A Doença Falciforme é uma alteração hemolítica hereditária do tipo autossômica recessiva com grande variabilidade clínica e importância epidemiológica envolvendo afrodescendentes. As complicações agudas estão relacionadas geralmente a vaso-oclusão, acarretando dores osteomioarticulares e abdominais e comprometimento crônico de múltiplos órgãos e sistemas. Estas complicações envolvem o sistema nervoso central, provocando acidentes vasculares encefálicos ou infartos cerebrais silenciosos. Há evidências de que o efeito cumulativo destas complicações, associado à fatores socioambientais e ao genótipo interferem no desempenho cognitivo, linguístico, pessoal-social e motor, levando a diminuição do rendimento acadêmico em idade escolar e repercutindo na qualidade de vida destes indivíduos. Os objetivos deste trabalho foram: verificar as habilidades do desenvolvimento infantil, com enfoque na linguagem, em pré-escolares com Doença Falciforme sem AVE comprovado em comparação com crianças saudáveis para a doença; verificar a influência dos aspectos motores, pessoais-sociais e cognitivos no desenvolvimento da linguagem; e verificar a influência de fatores socioambientais no desenvolvimento infantil. Trinta e quatro crianças (17 com Doença Falciforme - GDF e 17 saudáveis para a doença - Grupo controle: GC) com idade entre um ano e cinco anos e 11 meses, submeteram-se à avaliação das habilidades motoras, cognitivas, pessoais-sociais, linguísticas e psicolinguísticas por meio da aplicação dos seguintes instrumentos, de acordo com sua faixa etária: Teste de Screening do Desenvolvimento de DENVER-II; Early Language Milestone Scale; ABFW Teste de Linguagem Infantil Parte A (fonologia); Teste de Vocabulário por Imagem Peabody; e Teste Illinóis de Habilidades Psicolinguísticas. As crianças foram pareadas quanto à idade em anos e meses, sexo, nível socioeconômico e afrodescendência. Para análise estatística utilizou-se os Teste de Correlação de Spearman, de Mann-Whitney e de Fisher. O GDF apresentou resultados significativamente inferiores em habilidades de linguagem e psicolinguísticas relacionadas à fonologia, morfossintaxe, semântica, metalinguagem e memória de trabalho auditiva e visual, em relação ao GC. O vocabulário receptivo não apresentou alteração. Os resultados nas habilidades pessoal-social, motora grossa e motora fina-adaptativa demonstraram tendência de desempenho inferior para o GDF e correlação com o desempenho em habilidades de linguagem, indicando a influência dessas áreas no desenvolvimento de habilidades comunicativas. Déficits atencionais foram observados durante a realização das avaliações. Dados como idade no início da produção das primeiras palavras, número de internações, presença em pré-escola, independência em atividades de vida diária, nível socioeconômico e idade na avaliação tiveram correlação com o desempenho nas habilidades do desenvolvimento infantil, vocabulário receptivo, fonologia e habilidades psicolinguísticas, mostrando a influência dos fatores socioambientais no desenvolvimento destas crianças. As alterações observadas neste estudo, associadas às condições de saúde, podem acarretar prejuízos ao longo da vida desses indivíduos, com implicações negativas para o aprendizado escolar, vida profissional e qualidade de vida. Estudos longitudinais são importantes para acompanhar e prevenir os efeitos deletérios das Doenças Falciformes. / The Sickle Cell Disease is an inherited autosomal recessive hemolytic alteration with great clinical variability and epidemiological importance involving african descent. Acute complications are usually related to vascular occlusion, causing musculoskeletal and abdominal pain and chronic involvement of multiple organs and systems. These complications involve the central nervous system, causing strokes or silent cerebral infarcts. There is evidence that the cumulative effect of these complications associated with environmental factors and genotype interfere with cognitive, language, personal-social and motor performance, leading to decreased academic performance at school age and reflecting on the quality of life of these individuals. The objectives of this study were to verify the child development skills, with a focus on language, in preschool children with sickle cell disease without proven stroke compared to healthy children for the disease; verify the influence of motor, personal-social and cognitive aspects on language development; and verify the influence of environmental factors on child development. Thirty-four children (17 with Sickle Cell Disease - SCDG and 17 without the disease - Control Group: CG) with chronological age between one and five years and 11 months, underwent assessment of motor, cognitive, personal-social, linguistic and psycholinguistic skills through the following instruments, according to their age: DENVER-II Developmental Screening Test; Early Language Milestone Scale; ABFW Teste de Linguagem Infantil- Part A (phonology); The Peabody Picture Vocabulary Test; and Illinois Test of Psycholinguistic Abilities. The children were matched for age in years and months, sex, socioeconomic status and african ancestry. It was used the Spearman correlation, Mann-Whitney and Fish tests for the statistical analysis. The SCDG, compared with the CG, showed significantly lower results in language and psycholinguistic skills related to phonology, morphosyntax, semantics, metalanguage, and verbal and visual work memory. The receptive vocabulary doesnt showed alterations. The results in personal-social, gross motor and fine-adaptive motor skills showed tendency to underperform for SCDG and correlation with the performance in language skills, indicating the influence of these areas in the development of communication skills. Attentional deficits were observed during the conduct of evaluations. Data such as age at first words production onset, number of hospitalizations, attendance at pre-school, independence in daily living, socioeconomic status and age at assessment activities were correlated with performance on the child development skills, receptive vocabulary, phonology and psycholinguistic skills, showing the influence of environmental factors in the development of these children. The changes observed in this study, associated with health conditions, can cause damage throughout the life of these individuals, with negative implications for school learning, work and quality of life. Longitudinal studies are important to monitor and prevent the deleterious effects of sickle cell disease.

Os sistemas de informação em saúde permitem melhorias no processo de gestão e assistência ao paciente. A fundação HEMOBA é responsável pela assistência médica e transfusional de grande parcela da população baiana, pelo SUS, em seu ambulatório transfusional e de atendimento à pacientes com doenças hematológicas benignas. A doença falciforme (DF) é uma das doenças hereditárias mais prevalentes no mundo, sendo a Bahia o estado brasileiro onde é encontrada sua maior prevalência. A transfusão sanguínea é uma das bases para o seu tratamento. Não existe sistema informatizado no atendimento desses pacientes nem banco de dados sobre essa população na instituição. OBJETIVO: Desenvolver um Software para seguimento transfusional em hemoterapia, com ênfase no acompanhamento de pacientes falciformes, possibilitando descrever e analisar aspectos transfusionais dessa população e dos doadores. MATERIAIS E MÉTODOS: Foi desenvolvido um Software, denominado BDTrans, utilizando a metodologia de Ciclo de Vida de Desenvolvimento de Sistemas, que possibilitou um estudo analítico, transversal, com abordagem qualitativa e quantitativa, dos dados extraídos do sistema. Foram acompanhadas crianças falciformes, de 0 a 18 anos, em regime transfusional, atendidas no ambulatório da Fundação HEMOBA. RESULTADOS: Foram incluídos 108 pacientes, destes 58% apresentavam DTC alterado e 38% apresentavam passado de AVC. As crianças residentes em Salvador correspondiam a 34%. A maioria das transfusões foi iniciada na faixa etária entre 2-8 anos (61%) e 9-12 anos (24,7%). 28% dos pacientes iniciou o regime transfusional em 2011, seguido dos anos de 2012 com 16%. A prevalência de aloimunização eritrocitária foi de 26%, sendo os principais aloanticorpos contra antígenos do sistema Rh e Kell. CONCLUSÃO: A utilização do Software possibilitou tornar os dados mais acessíveis para análise clínica e epidemiológica, auxiliando na gestão e assistência à saúde. O sistema poderá ser utilizado como base para o desenvolvimento de um programa de fidelização de doadores fenotipados em um futuro próximo. / Softwares built for data collection from Health Centers are important tools for patient care and for public health decisions. The HEMOBA foundation is responsible for health assistance of a great proportion of the population from the State of Bahia, including medical care and transfusional assistance to patients with benign hematological disorders. Sickle cell disease is one of the most prevalent hereditary disorders in the world, and the State of Bahia has the highest prevalence of the S mutation in Brazil. Blood transfusion is one of the treatment modalities for sickle cell patients, and there is no software for data collection of the clinical and transfusional program. OBJECTIVE: to develop a software to help follow up the transfusional program of the HEMOBA foundation, including the sickle cell patients, collecting transfusional data and blood donor information. MATERIALS AND METHODS: we developed a software called \"BDTrans\", using the methodology of the \"Cicle of Life System Development\", that allowed an analytical, transversal study with both qualitative and quantitative approach of the data extracted from the program. Sickle cell children from 0 to 18 years who were on transfusion at The HEMOBA foundation were the subject of our study. RESULTS: 108 sickle cell patients were included, 58% had brain vasculopathy and 38% had a history of stroke. 34% of the children lived in Salvador. The age range of the children when the transfusion program started was between 2-8 years (61%) and 9-12 years (24.7%). 28% of the patients started the transfusional program in 2011, and 16% started in 2012. The prevalence of red cell alloimmunization was 26%, most of the antibodies were against Rh and Kell blood groups. CONCLUSION: The utilization of the BDTrans Software promoted the collection of clinical and transfusional data from sickle cell patients, possibilitating the evaluation of their transfusional program, and providing important information to the public health system. The software can also be used to develop a fidelization program of phenotyped blood donors in the near future.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2018-05-24T17:30:38Z No. of bitstreams: 1 keniadeassisboy.pdf: 53006692 bytes, checksum: 65f398b7012273fa08a2843e4d1f6878 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-06-14T11:54:22Z (GMT) No. of bitstreams: 1 keniadeassisboy.pdf: 53006692 bytes, checksum: 65f398b7012273fa08a2843e4d1f6878 (MD5) / Made available in DSpace on 2018-06-14T11:54:22Z (GMT). No. of bitstreams: 1 keniadeassisboy.pdf: 53006692 bytes, checksum: 65f398b7012273fa08a2843e4d1f6878 (MD5) Previous issue date: 2018-03-20 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / A doença falciforme (DF) é um grave problema de saúde pública mundial, com grande impacto na morbimortalidade da população acometida. Até o momento, a hidroxiureia (HU) é considerada a terapia farmacológica de maior sucesso para a DF, pois promove redução do número e gravidade dos eventos falcêmicos, melhora os parâmetros hematológicos, reduz o número de internações e aumenta a expectativa e qualidade de vida dos pacientes. Ainda que sejam evidentes os benefícios do tratamento com HU, existe grande variabilidade interindividual de resposta farmacológica e os fatores genéticos parecem estar associados, em parte, a essa variação. Assim, o objetivo do presente estudo foi investigar se polimorfismos de um único nucleotídeo (SNPs) em quatro genes candidatos relacionados à farmacocinética e farmacodinâmica da HU afetam a resposta hematológica a tal fármaco. Para tanto, foram avaliados 185 pacientes com DF tratados (n=93) ou não tratados (n=92) com HU. Os níveis médios de hemoglobina (Hb), hematócrito (Hct), reticulóticos (Rtc) e leucometria global (LG) foram medidos em cinco diferentes tempos ao longo de 18 meses, enquanto a concentração de hemoglobina fetal (HbF) foi analisada antes e após o tratamento farmacológico. Os pacientes foram agrupados como "respondedores" à HU se os níveis de HbF estivessem maiores que 20%, enquanto aqueles pacientes com níveis inferiores a esse foram considerados como "não respondedores". O DNA genômico foi extraído a partir do sangue total e amostras foram então genotipadas por PCR em tempo real (qPCR) para os polimorfismos G>T (rs1799983) e T>C (rs2070744) no gene da eNOS, C>T (rs17599586) da ARG1, A>C (rs766432) e G>A (rs4671393) do BCL11A e G>A (rs9960464) do gene do UTA. As análises de associação entre as variáveis categóricas foram feitas pelo teste do qui-quadrado ou teste exato de Fisher. Para as variáveis contínuas com distribuição normal, as análises foram realizadas utilizando ANOVA seguido pelo teste t não pareado e as variáveis que não seguiram distribuição normal foram analisadas pelos testes de Wilcoxon, Kruskal-Wallis seguidos por Mann-Whitney. As análises por regressão multivariada e logística foram realizadas através do método stepwise pelo software R. A população estudada apresentou idade de 15,8 ± 11,3 anos e foi constituída de 54% de voluntários do sexo masculino. As frequências genotípica e alélica para os seis SNPs estudados apresentaram-se em equilíbrio de Hardy-Weinberg e foram semelhantes àquelas encontradas em outras populações. Pacientes com o genótipo GT para o polimorfismo no rs1799983 do gene da eNOS apresentaram maiores valores de Hb quando comparados aos homozigotos para o alelo G (r=0,364; p=0,033). Adicionalmente, a frequência dos genótipos AC e CC no gene BCL11A (polimorfismo A>C rs766432) foi maior entre os pacientes respondedores quando comparado ao grupo dos não respondedores (p=0,03). Além disso, pacientes com o genótipo GA para o polimorfismo no gene UTA também responderam melhor à terapia com HU quando comparados àqueles com o genótipo GG (p=0,005). Não foram encontradas outras influências significativas nos demais polimorfismos avaliados após análise por regressão logística. Em conclusão, este trabalho é pioneiro ao avaliar a influência de polimorfismos nos genes da eNOS, ARG1, BCL11A e UTA na resposta à HU em pacientes com doença falciforme em Minas Gerais. Os achados nos sugerem que pacientes com genótipo GT no rs1799983 do gene da eNOS apresentam maiores valores de Hb quando comparados com genótipo GG. Os polimorfismos A>C (rs766432) no gene do BCL11A (p=0,001) e G>A (rs9960464) do gene UTA (p=0,005) parecem afetar a resposta hematológica à HU, sendo que pacientes que possuem pelo menos uma cópia do alelo de menor frequência possivelmente apresentam maior chance de resposta ao tratamento farmacológico. / Sickle cell disease (SCD) is a serious global public health problem, with great impact on the morbidity and mortality of the affected population. To date, hydroxyurea (HU) is considered the most successful pharmacological therapy for SCD since it promotes a reduction in the number and severity of sickle cell events, improves hematological parameters, reduces the number of hospitalizations and increases the expectation and quality of life of the patients. Although the benefits of the treatment with HU are evident, there is a large inter-individual variability of pharmacological response and genetic factors seem to be partially associated with this variation. Thus, the aim of the present study is to investigate whether single nucleotide polymorphisms (SNPs) in four candidates genes related to the pharmacokinetics and pharmacodynamics of HU affect the hematological response to such a drug. For this, 185 patients were evaluated with SCD, treated with HU (93) or untreated (92). The mean hemoglobin (Hb), hematocrit (Hct), reticulocytes (Rct) and global leukometry (LG) levels were measured at five different times over 18 months, while fetal hemoglobin (HbF) levels were analyzed before and after pharmacological treatment. Patients were grouped as "responders" to HU if HbF levels were higher than 20%, while those patients with levels below this value were considered "non-responders". Genomic DNA was extracted from the whole blood and samples were then genotyped by real-time PCR (qPCR) for the polymorphisms G>T (rs1799983) and T>C (rs2070744) on the eNOS gene, C>T (rs17599586) of ARG1 gene, A>C (rs766432) and G>A (rs4671393) of the gene BCL11A and G>A (rs9960464) of the UTA gene. The analysis of the association between the categorical variables was done by chi-square test or Fisher's exact test. For continuous variables with normal distribution, analyses were performed using ANOVA followed by the unpaired t-test and the variables that did not follow normal distribution were analyzed by the Wilcoxon, Kruskal-Wallis tests followed by Mann-Whitney. The multivariate and logistic regression analyses were performed through the stepwise method by software R. The population studied presented a mean age of 15.8 ± 11.3 years and was made up of 54% of male volunteers. The genotypic and allelic frequencies for the six SNPs studied were in Hardy-Weinberg equilibrium and were similar to those found in other populations. Patients with the GT genotype for rs1799983 polymorphism of the eNOS gene showed higher Hb values when compared to patients homozygous for the G allele (r=0,364; p=0,033). In addition, the frequency of AC and CC genotypes in the BCL11A gene (A>C polymorphism rs766432) was higher among the responders when compared to the non-responders group (p=0,03). In addition, patients with the GA genotype for the UTA gene polymorphism also responded better to HU therapy when compared to those with the GG genotype (p=0,005). No other significant influences were found in the other polymorphisms evaluated after logistic regression analysis. In conclusion, this work is a pioneer in evaluating the influence of polymorphisms in eNOS, ARG1, BCL11A and UTA genes in the response to HU in patients with sickle cell disease in Minas Gerais. The findings suggest that patients with the GT genotype for rs1799983 of the eNOS gene showed higher Hb values when compared to GG genotype. The A> C polymorphisms (rs766432) in the BCL11A (p=0,001) and G> A gene (rs9960464) of the UTA gene (p=0,005) appear to affect the hematological response to HU, and patients who have at least one copy of less frequent allele may present higher chance of respond to pharmacological treatment.

Orientadores: Nicola Amanda Conran Zorzetto, Fernando Ferreira Costa / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T05:42:46Z (GMT). No. of bitstreams: 1 Dominical_VeninaMarcela_D.pdf: 4297524 bytes, checksum: 86e7e426a479616f71a78d95e3333914 (MD5) Previous issue date: 2014 / Resumo: A anemia falciforme (AF) é uma hemoglobinopatia hereditária que resulta de uma mutação no gene da globina beta. Essa mutação leva a formação de uma hemoglobina (Hb) com propriedades físico-químicas anormais, denominada HbS. A vaso-oclusão é a principal complicação aguda e a principal causa de morbidade da doença falciforme, compreendendo um processo multicelular que parece ser iniciado pela adesão de hemácias e leucócitos ao endotélio ativado, causando a obstrução vascular e isquemia tecidual. A adesão de hemácias ao endotélio contribui para a redução do fluxo sanguíneo na AF, entretanto, leucócitos também parecem exercer um papel fundamental neste processo, pois são células maiores, menos flexíveis e seu recrutamento para a microvasculatura e subsequente interação com as células circulantes sanguíneas promove a redução do fluxo sanguíneo nos vasos. Assim, investigações na dinâmica de interações heterocelulares são áreas potencialmente atrativas para pesquisa, pois elas podem contribuir para melhorar o entendimento de mecanismos de inflamação vascular e para o desenvolvimento de novos alvos terapêuticos para doenças como a AF. O objetivo deste projeto foi estudar as interações heterotípicas dos neutrófilos a plaquetas, células vermelhas e células endoteliais em células de pacientes com AF e as moléculas de adesão celular envolvidas nestas interações, utilizando uma plataforma microfluidica (quantifica adesão celular em fluxo em biochips com canais paralelos), citometria de fluxo com imagem (imagem simultânea das células obtidas pelo citômetro) e o desenvolvimento de um biochip para estudo dos processos vaso-oclusivos (para utilização na plataforma microfluídica). Sangue periférico de indivíduos saudáveis (controles) e pacientes com anemia falciforme (em uso ou não da terapia de hidroxiureia ¿ HU) foi coletado e os experimentos realizados. Observamos que células vermelhas de pacientes AF sem uso da HU aderem mais, quando em fluxo, à laminina e interagem mais aos neutrófilos autólogos aderidos ao endotélio ativado. Quando avaliada a participação das principais moléculas de adesão expressas no endotélio, E-selectina e ICAM-1, na promoção das interações de eritrócitos a neutrófilos aderidos, observamos que a duração destas interações heterotípicas, em células provenientes dos pacientes AF, é mais prolongada na presença do ligante E-selectina. Neutrófilos de pacientes com AF também circulam mais em agregados a plaquetas ou células vermelhas no sangue periférico, comparados aos neutrófilos de indivíduos saudáveis. Os reticulócitos demonstraram ser o principal tipo de eritrócito envolvido nos agregados de neutrófilos circulantes e os níveis de hemoglobina fetal correlacionaram-se inversamente à porcentagem encontrada de agregados de neutrófilo-reticulócito no sangue periférico destes pacientes. As plaquetas demonstraram papel de destaque na formação e participação nos agregados circulantes de neutrófilos a células vermelhas e experimentos utilizando anticorpos bloqueadores ou inibidor, indicaram que as moléculas de adesão P-selectina, na plaqueta, Mac-1 no neutrófilo, VLA-4 nos reticulócitos e ICAM-4 nas hemácias podem ser as responsáveis pela interação dos neutrófilos a estas células. Neutrófilos de pacientes AF também obstruíram significativamente mais os microcanais com diâmetros de 25 a 40µm do biochip desenvolvido por nós para estudar os processos vaso-oclusivos, comparados aos neutrófilos de indivíduos controle. Quando misturamos suspensões de neutrófilos a eritrócitos, observamos uma obstrução ainda maior destes microcanais. Diante destes resultados, é possível concluir que neutrófilos de pacientes AF interagem significativamente mais às células vermelhas quando aderidos ao endotélio, circulam agregados a eritrócitos e plaquetas no sangue, além de possuírem maior capacidade de obstrução in vitro em microcanais que mimetizam vênulas de pequeno calibre. A terapia com HU parece afetar apenas as interações de neutrófilo na presença do endotélio vascular. Terapias que visem à inibição das moléculas de adesão Mac-1 e P-selectina na patologia da anemia falciforme parecem ser promissoras / Abstract: Sickle cell anemia (SCA) is a hereditary hemoglobinopathy that results from a mutation in the beta globin gene. This mutation leads to the formation of an abnormal hemoglobin (Hb), known as HbS. Vaso-occlusion is the major acute complication and the major cause of morbidity in SCA; it comprises a multicellular process that appears to be initiated by the adhesion of red blood cells (RBCs) and leukocytes to the activated endothelium, causing vascular obstruction and tissue ischemia. The adhesion of sickle RBCs to the endothelium contributes to decrease blood flow; however, leukocytes also seem to play a key role in this process as these cells are bigger, less flexible and their recruitment to the microvasculature and subsequent interaction with circulating blood cells promotes reduced blood flow in vessels. Research into the dynamics of heterocellular interactions is a potentially attractive area of research, since such data may improve our understanding of the mechanisms involved in vascular inflammation and contribute to the development of new therapeutic targets in diseases such as SCA. The aim of this project was to study the heterotypic interactions of neutrophils with platelets, red cells and endothelial cells in cells from SCA individuals and the possible adhesion molecules involved in these interactions, using microfluidic techniques (cell adhesion flow in biochips with parallel channels), imaging flow cytometry (simultaneous imagery of cells acquired by flow cytometry) and the development of a biochip for the study of vaso-occlusive processes (for use in conjunction with the microfluidic platform). Peripheral blood from healthy individuals (controls) and sickle cell anemia patients (with or without hydroxyurea therapy - HU) were collected and the experiments were performed. RBCs from SCA patients without HU were observed to adhere more, under flow, to laminin-coated biochips and they interact more with autologous neutrophils previously adhered to an activated endothelium. When evaluating the participation of the two main adhesion molecules expressed on activated endothelium, E- selectin and ICAM-1, in promoting interactions of RBCs to adherent neutrophils, we found that the duration of these heterotypic interactions for cells from SCA patients was longer in the presence of E-selectin ligand. Neutrophils from SCA patients also circulate aggregated to platelets or RBCs in the peripheral blood significantly more than the neutrophils of healthy individuals. Reticulocytes were the main RBC type involved in these neutrophil-RBC aggregates and the levels of fetal hemoglobin were inversely correlated to the percentage of the neutrophil- reticulocyte aggregates found in the peripheral blood of these patients. Platelets demonstrated a prominent role in the formation of the circulating neutrophil-RBCs aggregates, and function-blocking antibodies or inhibitors indicated that the adhesion molecules P-selectin, on platelets, Mac-1, on neutrophils, VLA-4, on reticulocytes, and ICAM-4, on mature erythrocytes, may be responsible for the interactions of neutrophils with these cells. Neutrophils from SCA patients also demonstrated a significant capacity to obstruct microchannels with diameters of between 25 and 40?m, of the biochip developed by us to study vaso-occlusive processes, compared to the cells from control subjects. When mixed suspensions of neutrophils and autologous RBCs were applied to the chips, we observed an even greater obstruction of these microchannels. In summary, we conclude that SCA neutrophils interact significantly more with red cells when adhered to endothelial cells, circulate aggregated to erythrocytes in the peripheral blood of these patients, and present a greater capacity to obstruct microchannels that mimic small venules in vitro. HU therapy appears to affect only neutrophil interactions in the presence of the vascular endothelium. Therapies that target molecules such Mac-1 and P-selectin in sickle cell disease seem to be promising strategies / Doutorado / Fisiopatologia Médica / Doutora em Ciências

Orientador: Sara Teresinha Olalla Saad / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T08:39:07Z (GMT). No. of bitstreams: 1 Zanoni_CamilaTatiana_M.pdf: 24918367 bytes, checksum: abb28cb6b7289665d1fb2d038126541e (MD5) Previous issue date: 2014 / Resumo: A doença falciforme é uma doença genética, que resulta em falcização das hemácias, desencadeando fenômenos de vaso-oclusão, episódios de dor e lesão de órgãos. O comprometimento ósseo é a manifestação clínica mais comum, podendo causar deficiências crônicas e progressivas, como a necrose avascular da cabeça femoral, principal causa de deformidade de quadril nestes pacientes, levando a distúrbios na marcha e limitação de dor, nível de atividade e função. Raros são os estudos encontrados na literatura sobre a atuação da fisioterapia como recurso capaz de prevenir e tratar as disfunções do aparelho locomotor presentes nos indivíduos portadores de doença falciforme. O objetivo deste estudo foi avaliar e comparar o efeito de dois programas de fisioterapia para pacientes portadores de doença falciforme visando diminuir a dor musculoesquelética em região do quadril e coluna lombar e aumentar a funcionalidade desses pacientes. Um dos programas foi a fisioterapia convencional realizada em solo, comparado com um protocolo de exercícios realizados em piscina aquática. A pesquisa teve início com a avaliação dos voluntários a partir de escalas funcionais (Escala LEFS ¿ Lower Extremity Functional Scale; Questionário Algofuncional de Lequesne e Índice de Incapacidade de Oswestry), medida da amplitude de movimento articular (ADM) de flexão e extensão do tronco, flexão, extensão, adução e abdução do quadril, avaliação da força muscular (FM) de flexores e extensores do tronco, flexores, extensores, adutores e abdutores do quadril através de célula de carga e eletromiografia de superfície (EMGs) dos músculos iliocostais, longuíssimo dorsal, glúteo máximo, glúteo médio e tensor da fáscia lata. A amostra final foi constituída por 10 voluntários, randomizados para dois grupos diferentes: fisioterapia aquática (FA) e fisioterapia convencional (FC). O Grupo FA foi composto por cinco voluntários com mediana de idade de 42 (25-67) anos. O Grupo FC foi composto por cinco voluntários com mediana de idade de 49 (43-59) anos. Após a randomização, os voluntários dos dois grupos foram submetidos à intervenção com duração de doze semanas, sendo duas sessões semanais, totalizando 24 sessões. Após a intervenção, os pacientes foram reavaliados para comparação dos resultados pré e pós intervenção. Para a análise estatística foi utilizado o teste ANOVA para medidas repetidas com transformação por postos. O nível de significância adotado foi de 5% (p<0,05). A comparação de medidas numéricas entre os dois grupos ao longo do tempo mostrou diferença estatisticamente significativa após a intervenção para as variáveis: índice de Lequesne (p=0,0217), índice de Incapacidade de Oswestry (p=0,0112), ADM de extensão do tronco (p=0,0320), FM de flexão do tronco (p=0,0459) e FM de extensão (p=0,0062) e abdução (p=0,0257) do quadril. As variáveis Escala LEFS, ADM de flexão do tronco, ADM de flexão, extensão, adução e abdução do quadril, FM de extensão do tronco, FM de flexão e adução do quadril e todas as variáveis de EMGs não apresentaram diferença estatisticamente significativa. Esses resultados sugerem que a fisioterapia parece ser um recurso capaz de prevenir e tratar as disfunções musculoesqueléticas de pacientes com doença falciforme, independentemente da técnica utilizada / Abstract: Sickle cell disease is a genetic disease that results in sickling of red blood cells, triggering phenomena of vaso-occlusion episodes of pain and organ damage. Bone involvement is the most common clinical manifestation, may cause chronic and progressive disorders such as avascular necrosis of the femoral head, leading cause of hip deformity in these patients, leading to disturbances in gait and limitation of pain, level of activity and function. There are few studies in the literature on the role of physiotherapy as a resource capable of preventing and treating disorders of the locomotor system present in individuals with sickle cell disease. The aim of this study was to evaluate and compare the effect of two physical therapy programs for patients with sickle cell disease to decrease musculoskeletal pain in the hip and lower back and increase the functionality of these patients. One of the programs was conventional physical therapy in the soil compared with a protocol of exercises performed in swimming pool. The research began with an evaluation of the volunteers the from functional scales (Scale LEFS ¿ Lower Extremity Functional Scale; Lequesne¿s Algofunctional Questionnaire and Oswestry Disability Index), measuring the range of motion (ROM) in flexion and extension of the trunk, flexion, extension, adduction and abduction of the hip, the assessment of muscle strength (MS) of the trunk flexors and extensors, flexors, extensors, adductors and hip abductors through load cell and surface electromyography (SEMG) of iliocostalis, dorsal longissimus, gluteus maximus, gluteus medius and tensor fasciae latae. The final sample consisted of 10 volunteers, randomized to two different groups: aquatic physiotherapy (AP) and conventional physiotherapy (CP). The AP group was composed of five volunteers with a median age of 42 (25-67) years. The CP group consisted of five volunteers with a median age of 49 (43-59) years. After randomization, subjects from both groups underwent intervention for twelve week, with two sessions per week, totaling 24 sessions. After the intervention, patients were reassessed for comparison of pre-and post-intervention results. For statistical analysis ANOVA was used for repeated measures with transformation stations. Significance was established at the 5% level (p<0,05). The comparison of numerical values between the two groups over time showed a statistically significant difference after the intervention for the variables Lequesne index (p=0,0217), Oswestry Disability Index (p=0,0112), trunk extension ROM (p=0,0320), ROM trunk flexion (p=0,0459) and MS extension (p=0,0062) and abduction (p=0,0257) of the hip. The variables Scale LEFS, trunk flexion ROM, ROM of flexion, extension, adduction and hip abduction, extension of MS trunk, MS flexion and hip adduction and all SEMG variables showed no statistically significant difference. These results suggest that physical therapy seems to be a resource capable of preventing and treating musculoskeletal dysfunctions of patients with sickle cell disease, regardless of the technique used / Mestrado / Clinica Medica / Mestra em Clínica Médica

Orientador: Marcus Alexandre Finzi Corat / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T05:45:50Z (GMT). No. of bitstreams: 1 Gimenes_AnaPaula_M.pdf: 8685522 bytes, checksum: 6c82475e18242cbd1ab92daf37c6b5b5 (MD5) Previous issue date: 2014 / Resumo: A anemia falciforme é uma doença hereditária que acomete milhões de pessoas Promove destruição crônica das células vermelhas (eritrócitos) do sangue, causando anemia, vaso-oclusão, isquemia e consequentes sintomas deintensa dor, susceptibilidade à infecções e, em alguns casos, a morte precoce. Nas últimas décadas, estudos têm mostrado que o aumento dos níveis de hemoglobina fetal (HbF) inibe o processo de falcização das Hemácias melhorando os sintomas de pacientes com anemia falciforme. Neste estudo, produzimos um modelo animal humanizado com traço falciforme e expressão concomitante de HbF persistente, associando as características genéticas dos camundongos transgênicos B-HPFH195 e Berk-SCM . O primeiro é animal transgênico com persistência de hemoglobina fetal, onde aprodução de HbF continua após o nascimento. A segunda linhagem corresponde ao modelo para doença falciforme, Hbatm1Paz Hbbtm1Tow Tg (HBA - HBBS ) 41Paz / J ( Berk - SCM) e mimetiza a doença humana em sua forma mais grave. Nestes animais a reprodução está comprometida, as fêmeas não levam a gestação ao termino e a maioria dos neonatos morrem horas depois do nascimento. Isto ocorre principalmente devido ao fato de que a (HbF) presente no transgene humano destes animais ser trocada pela HbS enquanto o feto ainda esta em gestação. O novo modelo desenvolvido foi analisado clinicamente e histologicamente para a caracterização e apresentou em sua constituição sanguínea hemoglobinas totalmente humanizadas com cadeias ?, ?s e ? persistente porém, ainda mantendo alterações histopatológicas semelhantes aos modelos da doença falciforme. Este novo animal representa um modelo potencial para uso em testes de drogas no aumento de HbF onde os resultados podem ser relevantes para o estudo e tratamento de hemoglobinopatias, bem como para compreender o comportamento das mutações hereditárias para a expressão persistente da cadeia de globina Y / Abstract: Sickle cell disease is a hereditary disease that affects millions of people promotes chronic destruction of red blood cells (erythrocytes), causing anemia, vascular occlusion, ischemia, pain, and susceptibility to infections and in some instances, death premature. In recent decades, studies have shown that increased HbF levels play an important role in improving the symptoms of patients with sickle cell anemia. In this study, we produced and characterized a humanized animal model with sickle cell trait and concomitant expression of persistent HbF, using the genetic characteristics of transgenic mice B - HPFH195 with Berk¿SCM. This model is a transgenic mice model with hereditary persistence of HbF. The second strain constitutes a mouse with sickle cell disease, Hbatm1Paz Hbbtm1Tow Tg ( HBA - HBBs ) 41Paz /J ( Berk - SCM ), an animal model used to study SCD with human hemoglobin S ( HbS ) in its blood. The Berkeley mouse mimics the human disease in severe form, which compromises in its, females do not lead to pregnancy termination and most newborns die hours after birth. This occurs mainly due to the fact that fetal hemoglobin (HbF), present in the human transgene of these animals,is exchanged to HbS while the fetus still in gestation. The new model produced was analyzed clinically and histologically for proper characterization and presents in its constitution humanized blood, hemoglobin chains with ?, ? ?s and persistent, but still maintains histopathological changes similar to models of sickle cell disease. This model may be a potential model for use in drug in testing increase HbF. And results may be relevant for the study and treatment of hemoglobinopathies as well as for understanding the behavior of hereditary mutations for the persistent expression of the Y globin chain / Mestrado / Clinica Medica / Mestra em Clínica Médica

Orientador: Fernando Ferreira Costa / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T03:49:55Z (GMT). No. of bitstreams: 1 Gambero_Sheley_D.pdf: 3649073 bytes, checksum: a76d9a7da22f0e08a3f4556b9b24330f (MD5) Previous issue date: 2011 / Resumo: A anemia falciforme (AF) é um distúrbio genético da hemoglobina causado por uma mutação de ponto no gene da beta-globina com consequente produção de hemoglobina S (HbS). A polimerização de HbS causa a deformação, enrijecimento e diminuição da flexibilidade das hemácias, resultando em uma série de eventos que levam a redução da sua vida média. Os principais fatores que influenciam a polimerização são: concentração de oxigênio e concentração de hemoglobina fetal (HbF). Pacientes com AF apresentam aumento dos níveis circulantes de citocinas, incluindo fator de necrose tumoral-'alfa' (TNF-'alfa') que possui efeitos pró-inflamatórios resultando no aumento das propriedades quimiotáxicas e a aderência de neutrófilos ao endotélio vascular. Muitos estudos têm sido realizados com o intuito de buscar novas estratégias terapêuticas que contribuam para o aumento dos níveis de HbF e diminuam os níveis de citocinas inflamatórias. Com este objetivo, novos compostos que agregam funções anti-inflamatórias e são moléculas doadoras de óxido nítrico, foram desenvolvidas. Deste modo, o objetivo deste trabalho foi avaliar os efeitos dos compostos derivados da hidroxiureia e da talidomida na produção de HbF, na atividade quimiotática e na produção de espécies reativas de oxigênio em células de pacientes com anemia falciforme e indivíduos controles, tratadas com o composto denominado Lapdesf 1, assim como a concentração de citocinas inflamatórias, em culturas de células mononucleares de camundongos falciforme. Os resultados obtidos demonstram que o composto Lapdesf 1 foi capaz de aumentar os níveis de HbF em cultura de células CD34+ e em linhagem celular K562. Os neutrófilos de indivíduos controles e pacientes com AF, tratados com este composto apresentaram a capacidade quimiotática induzida por Il-8 significativamente reduzida em relação ao controle, e o tratamento com Lapdesf 1 não alterou a geração de espécies reativas de oxigênio em plaquetas, neutrófilos, eritrócitos e células mononucleares. O tratamento de camundongos transgênicos para a AF demonstrou a capacidade desse composto em aumentar os níveis de HbF, além de diminuir a quantidade de citocinas inflamatórias no sobrenadante de culturas de células mononucleares de camundongos. Em resumo nossos resultados sugerem que o composto Lapdesf 1, apresenta-se como uma nova alternativa terapêutica, pela capacidade de aumentar a síntese de HbF e diminuir os níveis de citocinas inflamatórias e seus efeitos, que merece ser testada como possível tratamento da anemia falciforme / Abstract: Sickle cell anemia is a genetic hemoglobin disorder caused by a point mutation that produces hemoglobin S (HbS). Polymerization of HbS causes deformation, stiffness and decreased flexibility of red blood cells, resulting in different events. The main factors influencing polymerization are: oxygen concentration and intracellular concentration of fetal hemoglobin (HbF). It has been reported that patients with sickle cell disease have increased circulating levels of cytokines, including tumor necrosis factor-'alfa' (TNF-'alfa') which has pro-inflammatory effects, resulting in increased chemotactic properties and adhesion of neutrophils to vascular endothelium. Many studies have been conducted in order to pursue new therapeutic strategies that increase fetal hemoglobin levels and lower levels of inflammatory cytokines. New compounds have been developed for the treatment of some sickle cell anemia symptoms. These compounds have several functions: they act as antiinflammatory agents, and donate nitric oxide. Thus the objectives of this study were to evaluate effects of compounds derived from hydroxyurea and thalidomide in the production of HbF, chemotactic activity and production of reactive oxygen species in cells from patients with sickle cell anemia and controls treated with the compound called Lapdesf1, and also the concentration of inflammatory cytokines in cultures of mononuclear cells from sickle cell mice. Our results demonstrate that the compound, Lapdesf 1, was able to increase levels of fetal hemoglobin in CD34+ cultured cells and K562 lineage cells. Neutrophils from control subjects and patients with sickle cell anemia had their chemotactic capacity significantly reduced following treatment with this compound; furthermore, the compound did not alter the generation of reactive oxygen species in platelets, neutrophils, red cells and mononuclear cells. Treatment of transgenic sickle cell anemia mice demonstrated the ability of the compound to increase fetal hemoglobin in vivo and reduce the amount of inflammatory cytokines such as TNF-'alfa', IL-8, IL-6 and IL- 1ß in the supernatant of cultures of mononuclear cells from sickle mice. In summary, our results suggest that the compound Lapdesf 1 has the ability to increase HbF synthesis and decrease the levels of inflammatory cytokines and their effects. So this compound may present promise as a new drug for the treatment of sickle cell disease, minimizing the clinical complications associated with this disease / Doutorado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Doutor em Fisiopatologia Medica

IntroductionLa drépanocytose est l’affection génétique la plus répandue dans le monde plus particulièrement en Afrique subsaharienne, considérée à juste titre comme l’une des régions originaires de la mutation drépanocytaire avec de fortes prévalences. Elle est reconnue comme un problème de santé majeur par la communauté internationale en raison de sa morbidité et de sa mortalité élevées. Au Mali, environ 5 à 6 milles naissances de drépanocytaires sont enregistrées par an [Diallo, 2008] et ils auront besoin d’une prise en charge médicale spécifique. Le Centre de Recherche et de Lutte contre la Drépanocytose (CRLD) situé à Bamako est le seul centre de traitement spécifique dédié à la lutte contre la drépanocytose au Mali. Il reçoit des patients drépanocytaires du Mali et de la sous région. Ces patients sont pour la plupart vus au stade de complications puisqu’il n’existe pas de programme de dépistage systématique dès la naissance et à fortiori de suivi.La transfusion sanguine intervient dans une large mesure pour la prise en charge thérapeutique de ces patients. Acte thérapeutique essentiel sur le continent Africain en raison de la fréquence d’anémies de diverses origines (certaines nécessiteront un traitement de la cause).Cette transfusion sanguine comporte des risques non négligeables en Afrique, notamment dans le domaine des agents transmissibles par le sang. Un dépistage systématique des infections par le virus de l’immunodéficience humaine (VIH), le virus de l’hépatite C (VHC), le virus de l’hépatite B (VHB) et le tréponème, agent de la syphilis, est en vigueur sur tous les dons de sang à Bamako, mais les prévalences élevées de ces agents infectieux dans la population générale dont sont issus les donneurs de sang incitent à penser que le risque transfusionnel résiduel doit être important. Dans le but de renforcer la sécurité transfusionnelle au Mali, nous avons entrepris des études prospectives et rétrospectives chez les donneurs de sang et chez les drépanocytaires transfusés, ceci afin d’identifier les problèmes spécifiques liés à la thérapeutique transfusionnelle chez les drépanocytaires et de proposer une meilleure stratégie pour leur prise en charge.Méthodologie :Nous avons conduit une série d’études, visant à déterminer :- les caractéristiques des donneurs, des dons de sang et de l’organisation des centres de transfusion en Afrique subsaharienne francophone ;- la séroprévalence des agents infectieux transfusionnels majeurs (VIH, VHB, VHC) pour les dons de sang effectués au CNTS du Mali et chez les patients drépanocytaires recrutés au CRLD. - la fréquence de l’allo-immunisation anti-érythrocytaire avant et après la transfusion sanguine chez les drépanocytaires.- identifier les problèmes liés au dépistage néonatal et au suivi des drépanocytaires dépistés au Mali.Les donneurs de sang (volontaires et familiaux) ont été inclus selon les critères du don en vigueur au Mali. Le diagnostic de la drépanocytose a été réalisé par une technique de chromatographie liquide à haute performance (CLHP) avant inclusion des patients.Le dépistage des infections virales a été effectué par une méthode immunoenzymatique (ELISA) et la recherche des anticorps anti-érythrocytaire par un test de Coombs indirect.Résultats :Dans les sept pays, les donneurs de la tranche d’âge 18 à 30 ans étaient les plus nombreux, représentant plus de 45 % dans tous les centres, et plus de 70%dans quatre centres sur sept. Les donneurs masculins étaient les plus nombreux (plus de 70% de l’ensemble). Les donneurs étaient majoritairement volontaires (plus de 70 %), sauf au Cameroun et au Mali où ils représentaient respectivement 25,5 et 30 %. Quatre pays, dont ces deux derniers, avaient moins de 50 % de donneurs réguliers.Sur un total de 25 543 dons de sang recueillis au CNTS de Bamako en 2007, les séroprévalences des agents infectieux dépistés étaient de :2,6 % pour le VIH; 3,3 % pour le VHC et 13,9 % pour le VHB. En fonction du type de don, il y’avait une différence statistiquement significative (p <0,05) entre ces séroprévalences et plus élevées chez les donneurs familiaux que chez les donneurs volontaires bénévoles.Chez les 133 drépanocytaires transfusés au moment de leur inclusion dans l’étude, les séroprévalences des infections virales observées étaient de :1%, 3% et 1% respectivement pour les VIH, VHB et VHC. Trois cas de séroconversion post-transfusionnelle ont été observés. Tous avaient reçu du sang de donneurs familiaux. L’allo-immunisation anti-érythrocytaire était observée chez 4,4% (4/90) des drépanocytaires avec antécédents transfusionnels au moment de leur inclusion; les anticorps observés étaient de type anti D (un cas), anti C (deux cas) et un anti c (un cas). Elle n’a été observée chez aucun patient drépanocytaire ayant reçu leur 1ère transfusion au CRLD, avec exclusivement des concentrés de globules rouges phénotypés.Concernant le dépistage néo-natal de la drépanocytose, sur un total de 2480 nouveau-nés dépistés, 16 étaient atteints de l’affection. Aucun suivi médical programmé n’a pu être réalisé.Conclusion :Les prévalences relativement élevées des agents infectieux dans les dons de sang effectués par des donneurs familiaux majoritaires et les séroconversions observées après transfusion sanguine, justifient une politique de sécurisation des procédures de transfusions chez les drépanocytaires basée notamment sur le recrutement de donneurs volontaires.L’amélioration de la survie des patients drépanocytaires passe par la mise en place de programmes de dépistage précoce et de suivi régulier, mais si cette stratégie est réalisable du point de vue du diagnostic, il n’en demeure pas moins qu’elle soulève des problèmes de financement de cette activité et de sa pérennisation ;ces aspects doivent faire l’objet de réflexions pour une solution à long terme. / Introduction Sickle cell disease is the most common genetic disorder in the world, especially in sub-Saharan Africa where sickle cell mutation with high prevalence’s is originated high. It is recognized as a major health problem by the international community due to its morbidity and mortality. In Mali, around 5-6000 newborns annually affected by sickle cell disease [Diallo, 2008] and they will require specific medical that is by the “Centre de Recherche et de Lutte contre la Drépanocytose » (CRLD) in Bamako. This is the unique Malian center where sickle cell patients from Mali and the sub-region are treated. Because of the lack of systematic screening program at birth, most of the patients are seen at the stage of complications. Blood transfusion is largely used for therapeutic management of these patients. It constitutes an essential therapeutic approach against anemia of highly prevalent in Africa various origins (some requiring also treatment of the cause). However, blood transfusion means significant risks, particularly in area of high prevalence of transfusion transmissible infectious agents. A systematic screening for viral infections like human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus(HBV) and Treponema agent of syphilis is required for all blood donations in Bamako, but the high prevalence of these infectious agents in the general population, i.e. blood donors, suggest that the residual risk of transfusion must be important.In order to enhance blood transfusion safety in Mali, we undertook prospective and retrospective studies in the population of blood donor and sickle cell patient transfused to identify transfusion related adverse events and especially for SCD’ patients, suggest a better strategy for their follow-up. Methodology:We conducted a sery of studies which aims to determine:- The characteristics of donors, blood donation and the organization of blood transfusion centers in sub-Saharan French speaking Africa;- The seroprevalence of major infectious agents (HIV, HBV, and HCV) in blood donations at the CNTS in Mali and in sickle cell patients at CRLD. The frequency of anti-erythrocyte allo immunization before and after blood transfusion in sickle cell disease patients;- Identification of difficulties related to newborn screening and monitoring of sickle cell patients in Mali.Blood donors (volunteers and family) were included according to the criteria of blood donation in Mali.Hemoglobin type in sickle cell was determined by the technique of high performance liquid chromatography (HPLC) before patients’ inclusionScreening for viral infections was performed by enzyme immunoassay (ELISA) and the search for anti-erythrocyte antibodies by indirect Coombs test. ResultsIn the seven countries, donors aged from 18 to 30 years old were more represented i.e. 45% in all centers and more than 70%in four of the seven centers. More than 70% of blood donors were males. Donors were mostly volunteers (over 70%), except in Cameroon and Mali accounting for25.5% and30%, respectively four countries, including Cameroon and Mali had less than,50% of regulars donors.Of the 25 543 blood donations collected at the CNTS in Bamako in 2007, seroprevalence of infectious agents detected represented: 2.6%, 3.3%, and 13.9% for HIV, HCV, and HBV respectively. A statistical significative difference (p<0.05) was observed between family and volunteer donors in term of seroprevalence.the 133 sickle cell patients who received blood transfusion at inclusion, the seroprevalence of viral infections was1%, 3%, and 1%,for HIV, HBV, and HCV, respectively. Three cases of post-transfusion seroconversion were observed but only in sickle cell patients who received blood from family donors.Anti-erythrocyte alloimmunization was observed in 4.4% (4/90) among sickle cell patients with blood transfusion history at the time of inclusion; observed antibodies were anti type D (one case), anti C (two cases) and anti c (one case). However, no case was observed in any sickle cell patients, who received phenotyped RBC at CRLD,For neonatal screening, among the 2480 newborns, 16 were affected. However no scheduled medical follow-up was realized. Conclusion The relatively high prevalence’s of infectious agents in family donors, who represented the majority of blood donors, and of seroconversion observed after blood transfusion in sickle cell patients justify a security policy of blood transfusion procedures based, particulary for SCD patients, blood donations by volunteers. Improved survival of patients with sickle cell disease should be based on the development of early detection programs and regular monitoring. However if this strategy is feasible in terms of diagnosis ,it raises problems at funding for this activity and also of; those should be the subject of discussion for a long term solution / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Ce travail porte sur deux thèmes principaux. Le premier est relatif à la drépanocytose et comprend deux études. La première a examiné les connaissances qu’ont 178 hommes et femmes vivant au Bénin sur la maladie, ses causes, ses effets et sa prise en charge. Ils ont répondu à un questionnaire et, leurs réponses ont été comparées à celles d’un groupe d’expert. Il en est ressorti qu’il existait une méconnaissance globale de la maladie, et plus particulièrement de ses symptômes les plus graves et de son traitement. Les résultats révèlent que plus on a un niveau d’éducation élevé, moins on se fait de fausses idées concernant la maladie. En outre, cette méconnaissance était plus accrue chez les personnes se déclarant porteuses du trait génétique (4.83) ou drépanocytaire (5.19) que chez les personnes ayant déclaré ne pas être porteuses (3.72) ou saines (3.62). La deuxième étude a quant à elle cherché à savoir si les 137 personnes interrogées vivant au Bénin, avaient intégré de façon adéquate les règles de transmission génétique de la maladie, en se basant sur la théorie fonctionnelle de la cognition. L’analyse des données a permis de distinguer trois clusters distincts. Dans le premier groupe (n=46), les personnes jugeaient ainsi le risque de transmission de la maladie plus élevé en présence de l’un ou l’autre des deux parents atteints. Dans le deuxième groupe (n=51), le risque était jugé d’autant plus grand que chacun des parents était lui-même gravement atteint. Dans le troisième groupe (n=40), le risque n’avait été jugé élevé qu’en présence des deux parents atteints. Le deuxième thème a donné lieu à une étude, visant à examiner les motifs pouvant sous-tendre un refus d’amputation chez 224 personnes vivant au Bénin, par l’approche de la théorie du renversement. Les résultats montrent que la peur de la perte de l’identité personnelle, la peur des hôpitaux et du personnel médical, la conviction que la chirurgie était inutile, le manque de confiance dans la compétence et le dévouement des médecins, la peur de la perte de l’estime de l’autre et celle de la perte de la force spirituelle, font partie des facteurs principaux pouvant motiver un refus d’amputation. / This thesis focuses on two main themes. The first one is related to sickle cell disease and the second theme is related to limb amputations. For studying the first theme, this research proposes to examine the knowledge of 178 men and women living in Benin, on the disease, its causes, effects and care. They answered a questionnaire and their responses had been compared to those given by an expert group. It had been found that there was an overall lack of awareness on the disease, and especially its most severe symptoms and treatment. The results reveal that the higher level of education they have, the less misconceptions about the disease they have. In addition, this ignorance was increased by people declaring themselves carrying the genetic trait (4.83) or sickle cell (5.19) than those who reported not being carriers (3.72) or healthy (3.62). The second study about the first theme, investigated whether the 137 respondents living in Benin had integrated adequately the rules of inheritance of the disease, based on the functional theory of cognition. Three distinct clusters emerge with data analysis. In the first group (n=46), respondents considered a higher risk of transmission if the one or the other of two parents was/were affected by the disease. In the second group (n=51), the risk was considered even greater as both parents were seriously ill. In the third group (n=40), the risk was considered as high only if both parents were touched. The second theme, Accidents involving physical injury, has motivated a study which aim was to examine the reasons that may underlie a refusal of amputation for 224 people living in Benin, by the approach of the reversal theory. The results show that the fear of losing personal identity, the fear of hospitals and medical staff, the belief that the surgery was unnecessary, a lack of confidence in the competences and dedication of doctors, the fear of losing others esteem and the loss of spiritual strength, are among the main factors motivating a refusal of amputation.

Sickle cell disease (SCD) and depression are each major public health issues globally. Nigeria currently has the largest proportion of people with SCD worldwide, with up to 150,000 annual births. This study highlights the limitations of previous studies, which only utilize the biomedical model in explaining SCD, and which pay insufficient attention to the lived experiences of people with SCD. Extant literature reports strong associations between SCD and depression, and locates the problem ‘only’ in terms of disease severity, levels of service utilization or alleged psychological maladjustment to SCD condition. Biomedical research tends to treat stigma as a predicament that automatically correlates with SCD. Data collected was guided by a modified three-staged theoretical framework derived from Arthur Kleinman, with the use of questionnaires (incorporating Patient Health Questionnaire) to describe depression in persons with SCD; 15 in-depth interviews to explore the illness experience of SCD, and a series of six focus groups to examine depression and stigma in SCD as a form of ‘societal sickness’. In the first stage, questionnaires were administered to 103 outpatients at an SCD clinic in Lagos, Nigeria, and findings revealed an association of depression with age, and severity of SCD as indicated by symptoms such as leg ulcers. The first stage enabled those with moderate depression to be identified and invited into the subsequent stages (two and three) of the research. In the second stage, fifteen in-depth interviews with adults living with SCD were conducted and analysed using interpretive phenomenological analysis (IPA), also drawing on the influences of Herbert Blumer and Erving Goffman. Testimonies suggested that people with SCD face overwhelmingly negative criticisms from a wide range of significant others, including close family members; that the discrimination they face arises not from their condition per se but from the societal norms and expectation that they are assumed to break; and that they themselves identify pathways from the negative experience they endure to their own depression and mental distress. In the third stage, a series of three focus groups, each with five participants, found that people with SCD began to reject negative labels, identify challenges in their own terms, gain a sense of confidence and identity from their participation in groups, and began to identify social barriers to their full participation in society that they wished to challenge. The overall findings of the research suggest that by coming together in groups, people with SCD themselves suggest that rigorously researched social interventions may be considered an important adjunct to medical interventions in improving the lives of those living with SCD in Nigeria and throughout sub-Saharan Africa.