Orientador: Milton Artur Ruiz / Coorientador: Claudia Regina Bonini Domingos / Banca: Silma Maria Alves de Melo / Banca: Isabeth da Fonseca Estevão / Resumo: A anemia falciforme (AF) afeta milhões de pessoas em todo o mundo e está associada a altas taxas de morbidade e mortalidade. Apresenta uma série de manifestações fenotípicas, que são influenciadas por fatores genéticos e ambientais, resultando em fenótipos diversificados, e um tratamento bastante eficaz tem sido o uso de hidroxiureia (HU), que ameniza os sintomas e a necessidade de transfusão sanguínea e hospitalização. Estudos de associação de genomas já demonstraram que polimorfismos genéticos podem desempenhar influência no perfil clínico dos pacientes, assim como na resposta destes à medicação. Os polimofismos -308G/A no gene TNFA e -509C/T no gene TGFB aumentam a produção das suas respectivas citocinas que atuam principalmente em vias inflamatórias e são fortes candidatos a estarem envolvidos na ocorrência de episódios vaso-oclusivos característicos da doença. Dessa forma, o objetivo do trabalho foi verificar a frequência desses polimorfismos em portadores da AF, com e sem o uso de HU, e possível relação com a gravidade das manifestações clínicas da doença. Foram obtidas 588 amostras de sangue periférico de pacientes com doença falciforme em acompanhamento no HEMORIO. A partir destas, foram separados, aleatoriamente, 240 pacientes com AF, cujo genótipo foi confirmado por procedimentos laboratoriais clássicos e moleculares. Estes foram genotipados para os polimorfismos -308G/A (TNFA) e -509C/T (TGFB) por PCR-RFLP. Os dados hematológicos e clínicos parciais de 118, dos 240 pacientes, foram obtidos por questionário e consulta aos prontuários médicos e banco de dados. A frequência do polimorfismo -308G/A foi de 0,83 em homozigose e 17,92% em heterozigose. Para o polimorfismo -509C/T, foi de 6,25% e 48,33%, respectivamente. Não foi observada associação entre o polimorfismo -308G/A e as manifestações clínicas... (Resumo completo, clicar acesso eletrônico aba / Abstract: Sickle cell anemia (SCA) affects millions of people worldwide and is associated with high morbidity and mortality. This affection shows various phenotypic manifestations, which are influenced by genetic and environmental factors, resulting in many phenotypes, and the most effective treatment has been the use of hydroxyurea (HU), which improves the symptoms and the requirement for blood transfusion and hospitalization. Genome association studies have shown that genetic polymorphisms may play role on the clinical profile of patients, as well as in response to these medications. The -308G/A and -509C/T polymorphisms, in TNFA and TGFB genes respectively, increase production of their cytokines, which act on inflammatory pathways and are strong candidates to be involved in the occurrence of vaso-occlusive episodes. The aim of this study was to determine the frequency of these polymorphisms in patients with AF, with and without HU utilization, and possible relationship with the severity of clinical manifestations of disease. We obtained 588 peripheral blood samples of patients with sickle cell disease at HEMORIO. From these, were separated at random 240 patients with AF, whose genotype was confirmed by classical and molecular laboratory procedures. They were genotyped for polymorphisms-308G/A (TNFA) and-509C/T (TGFB) by PCR-RFLP. The hematological and clinical data of 118 of the 240 patients, were obtained by questionnaire and medical records and database. The frequency of polymorphism -308G/A was 0.83% in homozygous and 17.92% in heterozygous. For the polymorphism -509C/T, was 6,25% and 48.33% respectively. No association between polymorphism -308G/A and clinical manifestations in patients was found. Concerning the polymorphism-509C/T, the mutant allele (T) proved to be a risk... (Complete abstract click electronic access below) / Mestre

This research study was focused on two broad areas of exploration. The first area deals with the identification of various factors affecting a family when a family member has the anemia or symptomatic form of sickle cell disease. Data obtained from a personally administered questionnaire (Form A), enabled the researchers to determine if genetic counseling had been offered and received, and if this counseling was considered helpful by the respondents. In addition to this, data was collected on several demographic variables, including sex and age of patient, family income, religion, education, ethnic group, living arrangements and occupation, and response to and knowledge of sickle cell anemia.

Linus Pauling incorporated hemoglobin and a disease of the blood, sickle cell anemia, into many of his researches between the mid-1930s and mid-1970s. In the early 1930s Pauling became interested in organic chemistry and named hemoglobin as one of the first biochemical substances that he planned to analyze. In 1935 he published his first paper on hemoglobin, which determined the structure of the four hemes in hemoglobin. Pauling continued to study the structure of hemoglobin until the early 1950s when he proposed that it was an alpha-helix. In 1945 Pauling learned about sickle cell anemia and published an important paper in 1949 with Harvey A. Itano, S.J. Singer, and Ibert C. Wells titled "Sickle Cell Anemia, a Molecular Disease." Pauling investigated hemoglobin into the mid-1970s when he tried to find an orthomolecular therapy for sickle cell anemia. From the mid-1950s to early 1970s, Pauling also used sickle cell anemia to promote negative eugenics, point out the possible mutagenic effects caused by nuclear weapons testing, and propose an evolutionary theory. Additionally, in the final year of his life, Pauling wrote two forewords for books on sickle cell anemia, which were published in 1994, the year he died. Hemoglobin and sickle cell anemia can be considered a theme within Pauling's work. He often returned to normal and abnormal hemoglobin as his primary substance for examination, and his familiarity with hemoglobin and sickle cell anemia inspired new research. / Graduation date: 2004

Sickle cell anemia is a hematological disorder that is caused by a single point mutation in the beta-globin chain of hemoglobin. It results in several complications related to the small and large vessels in patients with the disease. Large vessel complications include cerebral infarcts, which are observed in children under ten years old. The mechanism behind this complication is not completely understood. It is the goal of this project to begin to understand the role sickle erythrocytes may play in causing endothelial dysfunction as a precursor to sickle related complications. The hypothesis of this work is that exposure of large vessel endothelium to sickle erythrocytes causes an increase in endothelial permeability through loosening of adherens junctions. In the first goal of this work, bovine aortic endothelial cells (BAECs) are grown on coverslips and exposed to sickle erythrocytes for 5 minutes and either immediately fixed or incubated in 30 minutes and then fixed. Immunofluorescent studies labeling VE cadherin show changes in VE cadherin dynamics, suggesting sickle erythrocytes may be involved in this observation. Next, BAECs were grown on transwell inserts and exposed to sickle erythrocytes for 5 minutes. The erythrocytes are washed off and the BAEC are incubated with 10,000 MW dextran conjugated to lucifer yellow or FITC-BSA or to determine BAEC permeability. When dextran is used as the test molecule, endothelial permeability did not show a significant change from baseline. However, when BSA is used as the test molecule, increases in endothelial permeability are observed. Explanations into the differences between the transport mechanisms of the two molecules are discussed. These experiments show changes in VE cadherin localization due to sickle erythrocyte exposure. This may cause increases in endothelial permeability and an experimental model and preliminary studies are performed. This study provides potential mechanisms to explain the changes in VE cadherin localization and provide suggestions for further studies to test the effect of sickle erythrocytes on endothelial permeability. This work provides a strong foundation for continuing studies on the effects of sickle erythrocytes on endothelial dysfunction within the confines of sickle related complications.

Thesis (M. S. in Psychology)--Vanderbilt University, May 2006. / Title from title screen. Includes bibliographical references.

No description available.

Thesis (Ph. D.)--Florida State University, 2003. / Advisor: Dr. Marcia L. Rosal, Florida State University, College of Visual Arts and Dance, Dept. of Art Education. Title and description from dissertation home page (viewed Jan. 31, 2005). Includes bibliographical references.

Thesis (PH.D.)--Michigan State University. Chemistry, 2008. / Title from PDF t.p. (viewed on Aug. 11, 2009) Includes bibliographical references. Also issued in print.

Thesis (Ph. D.)--Alliant International University, California School of Professional Psychology, San Francisco, 2005. / Includes bibliographical references (61-64) and abstract.

Made available in DSpace on 2014-06-11T19:26:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-02-28Bitstream added on 2014-06-13T19:53:58Z : No. of bitstreams: 1 torres_ls_me_sjrp.pdf: 665668 bytes, checksum: 4aaf2ab7e9956b74cfe43d4216ad0030 (MD5) / A anemia falciforme (AF) afeta milhões de pessoas em todo o mundo e está associada a altas taxas de morbidade e mortalidade. Apresenta uma série de manifestações fenotípicas, que são influenciadas por fatores genéticos e ambientais, resultando em fenótipos diversificados, e um tratamento bastante eficaz tem sido o uso de hidroxiureia (HU), que ameniza os sintomas e a necessidade de transfusão sanguínea e hospitalização. Estudos de associação de genomas já demonstraram que polimorfismos genéticos podem desempenhar influência no perfil clínico dos pacientes, assim como na resposta destes à medicação. Os polimofismos -308G/A no gene TNFA e -509C/T no gene TGFB aumentam a produção das suas respectivas citocinas que atuam principalmente em vias inflamatórias e são fortes candidatos a estarem envolvidos na ocorrência de episódios vaso-oclusivos característicos da doença. Dessa forma, o objetivo do trabalho foi verificar a frequência desses polimorfismos em portadores da AF, com e sem o uso de HU, e possível relação com a gravidade das manifestações clínicas da doença. Foram obtidas 588 amostras de sangue periférico de pacientes com doença falciforme em acompanhamento no HEMORIO. A partir destas, foram separados, aleatoriamente, 240 pacientes com AF, cujo genótipo foi confirmado por procedimentos laboratoriais clássicos e moleculares. Estes foram genotipados para os polimorfismos -308G/A (TNFA) e -509C/T (TGFB) por PCR-RFLP. Os dados hematológicos e clínicos parciais de 118, dos 240 pacientes, foram obtidos por questionário e consulta aos prontuários médicos e banco de dados. A frequência do polimorfismo -308G/A foi de 0,83 em homozigose e 17,92% em heterozigose. Para o polimorfismo -509C/T, foi de 6,25% e 48,33%, respectivamente. Não foi observada associação entre o polimorfismo -308G/A e as manifestações clínicas... (Resumo completo, clicar acesso eletrônico aba / Sickle cell anemia (SCA) affects millions of people worldwide and is associated with high morbidity and mortality. This affection shows various phenotypic manifestations, which are influenced by genetic and environmental factors, resulting in many phenotypes, and the most effective treatment has been the use of hydroxyurea (HU), which improves the symptoms and the requirement for blood transfusion and hospitalization. Genome association studies have shown that genetic polymorphisms may play role on the clinical profile of patients, as well as in response to these medications. The -308G/A and -509C/T polymorphisms, in TNFA and TGFB genes respectively, increase production of their cytokines, which act on inflammatory pathways and are strong candidates to be involved in the occurrence of vaso-occlusive episodes. The aim of this study was to determine the frequency of these polymorphisms in patients with AF, with and without HU utilization, and possible relationship with the severity of clinical manifestations of disease. We obtained 588 peripheral blood samples of patients with sickle cell disease at HEMORIO. From these, were separated at random 240 patients with AF, whose genotype was confirmed by classical and molecular laboratory procedures. They were genotyped for polymorphisms-308G/A (TNFA) and-509C/T (TGFB) by PCR-RFLP. The hematological and clinical data of 118 of the 240 patients, were obtained by questionnaire and medical records and database. The frequency of polymorphism -308G/A was 0.83% in homozygous and 17.92% in heterozygous. For the polymorphism -509C/T, was 6,25% and 48.33% respectively. No association between polymorphism -308G/A and clinical manifestations in patients was found. Concerning the polymorphism-509C/T, the mutant allele (T) proved to be a risk... (Complete abstract click electronic access below)