<p>Vitamin C inhibits the oxidation of biologically important molecules and may have a potential protective role against cancer, cardiovascular diseases, and aging. Clinically relevant models of vitamin C function are essential for understanding the role of the antioxidant in the pathogenesis of these complex diseases, and its therapeutic potential. In this thesis, we examine ascorbic acid synthesis and deficiency in animal models, and develop these animal models into powerful tools to examine specific questions of vitamin C function. This thesis first presents a review on the existing animal models for antioxidant function in human nutrition, focusing on their clinical relevance in chronic diseases. We concluded that equivocal proof of beneficial effects of high dose antioxidant supplementation has not been established, and further investigations of animal models of antioxidant function are needed to resolve outstanding questions.</p> <p>We then examined the feasibility and efficacy of an alternative vitamin C delivery method using gene therapeutic lentivirus vectors in a guinea pig model of vitamin C function. The guinea pig exhibits an inactivated gulonolactone oxidase gene (<em>Gulo</em>), which is required for endogenous ascorbic acid synthesis, and as such must acquire vitamin C from the diet. Using a lentivirus vector carrying the mouse <em>Gulo</em> under the murine cytomegalovirus (mCMV) promoter, which was previously developed as a part of my undergraduate thesis, we examined the ability of this gene therapeutic vector to mediate the expression of GULO and the production of ascorbic acid in guinea pigs. At a titre of 10¹⁰ viral particles per animal, the life of lentivirus-treated guinea pigs were prolonged by 35 days compared to the scorbutic control, which was given an ascorbic acid-free diet. Ascorbic acid was produced in the liver of the treated guinea pigs, but the amount produced was not sufficient to elevate plasma concentrations or fully correct the metabolic deficiency. We conclude that lenti-mCMV-<em>Gulo</em> is able to mediate the expression of GULO and endogenous production of vitamin C in guinea pigs.</p> <p>To test the role of vitamin C in cancer etiology and outcome, we are currently in the process of introgressing the <em>Gulo</em>^-/- inactivation mutation, developed by Maeda <em>et al.</em> in 2000, from the C57BL/6 strain background into the FVB/N strain background. The FVB/N strain is also the background for several models of <em>erbB2/neu</em> overexpression in human breast cancer, associated with increased metastasis and low patient survival rates. Taken together, this thesis develops two animal models of vitamin C function, which can be employed in future applications.</p> / Master of Science (MSc)

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No / Introduction: Potential-sensitive dyes have primarily been used to optically record action potentials (APs) in whole heart tissue. Using these dyes to record drug-induced changes in AP morphology of isolated cardiac myocytes could provide an opportunity to develop medium throughout assays for the pharmaceutical industry. Ideally, this requires that the dye has a consistent and rapid response to membrane potential, is insensitive to movement, and does not itself affect AP morphology. Materials and methods: We recorded the AP from isolated adult guinea-pig ventricular myocytes optically using di-8-ANEPPS in a single-excitation dual-emission ratiometric system, either separately in electrically field stimulated myocytes, or simultaneously with an electrical AP recorded with a patch electrode in the whole-cell bridge mode. The ratio of di-8-ANEPPS fluorescence signal was calibrated against membrane potential using a switch-clamp to voltage clamp the myocyte. Results: Our data show that the ratio of the optical signals emitted at 560/620 nm is linearly related to voltage over the voltage range of an AP, producing a change in ratio of 7.5% per 100mV, is unaffected by cell movement and is identical to the AP recorded simultaneously with a patch electrode. However, the APD90 recorded optically in myocytes loaded with di-8-ANEPPS was significantly longer than in unloaded myocytes recorded with a patch electrode (355.6 ± 13.5 vs. 296.2 ± 16.2ms; p< 0.01). Despite this effect, the apparent IC50 for cisapride, which prolongs the AP by blocking IKr, was not significantly different whether determined optically or with a patch electrode (91 ± 46 vs. 81 ± 20 nM). Discussion: These data show that the optical AP recorded ratiometrically using di-8- ANEPPS from a single ventricular myocyte accurately follows the action potential morphology. This technique can be used to estimate the AP prolonging effects of a compound, although di-8-ANEPPS itself prolongs APD90. Optical dyes require less technical skills and are less invasive than conventional electrophysiological techniques and, when coupled to ventricular myocytes, decreases animal usage and facilitates higher throughput assays.

This work is concerned with an attempt to clarify the role of cortisone in both the immune complement response and the progression of mouse leukemic tumor.

LLM / Department of Public Law / Human rights are those inalienable rights of an individual by virtue of being a human being. They are guaranteed by various domestic and international instruments. This research argues that despite the existence of these instruments and wide acceptances of international human rights standards that seek to protect the right to healthcare, the people infected with Ebola Virus Disease (EVD) are victims of a wide range of constraints to their right to healthcare as a result of the failure by the governments of the respective nations where the impacts of the EVD are mostly felt to discharge their obligations under those instruments. The rights of the people infected with EVD are often violated because of their presumed or known EVD status, causing them to suffer both the burden of the disease and the social burden of discrimination and stigmatisation which could deter the infected persons from accessing available treatment. This would invariably contribute to the spread of the disease. The research further exposes the dilemma posed by the EVD to the healthcare system, where healthcare providers are caught between the rock of selfpreservation from a highly virulent disease and the hard place of discharging their Hippocratic Oath which prescribes ethical guidelines for the discharge of the duties of the medical profession. The present research, which is novel in the field of medico-legal research, seeks to proffer answers to this conundrum.

My thesis addresses how Christianity can constitute itself as a creative force and a form of governance across different scales. I carried out 12 months of fieldwork between 2013 and 2015 in Papua New Guinea's National Parliament (Port Moresby). My interlocutors were bureaucrats, liberal professionals and pastors who formed a group known as the Unity Team. The Unity Team, spearheaded by the Speaker of the 9th Parliament, Hon. Theodor Zurenuoc, were responsible for controversial initiatives, such as the destruction and dismantling of traditional carvings from Parliament in 2013, which they considered ungodly and evil, and the placement of a donated KJV Bible in the chamber of Parliament in 2015. My interlocutors regard Christianity as central to eliciting modern subjects and institutions. They consider Christianity to be a universal form of discernment, contrasted to particularistic forms of knowing and relating which are thought to create corruption and low institutional performance. I show how the Unity Team regarded Christianity as more than a way of doing away with satanic forces and building a Christian self. They expected Christianity to be a frame of reference informing work ethics, infusing citizenship and, finally, productive of a public and national realm. By exploring Christianity ethnographically, I offer a contribution to Anthropological discussions concerning politics, bureaucracy, citizenship, and nation-making.