Effects And Mechanisms Of Direct Cardiac Compression In Interruption Of Myocardial Remodelling In Chronic Heart Failure.
Funder
National Health and Medical Research Council
Funding Amount
$392,250.00
Summary
Heart failure (HF) is a disease where the heart pumping function is insufficient to provide adequate blood supply to the rest of the body. It is a highly debilitating disease affecting nearly 10 million people worldwide and has a <50% one-year survival in severe cases. Despite significant advances in pharmacotherapy, heart transplant is the only alternative for severe HF but is restricted by lack of donor organs to only ~ 5% of those requiring it. Research has shown that progression of HF is ....Heart failure (HF) is a disease where the heart pumping function is insufficient to provide adequate blood supply to the rest of the body. It is a highly debilitating disease affecting nearly 10 million people worldwide and has a <50% one-year survival in severe cases. Despite significant advances in pharmacotherapy, heart transplant is the only alternative for severe HF but is restricted by lack of donor organs to only ~ 5% of those requiring it. Research has shown that progression of HF is related to many subsequent changes after an initial insult. In addition to pumping failure, HF is associated with deranged compensatory responses such as neurohumoral over-activation, heart chamber enlargement, loss of functional cells, increase of inflammatory mediators and changes in cardiac skeleton (extracellular matrix). The changes in the heart are collectively known as remodelling. Mechanical heart assist is now considered a potential destination therapy for severe HF, superior to pharmacotherapy alone. Improvement of cardiac pumping function and even successful weaning from devices has been reported, along with observations of reverse remodelling. The success of this approach has been limited however, particularly with HF due to coronary disease, the most prevalent form. We developed a novel HeartPatch mechanical assist device to compress the heart from its outer surface. It gives support to both main chambers and avoids blood contact, a feature of currently available devices associated with complications such as blood clotting and infection. Our device has proved effective in animals with acute HF and even with cardiac arrest. We propose to study the effects of our device on the process of remodelling in HF with coronary disease in a controlled manner. The project will enhance understanding of the mechanisms involved in reverse remodelling and further the development of a device which may potentially benefit many severe HF patients.Read moreRead less
Optimising Lung Protective Resuscitation Using A Newborn Premature Lamb Model
Funder
National Health and Medical Research Council
Funding Amount
$392,218.00
Summary
Premature babies are at risk of severe, and potentially long-term, lung damage. These complications can be minimised if babies are optimally resuscitated at birth. This project will use promising new imaging technologies to examine the influence of different strategies, using mechanical ventilators, to help inflate the lung at birth, and their interactions with other therapies used to enhance lung maturity. It will provide new insights into resuscitating preterm babies.
Prostaglandin G/H Synthase-2 (PGHS-2) Is A Key Regulator Of Skeletal Adaptation And Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$301,018.00
Summary
Knowledge of the biology underlying bone formation is important for developing novel approaches to stimulate new bone formation in skeletal diseases associated with ageing or disability, or for maintenance of new bone around orthopaedic or dental implants. The discovery that a prostaglandin enzyme (PGHS-2) is a key factor in activity-related bone formation and normal bone turnover, as well as a pharmacological target for reducing inflammation, has considerable clinical significance. Specific inh ....Knowledge of the biology underlying bone formation is important for developing novel approaches to stimulate new bone formation in skeletal diseases associated with ageing or disability, or for maintenance of new bone around orthopaedic or dental implants. The discovery that a prostaglandin enzyme (PGHS-2) is a key factor in activity-related bone formation and normal bone turnover, as well as a pharmacological target for reducing inflammation, has considerable clinical significance. Specific inhibition of PGHS-2 by recent anti-inflammatory drugs avoids formation of gastric ulcers, but their influence on normal bone remodelling and fracture repair is not known and must be investigated. Many such inhibitors are in advanced clinical trials, but their effect on bone metabolism has not been published. This project is important because it employs novel experimental models to advance our knowledge of prostaglandin biology in skeletal adaptation, and elucidates important clinical consequences for specific inhibition of PGHS-2 in the skeleton. This project will investigate the regulation of prostaglandin production by PGHS enzymes following mechanical loading in vivo. It will use cell, molecular and histochemical techniques to determine if the genes that regulate the enzymes are influenced by mechanical stimuli, and if they are dependent on other molecules, associated with structural proteins (stress fibres) within the cell. It will investigate if inhibition of PGHS-2 by antiinflammatory drugs or stress-fibre inhibitors, depresses normal bone turnover and healing responses. The outcome of these experiments could indicate new approaches to stimulate bone formation, preserve bone mass, or minimise adverse skeletal effects of anti-inflammatory treatments related to orthopaedic or dental procedures.Read moreRead less
Does Variable Ventilation Offer Physiological And Biological Benefits For The Preterm Lung?
Funder
National Health and Medical Research Council
Funding Amount
$320,278.00
Summary
Lung disease is a significant cause of illness at birth, subsequent breathing problems and death in very premature babies. We know that chronic preterm lung disease results in part from the immature state of the lung at birth, but it appears that inflammation of the lung also plays an important role. We, and others, have shown that this lung inflammation can be a response to injury from mechanical ventilation after birth. In the past, we have sought to strictly control the way that babies are ve ....Lung disease is a significant cause of illness at birth, subsequent breathing problems and death in very premature babies. We know that chronic preterm lung disease results in part from the immature state of the lung at birth, but it appears that inflammation of the lung also plays an important role. We, and others, have shown that this lung inflammation can be a response to injury from mechanical ventilation after birth. In the past, we have sought to strictly control the way that babies are ventilated. We have regulated the pressures used to inflate their lungs, the amount of volume delivered to the lung, the amount of time that the baby has to take a breath. This is a marked contrast to breathing patterns in healthy infants and adults, in which each of these things vary considerably from breath to breath. Recent studies have shown that the presence of variability in breathing patterns is actual essential to the process of staying healthy and maintaining resting lung volume above a critical lower limit. This study will provide unique insights into a new and potentially highly beneficial approaches to ventilation for preterm infants. We will determine if there is a significant clinical benefit of incorporating variability into the ventilatory waveform used to treat newborn babies with lung disease. has the potential to cause a paradigm shift in current concepts of preterm infant ventilatory strategies. Potential long term outcomes include significantly reducing illness and death associated with preterm birth, and promoting a healthier start to life for the over 6000 infants who require ventilatory assistance each year within the Australian and New Zealand neonatal network.Read moreRead less
Determination Of Irradiation Dose Efficacy For Use In Impaction Grafting At Revision Joint Replacement
Funder
National Health and Medical Research Council
Funding Amount
$411,517.00
Summary
Primary hip replacement is a successful intervention for hip disease, but 10-15% of hip prostheses fail and require revision surgery within 10-15 years. At the time of revision, significant bone loss around the failed prosthesis is not uncommon. A bone reconstruction procedure, called impaction grafting, where donor bone is minced and placed in the areas of deficient bone before implanting the new prosthesis, has shown to give good results at more than ten years in some centres. A high incidence ....Primary hip replacement is a successful intervention for hip disease, but 10-15% of hip prostheses fail and require revision surgery within 10-15 years. At the time of revision, significant bone loss around the failed prosthesis is not uncommon. A bone reconstruction procedure, called impaction grafting, where donor bone is minced and placed in the areas of deficient bone before implanting the new prosthesis, has shown to give good results at more than ten years in some centres. A high incidence of early complications of this procedure have included loss of fixation within the bone. Fracture of the bone around prostheses has also reported in some centres. These events require more surgery, putting the patient at higher risk greater complications and longer rehabilitations. Recent improvements in surgical technique and donor bone preparation have improved results. A current debate questions whether the dose of irradiation can be reduced from 25 kGy, while maintaining sterility of allografts. The risk of bacterial contamination in allografts is low, and irradiation reduces the mechanical strength of the graft, contributing to complications when irradiated bone is used. The benefits of decontaminating the bone may be outweighed by the higher risk for failure due to poor bone quality and resulting prosthesis instability. We will use ISO standards to test the validity of radiation dose for sterilising bone ex vivo. In the absence of controlled human studies, our aim is also to compare the results of impaction grafting with non-irradiated bone versus bone irradiated at current doses used by Australian bone banks, and lower doses indicated by ex vivo testing. We will use a large animal model of revision hip replacement, with precise measures of prosthesis stability. The results of this study will guide clinical decisions regarding the efficacy of current bone graft preparation procedures and the use of irradiated bone in human hip replacement surgery.Read moreRead less
A Clinical And Experimental Study Of The Biomechanical Factors Associated With Tooth Destruction
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
This project investigates the influence of biting force on the development of non-carious and carious defects of teeth. Strain gauges will be cemented to the neck region of extracted teeth and teeth in the mouth, forces applied to the biting surfaces of the teeth, and the stress which results will be measured by the strain gauge. A profiling technique and high-power microscopy will be used to determine the amount of tooth structure lost as a result of applying the forces in the presence of acid. ....This project investigates the influence of biting force on the development of non-carious and carious defects of teeth. Strain gauges will be cemented to the neck region of extracted teeth and teeth in the mouth, forces applied to the biting surfaces of the teeth, and the stress which results will be measured by the strain gauge. A profiling technique and high-power microscopy will be used to determine the amount of tooth structure lost as a result of applying the forces in the presence of acid. In addition, a computer model will be generated, to determine whether it can be used to predict the stresses. In a clinical study, patients with and without non-carious defects will be followed for three years in order to assess the morphological changes and measure the volume loss of tooth structure which occurs.Read moreRead less
Randomised Controlled Trial Of Therapeutic Pulmonary Lavage In Meconium Aspiration Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$182,550.00
Summary
Meconium aspiration syndrome (MAS) is a serious respiratory disease of full term infants, which can lead to very severe respiratory failure. It is caused by the inhalation of meconium, the secretion of the fetal intestine, into the lung at or prior to delivery. As a result, the airways and air sacs within the lung are damaged, leading to difficulty with breathing and poor oxygen levels. About one-third of all infants with MAS require mechanical ventilation in the first days of life, and are ofte ....Meconium aspiration syndrome (MAS) is a serious respiratory disease of full term infants, which can lead to very severe respiratory failure. It is caused by the inhalation of meconium, the secretion of the fetal intestine, into the lung at or prior to delivery. As a result, the airways and air sacs within the lung are damaged, leading to difficulty with breathing and poor oxygen levels. About one-third of all infants with MAS require mechanical ventilation in the first days of life, and are often extremely difficult to manage. At present, the main treatments given to a ventilated infant with severe MAS are supportive, rather than curative. Lung cleansing procedures are not part of routine care in this condition, even though removal of meconium from the lung may reduce the amount of damage that occurs. This project is a randomised controlled trial of a lung cleansing procedure called lung lavage in ventilated infants with severe MAS. During the lung lavage, a quantity of cleansing fluid containing a natural substance called surfactant is introduced into the lung, and then removed by suctioning. This procedure cleanses the lung of some of the meconium, and in preliminary testing, appears to be safe and well-tolerated even in the sickest infants. In the proposed trial, we will randomly allocate ventilated infants with severe MAS to receive either a lung lavage procedure, or routine care. This will take place within 24 hours of birth. We are looking to see whether the lavage procedure shortens the duration of ventilation, oxygen therapy or hospitalisation. Because there are only a small number of ventilated infants with MAS at any one centre per year, we will involve as many Australian neonatal intensive care units as we can in the study. We aim to enrol 66 infants in the trial, of whom half will receive lavage therapy.Read moreRead less