Medicine (St Vincent's) - Research Publications
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ItemLower Urinary Tract Symptoms, Depression, Anxiety and Systemic Inflammatory Factors in Men: A Population-Based Cohort Study(PUBLIC LIBRARY SCIENCE, 2015-10-07)BACKGROUND: The relationship between lower urinary tract symptoms (LUTS) and common mental health disorders such as depression and anxiety in men remains unclear. Inflammation has recently been identified as an independent risk factor for LUTS and depression. This study aimed to assess the association between depression, anxiety and LUTS, and the moderating influence of systemic inflammation, in the presence of other biopsychosocial confounders. METHODS: Participants were randomly-selected from urban, community-dwelling males aged 35-80 years at recruitment (n = 1195; sample response rate:67.8%). Of these, 730 men who attended baseline (2002-5) and follow-up clinic visits (2007-10), with complete outcome measures, and without prostate or bladder cancer and/or surgery, neurodegenerative conditions, or antipsychotic medications use, were selected for the present study. Unadjusted and multi-adjusted regression models of incident storage and voiding LUTS and incident depression and anxiety were combined with serum inflammatory markers (high-sensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), myeloperoxidase (MPO), soluble e-selectin (e-Sel)) and socio-demographic, lifestyle, and health-related factors. Hierarchical multiple regression was used to assessed the moderating effect of inflammatory markers. RESULTS: The incidence of storage, voiding LUTS, depression and anxiety was 16.3% (n = 108), 12.1% (n = 88), 14.5% (n = 108), and 12.2% (n = 107). Regression models demonstrated that men with depression and anxiety at baseline were more likely to have incident storage, but not voiding LUTS (OR: 1.26, 99%CI: 1.01-4.02; and OR:1.74; 99%CI:1.05-2.21, respectively). Men with anxiety and storage LUTS at baseline were more likely to have incident depression (OR: 2.77, 99%CI: 1.65-7.89; and OR:1.45; 99%CI:1.05-2.36, respectively), while men with depression and voiding LUTS were more likely to have anxiety at follow-up (OR: 5.06, 99%CI: 2.81-9.11; and OR:2.40; 99%CI:1.16-4.98, respectively). CRP, TNF-α, and e-Sel were found to have significant moderating effects on the development of storage LUTS (1.06, 0.91-1.96, R2 change: 12.7%), depression (1.17, 1.01-1.54, R2 change: 9.8%), and anxiety (1.35, 1.03-1.76, R2 change: 10.6%), respectively. CONCLUSIONS: There is a bidirectional relationship between storage, but not voiding, LUTS and both depression and anxiety. We observed variable moderation effects for selected inflammatory markers on the development of depression, anxiety and storage LUTS.
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ItemHigher skin autofluorescence in young people with Type 1 diabetes and microvascular complications(WILEY, 2017-04)AIM: To test the hypothesis that non-invasive skin autofluorescence, a measure of advanced glycation end products, would provide a surrogate measure of long-term glycaemia and be associated with early markers of microvascular complications in adolescents with Type 1 diabetes. METHODS: Forearm skin autofluorescence (arbitrary units) was measured in a cross-sectional study of 135 adolescents with Type 1 diabetes [mean ± sd age 15.6 ± 2.1 years, diabetes duration 8.7 ± 3.5 years, HbA1c 72 ± 16 mmol/mol (8.7 ± 1.5%)]. Retinopathy, assessed using seven-field stereoscopic fundal photography, was defined as ≥1 microaneurysm or haemorrhage. Cardiac autonomic function was measured by standard deviation of consecutive RR intervals on a 10-min continuous electrocardiogram recording, as a measure of heart rate variability. RESULTS: Skin autofluorescence was significantly associated with age (R2 = 0.15; P < 0.001). Age- and gender-adjusted skin autofluorescence was associated with concurrent HbA1c (R2 = 0.32; P < 0.001) and HbA1c over the previous 2.5-10 years (R2 = 0.34-0.43; P < 0.002). Age- and gender-adjusted mean skin autofluorescence was higher in adolescents with retinopathy vs those without retinopathy [mean 1.38 (95% CI 1.29, 1.48) vs 1.22 (95% CI 1.17, 1.26) arbitrary units; P = 0.002]. In multivariable analysis, retinopathy was significantly associated with skin autofluorescence, adjusted for duration (R2 = 0.19; P = 0.03). Cardiac autonomic dysfunction was also independently associated with skin autofluorescence (R2 = 0.11; P = 0.006). CONCLUSIONS: Higher skin autofluorescence is associated with retinopathy and cardiac autonomic dysfunction in adolescents with Type 1 diabetes. The relationship between skin autofluorescence and previous glycaemia may provide insight into metabolic memory. Longitudinal studies will determine the utility of skin autofluorescence as a non-invasive screening tool to predict future microvascular complications.
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ItemAssociations between circulating inflammatory markers, diabetes type and complications in youth(WILEY, 2019-12)BACKGROUND: Inflammation is implicated in the pathogenesis of diabetes and its complications in adults. Little is known about the relative contribution of inflammation in common types of diabetes in youth: type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis-related diabetes (CFRD). This study investigates inflammatory markers by diabetes type and complication status, and assesses indicators of inflammation and complications. METHODS: A cross-sectional study of 134 T1D, 32 T2D, 32 CFRD and 48 subjects without diabetes (including 11 with CF and normal glucose tolerance) was undertaken. Inflammation was assessed by sE-selectin by ELISA, hsCRP by turbidimetry, WCC and ESR. Nephropathy was defined by albuminuria, autonomic neuropathy by heart rate variability, and peripheral neuropathy by vibration and thermal threshold testing and retinopathy by seven-field stereoscopic fundus photography. Descriptive statistics, parametric and non-parametric ANOVA and regression analyses were performed, with significance at P < .05. RESULTS: Of 198 diabetic participants; 49% female, mean (SD) age, median diabetes duration and median HbA1c were 16 (2.5) and 6 (3-9) years, and 8.1 (6.9-9.3)%, respectively. All inflammatory markers were lower in T1D than in other diabetes groups (P < .05) but higher than in non-diabetic controls. T2D (n = 32) and CFRD (n = 32) subjects had comparable elevated levels of inflammation. Body mass index (BMI) was a strong independent explanatory variable of inflammation. In multivariate analysis, hsCRP and ESR were associated with complications in addition to HbA1c, BMI, and diastolic BP. CONCLUSIONS: Circulating inflammatory markers are elevated in adolescents with diabetes, being higher and comparable in T2D and CFRD than in T1D. Inflammation is independently associated with diabetes complications, consistent with inflammation driving vascular pathology in diabetes.
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ItemAttractions and barriers to Australian physician-researcher careers(WILEY, 2019-02)BACKGROUND: There is a global concern that physician-researchers are 'a dying breed'. Recent studies of clinical career choices of Australian medical students and doctors have signalled the rising age of medical graduates, generational shifts in work-life attitudes and increased proportion of female graduates. There are scant data regarding Australian physician-researchers. AIMS: To develop and utilise a questionnaire determining respondent characteristics and 'push' and 'pull' factors for medical graduates to incorporate research into their careers. METHODS: We developed and administered an 88-item online survey, including quantitative and qualitative questions, to medical students, faculty and alumni of Sydney Medical School, The University of Sydney, asking about their medical career, research experience and interest and reasons for doing or not doing medical research. Responses to all 74 quantitative questions are reported here. RESULTS: Data from 427 respondents (44% female; mean ± standard deviation age 38 ± 13 years; 56% completed or undertaking a PhD) were analysed. Attractions of research included a desire to improve human health, intellectual stimulation and career diversity. Barriers included low funding rates, job insecurity and low salaries. Although few were prepared to undertake or recommend full-time research, 71% would recommend part-time research. Respondents perceived a smaller-than-actual gap between clinical and research salaries, and if comparable (75-100% of a clinician's) salaries were available, 89% would like to spend 21-60% of their work time undertaking research. CONCLUSION: Many Australian medical students and doctors are interested in research, especially part time. Perceived obstacles include job insecurity, low funding rates and salary. Respondents underestimated clinical and research salary differences.
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ItemSuboptimal behaviour and knowledge regarding overnight glycaemia in adults with type 1 diabetes is common(WILEY, 2018-09)BACKGROUND: In people with type 1 diabetes (T1D), nocturnal hypoglycaemia (NH) can be slept through and can cause seizures, arrhythmias and death. Hypoglycaemia avoidance can induce hyperglycaemia and ketosis. Patient behaviour impacts clinical outcomes and may be changed by education. AIM: To develop and utilise a survey to evaluate patient self-management of overnight glycaemia in adults with T1D. METHODS: Adults with T1D attending two Australian tertiary referral diabetes clinics completed a survey about their diabetes self-management and glycaemic control, including responses to hypothetical pre-bed blood glucose (BG) levels (4-20 mmol/L). Statistical analyses included t-tests, Chi square tests and ANOVA with significance considered at P < 0.05. RESULTS: There were 205 participants (103 females), with a mean (SD) age of 41 (17) years, T1D duration of 20 (16) years, HbA1c of 7.8(1.4)%, (61.3(8.2) mmol/mol), 38% on insulin pump therapy (CSII) and 36% with impaired hypoglycaemia awareness (IHA). Mean (SD) number of BG tests/day was 5.4 (2.7). Patients set higher BG target levels at bedtime and overnight: 7.5(1.4) and 7.1(1.3) mmol/L, respectively, compared to daytime (6.9(1.0); P < 0.0001 and P = 0.002 respectively). Only 36% of participants reported treating nocturnal hypoglycaemia (NH) with the recommended refined, then complex, carbohydrate. Only 28% of patients made safe choices in all bedtime BG scenarios, with higher rates for CSII users, P = 0.0005. Further education was desired by 32% of respondents, with higher rates in those with (44%) versus without IHA (25%), P = 0.006. CONCLUSIONS: Many adults with T1D have suboptimal knowledge and behaviour regarding overnight BG self-management. A survey, piloted herein, may facilitate the identification of patients who could benefit from further education.
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ItemCross-sectional and longitudinal determinants of serum sex hormone binding globulin (SHBG) in a cohort of community-dwelling men(PUBLIC LIBRARY SCIENCE, 2018-07-11)Despite its widespread clinical use, there is little data available from population-based studies on the determinants of serum sex hormone binding globulin (SHBG). We aimed to examine multifactorial determinants of circulating SHBG levels in community-dwelling men. Study participants comprised randomly selected 35-80 y.o. men (n = 2563) prospectively-followed for 5 years (n = 2038) in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. After excluding men with illness or medications known to affect SHBG (n = 172), data from 1786 men were available at baseline, and 1476 at follow-up. The relationship between baseline body composition (DXA), serum glucose, insulin, triglycerides, thyroxine (fT4), sex steroids (total testosterone (TT), oestradiol (E2)), and pro-inflammatory cytokines and serum SHBG level at both baseline & follow-up was determined by linear and penalized logistic regression models adjusting for age, lifestyle & demographic, body composition, metabolic, and hormonal factors. Restricted cubic spline analyses was also conducted to capture possible non-linear relationships. At baseline there were positive cross-sectional associations between age (β = 0.409, p<0.001), TT (β = 0.560, p<0.001), fT4 (β = 0.067, p = 0.019) and SHBG, and negative associations between triglycerides (β = -0.112, p<0.001), abdominal fat mass (β = -0.068, p = 0.032) and E2 (β = -0.058, p = 0.050) and SHBG. In longitudinal analysis the positive determinants of SHBG at 4.9 years were age (β = 0.406, p = <0.001), TT (β = 0.461, p = <0.001), and fT4 (β = 0.040, p = 0.034) and negative determinants were triglycerides (β = -0.065, p = 0.027) and abdominal fat mass (β = -0.078, p = 0.032). Taken together these data suggest low SHBG is a marker of abdominal obesity and increased serum triglycerides, conditions which are known to have been associated with low testosterone and low T4.
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ItemAdvanced glycation end products acutely impair Ca2+ signaling in bovine aortic endothelial cells(FRONTIERS MEDIA SA, 2013)Post-translational modification of proteins in diabetes, including formation of advanced glycation end products (AGEs) are believed to contribute to vascular dysfunction and disease. Impaired function of the endothelium is an early indicator of vascular dysfunction in diabetes and as many endothelial cell processes are dependent upon intracellular [Ca(2+)] and Ca(2+) signaling, the aim of this study was to examine the acute effects of AGEs on Ca(2+) signaling in bovine aortic endothelial cells (BAEC). Ca(2+) signaling was studied using the fluorescent indicator dye Fura-2-AM. AGEs were generated by incubating bovine serum albumin with 0-250 mM glucose or glucose-6-phosphate for 0-120 days at 37°C. Under all conditions, the main AGE species generated was carboxymethyl lysine (CML) as assayed using both gas-liquid chromatograph-mass spectroscopy and high-performance liquid chromatography. In Ca(2+)-replete solution, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca(2+)] and attenuated the increase in intracellular [Ca(2+)] caused by ATP (100 μM). In the absence of extracellular Ca(2+), exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca(2+)] and attenuated subsequent intracellular Ca(2+) release caused by ATP, thapsigargin (0.1 μM), and ionomycin (3 μM), but AGEs did not affect extracellular Ca(2+) entry induced by the re-addition of Ca(2+) to the bathing solution in the presence of any of these agents. The anti-oxidant α-lipoic acid (2 μM) and NAD(P)H oxidase inhibitors apocynin (500 μM) and diphenyleneiodonium (1 μM) abolished these effects of AGEs on BAECs, as did the IP3 receptor antagonist xestospongin C (1 μM). In summary, AGEs caused an acute depletion of Ca(2+) from the intracellular store in BAECs, such that the Ca(2+) signal stimulated by the subsequent application other agents acting upon this store is reduced. The mechanism may involve generation of reactive oxygen species from NAD(P)H oxidase and possible activation of the IP3 receptor.
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ItemIncreased serum kallistatin levels in type 1 diabetes patients with vascular complications(BIOMED CENTRAL LTD, 2010)BACKGROUND: Kallistatin, a serpin widely produced throughout the body, has vasodilatory, anti-angiogenic, anti-oxidant, and anti-inflammatory effects. Effects of diabetes and its vascular complications on serum kallistatin levels are unknown. METHODS: Serum kallistatin was quantified by ELISA in a cross-sectional study of 116 Type 1 diabetic patients (including 50 with and 66 without complications) and 29 non-diabetic controls, and related to clinical status and measures of oxidative stress and inflammation. RESULTS: Kallistatin levels (mean(SD)) were increased in diabetic vs. control subjects (12.6(4.2) vs. 10.3(2.8) μg/ml, p = 0.007), and differed between diabetic patients with complications (13.4(4.9) μg/ml), complication-free patients (12.1(3.7) μg/ml), and controls; ANOVA, p = 0.007. Levels were higher in diabetic patients with complications vs. controls, p = 0.01, but did not differ between complication-free diabetic patients and controls, p > 0.05. On univariate analyses, in diabetes, kallistatin correlated with renal dysfunction (cystatin C, r = 0.28, p = 0.004; urinary albumin/creatinine, r = 0.34, p = 0.001; serum creatinine, r = 0.23, p = 0.01; serum urea, r = 0.33, p = 0.001; GFR, r = -0.25, p = 0.009), total cholesterol (r = 0.28, p = 0.004); LDL-cholesterol (r = 0.21, p = 0.03); gamma-glutamyltransferase (GGT) (r = 0.27, p = 0.04), and small artery elasticity, r = -0.23, p = 0.02, but not with HbA1c, other lipids, oxidative stress or inflammation. In diabetes, geometric mean (95%CI) kallistatin levels adjusted for covariates, including renal dysfunction, were higher in those with vs. without hypertension (13.6 (12.3-14.9) vs. 11.8 (10.5-13.0) μg/ml, p = 0.03). Statistically independent determinants of kallistatin levels in diabetes were age, serum urea, total cholesterol, SAE and GGT, adjusted r2 = 0.24, p < 0.00001. CONCLUSIONS: Serum kallistatin levels are increased in Type 1 diabetic patients with microvascular complications and with hypertension, and correlate with renal and vascular dysfunction.
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ItemA comparative analysis of high-throughput platforms for validation of a circulating microRNA signature in diabetic retinopathy(NATURE PORTFOLIO, 2015-06-02)MicroRNAs are now increasingly recognized as biomarkers of disease progression. Several quantitative real-time PCR (qPCR) platforms have been developed to determine the relative levels of microRNAs in biological fluids. We systematically compared the detection of cellular and circulating microRNA using a standard 96-well platform, a high-content microfluidics platform and two ultra-high content platforms. We used extensive analytical tools to compute inter- and intra-run variability and concordance measured using fidelity scoring, coefficient of variation and cluster analysis. We carried out unprejudiced next generation sequencing to identify a microRNA signature for Diabetic Retinopathy (DR) and systematically assessed the validation of this signature on clinical samples using each of the above four qPCR platforms. The results indicate that sensitivity to measure low copy number microRNAs is inversely related to qPCR reaction volume and that the choice of platform for microRNA biomarker validation should be made based on the abundance of miRNAs of interest.
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ItemHbA1c variability in adults with type 1 diabetes on continuous subcutaneous insulin infusion (CSII) therapy compared to multiple daily injection (MDI) treatment.(BMJ, 2019-12-29)OBJECTIVE: To determine if continuous subcutaneous insulin infusion (CSII) therapy is associated with lower glycated haemoglobin (HbA1c) variability (long-term glycaemic variability; GV) relative to multiple daily injection (MDI) treatment in adults with type 1 diabetes mellitus (T1DM). DESIGN: Retrospective audit. SETTING AND PARTICIPANTS: Clinic records from 506 adults with T1DM from two tertiary Australian hospitals. OUTCOME MEASURES: Long-term GV was assessed by HbA1c SD and coefficient of variation (CV) in adults on established MDI or CSII therapy, and in a subset changing from MDI to CSII. RESULTS: Adults (n=506, (164 CSII), 50% women, mean±SD age 38.0±15.3 years, 17.0±13.7 years diabetes, mean HbA1c 7.8%±1.2% (62±13 mmol/mol) on CSII, 8.0%±1.5% (64±16 mmol/mol) on MDI) were followed for 4.1±3.6 years. CSII use was associated with lower GV (HbA1c SD: CSII vs MDI 0.5%±0.41% (6±6 mmol/mol) vs 0.7%±0.7% (9±8 mmol/mol)) and CV: CSII vs MDI 6.7%±4.6% (10±10 mmol/mol) vs 9.3%±7.3% (14±13 mmol/mol), both p<0.001. Fifty-six adults (73% female, age 36±13 years, 16±13 years diabetes, HbA1c 7.8%±0.8% (62±9 mmol/mol)) transitioned from MDI to CSII. Mean HbA1c fell by 0.4%. GV from 1 year post-CSII commencement decreased significantly, HbA1c SD pre-CSII versus post-CSII 0.7%±0.5% (8±5 mmol/mol) vs 0.4%±0.4% (5±4 mmol/mol); p<0.001, and HbA1c CV 9.2%±5.5% (13±8 mmol/mol) vs 6.1%±3.9% (9±5 mmol/mol); p<0.001. CONCLUSIONS: In clinical practice with T1DM adults relative to MDI, CSII therapy is associated with lower HbA1c GV.