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Chronic obstructive pulmonary disease (COPD) is an umbrella term that encompasses chronic bronchitis, emphysema and airway obstruction. COPD patients are also prone to acute exacerbations (AECOPD) caused primarily by viral and bacterial infection, which leads to an increase in inflammation, a worsening of symptoms and can lead to death. There is an unmet clinical to better understand and treat AECOPD as well as COPD in general, but this is hindered by unreliable animal models of COPD and AECOPD. The aim of this thesis was to establish an animal model of COPD that could be exacerbated by an infectious agent. Firstly an LPS model of COPD was established in the guinea pig, which resulted in a macrophage and neutrophil inflammatory profile, emphysematous changes, a decrease in lung function and partial steroid insensitivity that could be partially reversed with low dose theophylline. Human parainfluenza 3 virus failed to cause any infection in the guinea pig, so a model of AECOPD could not be established in this model. A chronic cigarette smoke model in the mouse was established, which again demonstrated a similar phenotype to COPD. This model was able to be exacerbated by the bacteria nontypeable Haemophilus influenza (NTHi) with increases in neutrophils and the neutrophil chemoattractant CXCL1. However, it was also observed that while NTHi could exacerbate the model, responses to NTHi in cigarette smoke challenged mice compared to sham challenged animals were impaired, with significant decreases in CXCL8, TNF-α, IFN-γ and IL-10. This impairment was also observed in monocyte derived macrophages (MDMs) challenged with cigarette smoke extract (CSE) with significant impairment of Il-1β, while chronic LPS challenge also impaired Il-6 and phagocytosis. The data in this thesis highlights a possible increase in steroid responses by low dose theophylline in an LPS model in the guinea pig. It has also demonstrated chronic cigarette smoke exposure in the mouse can be exacerbated by NTHi, however the inflammatory response is impaired compared to sham challenged animals suggesting that cigarette smoke impairs the innate immune response. MDMs also demonstrated an impaired response to NTHi after CSE or LPS challenge.

Tuberous sclerosis is an autosomal dominant multisystem disorder characterised by the development of benign tumours in many organs, including the brain, skin, kidneys and heart, seizures and intellectual disability. The condition results from mutations in either of two genes, TSC1 (encoding TSC1) or TSC2 (encoding TSC2). Loss of functional TSC1 or TSC2 leads to activation of mTORCl (mammalian target of rapamycin complex 1), a key regulator of multiple cellular processes including cell growth and division. Lymphangioleiomyomatosis (LAM) is a lung disorder which can lead to respiratory failure and is characterised by the proliferation of abnormal 'LAM' cells LAM occurs in patients with tuberous sclerosis and can also occur as a sporadic disorder due to acquired mutations in TSC2. Renal angiomyolipomas are benign tumours which affects80% of patients with tuberous sclerosis and 40% of patients with sporadic LAM. Sirolimus is an inhibitor of mTORCl and is used in clinical practice as an immunosuppressant. Preclinical studies suggest that TSC1 or TSC2 deficiency renders cells sensitive to mTOR inhibition. This thesis describes a phase 2 trial to assess the safety and efficacy of 2 years of treatment with sirolimus for renal angiomyolipomas in patients with tuberous sclerosis or LAM. Response of angiomyolipoma was the primary efficacy end point. Effects of sirolimus on lung function and neurocognitive function are also reported. Our data show an angiomyolipoma response rate, by RECIST criteria, of 50% in the intention to treat population. There was little change in lung function. Recall but not recognition memory tended to improve. Adverse events were common and consistent with the known toxicities of sirolimus. Our findings suggest that mTOR inhibition is a potential therapeutic strategy in the treatment of tuberous sclerosis and lymphangioleiomyomatosis.

The post-16 stage of education is critical in securing and developing people entering engineering professions and related occupations. Engineering employers and employees alike have however highlighted problems regarding poorly designed curricula failing to prepare employees for industrial and commercial roles. The premise of this thesis is that the issue confronting education is one of quality management. Curriculum designers must know how to anticipate and understand customer requirements and practically translate these requirements into a deliverable curriculum package. The aim of this research is to realise the synergy of curriculum design and TQM by developing a theoretical integrated curriculum design method. Synergies between TQM and traditional curriculum design methods are investigated and an integrated curriculum design method based on the use of PDCA and incorporating a two-phase modified use of QFD is hypothesised and justified. Subsequently, application of the curriculum design method is completed in relation to a number of selected engineering companies within the South Wales region and an appropriate curriculum proposal, for the provision of engineering education within the 16-18 year age group is produced. The proposal has been constructed with characteristics complementary to the competencies required by these companies and incorporates the most suitable teaching, learning and assessment methods to maximise the development of the students. This is valuable information for those concerned.

Aim. The primary aim of this thesis was to investigate the reliability and validity of a multi-dimensional subjective measure of cravings for cigarettes - the Questionnaire of Smoking Urges (QSU - Tiffany & Drobes, 1991) in cigarette smokers. Another aim was to investigate the sensitivity and utility of objective, behavioural measures of the urge to smoke. Finally, an attempt was made to resolve the controversy as to whether the reported cognitive-enhancing effect of nicotine (e.g. Wesnes & Warburton, 1983) is a pharmacological effect or is instead merely the result of relief from withdrawal. Design. A series of laboratory studies were conducted. Abstinence periods, smoking- related cues, and in one study, pre-treatment with placebo or nicotine gum, were manipulated as independent variables. Two participant groups were used. Participants used in the first four experimental chapters were all regular smokers whereas those used in the final two experimental chapters were all occasional, non-dependant, smokers or tobacco "chippers". Findings. Evidence was found for both the reliability and the validity of the QSU. The QSU was shown to be sensitive to both periods of abstinence and exposure to smoking- related cues. In addition, the QSU was shown to have a reliable two-factor structure and that these two factors were measuring different aspects of cigarette craving. The PR was demonstrated to be an unreliable subjective measure of craving, and attempts to use two alternative measures were unsuccessful. Further, no evidence was found for the cognitive-enhancing effects of nicotine in chippers. Conclusions. The results support the multi-dimensional view of craving, and suggest that the multi-dimensional QSU is a valid and reliable measure of cravings for cigarettes.