Thesis (M.A.)--Catholic Theological Union at Chicago, 2004. / Vita. "September 2004." Includes bibliographical references (leaves 139-142).

Thesis (M.A.)--Catholic Theological Union at Chicago, 2004. / Vita. "September 2004." Includes bibliographical references (leaves 139-142).

Thesis (M.A.)--University of North Carolina at Greensboro, 2007. / Title from PDF t.p. (viewed Oct. 18, 2007). Directed by Hephzibah Roskelly; submitted to the Dept. of English. Includes bibliographical references (p. 73-75).

Thesis (M.A.)--University of Wisconsin--Madison, 1984. / Typescript. Title from title screen (viewed May 3, 2007). Includes bibliographical references (leaves 263-282). Online version of the print original.

The "first study" compared 3 methods of assessing arterial stiffness and found that: each method of assessment was comparable to the other and that reproducibility was similar throughout the systems. Since there are conflicting data associated with arterial stiffness and type-2 diabetes, the "second study" therefore assessed arterial stiffness, using pulse wave analysis and pulse wave velocity and found there to be increased arterial stiffness in a group of type-2 diabetics compared to healthy controls. The second study also found that South Asians had significantly lower arterial stiffness in the femoral vascular bed compared to the Caucasians. Although diabetes is known to increase arterial stiffness, the effect of impaired fasting glucose on arterial stiffness is unclear. The effect of impaired fasting glucose on arterial stiffness has therefore been investigated in the "third study" and the findings demonstrate that individuals with impaired fasting glucose have increased arterial stiffness compared to individuals with normal fasting glucose. Similar findings were observed when comparing diabetics and individuals with normoglycaemia. Finally, therapeutic intervention targeted at increased arterial stiffness should be of benefit in reducing the prevalence of cardiovascular disease. The "fourth study" has therefore also examined the effect of regular aerobic exercise on arterial stiffness and found that in older individuals, arterial stiffness was significantly lower in a group of individuals who exercised regularly compared to sedentary controls. Therefore, suggesting the potential benefit of aerobic exercise as a non-pharmacological intervention to decrease arterial stiffness and cardiovascular disease.

Acute myeloid leukaemia (AML) is a heterogeneous disorder characterised by the accumulation of immature haematopoietic cells blocked at various stages of differentiation. Despite improved survival rates over the past decade, relapse occurs in approximately 70% patients undergoing chemotherapy. A potential reason for this is that current clinical protocols do not take account of the level of residual disease present at remission. Therefore, one strategy to reduce relapse rates is to monitor minimal residual disease and continue to treat until the patient is minimal residual disease negative. Current minimal residual disease markers are available for patients with characterised fusion genes but approximately 50% of patients have no detectable chromosomal aberration and therefore are without markers. Gene expression profiling is a powerful tool for disease classification, prognosis and therapeutic predictions. This study aimed to investigate the use gene expression profiling to identify novel minimal residual disease markers for specific AML sub-groups. Patient diagnostic samples were profiled to identify genes specific to AML patients with a favourable translocation in order to establish the "proof-of-principle". Several genes identified were followed in patient diagnostic and follow- up samples and compared to the markers currently used. Continuing with normal karyotype AML, genes were identified as specific to this sub-group. Several homeobox (HOX) genes and the Wilms' tumour (WT1) gene were identified and their MRD levels followed in diagnostic and follow-up samples. Only WT1 identified as specific to normal karyotype AML met the necessary criteria to be an MRD marker. Although the majority of genes selected from the GEP in this study proved unsuitable as markers, the identification and validation of a marker already used for MRD monitoring, WT1, demonstrates the ability of gene expression profiling to identify potential minimal residual disease markers in normal karyotype AML.

No description available.

A high level of sedentary behaviour has recently emerged as a distinct risk factor for a number of diseases. On the other hand, a large body of evidence has shown that physical activity (PA) can prevent several illnesses. However, there are important issues regarding the accurate measurement of SB behaviour and physical activity in observational studies which are currently unresolved. Research is particularly needed to investigate the impact of characteristics of sedentary behaviour such as type/context, sedentary bout length, breaks in sedentary time on metabolic responses and accurate quantification of PA and SB is needed to evaluate current and changing physical activity and sedentary behaviour levels on health outcomes. A number of studies have demonstrated that replacing sedentary time with light-intensity physical activity such as standing can induce a measurable metabolic benefit. However, it is unclear whether these benefits could be stimulated by simply breaking up time spent sitting down by standing up, or whether the number of transitions from sitting to standing influences metabolic changes over and above the effects of total time spent standing. The first experimental study in this thesis demonstrated, in ten overweight/obese men, that prolonged standing – where participants alternated 15 minutes of sitting with 15 minutes of standing – energy expenditure was 10.7% higher than continuous sitting (p < 0.001) over an 8-hour observation period. Intermittent standing – where participants undertook 10, 1.5-minute bouts of standing in every half-hour – led to a further increase in energy expenditure of 9.0% (p < 0.001). Participants oxidised 7.1 g more fat and 7.7 g more carbohydrate with intermittent standing compared with prolonged standing, but there was no significant effects of either prolonged or intermittent standing breaks on postprandial incremental glucose, insulin or triglyceride (TG) responses.

Cardiovascular disease is a leading cause of mortality and morbidity worldwide. One of the key factors mediating cardiovascular disease risk, and the underlying atherogenic disease process, is disturbances to metabolism in the postprandial state, particularly with respect to lipoprotein metabolism. A number of studies have demonstrated that prior exercise can reduce postprandial triglyceride (TG) concentrations, with recent evidence indicating that increased clearance from the circulation of large very low density lipoproteins (VLDL1) plays an important role. However, it was unclear how exercise facilitated this potentially beneficial effect and this was the focus of the present work. The first experimental study in this thesis demonstrated, in 10 overweight/obese men, that 90 minutes of prior moderate exercise increased the affinity of VLDL1 for TG hydrolysis by lipoprotein lipase by 2.2-fold in the fasted state (p = 0.02) and 2.6-fold in the postprandial state (p = 0.001), but did not significantly alter the affinity of chylomicrons, a novel observation that adds to understanding of the mechanism by which exercise lowers TG concentrations. Postprandial responses to meal ingestion depend on the macronutrient composition of the food ingested. In the second experimental chapter, postprandial responses to ingestion of a test meal containing 75g glucose, or 75g fat, or a combination of 75g glucose and 75g fat were compared in 10 overweight/obese men. The main finding was that co-ingestion of fat with the glucose load reduced the postprandial glucose response, but not insulin response, compared with glucose ingestion alone. Co-ingestion of fat with the glucose load also substantially reduced the postprandial suppression of non-esterified fatty acids (NEFA) compared to glucose only ingestion. Postprandial TG responses were similar when only fat was consumed compared with co-ingestion of fat and glucose, but postprandial VLDL1 concentrations were lower in the latter condition. It is well established that ethnic differences exist in the prevalence of cardio-metabolic diseases. In particular, diabetes prevalence is high in Middle-Eastern populations. It is not known whether ethnic differences in postprandial metabolism contribute to these differences in risk. In the third experimental study, eight white European men and eight men of Middle-Eastern origin consumed a mixed-meal and postprandial responses were assessed. Postprandial insulin responses were higher in the Middle-Eastern men and postprandial TG concentrations were higher in the European men. This suggests that ethnic differences may exist in the inter-relationship between insulin resistance and lipoprotein metabolism. Thus, overall this thesis has provided insights into how postprandial metabolism is modulated by exercise, macronutrient intake and ethnicity.

Sudden death and pump failure death are two major modes of death in patients with heart failure and reduced ejection fraction (HF-REF) and in patients with heart failure and preserved ejection fraction (HF-PEF). There have been advances in evidence-based treatments in patients with HF-REF over the last two decades, along with the changing patient characteristics in both HF-REF and HF-PEF populations. It is of great interest and significance to discover if these changes have translated into temporal changes (and corresponding trends over time) in the risks of sudden death and pump failure death in both populations. Apart from examining any changes in the rates of mode-specific death in population level, it is also of interest and importance to estimate the risks for sudden death and pump failure death in individual patients. Accurate risk prediction can aid in better risk stratification. In patients with HF-REF, identifying high-risk subgroups would help target the device therapy to those most likely to benefit and identifying low-risk subgroups would avoid unnecessary implantation, thus improving the cost-effectiveness of the therapy. In patients with HF-PEF, identifying high-risk subgroups would enable further research into the efficacy of device therapy in this population. The aims of this work were to examine the trends in the rates of sudden death and pump failure death over time in patients with HF-REF and in patients with HF-PEF, and to separately develop validated models to predict sudden death and pump failure death in both populations. Given that there are limited data on mode-specific death from community-based studies, I used data from clinical trials which have more detailed and standardised sub-classification and adjudication of mortal events. Besides, compared to community-based studies, clinical trials have more detailed baseline characterisation, which allows more complete multivariable adjustment to account for confounding and between-study differences. Therefore, a cohort of 46,163 patients with HF-REF enrolled in 13 clinical trials conducted between 1995-2015 and a cohort of 10,517 patients with HF-PEF in 3 clinical trials over the period 1999-2013 were included in this thesis. Multiple linear regression analysis was used to examine the trends in the rates of sudden death and pump failure death over time in both populations respectively. The cumulative incidences for sudden death and pump failure death in each trial at different time points during follow-up were calculated with the cumulative incidence function method, counting the competing risk of death from other causes. The risk for each mode of death across trial arms and by HF duration was examined using the Cox regression models, with further adjustment for a number of confounding variables. The models to predict sudden death and pump failure death in patients with HF-REF were separately developed in PARADIGM-HF and validated in ATMOSPHERE. Models for both modes of death in HF-PEF were developed in I-PRESERVE and validated in CHARM-Preserved as well as TOPCAT. These models were constructed using a competing risk approach with the Fine-Gray sub-distributional hazards regression analysis. Model performance was examined by assessing calibration (i.e. the agreement between the observed and predicted cumulative incidences over time) and discrimination (i.e. the ability to separate patients at higher risk from those at lower risk). I found that the risks of sudden death and pump failure death in patients with HF-REF have fallen across 13 clinical trials over the period 1995-2015, consistent with a cumulative use of evidence-based therapies in this population. The absolute rates of sudden death and pump failure death were very low in the early follow-up after randomisation in patients with HF-REF who received modern evidence-based treatment. Longer standing HF was associated with greater risks of sudden death and, particularly, pump failure death in HF-REF. The risks of sudden death and pump failure death were consistently low across the 3 largest clinical trials in patients with HF-PEF, with little difference by experimental treatment in any trial. There was a downward trend in the rates of sudden death and pump failure death across these trials over time, in parallel with a changing characteristic of patients enrolled in these trials. Nevertheless, sudden death and pump failure death remained the most common modes of death, altogether accounting for the majority of CV death. The absolute rates of sudden death and pump failure death in patients with HF-PEF were extremely low in the early follow-up after randomisation. Longer standing HF was associated with a slightly higher risk of sudden death and a substantially higher risk of pump failure death in HF-PEF. The sudden death and pump failure death models in patients with HF-REF I developed in the largest and most contemporary cohort (PARADIGM-HF), included a number of variables collected in routine clinical practice, and accounted for the prognostic impact of the competing risk of death from other causes. The discriminating ability was modest for the sudden death model but excellent for the pump failure death model. Both models showed good calibration and were robust when externally validated in ATMOSPHERE. The prognostic models in patients with HF-PEF I developed in I-PRESERVE, using simple demographic and clinical variables, showed good discrimination and calibration for both sudden death and pump failure death, and were robust in external validation in CHARM-Preserved and TOPCAT. The performance of both models was further improved with the inclusion of NT-proBNP. In conclusion, I have found that the risks of sudden death and pump failure death have declined over time both in patients with HF-REF and in patients with HF-PEF based on clinical trial data. The patterns of change in the rates of both modes of death over time need to be examined in community-based populations. The prognostic models for both modes of death, showing reasonable performance, can be considered for use in risk stratification for mode-specific death in both populations, aiding in decision making in device therapy in similar patients in HF-REF and helping with patient selection for device interventions in future trials in HF-PEF.