Background Rheumatoid arthritis (RA) is a chronic inflammatory disorder that primarily affects synovial joints and is the commonest form of inflammatory polyarthritis. RA potentially confers significant morbidity, loss of function and reduced quality of life. It is a multisystem disorder with extra-articular manifestations affecting skin, cardiovascular, respiratory and haematological systems. There is an associated premature mortality associated with RA which is mainly attributable to cardiovascular disease (CVD). Much has been published on the associated increased CVD risk which RA confers, which includes increased incidence of myocardial infarction, congestive cardiac failure and hypertension. Active RA is associated with a higher burden of both traditional cardiovascular (CV) risk factors (cigarette smoking, dyslipidaemia and hypertension) and novel risk factors (endothelial dysfunction, arterial stiffness and insulin sensitivity) than would be expected in the general population. Furthermore, chronic inflammation may be atherogenic. Certain drug therapies may contribute to CV risk, such as steroids and anti-inflammatories. Whereas other drug therapies, such as anti-tumour necrosis factor agents, may modulate CV risk. There have been many recent controversies regarding anti-inflammatories, both non-selective non-steroidal anti-inflammatory drugs (NSAID) and cyclooxygenase2 (COX2) inhibitors. These include gastrointestinal system side-effects, renal dysfunction and hypertension. The most publicised of these issues was the withdrawal of rofecoxib in 2004 by its manufacturers after clinical trial data emerged which showed a 3.5% incidence of myocardial infarction or ischaemic stroke in patients with no pre-existing CVD who were receiving therapy. This lead to a scrupulous review in the medical journals of the relative CV risks of both NSAID and COX2 inhibitor groups as whole; as well as sub-analysis and comparison of individual preparations. In 2006 the American Heart Association recommended that in order to minimise CV risk, any patient prescribed an anti-inflammatory should have the lowest dose administered for the shortest possible time. Furthermore, it is clear from the literature that it is not just underlying disease processes and medication that can impact on CV risk. Dietary modification can have a large bearing on health outcomes. Large epidemiological studies from Greece and other countries of southern Europe have confirmed that adherence to a Mediterranean-type diet is associated with increased longevity and reduced CVD. A Mediterranean-type diet is typically rich in olive oil, fruit, vegetables, legumes and fish, with a low intake of red-meat. This type of diet is often complemented by a modest amount of alcohol, usually red wine, taken alongside meals. This contrasts starkly with the typical diet of the west of Scotland – ‘famed’ for its high amount of saturated fat and sugar and relatively low consumption of fruit and vegetables. Of late, much interest has been generated regarding the potential relationship between social deprivation and effect on health in general, particularly: diet, cardiovascular disease and RA outcomes. This is of particular relevance to Glasgow which has some of the most deprived areas in Scotland. While traditional CV risk assessment calculators have focussed on traditional markers such as blood pressure and cholesterol, newer validated scores include a score of deprivation, higher areas of social deprivation are associated with higher incidence of CVD, and family history of CVD. Aims In this thesis my aims were to explore the effect of novel interventions on various aspects of RA, predominately to assess CV risk further and review whether certain aspects of risk could be modified. First of all, I investigated the feasibility and effect of anti-inflammatory withdrawal in patients with well-controlled RA (that is to say, patients with mild disease activity scores). The rationale to the NSAID withdrawal study was that removal of therapy plus any required active intervention would provide equivalent symptom control to that achieved by continuing NSAID. Other prescribed RA therapies were continued. The impact of this intervention was assessed by disease activity score, pain score and functional assessments. Secondary study outcomes included the effect of drug withdrawal on blood pressure control, gastrointestinal symptoms and renal function. Subsequently, the impact of a Mediterranean-type diet on disease activity within the Glasgow RA population was reviewed. The study was set up to assess if existing resources could be used as much as possible and replicate a Mediterranean-type diet in a real-life setting, predominately in areas of social deprivation in the east end and south side of Glasgow. Feasibility and acceptability to participants was explored. Additionally, the impact of such a dietary intervention on disease activity, CV parameters and haematological markers was assessed. Finally, given recent evidence linking social deprivation with CV risk as well as poor RA outcomes, an analysis was undertaken using the cohort recruited to the Mediterranean-type diet. Results of CVD risk calculations according to conventional and new algorithms were compared. Results Thirty patients with RA and a 44-joint disease activity score of ≤2.8 were recruited to a 12-week anti-inflammatory withdrawal study. All completed the study period without requiring re-introduction of anti-inflammatories and all continued on their previously prescribed RA therapy. Eleven patients required a steroid injection at either the 6 or 12-week study visit and only 1 required escalation of disease modifying therapy. There was no significant deterioration in disease activity score or components at the 12-week assessment. A significant improvement in blood pressure was recorded with a maximal median reduction of 7 millimetres of mercury (p=0.037). Seventy-five patients with RA were recruited to the intervention arm of the Mediterranean-type dietary study and attended weekly cookery classes over a 6 week period. Fifty-five patients with RA were recruited to the control arm and received basic printed information only. All routine medication was continued and patients assessed at baseline, 3 and 6 months. Significant benefits were seen in the intervention group with regards to features of RA activity: reduced duration of early morning stiffness at 6 months (p=0.041), patient global health assessment score at 6 months (p=0.002) and pain score at 3 and 6 months (p= 0.011 and 0.049 respectively). Then intervention group demonstrated a benefit in systolic blood pressure. There was a significant increase in fruit, vegetable and legume consumption as assessed by food frequency questionnaire. The substantial amount of baseline demographic and CV data collected from the Mediterranean-type diet study allowed a comprehensive assessment of the influence of social deprivation on CV risk scores in a cohort of female patients with RA living in the Glasgow area to be undertaken. Three different CV risk calculators were used: Joint British Societies Coronary Risk Prediction, Framingham and the newer, Scottish, ASSIGN score which incorporates social deprivation. ASSIGN was more likely to classify an individual with a >20% 10-year CVD risk (23% of total cohort) than Framingham or JBSCRP. By using ASSIGN, an additional 16 individuals were identified as having a >20% 10-year CV risk than would have been identified by using traditional JBSCRP alone. Conclusions The anti-inflammatory withdrawal intervention was limited by an open-label design and small participant numbers (n=30). However, it was well tolerated and did not result in the need for significant medical intervention, nor loss of disease control. A significant improvement in systolic blood pressure was noted over the study follow-up.

General practice has undergone considerable change in the last two decades. New roles for nurses working in general practice have extended to include tasks that were previously delivered by general practitioners, in particular chronic disease management, and the development of new, advanced roles such as independent nurse prescribing. There have been few research studies investigating the impact of these changes, especially after the introduction of the new General Medical Services contract in April 2004. The overall aim of the work presented in this thesis was to examine the emerging roles of practice nurses, the forces influencing that development, and the effects of these changes on doctor-nurse skill mix in general practice within NHS Scotland. The work employed a mixed methods approach, with three inter-linked studies. The first study was a quantitative, desk-based analysis of workload and clinical activities of doctors and nurses working in 37 practices across Scotland for the year 2002. The second study was a postal questionnaire to all practice nurses working within NHS Greater Glasgow (n=329), conducted in autumn 2005 and achieving a 61% response rate. The third study was a qualitative study, consisting of eighteen interviews with a doctor and nurse inform each of nine general practices. The interviews were conducted between January and July 2006 and practices were selected according to the number of partners and the deprivation status of the practice population. Analysis of workload data showed that practice nurses and general practitioners dealt with 27.5% and 72.5% of total face-to-face encounters, respectively. Many of the encounters with nurses involved chronic disease management, with 20% of such encounters appearing similar in content to the work of GPs. The postal survey found that one third of practice nurses were aged over 50, and will be approaching retirement within 10 years. The majority worked in small teams of nurses, although 31% worked alone. This may have contributed to the finding that 52% (n=103) reported feeling isolated in their workplace. Many had attended CPD training on chronic conditions, but identified minor illness treatment as an area for future training. The qualitative study showed that the Quality and Outcomes Framework of the 2004 contract had been a key driver of changes in general practice service delivery. This has led to an increasing shift in routine care from doctors to nurses. As new roles for practice nurses have evolved, GPs have been able to focus on treating complex morbidities that need medical diagnosis and intervention. The incentivised targets of the new contract have made chronic disease management a predominant activity for practice nurses, with treatment room and non-incentivised activities featuring less and increasingly being provided by new, lower grade nurses or nurse replacements such as Health Care Support Workers (HCSW). There was no consensus between interview participants in terms of the most appropriate use of doctor-nurse skill mix in general practice. Nor did they agree on the merit of advanced roles for practice nurses. However, respondents did emphasise that nurses who wanted to have an independent/advanced role in the practice would need to combine three competencies (independent nurse prescribing, triaging, and minor illness treatment). Most practice nurses interviewed were concerned with obtaining a fair financial return to match their increasing responsibilities, especially after the introduction of the nGMS contract. GPs, however, tended to believe that nurses were appropriately remunerated for the level of responsibility they had within the practice. The continuing role of the GP as the employer of practice nurses was problematic for some nurses and many felt there would be advantages to being employed on Agenda for Change terms and conditions. However, the majority of nurses interviewed preferred being employed by a GP rather than the Health Board. There was little support amongst either nurses or GPs for the notion of nurse partners within practices. Overall, these studies provide lessons which will be of value in planning the future training and development of practice nurses. It suggests that practice nurses should obtain proper training and support in order to meet their individual needs and to carry out new responsibilities and roles. In addition, the impending shortage of practice nurses due to retirement, lack of retention and potential recruitment difficulties needs to be addressed urgently at the level of primary care policy and manpower planning.

The focus of this thesis was the disease senile dementia and in particular the impact that this condition has on the family carers of elderly people with dementia who live in the community. The study has two main aims. Primarily it set out to identify the stressful situations which carers were facing on a daily basis and to establish how they were coping with them. It also took this issue of coping further and attempted to quantify and measure the specific techniques used in the course of their general caring duties. Secondly, the study explored the concept of expressed emotion (EE) in this group of carers and linked this to coping. It was thought that those carers who were less able to cope with the situation may also have had a high level of EE. The EE concept has been shown to be a useful indicator of relapse in schizophrenia and it was thought that it may also have had predictive value in the outcome of care for the dementing elderly and their carers. The data was collected from 100 semi-structured interviews with carers of elderly people with dementia. The longitudinal aspect of this study allowed outcome data to be looked at one year after the initial interview. The results showed that carers identified stressful situations which were characterised by, inappropriate behaviour as a consequence of disorientation; refusal to co-operate with caregiving activities; incorrect interpretation of people or events; and provocative or hurtful comments. The carers dealt with these situations by, verbal action; practical action or withdrawal, which could be either physical or psychological. Running parallel to this was very often a lot of anger and frustration although this seemed to change over time.

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder of the haemopoietic stem cell, defined by the Philadelphia chromosome (Ph) - the outcome of a balanced, reciprocal translocation between the long arms of chromosomes 9 and 22. The novel fusion oncogene generated on chromosome 22 as a result of this translocation is called BCR-ABL. In the majority of patients, this oncogene transcribes a 210-kDa constitutively active protein tyrosine kinase, often referred to as p210BCR-ABL, which is necessary for the transformation of the disease. The introduction of the orally available, tyrosine kinase inhibitor (TKI) - imatinib mesylate (IM) - marked a major advance in CML treatment in terms of efficacy and tolerability and has now become the first line of therapy. IM acts by competing with ATP to block ABL-kinase activity, resulting in the selective apoptosis induction of BCR-ABL+ cells. However, despite the success of IM as standard therapy for CML, only a small proportion of patients obtain a complete molecular response, where they become negative for BCR-ABL transcripts by RTPCR. It is hypothesised that this minimal residual disease is the result of a primitive quiescent subpopulation of leukaemic cells, which may be the cause for relapse at a later date. Another major clinical concern is the observation of molecular resistance in IM-treated patients. Proposed mechanisms of resistance include BCR-ABL amplification, decreased intracellular IM concentrations caused by drug efflux proteins such as multi drug resistance-1 and the development of point mutations within the ABL-kinase domain. In an attempt to overcome IMresistance, a second generation of BCR-ABL inhibitors has been developed. Dasatinib (BMS-354825, Sprycel) is a TKI developed for the treatment of IM resistant or -intolerant patients with Ph+ leukaemias, which has a 325-fold greater potency than IM against cells expressing wild-type BCR-ABL, and is effective against all IM-resistant BCR-ABL mutants tested in vitro, except T315I. Previously, we showed that dasatinib induced durable inhibition of BCR-ABL and impressive clearance of Ph+ cells, however, the primitive quiescent cell population did not appear to undergo apoptosis even after several days TKI exposure. Therefore, it was still not clear whether early CML progenitor cells depend on BCR-ABL for their growth and survival. In this study we have attempted to determine whether CML stem cells are dependent on BCR-ABL TK activity for their survival and/or proliferation using dasatinib treatment and aimed to characterise the cells which survived drug exposure. We found that 10% of the CML cells were able to survive the dasatinib treatment. We also showed that maximal BCR-ABL TK inhibition was achieved in the surviving CML cells, both in the bulk population of cells and the more problematic primitive stem cell population. Those cells which survived the dasatinib treatment were found to be primitive, residing mainly in the undivided cell fraction and the very early cell divisions. Since these BCR-ABL TK-inhibited, resistant cells were also able to grow when re-cultured in cytokines and form longterm culture-initiating cell (LTC-IC) colonies; these data suggested that ~10% of primitive CD34+ CML cells are not addicted to BCR-ABL TK activity for their survival. This also suggested that these primitive, resistant CML cells appeared to survive and proliferate by BCR-ABL-independent mechanisms. Therefore, the next experiments were then designed to investigate the cellular process of autophagy as a potential means of primitive CML cell survival. Analysis of the properties of CD34+ CML cells which remained viable following dasatinib treatment, revealed the existence of cytoplasmic autophagic structures determined by electron microscopy and significantly increased autophagosome-asociated LC3-II, particularly in the cells cultured without growth factors (GF)s. This suggested that autophagy is induced following GF deprivation of CML cells and is significantly increased within these cells, upon BCR-ABL inhibition following dasatinib treatment. Furthermore, we also found that the inhibition of autophagy greatly potentiated the effect of TKI treatment on the reduction of primitive CML progenitor cells, in terms of the effective eradication of functionally defined colony forming cells and LTC-ICs. Overall, this thesis has shown for the first time that the most TKI-resistant primitive CML cells are likely to be independent of BCR-ABL TK activity for their proliferation and/or survival. Furthermore, we have shown that these resistant CML stem cells rely on the BCR-ABL independent autophagy process for survival in response to stressful conditions, such as, GF deprivation and TKI treatment.

Background: Allogeneic Haematopoietic stem cell transplant (HSCT) is a potentially curative treatment for haematological cancers however it is a particularly aggressive treatment that can impact individuals’ quality of life (QOL) in multiple ways. Due to the toxicity of the transplant, adults aged over fifty years have only recently become eligible for this treatment following the development of a reduced intensity regimen. As a result, little is known regarding the experience of QOL among recipients aged over fifty years. QOL information is an essential part of assessing the success of medical treatments and can help prepare recipients for any ways in which their lives and those of their families may be impacted post-transplant. Method Potential participants were recruited through the Beatson West of Scotland Cancer Centre (BWSCC) and a purposive sample of eight participants volunteered to take part in the study. A qualitative approach, Interpretative Phenomenological Analysis was used to explore the experience of QOL among recipients. Results Four superordinate themes emerged from the data; ‘Shifting sense of self and others’, ‘Adaptation and managing the impact’, ‘A new perspective on life and living’, and ‘Changing over time’. The findings helped highlight the challenges and gains experienced by HSCT recipients as well as the process of adaptation and adjustment which mediates the impact of HSCT on QOL. Conclusions The participants in this study demonstrated that there are a number of commonalities between younger and older recipients in terms of post transplant QOL when compared to the literature on younger recipients to date. However, increased age and stage of life was also shown to have a unique impact on the subjective experience of QOL after transplant. Increased age continues to represent a significant risk factor in terms of QOL and survival post transplant. However, the findings from this study suggest that this small sample of recipients is adjusting well to the challenges of HSCT. Further research is required in this area. Limitations of this study are discussed.

Type 1 diabetes mellitus (T1DM) is a complex metabolic condition that results in hyperglycemia due to insulin deficiency (Daneman, 2006). Diabetes has a range of effects on almost every system in the body including the kidneys, the eyes, the cardiovascular system, the genito-urinary system, the gastro-intestinal system and the nervous system (Daneman, 2006). The effects of this ondition are widespread and have a significant impact both on life expectancy and the quality of life of individuals suffering from diabetes (Scottish Diabetes Survey Monitoring Group, 2011). The impact of diabetes on oral health has been investigated over many decades, however, the conclusions have been varied and study design has not always been adequate (Mealey et al., 2006; Khader et al., 2006; Chávarray et al., 2009). Research presented in this thesis is largely the result of a cross-sectional clinical study examining the oral cavities of non-smoking T1DM patients, funded by the Chief Scientist Office of the Scottish Government. The clinical part of the study took place between January 2006 and May 2009 in Glasgow Dental Hospital. Chapter one provides an introduction and narrative review on the subject of T1DM, periodontal disease, and the various other reported oral manifestations of diabetes mellitus. The methods for measuring general and oral health related quality of life outcomes are also discussed. Chapter one reveals some of the inadequacies of studies nvestigating the link between T1DM and oral disease to date and ontextualises the studies presented in this thesis. Chapter two presents the main periodontal findings of a large cross-sectional study. 112 non-diabetic subjects and 203 subjects with type 1 diabetes were examined. 203 diabetic patients were divided into well controlled and poorly controlled groups based on their average blood sugar levels over the previous two years. 169 were poorly controlled. (PCD). Those with T1DM, (especially those with poor glycaemic control) had a greater extent and severity of periodontitis than those without diabetes. There was also some evidence that never smoking T1DM patients were more likely to have periodontal disease than non-diabetic subjects. The odds ratio (OR) was 1.43 [0.74 to 2.75] (p = 0.29) for all T1DM patients and 1.58 [0.75 to 3.33] (p = 0.23) for PCD. This difference remained even after the multivariable analysis took into account age, gender and lifestyle including: body mass index of the subject; whether they had smoked in the past; whether they attended a dentist; their level of education and how deprived the area they lived in was. Chapter three presents an analysis of the impact of age, HbA1c, and duration on the expression of periodontal disease in T1DM subjects. Cross-tabulations and multivariable logistic regression analysis was performed on the periodontal data from T1DM subjects and non-diabetic subjects in order to determine the relationship between age, HbA1c and duration, and periodontitis. Diabetic subjects developed periodontitis at a younger age than non-diabetes subjects. This will represent a significant impact on life time dental service provision for subjects affected at a young age. The relationship between HbA1c and severe periodontitis is not a simple one. It is possible that unknown factors confound the relationship between glycaemic control and periodontitis. There was no relationship between duration of diabetes and periodontitis when age was controlled for. Chapter four presents the results of a small study investigating biomarkers of bone turnover in patients with and without T1DM and in patients with and without periodontitis. Patients with T1DM had higher levels of osteoprotegerin an osteoprotective molecule that normally leads to a reduced propensity for bone loss. T1DM patients were also shown to have reduced levels of biomarkers of bone formation (osteocalcin). It is possible that a reduced capacity for bone repair and regeneration may account for the increase levels of periodontitis seen in T1DM. Further prospective studies would be required to confirm this hypothesis. Chapter five investigated the level of caries and oral mucosal abnormalities in T1DM. There was little difference in caries indicators or in oral mucosal lesions between the groups. There was no difference in the bacterial microflora and in the level of resistance to antibiotics found in this cohort. T1DM patients, however, did have an increase in the symptoms of dry mouth, an increased density of candida colonisation and reduced salivary flow rates.Chapter six reports the data derived from the oral health questionnaire, including the Oral Health Impact Profile -14 (OHIP-14) and the Audit of Diabetes Dependent Quality of Life (ADDQOL©). Patients with T1DM, despite having increased levels of periodontal disease, reduced salivary flow rates and increased symptoms of xerostomia did not have higher OHIP scores by any measure. The reasons for this apparently negligible impact of oral disease or oral health related quality of life are discussed. The OHIP-14 was shown to have construct validity in this population although the correlations were relatively weak and the differences were small. It is possible that patients with T1DM do not consider the impact of their oral health to be a significant problem in light of their other on-going medical issues. This finding requires further in-depth investigation of the psychology behind this apparent reduced impact. This is the first study of its kind to examine the oral and dental health of non-smoking type 1 diabetic patients. The conclusions from the clinical data support the view that patients with T1DM should be targeted with oral and dental health advice. Encouragingly the prevalence of periodontitis was lower in well controlled diabetic subjects suggesting that the effect of T1DM on the oral cavity can be ameliorated by good glycaemic control even though logistic regression analysis did not show a linear relationship. It is important that health rofessionals work together in order to prevent and manage the oral complications of T1DM in the same way that there are preventive and screening programmes for other diabetic complications. The pathogenesis behind the increased prevalence and severity of periodontal disease in T1DM requires further study.

Percutaneous coronary intervention (PCI) improves the blood supply to the heart by unblocking narrowed coronary arteries. Implantation of a coronary stent is usually required to scaffold the artery and improve long-term vessel patency. Drug-eluting stents (DES) have been developed to decrease the incidence of stent renarrowing, known as in-stent restenosis (ISR), the main limitation of bare metal stents (BMS). DES release potent drugs into the artery wall to inhibit cell division and attenuate ISR. However, this strategy can also impair vascular healing and increase the risk of stent thrombosis, which is a serious concern. Novel approaches to this problem are urgently required. Oxidative stress reflects a state in which reactive oxygen species (ROS) prevail over antioxidant defences. PCI causes a major release of ROS from the injured artery wall and these molecules appear to play an important role in critical signalling pathways involved in vascular repair. Numerous animal studies have found that oral antioxidants may reduce ISR and improve healing, yet these strategies have not been effective in humans. Stent-based delivery of antioxidants may offer more efficacious, targeted protection against oxidative stress than oral administration. The role of oxidative stress in endothelial repair mediated by bone marrow-derived endothelial progenitor cells (EPCs) in patients with coronary heart disease is also poorly defined. The main aims of this thesis were: to determine the in vitro effects of oxidative stress on key aspects of thrombosis and vascular healing; to evaluate a novel antioxidant-eluting stent in an in vivo porcine model; and to examine the relationship between oxidised low-density lipoprotein (oxLDL), EPCs and coronary endothelial function in patients with stable angina. Oxidative stress, generated by the xanthine/xanthine oxidase reaction, inhibited whole blood aggregation in a concentration-dependent fashion. This was probably due to an excess of ROS which impaired, rather than stimulated, thrombosis. Healthy endothelial cells (ECs) also inhibited whole blood aggregation, but this was not mitigated by oxidative stress. EC migration was assessed using an in vitro endothelial wound scratch assay. Oxidative stress was highly toxic to ECs and inhibited migratory activity. Nitrone D, a novel spin trapping antioxidant, was evaluated for its suitability as a novel DES coating. Nitrone D displayed weak antithrombotic effects, but markedly inhibited EC migration. Nitrone D was therefore unsuitable for a DES that was intended to improve re-endothelialisation. Oral probucol has established efficacy in animal models of restenosis, but not in humans. Probucol has been successfully incorporated as a dual DES coating with rapamycin in clinical trials. Succinobucol is a novel derivative of probucol with more potent antioxidant, anti-inflammatory and antiproliferative effects. A novel polymer-free succinobucol-eluting stent (SES) and succinobucol/rapamycin-eluting stent (SRES) were developed and compared to a commercially available polymer-free rapamycin-eluting stent (RES) and BMS. Pharmacokinetic studies demonstrated optimal drug elution from the SES. However, in a porcine coronary model, the SES significantly increased neointimal thickness and aggravated ISR. The RES reduced neointimal thickness non-significantly, whereas the SRES caused no difference in neointimal thickness, compared with the BMS. The SES was associated with greater inflammation and persistent fibrin deposition around the stent struts, which are signs of defective healing. There were no significant differences in endothelial regeneration between the groups. Subsequent cell culture studies found that succinobucol was toxic to ECs and smooth muscle cells. In the clinical study, circulating levels of EPCs were strongly correlated with coronary endothelial function, which is a novel finding. Plasma oxLDL levels were not correlated with EPCs or coronary endothelial function. In conclusion, ROS reflect a large array of molecules released after PCI that are multi-faceted regulators of platelets and vascular cells. As such, they represent a complex target for novel DES technologies. Excessive ROS may inhibit thrombus formation and delay re-endothelialisation. However, potent antioxidants delivered to injured arterial tissue after PCI may not necessarily encourage the physiological processes required to accelerate vascular repair. At high dose, local delivery of antioxidants may actually promote inflammation and aggravate ISR. Although oxLDL is known to induce endothelial dysfunction, it is not correlated with the number of circulating EPCs. These findings underline the complicated role of oxidative stress in vascular repair after PCI. Further studies are required to clarify whether antioxidants will ever provide advantages over existing options in the rapidly evolving field of interventional cardiology.

Infections due to Streptococcus pneumoniae (the pneumococcus) remain a substantial source of morbidity and mortality in both developing and developed countries despite a century of research and the development of effective therapeutic interventions (such as antibiotic therapy and vaccination). The ability of the pneumococcus to evade multiple classes of antibiotic through several genetically determined resistance mechanisms and its evasion of capsular polysaccharide based vaccines through serotype replacement and capsular switching, all reflect the extensive diversity and plasticity of the genome of this naturally transformable organism which can readily alter its genome in response to its environment and the pressures placed upon it in order to survive. The purpose of this thesis is to investigate this diversity from a genome sequence perspective and to relate these observations to pneumococcal molecular epidemiology in a region of high biodiversity, the pathogenesis of certain disease manifestations and assess for a possible bacterial genetic basis for the pneumococcal phenotypes of, “carriage” and, “invasion.” In order to do this, microarray comparative genomic hybridization (CGH) has been utilized to compare DNA from a variety of pneumococcal isolates chosen from 10 diverse serotypes and Multilocus Sequence Types and from clinically relevant serotypes and sequence types (particularly serotypes 3, 4 and 14 and sequence types ST9, ST246 and ST180)) against a reference, sequenced pneumococcal genome from an extensively investigated serotype 4 isolate – TIGR4. Microarray comparison of the transcriptional profiles of several isolates has also been undertaken to compare gene expression from isolates of serotype 1 (ST227 and ST306) and serotype 3 (ST180) related to particular disease states and exposure of a multi-resistant pneumococcus to an antimicrobial (clarithromycin) commonly used to treat pneumococcal pneumonia.

Pulmonary Hypertension (PH) is a rare but devastating illness which results in progressive right ventricular (RV) failure and early death. RV function determines survival in all patients with PH but it is difficult to measure accurately using existing clinical techniques. The choice and design of the experiments in this thesis was driven by a desire to improve our understanding of the reasons for right, and left,ventricular dysfunction in this context. Cardiovascular magnetic resonance (CMR)imaging was utilized throughout as it allows the non-invasive, direct and accurate study of both ventricles; at rest and during stress. In Chapter 3, CMR imaging was used to identify an NT-proBNP threshold (1685 ng/l, sensitivity 100%, specificity 94%) for the non-invasive detection of RV systolic dysfunction in patients with PH. In Chapter 4, contrast-enhanced-CMR was utilized for the first time in PH patients and revealed previously unidentified areas of myocardial fibrosis within the RV insertion points and interventricular septum. The extent of these areas correlated inversely with RV ejection fraction (r = -0.762, p < 0.001). Septal contrast enhancement was particularly associated with bowing of the interventricular septum. Finally, in Chapter 5, dobutamine stress-CMR was used to determine the individual reasons for right and left ventricular stroke volume impairment during exercise in PH patients. ∆ RV stroke volume appeared limited by diminished contractile reserve as ∆ RVEF was lower in PH patients (27%) compared to controls (38%) and ∆ RVEF correlated with ∆ RV stroke volume (r = 0.94, p < 0.001). ∆ LV stroke volume appeared limited by impaired filling, probably due to reduced LV preload as RV stroke volume and LV end-diastolic volume remained closely related at rest (r = 0.821, p < 0.001) and stress (r = 0.693, p = 0.003).

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are common partners with common problems. Both are chronic systemic disorders incurring significant morbidity and mortality. Although around one third of patients with HF have concurrent COPD,1 remarkably few reports have addressed this often ignored combination. The systematic review presented within this thesis defines the diagnostic challenges, prevalence and prognostic implications of HF with coexistent COPD. I then critically appraise the twin controversies of β-blockade in COPD and β-agonists in HF. The two are inextricably linked, each therapy exerting the reverse pharmacologic activity of the other. The evidence for symptomatic or prognostic benefit from either therapy is limited, and in the case of β-agonists adverse consequences appear more likely. A Cochrane meta-analysis concluded that long term cardioselective β-blockade is safe and well tolerated in patients with moderate to severe or reversible COPD.2 Although often cited,3 these conclusions are simply not true. Of the 20 randomised controlled trials included in the meta-analysis, 11 involved single doses and only one lasted longer than a month. The 9 ‘long term’ studies (defined as more than a single treatment dose) involved 147 young, predominantly male patients with moderate airways obstruction (mean forced expiratory volume in 1 second (FEV1) 1.8 litres). The effect on health status has never been assessed in any cohort with COPD. The long term impact of β-blockade on pulmonary function, symptoms and quality of life is therefore largely unknown. Most importantly, no study has included patients with HF. I randomised 27 patients with HF and coexistent moderate or severe COPD to receive bisoprolol or placebo, titrated to maximum tolerated dose over 4 months. Patients were elderly and predominantly male. Cardiovascular comorbidity, smoking history and pulmonary function were similar in each group (mean FEV1 1.37L vs 1.26L). There were several key findings. A reduction in FEV1 occurred after 4 months following treatment with bisoprolol compared with placebo (–70 ml vs +120 ml, p=0.01). Reversibility following inhaled β2-agonist and static lung volumes were not impaired by bisoprolol. All measures of health status exhibited a consistent non-significant improvement, including the Short Form 36 physical and mental component scores, Minnesota Living with Heart Failure Questionnaire, and Chronic Respiratory Questionnaire. The mean number of COPD exacerbations was similar in the bisoprolol and placebo groups. Although recruitment was limited, the results pose crucial questions and provide direction for larger randomised controlled trials. I analysed cross-sectional data from 61 primary care practices (377,439 patients) participating in the Scottish Continuous Morbidity Recording scheme. The prevalence of COPD in patients with HF increased year on year from 19.8% in 1999 to 23.8% in 2004. These changes may previously have been attributed to an ageing population or increasing age of presentation. However, the trend remained significant after age standardisation. A clear socioeconomic gradient was observed, with prevalence greatest in the most deprived. Consultation rates for HF or COPD in those with both conditions were greater than disease specific contact rates in patients with either condition alone. Cardiovascular comorbidity was similar in HF patients with and without COPD, despite differences in smoking history (respectively 76% vs 47%, p<0.001). This is concerning and suggests that common cardiovascular conditions are being under diagnosed (and likely under treated) in patients with HF and COPD. Although overall β-blocker prescribing increased over time, the adjusted odds of β-blocker prescription in patients with COPD was low (odds ratio 0.30 [95% CI 0.28–0.32], p<0.001). Whether the gap between patients with and without COPD is improving was previously unknown. Despite the overall improvement in beta-blocker prescribing, the relative difference in prescribing between those with and without COPD remained unchanged. By 2004, only 18% of individuals with HF and COPD were prescribed β-blockers. COPD is consistently an independent predictor of death and HF hospitalisation in patients with HF. However, the causes of increased mortality were unclear. I examined the relationship between COPD and cardiovascular outcomes in patients with myocardial infarction (MI) complicated by heart failure, left ventricular systolic dysfunction (LVSD), or both enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) trial. COPD was an independent predictor of mortality, largely due to increased non-cardiovascular (HR 1.86 [1.43–2.42]) and sudden death (HR 1.26 [1.03–1.53]). However, after multivariate adjustment COPD was not an independent predictor of atherosclerotic events (MI or stroke: HR 0.98 [0.77–1.23]). This is an important finding, as atherosclerotic consequences of chronic systemic inflammation in COPD have been postulated. These appear of limited clinical significance, at least during intermediate follow-up. Part of the adverse risk associated with COPD may be attributable to bronchodilators. The prognosis of patients with HF prescribed bronchodilators is however ill defined. I examined the prognostic implications of bronchodilator use in patients with HF enrolled in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme. The diversity and magnitude of adverse outcomes associated with bronchodilator therapy was surprising. Bronchodilator use was associated with increased all cause mortality (HR 1.26 [1.09–1.45]), cardiovascular death (HR 1.21 [1.03-1.42]), death due to HF progression (HR 1.40 [1.07-1.82]) and HF hospitalisation (HR 1.49 [1.29-1.72]). Although association is not causation, it is possible that bronchodilators compound maladaptive remodeling and further depress myocardial function. Finally, β-blockers were independently associated with better survival in both VALIANT and CHARM. No significant interaction was observed between either COPD or bronchodilators and β-blockade with respect to mortality. Furthermore, β-blocker use was not associated adversely with any pre-specified outcome in patients with COPD or those prescribed bronchodilators, including non-cardiovascular mortality. Although recruitment bias and the absence of spirometry limit inference to patients with severe or reversible airflow obstruction, the results should encourage β-blockade in patients with COPD. In summary, the studies presented in this thesis extend our understanding of HF with concurrent COPD. Only large randomised controlled trials will solve the quandary of β-blockers and β-agonists. Justification for these trials evolves from observational data and smaller prospective studies such as my own. In the meantime, I hope the evidence presented will stimulate physicians to re-evaluate the management of patients with HF and COPD.