Thesis (Ph. D.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 2001. / Includes bibliographical references. / The overall aim of this project was to investigate various cellular responses and toxic effects of nitric oxide, NO' and in vitro and in vivo. Nitric oxide gives rise to a complex spectrum of reactive species in oxygenated solution. The complexity of nitric oxide's chemistry is recapitulated in its effects on cells. Exposure to nitric oxide can result in changes on many different levels in cells ranging from protein and DNA damage, to damage to organelles and changes in gene expression, and even in cell death. Many models to study nitric oxide have been developed and will be used to study various responses to nitric oxide and related species. Nitric oxide and peroxynitrite-induced cellular damage has been and continues to be studied extensively using in vitro systems. Two systems have been used in this project, a delivery system for NO' as well as a cell line, which produces NO'. A Silasticʾ membrane delivery system can be used to treat bacteria or cells to mimic in vivo exposure to nitric oxide. Mutations induced by nitric oxide in a set of Salmonella tester strains can be studied utilizing this delivery system. Activated RAW264.7 macrophage cells have been used as an in vitro model of nitric oxide production and cytotoxicity SJL/J mice bearing the transplantable lymphoma RcsX have been established as an in vivo model of nitric oxide production and toxicity. / (cont.) This in vivo mouse model can be used to test results found in vitro. Specifically, the relationship between nitric oxide production and prostaglandin synthesis and glutathione homeostasis can be explored. Glutathione was found to be induced by nitric oxide production in this model, and this increase was due to increases in y-glutamylcysteinyl synthetase activity. This thesis studied both the regulatory and toxic effects of nitric oxide, both endogenously produced and from exogenous sources. / by Teresa Leah Wright. / Ph.D.

Thesis (Sc. D.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 2001. / Includes bibliographical references (p. 346-354). / Overall cancer mortality rates have risen from about 4% of all deaths in the early 20th century to about 25% of all deaths by the end of the century in the United States. To assess any potential hypotheses for this increase required knowledge of the mortality rate changes specific to each form of cancer, and the time points when these rates had changed. For this purpose, population and cancer mortality data of the U.S. were collected and organized to create age-specific mortality rates for each birth decade from the 1800s forward, delineated by the organ of incidence. Concurrently, cancer survival data were collected so as to correct for any effect of improved treatment on historical changes in cancer mortality rates. To analyze these data, a mathematical model for the three-stage process of carcinogenesis (initiation, promotion, and progression) was developed to estimate for each birth decade cohort the value of the fraction of the cohort at lifetime risk for that cancer, the value of the growth rate of the respective precancerous lesion, and the values for the mutation rates of normal and precancerous cells in the organ of incidence. This methodology permits the analysis of the potential historical effect of new chemical exposures during the last century on cancer mortality rates. These chemical exposures represent potential risk factors that determine the fraction of the population at risk of developing cancer (lifetime, primary risk factor), or that hasten death by cancer by altering either mutation or cell kinetic rates (accelerating, secondary risk factor.) / (cont.) COLON CANCER: Application of this model on the colon cancer mortality data resulted in the estimate that 42% of the population in the U.S. was at risk for developing colon cancer, independent of gender or race. More importantly, there was no significant historical change in the calculated fraction at risk for birthyear cohorts from 1860 to 1940, suggesting that the primary risk factors for colon cancer are not environmental. Although direct observation of in vivo mutation rates of colonic cells does not yet exist, the calculated rate for the first initiation mutation in the colon was interestingly found to be similar to the mutation rate observed for the hprt locus in human peripheral T-cells (-2.1 x 10-7 per cell year) and the spontaneous mutation rate of the hprt locus of human B-cells in culture. The estimate for initiation mutation rates increased no more than two-fold from the birthyear cohort of 1860 to the birthyear cohort of 1940, except for European American females for which calculated initiation mutation rates were historically invariant, but since the accuracy of primary data for mortality rates and survival rates cannot be ascertained, the apparent small differences might admittedly arise from unknown biases. Evaluation of the parameter of the growth rate of precancerous lesions showed no significant historical change on this parameter. Curiously, the calculated doubling rate of these lesions (-0.17-0.21) was found to be similar to the growth rate of children, suggesting that the required initiation events have the net effect of potentially reactivating pathways involved in child development. / (cont.) The predominant historical change in the observed mortality rates for colon cancer occurred only at old ages. ... / by Pablo Herrero Jimenez. / Sc.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Division of Bioengineering and Environmental Health, 2002. / Includes bibliographical references (leaves 176-200). / The study of human mutagenesis requires methods of measuring somatic mutations in normal human tissues and inherited mutations in human populations. Such methods should permit measurement of rare mutations in the presence of abundant wild-type copies and should be general to the human genome. A sensitivity of 2 x 10-6 for point mutations was recently achieved in human cells using a novel method of target isolation, constant denaturant capillary electrophoresis (CDCE), and high-fidelity polymerase chain reaction (hifi-PCR) (Li-Sucholeiki and Thilly, 2000). This method is applicable to 100-base pair (bp) DNA domains juxtaposed with a naturally occurring domain of a higher melting temperature, or a natural clamp. Such sequence domains represent about 9% of the human genome. To permit analysis of rare point mutations in the human genome more generally, this thesis developed a procedure in which a clamp can be ligated to any 100-bp sequence of interest. This procedure was combined with the previous method to create a new method of point mutational analysis that is not dependent on a naturally occurring clamp. To demonstrate the new method, a sequence with a natural clamp, a part of the human hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene (cDNA-bp 223-318), was analyzed using both the natural and ligated clamps. A sensitivity of 2 x 10-5 in human cells was demonstrated using the ligated clamp as opposed to 5 x 10-6 using the natural clamp. / (cont.) The sensitivity of the new method using the ligated clamp was demonstrated to be limited by the fidelity of Pfu DNA polymerase used for PCR. The sequence of the ligated clamp accounted for the differences in sensitivity as a result of causing a decreased efficiency of mutant enrichment by CDCE. The new method can be applied to measure somatic mutations in normal human tissues, such as lung tissues, in which point mutations at fractions above 10-5 have been observed. This method can also detect predominant inherited mutations even for genes carrying recessive deleterious alleles in pooled samples derived from a large number of individuals. / by Andrea Seungsun Kim. / Ph.D.

No description available.

Thesis (M. P. H.)--University of New South Wales, 2003. / Also available online.

Public health effects associated with rising temperatures resulting from global climate change are expected to increase significantly in this century. Projecting future heat-related mortality is challenging due to considerable uncertainties, and national-level, large-scale impacts under the latest greenhouse gas emission scenarios remain largely unexplored. Here I estimate excess heat-related mortality in the continental United States and in 50 largest metropolitan areas in China in the 2050s under two Representative Concentration Pathways (RCPs) emission scenarios: RCP4.5 and RCP8.5. Using model-simulated future and present climate variables that were dynamically downscaled by regional meteorology models, this study quantifies the potential increase in heat-related mortality during the warm season (May-September) in mid-century relative to the base period of 2000s. The projections are based on an integrated assessment framework that combines high-resolution climate model outputs, location specific temperature-mortality relationships, population projections and baseline mortality rates. Heat mortality risk estimates for both countries are derived from systematic reviews of current literature on temperature-mortality relationships. Potential human adaptation is likely to decrease heat-related mortality in the future. I evaluate future adaptation assumption with a scenario analysis based on empirical evidence of adaptation to heat in both countries. Findings from this study will provide valuable information to support climate policy decision making and heat-related risk management in both countries and globally

Thesis (Ph.D.) -- McMaster University, 1999. / Includes bibliographical references (p. 144-149). Also available via World Wide Web.

Thesis (D.P.H.)--University of Michigan, 1994.

Thesis (D.P.H.)--University of Michigan, 1994.

Thesis (D.P.H.)--University of Michigan, 1994.