MEDICAL EARLY RESPONSE INTERVENTION AND THERAPY (MERIT): A RANDOMISED CLINICAL TRIAL
Funder
National Health and Medical Research Council
Funding Amount
$530,500.00
Summary
Every year, between 12,000 and 23,000 deaths are associated with in-hospital adverse events, making them one of the leading causes of death in the general population. These adverse events lost Australia over three million bed-days per year, and cost the country up to $4.7 billion every year. Among the adverse events, death, cardiac arrest and unplanned admissions to intensive care unit (ICU) are the most serious occurrences. The majority of the events were preceded by serious clinical deteriorat ....Every year, between 12,000 and 23,000 deaths are associated with in-hospital adverse events, making them one of the leading causes of death in the general population. These adverse events lost Australia over three million bed-days per year, and cost the country up to $4.7 billion every year. Among the adverse events, death, cardiac arrest and unplanned admissions to intensive care unit (ICU) are the most serious occurrences. The majority of the events were preceded by serious clinical deterioration, which can be easily identified. Recognising these problems, a hospital-wide intervention system called the Medical Emergency Team (MET) has been developed in Australia over the last 10 years. Under this system, when a patient's clinical condition is unstable, a call is immediately placed to the MET for intervention. Preliminary data have shown that the MET can reduce in-hospital deaths, cardiac arrests and unplanned ICU admissions. However, past studies have been based on observational design and their results lack scientific credence due to uncontrolled confounders and biases. It is proposed to conduct a multi-centre randomised clinical trial to test the hypothesis that the implementation of the hospital-wide MET system will reduce the aggregate incidence of the following three adverse events: unplanned admissions to intensive care units, cardiopulmonary arrest, and in-hospital death. The study will involve 20 Australian and New Zealand hospitals, each with at least 20,000 admissions per year. This study will provide crucial scientific evidence for health managers and governments to make decision on the implementation of MET in Australian and New Zealand hospitals. If the MET system is shown to reduce adverse events as observed in preliminary studies, then the introduction of MET could save approximately 4000 lives, avoid 1500 cardiac arrests, and prevent 2500 unplanned ICU admissions every year.Read moreRead less
Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, ....Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, particularly in cells from the brain. Our recent studies indicate that this mitochondrial pool of glutathione is particularly important in limiting the death of cells from the brain when exposed to damaging substances that are increased in some diseases. Thus, the capacity of mitochondrial glutathione to deal with such substances might be a factor in determining the extent of cell loss in the brain, which is an important determinant of symptoms in some of the major neurological diseases. Consistent with this possibility, we have obtained evidence indicating that decreases in glutathione in the mitochondria contribute to the cell death and brain damage that results from a stroke. In our proposed studies, we will investigate the function of mitochondrial glutathione in the two major cell populations from the brain, neurons and astrocytes. We will characterise the protective role of the glutathione and investigate how it enters the mitochondria and what factors influence the amount that is present. This will provide new insights into the function of glutathione in the mitochondria and could also suggest novel approaches for manipulating this antioxidant pool. We will also study models of stroke and some related brain disorders to more directly test the role of this antioxidant in disease and to assess whether manipulating the content of glutathione in the mitochondria has the potential to reduce damage and improve function in these disordersRead moreRead less
Viral Interference With Apoptosis: Defining The Mechanisms And Effects On Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$551,328.00
Summary
Apoptosis, or programmed cell death, is an orderly process whereby unwanted or damaged cells are removed from an organism. Deregulation of apoptosis has been implicated in the development of diseases such as cancer and autoimmunity. Therefore, a precise understanding of the mechanisms controlling the initiation of apoptosis has important clinical implications. In addition to removing unwanted cells, apoptosis functions as a defence mechanism to inhibit viral replication. Hence, in order to repli ....Apoptosis, or programmed cell death, is an orderly process whereby unwanted or damaged cells are removed from an organism. Deregulation of apoptosis has been implicated in the development of diseases such as cancer and autoimmunity. Therefore, a precise understanding of the mechanisms controlling the initiation of apoptosis has important clinical implications. In addition to removing unwanted cells, apoptosis functions as a defence mechanism to inhibit viral replication. Hence, in order to replicate efficiently viruses have evolved means to inhibit or interfere with apoptosis. The central aim of this work is to understand how two genes encoded by murine cytomegalovirus (MCMV) inhibit apoptosis and contribute to viral replication. MCMV is used as a model for human CMV (HCMV) infection. The majority of the human population is infected with HCMV which poses no risk to healthy individuals. However, reactivation of HCMV in people who are immunosuppressed such as transplant recipients or AIDS patiens is a significant cause of mortality. The MCMV infection model has provided important insights as to how the immune system controls infection and the mechanisms utilized by viruses to circumvent these processes. The proposed studies will improve our understanding of the processes that regulate viral replication. Understanding how viruses subvert host defence mechanisms will allow us to better understand their role in causing human disease, and thus, will provide key information for the design of improved anti-viral strategies. Importantly, the type of analyses proposed here will also contribute critical insights into the normal processes that control cell survival.Read moreRead less
Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Centr ....Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Central to the apoptosis execution are a group of enzymes called caspases that target many cellular proteins for specific cleavage. In this proposal, we will investigate the function of one of the caspases (called caspase-2), in order to better understand its potential role in the apoptosis of cancer cells. A number of recent reports suggest that caspase-2 levels are reduced in many cancer cells. The human caspase-2 gene localizes to a chromosomal region frequently affected- deleted in leukaemia, and caspase-2 levels have been proposed to be predictors of remission and survival in patients with some types of leukaemia. We will study if loss of caspase-2 in cancer cells makes them resistant to killing by drugs and if mice lacking caspase-2 have an increased potential to develop cancer. Understanding caspase-2 function and its regulation is likely to provide new therapeutic opportunities and potential targets for cancer therapy.Read moreRead less
Caspase 8 Apoptotic Signalling Induced By The Inflammasome
Funder
National Health and Medical Research Council
Funding Amount
$603,126.00
Summary
The death of cells of our body can be an active and purposeful process. Programmed death occurs in response to infection or as a defence against cancerous changes. If a virally infected cell can die prior to replication of the virus, this will control the infection. We have investigated cell death in response to DNA found in the cytoplasm of cells, which can be an indication of infection. The novel cell death pathway we are characterising is relevant to defence against infection and tumours.
The Regulation And Role Of Puma And P53 In IL-3 Withdrawal Induced Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
It is the ultimate fate of most of our cells to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . When cell death fails to occur, abnormal cells can accumulate and lead to cancer. Signalling from growth-factors is required for many cell types to survive. When these signals are lost, the cells activate their cell death pathways. It is a hallmark of cancer cells that they ha ....It is the ultimate fate of most of our cells to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . When cell death fails to occur, abnormal cells can accumulate and lead to cancer. Signalling from growth-factors is required for many cell types to survive. When these signals are lost, the cells activate their cell death pathways. It is a hallmark of cancer cells that they harbour mutations in cell death genes and their dependence on growth factors for survival is diminished or lost. The genes of the apoptosis pathway function either to promote or inhibit cell death. Some genes in the apoptosis pathway allow apoptosis to proceed rapidly, but do not decide the fate of the cell. Other genes are required for a cell to commit to die, and if they are mutated then a functional cell, that is capable of proliferating, survives. This is a crucial distinction because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We have identified one particular gene, Puma, as an important regulator of cell survival. Without this gene, cells survive longer without growth-factor and, importantly, can proliferate when growth factor is restored. Understanding how this gene functions and is regulated will contribute to our understanding of the gene mutations that lead to cancer and may identify valid targets for cancer therapy. In our model we use growth factor dependent cell lines derived from mice lacking particular genes in the cell death pathway, including Puma. These cells proliferate in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Using this system, we will determine how Puma is able to induce cell death, what other genes are required to regulate this process and how loss of Puma function may contribute to cancer development.Read moreRead less
End-of-Life Care And Dying-at-Home: Choices And Needs Of People With Intellectual Disability And Their Carers
Funder
National Health and Medical Research Council
Funding Amount
$104,343.00
Summary
With the continued push towards community living for people with intellectual disability, how best to provide support at the end-of-life remains a neglected research area. This occurs against a backdrop of an increasingly ageing population, in an arena where end-of-life care and dying at home is the preferred option for most people. This research breaks new ground, aiming to establish supports such that people with intellectual disability may remain at home until the end of their life.
A Study Of Advance Care Planning In The Primary Care Context
Funder
National Health and Medical Research Council
Funding Amount
$104,664.00
Summary
Advance care planning (ACP) is the process through which a patient can have an input into the direction of their own medical care in case they lose their ability to make medical decisions at a later time. This research will initially explore the patient, their carers, their family and their General Practitioner's conceptualise and view as the aim of ACP . These findings will then be used to guide the development and testing of a more patient-centered approach to ACP.