Cells of the macrophage lineage, the immune system's scavenger cells which attack invading organisms and other infected cells, are important targets of HIV infection, are among the first cells to become infected when the virus is transmitted from person to person and serve as reservoirs of the virus throughout disease progression. Monocytes in the blood, the precursers to macrophages in the tissues, are not very susceptible to infection with HIV but we and others have shown that small numbers ar ....Cells of the macrophage lineage, the immune system's scavenger cells which attack invading organisms and other infected cells, are important targets of HIV infection, are among the first cells to become infected when the virus is transmitted from person to person and serve as reservoirs of the virus throughout disease progression. Monocytes in the blood, the precursers to macrophages in the tissues, are not very susceptible to infection with HIV but we and others have shown that small numbers are infected throughout an infected person's life and that they remain infected despite years of treatment with potent combination drug therapies which reduce the amount of virus in the blood to undetectable levels. We have evidence that suggests that a certain subset of monocytes may be preferentially infected with HIV and may contribute significantly to its persistence in the body. This subset is known to be expanded in response to certain infections, probably including HIV, and during inflammation. We have shown that these cells accumulate in the brains of HIV-infected people especially those with AIDS related dementia. In this project we will characterise these cells in the blood and test our hypothesis that ongoing infection in this subset of monocytes plays an important role in the course of HIV disease and contributes to the persistence of HIV infection and the failure of currently available therapies to eradicate it.Read moreRead less
Comprehensive Assessment Of Novel Artemisinin-based Combination Regimens For Treatment Of Malaria In Papua New Guinea
Funder
National Health and Medical Research Council
Funding Amount
$529,500.00
Summary
Malaria is one of the most important causes of death and disease in Australia's closest neighbour, Papua New Guinea (PNG). The cornerstone of strategies to tackle malaria is the provision of prompt and effective drug treatment for those at risk. Unfortunately older drugs are becoming ineffective due to development of resistance and most newer drugs are too expensive for poor countries. As in sub-Saharan Africa, a looming public health disaster awaits the imminent loss of effectiveness of afforda ....Malaria is one of the most important causes of death and disease in Australia's closest neighbour, Papua New Guinea (PNG). The cornerstone of strategies to tackle malaria is the provision of prompt and effective drug treatment for those at risk. Unfortunately older drugs are becoming ineffective due to development of resistance and most newer drugs are too expensive for poor countries. As in sub-Saharan Africa, a looming public health disaster awaits the imminent loss of effectiveness of affordable antimalarials in PNG. There are however some new drugs that may be highly effective and relatively cheap but require further evaluation before they can be deployed. The new artemisinin drugs from China are cheap, safe and effective. However they must be combined with a second drug to ensure cure and to prevent the development of resistance, a stragegy known as artemisinin combination therapy (ACT). The World Health Organisation has endorsed ACT but finding a suitable 2nd drug to combine with the artemisinin drug has been challenging. Our group has pioneered research into the drug piperaquine, which we believe may be the best affordable drug to combine with artemisinin drugs. Piperaquine was first synthesised in the 1960's and was shown to be effective in Chinese studies in the 1970's, but little is known of its blood levels, metabolism and interactions with other drugs in humans. We plan to carry out laboratory studies, studies in healthy volunteers, and field studies in PNG children with malaria that should provide detailed information about piperaquine and its potential role in ACT for malaria. This will help us to develop better dosing formulations and to maximise the effectiveness of this treatment. Development and registration of a piperaquine-containing ACT would consititute a new and potent weapon in the fight against malaria in PNG and other tropical countries.Read moreRead less
Determinants Of Immune Restoration Disease And Persistent Immune Dysfunction In HIV Patients Responding To ART
Funder
National Health and Medical Research Council
Funding Amount
$445,011.00
Summary
Many people throughout the world now receive antiretroviral treatment (ART) for HIV-AIDS. ART increases numbers of CD4 T-cells, but does not restore all functions the immune system. In addition, some patients experience serious exacerbations of pre-existing secondary infections when they respond to ART. We were the first to describe these Immune Restoration Diseases and will investigate the underlying mechanisms and the causes of persistent immune deficiency here.
NK Cells As The Missing Link Between Anti-cancer Chemotherapy And CD8 T Cell Responses
Funder
National Health and Medical Research Council
Funding Amount
$488,478.00
Summary
Cytotoxic chemotherapy is the standard of care for most tumors but it rarely cures. The immune system has the capacity to destroy malignant cells but tumors usually evade immune destruction. Combination of chemo- immunotherapy may change this. DNA damage in tumor cells, caused by chemotherapy, induces expression of a set of molecules that activate Natural Killer cells. These cells can then activate anti-tumor T cells. Therapies that enhance this pathway may induce sustained anti-tumor effects.
RCT Of Polypill Versus Usual Care Among Aboriginal And Torres Strait Islander People With High Cardiovascular Risk
Funder
National Health and Medical Research Council
Funding Amount
$1,855,205.00
Summary
Cardiovascular disease is a major contributor to the lower life expectancy of Aboriginal compared to non Aboriginal people. Guidelines recommend people at high risk of cardiovascular disease shoul be on a combination of blood thinning, blood pressure lowering and cholesterol lowering medications. There is a large gap between actual practice and these guidelines. We will test a combined polypill strategy aiming to simplify treatment and reduce costs to close this gap.
Osteoarthritis is the major cause of disability in elderly Australians. It is a disease of unknown aetiology that results in deterioration of the structure and function of articular cartilage. Current treatment is palliative or involves joint replacement, which is very costly. No preventive strategies are currently available. These facts have led to 2000-2010 being labelled the Bone and Joint decade. Studies have consistently indicated a higher risk of this disease in families. This study will e ....Osteoarthritis is the major cause of disability in elderly Australians. It is a disease of unknown aetiology that results in deterioration of the structure and function of articular cartilage. Current treatment is palliative or involves joint replacement, which is very costly. No preventive strategies are currently available. These facts have led to 2000-2010 being labelled the Bone and Joint decade. Studies have consistently indicated a higher risk of this disease in families. This study will examine for novel genes for this condition in a large family study involving over 500 subjects. Identification of susceptibility or severity genes in OA is of marked importance as it is likely to lead to a better understanding of the biochemical basis of these disorders, and translate to rational therapeutic strategies and preventative strategies in at-risk individuals in the longer term.Read moreRead less
Retinal Vascular Signs As Predictors Of Systemic Disease Outcomes: 10-year Evolution In A Population-based Cohort
Funder
National Health and Medical Research Council
Funding Amount
$389,575.00
Summary
Recent U.S. data from two population-based studies have highlighted retinal microvascular signs as being predictive of systemic vascular and other important health outcomes in middle-aged or older individuals, particularly stroke and heart attack and mortality, independent of traditional vascular risk factors. The present application proposes to evaluate the 10-year development and progression of retinal microvascular signs and their relations to the development of stroke and other important sys ....Recent U.S. data from two population-based studies have highlighted retinal microvascular signs as being predictive of systemic vascular and other important health outcomes in middle-aged or older individuals, particularly stroke and heart attack and mortality, independent of traditional vascular risk factors. The present application proposes to evaluate the 10-year development and progression of retinal microvascular signs and their relations to the development of stroke and other important systemic health outcomes in the population-based cohort of residents attending the Blue Mountains Eye Study (BMES. Two types of retinal signs will be evaluated: firstly, the presence of specific clinical signs, such as focal narrowing of small retinal vessels (arterioles), nicking of retinal veins as arterioles cross them or presence of retinopathy (haemorrhages and other signs) secondly, measures of generalized retinal vessel calibre (narrowing) using a computer-assisted method developed for the U.S. studies. We will also develop new grading methods for two other signs. Late and will compare computer-assisted grading from 35mm slides to automated grading of vessels using a scanning device (being developed) to screen the eyes of older persons. This project builds upon our current 3-year NHMRC grant (ID153948; 2001-2003) Retinal vascular signs as risk markers for incident stroke or cerebrovascular death: A population-based assessment . In the last 2 years, this has explored different aspects of measurement and grading of these signs, has documented their relation to blood pressure and has begun to assess whether these features predict vascular events and other systemic outcomes in older Australians. The new project will assess the evolution of retinal microvascular signs over a 10-year period, using data and retinal photographs from the 10-year examinations of the BMES cohort, currently being collected, in a further current NHMRC grant (ID211069; 2002-2004).Read moreRead less
Retinal Vascular Signs As Risk Markers For Incident Stroke Or Cerebrovascular Death: A Population-based Assessment
Funder
National Health and Medical Research Council
Funding Amount
$410,199.00
Summary
Stroke remains a major cause of disability and death in Australia. Preliminary data from the Blue Mountains Eye Study suggest that blood vessel changes observed in the retina at the back of the eye may provide signs of an increased risk of stroke or death from stroke. Importantly, although stroke is strongly associated with elevated blood pressure, the risk associated with these blood vessel signs seems to be independent of blood pressure. The proposed study will conduct a detailed re-grading of ....Stroke remains a major cause of disability and death in Australia. Preliminary data from the Blue Mountains Eye Study suggest that blood vessel changes observed in the retina at the back of the eye may provide signs of an increased risk of stroke or death from stroke. Importantly, although stroke is strongly associated with elevated blood pressure, the risk associated with these blood vessel signs seems to be independent of blood pressure. The proposed study will conduct a detailed re-grading of retinal photographs taken on people who attended the Eye Study during 1992-4 and 5-year follow-up exams during 1997-9. We will grade these photographs manually (using a stereo-viewer), and with computer assistance to measure changes in the diameter of small arteries in the retina and other signs. By closely matching our grading technique to that used in a large American Study, we hope to develop reliable grading for these signs and will be able to compare our findings internationally. Our aim is to assess the frequency of abnormal retinal vessel changes in people of different age groups as well as the development and progression of these signs over time. Their relationship to well known vascular risk factors like smoking, blood pressure, obesity, diabetes and cholesterol will also be investigated. We hope to be able to discriminate those changes associated with an increased stroke risk from those due to normal ageing. We expect that the increased stroke risk associated with abnormal retinal vessel changes may be greater than shown in our early data. If confirmed, then these findings may provide a more sensitive and objective measure of stroke risk than relying on traditional risk factors, which are difficult to quantify and change with time. We may be able to develop simple rules so that doctors using an ophthalmoscope or examining a retinal photograph could identify high risk patients. These people could benefit from interventions to reduce their risk.Read moreRead less
Practical Tools For Robust Analysis Of Large Epidemiological Studies With Incomplete Data
Funder
National Health and Medical Research Council
Funding Amount
$358,492.00
Summary
Studies of the causes and consequences of health outcomes follow large cohorts of individuals for long time periods. A major challenge in analysing data from these studies is that information is often incomplete. Participants rarely complete all waves of data collection, or provide all requested information. Statistical research has led to increased use of a statistical method (multiple imputation) that recovers information from incomplete cases. This project will develop and improve this method