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1
Kallis, Constantinos. "Construction and assessment of risk models in medicine." Thesis, University of Warwick, 2005. http://wrap.warwick.ac.uk/79266/.
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This thesis investigates the application of classical and contemporary statistical methods in medical research attempting to bridge the gap between statistics and clinical medicine. The importance of using simple and advanced statistical methods in constructing and assessing risk models in medicine will be demonstrated by empirical studies related to vascular complications: namely abdominal aortic aneurysm and diabetic retinopathy. First, data preprocessing and preliminary statistical analysis are examined and their application is investigated using data on abdominal aortic aneurysm. We illustrate that when dealing with missing data, the co-operation between statisticians and clinicians is necessary. Also, we show advantages and disadvantages of exploratory analysis. Second, we describe and compare classification models for AAA selective screening. Tow logistic regression models are proposed. We also show that it is important to assess the performance of classifiers by cross-validation and bootstrapping. We also examine models that include other definitions of abnormality, weighted classification and multiple class models. Third, we consider the application of graphical models. We look at different types of graphical models that can be used for classification and for identifying the underlying data structure. The use of Naïve Bayes classifier (NBC) is shown and subsequently we illustrate the Occam’s window model selection in a statistical package for Mixed Interactions Modelling (MIM). The EM-algorithm and multiple imputation method are used to deal with inconsistent entries in the dataset. Finally, modelling mixture of Normal components is investigated by graphical modelling and compared with an alternative minimisation procedure. Finally, we examine risk factors of diabetic sight threating retinopathy (STR). We show the complexity of data preparation and preliminary analysis as well as the importance of using the clinicians’ opinion on selecting appropriate variables. Blood pressure measurements have been examined as predictors of STR. The fundamental role of imputation and its influence on the conclusions of the study are demonstrated. From this study, we conclude that the application of statistics in medicine is an optimisation procedure where both the statistical and the clinical validity need to be taken into account. Also, the combination of simple and advanced methods should be used as it provides additional information. Data, software and time limitations should be considered before and during statistical analysis and appropriate modifications might be implemented to avoid compromising the quality of the study. Finally, medical research should be regarded for statisticians and clinicians as part of a learning process.
2
Carlin, Christopher M. "The effects of statins on hypoxia-induced proliferation and cell signalling pathways in pulmonary artery fibroblasts." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1484/.
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Chronic hypoxia, in animals and man, results in remodelling of the pulmonary vasculature with consequent pulmonary hypertension. The pulmonary artery fibroblast (PAF) has been shown to play an early and important role in hypoxia-induced pulmonary vascular remodelling. In acute and chronic hypoxia there is excess proliferation of PAFs. Morevoer, it is likely that cell-cell interactions between hypoxia-stimulated PAFs and other vascular cells – particularly smooth muscle cells - initiates and progresses the changes that occur in pulmonary vascular remodelling in the other vessel compartments. Although hypoxic proliferation of PAFs has been shown to be circulation specific and dependant on phosphorylation of p38 mitogen-activated protein (MAP) kinase, the cell signalling pathway(s)underlying this are incompletely characterised. Hypoxic activation of PAFs is a potential therapeutic target but, as p38 MAP kinase inhibitors are not established for clinical use, work was proposed to better characterise this pathway and identify agent(s) which may inhibit p38 MAPK indirectly. The HMG-CoA reductase inhibitor simvastatin was recently shown to inhibit hypoxic pulmonary vascular remodelling in rats, but the applicability of this finding to clinical practice is incompletely established and the mechanism of action of the statin is unclear. Statins have been shown to influence MAP kinase pathways in other cell types and, as their modes of action are well established, they can be used to interrogate uncharacterised upstream cell signalling pathways. On this basis, the aims of this study were firstly to determine whether statins had a therapeutically useful inhibitory effect on hypoxia-induced, p38 MAP kinase-mediated PAF proliferation. A second aim was to exploit the known effects of statins to better characterise hypoxic cell signalling upstream of p38 MAP kinase in PAFs. Lastly, comparison of the effects of statins with established pulmonary hypertension therapeutics and a preliminary assessment – also using statins as an experimental tool - of cell-cell interactions between PAFs and pulmonary artery smooth muscle cells (PASMCs) was proposed. 1μM of fluvastatin was found to selectively inhibit acute and chronic hypoxia-induced p38 MAP kinase phosphorylation and proliferation in rat PAFs. At this dose, fluvastatin had no effect on serum-induced proliferation in PAFs, no effect on systemic adventitial fibroblast proliferation, and no effect on the phosphorylation status of other MAP kinases. Selective use of mediators and inhibitors related to the HMG-CoA pathway indicated that a geranylgeranylated protein, probably Rac1, had an obligatory role upstream of p38 MAPK, in this signalling pathway. Co-culture and conditioned media experiments with bovine PAFs and PASMCs demonstrated the release of PASMC mitogens from hypoxic PAFs. 1μM fluvastatin and the p38 MAP kinase inhibitor SB203580 selectively blocked the hypoxic PAF-PASMC interaction. Results with hypoxic PAF proliferation with the prostacyclin analogue treprostinil, the phosphodiesterase-5 inhibitor sildenafil and the endothelin-1 antagonist bosentan were negative. Bosentan, however, inhibited the hypoxic PAF-PASMC interaction, suggesting endothelin-1 release by hypoxic PAFs, with proproliferative effects on PASMCs. The results reported in this thesis provide new information on hypoxic signalling,PAF proliferation and PAF cell-cell interactions in hypoxic states. A circulation and stimulus specific anti-proliferative effect of fluvastatin on PAFs was identified and this may be of clinical relevance in hypoxia-associated pulmonary hypertension.
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Neisius, Ulf. "Proteomic, circulating and functional biomarkers of cardiovascular disease." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4740/.
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Cardiovascular disease is the leading cause of morbidity and mortality in the Western world, mainly through cerebrovascular and coronary artery related events. Cardiovascular disease is a chronic progressive disease with different stages. These stages can be assessed by a variety of biomarkers. Biomarker quantification can be used for different purposes: screening, prediction of disease recurrence, therapeutic monitoring, diagnosis and prognostication. Noninvasive, inexpensive diagnostic tests currently applied in clinical practice have a relative high rate of false positive and false negative results. Therefore further refinement of the diagnostic process could improve clinical care. Regarding prognostication the need for improvement also remains as current risk models only predict a small quantity of occurring cardiovascular events. The concept of the cardiovascular continuum postulates that cardiovascular disease consists of a chain of events, is initiated by numerous cardiovascular risk factors and subsequently progresses through pathophysiological processes, ultimately leading to end-stage heart failure. For that reason cardiovascular diseases are chronic progressive conditions and can be divided into different stages, such as early tissue dysfunction or subclinical atherosclerosis prior to development of clinically overt disease. Biomarkers suitable for prognostication and diagnosis can differ at each stage. The general aim of this thesis was therefore the investigation of a variety of biomarkers in diagnosis and prediction of cardiovascular disease at different stages of the cardiovascular continuum, as covered by three different study cohorts contributing to this thesis. This included several approaches: the comparison of central and peripheral pulse pressure in middle aged hypertensive patients in regards of their prognostic potential; the application of established circulating, functional and structural biomarkers to the diagnostic process of coronary artery disease in stable angina patients; the development/refinement of a urinary proteomic biomarker for coronary artery disease and the examination of its diagnostic potential in stable angina patients. Biomarkers successful in the diagnosis of coronary artery disease were included in multiple biomarker models. Aside from biomarker development for the general population, investigations of specific cohorts, such as patients with certain diseases and belonging to certain age groups or sharing specific biochemical features provided advances in the past. To estimate the potential of a biomarker in risk prediction association studies with surrogate biomarkers are applicable. We collected a cohort of middle-aged hypertensive patients to assess if central pulse pressure, derived from non-invasive assessment of arterial stiffness, could improve risk prediction. Central pulse pressure has been previously shown to have prognostic value in populations with end-stage renal failure, coronary artery disease and high prevalence of diabetes mellitus. Considering the prognostic information of peripheral pulse pressure in the elderly, the hypothesis that central pulse pressure could improve risk prediction is comprehensive and was investigated as part of this thesis. This was accomplished by comparing the strength of correlation between central or peripheral pulse pressure and these surrogate biomarkers. When compared to peripheral pulse pressure, central pulse pressure had stronger associations with aortic pulse wave velocity, carotid intima-media thickness, and left ventricular mass index, but equal association with the albumin:creatinine ratio. In contrast, after adjustment for age, mean arterial pressure, heart rate and hypertension status there was no significant difference between central and peripheral pulse pressure for prediction of listed surrogate biomarkers in multivariate analysis. These results suggested that central pulse pressure is unlikely to provide more prognostic information than peripheral pulse pressure in middle-aged hypertensive patients. The diagnosis of coronary artery disease is clinically relevant in symptomatic patients, either acute or stable. The diagnosis of stable flow limiting coronary artery disease is especially challenging as non-cardiac as well as other cardiac conditions can mimic symptoms. Non-invasive diagnostic tools have either moderate sensitivities or specificities, or are not widely available. Therefore new biomarkers for the diagnosis of flow limiting coronary artery disease have the potential to improve current diagnostic strategies. This could be accomplished adjacent to existing biomarkers or by replacement of such, due to cost effectiveness, better discriminatory etc. As part of this thesis, a biomarker identification and validation study was conducted into urinary proteomics of coronary artery disease. First we tried to replicate a study conducted by our research group in the past. Therein, an established coronary artery disease specific polypeptide pattern was unable to differentiate between patients with severe coronary artery disease and healthy controls despite strong cohort similarities to the original study. We therefore recalibrated the urinary polypeptide pattern using an enlarged biomarker discovery cohort and adjusted the pattern for lipid lowering and angiotensin converting enzyme inhibitor treatment effects. We calculated a score from the resulting polypeptide pattern, which identified coronary artery disease patients with a sensitivity of 79% and a specificity of 88% in a biomarker validation cohort. As the next step of biomarker development we performed a diagnostic validation study. The investigated clinical cohort consisted of stable angina patients with or without coronary artery disease. The new polypeptide pattern score was unable to differentiate between these two groups. The score however correlated strongly with coronary artery disease extent as measured by the Gensini score, implying that urinary proteomics in the diagnosis of coronary artery disease is promising, yet requires further effort before clinical employment. In addition to the urinary proteomic biomarker development second diagnostic approach was selected. As coronary artery disease is a complex chronic disease, the combination of different biomarkers should result in a better discrimination between stable angina patients with or without coronary artery disease. This approach attempts to position the individual as precisely as possible on the cardiovascular continuum including serologic, functional vascular and imaging biomarkers of subclinical atherosclerosis. Serologic markers thereby present a plasma proteomic approach covering pathophysiological processes with known correlation or causative for coronary artery disease. Functional and structural changes of the peripheral vasculature resemble the coronary artery system. We investigated circulating biomarkers and vascular biomarkers separately. A variety of circulating biomarkers differentiated patients with severe coronary artery disease from healthy control subjects. When patients with stable angina and with or without coronary artery disease as diagnosed by coronary angiography were investigated no statistically significant differences could be detected for circulating biomarkers. In the same study a microvascular biomarker, the reactive hyperaemia index, and a macrovascular biomarker, the carotide plaque score, were able to differentiated between cases and controls. Both markers either added separately or together improved the risk classification of exercise treadmill test results. This suggests that a multiple biomarker approach in the diagnosis of coronary artery disease in stable angina patients could be successful. Different aspects of the cardiovascular continuum can be applied to diagnosis and prognostication of cardiovascular disease.
4
Martin, Steven Carl. "Homocysteine and vascular disease." Thesis, University of Glasgow, 2003. http://theses.gla.ac.uk/30939/.
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Cardiovascular disease is multifactorial. The main risk factors for developing cardiovascular disease (age, sex, smoking, diabetes, hyperlipidaemia and hypertension) do not explain its development in everyone. New risk factors are continually being sought in order to better understand and treat the disease process. In recent years homocysteine has been proposed as a risk factor for the development of premature cardiovascular disease as a consequence of the accelerated arterial and venous thrombotic disease seen in homocystinuria as a result of a single gene defect. This theory has been difficult to test because patients with premature cardiovascular disease are thankfully rare and because of the difficulties in measuring homocysteine itself. We propose that, if homocysteine is a causative risk factor for atherothrombosis, it will be involved in the development of cardiovascular disease regardless of age and have therefore studied affected patients from routine hospital clinics. Homocysteine analysis has become easier over the past decade with the development of HPLC methods utilising fluorescent detection, but these methods involve toxic chemicals and suffer from high background fluoresence. I have developed an HPLC method more suited to a routine hospital laboratory utilising coulometric detection for measuring plasma total homocysteine and used it to investigate the relationship between homocysteine levels and both micro- and macro-vascular atherothrombotic disease.
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Stevenson, Judith L. "An investigation of attitudes and attentional biases in trichotillomania." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/31012/.
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Trichotillomania (TTM) is a body focussed repetitive behaviour (BFRB) characterised by the repetitive pulling out of one’s hair. It is a moderately new disorder having only been classified in 1987 and it is under-researched relative to other psychological disorders. This thesis investigates TTM by presenting a series of experiments designed to further understand attitudes towards, and attentional biases in, TTM. The experiments in this thesis address 3 central issues: stigmatising attitudes towards TTM; attentional bias pertaining to the experience of shame in TTM; and attentional bias towards hair-related stimuli in TTM. Experiment 1 investigated differences in ratings of stigma towards perceived controllable (TTM, compulsive skin-picking) and perceived uncontrollable (alopecia, psoriasis) hair-loss and skin-lesioning conditions in a TTM and control group. The main findings indicated that stigma ratings varied as a function of group: the public rated perceived controllable conditions with higher stigma than perceived uncontrollable conditions while TTM participants rated these conditions equally. Experiment 2 used a modified emotional Stroop task using shame-related words to investigate the affective correlate of shame in individuals with TTM and a control group. TTMs did not demonstrate different response latencies to shame-related words, relative to other word types or the control group, indicating no evidence of attentional bias towards shame-related linguistic stimuli. Experiments 3, 4 and 5 focussed specifically on disorder-stimuli (i.e., hair-related) linguistic stimuli in a series of lexical paradigms. Experiment 3 was a lexical decision task and Experiment 4 was a modified Stroop task: these paradigms investigated response latencies towards hair-related words in TTMs and a control group. The main findings for both experiments showed that TTMs do not demonstrate an attentional bias towards hair-related words, relative to other word types and the control group. Experiment 5 investigated higher-level judgements of hair-related words in a word rating task. The findings revealed a group-by-word-type interaction for arousal ratings: TTMs rated hair-related words higher in arousal than body image and neutral words, and these ratings were higher than those of the control group for hair-related words. No group-by-word-type interaction for valence ratings was found. This indicates that TTMs rate hair-related words as more arousing but not more positive or negative, than other word types, relative to individuals without TTM. Finally, Experiment 6 utilised a modified dot probe paradigm to investigate attentional bias towards hair-related images. Our findings showed that TTMs disengage more slowly from hair-related images at a longer stimulus duration compared to neutral images, relative to control participants. This evidence is consistent with an attentional bias characterised by maintained attention towards hair-related stimuli in individuals with TTM. In conclusion, this thesis has presented evidence indicating that TTM (and other BFRBs) are associated with higher public stigma ratings than comparable perceived uncontrollable conditions. Results have also shown an attentional bias towards hair-related images but not words. This represents an important contribution towards the understanding of the processing of disorder-related stimuli in TTM. This may have implications for the maintenance mechanisms potentially involved in the hair-pulling condition.
6
Shaw, Aaron Robert James. "Sleep, anxiety and the effects on cognition." Thesis, University of Warwick, 2018. http://wrap.warwick.ac.uk/114458/.
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Poor sleep and high levels of anxiety have a detrimental effect on cognitive functioning. However, very little is known about what cognitive functions are affected by poor sleep or high levels of anxiety and if some are more affected than others. This thesis informs the understanding of poor sleep and anxiety with a focus on generalised anxiety disorder and how they affect specific cognitive functioning namely Attention and Working Memory. Chapter one is a systematic literature review of the qualitative research exploring how sleep deprivation impacts on the cognitive functioning of people with Autistic Spectrum Conditions (ASC) and the principal challenges associated with trying to study the impact of sleep deprivation in people with ASC. Following both database and manual searches, fifteen studies were included and reviewed. The review highlights the suggestions that poor sleep has a detrimental effect on the cognitive functioning of people with ASC. Also, the use of objective and subjective measures of sleep was discussed to help in the early detection of these problems and considerations of carers and families was reviewed. Future research/clinical implications are discussed. Chapter two is a quantitative research study that investigated the combined effects of GAD and poor sleep on Attention and Working Memory. Sleep quality and quantity were assessed using subjective and objective measures of sleep. Attention and Working Memory was measured using various neuropsychological measures. Groups were compared for differences in cognitive scores using a non-parametric test. Relationships between GAD-7 scores, sleep quality/quantity and cognition scores were investigated using correlation analyses. Implications for future research and clinical implications are discussed. Chapter three is a reflective account, exploring the role of reflexivity in personal and professional development during the research process.
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Spooner, Joshua. "People's experiences of living with severe health conditions." Thesis, University of Warwick, 2018. http://wrap.warwick.ac.uk/114471/.
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Treating people living with severe health conditions has, and always will be, a fundamental part of the National Health Service. Given the complex nature of conditions such as Huntington's Disease and Cancer, research exploring the impact severe health conditions can have on those affected is of paramount importance. Chapter one is a systematic review utilising a meta-ethnographic approach to explore qualitative research portraying people's experiences of genetic testing for Huntington's Disease (HD). Electronic databases cataloguing relevant research were searched which, combined with manual searches, resulted in eleven studies suitable for inclusion. Three meta-themes were identified, highlighting the complex and individual nature of undergoing genetic testing, together with the potential emotional and behavioural consequences. The implications of such findings, together with clinical recommendations are considered. There is a dearth of research exploring what it is like to live with cancer as a young person in the United Kingdom. Chapter two is a qualitative research study that explored the lived experiences of young people (13-24 years) who had recently been diagnosed with cancer. Utilising an interpretative phenomenological approach, emergent findings related to the adversarial nature of being diagnosed with cancer, with young people speaking to the unjust nature of battling this disease at such a youthful age, questioning their identity and having to navigate a new, and at times, uncertain world. The clinical and service implications of these findings are discussed, alongside areas of future research. Chapter three represents the author's reflective account of conducting this research. From exploring initial motivations, to evaluating the role of "insider" and "outsider" perspectives, the author explores the reciprocal nature of conducting qualitative research, particularly in relation to the mutuality felt between himself and his participants.
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Eddowes, Peter John. "The role of MRI in stratifying and evaluating chronic liver disease." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8126/.
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Chronic liver disease is a highly prevalent condition associated with significant morbidity and mortality. There is need for clinicians to stratify chronic liver disease and for researchers to define meaningful study endpoints. Currently this is often reliant on liver biopsy histology, which is known to be a flawed gold standard. There is a need to develop novel, non-invasive techniques for the evaluation of chronic liver disease that are accurate and reliable. In this thesis I have demonstrated that multiparametric MRI can stage hepatic fibrosis in an unselected cohort with performance comparable to existing non-invasive fibrosis markers. The assessment of fibrosis is however confounded by inflammation. The sensitivity of multiparametric MRI to inflammation allows the differentiation of simple steatosis and NASH but in a non-alcoholic fatty liver disease (NAFLD) cohort, multiparametric MRI fails to predict fibrosis stage. Evaluating NAFLD with magnetic resonance spectroscopy has shown that this technique is feasible and that lipidomic differences can be demonstrated in patients with NAFLD. Exploring the role of multiparametric MRI in primary sclerosing cholangitis (PSC) has demonstrated a characteristic pattern in the distribution of corrected Tl in PSC suggesting that multiparametric MRI may have a role in its diagnosis and evaluation.
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Redgrave, Liam Stephen. "The role of supercoiling in altering chromosome structure, gene expression and antibiotic resistance in bacteria." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7912/.
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Antibiotic resistance is a major problem estimated to cost $100 trillion and cause 10 million deaths per year by 2050. Despite novel molecules targeting Gram-positive bacteria, there are no new antibiotics active against Gram-negatives. To prolong use of current drugs, we need to understand mechanisms of resistance to inform prescribing practices and drug discovery. Quinolone resistance is primarily conferred by mutations in the target loci: DNA gyrase (gyrA) and topoisomerase IV. Quinolone resistance arising from gyrA mutations has also been shown to confer a low level of protection against a range of non-quinolone drugs. This thesis investigated the hypotheses that altered supercoiling levels, resulting from gyrA mutations, alter expression of stress response genes and confer a generic protective effect against other antibiotics and chemicals. The effects of equivalent gyrA mutations in Salmonella and E. coli upon supercoiling were analysed. Both GyrA Ser83Phe and GyrA Asp87Gly substitutions resulted in altered topoisomer profiles, although these were different between the species. When exposed to stresses, Salmonella gyrA mutants maintain supercoiling in a relatively fixed manner, providing a degree of antimicrobial protection but possibly limiting flexibility in response to environmental change. Fluorescent reporter assays showed a modest elevation of stress responses in Salmonella GyrA Asp87Gly cells, but highly upregulated stress responses in E. coli GyrA Asp87Gly cells. This correlated with a competitive fitness benefit of E. coli GyrA Asp87Gly cells vs the parent in the presence of low levels of triclosan. The elevated stress responses likely result from supercoiling-induced changes in promoter accessibility, and are probably responsible for the generic protective effect gyrA mutation confers against other chemicals and antibiotics. Non-quinolone antimicrobials can provide a selective pressure that favours gyrA mutants, although this is highly dependent on condition and species.
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Dinsdale, Robert Jonathon. "Production and impaired regulation of neutrophil extracellular traps following severe thermal injury, implications for sepsis and multiple organ failure." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7958/.
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Advancements in burn care have improved immediate outcome, however, the prevalence of sepsis and multiple organ failure (MOF) remain significant. Although well characterised the mechanisms responsible for the pathogenesis of MOF and increased propensity to infection are poorly understood. Neutrophil extracellular traps (NETs) provide protection against invading pathogens but also contribute to thrombosis. Sepsis is required for NET generation following severe thermal injury. Quantification of circulating NET biomarkers shows good discriminatory power for diagnosis of sepsis. Interestingly, neutrophils isolated from 24 patients with severe thermal injuries, ≥ 15% total body surface area, had a significantly reduced ability to form NETs ex vivo, potentially mediated by phenotypical changes of neutrophils and inhibitory effects of formyl peptides. This thesis identified a major biological mechanism driving MOF after severe thermal injury, namely the compromise to the actin scavenging system which leads to reduced DNAse activity and a build-up of circulating DNA. Preliminary analysis suggests that DNAse activity can be restored by prehospital use of fresh frozen plasma following major trauma. Thus, administration of blood products or manipulation of the actin scavenging system is a potential therapeutic target. This thesis has identified a number of novel mechanisms responsible for the regulation of NETs following severe thermal injuries and their implications for sepsis and MOF.
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Ward, Lewis Stuart Corey. "Interactions of mesenchymal stromal cells with their microenvironment." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8278/.
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Mesenchymal stromal cells (MSC) suppress the inflammatory infiltrate through crosstalk with neighbouring endothelium. However, this response is lost at chronic inflammatory sites where stromal cells instead support leukocyte recruitment and upregulate expression of podoplanin. The mechanism and function by which this inflammatory phenotype is established is unknown. We hypothesise that MSC modulation of endothelium is also altered by exposure to inflammatory cytokines, and that expression of podoplanin confers an invasive phenotype, enabling the interaction of these perivascular MSC with circulating platelets. MSC resisted functional transformation during acute or prolonged exposure to tumour necrosis factor alpha, instead maintaining their ability to suppress neutrophil recruitment in a flow-based assay. Expression of podoplanin promoted MSC migration through Ras-related C3 botulinum toxin substrate dependent signalling, enabling perivascular MSC to interact with cells confined to the circulation. Indeed, podoplanin induced the activation of platelets from flow through MSC protrusions in the endothelial lining. The retention of MSC suppressive function under inflammatory conditions supports their use in equivalent environments for therapy. However, the implications of platelet CLEC-2 activation by its ligand, podoplanin on inflamed stroma have yet to be elucidated and warrant further investigation, with specific focus drawn to the pathophysiology of thromboinflammation and associated disorders.
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Dominguez, Medina Carmen Coral. "Investigation of how antibody to the outer membrane porin D from Salmonella typhimurium binds and protects against infection." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8572/.
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The induction of specific-antibody that targets the surface of a pathogen or its secreted components is the basis of immunological memory to natural infection and vaccination. This antibody, induced after natural infection or vaccination, saves millions of lives every year. The few vaccines against Gram-negative bacteria either target one antigen, the surface capsular polysaccharides, or are complex vaccines involving the whole organism or complex mixtures of multiple antigens. In this project, we studied how antibody binds to the Salmonella outer membrane porin D (STm-OmpD) on the bacterial surface and why it is protective. Immunisation with STmOmpD provides serovar-specific protection because: 1) lgG can access a single epitope, which is under selective pressure; 2) lgG can access the bacterial surface in the "footprint" made by the OmpD trimer; and 3) Lipopolysaccharide (LPS) 0-antigen (0-Ag) influences the access of lgG to epitopes. Further, protection after immunisation with STm-OmpD is detectable by 4 hours after infection and requires GR1+ cells, IFNg, and Th1 responses for optimal protection, but not lgG2a/c. These data provide insights into how antibody to the Gramnegative bacterial surface can help protect against infection and will aid in the optimisation of subunit vaccines targeting Salmonella.
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Redzuan, Adyani Md. "Sodium-dietary intake, awareness and clinical outcomes in treated hypertensive patients." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/4418/.
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McElroy, Daniel. "Elucidating the functions of fibroblast growth factor 9 in multiple sclerosis." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30798/.
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Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. In around 85% of cases, the disease progresses through two distinct stages: relapsing-remitting MS (RRMS) is driven by repeated bouts of demyelination caused by autoimmune inflammation; and progressive MS, in which inflammation gives way to neurodegenerative processes that lead to axonal loss and the steady accumulation of disability. There is no cure for MS and the majority of disease-slowing treatments target the immune response in RRMS. These interventions are ineffective in progressive MS and other treatment options are extremely limited. Understanding the mechanisms underlying neurodegeneration in MS is critically important to developing therapeutics for progressive disease. Fibroblast growth factor 9 (FGF9) has recently been implicated in the pathogenesis of MS. FGF9 inhibits myelination and promotes the production of inflammatory chemokines. This led to the hypothesis that FGF9 is involved in remyelination failure and may promote neurodegeneration via tissue remodelling and inflammatory pathways. FGF signaling is complex and the findings in MS raised many questions: what cells respond to FGF9 in MS? Why is FGF9 expression induced in the first place? Can FGF9 cause demyelination as well as inhibit myelination? This thesis has focused on the roles of FGF9 in MS and tried to answer these questions. Through in vitro models, astrocytes, oligodendrocytes, and macrophages were shown to express feedback inhibitors of FGF signaling when treated with FGF9. Astrocytes produced FGF9 in response to hypoxic stress, macrophages expressed FGF9 when polarized towards an anti-inflammatory phenotype, suggesting hypoxia, and repair processes may drive FGF9 expression in the CNS. FGF9 did not cause demyelination in vitro but over-expression in vivo induced severe demyelination over the course of several months. Oligodendrocytes exposed to FGF9 failed to differentiate properly when the factor was removed which led to aberrant myelination. Long-term treatment with FGF9 induced axonal pathology, potentially via deficits in axon-transport. Over-expression of FGF9 in rat cortex also produced an axonal pathology, which suggests chronic exposure is detrimental to neurons. Together, these findings indicate that increased levels of FGF9 are detrimental to myelination and neurons in the CNS. Demyelination, and axonal pathology are hallmarks of MS and these studies provide evidence that FGF9 can mediate these processes in in vitro and in vivo models.
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Liu, Hui-Hsuan. "Investigation of the role of nutrients for protection against acute kidney injury." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/44162/.
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Ischaemia reperfusion injury and nephrotoxicity are the common insults of acute kidney injury. Drug induced nephrotoxicity can also lead to an ischaemic phenomenon. The key mediator to both insults is oxidative injury caused by reactive oxygen species, and prolonged injury can result in irreversible kidney fibrosis and chronic kidney disease. This thesis developed a simulated ischaemia reperfusion injury in an in-vitro model to investigate whether amino acid supplementation may facilitate human proximal tubule cell recovery and protect from H2O2 damage following starvation and whether this was mediated by pH. The findings showed that resupply of amino acids at pH 7.5 under H2O2 injury after starvation exacerbated cell death. The mammalian target of rapamycin was also activated in response to amino acids in a concentration dependent manner even if under H2O2 damage, but the link between mammalian target of rapamycin activation and endoplasmic reticulum stress leading to cell death was not yet identified in this thesis. The constant expression of chaperone protein Grp78 may suggest the persistent cellular stress caused by starvation. While amino acids at pH 6.4 failed to activate the mammalian target of rapamycin and potentially reduced protein synthesis, it still exacerbated cell death under H2O2 damage. It also inhibited Grp78 expression, but the link between Grp78 inhibition and cell death was unclear. Moreover, this thesis established an aristolochic acid induced nephrotoxicity in mice and investigated whether another putative nutrient, sodium nitrite, could be renoprotective. However, the therapeutic effects of sodium nitrite remain to be confirmed, as aristolochic acid did not induce any injury in this animal model. Overall, this thesis implicated that the return of circulating amino acids may be detrimental for ischaemia reperfusion injury and that antioxidant therapy may be the priority for acute kidney injury.
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Gaya, Daniel R. "Investigating the role of faecal calprotectin in luminal gastroenterology." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/8745/.
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Providing a sensitive, non-invasive, cheap marker of disease activity inflammatory bowel disease (IBD) comprises an area of ongoing interest and unmet clinical need. In previous years, options included only serum CRP (poorly sensitive and specific), colonoscopy (invasive, costly, perforation risk, inability to view proximal small bowel), CT (costly, ionising radiation risk) and radiolabelled white cell scanning (costly, poor sensitivity). My thesis describes a series of trials performed to establish the role of faecal calprotectin to define current disease activity in IBD patients. Prompted by studies demonstrating the potential role for a novel faecal marker of clinical utility in the context of NSAID enteropathy, we chose to investigate the role of this biomarker, faecal calprotectin (FC), in Crohn’s disease. To facilitate this I used existing cohorts and then generated new cohorts in which to address fundamental and clinically relevant questions of importance. We compared FC to radiolabelled white cell scanning in our first study which initiated and established a mutually beneficial collaboration between luminal gastroenterology and clinical biochemistry. Thereafter we recruited a rigorously phenotyped cohort of Crohn’s disease patients in remission to answer two separate research questions. First, was there a significant intra-individual variability of FC and secondly, would FC sampling in remission predict future relapse over the ensuing 12 months? Thereafter, in a new cohort, we investigated whether we were over-investigating new GP referrals to the GI clinic with only mildly elevated FC values. Finally, and most recently, we sought to investigate whether or not there was any correlation between serum calprotectin and FC in a new unselected GI cohort of patients, thereby potentially obviating the need for our patients to collect stool samples. Our data demonstrated that FC correlated well with radiolabelled white cell scanning in assessment of Crohn’s disease activity, thereby potentially avoiding this costly test as part of disease monitoring. In addition, we defined an acceptable intra-individual variability of FC in Crohn’s disease to support the clinical utility of one off testing using FC. Our prospective dataset revealed that an FC in remission can indeed stratify Crohn’s disease patients to estimate future relapse risk thereby allowing us to personalise medical therapies with more aggressive therapeutics employed in those with Crohn’s disease in remission but with residual high FC. The work we undertook in our primary care dataset revealed an extremely low yield of investigating mildly elevated FC and thus we developed a new shared protocol with our GP colleagues in which serial FC testing is recommended rather than referral to secondary care for such patients. Lastly, our most recent work demonstrated that there was no significant correlation between serum and FC in an unselected GI cohort meaning the search for a GI-specific serum biomarker of inflammation goes on – this is in accord with a variety of other chronic inflammatory diseases in which circulating biomarkers have proven challenging to find and especially to validate. This body of work has been presented nationally and internationally at meetings, and has been published in discipline relevant, peer reviewed medical journals. Moreover, it has supported the adoption of FC into everyday NHS GI practice. We were the first UK hospital to establish an NHS service for this biomarker in 2007 when we performed around 50 assays per month. Currently, the test is in widespread use and the Glasgow Royal Infirmary biochemistry lab now analyses 1400 samples per month. This has become an established non-invasive, cheap, sensitive marker of IBD activity in clinical practice, often avoiding the need for colonoscopy for the purposes of disease activity monitoring. This biomarker is also being used to gauge the success or failure of medical therapies in IBD and is a useful tool to differentiate irritable bowel syndrome from IBD. The clinical utility of the test has allowed GPs to triage referrals and often avoid referrals completely and has engaged patients in the self-monitoring of their IBD.
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Gay, David Michael. "Investigating the cooperation of APC and KRAS mutations in colorectal cancer." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9089/.
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Colorectal Cancer (CRC) progresses in a stepwise manner accumulating mutations in particular signalling pathways. Despite our knowledge of the genetic progression of the disease, the resulting phenotypes of the different mutation combinations remains poorly understood. I used genetically engineered mouse models to investigate the cooperation of two frequent early mutations - loss of the tumour suppressor gene APC and activating KRAS mutations, to try and identify potential therapeutic targets. Hyperactivated Wnt signalling is a hallmark of CRC, although efficacious therapies are limited. In chapter 3 I focussed on targeting this pathway at the level of β-catenin mediated transcription. I showed that deletion of BLC9 and BCL9l, two proteins involved in β-catenin mediated transcription, suppresses proliferation and the expression of a subset of Wnt target genes following loss of APC and KRAS activation. I showed that these two proteins are dispensable intestinal homeostasis. I also showed that deletion of BCL9 and BCL9l significantly accelerated tumour initiation. In chapter 4 I performed unbiased quantitative proteomics on crypt cultures from VillinCreER Apcfl/fl (APC) and VillinCreER Apcfl/fl KrasG12D/+ (APC KRAS) mice to identify deregulated signalling pathways between these two genotypes. I identified a ‘nutrient stress’ phenotype in APC KRAS crypts. I show that this might be driven by a significant increase in protein synthesis, since APC KRAS cells are trying to regulate their rates of protein synthesis via eIF2α signalling. In chapter 5 I investigated changes in the metabolomes between APC and APC KRAS cells. I show that APC KRAS crypt cultures are highly dependent on glutamine for growth and upregulate many genes involved in glycolysis and glutaminolysis. I show that APC KRAS cells are metabolically flexible and also highlight the role the environment plays in metabolic phenotypes. Overall, I have shown that intestinal epithelial cells with high-Wnt and high-MAPK signalling are sensitive to Wnt inhibition. I have also shown that these two signalling pathways cooperate to drive increased protein synthesis and deregulated metabolism to fuel proliferation.
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Sagar, Nidhi. "Describing the gut microbiome and metabolomic changes in bile acid diarrhoea (BAD)." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/101543/.
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The diagnosis of BAD is often missed or misdiagnosed for IBS-D as these conditions present similarly with chronic diarrhoea. The principal hindrance to diagnosis of BAD is limited access to the diagnostic SeHCAT scan. Mechanisms of aetiology underlying BAD have not been fully elucidated and to date, an alternative biomarker for BAD that is more accessible and patient preferable, has yet to make its way into clinical practice. One of the greatest scientific challenges this decade has been understanding the relationship between the gut microbiome, its functionality and role in human health. BAs are metabolised by the gut microbiota, therefore their role as signalling molecules in regulating intestinal homeostasis is influenced primarily by the gut commensals. This thesis is the first study to profile the gut microbiome in BAD and investigate the mechanisms of how bacterial metabolic products may influence the development of disease. This was achieved by conducting 16S ribosomal RNA gene analysis, the most important target of study in bacterial ecology. Bacterial metabolites (SCFAs and VOCs) and BAs were measured using gas and liquid chromatography, mass and ion mobility spectrometry. The results indicate intestinal dysbiosis with reduced bacterial diversity in patients with BAD. A statistically significantly greater total concentration of SCFAs with increases in the concentrations of acetate and propionate were observed in BAD compared to IBS-D. A statistically significant increase in the concentrations of faecal primary BAs and serum CDCA was observed in BAD compared to IBS-D. Separation of VOC profiles was evident between the BAD, IBS-D and HC groups but greatest discrimination was between the IBS-D and HC cohorts. In conclusion, intestinal dysbiosis with altered fermentation and resultant BA dysmetabolism were observed. The metabolic output of the microbiota rather than abundance of specific bacterial taxa appears to be more important in the aetiology of BAD.
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Wels, Simon. "Is mental disorder caused by internal dysfunction? : an updated critique of Wakefield's harmful dysfunction analysis." Thesis, University of Warwick, 2010. http://wrap.warwick.ac.uk/36757/.
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Alkawafi, Isma A. "Role of mammalian target of rapamycin (mTOR) signalling in BeWo trophoblast differentiation and fusion." Thesis, University of Warwick, 2015. http://wrap.warwick.ac.uk/76206/.
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Foetal growth and development is closely related to the placental transport function, since any defect in this function is associated with pathological foetal growth. Trophoblast differentiation into a multinucleate syncytium is a key biological mechanism. Transcriptional regulation of fusogenic genes to promote fusion and capacity for placental hormonogenesis is achieved by a coordinated action of signals such as cAMP and MAPKs. The mammalian target of rapamycin (mTOR) acts as a placental growth signalling sensor, and this has been implicated in the pathophysiology of diseases such as intrauterine growth restriction (IUGR). This is also implicated in the pathological mechanism of diabetes mellitus, a disease which is associated with excess nutrient availability and insulin resistance. Many researchers have reported a relationship between changes in placental amino acid transporter activity and altered foetal growth. The signalling pathway of the protein kinase mTOR has been proposed to regulate cellular growth in response to growth factors, nutrient and amino acids by inducing transcription and translation. The role of mTOR signalling pathway in early development is confirmed by post implantation lethality in mouse following a complete deletion of mTOR gene. mTOR is an evolutionarily conserved member of the phosphatidylinositol-3-OH (PI-3)-kinase-related kinase (PIKKs), and its upstream activators PI3K and Akt appear to be involved in the control of trophoblast fusion. The precise role of mTOR in the trophoblast differentiation mechanisms is not well understood. Previous studies have shown that, fusion processes in BeWo cells is stimulated by inhibition of intracellular calcium and down regulation of phosphatidylinositol 3 kinase (PI3K)/Akt pathway. Since PI3K/Akt pathway is the upstream signalling of mTOR pathway, we conducted this study to investigate the role of mTOR signalling pathway in BeWo cells differentiation. Our in-vitro studies showed that inhibition of mTOR by rapamycin, reduced forskolin-induced hCG release, whereas syncytin-1 and -2 mRNA expression was substantially augmented. These findings led us to investigate the effect of forskolin-driven adenylyl cyclase activation on mTOR expression and activity. Forskolin treatment for 24h significantly reduced mTOR protein expression. Moreover, within 10min of forskolin treatment, there was a substantial reduction in basal mTOR phosphorylation at Ser2481 and Ser2448, which is required for mTOR activity. This was associated with increased phosphorylation of p70S6K, at Ser371.Immunohistochemistry showed increased mTOR expression and phospho-mTOR (Ser2448/2481) staining in GDM placenta compared to controls. Our results identify distinct actions of mTOR on the biochemical and morphological differentiation of BeWo trophoblasts. In addition, it showed increased expression and activity of mTOR in gestational diabetes mellitus (GDM).
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Cossar, Johnathan Harvey. "Studies on illnesses associated with travel." Thesis, University of Glasgow, 1987. http://theses.gla.ac.uk/2862/.
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Huang, Xuya. "Tenecteplase and alteplase in acute ischaemic stroke thrombolysis : clinical and imaging study." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7507/.
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Introduction: Intravenous thrombolysis in acute ischaemic stroke with alteplase improves clinical outcomes, but it has limited efficacy and is associated with increased risk of intracranial haemorrhage. An improved tissue plasminogen activator, tenecteplase, was evidenced to be at least equally effective with lower risk of haemorrhage in acute myocardial infarction thrombolysis. To date, two completed phase II randomised controlled studies comparing tenecteplase and alteplase in acute ischaemic strokes showed variable results. Methods: A literature review of thrombolytic agents used in myocardial infarction and acute ischaemic stroke was performed, followed by a retrospective investigation of the bolus-to- infusion delay of alteplase administration. The main focus of this thesis is the report of our single centre phase II randomised controlled trial that compared tenecteplase (0.25mg/kg, maximum 25mg) and alteplase (0.9mg/kg, maximum 90mg, 10% as the initial bolus, following by one hour infusion with the rest of the dose) in acute ischaemic stroke thrombolysis using advanced imaging as biomarkers. Imaging comprised baseline computed tomography (CT), CT perfusion (CTP) and CT angiography (CTA), and CT+CTA at 24-48 hours. The primary end-point was penumbral salvage (CTP-defined penumbra volume minus follow-up CT infarct volume). A sub-study of coagulation and fibrinolysis analysis of the two agents was performed by comparing a group of coagulation variables measured pre-treatment, 3-12 hours, and 24±3 hours post thrombolysis. An individual patient data (IPD) meta-analysis was carried out using all three completed tenecteplase/alteplase comparison studies in stroke thrombolysis. We compared clinical outcomes including modified Rankin scale at 3 months, early neurological improvement at 24 hours, intracerebral haemorrhage rate and mortality at 3 months between all three tenecteplase doses (0.1mg/kg, 0.25 mg/kg, and 0.4mg/kg) examined and standard alteplase. Imaging outcomes including penumbra salvage, recanalisation rates were also compared using the data from the two studies that had advance imaging carried out. Results: Delay between the initial bolus and the subsequent infusion in administration of alteplase is common. This may reduce the likelihood of achieving a good functional outcome. Among the 104 patients recruited in ATTEST trial, 71 contributed to the imaging primary outcome. No significant differences were observed for penumbral salvage [68 (SD 28) % tenecteplase vs 68 (SD 23) % alteplase], mean difference 1% (95% confidence interval -10%, 12%, p=0·81) or for any secondary end-point. The SICH incidence (1/52, 2% vs 2/51, 4%, by SITS-MOST definition, p=0·55; by ECASS-2 definition, 3/52, 6% tenecteplase vs 4/51, 8% alteplase, p=0.59) did not differed significantly. There was a trend towards lower ICH risk in the tenecteplase group (8/52 tenecteplase, 15% vs 14/51 alteplase, 29%, p=0·091). Compared to baseline, alteplase caused significant hypofibrinogenaemia (p=0.002), prolonged Prothrombin Time (PT) (p=0.011), hypoplasminogenaemia (p=0.001) and lower Factor V (p=0.002) at 3-12 hours after administration with persistent hypofibrinogenaemia at 24h (p=0.011), while only minor hypoplasminogenaemia (P=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (p < 0.001) and fibrinogen (p=0.002) compared with alteplase. In a pooled analysis, tenecteplase 0.25mg/kg had the greatest odds to achieve early neurological improvement (OR [95%CI] 3.3 [1.5, 7.2], p=0.093), excellent functional outcome (mRS 0-1) at three months (OR [95%CI] 1.9 [0.8, 4.4], p= 0.28), with reduced odds of ICH (OR [95%CI] 0.6 [0.2, 1.8], P=0.43) compared with alteplase. Only 19 patients were treated with tenecteplase 0.4mg/kg, which showed increased odds of SICH compared with alteplase (OR [95% CI] 6.2 [0.7, 56.3]). In the two studies where advanced imaging was performed, the imaging outcomes did not differ in the IPD analysis. Conclusion: Tenecteplase 0.25 mg/kg has the potential to be a better alternative to alteplase. It can be given as a single bolus, does not cause disruption to systemic coagulation, and is possibly safer and more effective in clot lysis. Further phase III study to compare tenecteplase and alteplase in acute ischaemic stroke is warranted.
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McKinney, Clare Adele. "The role of Angiotensin-(1-7) and Angiotensin-(1-9) in vascular remodelling." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5752/.
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Vascular remodelling is an adaptive process that allows vessels to respond to changes in haemodynamic conditions, however this process also underlies the pathogenesis of atherosclerosis, vein graft failure following coronary artery bypass graft (CABG) surgery and restenosis following stent deployment to an atherosclerotic vessel. Injury to the vessel wall causes denudation of the endothelial cell (EC) layer and the resultant pathological vascular remodelling involves growth and migration of vascular smooth muscle cells (VSMC) and degradation and reorganisation of the extracellular matrix (ECM). Regeneration of the endothelial layer, known as re endothelialisation, is essential for healing of injured vessels and therefore therapies that specifically target VSMC growth and migration, without preventing re-endothelialisation are optimal in these pathologies. Dysregulation of the renin angiotensin system (RAS) is one of the key contributing factors to remodelling of the vasculature, with the majority of the pathological processes involved, being mediated by angiotensin II (Ang II) signalling at the angiotensin type I receptor (AT1R). A counter regulatory axis of the RAS has been identified, centred around the enzymatic actions of angiotensin converting enzyme 2 (ACE2), and the resultant production of Angiotensin-(1-9) [Ang-(1-9)] and Angiotensin-(1-7) [Ang-(1-7)] from Ang I and Ang II respectively. This axis counter-regulates the actions of Ang II via the AT1R, thereby providing a vasculoprotective role. Ang-(1-7) acts via the receptor Mas and inhibits Ang II induced VSMC cell migration, proliferation, and vascular remodelling in vivo. Comparatively, less is known about the actions of Ang-(1-9), however it has been identified as a functional ligand for the angiotensin type 2 receptor (AT2R), inhibiting cardiac hypertrophy in vitro and cardiac fibrosis in vivo. However, the role of Ang-(1-9) in the vasculature is unexplored. Therefore, the main aim of this thesis was to investigate the interaction of Ang II and the counter-regulatory peptides Ang-(1-7) and Ang-(1-9) in the vasculature using primary human VSMC and EC, and to provide a direct comparison of Ang-(1-7) and Ang-(1-9) in order to further understand their signal transduction pathways. First, a model of VSMC proliferation was established in VSMC isolated from human saphenous vein tissue (HSVSMC). Here it was demonstrated that while Ang II had no effect on HSVSMC proliferation, foetal calf serum (FCS) induced HSVSMC proliferation in a concentration dependent manner. Ang-(1-7) and Ang-(1-9) blocked FCS induced proliferation of HSVSMC via Mas or the AT2R, respectively. Ang II-induced HSVSMC migration via the AT1R, and was inhibited by both Ang-(1-7) and Ang-(1-9) via Mas and the AT2R, respectively. Further investigation into the functional interplay of Ang II, Ang-(1-7) and Ang-(1-9) in HSVSMC migration identified alterations in extracellular signal-related kinase 1/2 (ERK1/2) activity and matrix metalloproteinase 2 (MMP2) and MMP9 expression as potential mechanisms contributing to the observed results. Additionally, Ang II has recently been demonstrated to regulate expression of the microRNA-132/-212 (miR-132/-212) cluster in rat aortic VSMC, thereby regulating a number of target genes involved in VSMC migration. This pathway was assessed in HSVSMC and it was found that Ang II-mediated HSVSMC migration was associated with an increase in miR-132 but not miR-212 expression, and a decrease in phosphatase and tensin homologue (PTEN) expression, a miR-132 target, at the messenger RNA level. These changes were found to be via the AT1R and were inhibited by Ang-(1-7) and Ang-(1-9). However, PTEN protein levels were unchanged and no changes were observed in key proteins involved in the downstream signalling pathways of PTEN, such as Akt and monocyte chemoattractant protein 1 ( MCP-1). The role of miRNA-132 in Ang II induced HSVSMC migration was further investigated through the use of a miR-132 inhibitor and downregulation of DICER, a key enzyme involved in miRNA biogenesis. Here it was found that miR-132 or regulation of an alternative miRNA via DICER is not essential for Ang II induced HSVSMC migration. However, inhibition of miR-132 or DICER enhanced basal migration of unstimulated HSVSMC. Next, the effect of the RAS peptides, particularly Ang-(1-9), on EC growth, migration and function was assessed. Ang II, Ang-(1-7) or Ang-(1-9) have no effect on growth or migration of EC isolated from human saphenous veins (HSVEC). A direct effect of Ang-(1-9) on nitric oxide (NO) release from HSVEC and Chinese hamster ovary (CHO) cells expressing the AT2R was demonstrated. Although in cell culture Ang-(1-9) induced NO release in an AT2R sensitive manner, it was found that in vessels from AT2R knockout (AT2R-/-) mice the biological effect of Ang-(1-9) was maintained and promoted vasodilation of both aortic and mesenteric artery rings. Furthermore, Ang-(1-9)-induced relaxation of AT2R-/- aortic rings, but not mesenteric artery rings, was blocked by A779, suggesting that in large vessels Ang-(1-9) may mediate is vasodilatory effects via conversion to Ang-(1-7) and signalling via Mas, while in resistance vessels Ang-(1-9) promotes vasodilation through an alternative mechanism. The observation that Ang-(1-7) and Ang-(1-9) block HSVSMC, but not HSVEC, proliferation and migration, identified these peptides as potential therapeutic agents in vascular injury. A carotid artery wire injury model in mice was established, where injury to the carotid artery using a synthetic nylon fibre induced significant injury to the vessel, manifesting in the production of a large neointimal area at 28 days post injury. To assess the effects of Ang-(1-7) and Ang-(1-9), the peptides were delivered via subcutaneously via osmotic minipump. It was found that Ang-(1-7) infusion reduced neointimal formation and neointimal/media (NI/MA) ratio in comparison to control vessels via Mas. Similarly, Ang-(1-9) reduced neointimal formation and NI/MA ratio via the AT2R, as the AT2R antagonist PD123,319, but not the Mas antagonist A779,blocked the effects of Ang-(1-9), indicating that this was via a direct effect of Ang-(1-9), as opposed to conversion to Ang-(1-7) and signalling via Mas. An interesting finding from the in vivo study was that a large proportion of vessels from animals co-infused with Ang-(1-7) and A779, or Ang-(1-9) and PD123,319 developed more complex lesions with increased vessel remodelling and neovascularisation, largely within the media, in comparison to all other groups. Analysis of the composition of these complex lesions revealed that they were composed of disorganised ECM and were highly cellular, containing a large number of VSMC, macrophages and proliferating cells. Re-endothelialisation had occurred on the lumenal lining of these vessels and neovascularisation of the complex lesion was observed. In summary the data from this thesis demonstrates for the first time a direct biological role for Ang-(1-9) in the vasculature through inhibition of HSVSMC migration and proliferation, and increase NO bioavailability from HSVEC in vitro and reduced neointimal formation in an in vivo mouse model of vascular injury. Furthermore, this study provides a direct comparison of Ang-(1-9) and Ang-(1-7) in the vasculature and while the end biological effects are similar, they act via different receptors, the AT2R or Mas, respectively, and differences exist in their signal transduction mechanisms. These findings highlight the potential of Ang-(1-9) and Ang-(1-7) as therapeutic agents in the setting of vascular remodelling.
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Mani, Mohammad H. "Ultrasonic instrument for accurate measurements of spatial parameters in blood vessels." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33355/.
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The present research is aimed at the development of an ultrasonic medical instrument capable of measuring the intima-media thicknesses (IMT) of artery walls that are considered by medical practitioners as good indicators of the risk of atherosclerosis. This overcomes two notable limitations of the instruments available at present – insufficient axial resolution and lack of synchronisation to the heart cycle that make the measurements difficult to use, e.g., for annual screening of patients and like-for-like comparisons. These limitations were addressed by using a combination of on-the-fly averaging and interleaved sampling for acquiring echo waveforms, and triggering the scans at a particular instant of the heart cycle. The developed electronic instrumentation consisted of a battery powered electrocardiogram (ECG) monitor that transmitted the ECG data using an infrared link to the ECG processor that triggered the scans. Such architecture eliminated any possibility of accidentally connecting the patient to a source of voltage capable of causing serious injury and of causing radio frequency interference to medical equipment located in a close proximity. The algorithm for detecting the R-waves from noisy ECGs was fully verified with simulated and experimental ECG records, and implemented in firmware on board the ECG processor. The rate of R-wave detection of the developed algorithm is 88.24% out of 204 heartbeats recorded. In order to ease the interpretation of the recorded echoes, both mathematical and physical simulations of tubular objects were carried out. The calculated resolution of the system was estimated 2.5um. Spatial resolution of 15um was achieved during the in-vivo experiments. Some of the factors that might have caused this difference have been discussed with suggestions on possible methods of improvements. The set of experimental waveforms recorded in vivo demonstrated the correct operation of the developed instrument, appropriate consistency and some features that were expected and described in the literature. The developed instrument seems ready for application to a broader group of subjects.
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Zhang, Qimei. "Ultrasound mediated luminescence tomography using contrast agents." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33662/.
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The achievable spatial resolution of fluorescence and bioluminescence imaging in deep tissue is severely limited by strong tissue scattering and absorption. The hybrid technique ultrasound (US) mediated fluorescence tomography (USMFT) has been investigated in the past decade, with the aim to obtain fluorescence images with optical contrast and US resolution. However, the very low modulation depth due to the intrinsic incoherent properties of fluorescence leads to low signal-to-noise ratio. In this thesis, the techniques of US mediated luminescence tomography (USMLT, including US mediated bioluminescence tomgoraphy (USMBLT) and USMFT) are investigated with the aim to improve the effect of US on light intensity via application of contrast agents. The mechanisms of USMBLT are firstly studied through incorporating the effect of US into NIRFAST, an open source software package for simulation of light propagation. The influence of US on optical properties (reduced scattering coefficient, absorption coefficient, and refractive index) and concentration of source particles are studied. Effects of US pressure, US position, and source particle concentration on the modulation depth are investigated and the signal-to-noise ratio for in vivo detection is calculated. It is demonstrated that the dominant effect in the generation of USMBL signal is US induced variation in the concentration of the source particles, and this effect is at least two orders of magnitude greater than that caused by changes in the optical properties. It is also found that modulation depth increases linearly with increase of US pressure. The maximum modulation depth can be obtained when the US focal zone overlaps the bioluminescence source region. The modulated fluence rate increases linearly with increase of the concentration but the modulation depth is independent of the concentration. Results for signal-to-noise ratio calculation confirm the feasibility of applying USMBLT in preclinical imaging of mice to improve the spatial resolution of bioluminescence imaging. Secondly, fluorophore labelled microbubbles are studied as a contrast agent to increase the modulation depth of USMFT. Upon application of US the size of the microbubbles oscillate changing the intermolecular distances of the fluorophores labelled on the monolayer of the microbubbles resulting in modulated fluorescence emission intensity. Increased modulation depth is observed both from simulation and experiment. The influence of factors including microbubble radius, US pressure, labelling concentration on the US modulated fluorescence emission are simulated. It was shown that the effects of the three factors are closely related to each other, and it is difficult to decouple their effects. Generally the maximum modulated signal can be obtained within the region C ∈ (2 mol% 5 mol%) and R0 ∈ (1.5μm 5μm). However microbubbles with a higher fluorophore labelling concentration or a bigger radius require higher US pressure to obtain its maximum volumeric oscillation and the highest modulated signal. The results suggest that it is desirable to produce microbubble suspensions with narrow size distribution, so that most of the microbubbles can be labelled by an optimized concentration and exposed to an appropriate US pressure. Thirdly, liposome based contrast agents are studied for use in USMFT for the first time. Compared with microbubbles, liposomes have the advantages that they have better stability, less US scattering, and can be manufactured with a defined size in nanometer scale. Liposomes are labelled with pyrene which has well-known concentration dependent excimer formation characteristic. The acousto-fluorescence dynamics of liposomes containing lipids with pyrene labelled on the fatty acid tail group (PyPC) and the head group (PyPE) were compared. An increase in excimer emission intensity following exposure to US was observed for both cases studied. The increased intensity and rise time constants were found to be different for the PyPC and PyPE labelled liposomes, and dependent on the applied US pressure and exposure time. The greatest US On-to-Off ratio of excimer emission intensity (130%) and smallest rise time constant (0.33 s) are achieved through the use of the PyPC labelled liposomes. Possible mechanisms underlying the observed increase of the excimer emission intensity in PyPC system is considered to arise from the "wagging" of acyl chains which involves fast response and requires lower US energy. This is accompanied with the increased lipid lateral diffusivity, mechanisms also active in the PyPE system. Finally, DiD-DiR labelled liposomes based on fluorescence resonance energy transfer (FRET) are studied. The excitation and emission spectra are located close or within near-infrared window, where the penetration depth is up to several centimetres. Measurements of emisison spectra show that strong FRET and self-quenching exist in the DiD-DiR labelled liposomes. The fluorescence emission intensity changes upon application of US, with the change trend dependent on fluorophore types, detection wavelength, and fluorophore concentration. Line scanning of a tube buried at a depth of 1 cm in a heavily scattering phantom shows a contrast of 8.5% can be obtained using 0.5 mol% DiD-DiR labelled liposomes through detection at DiR emission wavelength (around 740nm - 790 nm). The resolution can be improved by a factor of 6.3 compared with its no US counterpart. These results suggest that DiD-DiR labelled liposome has potential to be used as contrast agent of USMFT for deep tissue imaging. Further application for in vivo imaging is discussed.
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Robertson, Elaine V. "Studies of the gastro-oesophageal junction in normal and overweight healthy volunteers." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7491/.
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Introduction: Oesophageal adenocarcinoma has increased dramatically in incidence over the past three decades with a particularly high burden of disease at the gastro-oesophageal junction. Many cases occur in individuals without known gastro-oesophageal reflux disease and in the absence of Barrett’s oesophagus suggesting that mechanisms other than traditional reflux may be important. Distal squamous mucosa may be prone to acid damage even in the absence of traditional reflux by the mechanism of distal opening of the lower oesophageal sphincter. This is splaying of the distal segment of lower oesophageal sphincter allowing acid ingress without traditional reflux. It has been suggested that the cardiac mucosa at the gastro-oesophageal junction, separating oesophageal squamous mucosa and acid secreting columnar mucosa of the stomach may be an abnormal mucosa arising as a consequence of acid damage. By this theory the cardiac mucosa is metaplastic and akin to ultra-short Barrett’s oesophagus. Obesity is a known risk factor for adenocarcinoma at the gastro-oesophageal junction and its rise has paralleled that of oesophageal cancer. Some of this excess risk undoubtedly operates through stress on the gastro-oesophageal junction and a predisposition to reflux. However we sought to explore the impact of obesity on the gastro-oesophageal junction in healthy volunteers without reflux and in particular to determine the characteristics of the cardiac mucosa and mechanisms of reflux in this group. Methods: 61 healthy volunteers with normal and increased waist circumference were recruited. 15 were found to have a hiatus hernia during the study protocol and were analysed separately. Volunteers had comprehensive pathological, physiological and anatomical assessments of the gastro-oesophageal junction including endoscopy with biopsies, MRI scanning before and after a standardised meal, prolonged recording of pH and manometry before and after a meal and screening by fluoroscopy to identify the squamo-columnar junction. In the course of the early manometric assessments a potential error associated with the manometry system recordings was identified. We therefore also sought to document and address this on the benchtop and in vivo. Key Findings: 1. In documenting the behaviour of the manoscan we described an immediate effect of temperature change on the pressure recorded by the sensors; ‘thermal effect’ and an ongoing drift of the recorded pressure with time; ‘baseline drift’. Thermal effect was well compensated within the standard operation of the system but baseline drift not addressed. Applying a linear correction to recorded data substantially reduced the error associated with baseline drift. 2. In asymptomatic healthy volunteers there was lengthening of the cardiac mucosa in association with central obesity and age. Furthermore, the cardiac mucosa in healthy volunteers demonstrated an almost identical immunophenotype to non-IM Barrett’s mucosa, which is considered to arise by metaplasia of oesophageal squamous mucosa. These findings support the hypothesis that the cardia is metaplastic in origin. 3. We have demonstrated a plausible mechanism of damage to distal squamous mucosa in association with obesity. In those with a large waist circumference we observed increased ingress of acid within but not across the lower oesophageal sphincter; ‘intrasphincteric reflux’ 4. The 15 healthy volunteers with a hiatus hernia were compared to 15 controls matched for age, gender and waist circumference. Those with a hiatus hernia had a longer cardiac mucosa and although they did not have excess traditional reflux they had excess distal acid exposure by short segment acid reflux and intrasphincteric acid reflux. Conclusions: These findings are likely to be relevant to adenocarcinoma of the gastro-oesophageal junction.
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Harris, Katy. "Service users' experiences of an early intervention in psychosis service : an interpretative phenomenological analysis." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11490/.
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Objectives: Previous research regarding Early Intervention in Psychosis (EIP) has mainly adopted quantitative methodologies, in order to study the effectiveness of EIP services. Research studies which have explored service-users’ experiences of EIP services are small in number. This research aimed to explore service-users’ experiences of being in contact with an EIP service, its impact of their experience of psychosis and current life situation. Design: Interpretative Phenomenological Analysis (IPA) was used to conduct an in-depth qualitative study of a small sample of EIP service-users, in order to explore their experiences of being in contact with the service. Method: Semi-structured interviews were conducted with eight service-users who had been receiving a service from an EIP team for more than two years and were recruited using a purposive sampling method. Verbatim interview transcripts were analysed using IPA. Results: Five super-ordinate themes, developed from the analysis, are discussed under the headings: Stigma, Relationships, Understanding the experiences, Sense of agency and Impact on sense of self. Sub-themes of these super-ordinate themes are also discussed. Conclusions: The themes developed from the analysis were envisioned as representing an overarching theme of ‘A personal journey of recovery’, which was influenced by participants’ involvement with the EIP service. Clinical implications include the need for EIP services, as with other mental health services, to find ways to promote recovery and create opportunities for agency and control. Future research directions are also discussed.
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Campbell, Amanda. "Assessment of executive functions in people with Human-Immunodeficiency Virus (HIV) infection using the Behavioural Assessment of the Dysexecutive Syndrome : a pilot study." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11491/.
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Impairments in executive functions (EF), for example planning and impulsivity, are often identified in people with Human-Immunodeficiency Virus-1 (HIV). Previous research has predominantly used ‘traditional tests’ such as the Stroop, which do not have good ecological validity (Bennett et al., 2005). The main aim of this study was to assess EF in people with HIV using a battery approach with good ecological validity, the Behavioural Assessment of the Dysexecutive Syndrome (BADS) (Wilson et al., 1996). The study used a comparison pilot design to compare performance on the BADS within a sample of participants with HIV to the published normative data. A total of 20 participants with HIV were assessed (13 men; 7 women). On average, participants scored significantly lower on the BADS relative to normative data. Further research should develop the use of neuropsychological batteries with good ecological validity to consider EF impairment in people with HIV. Clinical implications include the potential of EF screening for people with HIV.
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Goodman, Lisa. "Patients' perception and experience of using guided self-help for depression and anxiety in a primary care setting." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11523/.
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Objectives. There is a developing body of evidence that guided self-help can be effective in alleviating distress experienced from symptoms of depression and anxiety. However evidence is not consistently positive and clarification is required about how it achieves its effects. Furthermore, previous research into guided self-help has not investigated patients with milder depression or anxiety. Exploration of the therapy process in guided self-help has crucial importance in developing further understanding about its qualities and how it is experienced. This study aimed to explore the ways in which people experience guided self-help for depression or anxiety within primary care. Design. Qualitative research has been recommended to complement the quantitative work that has been published to date on guided self-help. The data used for analysis was gathered from semi-structured interviews. Method. Interpretative phenomenological analysis was used. Semi-structured interviews were carried out with seven participants who had accessed and completed guided self-help for either mild depression or anxiety. The verbatim transcripts of those interviews served as the data for analysis. Results. Four themes emerged which are described under the broad headings: participants’ intention to feel better, development of understanding and awareness, change: from dependency to independence, and relating to others. Conclusions. Participants experienced a positive outcome of using guided self-help, which included increased knowledge about their thoughts and feelings, and increased self-efficacy in managing their own mental health. These findings shed light on how the patients’ positive outcomes are related to the change process. Findings also suggest that self-determined motivation may impact upon accessibility to guided self-help in addition to patients’ attitudes and expectations.
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Boycott, Naomi E. "Exploring factors associated with strain in carers of patients with traumatic brain injury." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11534/.
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This study explored what factors are associated with strain in 48 carers of patients with traumatic brain injury (TBI). This was a cross-sectional cohort study of patients who were admitted to a Neurosurgical Unit with TBI over a period of nine years and followed up between five and 14 years post-injury. Their carers were assessed via postal survey for levels of strain using the Caregiver Strain Index (CSI) and asked for their perception of the patients’ disabilities using the family form of the Neurobehavioral Functioning Inventory (NFI). Elevated levels of strain were found in 42% of carers. Using logistic regression, outcome as rated by the patients’ GP on the Glasgow Outcome Scale (GOS) and all subscales of the NFI (except Somatic) contributed to explain 41 - 57% of the variance in strain, and predicted group membership correctly in 72.9% of cases. No individual variable contributed significantly to the explained variance in the model. The model was not significantly improved after removing outliers. Findings suggest that a number of factors combine to result in feelings of strain and illustrates the difficulty for clinicians to predict when strain may occur. The clinical implications of the study are discussed.
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Khan, Sobia T. "The assessment of dementia severity using non-verbal cognitive tests." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11907/.
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Objective: To explore the utility of cognitive tests, that did not rely on spoken language from participants for decision making about eligibility for treatment with Anti-cholinesterase Inhibitors (AchI). Methods: A cross-sectional design was used. Data was collected from 20 participants, aged 65 to 90 years (M, 77.6: SD, 7.2), with dementia, or cognitive difficulties. The sample comprised of eleven males and nine females. The Mini-Mental State Examination (MMSE), and six alternative cognitive tests were administered, these were; the Rey Complex Figure Test (RCFT), Ravens Colour Progressive Matrices (RCPM), Symbol Digit Modalities Test (SDMT), Brixton Test, Clock Drawing Test (CDT), and Colour Trails Test (CTT). Results: There was statistically significant correlations between the MMSE and the following cognitive tests: RCFT visual construction subtest(r= .609; P<.006), the RCFT recognition subtest (r= .496; P<.031), RCPM (r= .452; p<.045), the SDMT (r=.670; P<.001), the CTT 1 (Rho=-.576; P<.012) and the CDT (r=-.577; P<.008). The area under the ROC curve values were as follows: RCFT visual construction (0.750, 95%, CI .524 - .976), RCFT recognition memory (0.801, 95%, CI .590 – 1.012), RCPM (0.573, 95%, CI 0.298 – 0.848), SDMT (0.708, 95%, CI 0.469 – 0.947), CTT1 (0.818, 95%, CI 0.610 – 1.027) and the CDT (0.734, 95%, CI 0.479 – 0.990). Cut-off scores with adequate sensitivity and specificity were identified for all the above measures apart from the RCPM, which had predictive accuracy that was equal to chance. Conclusions: Cognitive tests which do not require spoken language have utility in differentiating between those who are and are not eligible for treatment with AchI, as defined by the cut-off (<20) on the MMSE in the National Institute for Clinical Excellence guidelines (NICE, 2007).
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Tew, Jerry. "The politics of the family and family therapy : a critical analysis of theory and practice." Thesis, University of Warwick, 1992. http://wrap.warwick.ac.uk/97170/.
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This thesis aims to develop a new theoretical framework by which to understand family organisation and the processes of family therapy from a political perspective - a framework that will highlight (changing) power relationships rather than assume some notion of functional order. In constructing and evaluating such a theoretical framework, I will draw upon the traditions of critical theory and qualitative research. My starting points are an overview of existing critical understandings of 'the family', and an examination of how 'power' itself may be theorised in a rigorous manner. I will review how such perspectives may expose specific relations of oppression or recognition that underpin particular forms of organisation, from the scale of the social formation as a whole to that of 'the individual'. Psychoanalysis and discourse theory have provided concepts whereby to deconstruct the dynamics of 'the individual' - in particular the concept of 'subjectivity' - which I will develop further so as to encompass participation, not just in discursive structures, but also in structures of emotional and material relations. In a critical appraisal of the various theoretical and practice traditions within family therapy, I will look at how the hegemony of systems theory has begun to be questioned and alternative metaphors for familial organisation proposed. However, as I will argue, none of these provide a satisfactory basis for understanding power relations in the family. I will therefore go on to apply a new conceptualisation of family organisation - that of 'subjectivity' - which is developed out of the theoretical traditions discussed earlier. I will theorise 'the family', not just as the context in which individual subjectivity may be constructed, but as an entity that may be seen to participate in the social formation as a subjectivity in its own right. Instead of understanding familial organisation as a natural outcome of self-regulating processes (as in systems theory), it may thus be seen to reflect the ways in which a family may have been constructed as a subjectivity in and by an oppressive social formation - its coherence only being maintained by a degree of internal violence and repression. Building on this, I will develop a theoretical framework by which to analyse, from a political perspective, the breakdown of family functioning and the specific ways in which the organisation of family life may be reconstructed through the processes of family therapy. Following on from this, I will test out the value of the theoretical framework in an analysis of three examples of family therapy practice. My source material is transcripts taken from videotapes of actual family sessions, and these are analysed in terms of the evidence they provide of minute-by-minute changes in power relations within family organisation (often in response to particular interventions by the therapist). Out of this in-depth study of a small number of case examples, my primary aim will be to assess the practical value of the various elements of the theoretical framework in exposing how familial power relations have been structured and how (and whether) they may be modified during the course of family therapy. In turn, this may enable me to reach some preliminary conclusions as to how specific family therapy interventions may affect family organisation in ways that are either oppressive or empowering.
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Saedon, Mahmud H. "Prediction, detection and suppression of cerebral microemboli associated with carotid disease." Thesis, University of Warwick, 2015. http://wrap.warwick.ac.uk/77581/.
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Background Transient cerebral microemboli detected by transcranial Doppler (TCD) have been demonstrated to be a reliable biomarker for short term stroke risk in two clinical settings; patients with carotid artery stenosis and those following carotid endarterectomy. Suppressing cerebral microemboli using TCD-directed antiplatelet treatment reduces risk of recurrent stroke. The association between classical cardiovascular risk factors and cerebral microemboli has not been studied. Furthermore, standard TCD method to detect cerebral microemboli is limited by lack of acoustic temporal bone window which is not available in approximately 1 in 7 patients. TCD is the only real-time imaging modality for detecting microemboli. The demonstration of the kinetic of the microemboli is invaluable in assessing the efficacy of antiplatelet agents. Hypotheses 1. Whether Pocock cardiovascular risk score and ABCD2 risk score are able to predict the presence of cerebral microemboli. 2. The feasibility of using transorbital Doppler as an alternative to transcranial Doppler. 3. The effectiveness of Tirofiban in suppressing cerebral microemboli. Methods 1. Pocock score was assessed for the newly developed Carotid Surgery Registry of 670 patients managed between January 2002 and December 2012. 2. ABCD2 score was determined in 206 patients with hyper-acute symptomatic critical carotid artery stenosis in which 102 of these patients were from Registry. A further 104 consecutive patients were recruited between February 2011 and May 2013 within a new prospective observational study. 3. The feasibility of using transorbital Doppler was assessed based on the Registry data. Further new prospective validation study of transorbital Doppler against standard TCD method involving 100 consecutive patients undergoing elective carotid endarterectomies were undertaken. 4. From the Registry, patients who had microembolic signals acutely following carotid surgery were assessed to evaluate the effectiveness of Tirofiban in suppressing microemboli. Findings 1. A high Pocock score (≥ 0.8%) predicts presence of cerebral microemboli acutely following carotid endarterectomy (Area Under Curve (AUC) 0.582 95% CI 0.507 – 0.658, P = 0.038). It also showed a high sensitivity for the presence of microemboli in patients with hyper-acute symptomatic carotid artery disease. 2. The ABCD2 score did not predict presence of cerebral microemboli ((AUC 0.49 95% CI 0.41 – 0.57, P = 0.860), or carotid disease in over one-quarter of patients with symptomatic critical carotid artery stenosis. 3. Transorbital Doppler imaging appears a valid alternative to transcranial Doppler for detecting microembolic signals in patients with no suitable temporal acoustic window (sensitivity 80 %, specificity 86 %. Bland and Altman analysis revealed no significant bias [bias 0.11 microemboli (95% CI: -0.52 to 0.74), P = 0.81]). 4. Tirofiban has been shown to be more effective in treating microemboli in comparison to other most commonly used antithrombotic agents. The time for complete microemboli resolution (Tirofiban 68 minutes (53-94); dextran 113 (79-146); or in controls 53(49-68); P<0.001, KW) were shorter with tirofiban.
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Gillis, Keith Andrew. "Oxidative stress and its haemodynamic consequences in chronic kidney disease." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7608/.
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Chronic kidney disease (CKD) is associated with increased cardiovascular risk in comparison with the general population. This can be observed even in the early stages of CKD, and rises in proportion to the degree of renal impairment. Not only is cardiovascular disease (CVD) more prevalent in CKD, but its nature differs too, with an excess of morbidity and mortality associated with congestive cardiac failure, arrhythmia and sudden death, as well as the accelerated atherosclerosis which is also observed. Conventional cardiovascular risk factors such as hypertension, dyslipidaemia, obesity, glycaemia and smoking, are highly prevalent amongst patients with CKD, although in many of these examples the interaction between risk factor and disease differs from that which exists in normal renal function. Nevertheless, the extent of CVD cannot be fully explained by these conventional risk factors, and non-conventional factors specific to CKD are now recognised to contribute to the burden of CVD. Oxidative stress is a state characterised by excessive production of reactive oxygen species (ROS) and other radical species, a reduction in the capacity of antioxidant systems, and disturbance in normal redox homeostasis with depletion of protective vascular signalling molecules such as nitric oxide (NO). This results in oxidative damage to macromolecules such as lipids, proteins and DNA which can alter their functionality. Moreover, many enzymes are sensitive to redox regulation such that oxidative modification to cysteine thiol groups results in activation of signalling cascades which result in adverse cardiovascular effects such as vascular and endothelial dysfunction. Endothelial dysfunction and oxidative stress are present in association with many conventional cardiovascular risk factors, and can be observed even prior to the development of overt, clinical, vascular pathology, suggesting that these phenomena represent the earliest stages of CVD. In the presence of CKD, there is increased ROS production due to upregulated NADPH oxidase (NOX), increase in a circulating asymmetric dimethylarginine (ADMA), uncoupling of endothelial nitric oxide synthase (eNOS) as well as other mechanisms. There is also depletion in exogenous antioxidants such as ascorbic acid and tocopherol, and a reduction in activity of endogenous antioxidant systems regulated by the master gene regulator Nrf-2. In previous studies, circulating markers of oxidative stress have been shown to be increased in CKD, together with a reduction in endothelial function in a stepwise fashion relating to the severity of renal impairment. Not only is CVD linked to oxidative stress, but the progression of CKD itself is also in part dependent on redox sensitive mechanisms. For example, administration of the ROS scavenger tempol attenuates renal injury and reduces renal fibrosis seen on biopsy in a mouse model of CKD, whilst conversely, supplementation with the NOS inhibitor L-NAME causes proteinuria and renal impairment. Previous human studies examining the effect of antioxidant administration on vascular and renal function have been conflicting however. The work contained in this thesis therefore examines the effect of antioxidant administration on vascular and endothelial function in CKD. Firstly, 30 patients with CKD stages 3 – 5, and 20 matched hypertensive controls were recruited. Participants with CKD had lower ascorbic acid, higher TAP and ADMA, together with higher augmentation index and pulse wave velocity. There was no difference in baseline flow mediated dilatation (FMD) between groups. Intravenous ascorbic acid increased TAP and O2-, and reduced central BP and augmentation index in both groups, and lowered ADMA in the CKD group only. No effect on FMD was observed. The effects of ascorbic acid on kidney function was then investigated, however this was hindered by the inherent drawbacks of existing methods of non-invasively measuring kidney function. Arterial spin labelling MRI is an emerging imaging technique which allows measurement of renal perfusion without administration of an exogenous contrast agent. The technique relies upon application of an inversion pulse to blood within the vasculature proximal to the kidneys, which magnetically labels protons allowing measurement upon transit to the kidney. At the outset of this project local experience using ASL MRI was limited and there ensued a prolonged pre-clinical phase of testing with the aim of optimising imaging strategy. A study was then designed to investigate the repeatability of ASL MRI in a group of 12 healthy volunteers with normal renal function. The measured T1 longitudinal relaxation times and ASL MRI perfusion values were in keeping with those found in the literature; T1 time was 1376 ms in the cortex and 1491 ms in the whole kidney ROI, whilst perfusion was 321 mL/min/100g in the cortex, and 228 mL/min/100g in the whole kidney ROI. There was good reproducibility demonstrated on Bland Altman analysis, with a CVws was 9.2% for cortical perfusion and 7.1% for whole kidney perfusion. Subsequently, in a study of 17 patients with CKD and 24 healthy volunteers, the effects of ascorbic acid on renal perfusion was investigated. Although no change in renal perfusion was found following ascorbic acid, it was found that ASL MRI demonstrated significant differences between those with normal renal function and participants with CKD stages 3 – 5, with increased cortical and whole kidney T1, and reduced cortical and whole kidney perfusion. Interestingly, absolute perfusion showed a weak but significant correlation with progression of kidney disease over the preceding year. Ascorbic acid was therefore shown to have a significant effect on vascular biology both in CKD and in those with normal renal function, and to reduce ADMA only in patients with CKD. ASL MRI has shown promise as a non-invasive investigation of renal function and as a biomarker to identify individuals at high risk of progressive renal impairment.
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Chandratre, Priyanka Narendra. "Health-related quality of life in gout : a primary care-based mixed methods study." Thesis, Keele University, 2015. http://eprints.keele.ac.uk/2369/.
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Background: Gout is the most prevalent inflammatory arthritis (2.5%) and may affect Health Related Quality Of Life (HRQOL) through its disease features, associated co‐morbid and sociodemographic characteristics. Methods: A systematic review of HRQOL in gout and the instruments used to measure it was performed. 1805 eligible patients in primary care were mailed a questionnaire to ascertain selfreported HRQOL (measured using Health Assessment Questionnaire Disability Index (HAQ‐DI), Short‐Form 36 Physical Function subscale (PF‐10) and Gout Impact Scale (GIS)), gout, co‐morbid and socio‐demographic characteristics. Univariate unadjusted (T‐test and analysis of variance) and multivariate adjusted (linear regression models) associations between HRQOL and independent variables were examined. Focus group interviews of participants’ perspectives towards gout and its treatments affecting HRQOL were conducted and thematic analysis performed. Results: 22 studies in the systematic review identified poor physical HRQOL in those with gout and co‐morbidities. Existing studies were limited by use of either generic or gout‐specific HRQOL questionnaires and mostly secondary care settings. 1184 completed questionnaires were received (response 65.5%). On multivariate adjusted analysis, worse generic and gout‐specific HRQOL was associated with higher attack frequency, history of oligo/polyarticular attacks, allopurinol, body pain, depression, alcohol consumption and age. HRQOL measured using the GIS only was associated with serum uric acid >360μmol/L and currently having an attack and using the PF‐10 and HAQ‐DI only with female gender, stroke and angina. The key themes arising from the qualitative interviews were the impact of gout characteristics, misunderstanding of gout and lack of information from physicians. Conclusions: HRQOL in gout is affected by disease severity, medical and psychological comorbidities and socio‐demographic characteristics. Urate‐lowering treatment should be initiated early to prevent disease progression. Co‐morbidities should be screened for and treated alongside gout. Factors associated with HRQOL differ according to the instrument used and the choice of instrument will depend upon the objectives of future research studies.
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Judah, Sunita Maya. "Biomarker profiling in rheumatoid arthritis : an investigation of markers of immune dysfunction and their relationship to disease phenotype." Thesis, Keele University, 2016. http://eprints.keele.ac.uk/2392/.
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Rheumatoid arthritis is an autoimmune disease in which various mediators of immune function play a vital role in the pathological process, influencing its development, progression and severity. The aim of this study was to investigate the relationship between markers of immune dysfunction and the disease process. One of the main objectives was to identify key biomarkers involved in early RA (< 1 year) and their association with disease measures and development of established disease (> 5 years). Another objective was to determine the relationship between biomarkers of the peripheral circulation and the synovial joint, and to investigate the association of markers from both environments with disease activity and severity. The influence of smoking on biomarker expression and its relationship with disease activity and severity was also investigated. Using ELISAs and bead-based multiplex assays, 41 mediators were analysed in the sera of early RA (n=86), established RA (n=77), OA (n=20), PsA (n=34) and ReA (n=26) patients as well as in paired sera and synovial fluid of 52 RA patients. Data were analysed using a variety of statistical methods including hierarchical clustering, principal component analysis, regression analysis and ROC analysis. This study demonstrated the involvement of numerous interleukins, matrix remodelling mediators and pro-inflammatory mediators in the disease process in both early and established RA, and enabled its differentiation from other arthritides. In addition, biomarkers from both the synovial fluid and the peripheral circulation were found to be associated with disease activity and severity. Cigarette smoking influenced biomarker expression in both the systemic and local environment, and a smoking associated biomarker profile was associated with worse disease. This study reveals that RA is an extremely heterogeneous disease involving many mediators in a complex network which may include various pathological routes. Many of these biomarkers could potentially become new targets for disease intervention.
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Helliwell, Toby. "Polymyalgia rheumatica in primary care : an exploration of the challenges of diagnosis and management using survey and qualitative methods." Thesis, Keele University, 2016. http://eprints.keele.ac.uk/2446/.
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Background: Polymyalgia rheumatica (PMR) is one of the most common inflammatory arthritic disorders seen in older people and is closely related to giant cell arteritis (GCA). Most PMR patients are diagnosed and managed in general practice yet primary care focused research is lacking. Methods: Three complimentary studies were undertaken to investigate PMR and GCA in primary care. 1. A systematic review investigating the diagnosis and diagnostic criteria for PMR 2. A national questionnaire survey of 5000 randomly selected general practitioners (GPs) 3. Qualitative telephone interview study of GPs. Results: No validated diagnostic criteria or combination of investigations were identified that could be used for definitive PMR diagnosis. 1249 (25%) GPs responded to the questionnaire survey. 24 GPs were interviewed for the qualitative study. Features used by GPs to identify PMR were largely in-line with current guidance. Diagnosis was found to be challenging with GPs relying heavily on response to treatment with glucocorticoids. Guideline advised investigations were not routinely requested. Concerns surrounding long term treatment with glucocorticoids were widespread in relation to both potential adverse effects and on-going monitoring. Headache was the main symptom used to identify potential patients with GCA. Other symptoms indicative of GCA were less frequently used. Significant fears relating to missing a diagnosis of GCA exist as well as frustrations in forward treatment and investigation of potential GCA patients with clear regional variations in assessment and referral pathways. Conclusion: For PMR, focused GP educational strategies are needed to promote the need to exclude relevant differential diagnoses and on-going vigilance for treatment complications. Raising awareness of the range of potential features that GCA can present with could aid and improve diagnosis. To complement this, a national standard for fast track pathways for suspected GCA patients to relevant expertise could help to improve care and outcomes for patients with GCA.
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Kuforiji, Folashade. "The investigation of surface chemical and nanotopographical cues to engineer biointerfaces." Thesis, Keele University, 2015. http://eprints.keele.ac.uk/2351/.
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This thesis is focused on understanding the fundamental physical interaction occurring, when a material interacts with a biological fluid containing protein molecules and cells. The interaction of proteins with defined surface chemistry and nanotopography is of major interest in the field of biomaterials. Despite the degree of research undertaken to study this interface, there is still a lack of understanding of how the protein layer evolves with respect to surface parameters, and further how cells condition the surface. By understanding these processes, advanced biomaterial coatings may be developed that allow control over specific cell responses to direct healing processes. Colourimetric and fluorometric assays were carried out to assess protein-surface affinity and amount of protein adsorption. Infrared spectroscopy was used to quantify protein conformational changes incurred upon adsorption on defined nanoscale surfaces presenting a range of chemical functional groups. Model experiments were performed using bovine albumin and fibrinogen adsorbing onto surfaces presenting defined surface chemistry: OH, COOH, NH2, and CH3. Surface curvature on the nanoscale was used to model topography on the same length scale as protein molecules. Silica colloidal dispersions were prepared in batches,11-215 nm diameters allowing chemical modification whilst keeping nanotopography constant. 3T3 fibroblasts were cultured over a library of surfaces presenting a spectrum of batches chemical functionality and nanostructure. Changes in cell attachment, morphology, migration and proliferation were examined. Media was removed at two different time points of 30 minutes and 24 hours, and examined to identify changes in fibroblast secreted proteins. Liquid chromatography was used to separate the cell culture media after incubation with cells over various chemically functionalised surfaces. Electrospray ionisation (ESI) and matrix assisted laser desorption (MALDI) mass spectrometry were used to identify changes in media with respect to the varying surfaces used and over time. The studies presented in this thesis give a better understanding of the interaction between silica nanoparticles and protein molecules, including conformational changes that occur when protein adsorbs on the nanoparticle; the effect of surface nanotopography and defined chemistry on protein adsorption is examined with respect to both chemical functionality and nanotopography. Clear differences were observed in the amount of protein adsorbed and its structural presentation when bound. The strength of the interaction, described through isotherm fitting, gave insight into the mechanism of competitive protein binding. Surface curvature on the nanoscale was also found to act synergistically with surface chemistry to dictate the dynamic accumulation of protein at the surface interface. In the later chapter discussion is given in terms of cell-surface interaction. Experimental evidence is shown for different mass spectroscopic analysis of reduced complexity media following initial cell-surface interaction and that after 24 hours. From this it is postulated that cell secretions are effected through interaction with the surface, with these changes being significant even after 30 minutes of cell culture with the defined surfaces. These changes are specific to the presented surface as they do not alter with respect to longer culture periods, but media are clearly different collected from cells cultured on different surfaces. This research will help solve challenges facing materials science, understand biological responses to surroundings and help in the development and advance of medical devices, drug delivery, therapeutics and diagnostics.
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Rushton, Claire Alexandra. "Time-dependent markers of comorbidity and prognosis in heart failure patients : transitions across the life course." Thesis, Keele University, 2016. http://eprints.keele.ac.uk/2493/.
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Heart failure (HF) disease carries a poor prognosis despite optimisation of cardiovascular (CVD) treatments. Non-CVD comorbid diseases are common and known to influence the HF clinical course. These comorbidities change in severity over time from new onset yet, only static measures of comorbidity have been included in prognosis. A major gap in the management and prognosis of HF is how non-CVD comorbidity severity and longitudinal change influences individual risk. A systematic review (SR) and two phase observational study were conducted in the general HF population to test the hypothesis that increasing severity and change of non-CVD comorbidity would be associated with worse outcomes. The SR showed that the three most common non-CVD comorbidities included in prognosis were diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Hospital admission outcome studies were limited and there were no studies on quality of life. With the exception of hospital based renal studies, comorbidity severity and change evidence was scarce. The observational studies used a case-control study nested within the UK Clinical Practice Research Datalink database (2002- 2014), of 50,114 incident HF patients. Using risk set sampling, multiple controls were matched to cases on follow-up time. A framework for measuring recent comorbidity severity and change was devised using drug or physiological indicators for DM, COPD and CKD measured in two time-windows prior to the match date. Conditional logistic regression was used to estimate adjusted odds ratios for all-cause hospital admission and mortality. The observational study findings were that all three comorbidities were common and associated with both outcomes. Severe and worsening comorbid disease was also common and independently and significantly associated with increased risk of hospital admission and mortality. These dynamic measures of non-CVD comorbidity significantly improved HF prognostic models which has important implications for HF management and prognosis.
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Abdul, Sani Suraya. "Evaluating inhibitory potential targeting cholesteryl ester transfer protein (CETP) by hydroxycitric acid (HCA) found in Garcinia species through kinetic and in-silico technique." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33753/.
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Cardiovascular disease has emerged in developing countries and becoming the leading cause of death recorded. Many scientific studies have been conducted in order to understand the specific mechanism on how atherosclerosis develop, searching for the real culprit that responsible in the progression of the disease and suggesting the possible prevention to overcome this problem. This piece of work examined and revealed the mechanism of action on how secondary metabolites that has been isolated from Malaysian local plants which have the properties to impede the action of cholesteryl ester transfer protein (CETP) in order to prevent the atherosclerosis. Preliminary results of the crude plant extracts from the initial screening showed positive results. A similar trend of inhibition can be obtained for twigs and leaves extracts of Garcinia atroviridis and Garcinia parvifolia. Ethanol extracts of fruit parts of Garcinia atroviridis give IC50 of 19.28 ± 0.021 mg/ml which shows the highest inhibitory compared to the other extracts of other plant parts. The remarkable results that are obtain from fruit rinds of Garcinia atroviridis do give some hints that the secondary metabolites that are present might have the ability to inhibit CETP. Based on literature review, it is postulated hydroxycitric acid (HCA) might be responsible for inhibiting CETP activity and HCA has been selected for further studies. Kinetic studies have been employed in this piece of work in order to see the types of inhibition that HCA possess against CETP. The kinetic study has revealed that HCA is a noncompetitive inhibitor because of the Km (-0.12) that is unchanged for every substrate and the Vmax is increased when the concentration of the inhibitor increase. Further in-silico works such as molecular docking and molecular dynamic has been implemented as well in order to see the interaction and mechanism of action between HCA and CETP. The molecular docking work has revealed that HCA binds to the same side as torcetrapib does and the RMSD obtained was 2.703Å. Molecular dynamics has been employed as well in order to see the extensive structural and functional analysis and also to evaluate the strengthness of the complex between HCA and CETP. The complex were found to be stable due to the existence of the hydrogen bonding to SER230 and the overall RMSD reading are between the range of 0.8Å, 2.4Å and 3.2Å. Overall, this work are pioneering and pave the way for further studies in establishing a new chemical template form of natural products for CETP research with an objective to extend the scope of work into in-vivo studies and x-ray crystallography in order to enable us to understand the mechanism of action in protein level. The in-silico studies in this work provides a preliminary understanding on the structural basis of CETP structure and its active sites which could accommodate the exact template of chemical molecule. With this new understanding, an inhibitor drug which are effective with lesser side effect, targeting atherosclerosis could be developed.
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Osborne, Scott. "Immunopathology of complex regional pain syndrome." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/14485/.
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Both increased mast cells numbers and raised immune mediator concentrations indicate immune activation in the affected skin of patients with early CRPS, but little is known about regional immune cell involvement in late stage CRPS. The aim of the current study was to determine skin immune cell populations in longstanding CRPS. Using 6mm skin punch biopsies from CRPS-affected and non-affected tissues, and a combination of chemical and immunofluorescence staining, we examined the density and function of key cell populations including mast cells, epidermal Langerhans cells (LCs), and tissue resident T-cells. We found no significant differences in either overall immune cell infiltrates, or mast cell density between CRPS-affected and non-affected sub-epidermal tissue sections, contrasting recent findings in early CRPS by other groups. However, CD1a+ LC densities in the epidermal layer were significantly decreased in affected compared to non-affected CRPS limbs (p = <0.01). T-cell clones isolated from CRPS- affected sub-epidermal tissues displayed a trend towards increased IL-13 production in ELIspot assays when compared to T-cells isolated from non-affected areas, suggesting a Th2 bias. Immune cell abnormalities are maintained in late stage CRPS disease as manifest by changes in epidermal LC density and tissue resident T-cell phenotype.
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Gillani, Syed M. R. "An evaluation of the impact of a data driven, individualised, diabetes specific, structured information delivered by mail to people with diabetes : the WICKED (Wolverhampton Interface Care-Knowledge Empowered Diabetes) Project." Thesis, University of Warwick, 2015. http://wrap.warwick.ac.uk/81980/.
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Background Does promoting patient activation improve outcomes? We tested the hypothesis that provision of structured and personalised information can activate patients, promote selfcare, and improve outcomes. Methods We recruited all eligible people with diabetes in Wolverhampton CCG (n= 14,559), randomizing them into two groups. The active group was mailed their “My diabetes, My information, My plan” report at baseline, 3 and 6 months; the control group received standard care for first 3 months, then a single mailing. We compared a Failed Process Score (FPS = completion of nine processes; zero = full attainment) and HbA1c. A patient feedback survey was sent to 1000 randomly selected patients from the active cohort to assess the qualitative impact of this individualised report. Results At three months, the FPS score (1.25 ± 1.87 vs. 1.35 ± 1.97, P < 0.01) and the change in FPS score (0.48 ± 1.55 vs. 0.42 ± 1.49, P < 0.02) were significantly better in the active group. At 12 months FPS score between group differences just failed overall significance (F=3.459, p=0.06). However, in those with lower baseline activation (FPS of ≥2), FPS was significantly better (F=4.369, p=0.037, 3 month (p<0.01), 12 month (p=0.01)) in the multi mailed and their likelihood of achieving the good attainment category (12 month FPS ≤1) with mailing was 1.15 (95% CI 1.02 – 1.29, p=0.022). Considering baseline HbA1c% categories as ≤7.5, 7.6-8.4 and ≥8.5, and adjusting for variables in univariate analysis (r2=0.39, p<0.001; age p<0.001, gender (ns), ethnicity (ns), IMD score (ns), type of diabetes (ns)), the impact of being mailed multiple times was significant (F= 6.2, p=0.013).In the patient feedback survey, patients found this report useful (89%), a source of knowledge (78%) and confidence (74%) and it helped them in understanding their diabetes (78%). Conclusion The provision of structured and individualized information to people with diabetes can positively influence the level of patient activation, promote better engagement and open the potential to improve other crucial diabetes outcomes.
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Blaxter, Laurence. "Non-invasive monitoring of peripheral perfusion : an exploration of non-invasive peripheral perfusion monitoring for applications in research & healthcare." Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/28735/.
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The need for real-time, prognostic perfusion data has been widely recognised in clinical practice and academia. Perfusion, the volumetric blood low to tissue, is an important tool for haemodynamic monitoring, since perfusion adequacy is vital to tissue health. Perfusion can serve as both a diagnostic indicator and a fundamental research tool. However, lack of a low cost, easily applied, and non-invasive sensor technology capable of measuring peripheral perfusion in absolute volumetric units is clearly a major factor preventing the widespread clinical use of perfusion monitoring. This thesis explores and evaluates potential techniques for the non-invasive measurement of peripheral perfusion in absolute volumetric units. Following a review of applicable technologies, a small selection of complementary optical methods are selected for study based on economic and technology readiness arguments, and a series of volunteer studies conducted to evaluate these using both of the shelf and prototype apparatus. A study of healthy adult and child volunteers demonstrates that Laser Doppler flowmetry (LD) outperforms both pulse oximeter derived Perfusion Index (PI), and a novel Capillary Refill Time (CRT) measurement device by a considerable margin in a cold challenge test. The PI metric had the lowest correlation with temperature, suggesting it is the least effective perfusion analogue of the three. A novel filtering algorithm is presented for removal of artefacts from raw LD flowmetry data. CRT was found to significantly correlate with short period oscillations in LD perfusion. A second study combined CRT with NIRS, allowing tissue haemoglobin concentrations to be estimated. Studies of the palm of healthy volunteers hands using this device, in combination with cooling and/or venous and arterial occlusion, demonstrate both that capillary refill measures blood mobility within the capillary bed, and that NIRS with venous occlusion is an effective method for measurement of absolute perfusion. Although LD was the most effective existing solution, and CRT has potential, only thermal techniques and NIRS with venous occlusion allow practical, low cost quantification of absolute perfusion. Development of a thermal diffusion sensor is recommended.
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Paul, Julie. "Evaluating the impact of a universal FRIENDS for Life Programme on emotional distress and academic self-perceptions." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12978/.
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FRIENDS For Life' (Barrett, 2004) is a ten-week programme for children aged 7 - 11 years, based on cognitive behavioural principles, designed to teach coping skills and techniques to manage anxiety and depression. This study describes an evaluation of a universal programme, delivered to a class of Year 5 children in a school in a socio-economically disadvantaged community located in the East of England. A review of literature, combining narrative and systematic approaches, presents what is known about the development of emotional distress and academic self-perceptions in children, underpinned by the principles of Social Cognitive Theory (Bandura, 1986). Evidence for the effectiveness of Cognitive Behavioural Therapy with children is critiqued, with specific attention to the FRIENDS programme delivered as a universal intervention. A quasi-experimental non-equivalent groups design (intervention group and wait-list control) was employed to evaluate the impact of the programme upon children's levels of emotional distress, their academic self-perceptions and teacher ratings of pupil behaviour. Pre and post-test measures comprised the Paediatric Index of Emotional Distress, (O'Connor et al, 2010), the Myself-As-Learner Scale (Burden, 1998) and the Strengths and Difficulties Questionnaire (Goodman, 1997). A change score analysis revealed statistically significant reductions in self-reported levels of emotional distress and teacher-rated hyperactivity for the intervention group in comparison to the control group. Both groups showed significantly improved overall behaviour and prosocial skills. There was no evidence of a significant change between or within groups for academic self-perceptions. The limitations associated with quasi-experimental designs are highlighted, together with the difficulties of operationalising abstract constructs such as 'emotional distress' and 'academic self-concept.' The results are discussed in relation to the theoretical and methodological implications highlighted in previous chapters. Particular attention is paid to the significance of contextual influences operating in concert with the programme components in mediating outcomes. Implications for future research and the role of the Educational Psychologist supporting universal therapeutic programmes in schools are discussed.
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Weiner, Kate. "Patient and professional constructions of familial hypercholesterolaemia and heart disease : testing the limits of the geneticisation thesis." Thesis, University of Nottingham, 2006. http://eprints.nottingham.ac.uk/10190/.
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This thesis provides an empirical investigation of the geneticisation thesis. Geneticisation is one of the most prominent critiques of the social and cultural implications of developments in genetics. It incorporates a set of claims and expectations about the way genetic knowledge and technologies are transforming or will transform ideas about health and illness, and health care practices. This research aims to explore the empirical basis of these claims, by looking at the place of genetic discourses and practices in one specific area. The thesis focuses on familial hypercholesterolaemia (FH), a treatable hereditary cholesterol condition associated with high rates of coronary heart disease (CHD). It asks how much and in what ways patients with FH and professionals involved with the condition construct FH and CHD as genetic conditions. The thesis draws on three main areas of data - biomedical literature concerning CHD and FH; ethnographic work concerning the activities of HEART UK, the main UK health charity involved with inherited lipid disorders and cholesterol; and interviews with patients with FH and with staff and members of HEART UK. The analysis suggests that FH is not understood or managed within a strong genetic frame, and that neither professionals involved in HEART UK, nor patients with FH, provided or contributed to radically new or geneticised accounts of CHD. In short, the research suggests that geneticisation overstates the transformatory potential of genetics, and that factors such as the availability of effective therapeutics, the sites where care takes place, the disciplines involved, and existing lay and professional models of disease are important for the construction of a particular field. Furthermore, in arguing that FH is not associated with a strong specific disease identity or community, the analysis questions the notion of biosociality, suggesting that is may be less relevant to some biological states or conditions than to others.
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Langley, Alyson. "Evaluation of the median nerve within the wrist during functional hand activity using ultrasonography." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11669/.
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Over the last 20 years, an increasing number of research studies have shown that ultrasonography can provide a valid and accurate assessment of the median nerve and the pathological changes associated with median nerve disorders. More recently ultrasonographic technology has advanced and it now allows for dynamic imaging of the nerve during physical movement of the hand. However dynamic ultrasonographic imaging is still a relatively new application as is yet to be explored to its full potential in the study of median nerve dynamics and the associated pathological changes. The primary aim of this research is to study median nerve activity during physical hand movement using ultrasonography with 8-16MHz linear array transducer. The objectives are to establish an ultrasonographic technique for the dynamic imaging of the median nerve, along with an analytical method that can quantify its changing size, shape and location during four hand movements. The data obtained from participants with normal median nerve function is compared to values from participants who are either moderately symptomatic or fully symptomatic of a median nerve disorder, to investigate whether the novel method and technique could distinguish between the groups. Three studies were designed to investigate median nerve activity during physical movement using ultrasonography. The aim of the first study was to investigate if the novel quantification method and ultrasonographic technique could measure the changing parameters of the median nerve between the start and end positions of a finger grip, power grip, pinch grip and thumb opposition movement, in non-symptomatic participants who have normal median nerve function. The second study investigated whether the novel quantification method and ultrasonographic technique could distinguish between the non-symptomatic participants and participants who are either moderately symptomatic or fully symptomatic of a median nerve disorder, during each movement. The third study examined the change in size, shape and location of the median nerve at five intervals during the four movements and compared the data obtained from the non-symptomatic group with the values obtained from the moderate and fully symptomatic groups. The findings from the studies show that the dynamic ultrasonographic technique can be used to image the median nerve during physical activity of the hand and that the novel quantification method can be used to measure the change in the parameters of the median nerve during physical hand activity and distinguish significant differences between the non-symptomatic median nerve and those symptomatic of an median nerve disorder.
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English, Christine. "Intrapsychic dimensions of addiction : the wearing down of help seeking capacities by cruel and tyrannical objects." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12317/.
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Research had two aims: firstly, to explore the clinical observation that dependent drug users are often apparently unwilling, or are unable to reflect in any depth on experience, including thinking about mental states in self and other. Secondly, to consider the intrapsychic elements that exist alongside, and which may motivate drug addiction (including heavy and dependent alcohol use). 34 drug users were interviewed using the Adult Attachment Interview, and interviews coded for Reflective Function (RF), an objective measure of the capacity to mentalize. Low RF was identified across the sample. Data from Adult Attachment Interviews also revealed that a climate of violence and/or cruelty, deprivation and a lack of basic care nearly always precede chronic drug or alcohol addiction. I suggest that as a result of this the individuals interviewed had minimised thinking about their own & others’ states of mind. Ten of the sample were then interviewed twice more using a research interview based on the clinical psychotherapeutic interview, which explored internal dynamics and object relational aspects of participants’ narratives. The data obtained revealed the presence of two kinds of internal object relating in a very specific way. A cruel, bullying, depriving object was found to dominate, and to severely restrict access to, a much weaker, though potentially helpful internal object. There was an over-reliance on the dominant bad object which was felt at one time to have saved the addict from unbearable psychic pain, but had then demanded he turn forever away from human help, denying the need for this or indeed any vulnerability or ‘weakness’. Whilst intoxication was initially found both to help the addict sustain this position, and to obliterate psychic pain, ongoing addiction actually cemented the dynamic described, and further inhibited access to helpful, human objects.
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Naseeba, Alozaibi. "Patient and professional perceptions of metabolic syndrome and its management : a qualitative study in the United Arab Emirates." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12884/.
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Metabolic syndrome (MetS) is defined as the clustering of medical conditions (that is impaired fasting glucose (IFG) or type 2 diabetes mellitus (T2DM), hypertension (HTN), obesity and dyslipidaemia) that increase an individual's risk of developing diabetes or cardiovascular diseases (CVD). In the United Arab Emirates (UAE), the prevalence of MetS and its features are among the highest in the world. However, research that explores the health needs of patients with MetS within the socio-cultural context of the UAE is lacking. This study aimed to explore patient and professional perceptions of MetS and its management in the UAE. A qualitative approach that drew on the broad principles of grounded theory was undertaken to meet the aims of the study. Following ethical approval, semi-structured interviews were conducted with 29 patients with MetS and 27 health care professionals (HCP) involved in the management of patients with MetS (10 physicians, 11 pharmacists, 4 dieticians and 2 health educators). This was followed by one focus group discussion with nine pharmacists for further exploration of identified themes. Interviews were audio-recoded and transcribed verbatim. NVivo aided the organisation of data. Thematic analysis based on the principles of grounded theory was conducted. This study was able to identify a number of factors that influenced patients' perceptions of their health and attitude towards their treatment plan. All patients interviewed were unfamiliar with the MetS concept and claimed to have never been informed by their physicians about their MetS diagnosis. Patients' awareness of the high prevalence of MetS features in the UAE, the asymptomatic nature of the cardiometabolic risk factors (CRFs) and the availability of treatment resulted in downplaying of MetS risk. Not all HCPs were familiar with the MetS concept or definition. Factors such as the complexity of the MetS name and the absence of the MetS diagnosis from the list of reimbursed medical conditions discouraged physicians from informing patients of their MetS diagnosis and limited the clinical utility of the MetS concept respectively. The study found that a number of socio-cultural factors hindered successful implementation of lifestyle interventions. Such factors included family restrictions of outdoor exercising by women, lack of culturally sensitive health clubs, food-centric activities and eating habits. Patients' beliefs about medicine and medicine brands affected their medicine-taking habits and altered their adherence. HCPs believed that a population-focused health approach would result in behavioural change. They also emphasised the key role of the public health policy to prevent MetS and promote a healthy lifestyle. Patients acknowledged the importance of adhering to lifestyle interventions to control their clustering risk factors. However, they believed that their lack of motivation, willpower, and limited physical mobility, due to coexisting health condition, were detrimental to adherence to lifestyle interventions. This study provides important new information for understanding the dynamics of patients' health behaviour and attitude towards MetS treatment in the UAE. It also demonstrates how aspects of the health policy and professionals' clinical practice limit the clinical utilisation of the MetS concept. Efforts to promote healthy behaviour and enhance the prevention and management of MetS in the UAE need to be stepped up and be tailored to patients' personal, social and cultural needs.
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Ramachandran, Rajani. "Are individuals with autism spectrum disorders sensitive to traits?" Thesis, University of Nottingham, 2007. http://eprints.nottingham.ac.uk/12016/.
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This thesis examined whether individuals with Autism Spectrum Disorders are sensitive to traits. The ability of individuals with Autism Spectrum Disorders to infer traits from descriptions of behaviour was investigated by asking participants to read trait implying sentences and then to chose one of two words that best related to the sentence. In experiment 1, individuals with Autism Spectrum Disorders performed similarly to matched controls in being faster at choosing the trait in comparison to the semantic associate of one of the words in the sentence. The results from experiments 1 and 2 provided converging evidence in suggesting that inferring traits from textual descriptions of behaviour occurs with relatively little effort. The results of experiment 3 suggested that making trait inferences took priority over inferring actions or making semantic connections between words. Experiment 4 investigated whether individuals with Autism Spectrum Disorders associated the inferred trait with the person carrying out the behaviour (actor). Participants were presented with a pair of faces and sentences followed by the same pair of faces being presented with a single word. Participants had to choose which actor is best described by the word. The results provided evidence that participants with Autism Spectrum Disorders were able to associate inferred traits with the actor easily, even when the actor was represented by his face. The experiments described in this thesis provide evidence for the possibility of trait inference as relating to behaviour being a spared socio-cognitive function in autism.
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Tonge, Daniel Paul. "The role of skeletal muscle in the initiation and progression of knee osteoarthritis." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11820/.
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It is established that patients with knee osteoarthritis (OA) exhibit marked muscle weakness, one of the most frequent and earliest reported symptoms associated with knee OA. Weakness primarily affects the quadriceps muscle with little evidence of hamstring involvement. Traditionally, muscle weakness has been considered a secondary effect in knee OA, resulting from disuse of the affected joint due to the presence of pain and/or inflammation, and therefore has received little attention with regards to its involvement in the initiation or progression of OA. However, there is clinical evidence which suggests that quadriceps weakness may precede the onset of radiographic evidence of OA and subsequent pain, and therefore may be directly involved in its pathogenesis. Furthermore, targeted exercise regimes aimed at improving quadriceps function indicate therapeutic benefits with regards to both the initiation and progression of knee OA. Quadriceps muscle dysfunction in knee OA is currently poorly understood and represents an unmet clinical need. Consequently, the main aims of this work were to characterise quadriceps muscle dysfunction in the rodent meniscectomy-induced (MNX) and spontaneous guinea pig model of OA at the molecular level determining changes in muscle fibre type, metabolic potential, and muscle atrophy signalling. Furthermore, the effects of clenbuterol-induced quadriceps hypertrophy, prior to the induction of OA, on disease severity were considered in the rat MNX model. Thus far, the cDNA sequences encoding each member of the myosin heavy chain (MHC) gene family have yet to be determined in the guinea pig. Therefore, a further aim of this work was to generate novel cDNA sequence pertaining to the skeletal muscle-associated isoforms of MHC in the guinea pig, and to develop specific oligonucleotide primers to determine the abundance of each specific mRNA. The development of MNX-induced and spontaneous OA was associated with changes in MHC I expression indicative of an increase in slow, type I muscle fibres. The assessment of muscle atrophy-associated genes revealed that neither model was associated with overt quadriceps muscle atrophy, or increased muscle atrophy signalling. Combined, these data suggest that OA associated quadriceps dysfunction may result predominantly from altered contractile properties, as evidenced by altered MHC expression, rather than from reduced quadriceps mass per se. The administration of clenbuterol for 14 days induced marked increases in quadriceps mass relative to bodyweight. However, clenbuterol induced hypertrophy was unable to favourably modulate OA severity in the MNX-induced model in this experimental setting. In conclusion this work has shown that OA is associated with altered quadriceps muscle properties, suggestive of a switch towards a slow-twitch muscle fibre type, in two independent animal models. Such data have important implications for the development of targeted pharmaceuticals and in the prescription of rehabilitation regimes aimed at improving OA severity or reducing disease progression. Moreover, the relationship of increased MHC I expression to joint stability and muscle function warrants further investigation in the OA setting.