HLA-G DNA sequence variants and risk of perinatal HIV-1 transmission

BACKGROUND: HLA-G gene is a non-classical MHC class 1 molecule that is highly expressed in the trophoblast at the maternal-fetal interface. In an attempt to elucidate possible immunological mechanisms facilitating protection of infants born to human immunodeficiency virus type (HIV-1) infected mothers, we have been studying genetic variations in the coding and untranslated regions of HLA-G antigen between HIV-1-infected mothers and their infected or uninfected infants. This study investigated whether HLA-G DNA sequence variants are associated with perinatal HIV-1 transmission. RESULTS: Genomic DNA samples were obtained from a nested case-control study of 34 mother-child pairs co-enrolled in a cohort of the Perinatal AIDS Collaborative Transmission Study in New York. The samples were from two groups predominantly of African-American and Hispanic origin: In the first group, both mother and child were HIV-1-infected; in the second group, only the mother was infected while the child remained uninfected. Genotyping of HLA-G gene were performed on the extracted DNA from peripheral blood mononuclear cells using PCR based sequencing and restriction fragment-length polymorphism analyses. Among the studied HLA-G exons, dissimilarities in HLA-G DNA sequence variants between the HIV-1 non-transmitting mother child pairs were mostly observed in exon 8-3'-untranslated region at nucleotide positions T3742A, C3743T, G3777C (P = 0.001). Non-transmitting HIV-1 mother child pairs exhibited dissimilarities at nucleotide position C3743T allele with decreased risk of perinatal HIV-1 transmission, compared with HIV-1 transmitting mother-child pairs carrying this allele (odds ratio 0.02 [95% confidence interval 0.00–0.15] P = 0.00001). In addition, heterozygous dissimilarities at nucleotide positions C634G and 714 insT/G in the 5'-upstream regulatory region were observed between the mother child pairs of the HIV-1-non-transmitting group while homozygous similarities of C634C, and either 714insG/G or mother-child pairs with similar 714insT/G were observed among the transmitting group in the same region. CONCLUSION: This study identified new variants in the HLA-G gene and provides further evidence that dissimilarities in the HLA-G DNA sequence variants could influence the transmission of HIV-1 from infected mothers to their infants

Plasmodium berghei ANKA infection increases Foxp3, IL-10 and IL-2 in CXCL-10 deficient C57BL/6 mice

<p>Abstract</p> <p>Background</p> <p>Cerebral malaria (CM) is a major cause of malaria mortality. Sequestration of infected red blood cells and leukocytes in brain vessels coupled with the production of pro-inflammatory factors contribute to CM. CXCL-10 a chemokine that is chemotactic to T cells has been linked to fatal CM. Mice deficient for CXCL-10 gene are resistant to murine CM, while antibody ablation of CXCL-10 enhanced the production of regulatory T cells (CD4+Cd25+Foxp3+) and IL-10 which regulate the immune system. Interleukin-2 (IL-2), a pro-inflammatory cytokine implicated in malaria pathogenesis has also been shown to be a key regulator of Foxp3. However the role of Foxp3 in resistant murine CM is not well understood.</p> <p>Methods</p> <p>The hypothesis that resistance of CXCL-10-/- mice to murine CM may be due to enhanced expression of Foxp3 in concert with IL-10 and IL-2 was tested. CXCL-10-/- and WT C57BL/6 mice were infected with <it>Plasmodium berghei </it>ANKA and evaluated for CM symptoms. Brain, peripheral blood mononuclear cells (PBMCs) and plasma were harvested from infected and uninfected mice at days 2, 4 and 8. Regulatory T cells (CD4+CD25+) and non-T regs (CD4+CD25-) were isolated from PBMCs and cultured with <it>P. berghei </it>antigens in vitro with dendritic cells as antigen presenting cells. Regulatory T cell transcription and specific factor Foxp3, was evaluated in mouse brain and PBMCs by realtime-PCR and Western blots while IL-10, and IL-2 were evaluated in plasma and cultured supernatants by ELISA.</p> <p>Results</p> <p>Wild type mice exhibited severe murine CM symptoms compared with CXCL-10-/- mice. Foxp3 mRNA and protein in brain and PBMC's of CXCL-10-/- mice was significantly up-regulated (p < 0.05) by day 4 post-infection (p.i) compared with WT. Plasma levels of IL-10 and IL-2 in infected CXCL-10-/- were higher than in WT mice (p < 0.05) at days 2 and 4 p.i. Ex-vivo CD4+CD25+ T cells from CXCL-10-/- re-stimulated with <it>P. berghei </it>antigens produced more IL-10 than WT CD4+CD25+ T cells.</p> <p>Conclusion</p> <p>The results indicate that in the absence of CXCL-10, the resulting up-regulation of Foxp3, IL-10 and IL-2 may be involved in attenuating fatal murine CM.</p

Incoherence between systemic hemodynamic and microcirculatory response to fluid challenge in critically ill patients

Background: The aim of the study was to assess the coherence between systemic hemodynamic and microcirculatory response to a fluid challenge (FC) in critically ill patients. Methods: We prospectively collected data in patients requiring a FC whilst cardiac index (CI) and microcir-culation were monitored. The sublingual microcirculation was assessed using the incident dark field (IDF) CytoCam device (Braedius Medical, Huizen, The Netherlands). The proportion of small perfused vessels (PPV) was calculated. Fluid responders were defined by at least a 10% increase in CI during FC. Responders according to changes in microcirculation were defined by at least 10% increase in PPV at the end of FC. Cohen’s kappa coefficient was measured to assess the agreement to categorize patients as “responders” to FC according to CI and PPV. Results: A total of 41 FC were performed in 38 patients, after a median time of 1 (0–1) days after ICU admission. Most of the fluid challenges (39/41, 95%) were performed using crystalloids and the median total amount of fluid was 500 (500–500) mL. The main reasons for fluid challenge were oliguria (n = 22) and hypotension (n = 10). After FC, CI significantly increased in 24 (58%) cases; a total of 19 (46%) FCs resulted in an increase in PPV. Both CI and PPV increased in 13 responders and neither in 11; the coefficient of agreement was only 0.21. We found no correlation between absolute changes in CI and PPV after fluid challenge. Conclusions: The results of this heterogenous population of critically ill patients suggest incoherence in fluid responsiveness between systemic and microvascular hemodynamics; larger cohort prospective studies with adequate a priori sample size calculations are needed to confirm these findings

Adipose‐Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA‐31

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135340/1/sct3201654440.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135340/2/Supplemental_Information.pd

One Health approach to controlling a Q fever outbreak on an Australian goat farm

A recent outbreak of Q fever was linked to an intensive goat and sheep dairy farm in Victoria, Australia, 2012-2014. Seventeen employees and one family member were confirmed with Q fever over a 28-month period, including two culture-positive cases. The outbreak investigation and management involved a One Health approach with representation from human, animal, environmental and public health. Seroprevalence in non-pregnant milking goats was 15% [95% confidence interval (CI) 7&ndash;27]; active infection was confirmed by positive quantitative PCR on several animal specimens. Genotyping of Coxiella burnetii DNA obtained from goat and human specimens was identical by two typing methods. A number of farming practices probably contributed to the outbreak, with similar precipitating factors to the Netherlands outbreak, 2007-2012. Compared to workers in a high-efficiency particulate arrestance (HEPA) filtered factory, administrative staff in an unfiltered adjoining office and those regularly handling goats and kids had 5&middot;49 (95% CI 1&middot;29&ndash;23&middot;4) and 5&middot;65 (95% CI 1&middot;09&ndash;29&middot;3) times the risk of infection, respectively; suggesting factory workers were protected from windborne spread of organisms. Reduction in the incidence of human cases was achieved through an intensive human vaccination programme plus environmental and biosecurity interventions. Subsequent non-occupational acquisition of Q fever in the spouse of an employee, indicates that infection remains endemic in the goat herd, and remains a challenge to manage without source control

Comparative Toxicity of Fumigants and a Phosphine Synergist Using a Novel Containment Chamber for the Safe Generation of Concentrated Phosphine Gas

BACKGROUND: With the phasing out of ozone-depleting substances in accordance with the United Nations Montreal Protocol, phosphine remains as the only economically viable fumigant for widespread use. However the development of high-level resistance in several pest insects threatens the future usage of phosphine; yet research into phosphine resistance mechanisms has been limited due to the potential for human poisoning in enclosed laboratory environments. PRINCIPAL FINDINGS: Here we describe a custom-designed chamber for safely containing phosphine gas generated from aluminium phosphide tablets. In an improvement on previous generation systems, this chamber can be completely sealed to control the escape of phosphine. The device has been utilised in a screening program with C. elegans that has identified a phosphine synergist, and quantified the efficacy of a new fumigant against that of phosphine. The phosphine-induced mortality at 20°C has been determined with an LC(50) of 732 ppm. This result was contrasted with the efficacy of a potential new botanical pesticide dimethyl disulphide, which for a 24 hour exposure at 20°C is 600 times more potent than phosphine (LC(50) 1.24 ppm). We also found that co-administration of the glutathione depletor diethyl maleate (DEM) with a sublethal dose of phosphine (70 ppm, <LC(5)), results in a doubling of mortality in C. elegans relative to DEM alone. CONCLUSIONS: The prohibitive danger associated with the generation, containment, and use of phosphine in a laboratory environment has now been substantially reduced by the implementation of our novel gas generation chamber. We have also identified a novel phosphine synergist, the glutathione depletor DEM, suggesting an effective pathway to be targeted in future synergist research; as well as quantifying the efficacy of a potential alternative to phosphine, dimethyl disulphide

Securitization and Community-Based Protection Among Chin Refugees in Kuala Lumpur

This article examines refugee-led community organizations among Chin refugees from Myanmar in Kuala Lumpur. It uses a structuration analysis that recognizes refugee-led organizations as complex governance entities engaged in a dynamic relationship with (among others) national policies of securitization of forced migration and international humanitarian governance. This approach expands the existing literature on the securitization of forced migration by exploring refugees’ lived experiences in a context of south–south migration. It expands the literature on community-based protection by going beyond recognizing the existence of refugee-led organizations to analyse their construction, constitution and consequences. Three primary areas of work by Chin refugee groups are analysed in relation to their immediate activity and longer term effects: organization (‘building ethnic unity in adversity’), documentation (‘asserting a bureaucratic identity’) and socialization (‘learning to be illegal’). These long-term effects indicate the possible impact of local protection activities on macrostructural processes such as identity construction and migration choices.construction, constitution and consequences. Three primary areas of work by Chin refugee groups are analysed in relation to their immediate activity and longer term effects: organization (‘building ethnic unity in adversity’), documentation (‘asserting a bureaucratic identity’) and socialization (‘learning to be illegal’). These long-term effects indicate the possible impact of local protection activities on macrostructural processes such as identity construction and migration choices

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

The health and well-being of children and young people who are looked after: Findings from a face-to-face survey in Glasgow

Evidence suggests children and young people who are looked after (LACYP) may have poorer health outcomes than children and young people in the general population, particularly in relation to mental health. This paper discusses findings from a survey of the health and well-being of LACYP in Glasgow. A structured questionnaire used in the 2010 Glasgow Schools Survey (GSS) was adapted and administered in face-to- face interviews with 130 young people aged 11–18 in 2014–2015 to investigate various aspects of health and well-being including physical activity, diet and sleep, smoking, alcohol and drugs, health feelings and worries, behaviours, attitudes and expectations. LACYP were more likely to report that they had tried drugs, slightly more likely to have scores indicating a high level of difficulties on the Strengths and Difficulties Questionnaire (SDQ) and less likely to report that they ate fruit and vegetables, used active transport methods to get to school and expected to go on to further or higher education; however, reported rates of physical activity, smoking and drinking were similar. LACYP were less likely to report that they had engaged in antisocial behaviour, truancy or bullying or been exposed to environmental tobacco smoke, less likely to worry or have low self-esteem, and more likely to rate their health positively. There were some variations according to placement type. The findings of this study present a more positive picture of the health and well-being of LACYP in Glasgow than might have been expected but should be treated with caution due to small sample size. Further research is needed to identify differences in relation to placement type and to determine whether being looked after might be associated with improved health and well-being outcomes for some children and young people