Medical Education - Research Publications
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ItemDiacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-12-23)Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
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ItemA survey of acute self-reported infections in pregnancy(BMJ PUBLISHING GROUP, 2011)OBJECTIVE: The objective of this study was to estimate the weekly prevalence of self-reported recently acquired infections in women at least 20 weeks pregnant. DESIGN: We conducted a cross-sectional survey of pregnant women in a hospital antenatal clinic in Sydney, Australia between August 2008 and April 2009. Women were asked to report whether they had onset of a new infection in the 7 days before completing the questionnaire, and were asked for details of symptoms and medication taken. RESULTS: 737 women at least 20 weeks pregnant completed the survey (94% of women approached). Five per cent of the completed questionnaires reported the onset of an infection in the 7 days prior to survey completion. When symptoms were analysed, 3.5% of women were classified as having a moderate or severe infection in the past 7 days. The most common infection reported was a cold/upper respiratory tract infection followed by gastroenteritis. Women pregnant with their first child had a lower rate of self-reported infection than women who had other children (2.9% vs 7.2%). CONCLUSIONS: These results can be used to inform future research examining acute infection as a trigger for pregnancy complications.
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ItemContinuity of midwifery care and gestational weight gain in obese women: a randomised controlled trial(BMC, 2011-03-22)BACKGROUND: The increased prevalence of obesity in pregnant women in Australia and other developed countries is a significant public health concern. Obese women are at increased risk of serious perinatal complications and guidelines recommend weight gain restriction and additional care. There is limited evidence to support the effectiveness of dietary and physical activity lifestyle interventions in preventing adverse perinatal outcomes and new strategies need to be evaluated. The primary aim of this project is to evaluate the effect of continuity of midwifery care on restricting gestational weight gain in obese women to the recommended range. The secondary aims of the study are to assess the impact of continuity of midwifery care on: women's experience of pregnancy care; women's satisfaction with care and a range of psychological factors. METHODS/DESIGN: A two arm randomised controlled trial (RCT) will be conducted with primigravid women recruited from maternity services in Victoria, Australia. Participants will be primigravid women, with a BMI ≥ 30 who are less than 17 weeks gestation. Women allocated to the intervention arm will be cared for in a midwifery continuity of care model and receive an informational leaflet on managing weight gain in pregnancy. Women allocated to the control group will receive routine care in addition to the same informational leaflet. Weight gain during pregnancy, standards of care, medical and obstetric information will be extracted from medical records. Data collected at recruitment (self administered survey) and at 36 weeks by postal survey will include socio-demographic information and the use of validated scales to measure secondary outcomes. DISCUSSION: Continuity of midwifery care models are well aligned with current Victorian, Australian and many international government policies on maternity care. Increasingly, midwifery continuity models of care are being introduced in low risk maternity care, and information on their application in high risk populations is required. There is an identified need to trial alternative antenatal interventions to reduce perinatal risk factors for women who are obese and the findings from this project may have application in other maternity services. In addition this study will inform a larger trial that will focus on birth and postnatal outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610001078044.
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ItemStargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011-04)Absence-like seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model are believed to arise in hyperexcitable somatosensory cortical neurons, however the cellular basis of this increased excitability remains unknown. We have previously shown that expression of the Transmembrane AMPA receptor Regulatory Protein (TARP), stargazin, is elevated in the somatosensory cortex of GAERS. TARPs are critical regulators of the trafficking and function of AMPA receptors. Here we examine the developmental expression of stargazin and the impact this may have on AMPA receptor trafficking in the GAERS model. We show that elevated stargazin in GAERS is associated with an increase in AMPA receptor proteins, GluA1 and GluA2 in the somatosensory cortex plasma membrane of adult epileptic GAERS. Elevated stargazin expression is not seen in the epileptic WAG/Rij rat, which is a genetically distinct but phenotypically similar rat model also manifesting absence seizures, indicating that the changes seen in GAERS are unlikely to be a secondary consequence of the seizures. In juvenile (6 week old) GAERS, at the age when seizures are just starting to be expressed, there is elevated stargazin mRNA, but not protein expression for stargazin or the AMPA receptor subunits. In neonatal (7 day old) pre-epileptic GAERS there was no alteration in stargazin mRNA expression in any brain region examined. These data demonstrate that stargazin and AMPA receptor membrane targeting is altered in GAERS, potentially contributing to hyperexcitability in somatosensory cortex, with a developmental time course that would suggest a pathophysiological role in the epilepsy phenotype.
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ItemNo Preview AvailableDrug-induced psychosis: how to avoid star gazing in schizophrenia research by looking at more obvious sources of light.(Frontiers Media SA, 2011)The prevalent view today is that schizophrenia is a syndrome rather than a specific disease. Liability to schizophrenia is highly heritable. It appears that multiple genetic and environmental factors operate together to push individuals over a threshold into expressing the characteristic clinical picture. One environmental factor which has been curiously neglected is the evidence that certain drugs can induce schizophrenia-like psychosis. In the last 60 years, improved understanding of the relationship between drug abuse and psychosis has contributed substantially to our modern view of the disorder suggesting that liability to psychosis in general, and to schizophrenia in particular, is distributed trough the general population in a similar continuous way to liability to medical disorders such as hypertension and diabetes. In this review we examine the main hypotheses resulting from the link observed between the most common psychotomimetic drugs (lysergic acid diethylamide, amphetamines, cannabis, phencyclidine) and schizophrenia.
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ItemThe effects of intramuscular tenotomy on the lengthening characteristics of tibialis posterior: high versus low intramuscular tenotomy(BRITISH EDITORIAL SOC BONE JOINT SURGERY, 2011-06)BACKGROUND: Lengthening of soft-tissue contractures is frequently required in children with a wide variety of congenital and acquired deformities. However, little is known about the biomechanics of surgical procedures which are commonly used in contracture surgery, or if variations in technique may have a bearing on surgical outcomes. We investigated the hypothesis that the site of intramuscular tenotomy (IMT) within the muscle-tendon-unit (MTU) of the tibialis posterior (TP) would affect the lengthening characteristics. METHODS: We performed a randomized trial on paired cadaver tibialis posterior muscle-tendon-units (TP-MTUs). By random allocation, one of each pair of formalin-preserved TP-MTUs received a high IMT, and the other a low IMT. These were individually tensile-tested with an Instron(®) machine under controlled conditions. A graph of load (Newtons) versus displacement (millimetres) was generated for each pair of tests. The differences in lengthening and load at failure for each pair of TP-MTUs were noted and compared using paired t tests. RESULTS: We found 48% greater lengthening for low IMT compared to high IMT for a given load (P = 0.004, two tailed t test). Load at failure was also significantly lower for the low IMT. These findings confirm our hypothesis that the site of the tenotomy affects the amount of lengthening achieved. This may contribute to the reported variability in clinical outcome. CONCLUSIONS: Understanding the relationship between tenotomy site and lengthening may allow surgeons to vary the site of the tenotomy in order to achieve pre-determined surgical goals. It may be possible to control the surgical "dose" by altering the position of the intramuscular tenotomy within the muscle-tendon-unit.
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ItemWhite Matter and Cognition in Adults Who Were Born Preterm(PUBLIC LIBRARY SCIENCE, 2011-10-12)BACKGROUND AND PURPOSE: Individuals born very preterm (before 33 weeks of gestation, VPT) are at risk of damage to developing white matter, which may affect later cognition and behaviour. METHODS: We used diffusion tensor MRI (DT-MRI) to assess white matter microstructure (fractional anisotropy; FA) in 80 VPT and 41 term-born individuals (mean age 19.1 years, range 17-22, and 18.5 years, range 17-22 years, respectively). VPT individuals were part of a 1982-1984 birth cohort which had been followed up since birth; term individuals were recruited by local press advertisement. General intellectual function, executive function and memory were assessed. RESULTS: The VPT group had reduced FA in four clusters, and increased FA in four clusters relative to the Term group, involving several association tracts of both hemispheres. Clusters of increased FA were associated with more severe neonatal brain injury in the VPT group. Clusters of reduced FA were associated with lower birth weight and perinatal hypoxia, and with reduced adult cognitive performance in the VPT group only. CONCLUSIONS: Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function.
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ItemImpact of metabolic syndrome and its components on cardiovascular disease event rates in 4900 patients with type 2 diabetes assigned to placebo in the field randomised trial(BMC, 2011-11-21)BACKGROUND: Patients with the metabolic syndrome are more likely to develop type 2 diabetes and may have an increased risk of cardiovascular disease (CVD) events.We aimed to establish whether CVD event rates were influenced by the metabolic syndrome as defined by the World Health Organisation (WHO), the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and the International Diabetes Federation (IDF) and to determine which component(s) of the metabolic syndrome (MS) conferred the highest cardiovascular risk in in 4900 patients with type 2 diabetes allocated to placebo in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. RESEARCH DESIGN AND METHODS: We determined the influence of MS variables, as defined by NCEP ATPIII, IDF and WHO, on CVD risk over 5 years, after adjustment for CVD, sex, HbA1c, creatinine, and age, and interactions between the MS variables in a Cox proportional-hazards model. RESULTS: About 80% had hypertension, and about half had other features of the metabolic syndrome (IDF, ATPIII). There was no difference in the prevalence of metabolic syndrome variables between those with and without CVD at study entry. The WHO definition identified those at higher CVD risk across both sexes, all ages, and in those without prior CVD, while the ATPIII definition predicted risk only in those aged over 65 years and in men but not in women. Patients meeting the IDF definition did not have higher risk than those without IDF MS.CVD risk was strongly influenced by prior CVD, sex, age (particularly in women), baseline HbA1c, renal dysfunction, hypertension, and dyslipidemia (low HDL-c, triglycerides > 1.7 mmol/L). The combination of low HDL-c and marked hypertriglyceridemia (> 2.3 mmol/L) increased CVD risk by 41%. Baseline systolic blood pressure increased risk by 16% per 10 mmHg in those with no prior CVD, but had no effect in those with CVD. In those without prior CVD, increasing numbers of metabolic syndrome variables (excluding waist) escalated risk. CONCLUSION: Absence of the metabolic syndrome (by the WHO definition) identifies diabetes patients without prior CVD, who have a lower risk of future CVD events. Hypertension and dyslipidemia increase risk.
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ItemAcquired bloodstream infection in the intensive care unit: incidence and attributable mortality(BMC, 2011)INTRODUCTION: To estimate the incidence of intensive care unit (ICU)-acquired bloodstream infection (BSI) and its independent effect on hospital mortality. METHODS: We retrospectively studied acquisition of BSI during admissions of >72 hours to adult ICUs from two university-affiliated hospitals. We obtained demographics, illness severity and co-morbidity data from ICU databases and microbiological diagnoses from departmental electronic records. We assessed survival at hospital discharge or at 90 days if still hospitalized. RESULTS: We identified 6339 ICU admissions, 330 of which were complicated by BSI (5.2%). Median time to first positive culture was 7 days (IQR 5-12). Overall mortality was 23.5%, 41.2% in patients with BSI and 22.5% in those without. Patients who developed BSI had higher illness severity at ICU admission (median APACHE III score: 79 vs. 68, P < 0.001). After controlling for illness severity and baseline demographics by Cox proportional-hazard model, BSI remained independently associated with risk of death (hazard ratio from diagnosis 2.89; 95% confidence interval 2.41-3.46; P < 0.001). However, only 5% of the deaths in this model could be attributed to acquired-BSI, equivalent to an absolute decrease in survival of 1% of the total population. When analyzed by microbiological classification, Candida, Staphylococcus aureus and gram-negative bacilli infections were independently associated with increased risk of death. In a sub-group analysis intravascular catheter associated BSI remained associated with significant risk of death (hazard ratio 2.64; 95% confidence interval 1.44-4.83; P = 0.002). CONCLUSIONS: ICU-acquired BSI is associated with greater in-hospital mortality, but complicates only 5% of ICU admissions and its absolute effect on population mortality is limited. These findings have implications for the design and interpretation of clinical trials.
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ItemSerum 25-Hydroxyvitamin D, Calcium Intake, and Risk of Type 2 Diabetes After 5 Years Results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study)(AMER DIABETES ASSOC, 2011-05)OBJECTIVE: To examine whether serum 25-hydroxyvitamin D (25OHD) and dietary calcium predict incident type 2 diabetes and insulin sensitivity. RESEARCH DESIGN AND METHODS: A total of 6,537 of the 11,247 adults evaluated in 1999-2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004-2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted for multiple potential confounders, including fasting plasma glucose (FPG). RESULTS: During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58 vs. 65 nmol/L; P < 0.001) and calcium intake (mean 881 vs. 923 mg/day; P = 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63-0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-S at 5 years. CONCLUSIONS: Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adult men and women.