Medicine (Austin & Northern Health) - Theses
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ItemThe therapeutics of Diabetes Mellitus : developmental and regulatory aspects(University of Melbourne, 2006)
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ItemThe expression and functional roles of angiotensin II receptors in prostate cancer(University of Melbourne, 2006)
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ItemThe physical function of the elderly with rheumatoid arthritis( 1997)This thesis contains a body of work concerned with the physical function of the elderly with rheumatoid arthritis (RA). Chapter 2 reviews the relevant literature including that concerned with functional status measurement, functional outcome in RA and RA in the elderly. Chapter 3 describes a study validating the adapted Barthel Index - which is commonly used to measure personal care and mobility activities of daily living (ADL) - in a self-report format. This study was performed on a sample of geriatric day hospital attendees in Edinburgh, Scotland. Chapter 4 outlines the methods used in the main study describing the physical function of the elderly with RA (ER), as compared with that in younger people with the disease (YR) and elderly unaffected control subjects (EC). This study was also conducted in Edinburgh, between 1988 and 1989. Physical functional performance and capacity were measured using the adapted Barthel Index in its previously validated self-report format. Chapter 5 presents the results of the main study, and Chapter 6 discusses these results and a number of other important issues relating to study methodology, general health status, unmet needs and physical function. The main research objectives of this thesis were to determine: 1.the level of physical functioning of older people with RA, in terms of self-care, mobility and instrumental activities of daily living, 2.if age or the rheumatoid process has a greater influence in determining physical functional outcome in older people with RA, 3.whether older people with RA are able to perform physically at, or near their level of functional capacity, and if not why, 4.the main determinants of physical functional performance, in terms of medical, social and psychological health status measures, and if they differ in older and younger people with RA.
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ItemThe effect of laser induced thermal ablation on liver tumours( 2005-11)Laser thermal ablation (LTA) is an in situ ablative technique that induces heat destruction of liver tumours. Despite increasing clinical use of LTA, reports of long-term outcomes and limitation of treatment in specific cohorts of patients with liver tumours are lacking. In addition, the mechanisms of action of therapy have not been fully elucidated. This study highlights the long-term clinical results and limitations of LTA in the treatment of a cohort of patients with unresectable colorectal liver metastases and examines the mechanisms of action of thermal ablative injury in a murine model.
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ItemA study to identify risk factors in the aetiology and cause of traumatic spinal cord paralysis( 1986)This thesis is primarily concerned with determining: I. Primary and Secondary risk factors in traumatic spinal cord paralysis. (a) PRIMARY RISK FACTORS are those factors which predispose an individual to develop traumatic spinal cord paralysis. (b) SECONDARY RISK FACTORS are those factors which determine prognosis from time of injury to the time the patient is admitted to the emergency room of the Spinal Injuries Unit. II. Developing a preventive programme based on the elucidated Primary and Secondary risk factors. All patients who sustained significant spinal cord injuries in Victoria or within 25 kilometres of the Victorian border who were admitted to the Victorian Spinal Injuries Unit, Austin Hospital during the study period (1st March 1983 to 28th December 1984) were included in the study.
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ItemThe pharmacokinetics and pharmacodynamics of calcium antagonists( 1988)This thesis describes the development of a specific, sensitive and reliable method for the simultaneous measurement of the parent drug and one of its metabolites at nanogram/ml levels for the dihydropyridines - nicardipine and. PY-108-068 in plasma. It demonstrates the application of pharmacokinetic principles and their relationship to the pharmacodynamic properties of these compounds. Increased systemic bioavailability of nicardipine with a corresponding increase in pharmacodynamic effect is shown in patients with liver disease, demonstrating the importance of the hepatic first-pass metabolism for this compound. Saturation kinetics are demonstrated for the PY-108-068 within the single dose range of 50-200mg orally. Age and concominant food ingestion does not significantly affect the elimination half-lives of PY- 108-068. This study demonstrates that PY-108-068 is more effective in lowering the blood pressure of patients in the old age-group, as compared to that in the young age-group, and that inhibition of reflex tachycardia occurs at higher blood levels than those producing a vasdilator effect. There is good correlations between plasma levels and blood pressure response for both nicardipine and PY-108-068.
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ItemIntensive care access, patient flow, and outcome from critical illness( 2004)Does resource allocation, timely access to intensive care, patient flow, and continuity of care during hospitalisation impact on the outcome of critically ill patients? A 3-month audit (pilot study) of 10 public hospitals within metropolitan Melbourne revealed that 9.4% of ICU admissions (3.1 patients per day) were unable to be admitted to the ICU of first choice due to limited staffing (52%) and bed shortage (46%.) Acute inter-hospital transfer (AIHT; 1.7 per day) was the most common (57%) immediate triage outcome. A cohort of 3,548 consecutive critically ill patients, admitted to the Intensive Care Unit (ICU) of The Northern Hospital, formed the core dataset for further study. Patient outcomes from this cohort compared favourably to the national benchmarks and therefore the conclusions are likely to be applicable to other Australian hospitals. A three-year case-control study of 73 AIHT (unable to be admitted to the ICU of first choice) revealed that AIHT was associated with a significant delay in admission to ICU (median = 5.0 hours), and a significant increase in length of stay in ICU and in hospital, and 6.9% increase in mortality-risk (OR= 1 .5; 95% CI = 0.68-3.4.) Management of low-risk patients in the general medical or surgical ward (instead of ICU or HDU) was associated with a 26% risk of delayed admission to ICU. A prospective cohort study of 619 critically ill patients requiring ventilator support and/or renal replacement therapy, admitted directly to ICU within 24 hours of arrival in the Emergency Department revealed that ICU lead-time (admission delay) is associated with an increased mortality risk (OR=1.06 per hour, 95% CI =1.01-1.10.) A prospective cohort study of 1870 ICU survivors found that at the time of ICU discharge to the ward three factors are predictive of hospital outcome: nightshift discharge (RR=1.7; 95% CI 1.03-2.9), limitation of treatment or resuscitation orders, and initial illness severity. Premature ICU discharge (of ICU survivors) is also associated with an increased mortality risk and unexpected ICU readmission rate.
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ItemFamily studies of epilepsy with simple and complex inheritance( 2002)The epilepsies are a group of disorders where genetic factors have been long known to play an important role. Genetic research in the last decade has led to the discovery of several mutated genes in some uncommon human epilepsies with autosomal dominant inheritance. The search of genes for epilepsies with complex inheritance has however been less successful. The general aim of this thesis was to study the genetics of epilepsies with simple and complex inheritance, using families with multiple affected family members. Accurate phenotyping was a strategy I used to try and minimise the problem of genetic heterogeneity. The study involved a long interview with all available living family members to collect clinical and genealogical information. Detailed electro-clinical characterisation of each individual's epilepsy syndrome was obtained. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was studied as a prototype of simple inheritance. Detailed clinical analysis of 5 ADNFLE families revealed some new clinical features including seizures triggered by sound or movement, and precipitated by fever, extreme tiredness or stress. In order to help distinguishing NFLE from parasomnias, I developed a motor activity scoring system in sleep (MAISS). In most cases this confirmed the clinical and or electrographic diagnosis. Molecular genetic analysis of 5 families and 11 sporadic cases by our collaborators revealed 2 new mutations in the genes coding for α4 and β2 subunits of the acetylcholine receptors (CHRNA4 and CHRNB2). A de novo CHRNA4 mutation was found in the proband and her second son in family A. This is the first de novo mutation found in epilepsy suggesting also that sporadic cases could have a genetic aetiology and such patients should be tested for the known mutations. A new mutation in CHRNB2 was found in family B, the mutation was present in family members with ADNFLE but was not found in family members with parasomnias defined by their MAISS score. The finding does not support the hypothesis of a common genetic aetiology between ADNFLE and parasomnias. Idiopathic generalized epilepsies (IGEs) are the most common and important group of epilepsies with complex inheritance. An exceptionally large family with 35 affected individuals was studied. The phenotypes included childhood absence epilepsy (CAE), febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+). Molecular genetic analysis showed that affected individuals had a mutation in the gene coding for the γ2 subunit of the GABAA receptor (GABRG2). The structure of the pedigree suggested that, in this family FS were inherited in an autosomal dominant fashion and caused by GABRG2 mutation. However, clinical genetic analysis suggested that whilst this mutation contributed to the CAE and GEFS+ phenotypes, it was likely that other genes were also involved. A second linkage analysis inclusive of only subjects with CAE disclosed a number of putative loci that could contain genes contributing to the absence epilepsy phenotype. I also studied 55 small families with IGEs that were more representative of IGEs found in the community. The clinical genetic analysis of the families showed a relatively homogeneous pattern of syndrome distribution within families. The phenotypic concordance with the proband was higher in first degree relatives compared to more distant relatives. The family analysis showed that the two recognized absence epilepsy syndromes were genetically closely related whilst juvenile myoclonic epilepsy was more distinct. The GABRG2 mutation was not found in any of these families. Two families with biparental IGEs were studied. The affected offspring of the 2 families had epilepsy phenotypes with characteristics of both parents' epilepsies. Finally, of 121 consecutive patients with new-onset IGE, 28% had seizures beginning at age 20 years or later (adult-onset). Similar to the classical IGE with age of onset before 20 years (as described by the ILAE classification), patients with adult-onset IGE could also be divided in subgroups depending on the predominant seizure types including absences, tonic-clonic and myoclonic seizures. Pedigree analysis of the 121 IGE patients and the comparison of the proportion of affected relatives between classical and adult-onset IGEs patients suggested a predominant genetic aetiology in both. In some pedigrees classical and late-onset IGEs patients co-occurred suggesting that they might share genetic determinants. Therefore adult-onset IGEs should be included in studies were genes for IGEs are sought. In conclusion the data from the large family in which a GABRG2 mutation was found, from the small multiplex families including biparental families and from patients with adult-onset IGEs all underscore the genetic basis of IGEs. Moreover, the clinical analyses, with distinct identifiable subsyndromes, is more suggestive of an oligogenic model of inheritance, involving few genes, rather than a polygenic model where many genes of small effect contribute to the individual phenotype.