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The prevalence of peripheral arterial disease is known to be higher in subjects with diabetes mellitus or impaired glucose tolerance compared with non-diabetic subjects. The objective of study 1 was to determine whether this could be explained by differing levels of 'traditional' risk factors, such as smoking, hypertension, dyslipidaemia and obesity. Methods: 1,592 men and women aged 55-74 years were selected at random from the age-sex registers of 11 general practices throughout Edinburgh, Scotland. Subjects underwent a comprehensive medical examination, including assessment for peripheral arterial disease (positive intermittent claudication questionnaire or major asymptomatic disease on non-invasive testing), a glucose tolerance test and measurement of cardiovascular risk factors (including smoking, blood pressure, body mass index and serum lipids and lipoproteins). Results: 288 subjects (18.7%) were found to have diabetes or impaired glucose tolerance (IGT). The prevalence of peripheral arterial disease was greater in subjects with diabetes or IGT (20.6%) compared to those with normal glucose tolerance (12.5%) (age and sex adjusted OR 1.45; 95% CI 1.03, 2.04). In subjects with diabetes or IGT, mean levels of smoking, systolic blood pressure and serum triglycerides were significantly higher in subjects with peripheral arterial disease than in those without disease (p£0.05). In general, levels of cardiovascular risk factors were higher in subjects with diabetes or IGT compared with normal glucose tolerant subjects; this included systolic blood pressure and triglycerides, but not smoking. In multivariate analysis, subjects with diabetes or IGT no longer had a significantly higher risk of peripheral arterial disease after adjusting separately for systolic blood pressure (OR 1.22, 95% CI 0.85, 1.73) or serum triglycerides (OR 1.26 95% CI 0.89, 1.79). Simultaneous adjustment for both risk factors reduced the odds of disease further to 1.11 (95% CI 0.78, 1.58). Conclusions: Raised levels of serum triglycerides and systolic blood pressure in subjects with diabetes or IGT may explain a major portion of their increased risk of peripheral arterial disease. The objectives of study 2 were to determine whether, in non-diabetic men and women from the general population, there was an association between peripheral arterial disease and (i) plasma insulin levels or (ii) endogenous steroid sex hormones.

Title: Amylin peptide: An association with feed intolerance in preterm neonates and infants of diabetic mothers Introduction: Delayed enteral nutrition due to feed intolerance is common in preterm infants and infants of mothers whose pregnancy was complicated by diabetes mellitus (IMDM). Amylin, a 37 amino-acid polypeptide hormone, is a potent inhibitor of gastric emptying that may play a role in the patho-physiology of feed intolerance in these infants. Aims and Objectives: To determine serum amylin levels (i) at birth (umbilical cord) and postnatal day 5 (Guthrie) in healthy preterm and term infants-Study A, (ii) at birth (umbilical cord) and postnatal day 5 (Guthrie) in preterm and term IMDM-Study B, and (iii) in preterm infants experiencing feed-intolerance (nTOL) and feed-tolerance (TOL)-Study C. Hypothesis: Serum amylin levels are raised in (i) IMDM and (ii) preterm infants with increased gastric residual volumes (GRV); which may explain their feed intolerance. Methods and Material: Blood samples were analysed for total amylin immunoreactivity using monoclonal antibody based sandwich immunoassay. Results: Serum amylin concentrations (median (interquartile range)) in healthy term infants at birth (n=138) and postnatal day 5 (n=14) were 6.10 (3.30-9.70) pmol/L and 5.65 (3.10-8.20) pmol/L respectively. Similarly, the amylin concentrations in healthy preterm infants at birth (n=43) and postnatal day 5 (n=25) were 4.60 (1.90–8.30) pmol/L and 6.9 (2.75–9.50) pmol/L respectively. The amylin concentrations were significantly raised in both term IMDM at birth [n=17, 34.30 (28.35-50.00) pmol/L, p<0.0001] and postnatal day 5 [n=4, 25.20 (22.20-48.75) pmol/L, p<0.0001] and preterm IMDM at birth [n=14, 32.0 (18.65-44.27) pmol/L, p<0.0001] and postnatal day 5 [n=9, 23.4 (15.37-46.57) pmol/L, p<0.0001]. The amylin concentration was significantly elevated in nTOL group [n=30, 47.9 (21.4-79.8) pmol/L, p<0.0001)] compared to TOL group [n=30, 8.7 (5.7-16) pmol/L]. Conclusions: Amylin by virtue of its inhibitory effect on gastric emptying may be responsible in delaying establishment of enteral nutrition in preterm infants and infants of mothers whose pregnancy was complicated by diabetes mellitus.

Adult congenital heart disease (ACHD) patients have markedly depressed exercise capacity. This thesis examined (i) the prevalence of chronotropic incompetence, its relationship to symptoms and exercise capacity and its prognostic value in ACHD patients; (ii) investigated exercise capacity in patients with Eisenmenger syndrome and assessed survival prospects in this cohort as well as risk factors for mortality. In addition, clinical effects of Bosentan (a pulmonary vasodilator) were examined during longer-term follow-up. (iii) Mathematical modelling studies were employed to assess the impact of intracardiac shunting on oxygen delivery and tissue oxygenation potentially affecting exercise capacity, (iv) As pulmonary and systemic endothelial dysfunction are integral features of pulmonary arterial hypertension (and are related to exercise intolerance in this setting), this thesis examined the number and function of endothelial progenitor cells (EPC) in patients with idiopathic pulmonary hypertension and Eisenmenger syndrome.

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As a result of rising right-wing populism and widespread Islamophobic discourse, many of the most ‘tolerant’ societies of Western Europe appear to be regressing after decades of post-WWII progress. This thesis questions whether or not there has been a shift in the standard of ethnic tolerance in Western Europe. This thesis asserts that post-War ‘progress’ was not universal and certainly never extended to the tolerance of ethnic diversity. The reality is that ethnic intolerance lingered after the Second World War, in spite of the attempts by post-War leaders to forget the past as quickly as possible. A post-War failure to adequately acknowledge the impact of racism on Western European societies has allowed the current anti-Islamic sentiment visible in policies, politics and public discourse in many nations to flourish. This thesis traces the evolution of ethnic intolerance in the Netherlands since the end of WWII. In the twenty-first century, the Dutch have abandoned the ‘multicultural’ policies of the previous century in favour of some of Western Europe’s strictest immigration and integration requirements. Due mainly to the success of key figures that pushed forward a lingering ethnic intolerance, the reputation for ‘tolerance’ that has previously been ascribed to the Dutch is now being called into question. Based on these developments, this thesis concludes that in the Netherlands ‘progressive’ social values have, until recently, overshadowed the more stagnant and, at times regressive, attitudes and policies directed at ethnic minorities. Finally, this thesis assesses the impact of Dutch developments on the rest of Western Europe, concluding that the ‘new’ right politics that emerged out of the Netherlands have legitimized ethnic intolerance, thereby enabling other Western European nations to adopt similar approaches to the immigration and integration of ethnic minorities while maintaining ‘liberal’ values. / Arts, Faculty of / Central Eastern Northern European Studies, Department of / Graduate

Abstract not available.

Obesity has reached epidemic proportions, highlighting the need to better understand contributors to under-exercise and overeating. Anxiety Sensitivity (AS) is hypothesized to amplify negative affect and avoidance motives, and has been linked to maladaptive coping behaviors such as eating pathology as well as distress during and avoidance of exercise. The current series of studies was designed to extend research that relied on self-report assessments, and investigate the role of AS in objectively-assessed eating and exercise behavior across three community samples. The first two studies examined eating in the context of experimentally-induced negative affect in a sample representing all weight categories (N = 57); and distress, perceived exertion, and affect changes during exercise in normal and obese weight groups (N = 38). The third study extended this investigation to a naturalistic setting, using actigraphy, affect, and dietary monitoring across a three-day period in normal and obese weight groups (N = 32). The hypotheses were that AS would predict more eating in the context of negative affect; greater perceived exertion and distress during exercise, as well as avoidance of exercise, with findings most pronounced in obese participants. Results were as follows. In the first study, more calories consumed following a negative affect induction was predicted by the interaction between a dimension of AS (mental concern) and the expectancy of loss of control from eating in overweight/obese participants. In the second study, there was no significant association between AS and ratings of exertion or distress during exercise; however, a trend suggested the expected affective benefits of acute exercise were not evident in obese participants with greater AS and exertion. The final study found that AS was associated with more calories consumed across the monitoring period in women but not men (who were equally represented across AS and weight groups), and was also predictive of more calories consumed in the context of negative affect. Additionally, high AS predicted less engagement in moderate-intensity exercise in obese participants and more in normal weight participants. Overall, these studies provide support for the hypothesis that AS is a predictor of both exercise avoidance and overeating behavior.

Over the past forty years, there has been an increase in obesity, diabetes, and heart disease, collectively known as metabolic syndrome (MetS), in which fructose has been implicated. In addition to MetS, hereditary fructose intolerance (HFI) has no known treatment aside from the difficult removal of fructose from the diet. Ketohexokinase (KHK) is the first enzyme in the fructose metabolic pathway and catalyzes an ATP-dependent reaction that phosphorylates fructose to fructose 1-phosphate. For effective inhibitor development, it is key to understand the KHK-catalytic mechanism. To that end, the research described in this thesis focuses on two goals: 1) understanding how KHK functions in its role as a metabolic enzyme, using structure-function analysis to inform the development of KHK inhibitors, and 2) investigating how these findings can be used to make KHK a prime therapeutic target for alleviating diseases such as HFI and MetS. The X-ray crystal structure of the mouse-liver isozyme, KHK-C (mKHK-C), was determined at a resolution of 1.79 Å. The mKHK-C structure is in complex with the substrate fructose and the product of catalysis, ADP, forming a ground-state complex. The mKHK-C structure has nearly identical secondary structure to its human homolog and has similar steady-state kinetic parameters validating the use of mouse models for exploring the pre-clinical efficacy of KHK-C inhibitors. Furthermore, six structures of human KHK-C in complex with inhibitors and ligands are presented. These structures support the kinetic analyses showing these inhibitors are all competitive with ATP and reveal the shape and polarity of the ATP-binding pocket to achieve inhibition constants (Ki) as low as 50 nM. Lastly, comparison of all KHK structures demonstrate that the β-sheet domain of KHK is capable of 30.3° rotation of the β-sheet domain towards the active site of the opposing dimer subunit. Kinetic experiments using site-directed mutants of human KHK-C and various viscogens confirmed that a conformational change is linked to KHK’s catalytic function. This research provides a foundation for further development of more specific KHK inhibitors aimed at HFI and MetS therapies. / 2022-10-30T00:00:00Z

No description available.