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Nedlands, Australia

Radeski D.,Path West Laboratory Medicine | Cull G.M.,Path West Laboratory Medicine | Cain M.,Sir Charles Gairdner Hospital | Hackett L.P.,Clinical Pharmacology and Toxicology Laboratory | And 2 more authors.
Cancer Chemotherapy and Pharmacology

Purpose: We report that hemodialysis clears Ara-U from the blood after high-dose Ara-C treatment in a patient with lymphoma and end-stage renal failure. Methods: The patient received two doses of Ara-C 1 g/m2 24 h apart and was hemodialyzed at about 6 h after each dose and subsequently as per her usual dialysis schedule. Multiple blood samples were collected after dosing. Blood and dialyzate were also collected from the dialysis circuit during a second identical treatment cycle. Ara-C and its metabolite Ara-U in plasma and dialyzate were measured chromatographically, and the data subjected to pharmacokinetic analysis. Results: The distribution and elimination half-lives, steady-state volume of distribution and clearance values were 0.5 h, 7 h, 181 L and 307 l/h for Ara-C and 4.1 h, 34 h, 118 L and 2.64 l/h for Ara-U, respectively. The dialysis sessions immediately after the first and second doses cleared 39 and 52% (as Ara-U) of the respective Ara-C doses. Some 63% of Ara-U in plasma was extracted by dialysis. The patient showed no signs of neurotoxicity or other drug-related adverse effects. Conclusion: Hemodialysis is very effective in clearing Ara-U from the plasma in renal failure, and this maneuver could easily be used routinely to prevent Ara-U accumulation and minimize adverse effects in patients with renal failure. © 2010 Springer-Verlag. Source

Alfonso H.,University of Western Australia | Franklin P.,University of Western Australia | Ching S.,University of Western Australia | Croft K.,University of Western Australia | And 8 more authors.

Background and objective Many of the pathological consequences in the lung following inhalation of asbestos fibres arise as a consequence of persistent oxidative stress and inflammation. Inflammatory responses can be observed in asymptomatic asbestos-exposed individuals. There are currently no interventions to reduce inflammatory or oxidative responses to asbestos before disease develops. We investigated the effects of oral N-acetylcysteine (NAC) on indicators of inflammation or oxidative stress in asymptomatic people previously exposed to asbestos. Methods A double-blind, randomized, placebo-controlled study was conducted to assess the effectiveness and safety of 1800 mg of NAC given orally over a period of 4 months. This was a proof of principle study. Effectiveness was assessed using indicators of inflammation or oxidation as primary end-points. Serum levels of total combined thiols (cysteine, cysteinylglycine, glutathione and homocysteine) were used to monitor the NAC supplementation. Results Thirty-four subjects were randomly allocated to NAC and 32 to placebo. Serum levels of total combined thiols were similar between the groups after intervention. There were no differences in levels of inflammatory or oxidative stress end-points between the groups. No adverse effects were identified. Conclusions No evidence was found that NAC supplementation replenishes total combined thiols in the blood of healthy subjects with a history of asbestos exposure. There was also no evidence of reduced indicators of inflammation or oxidative stress. Further studies should determine the conditions required to increase levels of total anti-oxidant capacity in the blood and in the lungs of subjects with either asbestos-related diseases or subclinical lung inflammation. © 2015 Asian Pacific Society of Respirology. Source

Abudulai L.N.,University of Western Australia | Fernandez S.,University of Western Australia | Corscadden K.,University of Western Australia | Hunter M.,Prince of Wales Hospital | And 6 more authors.
Journal of Acquired Immune Deficiency Syndromes

Objectives: To determine the effect of long-term antiretroviral therapy (ART) on HIV-1-induced B-cell dysfunction. Design: Comparative study of ART-naive and ART-treated HIVinfected patients with non-HIV controls. Methods: B-cell dysfunction was examined in patients with HIV-1 infection (n = 30) who had received ART for a median time of 9.25 years (range: 1.3-21.7) by assessing proportions of CD21lo/-B cells (a marker of B-cell exhaustion) and proportions of tumor necrosis factor-related apoptosis-inducing ligand+ or B and T lymphocyte attenuator+ B cells, and serum levels of immunoglobulin free light chains (markers of B-cell hyperactivation). The association of these markers with serum levels of IgG1 and IgG2, and production of IgG antibodies after vaccination with pneumococcal polysaccharides were also examined. ART-naive patients with HIV (n = 20) and controls (n = 20) were also assessed for comparison. Results: ART-treated patients had increased proportions of CD21lo/-and tumor necrosis factor-related apoptosis-inducing ligand+ B cells and, furthermore, although proportions of B and T lymphocyte attenuator+ B cells were not significantly different from controls, they correlated negatively with CD21lo/-B cells. Proportions of CD21lo/-B cells also correlated negatively with current CD4+ T-cell counts. In ART-naive patients with HIV, free light chains correlated with CD21lo/-B cells and IgG1, but not IgG2. Serum IgG2:IgG1 ratios were substantially lower than normal in patients with HIV and did not resolve on ART. In ART-treated patients, IgG antibody responses to pneumococcal polysaccharides after vaccination were not associated with markers of B-cell dysfunction. Conclusions: B-cell dysfunction persists in patients with HIV receiving long-term ART. The causes and consequences of this require further investigation. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Shetty V.B.,Khan Research Laboratories | Bower C.,Western Australian Register of Developmental Anomalies | Bower C.,Telethon Institute for Child Health Research | Jones T.W.,Khan Research Laboratories | And 6 more authors.
Journal of Paediatrics and Child Health

Aim: To evaluate the incidence, sex distribution, ethnicity, age at diagnosis, clinical presentation and morbidity of all childhood-onset congenital adrenal hyperplasia (CAH) cases in Western Australia (WA) between 1990 and 2010, a state where newborn screening for CAH is not in place. Methods: The total number of all known CAH cases was identified. Case files were reviewed retrospectively to determine clinical details. Classical CAH (C-CAH) was defined as patients presenting before 6 months of age and non-classical (NC-CAH) as presenting after 6 months. Results: Of the 41 CAH cases (26 female) born in WA, 5(12.2%) were of Aboriginal ethnicity. CAH was due to 21-hydroxylase deficiency in 40 cases. Of those with 21-hydroxylase deficiency, 37 were C-CAH (25 female) and 3 NC-CAH (all male). The incidence of C-CAH in WA was estimated to be 0.67 per 10 000 live births (1:14 869). The incidence rate ratio of Aboriginal compared with non-Aboriginal C-CAH was 2.45 (95% confidence interval 0.96-6.29). The mean age of diagnosis of C-CAH cases was lower in females (8.9 ± 2.5 days) compared to males (23.4 ± 9.8 days). Among these males, 72.7% presented initially with adrenal crisis. Conclusion: The estimated incidence of classical CAH is similar to composite worldwide data. The increased female-to-male ratio is not in keeping with the expected sex distribution seen in a recessively inherited disease. The delayed diagnosis in males, with a significant proportion presenting with adrenal crisis, could be avoided with newborn screening. The higher rate of CAH in patients with Aboriginal ethnicity is a novel observation. © 2012 The Authors. Journal of Paediatrics and Child Health © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians). Source

Chang C.C.,Monash University | Chang C.C.,University of KwaZulu - Natal | Chang C.C.,Burnet Institute | Lim A.,University of Western Australia | And 14 more authors.
Journal of Infectious Diseases

Background. Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART).Methods. Mitogen-and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and-induced production of interferon-gamma (IFN-γ), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients.Results. Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-γ production in 24-hour cultures pre-cART and 4 weeks post-cART (P =. 0437 and. 0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P =. 0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P =. 0053,. 0436 and. 0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART.Conclusion. Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-γ production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS. © 2013 The Author. Source

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