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The prevalence of sleep-disordered breathing (SDB) in stroke is high. We hypothesised that treatment of SDB in stroke patients would improve rehabilitation. 71 patients were recruited for overnight limited sleep study 14-19 days following stroke. Sixty-six patients with adequate recording were included in the study, 45 men and 21 women, median age 74yrs. The sleep study showed 50% of patients had more than 30 apnoeas + hypopnoeas per hour in bed [expressed as (A+H)•h^-1]. Pulse oximetry alone had lower sensitivity (70%) but high specificity (90%) to predict (A+H)•h^-1 ³ 30. Thirty patients who had (A+H)•h^-1 ³ 30, with < 30% central apnoea or Cheyne-Stoke respiration, proceeded to a randomized controlled trial starting from the 4th week after stroke with 15 patients randomized to CPAP and 15 to conventional stroke treatment only. Duration of treatment was 8 weeks and blind outcome assessment was performed at 3 months and 6 month after stroke. The result showed compliance with CPAP was poor with mean 1.40 hours and median 0.16 hours per night. There was no statistically significant difference in the outcomes, sleepiness and ambulatory blood pressure with CPAP therapy. Increased length of keeping CPAP was correlated with higher score of language subscale in the Addenbrooke’s Cognitive Examination (Spearman’s rho = 0.544, p = 0.036) and lower score in the depression subscale of the Hospital Anxiety and Depression Scale (HADS, Spearman’s rho =-0.538, p = 0.039). All 66 patients with adequate sleep studies received longitudinal follow-up at 3, 6 12 and 18 months following stroke. The patients with (A+H)•h^-1 ³ 30 had a trend to worse functional capacity in both Barthel Index and Nottingham Extended ADL Index (EADL) than patients with (A+H)•h^-1< 30 but there was only a statistically significant difference in the mobility subscale of EADL. The negative influence of (A+H)•h^-1 ³ 30 on functional capacity and health-related quality of life following stroke was only statistically significant in patients with mild stroke (NIH Stroke Scale, NIHSS < 7) at both 3 and 6 months, lesser emotional distress (HADS < 8) at both 3 and 6 months and lesser cognitive impairment (Mini Mental State Examination ³ 28) at 6 months after stroke in subgroup analysis. The difference of Modified Rankin Scale between groups was significant at 6 months after stroke (p = 0.026). There was no difference in cognitive or emotional outcome. No significant difference of mortality rate was noted. We focused on a group of patients with mild to moderate stroke (median NIHSS = 6) in a narrow time span (14-19 days) and confirmed a high prevalence of SDB in stroke. CPAP compliance was a major problem but might be enhanced by selecting patients with higher functional capacity, higher cognitive function especially language and less depression in the acute or subacute phase of stroke.

Firstly, this thesis describes 1) the development and quantification of methods for the delivery of bacteria to the murine lung and 2) the analysis of the histopathological phenotype of mouse models of CF congenic on a C57B1/6N background, in response to such techniques. These studies were performed using a clinical strain of <i>Staphylococcus aureus,</i> a pathogen that is characteristic of the early stages of lung infection in CF. The experiments addressed the null hypothesis that there was no difference between the histopathological responses of 1) <i>Cftr ^tm1Hgu/Cftr^tm1Hgu </i>mice or 2) <i>Cftr^tm1Hgu/Cftr^tm1Unc</i> compound heterozygote mice, and non-CF littermates. The results led to the following conclusions; a) mouse models of CF (<i>Cftr^tm1Hgu/Cftr^tm1Hgu</i> and <i>Cftr^tm1Hgu/Cftr^tm1Unc)</i> congenic on a C57B1/6N background developed lung pathology in response to repeated exposure to nebulised <i>S. aureus, </i>b) significantly more severe pathology was observed in CF mice compared to non-CF littermate controls, c) the spectrum of disease observed in CF mice and non-CF littermates congenic on a C57B1/6N background was narrowed in comparison to those on an outbred MF1 background, with wild type mice more severely affected, d) No difference was observed between the severity of disease in the <i>Cftr^tm1Hgu/Cftr^tm1Unc</i> mice in comparison to the <i>Cftr^tm1Hgu/Cftr^tm1Hgu </i>mice, implying that the reduction in background levels of wild type CFTR did not have a major influence upon the observed response to pathogen exposure, and e) assessment of the histopathology suggested an exaggerated response rather than abnormality in any one aspect of this response. Until recently the mechanisms by which dysfunction of CFTR could lead to the development of characteristic CF lung pathology remained unclear. However, several compelling, and competing, hypotheses have been proposed, based largely on <i>in vitro</i> studies. This thesis describes studies designed to complement the published research by utilising mouse models of CF and address the relevance of several of these theories in this model system.

CF lung infections are caused by a surprisingly narrow spectrum of pathogens and include <i>Staphylococcus aureus,</i> non-capsulate <i>Haemophilus influenzae, Pseudomonas aeruginosa</i> and <i>Burkholderia cepacia. Stenotrophomonas maltophila</i> is recovered from respiratory secretions with increasing frequency; however, its pathogenic role remains unclear. The primary aims of this thesis include the development and use of genomic fingerprinting systems to assist epidemiological investigations of CF pathogens, including <i>S. maltophilia.</i> Genomic fingerprinting is based on digestion of total bacterial chromosomal DNA with rare cutting enzymes, chosen on the basis of the bacterium's GC content. Separation of the DNA fragments, is then achieved by pulsed-field gel electrophoresis (PFGE) in an appropriate apparatus such as the Bio-Rad contour clamped homogeneous electric field (CHEF) system. Although a variety of other genomic typing systems are available, the thesis focused on PFGE, potentially the most discriminating system at present. Another major theme of the thesis concerned the epidemiology of <i>B. cepacia.</i> This highly adaptable plant and human pathogen causes great anxiety in the CF community on account of its inherent resistance, transmissibility and association with cepacia syndrome, a rapidly fatal pneumonia affecting approximately 30% of colonised patients. PFGE is technically demanding, time consuming and relatively expensive, thus attempts were made to assess the reliability and potential of other systems, in particular, PCR-ribotyping as a simple and rapid screening system for clonal analyses. The project provided a limited opportunity for fingerprinting and other microbiological studies of the commensal and pathogenic respiratory flora in CF patients participating in the first human trials of CF gene therapy. Specimens were examined before, during and after local nasal administration of a DNA/liposome complex. Although only a Phase 1 study was achieved during the duration of the thesis, microbiological analyses provided interesting results, in particular an unexpected lack of clonal relationship between <i>S. aurens</i> colonising the upper and lower airways.

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Background: Globally, Chronic Obstructive Pulmonary Disease (COPD) constitutes a significant healthcare burden. In the developed world setting of a large urban hospital, this thesis defines which bedside variables recorded at baseline best predicts outcome from N on Invasive Ventilation (NIV) in the acute setting focusing on the presence of hyperglycaemia. Furthermore, whilst informed patient choice is central to modern clinical care, little is known about how COPD patients respond to information regarding complex therapies. This thesis explores COPD patient attitudes towards Ventilatory support and Advanced Directives of Care (ADCs). In contrast, in the developing world, the thesis aimed to better understand risk factors associated with the finding of airflow obstruction with emphasis on low Body Mass Index (BMI).

The hypothesis underlying this thesis was that abnormal, dysfunctional breathing may occur commonly in people with asthma, and when identified and treated using a breathing training programme supervised by a physiotherapist, will result in improved asthma control.  The thesis is based around four original research papers published in peer-reviewed journals.  These papers present epidemiological surveys quantifying the extent of symptoms attributable to dysfunctional breathing in adults with asthma in comparison with the non-asthmatic adult population, and randomised controlled trials investigating the effectiveness of a breathing training programme in improving asthma control. Initially, a review of the existing evidence of co-morbidity between asthma and dysfunctional breathing is presented, together with that of effectiveness of breathing training interventions.  In subsequent chapters, two epidemiological surveys are presented, showing that symptoms consistent with dysfunctional breathing were more common in the asthmatic than the non-asthmatic adult population.  Data from a pilot and a subsequent full randomised controlled trial are then presented.  These show that breathing training was associated with improved patient-reported outcomes in comparison with a control intervention of asthma education (chosen to control for the non-specific effects of professional contact and interest on a symptomatic patient). The thesis shows that in a clinical trial situation, many people with asthma can benefit from breathing training.