Interventions for neurocognitive dysfunction

Purpose of review: To evaluate current barriers to HIV cure strategies and interventions for neurocognitive dysfunction with a particular focus on recent advancements over the last three years. Recent findings: Optimal anti-retroviral therapy (ART) poses challenges to minimise neurotoxicity, whilst ensuring blood brain barrier penetration and minimising the risk of cerebrovascular disease. CSF biomarkers, BCL11B and neurofilament light chain may be implicated with a neuroinflammatory cascade leading to cognitive impairment. Diagnostic imaging with diffusion tensor imaging as well as resting-state fMRI show promise in future diagnosis and monitoring of HAND. Summary: The introduction of ART has resulted in a dramatic decline in HIV-associated dementia. Despite this reduction, milder forms of HIV-associated neurocognitive disorder (HAND) are still prevalent and are clinically significant. The central nervous system (CNS) has been recognised as a probable reservoir and sanctuary for HIV, representing a significant barrier to management interventions

Plankton community composition, organic carbon and thorium-234 particle size distributions, and particle export in the Sargasso Sea

Measurements of plankton community composition (eight planktonic groups), particle size-fractionated (10, 20, 53, 70, and 100-μm Nitex screens) distributions of organic carbon (OC) and 234Th, and particle export of OC and 234Th are reported over a seasonal cycle (2006–2007) from the Bermuda Atlantic Time-Series (BATS) site. Results indicate a convergence of the particle size distributions of OC and 234Th during the winter-spring bloom period (January–March, 2007). The observed convergence of these particle size distributions is directly correlated to the depth-integrated abundance of autotrophic pico-eukaryotes (r = 0.97, P \u3c 0.05) and, to a lesser extent, Synechococcus (r = 0.85, P \u3c 0.14). In addition, there are positive correlations between the sediment trap flux of OC and 234Th at 150 m and the depth-integrated abundance of pico-eukaryotes (r = 0.94, P \u3c 0.06 for OC, and r = 0.98, P \u3c 0.05 for 234Th) and Synechococcus (r = 0.95, P \u3c 0.05 for OC, and r = 0.94, P \u3c 0.06 for 234Th). An implication of these observations and recent modeling studies (Richardson and Jackson, 2007) is that, although small in size, pico-plankton may influence large particle export from the surface waters of the subtropical Atlantic

Exogenously added GPI-anchored tissue inhibitor of matrix metal loproteinase-1 (TIMP-1) displays enhanced and novel biological activities

The family of tissue inhibitors of metalloproteinases (TIMPs) exhibits diverse physiological/biological functions including the inhibition of active matrix metalloproteinases, regulation of proMMP activation, cell growth, and the modulation of angiogenesis. TIMP-1 is a secreted protein that can be detected on the cell surface through its interaction with surface proteins. The diverse biological functions of TIMP-1 are thought to lie, in part, in the kinetics of TIMP-1/MMP/surface protein interactions. Proteins anchored by glycoinositol phospholipids (GPIs), when purified and added to cells in vitro, are incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to generate a reagent that could be added directly to cell membranes and thus focus defined concentrations of TIMP-1 protein on any cell surface independent of protein-protein interaction. Unlike native TIMP-1, exogenously added GPI-anchored TIMP-1 protein effectively blocked release of MMP-2 and MMP-9 from osteosarcoma cells. TIMP-1-GP1 was a more effective modulator of migration and proliferation than TIMP-1. While control hTIMP-1 protein did not significantly affect migration of primary microvascular endothelial cells at the concentrations tested, the GPI-anchored TIMP-1 protein showed a pronounced suppression of endothelial cell migration in response to bFGF. In addition, TIMP-1-GPI was more effective at inducing microvascular endothelial proliferation. In contrast, fibroblast proliferation was suppressed by the agent. Reagents based on this method should assist in the dissection of the protease cascades and activities involved in TIMP biology. Membrane-fixed TIMP-1 may represent a more effective version of the protein for use in therapeutic expression

HopScotch - a low-power renewable energy base station network for rural broadband access

The provision of adequate broadband access to communities in sparsely populated rural areas has in the past been severely restricted. In this paper, we present a wireless broadband access test bed running in the Scottish Highlands and Islands which is based on a relay network of low-power base stations. Base stations are powered by a combination of renewable sources creating a low cost and scalable solution suitable for community ownership. The use of the 5~GHz bands allows the network to offer large data rates and the testing of ultra high frequency ``white space'' bands allow expansive coverage whilst reducing the number of base stations or required transmission power. We argue that the reliance on renewable power and the intelligent use of frequency bands makes this approach an economic green radio technology which can address the problem of rural broadband access

Blood-brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV

OBJECTIVE: Although blood-brain barrier (BBB) impairment has been reported in HIV-infected individuals, characterization of this impairment has not been clearly defined. METHODS: BBB integrity was measured by CSF/plasma albumin ratio in this cross-sectional study of 631 HIV-infected individuals and 71 controls. We also analyzed CSF and blood HIV RNA and neopterin, CSF leukocyte count, and neurofilament light chain protein (NFL) concentrations. The HIV-infected participants included untreated neuroasymptomatic patients, patients with untreated HIV-associated dementia (HAD), and participants on suppressive antiretroviral treatment (ART). RESULTS: The albumin ratio was significantly increased in patients with HAD compared to all other groups. There were no significant differences between untreated neuroasymptomatic participants, treated participants, and controls. BBB integrity, however, correlated significantly with CSF leukocyte count, CSF HIV RNA, serum and CSF neopterin, and age in untreated neuroasymptomatic participants. In a multiple linear regression analysis, age, CSF neopterin, and CSF leukocyte count stood out as independent predictors of albumin ratio. A significant correlation was found between albumin ratio and CSF NFL in untreated neuroasymptomatic patients and in participants on ART. Albumin ratio, age, and CD4 cell count were confirmed as independent predictors of CSF NFL in multivariable analysis. CONCLUSIONS: BBB disruption was mainly found in patients with HAD, where BBB damage correlated with CNS immunoactivation. Albumin ratios also correlated with CSF inflammatory markers and NFL in untreated neuroasymptomatic participants. These findings give support to the association among BBB deterioration, intrathecal immunoactivation, and neuronal injury in untreated neuroasymptomatic HIV-infected individuals

Breastfeeding, asthma, and allergy : a tale of two cities

BACKGROUND: The effect of breastfeeding duration on subsequent asthma and allergy remains the subject of much controversy. OBJECTIVE: To investigate whether differences in study design or disease-related exposure modification were the cause of the differences in study findings. METHOD: The data from two cohorts, the Childhood Asthma Prevention Study (CAPS) from Australia and the Barn Allergi Miljo Stockholm cohort from Sweden, which had reported different findings on the association between breastfeeding and asthma, were combined. For this analysis, the definitions for breastfeeding, asthma, and allergy were harmonized. Subjects were included if they had at least one parent with wheeze or asthma and had a gestational age of more than 36 wks (combined n = 882). The risk of disease-related exposure modification was assessed using survival analysis. RESULTS: Breastfeeding reduced the risk of asthma at 4/5 and 8 yrs of age in children with a family history of asthma. The effect was stronger in the Swedish cohort. Breastfeeding had no effect on the prevalence of sensitization to inhaled allergens in this cohort with a family history of asthma but was a risk factor for sensitization to cow's milk, peanuts, and eggs in the CAPS cohort at 4/5 yrs and in the combined cohort at 8 yrs. There was no evidence to support the existence of disease-related exposure modification in either cohort. CONCLUSION: These findings point to the importance of harmonization of features of study design, including subject selection criteria and variable definitions, in resolving epidemiological controversies such as those surrounding the impact of breastfeeding on asthma and allergic sensitization.National Health and Medical Research Council of AustraliaStockholm County CouncilHjärt- och LungfondenThe Swedish Asthma and Allergy AssociationVetenskapsrådetThe Centre for Allergy research Karolinska InstitutetManuscrip

Using fathers as a negative control exposure to test the developmental origins of health and disease hypothesis : a case study on maternal distress and offspring asthma using Swedish register data

Background: Developmental Origins of Health and Disease Hypothesis (DOHaD) studies are often observational in nature and are therefore prone to biases from loss to follow-up and unmeasured confounding. Register-based studies can reduce these issues since they allow almost complete follow-up and provide information on fathers that can be used in a negative control analysis to assess the impact of unmeasured confounding. Aim: To propose a causal model for testing DOHaD using paternal exposure as a negative control, and its application to maternal distress in pregnancy and offspring asthma. Methods: A causal diagram including shared and parent-specific measured and unmeasured confounders for maternal (fetal) and paternal exposures is proposed. The case-study consisted of all children born in Sweden from July 2006 to December 2008 (n=254 150). Information about childhood asthma, parental distress and covariates was obtained from the Swedish National health registers. Associations between maternal and paternal distress during pregnancy and offspring asthma at age 5 years were assessed separately and with mutual adjustment for the other parent’s distress measure, as well as for shared confounders. Results: Maternal distress during pregnancy was associated with offspring asthma risk; mutually adjusted Odds Ratio (OR) 1.32 (95% CI 1.23, 1.43). The mutually adjusted paternal distress-offspring asthma analysis (OR 1.05 95% CI 0.97, 1.13) indicated no evidence for unmeasured confounding shared by the mother and father. Conclusions: Using paternal exposure in a negative control model to test the robustness of fetal programming hypotheses can be a relatively simple extension of conventional observational studies but limitations need to be considered.NoneManuscrip

Research productivity and academics’ conceptions of research

This paper asks the question: do people with different levels of research productivity and identification as a researcher think of research differently? It discusses a study that differentiated levels of research productivity among English and Australian academics working in research-intensive environments in three broad discipline areas: science, engineering and technology; social science and humanities; and medicine and health sciences. The paper explores the different conceptions of research held by these academics in terms of their levels of research productivity, their levels of research training, whether they considered themselves an active researcher and a member of a research team, and their disciplinary differences