Dissertation submitted in compliance with the requirements for Masters Degree in Technology in the Department of Electrical Engineering, Technikon Natal, 2000. / The purpose of this study is the development of an affordable computer-based electrocardiogram, heart rate and temperature monitoring system, that would complement those that are available on the market and contribute to the reduction of the shortage of these medical instruments in South African hospitals and clinics. Electrocardiogram (ECG) refers to the graph that results from time versus voltage in a patient's chest. It reflects the rhythmic activity of the heart. For this reason the electrocardiogram has a diagnostic value that can be used by medical personnel to examine the biological (hence, clinical) behavior of the heart. The electrocardiogram can also be used to get the heart rate. This thesis explained how to acquire ECG signals from the patient and also how to achieve a cheaper way of providing galvanic isolation, which is required for sensors that are attached to the human body. It also explains computer interfacing using the parallel port and computer-based processing of these ECG signals to determine the instantaneous value of the heart rate and also to reduce the interference that contaminates these signals. In reducing interference, the performance of traditional IIR notch and adaptive filters, as noise cancelers, has been analyzed and compared. Least Mean Squares (LMS) and Normalized Least Mean Squares (NLMS) algorithms are the two algorithms that were considered in this study for adaptive noise canceling and their performance is evaluated and is compared based on their convergence rate, complexity and noise reduction. / M

PhD, Virology, Faculty of Health Sciences, University of the Witwatersrand / HIV-associated cardiomyopathy is a multifactorial disease with a broad spectrum of aetiologies that arise due to chronic immunosupression during HIV infection. The intricate relationship between HIV infection and cardiac co-morbidity was investigated with the aid of HIV-neutralizing aptamers. These synthetic nucleic acid ligands with antibody-like properties are molecular tools with multifunctional applications ranging from drug discovery to diagnostics and therapeutics. The advent of the HIV/AIDS pandemic has naturally married the field of HIV therapy and diagnostics with that of aptamer technology. By employing a HIV-1 neutralizing aptamer, named UCLA1, raised against the viral surface envelope glycoprotein 120, I dissected some of the pathways leading to cardiomyocyte apoptosis in a cell culture system. In chapter one I investigated the potential cytotoxic effects of UCLA1 by comparing it against a panel of 17 antiretrovirals (ARVs) in clinical use with the goal of establishing a safety portfolio geared towards its use as a therapeutic agent. Using cultured human cardiomyocytes and primary peripheral blood mononuclear cells (PBMCs), I selected some of the major biological markers of ARV-induced cytotoxicity and found no measurable deleterious effect, especially when compared to other ARVs used in the same study. In chapter two, the permissiveness of cardiomyocytes to HIV infection as well as the relationship between virus-host interaction and caspase-mediated apoptosis were investigated. Non-productive, receptor and tropism-independent infection was observed, which was arrested after the reverse transcription stage. However, interaction between the virus gp120 and the host’s CXCR-4 chemokine receptor preferentially activated caspase-9 triggering robust mitochondria-mediated apoptosis. A shift from mitochondrial-initiated, caspase-9 mediated to Fas-ligand initiated, caspase-8 mediated was observed when CM were co-cultured with HIV-infected MDM. UCLA1 protected against caspase-9 mediated vii apoptosis but not caspase-8 mediated. Finally in chapter three I provided answers for the shift in caspase activation by showing that supraphysiological levels of IL-1β and IL-6 during HIV infection of MDM augment the effects of tumor necrosis factor (TNF). These observation provide new insight into the complex pathophysiology of HIVCM and highlight the potential of UCLA1 as a novel therapeutic agent to fight HIV and some of its associated diseases.

Kok Dick Shun , Louis. / Thesis (Ph.D.)--Chinese University of Honbg Kong, 1997. / Includes bibliographical references (p. i-xiii). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Cardiac disease is the leading cause of death in the United States, despite the continuing efforts contributed to scientific research and disease management in the past few decades. However many advances have been made in cardiovascular research in recent decades and one of the advances is the development of human induced pluripotent stem cell(iPSC)-based disease models. The human iPSC-based disease models are derived from the somatic cells of patients with cardiac diseases and capture the genotypes of the original patients, which make them more ideal for mimicking human diseases compared with conventional rodent models. So far, the iPSC-based disease models have been used to model several types of cardiac diseases, one of which is the focus of this work-Timothy syndrome. Timothy syndrome is caused by the missense mutations in the CACNA1C gene encoding the voltage-gated calcium channel CaV1.2, which plays an essential role in cardiac function. The disease is a multisystem disorder that is featured by long QT syndrome and syndactyly. Timothy syndrome patients are treated clinically with beta-adrenergic blockers, calcium channel blockers, and sodium channel blockers. However, these regimens are insufficient to prevent lethal arrhythmias in Timothy syndrome patients, especially infants with Timothy syndrome. Therefore, new therapeutics to prevent the lethal arrhythmias in Timothy syndrome patients are needed until the age when an implantable defibrillator is available. The iPSC-based model of Timothy syndrome was first reported in 2011. The previous report showed that the Timothy syndrome iPSC-derived cardiomyocytes demonstrated several cellular phenotypes including abnormal contractions, abnormal electrophysiological properties and abnormal calcium handling, which were consistent with the clinical features of the patients that the iPSCs were derived from. In addition, the authors demonstrated that Roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the cellular phenotypes in Timothy syndrome cardiomyocytes. However, the mechanisms underlying the beneficial effects of Roscovitine on Timothy syndrome cardiomyocytes were not fully elucidated. This work will employ the iPSC-based model of Timothy syndrome to investigate the mechanisms underlying the beneficial effects of Roscovitine on Timothy syndrome cardiomyocytes and search for additional therapeutic compounds and targets for Timothy syndrome. In chapter 1 of this work, we presented new methods to generate iPSCs from human skin fibroblasts or hair keratinocytes, and to differentiate iPSCs into cardiomyocytes in a monolayer format. The major advantage of the two new methods is that they are technically simple and generally applicable for samples from healthy control donors and patients with cardiac diseases. The new methods enabled us to generate a sufficient amount of Timothy syndrome cardiomyocytes from iPSCs derived from the skin fibroblasts of Timothy syndrome patients, which became the foundation for the subsequent mechanistic study. Chapter 2 presents the identification of CDK5 as a new therapeutic target for Timothy syndrome. As introduced above, the previous report demonstrated that Roscovitine, a CDK inhibitor, could rescue the cellular phenotypes in Timothy syndrome cardiomyocytes. However, the mechanisms underlying the beneficial effects of Roscovitine on Timothy syndrome cardiomyocytes were not fully elucidated. To identify additional therapeutic compounds for Timothy syndrome and investigate the mechanisms underlying the therapeutic effects of Roscovitine on Timothy syndrome cardiomyocytes, we conducted a phenotypic screen using Timothy syndrome cardiomyocytes to screen through twenty Roscovitine analogs and four CDK inhibitors with different specificities for different CDKs. Four positive compounds were identified from the screen. When we summarized the CDK targets of the four positive compounds and the lead compound Roscovitine, it was found that four out of the five positive compounds shared a common CDK target, which is CDK5, indicating that CDK5 could be involved in the pathogenesis of Timothy syndrome as a therapeutic target. We next validated CDK5 as a new therapeutic target for Timothy syndrome using two independent approaches. The two approaches are expressing a dominant negative mutant of CDK5 and expressing short hairpin RNAs targeting CDK5 in Timothy syndrome cardiomyocytes using lentiviruses. Both approaches led to CDK5 inhibition in Timothy syndrome cardiomyocytes and we examined the changes in the cellular phenotypes in Timothy syndrome cardiomyocytes with CDK5 inhibition. The results indicated that CDK5 inhibition alleviated all the previously-reported phenotypes in Timothy syndrome cardiomyocytes. To investigate the mechanisms underlying the beneficial effects of CDK5 inhibition on Timothy syndrome cardiomyocytes, we examined the expression of CDK5 activator p35 and the activity of CDK5 in Timothy syndrome cardiomyocytes. We found that Timothy syndrome cardiomyocytes showed a higher expression of CDK5 activator p35 and a higher activity of CDK5 compared with control cardiomyocytes. When we over-expressed CDK5 in control cardiomyocytes, we found that CDK5 over-expression caused a change in the function of CaV1.2 channels in control cardiomyocytes that resembled the phenotype in Timothy syndrome cardiomyocytes. In summary of the results, we propose that in Timothy syndrome cardiomyocytes, the increased expression of CDK5 activator p35 causes CDK5 hyper-activation, which enhances the abnormal function of the mutant CaV1.2 channels, leading to more severe phenotypes. Thus, CDK5 inhibition alleviates the phenotypes in Timothy syndrome cardiomyocytes. The results in this chapter reveal that CDK5 is a new therapeutic target for Timothy syndrome and CDK5-specific inhibitors can potentially be developed into new therapeutics for Timothy syndrome. However, we found that the currently-available chemical inhibitors for CDK5 are not highly-selective and have several significant side effects that make them not ideal candidates to be developed into new therapeutics for cardiac diseases. Therefore new therapeutic compounds and targets are still needed for Timothy syndrome. Chapter 3 presents the identification of the sigma-1 receptor as a new therapeutic target for Timothy syndrome. Due to the side effects associated with the currently-available chemical inhibitors for CDK5, we made an effort to search for an additional therapeutic target and therapeutic compounds for Timothy syndrome. We reasoned that instead of directly inhibiting CDK5, we could potentially alleviate the phenotypes in Timothy syndrome cardiomyocytes by affecting the CDK5 activator p35 and this idea led us to the sigma-1 receptor. After we looked into the sigma-1 receptor, we found that in addition to being reported to modulate p35 protein level, the sigma-1 receptor had also been reported to modulate calcium homeostasis, which is another favorable effect for Timothy syndrome cardiomyocytes. Therefore we hypothesized that the activation of the sigma-1 receptor could be beneficial for Timothy syndrome cardiomyocytes, which feature an increased expression of p35 and a dysregulation of calcium homeostasis. To test this hypothesis, we examined the effects of two sigma-1 receptor agonists, one of which is a FDA-approved drug, on the phenotypes in Timothy syndrome cardiomyocytes. The results demonstrated that the treatment of the two sigma-1 receptor agonists alleviated the previously-reported phenotypes in Timothy syndrome cardiomyocytes. We also examined the effects of the two sigma-1 receptor agonists on the functions of control cardiomyocytes and found that the treatment of the two sigma-1 receptor agonists did not have significant side effects on the regular contractions and normal calcium transients in control cardiomyocytes. Overall, the results reveal that the sigma-1 receptor is a new therapeutic target for Timothy syndrome. The results also demonstrate that the two sigma-1 receptor agonists that we tested are promising lead compounds that can developed into novel therapeutics for Timothy syndrome in the future. Since one of the sigma-1 receptor agonists that we tested is a FDA-approved drug, this drug could potentially be used directly in Timothy syndrome patients for treating the cardiac arrhythmias in the near future. In summary, this work is a proof of concept that the iPSC-based models of cardiac diseases can be used to generate novel insights into disease pathogenesis, and to identify new therapeutic targets and compounds for cardiac diseases, and in particular for Timothy syndrome. The therapeutic targets and compounds that we have identified in this work would be helpful for the development of novel therapeutics for treating the lethal arrhythmias in Timothy syndrome patients in the future.

Heart failure has a significant impact on mortality and morbidity. Dilated cardiomyopathy (DCM) is the third most common cause of heart failure and the most common reason for heart transplantation. Familial DCM is known to be caused by mutations in the LMNA gene encoding lamins A and C. New methods to enhance cardiac contractility would be beneficial in the treatment or prevention of heart failure. The focus of this thesis was to evaluate the mechanisms of altered contractility in two mouse models: the LMNA knockout model (homozygous, Lmna-/-; heterozygous, Lmna+/-) generated by targeted deletion of the lmna gene, and the model of enhanced contractility due to cardiac alpha1A-adrenergic receptor (???1A-AR) overexpression (A1A1). Previous studies have found altered nuclear-desmin connections in lamin A/C deficient mice. It was proposed that these alterations result in ???defective force transmission???, which leads to DCM. Studies in this thesis have supported this hypothesis. Studies of isolated single cardiomyocytes from mice aged 4-6 weeks demonstrated abnormal cell morphology and contractile dysfunction in Lmna-/- cardiomyocytes, while Lmna+/- cells showed no overt phenotype. Excitation-contraction coupling experiments and forcecalcium studies in skinned fibers excluded altered calcium kinetics as a primary cause of DCM in this model, but there was evidence of reduced sarcomere numbers and reduced sarcomere lengths as a contributor to reduce force generation in Lmna-/- and Lmna+/- mice. Previous in vivo studies showed that A1A1 mice had enhanced contractility with the absence of hypertrophy. Studies on isolated single cardiomyocytes from A1A1 mice aged 8-12 weeks showed reduced contractility in the absence of ???1A-AR stimulation, but an exaggerated response to ???1A-AR stimulation. In contrast isolated isovolumic Langendorff perfused A1A1 hearts without ???1A-AR stimulation replicated the enhanced contractility observed in vivo. These studies are consistent with down-regulation of contractility due to the hyperactivity of the overexpressed ???1A-AR in vivo, which only becomes evident in isolated cells without ???1A-AR stimulation due to the loss of functional receptor numbers during isolation. Sufficient spontaneously active ???1A-ARs are preserved in the isolated Langendorff heart preparation to ensure maximum contractility driven by increase calcium release.

Includes bibliographical references (21 leaves). Previous studies have found that green tea and its antitoxidant constituents, the catechins, are hypocholesterolaemic in both epidemiological and animal intervetion studies. The main objectives of the present study were to investigate the mechanism by which green tea and its most abundant catechin constituent epigallocatechin gallate increase the low-density lipoprotein (LDL) receptor of HepG2 cells. In addition, it was hoped to determine if a crude catechin extract from green tea could lower plasma cholesterol levels in the hypercholesterolaemic rabbit and ascertain if this effect was due to an increase in the LDL receptor. The study provides evidence that green tea and its catechins exhibit hypocholesterolaemic properties and may therefore provide protection against heart disease.

"August 2003" / Includes biblographical references. / 227 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (D.Nurs.)--University of Adelaide, Dept. of Clinical Nursing, 2004

Includes bibliographical references (21 leaves). / 1 v. (various pagings) : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Previous studies have found that green tea and its antitoxidant constituents, the catechins, are hypocholesterolaemic in both epidemiological and animal intervetion studies. The main objectives of the present study were to investigate the mechanism by which green tea and its most abundant catechin constituent epigallocatechin gallate increase the low-density lipoprotein (LDL) receptor of HepG2 cells. In addition, it was hoped to determine if a crude catechin extract from green tea could lower plasma cholesterol levels in the hypercholesterolaemic rabbit and ascertain if this effect was due to an increase in the LDL receptor. The study provides evidence that green tea and its catechins exhibit hypocholesterolaemic properties and may therefore provide protection against heart disease. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2000

Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / School of Physical Education, Sport, and Exercise Science

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2008. / Vita. Includes bibliographical references.