http://www.dspace.cam.ac.uk:80/handle/1810/219488 Thu, 23 May 2013 05:09:12 GMT 2013-05-23T05:09:12Z http://www.dspace.cam.ac.uk:80/handle/1810/243942 Title: Closed-loop insulin delivery in adults with type 1 diabetes Authors: Kumareswaran, Kavita Abstract: Achieving tight glucose control safely in type 1 diabetes with currently available methods of insulin delivery is challenging. Aggressive regimens carry an increased risk of hypoglycaemia, particularly overnight. Both alcohol consumption and exercise predispose further to low glucose levels. The demands are even greater in pregnancy where, in addition to limiting hypoglycaemia, avoidance of postprandial hyperglycaemia is critical to minimising adverse obstetric outcomes. The aim of my studies was to evaluate feasibility and safety of a closed-loop or ’artificial pancreas’ system linking insulin delivery with continuous glucose monitoring (CGM), in adults with type 1 diabetes in a controlled setting. Three randomised crossover studies compared closed-loop insulin delivery with conventional insulin pump therapy on two separate occasions, matched in meals and activities. During closed-loop visits, CGM values were entered into a computer containing a model predictive control algorithm which advised on basal insulin infusion for subcutaneous delivery, every 15 minutes. During control visits, usual insulin pump regimen was continued. The feasibility study evaluated overnight closed-loop in 12 adults (seven females, mean age 37.7 years, HbA1c 7.8%) following 60g- carbohydrate evening meal. A follow-up study assessed overnight closed-loop in 12 further adults (seven females, mean age 37.2 years, HbA1c 7.8%) following 100g-carbohydrate meal and (mean 564 ml) white wine. The third study evaluated 24 hours of closed-loop in 12 pregnant women (mean age 32.9 years, 19 to 23 weeks gestation, HbA1c 6.4%) during normal daily activities, including low and moderate intensity exercise. Activity and glucose levels were also measured during free-living. CGM performance during exercise was evaluated. Overnight closed-loop insulin delivery in adults, compared with conventional pump therapy, increased time spent with plasma glucose in target range (3.9−8.0 mmol/l) following both standard meal (81% versus 57%; p = 0.012) and large meal accompanied by alcohol (70% versus 46%; p = 0.012). Glycaemic variability, and time spent in hypo- and hyper- glycaemia were lowered. In pregnant women, day and night closed-loop insulin delivery was as effective as usual pump regimen (81% versus 81% time spent with plasma glucose 3.5−7.8 mmol/l; p = 0.754). Hypoglycaemia occurred following exercise, although closed-loop prevented nocturnal episodes. Glycaemic control during free-living was suboptimal, compared with controlled diet and exercise conditions. Accuracy of CGM was lower during exercise. In conclusion, these studies confirm the feasibility and efficacy of overnight closed-loop insulin delivery in adults with type 1 diabetes. Closed-loop is safe during pregnancy and may be beneficial in women with suboptimal glycaemic control. Meals and physical activity currently limit optimal daytime use of closed-loop. Mon, 08 Oct 2012 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/243942 2012-10-08T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/243719 Title: Imaging atherosclerotic plaque inflammation with [18F]- fluorodeoxyglucose positron emission tomography Authors: Rudd, James H. F. Abstract: Inflammation is important in both the pathogenesis and outcome of atherosclerosis. Plaques containing numerous inflammatory cells, particularly macrophages, have a high risk of rupture, whereas those with fewer inflammatory cells are at lower risk. The current ‘gold standard’ technique for imaging atherosclerosis is x-ray contrast angiography, which provides high-resolution definition of the site and severity of luminal stenoses, but no information about plaque inflammation. Quantification of plaque inflammation is desirable both to predict risk of plaque rupture and to monitor the effects of atheroma-modifying therapies. This is important since recent studies strongly suggest that HMG Co-A reductase inhibitors promote plaque stability by decreasing plaque macrophage content and activity without substantially reducing plaque size and therefore angiographic appearance. FDG is a glucose analogue that is taken up by cells in proportion to their metabolic activity. In this work, the central hypothesis was that plaque inflammation could be visualised and quantified non-invasively using FDG-PET. Initially, THP-1 monocytes and buffy-coat macrophages were stimulated with cellular activators, and the effect on deoxyglucose uptake was observed. It was demonstrated that both types of cell accumulated deoxyglucose in proportion to their metabolic activity. Next, FDG uptake was assessed in endarterectomy specimens from patients with symptomatic carotid disease. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas. Subsequently, co-registered FDG-PET imaging was performed in patients with transient ischaemic attack. FDG accumulated within carotid plaques, with significantly more FDG being taken up into symptomatic plaques than contralateral asymptomatic lesions. Finally, a rabbit model of atherosclerosis was established to investigate two related questions: firstly, whether an animal PET scanner (MicroPet) might detect atheroma, and secondly whether FDG-PET could image and perhaps quantify both atheroma progression and regression. Aortic atheroma was identified by FDG-PET, but full quantification was not possible, because the microPet system is currently unable to perform studies with attenuation correction. In summary, it has been shown, both in vitro and in vivo, that inflammation within atherosclerotic plaques can be successfully imaged by FDG-PET. In addition, pilot data from an experimental study of atherosclerosis in rabbits suggested that serial imaging with this technique might be useful for monitoring the effects of anti-atheroma drugs. Mon, 06 Oct 2003 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/243719 2003-10-06T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/242187 Title: The effect of glibenclamide on the pathogenesis of melioidosis Authors: Koh, Gavin Christian Kia Wee Abstract: Melioidosis is an important cause of community-acquired sepsis, endemic to Southeast Asia and Northern Australia. Melioidosis is caused by the soil saprophyte, Burkholderia pseudomallei, a motile Gram-negative bacillus, and is associated with a mortality rate that approaches 50% in Northeast Thailand. The most important risk factor for melioidosis is diabetes mellitus, and two-thirds of all adult patients with melioidosis have diabetes as a risk factor. It has been noted previously, however, that patients with diabetes have lower mortality than patients without diabetes. In this dissertation, we look at a cohort of 1160 consecutive adult melioidosis patients presenting to Sappasithiprasong Hospital in Ubon Ratchathani, Thailand, 410 (35%) of whom were diagnosed with diabetes prior to admission. We confirmed previous findings that diabetes protected from mortality in melioidosis, but also found that this protective effect was confined to a smaller subset of patients (208 patients) who were treated with glibenclamide prior to admission. Patients with hyperglycaemia (but no diagnosis of diabetes prior to admission) had the same mortality rate as patients without diabetes. In vitro experiments found no inhibitory effect of glibenclamide on bacterial growth, and we therefore looked for evidence of an effect of glibenclamide on the host. We conducted a gene expression study of circulating blood leukocytes in melioidosis patients and compared them to uninfected controls. In this study, we found that glibenclamide was associated with an anti-inflammatory effect on the host response to melioidosis. To further elucidate a mechanism for the action of glibenclamide, we studied the effect of glibenclamide therapy in a mouse model of melioidosis and found that the effect of glibenclamide was specific to interleukin-1β secretion. This reduction in interleukin-1β secretion was associated with reduced cellular influx into the lungs as well as lower bacterial loads in blood, liver and spleen. Tue, 06 Mar 2012 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/242187 2012-03-06T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/240684 Title: Statistical analysis of end-points in cancer clinical trials Authors: Campbell, Ian Abstract: The major end-points arising from cancer clinical trials are reviewed. These are: tumour response, treatment morbidity, survival with related data, and quality of life. A survey of tumour response data from 81 published clinical trials found the most common statistical test in use to be a Chi squared test of the total response rate, but a total of 21 different statistical methods were used. The various statistical tests available are reviewed, including the Mann-Whitney test and the Chi squared test for trend which make use of all the categories of response and their intrinsic order. The assumptions underlying the tests are described. Theoretical considerations support the Mann-Whitney test as the optimum choice for the analysis of tumour response data. Methods for comparing alternative statistical tests are summarised, and a new method is described which uses a number of typical sets of data to estimate the relative efficiency of two statistical tests by the median value of the square of the ratio of the z-values. Using this technique, and data from the 81 trials, the Mann-Whitney test is found to be around 40% more efficient than the Chi squared test of the total response rate (this increased efficiency is equivalent to increasing the recruitment to the trial by 40%). This practical result is confirmed by mathematical modelling of tumour response using the power relation of the Mann-Whitney test for ordered categorical data, which is derived. Clinical data is found to fit best a shift model which assumes homogeneity of treatment effect across the different grades of response. On the basis of this model, the Mann-Whitney test is found to be 30% to 110% more efficient than a Chi squared test of the total response rate. The similarities of acute morbidity data to tumour response data lead to similar general conclusions on the optimum method of statistical analysis. In a survey of 36 published clinical trials, the most common method of statistical analysis was again a Chi squared test of a dichotomy (such as no morbidity versus morbidity of any grade). Analysis of data from these trials shows the Mann-Whitney test to be more efficient by around 30%. A survey of 81 papers reporting tumour response in clinical trials found that few of them used methods of estimation of the difference between the treatments, or derived confidence intervals of the size of such a difference. Methods of estimation and calculation of confidence intervals were found even less often in a survey of methods of presentation of morbidity results. The possible reasons for this are discussed. It is concluded that the current methods of analysis of tumour response data and many sets of acute treatment morbidity data are not optimum, and a change should be made from the Chi squared test to the Mann-Whitney test. Such a change could be equivalent to an increase in recruitment into many cancer clinical trials of around 40%. Tue, 01 Mar 1994 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/240684 1994-03-01T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/226746 Title: T-lymphocyte senescence and hepatitis C virus infection Authors: Hoare, Matthew Abstract: Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. The degree of fibrosis progression and treatment-related outcomes are critically dependent on the age of the infected individual. Progressive ageing is associated with a decline in the efficacy of adaptive immune system function. T-lymphocytes from aged subjects demonstrate multiple phenotypic and functional changes, including telomere shortening. Short telomeres are associated with poor proliferative capacity, pro-inflammatory responses and increased mortality in clinical studies. This research aimed to study telomere length changes in T-lymphocytes in chronic HCV infection and its relationship to clinical endpoints. Further, the intracellular signalling changes in T-lymphocytes with short telomeres were studied in subjects with chronic HCV. Short CD4+ T-lymphocyte telomeres were associated with the presence of severe hepatic fibrosis independent of other known factors. Telomere length was associated with blood markers of hepatic damage and dysfunction as well as histological markers of inflammation and fibrosis. Further, on prospective follow-up, short CD4+ telomere length at enrolment predicted progression to clinical endpoints of hepatic decompensation, development of hepatocellular carcinoma and death. Short CD4+ telomere length predicted a failure to respond to anti-viral treatment for HCV infection. Unexpectedly, subjects with non-viraemic HCV had short CD8+ telomere length. Liver biopsy tissue from a cohort of subjects with non-viraemic HCV was studied and demonstrated significant inflammation or fibrosis in most. To study the IFN-α signalling pathway in cells with short telomeres, I utilised the phospho-histone γ-H2AX, a downstream signal from short telomeres. CD8+ T-lymphocytes expressing γ-H2AX had the form and function of cells with end-stage differentiation. γ-H2AX+ cells had a pro-inflammatory cytokine secretion profile with high expression of IFN-γ and low IL-2. Further γ-H2AX+ cells were unable to respond to exogenous IFN-α by phosphorylating Stat1. This failure was attributable to a post-receptor defect. T-lymphocyte telomere length changes in HCV may underpin the effect of age on clinical and treatment-related outcome. Short telomeres are associated with intracellular signalling defects which may explain the failure to respond to anti-viral therapy. Mon, 05 Jul 2010 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/226746 2010-07-05T23:00:00Z