2002 Projects - 10 projects, $81,554 The role of SPARC in inflammatory bowel disease Chief Investigator: Dr I Lawrance Amount Awarded: $9,991.00 Crohn's Disease (CD) is a life-long, chronic, relapsing condition that involves the full-thickness of the bowel wall in young adults, and often leads to scarring and bowel obstruction. SPARC (Secreted Protein Acidic and Rich in Cysteine) - is a protein that is transiently expressed in actively inflamed tissue and is associated with wound healing. The central hypothesis of this project was that SPARC might influence the formation of scar tissue in the inflamed bowel, and they investigated this by two specific aims - 1) is SPARC present in greater or lesser amounts in the scarred bowel or is there no correlation with the presence of scarring?, and 2) does SPARC change the way the cells behave so that they are more or less likely to produce the scarring of the bowel? Bowel specimens were examined for the amount of SPARC and this was correlated to the amount of collagen and scarring present in each specimen. Specimens were taken from inflamed, scarred Crohn's Disease as well as normal bowel, inflamed, non-scarred ulcerative colitis as well as scarred diverticular disease and inflamed ischaemic bowel. The cells primarily responsible for scar formation (the fibroblast) were grown in culture and exposed to SPARC, PMA, indomethacin and retinoic acid to determine the effect that each of these agents had on the propensity for scar formation. SPARC levels of RNA were greater in inflamed non-scarred ulcerative colitis when compared to scarred Crohn's Disease and control colonic tissue, suggesting a protective role for SPARC against scarring. In inflamed tissues, the protein levels of SPARC were greater when there was no scarring than if scarring was present - SPARC expression was inversely related to the level of scarring. This was true for inflamed Ulcerative Colitis compared to fibrosed Crohn's Disease and inflamed ischaemic bowel compared to scarred diverticular disease. At the time of going to print, the fibroblast cells have been exposed with the same agents but the examination was ongoing. These results support the hypothesis that SPARC regulates scar formation and further tests will be conducted. Factors Influencing Ineffective Anticoagulation During Open Heart Surgery Chief Investigators: Dr B Dale, Dr M Leahy, Dr E Avraamides Amount Awarded: $8,960 A bypass pump is usually used during cardiac surgery to perform the functions of the heart and lungs while surgery is performed on the heart. Contact of the blood with the pump is sufficient to cause clotting and to prevent blood coagulation, a substance called heparin is used. Some individuals are resistant to the effects of heparin, creating difficulties for the surgical team and higher risk for the patient. The cause of heparin resistance is currently unclear. This project aimed to investigate the role of two blood proteins that may be important in the development of heparin resistance in cardiac bypass surgery patients. Blood samples were collected from consenting patients scheduled for cardiac bypass surgery at four pre-determined time points, both before and during bypass surgery. Preliminary evaluation of the obtained data revealed that findings were consistent with those obtained in a previous pilot project. Both low plasma ATIII and high PF4 levels contribute to the development of heparin resistance during cardiac bypass. However, the combination of both low plasma ATIII and high plasma PF4 levels creates a strong predisposition to developing heparin resistance. Occasional exceptions were found suggesting that other heparin binding proteins may also exert an influence. Consistently very high levels of PF4 were found in fresh frozen plasma (FFP), a blood product that is sometimes used to treat heparin resistance. The findings of this project suggest that the use of FFP may be contra-indicated in the treatment of heparin resistance and a paper will shortly be published on these results. Due to time constraints, aspects of the project looking at the development of a plasma product with low levels of PF4 were not investigated, but this would be a logical developmental or "spin-off" project. Measuring Patient Responses to New Drugs for Treating Dementia Using Nuclear Medicine Brain Scans Chief Investigators: Dr S Maher, Dr R Clarnette, A/Prof JH Turner, Dr W MacDonald Amount Awarded: $10,000 New drugs are available to treat the symptoms of dementia due to Alzheimer's disease but these can cause side effects and don't help everyone. The researchers believed that nuclear medicine brain scans may be able to predict which patients will respond to the drugs as well as helping with the initial diagnosis of dementia. Patients seen in a Memory Clinic for possible early Dementia were assessed with a full history, examination, psychological tests and assessments of abnormal behaviour and daily living skills. Evaluation also included a CT scan of the brain and a nuclear medicine scan showing blood flow within the brain to distinguish Alzheimer's Disease from other types of dementia. Patients were treated with medication (cholinesterase inhibitors) according to standard management guidelines. Patients were reassessed after 2, 6 and 12 months, including a nuclear medicine scan. Patients are still being followed in the study which extends over two years. Recruiting patients has proved more difficult than anticipated. 18 patients have taken part in the study. One patient has had all 4 scans and the remainder are still due for follow up. Most patients have had 2 or 3 scans so far. Technical problems delayed analysis of the nuclear medicine scans, but these have nearly all been resolved. No conclusions will be available until all follow up nuclear medicine scans are completed in late 2003. We hope that the project will allow prediction of which patients will respond to medication. Results should be presented at the Australian Society for Geriatric Medicine Annual Scientific Meeting in 2004. This study has encouraged many new referrals for nuclear medicine brain scanning that were not part of this study. This will allow the formulation of a database derived from local patients of the right age that will be helpful for diagnosing early dementia. A 12 month follow up scan in the form of a clinical audit is planned for these patients, resulting in another complimentary study. Treatment of the Fixed Kangaroo Aortic Wall Tissue with Anticalcification Agents Chief Investigator: Dr WML Neethling, Dr A Hodge Amount Awarded: $6,078 Diseased heart valves of patients are usually replaced with frame-mounted mechanical or fixed biological heart valves, or biological heart valves without a frame. Valves without a frame contain part of the main vessel called the aorta. The aorta is highly susceptible to calcification (hardening) which reduces the life-span of such a valve. The aim of this study was to treat the kangaroo aortic wall tissue with an amino acid, an alcohol and a metal ion in order to reduce the calcification potential. The study involved harvesting of kangaroo heart valve tissue, treatment of these tissues with the anticalcification solution, implantation into a rat model, retrieval after 8 weeks, determination of calcium levels in the tissue and microscopic examination of the tissue to determine the presence of calcification deposits. Calcium levels of treated tissue samples were reduced by 95%, confirmed by microscopic examination. The researchers concluded that their method of treatment was successful in reducing calcification of the aortic wall, and therefore this method could be used in future treatment of bioprosthetic heart valve tissue which should increase the lifespan of such a heart valve. A prospective electrocardiograph study of silent myocardial ischaemia, dysrhythmias and QT interval abnormalities in a community-based cohort of diabetic patients Chief Investigators: Dr V Rakic, Prof T Davis, A/Prof D Bruce Amount Awarded: $9,100 Diabetes is a disease that is strongly associated with cardiac disease. Patients with diabetes who sustain damage to nerves supplying the heart can have a silent heart attack and angina without experiencing typical chest patin. There may be an increased risk of damage to the heart's conduction system and irregular and potentially dangerous rhythms can result. The researchers wished to use a unique resource, namely stored ECGs from the Fremantle Diabetes Study (FDS), to assess how common and life-threatening cardiac disease is in diabetic patients. The FDS is a prospective study of care, metabolic control and complications in 1,426 diabetic patients that were recruited during a three year period in the Fremantle area and followed up until the end of September 2002. Each patient had a standardised assessment each year following their initial visit, including a resting 12-lead ECG. Preliminary coding of all ECGs has been completed. While no conclusions can be drawn at this early stage, the data is being entered into a database and a statistical analysis will be performed to determine the prevalence and estimate the incidence of heart attacks and chest pain in this group of people. Did the Recall of Paracetamol Tablets Lead to a Reduction in the Number of Paracetamol Overdoses in Western Australia? Chief Investigators: Dr S Kisely, Mr N Preston, Dr D Lawrence Amount Awarded: $2,150 The removal of paracetamol tablets from supermarket shelves in 2000 gave an opportunity to examine if this had any impact on the rate of paracetamol overdose attempts. There is evidence from overseas that restricting the sale of paracetamol leads to a reduction in paracetamol overdoses. The researchers examined trends over five years covering before and after restrictions on paracetamol using data from the WA Health Services Research Linked Database, which records all admissions to public and private hospitals throughout the State. They looked at hospital admissions for poisonings with all agents, including paracetamol and other over-the-counter analgesics. There were 11,752 admissions for poisoning from 1996 to 2001. Paracetamol was the primary poisoning agent in 2,266 admissions (19.3%), aspirin in 120 admissions (1%) and ibuprofen in 277 admissions (2%). There was a statistically significant decrease in the admission rate for paracetamol poisoning when sales were restricted compared to the same period of other years. There was no increase in poisoning with other agents at this time however admissions for paracetamol overdose also showed a large random variation that tended to cancel out any effect. The researchers found mixed results on whether paracetamol overdoses fell during the recall. Their study highlights the need to control for random, as well as seasonal, fluctuations in admission rates, and for restrictions on paracetamol sales to last for several months across all retail outlets. It is premature to exclude the possibility that limiting access to paracetamol may reduce paracetamol poisonings without a coincident increase in the use of other agents. Evaluating the role of HFE mutations and iron in cardiovascular outcomes Chief Investigators: A/Prof J Olynyk, Dr D Cullen, A/Prof M Knuiman Amount Awarded: $9,000 The aims of this study were to determine, in a stable community population, whether increased iron stores or haemochromatosis gene mutations were risk factors for coronary heart disease. As you can understand, it is equally important to rule out factors for heart disease as it is to identify those that can contribute to it. The team evaluated 1,185 men and 1,141 women aged 20-79 years, of predominantly Anglo-Celtic descent, from the 1994/95 assessment of the Busselton Population Study. This study is actually a series of studies of the Busselton population performed over the past 30 years and an excellent tool for research. In this particular study, the people underwent haemochromatosis genotyping, serum iron studies, clinical, biochemical and ECG evaluation for coronary heart disease and associated risk factors. Hospital admissions or death from cardiovascular disease were determined by linkage with the WA Morbidity and Mortality Database. The study design was cross sectional for people in the 1994/95 assessment, comparing coronary heart disease cases to unaffected subjects, and unaffected subjects were followed until December 1998. The researchers found that increased iron stores or haemochromatosis gene mutations are not significant risk factors for coronary heart disease. Assessing the outcome of compulsory psychiatric treatment in the community Chief Investigators: Mr N Preston, Dr S Kisely, Mr A Xiao Amount Awarded: $6,275 The purpose of the study was to examine the effectiveness of Community Treatment Orders (CTO) under the Western Australian Mental Health Act. CTOs are orders that require mental health patients to comply with a stipulated treatment regime within the community. If they fail to comply, the CTO is revoked and the patient can be sent into hospital for treatment. 228 cases with a CTOI from around WA were compared to a matched control group and examined to see whether CTO cases had significantly reduced inpatient hospitalisation and bed days one year after being placed on a CTO, compared to the matched control group. The results showed that both groups reduced their hospital admissions and bed days. Although the CTO group improved its hospitalisation rates one year after CTO placement, so also did the matched control group. The differential between the improvement between the two groups was not significant. This study suggests that the introduction of compulsory treatment in the community in isolation will not lead to reduced health service use. Assertive community treatment may be a more effective alternative. Regulation of Tubular Cell Growth in Chronic Renal Disease Chief Investigators: Dr G Rangan, Mr J Steer, A/Prof D Joyce Amount Awarded: $10,000 A universal feature of human chronic kidney disease is unregulated and abnormal growth of kidney tubular cells - the main cell type in the kidney. This growth contributes to disease progression. Previously, the researchers identified that an important intracellular protein which regulates the expression of multiple genes, called Nuclear Factor, is "turned on" when tubular cells are exposed to an environment that mimics the diseased kidney - that is, high concentrations of albumin being present. The aim of the project was to investigate whether Nuclear Factor has a role in regulating the growth of kidney tubular cells. The researchers examined the growth of the kidney tubular cells in a culture, and in vivo (in an animal model). In the culture experiment, exposure of cells to albumin caused a significant increase in growth. The study was then performed in vivo, which demonstrated that tubular growth in a damaged kidney correlated with an increased excretion of protein in the urine, and Nuclear Factor activation. These studies provide the first evidence to suggest that Nuclear Factor activity is linked to cellular growth in kidney cells. The significance of this study is that drugs that target Nuclear Factor may potentially modify the growth of tubular cells in chronic kidney disease, and thereby prevent progression to end-stage renal failure. Thanks to the initial funding from the Fremantle Hospital Medical Research Foundation, the Researchers received further funding of $210,000 from the National Health and Medical Research Council for 2003-2006, a significant achievement. The role of the Nuclear Receptor PPAR Gamma In Prostate and Breast Cancer Chief Investigator: Dr BB Yeap Amount Awarded: $10,000 Prostate and breast cancer are important causes of ill health and death in Australians. Hormonal treatment and anticancer chemotherapy are initially effective, but many cancers progress after a period of time, despite continuing treatment with these agents. Thus newer and more effective treatments are needed. The thiazolidinedione class of drugs used to treat patients with diabetes activate a receptor called the Peroxisome Proliferator-Activated Receptor Gamma (PPAR Gamma). Recently it has been proposed that PPAR Gamma may play a key role in controlling the growth of prostate and breast cancer cells, and thus activation of PPAR Gamma might be of use in treating patients with these cancers. In this project, samples from patients with breast cancer were examined to assess the quantity of PPAR Gamma present and it was found that breast cancer tissue contained less PPAR Gamma than normal breast tissue. Human prostate and breast cancer cells were grown in the laboratory to study the effect of activating PPAR Gamma, which resulted in slowing of cancer cell growth. The amount of PPAR Gamma messenger RNA (mRNA) and protein in these cells was then examined, showing that the level and turnover of mRNA for PPAR Gamma is closely controlled by a thiazolidinedione in prostate cancer cells. The level of PPAR Gamma protein in prostate and breast cancer cells was also affected by the presence of thiazolidinedione. This research supports the role of PPAR Gamma as a key factor influencing the growth of prostate and breast cancers. A better understanding of the biology of PPAR Gamma in these cancers would assist the development of new anticancer therapy.

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