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The replacement of a hydrogen or hydroxy group with a fluorine atom is a popular strategy to alter the activity of biologically important molecules, as their similar sizes mean that such a replacement has little steric impact. The effect of fluorine substitution in a number of enzyme mediated processes has been investigated. 3-Fluorocyclohex-l-enylcarbonyl-CoA has been synthesised and the reaction with cyclohexenylcarbonyl-CoA reductase investigated. The fluorinated substrate has a comparable K(_m) value to that of the natural substrate but a V(_max) that is five times greater. A change in the rate-determining step of the reduction was also observed upon fluorine incorporation. The enzyme showed a small but significant stereochemical preference for the production of the axial isomer, consistent with an Anh-Eisenstein model for the transformation. The 6а and 6β isomers of benzyl fluoropenicillanate were synthesised and their methoxide-mediated hydrolyses were investigated. Competitive hydrolysis, using (^19)F NMR spectroscopy, demonstrated that the β isomer was hydrolysed preferentially. A frill kinetic analysis was undertaken, which furnished the rate and equilibrium constants. Monofluorinated enamines were treated in situ with a range a Michael acceptors to afford a variety of novel substituted a-fluoro ketones. 2-Fluorohexanal was synthesised from methyl hexanoate and was demonstrated to be a substrate for the enzyme transketolase with hydroxypyruvate. The enzyme reaction was monitored by (^19)F NMR spectroscopy. The enzyme showed a diastereoselectivity of 9:1 in the condensation of the aldehyde and hydroxypyruvate, and a self-condensation product was also produced. The enzymatic oxidation of the mono- and di-fluoromethylenephosphonate analogues of glycerol-3-phosphate was investigated at neutral pH using a co-factor recycling protocol. The reactions allowed for the first time the identification of the products of oxidation and demonstrated the lability of fluoride via non-enzymatic elimination and stoichiometric defluorination.

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A common goal in medical research is to determine the effect that a treatment has on subjects over time. Unfortunately, the analysis of data from such clinical trials often omits several aspects of the study design, leading to incorrect or misleading conclusions. In this paper, a major objective is to show via case studies that randomized controlled trials with longitudinal designs must account for correlation and clustering among observations in order to make proper statistical inference. Further, the effects of outliers in a multi-center, randomized controlled trial with multiple layers of clustering are examined and strategies for detecting and dealing with outlying observations and clusters are discussed. / McAnulty College and Graduate School of Liberal Arts; / Computational Mathematics / MS; / Thesis;

Of major concern in the present study will be the effects of anxiety on future time perception.

In these studies several different types of antimetabolites were synthesized, and their biological effects were examined in various assay systems. More extensive investigations were done in microbial systems in which many of the compounds proved to be inhibitory to growth, and attempts were made to determine the mode of biochemical action by adding supplements of the appropriate natural metabolite.

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A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine / Fetal Alcohol Syndrome (F AS), the most severe form of Fetal Alcohol Spectrum Disorder (F ASD), has traditionally been associated with maternal alcohol consumption during pregnancy. However, a number of animal studies have shown an association between paternal preconception alcohol consumption and developmental abnormalities in the offspring that resemble the features of F AS. Dysregulation of epigenetic factors (such as DNA methylation) in the presence of alcohol may provide a plausible mechanism by which paternal alcohol consumption could result in offspring affected with features of F AS. Imprinted genes are expressed in a parentof- origin manner due to DNA methylation at distinct differentially methylated regions (DMRs) and are essential for normal embryonic development. There are only two known paternally methylated DMRs in humans, with an additional one described in mice - associated with Rasgrfl. The first aim of this study was to determine whether the human RASGRFl gene contains a DMR and whether this DMR is paternally methylated. In order to assess the imprint status of RASGRF 1, a number of computational assessments were done to identify key features of imprinted loci. Pyrosequencing analysis was used to assess the methylation status of various CpO islands surrounding RASGRFi in peripheral blood and sperm DNA samples. The RASGRF i-associated CpO regions were not found to exhibit differential methylation in a parent-of-origin manner. The second aIm of the study was to examine the effect of paternal alcohol consumption on the methylation status of the IG-DMR locus in male gametes and to detennine whether alcohol is correlated with methylation in a dose-dependant manner. Methylation assessment was done using the quantitative pyrosequencing technology. While an overall reduction in methylation was noted in males who consumed alcohol after adjusting for confounding variables, the amount of alcohol consumed did not correlate with overall methylation. When analyzed by individual CpG sites, alcohol consumption was found to correlate preferentially with demethylation at CpG 3 while alcohol-dosage preferentially correlated with demethylation at CpG 7. Age was significantly correlated with an increase in the overall methylation at JG-DMR and at individual sites within JG-DMR. In conclusion, these findings support the hypothesis that paternal preconception alcohol consumption can lead to hypomethylation of nonnally hypennethylated DMRs of specific imprinted genes in human spenn. This in tum could have significant implications with regard to the regulation of developmentally significant genes in the zygote and fetus, resulting in developmental, behavioral and neurocognitive disorders.

Introduction To measure the radiation exposure to the surgeon during axillary sentinel lymph node biopsy using the radioactive isotope technetium-99m. Method A prospective analysis of 36 patients undergoing axillary sentinel lymph node biopsy using technetium-99m, between 15th January 2013 to the 20th February 2013.. Results The exposure to the surgeon during axillary sentinel lymph node dissection was measured in 36 patients by placing a thermoluminescent dosimeter (TLD) on the surgeon’s finger. The TLDs recorded the total radiation exposure to the surgeon. The recommended occupational dose limit for non radiation workers extremity exposure is less than 500 μSv. The analysed and extrapolated data showed an average exposure dose to the surgeon per patient of 2.7 μSv. Conclusion One surgeon would need to perform more than 85 such procedures per year in order to exceed the advised annual extremity dose limit. The data also suggests that regular measurements of radiation exposure and radiation protective measures need not be undertaken in theatres where surgeons are working with radioactive isotope for axillary sentinel lymph node biopsies.