Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 4 uppsatser.

A dissertation submitted to the Faculty of Health Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Masters of Science in Medicine, 2014 / Many loci coding for xenobiotic metabolising enzymes, especially those involved in carcinogen metabolism, confer susceptibility to various types of cancers. These genes have been poorly investigated in sub-Saharan African populations, where the genetic variation that exists is relatively unknown. The primary objectives of the study are to determine the frequency variation among 15 loci in sub-Saharan Africans, the level of genetic diversity, and the genetic affinities among sub-Saharan Africans. Secondary, the study aims to evaluate the implication of these variants in disease susceptibility, especially cancer. The study population comprised of 1880 unrelated individuals from 18 sub-Saharan African populations. DNA samples were used to examine genetic variation for phase I metabolism genes CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP2E1, and phase II metabolism genes GSTM1, GSTT1, GSTP1 and NAT2. A single base extension (SBE) method was designed and used to genotype single nucleotide polymorphisms (SNP): CYP1A1*2A and *2C; CYP1A2*1C and *1F; CYP2A6*7 and *8; CYP2D6*3A (2549delA) and CYP2D6*4(1846G>A); CYP2E1*5B(PstI) and CYP2E1*5B(RsaI); GSTP1*Ile105Val and *Ala114Val; and NAT2*14A. To investigate the presence of null mutations GSTM1*0 and GSTT1*0 a previously reported multiplex PCR method was used. The distribution of mutations in the sample was interpreted and compared with data from literature respectively. Mutations CYP1A1*2A, CYP1A2*1C, CYP1A2*1F, CYP2A6*7, CYP2D6*4 and GSTP1*Ile105Val mutations was found in most sub-Saharan Africans, while CYP1A1*2C, CYP2A6*8, CYP2D6*3A and GSTP1*Ala114Val mutations were almost non-existent. Both GSTM1*0 and GSTT1*0 mutations were present in all populations, with GSTT1*0 most frequent. The distribution of NAT2*14A confirms previous reports of its exclusive existence in Africans. Hardy-Weinberg Equilibrium (HWE) and Tajima’s D statistic tests showed none of the mutations were under selection. The genetic affinities of sub-Saharans were analysed. Bantu-speakers were closely related with little correlation to their geographic locations. Khoisan-speakers were closely related, genetically most distinct and oldest among populations. Pygmies were similarly distinct from most populations and one of the oldest surviving populations. The data further supports previous reports that the Khwe are descendants of an east African pastoralist group. AMOVA analyses revealed language as a major confounder among sub-Saharans. Haplotypes were inferred to determine their distribution and to understand their significance in populations with respect to their functional relevance. The study has confirmed previous reports of genetic histories of these sub-Saharan African populations. In unravelling the distribution of these mutations, the study has added to the global picture of these mutations. In doing so, the data may add value to the design of future cancer studies and pharmacological studies. The study also highlights the importance of elucidating ancestral relations of populations, more specifically linguistic and anthropological relationships, and to include in the design of future clinical trials in Africa.

Research Project (M.B.A.) - Simon Fraser University, 2007. / Theses (Faculty of Business Administration) / Simon Fraser University. Senior supervisor: Dr. Aidan Vining -- Faculty of Business Administration. MBA-MOT Program. Also issued in digital format and available on the World Wide Web.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 5 uppsatser.

Thesis (Ph.D. in Clinical Sciences) -- University of Colorado at Denver and Health Sciences Center, 2005. / Typescript. Includes bibliographical references (leaves 134-149). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

O íon fluoreto (F) provém do elemento flúor. Sua absorção é inversamente relacionada ao pH e ocorre rapidamente no estômago e posteriormente no intestino delgado. Após sua absorção, o F é distribuído pelos tecidos através da corrente sanguínea e armazenado nos tecidos calcificados e moles. Sua excreção acontece por via renal. Trata-se de um elemento relevante em termos de Saúde Pública, devido às suas propriedades de prevenir ou reverter lesões cariosas em indivíduos de todas as idades. No entanto, sua ingestão excessiva é capaz de afetar o metabolismo ósseo e desenvolvimento do esmalte dentário. Estudos sugerem que o F pode interferir em vias metabólicas, inibindo a ação de diversas enzimas. Entretanto, a literatura é conflitante em relação aos seus efeitos na homeostasia da glicose, o que poderia, talvez, ser explicado pela diferença genética entre as linhagens utilizadas. Sabe-se que camundongos da linhagem A/J são extremamente sensíveis aos efeitos do F, enquanto que os camundongos da linhagem 129P3/J são altamente resistentes ao tratamento com esse íon. Por este motivo, foi investigado se esses animais que sabidamente apresentam uma expressão proteica diferencial em função do F devido ao seu background genético apresentam também respostas diferentes em parâmetros bioquímicos (glicemia jejum, insulinemia, índice de resistência à insulina [HOMA2-IR] e teste de tolerância à insulina) e imunológicos (TNF-&alpha;). Após aprovação da Comissão de ética, 156 animais (78 da linhagem A/J e 78 da linhagem 129P3/J) foram divididos em 3 grupos para cada linhagem, e tratados por um período de 42 dias com doses de 0, 15 ou 50 ppm de F na água e ração com baixo teor de F. Após o término do tratamento, os camundongos foram eutanasiados para a obtenção de amostras de sangue. Os dados foram analisados por ANOVA a 2 critérios e testes de Tukey e Sidak para comparações individuais (p<0,05). Para a glicemia, os animais A/J que receberam água sem F e com a dose de 15 ppm F tiveram glicemia significativamente mais alta que os animais 129P3/J que receberam o mesmo tratamento. Para as dosagens de insulina no plasma, houve diferença significativa apenas entre os camundongos A/J 0 ppm F e 50 ppm F, sendo mais baixa a insulinemia para os animais tratados. O índice HOMA2-IR mostrou diferença significativa somente entre os animais da linhagem A/J, sendo que o grupo que recebeu água contendo 50 ppm F apresentou valores menores quando comparado para os grupos 0 ppm F e 15 ppm F. Quanto ao TNF-&alpha;, não foi observada diferença significativa entre as linhagens e entre os tratamentos. Entretanto, houve uma tendência para seu aumento nos grupos tratados com água contendo 15 ppm F nas duas linhagens. Para o teste de tolerância à insulina, também não foram observadas diferenças significativas entre as linhagens, nem entre os tratamentos. Levando em consideração os resultados, percebe-se que as diferentes concentrações de F alteram os resultados para os parâmetros analisados, e, as linhagens respondem diferentemente a essas alterações. No entanto, é necessário que se analisem outras variáveis para que esse assunto seja melhor elucidado. / Fluoride (F) comes from the element fluorine. Its absorption is inversely related to the pH and occurs quickly in the stomach and later in the small intestine. After absorption, F is distributed to the tissues through the bloodstream and stored in calcified and soft tissues. Excretion occurs via the kidneys. It is an important element in terms of public health, due to its properties to prevent or reverse caries in individuals of all ages. However, its excessive intake can affect bone metabolism and the development of tooth enamel. Studies suggest that F can interfere with metabolic pathways, by inhibiting the action of several enzymes. However, there is contradiction in the literature regarding its effects on glucose homeostasis, which could possibly be explained by genetic differences between the strains used. A/J mice are extremely sensitive to the effects of F, whereas 129P3/J mice are highly resistant to treatment with this ion. For this reason, it was investigated whether these animals which are known to exhibit differential protein expression upon exposure to F due to their genetic background also exhibit distinct responses in biochemical (fasting glucose, insulin, insulin resistance index [HOMA2-IR] and insulin tolerance test) and immune (TNF-&alpha;) parameters. After approval by the Ethics Committee, 156 animals (78 of A/J strain and 78 of 129P3/J strain) were obtained, divided into 3 groups for each strain and treated for a period of 42 days with 0, 15 or 50 ppm F in the drinking water. They received low-F diet. After treatment, the mice were euthanized and blood samples were obtained. Data were analyzed by 2-way ANOVA and Tukey and Sidak tests for individual comparisons (p<0.05). For blood glucose analysis, A/J mice treated with water containing no F containing 15 ppm F had significantly higher levels of glucose than 129P3/J animals receiving the same treatment. For plasma insulin, there was significant difference only between A/J mice treated with no F and 50 ppm F, with lower values for the treated animals. HOMA2-IR index showed a significant difference only between A/J animals, where the group received water containing 50 ppm F had lower values when compared to those receiving water containing no F or 15 ppm F. Regarding TNF-&alpha;, no significant differences were observed between the strains or among the treatments. However, there was a trend towards an increase in the groups treated with water containing 15 ppm F for both strains. For insulin tolerance test, also no significant differences between the strains or among treatments were observed. The results suggest that the different F concentrations alter the results of the parameters analyzed, and the strains respond differently to these changes. However, it is necessary to analyze other variables in order to better elucidate these findings.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 75-83).

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.