Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate metabolism. We examined whether major genetic variants of folate metabolism modify susceptibility of humans to choline deficiency. Fifty-four adult men and women were fed diets containing adequate choline and folate, followed by a diet containing almost no choline, with or without added folate, until they were clinically judged to be choline-deficient, or for up to 42 days. Criteria for clinical choline deficiency were a more than five times increase in serum creatine kinase activity or a >28% increase of liver fat after consuming the low-choline diet that resolved when choline was returned to the diet. Choline deficiency was observed in more than half of the participants, usually within less than a month. Individuals who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele were more likely than noncarriers to develop signs of choline deficiency (odds ratio, 7.0; 95% confidence interval, 2.0-25; P < 0.01) on the low-choline diet unless they were also treated with a folic acid supplement. The effects of the C677T and A1298C polymorphisms of the 5,10-methylene tetrahydrofolate reductase gene and the A80C polymorphism of the reduced folate carrier 1 gene were not statistically significant. The most remarkable finding was the strong association in premenopausal women of the 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele polymorphism with 15 times increased susceptibility to developing organ dysfunction on a low-choline diet

Offshore Code Comparison Collaboration within IEA Wind Task 23: Phase IV Results Regarding Floating Wind Turbine Modeling

1

Alcohol intake and risk of breast cancer: the euramic study

To evaluate the association of alcohol intake with the risk of breast cancer in post-menopausal women, we analyzed the data from an international case-control study conducted in five European countries (FRG, Switzerland, Northern Ireland, the Netherlands and Spain). Information on alcohol intake was available in 315 cases and 364 controls. Medians for the tertiles of alcohol intake among current drinkers were 1.7, 6.0, and 20.0 g/day. Adjusted relative risks (and 95% confidence intervals) of breast cancer for each tertile of intake in current drinkers, compared to never drinkers, were 1.00 (0.60-1.67), 1.01 (0.60-1.73), and 1.18 (0.69-2.03). The adjusted relative risk for ex-drinkers was 1.73 (1.07-2.79). Among both current drinkers and ex-drinkers, the relative risk was higher for those with body mass index above the median compared to those with body mass index below the median. These results do not support a dose-response effect of alcohol on breast cancer risk, although consumption levels were too low to exclude increased risk with high regular intake. Further research is necessary to evaluate the risk of developing breast cancer among ex-drinkers and the potential interaction between body mass index and alcohol drinking.Thc EURAMIC Study was supported as an European Community Concerted Action by the Commission of the European Communities (con-tracts number MR4*/265/NL and MR4*/CT91/0369[SSMA]). The natio-nal studies were financed by grants from the Dutch Ministry of Health, the Spanish "Fondo de Invcstigacioncs Sanitarias" (91E0575), the German Fe-deral Health Office, the Cancer Research Switzerland (AKT76), the Swiss National Science Foundation (32-9257-87), the Yrjö Jahnsson Foundation, the Ulster Cancer Foundation and Milk Intervention Board (co-responsibi-lity Levy Disbursement Reg EEC 110/90 Contract 77.2).S

Association Between Toenail Selenium and Risk of Acute Myocardial Infarction in European Men: The EURAMIC Study

The association between selenium status and risk of acute myocardial infarction was examined in a multicenter case-control study in 10 centers from Europe and Israel in 1991-1992. Selenium in toenails was assessed for 683 nonfatal male cases with first acute myocardial infarction and 729 controls less than 70 years of age. Median toenail selenium content was 0.553 μg/g for cases and 0.590 μg/g for controls. After adjustment for age, center, and smoking, the odds ratio for myocardial infarction in the highest quintile of selenium as compared with the lowest was 0.63 . The observed inverse trend was somewhat stronger when the authors adjusted for vitamin E status (p = 0.05). Analysis stratified for smoking habits showed an inverse association in former smokers (odds ratio for the 75th-25th percentile contrast = 0.63 (95 percent confidence interval 0.43-0.94)), but not in current smokers (odds ratio = 0.97 ( 0.71-1.32)) or in those who had never smoked (odds ratio = 1.55 (0.87-2.76)). Analysis stratified by center showed a significant inverse association between selenium levels and risk of myocardial infarction for Germany (Berlin) only (75th to 25th percentile odds ratio = 0.62 (95 percent confidence interval 0.42-0.91)), which was the center with the lowest selenium levels. It appears that the increased risk of acute myocardial infarction at low levels of selenium intake is largely explained by cigarette smoking; selenium status does not appear to be an important determinant of risk of myocardial infarction at the levels observed in a large part of Europe. Am J Epidemiol 1997; 145: 373-

Early Priming Minimizes the Age-Related Immune Compromise of CD8+ T Cell Diversity and Function

The elderly are particularly susceptible to influenza A virus infections, with increased occurrence, disease severity and reduced vaccine efficacy attributed to declining immunity. Experimentally, the age-dependent decline in influenza-specific CD8+ T cell responsiveness reflects both functional compromise and the emergence of ‘repertoire holes’ arising from the loss of low frequency clonotypes. In this study, we asked whether early priming limits the time-related attrition of immune competence. Though primary responses in aged mice were compromised, animals vaccinated at 6 weeks then challenged >20 months later had T-cell responses that were normal in magnitude. Both functional quality and the persistence of ‘preferred’ TCR clonotypes that expand in a characteristic immunodominance hierarchy were maintained following early priming. Similar to the early priming, vaccination at 22 months followed by challenge retained a response magnitude equivalent to young mice. However, late priming resulted in reduced TCRβ diversity in comparison with vaccination earlier in life. Thus, early priming was critical to maintaining individual and population-wide TCRβ diversity. In summary, early exposure leads to the long-term maintenance of memory T cells and thus preserves optimal, influenza-specific CD8+ T-cell responsiveness and protects against the age-related attrition of naïve T-cell precursors. Our study supports development of vaccines that prime CD8+ T-cells early in life to elicit the broadest possible spectrum of CD8+ T-cell memory and preserve the magnitude, functionality and TCR usage of responding populations. In addition, our study provides the most comprehensive analysis of the aged (primary, secondary primed-early and secondary primed-late) TCR repertoires published to date

Measuring Organizational Power: Resources and Autonomy of Government Agencies

Although power is a major concern of organization theory, little research has focused on the horizontal dimension of power between organizations at relatively equal hierarchical levels. This study attempts to fill that void by operationalizing organizational power for 127 federal government agencies. The derived measure is subjected to tests for internal and external validity by empirically testing one promising theory of agency power.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

A novel outbred mouse model of 2009 pandemic influenza and bacterial co-infection severity

Influenza viruses pose a significant health risk and annually impose a great cost to patients and the health care system. The molecular determinants of influenza severity, often exacerbated by secondary bacterial infection, are largely unclear. We generated a novel outbred mouse model of influenza virus, Staphylococcus aureus, and coinfection utilizing influenza A/CA/07/2009 virus and S. aureus (USA300). Outbred mice displayed a wide range of pathologic phenotypes following influenza virus or co-infection ranging broadly in severity. Influenza viral burden positively correlated with weight loss although lung histopathology did not. Inflammatory cytokines including IL-6, TNF-α, G-CSF, and CXCL10 positively correlated with both weight loss and viral burden. In S. aureus infection, IL-1β, G-CSF, TNF-α, and IL-6 positively correlated with weight loss and bacterial burden. In co-infection, IL-1β production correlated with decreased weight loss suggesting a protective role. The data demonstrate an approach to identify biomarkers of severe disease and to understand pathogenic mechanisms in pneumonia. © 2013 McHugh et al

Preferential Amplification of CD8 Effector-T Cells after Transcutaneous Application of an Inactivated Influenza Vaccine: A Randomized Phase I Trial

Background: Current conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses. Methods and Findings: We chose the inactivated influenza vaccine – a conventional licensed tetanus/influenza (TETAGRIP®) vaccine – to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination. Conclusions: This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role

Unique Type I Interferon Responses Determine the Functional Fate of Migratory Lung Dendritic Cells during Influenza Virus Infection

Migratory lung dendritic cells (DCs) transport viral antigen from the lungs to the draining mediastinal lymph nodes (MLNs) during influenza virus infection to initiate the adaptive immune response. Two major migratory DC subsets, CD103+ DCs and CD11bhigh DCs participate in this function and it is not clear if these antigen presenting cell (APC) populations become directly infected and if so whether their activity is influenced by the infection. In these experiments we show that both subpopulations can become infected and migrate to the draining MLN but a difference in their response to type I interferon (I-IFN) signaling dictates the capacity of the virus to replicate. CD103+ DCs allow the virus to replicate to significantly higher levels than do the CD11bhigh DCs, and they release infectious virus in the MLNs and when cultured ex-vivo. Virus replication in CD11bhigh DCs is inhibited by I-IFNs, since ablation of the I-IFN receptor (IFNAR) signaling permits virus to replicate vigorously and productively in this subset. Interestingly, CD103+ DCs are less sensitive to I-IFNs upregulating interferon-induced genes to a lesser extent than CD11bhigh DCs. The attenuated IFNAR signaling by CD103+ DCs correlates with their described superior antigen presentation capacity for naïve CD8+ T cells when compared to CD11bhigh DCs. Indeed ablation of IFNAR signaling equalizes the competency of the antigen presenting function for the two subpopulations. Thus, antigen presentation by lung DCs is proportional to virus replication and this is tightly constrained by I-IFN. The “interferon-resistant” CD103+ DCs may have evolved to ensure the presentation of viral antigens to T cells in I-IFN rich environments. Conversely, this trait may be exploitable by viral pathogens as a mechanism for systemic dissemination