Can Skin Infection With Group A Streptococcus Cause Acute Rheumatic Fever?
Funder
National Health and Medical Research Council
Funding Amount
$459,450.00
Summary
It is traditionally taught that the cause of acute rheumatic fever (ARF) is always infection of the throat with the bacterium group A streptococcus (GAS). However, in Aboriginal communities of the Top End of the Northern Territory the incidence of ARF is the highest reported in the world, yet GAS is uncommonly isolated from the throat. There is further information to suggest that GAS skin sores may underlie many cases of ARF. If this were proven, it would completely alter the traditional view of ....It is traditionally taught that the cause of acute rheumatic fever (ARF) is always infection of the throat with the bacterium group A streptococcus (GAS). However, in Aboriginal communities of the Top End of the Northern Territory the incidence of ARF is the highest reported in the world, yet GAS is uncommonly isolated from the throat. There is further information to suggest that GAS skin sores may underlie many cases of ARF. If this were proven, it would completely alter the traditional view of the cause of ARF, and have important implications for prevention of ARF around the world. Presently, these approaches focus on diagnosing and treating sore throat, but no country has proven that such a program can be successful in substantially reducing new cases of ARF. If it was known that skin infection could lead to ARF, then countries (including Australia) could emphasise the importance of skin health programs. A further benefit of this knowledge would be to influence GAS vaccine development, which presently is largely focused on the prevention of sore throat. A different possibility has recently been raised - that the cause of ARF may not always be GAS, but instead that the related bacteria GCS and GGS may have the potential to cause this disease. Proof of this hypothesis would even more dramatically alter our understanding of disease causation, prevention, and vaccine development. We propose to determine the cause of ARF in Aboriginal communities by regularly swabbing families of people with a history of ARF, and using genetic fingerprinting of the bacteria from the skin and throat swabs. When cases of ARF occur, we will be able to determine the site and type of infection that precipitated the attack. We will conduct a related study in more communities, in which we will swab family members of people with ARF and of control families (without ARF) to determine the bacteria most commonly isolated from ARF families.Read moreRead less
A Randomised Control Trial Of Non-specific Clinical Management Versus CBT In Chronic Anorexia Nervosa
Funder
National Health and Medical Research Council
Funding Amount
$555,843.00
Summary
Anorexia nervosa (AN) is a serious mental illness that usually starts in adolescence and often runs a chronic course. With an estimated prevalence rate between 0.5% and 3.7% of women, and up to 50% remaining chronically ill, the illness poses a disproportionate burden on health and social services. AN has inpatient costs alone that exceed that for schizophrenia. Chronic AN has the highest mortality rate of any mental illness. Chronic AN patients are known for their ambivalence about engaging in ....Anorexia nervosa (AN) is a serious mental illness that usually starts in adolescence and often runs a chronic course. With an estimated prevalence rate between 0.5% and 3.7% of women, and up to 50% remaining chronically ill, the illness poses a disproportionate burden on health and social services. AN has inpatient costs alone that exceed that for schizophrenia. Chronic AN has the highest mortality rate of any mental illness. Chronic AN patients are known for their ambivalence about engaging in treatment and poor motivation to change their eating disorder behaviours. They often fail to respond to traditional treatments and develop a history of negative treatment experiences and repeated treatment failures. A new approach is needed to reduce both the personal suffering and the burden of the illness on social and medical services. To date, there has been little scientific investigation into the development of specific treatment for those patients with chronic AN. This study will trial a recently manualised therapy - non-specific supportive clinical management - which initial evidence suggests may hold promise for chronic AN because it offers a more indirect, motivationally-matched approach. This treatment will be compared to the establishment therapy Cognitive Behavioural Therapy. Patients will be randomly allocated to one of the two treatment conditions and will receive 40 sessions over 12 months. They will be thoroughly assessed prior to during and after they have completed treatment and followed up for 6 months. This is the worlds first trial of a psychological treatment for chronic AN; it is hoped the study will establish an effective treatment for this debilitating and expensive illness. Further, as the project aims to explore the core, but often over-looked, feature of AN - poor motivation for recovery - it will also be in a position to shed light on the deep psychological processes that maintain this illness.Read moreRead less
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$551,560.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recre ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recreational drugs (eg. alcohol, nicotine). They are also targets for development of new therapeutic drugs, such as allosteric modulators of nAChR for memory enhancement, or modulating GlyR to relieve spasticity or chronic pain. The project will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, gives rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
A NOVEL MOUSE MODEL TO INVESTIGATE THE MECHANISMS OF VIRUS-INDUCED ARTHRITIS
Funder
National Health and Medical Research Council
Funding Amount
$336,000.00
Summary
We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators ( ....We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators (cytokines-chemokines) and antibodies is an overwhelming positive aspect of our physiological response to infection by microbes. Protection from disease by these immune compounds can happen naturally, or the body's ability to produce these factors can be exploited to our benefit via the administration of vaccines. However, these factors can also be detrimental to the host contributing to severe disease. For instance, work performed almost 40 years ago showed for the first time that under particular conditions, antibodies against viruses can enhance infection, instead of inhibiting infection as normally seen. In the intervening years work by scientists all over the world has associated antibody-dependent enhancement (ADE) of infection to many types of viruses; ADE is even thought to be a risk factor to serious disease with dengue virus, and has been shown in vitro for the AIDS virus and Ebola virus. We have recently discovered a molecular mechanism which explains how antibody enhances viral infection in vitro. In studies on immune cells infected with Ross River Virus (RRV) we found that infection helped by antibody resulted in the specific disruption to the production of cellular chemicals which are toxic to viruses. Are these mechanisms of antibody-enhanced infection also found in animals? Will such mode of infection cause enhanced disease and tissue pathology (arthritis) in animals?Read moreRead less
Estimating The Burden Of Group A Streptococcal Diseases In Victoria
Funder
National Health and Medical Research Council
Funding Amount
$386,760.00
Summary
Despite the considerable advances in the diagnosis and treatment of group A streptococcal (GAS) diseases made during the last century, the impressive spectrum of infections caused by this organism continues to have a significant impact in developed countries. This spectrum includes diseases that are mild but common (e.g. sore throat, skin sores), rare but very severe (e.g. bloodstream infections, flesh-eating bacteria) and those that are more common in developing countries and the Aboriginal pop ....Despite the considerable advances in the diagnosis and treatment of group A streptococcal (GAS) diseases made during the last century, the impressive spectrum of infections caused by this organism continues to have a significant impact in developed countries. This spectrum includes diseases that are mild but common (e.g. sore throat, skin sores), rare but very severe (e.g. bloodstream infections, flesh-eating bacteria) and those that are more common in developing countries and the Aboriginal population (e.g. rheumatic fever, kidney disease). Streptococcal sore throat remains one of the most common childhood infections, and severe group A streptococcal diseases are thought to be increasing in incidence in Australia. Yet, there are no accurate data on the incidence and costs of these or other GAS diseases in non-Aboriginal Australians, or in most other populations around the world. It is becoming more urgent to collect this data as numerous vaccine candidates are entering human trials, new approaches to the treatment of sore throat are emerging, and new strategies to treat and control the spread of severe disease are being developed. We propose a comprehensive strategy to measure the incidence, prevalence and costs of each group of GAS diseases. We will follow a group of families for 12 months to detect cases of GAS sore throat and skin sores and measure the impact on the family. We will survey children in schools to estimate the prevalence of skin sores. We will check hospital records to calculate the number of cases of rheumatic fever and kidney disease. And we will maintain surveillance for severe diseases by checking hospital and laboratory records. We will also check to see if family members of people with severe disease have the GAS bacterium in their throats. We will then compile these data into a comprehensive estimate of the burden of disease in Victoria, and estimate the cost-effectiveness of different treatment and prevention strategies.Read moreRead less
Molecular Studies Of The Astrocyte Reservoir Of HIV-1 In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
HIV infects the brain causing dementia in 10-20% patients. Strategies aimed at eradicating HIV infection fail to take into account CNS infection. Understanding the way in which HIV enters, infects and replicates in the brain is pivotal in development of drugs to prevent brain infection and dementia. Our studies have shown that HIV infection of the brain involves mechanisms distinct to those observed for blood and other organs. This study seeks to clarify such mechanisms.
Immunising Aboriginal Mothers With Pneumococcal Polysaccharide Vaccine To Prevent Infant Ear Disease And Carriage
Funder
National Health and Medical Research Council
Funding Amount
$1,131,530.00
Summary
Aboriginal children experience the highest rates of acute and chronic ear infections in the world, with resultant permanent ear damage, hearing loss and educational disadvantage. These infections are mainly bacterial, and Streptococcus pneumoniae (pneumococcus) is the predominant pathogen. Pneumococcal colonisation and infection begins within days of birth, many months before any potential immunological protection from infant pneumococcal conjugate vaccine may be expected. New strategies are nee ....Aboriginal children experience the highest rates of acute and chronic ear infections in the world, with resultant permanent ear damage, hearing loss and educational disadvantage. These infections are mainly bacterial, and Streptococcus pneumoniae (pneumococcus) is the predominant pathogen. Pneumococcal colonisation and infection begins within days of birth, many months before any potential immunological protection from infant pneumococcal conjugate vaccine may be expected. New strategies are needed to eliminate, or at least delay, this early-onset pneumococcal colonisation. One such strategy is the administration to the mother of pneumococcal vaccine, which may protect the newborn infant by leading to higher titres of transplacental or breast milk pneumococcal antibodies and-or by reducing carriage (and transmission to the infant) of maternal pneumococci. Previous small studies using this strategy have been encouraging, but there have been no studies properly evaluating carriage or disease endpoints in infants. The polysaccharide pneumococcal vaccine is currently recommended for all Aboriginal and Torres Islander persons aged 15 years or more in the Northern Territory but uptake of the vaccine has been poor. We propose to conduct a pilot study to determine if maternal immunisation with this vaccine, either in the third trimester of pregancy of immediately following delivery, can reduce pneumococcal carriage and the prevalence of middle ear disease among Aboriginal infants at seven months of age. We aim to recruit 210 Aboriginal women who have uncomplicated pregnancies from Darwin and remote communities in the Top End of the Northern Territory. Each subject and their infant offspring will be followed-up after vaccination and at birth, one , two and seven months after birth.Read moreRead less
Surveillance Of LGV Chlamydia Trachomatis Types Among Men Who Have Sex With Men (MSM)
Funder
National Health and Medical Research Council
Funding Amount
$194,875.00
Summary
Chlamydia is a common sexually transmitted infection (STI) caused by the bacterium, Chlamydia trachomatis (CT). Annually, 50 million new cases of chlamydia are estimated to occur worldwide which if untreated, can lead to serious complications such as pelvic inflammatory disease and infertility in women and epididymitis in men. Over the past decade, there has been a sharp increase in diagnoses of chlamydia in Australia, coinciding with a reported upsurge in sexual risk behaviour (increased partne ....Chlamydia is a common sexually transmitted infection (STI) caused by the bacterium, Chlamydia trachomatis (CT). Annually, 50 million new cases of chlamydia are estimated to occur worldwide which if untreated, can lead to serious complications such as pelvic inflammatory disease and infertility in women and epididymitis in men. Over the past decade, there has been a sharp increase in diagnoses of chlamydia in Australia, coinciding with a reported upsurge in sexual risk behaviour (increased partner numbers and-or practices of unprotected sex), particularly among men who have sex with men (MSM). In addition, there are current outbreaks of an invasive CT strain, causing lymphogranuloma venereum (LGV), throughout Western Europe, with cases now reported in the USA. LGV can lead to severe anogenital ulcers, which can increase transmission of HIV, hepatitis C, and other STIs. With growing international travel, the likelihood of LGV outbreaks in Australia, particularly in MSM, is increased. Recently, isolated cases of LGV have been noted in MSM attending Sydney and Melbourne Sexual Health Centres, indicating LGV is possibly already in circulation. Since we know little about circulating CT types in Australia it would be difficult to assess the burden of an LGV outbreak. Due to increasing CT infections and likely risk of increased HIV transmission, particularly with LGV strains, surveillance of CT genotypes in Australia, especially in MSM, is important. The purpose of this study is to type CT strains in our population by looking at their genetic makeup. CT-positive specimens from Melbourne and Sydney will be used to identify CT types in circulation and to assess if LGV types are present. The knowledge obtained from this study will be novel and invaluable, and could contribute considerably to the development of improved disease prevention and intervention strategies, including the design of vaccines.Read moreRead less
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin i ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.Read moreRead less
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$606,000.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that c ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that cause severe damage. Further, cells deficient in frataxin are sensitive to oxidant stress and Fe chelators rescue oxidant-mediated death of cells from FA patients. Indeed, free radical scavengers have shown to be of use in the treatment of this disease. Studies in DR's lab during this NHMRC grant have shown that frataxin is down-regulated by erythroid differentiation or the haem precursor, protoporphyrin IX (BLOOD 2002;99:3813-22). These data indicate a role for frataxin in Fe metabolism and the pathogenesis of FA. In this study we will continue to examine the role of frataxin in the way cells handle Fe using experimental models developed under the current NHMRC grant. These include transfected cell lines with low frataxin expression generated using an expression vector containing anti-sense frataxin cDNA. Further we obtained the frataxin conditional KO mouse and generated a breeding colony. These animals display many of the pathological features of FA and are the best current model of the disease. Indeed, they will be critical for assessing the role of frataxin in Fe metabolism and as a model to test the ability of Fe-binding drugs to prevent the pathology observed. We designed lipid-soluble chelators that can enter the mitochondrion to bind Fe (Biochim Biophys Acta 2001;1536:133-140) and these ligands will be tested to prevent disease progression in the KO mice. This exciting research is crucial for understanding the pathogenesis of FA and in creating new therapies.Read moreRead less