively by using the B-mode ultrasound technique. In a prospective study among 638 independently living elderly aged 65 to 85, no significant association was observed between cholesterol adjusted serum levels of vitamin E and 7.2 years total mortality. (Hazard ratio for lowest tertile vs. highest of 1.11, 95% confidence interval 0.74 to 1.65).Intervention trials. In a randomized placebo-controlled double-blind trial among 218 lifelong male smokers, 400 IU (364 mg) vitamin E was administered daily for two years. A non significant (p=0.34) reduced progression of carotid IMT by 47% was observed compared to a significant spontaneous progression in the placebo group of 0.030 mm (p=0.006). Results were adjusted for initial IMT values and traditional CVD risk factors. Vitamin E significantly reduced the in vitro susceptibility of LDL to oxidation, which was not related to progression.In this trial results were stratified by genetic predisposition. Smokers lacking the detoxifying enzyme activity of glutathion S -transferase µ (genotype GSTM1- 0 ) were compared with those with the positive genotype (GSTM1- 1 ). In the GSTM1- 0 group vitamin E reduced the proportion of smokers with increased carotid IMT by 62% (p=0.06) for the left posterior and by 73% (p=0.01) for the left anterior wall. No effects were observed for the IMT at the right side.In a 3-month randomized double-blind placebo-controlled trial among 83 apparently healthy elderly, aged 67-87 years, 100 mg vitamin E supplementation significantly decreased the percentage of oxidized linoleic acid in LDL (10.4%) compared to the placebo group (4.6%). In this trial vitamin E supplementation did not affect the cellular and humoral immune response.In conclusion , no supportive evidence is provided that vitamin E supplementation has beneficial effects on atherosclerosis and immune response among smokers and elderly. The observations for GSTM1- 0 genotype needs further confirmation. The protective effect of vitamin E on LDL oxidation in vitro lacks validation in vivo. Research on biomarkers of lipid oxidation and arterial damage needs priority to more adequately assess the clinical relevance and optimal intake of vitamin E.</p

Cyber and traditional bullying victimization as a risk factor for mental health problems and suicidal ideation in adolescents

Purpose: To examine whether traditional and cyber bullying victimization were associated with adolescent's mental health problems and suicidal ideation at two-year follow-up. Gender differences were explored to determine whether bullying affects boys and girls differently. Methods: A two-year longitudinal study was conducted among first-year secondary school students (N = 3181). Traditional and cyber bullying victimization were assessed at baseline, whereas mental health status and suicidal ideation were assessed at baseline and follow-up by means of self-report questionnaires. Logistic regression analyses were conducted to assess associations between these variables while controlling for baseline problems. Additionally, we tested whether gender differences in mental health and suicidal ideation were present for the two types of bullying. Results: There was a significant interaction between gender and traditional bullying victimization and between gender and cyber bullying victimization on mental health problems. Among boys, traditional and cyber bullying victimization were not related to mental health problems after controlling for baseline mental health. Among girls, both traditional and cyber bullying victimization were associated with mental health problems after controlling for baseline mental health. No significant interaction between gender and traditional or cyber bullying victimization on suicidal ideation was found. Traditional bullying victimization was associated with suicidal ideation, whereas cyber bullying victimization was not associated with suicidal ideation after controlling for baseline suicidal ideation. Conclusions: Traditional bullying victimization is associated with an increased risk of suicidal ideation, whereas traditional, as well as cyber bullying victimization is associated with an increased risk of mental health problems among girls. These findings stress the importance of programs aimed at reducing bullying behavior, especially because early-onset mental health problems may pose a risk for the development of psychiatric disorders in adulthood

Risky music listening, permanent tinnitus and depression, anxiety, thoughts about suicide and adverse general health

Objective: To estimate the extent to which exposure to music through earphones or headphones with MP3 players or at discotheques and pop/rock concerts exceeded current occupational safety standards for noise exposure, to examine the extent to which temporary and permanent hearing-related symptoms were reported, and to examine whether the experience of permanent symptoms was associated with adverse perceived general and mental health, symptoms of depression, and thoughts about suicide. Methods: A total of 943 students in Dutch inner-city senior-secondary vocational schools completed questionnaires about their sociodemographics, music listening behaviors and health. Multiple logistic regression analyses were used to examine associations. Results: About 60% exceeded safety standards for occupational noise exposure; about one third as a result of listening to MP3 players. About 10% of the participants experienced permanent hearing-related symptoms. Temporary hearing symptoms that occurred after using an MP3 player or going to a discotheque or pop/rock concert were associated with exposure to high-volume music. However, compared to participants not experiencing permanent hearing-related symptoms, those experiencing permanent symptoms were less often exposed to high volume music. Furthermore, they reported at least two times more often symptoms of depression, thoughts about suicide and adverse self-assessed general and mental health. Conclusions: Risky music-listening behaviors continue up to at least the age of 25 years. Permanent hearing-related symptoms are associated with people's health and wellbeing. Participants experiencing such symptoms appeared to have changed their behavior to be less risky. In order to induce behavior change before permanent and irreversible hearingrelated symptoms occur, preventive measurements concerning hearing health are needed

Serum carotenoids, alpha-tocopherol and mortality risk in a prospective study among Dutch elderly

Background Although beta -carotene has shown inverse associations with chronic diseases involving free radical damage in observational epidemiological studies less attention has been paid to five other major carotenoids also showing antioxidant activity irt vitro. Methods We studied the associations between 7.2-year mortality and serum levels of six caroteneids, and alpha -tocopherol, measured in stored serum, sampled in 1991/1992 during a health survey among 638 independently Living elderly subjects aged 65-85 years. Proportional hazards regression was used to estimate hazard ratios of all-cause mortality for the lowest tertiles of serum vitamins with the highest tertiles, adjusting for possible confounding effects. Results During a follow-up period of 7.2 years 171 elderly died. The adjusted hazard ratios for ail-cause mortality for the lowest tertiles of vitamins compared with the highest tertiles were between 1.02 and 1.73. The strongest increase in mortality risk was seen for beta -cryptoxanthin (1.52, 95% CI: 1.00, 2.32), lutein (1.56, 95% CI : 1.05, 2.31) and zeaxanthin (1.32, 95% CI : 0.89, 1.97) and their sum (oxygenated carotenoids: 1.73, 95% CI: 1.12, 2.67). Tests for trend were significant (P <0.05) for all-cause mortality risk and serum levels of total carotenoids, oxygenated carotenoids and -cryptoxanthin. Conclusions Our findings suggest that serum levels of individual carotenoids, particularly the oxygenated species are inversely associated with all-cause mortality and should be considered as candidates for further investigations

Hosting elite sport events to target recreational sport participation: an interrupted time series analysis

Increasing sport participation by hosting elite sport events is a muchdebated policy. This study evaluated the effect of hosting elite sport events on sport participation against the background of a shift in focus towards targeting recreational sport participation. We included 10 international elite sport events organised between 2000 and 2017 in the city of Rotterdam, the Netherlands. Sport-specific participation in the pastyear was obtained from abiannual cross-sectional survey. Per event, interrupted time series analyses were employed using 3 pre- and post-event measures. Data were summarised by means of random-effects metaanalyses. We tested for group differences to evaluate if events organised in the period with amore explicit aim to target recreational sport participation, and associated policies, had alarger impact. Three events concerning cycling, table tennis and gymnastics were followed by an increase in sport-specific participation 1-year after the event was organised, whereas the korfball event was followed by adecrease. The pooled effect of the 10 events did not show any change in sport-specific participation (0.2%-point (95% CI: −0.3; 0.8)). Significant group differences by period were found. More recent events targeting sport participation were followed by an increase in sport-specific participation (1.1%-point (95% CI: 0.0; 2.1)), but not for other events (−0.3%-point (95% CI: −0.6; 0.1)). No group differences were found for the number of visitors and location. Hosting elite sport events that explicitly target sport participation may increase sport participation among citizens. Longitudinal data following individuals over time are needed to support this finding

Statistical M-Estimation and Consistency in Large Deformable Models for Image Warping

The problem of defining appropriate distances between shapes or images and modeling the variability of natural images by group transformations is at the heart of modern image analysis. A current trend is the study of probabilistic and statistical aspects of deformation models, and the development of consistent statistical procedure for the estimation of template images. In this paper, we consider a set of images randomly warped from a mean template which has to be recovered. For this, we define an appropriate statistical parametric model to generate random diffeomorphic deformations in two-dimensions. Then, we focus on the problem of estimating the mean pattern when the images are observed with noise. This problem is challenging both from a theoretical and a practical point of view. M-estimation theory enables us to build an estimator defined as a minimizer of a well-tailored empirical criterion. We prove the convergence of this estimator and propose a gradient descent algorithm to compute this M-estimator in practice. Simulations of template extraction and an application to image clustering and classification are also provided

Separating Lentiviral Vector Injection and Induction of Gene Expression in Time, Does Not Prevent an Immune Response to rtTA in Rats

BACKGROUND: Lentiviral gene transfer can provide long-term expression of therapeutic genes such as erythropoietin. Because overexpression of erythropoietin can be toxic, regulated expression is needed. Doxycycline inducible vectors can regulate expression of therapeutic transgenes efficiently. However, because they express an immunogenic transactivator (rtTA), their utility for gene therapy is limited. In addition to immunogenic proteins that are expressed from inducible vectors, injection of the vector itself is likely to elicit an immune response because viral capsid proteins will induce "danger signals" that trigger an innate response and recruit inflammatory cells. METHODOLOGY AND PRINCIPAL FINDINGS: We have developed an autoregulatory lentiviral vector in which basal expression of rtTA is very low. This enabled us to temporally separate the injection of virus and the expression of the therapeutic gene and rtTA. Wistar rats were injected with an autoregulatory rat erythropoietin expression vector. Two or six weeks after injection, erythropoietin expression was induced by doxycycline. This resulted in an increase of the hematocrit, irrespective of the timing of the induction. However, most rats only responded once to doxycycline administration. Antibodies against rtTA were detected in the early and late induction groups. CONCLUSIONS: Our results suggest that, even when viral vector capsid proteins have disappeared, expression of foreign proteins in muscle will lead to an immune respons

Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs

Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1-/-, Abcb1a/1b;Abcg2-/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2-/- << Slco1a/1b/2b1-/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2-/- or Slco1a/1b/2b1-/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety

In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice

We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub-compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale