Background: Exercise may acutely and chronically up-regulate appetite and energy intake in overweight and obese women preventing body mass reduction in the long term. Overweight and obese women may be most prone to compensatory responses to exercise but the possible mechanism for this is unclear. Appetite regulating hormones have been investigated as a possible mechanism but to date the evidence is somewhat mixed. Identifying compensatory energy intake responses in overweight and obese women is complicated by the high prevalence of dietary under-reporting in this group. The laboratory-based buffet meal method has frequently been used in research studies that have assessed food intake in these women, but this method has only undergone preliminary validation. Dietary restraint may also affect individual appetite responses to exercise; it has been theorised that restraint may be a behavioural adaptation to diminished energy requirements, and differences in physical activity levels could also contribute. Evidence thus far has produced mixed results, possibly because two distinct sub-groups of restrained eaters exist, those with flexible and rigid control of restraint. It is not known if there are differences in energy requirements between these two sub-groups. Participants and Methods: Participants in all studies were sedentary, healthy, pre-menopausal, overweight and obese, adult women. Study 1: Fourteen women completed four trials; two exercise and two control, following the same protocol as study 1. Energy intake at three buffet meals and subjective appetite ratings were measured, and the reproducibility of these values under control and exercise conditions was tested using intraclass correlation coefficient (ri). Study 2: Twenty-nine women completed two trials in a randomised, counterbalanced order; exercise and control. Each trial lasted 24 hours spanning 2 days; the afternoon of day 1 and morning of day 2. An exercise session to expend 1.65 MJ was completed on day 1 of exercise trials, and three buffet meals were served during each trial to measure energy intake. Appetite was assessed using a visual analogue scale and blood samples were taken to determine acylated ghrelin (n=15) and peptide YY (n=10) concentrations. A repeated measures ANOVA was used to investigate the effects of trial and time on appetite hormones, EI and appetite. Study 3: Fifteen women participated in a sixteen week exercise intervention to expend 8360 kJ week-1. Participants exercised unsupervised in the University gym, and compliance was measured via heart rate monitoring. Sub-maximal fitness and body composition assessments were carried out at baseline, and after 8 and 16 weeks of exercise. Energy expenditure, energy intake, appetite, and acylated ghrelin (n=14) and peptide YY concentrations (n=11) were measured at baseline and after 8 weeks of exercise. Paired t tests were used to assess differences in time-averaged AUC for appetite, total and relative EI, metabolic rate, and exercise responses between trials. Repeated measures ANOVA was used to assess changes over time in body composition, appetite ratings, EI, acylated ghrelin, peptide YY, and cardiovascular fitness levels. Study 4: Forty-one sedentary women in a one week observational study. Participants were classed as restrained or unrestrained using the three factor eating questionnaire, and the former group were further classified as having flexible or rigid control of restraint. All participants completed a food frequency questionnaire, sub-maximal fitness test, body composition assessment and two fasted metabolic rate measurements. Average daily energy expenditure was calculated from a seven day physical activity diary combined with continuous heart rate data. Differences between restrained and unrestrained eaters, and restrained eaters with flexible and rigid control, were assessed using a paired t-test. Results Study 1: The ri for energy intake in control trials was significant but had large associated confidence intervals (ri 0.50 (95% CI 0.03, 0.80) p=0.0003). The ri was for energy intake in exercise trials was (ri 0.04 (95% CI -0.53, 0.55; p=0.45) and for the difference between control and exercise trials was (ri -0.05 (95% CI -0.54, 0.48; p=0.57) this was not significant. The ri values for satiety, fullness and desire to eat were significant in both control and exercise trials (p<0.05), but the associated confidence intervals were large. Study 2: There was no effect of exercise on subjectively rated appetite, acylated ghrelin, or peptide YY concentrations (all p>0.05). Total energy intakes were not significantly different between trials (exercise: 10.9 ± 0.5 MJ, control: 10.8 ± 0.5 MJ; mean ± SEM). Study 3: Total exercise energy expenditure during the intervention was 80.8 ± 7.7 MJ, which resulted in a significant reduction in total body mass (-1.9 ± 0.9 kg), fat mass (-1.7 ± 0.7 kg) and BMI (-0.7 ± 0.4 kg m-2). However individual changes in body and fat mass ranged from +2.8 to -9.9kg, and +1.78 to -6.55 kg respectively. There were no significant differences in appetite, energy intake, or expenditure after 8 weeks of exercise (p>0.05). Study 4: There were no differences in metabolic rate, daily energy expenditure or physical activity patterns between restrained and unrestrained eaters (p>0.05), or between restrained eaters with flexible and rigid control of restraint (p>0.05). Conclusions: Study 1: The laboratory-based buffet meal method of measuring energy intake does not provide reliable, reproducible values in overweight and obese, pre-menopausal women either under control or exercise conditions. Study 2: A walking-based exercise session which induces a moderate energy deficit of 1.65 MJ does not appear to affect subsequent twenty four hour energy intake, subjectively rated appetite, or plasma acylated ghrelin and peptide YY concentrations during the subsequent twenty four hours. Study 3: This study concluded that 16 weeks aerobic exercise in overweight and obese women produces a small, but significant, reduction in body and fat mass (-1.9 ± 0.9 kg); however the extent of these changes varies greatly between individuals (+2.8 to -9.9kg). No evidence of compensatory changes in energy intake or expenditure, subjective appetite ratings, or circulating levels of acylated ghrelin and peptide YY was apparent after 8 weeks of exercise. Study 4: This study concluded that there is no evidence of a difference in body composition or energy requirements between overweight and obese female restrained and unrestrained eaters, or between sub-groups of restrained eaters. Dietary restraint does not appear to be an adaptation to diminished energy requirements.

Abstract Chapter 1 provides an introduction to stroke including its current prevalence both nationally and globally, aetiology, global importance and social & financial burden. We also describe here current acute stroke management practices, the role of clinical trials in the development of therapies, the richness of data within clinical trials and changes in regulatory thinking regarding data access. We provide recommendations for the use of trial data for novel exploratory investigations of clinical trial design and epidemiological studies. In Chapter 2 we describe the establishment of the Virtual International Stroke Trials Archive (VISTA) to address the need for reliable data on which to plan future clinical trials. This chapter details the methodology and logistics of establishing the resource, including details of regulatory policy for data collection and use, establishment of a Steering Committee and development of a constitution to safeguard data access and use. As of June 2008, VISTA contains 28 acute stroke clinical trials and one acute stroke registry. We collated data on over 27,500 patients with either ischaemic or haemorrhagic stroke. Patient age ranges from 18 to 103 years and outcome measures include Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset to treatment times are readily available and computed tomography (CT) lesion data are available for selected trials. We discuss the establishment and potential uses of this resource in the context of existing stroke resources. Chapter 3 demonstrates how we utilised VISTA to investigate natural history patterns in acute stroke. There are prominent differences in stroke incidence and outcome across different geographical locations; these are not confined to the Eastern- Western axis. We aimed to examine whether there were any differences in index stroke severity, stroke risk factors, and stroke outcome between geographical locations, after adjusting for case-mix. We found that patients who were enrolled in the USA and Canada had the worst index strokes, whilst patients enrolled in Austria and Switzerland had the mildest index stroke, and better functional (p=0.023) and neurological outcome (p=0.034) at 90 days. 90 –day survival was greater in patients who were enrolled in Spain and Portugal (p<0.0001). Chapter 4 demonstrates the use of VISTA to inform stroke clinical trial design by examining the impact of early follow up on adverse event and functional outcome profiles. We aimed to assess the contribution of adverse complications unrelated to stroke, to 30 and 90- day functional outcome. If fewer ‘stroke-unrelated’ adverse events were seen at later time points, and if the absence of these events appeared to influence functional outcome, then further investigation into shortening the follow up period of clinical trials with a view to minimizing complications may be warranted. We identified idiopathic post-stroke complications (deemed to be ‘stroke- unrelated’) but their absence did not beneficially alter outcome at either 30 days (p<0.0001, adjusted OR for good outcome =0.47, 95% CI [0.26, 0.67]), or 90 days (p=0.002, adjusted OR for good outcome =0.38, 95% CI [0.14, 0.61]). We concluded that shortening the follow up period with the aim of minimizing ‘stroke-unrelated’ complications did not benefit functional outcome, however further investigation is required. Chapter 5 illustrates the use of VISTA to investigate the natural history of complications after intracerebral haemorrhage (ICH). Treatments available for ICH remain limited. The use of haemostatic agents to promote local coagulation has had no significant benefit on outcome. However promising results from a subgroup analysis of patients from the FAST trial has raised the possibility of treatment with recombinant factor VIIa (rFVIIa) in patients with ICH. We sought to document the natural history of complications after ICH in order to inform safety in future trials of haemostatic agents for ICH. We found that the risk of thromboembolic complications after ICH was low (4 events affecting 2% of patients). The absence of these thromboembolic complications did not significantly affect the attainment of good functional outcome (p>0.05). The occurrence of haemorrhagic expansion was common, affecting 14% of patients, and significantly influenced attainment of good functional outcome at 90 days (p= p<0.0001, adjusted odds ratio for good functional outcome=21.9, 95% confidence interval [5.5, 88.3]). Although infection occurred in 11% of patients, this did not significantly influence attainment of good functional outcome at 90 days (p=0.8). The complications encountered in this investigation and their time to onset will serve to inform prophylaxis in future ICH clinical trials. Chapter 6 describes the processes involved in drug development from phase I, first- in – man studies to phase III efficacy trials and identifies a key area in the drug development process where use of VISTA as a historical comparator resource could be of benefit: phase II studies. We detail here the types of conventional comparator groups available for use in a phase II investigation, advantages and disadvantages of using each of these comparator groups, the potential for use of historical comparators in some scenarios where use of conventional comparator groups is infeasible, and possible solutions to address the limitations associated with use of historical comparators. Chapter 7 illustrates the use of VISTA as a resource for historical comparators in the context of an acute stroke device trial conducted by a small company with limited resources. BrainsGate, the manufacturers of the NeuroPath™ Device for treatment of ischaemic stroke, sought to collaborate with the VISTA group to examine initial efficacy of their device against outcomes derived from VISTA historical comparators. We discuss the example of this device in early phase testing, where VISTA was primed for use as a resource for historical comparators. We also describe the limitations associated with the use of historical comparators, how these limitations could be overcome in practice through use of matched patients, implementation of strict eligibility criteria and use of similar follow up periods and stroke scales, as well as the measures taken to ensure the validity of results. Chapter 8 describes a collaboration with the DESTINY trial group to investigate stroke outcomes after malignant middle cerebral artery occlusion (mMCAO). The DESTINY trial examined the impact of decompressive hemicraniectomy on outcome after mMCAO, compared with randomised controls. We compared the outcomes of operated patients from the DESTINY trial with historical comparators from VISTA to determine whether the findings could be replicated and if historical comparators could be used as an alternative in a situation where a randomised controlled trial (RCT) is infeasible or unethical. We found that fewer patients in the VISTA comparator group achieved a good functional outcome by mRS at final follow up (19%), when compared with the DESTINY surgical group (47%, Chi- Square test p=0.04). This difference persisted after adjusting for baseline NIHSS (logistic regression p=0.04). Analysis of Barthel Index at final follow up revealed no significant difference between the two groups and we also found no difference in 6 month survival rates between the surgical and VISTA comparator groups (Cox Proportional Hazards model p>0.05). We concluded that for effective replication of results, the database from which historical comparators are to be drawn should cover a similar or broader spectrum of patient prognostic factors. Chapter 9 discusses the implications of the investigations described in this thesis, outlines the scope for expanding the resource and proposes areas for future research.

Background - Magnetic Resonance Myocardial Perfusion Imaging (MRMPI) has been used for the detection of reversible myocardial ischaemia in humans since the early 1990’s. This non-invasive method of diagnosing reversible myocardial ischaemia has a number of advantages over the other more commonly used non-invasive tests such as ETT, stress echocardiography and radionuclide single photon emission computerised tomography (SPECT). There is no need to perform physical exercise, no image orientation constraints, excellent spatial and temporal resolution, no photon scatter or attenuation artefacts and no exposure to ionising radiation. The use of MRMPI for the detection of reversible myocardial ischaemia has been extensively investigated in the past using other non-invasive tests as the gold standard namely PET and SPECT. Invasive comparisons have been made with visual coronary angiography and quantitative coronary angiography (QCA). This previous work has been summarised in a meta-analysis which estimated the sensitivity and specificity to be 84% and 85% respectively. The majority of previous studies have used QCA or visual estimation of stenosis severity to determine the diameter of stenosis (DS). This however has been shown to correlate poorly with the functional significance of disease within a coronary artery. Prior to the commencement of this study no comparison had been made with the invasive gold standard of FFR. This is measured using a coronary pressure wire at the time of coronary angiography and is regarded by many cardiologists to be the current invasive gold standard for determining if coronary artery disease (CAD) is physiologically significant. We therefore undertook the present study to determine the true accuracy of MRMPI for the diagnosis of physiologically significant CAD. We also assessed the ability of MRMPI to detect isolated microcirculatory disease as determined by thermodilution derived CFR. Our other aims included an analysis of troponin release following PCI and its relation to QCA, pressure wire data and the occurrence of new late gadolinium enhancement (LGE). New LGE post CABG was also quantified and compared with that encountered post-PCI. Methods - One hundred and three patients with chest pain were referred for coronary angiography and underwent MRMPI in the week prior to the angiogram. This was performed on a Siemens Sonata 1.5Tesla scanner (Erlangen, Germany). Scanning commenced with localisers and cine long and short axis scans (TrueFISP sequence) to provide left ventricular mass, volume and ejection fraction data. This was followed by perfusion imaging of 3 short axis slices using a turboFLASH sequence (TI 90ms, TE 0.99ms, TR 173ms, Flip Angle 8 degrees, Matrix 80 x 128). Thereafter long and short axis slices were acquired for the detection of LGE (turboFLASH). Maximal hyperaemia was achieved using intravenous adenosine (140µg/kg/min). The first pass bolus contained 0.1mmol/kg of gadolinium (Omniscan, Amersham Health, Oslo, Norway) power injected at 5ml/sec (Medrad, Pittsburgh, PA) followed by a 20ml saline bolus. Twenty minutes after the initial bolus of gadolinium a further bolus was administered to obtain rest perfusion images. During coronary angiography the FFR was recorded in all patent major epicardial coronary arteries using a coronary pressure wire (RADI Medical Systems Ltd, Uppsala, Sweden) with hyperaemia induced using intravenous adenosine as above. An FFR value of <0.75 was taken as the cut off for the diagnosis of significant CAD. CFR measurements were obtained at rest and during maximal hyperaemia by means of thermodilution using 3ml boluses of saline. Following coronary angiography those patients who underwent PCI returned for a repeat MRMPI scan at 24 hours and 4 weeks and CABG patients returned for a 4 week scan. PCI patients had a troponin I measurement performed at approximately 24 hours, just prior to their repeat MRMPI. Qualitative MRMPI analysis, left ventricular mass, volume and ejection fraction analysis and QCA were all performed by two blinded independent experienced observers. Results - Of the 103 enrolled patients, two were excluded from the final analysis. Seventy-six (74%) were male with a mean age of 60 years (SD = 9). 25 (24.8%) of 101 scans were normal, 40 (39.6%) had single-vessel disease, 26 (25.7%) had two-vessel disease and 10 (9.9%) had triple-vessel disease. 121 perfusion defects were reported in 300 coronary territories (3 patients had complete data for only 2 coronary territories) of which 110 had an FFR<0.75. 168 of 179 normally perfused territories were confirmed normal with an FFR greater than or equal to 0.75. The sensitivity, specificity, PPV and NPV of MRMPI for the detection of significant CAD were 91, 94, 91 and 94%. Cohen’s kappa was 0.97 per patient and 0.76 per coronary territory indicating excellent and substantial agreement between observers. Twenty-eight coronary arteries were identified as having an FFR>0.8 and a CFR<2.0 indicative of isolated microcirculatory disease with no physiologically significant epicardial disease. No coronary territories were found to have a perfusion defect on MRMPI suggesting that by visual analysis MRMPI is unable to detect isolated microvascular disease. The median post PCI troponin level was 0.57µg/L (SD=2, Range undetected - 13.1). The only parameters found to correlate with troponin I levels post-PCI were increasing lesion length (r=0.6, p<0.0001) and increasing total stent length (r=0.37, p=0.02). We compared the increase in mass of LGE between the post-PCI scans and the pre-PCI scan and compared this with the troponin measurement. No significant correlation was found to exist between these parameters at 24 hours (r=0.25, p=0.07) or at 4 weeks (r=-0.19, p=0.2). The change in mass of LGE was calculated for the PCI and CABG patients. The mean difference in the PCI group was -0.12g (Median=0, SD=0.8, Interquartile Range 0 – 0) and for the CABG group was 1.08g (Median=0.11, SD=2.3, Interquartile Range -0.11 – 1.38). There is a trend towards the development of more LGE following CABG than PCI however the difference between groups did not reach statistical significance (p=0.07). Conclusion - MRMPI can accurately detect significant CHD with excellent results using FFR as the gold standard. Interobserver agreement is also very good even when examining individual coronary artery territories. Qualitative analysis of MRMPI is unable to detect isolated microcirculatory disease as defined by an FFR>0.8 and a CFR<2.0. Small troponin releases are common post-PCI and are related to the length of the lesion being treated and the length of stent deployed to treat the lesion. These small troponin releases do not accurately correlate with the occurrence of new LGE. CABG did result in a trend towards more new LGE compared to PCI.

The mobility impairment caused by a paralysis like a spinal cord injury or a stroke has, beside many other impacts, an influence on the transfer of signals between the muscles of the lower extremities and the brain. In a paraplegic person, this means that she or he can not stand without holding onto a support or standing in a standing frame while the impact on the ability to balance in a hemiplegic person can be less severe. Although the connection between the muscles and the brain is impaired by the injury, the muscles still retain the ability to contract if innervated. This thesis describes control approaches which combine the remaining voluntary control of the paraplegic and stroke patients with the artificially controlled stimulation of the muscles of the paralysed limbs to aid the subject in balancing. The aim was to develop new control approaches which would assist balance in paraplegic subjects and in stroke. To support standing in paraplegic subjects, the moment generated at the ankle using electrical stimulation of the shank muscles was integrated with the voluntary control of the upper body, resulting in the concept of Integrated Voluntary Control (IVC). In the outer loop the ankle moment produced by the paraplegic subject due to his voluntary upper body movement was estimated using a mathematical model based on the inclination angles of upper and lower body. This estimated ankle moment was then compared with the actual moment applied at the force plates the subject was standing on, and an appropriate stimulation signal was applied to the paralysed shank muscles. Experimental evaluation initially involved four able bodied volunteers in which base line results with stiffness and stiffness-viscosity controllers using a rotating standing platform were obtained. This was extended to the paraplegic subject, where electrical muscle stimulation was used to generate the required ankle moment. The IVC concept was then evaluated with the paraplegic subject and compared to the base line results. Due to the nature of the system and implied perturbation onto the control system controlling the posture of the paraplegic subject the known evaluation values (e.g. rise time, steady state value, overshoot value etc.) are not suitable. Therefore, the variance of a time signal around its mean value was used as an evaluation value which allowed to compare the achieved performance of the paraplegic subject employing the new control approach with the stiffness and stiffness-viscosity controllers directly. To assist balance in stroke patients, a new training approach was introduced based on the concept of integrating the voluntary abilities of the patient with mechanical balance support and sensory electrical stimulation. This concept was evaluated in a training program with one stroke subject which demonstrated the feasibility and potential balance improvement resulting from this approach.

There is plentiful evidence that the pathology of Guillain Barré syndrome (GBS) is driven by autoantibodies generated following infection. A number of inconsistencies with this theory remain, and in many clinical cases such antibodies are not detected. Recent descriptions of ganglioside complex (GSC) antibodies suggest a potential explanation for this. This study aimed to further investigate GSCs and associated antibodies with a particular focus on GBS. GSCs were found to modulate the binding of other lectins such as bacterial toxins, immunomodulatory receptors, and monoclonal antibodies. The development of a semi-automated array system allowed screening of a large cohort of GBS sera against multiple complexes, revealing a greater antibody detection rate (particularly in demyelinating forms) than had previously been achieved. Binding that was both enhanced and attenuated by complexes was seen, and this varied between disease and control sera. Immunisation experiments provided insights into the generation of the GSC immune response. A transgenic mouse model of GBS was also developed, demonstrating that local axonal expression of gangliosides does not induce systemic tolerance. The work described in this thesis has thus significantly advanced knowledge in the field of glycolipid complexes, particularly with respect to anti-glycolipid complex antibodies and their association with inflammatory neuropathies such as Guillain-Barré syndrome.

Introduction: Protected learning time (PLT) has been adopted by a number of NHS primary health care organizations throughout the United Kingdom as a resource for learning. Primary health care teams are protected from service delivery by Out-of-hours services for a small number of afternoons per year. Learning events are generally of two types: practice-based PLT events organised by the primary health care team and usually held in practice premises; and large centrally organised meetings held in large conference venues, and arranged by a PLT committee. PLT schemes were started by NHS Ayrshire and Arran in 2002 after a pilot study in 2001 was considered successful. A quantitative evaluation of the PLT scheme in two Community Health Partnerships within NHS Ayrshire and Arran in 2004 showed a significant difference in the views of Administrative and Clerical staff (A & C staff) and practice managers compared with clinicians in the team. Only 41% of A & C staff and 51% of practice managers wanted PLT to continue in one of the areas surveyed. An additional questionnaire study answered by practice managers in 2005 in NHS Ayrshire and Arran suggested that attendance of community nurses (health visiting and district nursing teams) at practice-based PLT events had fallen sharply, and that only a few were attending regularly. The questionnaires were unable to give the reasons for the low attendance, nor could they explain why some wanted the scheme to end. Two research questions were developed to improve the understanding of what was happening during PLT: 1. What are the perceptions and experiences of A & C staff, and of practice managers with regards to PLT? 2. What are the perceptions and experiences of the community nursing team (community nurses and nursing managers) with regards to PLT? Method: A Charmazian grounded theory approach was adopted, both as a method of data analysis, and as a research strategy. The data collection consisted of two phases: A & C staff, and practice managers (2005); and the community nursing team (2007). Focus groups were recruited, and the interviews were audio-recorded and transcribed. Transcriptions were coded, and themes and categories of themes were constructed from the codes. Mind mapping software was used to show the connections between the participants’ quotes and the themes and categories. A grounded theory was then constructed from the three categories. Findings: 12 focus group interviews were held with a total of 88 staff members participating. Details of the categories constructed are as follows: Structures in primary health care Physical structures were important. There were perceptions of the organizational schism between individual practices and the community nursing team. Community nurses valued co-location with their general practice as this improved close working. Different working patterns of district nurses meant that they could not always be protected during PLT, and they felt their managers did not provide sufficient cover. The introduction of the 2004 GMS Contract emphasized the separation of community nurses from general practices. Some nurses felt that practice-based PLT was irrelevant as it was centred on the learning needs of the practice. Some practices were strongly hierarchical resulting in separate learning events for individual staff groups during PLT. Relationships in primary health care: Relationships between community nurses and practices varied greatly. Some health visitors felt very isolated from the general practice. Community nurses wanted to work closely with practices and wanted their work to be visible and valued. Relationships between A & C staff and GPs varied considerably. Those practices with a high degree of hierarchy found collective learning difficult to do. Other practices had good relationships between different staff groups, and made good use of PLT. Learning processes: In general, participants did not feel their learning needs were identified or acted upon. As a result, learning offered to them was usually considered irrelevant, and based on the needs of others. A & C staff found some events to be dull and uninteresting, when passive learning methods were employed. Some practice managers perceived a lack of resources for learning events, and pharmaceutical representatives were keen to provide learning for clinicians. In some teams, practice-based PLT could be uncomfortable for community nurses, and some felt unwelcome by GPs. Practice managers were considered to be the natural leaders of practice-based PLT. Grounded theory: A theory with three elements was constructed from the findings. Proximity was an important factor in the ability of teams to learn from each other. Those teams who were not co-located, or did not work together in the provision of patient care, found PLT to be difficult. Perceptions of power affected the experiences of PLT. GPs usually had learning based on needs, and they could influence who attended PLT with them, and what was learnt. Some staff groups had little power, namely A & C staff and community nurses, and at times, the quality of learning for these groups was low. Authenticity was important. Participants wanted PLT to be for the whole team and to involve everyone in learning together. Many were disappointed when this was not achieved, and considered it to be contrary to the original aims and objectives of the scheme. Comparisons with other theories: The grounded theory was compared to Bourdieu’s theory of practice. This helped with the understanding of issues relating to the element of power. The element of proximity had similarities to Wenger’s theory of Communities of Practice. Those primary health care teams who displayed high levels of proximity were working as a Community of Practice. Conclusions: A deeper understanding of participants’ perceptions and experiences was gained and explored by the thesis. A number of recommendations were made to improve PLT in the future. These included improved learning needs assessment and aiding practice managers with the delivery of practice-based events. Individuals within primary health care teams need to improve team-working and need learning to help them with this endeavour. Health authorities need to value teamwork more, and require to locate teams together to facilitate the delivery of primary health care.

This thesis provides a comprehensive analysis of spiritual healing in England in its various different guises during the late-nineteenth and early- to mid-twentieth centuries. It considers the interplay between the various spiritual healing groups themselves and between their philosophies and practices and orthodox medical theory more generally. The first half examines how spiritual healing was conceptualised by those who practised it - who spiritual healers were, what they believed and how they defined illness and healing. The specific therapeutic techniques used by healers are delineated, and the themes of touch and morality explored in detail. The second half of this thesis then examines how spiritual healing was perceived by the religious and medical establishments, and explores their co-operational discourse. Firstly, the reaction of the orthodox Christian churches to spiritual healing and their fractured and inherently conservative attempts to utilise it as a means of revitalising orthodox Christianity are analysed. The final chapters then chart the chronological relationship between spiritual healing and orthodox medicine during three specific periods, and explore the way in which spiritual healing intersected and impacted upon medical reactions to the new psychology of the twentieth century.

This study presents an investigation of the underlying linguistic profiles often Hyperlexic children and explores the nature of the problems which give rise to their diagnosis. The subjects' unexpected exceptional decoding strength together with their similarly unusual reading comprehension failure form the focus of this study. Reasons accounting for both these phenomena are explored. Diagnosis of these subjects is considered in relation to previous definitions of Hyperlexia and claims about its symptoms, nature and association with other deficits. An overview of the controversy and conceptual confusion regarding explanations of Hyperlexia is emphasized. The sources of the Hyperlexic symptoms observed in the subjects are explored and discussed in relation to current psycho-linguistic models of reading and its development. This inquiry leads to two sets of investigations, the first focusing on the subjects' decoding skills and the second on their comprehension and inferencing abilities. The investigation explores a number of questions regarding the subjects' reading skills. These include determining whether the Hyperlexic subjects prefer one route to reading over another (use lexical or sublexical strategies), whether the deficit is modality specific, whether their unusual reading pattern is consistent over time, whether the subjects can access the semantic system and understand words they read as well as the manner in which they approach the learning of novel words (whether semantic cues help or hinder the learning of new words). Findings from the first set of questions leads to a further investigation of the subjects' comprehension failure. Word, sentence and paragraph level semantic and syntactic skills are explored and ruled out as primary sources of the comprehension breakdown. Instead, pr~gmatic language weaknesses are confirmed and a relationship is established between these symptoms and the comprehension failure. The notions of Relevance, Theory of Mind and Central Coherence are discussed and their application to Hyperlexia considered. The concluding discussion addresses a number of theoretical questions regarding the nature of Hyperlexia. Implications for intervention and possible future directions for research are proposed.

Introduction: Opioids are widely used for the management of cancer and chronic non-cancer pain and the maintenance management of patients with a history of substance misuse. Increasingly the use of opioids is being scrutinised as patients are prescribed opioids for longer periods and the long-term effects of the opioids becomes clinically more relevant and evident. Our work has explored the prevalence of opioid-related side-effects in patients who are prescribed opioids and explored the clinically relevant phenomenon of opioid-induced hyperalgesia. . Methods: Patients were recruited who were prescribed opioids for the management of cancer and non-cancer pain or substance misuse. Quantitative data was collected to explore the prevalence and severity of opioid related side-effects, the impact of opioids on cognitive function and the effect of opioids on peripheral nerve function through quantitative sensory testing. Testing the sensory processing of patients who are on opioids has revealed altered thermal thresholds and the presence of wind-up at non-painful sites indicating central sensitisation. Qualitative description was used to explore the patient experience of an episode of opioid toxicity. Results: Patients have a significant burden of side-effects which have often not been recognised by clinicians. Using the Addenbrooke’s Cognitive Examination much more cognitive impairment has been revealed than has previously been recognised. Altered thermal thresholds and wind-up at non-painful sites suggests altered pain processing as a result of opioids. Themes from the qualitative description highlighted the coping strategies patients’ develop when managing with significant side-effects and toxicity, the covert self-management of their pain and the need to exert control. One of the most significant findings from the qualitative research was the finding of altered sensation and pain description associated with other features of opioid toxicity. Conclusions: The impact of opioids on the cognitive function of patients has significant implications in terms of patients’ involvement in decision-making and functioning in everyday life. The qualitative data reflects the burden of side effects and the descriptions of patients suggest that opioid-induced hyperalgesia exists as part of the spectrum of opioid toxicity. This finding may help physicians identify patients who are developing opioid-induced hyperalgesia and allow them to intervene earlier with a proactive approach.

RNA Polymerase III (Poll III) contributes to about 10% of nuclear transcription and is essential for the synthesis of short untranslated transcripts, including tRNA and 5S rRNA. Pol III deregulation has been implicated in driving cellular proliferation and transformation, along with increased expression of a number of Pol III specific transcription factors and transcripts. The significance of Pol III in clinical pathology, including that of human malignancies, remains to be formally tested. Using prostate cancer as a model, two key components of the Pol III complex, namely Brf1 and tRNAiMet, were investigated. The expression patterns of Brf1 and tRNAiMet were studied in this thesis using immunohistochemistry (IHC) and in situ hybridisation (ISH) respectively. Brf1, a subunit of transcription factor IIIB (TFIIIB), was detected predominantly in the nucleus with heterogenous staining intensity, its presence ranging from weak to strong. Examination across a wide range of tissue types and organs, both normal and tumour tissues revealed high levels of Brf1 expression in the epithelium. In addition, Brf1 expression could also be detected in connective tissues and, to a lesser extent, in muscular and nervous tissues. A number of tumour types exhibited elevated expression of Brf1 protein relative to their normal control tissues. These included prostate adenocarcinoma, B-cell lymphoma and, interestingly, tumours arising from connective tissues (sarcoma, fibrosarcoma and chondrosarcoma). As expected, tRNAiMet expression, as revealed by ISH analysis, was mostly observed in the cytoplasm, although some nuclear staining was also present. Similar to Brf1, tRNAiMet expression was detected predominantly in epithelial tissues such as the skin epidermis, prostate gland and epithelial lining of the cervix. A number of tumours were found to overexpress tRNAiMet. These included breast ductal carcinoma, oesophageal carcinoma and melanoma. The clinical impact of Brf1 and tRNAiMet overexpression was examined using tissue microarrays (TMA) containing tissue samples obtained from patients with prostate cancer (PCa) and benign prostate hyperplasia (BPH). Collectively, data from two independent patient cohorts, Glasgow TMA: BPH (n=21), PCa (n=151) and Newcastle TMA: BPH (n=113), PCa (n=365), showed that Brf1 expression was upregulated in prostate cancer relative to BPH (p=0.0034). Brf1 expression was not found to be associated with the following clinical and biologic parameters: Gleason sum score (indicative of tumour differentiation and morphology, p=0.653); prostate specific antigen (PSA level, indicative of tumour bulk or volume, p=0.381) and Ki-67 expression (signifying cellular proliferation, p=0.034). However, and importantly, within the prostate cancer patient cohorts studied, high Brf1 expression was associated with a significantly less favourable survival outcome (Kaplan Meier analysis, p<0.001). Together, the data presented in this study support the relevance of Brf1 and tRNAiMet overexpression as part of Pol III deregulation in tumours, especially of epithelial origin. This study also suggests the potential application of Brf1 as a prognostic marker in cancer, however, this warrants a further study.