No description available.

No description available.

No description available.

No description available.

No description available.

Aspirin is the first line treatment for the majority of stroke patients. Despite national guidelines and overwhelming evidence of the benefits of therapy, prescribing is sub-optimal: Research has identified that general practitioners (GPs) are unsure whether to prescribe for patients because of uncertainty about the balance of risks and benefits for individuals with unique characteristics. This thesis aimed to reduce uncertainty by enhancing the evidence base available to practitioners. Fresh data on the risks and benefits of treatment were produced specific to individuals with unique combinations of characteristics such as their age, time since onset of the initial stroke and history of diabetes and myocardial infarction. To improve the likelihood of the new data being drawn upon in a time constrained primary care consultation, an original computerised decision support system was also developed. This presents the new evidence in a format more likely to be accessed by practitioners. The system and the data were then evaluated among GPs. Specifically, the first phase of research developed a decision analysis model to simulate the benefits and risks of 'aspirin' and 'no treatment' (chapter 2). For each of 960 profiles the model utilised the best available evidence from published literature (chapter 3) and primary research (chapter 4) to reflect the risks of possible outcomes for individuals with each set of characteristics. Patient preferences of potential outcomes were then combined with the probabilities of these occurring to generate a prescribing recommendation and other risk data (chapter 5). The second phase of research developed a user-friendly computer interface to enable GPs to draw upon the data in a consultation (chapter 6). This provides GPs with easy access to a range of risk data in several styles,including numerical, graphical and pictorial formats. Fifteen GPs evaluated the system (chapter 7). Both quantitative and qualitative results indicated that GP 'decision certainty' improved and 'decision conflict' decreased. GPs felt more organised about their decision-making, were more able to consider the pros and cons and felt better prepared. Practitioners also felt that the system would help them communicate the decision to patients, would aid patient understanding and encourage them to involve patients in decision making. This study therefore generated fresh evidence to support decision making in the secondary prevention of stroke and developed a new decision support system to help GPs draw upon this in a time constrained patient consultation. The positive evaluation results demonstrate the potential value of this system and the wider potential of decision analysis to general practice

No description available.

Over the last two decades the use of the environment as a therapeutic tool in the care of people with dementia has become more popular. Despite this, there is a lack of research which includes an empirical measure of behaviour to assess the impact that dementia friendly interventions have on people with dementia. Much of the current research focuses on the perceptions of the staff and relatives on the impact the environment has on people with dementia. There is a small body of research which attempts to include an empirical measure of behaviour, however due to small sample sizes in this type of research it is difficult to generalise the findings to a wider population. An extensive literature review identified the living area of care homes as the area most commonly used by residents yet it is the area that has received the least attention in terms of creating a dementia friendly environment.

Background/ aims: Bipolar disorder is associated with significant impairment in a broad range of neuropsychological processes in addition to hypothalamic-pituitary-adrenal (HPA) axis dysfunction and hypercortisolaemia. As both animal and human models have highlighted the role of cortisol in the modulation of memory processes, attempting to understand this link is of critical importance. The aims of this thesis are to first profile neuropsychological and HPA axis function in individuals with a diagnosis of bipolar disorder, before examining if these functions can be altered through an intervention with an antiglucocorticoid drug. The subsequent chapters of this thesis will report analyses designed to explore specific aspects of these changes in more detail, principally alterations in spatial memory processes. Method: The thesis reports two broad phases of research. The first is a study of 20 participants diagnosed with bipolar disorder (with depressive symptoms) who first completed a broad neuropsychological assessment and profiling of afternoon cortisol and DHEA levels. These individuals then entered a randomised crossover study to examine the effects of mifepristone (RU-486), a glucocorticoid receptor antagonist, on neuropsychological functions and mood. A second cohort of 53 participants diagnosed with bipolar depression (BD) and 47 healthy controls was recruited to explore aspects of the results in more detail, particularly the fractionation of spatial memory and the integration of neuropsychological processes and their relationship with measures of HPA axis function. Results: 1) BD participants exhibited broad neuropsychological impairment across a range of cognitive domains in addition to hypercortisolaemia. 2) Administration of an antiglucocorticoid drug significantly reduced cortisol levels and improved spatial working memory performance. 3) The underlying neuropsychological component structure of BD and controls differed. 4) BD participants exhibited impairments in fine-grain metric spatial memory which, unlike other spatial processes, could not be explained by other measures. 5) A unique profile of processes underpinning aspects of visuospatial memory was observed in BD, suggesting a form of cognitive ‘scaffolding’. 6) A simple link between neuropsychological processes and peripheral HPA axis measures was not observed. Conclusion: Spatial memory processes in bipolar depression can be altered by direct HPA axis manipulation. A number of interesting avenues for future research have been identified that will further our knowledge of the integration between the biological mechanisms underlying neuropsychological impairment in mood disorders and should develop our understanding of integration between cognitive processes in general.

Zinc is essential to the structure and function of numerous proteins and enzymes so requires tight homeostatic control at both the systemic and cellular level. Two families of zinc transporters – ZIP (SLC39) and ZnT (SLC30) – contribute to zinc homeostasis. There are at least 10 members of the human ZnT family, and the expression profile and regulation of each varies depending on tissue type. Little is known about the role and expression pattern of ZnT10; however in silico data predict restricted expression to foetal tissue. In this thesis I show a differential expression profile for ZnT10 in adult human tissue by RT-qPCR and detect highest levels of expression in small intestine, liver and brain tissues. I present data revealing the functional activity of ZnT10 to be in the efflux direction. Using a plasmid construct to express ZnT10 with an N-terminal FLAG-epitope tag, subcellular localisation in a neuroblastoma cell line (SH-SY5Y) is shown to be at the Golgi apparatus under standard conditions of culture, with trafficking to the plasma membrane observed at higher extracellular zinc concentrations of 100 μM. I demonstrate using RT-qPCR down-regulation of ZnT10 mRNA levels in cultured intestinal and neuroblastoma cell lines in response to extracellular zinc, a response which is mirrored at the protein level. Furthermore, I demonstrate reduced transcription from the putative ZnT10 promoter at an elevated extracellular zinc concentration. Reduction in ZnT10 mRNA expression in response to increased extracellular cobalt and conversely, an up-regulation of ZnT10 mRNA levels in response to increased extracellular nickel has also been observed by RT-qPCR in both SH-SY5Y and Caco-2 cells. Neither of these responses were reflected at the level of transcription using the ZnT10 promoter construct. In transiently transfected SH-SY5Y cells Western blotting reveals a reduction in p3xFLAG-ZnT10 protein levels in response to extracellular zinc; however both extracellular cobalt and nickel caused an increase in the level of p3xFLAG-ZnT10 protein measured. Trafficking was observed with both cobalt and nickel treatments. Movement from the Golgi apparatus to a more diffuse localisation pattern was observed with cobalt treatment, whereas nickel elicited a response similar to zinc, with trafficking toward the plasma membrane. Extracellular copper did not induce a change at any level of investigation. These features of ZnT10 localisation, regulation and function, together with the discovery that ZnT10 is expressed at high levels in brain tissue, indicate that ZnT10 has a role in regulating zinc homeostasis in the brain. Further investigation highlighted a down-regulation of ZnT10 in human Alzheimer’s disease brain tissue and in the APP/PS1 transgenic mouse brain. Zinc was also shown to influence splicing events of β-secretase enzyme, known to be involved in Alzheimer’s disease pathology. Zinc promoted an increase in the most active isoform at the mRNA level and thus the measured dysregulation of ZnT10 and therefore potential changes in levels of zinc may have relevance to the development of neurodegenerative disease.