There is considerable research to date in the field of stress, particularly with respect to questionnaire research. There is, however, a lack of recent research on stress in the British Army which addresses either traumatic or organisational stress. This study considers soldiers' experiences of both occupational and traumatic stress, in addition to identifying the contribution of an individual's expectations and evaluations of a deployment, on mental well-being. Furthermore, this research methodology incorporates standardised psychological questionnaires, free response items and interviews with personnel, which serve to provide a comprehensive approach with high face validity. This study aims to encompass the major aspects which influence the onset and course of stress, including stress experiences, individual differences and coping, in one model. Both studies incorporate traumatic and organisational stress, which is particularly relevant in the military profession, where there is risk of exposure to traumatic events. This study attempts to redress the paucity of research on stress in the British Army as a result of conflicts since WWII, in addition to countering the lack of research into occupational stress in the British Army, or information of a longitudinal nature. This study also provides a much needed 'baseline' of data across the British Army regarding stress experiences and reactions. The study also incorporates qualitative aspects, where the respondents are asked what they define as stressful experiences, as opposed to completing a list of pre-defined 'stressors', in addition to incorporating interviews to validate the responses. Finally, an individual's evaluation of a situation, or belief in their actions is taken into account in this research. It is argued that this is of particular importance in a military operational context, when soldiers are no longer deploying in defence of their country against an external threat. It was therefore considered important to establish if there were any effects on psychological well-being based on an individual's evaluation of the deployment situation. This research was conducted in two phases: Study 1 which is a cross-sectional study, proportionate to size across the British Army, and Study 2 which is a longitudinal survey, before and after a six month operational deployment to Northern Ireland. The questionnaire material incorporates both standardised questionnaires and a specific Army questionnaire designed for the study. Support was found for the proposed models of both general (Study 1) and operational stress (Study 2). Previous findings were supported concerning the interrelationships between neuroticism, anxiety, emotion focused coping and adverse life events, and were independent of mastery, self esteem, problem focused coping and well-being. Thirty three and thirty nine percent of respondents reported General Health Questionnaire (GHQ12) values above the cut off criteria for Study 1 and Study 2, respectively. Individual differences concerning reported mental health were noted, particularly with respect to age, marital status and the occurrence of a significant life event. Recommendations addressed the lack of clear evidence for adopting a 'screening out' procedure based upon personality characteristics for mainstream Army deployments. It was suggested that the traumatic aspects of the research could benefit from an alternative questionnaire to the Impact of Events Scale (IES), due to some of the difficulties found in using the questionnaire. It was also suggested that coping strategies should be investigated in greater detail, within a more context specific manner with tighter response definitions. Finally, it is believed that the impact of cumulative operational deployments on the mental health of soldiers needs to be thoroughly researched.

The purpose of this thesis was to examine the nature of executive function deficits in ecstasy users, and the contribution of these executive functions to performance on other cognitive tasks. Using recent theoretical models of executive functioning recreational ecstasy-polydrug users were tested in laboratory settings on measures of mental set switching, response inhibition, memory updating and access to semantic memory. It was found that ecstasy users performed significantly worse than nonusers on measures of updating and access, although cocaine also emerged as an important factor in deficits in access. The contribution of access and updating to performance on more complex executive function tasks was then assessedI.t was found that while associative learning is relatively independent of access and updating, the same was not true for everyday memory and syllogistic reasoning. Ecstasy group related deficits in syllogistic reasoning were slightly attenuated following control for access and substantially following control for updating. It emerged that everyday memory deficits were more related to the use of cannabis than the use of ecstasy. The results of this thesis have serious implications for those who use ecstasy and should be used in educating such individuals. Outside the area of Psychopharmacology this thesis provides further support for the nature of executive functions and their relationship with syllogistic reasoning and everyday memory. Future research should assess executive functions along the same paradigm and seek to recruit polydrug control groups.

It is commonly observed that people with autism spectrum disorder (ASD) make fewer attempts to have social contact. A recent theory suggests that reduced motivation to have social interactions might be the root for social difficulties in ASD (Chevallier, Kohls, Troiani, Brodkin, & Schultz, 2012). There are currently few simple behavioural ways to test these claims. The aim of this research was 1) to develop a measure of social seeking component of social motivation that is simple enough to be used with a large population of people with ASD; and 2) to test if there is evidence of reduced social seeking in people with ASD. As the first part of this research, I developed and tested a simple behavioural paradigm “Choose-A-Movie” (CAM) that evaluates the effort participants make to view social vs non-social stimuli hence estimating the reward value of the stimuli. It was found that typical adults prefer to watch social stimuli more but they trade-off their stimuli preference for effort. In experiment 2 I used the same paradigm with adults with and without ASD and found that unlike typical adults people with ASD prefer non-social stimuli but they too trade-off their stimuli preference for effort. Having established the efficacy of the CAM paradigm in adults with and without ASD, in experiment 3 I explored CAM’s efficacy for younger participants. A comparison between adolescents with and without ASD on CAM showed that both groups prefer choice requiring less effort, and participants with ASD prefer non-social stimuli to social. However unlike typical adults, typical adolescents did not show a preference for social stimuli. Though these experiments supported the reduced social motivation theory of ASD, they raised questions about the development of social seeking in typical people. Therefore, in experiment 4 I tested participants between ages 4-20 years on CAM. The results showed that typical individuals undergo a decline in their social seeking tendencies during pre-adolescence. This highlights the need for developmental evaluation of social seeking in both ASD and non-ASD populations. Finally, in experiment 5 the CAM paradigm was compared with an Approach-avoidance (AA) task, a frequently used measure of social seeking (Aharon et al., 2001). The findings suggested that social preference could be elicited more strongly in typical adults using CAM paradigm. Furthermore the autistic traits of participants were a reliable predictor of social seeking on CAM but not on AA task. These results raise the question of whether different tools claiming to measure social seeking target the same behaviour. Overall, this research shows that social motivation can be quantified using a simple behavioural paradigm – CAM that targets social seeking component of it, and also that social motivation is reduced in people with ASD. At the same time this research raises important questions about 1) developmental changes in social seeking in typical people, and 2) if different tools of social seeking, measure the same underlying construct. It is important to explore these questions to have a better understanding of social seeking in people with ASD.

The Stroke Drivers Screening Assessment (SDSA) is a collection of three cognitive tests found predictive of driving in stroke patients. Whilst two of the test (Square Matrices and Road Sign Recognition) were good predictors of on-road performance, it remained unknown whether the SDSA could predict fitness to drive for people with other acquired neurological disabilities. The on-road test, considered the 'gold standard' of driving ability, was the criterion against which SDSA performance was compared. Since the SDSA's validity depends on the reliability of the driving instructor's decision, it seemed important to check that this was consistent with instructors elsewhere. Therefore this study had three aims:- i)To examine the content and concurrent validity of the SDSA sub test. ii)To determine whether the SDSA, either alone or in conjunction with other cognitive tests, could predict fitness to drive for patients with acquired neurological disabilities other than stroke. iii) to check the inter-rater reliability of the gold standard of driving ability (used in studies to validate the SDSA).

Alzheimer’s disease is the most common of the degenerative brain diseases and is characterised by impairment of cognitive function. Patients with this disorder lose the ability to encode new memories. Eventually, both declarative and non-declarative memory is significantly impaired, resulting in the capacity for reasoning, abstraction and language becoming progressively reduced. Alzheimer’s disease and other dementias have devastating effects on families and caregivers, and is an increasing burden in an ageing society. It is estimated that 36 million people worldwide are living with dementia and this figure is expected to double every 20 years. The worldwide costs of dementia in 2010 were estimated to be $604 billion, an exorbitant figure that represents 1% of global GDP (World Alzheimer Report 2011). Alzheimer’s disease is the fourth leading cause of death in industrialised nations, preceded by cardiovascular disease, cancer and stroke. As yet there are currently no disease-modifying drugs approved to treat Alzheimer’s disease. The therapeutics that are available only temporarily alleviate symptoms of cognitive impairment, however, they do not halt the inevitable progression of the disease. As such, major scientific efforts are underway in order to develop drugs which can help stabilise the disease. The publication of the “Amyloid Hypothesis” by Dennis Selkoe in 1991 helped to focus research efforts towards a causative protein involved in the disease, the amyloid β protein (Aβ). Aggregation and deposition of the Aβ protein is fundamental in the aetiology of Alzheimer’s disease and its importance has been demonstrated by a number familial heterogeneous mutations in the amyloid precursor protein that promote increased Aβ deposition, resulting in early onset phenotypes. There are several other aspects involved in disease progression such as neuroinflammation and aberrant neuronal signalling, however, therapies targeting amyloid β aggregation have the potential to slow or even halt further neurodegeneration and anti-Aβ therapies are regarded as a logical approach to treating Alzheimer’s disease. Several endogenous pathways exist to prevent protein misfolding and subsequent aggregation following stressful cellular conditions. One pathway includes the amateur chaperones of the small heat-shock protein family, which have recently garnered interest due to their ability to inhibit the aggregation of amyloid-like proteins. In particular, Hsp20 was previously identified as having the ability to inhibit the aggregation of Aβ and could Abstract ii attenuate subsequent toxicity associated with Aβ peptides. Hsp20 was of particular interest to the Baillie group as it has well established cardio-protective functions, which are triggered by the phosphorylation of a serine residue (S16) at a consensus protein kinase A/G site. Hsp20 “activity” can therefore be readily modulated via inhibition of second messenger signal degradation by phosphodiesterases. The first part of this thesis investigated the interaction between Hsp20 and Aβ using Peptide Array technology. This technique allowed rapid characterisation of interacting domains and pinpointed key residues that mediated the protein-protein interaction. Using this approach, I demonstrated that the domain within Hsp20 that interacted with Aβ included the consensus PKA phosphorylation site (R-R-X-S). Upon introduction of a phospho-serine residue or a phospho-mimetic substitution, I was able to show that the binding of Aβ was enhanced. Reciprocal peptide array experiments highlighted that Hsp20 bound to a domain within Aβ, which is key to the aggregation of the Aβ peptide and is required to produce the higher order toxic Aβ species. The Peptide Array data was then verified using full-length recombinant proteins and several Hsp20 mutants were developed including a phospho-mimetic. The phospho-mimetic Hsp20 was shown to outperform the wild-type variant in several assays such as, in vitro pull-down assays, Aβ aggregation measured using nuclear magnetic resonance spectroscopy, and also a novel Aβ aggregation assay which can differentiate between two distinct aggregation pathways, namely fibrillisation and oligomerisation. These data demonstrated for the first time how the interaction between Hsp20 and Aβ may be modulated by cell signalling cascades. I then moved to investigate the cytotoxicity of Aβ in order to investigate whether increasing Hsp20 expression in neuronal-like cells would confer protection against Aβ-mediated toxicity. This was initially carried out using a standard MTT-based cell viability assay, before utilising a real-time cell monitoring device to develop a novel Aβ toxicity assay. In both assays, increasing Hsp20 expression was shown to be cytoprotective. The wild-type variant of Hsp20 was found to be more effective in cell-based assays due to increased levels of phosphorylated Hsp20. The real-time Aβ toxicity monitoring assay also gave me a platform for testing agents with potential neuroprotective properties. Given that increasing levels of phosphorylated Hsp20 could attenuate Aβ-mediated cytotoxicity, I logically was drawn to study ways that this event could be targeted therapeutically. Several drugs that target cAMP- and cGMP-dependent phosphodiesterases have been shown to be effective in alleviating symptoms of Alzheimer’s disease in rodent iii models have also been studied here in cellular systems. These included the “blockbuster” PDE5 inhibitor Viagra® (sildenafil), two novel compounds which selectively inhibit PDE9, which were developed by the pharmaceutical company Lundbeck specifically as Alzheimer’s treatments, and rolipram, a well established cognitive enhancer that was developed originally as an anti-depressant. All of these compounds were shown to “activate” endogenous Hsp20 to varying degrees in neuronal-like cells and the levels of Hsp20 activation was found to correlate with both the level of induced Hsp20/Aβ co-localisation, and subsequent attenuation of Aβ-mediated cytotoxicity. This suggests that this endogenous protection pathway can be targeted by currently available therapeutics in order to reduce the neurotoxic effects of Aβ. Finally, we wanted to develop novel agents of our own that could promote Hsp20 phosphorylation. To do this, in silico docking of all FDA approved drugs against the catalytic domain of PDE4 was undertaken in an attempt to find a novel compound with the potential to reposition as an Alzheimer’s treatment. Using this methodology we discovered an angiotensin converting enzyme inhibitor, moexipril to be a PDE4 inhibitor in the low micro molar range. Unfortunately, moexipril works as an ACE inhibitor in the low nano molar range making repositioning unviable. However, moexipril treatment was more effective than rolipram in reversing Aβ toxicity and I speculate that this may be due to the sub-family selective nature of its (moexipril) PDE4 inhibition. Furthermore, the lack of emetic side effects associated with moexipril makes this compound an ideal starting point for the development of isoform selective and/or non-emetic PDE4 inhibitor. In summary, these studies describe a novel endogenous mechanism for combating the toxic effects of the Aβ protein, which underpins the development and progression of Alzheimer’s disease. Given that the interaction between Hsp20 and Aβ can be manipulated via cAMP/cGMP signalling, the interaction could be targeted therapeutically. As there are currently no effective drugs on the market for stabilising Alzheimer’s disease, I believe that the data presented here opens up a potential new avenue that could lead to the development of a new class of AD drugs.

This study is an evaluation of the 'Circle of Friends' (CoF) intervention used to support five pupils with a diagnosis of autism (the focus pupils) in their mainstream classrooms. Relevant theory and existing research is outlined before the study is described. A single case experimental design is used to evaluate the impact of the CoF intervention on the focus children's level of social inclusion (calculated from peer ratings). Results suggest that the CoF whole class meeting had an initial positive impact on all focus children's levels of peer acceptance and rejection. During the course of weekly CoF meetings, however, results suggest that this level of change was not maintained. For four of the five focus children, levels of peer acceptance and rejection generally returned to levels comparable to those observed prior to the start of the intervention. The study also reports some changes in measures taken before and after the CoF intervention. For four out of the five cases, a positive change in the focus children's happiness was observed. For three out of the five cases generally positive changes in adults' ratings of the focus children's behaviour were observed. In an attempt to understand how the CoF intervention works, attributions made by peers about one of the focus children's behaviour were explored before and after the CoF intervention though no clear overall change following the intervention was found. The results reported are examined in relation to the theory and research outlined in the Literature Review and the design, measures and procedures described in the Methodology. Limitations of the research are discussed and implications for practice and future research outlined.

Personality disorders (PDs) are common, chronic, mental health problems. The majority of treatment outcome research, which has focused specifically on Borderline PD, has provided substantial empirical support for Dialectical Behaviour Therapy (DBT; Linehan, 1993), particularly in terms of self-harm reduction. Nevertheless, DBT graduates can continue to experience poor personality functioning across PD diagnostic categories, Axis I disorders, and restricted lives. Acceptance and Commitment Therapy (ACT; Hayes, Strosahl, & Wilson, 1999), might be suitable as a follow-up intervention for DBT graduates, to address their continued difficulties: to date, however, there has been little empirical investigation of its utility in relation to PD. This thesis was therefore designed to examine theoretical underpinnings of ACT relevant to the development of an ACT intervention for DBT graduates. Study 1 tested the performance of a new self-report measure of cognitive fusion (CF), the Cognitive Fusion Questionnaire (CFQ), with a mental health sample, including individuals with PD. CF is a key ACT concept, and the CFQ proved to be a psychometrically sound measure of CF with people with mental health problems. Study 2 used cross-sectional modelling to show that CF fully mediated the relationships between two PD risk factors, negative affectivity and childhood trauma, and personality functioning in adulthood. Study 3 used the CFQ to investigate the behavioural correlates of CF. These findings strengthened the possibility that an ACT-based intervention might prove effective in improving outcomes for DBT graduates. To explore this further, Studies 4 and 5 were designed as very small-scale uncontrolled treatment development trials for this population. Study 4 suggested that ACT had a positive impact on engagement in life, but produced little improvement in psychiatric symptomology. Study 5 tested a revised protocol, which yielded more consistently positive findings, with improvements in both engagement in life and psychiatric symptoms. These findings tentatively suggest that ACT may have a role to play as a DBT follow-up intervention.

Recent increases in youth unemployment have driven reforms to educational provision. This has created an increased focus on gaining a formal qualification in maths because it affects access to jobs/course places. These governmental reforms have placed a heightened responsibility on schools to provide appropriate interventions to meet pupils’ needs. Theoretical models developed to understand what affects maths achievement have highlighted the importance of providing appropriate learning opportunities to develop requisite cognitive skills of Working Memory (WM) and Metacognition (MC). Support has been found for these models through correlational research demonstrating the link between WM, MC and maths. Studies have also shown that anxiety, both general and maths specific can interact with WM and MC to affect performance in maths. A review of research indicated that WM training and MC interventions delivered in a maths context can contribute to improved maths achievement, however none of these studies considered the effect of anxiety. The current empirical study examined the effect on 13 and 14 year olds’ maths achievement of WM training (CogMed) and a MC intervention (in the form of one-to-one tutoring). Maths achievement, WM, MC and anxiety (maths and general) were measured at pre, post and follow-up (8 weeks) to explore their contribution to maths achievement. Significant improvements for both intervention groups from pre to post and from pre to follow-up were found for WM and maths achievement. A significant reduction in maths anxiety was found in both groups over the same timescale, but there were no significant changes in MC or general anxiety. Evidence was found for a link between changes in WM and general anxiety and a link between changes in MC and maths anxiety. Results are discussed in relation to understanding what factors are important in the observed changes, and implications for educational interventions are considered.

Four methods for measuring disorders of vascular function and neurological function associated with occupational exposure to hand-transmitted vibration have been defined by reference to the available literature. For measuring vascular function the methods are: i) measures of the finger systolic blood pressure (FSBP) response to local cooling and ii) measures of the finger skin temperature (FST) response to local cooling. For measuring neurological function the methods are: i) measures of vibrotactile thresholds at the fingertips and ii) measures of thermal thresholds at the fingertips. Measures of the FSBP and the FST response to cold provocation were appraised in 109 dockyard workers. The FST test did not differentiate between 82 healthy subjects and 27 subjects with vibration-induced white finger (VWF) whilst the FSBP test was found to be sensitive, specific and responsive to VWF. Vibrotactile and thermal thresholds were found to be sensitive, specific and responsive to symptoms of numbness in another study of 104 dockyard workers, of whom 67 reported neurological disorders. It was concluded that whilst the above tests could be useful for monitoring the vascular and neurological disorders, a number of improvements to the measurement methods could be worthwhile. Further experiments were carried out to investigate these improvements. The simultaneous measurement of FSBPs on multiple test fingers was developed to improve the practicality of this test when measuring FSBPs on more than one test finger. Increased central sympathetic activity was hypothesised to result from increasing the stimulus by cooling more fingers. In two experiments on 12 healthy subjects, it was found that FSBPs measured simultaneously on four test fingers gave similar results to FSBP measurements on one test finger. Simultaneous FSBP measurements on four test fingers had comparable repeatability to measurements on one test finger. It was concluded that measuring FSBPs on multiple test fingers is a useful improvement to this test. When measuring FSBPs, changing the order of presentation and the period of recovery between thermal stimuli was hypothesised to influence the results by altering central sympathetic activity. In 12 healthy subjects it was found that the order of presentation of thermal stimuli was not important but that inter-subject variability increased when recovery was allowed between thermal stimuli. It was concluded that minimising the time interval between successive applications of thermal provocation reduces undesirable inter-subject variability. Another study on 12 healthy subjects showed that different reference measurement locations give different results. It was concluded that the thumb is suitable location for making reference measurements. The FSBP test and the FST test both involve application of cold provocation. The two tests are sometimes performed in succession but multiple thermal provocations may have cumulative effects on central sympathetic activity. When the two vascular tests were performed in succession on 36 subjects, including 12 subjects with VWF, any effects of the order of test presentation were small although a test performed first tended to be more repeatable. It was concluded that if both tests are performed consecutively, greater emphasis should be placed on the test performed first. The data for the FST test were reanalysed and showed that the sensitivity and specificity to VWF of this test is improved by changing the method of interpreting the results. Three methods of interpreting the FST response to cold provocation that represent an improvement to the test are suggested. The two vascular tests have been shown in the literature to be repeatable for healthy subjects but not for subjects with VWF. The repeatability of the vascular tests was assessed in 36 subjects (12 manual workers, 12 office workers and 12 subjects with VWF). The repeatability of both tests was found to be low amongst workers with VWF; some of these subjects showed a negative test result on one occasion and a positive test result on another occasion. It was concluded that a repeat test may be required when a false negative result is obtained. For the vibrotactile threshold test, the skin-stimulus contact force is usually controlled. Controlling the skin indentation would simplify measurement equipment. An experiment on ten healthy subjects investigated the relationship between skin-stimulus contact force, skin indentation and vibrotactile thresholds. It was concluded that the vibrotactile threshold test could be improved by implementing control of skin-indentation. Skin indentations giving comparable vibrotactile thresholds to those obtained using controlled contact forces were identified. It is concluded that a test battery comprising the four test methods identified from the literature and subsequently developed during the course of this research can be used to monitor disorders of both vascular and neurological function associated with occupational exposure to hand-transmitted vibration. A number of recommendations are made for further improvements that might be achievable as a result of further work.

Stroke represents the second leading cause of global mortality. Despite improvements in acute stroke management in recent years, many patients suffer a poor outcome and stroke represents a leading cause of adult disability. Beyond the human impact of disease, societal costs are huge. Stroke is principally a disease of the elderly population, which is increasing in size. Incidence is increasing in the younger population and the developing world. Accordingly, the global burden of stroke is anticipated to increase substantially in the coming decades. Fatal and disabling strokes are frequently preceded by either a milder, non-disabling stroke or a transient ischaemic attack (TIA). The optimised implementation of effective preventative strategies and the evaluation of potentially novel therapeutic agents, both represent crucial strategies in reducing the burden of cerebrovascular disease. This thesis addresses two aspects of secondary prevention following ischaemic stroke: Firstly, improved identification and optimised use of anticoagulant based secondary prevention for an established but frequently occult risk factor for recurrent stroke; paroxysmal atrial fibrillation (PAF). Secondly, the evaluation of xanthine oxidase inhibition (XOI), as a potential therapeutic strategy for the prevention of stroke and cardiovascular disease. Chapter 1 highlights the importance of optimising secondary preventative strategies following ischaemic stroke and TIA. The anticipated increase in the global burden of cerebrovascular disease is described, together with review of stroke outcomes in the context of contemporary acute stroke management. The risk of stroke recurrence following ischaemic stroke and TIA is reviewed, followed by discussion of available secondary preventative strategies. In Chapter 2, the role of AF in the aetiology of stroke disease is reviewed in greater detail. The early and subsequent risk of stroke recurrence in patients with AF is considered, together with review of the evidence for antithrombotic therapy. The potential for increased detection of paroxysmal AF in the ischaemic stroke and TIA population is discussed, with particular reference to the therapeutic implications and potential for reduced stroke recurrence. In Chapter 3, details of a randomised, open-label trial with objective outcome assessment, in patients with recent (< 7 days) ischaemic stroke or TIA, are presented. This study evaluated the use of non-invasive cardiac event monitoring to detect AF, in patients with ischaemic stroke or TIA presenting with sinus rhythm, an area of management for which a robust evidence base is lacking. The primary endpoint was the difference in AF detection at 14 days, between patients randomised to receive supplemental cardiac event monitoring of 7 days duration, compared to those receiving standard guideline based investigation alone. Detection of AF was defined as evidence of “sustained” PAF and “any duration” PAF episodes. Secondary endpoints were the difference in AF detection at 90 days and the difference in AF-thromboembolic prophylaxis-related anticoagulation (e.g. warfarin) at 14 & 90 days. 100 patients were enrolled and completed 90 day follow up. “Sustained” and “any duration” PAF episodes were detected, respectively, in 16% (95% CI, 7.2 – 29.1%) and 42% (95% CI, 28.2 – 56.8%) of patients through 7 days non-invasive cardiac event monitoring. Supplementation of standard guideline based investigation with 7 days’ cardiac event monitoring resulted in detection of “sustained” and “any duration” PAF episodes in an additional 16% (4.7 – 27.3%) and 40% (25.2 – 54.8%) of patients, respectively, at 14 days follow up. These differences persisted at 90 days. Anticoagulant therapy was commenced within 14 days in 16% of the group randomised to receive supplemental monitoring, versus none randomised to standard investigation alone (p<0.01). This difference persisted to 90 days (22% versus 6%, p<0.05). This study provided the first randomised controlled evidence for a specific investigation strategy for the detection of occult PAF in unselected patients with ischaemic stroke and TIA. These data should support guidelines regarding the management of this patient group. In addition, the study provided evidence that this strategy is not reliant on specialist electrocardiological service support, with very good agreement [(96%; 95% CI, 86.3 – 99.5%), Fleiss’ Kappa 0.86, p < 0.00001] observed between non-cardiology trained stroke clinicians and the independent reporting electrocardiology laboratory for “sustained” PAF detection. In a related observational study, the predictive value of detection of AF in the period immediately following ischaemic stroke or TIA was examined, relative to interval evaluation for AF by non-invasive cardiac event monitoring, performed 90 days following the index event. This study demonstrated that identification of AF immediately following stroke holds strong positive predictive value for subsequent AF detection following a 90 day interval, supporting treatment decisions being based on the findings of early monitoring. Negative predictive value of failure to identify AF through early monitoring was only modest, suggesting that repeated investigation may be of value. In Chapter 4, the hypothetical role of uric acid (UA) in the pathogenesis of cardiovascular disease is reviewed. Conflicting data are discussed, including those which support the hypothesis that serum UA represents a surrogate marker of elevated cardiovascular risk attributable to either its association with established cardiovascular risk factors or, alternatively, as a surrogate marker for a novel mechanism of vascular injury: harmful oxidative stress produced by the xanthine oxidase enzymatic system. XOI is discussed as a potential novel therapeutic strategy in the prevention and management of cardiovascular disease. In chapter 5 a systematic review and meta-analysis of studies evaluating the effect of XOI on cardiovascular health in humans are presented. This study identified a body of heterogeneous studies, reporting largely positive results. In meta-analysis, improvement in brachial artery flow mediated dilatation, [2.50% increase (95% CI, 0.15 – 4.84%)] and venous occlusion plethysmography derived forearm blood flow response to acetylcholine, [69% increase relative to control arm (95% CI, 18 – 119%)], indicated that XOI improves endothelial function amongst patients with, or at risk of, cardiovascular disease. In addition, XOI reduces vascular oxidative stress, Malondialdehyde reducing by 0.56 nmol/ml (95% CI 0.26 – 0.87 nmol/ml). Several studies indicated that the benefits of treatment may be limited to patients with hyperuricaemia. Definitive clinical endpoint studies were lacking. The study confirmed that XOI has beneficial effects within the cardiovascular system, providing supportive evidence for further study in the stroke patient population and in relation to more definitive clinical endpoints. In Chapter 6, three surrogate measures of cardiovascular risk: Carotid intima media thickness (CIMT); blood pressure pulse wave analysis (BP-PWA); and endothelial function are reviewed. Each is considered with respect to their independent predictive value for risk of cardiovascular disease, and utility as surrogate outcome measures in clinical trials. Together with chapter 4 and the systematic review reported in chapter 5, this chapter provides additional background to the randomised controlled trial reported in chapter 7. In Chapter 7, the details of a double blind, randomised placebo-controlled trial, evaluating XOI (with Allopurinol 300 mg once daily) in a population with recent (< 12 months) ischaemic stroke or TIA, are presented. Patients were followed up at 1, 3, 6 & 12 months in relation to several prognostically important surrogate measures of cardiovascular function.