Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Thesis (M.Med.Sc.)--University of Hong Kong, 2003. / Includes bibliographical references (leaves 49-53). Also available in print.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

The hypervariable locus DXS255 in human Xp11.22 has a heterozygosity exceeding 90% and has therefore facilitated the localization of several disease genes which map to the proximal short arm of the X chromosome, including the immune deficiency Wiskott-Aldrich syndrome and the eye disorders retinitis pigmentosa, congenital stationary night blindness and Aland Island eye disease. In addition, a microdeletion involving DXS255 has been identified in patients suffering from Dent's disease, a familial X-linked renal tubular disorder which is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis (kidney stones) and eventual renal failure. Two YAC contigs were constructed in Xp11.23-p11.22 in order to aid transcript mapping; the first centred on the DXS255 locus, the second mapping distal to the first and linking the genes GATA, TFE3 and SYP to the OATL1 cluster. Eleven novel markers were generated, one of which contains an exon from a novel calcium channel gene. Four putative CpG islands were detected in the region. Analysis of the microdeletion associated with Dent's disease using markers from the DXS255 contig demonstrated that it is confined to a 370kb interval. A YAC overlapping this deletion was hybridized to a kidney-specific cDNA library to isolate coding sequences that might be implicated in the disease aetiology. The clones thus identified detect a 9.5kb transcript which is expressed predominantly in kidney, and originate from a novel gene (CLCN5) falling within the deleted region. Sequence analysis indicates that the 746 residue protein encoded by this gene is a new member of the C1C family of voltage-gated chloride channels. The coding region of CLCN5 is organized into twelve exons, spanning 25-30kb of genomic DNA. Using the information presented in this thesis, other studies have identified deletions and point mutations which disrupt CLCN5 activity in further patients affected with X-linked hypercalciuric nephrolithiasis, confirming the role of this locus in renal tubular dysfunction.

Bibliography : leaves 182-203. / 203 leaves : ill, map ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes the molecular analysis of the HLA class I and class II genes in the Australian Aboriginal population and also provides a comparison of serological and molecular tissue typing methods in view of genetic mutations at the HLA loci and the expression of serological HLA "blanks". / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1996?

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliography.

Thesis (Ph.D.)--Memorial University of Newfoundland, Faculty of Medicine, 2000. / Includes bibliographical references.

Orientador: Ricardo Luiz Dantas Machado / Coorientador: Cláudia R. Bonini-Domingos / Banca: Carlos Eugênio Cavasini / Banca: Maria Tercilia Vilela / Banca: Érika Cristina Pavarino / Banca: Lilian Madi Ravazzi / Resumo: No Brasil o Plasmodium vivax é a espécie mais prevalente, responsável por aproximadamente 85% dos casos de malária. Ademais as variantes da proteína circumesporozoíta (CSP - VK210, VK247 e P. vivax-like) já foram identificadas em várias áreas endêmicas no país. Diversos estudos analisando a influência da variabilidade genética de receptores celulares e moléculas envolvidas na resposta imune, com diferentes peptídeos do Plasmodium, têm obtido resultados variáveis de acordo com o antígeno utilizado e a população analisada. Este trabalho apresenta resultados sobre o estudo de polimorfismos genéticos no TCR (T cell Receptor) e nas Interleucinas 1 e 2 em pacientes infectados por P. vivax provenientes do município de Goianésia do Pará, no Estado do Pará. Avaliou-se estes polimorfismos com a parasitemia do indivíduo, com os genótipos da CSP e com a resposta sorológica contra os peptídeos da CSP. Foram relacionados também estes polimorfismos com os níveis de citocinas. Os polimorfismos foram analisados por técnicas de PCR-RFLP e PCR alelo específico. As análises sorológicas da CSP foram realizadas por ELISA. Foram comparadas as frequências genotípicas observadas segundo o teorema de Hardy-Weinberg (HW). Os níveis de IL1 e IL2 foram avaliados por citometria de fluxo, seguindo protocolo descrito pelo fabricante. Associação dos polimorfismos com os níveis de interleucinas foi avaliada por Análise de variância. As frequências genotípicas e alélicas foram obtidas no programa R v 2.11.1.... / Abstract: In Brazil, Plasmodium vivax is the most prevalent species responsible for approximately 85% of malaria cases. In addition, variants of the circosporozoite protein (CSP - VK210, VK247 and P. vivax - like) have already been identified in several endemic areas in the country. Several studies analyzing the influence of the genetic variability of cellular receptors and molecules involved in the immune response with different Plasmodium peptides have obtained variable results according to the antigen used and the analyzed population. This work presents results on the study of genetic polymorphisms in TCR (T cell Receptor) and in Interleukins 1 and 2 in patients infected by P. vivax from the city of Goianésia do Pará, in the State of Pará. These polymorphisms were evaluated with Parasitemia, CSP genotypes and serological response to CSP peptides. These polymorphisms were also related to cytokine levels. Polymorphisms were analyzed by PCR-RFLP and allele-specific PCR techniques. Serological tests of CSP were performed by ELISA. The genotypic frequencies observed according to the Hardy-Weinberg (HW) theorem were compared. Levels of IL1 and IL2 were evaluated by flow cytometry following the protocol described by the manufacturer. Association of polymorphisms with interleukin levels was evaluated by analysis of variance. The genotypic and allelic frequencies were obtained in program R v 2.11.1. The parasitemia ranged from 15 to 70,000, with a median of 1,500 parasites / mm3. The SNPS investigated showed varied frequencies in the sample studied. All polymorphism evaluated is in Hard Wenberg Equilibrium. There was no significant difference in parasitemia in relation to the investigated SNPs. Infections containing only the VK247 variant were the most common and also no significant difference in antibody response was observed according to the CSP variant present at the time of infection ... / Doutor

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Orientador: Claudia Regina Bonini Domingos / Banca: Gustavo Orlando Bonilla Rodriguez / Banca: Nicola Amanda Conran Zorzetto / Resumo: A anemia falciforme (AF) é uma anemia hemolítica hereditária que acarreta ao portador manifestações clínicas complexas e diversificadas. Na AF o estresse oxidativo é um dos fatores que interferem no fenótipo do portador, uma vez que influencia nos processos de vaso-oclusão aumentando as propriedades adesivas dos eritrócitos, leucócitos e plaquetas ao endotélio. Durante a transformação do eritrócito discóide com hemoglobina (Hb) S em eritrócito afoiçado, dentre os eventos bioquímicos e polimerizantes da célula, ocorre a degradação oxidativa dessa Hb, com a liberação agentes pró-oxidantes. Estes promovem a oxidação de lipídeos e também de proteínas e DNA, modificando mecanismos celulares que levam a célula a apoptose e, consequentemente, causam danos aos tecidos. Neste contexto, os principais meios de defesa no organismo são divididos em dois grupos, enzimáticos e não enzimáticos. Entre as enzimas detoxificantes de fase II mais estudadas estão as GSTs, que pertencem a uma família multifuncional de enzimas que catalisam a conjugação da molécula de GSH e possuem papel fundamental em mecanismos de defesa contra compostos endo e xenobióticos. Considerando a grande incidência da AF em nosso país e as manifestações clínicas diferenciadas nos portadores, o presente trabalho pretendeu investigar os polimorfismos das GSTs (GSTM1, GSTT1 e GSTP1) e verificar sua influência sob parâmetros oxidativos - peroxidação lipídica por TBARS, e lesão de DNA pela avaliação de Corpos de Howell-Jolly e Ensaio Cometa em portadores da AF. Foram avaliadas amostras de 91 indivíduos com AF com e sem o uso de HU e 99 amostas de um grupo controle. Para o desenvolvimento do trabalho, as amostras foram separadas em três grupos: indivíduos portadores de anemia falciforme em uso de hidroxiureia (AF + HU: 46 indivíduos), indivíduos portadores de anemia falciforme sem uso de hidroxiureia (AF - HU: 45 indivíduos) e o grupo ... / Abstract: Sickle cell anemia (SCA) is an inherited hemolytic disease that leads complex and diverse clinical manifestations. In SCA, oxidative stress is one of the factors that affect the phenotype of the carrier, in response of its influences on vaso-occlusion processes that increases the adhesive properties of erythrocytes, leukocytes and platelets to the endothelium. During the transformation of discoid erythrocytes with hemoglobin (Hb) S into sickle cells, among the biochemical and polymerizing events, the oxidative degradation of this Hb occurs, releasing pro-oxidants agents. They promote oxidation of lipids and proteins and modify cellular mechanisms that lead to cell apoptosis and cause tissue damage. In this context, the main means of body defense are divided in two groups: enzymatic and non-enzymatic. Among the phase II detoxifying enzymes, the most studied are Glutathione S-transferases (GSTs), which belong to a family of multifunctional enzymes that catalyze the combination of the glutathione (GSH) molecule and have a central role in mechanisms of defense against xenobiotic compounds. Considering the high incidence of SCA in our country and the different clinical manifestations in patients, this study aimed to investigate polymorphisms of GSTs (GSTM1 , GSTT1 and GSTP1 ) and determine its influence on oxidative parameters - lipid peroxidation by TBARS and DNA damage by evaluation of Howell -Jolly bodies (HJB) and comet assay in patients with SCA. Samples of 91 patients with SCA with and without hydroxyurea (HU) use and 99 samples of a control group were evaluated. For the work development, the samples were separated into three groups: individuals with sickle cell anemia using hydroxyurea (SCA + HU: 46 individuals), individuals with sickle cell disease without use of hydroxyurea (SCA - HU: 45 individuals) and control group (CG: 99 individuals) to verify the influence of medication on the evaluated parameters. Only the genotypic profile ... / Mestre