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Human ageing is characterised by reduced appetite and food intake, so that average body weight decreases after 70-75 years. This physiological anorexia predisposes to pathological weight loss and malnutrition, worsening of other illnesses, and increased mortality. This project aims to identify causes of this anorexia of ageing, with a view to developing prevention and treatment strategies. We hypothesise that (1) Satiety signals are overactive in the elderly. We will determine whether older peop ....Human ageing is characterised by reduced appetite and food intake, so that average body weight decreases after 70-75 years. This physiological anorexia predisposes to pathological weight loss and malnutrition, worsening of other illnesses, and increased mortality. This project aims to identify causes of this anorexia of ageing, with a view to developing prevention and treatment strategies. We hypothesise that (1) Satiety signals are overactive in the elderly. We will determine whether older people are more sensitive to gastric distension, which reduces appetite and food intake, by measuring perceptions (fullness, hunger, etc), gastric compliance and food intake during intragastric balloon inflation. This will also be done during nutrient infusion into the small intestine, to assess the interaction between gastric and intestinal satiety factors. The contribution of age-related slowing of gastric emptying to the anorexia of ageing will be assessed and the possibility that reduced energy intake worsens the anorexia of ageing will be examined in a nutrient supplementation study. We will have shown that the release of the satiety hormone cholecystokinin (CCK) is greater in older than young adults and that CCK administration causes a greater suppression of food intake in older people, suggesting that increased CCK activity may be a cause of the anorexia of ageing. We will pursue these findings by attempting to increase appetite and food intake in the lderly by administration of a CCK antagonist (blocker). We will also measure the satiating effects of two other probable satiety hormones, amylin and glucagon like peptide 1 in older and young people. (2) The feeding drive is reduced in the elderly Opioids stimulate feeding. In animals this effect is reduced by ageing. To determine whetther this is also so in humans, the suppressive effect of the opioid antagonist naloxone on feeding will be assessed in young and older subjects.Read moreRead less
ProbioticTreatment Of Diarrhoeal Disease And Malnutrition In Top End Aboriginal Children
Funder
National Health and Medical Research Council
Funding Amount
$332,036.00
Summary
Aboriginal children in the Top End of Australia have high rates of hospital admission for diarrhoea and malnutrition. We have discovered that underlying small intestinal damage in these children is an important contributor to the high complication rates and longer lengths of stay in hospital compared to non-Aboriginal children. This research proposes to continue our work on small intestinal damage by using two non-invasive tests of gut function, namely a sugar absorption test and novel breath te ....Aboriginal children in the Top End of Australia have high rates of hospital admission for diarrhoea and malnutrition. We have discovered that underlying small intestinal damage in these children is an important contributor to the high complication rates and longer lengths of stay in hospital compared to non-Aboriginal children. This research proposes to continue our work on small intestinal damage by using two non-invasive tests of gut function, namely a sugar absorption test and novel breath test. The sugar permeability test involves the children drinking a solution of the two sugars lactulose and rhamnose, and measuring their absorption into the blood 90 minutes later using a sophisticated measuring instrument called HPLC, which can measure minuscule amounts of sugars and is set up at Royal Darwin Hospital. The breath test involves children drinking another sugar solution with a special non-radioactive marker called a stable isotope of carbon, and measuring changes in the amount of this marker in carbon dioxide from the breath at timed periods after drinking the sugar solution. The breath is analysed in Adelaide using another sophisticated instrument. These tests are being used to measure abnormal sugar absorption due to intestinal damage, which is particularly common in Aboriginal children during the weaning period of 4-18 months. Our hypothesis is that treatment with 'healthy germs' (probiotics) like those in certain yoghourts will colonise the gut, stimulate immunity and reduce the presence of 'nasty germs' (pathogenic bacteria) in the intestines of Aboriginal children which contribute to the need for their hospitalisation with diarrhoea and malnutrition. If this hypothesis is correct, then this research will provide the best kind of evidence for reducing the need for hospital treatment by treating all cases of diarrhoea with these probiotics and possibly even decreasing the gut damage of children in the weaning period by including probiotics in their dietsRead moreRead less
MATERNAL UNDERNUTRITION, INFANT REFEEDING, ADIPOSITY AND DIABETES
Funder
National Health and Medical Research Council
Funding Amount
$297,323.00
Summary
Malnutrition is a major health problem throughout the world and one of the priority areas for the WHO. Refeeding program guidelines have been established and implemented when children are assessed as being malnourished. Recent studies on the effect of these important programs throughout the world have suggested they may not have been as successful as wished. Indeed, even though many of the subjects are the urban poor, it has been found that many are developing diabetes in their twenties. This is ....Malnutrition is a major health problem throughout the world and one of the priority areas for the WHO. Refeeding program guidelines have been established and implemented when children are assessed as being malnourished. Recent studies on the effect of these important programs throughout the world have suggested they may not have been as successful as wished. Indeed, even though many of the subjects are the urban poor, it has been found that many are developing diabetes in their twenties. This is associated with an increase in abdominal fatness, out of proportion to the rest of the body's size and shape. The increase in diabetes in this group is most worrying and a major public health problem. It is not known whether the diabetes and abdominal fatness are caused by the refeeding programs or whether they are due to the fact that the body's metabolism was programmed during pregnancy. Perhaps the infants were malnourished whilst they were developing during pregnancy and metabolism was changed so they could store fat easily and not use glucose as readily in the rest of the body. This study is designed to show whether there are metabolic changes which predispose to diabetes and fatness present at birth in those who are malnourished or whether the refeeeding program designed to help them grow is the cause of these later problems.Read moreRead less
Identification And Characterisation Of Novel Virulence Genes In Attaching And Effacing Strains Of Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$281,320.00
Summary
Some varieties of Escherichia (E.) coli are harmless bacteria that live in the healthy intestinal tract, whereas others can cause diarrhoea. Those varieties of E. coli which cause diarrhoea include so-called enteropathogenic E. coli (EPEC), which is a leading cause of life- diarrhoea in infants and young children in less developed countries, and enterohaemorrhagic E. coli (EHEC) the cause of hamburger disease. These bacteria are able to cause disease because they possess specific genetic informa ....Some varieties of Escherichia (E.) coli are harmless bacteria that live in the healthy intestinal tract, whereas others can cause diarrhoea. Those varieties of E. coli which cause diarrhoea include so-called enteropathogenic E. coli (EPEC), which is a leading cause of life- diarrhoea in infants and young children in less developed countries, and enterohaemorrhagic E. coli (EHEC) the cause of hamburger disease. These bacteria are able to cause disease because they possess specific genetic information that is absent from harmless varieties of E. coli. Although many of these disease-associated genes have been identified, the specific role of many of them is not known. In addition, it seems likely that many more genes of this type remain to be discovered. The fact that EPEC is host specific means that the mechanisms by which these bacteria cause disease can only be investigated in humans. This is extremely limiting for the number and type of investigations that can be performed. However, there are rabbit-specific strains of EPEC which cause a disease in rabbits that is indistinguishable from that caused by EPEC in children. The aims of this study are to use the rabbit model of diarrhoea to learn more about the contribution of certain specific factors of EPEC to disease causation and to discover new factors of this type. This will be achieved by three complementary strategies: (1) investigating rabbit E. coli for virulence genes and determining if they are present in human strains; (2) examining the effect of inactivating these genes on the ability of E. coli to cause diarrhoea in rabbits; and (3) infecting rabbits with pools of mutant E. coli strains to identify factors that the bacteria require to survive in rabbits. The results of these studies will improve understanding of the mechanisms by which E. coli cause disease and may provide opportunities for the development of novel tools to diagnose, treat and prevent E. coli-associated diarrhoea.Read moreRead less
The Effect Of Ghrelin, Leptin And Orexins On The Function Of Pituitary Somatotropes In Rat, Mouse And Human.
Funder
National Health and Medical Research Council
Funding Amount
$447,000.00
Summary
Malnutrition such as obesity or wasting syndrome is accompanied by GH deficiency. Three newly discovered metabolic regulatory hormones, leptin from fat tissue, ghrelin from stomach and orexins from hypothalamus, play important roles in regulating appetite, energy expenditure, and adiposity. Receptors for three metabolic regulatory hormones are all present in pituitary GH secreting cells (somatotropes) and accumulated laboratory data indicate a modification of GH secretion by three hormones. Cont ....Malnutrition such as obesity or wasting syndrome is accompanied by GH deficiency. Three newly discovered metabolic regulatory hormones, leptin from fat tissue, ghrelin from stomach and orexins from hypothalamus, play important roles in regulating appetite, energy expenditure, and adiposity. Receptors for three metabolic regulatory hormones are all present in pituitary GH secreting cells (somatotropes) and accumulated laboratory data indicate a modification of GH secretion by three hormones. Contradictory results have however been reported. Mechanisms of action of these three hormones are not clear and the interrelationship between metabolic regulatory hormones and intrinsic GH regulatory system is unknown. We propose to clarify this issue by investigating the effect of in vivo treatment of mice and in vitro treatment of cultured pituitary cells with leptin, ghrelin, and orexins. GH secretion, GH and GH-regulatory hormones' receptor synthesis in pituitary somatotropes will be measured. We will also use GH-GFP transgenic mice, in which somatotropes are specifically marked with green fluorescent signal, to study morphological change of somatotropes in mouse pituitary glands after in vivo treatment. By completing this project, we will be able (1) to clarify the physiological role of metabolic regulatory hormones in control of GH levels and (2) to clarify the pathological role of metabolic regulatory hormones in GH deficiency occurred in malnutritional conditions.Read moreRead less
Structural Diversity And Evolution Of Variant-specific Surface Proteins In The Protozoan Parasite, Giardia
Funder
National Health and Medical Research Council
Funding Amount
$436,417.00
Summary
Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect ....Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect the parasites against digestion, enabling them to reside indefinitely within the intestine. However, the proteins are also the principal target of host immunity. Analysis of Giardia populations has shown that as many as 150-200 different coat proteins can be made. Although individual cells have coats comprised of only a single protein type, these can 'switch' spontaneously to production of another type - a phenomenon known as 'antigenic variation'. This process occurs slowly but continuously, giving rise to 'variants' which survive successive host responses (directed against each predominant coat type) and occupy the vacancies left by the destruction of their immediate forebears. It is important to gain information about the structural diversity of these variant-specific proteins (VSP), as any 'Giardia' vaccine is likely to require inclusion of each major type. It is also important to elucidate how the 'switching' process occurs, as this may provide clues as to how it might be interrupted. The project addresses both aspects.Read moreRead less
Impact Of Gastrointestinal Dysmotility On Enteral Nutrition In The Critically Ill
Funder
National Health and Medical Research Council
Funding Amount
$533,792.00
Summary
Critically ill patients require nutrition for optimum recovery. Ideally, this is provided via the gut, but oesophageal reflux, slow gastric emptying and small intestinal dysfunction frequently prevent adequate delivery of nutrients to these patients, exposing them to complications such as pneumonia and gastrointestinal bleeding. The work performed by the applicants will improve the ability of doctors in the Intensive Care Unit to feed patients and prevent the development of such complications.
Neonatal Vitamin D Status And Risk Of Schizophrenia: A Study Using Danish Dried Bloods Spots
Funder
National Health and Medical Research Council
Funding Amount
$164,980.00
Summary
There is increasing evidence that low levels of vitamin D (i.e. the 'sunshine hormone') during early development can alter brain development. In particular, it has been proposed that low vitamin D during development (e.g. prenatal and in early life), increases the risk of developing schizophrenia during adulthood. A previous study based on stored third trimester blood samples from US women suggested that very low levels of maternal vitamin D may be associated with an increased risk of schizophre ....There is increasing evidence that low levels of vitamin D (i.e. the 'sunshine hormone') during early development can alter brain development. In particular, it has been proposed that low vitamin D during development (e.g. prenatal and in early life), increases the risk of developing schizophrenia during adulthood. A previous study based on stored third trimester blood samples from US women suggested that very low levels of maternal vitamin D may be associated with an increased risk of schizophrenia in the offspring. We have the opportunity to explore this hypothesis using a large, well-described Danish 'bio-bank'. Since 1981, blood samples from newborn babies have been kept by a central agency in Denmark. In collaboration with senior Danish medical researchers, 900 blood samples of babies who have subsequently developed schizophrenia and 1800 from matched healthy individuals have been identified. We will measure vitamin D levels in these blood samples. We predict that babies with low levels of vitamin D will have an increased risk of developing schizophrenia. If low prenatal vitamin D does increase the risk of schizophrenia, this finding will have important implications from a public health perspective. Just as the number of infants affected by spina bifida has been reduced by adding folate supplements to foods, optimizing maternal vitamin D levels may lead to a reduction in the incidence of schizophrenia.Read moreRead less