Alzheimer's disease (AD) is associated with decreased brain energy metabolism. Hypometabolism in the posterior cingulate cortex (PCC) occurs before the onset of memory deficits in subjects at genetic risk for AD who are not yet cognitively impaired. There is a specific inhibition in cytochrome oxidase (C.O.) in the PCC, an area involved in spatial navigation. Creating an animal model that exhibits the early pathophysiology of AD is important for developing and testing drugs that could reverse memory problems associated with such deficits. Methylene blue (MB) is a compound that improves C.O. activity and memory retention in rats. This dissertation had three specific aims: 1) to examine if isolated PCC hypometabolism causes spatial memory deficits in rats; 2) to find a dose of MB that improves memory without nonspecific behavioral effects; and 3) to prevent memory deficits from PCC hypometabolism with low dose MB. PCC hypometabolism was produced by focal administration of sodium azide, an inhibitor of C.O. activity. PCC hypometabolism resulted in impaired spatial memory in a hole board food-search task, increased oxidative damage, and neurotoxicity in the PCC. In addition, PCC hypometabolism resulted in reduced inter-regional correlations in brain activity. Our second set of studies examined the dose-response effects of MB. Our findings demonstrated that a low dose of MB: 1) enhanced memory in open field habituation and object recognition tasks; 2) did not affect general locomotor activity, exploration, motivation, or anxiety; and 3) increased brain oxygen consumption 24 hr after in vivo administration. Finally, our last study found that low dose MB prevented the deficits caused by PCC hypometabolism. MB did not prevent PCC inhibition or cell loss caused by sodium azide. Inter-regional correlations of brain metabolic activity suggested that rats treated with MB were using a different, but equally efficient, strategy for memory retrieval. This animal model of C.O. hypometabolism in the PCC can provide information to understand the mechanisms that regulate early pathological degeneration and reveal new therapeutic strategies aimed at reducing or preventing cognitive decline. Studies of low dose MB in humans are needed to examine its effects in AD patients.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / Medicine / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Master of Philosophy

The purpose of this thesis is to describe the organization of the movements of skilled reaching. Our knowledge of reaching behaviour has been limited to an understanding of specific actions. Results from this thesis describe how reaching is the product of interactions of various parameters that assemble in an integrative way in ontogeny, yet can become dismantled on one level, or generally, throughout multiple levels of what constitutes the behaviour after stroke in adults. These findings demonstrate that skilled reaching constitutes motor parameters that may not be visible in a healthy adult, but that function through development, and by inhibitory systems in adults, to create a smooth and finely articulated action. An examination of the movement patterns of reaching within the full context of the behaviour can be applied to therapeutic strategies for motor disorders and, most importantly, deepen our understanding of the relations between reaching and cognition. / xiii, 254 leaves : ill. (some col.) ; 29 cm

Stroke is a preventable disease. Minor stroke and transient ischaemic attack (TIA) are important warning signs of the possibility of a major stroke. Worldwide, stroke is the third most common killer and the largest cause of disability. The incidence of stroke is predicted to increase with the predominance of unhealthy lifestyles and the aging population. The adoption of a healthy lifestyle can reduce many of the risk factors. This descriptive study was designed to explore patients’ understanding of modifiable risk factors of cerebrovascular disease. It investigated lifestyle changes actually made, as well as the factors affecting patients’ decisions about whether to make lifestyle changes. The two major factors considered were patients’ sources and level of knowledge and their attitudes and beliefs around making changes. A convenience sample of patients who had suffered a minor stroke or TIA was recruited through a major metropolitan hospital. Thirty-five subjects responded to a postal questionnaire. The mean age was 68 years and 37% of the subjects had sustained some disability as a result of the TIA or minor stroke. The results demonstrated that many subjects had a poor understanding of risk factors of stroke. While smoking was well recognised as a risk factor, subjects showed less awareness of other risk factors, such as excessive alcohol consumption and obesity. Subjects also reported significant confusion regarding diet. Sixty-six percent of subjects depended on doctors as their main source of health information. This may be problematic as the current shortages of General Practitioners has put pressure on doctors to keep appointment times short and reduce the time available for health education. The main barriers to lifestyle change, were lack of motivation, and inadequate, knowledge, guidance, and support and the inability to access good information. Although 83% of subjects suffered from hypertension, medication was the accepted method of control, few subjects realised the significance of lifestyle factors. Nine percent of subjects were only diagnosed with hypertension after their stroke or TIA and few monitor their own blood pressure, despite the wide availability of home monitoring devices. From the findings of this study it is concluded that health promotion and education are very important strategies in the prevention of stroke and it is recommended that this kind of education begins in childhood with tailored, age-specific programs delivered to the public over the lifespan. The role of health screening cannot be underestimated in the detection of risk factors such as hypertension and obesity. Early detection makes effective treatment possible and helps prevent the occurrence of strokes, thus reducing the cost to the community. Long-term health strategies such as improving health resource distribution and enhancing health education are needed where patients and their families participate together in comprehensive education programs. It is hoped that this may lead to a shared understanding, which may translate to patients being more supported, and therefore more able, to make the necessary lifestyle changes. Dysphagia is a common complication following stroke, which can result in significant morbidity and mortality. Multidisciplinary collaboration facilitates management strategies, decision-making and the efficiency of rehabilitation. Nurses are responsible for coordination of management and in particular for continuous monitoring, assessment of swallowing and nutritional state, maintaining safety and preventing complications. An understanding of the issues and strategies relating to management may provide valuable information to enhance the safety, cost-effectiveness and quality of care. A retrospective review of patients’ medical records was used to collect data. A sample of ninety-five adults who were admitted to an Australian public hospital between January 2003 and April 2006, with a diagnosis of dysphagic stroke were recruited. Statistical Package for Social Sciences (SPSS) was used to analyse the quantitative data, while content analysis was used to analyse the qualitative data. All subjects were assessed by a speech pathologist, the mean age was 75 years and 50.5% were male. Except for critically ill subjects, almost all were assessed within three days. Ninety-six percent of subjects had communication problems and 81% had upper limb motor impairment. During hospitalisation almost 60% of subjects had an improvement in their oral intake including 8% resuming their premorbid diet. Eighteen percent were on enteral tube feeding upon discharge, 4% deteriorated and 16% died. It appears that oral intake of most subjects was unsatisfactory. When recorded the mean body weight lost was 2.3kg. At least 22% had malnutrition or dehydration. Forty-five percent aspirated and 22% had respiratory infection. Almost half of the subjects (48%) were discharged to aged care facilities. Eighty percent had no documented follow-up scheduled for management of their dysphagia. Early identification of dysphagia, prudent supervising of appropriate oral intake and mouth care may help to maintain safe swallowing, preventing aspiration and chest infection. Regular checks of body weight, serum albumin level, oral intake and early enteral feeding are essential to guide nutritional support, minimise malnutrition and problematic medication administration. Encouraging oral intake and providing families with support could promote recovery of swallowing skills and help patients to regain the ability to eat independently. Providing helpful information on the care options available may allay patient and family anxiety. A qualified nurse practitioner could assess patients and ensure that a tailored care plan was designed to meet patients’ needs and this may improve the outcomes considerably. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1320650 / Thesis (D.Nurs.) - University of Adelaide, School of Population Health and Clinical Practice, 2008

More than 15 million people worldwide will suffer a stroke each year two thirds will die or be left permanently disabled. Accordingly, stroke represents an enormous financial burden on the community, due to the cost of hospitalisation, treatment and rehabilitation of stroke patients. Despite the significance of this public health problem, a safe and widely applicable stroke therapeutic remains elusive. Cerebral oedema is widely recognised as a common and often fatal complication of stroke that is associated with worsened outcome. However, the exact mechanisms of oedema formation remain unclear, with current therapies largely ineffective in addressing the mechanisms of cerebral swelling, and also being associated with their own negative side-effect profile. This thesis characterises the role of neurogenic inflammation and the neuropeptide, substance P (SP), in mediating the development of blood brain barrier breakdown, cerebral oedema and resultant functional deficits following stroke, using a rodent model of reversible cerebral ischaemia. The findings of this thesis demonstrate that increased SP immunoreactivity, particularly of the penumbral tissue vasculature, is a feature of tissue perfusion following stroke, but not in non-reperfused infarcts. The central role for SP in the breakdown of the BBB following stroke and the associated deleterious effects of such breakdown was confirmed by studies using an NK₁ receptor antagonist. These antagonists conferred a profound attenuation of BBB breakdown, cerebral oedema formation, neuronal death and injury, and the associated development of functional deficits following reversible stroke. Similarly, depletion of all neuropeptides by capsaicin pre-treatment also reduced both histological abnormalities and functional deficits following stroke, confirming the central role of neuropeptides in the secondary injury process after stroke. The NK₁ receptor antagonist was able to be safely combined with the currently approved treatment for stroke, tPA, producing a synergistic effect of greater protection from the ischaemic insult. In particular, histological and functional outcome were markedly improved, as well as a reduction in the risk of intracerebral haemorrhage and death. Furthermore, the NK₁ receptor antagonist was effective even when administered up to 8 h following the onset of ischaemia, and in a variety of stroke severities. We conclude that SP plays a central role in the secondary injury that occurs following stroke, in particular, the genesis of BBB breakdown and cerebral oedema. Accordingly, combination therapy of tPA and an NK₁ receptor antagonist may offer a novel therapeutic strategy for the clinical management of ischaemic stroke of varying severity. / http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1298280 / Thesis (Ph.D.) -- The University of Adelaide, School of Medical Sciences, 2007

More than 15 million people worldwide will suffer a stroke each year two thirds will die or be left permanently disabled. Accordingly, stroke represents an enormous financial burden on the community, due to the cost of hospitalisation, treatment and rehabilitation of stroke patients. Despite the significance of this public health problem, a safe and widely applicable stroke therapeutic remains elusive. Cerebral oedema is widely recognised as a common and often fatal complication of stroke that is associated with worsened outcome. However, the exact mechanisms of oedema formation remain unclear, with current therapies largely ineffective in addressing the mechanisms of cerebral swelling, and also being associated with their own negative side-effect profile. This thesis characterises the role of neurogenic inflammation and the neuropeptide, substance P (SP), in mediating the development of blood brain barrier breakdown, cerebral oedema and resultant functional deficits following stroke, using a rodent model of reversible cerebral ischaemia. The findings of this thesis demonstrate that increased SP immunoreactivity, particularly of the penumbral tissue vasculature, is a feature of tissue perfusion following stroke, but not in non-reperfused infarcts. The central role for SP in the breakdown of the BBB following stroke and the associated deleterious effects of such breakdown was confirmed by studies using an NK₁ receptor antagonist. These antagonists conferred a profound attenuation of BBB breakdown, cerebral oedema formation, neuronal death and injury, and the associated development of functional deficits following reversible stroke. Similarly, depletion of all neuropeptides by capsaicin pre-treatment also reduced both histological abnormalities and functional deficits following stroke, confirming the central role of neuropeptides in the secondary injury process after stroke. The NK₁ receptor antagonist was able to be safely combined with the currently approved treatment for stroke, tPA, producing a synergistic effect of greater protection from the ischaemic insult. In particular, histological and functional outcome were markedly improved, as well as a reduction in the risk of intracerebral haemorrhage and death. Furthermore, the NK₁ receptor antagonist was effective even when administered up to 8 h following the onset of ischaemia, and in a variety of stroke severities. We conclude that SP plays a central role in the secondary injury that occurs following stroke, in particular, the genesis of BBB breakdown and cerebral oedema. Accordingly, combination therapy of tPA and an NK₁ receptor antagonist may offer a novel therapeutic strategy for the clinical management of ischaemic stroke of varying severity. / http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1298280 / Thesis (Ph.D.) -- The University of Adelaide, School of Medical Sciences, 2007

ENGLISH ABSTRACT: HIV/AIDS is the leading cause of death in Sub-Saharan Africa. According to 2001 estimates, there are 28.5 million people living with HIV in Africa, comprising more than 70% of the world’s HIV-infected population. HIV/AIDS remains one of the most important social and public health threats in Sub-Saharan Africa. UNAIDS 2006 estimates that 5.5 million people are living with HIV, and almost 1,000 AIDS deaths occur every day in South Africa. South Africa is currently one of the most severely affected countries in the world. Antiretroviral therapy (ART) is currently the only treatment available for HIV. It does not cure HIV infection, but reduces HIV related mortality and morbidity. / AFRIKAANS ABSTRACT: No abstract available

In response to the urgent call for investigations into antiretroviral (ARV)-African traditional medicine (ATM) interactions, this research was undertaken to ascertain whether chronic administration of the ATM, Sutherlandia frutescens (SF) may alter the bioavailability of the protease inhibitor (PI), atazanavir (ATV), which may impact on the safety or efficacy of the ARV. Prior to investigating a potential interaction between ATV and SF in vitro and in vivo, a high performance liquid chromatography method with ultraviolet detection (HPLC-UV) was developed and validated for the bioanalysis of ATV in human plasma and liver microsomes. An improved and efficient analytical method with minimal use of solvents and short run time was achieved in comparison to methods published in the literature. In addition, the method was selective, linear, accurate and precise for quantitative analysis of ATV in these studies. Molecular docking studies were conducted to compare the binding modes and affinities of ATV and two major SF constituents, Sutherlandioside B and Sutherlandin C, with the efflux transporter, P-glycoprotein (P-gp) and the CYP450 isoenzyme, CYP3A4 to determine the potential for these phytochemicals to competitively inhibit the binding of ATV to these two proteins, which are mediators of absorption and metabolism. These studies revealed that modulation of P-gp transport of ATV by Sutherlandioside B and Sutherlandin C was not likely to occur via competitive inhibition. The results further indicated that weak competitive inhibition of CYP3A4 may possibly occur in the presence of either of these two SF constituents. The Caco-2 cell line was used as an in vitro model of human intestinal absorption. Accumulation studies in these cells were conducted to ascertain whether extracts and constituents of SF have the ability to alter the absorption of ATV. The results showed that the aqueous extract of SF significantly reduced ATV accumulation, suggesting decreased ATV absorption, whilst a triterpenoid glycoside fraction isolated from SF exhibited an opposing effect. Analogous responses were elicited by the aqueous extract and a triterpenoid glycoside fraction in similar accumulation studies in P-gp overexpressing Madin–Darby Canine Kidney Strain II cells (MDCKII-MDR1), which signified that the effects of this extract and component on ATV transport in the Caco-2 cells were P-gp-mediated. The quantitative analysis of ATV in human liver microsomes after co-incubation with extracts and components of SF was conducted to determine the effects of SF on the metabolism of ATV. The aqueous and methanolic extracts of SF inhibited ATV metabolism, whilst the triterpenoid glycoside fraction had a converse effect. Analogous effects by the extracts were demonstrated in experiments conducted in CYP3A4-transfected microsomes, suggesting that the inhibition of ATV metabolism in the liver microsomes by these SF extracts was CYP3A4-mediated. A combination of Sutherlandiosides C and D also inhibited CYP3A4-mediated ATV metabolism, which was in contrast to the response elicited by the triterpenoid fraction in the liver microsomes, where other unidentified compounds, shown to be present therein, may have contributed to the activation of ATV metabolism. The in vitro studies revealed the potential for SF to alter the bioavailability of ATV, therefore a clinical study in which the effect of a multiple dose regimen of SF on the pharmacokinetics (PK) of a single dose of ATV was conducted in healthy male volunteers. The statistical analysis showed that the 90 % confidence intervals around the geometric mean ratios (ATV + SF/ATV alone) for both Cmax and AUC0-24 hours, fell well below the lower limit of the "no-effect" boundary of 0.8 – 1.25, implying that the bioavailability of ATV was significantly reduced in this cohort of subjects. It may thus be concluded that if the reduction in bioavailability observed in this clinical study is found to be clinically relevant, co-administration of SF commercial dosage forms and ATV in HIV/AIDS patients may potentially result in subtherapeutic ATV levels, which may in turn contribute to ATV resistance and/or treatment failure. This research has therefore highlighted the potential risk for toxicity or lack of efficacy of ARV regimens which may result when ATMs and PIs are used concurrently and that patients and health care practitioners alike should be aware of these perils.