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No description available.

This study was conducted in two parts, a survey study and a comparative balance and mobility pilot study. Firstly, a series of self-administered questionnaires were mailed to people in Queensland with chronic fatigue syndrome (CFS). The main purpose of the survey study was to 1) develop a demographic and health profile of the population of people who suffer from CFS in Queensland; 2) to establish the reliability and validity of an alternate measure of fatigue, the Multidimensional Assessment of Fatigue (MAF) and 3) to document functional mobility, history of falls and degree of fear of falling experienced by those with CFS. The average age of CFS subjects who participated in the survey study was 52 years, and 69 percent were between the ages of 40 and 70 years. Seventy-seven percent of the subjects were women. CFS subjects reported a mean duration of CFS symptoms of 16.95 years. Sixty-three percent of CFS subjects suffered from a concomitant diagnosis of fibromyalgia. Fatigue severity was measured by the Fatigue Severity Scale (FSS) and the MAF. The mean fatigue score obtained from the FSS and the MAF was 6.3 (SD+/-0.7) and 37.81 (SD+/-6.96) respectively. The FSS (Intraclass Coefficient=0.9, p<0.001) and the MAF (Intraclass Coefficient=0.84, p<0.001) were highly reliable when measuring fatigue in CFS over two occasions within a one-month period. There was a weak, but significant correlation between the MAF and the FSS (Spearman’s Rank Order Coefficient=0.476, p<0.001), indicating that the MAF is a reliable and valid measure of fatigue in the CFS population. Fifty-one percent of the CFS cohort reported a history of a fall occurring in the past six months, while thirty-nine percent of the total CFS cohort were identified as recurrent fallers. A fear of falling was reported by fifty-two percent of CFS subjects. The mean modified falls efficacy score for the CFS cohort was 7.7 (SD. +/-2.24). Falls and fear of falling appeared to be related to a concurrent diagnosis of fibromyalgia. The high incidence of falls and fear of falling in the CFS population prompted a pilot comparative study of balance and mobility function in women with CFS. The main aims of this study were to 1) identify the type of balance and mobility deficits experienced by a cohort of younger women with CFS; 2) to compare balance and mobility function of women with CFS to an age matched control group and 3) to identify the test conditions that are best able to differentiate the balance and mobility performance of the CFS cohort and controls. The grip strength, gaze stability and balance and mobility function of 14 females with a current diagnosis of CFS and 20 age matched control females was tested. Upper limb strength (p<0.003) and dynamic visual acuity (p<0.003) were significantly reduced in CFS subjects when compared to control subjects. There were no significant differences between CFS and control subjects for postural stability measures of bilateral stance on the Clinical Test of Sensory Integration of Balance. There was a strong trending increase in velocity of postural sway demonstrated when CFS females stood on a firm surface with eyes closed (p=0.018). No significant difference between the CFS cohort and the controls was demonstrated for all single leg stance (SLS) time and sway measures. However there was a strong trend for increased postural sway and less time measured for left and right SLS with eyes open. Slower reaction times when weight shifting in a mediolateral direction ((R) p=0.004, (L) p=0.007) were demonstrated in CFS subjects. CFS subjects performed the Timed Up and Go (TUG) test, manual TUG and the combined TUG significantly slower than control subjects (p=0.001). Gait parameters were significantly different between the two groups on all 10m walk tests. CFS subjects exhibited a slower gait velocity, shorter step length, less cadence and longer duration of gait cycle. Dual tasking did not appear to effect the gait pattern of CFS subjects more than controls, however, more complex multitask conditions may have identified greater differences between the two groups. This study has demonstrated that a community based cohort of the CFS population in Queensland experience significant levels of impairment and disability associated with fatigue and other CFS symptoms, falls and perceived fear of falling. Preliminary findings suggest that people with CFS exhibit mild balance and mobility deficits and impaired upper limb strength and gaze stability. Recommendations are made regarding the future delivery of intervention programmes for people with CFS in Queensland.

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No description available.

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Background Congestive heart failure is a common clinical syndrome, the incidence and prevalence of which appear to be increasing. Mortality and morbidity remain high despite major advances in the understanding of the pathophysiology and management of heart failure over recent years. Consequently there is a need for further therapies which can improve the outlook for patients with heart failure. The beta-blockers have traditionally been contraindicated in patients with heart failure. However, there is a strong rationale for using these agents in addition to the ACE inhibitors. The aims of this thesis were several fold. Firstly, to determine the magnitude of the problem which heart failure represents in New Zealand. Secondly, to determine the effects of beta-blockers, on LV size and function, symptoms, and exercise tolerance in patients with heart failure due to ischaemic heart disease. Finally, to conduct a systematic overview to determine the effects of beta-blockers on total mortality in patients with heart failure. Methods Data were obtained from the New Zealand Health Information Service regarding hospitalisations and deaths due to heart failure in New Zealand. A randomised, placebo-controlled trial of the effects of carvedilol, a vasodilator beta-blocker, was carried out in 20 hospitals in Australia and New Zealand. In this study patients with heart failure due to ischaemic heart disease were randomised to either carvedilol or placebo in addition to their usual treatment. An echocardiographic substudy was carried out in 10 of the 20 centres. The aims of this substudy were to determine the effects of carvedilol on left ventricular size and function, using quantitative 2D-echocardiography. Finally, the effects of beta-blockers on total mortality was examined in a systematic overview. Results The data regarding heart failure in New Zealand showed that each year there were an average of 8000 hospital admissions each year of 5000 patients with heart failure. In addition, there were at least 850 deaths each year directly related to heart failure. The cost associated with the hospital admissions was estimated at NZ$50 million per year, or 1% of the total health budget in New Zealand. The ANZ carvedilol study demonstrated firstly, that carvedilol is well tolerated in patients with heart failure due to ischaemic heart disease. Left ventricular ejection fraction improved compared with placebo treated patients and left ventricular size was reduced when assessed by M-mode echocardiography. Despite these improvements in left ventricular function, symptoms and exercise tolerance were unchanged. However, there was a reduction in a combined end-point of death or hospital readmission in the carvedilol group compared with placebo. The 2D-echocardigraphy substudy demonstrated that carvedilol reduced both end-diastolic and end-systolic volumes and prevented the progressive LV dilatation which occurred in the placebo group. These changes occurred with the improvement in LV ejection fraction which had previously been reported. In addition to these favourable effects on LV size and function, left ventricular regional wall motion was improved. The overview of 24 randomised trials involving 3141 patients showed that beta-blocker therapy reduced total mortality by 31% compared with control. Conclusions Firstly, the NZ data has confirmed that heart failure remains a major public health problem in New Zealand. The ANZ Carvedilol Trial has shown the carvedilol is safe and well tolerated in patients with heart failure due to ischaemic heart disease. Carvedilol improved left ventricular ejection fraction, reduced left ventricular volumes and improved left ventricular regional wall motion. In addition, carvedilol reduced death or hospital readmission but had little effect on symptoms or exercise tolerance. The results from the meta-analysis have shown that beta-blocker therapy reduced total mortality by approximately one-third. Such data support the use of beta-blockers in addition to ACE inhibitors in the treatment of patients with heart failure. However, further randomised, controlled trials are required to reliably determine the effects of beta-blockers in different patient subgroups, such as the elderly and those with more severe heart failure, as well as the effects on total mortality before such therapy can be recommended for widespread use in all patients with heart failure. / Whole document restricted, but available by request, use the feedback form to request access.

The search for new compounds with anti-tumour activity is driven by the high mortality from disseminated visceral carcinomas for which few effective treatments exist. The experimental agent flavone acetic acid (FAA) has stimulated interest because of its broad spectrum of activity against solid tumours in mice. This remarkable activity spectrum suggested an unusual mechanism of action. The aim of the thesis was to elucidate the mechanism of action of FAA and its analogues in mouse tumours, particularly the rapid induction of haemorrhagic necrosis Light and electron microscopic studies of Colon 38 tumours treated with 1.2 mmo1/kg FAA revealed a sequence of tumour cell separation and rounding focal apoptosis and finally confluent necrosis with blood vessel engorgement and rupture within 4 - 8 h. This was accompanied by a loss of energy metabolites. The combination of apoptotic and necrotic modes of cell death suggested that both ischaemic and non-ischaemic mechanisms were involved. The role of blood flow failure was further investigated in Colon 38 and EMT6 tumours using a double label fluorescent vessel-labelling technique, which demonstrated a progressive and sustained fall in blood flow, beginning within 15 min of treatment. A mathematical model of ischaemic tumour cell killing using data from measurements of tumour perfusion, the rate of FAA-induced cell killing and the rate of cell death following global ischaemia indicated that mechanisms in addition ischaemia were involved. However, comparison of the resistance to FAA of avascular intraperitoneal tumour multicellular spheroids and vascularised tumours suggested that the major component of the anti-tumour effect was indeed blood vessel-dependent. The vessel-independent effects of FAA were then studied in vitro, using EMT6 tumour multicellular spheroids which had been placed for six days in the peritoneal cavities of mice to become infiltrated by macrophages and lymphocytes. These ex vivo spheroids were more that twice as sensitive as spheroids grown entirely in vitro, when exposed to 2.5 mM FAA for 24 h. This provides evidence for immune cell mediation of the FAA anti-tumour effect. To determine the relative importance of the vessel dependent and the immune mediated effects of FAA, a novel vascularised spheroid tumour system, which contained both avascular and vascular component was developed and studied. FAA treatment caused necrosis only in the vascularised component preceded by a loss in perfusion. The avascular tumour tissue also showed evidence of some cell loss by apoptosis. Thus, in tumour tissue not relying directly on blood vessels for metabolite exchange only limited cell killing occurs suggesting that treatment with FAA-like agents alone would have limited ability to cure. The anti-tumour activities of a series of xanthenone acetic acid (XAA) analogues of FAA, were then compared with FAA by examination and measurement of morphological changes in subcutaneous tumours and spheroids, and by measurement of blood perfusion In tumours. Those XAA analogues which were active in inducing haemorrhagic necrosis also caused FAA-like morphological changes in tumours and spheroids and inhibited blood flow, indicating a similar mode of action to FAA. The parent XAA and FAA were approximately equipotent, and 5-methyl XAA and 5,6-dimethyl XAA were about ten times as potent as FAA. 3-O-methyl XAA, 8-methyl XAA and xanthenone-4,5-diacetic acid showed no FAA-like activities. Examination of non-tumour tissues after therapeutic doses of FAA and 5,6-dimethyl XAA showed cytolytic lesions Including necrosis In the peripheral lymphoid tissues, the thymus and the uterus. Thus, although these agents lack the myelosuppressive effects of conventional chemotherapeutic agents cell killing is not entirely specific for tumours. The sensitive tissues, including tumours, have in common a high content of macrophages or neutrophils, and regions of low vascular density. The thesis studies have shown that FAA and its analogues differ from conventional cytotoxic (anti-proliferative) agents in their mechanism of action. Direct toxicity against tumour cells is of minor importance compared to macrophage mediated cytotoxicity and perfusion failure. If biological activity can be demonstrated in humans FAA-like agents may show clinical utility in combination with radiotherapy, conventional or hypoxia selective cytotoxic agents.

Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Status epilepticus (SE) is a prolonged and dangerous epileptic condition that can cause brain damage and may be one of the predisposing factors for the subsequent development of temporal lobe epilepsy. In this thesis, I investigate causes of SE as well as the receptors maintaining seizures and the associated neuropathological changes (cell death, sprouting) that occur in SE brain. An unequivocal role for a defect in either excitatory and inhibitory systems in SE generation has not been established. An alternative approach to unravelling the causes of SE may be to investigate whether an impairment of endogenous seizure termination mechanisms, likely to be mediated by adenosine may lead to SE development. The findings that specific A1-adenosine receptor antagonists with a central site of action were able to transform brief electrically-induced seizures into SE, while co-administration of specific A1-adenosine receptor agonists blocked this effect supports this hypothesis. Pertussis toxin-treated animals also developed SE after elicitation of a seizure suggesting inactivation of Gi-protein linked receptors are involved in SE development. Although GABAB and 5HT1A receptors are also coupled to the same subset of anticonvulsant K+ channels as the A1-adenosine receptor, antagonists at these receptors could not transform brief seizures into SE following seizure elicitation, although a GABAB, agonist had anticonvulsant effects. While chemically-induced SE models suggest that glutamatergic and cholinergic mechanisms are involved in SE initiation and maintenance, whether similar receptor mechanisms operate to initiate and maintain electrically-induced SE are unclear. Using specific antagonists of muscarinic and glutamate receptors, I have shown that NMDA receptors and possibly AMPA/kainate receptors are involved in the initiation of electrically-induced SE. AMPA/kainate receptors may be predominantly involved in maintaining SE, although NMDA receptors may sustain seizures in neocortical regions. Muscarinic and metabotropic glutamate receptors do not appear to have a role in initiation and maintenance of electrically-induced SE. Distinct neuropathological features associated with SE including cell loss and morphological changes in the hippocampus were observed. As early as six days after SE, selective damage to hippocampal neurons in the hilus, CA1 and CA3 pyramidal regions and interneurons immunoreactive for parvalbumin and somatostatin were observed after SE in the absence and presence of the A1-adenosine receptor antagonist 8-cyclopentyl-l, 3-dimethylxanthine (8-CPT). Seizure severity generated in the presence of 8-CPT is likely to account for the increased neuronal damage found in this model. Other changes included increases in selected GABAA receptor subunit (α1, α2, β2/β3 and γ2) immunoreactivity in the dentate granule cell and molecular layer of the hippocampus suggesting the possible increased formation of GABAA receptors with the subunit configurations α1,β2,γ2 and α1,β3,γ2. Neuronal injury was also accompanied by reactive gliosis and microglial proliferation and astrocytic expression of the growth factors basic fibroblast growth factor (bFGF) and insulin-like growth factor 1 (IGF-1). Long-term sequelae of SE-induced hippocampal damage such as the appearance of spontaneous seizures in the animals and synaptic reorganisation in the supragranular layer of the dentate gyrus were found 1-2 months after SE. The sprouting response was associated with an increase in brain-derived neurotrophic factor (BDNF) immunoreactivity in dentate granule cells and mossy fibre axons 1 and 2 months after SE. A BDNF and clusterin-immunoreactive band was also present in the supragranular layer at 2 months, suggesting these molecules may be involved in mediating the sprouting response. BDNF immunoreactivity was also present in mossy fibre axons in normal and epileptic human hippocampi but was only present in the inner molecular layer in epileptic tissue. In conclusion, the results in this thesis provide some new insights into possible mechanisms of SE development and associated neuropathological changes, which may be applicable to that found in humans.