2000 RESEARCH - 8 projects, $60,000 Antibiotic Tolerance of a Serious Bacteria Chief Investigators: Dr M Wilson, Mr N Stingemore, Dr J McCarthy Amount Awarded: $10,000 There is growing concern in the medical community about the increasing resistance of bacteria to antibiotics commonly used to treat significant infections. The bacteria Streptococcus Pneumoniae is an important cause of pneumonia, ear infections and meningitis in humans, and until recently was very sensitive to penicillin - meaning these infections were, on the whole, relatively easy to cure. However there has been a worldwide increase in the resistance of this bacteria to penicillin, and in Australia, a combination of antibiotics is now recommended for the treatment of serious infections to guard against the possibility of antibiotic failure. Among the important substitute antibiotics for the pneumococcus infection is the drug Vancomycin. Generally, antibiotics kill bacteria when they are exposed to them. However some bacteria have the ability to withstand the presence of antibiotics and just simply stop growing on exposure, rather than dying altogether. This is called "antibiotic tolerance". The aim of a research project conducted at Fremantle Hospital by Drs James McCarthy and Moira Wilson from the Infectious Diseases Department, Mr Neil Stingemore from Microbiology and their team aimed to determine if the Australian strain of the pneumococcus infection showed evidence of antibiotic tolerance to Vancomycin. The team obtained 56 different specimens of the pneumococcus infection from Western Australian sources and from a national collection of drug resistant pneumococci. The result was that only one specimen from the 56 appeared to show Vancomycin tolerance, and while this was a very low failure rate, as you would appreciate the possibility of failure of an antibiotic therapy is of concern. The team is now undertaking a detailed study of that one sample to determine if the bacteria may have specific DNA mutations that other researchers have associated with Vancomycin tolerance. This work has significant importance for our understanding of various bacterial infections and how we should select antibiotics for infections such as pneumonia and meningitis. The Prevalence of Coeliac Disease in the Population of Busselton Chief Investigators: Dr JA Collett, Dr DJ Cullen, Dr CJ Hovell and Dr DF Mallon Amount Awarded: $10,000 Coeliac Disease (CD) is an intolerance to gluten or wheat products. In its severe form symptoms can include weight loss and abdominal pain, and in its milder form people may demonstrate indigestion or be symptom free. When gluten is withdrawn from the diet, clinical symptoms of the disease usually resolve. CD is increasingly being recognised as a disorder which affects adults, often older adults, rather than just young children and there is also an increasing awareness of this disorder as a cause for iron deficiency and anaemia. The prevalence of CD in Australia was unclear, so the researchers wished to access a stable community for their study. The Busselton Health Study is a series of studies of the Busselton population conducted over the past 30 years and the team obtained blood serum samples from 3011 randomly selected subjects aged between 20-79. One in 301 subjects showed positive for IgA AEA, which is a reliably predictive screening tool for Coeliac Disease. One in 430 subjects had a small bowel biopsy which proved CD. A further 3 subjects were AEA positive but were not biopsied, however given the specificity of the AEA test, they were likely to have CD. Two subjects had CD diagnosed prior to the start of the study. One subject with CD had iron deficiency anaemia, whilst two others were iron deficient. Thus the overall prevalence of Coeliac Disease in this study was one in 251 subjects, which is relatively high. Over the years there has been a shift in the severity of the symptoms of those with Coeliac Disease and a corresponding lack of clinical suspicion, so only a portion of patients are diagnosed. With the emergence of highly sensitive and specific screening tools, the researchers raise the issue of population screening. The benefit of diagnosis is that adherence to a gluten free diet decreases the incidence of small bowel lymphoma, increases bone mineral density and decreases the likelihood of developing autoimmune disorders. Disadvantages include stress and stigmatisation of previously apparently healthy individuals. The team advises increased awareness of the subtle forms of Coeliac Disease and screening of high risk groups by blood tests and small bowel biopsy if the clinical suspicion is high. They also recommend further research into screening to take account of cost benefits and quality of life. Do Specific Changes to Blood Platelets Increase the Risk of Arterial Blockage? Chief Investigators: Mr B Dale, Dr M Webb, Dr M Leahy, Dr R Baker Amount Awarded: $7,000 Platelets are blood cells involved in blood clotting. Increased platelet activity causes arterial thrombosis (blockage in the coronary artery) and inflammation also causes arterial thrombosis. The researchers believed that an enzyme (neutrophil elastase) released during inflammation may be one cause of increased platelet activity. Blood samples were collected from healthy volunteers and the platelets were isolated. Adding the enzyme neutrophil elastase did not increase platelet reactivity, but it enhanced platelet reactivity when immunoglobin was added. The conclusion then is that neutrophil elastase induced increase of platelets is caused by immune related stimulation of platelets. The results of these investigations strengthened the connection between inflammation and platelet-related thrombosis, and suggests that inflammatory disease with an accompanying or secondary immunological component may be a significant factor contributing to arterial thrombosis. The prevalence of osteoporosis in diabetic patients from a community sample: relationship to diabetes control and treatment Chief Investigators: Prof TME Davis, Ms D Jackson, Dr G Stewart, A/Prof DG Bruce Amount Awarded: $9,200 Diabetes and osteoporosis are two common diseases. There is some evidence that diabetes may predispose people to osteoporosis but firm conclusions cannot be made from available data. It is likely that younger, insulin-treated patients with type 1 diabetes may be more at risk of osteoporosis than older non-insulin-dependent patients with type 2 diabetes. However, a lot of previous studies have not used patients drawn from the community in a representative fashion. The researchers decided to study subjects participating in the ongoing Fremantle Diabetes Study as each patient has a full annual assessment and the patients are representative of diabetes in the Fremantle community. The researchers planned to select 60 patients with type 1 diabetes and 240 patients with type 2 diabetes, none of whom had osteoporosis. 83% of the original target group have been recruited and DEXA (bone density) scanning has been performed on each to determine whether unrecognised osteoporosis was common to diabetes and whether there were any diabetes-related predisposing factors. A full report of the results will be available in July 2001, once all data has been collected, validated and statistical analyses performed. The effect of a Chinese herbal medicine preparation (CH 100) for the treatment of Hepatitis C Chief Investigators: Dr LC Mollison, Ms L Totten, Dr M Belbin Amount Awarded: $3,000 The Hepatitis C virus is a long-lasting inflammation of the liver which can lead to cirrhosis of the liver over 20-30 years, with some cases ultimately developing liver cancer. Hepatitis C is contracted by contact with infected blood through injecting drug use, blood transfusions, tattooing, body piercing etc. Traditional Chinese Medicine is one of the world's oldest and most comprehensive systems of herbal medicine and combining this knowledge with modern science and research may lead to more effective treatments with fewer significant side effects. It is known that Hepatitis C sufferers turn to alternative treatments due to unsatisfactory results from conventional treatment and following initial promising results from a small trial, a larger trial of Chinese herbal medicine preparation was initiated. The herbal medicine CH100 is a combination of 19 ground Chinese herbs including liquorice, turmeric, rough gentian, locoweed, Mongolian dandelion, jujube berries, mugwort and fungi. Of the 97 patients taking part in the trial, one third received a sugar pill placebo, while two-thirds received the Chinese medicine, taking five capsules, three times per day for 24 weeks. The trial was "double blind" which meant that neither the medical practitioner nor the patient knew which treatment they were receiving. Before and after the trial, patients had their blood tested for ALT (alanine amino transferase) levels which show the amount of liver inflammation. Subjects in the trial reported improved symptoms while on treatment and there was an immense improvement in the blood tests of the group, with preliminary data suggesting that the combination of herbs contained in CH100 may be beneficial in lowering ALT and in improving symptoms and quality of life in patients with chronic hepatitis C infection. A follow up trial aims to use the same herbs on animals to see if CH100 is useful in stopping scarring to the liver, which is a long term consequence of Hepatitis C. An intervention to reduce smoking in mental health settings using a targeted health promotion package: A Pilot Study Chief Investigators: Dr S Kisely, Mr N Preston, Dr P Shannon Amount Awarded: $5,400 There is a close relationship between smoking and psychiatric disorder, with between 50 - 80% of psychiatric patients being smokers. Those with a past history of depressive illness find it twice as difficult to give up as individuals with no such history, and there are higher than average rates of major depressive disorder amongst smokers, especially those who are nicotine dependent. Smoking is particularly high in patients with schizophrenia, alcohol dependence, agoraphobia, panic disorder and major depression. Psychiatric patients are particularly disadvantaged by their use of tobacco. They spend approximately $43 per week on tobacco, amounting to 40% of the Disability Support Pension. Nicotine also lowers the level of serum psychotropic medications, so smokers require larger doses of medication with consequent increased side effects and the risk of chronic neurological problems. Smoking may also be partly responsible for the increased death rate of psychiatric patients from cardiological and respiratory disorders. Many of the interventions that are effective in the general population have not been validated in this group. The proposed research is a pilot study to evaluate the feasibility and efficacy of two approaches to reduce smoking in patients with psychiatric disorder: 1) brief physician advice, and 2) a tailored health promotion package incorporating health education and cognitive behavioural therapy. The research used questionnaires to assess knowledge, attitudes and behaviour of patients and staff about smoking. The disposable income and the proportion spent on tobacco was also be assessed. Subjects included in the study were then randomly allocated to the two intervention groups In the first stage, 87 subjects were interviewed. 77% of patients at the psychiatric day unit were smokers compared to only 29% of the comparison group. Younger individuals were more likely to report nicotine dependence & smoke high tar cigarettes. Individuals with schizophrenia were three times more likely to be smokers & 13 times more likely to smoke high tar cigarettes. A second group has now been recruited and the project is part of a larger project funded by Healthway. The Control of Iron Transport by Immune Cells in Patients with Iron Overload (Haemochromatosis) Chief Investigators: A/Prof J Olynyk, Dr D Trinder Amount Awarded: $9,985 Hereditary haemochromatosis is a common genetic disease that alters the way the body uses iron. Excessive iron - which is toxic to the body - is absorbed from the diet and deposited in many organs causing liver cirrhosis, heart disease, diabetes and cancer, while immune cells are relatively spared of excess iron. The gene that is defective in hereditary haemochromatosis has been identified and called HFE, but what it does in the body is not known. The researchers undertook experiments using immune cells isolated from the blood of untreated and treated haemochromatosis and control patients to determine how HFE controls the delivery of iron to the immune cells and if these processes are altered in haemochromatosis. The results showed that the transport of iron into the immune cells from the untreated haemochromatosis patients was reduced compared with the cells from control patients. However, when cells were taken from the blood of patients who had been treated there was no difference in how much iron was taken up compared with the cells obtained from control patients. The researchers demonstrated that the iron transport by the immune cells from the untreated patients was impaired, and this is likely to account for the lack or iron deposited in immune cells in haemochromatosis. However, treatment of the patients effectively restored to normal the delivery of iron to the immune cells. These findings suggest that the changes in the amount of iron accumulated by immune cells in haemochromatosis is dependent on whether the patient has undergone treatment rather than the presence of the defective gene HFE associated with haemochromatosis. Does an abnormal immune response contribute to pregnancy-induced high blood pressure (preeclampsia)? Chief Investigators: Dr DFJ Mallon, Dr I Beckman, Ms A Hall, Ms A Franchina Amount Awarded: $5,400 Preeclampsia is a disease of late pregnancy (>20 weeks gestation) that is recognised by elevated blood pressure, protein in the urine, and rapid and sudden weight gain. Unpredictable in onset and progression, preeclampsia poses a serious threat to both mother and child, the only cure being immediate delivery. Whilst the causes are unknown, recent evidence has suggested that women with preeclampsia produce antibodies directed against a component of blood vessel walls called the Angiotensin II Type I receptor (AT1R). The primary aim of this project was to develop a simple but sensitive test to detect women at risk of preeclampsia, as detection of these antibodies prior to the appearance of clinical symptoms would potentially play an important role in the management of this disease. The study involved testing separated blood (serum) from women with preeclampsia and from healthy pregnant women. A panel of frozen sera collected before and after pregnancy from women with preeclampsia and from healthy pregnant women was provided by Professor L J Beilin and colleagues at the University Department of Medicine, Royal Perth Hospital. Occasional samples were also received from Dr B Walters, Obstetric Physician, from clinically diagnosed women with preeclampsia. The sera were initially tested using a technique called indirect immunofluorescence (IIF) microscopy. IIF is routinely used for detecting autoantibodies in patients with other immunological disorders such as diabetes or SLE (Systemic Lupus Erythematosus). This procedure requires tissue/cells of interest to be fixed onto a glass slide, and the patient sera to be placed over the tissue/cells and incubated in a damp chamber for 30 minutes. After 30 minutes, the slide is washed and antiserum bound to a fluorescent dye is placed over the tissue/cells for another 30 minutes. The fluorescent dye allows you to see staining of the tissue/cells under a UV microscope and positive results show a fluorescent green staining pattern. To find the best substrate (or medium), a number of cell and tissue types were tried. In addition, a number of methods were tried to enhance the fluorescence signal. Unfortunately, all substrates failed to demonstrate specificity for AT1 receptor autoantibody, either in a commercial preparation know to contain the antibody, or in positive patients with preeclampsia. The team was unable to detect antibodies to the AT1 receptor in patients with preeclampsia. This proved that either these antibodies are not required for the development of this disease, or further development of the research team's technique would be required to detect these antibodies. The team plans to try a number of techniques to modify their testing method.

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