New Measure of Insulin Sensitivity Predicts Cardiovascular Disease Better than HOMA Estimated Insulin Resistance

10.1371/journal.pone.0074410PLoS ONE89-POLN

Determinants of Health-Related Quality of Life (HRQoL) in the Multiethnic Singapore Population - A National Cohort Study

Background: HRQoL is an important outcome to guide and promote healthcare. Clinical and socioeconomic factors may influence HRQoL according to ethnicity. Methodology: A multiethnic cross-sectional national cohort (N = 7198) of the Singapore general population consisting of Chinese (N = 4873), Malay (N = 1167) and Indian (N = 1158) adults were evaluated using measures of HRQoL (SF-36 version 2), family functioning, health behaviours and clinical/laboratory assessments. Multiple regression analyses were performed to identify determinants of physical and mental HRQoL in the overall population and their potential differential effects by ethnicity. No a priori hypotheses were formulated so all interaction effects were explored. Principal Findings: HRQoL levels differed between ethnic groups. Chinese respondents had higher physical HRQoL (PCS) than Indian and Malay participants (p<0.001) whereas mental HRQoL (MCS) was higher in Malay relative to Chinese participants (p<0.001). Regressions models explained 17.1% and 14.6% of variance in PCS and MCS respectively with comorbid burden, income and employment being associated with lower HRQoL. Age and family were associated only with MCS. The effects of gender, stroke and musculoskeletal conditions on PCS varied by ethnicity, suggesting non-uniform patterns of association for Chinese, Malay and Indian individuals. Conclusions: Differences in HRQoL levels and determinants of HRQoL among ethnic groups underscore the need to better or differentially target population segments to promote well-being. More work is needed to explore HRQoL and wellness in relation to ethnicity

Deficiency of Leishmania phosphoglycans influences the magnitude but does not affect the quality of secondary (memory) anti-Leishmania immunity

Despite inducing very low IFN-γ response and highly attenuated in vivo, infection of mice with phosphoglycan (PG) deficient Leishmania major (lpg2-) induces protection against virulent L. major challenge. Here, we show that mice infected with lpg2- L. major generate Leishmania-specific memory T cells. However, in vitro and in vivo proliferation, IL-10 and IFN-γ production by lpg2- induced memory cells were impaired in comparison to those induced by wild type (WT) parasites. Interestingly, TNF recall response was comparable to WT infected mice. Despite the impaired proliferation and IFN-γ response, lpg2- infected mice were protected against virulent L. major challenge and their T cells mediated efficient infection-induced immunity. In vivo depletion and neutralization studies with mAbs demonstrated that lpg2- L. major-induced resistance was strongly dependent on IFN-γ, but independent of TNF and CD8(+) T cells. Collectively, these data show that the effectiveness of secondary anti-Leishmania immunity depends on the quality (and not the magnitude) of IFN-γ response. These observations provide further support for consideration of lpg2- L. major as a live-attenuated candidate for leishmanization in humans since it protects strongly against virulent challenge, without inducing pathology in infected animals

Molecular Cloning and Characterization of Two Genes Encoding Dihydroflavonol-4-Reductase from Populus trichocarpa

Dihydroflavonol 4-reductase (DFR, EC 1.1.1.219) is a rate-limited enzyme in the biosynthesis of anthocyanins and condensed tannins (proanthocyanidins) that catalyzes the reduction of dihydroflavonols to leucoanthocyanins. In this study, two full-length transcripts encoding for PtrDFR1 and PtrDFR2 were isolated from Populus trichocarpa. Sequence alignment of the two PtrDFRs with other known DFRs reveals the homology of these genes. The expression profile of PtrDFRs was investigated in various tissues of P. trichocarpa. To determine their functions, two PtrDFRs were overexpressed in tobacco (Nicotiana tabacum) via Agrobacterium-mediated transformation. The associated color change in the flowers was observed in all 35S:PtrDFR1 lines, but not in 35S:PtrDFR2 lines. Compared to the wild-type control, a significantly higher accumulation of anthocyanins was detected in transgenic plants harboring the PtrDFR1. Furthermore, overexpressing PtrDFR1 in Chinese white poplar (P. tomentosa Carr.) resulted in a higher accumulation of both anthocyanins and condensed tannins, whereas constitutively expressing PtrDFR2 only improved condensed tannin accumulation, indicating the potential regulation of condensed tannins by PtrDFR2 in the biosynthetic pathway in poplars

Adaptive Immunity against Leishmania Nucleoside Hydrolase Maps Its C-Terminal Domain as the Target of the CD4+ T Cell–Driven Protective Response

Nucleoside hydrolases (NHs) show homology among parasite protozoa, fungi and bacteria. They are vital protagonists in the establishment of early infection and, therefore, are excellent candidates for the pathogen recognition by adaptive immune responses. Immune protection against NHs would prevent disease at the early infection of several pathogens. We have identified the domain of the NH of L. donovani (NH36) responsible for its immunogenicity and protective efficacy against murine visceral leishmaniasis (VL). Using recombinant generated peptides covering the whole NH36 sequence and saponin we demonstrate that protection against L. chagasi is related to its C-terminal domain (amino-acids 199–314) and is mediated mainly by a CD4+ T cell driven response with a lower contribution of CD8+ T cells. Immunization with this peptide exceeds in 36.73±12.33% the protective response induced by the cognate NH36 protein. Increases in IgM, IgG2a, IgG1 and IgG2b antibodies, CD4+ T cell proportions, IFN-γ secretion, ratios of IFN-γ/IL-10 producing CD4+ and CD8+ T cells and percents of antibody binding inhibition by synthetic predicted epitopes were detected in F3 vaccinated mice. The increases in DTH and in ratios of TNFα/IL-10 CD4+ producing cells were however the strong correlates of protection which was confirmed by in vivo depletion with monoclonal antibodies, algorithm predicted CD4 and CD8 epitopes and a pronounced decrease in parasite load (90.5–88.23%; p = 0.011) that was long-lasting. No decrease in parasite load was detected after vaccination with the N-domain of NH36, in spite of the induction of IFN-γ/IL-10 expression by CD4+ T cells after challenge. Both peptides reduced the size of footpad lesions, but only the C-domain reduced the parasite load of mice challenged with L. amazonensis. The identification of the target of the immune response to NH36 represents a basis for the rationale development of a bivalent vaccine against leishmaniasis and for multivalent vaccines against NHs-dependent pathogens

More stories on Th17 cells

For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. the Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4(+) T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4(+) T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. the Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-beta or TGF-beta plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.Crohn's and Colitis Foundation of AmericaNIHLa Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USAUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilNIH: RO1 AI050265-06Web of Scienc

BALB/c Mice Infected with Antimony Treatment Refractory Isolate of Leishmania braziliensis Present Severe Lesions due to IL-4 Production

Leishmaniasis is a neglected disease that affects more than 12 million people worldwide. In Brazil, the cutaneous disease is more prevalent with about 28,000 new cases reported each year, and L. braziliensis is the main causative agent. The interesting data about the infection with this parasite is the wide variety of clinical manifestations that ranges from single ulcerated lesions to mucocutaneous and disseminated disease. However, experimental models to study the infection with this parasite are difficult to develop due to high resistance of most mouse strains to the infection, and the mechanisms underlying the distinct manifestations remain poorly understood. Here, the authors use a mouse experimental model of infection with different L. braziliensis isolates, known to induce diseases with distinct severity in the human hosts, to elucidate immune mechanisms that may be involved in the different manifestations. They showed that distinct parasite isolates may modulate host response, and increased IL-4 production and Arg I expression was related to more severe disease, resulting in longer length of disease with larger lesions and reduced parasite clearance. These findings may be useful in the identification of immunological targets to control L. braziliensis infection and potential clinical markers of disease progression