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The aim of this thesis was to look for evidence of increased serum free radical activity in elderly hospital patients with delirium. The following parameters were measured: serum iron, copper, zinc, ascorbic acid, antioxidant activity and markers of lipid peroxidation. The results did not show evidence of increased free radical activity in patients with delirium compared to non-delirious control patients. However, the results did show that, compared to healthy community controls, inpatients with infection and delirium (Group A), or with infection only (Group C) or (unexpectedly) with delirium but without clinical or microbiological evidence of infection (Group D) showed biochemical evidence of a systemic inflammatory response. The pattern of change observed in the inpatient groups was: a reduced serum iron and transferrin saturation, reduced serum zinc, elevated serum copper and reduced plasma ascorbic acid. This pattern of change is associated with inflammation. As a result of these findings, the hypothesis is proposed that delirium represents an epiphenomenon of the systematic inflammatory response syndrome (SIRS). Reduced iron levels, reduced zinc levels and low ascorbic acid levels have all, separately, been associated with altered brain function or cognitive impairment in studies of non-inflammatory states. It is therefore argued that these biochemical changes, individually or in combination with other biochemical and immunological changes that occur during the SIRS, such as HPA axis dysfunction, may result in cognitive impairment during inflammation, and, in severe or predisposing cases, contribution to the clinical manifestation of delirium. It is suggested that the area of the brain most vulnerable to the effects of these changes and, in consequence, most likely to produce cognitive dysfunction during delirium is the limbic system and, in particular, the thalamus, hypothalamus and hippocampus.

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The diagnosis and treatment planning of disease may require image data acquisition using a range of 3D medical imaging modalities. These modalities include computed tomography, magnetic resonance, single photon emission computed tomography and positron-emission tomography. In combining images from such modalities, clinicians are provided with aligned data sets that have structural and functional information from within the body. However, no external textural data of the body surface (skin, wounds, and surface disease) is collected. Stereophotogrammetry can produce high resolution topographical surfaces with texture information and is becoming more readily available in the clinical environment. Combining stereophotogrammetry surface data with conventional 3D medical imaging data has the potential to allow improved visualisation of the 3D image data and to provide information on how surface data relates to the patient's internal anatomy. Medical image data is prone to outliers and artefacts due to physical limitations of the modalities involved and patient specific characteristics. To combine a variety of image data into a universal co-ordinate frame an image registration method is required. Outlier-robust registration is required due to the presence of artefacts and noise within the surfaces and images. A range of registration methods are evaluated using phantom test objects in the presence of outliers, simulated as noise, to determine the performance of the registration algorithms. A novel automated method is proposed to identify and examine artefacts at the surface edge of stereophotogrammetry data, using previously acquired registered volumetric image data as a reference. The largest stereophotogrammetry artefacts are observed at the surface edge and have a negative impact on the registration accuracy. Identification and removal of these surface edge artefacts is investigated using novel automated cleansing algorithms. The proposed cleansing methods are evaluated using quantitative and qualitative measures to assess the level of success for the implemented approaches. Results are presented in which stereophotogrammetry surface accuracy can be increased whilst ensuring that the surface is suitable for visualisation. Surface change can potentially indicate underlying anatomical change due to patient growth or disease. An automated algorithm is proposed to identify and measure regions of surface change in phantom stereophotogrammetry surfaces. These surface change regions are identified using information obtained from the registration of the stereophotogrammetry surfaces and the corresponding volumetric image. The preliminary results indicate that the proposed method can be used to locate and measure regions of surface change over time in stereophotogrammetry data.

HCMV is a ubiquitious p herpesvirus that usually causes asymptomatic primary infection. Individuals infected with HCMV mount a strong immune response that suppresses persistent viral replication and is paramount for the prevention of HCMV disease. HCMV encodes a large number of immunomodulatory functions that modulate both the innate and adaptive arms of the immune system. The project undertaken in this thesis was to investigate and characterise immunomodulatory functions encoded by HCMV. A novel and highly efficient method of Natural Killer (NK) cell cloning was developed to investigate modulation of the NK response by HCMV. This technology was utilised to further investigate the finding that CD94/NKG2A+ NK cells are inhibited by UL40-stabilised HLA-E. Analyses of polyclonal NK cell responses and NK clones showed that more CD9410 than CD94hl NK cells were activated by HCMV strain AD169 in comparison to uninfected targets. Flow cytometry showed that there was an increase in the frequency of NK cells expressing the activatory receptor CD94/NKG2C and a decrease in the frequency of cells expressing the inhibitory receptor CD94/NKG2A in HCMV seropositive individuals. The response of NK clones expressing CD94/NKG2A or CD94/NKG2C to targets infected with strain AD169 or RAdUL40 indicated that some CD94/NKG2A clones can be inhibited by gpUL40 while some CD94/NKG2C clones can be activated by gpUL40. Comparative analysis of NK responses to HCMV strain Towne, indicated that strain Towne encoded a novel NK modulatory function that differentially targeted the CD94to and CD94hi NK cell subset in certain individuals. HCMV strain Toledo is known to encode a powerful inhibitor of NK function. Analysis of polyclonal NK cell responses mapped this inhibitory function to gpUL141. In depth analysis of 98 NK clones demonstrated that gpUL141 inhibited a large proportion of NK cells and this was independent of CD94 expression. The initial aim of this study was to characterise the immunomodulatory function of pp65, an HCMV protein that has previously been shown by others to abrogate recognition of HCMV infected cells by HCMV-IE1 specific CTL. Fluorescence microscopy showed that pp65 did not alter the localisation of IE1 and a yeast two-hybrid assay indicated that there was no direct interaction between these 2 proteins. A functional assay using IE1 specific CTL was not performed because sufficient numbers of peptide specific CTL could not be cultured. Nevertheless, this study has contributed to the characterisation of powerful HCMV immunomodulatory functions that selectively target NK cell subsets and are sufficient to alter frequencies of cells in the innate immune system. The results presented here enhance our understanding of HCMV pathogenesis, the regulation of NK cell function and the biology of the innate immune system.