Mitochondrial dysfunction, particularly in relation to electron transport chain (ETC) derived oxidative stress, is widely held to be important in numerous pathologies. However, mitochondrial levels of the bioenergetically critical small inorganic molecules are still debatable or unknown. Nevertheless, investigation of the behavior of the ETC components, individually and collectively, in response to varying the levels of these species is still of considerable importance. This dissertation investigated the reaction of the reduced forms of isolated bovine complex III, cytochrome c and complex IV with peroxynitrite in the presence and absence of CO2. The presence of CO2 significantly modulates the mechanisms and extent of the cofactor oxidations. The characteristics of peroxynitrite-modified ferricytochrome c, prepared in the presence and absence of CO2, was examined by a variety of spectroscopic methods. In the absence of CO2, oxidation of the methionine 80 axial heme ligand to methionine sulfoxide results. During complex IV turnover by native ferrocytochrome c at low ionic strength increased rates were observed when the peroxynitrite modified cytochrome c is added - indicating preferential binding of the modified cytochrome to a high affinity/low activity electron-entry site on the enzyme, directing native ferrocytochrome c to bind to a lower affinity/higher activity site. It is unclear that formation of small quantities of either peroxynitrite-modified cytochrome c is proapoptotic. Since the limiting reagent in the reaction of superoxide with nitric oxide is peroxynitrite, the amount of superoxide formed biologically is critical information. The commonly employed molecular probes for superoxide, hydroethidine, and its mitochondrially-targeted derivative, MitoSoxTM, were shown to undergo reactions with components of the mitochondrial ETC including reduction of complex IV and partial reduction of complex III. The reaction with complex IV accounts for an oxygen (and hence superoxide), independent fluorescent response of MitoSox™ in cultured endothelial cells. However, the cationic ethidium species formed during oxidation of the probes by the ETC enzymes inhibit the normal turnover of complex IV by blocking transfer of electrons from ferrocytochrome c to the oxidase. In the case of oxidized MitoSox™, the observed inhibition under typical assay conditions was substantial at inhibitor levels comparable to the concentration of substrate cytochrome c. Therefore, this work has special public health relevance since it not only reviews the possible mechanisms for oxidative stress in mitochondria but also reassesses the use of MitoSox™ as it is a net generator of superoxide.

Aflatoxin, produced by the fungi Aspergillus flavus and A. parasiticus, is the most potent naturally occurring human hepatocarcinogen. Food crops colonized by these fungi, especially maize and groundnut, are the major sources of dietary aflatoxin exposure. Aflatoxin and chronic hepatitis B virus (HBV) infection, two liver cancer risk factors that synergize with each other, are prominent in sub-Saharan Africa and certain parts of Asia. Furthermore, increasing evidence from epidemiological studies suggests that aflatoxin may cause child growth impairment, which can increase risks of premature deaths. A broad range of aflatoxin control strategies, developed to reduce aflatoxin exposure or its toxicity, include preharvest, postharvest, and dietary interventions; as well as the HBV vaccine, which does not reduce aflatoxin exposure but reduces the risk of aflatoxin-induced liver cancer. We compared the efficacy and the cost-effectiveness of four aflatoxin risk-reduction strategies: HBV vaccine, biocontrol (preharvest), a postharvest intervention package, and NovaSil clay (dietary) in preventing liver cancer and stunting in Nigeria. Aflatoxin and chronic HBV infection are attributable for 8-27%, and 59-62%, respectively, of total liver cancers in Nigeria. We found that the HBV vaccine provides the greatest health-based efficacy and the lowest cost to avert one disability-adjusted life year (DALY) in Nigeria, compared with the selected aflatoxin control interventions. The prospective burden of aflatoxin-related stunting in Nigeria varies depending on aflatoxin exposure levels, which can vary substantially by year and location. At higher levels of aflatoxin exposure, the burden of aflatoxin-associated stunting is significant. Preventing stunting by any of these interventions would greatly reduce the cost per DALY and turn these interventions from non-cost-effective to very cost-effective. Our technical feasibility assessments of these four interventions suggest some advantages and disadvantages of each intervention over the others. These data are crucial components in a decision making process to effectively allocate public health resources, and to position interventions for further development of public health interventions to prevent some aflatoxin-related public health problems, especially in high risk populations.

This study examines three process measures of diabetic care and their association with four complications of diabetes - Coronary Artery Disease (CAD), Heart Failure (HF), Stroke and Renal Disease (RD) - in a cohort comprised of hourly and salaried employees of a single large manufacturing company at geographically diverse regions in the United States. Quality of care was measured by adherence to consensus standards for A1C and lipid testing and screening for microalbuminuria. A retrospective cohort study was conducted from January 1, 2003 to December 31, 2009 of 1,797 diabetic employees of a US manufacturer who were enrolled in the same health insurance plan. Diabetics who received all three QOCM in the baseline year were compared to diabetics who received less than three QOCM in the baseline year and were analyzed to address their association with the four complications. Cox proportional hazard regression models were used to assess potential associations between diabetes QOCM and time to complication. Potential confounding risk factors included sex, age, ethnicity, income, marital status, education, smoking, diabetes severity and health comorbidity risk scores. The overall health benefits for diabetics who received all three QOCM at baseline were noteworthy; they experienced reduced risk for HF (HR 0.39, CI [.19 - .81], p = 0.0117) and RD (HR 0.48, CI [.24 - .95] p = 0.0339) compared to the people who received less than three QOCM. Results suggest that diabetics who received all three QOCM experienced lower complications and is associated with reduced complication risk - regardless of access to care and other factors. These results suggest that any improvement in screening is likely to reduce the risk of diabetes complications. This study contributes to the literature by examining adherence to recommended processes of care and patient complications together. The public health implications of this study can be used to inform the design or revision of disease management programs and process of care measures.

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Carta al editor

Source: Dissertation Abstracts International, Volume: 57-08, Section: B, page: 5173. Advisor: Lawrence W. Whitehead. Includes bibliographical references.

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