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Neuroinflammation is an early feature of a number of nervous system disorders. Inflammation in the brain is primarily mediated via microglial cells, which are active components of circuit development in the central nervous system. Schizophrenia is a psychiatric illness with deficits in perceptual, cognitive and emotional function. Prior to the onset of psychosis, there is a period of attenuated psychotic symptoms, where individuals experience sub threshold features of psychosis. This 'ultra high risk' period can provide unique opportunities to investigate the development of psychosis. It has been demonstrated through translocator protein (TSPO) positron emission tomographic (PET) imaging that microglial activity is elevated in chronic schizophrenia, however it is unknown whether this elevation is present prior to the onset of psychosis. It is also uncertain what effect antipsychotic medication has on microglia in vivo. This thesis is divided between clinical and animal investigation, the results can be split into four findings; Firstly we demonstrate that there is a higher binding of [11C]PBR28 (a novel TSPO PET ligand) in ultra high risk subjects and patients with schizophrenia compared to healthy controls. Symptoms in the ultra high risk subjects also correlate with the level of ligand binding. Secondly, brain volumes are not correlated with [11C]PBR28 binding or inflammatory cytokine levels in peripheral blood samples. The third finding of this thesis is that antipsychotic drug administration does not appear to alter cortical microglial cells in naïve and systemically inflamed animals. The final finding is that brain volume is reduced by antipsychotic medication. Together these findings demonstrate that inflammation is present in subjects experiencing subthreshold psychotic symptoms. The animal experiments suggest medicated patients would not be expected to have higher levels of microglial activity than their un-medicated counterparts. Further investigation is needed to determine the mechanism of cortical volume changes after medication and how this relates to TSPO.

The work reported in this thesis is an inherent part of research carried out in Edinburgh to assess the performance and durability of heart valve prostheses. From 1975 to 1979 540 patients undergoing heart valve replacement in Edinburgh Royal Infirmary were entered into a randomised trial and received either a mechanical (Bjork-Shiley), or porcine heterograft (Hancock or Carpentier-Edwards) prosthesis. Starting in 1977 in the United States the Veterans Administration carried out a similar randomised trial on 575 patients. After a mean period of 5 years no significant advantage to any of the three prostheses was observed, although there were some differences in the results reported in the Edinburgh and the US trials and possible explanations for these are proposed. This thesis extends the analysis of the trial to a mean period of 10.5 years with respect to survival, and the incidence of reoperation, complications of anticoagulation, systemic embolism and bacterial endocarditis. It also presents a Doppler ultrasound comparison of the haemodynamic performance of the different valves in a subset of 102 patients. After this extended follow-up period we have again observed no difference in survival between those receiving a mechanical or porcine prosthesis. Recuperation for valve failure was necessary significantly more often in patients with porcine prostheses (53 patients) than in those with the Bjork-Shiley prosthesis (17 patients). This difference was almost entirely due to cusp failure of porcine prosthesis occurring more than 5 years after implantation. An actuarial analysis of valve survival using reoperation or cardiac death as end-points showed significantly better valve survival for patients receiving the Bjork-Shiley prosthesis when all patients and the subgroup undergoing mitral valve replacement were considered, but not in the subgroup receiving an aortic valve replacement. Doppler ultrasound techniques have been used to compare the haemodynamic performance of the Bjork-Shiley and porcine prostheses an average of 10 years after implantation in 102 patients enrolled in the Edinburgh trial. No significant difference in peak instantaneous or mean pressure gradient across the prosthesis was observed in patients who had undergone aortic or mitral valve replacement. There was however a significantly lower pressure half-time in patients with Bjork-Shiley compared with those with porcine mitral prosthesis, suggesting that this difference observed at rest does not indicate better haemodynamic performance of the Bjork-Shiley prosthesis.