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This thesis is presented in three parts. Part one reviews published studies utilising the 'trauma film paradigm'; an experimental analogue method for investigating the effect of pre-, peri-and post-trauma variables on PTSD symptomatology. It reports results from the reviewed trauma "film paradigm studies in relation to intrusive memories and compares these findings with clinical literature and cognitive processing models of PTSD. Part two presents the empirical paper; an investigation of the effect of rumination on analogue-PTSD intrusive memories and mood using the trauma film paradigm. Results indicate that both trauma-and non trauma-related rumination affects intrusions and negative mood. This was the first experimental study to specifically examine the role of rumination in the maintenance of symptoms. Findings support clinical research regarding the effects of rumination in persistent PTSD. The findings are presented in the context of theoretical explanations for the effect of rumination. Strengths and limitations of the study, as well as clinical implications, are discussed. Part three is a critical appraisal of the research study, which draws on the literature review presented in part one, and reflects in more detail on the methodological and conceptual strengths and limitations of the research. It also discusses the development of ideas underlying the study and the implications for future trauma film paradigm studies and clinical treatment.

This thesis addresses household saving behaviour, characterising the extent of self-insurance and public insurance over the life-cycle. Understanding how household saving varies in response to different forms of uncertainty is vitally important. Some risks are not fully insurable when markets are incomplete: for example, it is difficult for private insurers to cover layoff and productivity risk because of moral hazard issues. In these situations saving decisions determine households’ ability to avoid adversity, or to self-insure against such outcomes. While there has been substantial research into the broad questions concerning saving and expenditure choices, issues such as household asset allocation, the adequacy of self-insurance, and the interplay between these decisions and public insurance are less well understood. This thesis investigates these questions, combining theory and empirics in order to further our understanding of the underlying mechanisms of household saving choices. I begin with theory, presenting two structural papers that enrich the basic life-cycle model by increasing the realism of the modelling structure. In the first chapter I formulate a number of extensions to the standard framework, and detail how these permit simultaneous matching of key wealth and asset allocation statistics. In the second, I propose a novel identification strategy that enables us to elicit households’ beliefs about the risk and return of investing in stocks, and allows us to estimate intertemporal allocation parameters harmonising both consumption and financial wealth data. In the third chapter I undertake a reduced form approach to estimate the consumption loss associated with serious health shocks, using the life-cycle model as an organising framework. I develop a systemic analysis of household saving choices in order to better analyse questions about the effectiveness of self-insurance, the degree of preparedness for retirement, and how these respond to different levels of public insurance.

People with Down’s syndrome (DS) are known to be at very high risk of developing Alzheimer’s disease (AD) in middle-age. Recent research has suggested that the early presentation of dementia in this population may differ from the typical of AD in the general population, with the majority of the earliest changes occurring in personality or behaviour rather than in memory. The similarity of this clinical picture to that of Frontal Type Dementia (FTD) has led to the hypothesis that the functions of the frontal lobes are compromised early in the progression of AD in DS, perhaps as a consequence of the developmental abnormality of this brain region. Within this thesis, two studies are described that test this hypothesis. The first, involving the longitudinal follow-up of a previously identified population sample of older people with DS, examines progression in clinical presentation over time and the sequence of decline on measures of memory and executive function (EF; the cognitive processes associated with the frontal lobes). The second, a cross-sectional study in an expanded sample, examines in detail the relationship between early informant-reported changes and performance on an extensive battery of EF tests (developed specifically for use in this study) as well as on memory measures. The findings of both studies are supportive of the hypothesis outlined above. Individuals showing personality or behaviour changes at baseline were found to progress to the full clinical presentation of AD over time. In individuals without dementia, such changes were found to be related to poorer performance on EF but not memory measures, indicative of an early selective impairment in frontal lobe functioning. A model for the clinical course of dementia in DS is presented and the clinical implications of these findings are discussed, with particular reference to the assessment, diagnosis, management and treatment of dementia in this population.

The main finding of this work is evidence that the AT1R is constitutively active and can undergo endocytosis and subsequent recycling in the absence of agonist. The application of a putative inverse agonist was able to increase the relative surface density in the presence of an inhibitor of novel protein synthesis. The internal pool partially colocalised with markers for early endosomes and the Golgi Apparatus, and was estimated to be 20% of the surface receptor density. This work has determined the presence of extracellular proteases that cleave the ang II into smaller peptide fragments within experimental assay timeframes. The putative cleavage product, ang III, was determined to induced AT1R endocytosis if present in sufficient concentrations. Simple mathematical models have been used to describe the changes in the surface receptor number in the presence of drugs, one of which is the Two-compartment model’. This model assumes that there are only two compartments in which the receptor can exist, the plasma membrane and inside the cell. It ignores trafficking time via endosomes to intracellular organelles such as sorting endosomes and lysosomes. A modified version of the two-compartment model was derived to include agonist depletion by internalisation or degradation and the effect of a basal level of constitutive internalisation. This work has determined that the internalisation profile of the AT1R can be fitted to the two-compartment model, although it is inadequate to describe the AT1R recycling profile and suggests that there is more than one internal receptor recycling pool. This work has also attempted to perform a detailed characterisation of an AT1R antagonist ZD 7155 in terms of receptor responses, and it effects upon ligand internalisation and receptor trafficking. It was concluded that insurmountable antagonism is a result of slow dissociation kinetics, but also may be due to residual antagonist during experimental procedures.

This thesis describes the syntheses and characterisations of new mono- and di-lithiated complexes of organic molecules of the general formula [(R^x-).xLi⁺].yL. The anion R^x- is either derived from a primary amine or is from a multifunctional organic molecule, containing one or more heteroatoms (usually N or S). The complexes have been prepared either by direct reaction of a simple amine with a metal source (solutions of ⁿBuLi, ^tBuLi, LDA), or via a multi-stage reaction following an established synthetic organic protocol, attempt to isolate the lithiated intermediates at each stage. A variety of solvents, both hydrocarbon (toluene, hexane) and polar solvents (diethylether, THF), were used and all of the metallated complexes contain stoichiometric quantities of Lewis base donors, L (TMEDA, PMDETA, THF, Et₂O). One mono-sodiated complex is also described. The work presented concentrates on the preparation and characterisation of new dilithiated complexes both in the solid state and in solution. The lithiated intermediates in many organic reactions provide a source of such dilithiated molecules. In general deprotonation of an organic acid, followed by insertion of a functional group (CS₂, RCN) into the E-M bond (E=C, N; M=Li, Na) and in some cases further metallation, forms the basis of the reactions described. Chapter 1 provides a general introduction to the area of lithiated organics, with a brief review of X-ray structure analyses and solution studies on such complexes. In Chapter 2 the general experimental methods used to synthesise and characterise these complexes are described. Chapter 3 reports an investigation into an established synthetic protocol for the conversion of β-substituted N-containing heterocycles to their pyrrolo derivatives via metallation and nitrile insertion. Details of complexes 3-C₅H₄NCH=C(Ph)NHC(Ph)=NLi.PMDETA and 2,3-C₅H₄NCH=C(R)NX.xTHF ("problem") are provided where R=Ph or ^tBu and X=Li (L=THF) or X=H. The preparation and characterisation of the mono- and di-lithiated complexes of the related α-substituted pyridine derivatives are also described.