Diabetes is a chronic metabolic disease that leads to vasculopathy involving the small and large blood vessels. Studies on animal models indicate that, GLP-1 analogues might have beneficial effects on the above mentioned complications over and above the improvements due to glycaemic control. The aims of this study were to explore effects of the GLP-1 analogue, liraglutide on the microvascular complications and cardiovascular risk in human subjects with diabetes. In a retrospective cohort study, I compared a group of patients who received liraglutide with a matched group of subjects with type 2 diabetes on other treatments. The changes in urinary albumin:creatinine ratios and retinopathy grades of these patients were compared after 12 months. In a prospective study, the serum biomarkers of diabetic nephropathy and diabetic retinopathy were measured in a group of subjects with type 2 diabetes, before and 3 months after treatment with liraglutide. In addition body composition analysis of a group of morbidly obese patients with type 2 diabetes was performed before, and 3 months after treatment with liraglutide. In subjects with established microalbuminuria, treatment with liraglutide for 12 months did not have any effect on albumin excretion rate. Similarly, no changes in urinary albumin:creatinine ratios were evident in normoalbuminuric subjects after 12 months of treatment with liraglutide. I did not find any significant changes in the biomarkers of diabetic nephropathy following treatment with liraglutide. In patients with type 2 diabetes, therapy with liraglutide for 12 months did not influence the course of diabetic retinopathy. No changes in the serum concentrations of VEGF (which is a biomarker for retinopathy) were noted in patients after treatment with liraglutide. In morbidly obese subjects with type 2 diabetes, 3 months of treatment with liraglutide induced significant improvements in the markers of cardiovascular risk and reduced total body fat mass. An improvement in the mean insulin sensitivity was noted after treatment; however this did not reach statistical significance. In conclusion, my study has shown that treatment of patients with type 2 diabetes and obesity with liraglutide was associated with improvements in markers of cardiovascular risk; but no changes in diabetic renal disease or diabetic retinopathy were evident.

Objective. The present study explored people‘s subjective experiences of positive change to understand if experiences of growth are evident in people who have experienced trauma and psychosis. Design. Purposive sampling was used to recruit seven participants from local mental health support groups. All participants reported a diagnosis on the schizophrenia spectrum of disorders and were interviewed using a semi-structured interview schedule designed for the purpose of this study. Methods. Interviews were transcribed and analysed using interpretative phenomenological analysis. Results. Participants described the processes involved in moving towards positive change, with the overarching theme describing a journey towards recovery. Two superordinate themes were identified in the study and included: 'barriers to change' and 'the adapting self'. A number of subordinate themes were discussed within these. Conclusion. Participants described key changes in facilitating psychological growth and recovery, including: self-acceptance, adapting to their experiences and self-integration and identity re-formation. Social support, finding meaning and purpose and regaining control over their lives were also integral in facilitating the process towards psychological growth. The study discussed clinical implications in relation to the changes needed in the provision of psychological therapies to aid and promote psychological growth in this population. Methodological considerations of the research are discussed and future research ideas are suggested.

Objectives: The evidence base for Acceptance and Commitment Therapy’s (ACT) overall effectiveness is highly promising. However, the extent to which the six processes comprising ACT have been investigated is extremely variable. In particular, the process regarding the self and therapeutic change is in need of validation, having never been subjected to empirical investigation The objective of the present study was to achieve this by testing whether the predictions ACT makes regarding the self and therapeutic change are supported by quantitative data. The specific prediction to be tested were that a) those with a fixed sense of self and low psychological flexibility will display high therapeutic resistance and b) those with a fluid sense of self and high psychological flexibility will display a strong tendency towards value-based behaviour. Method: Data from 171 non-clinical participants was subjected to a two-way between subjects ANCOVA, with self-theory and psychological flexibility as independent variables and therapeutic reactance as the dependent variable, co-varying out the effects of gender. Results: A significant interaction effect between psychological flexibility and sense of self was found. Post-hoc tests revealed two specific findings: Firstly, people with low psychological flexibility and a fixed sense of self displayed therapeutic reactance that was likely to impede therapeutic change. Secondly, people with high psychological flexibility and a fluid sense of self displayed therapeutic reactance that was more likely to be consistent with value-driven, goal-oriented behaviour. Conclusions: These findings are consistent with ACT’s theorised process regarding the self and therapeutic change. Thus, ACT’s predictions regarding the self and therapeutic change have received their first empirical validation. Clinically, the overarching psychotherapeutic focus is on the client’s process of relating to their self-concept, rather than altering its contents.

This study has a manifest and a latent aspect. The manifest aspect tells a story about some key developments within the counselling and psychotherapy professions in recent years. 1 begin by looking at three phenomena which have been referred to as Schoolism, the research-practice gap and the hierarchy of evidence. I argue that it is important to address these phenomena as the profession moves towards statutory registration under the aegis of the Health Professions Council. I also argue that, in order to achieve this and develop a cohesive profession, traditional research methodologies which the profession promotes in, for example, such journals as Counselling and Psychotherapy Research, need to be supplemented by 'psychotherapeutic' research methodologies (or what, in academic terms, I have referred to as reflexive action research). In other words I posit that the adoption of both traditional and psychotherapeutic/reflexive action research methods will further the development of the profession, meet the aims of such organizations as the British Association for Counselling and Psychotherapy and address the issues of Schoolism, the gap and the hierarchy of evidence. I use psychotherapeutic/reflexive action research methodology as an integrating framework for examining professional experiential data with a view to bringing about change and transformation within the profession and as a way of incorporating a bricolage of methodologies - autobiographical and autoethnographic, heuristic, narrative, deconstructive, phenomenological, reflexive and action research. The latent aspect of the study engages in a discursive examination of some key discourses and knowledge systems within the profession. In so doing, I argue for an approach to research which emancipates practitioners from the confining web of professional discourses and methodological systems so that they can get in touch with their lived embodied professional experience. I thus examine the powerful influence of professional discourses, including my own, and incorporate the principles of critical theory as a means of becoming aware of the influence of these discourses and encouraging practitioners to liberate themselves from them in order to promote change and transformation within the profession. I also take the view that our understanding and activities are influenced for better or worse by our beliefs. Consequently all aspects of the study are influenced by my core belief – a spiritual monistic belief system called Anthroposophy - and, towards the end of the investigation, I attempt to make the relevance of this belief to research transparent and also engage in some reflection on the role of belief in professional life and activity generally and some of the contradictions and tensions in the text.

Increased left ventricular (LV) size and deformation of LV geometry are associated with LV dysfunction. Regional shape distortion (RSD), detected on two-dimensional echocardiography (2D-Echo) after acute myocardial infarction (MI), is associated with poor outcome. Two hypotheses were tested: i) early RSD of the asynergic infarct zone after MI is followed by progressive global LV dilatation, remodelling towards a spheroidal shape, and more LV dysfunction; and ii) the progressive remodelling of LV geometry spans the phases of early infarction and healing and may be modified by early and prolonged therapies applied over the phases of infarction and healing. A bench to bedside approach was used, with concurrent studies in a dog model of healing over 6 weeks after MI and patients with first MI's. Computer- assisted analysis of the 2D-Echo images with 3D reconstruction was used to quantify LV asynergy (akinesis + dyskinesis), LV volumes, LV ejection fraction, RSD bulge and global LV shape. The animal studies showed that collagen deposition during healing after MI increases progressively, reaching a plateau around 2 weeks, and deposition of collagen in already dilated infarct zones is followed by late thinning and further RSD associated with LV aneurysms. Importantly, serial 2D-Echo tracked the in- vivo changes in LV geometry and function and showed greater RSD and LV dysfunction with anterior than inferior MI, and with transmural MI than nontransmural MI. Other studies showed: i) lower LV resistance to distension and rupture in infarcted hearts; ii) marked extracellular matrix (ECM) disruption and RSD in transmural MI; ill) delayed effects on LV remodelling after infarct-limiting therapies given during acute MI; iv) loss of beneficial effects of the vasodilator nitroglycerin (NTG) with hypotension induced by high doses during acute MI; v) decreased wall stress by prolonged LV unloading after MI, with nitrates (eccentric dosing) and angiotensin-converting enzyme (ACE) inhibitors, limited early RSD and progressive LV remodelling and dysfunction; this effect was greater with therapy over 6-weeks than just over the first 2 weeks; vi) late reperfusion limited early RSD and adverse LV remodelling, and preserved ECM in the epicardial rim; vii) the resistance of the healed left ventricle to distension and rupture was further reduced by prolonged anti-inflammatory therapy (ibuprofen); viii) prolonged ACE inhibitor therapy decreases infarct collagen, which may be harmful under certain conditions. The clinical studies with serial 2D-Echo showed that systematic tomographic imaging could provide quantitative data on regional and global LV geometry and function including the degree of RSD (depth, area, and volume). An early 2D-Echo not only provided diagnostic data on LV thrombi and complications of MI, but the extent of LV asynergy on the initial 2D-Echo predicted outcome at 3 months and 1 year. Importantly, the degree of RSD on the initial 2D-Echo predicted patients at high risk of adverse remodelling with infarct expansion, greater LV dysfunction, progressive LV dilatation, and poor outcome at 1 year. Survivors of MI with > 18% LV asynergy and significant RSD on a baseline 2D Echo were at increased risk of topographic deterioration on exercise programs. Anti-inflammatory therapy after MI resulted in more RSD and adverse remodelling. Short-term LV unloading with low-dose intravenous NTG therapy during the acute MI, as well as prolonged nitrate (eccentric dosing) and captopril therapy during healing over 6 weeks after MI, improved 2D-Echo indexes of LV geometry and function, decreased complications and improved outcome. Acute thrombolytic therapy also limited LV remodelling after MI. In all these studies, the degree of RSD and severity of LV dysfunction were greater with anterior than inferior MI, and with Q-wave than non-Q wave MI. In Conclusion, the overall results indicate that early RSD in the infarct zone leads to progressive global LV dilatation, LV dysfunction and poor outcome and the changes in LV geometry and function can be quantified by serial quantitative 2D-Echo imaging. Marked RSD is associated with early ECM disruption and aneurysm formation after transmural MI. During healing, infarct zones may be thinned and dilated before the collagen plateau, and collagen deposition into these zones result in further RSD and chronic aneurysms. Prolonged anti-remodelling therapy during healing, with agents that decrease wall stress without damaging the ECM, or decreasing infarct collagen, or causing infarct thinning, or impairing healing, might be more effective for reducing RSD, LV aneurysm, global dilatation and poor outcome. The 2D-Echo measurement of RSD early after MI might be potentially important for stratifying patients according to their topographic status and for the objective assessment of the effects of anti-remodelling strategies during healing after MI.

Treating people living with severe health conditions has, and always will be, a fundamental part of the National Health Service. Given the complex nature of conditions such as Huntington's Disease and Cancer, research exploring the impact severe health conditions can have on those affected is of paramount importance. Chapter one is a systematic review utilising a meta-ethnographic approach to explore qualitative research portraying people's experiences of genetic testing for Huntington's Disease (HD). Electronic databases cataloguing relevant research were searched which, combined with manual searches, resulted in eleven studies suitable for inclusion. Three meta-themes were identified, highlighting the complex and individual nature of undergoing genetic testing, together with the potential emotional and behavioural consequences. The implications of such findings, together with clinical recommendations are considered. There is a dearth of research exploring what it is like to live with cancer as a young person in the United Kingdom. Chapter two is a qualitative research study that explored the lived experiences of young people (13-24 years) who had recently been diagnosed with cancer. Utilising an interpretative phenomenological approach, emergent findings related to the adversarial nature of being diagnosed with cancer, with young people speaking to the unjust nature of battling this disease at such a youthful age, questioning their identity and having to navigate a new, and at times, uncertain world. The clinical and service implications of these findings are discussed, alongside areas of future research. Chapter three represents the author's reflective account of conducting this research. From exploring initial motivations, to evaluating the role of "insider" and "outsider" perspectives, the author explores the reciprocal nature of conducting qualitative research, particularly in relation to the mutuality felt between himself and his participants.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. In around 85% of cases, the disease progresses through two distinct stages: relapsing-remitting MS (RRMS) is driven by repeated bouts of demyelination caused by autoimmune inflammation; and progressive MS, in which inflammation gives way to neurodegenerative processes that lead to axonal loss and the steady accumulation of disability. There is no cure for MS and the majority of disease-slowing treatments target the immune response in RRMS. These interventions are ineffective in progressive MS and other treatment options are extremely limited. Understanding the mechanisms underlying neurodegeneration in MS is critically important to developing therapeutics for progressive disease. Fibroblast growth factor 9 (FGF9) has recently been implicated in the pathogenesis of MS. FGF9 inhibits myelination and promotes the production of inflammatory chemokines. This led to the hypothesis that FGF9 is involved in remyelination failure and may promote neurodegeneration via tissue remodelling and inflammatory pathways. FGF signaling is complex and the findings in MS raised many questions: what cells respond to FGF9 in MS? Why is FGF9 expression induced in the first place? Can FGF9 cause demyelination as well as inhibit myelination? This thesis has focused on the roles of FGF9 in MS and tried to answer these questions. Through in vitro models, astrocytes, oligodendrocytes, and macrophages were shown to express feedback inhibitors of FGF signaling when treated with FGF9. Astrocytes produced FGF9 in response to hypoxic stress, macrophages expressed FGF9 when polarized towards an anti-inflammatory phenotype, suggesting hypoxia, and repair processes may drive FGF9 expression in the CNS. FGF9 did not cause demyelination in vitro but over-expression in vivo induced severe demyelination over the course of several months. Oligodendrocytes exposed to FGF9 failed to differentiate properly when the factor was removed which led to aberrant myelination. Long-term treatment with FGF9 induced axonal pathology, potentially via deficits in axon-transport. Over-expression of FGF9 in rat cortex also produced an axonal pathology, which suggests chronic exposure is detrimental to neurons. Together, these findings indicate that increased levels of FGF9 are detrimental to myelination and neurons in the CNS. Demyelination, and axonal pathology are hallmarks of MS and these studies provide evidence that FGF9 can mediate these processes in in vitro and in vivo models.

A large number of patients with epilepsy have drug-resistant seizures. Therefore, there is a need for the development of new therapies. The purine nucleoside adenosine is an endogenous anticonvulsant that acts to supress neuronal excitability via adenosine A1 receptors. The aim of this thesis was to investigate whether manipulating ATP bioenergenetics and importantly adenosine levels had any effects on activity-dependent release of adenosine and seizure activity. ATP bioenergetics and adenosine levels were manipulated by pre-treating rat hippocampal slices with a combination of the sugar backbone of ATP (D-ribose) and the free purine base adenine (RibAde) and the phosphate buffer creatine. The role that the adenosine A2A receptor plays in relation to epileptiform activity was also investigated. Biosensors were used to measure the real-time release of adenosine. The K+ channel blocker 4-aminopyridine (4-AP; 50 μM) in Mg2+-free medium was the model used for inducing spontaneous bursting epileptiform activity. Additionally, homocysteine thiolactone (HTL) was used to “trap” intracellular adenosine to test if extracellular adenosine measured with biosensors, is released as adenosine per se and if this had any effects on seizure activity. I show that during bursting epileptiform activity, the amount of adenosine released is increased in RibAde slices compared to creatine and untreated (control) slices and increased the time between seizures compared to both creatine and control slices. No differences was found between creatine and control slices. My data also suggest that adenosine A2A receptors may partially contribute to seizure activity. HTL reduced adenosine release in a burst-dependent manner and also increased the frequency of seizures. HTL influenced the intensity of bursts in control but not RibAde-treated slices. This thesis provides evidence for the beneficial role of the ATP precursors ribose and adenine on reducing seizure activity and will hopefully contribute to ongoing attempts to establish adenosine-based epilepsy therapies.

Poor sleep and high levels of anxiety have a detrimental effect on cognitive functioning. However, very little is known about what cognitive functions are affected by poor sleep or high levels of anxiety and if some are more affected than others. This thesis informs the understanding of poor sleep and anxiety with a focus on generalised anxiety disorder and how they affect specific cognitive functioning namely Attention and Working Memory. Chapter one is a systematic literature review of the qualitative research exploring how sleep deprivation impacts on the cognitive functioning of people with Autistic Spectrum Conditions (ASC) and the principal challenges associated with trying to study the impact of sleep deprivation in people with ASC. Following both database and manual searches, fifteen studies were included and reviewed. The review highlights the suggestions that poor sleep has a detrimental effect on the cognitive functioning of people with ASC. Also, the use of objective and subjective measures of sleep was discussed to help in the early detection of these problems and considerations of carers and families was reviewed. Future research/clinical implications are discussed. Chapter two is a quantitative research study that investigated the combined effects of GAD and poor sleep on Attention and Working Memory. Sleep quality and quantity were assessed using subjective and objective measures of sleep. Attention and Working Memory was measured using various neuropsychological measures. Groups were compared for differences in cognitive scores using a non-parametric test. Relationships between GAD-7 scores, sleep quality/quantity and cognition scores were investigated using correlation analyses. Implications for future research and clinical implications are discussed. Chapter three is a reflective account, exploring the role of reflexivity in personal and professional development during the research process.

Post-transplant lymphoproliferative disease (PTLD) is a life threatening complication of transplantation, often associated with the B-lymphotrophic Epstein-Barr virus (EBV). In order to further our understanding of the relationship between EBV infection and PTLD, a series of clinical and laboratory studies were undertaken. A multicentre United Kingdom study defined current outcomes and prognostic factors for patients with PTLD arising after solid organ transplant. A study to define incidence and risk factors for EBV reactivation and PTLD amongst patients undergoing allogeneic haematopoietic stem cell transplant (allo-HSCT) revealed greatly reduced risk amongst patients with Non-Hodgkin lymphoma previously treated with Rituximab. Complementary laboratory studies to explore the pathophysiology of EBV reactivation after allo-HSCT demonstrated that the virus maintains selectivity for, and can drive the expansion of, circulating CD27+ memory B-cells; these are normally scarce for many months after transplant. Investigations were also performed to examine the role of cell survival, DNA damage signalling and mutations as possible drivers of clonal selection in EBV-infected B-cell cultures, as an \(in\) \(vitro\) model for PTLD. Finally, work was undertaken to characterise EBV-epitope specific T-cell responses expanding in patients successfully treated with donor lymphocyte infusion for Rituximab-refractory PTLD arising after allo-HSCT.