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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ItemFactors influencing cryopreserved allograft heart valve degeneration( 2006)Heart valve replacement is becoming more commonplace in developed nations. Despite this the ideal valve prosthesis has not been found. The allograft valve has been used for over 40 years and remains an important prosthesis with many advantages. However, like other biological valve prosthesis, they have a finite durability. The causes of allograft valve degeneration are still unknown. The study aims to identify factors associated with cryopreserved allograft valve degeneration. Knowledge of such factors will improve our understanding of the potential causes and mechanisms of allograft heart valve degeneration. (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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ItemPatterns of pain in patients with advanced cancer( 2000)Extensive literature detailing pain in cancer has been published in the past 15 years with point prevalence studies for populations, effects of interventions and general pain management approaches receiving most attention. The experience of pain over time for individual patients has not been studied. There is value in identifying patterns that pain may follow in order to predict future pain levels for a particular patient. Aims: This prospective longitudinal study of patients with cancer, for whom treatment is palliative, seeks to determine if pain reported by patients follows characteristic patterns. The study took place in the context of a larger epidemiological study of symptoms, quality of life, health service utilization and the quality of information regarding cancer and treatment for patients and their carers. Within this epidemiological study, an observational study of pain intensity, characteristics and analgesic levels was undertaken over a 6 month period. The investigators enrolled 202 participants, with 165 participants completing data for evaluation. Method: Data series were examined as a whole group, then individual participants' time series data were examined for visual and mathematical patterns. A series of mathematical models were fitted to successive pain scores based on the assumption that current pain scores are not independent of previous pain scores. Results: As a group, mean pain levels did not alter over the 6 months, but differences between individuals within the group were marked. Considered as a whole, 20.50/0 reported using paracetamol at assessment, and just 16.3% used slow release morphine. Visual examination of pain levels over time revealed three broad groups of patients: those for whom pain scores were always high, those for whom pain scores were always low, and those who had fluctuating pain scores. Those with consistently high pain scores were more likely to have bone metastases (p <0.05), arthritis (p <0.005), to describe pain as burning (p <0.003), stabbing (p <0.001), present with light touch (p <0.001), than the fluctuating or consistently low pain scores groups. In addition these patients used more paracetamol, codeine, slow release morphine and morphine mixture (p < 0.001), though not nonsteroidal anti-inflammatory drugs. There was no significant difference in gender, treatments planned or survival between the groups. A series of mathematical models were fitted to each individuals’ time series data in an attempt to simply describe patterns within the data. The model that most followed the plotted data points with the least variation of points from that model was a 'cubic' pattern for 95% of patients. This pattern is best described as fluctuating, typically with an initial increase of pain early in the study, followed by some lessening of pain, to again increase more steeply towards the end of the study. The degree to which this model 'fitted' or the mean residual square value for all time series ranged from r2=0.02 - 1.0 (median r2=0.38, mode r2=1.0). For 22 subjects the mean residual square value for cubic modeling was r2=0.8 or greater indicating an excellent correlation between the data and the model. These patients were significantly more likely to be treated with radiotherapy (p <0.01), codeine (p <0.05) and morphine mixture (p <0.05), and had a poorer ECOG performance status (p <0.001) and shorter survival (p <0.05) than the other patients. Therefore a cubic model may assist to predict future pain levels for patients with poor performance status. Clinical Implications: The results of this study have implications for the clinician caring for patients with advanced cancer, enabling forecasting of likely future pain levels for a particular patient. This information will assist when planning analgesic interventions, frequency of consultations and resource allocation for a patient, as well as interpreting information gleaned from analgesic trials. Conclusion: Mean pain scores for a whole population with advanced cancer do not change considerably with time, but for individuals marked fluctuations are apparent. Patients with a poor performance status, arthritis, bone metastases and describing certain pain descriptors are more likely to have consistently high pain levels. For 95% of patients a cubic function model best fitted their time series data, and this model is likely to be most reliable in forecasting pain levels when patients have a poor performance status.
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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.
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ItemOver-expression of human CD39 in mouse liver protects against ischemia reperfusion injury in a model of liver transplantation( 2009)Primary graft non-function is one of the major limitations of organ transplantation increasing the risk of rejection and early graft failure. A major cause of primary non-function is ischemia reperfusion injury (IRI), an obligatory insult in transplantation. During procurement, the donor is subjected to a period of ischemia inducing the release of tissue-damaging factors such as nitric oxide and reactive oxygen species. Upon engraftment and reperfusion with the recipient blood, these ischemia-induced factors cause rapid cell death and amplification of the inflammatory response leading to further tissue damage. CD39 is an integral vascular and immune ectonucleotidase. CD39 hydrolyses extracellular nucleotides ATP and ADP into AMP, which is then hydrolysed into adenosine by CD73. Extracellular adenosine produced by the concerted action of CD39 and CD73 has potent anti-inflammatory and anti-coagulation effects acting principally via the purinergic adenosine receptor A2a. NKT cells have only recently been recognised and constitute an important subset of T lymphocytes that display both effector and suppressive functions. NKT cells are found in high proportion in the liver of mice and are implicated by depletion studies in protection against hepatic IRI. We have generated mice transgenic for human CD39 (hCD39) and have shown they have an anti-coagulant phenotype. As CD39 is also critical to immune regulation we hypothesised that transgenic expression of hCD39 would modify lymphocyte development and/or function and consequently impact on ischemia reperfusion injury. Flow cytometric analysis was used to assess the number and phenotype of lymphocytes within the thymus and in the periphery of hCD39 transgenic mice. In vitro and in vivo assays were used to test the function of CD4+ T cells and invariant NKT cells from hCD39 transgenic mice. Bone marrow adoptive transfers experiments defined the role of hCD39 expression on bone marrow progenitor cells in comparison to tissue expression. The importance of adenosine signalling through the A2a receptor was studied by crossing hCD39 transgenic mice with A2a receptor knock-out (KO) mice. The effect of hCD39 expression on ischemia reperfusion injury was evaluated in a model of murine liver transplantation A high level of hCD39 expression in the transgenic thymus resulted in lymphocyte maturation blockade and peripheral lymphopenia of CD4+ T cells and invariant NKT cells. Both lymphocyte populations were functionally deficient. The observed phenotype resulted from the expression of hCD39 on bone marrow progenitor cells but was independent of A2a receptor signalling. Over-expression of hCD39 in transgenic livers was protective against ischemia reperfusion injury induced by cold storage and liver transplantation.