Cellular Mechanisms Of Pacemaking In The Upper Urinary Tract: Effects Of Sensory Neuropeptides And Prostaglandins
Funder
National Health and Medical Research Council
Funding Amount
$80,680.00
Summary
The mammalian upper urinary tract (UUT) serves to propel urine from the renal pelvis within the kidney through the ureter to the bladder, where it is stored until micturition. This propulsion of urine from the renal pelvis to the bladder occurs by the means of spontaneous peristaltic contractions in the smooth muscle wall of the UUT, intimately dependent on the localized release of prostaglandins. Approximately 10% of the population suffer from renal calculi (kidney stones) at some stage of thei ....The mammalian upper urinary tract (UUT) serves to propel urine from the renal pelvis within the kidney through the ureter to the bladder, where it is stored until micturition. This propulsion of urine from the renal pelvis to the bladder occurs by the means of spontaneous peristaltic contractions in the smooth muscle wall of the UUT, intimately dependent on the localized release of prostaglandins. Approximately 10% of the population suffer from renal calculi (kidney stones) at some stage of their lifetime, with men being 2-4 times more likely than women to have calculi. Pain management of renal colic usually involves the prescribing of strong analgesics, and antispasmodic and nonsteroidal anti-inflammatory agents. Most stones are expelled spontaneously if they are small. Larger stones require interventions such as fragmentation (extracorpereal lithotripsy), which is an out patient procedure, or physical removal, using ureterscopes or endoscopes or open surgery under general anesthesia; procedures usually requiring hospital stays of 2-7 days. This project will provide valuable information on the mechanisms by which sensory nerves and endogenous prostaglandins control motility in the mammalian UUT. In particular, these studies will contribute to the search of specific anti-inflammatory agents which will affect particular aspects of UUT motility. A clearer understanding of the cellular origin of UUT rhythmicity will lead to more informed non-surgical interventions to encourage the passing of painful calculi. Such information will also aid in the treatments of other forms of renal colic, during ureteric obstruction, and urinary tract infection. Ureteric stasis is an important condition to avoid, if left untreated permanent kidney damage usually occurs within 6 weeks.Read moreRead less
Neurochemicals In The Control Of Human Bladder Function
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
The problem of urinary incontinence has received little attention from the medical and scientific research community until the last 10-15 years. Urinary incontinence can cause severe distress and is a taboo subject, even though it affects 30-40% of women. Public figures speak out about their experiences with breast cancer or heart disease, but not about leakage of urine. Elderly people with incontinence are forced into nursing homes, with major costs to the community. Incontinence is a major cli ....The problem of urinary incontinence has received little attention from the medical and scientific research community until the last 10-15 years. Urinary incontinence can cause severe distress and is a taboo subject, even though it affects 30-40% of women. Public figures speak out about their experiences with breast cancer or heart disease, but not about leakage of urine. Elderly people with incontinence are forced into nursing homes, with major costs to the community. Incontinence is a major clinical problem: although over 800 new patients per annum are seen at our Pelvic Floor Unit, the waiting time for a first appointment is 14-15 weeks. There are four main types of urine leakage: - stress incontinence (weak pelvic floor muscles); - overflow incontinence (seen in men with prostatic hypertrophy); - sensory urgency (frequent, uncomfortable desire to urinate); and - detrusor instability (bladder muscle spasms with leakage). We are primarily interested in detrusor instability and sensory urgency, which cause 35% of incontinence in general, but up to 85% of cases in the elderly. Patients suffer from an urgent desire to visit the toilet frequently, and may leak urine if they cannot reach the toilet quickly. Unlike stress incontinence, it cannot be corrected by pelvic floor surgery. Drug treatment is often unsuccessful, with many unacceptable side effects. In our research group, we have found that the sensory nerve which convey the sensation of bladder fullness, are overabundant and display increased amounts of neurochemicals. Our studies in isolated bladder muscle from these patients have shown abnormalities in responsiveness. Thus bladder from women with urge incontinence is resistant to drugs which abolish contraction in normal bladder. In this project we plan to find out why such changes occur. We will use new techniques to study bladder nerves and the receptors which convey the message to contract the bladder muscle.Read moreRead less
Sensory Mechanisms In Normal Bladder And In Cystitis
Funder
National Health and Medical Research Council
Funding Amount
$408,861.00
Summary
The function of the lower urinary tract is to store urine and release it at appropriate times. This requires neural circuits in the brain, spinal cord and peripheral ganglia. When the bladder fills, sensory neurones fire and activate these neural circuits to store urine or to empty the bladder. If sensory neurones are too easily excited (a process called sensitisation ) this will lead to clinical disorders, including the common painful bladder syndromes, whose cause is not known (interstitial cy ....The function of the lower urinary tract is to store urine and release it at appropriate times. This requires neural circuits in the brain, spinal cord and peripheral ganglia. When the bladder fills, sensory neurones fire and activate these neural circuits to store urine or to empty the bladder. If sensory neurones are too easily excited (a process called sensitisation ) this will lead to clinical disorders, including the common painful bladder syndromes, whose cause is not known (interstitial cystitis, sensory urgency etc). These are characterised by pelvic pain, urinary urgency, frequency and, in some cases, urge incontinence (loss of urine for no apparent reason) which results from unstable or overactive bladder. Despite a large database of knowledge about the sensory innervation of the bladder, many important gaps still exist. These gaps have restricted the development of new therapies. For example, we have little idea about exactly which functional classes of sensory neurones signal filling of the normal bladder or what different types of information they carry. This is vital information for understanding which neurones are affected in disease states and whether they are all affected in the same way. We have developed new methods that will allow us to identify the major classes of sensory neurones that innervate the bladder, what they respond to and how they are activated. We will also determine whether some classes are preferentially sensitised by inflammation and the most important mechanisms that are likely to underlie this. The significance of this project is that it provides the basic scientific understanding of sensory innervation of the bladder and will identify potential targets for selective pharmacological intervention in common bladder disorders.Read moreRead less
A Randomised Placebo-controlled Trial Of Antibiotics To Prevent Urinary Tract Infection In Children
Funder
National Health and Medical Research Council
Funding Amount
$735,000.00
Summary
This study is needed to determine whether a common clinical practice long-term antibiotic treatment for children following urinary tract infection (UTI) - is safe and effective in preventing further UTI and if so, whether all appropriate children are being treated. UTI will affect about 10% of Australian children by high school age (88,000 children per year). Because UTI may damage the kidneys, the management priority for children with UTI has been prevention of further infection. Currently this ....This study is needed to determine whether a common clinical practice long-term antibiotic treatment for children following urinary tract infection (UTI) - is safe and effective in preventing further UTI and if so, whether all appropriate children are being treated. UTI will affect about 10% of Australian children by high school age (88,000 children per year). Because UTI may damage the kidneys, the management priority for children with UTI has been prevention of further infection. Currently this means the identification of children thought to be most at risk of recurrent UTI by renal tract imaging. Those found to have reflux of urine from the bladder to the kidney (present in about 30% of those with UTI) are then placed on antibiotics fro 2-5 years. Unfortunately there has never been a properly designed trial to test whether antibiotics do really prevent UTI and if so, whether children with reflux are the appropriate and only group requiring treatment. Long term antibiotics may in fact do more harm than good because of side effects like skin, bowel and blood problems and because resistant bacteria may develop. The design of this study involves the random allocation of placebo or antibiotic (cotrimoxazole, the usual antibiotic given in this case) to about 800 children after their first symptomatic UTI. These children are treated and followed for one year to determine the rate of futher UTI in both groups. Any difference in outcome between the two groups of children will be because of the antibiotic treatment. This study may prove long-term antibiotics are ineffective and therefore should not be routinely used. In this case investigation of children to detect vesicoureteric reflux would serve little purpose and should be abandoned. Alternatively antibiotic treatment may be shown as effective treatment for preventing further UTI and in this case the study will clearly identify those children who will benefit.Read moreRead less
Targeted Pelvic Floor Muscle Training For Urinary Incontinence After Radical Prostatectomy: A Randomised Controlled Trial With Embedded Physiological Studies
Funder
National Health and Medical Research Council
Funding Amount
$966,377.00
Summary
Prostatectomy is a common treatment for the most common cancer in men. Survival is good, but many develop debilitating urinary incontinence. Past pelvic floor muscle training has had limited effect, but recent work has changed understanding of how muscles control continence and compensate for surgery. This clinical trial compares innovative training individually tailored to optimise continence, usual exercise and no treatment, and aims to identify men most likely to benefit from treatment.
Urinary Tract E. Coli: The Good Guys Versus The Bad Guys
Funder
National Health and Medical Research Council
Funding Amount
$296,150.00
Summary
Escherichia coli is the primary cause of urinary tract infection (UTI) in the developed world. In Australia alone, E. coli affects more than 250,000 yearly to the extent where they require medical intervention. It is estimated that one in four women and one in twenty men will develop a UTI in their lifetime and in the USA UTIs result in $1.6 billion in medical expenses each year. Uropathogenic E. coli (UPEC) strains readily form biofilms on indwelling catheters and recent evidence suggests that ....Escherichia coli is the primary cause of urinary tract infection (UTI) in the developed world. In Australia alone, E. coli affects more than 250,000 yearly to the extent where they require medical intervention. It is estimated that one in four women and one in twenty men will develop a UTI in their lifetime and in the USA UTIs result in $1.6 billion in medical expenses each year. Uropathogenic E. coli (UPEC) strains readily form biofilms on indwelling catheters and recent evidence suggests that they also form biofilm-like aggregates in the bladder. No treatment other than antibiotics (often inefficient due to resistance) is currently available. E. coli is also the most frequent cause of asymptomatic bacteriuria (ABU). ABU occurs in up to 6% of healthy individuals and affects high risk groups such as the elderly and diabetics. In general, most patients with ABU do not need treatment and in many cases the colonizing organism actually helps to prevent infection by other more virulent bacteria. The aim of this project is to compare UPEC and ABU E. coli for differences associated with virulence and biofilm growth. The project will generate a comprehensive and defined strain bank relative to E. coli that cause UTI. Understanding biofilm growth by this organism may lead to the development of improved and-or novel treatments. Furthermore, increased knowledge of ABU E. coli is essential if we are to fully explore the possibility of employing these organisms as probiotic agents to prevent infection by other pathogens in specific high risk patient groups.Read moreRead less
Role Of Macrophages In Uropathogenic E. Coli Infections
Funder
National Health and Medical Research Council
Funding Amount
$574,890.00
Summary
Urinary tract infections (UTI) are one of the most common types of infections in humans. They are also a major cause of septic shock, a condition with high fatality rates. Uropathogenic Escherichia coli (UPEC) are the major microbes causing UTI in humans. This project addresses the role of an immune cell type, the macrophage, in UPEC-mediated disease. The outcomes of this project will be a better understanding of how UPEC causes disease, and potentially new treatment regimes for UTI.
Therapeutic Targeting Of Interleukin-22 For Severe Paediatric Urinary Tract Infection And Associated Renal Complications
Funder
National Health and Medical Research Council
Funding Amount
$997,139.00
Summary
Urinary tract infections are among the most common bacterial infections and are associated with the development of chronic kidney disease. The bacteria that cause these infections are becoming increasingly resistant to antibiotic therapy. Therefore, new strategies that target the immune system rather than the bacteria are urgently needed. This study will provide evidence for re-purposing novel immunotherapies targeting the protein interleukin-22 that are being developed for other diseases.