Medicine (Austin & Northern Health) - Research Publications

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    Laparoscopic adjustable gastric band in an obese unrelated living donor prior to kidney transplantation: a case report.
    Koshy, AN ; Wilkinson, S ; Coombes, JS ; Fassett, RG (Springer Science and Business Media LLC, 2010-04-19)
    INTRODUCTION: Obese living donors who undergo donor nephrectomy have higher rates of intra-operative and post-operative complications. Many centres exclude obese donors from living donor transplant programs. Diet, exercise and medication are often ineffective weight loss interventions for donors, hence bariatric surgery should be considered. CASE PRESENTATION: We report the case of a 53-year-old Caucasian woman who underwent laparoscopically adjustable gastric banding. The procedure enabled her to lose sufficient weight to gain eligibility for kidney donation. After losing weight, she had an uncomplicated laparoscopic donor nephrectomy surgery, and the recipient underwent successful kidney transplantation. CONCLUSION: Laparoscopically adjustable gastric banding should be considered for obese potential living kidney donors whenever transplantation units restrict access to donor nephrectomy based on the increased surgical risk for donors.
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    Genetics of type 1 diabetes: what's next?
    Pociot, F ; Akolkar, B ; Concannon, P ; Erlich, HA ; Julier, C ; Morahan, G ; Nierras, CR ; Todd, JA ; Rich, SS ; Nerup, J (American Diabetes Association, 2010-07)
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    MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to the viral by-product double-stranded RNA
    Colli, ML ; Moore, F ; Gurzov, EN ; Ortis, F ; Eizirik, DL (OXFORD UNIV PRESS, 2010-01-01)
    beta-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a 'dialog' between beta-cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects beta-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic beta-cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat beta-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinic-polycitidilic acid-PIC). Real-time RT-PCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary beta-cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify beta-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate beta-cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic beta-cell level.
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    Antiatherosclerotic and Renoprotective Effects of Ebselen in the Diabetic Apolipoprotein E/GPx1-Double Knockout Mouse
    Chew, P ; Yuen, DYC ; Stefanovic, N ; Pete, J ; Coughlan, MT ; Jandeleit-Dahm, KA ; Thomas, MC ; Rosenfeldt, F ; Cooper, ME ; de Haan, JB (AMER DIABETES ASSOC, 2010-12)
    OBJECTIVE: To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress. RESEARCH DESIGN AND METHODS: The study was performed using diabetic apolipoprotein E/GPx1 (ApoE(-/-)GPx1(-/-))-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks. RESULTS: Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways. CONCLUSIONS: Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.
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    Hypothermia predicts mortality in critically ill elderly patients with sepsis.
    Tiruvoipati, R ; Ong, K ; Gangopadhyay, H ; Arora, S ; Carney, I ; Botha, J (Springer Science and Business Media LLC, 2010-09-27)
    BACKGROUND: Advanced age is one of the factors that increase mortality in intensive care. Sepsis and multi-organ failure are likely to further increase mortality in elderly patients.We compared the characteristics and outcomes of septic elderly patients (> 65 years) with younger patients (≤ 65 years) and identified factors during the first 24 hours of presentation that could predict mortality in elderly patients. METHODS: This study was conducted in a Level III intensive care unit with a case mix of medical and surgical patients excluding cardiac and neurosurgical patients.We performed a retrospective review of all septic patients admitted to our ICU between July 2004 and May 2007. In addition to demographics and co-morbidities, physiological and laboratory variables were analysed to identify early predictors of mortality in elderly patients with sepsis. RESULTS: Of 175 patients admitted with sepsis, 108 were older than 65 years. Elderly patients differed from younger patients with regard to sex, temperature (37.2°C VS 37.8°C p < 0.01), heart rate, systolic blood pressure, pH, HCO3, potassium, urea, creatinine, APACHE III and SAPS II. The ICU and hospital mortality was significantly higher in elderly patients (10.6% Vs 23.14% (p = 0.04) and 19.4 Vs 35.1 (p = 0.02) respectively). Elderly patients who died in hospital had a significant difference in pH, HCO3, mean blood pressure, potassium, albumin, organs failed, lactate, APACHE III and SAPS II compared to the elderly patients who survived while the mean age and co-morbidities were comparable. Logistic regression analysis identified temperature (OR [per degree centigrade decrease] 0.51; 95% CI 0.306- 0.854; p = 0.010) and SAPS II (OR [per point increase]: 1.12; 95% CI 1.016-1.235; p = 0.02) during the first 24 hours of admission to independently predict increased hospital mortality in elderly patients. CONCLUSIONS: The mortality in elderly patients with sepsis is higher than the younger patients. Temperature (hypothermia) and SAPS II scores during the first 24 hours of presentation independently predict hospital mortality.
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    Hyperlactatemia in critical illness and cardiac surgery
    O'Connor, ED ; Fraser, JF (BIOMED CENTRAL LTD, 2010)
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    Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review
    Merritt, RW ; Walker, ED ; Small, PLC ; Wallace, JR ; Johnson, PDR ; Benbow, ME ; Boakye, DA ; Phillips, RO (PUBLIC LIBRARY SCIENCE, 2010-12)
    Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4-15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the "mysterious disease" because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge.
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    Prospective meta-analysis using individual patient data in intensive care medicine
    Reade, MC ; Delaney, A ; Bailey, MJ ; Harrison, DA ; Yealy, DM ; Jones, PG ; Rowan, KM ; Bellomo, R ; Angus, DC (SPRINGER, 2010-01)
    Meta-analysis is a technique for combining evidence from multiple trials. However, meta-analyses of studies with substantial heterogeneity among patients within trials-common in intensive care-can lead to incorrect conclusions if performed using aggregate data. Use of individual patient data (IPD) can avoid this concern, increase the power of a meta-analysis, and is useful for exploring subgroup effects. Barriers exist to IPD meta-analysis, most of which are overcome if clinical trials are designed to prospectively facilitate the incorporation of their results with other trials. We review the features of prospective IPD meta-analysis and identify those of relevance to intensive care research. We identify three clinical questions, which are the subject of recent or planned randomised controlled trials where IPD MA offers advantages over approaches using aggregate data.
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    The health loss from ischemic stroke and intracerebral hemorrhage: evidence from the North East Melbourne Stroke Incidence Study (NEMESIS)
    Cadilhac, DA ; Dewey, HM ; Vos, T ; Carter, R ; Thrift, AG (BMC, 2010-05-14)
    BACKGROUND: People suffering different types of stroke have differing demographic characteristics and survival. However, current estimates of disease burden are based on the same underlying assumptions irrespective of stroke type. We hypothesized that average Quality Adjusted Life Years (QALYs) lost from stroke would be different for ischemic stroke and intracerebral hemorrhage (ICH). METHODS: We used 1 and 5-year data collected from patients with first-ever stroke participating in the North East Melbourne Stroke Incidence Study (NEMESIS). We calculated case fatality rates, health-adjusted life expectancy, and quality-of-life (QoL) weights specific to each age and gender category. Lifetime 'health loss' for first-ever ischemic stroke and ICH surviving 28-days for the 2004 Australian population cohort was then estimated. Multivariable uncertainty analyses and sensitivity analyses (SA) were used to assess the impact of varying input parameters e.g. case fatality and QoL weights. RESULTS: Paired QoL data at 1 and 5 years were available for 237 NEMESIS participants. Extrapolating NEMESIS rates, 31,539 first-ever strokes were expected for Australia in 2004. Average discounted (3%) QALYs lost per first-ever stroke were estimated to be 5.09 (SD 0.20; SA 5.49) for ischemic stroke (n = 27,660) and 6.17 (SD 0.26; SA 6.45) for ICH (n = 4,291; p < 0.001). QALYs lost also differed according to gender for both subtypes (ischemic stroke: males 4.69 SD 0.38, females 5.51 SD 0.46; ICH: males 5.82 SD 0.67, females 6.50 SD 0.40). DISCUSSION: People with ICH incurred greater loss of health over a lifetime than people with ischemic stroke. This is explained by greater stroke related case fatality at a younger age, but longer life expectancy with disability after the first 12 months for people with ICH. Thus, studies of disease burden in stroke should account for these differences between subtype and gender. Otherwise, in countries where ICH is more common, health loss for stroke may be underestimated. Similar to other studies of this type, the generalisability of the results may be limited. Sensitivity and uncertainty analyses were used to provide a plausible range of variation for Australia. In countries with demographic and life expectancy characteristics comparable to Australia, our QoL weights may be reasonably applicable.
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    INCITE: A randomised trial comparing constraint induced movement therapy and bimanual training in children with congenital hemiplegia
    Boyd, R ; Sakzewski, L ; Ziviani, J ; Abbott, DF ; Badawy, R ; Gilmore, R ; Provan, K ; Tournier, J-D ; Macdonell, RAL ; Jackson, GD (BMC, 2010-01-12)
    BACKGROUND: Congenital hemiplegia is the most common form of cerebral palsy (CP) accounting for 1 in 1300 live births. These children have limitations in capacity to use the impaired upper limb and bimanual coordination deficits which impact on daily activities and participation in home, school and community life. There are currently two diverse intensive therapy approaches. Traditional therapy has adopted a bimanual approach (BIM training) and recently, constraint induced movement therapy (CIMT) has emerged as a promising unimanual approach. Uncertainty remains about the efficacy of these interventions and characteristics of best responders. This study aims to compare the efficacy of CIMT to BIM training to improve outcomes across the ICF for school children with congenital hemiplegia. METHODS/DESIGN: A matched pairs randomised comparison design will be used with children matched by age, gender, side of hemiplegia and level of upper limb function. Based on power calculations a sample size of 52 children (26 matched pairs) will be recruited. Children will be randomised within pairs to receive either CIMT or BIM training. Both interventions will use an intensive activity based day camp model, with groups receiving the same dosage of intervention delivered in the same environment (total 60 hours over 10 days). A novel circus theme will be used to enhance motivation. Groups will be compared at baseline, then at 3, 26 and 52 weeks following intervention. Severity of congenital hemiplegia will be classified according to brain structure (MRI and white matter fibre tracking), cortical excitability using Transcranial Magnetic Stimulation (TMS), functional use of the hand in everyday tasks (Manual Ability Classification System) and Gross Motor Function Classification System (GMFCS). Outcomes will address neurovascular changes (functional MRI, functional connectivity), and brain (re)organisation (TMS), body structure and function (range of motion, spasticity, strength and sensation), activity limitations (upper limb unimanual capacity and bimanual motor coordination), participation restrictions (in home, school and recreation), environmental (barriers and facilitators to participation) and quality of life. DISCUSSION: This paper outlines the theoretical basis, study hypotheses and outcome measures for a matched pairs randomised trial comparing CIMT and BIM training to improve outcomes across the ICF. TRIAL REGISTRATION: ACTRN12609000912280.