Inhibition of tumour necrosis factor alpha in the R6/2 mouse model of Huntington’s disease by etanercept treatment

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the huntingtin (HTT) gene, which results in a mutant protein with an extended polyglutamine tract. Inflammation occurs in both the brain and the periphery of HD patients and mouse models, with increases in brain and/or plasma levels of neurotoxic TNFα and several other proinflammatory cytokines. TNFα promotes the generation of many of these cytokines, such as IL6, which raises the possibility that TNFα is central to the inflammatory milieu associated with HD. A number of mouse studies have reported that the suppression of chronic immune activation during HD has beneficial consequences. Here, we investigated whether TNFα contributes to the peripheral inflammation that occurs in the R6/2 mouse model, and whether the in vivo blockade of TNFα, via etanercept treatment, can modify disease progression. We found that etanercept treatment normalised the elevated plasma levels of some cytokines. This did not modify the progression of certain behavioural measures, but slightly ameliorated brain weight loss, possibly related to a reduction in the elevated striatal level of soluble TNFα

Integrated vs. referred management of CVD risk factors for HIV positive patients on antiretroviral therapy in Swaziland

Cardiovascular disease risk factors (CVDRF) are prevalent in people living with HIV (PLHIV), but the optimal clinical management strategy for patients with both HIV and CVDRF in low resource settings is unknown. In some contexts, care for both HIV and CVDRF is provided in the HIV clinic (“integrated care”), which may be more convenient for patients. In others, PLHIV are referred to specialist clinics for management of their CVDRF (“referred care”) which may lead to higher quality CVDRF management. We compared integrated vs. referred strategies for patients with HIV and CVDRF at an urban health facility in Swaziland, exploring linkage to and retention in CVDRF care, intervention fidelity, and HIV and CVDRF-related health outcomes

Inhibition of tumour necrosis factor alpha in the R6/2 mouse model of Huntington’s disease by etanercept treatment

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the huntingtin (HTT) gene, which results in a mutant protein with an extended polyglutamine tract. Inflammation occurs in both the brain and the periphery of HD patients and mouse models, with increases in brain and/or plasma levels of neurotoxic TNFα and several other proinflammatory cytokines. TNFα promotes the generation of many of these cytokines, such as IL6, which raises the possibility that TNFα is central to the inflammatory milieu associated with HD. A number of mouse studies have reported that the suppression of chronic immune activation during HD has beneficial consequences. Here, we investigated whether TNFα contributes to the peripheral inflammation that occurs in the R6/2 mouse model, and whether the in vivo blockade of TNFα, via etanercept treatment, can modify disease progression. We found that etanercept treatment normalised the elevated plasma levels of some cytokines. This did not modify the progression of certain behavioural measures, but slightly ameliorated brain weight loss, possibly related to a reduction in the elevated striatal level of soluble TNFα

Nuclear Factor 90(NF90) targeted to TAR RNA inhibits transcriptional activation of HIV-1

<p>Abstract</p> <p>Background</p> <p>Examination of host cell-based inhibitors of HIV-1 transcription may be important for attenuating viral replication. We describe properties of a cellular double-stranded RNA binding protein with intrinsic affinity for HIV-1 TAR RNA that interferes with Tat/TAR interaction and inhibits viral gene expression.</p> <p>Results</p> <p>Utilizing TAR affinity fractionation, North-Western blotting, and mobility-shift assays, we show that the C-terminal variant of nuclear factor 90 (NF90ctv) with strong affinity for the TAR RNA, competes with Tat/TAR interaction <it>in vitro</it>. Analysis of the effect of NF90ctv-TAR RNA interaction <it>in vivo </it>showed significant inhibition of Tat-transactivation of HIV-1 LTR in cells expressing NF90ctv, as well as changes in histone H3 lysine-4 and lysine-9 methylation of HIV chromatin that are consistent with the epigenetic changes in transcriptionally repressed gene.</p> <p>Conclusion</p> <p>Structural integrity of the TAR element is crucial in HIV-1 gene expression. Our results show that perturbation Tat/TAR RNA interaction by the dsRNA binding protein is sufficient to inhibit transcriptional activation of HIV-1.</p

Exposure to Apoptotic Activated CD4+ T Cells Induces Maturation and APOBEC3G- Mediated Inhibition of HIV-1 Infection in Dendritic Cells

Dendritic cells (DCs) are activated by signaling via pathogen-specific receptors or exposure to inflammatory mediators. Here we show that co-culturing DCs with apoptotic HIV-infected activated CD4+ T cells (ApoInf) or apoptotic uninfected activated CD4+ T cells (ApoAct) induced expression of co-stimulatory molecules and cytokine release. In addition, we measured a reduced HIV infection rate in DCs after co-culture with ApoAct. A prerequisite for reduced HIV infection in DCs was activation of CD4+ T cells before apoptosis induction. DCs exposed to ApoAct or ApoInf secreted MIP-1α, MIP-1β, MCP-1, and TNF-α; this effect was retained in the presence of exogenous HIV. The ApoAct-mediated induction of co-stimulatory CD86 molecules and reduction of HIV infection in DCs were partially abrogated after blocking TNF-α using monoclonal antibodies. APOBEC3G expression in DCs was increased in co-cultures of DCs and ApoAct but not by apoptotic resting CD4+ T cells (ApoRest). Silencing of APOBEC3G in DC abrogated the HIV inhibitory effect mediated by ApoAct. Sequence analyses of an env region revealed significant induction of G-to-A hypermutations in the context of GG or GA dinucleotides in DNA isolated from DCs exposed to HIV and ApoAct. Thus, ApoAct-mediated DC maturation resulted in induction of APOBEC3G that was important for inhibition of HIV-infection in DCs. These findings underscore the complexity of differential DC responses evoked upon interaction with resting as compared with activated dying cells during HIV infection

Trends in the incidence of primary liver cancer in Central Uganda, 1960–1980 and 1991–2005

Primary liver cancer (PLC) incidence trends from Africa are unknown. Using Kampala Cancer Registry data from 1960 to 1980 and 1991 to 2005, we identified 771 PLCs. Although rates were stable among men, PLC incidence among women increased >50%. Investigations of viral hepatitis, aflatoxin, obesity, and human immunodeficiency virus (HIV) may help to explain the increasing incidence of hepatocellular carcinomas (HCCs)

The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection

Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8-8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log10 copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms

Fisheries trade and social development in the Philippine-Malaysia maritime border zone

© The Authors 2014. © 2014 Overseas Development Institute. Weakly regulated natural-resource trading activities in the remote borderlands of developing countries are commonly viewed both as a means of improving economic development and as a way of smuggling valuable natural resources. Based on data from the Philippine-Malaysia maritime border that focus on the trade in high-value live reef fish, this article points to the need to situate such cross-border activities more closely within the context of local perspectives and priorities. A locally-grounded perspective is necessary in order to understand the context of social-development challenges that mediate both macroeconomic and environmental policy outcomes

Luxury seafood consumption in China and the intensification of coastal livelihoods in Southeast Asia: The live reef fish for food trade in Balabac, Philippines

An important contemporary driver of livelihood change in coastal Southeast Asia is the growing demand for luxury seafood in China. Based on fieldwork in the municipality of Balabac in Palawan province, western Philippines, this paper takes stock of this trend, and investigates the implications of the relationship between Chinese patterns of luxury seafood consumption and the intensification of coastal livelihoods in Southeast Asia. The paper focuses mostly on the trade in live reef fish, with reference also to sea cucumber and shark fin. In the light of recent discussions of social and environmental change in Southeast Asia, the paper addresses how the intensification of coastal livelihoods has manifested in important trends, including an increasing reliance on high-value commodity fisheries such as the trade in luxury seafood. Important consequences of this intensification of coastal livelihoods include environmental degradation, and social change due to the development of broader trading networks. The paper argues that the live reef fish for food trade is an important contemporary livelihood that highlights the ways in which Chinese consumption is having diverse social and environmental consequences for source countries in Southeast Asia. © 2012 Victoria University of Wellington

Operationalizing the Ecosystem Approach to Small-Scale Fisheries Management in the Philippines: The Iligan Bay Alliance of Misamis Occidental

This paper describes the application of the participatory diagnosis and adaptive management (PDAM) framework to analyze the governance of small-scale fisheries and the potential for adopting the Ecosystem Approach to Fisheries (EAF) in Misamis Occidental, Philippines. Using the Rapid Appraisal of a Fisheries Management System (RAFMS) as a complementary methodology, the paper provides key information on stakeholders’ perception on scaling-up of fisheries management. More specifically, the paper focuses on the strengthening of the Iligan Bay Alliance for Misamis Occidental (IBAMO), a multi-stakeholder body to provide a governance framework for inter-LGU collaboration. Stakeholder participation during the diagnostic phase is also described as well as potential areas for capacity building in addition to information and education activities that are needed to promote EAF in this important fisheries area