Occupational Therapists (OTs) who recommend housing adaptations for people with disabilities, funded through public finance, must satisfy professional codes of practice and the employing local authority requirement to allocate finite resources effectively and fairly. At the same time they must also meet service user expectations. Ethical reasoning will be required to balance these demands whilst practising to a personally acceptable professional standard. This study investigates how OTs understand themselves to develop a sense of fairness and how they use their community of practice in developing professional ethical practice. This was a 2 part methodology. Firstly, OTs from 2 community services were invited to participate in small discussion groups. 3 group sessions, of different sizes ranging from 2-6 participants and duration of 2-3 hours, were recorded in which OTs discussed cases which posed ethical challenges with respect to fairness. All participants were female. Secondly, 4 individual interviews with volunteers from the groups were recorded to collect OT narratives of personal ethical development. Transcripts were analysed using a literary-critical approach focussing for transcripts of group sessions on dialogue in community of practice and ethical approaches used; focussing for interview transcripts on the process of ethical development. OTs were shown developing professional practice dialogically within their own community of practice groups. This finding confirms the importance for professional development of encouraging opportunities for dialogical interaction between OTs. Practical reasoning about justice as theorised by Sen (2009) better characterised OT ethical reasoning practices than biomedical-ethical approach applying universal, abstract ethical principles. OT narratives of ethical development fitted the Aristotelian model of growth in virtue as a whole, across both professional and personal aspects of life. Empathy was tentatively categorised as a virtue rather than a technical skill in this context. Empathy contributed to OT clinical reasoning processes as well as ethical reasoning.

BACKGROUND: Aggression can have a wide range of damaging consequences for both perpetrators and victims. Theoretical and empirical studies into problems of aggression increasingly show the importance of social and cognitive factors in aggressive behaviour. Such research has commonly been approached through the framework of the Social-Information Processing (SIP) model. SIP explains social behaviours by the sequence of cognitive processes that occur between encountering a social stimulus and enacting a response to it. Crucially, it is apparent that particular processing styles, such as the way in which people interpret others’ behaviour, play important roles in aggression. However, while SIP has long been used to explain aggression in the non-disabled population, it is only in more recent years that this approach has been applied to people with intellectual disabilities (IDs). This is important because a significant minority of people with IDs demonstrate frequent aggressive behaviour. Although several studies have already indicated that particular cognitive processing tendencies and aptitudes contribute to aggression in adults with ID, no research has considered younger people in the transition to adulthood. To this end, the present thesis sought to investigate the possible influences of certain psychosocial factors on this group of young people with mild to moderate IDs. OBJECTIVES: To identify which specific factors to investigate, a systematic review was conducted of existing research into SIP and aggression with people who have IDs. On the basis of these findings, the thesis examined 1) the social interactions that typically elicit anger, 2) experiences of parental aggression 3) ability to discern affect from dynamic social cues and 4) beliefs about the consequences of aggressive and submissive behaviour. With the review also stressing the importance of examining aggression at specific developmental stages, the studies focused on individuals in the transition from adolescence to adulthood (between 16 and 20 years). Although this stage is thought to be important in the development of cognitive factors associated with aggression, there is little or no research in this area with young adults with IDs. METHODS: The thesis comprised four distinct research studies. Each adopted a group-comparison design, comparing aggressive and non-aggressive young people with IDs. To evaluate the extent to which findings were specific to people with IDs, additional comparisons were conducted between aggressive and non-aggressive individuals without IDs. For Study 1, 26 young adults with IDs and 20 non-disabled young adults completed a semi-structured interview about a recent experience of interpersonal conflict. Participants were asked to describe their beliefs and feelings about the event and their subsequent response. Studies 2, 3 and 4 used data from a second phase of data collection involving 46 young people with and 48 people without IDs. Study 2 used a task in which participants were asked to rank different types of social conflict in order of provocativeness. The author developed these scenarios to reflect the experiences of conflict reported by participants in Study 1. Participants also indicated how recently they had encountered each type of scenario. Study 3 used motion-capture stimuli of people walking in different emotional states to examine whether groups differed in how they encode dynamic social cues. Study 4 used provocative vignettes to examine whether aggressive young people with IDs expect different outcomes from aggressive and submissive responses to such scenarios. RESULTS: Study 1 found that participants with IDs were more likely to encounter conflict with strangers or peers outside their friendship group. They were also more likely to describe incidents of aggression and to characterise people with whom they were in conflict globally as “bad” and to perceive their actions as being personally directed at them. Study 2 did not suggest that experiences of being victimised by peers were more common for people with IDs, but did show that aggressive individuals were more likely to encounter incidents of physical aggression from peers. Parental conflict was the most recently encountered, but was perceived to be the least provocative form of conflict for all groups. In Study 3, no group differences were found in accuracy or response tendencies for the emotion recognition task. Aggressive and non-aggressive participants with IDs in Study 4 did not predict different outcomes form aggression and submission. However, the aggressive participants without IDs predicted more positive outcomes from aggression and more negative outcomes for submission. While aggressive participants with IDs were more likely to give aggressive responses, they were just as likely as the non-aggressive group to respond actively (assertively or aggressively) rather than passively. CONCLUSION: The findings of this thesis, viewed from the perspective of the SIP model, suggest that there are key cognitive and contextual differences between individuals who show frequent aggression, both with and without IDs. Although, somewhat surprisingly, emotion recognition skills did not appear to be associated with a tendency toward aggressive behaviour, the non-ID aggressive and non-aggressive groups differed in their anticipated outcomes for aggressive and submissive behaviour. The context in which conflict occurred also appeared to differ between those young people with and without IDs. However, the absence of some predicted findings from these studies may be related to methodological shortcomings; these possible limitations are considered, and directions for future work are suggested. Applications for clinical practice and policy are also discussed and recommendations for future research are given.

The process of parturition resulting in the delivery of a newborn is a fundamental event ensuring survival of the species. In humans, the main clinical problems of parturition include activation of the process too early or too late resulting in the delivery of pre-term and post-term infants, both with their own implications for future health for the mother and baby. Additionally, where parturition systems are not activated correctly, dysfunctional labour with the resulting need for caesarean delivery (CS), in addition to atonic post-partum haemorrhage can also ensue. Overall, in the UK up to 40% of pregnancies are affected by one of these problems. However, the exact processes involved in the initiation and maintenance of parturition in the human are not fully understood. With such an important event, influences are most likely to be multi-factorial, with hormonal, mechanical, inflammatory, biochemical and maternal environmental factors playing a part. The aims of this thesis were to investigate influences on parturition in human pregnancy. Firstly, the myometrial transcriptional effects of long term exposure to the uterotonic oxytocin (OT) were examined. Further investigation of the myometrial and maternal peripheral response to uterine contractions in-vitro and in-vivo was also made with particular reference to the role of inflammation and myocyte damage. Additionally, the influence of maternal factors, particularly obesity, on the myometrial in-vitro contractile function and response to OT was studied. Initially, 150 gene arrays were produced using the Illumina platform. The samples were derived from myometrium taken at pre-labour CS which subsequently underwent functional contractility experiments in an organ bath. Five drug environments were studied, namely OT, acetic acid (OT vehicle), ML7(a tocolytic acting via inhibition of myosin light chain kinase), ML7 & OT and finally DMSO (ML7 vehicle). Additionally, five time-points of 0, 1, 2, 4, and 6 hours after drug addition were used, resulting in 5 samples for each drug and time combination. The results indicated that despite a clear enhancement of myometrial contractile activity by OT, this functional response does not appear to be mediated by cellular transcription. However, there was a clear contraction and time dependent transcriptional wave, with overrepresentation of genes associated with inflammation and cellular damage/apoptosis, and down-regulation of pathways concerning cellular metabolism. These findings were confirmed by QPCR on further myometrial samples undergoing additional in-vitro functional studies. In addition to the temporal and contractile association with the inflammatory response, our data suggest inflammation occurs in response to myocyte cellular damage regardless of mode of damage e.g. contractile or chemically induced. This was demonstrated by inflammatory upregulation in myometrium exposed to the tocolytic agents nifedipine and ritodrine, which is not seen in response to ML7. Additionally, the myometrial inflammatory response was enhanced by the infective agent LPS. However, contrary to other proposals, the enhanced inflammatory response of the myometrium did not alter or promote the in-vitro contractile ability of the myometrium or its response to OT. This myometrial transcriptional data therefore suggests that the inflammatory response of labour is associated with contraction, chemical or infection induced myometrial cellular damage, but would not be considered necessary for a contractile response. Our in-vivo study of peripheral changes in the maternal circulation again supported our in-vitro myometrial data. Data showed that the effect of pregnancy at term was limited to increased white cell count driven by a neutrophilia, with no suggestion of leukocyte priming prior to labour. Additionally, term pregnancy is associated with an increase in CRP, an increase in GCSF (corresponding with the neutrophilia) in addition to suppression of the chemokines CCL11 and CCL22. Subsequently, we found that repeated blood samples taken at 2 hourly intervals during term labour induced dramatic changes in inflammatory cells and inflammatory mediators in the maternal circulation. Importantly, these changes occur in a co-ordinated time and contraction dependent manner, with the degree of inflammation associated with the length of time in labour and the degree of myocyte damage as measured by circulating CK and Mb. Our study of the influence of maternal factors on myometrial contractile ability and response to OT examined in-vitro myometrial contractility of 609 myometrial strips from 85 women. We demonstrated that maternal obesity does not impair spontaneous or OT induced myometrial contractions in-vitro. Furthermore, maternal age, ethnicity, parity, previous caesarean delivery,gestation at delivery and birthweight do not influence in-vitro myometrial spontaneous or OT induced contractile activity. This therefore suggests that the observed implication of these maternal and infant factors on parturition in-vivo (high rates of induction of labour, high rates of intrapartum caesarean delivery and post partum haemorrhage) cannot be explained by an effect on myometrial contraction per se. This therefore merits further investigation as to alternative mechanisms to ultimately promote and effective, uncomplicated and safe labour and vaginal delivery for at risk mothers. In summary, this thesis provides evidence that the myometrial contractions of human labour, whether spontaneous or OT induced are capable of inducing a temporal wave of transcriptional changes associated with the processes of inflammation, cellular damage/apoptosis with inhibition of cellular metabolic processes. In addition, maternal peripheral circulating factors mirror the myometrial transcriptional changes. These changes are highly comparable with those seen in response to exercising skeletal muscle, and in this model have been shown to play an important role in muscle repair and remodelling after exercise. Therefore, we would suggest that the inflammatory reaction typically associated with human labour occurs as a non-specific response to contraction induced cellular damage and may play a role in postpartum repair and remodelling of the uterus.

Background: There is a high cellular turnover in the haematopoietic system which necessitates that new cells are continuously produced to replace old and senescent ones. The haematopoietic stem cells and its progenitors meet this requirement. In adults, haematopoietic stem and progenitor cells (HSPCs) generally occupy a unique microenvironment in the bone marrow called the niche. However, recent findings have shown that approximately 0.06% of HSPCs circulate between bone marrow and periphery in steady state. Evidence shows that HSPC express cytokine receptors and pathogen recognition receptors [e.g. Toll-like receptors (TLRs)], which suggest that HSPCs may directly respond to inflammation and infection. The capacity of HSPCs to directly respond to infection is demonstrated in models of bacterial infection using LPS injection that significantly increases the number of circulating HSPCs. However, the underlying mechanism is not clearly understood. As chemokines orchestrate in vivo cellular migration, it was hypothesised that HSPC inducibly express inflammatory chemokine receptors that enable them to respond to circulating chemokines during infection and inflammation. Methods and results: Here, the impact of systemic or peripheral inflammation on HSPC of mice was investigated using LPS injection and topical imiquimod cream/TPA treatment respectively. Using haematopoietic progenitor colony-forming assays, RT-QPCR on isolated progenitors, gene-knockout mice, flow cytometric analysis and in vivo antibody-mediated neutralisation experiments, data are provided showing that HSPC inducibly express chemokine receptors in response to inflammation. Critically, the topical imiquimod inflammation model required functional chemokine receptor 2 (Ccr2) for HSPC mobilisation in contrast to both systemic LPS and topical TPA models, which were Ccr2-independent. Furthermore, dermal inflammation was necessary for imiquimod-mediated HSPC mobilization, as subcutaneously administered imiquimod did not result in significant HSPC mobilization. Conclusion: The data suggest that, in addition to the established CXCR4-CXCL12 axis that regulates homeostatic HSPC trafficking, the inflammatory chemokine-chemokine receptor axes may also be crucial in modulating HSPC functions during infection and inflammation.

D6 is an atypical chemokine receptor related to CCR1-5 that binds to many inflammatory CC chemokines. Experiments using transfected cell lines have shown that upon binding to a chemokine ligand D6 does not trigger cellular signalling pathways, but rather acts to scavenge the bound ligand. It achieves this by constitutively travelling to and from the cell surface via early and recycling endosomes, internalising chemokines bound when it is at the cell surface. Over time, D6 removes a large amount of ligands from the extracellular compartment. In vivo, this scavenging activity is thought to regulate the level of CC chemokines, and thus controls inflammation locally and systemically. Lack of D6 has been shown to result in elevated amounts of bioavailable chemokines, and is associated with over exuberant inflammatory responses. In human, D6 mRNA and protein is highly expressed in trophoblast-derived gestational tissues. The expression of D6 mRNA in the placenta is by far the highest, compared to other solid tissues being studied. The importance of D6 in protecting the offspring has been demonstrated in animals. In pigs, a defect in D6 expression was discovered in placental attachment sites in endometrium from arresting fetuses. In mice, lack of D6 results in an increase in fetal loss after challenge with lipopolysaccharide (LPS) or antiphospolipid autoantibodies (aPL), and an increase in the number of abnormal pups when mouse embryos are transferred into fully allogeneic pseudo-pregnant female recipients. In view of these results suggesting a critical role for D6 in placental mediated complications, the expression and molecular function of D6 in primary human trophoblast cells were studied, as to date in vitro human studies have utilised the choriocarcinoma cell line BeWo or immortalised cell lines engineered to over-express exogenous D6. Secondly the impact of D6 deficiency on placental structure, chemokine expression and leukocyte abundance in mice was examined. Chapter 3 presents the results of experiments on primary human trophoblasts. Protocols for routine primary trophoblast isolation, purification and culture from fresh term placentas were optimised in our laboratory. D6 mRNA was detected in these primary cells. Using Western blotting, immunofluorescence and flow cytometry, D6 was shown to be present predominantly in the intracellular vesicles of the cells. Competition chemokine uptake assays, analysed by flow cytometry, showed that CCL2 was internalised by trophoblasts using D6. Competitive chemokine scavenging assays, analysed by quantitative Western blot, confirmed that D6 was functioning as a chemokine scavenger on primary human trophoblasts and that it progressively removed substantial quantities of chemokine from medium bathing the cells. This is the first set of experiments that confirms D6 is present, and functioning as a chemokine scavenger in primary human cells. Chapter 4 contains the results from the mouse experiments. Even in an unchallenged environment it was shown that, on the DBA-1 genetic background, D6 deficiency in the mother and pups leads to higher rates of stillbirth and neonatal deaths, resulting in a reduction in the number of pups weaned per litter than their WT counterparts. By gestational age E14, pup weight was significantly smaller in the D6 KO mice. Using stereological techniques, the placenta of the D6 KO mice at this gestation was found to have a smaller labyrinthine zone. The volume of the labyrinthine zone was positively correlated with pup/placenta ratio. These phenotypes could be due to a maternal or fetal effect of D6 deficiency. To ascertain the answer to this question, the experiment at E14 was extended by breeding DBA-1 females heterozygous for the deleted D6 allele (D6 HET) with D6 deficient (D6 KO) males. In this model the phenotypes of D6 KO pups and placentas could be compared with their D6 HET siblings that developed in a mother expressing some D6 (i.e. D6 HET). Although there were no differences in pup weight, placental weight and pup/placenta ratio between these two groups, stereology revealed a decrease in labyrinthine zone volume fraction in the D6 KO placentas in comparison to their D6 HET siblings. The observed fetal compromise and placental defect at E14 was not apparent at the later gestational age of E18. Luminex multiplex protein assay showed an elevated level of circulating chemokine CCL2 in the serum of D6 KO pregnant mice in comparison to their WT counterpart, so loss of chemokine regulation could be responsible for the defects observed in D6 deficient placentas. In summary, D6 deficiency results in an increase in perinatal death, a fundamental defect in placental formation (reduced labyrinthine zone) and dysregulation of circulating chemokine levels. Chapter 5 discusses the mechanisms of D6 in regulating placental formation and reproductive outcome and the novel insights that this work provided into placental D6 function. It also describes the design of future experiments to reveal the precise role of D6 in chemokine regulation and cell signalling in reproductive immunology, and discusses how D6 might contribute to pregnancy outcome in humans.

Background: In the past 60 years, the median age of the entire world population has increased and ageing and chronic diseases are now the main medical concerns in the developed world. The identification of early signs of disease pathogenesis is vital for prevention and targeting populations at risk in order to reduce morbidity and mortality. Glycation is well-established as an index of control, or otherwise, and a predictor of end-organ damage, for people with type 2 diabetes. At the beginning of the work for this thesis (2010), evidence was beginning to be raised to suggest that since glycation levels vary considerably, in normoglycaemic, non-diabetic individuals, glycation cannot be solely related to glucose levels and early reports allowed for speculations about a relationship between early glycation and oxidative stress. The aim of this thesis was to establish the relationship between early glycation and oxidative stress in normoglycaemia using techniques from the full breadth of Human Nutrition Research. Methods: In study 1, existing epidemiological data were used to identify relationships between proxies for redox status and early glycation in non-diabetic individuals. One-way ANOVA, Chi-squared and multivariate linear regressions, adjusted for all known confounders were used to explore associations of HbA1c with self-reported smoking status and fruit & vegetables consumptions in the Scottish Health Surveys 2003-2010, among individuals without known diabetes and HbA1c<6.5%. In studies 2 and 3, the associations from epidemiology were explored in mechanistic laboratory studies with high physiological relevance (using physiological concentrations and conditions) to better characterise the effect of oxidative stress and antioxidants on early glycation. In study 2, bovine serum albumin (BSA), reduced BSA (mercaptalbumin) (both 40g/L), and human plasma were incubated with glucose concentrations 0-30 mM for 4 weeks at 37oC. All were tested pre-oxidized for 8 hours prior to glycation with 10nM H202, or continuously exposed to 10nM H2O2 throughout the incubation period. Fructosamine was measured (nitroblue tetrazolium method) at two and four weeks. In study 3, Bovine Serum Albumin (BSA) was pre-treated prior to in vitro glycation: either no treatment (native), pre-oxidised (incubated with 10nM H2O2, for 8 hours) or incubated with a mixture of phenolic acids at physiologically relevant concentrations, for 8 hours). In-vitro glycation was carried out in presence of i) glucose only (0, 5 or 10mM), ii) glucose (0, 5 or 10mM) plus H2O2 (10nM), or iii) glucose (0, 5 or 10mM) plus phenolic acids (10-160nM). Fructosamine was again measured using the nitroblue tetrazolium method. Prior to the experimental study we carried out a systematic literature review of dietary interventions reporting plasma concentrations polyphenol metabolites, to inform the design of a physiologically relevant in-vitro study. In study 4, clinical trial data and biological samples were analysed from a randomised controlled dietary advice trial in obese pregnant women, a group at risk from higher glycation and oxidative stress. Samples and data from the UPBEAT study trial (n=117) were analysed. Plasma fructosamine, plasma sRAGE, urinary Ferric Reducing Ability of Plasma (FRAP), urinary Total Phenol (TP) and urinary Advanced Oxidised Protein Products (AOPPs) were measured at 16-18+6 and 27-28+6 weeks gestation. Dietary recalls were used to calculate fruit and vegetable and polyphenol intake at the same timepoints. Data were analysed to identify associations between dietary variables and biochemical markers, as well as their relationships with diagnosis of complications. Associations between maternal variables and neonatal anthropometry were also investigated. Results: In study 1, HbA1c was higher in smokers by 0.25 SDs (0.08%), and 0.38 SDs higher (0.14%) in heavy smokers (>20cigarettes/day) than non-smokers (p<0.001 both). Smokers were twice as likely to have HbA1c in the ‘pre-diabetic’ range (5.7-6.4%) (p<0.001, adj.model). Pre-diabetes and low grade inflammation did not affect the associations. For every extra 80g vegetable portion consumed, HbA1c was 0.03 SDs (0.01%) lower (p=0.02), but fruit consumption did not impact on HbA1c, within the low range of consumptions in this population. In study 2, oxidized BSA (both pre-oxidised and continuously exposed to H2O2) was more readily glycated than native BSA at all glucose concentrations (p=0.03). Moreover, only oxidized BSA was glycated at physiological glucose concentration (5mM) compared to glucose-free control (glycation increased by 35% compared to native albumin p<0.05). Both 5mM and 10mM glucose led to higher glycation when mercaptalbumin was oxidised than un-oxidised (p<0.05). Fructosamine concentration in human plasma was also significantly higher when oxidized and exposed to 5mM glucose, compared to non-oxidised plasma (p=0.03). The interaction between glucose concentration and oxidation was found to be significant in all protein models (p<0.05). In study 3, the presence of six phenolic acids with BSA during in-vitro glycation did not lower fructosamine formation. However, when BSA was pre-incubated with phenolic acids, significantly lower concentration of fructosamine was detected under glycoxidative conditions (glucose 5 or 10mM plus H2O2 10nM) (p<0.001 vs. native BSA). In study 4, women in the lowest quartile of total polyphenol intake had 8% greater fructosamine levels compared to those in the top quartile. Total polyphenol intake was negatively correlated with sRAGE levels. Diagnosis of severe preeclampsia was associated with elevated AOPPs. Maternal polyphenol intake was positively correlated with birth weight, while maternal glycoxidation showed the opposite relationship. Conclusions: Study 1 added evidence to relate smoking (an oxidative stress proxy) to protein glycation in normoglycaemic subjects. This association has implications for individuals exposed to ROS and for epidemiological interpretation of HbA1c and its clinical usefulness. Study 2 offered a mechanistic background to the previously shown epidemiological association. This study demonstrated for the first time albumin glycation in-vitro, using physiological concentrations of albumin, glucose and hydrogen peroxide. These results identified low-grade oxidative stress as a key element early in the glycation process, especially in glucose concentrations relative to normoglycaemia. Furthering those findings, study 3 showed that protein-phenolic acid interactions are important regulators of protein glycation. Together those studies highlighted that protein pre-treatment, either with oxidants or phenolic acids, is an important regulator of subsequent glycation in a physiologically relevant system. An important outcome of those studies is that high quality in-vitro studies under conditions closer to physiology are feasible and should be employed more frequently. Finally, study 4 demonstrated an association between polyphenol intake and glycation during pregnancy, with an impact on neonatal outcome measures. Maternal glycoxidation is a promising marker of pre-eclampsia and neonatal anthropometry and could be modulated by maternal lifestyle and dietary habits. Overall, the results of this thesis implicate that drivers of redox status have the capacity to modulate protein glycation in normoglycaemia. These results challenge the assumption that glycation levels are solely dependent on circulating glucose levels and suggest a useful application of glycation outside the field of diabetes.

The ability to quantify kinematic parameters of the knee is crucial in understanding normal biomechanics, recognising the presence of pathology and its severity, planning treatment and evaluation of outcomes. Current methods of quantifying lower limb kinematics remain limited in allowing accurate dynamic assessment. Computer assisted surgery systems have been validated in quantifying kinematic parameters, but remain limited to the operative setting. Recently, image-free computer assisted surgery technology has been adapted for non-invasive use and validated in terms of repeatability in measuring coronal and sagittal femorotibial mechanical alignment in extension. The aim of this thesis was to develop and implement a set of validation protocols to quantify the reliability, precision and accuracy of this non-invasive technology in quantifying lower limb coronal and sagittal femorotibial mechanical alignment, anteroposterior and rotatory laxity of the knee by comparison with a validated, commercially available image-free computer assisted surgery system. Pilot study confirmed feasibility of further experimental work and revealed that the noninvasive method measured with satisfactory precision and accuracy: coronal mechanical femorotibial alignment (MFTA) from extension to 30° knee flexion, anteroposterior translation in extension and tibial rotatory laxity during flexion. Further experiments using 12 fresh cadaveric limbs revealed that the non-invasive method gave satisfactory precision and agreement with the invasive system measuring MFTA without stress from extension to 40° knee flexion, and with 15Nm coronal stress from extension to 30° knee flexion. Using 100N of anterior force on the tibia, the non-invasive system was acceptably precise and accurate in measuring sagittal tibial displacement from extension to 40° flexion. End of range apprehension, such as has been proven repeatable in measuring tibial rotatory laxity was used and the non-invasive method gave superior 3 precision and accuracy to most reported non-invasive devices in quantifying tibial rotatory range of motion. Non-invasive optical tracking systems provide a means to quantify important kinematic parameters in health and disease, and could allow standardisation of knee examination increasing communicability and translation of findings from the out-patient to operative setting. This technology therefore could allow restoration of individual specific kinematics in knee arthroplasty and soft-tissue reconstruction.

Phenomenal rise in prevalence of obesity and its complications has made it imperative to tackle the issue on a war footing, especially given the failure of current life style and medical approaches. Clearly, alternate means of treating obesity need to be explored. In contrast to white adipose tissue (WAT), which stores excess energy, brown adipose tissue (BAT) dissipates chemical energy in the form of heat by uncoupling oxidative phosphorylation from electron transport chain, to maintain body temperature homeostasis. Recent revelation of functionality of BAT in adult humans provides an excellent opportunity of stimulating it to increase energy expenditure, in turn causing weight loss alongside improving lipid and glucose homeostasis. This thesis sought to investigate the physiological nature of brown fat, by exploring the environmental, biophysical and behavioural factors that can activate BAT. ¹⁸Fluoro-labelled-2-deoxyglucose Positron Emission Tomography (18F-FDG PET) is currently the gold standard and the most sensitive method to study BAT and its function. These studies concluded that younger-age, lower body mass index, female sex and cooler outdoor temperatures are strong determinant factors of BAT prevalence, activity and mass. Interestingly, modest elevation of thyroid hormones in a sustained iatrogenically created thyrotoxic state did not influence any of the BAT indices, contrary to conventional wisdom of strong stimulation, thus highlighting the complexity of BAT metabolism. Arguably, BAT has a role in diet-induced thermogenesis. Manipulation of diet-induced thermogenesis by prolonging meal duration to 40 minutes resulted in excess postprandial energy expenditure loss than shorter meal duration of 10 minutes. However, prolonged meal duration had weakly positive effect on metabolic biochemical markers and no influence on pancreatic and gut hormones relevant to appetite. These studies advocate life style and behavioural public health messages of lowering thermostat in living spaces and chewing the food adequately in order to obtain potential metabolic benefits. As a follow-up of exploring BAT's physiology, a successful attempt at characterising BAT's anatomy was made through novel imaging technique of Iterative Decomposition of Echo Asymmetry and Least Squares Estimation (IDEAL) Magnetic Resonance Imaging. The first ever non-PET imaging demonstration of adult human BAT using IDEAL MRI was achieved with immunohistochemical confirmation, and provided proof of concept for developing MR as a safe, non-radiation exposure imaging biomarker of BAT. In summary, this thesis provided useful insights into environmental, anthropometrical, behavioural, and hormonal factors regulating BAT, whilst also providing a proof of principle of an imaging tool to visualise full extent of both metabolically active and inactive BAT, aiding future pursuits of BAT therapeutics to combat the global obesity epidemic.

The Liver X receptors, LXRα and LXRβ, belong to the superfamily of nuclear receptor ligand activated transcription factors. LXRs have been well characterised in the context of metabolism through their ability to induce reverse cholesterol transport leading to the excretion of cholesterol from the body. More recently, LXRs have been shown to play a role in inflammation in which they are often ascribed an anti-inflammatory effect. Rheumatoid arthritis (RA) is a chronic auto-immune condition manifest as inflammation of the diarthrodial joints predominantly in the hands and feet. It is now well recognised that RA is not just a local but rather a systemic disease that is associated with several co-morbidities including atherosclerosis. A major focus in the field of rheumatology is now to understand how cardiovascular disease might contribute to the pathogenesis of RA and vice versa and thereby connect metabolism with inflammation. Hypothesis: Since LXRs are central to the maintenance of a cholesterol homeostasis and have been shown to regulate inflammation we hypothesised that LXR agonists would be beneficial for the treatment of RA. Methods & Results: Treatment of male DBA1 mice with GW3965 or T1317 in the murine model of collagen-induced arthritis dramatically increased the onset and severity of disease. Exacerbation of disease severity was characterised by increased concentrations of multiple serum pro-inflammatory cytokines and chemokines, increased numbers of lymph node derived Th1 and Th17 cells and elevated titres of anti-collagen auto-antibodies. The effect of LXR agonist administration was mediated specifically by LXRs as the severity of disease was not altered in LXR null mice treated with GW3965. Furthermore, activation of LXRs in primary human monocytes potentiated the secretion of multiple proinflammatory cytokines in response to stimulation with LPS. Similarly, the concentration of multiple pro-inflammatory cytokines was also increased in an in vitro model of synovitis. Conclusion: These studies demonstrate a novel pro-inflammatory role of LXR activation in the context of arthritis. Furthermore, these results suggest that the development of LXR agonists as a therapy for metabolic disorders should be done so with caution.

In summary, the current thesis showed that, during the systemic inflammatory response, intracellular vitamin concentrations may be more accurate than plasma concentrations as indicators of vitamin status in patients with critical illness.