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Background Ultrasmall superparamagnetic particles of iron oxide (USPIO)- enhanced magnetic resonance imaging (MRI) can detect tissue-resident inflammatory macrophages and identify cellular inflammation. Clinical studies using this non-invasive technique are now emerging. Objectives The aims of this thesis were (i) to determine whether USPIO-enhanced MRI can detect and serially monitor myocardial inflammation after myocardial infarction (MI) using single and repeated USPIO administration, (ii) to report a range of normal R2* (1/T2*) values at 1.5 tesla (T) and 3 T in healthy myocardium and other tissues before and after USPIO administration, (iii) to determine whether USPIO-enhanced MRI can detect myocardial inflammation in acute myocarditis, and (iv) to determine whether USPIO-enhanced MRI can detect myocardial inflammation in patients with a prior cardiac transplant. Methods Thirty-one patients were recruited following acute MI and followed up for 3 months with repeated T2 and USPIO-enhanced T2* mapping 3 T MRI. Twenty healthy volunteers were recruited: 10 imaged each at 1.5 T and 3 T. T2 and USPIO-enhanced T2* mapping MRI was conducted. Fourteen patients with suspected acute myocarditis underwent T2 and USPIO-enhanced T2* mapping 3 T MRI, with further imaging at 3 months. Eleven patients with prior cardiac transplant underwent T2 and USPIO-enhanced T2* mapping 1.5 T MRI with further imaging at 3 months. Regions of interest within the myocardium, along with other tissues, were selected for analysis. Pre-contrast T2 values, and the change in R2* due to USPIO from baseline to 24 hours after USPIO were compared for each region of interest. Results In patients with MI, USPIO uptake in the infarct zone peaked at days 2-3, and greater USPIO uptake was detected in the infarct zone compared to remote myocardium in the first 2 weeks after myocardial infarction. In contrast, T2-defined myocardial oedema peaked at days 3-9 and remained increased in the infarct zone throughout the 3-month follow up period. Histology confirmed colocalisation of iron and macrophages within the infarcted, but not the non-infarcted, myocardium. In healthy volunteers, we reported a range of normal myocardial and tissue R2* values at baseline, and following USPIO. Tissues showing greatest USPIO enhancement were organs of the reticuloendothelial system: the liver, spleen and bone marrow. Myocarditis was confirmed in 9 of the 14 suspected cases of myocarditis. There was greater myocardial oedema, but no demonstrable difference in USPIO enhancement, in inflamed myocardial regions in patients with myocarditis when compared to healthy myocardium. We recorded an improvement in cardiac function and reduced imaging measures of inflammation after 3 months. Ten patients with cardiac transplant were retained for analysis. Measures of myocardial oedema were greater in patients with cardiac transplant than healthy volunteers. There was no difference in the change in R2* due to USPIO between patients with transplantation and healthy volunteers. Imaging recordings did not change when repeated at 3 months. Conclusions Myocardial macrophage activity can be detected using USPIO-enhanced MRI in the first 2 weeks following acute MI. This observed pattern of cellular inflammation is distinct, and provides complementary information to, the more prolonged myocardial oedema detectable using T2 mapping. In patients with acute myocarditis, USPIO-enhanced MRI does not provide additional clinically relevant information to standard clinical MRI sequences. This suggests that tissue-resident macrophages do not provide a substantial contribution to the myocardial inflammation in this condition. Stable patients with cardiac transplantation have increased myocardial T2 values, consistent with resting myocardial oedema or fibrosis. In contrast, USPIO-enhanced MRI is normal and stable over time suggesting the absence of chronic macrophage-driven cellular inflammation. In conclusion, this imaging technique holds promise as a non-invasive method of assessing and monitoring macrophage-driven myocardial inflammation after myocardial infarction with potential application to diagnosis, risk stratification and assessment of novel anti-inflammatory therapeutic interventions. It remains to be determined whether USPIO-enhanced MRI may be able to identify myocardial inflammation in other myocardial inflammatory conditions including acute cardiac transplant rejection.

This phenomenological study explores how certain “innovative” pedagogies were experienced by a group of Chinese students studying Business Management at a mid-ranking UK university. Analysis of the transcripts of interviews (some in Chinese) with 24 students using NVivo shows that whilst most students felt that Active Learning pedagogies effectively supported their learning, for some students the “zone of indeterminacy” in which group projects and simulations were carried out was an uncomfortable space. Salient aspects of these students’ experiences were language, relationships and metacognitive skills, and the discussion explores the way in which these three experiential themes can be conceptualised as interrelated elements of the action (Biesta, 2006) which takes place in Active Learning classrooms. The following recommendations are made: HEIs should attempt to provide students with the advanced skills of negotiation which they will need to use in the flexible, ill-structured environments associated with Active Learning pedagogies; tutors should develop consistent approaches to collaborative assignments focussing on group work processes as well as task completion; the development of metacognitive skills through Active Learning pedagogies should be promoted through the use of explicit reflective elements embedded within the teaching, learning and assessment activities. The concluding discussion proposes that the successful use of Active Learning pedagogies requires a reconceptualisation of the purpose of education and that these pedagogies provide a potential readjustment of the balance between the functions of qualification, socialisation and subjectification (Biesta, 2010).

My early clinical experience had demonstrated that abnormalities of endocrine testing particularly with regards to thyroid function are common in ill patients. Interest in endocrine effects of illness was further stimulated by my study of hormone levels of uraemic patients undergoing differing forms of dialysis therapy. Chronic renal failure resulted in abnormal hypothalamic-pituitary-testicular and hypothalamic-pituitary-thyroid function irrespective of the nature of dialysis. Evidence for low levels of adrenal androgen in serum of uraemic patients was also found. As it was well known that abnormalities of thyroid function occurred in a variety of illnesses so it appeared possible that abnormalities of adrenal androgen status and hypothalamic-pituitary-testicular function might also be non-specific consequences of illness. To investigate this hypothesis these endocrine parameters were measured in several groups of patients:- those ill in a general medical ward, in diabetic men with ketoacidosis, during recovery from burns injury and before and after surgery. Serum levels of the most abundant adrenal androgen dehydroepiandrosterone sulphate (DHAS) were low in patients with a variety of non-endocrine medical illnesses only if they had been unwell for more than two weeks while serum androstenedione concentrations were higher than in controls irrespective of the duration of illness. Testosterone levels were also low but this was not related to the duration or severity of illness nor could it be accounted for by changes in binding proteins, hyperprolactinaemia nor on the basis of classical primary or secondary testicular failure. A study of men during an episode of diabetic ketoacidosis revealed that this complication of diabetes mellitus is also accompanied by depression of serum testosterone concentrations. However serum testosterone concentrations of non-ketotic diabetic men at routine review were not found to be related to diabetic control as assessed by glycosylated haemoglobin estimation. There was some limited evidence in the literature to suggest that adrenal androgen levels in diabetic men might be low and that this might have a deleterious effect on islet cell function but no abnormality of these hormones could be demonstrated in this group of patients. 19 burned men were followed sequentially for several weeks. Profound depression of serum testosterone concentrations for several weeks was found with levels falling into the range found in healthy females in the majority of patients studied. This could not be explained on the basis of binding protein changes nor by alterations in the concentrations of prolactin or gonadotrophins. DHAS levels although normal within 24 hours of admission fell to subnormal levels and remained low for several weeks. Serum androstenedione levels were high following admission and tended to remain so for several weeks. These changes in adrenal androgen concentrations were reminiscent of my observations during medical illness. Serum gonadotrophin levels of post-menopausal females were studied following cholecystectomy. Unlike the situation in medically ill men this operation led to a marked reduction in gonadotrophin levels sometimes down to the pre-menopausal range. Serum DHAS levels fell to below control values four days after surgery while serum androstenedione concentrations rose transiently post-operatively. The situation was however complicated by the administration of several drugs in particular parenteral opioids which might have affected gonadotrophin levels. As such profound endocrine changes had been observed with illness, it was of interest to discover whether these were specific to illness or whether other forms of stress such as the physical stress associated with exercise or the psychological stress accompanying academic examinations might result in similar changes. Following marathon running there was a small fall in serum testosterone concentrations. The situation differed from that following illness in that there was a massive elevation of serum cortisol as well as a fall in luteinising hormone (LH) levels. On the other hand veteran athletes who had run at least 25 miles a week for many years and who are therefore exposed to recurring and chronic physical stress had normal serum testosterone levels. Neither veteran athletes nor marathon runners showed evidence of a reduction in serum concentrations of adrenal androgens. The stress of physical exercise has a short-lived adverse effect on testicular function but unlike illness there are no changes in adrenal androgen levels. Review of the literature suggested that psychological stress can adversely affect gonadal function.