Self-monitoring blood pressure (SMBP) has been shown to more accurately estimate true underlying BP but it is unclear how commonly it is practiced in the UK and why patients engage in this behaviour from a psychological perspective. A survey was first sent to primary care patients with hypertension (n=955) in the West Midlands, UK to establish the prevalence of SMBP. Secondly, interviews with respondents (n=16) combined with a review of previous empirical research informed the design of an in-depth questionnaire sent in the final stage of the study (n=236) to confirm the investigative associated factors. A third of the survey population 293/955 (31%) reported SMBP which was predicted by education, self-efficacy and doctors’ health locus of control (DHLOC) (p<0.01). Age and negative outcome expectations about SMBP potentially moderated this relationship. A lack of available guidelines and poor communication with the General Practitioner (GP) about self-monitoring however resulted in a negative perception about whether engaging in SMBP had any real benefit. Self-monitoring was practiced by an appreciable minority in the UK, potentially enabling patients to gain control over managing their own BP. Better education and shared decision making between the patient and the GP might remove negative perceptions about SMBP ensuring its long term practice.

Neurotrophins are neuromodulatory proteins utilised within neuronal networks for development and survival. Based on previous evidence revealing the expression of neurotrophin components in immune cells, the present study investigates neurotrophin component expression within Burkitt’s Lymphoma B cells. Different latency stages within Burkitt’s Lymphoma B cells are observed due to the expression of resident EBV latency genes. These B cells are said to display germinal centre B cell markers and interact with other cells within a germinal centre environment, such as Follicular Dendritic Cells (FDCs) and T cells. EBV latency phenotypes were characterised for the lines used here; these lines were then screened for the expression of neurotrophin ligands and their receptors: the selective high affinity Tropomyosin receptor kinases TrkA, TrkB and TrkC and the (common) low affinity, tumour necrosis factor receptor member, p75NTR. FDC-like cell lines were also analysed for neurotrophin component expression. This was to question FDCs as potential providers of paracrine neurotrophin signalling to Burkitt’s lymphoma B cells. Neurotrophin and neurotrophin receptor expression was detected by flow cytometry, confocal microscopy, reverse transcription polymerase chain reaction (PCR) and real time PCR methods. Cell lines with the full complement of EBV latency genes expressed were positive for the neurotrophin, Brain Derived Neurotrophic Factor (BDNF) and all neurotrophin receptors in question. Burkitt’s lymphoma cells expressing limited EBV latency genes revealed more restricted expression of neurotrophin components. FDC-like lines also express neurotrophin and neurotrophin receptors, thus paracrine signalling between Burkitt’s lymphoma cells and FDCs may occur via this axis, perhaps to enhance B cell survival.

Patient experience of serious ADRs and their impact on patients’ lives have not been previously explored. This thesis aims to explore the experiences of patients diagnosed with drug-induced Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN). In addition, the very elderly are a group particularly vulnerable to ADRs, and in particular, those due to antihypertensives. This thesis thus also explores the impact of such ADRs in the elderly, on managing their hypertension optimally. Firstly, I undertook a retrospective qualitative study of adult survivors of SJS and TEN, to explore their experiences, views and perceptions. The ADR continued to affect patients’ lives long after the event. Their interpretations regarding why the ADR occurred differed and may have influenced their trust in healthcare professionals and in medicines. Clear communication, and patient education and support after the event, may therefore be important. Secondly, I undertook an analysis of internet-based personal descriptions of SJS and TEN. Authors wished to share experiences and seek advice from others, and had common concerns regarding the ADR. These findings could be used to improve the management of such patients. Finally, I undertook a retrospective cohort study in very elderly patients to determine whether ADRs to antihypertensive drugs limit the clinician’s ability to achieve blood pressure targets. Almost half the patients studied had documented ADRs which limited further intervention. Aggressive treatment of hypertension in the very elderly may therefore be difficult to achieve in practice.

NAFLD is characterized by simple steatosis, which can progress to chronic inflammation and fibrosis. Vascular Adhesion Protein-1 (VAP-1) is an adhesion molecule with semicarbazide- sensitive amine oxidase (SSAO) activity, which is also expressed as a soluble protein in serum (sVAP-1) and elevated in inflammatory liver diseases such as NAFLD. VAP-1 has been shown to modulate glucose and lipid uptake in muscle and adipose tissue and thus we investigated whether it may contribute to glucose and lipid homeostasis in human liver tissue. Recreating the multicellular liver environment using an ex-vivo model we have shown that activation of VAP-1 by its substrate methylamine leads to activation of NF-κB, glucose uptake and lipid accumulation in the human liver with changes in transporter expression of GLUT4, GLUT10 and GLUT13, as well as FABP2, LRP1, FATP2, FATP3, FATP4 and FATP6. We have also documented changes in transporter expression profiles in human disease. In conclusion, we demonstrate for the first time global alterations in cellular expression of glucose and lipid transporter proteins in NASH. We confirm that VAP-1 is elevated in disease and that SSAO activity of VAP-1 results in enhanced hepatic glucose and lipid accumulation with changes in transporter expression. Thus we propose that bioactive metabolites of SSAO activity contribute to the metabolic derangement evident in fatty liver disease.

Despite major advances in therapies, chronic heart failure (CHF) and hypertrophic cardiomyopathy (HCM) are still associated with significant morbidity and mortality. These patients often have a significant limitation in their exercise capacity. We showed that there are widespread abnormalities of both systolic and diastolic function in HCM patients. These abnormalities contribute significantly to exercise limitation observed in these patients. Furthermore, we showed that HCM manifest a myocardial energy defieciency which was accompanied by a slowing of the energy-dependent early diastolic LV active relaxation during exercise. The present study supports the hypothesis that HCM is, at least in part, a disease of energy deficiency. Consistent with this hypothesis, we showed that metabolic modulation by perhexiline augmented myocardial energetics, and normalised diastolic ventricular filling which translated into significant subjective (improved symptoms) and objective (increased exercise capacity [peak VO2]) clinical improvement in HCM patients. These findings suggest that metabolic modulators, such as perhexiline, have the potential role in the management of patients with symptomatic non obstructive HCM, a condition for which there are currently limited therapeutic options. However, large scale longterm studies are still required to examine the effects of these agents on morbidty and mortality in these patients.

Contemporary pacemakers allow quantification of atrial high-rate episodes (AHREs) and atrial fibrillation burden (AFB) accurately. It is generally believed that left atrial (LA) remodelling may precede the development of atrial arrhythmias (AA), and AHRE precede the clinical manifestation of atrial flutter or fibrillation. However, the relationship between LA remodelling with AHRE has not been studied. Furthermore, the relationship of AFB to progressive LA remodelling and how this relates to indices of thrombogenesis is unclear. The aim of my study is to investigate the inter-relationship between LA remodelling, AA burden and indices of thrombogenesis in patients with pacemakers. My findings suggest that the incidence of AHRE was 35%. Increased frequency of right ventricular pacing is associated with LA enlargement and reduced global left and right ventricular function. However, there was no clear association between the right atrial pacing with cardiac remodelling. The cumulative percentage right ventricular pacing and increased LA volume are associated with the development of AHREs, but AFB is independently associated with changes in LA function, left ventricular diastolic function and indices of platelet activation and thrombosis. In addition, I demonstrated the feasibility and reproducibility of a novel method of IACT measurement in patients with permanent pacemakers.

Background The revised 2011 GOLD strategy presented a new classification and treatment of usual Chronic Obstructive Pulmonary disease (COPD) based on symptom assessment by CAT or mMRC and risk assessment based on exacerbations estimated from the spirometric grade or number of exacerbations in previous year (1). This new strategy has not previously been applied to patients with Alpha one antitrypsin deficiency (AATD). Aims To apply new GOLD strategy/categories in AATD and assess comparable symptom thresholds and predictability of mortality, future exacerbations and lung function decline (FEV1, Kco) and the role of comorbidities. Results The results have validated the strategy/classification in AATD with a suggested threshold of 13 rather than 10 for CAT to match with mMRC 1. Mortality and Kco decline was worse in the more severe category D which also had patients with more comorbidity. Applying COTE index to patients with AATD did not help in predicting mortality. Conclusion The new GOLD classification helps identify AATD patients who are at risk of poorer outcome based on lung function decline, mortality and exacerbation risk with patients in group D being most at risk. Presence of comorbidities does not appear to influence outcomes in AATD although they do tend to indicate a poorer quality of life. References 1. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, et a!. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. American journal of respiratory and critical care medicine. 2013;187(4):347-65.

The Mixed-Lineage Leukaemia (MLL1) protein is a key developmental factor that acts to regulate genes via its histone methyl-transferase activity. This study aimed to examine how MLL1 and its associated complex contribute to gene regulation in a functionally relevant cell background. To assess dynamic processes involved, we developed a haematopoietic Stem Cell (hSC) -based system, in which Hoxa genes are down-regulated in a differentiation- induced manner. I characterised the histone modification distribution on two MLL-target genes showing the largest changes upon differentiation: Hoxa4 and Hoxa5. When active, these genes are associated with a peak of “activating” histone marks (H3K4me3, H3K9ac, H4K16ac) over the transcriptional start site, which are lost when the gene is repressed. This correlated with the recruitment of enzymes that deposit these marks, including components of the MLL complex (MLLC, MLLN and menin) as well as HATs that may be associated with the complex (CBP and MOF). Interestingly, the location of these proteins does not always correlate with the marks they deposit. We show that the dual mark H3K9acS10p is present on active Hoxa4 and Hoxa5 genes, and correlates with the presence of the histone kinase Msk1. We speculate that Msk1 contributes to regulating MLL1 HMT’ase activity on these genes.

There are over one million deaths from road traffic collisions. In Afghanistan, there have been 2005 UK battle injuries over 10 years. Advances in military trauma care have improved survival, resulting in more severely injured individuals entering the trauma care pathway. Improved understanding of immunoendocrine changes after severe trauma may facilitate novel interventions to improve outcomes. We prospectively recruited 102 severely injured patients at the QEH Birmingham; 52 military and 50 civilian patients with a mean Injury Severity Score of 27.2±13.9. Blood and 24-hr urine were collected at baseline (injury < 24h) and at regular intervals from while in hospital and at 3,4, and 6 months. Results demonstrated a reduced neutrophil function following a surge of DAMPs and cytokines that were released into the circulation. Both DHEA and DHEAS were significantly down-regulated (p < 0.0001). Serum testosterone was initially completely suppressed (p < 0.0001) but normalised after week 4. Protein and muscle loss followed a U-shaped curve; catabolism began to recovery 4-6 weeks following injury. In conclusion, the acute response to severe injury comprises increased glucocorticoid activation and down-regulation of adrenal and gonadal androgens. Delineation of whether the endocrine changes are beneficial or adverse will determine the potential for future intervention studies.

Nasal polyposis is a common disease affecting 2-4% of the general population. The aetiology and pathogenesis are far from clear. Recent publications have suggested up-regulation of several pro-angiogenic factors including VEGF. The aim of this study was to assess and quantify the degree of angiogenesis in nasal polyposis and to determine if angiogenesis was the driving force behind polyposis. We started by developing a novel triple stain to assess remodelling in the nasal mucosa. For the first time we were able to categorically refute the common belief of angiogenesis driven polyposis. We then carried out genomic studies and identified upregulation of genes controlling the cell cycle and apoptosis, suggesting cell turnover is an important part of the pathogenesis of nasal polyps. Our gene expression data was confirmed by TUNEL staining, indicating an increased level of apoptosis in nasal polyp tissue, counterbalancing the increased cell proliferation. Inflammatory genes are also upregulated, however the data collected so far cannot distinguish between different types of inflammatory response. We carried out proteomic studies using the lu minex system but this did not clarify the situation despite using matched samples that were used in the gene array. They highlight the protein differences occurring in the polyps themselves. We have shown chemoattractants for eosinophils & macrophages (which are found in polyps), and significantly in iNOS, which is novel.