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In this thesis, a candidate approach was taken to analyse the temporal characteristics of gene expression during TNF-α induced anti-adipogenesis. This suggested that TNF-α might activate Wnt/β-catenin signalling during anti-adipogenesis. Further investigations revealed stabilisation of β-catenin, enhanced TCF7L2 promoter activity and enhanced expression of Wnt/TCF7L2 target genes. The requirement of Wnt/β-catenin signalling for this process was investigated in preadipocytes with either stable knockdown of β-catenin or overexpression of a dominant-negative mutant of the transcription factor TCF7L2. Knockdown of β-catenin attenuated anti-adipogenesis and enhanced apoptosis by TNF-α, whereas overexpression of dnTCF7L2 prevented TNF-α-induced anti-adipogenesis without affecting cytotoxicity. The studies presented in this thesis also identify the serine kinase IKKi as a negative regulator of adipogenesis. IKKi expression was downregulated during adipogenesis but elevated during early TNF-α-induced anti-adipogenesis. Forced expression of IKKi attenuated adipogenesis, whereas stable knockdown of IKKi enhanced adipogenesis. TNF-α also regulated IKKi in mature adipocytes, and knockdown of IKKi in these cells blunted both the suppression of adipocyte genes and the induction of insulin resistance by TNF-α. Importantly, IKKi expression was found to be upregulated in the adipose tissue of obese and insulin-resistant mice and humans, conditions where TNF-α levels are known to be elevated and where adipogenesis may be impaired. In conclusion, the studies have identified two novel mechanisms by which TNF-α can inhibit adipogenesis: via a β-catenin/TCF7L2-dependent pathway and via induction of IKKi. These novel mechanisms of TNF-α action may impact on other aspects of cell fate determination, such as cell proliferation and survival.

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Gastro-oesophageal reflux, GORD is a common condition. It predisposes to 8arreU's oesophagus, a premalignant condition leading to oesophageal adenocarcinoma. Oesophageal cancer is one of the faster rising cancers in the Western world. Proton pump inhibitors are the standard pharmacological treatment for symptoms of GORD. The impact of these drugs in the prevention of complications of GORD is however still unclear. Using the general practice research database (GPRD), we looked at temporal trends of GORD incidence and prevalence in the UK as well as its associated complications of BarreU's oesophagus and oesophageal cancer. Parallel trends in peptic ulcer disease are also investigated. The effect of proton pump inhibition in the development of oesophageal cancer in acid reflux is explored . We explored factors known to influence the intragastric acid levels and prevalence of GORD eg Helicobacter pylori prevalence and obesity. The prevalence of other gastro-intestinal conditions as well as GORD in candidates for bariatric surgery is also assessed. Optimising acid reflux control in Barrett's oesophagus by means of lifestyle adaptations in conjunction with use of proton pump inhibition is also investigated. Finally, aspects of the pathophysiology of eosinophilic oesophagitis, a newly recognised condition, and its relationship with GORD are also examined.

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The aims of the study were 1) to assess blood group and secretor status of local patients with peptic ulcer disease; 2) to determine if <I>H. pylori </I>binds to blood group antigens and if environmental factors such as fasting or smoking affect the binding; 3) to isolate bacterial adhesins that bind to the blood group antigens; 4) to determine if there are differences in the immune or inflammatory responses to <I>H. pylori </I>associated with ABO blood group or secretor status. There was a higher proportion of group O and non-secretors in the local patient group. In studies in which flow cytometry was used to assess bacterial binding to buccal epithelial cells or the gastric adenocarcinoma cell line (Kato III), binding of <I>H. pylori </I>was inhibited by pretreatment of the cells with monoclonal antibodies against Lewis<SUP>a</SUP>, Lewis<SUP>b</SUP> and H type 2 (the antigen of blood group O). Binding indices of <I>H. pylori </I>to buccal epithelial cells correlated with binding induces for H type 2 and Le<SUP>b</SUP> but not with Le<SUP>a</SUP>, suggesting the terminal fucose moieties of H type 2 and Lewis <SUP>b</SUP> are important epitopes for bacterial binding. Binding of <I>H. pylori </I>to buccal epithelial cells from smokers was significantly higher than to cells from non-smokers among patients referred to the gastroscopy clinic. In other experiments with cells from health volunteers, binding of <I>H. pylori </I>to cells from smokers was higher than to cells of non-smokers but the differences were not significant. Because each patient had fasted for approximately 12 hours before the cells were collected at the clinic, the effect of fasting and smoking were examined with buccal cells from1 5 pairs of smokers when fasting during Ramadan and after the fast when the donors were eating and drinking normally. In this group, binding of <I>H. pylori </I>and expression of H type 2 were significantly lower among the smokers.