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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ItemNo Preview AvailableHuman immune responses to infective stage larval-specific chitinase of filarial parasite, Onchocerca volvulus, Ov-CHI-1.(Springer Science and Business Media LLC, 2003-03-14)BACKGROUND: Ov-CHI-1 is a chitinase specifically expressed in the infective stage larvae of the human filarial parasite Onchocerca volvulus. Evidence has show that it could be a vaccine candidate, however, there is no data available regarding the immunological status of people naturally exposed to infective stage larvae and thus provoked by this antigen. METHOD: We analysed the Ov-CHI-1-specific immune response present in four endemic foci of human onchocerciasis (Ecuador, Nigeria, Togo and Cameroon) by enzyme-linked immunosorbent assays and T-cell proliferation assays. RESULTS: In these foci of infection, antibodies to Ov-CHI-1 were found to be present in only 22% of individuals from Ecuador, but were detected in 42-62% of infected individuals in the three foci from West Africa (Nigeria, Togo and Cameroon). There was found to be no relationship between antibody level and age, gender, or infection intensity as indicated by microfilarial density and numbers of skin nodules. The isotype response to Ov-CHI-1 was dominated by the presence of IgG3, IgG1 was present to a lesser extent. Our results show a positive correlation between N- and C-termini of Ov-CHI-1 in their ability to provoke humoral and cellular immune responses in the human. Peripheral blood mononuclear cell (PBMC) proliferative responses to Ov-CHI-1 when assayed, were found to be significantly higher in the individuals from endemic areas and there was a statistically elevated response to Ov-CHI-1 in the infected individuals when compared to putative immune individuals. CONCLUSION: Ov-CHI-1 is an antigen that we have found strongly induces both humoral and cellular immune responses in humans.
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ItemPPAR Agonists and Cardiovascular Disease in Diabetes(HINDAWI LTD, 2008)Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.
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ItemTim-2 regulates T helper type 2 responses and autoimmunity.(Rockefeller University Press, 2005-08-01)Identification of the T cell immunoglobulin mucin-domain containing (Tim) gene family introduced a new family of cell surface molecules that is involved in the regulation of immune responses. We previously demonstrated that Tim-3 is expressed on terminally differentiated T helper (Th)1 cells, and serves to regulate Th1 immune responses. Here, we describe the identification and function of Tim-2, a novel member of the Tim gene family. In contrast with Tim-3, we demonstrate that Tim-2 is expressed preferentially in differentiated Th2 cells. Blockade of the Tim-2/Tim-2 ligand interaction, by administration of soluble Tim-2 fusion protein (Tim-2 immunoglobulin [Ig]), results in T cell hyperproliferation and the production of Th2 cytokines. Administration of Tim-2 Ig during the induction phase reduces the severity of experimental autoimmune encephalomyelitis, a Th1-mediated autoimmune disease model of multiple sclerosis. We propose that Tim-2, an orthologue of human Tim-1, is critical for the regulation of Th2 responses during autoimmune inflammation.
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ItemNo Preview AvailableOligonucleotide array for simultaneous detection of respiratory viruses using a reverse-line blot hybridization assay(WILEY-LISS, 2005-06)The interest in developing new diagnostic methods based on arrays of multiple probes to detect and type simultaneously a wide range of different infectious agents is increasing. This becomes a necessity in the case of infectious agents such as respiratory viruses that cause diseases with very similar signs and symptoms. Such tools will permit rapid and accurate diagnosis of different agents causing respiratory infection leading to the most adequate prevention and/or treatment measures. In this article a reverse-line blot hybridization (RLB) assay for the detection of a wide range of respiratory viruses is presented and evaluated for its usefulness in routine diagnosis. This assay employs an array of 18 oligonucleotide probes immobilized on a nylon membrane. Biotin-labeled PCR products obtained with two multiplex reverse transcription (RT)-polymerase chain reaction (PCR) assays described previously, which allow for the detection of fourteen different groups of respiratory viruses, were hybridized to the oligonucleotide array. Detection was performed using a chemiluminescent method. The standardization of the method showed that the RLB assay could be an alternative to the nested PCR assay for enhancing the sensitivity in the detection of the amplified products, avoiding the problem of cross-over contamination, increasing the specificity, and therefore simplifying the method. This is of main interest in laboratories with few facilities. The feasibility and accuracy of the RT-PCR-RLB assay for detecting respiratory viruses proves that such approach could be a first stage to develop a microarray assay for routine diagnosis of infectious diseases.
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ItemNo Preview AvailableCan physical activity improve the mental health of older adults?(Springer Science and Business Media LLC, 2004-06-29)The world population is aging rapidly. Whilst this dramatic demographic change is a desirable and welcome phenomenon, particularly in view of people's increasing longevity, it's social, financial and health consequences can not be ignored. In addition to an increase of many age related physical illnesses, this demographic change will also lead to an increase of a number of mental health problems in older adults and in particular of dementia and depression. Therefore, any health promotion approach that could facilitate introduction of effective primary, secondary and even tertiary prevention strategies in old age psychiatry would be of significant importance. This paper explores physical activity as one of possible health promotion strategies and evaluates the existing evidence that supports its positive effect on cognitive impairment and depression in later life.
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ItemNo Preview AvailableOsteoporosis in men: its pathophysiology and the role of teriparatide in its treatment(DOVE MEDICAL PRESS LTD, 2008)As the population ages, the burden of osteoporosis in men is expected to rise. Implementation of preventive measures such as falls prevention strategies, exercise and adequate calcium and vitamin D intake is recommended. However, when the diagnosis of osteoporosis is made, effective treatments need to be initiated to prevent fractures. As opposed to postmenopausal women, reduced bone formation is the predominant mechanism of age-related bone loss in men, making anabolic agents a logical treatment option for men with osteoporosis. Teriparatide is the only anabolic agent currently approved for treatment of osteoporosis in men. This paper summarizes the mechanism of action of teriparatide, as well as its tolerability and safety. Furthermore, the evidence supporting the efficacy of teriparatide treatment in men with osteoporosis is reviewed and its current role in the management of osteoporosis in men is discussed.
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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.