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Centromere binding factor 1 (Cbf1) is a transcription factor that controls the transcription of many genes involved in cellular respiration and lipid biogenesis and, as such, has been associated with hypolipidemia in humans. It is a known substrate for PAS kinase, which phosphorylates Cbf1 and alters its activity. Our hypothesis is that this phosphorylation affects the genes it regulates and the DNA motifs it binds to, perhaps due to different transcription complexes being formed. In this study, we conduct a chromatin immunoprecipitation in Saccharomyces cerevisiae to determine what genes and DNA motifs Cbf1 binds to in its wild type versus phosphosite mutant forms. We discovered several motifs that may be specific to each Cbf1 form, however further evidence is necessary. We were able to identify five motifs in reads associated with phosphosite Cbf1, while reads associated with wild type Cbf1 had 16 motifs, with no overlap between the motifs found from the two forms. This may be due to phosphorylated Cbf1 having more binding partners. Cbf1 regulated genes and possible transcription complex binding partners are proposed.

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / "May 2001." Typescript. Vita. Includes bibliographical references (leaves 176-195). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri--Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 121-137).

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / "May 2001." Typescript. Vita. Includes bibliographical references (leaves 176-195). Also available on the Internet.

Die Hyperlipidämie wird als Risikofaktor für die Nierentransplantatfunktionsverschlechterung und den -verlust diskutiert. Wir untersuchten den Zusammenhang zwischen Lipidstoffwechsel und Nierentransplantatfunktion und ihre Beziehungen zu Immunsuppression, Rejektionen, Transplantatalter und Dialysedauer. Im 1. Quartal 1996 wurde allen nierentransplantierten Patienten der Ambulanz die Bestimmung eines umfassenden Lipidstatus (Cholesterine (HDL, LDL, VLDL), Triglyzeride, Apolipoproteine A1, A2, B, Lp(a) und Apo E-Genotyp) angeboten. Die ermittelten Laborwerte wurden zum klinischen Verlauf der Patienten in Beziehung gesetzt. Es wurden 201 Patienten in die Studie eingeschlossen, deren mittleres Alter bei 46,2 ± 11,4 Jahren lag. Die Transplantation lag bei den 146 Männer (72,6 %) und 55 Frauen (27,4 %) 7,7 ± 4,9 Jahre zurück. Eine auf Cyclosporin A basierende Immunsuppression erfolgte bei 143 Patienten (71,1 %), 87 Patienten (43,3 %) erhielten eine lipidsenkende Therapie. Kreatinin 122 ± 86,9 µmol/l; Cholesterin 253,6 ± 52,9 mg/dl; atherogene Risikoratio (Chol/HDL) 5,3 ± 2,3. Das Kreatinin korreliert signifikant mit dem Cholesterin (p < 0,001) und der atherogenen Risikoratio (p < 0,001) - auch in der Untergruppe ohne lipidsenkende Therapie (p = 0,001 bzw. p < 0,001), ebenso LDL, Triglyzeride, VLDL und Apo B. Die Rejektionshäufigkeit war bei Patienten mit und ohne Fettstoffwechselstörung nahezu gleich. Der Apo E-Genotyp scheint keinen Einfluss auf den Lipid- und Nierenstoffwechsel zu haben. Die Lipidparameter unserer Patienten korrelieren in der Querschnittsuntersuchung signifikant mit der Nierentransplantatfunktion, scheinen aber keinen Einfluss auf die Rejektionshäufigkeit zu haben / Hyperlipidemia is discussed as a risk factor for deterioration of the renal transplant function and the graft loss. We examined the relations between the lipid metabolism and renal transplant function and their connections to factors like immunsuppression, rejections, transplant age und time of dialysis. In the first months of 1996 all patients having a renal transplant were offered an extensive blood control including cholesterol, HDL, LDL, VLDL, triglycerides, apolipoproteins A1, A2, B, Lp(a) und Apo E-Genotype. Afterwards the lipid parameters were put into relation to the clinical course of each patient. We included 201 patients in our study, they were 46,2 ± 11,4 years old. The renal transplantation was in 146 men (72,6 %) und 55 women (27,4 %) 7,7 ± 4,9 years ago. 143 patients got a Cyclosporin A based immunsuppression (71,1 %), 87 patients (43,3 %) were set on lipid lowering therapie. Creatinin 122 ± 86,9 µmol/l; cholesterol 253,6 ± 52,9 mg/dl; Chol/HDL-quotient 5,3 ± 2,3. Creatinin correlates significantly with cholesterol (p < 0,001) and the Chol/HDL-quotient (p < 0,001) - even in the group of patients without lipid lowering therapie (p = 0,001 and p < 0,001) - and LDL, Triglyzeride, VLDL and Apo B. The frequency of rejections did not differ between patients with and without hyperlipidemia. The Apo E-Genotype seems to have no influence on the lipid- and renal metabolism. The lipid parameters our patients correlate in our study significantly with the renal transplant function, but seem to have no influence on the frequency of rejections.

Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 186-210). Also available on the Internet.

Les lymphomes T cutanés constituent un ensemble hétérogène de lymphomes non-hodkinniens. Les lymphomes T cutanés sont définis par une prolifération clonale de lymphocytes T malins et de cellules NK (natural killers) de localisation cutanée. Dans l'Union Européenne, l'indication du bexarotène par voie orale est le traitement des manifestations cutanées des lymphomes cutanés T épidermotropes (LCT), au stade avancé (ou dès un stade précoce aux États Unis). L'objectif de ce travail a été d'étudier les effets indésirables du bexarotène chez les patients atteints de lymphome cutané. Nous nous sommes plus particulièrement intéressés aux interactions du bexarotène avec le système de la coagulation et avec le métabolisme lipidique.Dans la première partie de nos travaux, nous avons étudié l'origine de la coagulopathie induite par le bexarotène. Nous avons montré que le bexarotène inhibe les facteurs IX et X de la coagulation, ce qui provoque le prolongement du temps de coagulation ; ces effets pourraient être à l'origine de la coagulopathie observée chez les patients traités au bexarotène.Dans la deuxième partie, nous avons montré que le bexarotène interagit également avec le métabolisme lipidique par l'activation du CETP et par l'inhibition de la lipoprotéine lipase, ce qui provoque une chlolésterémie et une triglyéridémie.Enfin, nous avons présenté les résultats préliminaires de l'essai clinique organisé au niveau de la région ouest de la France sur les effets indésirables du bexarotène.Les résultats de ce travail mettent en évidence l'importance de la structure chimique du bexarotène (effets de charges) dans la neutralisation des facteurs de coagulation d'une part et dans le mécanisme d'interaction avec le métabolisme lipidique (CETP et lipoprotéine lipase) d'autre part. La compréhension des mécanismes moléculaires conduisant à une coagulopathie et à la dyslipidémie représente un enjeu majeur pour prévenir la toxicité du bexarotène et pour permettre une meilleure prise en charge du patient. / The cutaneous T cell lymphomas are a heterogeneous group of non-lymphoma hodkinniens. The cutaneous T cell lymphomas are defined by a clonal proliferation of malignant T cells and NK (natural killer) cells from skin location. In the European Union, the indication of oral bexarotene is the treatment of cutaneous manifestations of cutaneous T-cell lymphomas epidermotropic (LCT) to advanced (or at an early stage in the United States). The objective of this work was to study the adverse effects of bexarotene in patients with cutaneous lymphoma. We are particularly interested in the interactions of bexarotene with the coagulation system and lipid metabolism.In the first part of our work, we studied the origin of the coagulopathy induced by bexarotene. We have shown that bexarotene inhibited factors IX and X of the coagulation causing the extension of clotting time and coagulopathy that was observed in bexarotene-treated patients. In a second part, we showed that Bexarotene induces in vitro cholesteryl ester transfer protein activity, and suppress lipoprotein lipase activity in human plasma.Finally, we presented the preliminary results of the clinical trial conducted at the western region of France on the adverse effects of bexarotene.The results of this study highlight the importance of the chemical structure of bexarotene (charge effects) in the neutralization of coagulation factors mechanisms on the one hand and in its interaction with lipid metabolism (CETP and lipoprotein lipase) on the other hand. Understanding the molecular mechanisms leading to coagulopathy and dyslipidemia is a major issue to prevent the toxicity of bexarotene and to elicit better management of the bexarotene-treated patient.

A hiperlipemia causa sérias complicações aos equinos hospitalizados, principalmente quando associada ao estresse, doenças e traumas. Tratamentos convencionais com soluções de heparina, glicose a 5%, insulina, entre outras, têm sido utilizados em equídeos predispostos, mas são questionados quanto ao seu real efeito. O interesse e as pesquisas em relação à utilização da nutrição clínica no equino, em especial a nutrição parenteral, vêm crescendo. Sua ação visa evitar a doença e o catabolismo através da regulação do balanço energético negativo, inclusive servindo de adjuvante às terapias já implementadas no tratamento da doença primária, fornecendo o requerimento básico nutricional para a manutenção e recuperação do organismo. Para avaliar a eficácia das soluções de nutrição parenteral em equinos que desenvolveram hiperlipidemia durante a internação, foram avaliados 14 equinos atendidos com afecções diversas e que apresentaram triglicérides séricos (TG) acima de 150mg/dl. Os mesmo foram divididos em dois grupos: grupo controle (G1), sem interferência do manejo e grupo tratamento (G2), que recebeu nutrição parenteral parcial sem lipídeos. Tais soluções eram compostas de glicose a 50%, aminoácido a 10%, oligoelementos, complexo vitamínico e eletrólitos e foram infundidas até a resolução da hiperlipidemia. Os animais dos dois grupos foram monitorados diariamente em relação aos valores de glicemia, triglicérides e colesterol. A média do tempo de redução dos TG no G1 foi de 209,2 ± 131,9 horas e no G2 foi de 34,9 ± 41,8 horas, com diferença estatística entre eles. Os valores de colesterol não acompanharam a elevação dos TG. Em relação à perda de peso e escore corporal, os dois grupos apresentaram redução durante a internação, sem diferença estatística entre eles. Nenhum animal do G2 desenvolveu hiperlipemia, ao contrário do G1, em que cinco equinos apresentaram, em algum momento da internação, triglicérides acima de 500mg/dl. Embora outros critérios devam ser utilizados na escolha dos pacientes que necessitam deste tipo de tratamento devido principalmente aos custos e necessidade de constante monitorização, conclui-se que a nutrição parenteral é um método rápido e seguro para a prevenção da hiperlipemia em equinos com hiperlipidemia durante a internação por outras enfermidades. / The hyperlipemia cause serious complications for hospitalized horses, especially when associated with stress, diseases and traumas. Conventional treatments with solutions of heparin, 5% glucose, insulin, among others, have been used in susceptible equine, but they are asked about their real purpose. The interest and research on the use of clinical nutrition in the horse, especially parenteral nutrition, growing. Its action is to avoid disease and catabolism by regulating the negative energy balance, including serving as adjuvant therapies have been implemented in the treatment of primary disease, providing the basic nutritional requirement for the maintenance and recovery of the body. To evaluate the effectiveness of parenteral nutrition solutions in horses that developed hyperlipidemia during hospitalization were evaluated 14 horses treated for various diseases and who had serum triglycerides (TG) above 150mg/dl. The same were divided into two groups: control group (G1), without interference from management and treatment group (G2), which received partial parenteral nutrition without lipids. Such solutions were composed of 50% glucose, 10% amino acid, trace elements, electrolytes and vitamin and were infused until resolution of hyperlipidemia. The animals of both groups were monitored daily in relation to blood glucose, triglycerides and cholesterol. The median reduction in TG G1 was 209.2 ± 131.9 hours and G2 was 34.9 ± 41.8 hours, with no statistical difference between them. Cholesterol values did not follow the elevation of TG. In relation to weight loss and body score, both groups decreased during hospitalization, with no statistical difference between them. No animals developed hyperlipidemia G2, unlike the G1, in which five horses had, at some time in hospital, triglycerides greater than 500mg/dl. Although other criteria should be used to select patients in need of such treatment primarily due to cost and the need for constant monitoring, it is concluded that parenteral nutrition is a rapid and reliable method for the prevention of hyperlipemia with hyperlipidemia in horses during the hospitalization for other diseases.

Esse estudo pretendeu fazer uma análise custo-eficácia de duas estratégias de tratamento de hiperlipidemia em pacientes HIV/AIDS, uma de carácter nutricional e a outra de carácter medicamentosa, mais precisamente com pravastatina e bezafibrato, respectivamente para casos de colesterol e triglicérides elevados, num horizonte entre 3 e 12 meses. Os dados foram coletados no CRT-AIDS de São Paulo. Encontraram-se resultados similares em termos de eficácia no caso da hipercolesterolemia, a um custo menor via abordagem nutricional. As dosagens iniciais em ambos os grupos se revelaram similares. No caso da hipertrigliceridemia, verificou-se o mesmo efeito proporcional, apesar de que se deve considerar que as dosagens iniciais eram bastante diversas, apresentando os pacientes medicados níveis mais altos de triglicérides. Essa maior custo-eficácia da abordagem nutricional aqui encontrada, deve ser ponderada, também, com as limitações encontradas no estudo, quanto à abordagem de questões como a adesão dos pacientes aos tratamentos, e características do próprio processo diagnóstico. Apesar disso, os resultados do trabalho sugerem uma especial atenção com questões ligadas à dieta e estilo de vida, não num sentido competitivo, mas complementariamente em relação às terapias medicamentosas, quando estas se fizerem necessárias. / This study intended to make a cost-efficacy analysis of 2 options for the treatment of dyslipidemia in HIV/AIDS patients, the nutritional and the medical one, more strictly with pravastatin and bezafibrate, respectively for cases of raised cholesterol and triglycerides leveis, within 3 and 12 months. The data were collected at the CRT/AIDS de São Paulo. The study found similar results in terms of effectiveness in the hypercholesterolemia groups, with a smaller cost through the nutritional strategy. The initial leveis of cholesterol In both groups were similar. In the case of the hypertriglyceridemic groups the same proportional effect was verified,although it must be considered that the initial dosages were significantly diverse, presenting the medicated patients higher leveis of serum triglycerides. The higher cost-efficacy of nutritional strategies must be weighed with the limitations of this study, as the question of compliance to the treatments and even the diagnostic processo The criteria to choose the appropriate prices were basic to the differentiation between the options and they are a point of permanent discussion by themselves. In spite of these problems the study suggests that a special attention should be given to aspects linked with diet and life style in general, not in a competitive sense, but with complementary objetives in relation with the pharmacologic therapy, if the latter be necessary.