Background Stroke is the leading cause of long-term neurological disability in adults and the third most common cause of death in Britain. It is well known that in addition to the patient characteristics of age and severity, the treatment a stroke patient receives in hospital signifcantly affects outcome. The effectiveness of complex service interventions, how the benefits of these interventions are achieved and the economic impact of different types of service delivery were explored. Methods The Stroke Unit Trialists' Collaboration systematic review was updated and currently contains 31 clinical trials (6936 subjects). The aims were explored using various basic frequentist and Bayesian meta-analysis techniques as well as more complex meta-analysis ideas. These more complex ideas include: meta-regression where covariate information is incorporated into the model; and network meta-analysis where direct and indirect information is used in a mixed treatment comparisons model while also incorporating covariate information. Results Organised inpatient (stroke unit) care showed reductions in death, death or dependency and death or institutional care compared to general medical wards. Stroke unit care appears to reduce the risk of adverse outcomes through prevention and treatment of complications. Acute, comprehensive and rehabilitation stroke unit care appeared to be most effective and acute stroke unit care appeared to be the most cost-effective. However, acute followed by rehabilitation stroke unit care, if required, appears to be the most cost-effective pathway of care compared to the other pathways analysed. Discussion Future research should focus on rehabilitation, acute and comprehensive systems of inpatient care, and explore the best ways of preventing and managing specific complications. Effort should be made to make individual patient data and information on the care pathway of a stroke patient available for meta-analysis.

Smokers with asthma display reduced responses to both inhaled and oral corticosteroids with associated increased symptoms, accelerated decline in lung function and increased use of health care services. Little work has been undertaken to address the possible causes of this reduced response and to find effective replacement therapies. Therefore this thesis was carried out with the aim of identifying potential mechanisms and new therapies for this group. The oral bronchodilator theophylline has been suggested as a treatment for corticosteroid insensitivity due to its ability to increase HDAC activity in-vitro. I undertook an exploratory proof of concept clinical trial based on the hypothesis that low dose theophylline would restore corticosteroid sensitivity in smokers with asthma through theophylline induced recovery of HDAC activity. Low dose oral theophylline added to inhaled corticosteroid increased pre-bronchodilator lung function and reduced symptoms of asthma whilst low dose theophylline given alone reduced symptoms but had no effect on pre-bronchodilator lung function. This research provides a foundation for future studies designed to examine the efficacy of theophylline in smokers with asthma. Agonists of the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ) have been demonstrated to be effective at reducing inflammation in both in-vitro and animal models of asthma. Therefore to examine the hypothesis that PPARγ stimulation would reduce the inflammation present in smokers with asthma I undertook an exploratory, proof of concept clinical trial using the PPARγ agonist rosiglitazone. Treatment with rosiglitazone was associated with a trend to improvement in FEV1 and improvement in a marker of small airway lung function and as such may provide an alternative treatment for small airways obstruction in conditions such as asthma and chronic obstructive airways disease. This trial will enable powering of future confirmatory studies. Altered cytokine profiles, specifically the combination of increased interleukin (IL)-2 and 4, are observed in asthmatic subjects with corticosteroid insensitivity. Based on this work I examined the hypothesis that the altered response to corticosteroids in smokers with asthma was associated with an altered cytokine milieu including raised levels of IL-2 and 4. Smokers with asthma, characterised as corticosteroid resistant by oral corticosteroid trial, demonstrated significantly raised sputum supernatant IL-6 levels and raised levels of a number of other sputum cytokines compared to non smokers with asthma. This altered phenotype suggests cigarette smoking in asthma may be associated with a deviation to Th1 mediated inflammation and could provide an explanation for the reduced corticosteroid response of smokers with asthma. The cell type/s responsible for both this shift in immunological phenotype and production of increased levels of sputum cytokines is unclear and will require further study. Previous in-vitro and in-vivo research has identified altered histone acetylation patterns in subjects with relative corticosteroid resistance. Therefore I examined the hypothesis that smokers with asthma displayed reduced responses to corticosteroids as a result of a cigarette smoke induced reduction in histone de-acetylase (HDAC) activity. Smokers with asthma provided sputum macrophages and blood for peripheral blood borne monocytes to examine total HDAC activity. Sputum and blood macrophage total HDAC activity was equivalent in smokers and non-smokers with asthma. Therefore reduced blood total HDAC activity does not appear to explain the altered corticosteroid response in this group. However the number of sputum macrophages obtained may have been too low to allow conclusive examination of this endpoint. Another consideration is that contamination of the sample due to the technique used may be altering the signal obtained. Further work either through modification of sputum induction techniques to increase macrophage number or bronchoscopic sampling is required to conclusively address the role of alveolar macrophage HDAC activity in the reduced corticosteroid response displayed by smokers with asthma. Exhaled nitric oxide has been exploited as a useful exploratory and confirmatory endpoint in asthma. However exhaled nitric oxide, measured using standard flow rates and methodology, is unhelpful in smokers with asthma as cigarette smoking is associated with a marked reduction in exhaled nitric oxide levels in the majority of subjects. Recent research has demonstrated that measurement of exhaled nitric oxide at multiple flow rates followed by mathematical modelling reveals increased levels of alveolar nitric oxide that were unaltered by current smoking. Therefore to examine the hypothesis that smokers with asthma display altered levels of alveolar nitric oxide and flow independent parameters compared to non-smokers with asthma I carried out a cross-sectional study. Alveolar nitric oxide, determined by linear modelling, was significantly reduced in smokers with asthma compared to non smokers with asthma. The concentrations observed were within the range for normal subjects and therefore this method does not overcome the problems inherent in measuring exhaled nitric oxide at standard flows. The use of non-linear modelling did demonstrate parity between smokers and non-smokers with asthma for alveolar nitric oxide. Nitric oxide flux was lower in smokers with asthma when derived by both linear and non-linear modelling and displayed sensitivity to oral corticosteroids. Therefore nitric oxide flux is worthy of further investigation as an exploratory endpoint in smokers with asthma. In conclusion treatment of smokers with asthma with low dose theophylline alone, the combination of low dose theophylline and inhaled corticosteroid and the PPARγ agonist rosiglitazone was associated with clinical improvements and further clinical trials to assess the role for these treatments in the management of smokers with asthma are justified. Smokers with asthma display an altered sputum cytokine profile with raised levels of the proinflammatory cytokine IL-6, equivalent blood total HDAC activity and reduced alveolar nitric oxide compared to non-smokers with asthma. Sputum HDAC activity requires further development before it can be confidently employed as a method of assessing total pulmonary HDAC activity.

Objectives: Previous research has identified negative staff attitudes towards patients who self-harm, as well as stigma towards mental health problems in general hospital settings. This study extended this existing research to patients who present to general hospital settings with self-harm by measuring their perceptions of stigma in comparison with a control group of other hospital patients. The study also examined whether perceived stigma was related to aspects of current psychological distress. Method: Ten patients who were admitted to hospital following an episode of self-harm and ten hospital control patients completed a demographic questionnaire, the SCL-90-R measure of current psychological distress and a purpose-designed measure of perceived stigma. Results: Mann-Whitney U-tests revealed significant differences on SCL-90-R Interpersonal Sensitivity (U=17.50, p=0.011), Paranoid Ideation (U=21.00, p=0.029) and Psychoticism (U=23.00, p=0.043), together with marginally significant differences on Depression (U=24.50, p=0.052) and Hostility (U=24.50, p=0.052), between the two groups. A significant difference in perceived stigma scores (U=16.00, p=0.009) was also identified. One-tailed Spearman’s correlations highlighted positive associations between perceived stigma and SCL-90-R Interpersonal Sensitivity (ρ=0.685, p=0.014) and Depression (ρ=0.723, p=0.009) in the self-harm group, and SCL-90-R Depression (ρ=0.596, p=0.035) and Phobic Anxiety (ρ=0.595, p=0.035) in the control group. Conclusions: The results suggested that patients who self-harm perceive higher levels of stigma in general hospital settings compared to patients presenting with other types of injury. These differences appeared to relate to aspects of current psychological distress. Further research employing larger samples would help clarify this association.

Multiple sclerosis (MS) is a chronic disease of the human central nervous system (CNS) in which repeated episodes of inflammatory demyelination result in formation of persistently demyelinated plaques of gliotic scar tissue associated with varying degrees of axonal loss. MS is now considered a “complex trait” that is triggered in genetically susceptible individuals by environmental factors. The disease is also considered to contain an autoimmune component where both the adaptive and innate immune systems have been implicated in disease pathogenesis. There has been a steady accumulation of circumstantial evidence from both clinical and experimental studies that implicate a role for autoantibody dependent mechanisms. However this issue remains controversial in the absence of formal evidence that patients actually develop a pathogenic autoantibody response. The aim of this thesis was to resolve this question. To do this we developed an in vitro bioassay based on a dissociated myelinating culture system from embryonic rat spinal cord. We demonstrated that this in vitro system could reproduce many features of in vivo myelinated axons. To validate this model as a viable screening assay characterised complement mediated autoantibody responses using a series of monoclonal antibodies and anti-sera. Due to their significance in the literature we focussed in particular on the MOG specific and Nfasc specific responses and comprehensively demonstrated that our bioassay offered a robust screening strategy in which to detect pathogenic antibody responses in the presence and absence of exogenous complement. To determine whether we could use our model to detect pathogenic autoantibody responses in MS patients, we purified the IgG fraction from a cohort of MS patients (n=20), OND (n=10) and healthy controls (n=13). Using this patient purified IgG we demonstrated a MS specific demyelinating activity, which was present in ~50% of samples screened. However in 10% of patients demyelination occurred secondary to pronounced axonal injury. These effects were dependent on exogenous complement and were unique to the MS cohort. Pathogenic antibody responses tended to be most prevalent in those patients with an aggressive disease course. In addition to complement mediated CNS injury we also demonstrated that this pathogenic MS IgG could disrupt myelin formation in developing myelinating cultures. Attempts to define the specificity revealed that this was heterogeneous, however in one MS patient we discovered that Nfasc155 provided a dominant antigen for pathogenic autoantibody responses. Together these data provide formal demonstration that MS is associated with pathogenic autoantibody responses. This has significant long term consequences for the clinical management of the disease

Asthma is a common and complex inflammatory disease of the airways characterized by deregulated immune responses that involves activation of multiple cell types including Th2 cells, IgE producing B cells, mast cells, basophils and eosinophils as well as resident lung cells such as epithelial, smooth muscle cells and macrophages. Despite intensive research, there are still unmet needs in the treatment of asthma. Recently, a new cytokine of IL 1 family, named IL 33 emerged as a potentially important factor in the immunopathogenesis of allergy and asthma. It was recently shown in our laboratory that intranasal administration of IL 33 can induce certain physiological features that are characteristic of experimental asthma, such as eosinophilic inflammation, Th2 cytokine and antibody production as well as increased airway hyperresponsiveness. The effect of IL 33 on the activation and differentiation of allergen specific Th2 cells has been well studied. However, the contribution of IL 33 to the activation of lung resident and inflammatory innate cells remains undefined. In this project I focused on alveolar macrophages and eosinophils as both cell types were reported to express IL 33R, ST2L and are thought to play a crucial role in asthma pathogenesis. I raised the hypothesis that IL 33 released locally in the lungs may trigger symptoms resembling asthma through the activation of airway alveolar macrophages. Furthermore, I hypothesize that IL 33 may exacerbate and maintain inflammation in the lungs by the direct activation of eosinophils. In our previous study we showed that IL 33 could switch the quiescent phenotype of alveolar macrophages toward the alternatively activated phenotype (M2, AAM). In the first part of my thesis I looked at the consequences of this phenomenon for airway inflammation. Using clodronate liposomes in vivo I was able to eliminate macrophage population from the lungs and demonstrated that resident alveolar macrophages are crucial for the development of IL 33 induced eosinophilic inflammation in the airways. I then examined the contribution of IL 13, a known M2 differentiation factor, to airway inflammation. Using anti IL 13 neutralizing antibodies I showed that IL 13 is required for the IL 33 triggered differentiation of alveolar macrophages toward M2 phenotype as well as for eosinophilic inflammation. Next, I looked at how IL 33/ST2 pathway modulates the differentiation and activation of eosinophil. I demonstrated that bone marrow hematopoietic progenitors CD117+ express ST2L and that IL 33 is able to differentiate these cells toward eosinophils. By employing deficient mice or neutralizing antibodies I found that this process is ST2 and IL 5 dependent and independent of IL 13. I then extended my research interests to include mature mouse and human eosinophils. I showed that both human and mouse resting eosinophils express low levels of ST2L which can be markedly increased by IL 33. Moreover, I demonstrated that eosinophils that are recruited to the lungs during experimental allergic airway inflammation express high levels of ST2L. Furthermore, I carried out a study on effector function of eosinophils. I found that IL 33 induces IL 13, IL 6 and increases TARC, TGF production by mouse eosinophils. In addition, IL 33 exacerbated IgG induced human and mouse eosinophil degranulation, likely by enhancing FcRII expression. Having shown earlier that IL 13 is requited for the polarization of alveolar macrophages toward AAM by IL 33 in vitro and in light of the fact that IL 33 stimulated eosinophils can be a significant source of IL 13; I went on to investigate the interaction between macrophages and eosinophils. Using co cultures of ST2 / macrophages with WT eosinophils in Transwell system, I demonstrated that IL 33 but not IL 5 activated eosinophils can support macrophage polarization toward the pro inflammatory AAM phenotype, partially through the production of IL 13. Finally, given the role of IL 33/ST2L axis in eosinophil activation in vitro, I investigated the contribution of IL 33 activated eosinophils to airway inflammation in vivo. Using adoptive transfer protocol I showed that the contribution of IL 33 activated eosinophils to airway inflammation is mediated primarily by the release of cytokines from these cells which, in turn, recruits other inflammatory cells and supports the differentiation of alveolar macrophages towards AAM. These data show that IL 33/ST2 pathway regulates multiple features of alveolar macrophage and eosinophil biology that can have a significant impact on asthma pathophysiology in the airways. Studies carried out in our laboratory and elsewhere suggest that IL 33 is equally capable of activating other cell types that have been implicated in asthma pathology such as Th2, B1 cells, DCs, mast cells and basophils. Therefore, targeting IL 33/ST2 pathway may potentially offer a promising therapeutic approach to asthma and allergy.

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The aim of this thesis is to deconstruct the ethical framework, in which the theological community deliberates the new reproductive technologies (NRTs) and to interrogate the constructions of woman and the embryo that have correlated into the ensuing discourses from ecclesiastic traditions. The foundational premise is that the church does not fulfil its pastoral and prophetic role in this increasingly vital socio-cultural area, predominantly because woman’s subject position of invisibility in theological discourses prevents the church from speaking differently to the secular world. The methodology establishes the validity of using critical discourse analysis as a tool of deconstruction based on the insights of Michel Foucault. This is then deployed to interrogate the constructions of woman and the embryo circulating in the popular NRT narratives of the media in order to ground a secular baseline. From this vantage point, critical discourse analysis is undertaken on two church reports and three theological texts. The concluding chapter sketches a different framework of moral perception, within which the church would be enabled to offer greater empathy in its pastoral care and also to prophetically challenge macro-systems of power more effectively.