1999 RESEARCH - 6 projects, $47,000 Investigating the Use of Kangaroo Heart Valves for an Improved Treatment of Heart Valve Disease in Humans Chief Investigators: Mr A Hodge, Dr WML Neethling Amount Awarded: $7,000 Today, degenerative heart valve disease can be treated surgically by means of heart valve repair procedures, prosthetic valve replacements (mechanical or biological) or replacement with a human graft. Valve repair procedures are limited to the early stage of heart valve disease where the valve is still functional after minor surgical adjustments. Mechanical valves, although highly reliable and durable, do present some problems such as anti-coagulation, which makes them a less favourable option in many patients. Currently available tissue valves for use in biological prosthetic valve replacement (avoiding anti-coagulation) comes from pigs, however their long term usefulness is limited because of degeneration accompanied by an accumulation of calcium. Over the past 10 years several methods to reduce the calcification process were introduced with some success however calcification remains a challenge to heart valve research. Recently research has been conducted on kangaroo heart valves as a potential prosthetic valve replacement for humans. Kangaroo heart valves act more like a human heart valve than a pig's valve, as kangaroos "stand" in a similar way to humans. Studies of kangaroo heart valve tissue have indicated a reduced calcification compared to pig valves, even when untreated by anti-calcification methods. The researchers believed that a further reduction in the calcification process by investigating the effect of different amino acids on blocking the calcification potential of Kangaroo aortic wall tissue could result in a significantly superior product for valve replacement surgery. The study was initiated in March 1999 and completed at the end of April 2000 and consisted of harvesting of study material, treatment of the tissue with special biochemical agents, implantation of these tissues into an animal model and assessment of the implants after a certain period of time according to certain scientific parameters. Results showed that the current method of treating animal heart valve tissue is responsible for tissue calcification. Additional detoxification with an amino-acid at a low pH reduces the calcification potential approximately 55% in pig heart valve tissue and approximately 65% in kangaroo heart valve tissue. This is a significant contribution that would increase the life span of implanted heart valve tissue. This research project is the beginning of a long-term research program regarding all aspects of the physiology and hemodynamics of the Kangaroo heart valve tissue as a possible substitute in valve replacement surgery. Following the seeding grant provided by the Foundation, the project has attracted approximately $45,000 in additional funds to continue this important research work. Development of a New Radiopharmaceutical Treatment for Bone Marrow Cancers Chief Investigators: Dr JH Turner, Dr M Webb, Dr NP Lenzo Amount Awarded: $10,000 Life-threatening radiation toxicity from standard total body external beam irradiation and chemotherapy and failure to guarantee success of marrow transplantation or eradication of malignancy promoted the research team to look at a new radiopharmaceutical regimen for treatment of cancer affecting bone marrow. With favourable results in small animals, the team planned to trial a safe effective dose regimen of Samarium-153 bone-targeted radiopharmaceutical combined with melphalan chemotherapy and marrow transplantation in a large animal, for planned clinical trial in patients with haematologic cancer at Fremantle Hospital. The research project went into recess in June 1999 when one of the researcher team left for further training in the US. He is expected to return with new methodology to enhance the project. Discovering the ways that parasites develop resistance to drugs Chief Investigators: Dr J McCarthy Amount Awarded: $4,166 A major problem in human infections is the development of drug resistance by microbes. The aim of this project was to discover how parasitic worms infecting humans become resistant to Ivermectin, an important drug for the treatment of several parasitic diseases, particularly the worm Strongyloides. This disease is a significant clinical problem in Australia among immigrants from tropical countries, ex-prisoners of war and among Aboriginal populations in the Tropical North (including WA) where it causes considerable suffering. Knowledge of how the parasites resist this drug will enable the development of tests to detect drug-resistant infection, and lead to ways to prevent or overcome this problem. The approach used to study this problem was to look at genetic mutations in the worms then to see which worms survived after the animal infected with the worms was treated with the antiparasitic drug Ivermectin. A drug resistant strain of worm has been identified and work is now underway to characterize this drug resistant strain with the aim to identify which genes have been mutated leading to the drug resistance. Do nutritional supplements improve nutrition in the elderly? Chief Investigators: A/Prof DG Bruce, Ms A Jarman Amount Awarded: $5,933 Surveys have shown that undernutrition and serious malnutrition are surprisingly common in hospitalised elderly patients. There are many causes of low food intake in elderly people - social factors such as poverty or lack of socialisation at meal times, physical factors including immobility or being unable to feed oneself, medications which affect the taste and smell of food, medical problems such as dementia, depression or disease, and many elderly people commonly complain of a loss of appetite for reasons unknown. The consequences of serious undernutrition include immune deficiencies, an increased incidence of serious infections and impaired wound healing. Improving patient nutrition is thought to confer important health benefits, and the use of commercial nutritional supplements has become common. When healthy young people are given a snack before a meal they have been shown to automatically regulate their subsequent food intake, so that their total caloric intake remains virtually unchanged. Healthy older people have been shown to have an impairment in this regulation - they do not eat less after the snack and consequently consume more calories. Such studies have not been carried out in frail or hospitalised elderly subjects, and it is was unknown whether the regulation of food intake is different. 14 females were studied (13 patients with hip fracture and 1 with pelvic fracture, with a mean age of 79.4 years) at least 14 days after fracture, when they were well and eating reasonably. Hip fracture patients were selected to minimise variation in presenting illness and because of the attention this condition has received. Patients were offered a self-selected, attractive buffet lunch meal on two occasions in random order. A food weighing technique allowed a detailed assessment of caloric intake. In the first study, 7 patients received a standard nutritional supplement (250 Kcal) or a control drink (0 Kcal) given 90 minutes before the meal. Study B was identical but patients received the drinks 30 minutes before the meal. A net gain in consumed calories would confirm the potential usefulness of this form of nutritional supplementation. No net gain in consumed calories would imply that such therapy may be of little or no value. A negative result would provoke the need for considering alternative nutritional strategies, such as different foods or supplements given at different times. Results showed that caloric intake was low, even with nutritional supplementation. Only 3 of 14 patients exceeded 30% of Recommended Daily Intake for the lunchtime meal. However in both studies, nutritional supplementation failed to suppress subsequent food intake. It was concluded that nutritional supplementation given before a meal did not suppress subsequent caloric intake. This failure of suppression is abnormal and indicates that there is a defect in the regulation of appetite and food intake in these patients of unknown cause. Identifying the Cause of Serious Infections by Detecting Bacterial DNA Chief Investigators: Dr H van Gessell, Dr J McCarthy, Dr H Darragh Amount Awarded: $10,000 The effective diagnosis and treatment of bacterial infections in patients often depends on identifying specific microorganisms. Traditionally, a sample of the bacteria is taken and grown in culture media, then tests are performed to identify the bacteria. Identification takes a minimum of 2 days, and often longer. This delay is of serious concern, as medical staff are unable to effectively combat the bacteria until they know which particular bacteria they are dealing with. Different bacteria have different genetic codes. The researchers proposed to study a portion of the genetic code of bacteria that cause infections in humans to test whether this technique would be a faster and more useful way of identifying which bacteria was causing the infections. They used a technique called Polymerase Chain Reation (PCR), where portions of genes were analysed and their DNA code compared with a database of genetic sequences from many different bacteria. The technique was successfully applied to a range of known bacteria and to one human isolate which had previously proven to be very difficult to identify. The project established that this technique has the potential to allow rapid and accurate diagnosis of bacterial infections, which can otherwise be difficult and time-consuming. Identification of Factors that Regulate Healing in Chronic Wounds Chief Investigators: A/Prof MC Stacey, Dr NJ Trengove, Dr HJ Wallace Amount Awarded: $9,968 Chronic leg ulcers affect approximately 3% of the elderly population and are characterised by both impaired and prolonged healing, as well as a high frequency of recurrence of ulceration. In Australia alone, it has been estimated that annual costs of treating chronic venous ulcers is in the region of $400 million per year. This is a problem that has long been neglected both in medical research and, indeed, in clinical practice. The underlying physiological problem is due to an abnormally high pressure in the superficial leg veins during exercise. This may be caused either by previous deep vein thrombosis or by an abnormality in the valves of the deep veins. A number of theories have been put forward as to why the different pressure affects the healing process, but none of these have been proven and there is no simple connection between the theories and why the wounds fail to heal. Currently there are no treatments available for chronic leg ulcers that specifically target the events that are the cause of delayed healing. The identification of the underlying mechanisms will enable the development of new therapeutic measures that may specifically target the events that cause a chronic non-healing wound. The development of new therapies that stimulate the healing of these chronic wounds will help to reduce the time taken for the wounds to heal, and will reduce patient morbidity. While it is possible to screen the wound fluid for a wide variety of known factors that may potentially have an influence on healing, the team believe it is possible that many factors exist that have not been previously considered and the aim was to identify new proteins that may be playing a role in the healing process. Using a novel technique called cDNA expression array, they plan to show proteins that are produced in significantly different levels when the wounds change from the non-healing to the healing phase. This technique has not been undertaken before in chronic wounds, or in human wounds of any description. The technique is very complex and involves isolating messenger RNA from healing and non-healing wounds and comparing the two. The funds provided by the Foundation enabled the team to refine the process used to extract and purify the RNA from biopsies which is necessary for the experiment. This exciting research has now attracted additional funding of over $250,000 from Pfizer Global Research and Development (Sandwich, UK) which will support a research officer and the laboratory disposables necessary to run the project for the next two years.

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