Medicine (St Vincent's) - Theses
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ItemThe doctor as moral agent, with reference to the distinction between killing and "letting die"( 2007-07)In the bioethics literature, arguments about the nature of the distinction between killing and “letting die” seem irresolvable. There is a disparity between the dominant (consequentialist) opinion on this issue and that of the medical profession. No previous studies have investigated how doctors who work with the dying understand the distinction in the medical context. The aim of my research was to explore the moral reasoning of these clinicians in relation to this question. A focused ethnographic study involved thirty Melbourne doctors (thirteen palliative care physicians, nine oncologists, six intensivists, and two advocates of physician-assisted suicide) of whom eighteen were male and twelve female, with an age range from 31 to 77 years. Half had a religious belief (Jewish or Christian) and half were atheist/agnostic. (For complete abstract open document)
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ItemSmall animal models of Gal-mediated and xenograft rejection( 2004-11)Xenotransplantation is the final frontier of using vascularised organs or cellular grafts to treat end-organ disease and offers a potential solution to the worldwide shortage of human tissue available for transplantation. The main immunological barrier to xenografting from pig-to-primate is the antigen, Galactose-α1,3-Galactose (Gal) which is found in all species except humans and other higher primates. Even with the major advancement of deleting Gal from the potential pig donor species with the aid of cloning technology, complete elimination may be elusive as alternative genes yet to be fully characterised, may still produce Gal at low levels. Thus, the human immune response against Gal may continue to be a barrier to successful xenotransplantation. The aim of this project was to develop small animal models of the important components of xenograft rejection that largely relate to the anti-Gal immune response. These include models of hyperacute, acute vascular and chronic xenograft-like rejection that in turn, provide new insights in the immune mechanisms of the rejection processes. The role of antibody and both innate and cognate cellular immunity are explored. Both vascularised heart grafts and non-vascularised skin graft models are examined as rejection of solid organs may differ from cellular transplantation. The project also provides a platform for future studies in testing genetic and pharmacotherapeutic strategies to overcome the rejection processes uncovered.
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ItemCoaching patients on achieving cardiovascular health: the COACH program a patient targeted strategy for the secondary prevention of coronary heart disease( 2002)It is well recognised that there is a treatment gap in the management of risk factors in coronary heart disease (CHD) - a gap between what is known from published evidence and what is actually practised. Despite major advances in scientific evidence for aggressive risk factor management, only a minority of patients with CHD are achieving the target levels for their modifiable coronary risk factors. Strategies to address the treatment gap have been usually aimed at the physician and these have often been ineffective. Few strategies have been directed at the patient. Patient targeted strategies can be subdivided into those that permit the prescribing of medication ('competitive' with usual care) such as secondary prevention clinics or disease management programs, and those where support staff do not have prescribing rights ('cooperative' with usual care). Although intuitively it may appear that any program providing attention to patients would result in improvements in risk factor levels, published work shows that only the competitive programs resulted in significant improvement in coronary risk factor status. All of the cooperative programs failed to effect an improvement in risk factor status. While competitive programs are clearly effective, they risk alienating usual medical care and in a competitive environment may be counterproductive. There is a role for a cooperative program in an environment where primary care is competitive. This has been the rationale for the development of The Coach Program to bridge the treatment gap in CI-ID. The Coach Program was not founded on sociological or psychological theory. It is an empirical technique developed by the PhD Candidate on the basis of the Candidate's experience as a secondary school teacher. Although there is no coherent theory of coaching, coaching has been used in clinical medicine to improve doctor-patient interaction in the consultation process, assist patients to cope with painful procedures, for exercise training of patients to improve medical conditions and in staff teaching. Thus far, coaching has not been applied and evaluated in chronic disease management such as for the achievement of specific secondary prevention goals. The Coach Program is a training program for patients with CHD in which a health professional coach trains patients to aggressively pursue the target levels for their particular coronary risk factors. The coach is hospital-based and uses the telephone and mailouts to provide regular coaching sessions to patients after discharge from hospital. Coaching is directed at the patient and not at the treating doctor. Patients are coached to know their risk factor levels, know the target levels for their risk factors and how to achieve the target levels for their risk factors. Patients are persuaded to go to their own doctor(s) and ask for appropriate prescription of medication(s). Coaching also trains patients to follow appropriate lifestyle measures. The Coach Program has been validated by two randomised controlled trials. Pilot project carried out at St. Vincent's Hospital only by the PhD Candidate, a qualified dietitian. This study targeted cholesterol levels only, with the aim of achieving a TC < 4.5 mmol/L. At the end of the 6 month intervention, 107 patients who were coached achieved a mean TC (95%CI) of 5.00 (4.82-5.17) mmol/L versus 5.54 (5.36-5.72) mmol/L in 112 usual care patients (P<0.0001). Multivariate analysis showed that being coached was of equal magnitude in its effect on TC as was prescription of lipid-lowering medication. The Coach Program achieved a significantly greater ΔTC than usual care alone: mean ΔTC (95%CI) 0.54 (0.42 to 0.65) mmol/L (n=398) in The Coach Program group versus 0.18 (0.07 to 0.29) mmol/L (n=394) in the usual care group (P<0.0001). Thus, the reduction in TC from baseline to 6 months post-randomisation was 0.36 (95%CI: 0.20 to 0.52) mmol/L greater in The Coach Program group than in the usual care group. Coaching produced substantial improvements in most of the other coronary risk factors and in the patient's quality of life. The results of these two randomised controlled trials prove that coaching, delivered as The Coach Program, is a highly effective strategy in reducing TC and many other coronary risk factors in patients with CHD.
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ItemMetabolic consequences of lipid-oversupply in key glucoregulatory tissues.( 2009)Obesity and type 2 diabetes are the most prevalent metabolic diseases in the western world and affect over 50% of the world’s population. During obesity non-adipose tissues such as the liver and skeletal muscle take up and store excess fatty acids (FA) as lipids such as triacylglycerols (TAG) and diacylglycerols (DAG). Excessive lipid storage in non-adipose tissues can result in the dysfunction of cellular processes and lead to programmed cell death (apoptosis). Lipid-induced apoptosis was investigated in the key glucoregulatory tissues, the liver and skeletal muscle. Lipid-induced apoptosis was detected in vitro in both hepatocytes and myotubes but was not detected in the livers or skeletal muscles of genetically obese mice or high-fat fed mice. Further investigation discovered despite exacerbated TAG accumulation, endoplasmic reticulum stress (ER) was not activated in the liver and pathways of cellular remodelling (proteolysis and autophagy) were not initiated in skeletal muscle. These studies demonstrated that the liver and skeletal muscle are adaptable to increased lipid storage in physiological models but not isolated cell culture systems. In vitro experiments demonstrated unsaturated FAs could protect hepatocytes from lipoapoptosis and it has been suggested this is due to driving FA accumulation into TAG lipid droplets. Adipose triglyceride lipase (ATGL) is one of the primary TAG lipases. To explore TAG metabolism in the liver, primary hepatocytes were derived from ATGL null mice and ATGL was over-expressed in the livers of chronically obese mice. It was found that cellular FA uptake and TAG esterification was increased and TAG lipolysis and FA oxidation were decreased in the ATGL null hepatocytes. This resulted in exacerbated TAG and diacylglycerol (DAG) storage. The gene expression of metabolic regulators such as cytochrome c oxidase subunit 2 (COX2), medium chain acyl Co-A dehydrogenase (MCAD), peroxisome proliferators-activated receptor co-activator 1! (PGC1!), nuclear respiratory factor 1 (NRF1) and FA translocase/cluster of differentiation 36 (FAT/CD36) were increased in ATGL null hepatocytes compared with wild type hepatocytes, suggesting that the reduction in FA oxidation in the ATGL null hepatocytes was probably due to limited FA substrate availability. Interestingly, despite increased TAG and DAG, the hepatocytes remained insulin sensitive. To investigate hepatic ATGL over-expression an adenovirus containing an ATGL insert was injected into chronic high fat fed mice. Hepatic ATGL over-expression in the iii chronically obese mice reduced TAG, DAG and ceramide content in the liver. This resulted in improved hepatic insulin signalling and whole body insulin sensitivity. In summary, studies from this thesis suggested the use of in vitro systems are not a substitute for in vivo models when assessing the toxic effects of lipid oversupply, TAG accumulation may be a protective mechanism against cellular remodelling and programmed cell death, and increased ATGL expression in the liver can reduce hepatic steatosis and enhance whole body insulin sensitivity. Therefore, increasing hepatic ATGL expression could be a therapeutic approach to treat obesity and type 2 diabetes.