Melbourne Medical School Collected Works - Research Publications
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ItemA new technique for assessing arterial pressure wave forms and central pressure with tissue Doppler.(Springer Science and Business Media LLC, 2007-01-31)BACKGROUND: Non-invasive assessment of arterial pressure wave forms using applanation tonometry of the radial or carotid arteries can be technically challenging and has not found wide clinical application. 2D imaging of the common carotid arteries is routinely used and we sought to determine whether arterial waveform measurements could be derived from tissue Doppler imaging (TDI) of the carotid artery. METHODS: We studied 91 subjects (52 men, age 52 +/- 14 years) with and without cardiovascular disease. Tonometry was performed on the carotid artery simultaneously with pulsed wave Doppler of the LVOT and acquired digitally. Longitudinal 2D images of the common carotid artery with and without TDI were also acquired digitally and both TDI and tonometry were calibrated using mean and diastolic cuff pressure and analysed off line. RESULTS: Correlation between central pressure by TDI and tonometry was excellent for maximum pressure (r = 0.97, p < 0.0001). The mean differences between central pressures derived by TDI and tonometry were minimal (systolic 5.36 +/- 5.5 mmHg; diastolic 1.2 +/- 1.2 mmHg). CONCLUSION: Imaging of the common carotid artery motion with tissue Doppler may permit acquisition of a waveform analogous to that from tonometry. This method may simplify estimation of central arterial pressure and calculation of total arterial compliance.
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ItemReceptor for advanced glycation end products Glycine 82 Serine polymorphism and risk of cardiovascular events in rheumatoid arthritis(BIOMED CENTRAL LTD, 2007)Patients with rheumatoid arthritis (RA) are at risk of excess mortality, predominantly owing to cardiovascular (CV) events. The receptor for advanced glycation end products (RAGE) has been implicated in the perpetuation of the chronic inflammatory response in vascular disease. A Gly82-->Ser polymorphism in the RAGE gene, which is associated with enhanced RAGE signaling, is present more frequently in patients with RA than the general population. To investigate whether RAGE Gly82-->Ser polymorphism is associated with CV events in RA, we examined CV events, CV risk factors, features of RA and RAGE Gly82-->Ser polymorphism in 232 patients with RA attending a tertiary referral hospital. CV events, the duration and severity of RA, and risk factors for CV disease were determined using patient questionnaires, chart review, laboratory analysis and radiographs. DNA was typed for HLA-DRB1 genes and RAGE Gly82-->Ser polymorphism. The RAGE Ser82 allele, which is in linkage disequilibrium with the RA susceptibility allele HLA-DRB1*0401, was carried by 20% of patients. More than 20% of the cohort had suffered a vascular event; a shorter duration of RA, but not the RAGE genotype, was significantly associated with CV events. However, a history of statin use was protective. Thus, the RAGE Ser82 allele, associated with enhanced RAGE signaling, does not predispose to CV events in RA. However, treatment of hyperlipidemia with statins reduces the probability of a CV event.
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ItemTissue Doppler in critical illness: a retrospective cohort study(BIOMED CENTRAL LTD, 2007)BACKGROUND: There is a paucity of published data on tissue Doppler imaging (TDI) in the critically ill. In a critically ill cohort, we studied the distribution of TDI and its correlation with other echocardiographic indices of preload. To aid hypothesis generation and sample size calculation, associations between echocardiographic variables, including the ratio of peak early diastolic transmitral velocity (E) to peak early diastolic mitral annular velocity (E'), and mortality were also explored. METHODS: This retrospective study was performed in a combined medical/surgical, tertiary referral intensive care unit. Over a 2-year period, 94 consecutive patients who underwent transthoracic echocardiography with E/E' measurement were studied. RESULTS: Mean Acute Physiology and Chronic Health Evaluation III score was 72 +/- 25. Echocardiography was performed 5 +/- 6 days after intensive care unit admission. TDI variables exhibited a wide range (E' 4.7-18.2 cm/s and E/E' 3.3 to 27.2). E' below 9.6 cm/s was observed in 63 patients (rate of myocardial relaxation below lower 95% confidence limit of normal individuals). Fourteen patients had E/E' above 15 (evidence of raised left ventricular filling pressure). E/E' correlated with left atrial area (r = 0.27, P = 0.01) but not inferior vena cava diameter (r = 0.16, P = 0.21) or left ventricular end-diastolic volume (r = 0.16, P = 0.14). In this cohort, increased left ventricular end-systolic volume, but not E/E', appeared to be an independent predictor (odds ratio 2.1, P = 0.007) of 28-day mortality (31%; n = 29). CONCLUSION: There was a wide range of TDI values. TDI evidence of diastolic dysfunction was common. E/E' did not correlate strongly with other echocardiographic indices of preload. Further evaluation of echocardiographic variables, particularly left ventricular end-systolic volume, for risk stratification in the critically ill appears warranted.
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ItemAtherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation(BIOMED CENTRAL LTD, 2007)Rheumatoid arthritis (RA) patients have increased mortality and morbidity as a result of cardiovascular and cerebrovascular disease. What is not clear, however, is either how early accelerated atherosclerosis begins in RA or how soon risk factors must be rigorously controlled. Furthermore, given the strong relationship of vascular disease to RA mortality and of inflammation to the accelerated atherosclerosis associated with RA, it is important to evaluate indices that could serially and noninvasively quantify atherosclerotic disease in RA patients. The carotid intima-media thickness (cIMT) and plaque, measured by ultrasound, correlate closely with direct measurement of the local and systemic atherosclerotic burden. To investigate the presence of subclinical atherosclerosis in the early stages of RA, the cIMT and plaque were measured using carotid duplex scanning in 40 RA patients with disease duration < 12 months and in 40 control subjects matched for age, sex and established cardiovascular risk factors. Patients with RA had significantly higher average cIMT values and more plaque than the control group (cIMT 0.64 +/- 0.13 mm versus 0.58 +/- 0.09 mm, respectively; P = 0.03). In RA patients, the cIMT was predicted by age and C-reactive protein level at first presentation to the clinic (R2 = 0.64). C-reactive protein was associated with age of disease onset and history of smoking. Since inflammation has been shown to predate onset of clinical RA, the accelerated atherogenic process related to inflammation may precede RA symptom onset.
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ItemSYMBIOmatics: Synergies in Medical Informatics and Bioinformatics - exploring current scientific literature for emerging topics(BMC, 2007)BACKGROUND: The SYMBIOmatics Specific Support Action (SSA) is "an information gathering and dissemination activity" that seeks "to identify synergies between the bioinformatics and the medical informatics" domain to improve collaborative progress between both domains (ref. to http://www.symbiomatics.org). As part of the project experts in both research fields will be identified and approached through a survey. To provide input to the survey, the scientific literature was analysed to extract topics relevant to both medical informatics and bioinformatics. RESULTS: This paper presents results of a systematic analysis of the scientific literature from medical informatics research and bioinformatics research. In the analysis pairs of words (bigrams) from the leading bioinformatics and medical informatics journals have been used as indication of existing and emerging technologies and topics over the period 2000-2005 ("recent") and 1990-1990 ("past"). We identified emerging topics that were equally important to bioinformatics and medical informatics in recent years such as microarray experiments, ontologies, open source, text mining and support vector machines. Emerging topics that evolved only in bioinformatics were system biology, protein interaction networks and statistical methods for microarray analyses, whereas emerging topics in medical informatics were grid technology and tissue microarrays. CONCLUSION: We conclude that although both fields have their own specific domains of interest, they share common technological developments that tend to be initiated by new developments in biotechnology and computer science.
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ItemCOMT Val158Met and 5HTTLPR functional loci interact to predict persistence of anxiety across adolescence:: results from the Victorian Adolescent Health Cohort Study(BLACKWELL PUBLISHING, 2007-10)We investigated whether a composite genetic factor, based on the combined actions of catechol-O-methyltransferase (COMT) (Val(158)Met) and serotonin transporter (5HTTLPR) (Long-Short) functional loci, has a greater capacity to predict persistence of anxiety across adolescence than either locus in isolation. Analyses were performed on DNA collected from 962 young Australians participating in an eight-wave longitudinal study of mental health and well-being (Victorian Adolescent Health Cohort Study). When the effects of each locus were examined separately, small dose-response reductions in the odds of reporting persisting generalized (free-floating) anxiety across adolescence were observed for the COMT Met(158) [odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76-0.95, P = 0.004] and 5HTTLPR Short alleles (OR = 0.88, CI = 0.79-0.99, P = 0.033). There was no evidence for a dose-response interaction effect between loci. However, there was a double-recessive interaction effect in which the odds of reporting persisting generalized anxiety were more than twofold reduced (OR = 0.45, CI = 0.29-0.70, P < 0.001) among carriers homozygous for both the COMT Met(158) and the 5HTTLPR Short alleles (Met(158)Met + Short-Short) compared with the remaining cohort. The double-recessive effect remained after multivariate adjustment for a range of psychosocial predictors of anxiety. Exploratory stratified analyses suggested that genetic protection may be more pronounced under conditions of high stress (insecure attachments and sexual abuse), although strata differences did not reach statistical significance. By describing the interaction between genetic loci, it may be possible to describe composite genetic factors that have a more substantial impact on psychosocial development than individual loci alone, and in doing so, enhance understanding of the contribution of constitutional processes in mental health outcomes.
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ItemVariation in the gene coding for the M5 Muscarinic receptor (CHRM5) influences cigarette dose but is not associated with dependence to drugs of addiction:: evidence from a prospective population based cohort study of young adults(BMC, 2007-07-03)BACKGROUND: The mesolimbic structures of the brain are important in the anticipation and perception of reward. Moreover, many drugs of addiction elicit their response in these structures. The M5 muscarinic receptor (M5R) is expressed in dopamine-containing neurones of the substantia nigra pars compacta and ventral tegmental area, and regulates the release of mesolimbic dopamine. Mice lacking M5R show a substantial reduction in both reward and withdrawal responses to morphine and cocaine. The CHRM5, the gene that codes for the M5R, is a strong biological candidate for a role in human addiction. We screened the coding and core promoter sequences of CHRM5 using denaturing high performance liquid chromatography to identify common polymorphisms. Additional polymorphisms within the coding and core promoter regions that were identified through dbSNP were validated in the test population. We investigated whether these polymorphisms influence substance dependence and dose in a cohort of 1947 young Australians. RESULTS: Analysis was performed on 815 participants of European ancestry who were interviewed at wave 8 of the cohort study and provided DNA. We observed a 26.8% increase in cigarette consumption in carriers of the rs7162140 T-allele, equating to 20.1 cigarettes per week (p=0.01). Carriers of the rs7162140 T-allele were also found to have nearly a 3-fold increased risk of developing cannabis dependence (OR=2.9 (95%CI 1.1-7.4); p=0.03). CONCLUSION: Our data suggest that variation within the CHRM5 locus may play an important role in tobacco and cannabis but not alcohol addiction in European ancestry populations. This is the first study to show an association between CHRM5 and substance use in humans. These data support the further investigation of this gene as a risk factor in substance use and dependence.
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ItemMitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau(PUBLIC LIBRARY SCIENCE, 2007-06-20)Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and beta-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Ass load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.
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ItemNegotiating meanings and scaffolding learning: writing support for non-english speaking background postgraduate students(Informa UK Limited, 2007-01-01)