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Viardot A.,Garvan Institute of Medical Research | Lord R.V.,St Vincents Center For Applied Medical Research | Samaras K.,Garvan Institute of Medical Research
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Obesity-related chronic inflammation is implicated in the pathogenesis of type 2 diabetes (T2D). Objective: The objective of the study was to determine the effects of weight loss on immune cells in T2D and prediabetes. Design and Setting: Thirteen obese subjects with T2D or prediabetes underwent 24 wk dietary energy restriction with gastric banding surgery at 12 wk. Main Outcome Measures: Measures included weight, waist, and insulin resistance; surface activation marker expression on circulating immune cells; T-helper cell polarization: type 1 (Th1), type 2 (Th2); adipose tissue macrophage number and activation in sc and visceral adipose tissue. Results: Mean total weight loss was 13.5%. There were significant decreases in expression of proinflammatory activation markers: granulocyte CD11b, monocyte CD66b, and T cell CD69 and CD25. Proinflammatory Th1 cell numbers fell by greater than 80%, as did the Th1 to Th2 ratio. The fall in Th1 to Th2 ratio related to weight (P < 0.05) and waist loss (P < 0.05). Reduction in immune cell activation was more pronounced in subjects with prediabetes. Weight and abdominal fat loss were predicted by lower activation of adipose tissue macrophage in sc and visceral adipose tissue (P < 0.05). Conclusions: Energy restriction before and after gastric banding attenuates activation of circulating immune cells of the innate and adaptive immune system in T2D and prediabetes. The role of immune cells in the chronic inflammation of obesity and T2D requires further investigation. Copyright © 2010 by The Endocrine Society. Source

Mothobi N.Z.,St. Vincents Hospital | Brew B.J.,St. Vincents Hospital | Brew B.J.,St Vincents Center For Applied Medical Research
Current Opinion in Infectious Diseases | Year: 2012

PURPOSE OF REVIEW: The aim is to review the recent confirmation of the continued high prevalence of HIV-associated neurocognitive disorders (HAND) despite highly active antiretroviral therapy (HAART) in a large cohort study and to review the recent studies that have begun to address the potential reasons for such persistence. RECENT FINDINGS: HAND remains prevalent, despite effective viral suppression in cerebrospinal fluid and plasma. Several studies have shown the benefit of a central nervous system (CNS) penetrating HAART regimen (neuro-HAART) in improving neurocognitive outcomes. New evidence supports the early initiation of HAART. There are recent data to suggest that HAART may be CNS toxic, but evidence is still limited. Ageing does not currently explain the persistence of HAND. A recent study has also shown a correlation between cardiovascular risk factors and HAND. SUMMARY: The prevalence of HAND remains high in the HAART era. Most studies point towards the benefit of neuro-HAART in the prevention and treatment of HAND. The possible neurotoxicity of HAART needs to be further evaluated. It may be too early to detect a combined ageing and HIV effect and long-term studies are required. The link between cardiovascular disease and neurocognitive decline in HIV needs further exploration. Effective screening in clinical practice is paramount in prevention of the morbidity and mortality associated with HAND. Copyright © Lippincott Williams & Wilkins. Source

Guillemin G.J.,University of New South Wales | Guillemin G.J.,St Vincents Center For Applied Medical Research
FEBS Journal | Year: 2012

Over the last two decades, evidence for the involvement of quinolinic acid (QUIN) in neuroinflammatory diseases has been exponentially increasing. Within the brain, QUIN is produced and released by infiltrating macrophages and activated microglia, the very cells that are prominent during neuroinflammation. QUIN acts as an agonist of the N-methyl-d-aspartate receptor and as such is considered to be a brain endogenous excitotoxin. Since the discovery of the excitotoxic activity of QUIN in the early 1980s, several other cytotoxic mechanisms have been identified. We know today that QUIN acts as a neurotoxin, gliotoxin, proinflammatory mediator, pro-oxidant molecule and can alter the integrity and cohesion of the blood-brain barrier. This paper aims to review some of the most recent findings about the effects of QUIN and its mode of action. Quinolinic acid (QUIN) is a brain endogenous excitotoxin produced by infiltrating macrophages and activated microglia during neuroinflammation. QUIN acts as a neurotoxin; gliotoxin, proinflammatory mediator, pro-oxidant molecule and can alter the integrity and cohesion of the blood-brain barrier. We review here some of the most recent findings about the effects of QUIN and its mode of action © 2012 The Author Journal compilation © 2012 FEBS. Source

Swaminathan S.,Frederick National Laboratory for Cancer Research | Murray D.D.,St Vincents Center For Applied Medical Research | Murray D.D.,University of New South Wales | Kelleher A.D.,St Vincents Center For Applied Medical Research | Kelleher A.D.,University of New South Wales
Immunological Reviews | Year: 2013

Our understanding of the complexity of gene regulation has significantly improved in the last decade as the role of small non-coding RNAs, called microRNAs (miRNAs), has been appreciated. These 19-22 nucleotide RNA molecules are critical regulators of mRNA translation and turnover. The miRNAs bind via a protein complex to the 3′ untranslated region (3′ UTR) of mRNA, ultimately leading to mRNA translational inhibition, degradation, or repression. Although many mechanisms by which human immunodeficiency virus-1 (HIV-1) infection eventually induces catastrophic immune destruction have been elucidated, the important role that miRNAs play in HIV-1 pathogenesis is only now emerging. Accumulating evidence demonstrates that changes to endogenous miRNA levels following infection is important: in maintaining HIV-1 latency in resting CD4+ T cells, potentially affect immune function via changes to cytokines such as interleukin-2 (IL-2) and IL-10 and may predict disease progression. We review the roles that both viral and host miRNAs play in different cell types and disease conditions that are important in HIV-1 infection and discuss how miRNAs affect key immunomodulatory molecules contributing to immune dysfunction. Further, we discuss whether miRNAs may be used as novel biomarkers in serum and the potential to modulate miRNA levels as a unique approach to combating this pathogen. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source

Brew B.J.,University of New South Wales | Brew B.J.,St Vincents Center For Applied Medical Research | Chan P.,Neurology Team
Current Neurology and Neuroscience Reports | Year: 2014

The introduction of combined antiretroviral therapy (cART) has dramatically reduced the risk of central nervous system opportunistic infection and severe dementia secondary to HIV infection in the last two decades. However, a milder form of HIV-associated neurocognitive disorder (HAND) remains prevalent in the cART era and has a significant impact on patients' quality of life. In this review, we outline updated research findings on investigating and monitoring cognitive impairment in HAND patients. The outcomes of recent research on the pathogenesis of HAND and how it overlaps with neurodegenerative diseases are discussed. Lastly, there is a brief discussion of the results of clinical trials using a brain-penetrating cART regimen. © 2014 Springer Science+Business Media. Source

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