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Liver treatment is technically demanding due to the breathing motion and the presence of the ribcage around it, and non-invasive options are desirable. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is a promising treatment option due to its non-invasive nature and due to the ability to perform MR Thermometry. Thermometry can provide real-time temperature feedback and temperature maps indicating the ablated area. Despite considerable research on liver treatment with MRgFUS, developing a repeatable, safe and efficient ex vivo liver model has not been achieved. The Thiel embalmed model is more favourable than the fresh or formalin-fixed cadavers, due to its long-lasting, tissue-mimicking properties, and limited health risks. This thesis verified the Thiel embalmed liver, as a model for MRgFUS treatment before clinical practice, by using explanted organs and whole cadavers. The first set of experiments involved the measurement of acoustic parameters of Thiel embalmed tissue, and the scrutiny on the temperature response of the embalmed liver on FUS heating. Secondly, baseline phase-referenced Proton Resonance Frequency (PRF) MR Thermometry method was applied on Thiel liver to measure its thermal property (PRF coefficient). By this, the accurate temperature monitoring can be achieved on Thiel tissue. Thirdly, it was examined if the Thiel model is suitable to perform of reference-less PRF Thermometry during MRgFUS sonication. Fourthly, the MRgFUS sonication was performed on explanted liver and on whole human cadaver, in real-patient conditions. These conditions involved vascular visualization (with contrast agent), perfusion, respiratory motion, MR imaging and FUS heating under real-time temperature mapping. The results demonstrate that the acoustic parameters of the Thiel embalmed liver were different from the fresh liver, meaning that more acoustic power needs to be delivered to the target, to achieve ablative levels. Additionally, embalming with Thiel solution affected the temperature response, and resulted in different PRF coefficient. However, by using the measured coefficient, accurate thermometry can be performed with MRgFUS. Testing reference-less Thermometry algorithms was found suitable in a whole cadaver, with similarity between the reference-less algorithm temperatures and the actual temperatures. Vascular visualization with contrast agent was achieved in the explanted liver, and the cadaver proved feasible for respiration, vessel visualization and MRgFUS heating. Thus, the Thiel embalmed ex vivo model is favourable for MRgFUS treatment, in life-like conditions, before clinical practice. Additional spinous work suggested that the maximum temperatures achieved in the vertebrae and the intervertebral discs could achieve coagulative necrosis. The technologies and the research described in this thesis have been shown to overcome many of the present limitation and should therefore be useful for ongoing pre-clinical research on MRgFUS for liver treatment. Nevertheless, it is acknowledged that many crucial issues remain to be solved. These include repeatability studies to scrutinize if the PRF coefficient would change over a wider population of samples, investigation on magnetic susceptibility during measurement of the coefficient, and the combination of the real-time treatment of the liver, during respiratory motion and reference-less temperature mapping in a fully functional human cadaver. This thesis provided the fundamental starting point for testing different process parameters, such as real-time thermometry, FUS beam steering and tracking of the tumour location by using Thiel embalmed human cadavers.

A stigma is ‘an attribute that is deeply discrediting,’ often contravening social norms, and perceived by others as being undesirable. Inflammatory Bowel Disease (IBD) is a chronic illness characterised by symptoms of diarrhoea, urgency, and vomiting occurring in a relapsing and remitting pattern. Regular or temporary loss of bowel control is a prominent feature of the disease and may lead to stigmatisation through infringement of social hygiene rules. Although stigma in IBD has been measured in quantitative studies, there is a dearth of qualitative evidence. This Heideggerian (hermeneutic) phenomenological study explores the lived experience of IBD-related stigma. Using purposive stratified sampling, 40 members of a national IBD charity were recruited. Participants did or did not experience faecal incontinence, and did or did not feel stigmatised. Unstructured individual interviews (digitally recorded and professionally transcribed) took place in consenting participants’ homes between May and November 2012. Data were analysed using Diekelmann’s hermeneutic method. Seven relational themes (present in some transcripts) and three constitutive patterns (present in all transcripts) emerged. IBD-related stigma is a complex experience, mostly of anticipated or perceived stigma, which often decreases over time. Stigma changes according to social settings and relationships, but arises from the challenges the disease presents in maintaining social privacy and hygiene rules. Stigma resilience appears most likely in those with a positive sense of control, a support network (particularly of close and intimate others) which suits their needs, and mastery over life and illness. IBD-related stigma occurs regardless of continence status and can cause emotional distress. Time, experience, and robust social support enhance stigma resilience. Further research is needed to confirm features which enable resilience, and to develop stigma-reduction strategies that will promote resilience in this patient group.

Liver fibrosis is one of the leading causes of morbidity and mortality in the western world and represents a significant burden to the health system. The continued elucidation of the mechanisms governing liver fibrosis has identified the hepatic myofibroblast, derived from quiescent hepatic stellate cells, as the principle cell type involved in disease progression with several studies demonstrating that hepatic myofibroblast apoptosis correlated with attenuated fibrosis severity. A recombinant single chain antibody (scAb), termed C1-3, has been developed and shown to actively target hepatic myofibroblasts expressing synaptophysin both in vitro and in vivo. The aim of this thesis was to use C1-3 (conjugated to an appropriate agent) as an imaging agent; to examine the effect of hepatic myofibroblast depletion on regeneration following two thirds partial hepatectomy (PHx) and to examine if hepatic myofibroblast depletion in a cirrhosis model promotes fibrosis regression. The data in this thesis show that conjugation of C1-3 to a fluorophore provides a novel non invasive method for differentiating between the different stages of carbon tetrachloride induced liver fibrosis in animal models, with increasing hepatic myofibroblast number (determined by αSMA staining) correlating with disease progression. Hepatic myofibroblast depletion prior to and during PHx revealed a complex role for these cells during liver regeneration through the provision of factors that both stimulated and reduced parenchymal cell proliferation. C1-3 mediated-depletion of hepatic myofibroblasts in a sustained model of liver injury revealed that removal of these cells was not sufficient to stimulate fibrosis regression since no difference in collagen deposition was observed. The data in this thesis demonstrate the complex role of hepatic myofibroblasts during liver regeneration and sustained injury and suggest that further studies are required to elucidate the exact mechanisms involved before depletion of hepatic myofibroblasts can be a viable therapeutic option.

Several intemet sites sucp as 'Live Well' run by the National Health Service of the United Kingdom promote a 'healthy lifestyle' among citizens by providing information on how to avoid weight gain. A common recommendation to achieve and maintain a 'healthy' body weight is to balance body metabolism. That is, the energy we put in our body (calories we eat) must be the same as the energy we spend (physical activity). This thesis questions the universality of this recommendation and explores the complexity of balancing metabolism in daily life. In order to tackle this issue, this dissertation is premised by posthuman Science, Technology and Society studies (STS). This implies understanding metabolic balance as a set of practices that involve the association of human and non-humans actors. An attention to everyday practices is the guiding principle as this dissertation locates a study of metabolic balance in a case study of how people who suffer from morbid obesity live with bariatric surgery. Empirically this thesis demonstrates that in practice metabolism needs to be continuously re-balanced in daily life to avoid weight (re )gain. I suggest that the process of balancing metabolism may include sets of practices which are beyond the decision making of an informed individual. Metabolic balance, in the case of bariatric surgery, is shared work, an effect of collaborative work by the collective of cure (' healthy' lifestyle recommendations) and secondary care practices (coping with aspects of embodied living such as eating, masticating, drinking, buying, digesting or exercising). Theoretically, it argues that when metabolic balance after a gastric bypass is achieved, it is an effect of tinkering with secondary care practices of body metabolism. Thus, instead of putting big efforts into patient's adherence to a set of general healthy lifestyle recommendations, more attention should be given to care practices which (im)balance metabolism.

Aims: To elucidate individual susceptibility to acute and chronic pancreatitis by examining candidate genes: tumour necrosis factor (TNF), cationic trypsinogen (PRSS1) and serine protease inhibitor, Kazal type 1 (SPINK1) in patients with acute and chronic pancreatitis. To examine the role of the transcription factors, nuclear factor-?B (NF-?B) and heat shock factor-1 (HSF-1) in acute pancreatitis. Results: The TNF a6b5c1d3e3 haplotype is positively associated with chronic pancreatitis (OR= 2.08 (95% CI: 1.12-3.88; X2=5.49, P=0.019); the TNF a2b3c1d1e3 and a2b5c2d4e3 haplotypes are negatively associated (OR= 0.48 (95% CI: 0.23-0.99; X2=4.08, P=0.043 and OR= 0.20 (95% CI: 0.05-0.77; Fisher's P=0.014, respectively). The PRSS1 R122H mutation was detected in 1 out of 36 patients with alcoholic pancreatitis and 3 members of a hereditary pancreatitis family. The N291, A16Vand -28deITCC mutations were not detected in patients or controls. The SPINK1 N34S mutation is associated with acute pancreatitis in UK and German populations (OR= 3.312 (95% CI: 1.805-6.078), P<0.001, X2 test). The mean age of those AP patients with the N34S variant was 11.9 years younger than those AP patients without N34S in the UK population. A novel variation (c.274C>T) in the 3' untranslated region was found in an acute pancreatitis patient. N34S is also associated with alcoholic chronic pancreatitis in UK, German and Swiss populations (P<0.001). Systemic NF-?B activation occurs in acute pancreatitis compared to healthy controls (P=0.004). Systematic activation of HSF-1 was observed in acute pancreatitis compared to healthy controls (P=0.053). However, activation was significantly greater in those who had mild pancreatitis compared to those who had severe acute pancreatitis (P=0.036). HSF-1 was inversely correlated with acute physiology score (r=-0.49; P=0.019) and APACHE II score (r=-0.47; P=0.026).

<i>INTRODUCTION</i>: Abnormalities of energy expenditure (EE) in obesity and type II diabetes mellitus have been described in animal models and adult man and it has been suggested that these abnormalities predispose to weight gain. In rodents there is evidence for a requirement for insulin in regulatory thermogenesis mediated via brown adipose tissue (BAT). The hypotheses that, firstly, insulin has a role in the control of EE and, secondly, that this is mediated by BAT in adult man were tested in the present studies. <i>METHODS</i>: Three components of daily EE resting metabolic rate (RMR), and the thermic responses to a mixed liquid meal (32.6 KJ/kg) and to an infusion of noradrenaline (NA), 0.1 μg/kg/min, were measured using indirect calorimetry in type I and type II diabetic subjects. The components of EE were measured in 9 lean type I diabetics initially while poorly controlled on conventional therapy (CT), HbA_1 12.1±0.7%; (mean±SEM), and then when optimally controlled on continuous subcutaneous insulin infusion (CSII) (HbA_1 7.5±0.2%). The response to fat supplementation for one week (5.23 MJ/day) was assessed and the results compared to 8 non-diabetic control subjects. These parameters were also measured in 8 type II diabetics controlled on diet and oral hypoglycaemic agents (HbA<SUB>1</SUB> 8.6±0.7%) in order to ascertain whether the alterations in body weight during metformin therapy (weight loss) or sulphonylurea therapy (weight gain) were reflected in alterations of EE. An estimation of the thermogenic potential of BAT in adult man was attempted by histological (light and electron microscopy) and biochemical (GDP binding, cytochrome c oxidase activity and respiration of isolated mitochondria and adipocytes) studies on perirenal BAT obtained at post mortem and during surgery. <i>RESULTS</i>: Poorly controlled type I diabetic subjects had a significantly (p< .01)) raised RMR (4.92±0.27 KJ/min) which returned to predicted value (4.6±0.34 KJ/min) on attainment of optimal glycaemic control. This decrease in RMR may partly explain the mean gain in weight (3.5 kg) observed during CSII. The thermic response to infused NA was decreased by over 50% during CT (27.1±3.4 KJ controls vs. 11.1±3.7 KJ diabetic CT; p< 01) and did not significantly improve during CSII (13.4±3.7 KJ). A blunted thermic response to a meal was observed during fat supplementation with CT (44.8±14.0 KJ) but CSII corrected this (71±9.9 KJ). Hence insulin has a role in the control of EE but precise replacement does not correct all these abnormalities in Type I diabetes mellitus. 2. Type II diabetic subjects had a normal RMR and thermic responses and these were similar whether on metformin or sulphonylurea therapy. This suggests that alterations in EE do not account for the changes in weight during treatment with these agents. 3. Histological and biochemical studies demonstrated the presence of functional BAT in adult man with activity equivalent to the partially cold-adapted guinea pig suggesting some potential for thermogenesis in adult man. However, it was calculated that this tissue can account for only 0.2% of the rise in oxygen consumption during NA infusion and suggests that this tissue has little energetic significance in adult man. <i>CONCLUSIONS</i>: These data suggest that although type I diabetes mellitus may be associated with abnormalities of EE these are unlikely to be mediated through BAT metabolism in man.

No description available.

Patients with cirrhosis characteristically develop haemodynamic changes which include increased cardiac output, decreased systemic vascular resistance and paradoxically, increased portal pressure. Studies to date largely in animal models, have suggested that a decrease in hepatic nitric oxide may be important. The studies described in this thesis provide evidence for significantly elevated portal pressure in alcoholic hepatitis patients, who were shown to have a marked additional inflammatory response on the background of cirrhosis, and a more severe expression of disease. Studies in patients and a galactosamine rodent model confirmed a decrease in endothelial nitric oxide synthase (NOS) activity in the context of inflammatory liver injury. Following on from these observations, further studies explored the role of potential regulators of NOS which may have accounted for its decrease in activity in liver disease. Studies of asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, showed that it was markedly increased in liver failure in both patients and in an animal model. The data suggested this may result from a decreased metabolism (through reduced expression of its metabolizing enzyme, dimethylarginine-dimethylaminohydrolase) or/and increased synthesis by protein arginine methyltransferases. ADMA was shown to correlate with severity of portal pressure, and with increased organ failure and death in decompensated cirrhosis, suggesting that it may have a potential use as a biomarker of disease severity. Other novel regulators of endothelial NOS were also explored including the recently described potential NOS inhibitor, NOSTRIN (nitric oxide synthase traffic inducer). It was demonstrated that NOSTRIN was up-regulated at both message and protein levels in liver disease patients and this was most marked in those with additional inflammation. A further novel observation was the identification of a variant of NOSTRIN which was only found in cirrhosis patients and not in normal liver tissue. The findings from these studies provide a better understanding of the importance of inflammation in the context of vascular dysfunction in cirrhosis and highlight some potential novel therapeutic targets.

Introduction: A liver support device can bridge a patient in acute liver failure safely to transplant. An extracorporeal perfused porcine liver (ECLP) circumvents the limitations of hepatocyte based bioartificial liver, but its clinical application has been limited so far due to the potential risk of transmission of porcine endogenous retroviruses. Aim of this study was to develop an ECLP model that can provide artificial hepatic support across a semi-permeable membrane which should block porcine viruses due to its pore size. Methods: 50-60 Kg white landrace pigs treated with standard abattoir animal procedures were used as donors. The liver was perfused with normothermic autologous oxygenated blood using Medtronic BioMedicus BP560 driven centrifugal pump for 6 hours. This ECLP system was used to support a surrogate patient circulation across the filter Evaclio EC4A. Substances like galactose, ammonia, midazolam and para-aminobenzoic acid, were infused into the surrogate patient and their clearance was calculated. The study was designed as test (n=15) vs. control (n=5); with control experiments having no liver in the circuit. Results: After the optimization phase (n=23), we successfully perfused 15 porcine livers with the mean hepatic artery pressure of 87 mm Hg and flows of 1.2 L /min. Retention of Indocyanine green at 15 minutes was 11% in test and 96% in controls. Mean ammonia clearance of 945 mg/min/kg, galactose Vmax of 111.7 mg/min/Kg, hippurate ratio of 91% and a variable midazolam clearance was seen in the test experiments. Conclusion: The study was successful in proving the feasibility of an ECLP model based on abattoir animals that can be utilised for future research work. This model was able to provide adequate support to the surrogate patient across a hollow filter. Further work is needed to show that an ECLP system can be used in an anhepatic animal prior to application in human trials.