Phylogenetic relationships between pinworms (Nematoda: Enterobiinae) parasitising the critically endangered orang-utan,according to the characterisation of molecular genomic and mitochondrial markers

Pinworms (Nematoda: Enterobiinae) include 52 species parasitising primates throughout the world. In the present study, we performed the first ever molecular analysis to investigate the phylogenetic position of recently described pinworms parasitising the Sumatran orang-utan. The phylogenetic analysis of mitochondrial CO1 and chromosomal 18S rDNA and ITS1 regions could support the independent status of several Nematoda species. Our molecular data clearly suggest that Enterobius (Colobenterobius) buckleyi and Lemuricola (Protenterobius) pongoi together with Pongobius hugoti form separate clades among other studied species, which significantly supports the hypothesis of recently described new species parasitising the orang-utan (Pongo abelii and Pongo pygmaeus). The phylogenetic tree based on cytochrome oxidase 1 (CO1) gene variability showed possible close relationships between L. (Protenterobius) pongoi and P. hugoti; thus, we can assume that these species could have initially diverged in sympatry from a common ancestor.     

Salmonella enterica Serovar Typhimurium Infection-Induced CD11b+ Gr1+ Cells Ameliorate Allergic Airway Inflammation

Allergies are mainly characterized as an unrestrained Th2-biased immune response. Epidemiological data associate protection from allergic diseases with the exposure to certain infectious agents during early stages of life. Modulation of the immune response by pathogens has been considered to be a major factor influencing this protection. Recent evidence indicates that immunoregulatory mechanisms induced upon infection ameliorate allergic disorders. A longitudinal study has demonstrated reduced frequency and incidence of asthma in children who reported a prior infection with Salmonella. Experimental studies involving Salmonella enterica serovar Typhimurium-infected murine models have confirmed protection from induced allergic airway inflammation; however, the underlying cause leading to this amelioration remains incompletely defined. In this study, we aimed to delineate the regulatory function of Salmonella Typhimurium infection in the amelioration of allergic airway inflammation in mice. We observed a significant increase in CD11b⁺ Gr1⁺ myeloid cell populations in mice after infection with S. Typhimurium. Using in vitro and in vivo studies, we confirmed that these myeloid cells reduce airway inflammation by influencing Th2 cells. Further characterization showed that the CD11b⁺ Gr1⁺ myeloid cells exhibited their inhibitory effect by altering GATA-3 expression and interleukin-4 (IL-4) production by Th2 cells. These results indicate that the expansion of myeloid cells upon S. Typhimurium infection could potentially play a significant role in curtailing allergic airway inflammation. These findings signify the contribution of myeloid cells in preventing Th2-mediated diseases and suggest their possible application as therapeutics.     

Calcineurin determines toxic versus beneficial responses to α-synuclein

Calcineurin (CN) is a highly conserved Ca²⁺–calmodulin (CaM)-dependent phosphatase that senses Ca²⁺ concentrations and transduces that information into cellular responses. Ca²⁺ homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca²⁺, thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN''s spectrum of substrates toward protective pathways. Modulating CN or CN''s substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase’s activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.Cells must tightly regulate Ca²⁺ homeostasis to avoid pathological perturbations and cell death (1). For example, a profound disruption of Ca²⁺ homeostasis is seen in Parkinson disease (PD), the second most common neurodegenerative disorder. Mutations or aberrant expression of α-synuclein (α-syn), a major protein involved in the pathogenesis of PD, can induce Ca²⁺ overload and cell death (2–5). Additional clinical and experimental observations highlight the importance of Ca²⁺ homeostasis in the pathogenesis of PD. Midbrain dopaminergic (DA) neurons that overexpress Ca²⁺-binding proteins, which buffer intracellular Ca²⁺, are characteristically spared from degeneration (6). Patients with hypertension who are treated with the L-type Ca²⁺ channel blocker, isradipine, have a lower incidence of PD (7). Moreover, isradipine protects DA neurons incubated with α-syn fibrils and is protective in animal models of toxin-induced PD (8–10).From yeast to mammals, calcineurin is largely responsible for transducing the signals generated by changes in Ca²⁺ levels (11). Calcineurin (CN) is a calmodulin (CaM)-dependent serine/threonine phosphatase composed of a catalytic subunit (calcineurin A, CNA) and an activating regulatory subunit (calcineurin B, CNB). As intracellular Ca²⁺ levels rise, Ca²⁺ binds to CNB and CaM, another key calcium signaling protein. Together, Ca²⁺-bound CNB and CaM bind CNA, inducing a conformational change that fully activates the phosphatase (11). Signaling through CN plays critical roles in processes ranging from stress response survival in yeast (12) to mammalian development (13).Despite the compelling link between Ca²⁺ homeostasis and PD, we know little about the signaling pathways driven by sustained Ca²⁺ elevations and how they might lead to cell death (4, 5). Yeast provide a powerful model system for such investigations, given their genetic tractability and the remarkable conservation of Ca²⁺-signaling pathways from yeast to humans (14, 15). Moreover, the expression of human α-syn in yeast leads to cellular pathologies directly relevant to neurons and PD, including nitrosative stress (16, 17), defects in vesicle trafficking (18–20), and faulty mitochondrial function (21, 22).     

Anthropometric measures, cytokines and survival in haemodialysis patients.

BACKGROUND: Lower serum albumin concentration (sAlb) and higher levels of pro-inflammatory cytokines have been reported to predict death in patients treated with haemodialysis (HD). SAlb, along with anthropometric measures, has been used as a surrogate marker for nutritional status in patients with chronic disease. Though adequate nutrition has been considered an important factor for patients treated with HD, it has not been established if any nutritional markers other than lower serum albumin and lower body mass index (BMI) predict death. Furthermore, it has not been shown whether anthropometric measures other than BMI are associated with predictors of mortality. METHODS: At the outset of the study, patients were assessed using demographic and anthropometric indices including arm fat area (AFA), arm muscle area (AMA), BMI, per cent ideal weight (PIW), pre-dialysis sAlb, and circulating levels of tumour necrosis factor-alpha (TNF-alpha), IL-1 and IL-6. A severity index, previously demonstrated to be a mortality marker, was used to grade medical co-morbidity. RESULTS: Two-hundred and forty patients entered the study. The mean age was 55.1+/-14.3 years, mean sAlb 3.76+/-0.60 mg/dl, mean AFA 1742+/-1225 mm(2), mean AMA 5464+/-1817 mm(2), mean PIW 101.0+/-21.3% and mean BMI 24.9+/-5.6 kg/m(2). PIW, BMI, AFA and AMA were, as expected, all highly correlated with one another. SAlb correlated with serum transferrin; however, neither sAlb nor serum transferrin concentration correlated with circulating cytokine levels. Circulating cytokines and sAlb did not correlate with PIW, BMI, AFA or AMA. In Cox regression analyses using multiple control variables, IL-6 predicted survival, while the anthropometric measures did not. CONCLUSIONS: Pro-inflammatory cytokines and sAlb are robust predictors of death in patients treated with HD. PIW and BMI correlate well with other anthropometric measures in patients treated with HD, but these measures do not correlate with markers of inflammation. Anthropometric measures are poor predictors of survival compared with measures linked to the acute-phase response.     

Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability

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Quality standards for child and adolescent mental health in primary care

ABSTRACT: BACKGROUND: Child and adolescent mental health problems are common in primary healthcare settings. However, few parents of children with mental health problems express concerns about these problems during consultations. Based on parental views, we aimed to create quality of care measures for child and adolescent mental health in primary care and develop consensus about the importance of these quality standards within primary care. METHODS: Quality Standards were developed using an iterative approach involving four phases: 1) 34 parents with concerns about their child's emotional health or behaviour were recruited from a range of community settings including primary care practices to participate in focus group discussions, followed by validation groups or interviews. 2) Preliminary Quality Standards were generated that fully represented the parents' experiences and were refined following feedback from an expert parent nominal group. 3) 55 experts, including parents and representatives from voluntary organisations, across five panels participated in a modified two-stage Delphi study to develop consensus on the importance of the Quality Standards. The panels comprised general practitioners, other community-based professionals, child and adolescent psychiatrists, other child and adolescent mental health professionals and public health and policy specialists. 4) The final set of Quality Standards was piloted with 52 parents in primary care. RESULTS: In the Delphi process, all five panels agreed that 10 of 31 Quality Standards were important. Although four panels rated 25-27 statements as important, the general practitioner panel rated 12 as important. The final 10 Quality Standards reflected healthcare domains involving access, confidentiality for young people, practitioner knowledge, communication, continuity of care, and referral to other services. Parents in primary care agreed that all 10 statements were important. CONCLUSIONS: It is feasible to develop a set of Quality Standards to assess mental healthcare provision for children and adolescents seen within primary healthcare services. Primary care practitioners should be aware of parental perspectives about quality of care as these may influence helpseeking behaviours.