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The criteria and tests for death have changed throughout the history of medicine; these criteria and tests are underpinned by a variety of concepts of death. Recent advances in medicine and especially in the areas of resuscitation, mechanical ventilation and cardiac pacemakers have posed great philosophical and practical problems with the traditional concepts of death and their associated criteria and tests. The concept of brain death has been formulated in an attempt to deal with the practical decisions that have to be made in deciding whether a person is dead or alive. The original concept of brain death has been subdivided into whole-brain death, brainstem death and neocortical death in different geographical areas and by a variety of people. In addition, there are groups of people who do not adhere to any formulation of brain death. In this thesis I put forward reasons for rejecting all the present formulations of brain death. I also put forward a concept of death derived from philosophical argument. This proposed concept of death views death as death of the organism as a whole and, while I argue mainly in terms of human beings, the concept that I propose could be applied equally to other animals. I also present arguments to demonstrate that the proposed concept of death can encompass the traditional criteria and tests for death and does not entail any significant operational changes in the way in which death is diagnosed.

Clinical consultation begins when a patient seeks help from a doctor. The doctor is called upon to advise and this advice is based on judgments in the areas of diagnosis, treatment, and prognosis. The logic of diagnosis is discussed and the importance of probability emphasised. Theories of knowledge, interpretation, and the use of models are reviewed. Judgment analysis is noted as a developing area and mistakes in clinical practice are discussed. Mention of treatment includes orthodox therapy, complementary methods, and factors contributing to quality of life. Prognosis is considered in relation to some common conditions and the impact of chaos theory. Clinical judgment is concerned with prudence and knowledge sufficient for action. The ability to make an appropriate judgment from imperfect materials is of crucial importance in medical consultation. It requires a capacity to take account of all relevant factors bearing on the case and apportioning due weight to each. Good clinical judgment is closely linked to wisdom. This thesis considers the meaning of normal in the setting of health, examines the relationship between traditional medical practice, models and computer methods, and assesses whether the capacity for clinical judgment can be improved by teaching and experience. It explores the new methods and the extent to which they can supplement or replace established practices. It is concluded that clinical judgment based on extensive knowledge and appreciation of the circumstances of the individual is a continuing need which cannot be replaced by an artificial system.

This study investigates the identities of modified nucleosides from cancer patients’ urine. This was conducted using a Q – ToF MS and accurate mass program to determine the fragmentation pathway of each nucleoside investigated. The identities of the modified nucleosides confirmed in this study are: methyl-acetyl cytidine, 5’-O-methyl cytidine, ethyl-acetyl cytidine and 5’ – formylcytidine. The fragmentation profile of pseudouridine is also investigated as this nucleoside has been found in various types of cancer. With several of the elevated modified nucleosides in cancer patients’ urine being cytidine compounds, and given the elevation of cCMP levels in hyperproliferating cells, this study also considers the fragmentation pathways of cCMP analogous by using the fragmentation pathways of chlorinated adenine compounds: 8-Cl –adenine, - adenosine, - 5’AMP and Sp/Rp-8-Cl-cAMPS. Q-ToF MS was utilised for accurate mass analysis and LCQ- Deca ESI MS for MSⁿ analysis. A proposed theoretical fragmentation pathway has been designed for 5-Cl-3’,5’-cCMP from the known pathways and investigated profiles in this study. The identification of the proteins specifically phosphorylated in response to cCMP is also investigated in this study. Murine brain tissue was utilised and following incubation with cyclic nucleotides: cyclic AMP, cyclic GMP, cyclic CMP and control (blank), these preparations were initially analysed using 2-D gel electrophoresis. However, there was insufficient acquisition of data to generate any conclusive deductions, so the continuation of the studies took place with the use of other techniques i.e. immobilised metal (ion) affinity chromatography and mass spectrometry.

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Merkel cell carcinoma (MCC) is a highly aggressive human cancer and its incidence is increasing worldwide. In 2008 a novel human polyomavirus named Merkel cell polyomavirus (MeV) was isolated from MCC tumours. MCV is monoclonally integrated into the genomic DNA of 80% of these tumours and is now recognised as a causative factor in MCC pathogenesis. The Small Tumour (ST) antigens of mammalian polyomaviruses have been demonstrated to regulate viral promoter activation and contribute to cellular transformation. Mechanisms central to these putative functions are typically dependent on an interaction between ST and the major cellular phosphatase: protein phosphatase 2A (PP2A). In contrast, MCC ST alone transforms rat fibroblast cells in a PP2A-independent manner. Therefore, elucidation of novel mechanisms regarding the putative functions of MCV ST is required. Results in Chapter 3 describe the generation of various MCV ST reagents produced from an MCC tumour section. Initial characterisation indicated that MCV ST is involved in activating the early viral promoter and contributes to increased cell invasiveness/motility. Subsequent work in Chapter 4 demonstrated that MCV ST specifically downregulates NF-kB-driven transcription. Moreover, a novel protein-protein interaction between MCV ST and NF-KB Essential Modulator (NEMO) was observed. Further analysis showed that tumour necrosis factor (TN F)-induced phosphorylation of the inhibitor of KB (IKB) protein and nuclear translocation of NF-KB are down regulated upon MCV 5T expression. Together, these findings suggest that MCV 5T-mediated NFKB inhibition is dependent on NEMO binding. Additional novel interacting partners of MCV ST were identified in Chapter 5; including the PP2Aβ scaffolding subunit and the protein phosphatase 4 catalytic subunit (PP4C). Results indicated that (i) these phosphatases are involved in NF-KB inhibition by MCV 5T and (ii) the PP4C interaction is required for MCV 5T-mediated microtubule destabilisation. Overall, data presented herein will increase our understanding of this oncogenic viral protein and provide new routes of therapeutic intervention for MCC.

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