Introdução: a doença falciforme é uma alteração hereditária, que causa malformação nas hemácias com consequências vaso-oclusivas de potencial dano auditivo. Os estudos que tratam da relação entre alteração auditiva e doença falciforme apresentam grande disparidade de resultados. Em todos os trabalhos consultados, não foram encontrados artigos sobre o potencial evocado auditivo com estímulo de fala nesta população. Objetivo: analisar as respostas obtidas pelos potenciais evocados auditivos em crianças, adolescentes e jovens com a doença falciforme. Métodos: trata-se de um estudo observacional, transversal, com amostra de sujeitos com diagnóstico de doença falciforme, advindos de um ambulatório de hemoglobinopatia de um hospital público, localizado no sul do país. A avaliação audiológica ocorreu após liberação médica e foi realizada por meio dos seguintes procedimentos: anamnese, audiometria tonal liminar, audiometria tonal de altas frequências, timpanometria, emissão otoacústica evocada transiente, potencial evocado auditivo de tronco encefálico com estímulo clique (PEATE) e com estímulo de fala (PEATE-f). Resultados: a amostra foi constituída de 54 sujeitos, com idade entre seis e 24 anos. Em relação ao PEATE, verificou-se alteração em 88,9% da amostra, com diferença estatisticamente significativa no aumento da latência absoluta da onda V (p=0,009) e no interpico I-III (p=0,004), no grupo do sexo masculino (p=0,028). A faixa etária em que a alteração mais se evidenciou foi a dos adolescentes (12 a 18 anos) (p=0,017). Quanto ao PEATE-f, 98,1% da amostra apresentaram alguma alteração, mas não houve diferença estatisticamente significativa entre os gêneros. A latência da onda A foi mais tardiamente detectada na orelha esquerda, na faixa etária da adolescência (p=0,021). Conclusões: verificou-se que a maior parte dos sujeitos da amostra apresentou alterações no PEATE e PEATE-f, apesar de possuir limiares auditivos, medidas de imitância acústica e emissões otoacústicas evocadas transientes normais. É recomendável, portanto, que a avaliação auditiva dos indivíduos com a doença falciforme inclua a pesquisa de potenciais evocados auditivos, visando ao diagnóstico e ao encaminhamento para tratamento específico, tendo em vista a adequada capacidade de compreensão de fala e a prevenção de distúrbios linguísticos, biopsicoemocionais e sociais. / Introduction: sickle cell disease is a hereditary disorder that causes malformation in the red blood cells with vaso-occlusive consequences of potential hearing damage. Studies that deal with the relationship between auditory alteration and sickle cell disease present a great disparity of results. In all the studies consulted, no articles on the auditory evoked potential with speech stimulus in this population were found. Objective: to analyze the responses obtained by evoked auditory brainstem response in children, adolescents and young people with sickle cell disease. Methods: it is an observational, cross-sectional study with a sample of subjects with sickle cell disease diagnosed from a hemoglobinopathy outpatient clinic located in the south of the country. The audiological evaluation occurred after medical release and was performed through the following procedures: anamnesis, tonal threshold audiometry, high frequency tone audiometry, tympanometry, transient evoked otoacoustic emission, evoked auditory brainstem response (ABR) and peech-evoked auditory brainstem response (cABR). Results: the sample consisted of 54 subjects, from six to 24 years old. In relation to ABR, there was change in 88,9% of the sample, with a statistically significant difference in the increase of the absolute latency of the V wave (p = 0.009) and in the interpeak I-III (p = 0.004) in the male group (p = 0.028). The age group in which the change was most evident was the adolescent (12 to 18 years) (p = 0.017). Concerning cABR, 98,1% of the sample had some alteration, but there was no statistically significant difference between the genders. The latency of wave A was later detected in the left ear in the adolescence age group (p = 0.021). Conclusions: It was verified that most of the subjects of the sample presented alterations in ABR and cABR, despite having auditory thresholds, acoustic immitance measures and normal transient evoked otoacoustic emissions. It is recommended, therefore, that the auditory evaluation of individuals with sickle cell disease should include the search for auditory evoked potentials, aiming at diagnosis and referral for specific treatment, in view of the adequate ability to understand speech and the prevention of language disorders, biopsychological and social.

O consumo de drogas e álcool constitui cada vez mais um problema social e de saúde pública, pelas consequências negativas que provocam no desenvolvimento emocional e físico dos indivíduos. Existem poucas referências na literatura avaliando o uso destas substâncias por portadores de doença falciforme (DF). Estes pacientes apresentam crises álgicas severas, recorrentes, frequentemente controladas por opióides. O comprometimento da qualidade de vida predispõe a ocorrência de transtornos psiquiátricos não-psicóticos, como depressão por exemplo, tornando o grupo vulnerável ao uso abusivo de substâncias. Objetivos: avaliar o consumo de álcool e drogas em pacientes portadores de DF acompanhados pelo Centro de Referência de Doença Falciforme (CRAF) do Hospital de Clínicas de Porto Alegre (HCPA), estimar o percentual de pacientes em tratamento da doença falciforme que fazem uso abusivo de álcool e drogas, e colaborar com o estudo que avaliará a efetividade de um centro de referência multidisciplinar para esta população. Métodos: estudo transversal, de uma amostra de conveniência, com 139 pacientes portadores de DF acompanhados no CRAF do HCPA. Resultados: a prevalência do uso abusivo foi de 1,5% para o álcool e 3,0% para o tabaco, e não se identificou o uso abusivo de outras substâncias, inclusive opióides. O padrão para o uso de substâncias não foi influenciado pela exposição ou por transtornos psiquiátricos não-psicóticos. Conclusão: São necessários mais estudos para reforçar estes achados, mas demonstra-se a segurança do uso de analgésicos opióides para o manejo das crises dolorosas apresentadas pelos portadores de DF. / Drug abuse is increasingly becoming a social and public health problem, because of the negative consequences that such abuse causes on the emotional and physical development of individuals. There are few references in the literature evaluating the use of these substances by individuals with sickle cell disease (SCD). These patients have severe and recurrent pain crises, frequently needing opioids drugs to control it. The compromised quality of life can predispose this population to the occurrence of non-psychotic psychiatric disorders such as depression, making them vulnerable to substance abuse. Objectives: To evaluate the level of consumption of alcohol and drugs in patients with SCD followed by Sickle Cell Disease Reference Center (CRAF) at Hospital de Clínicas de Porto Alegre; to estimate the percentage of patients in treatment of SCD who abuse alcohol and drugs, and to collaborate with the study evaluating the effectiveness of the CRAF. Methods: cross-sectional study of a convenience sample of 139 patients with SCD treated at CRAF. Results: the prevalence of abusive use of the studied population was 1.5% for alcohol and 3.0% for tobacco, and no abusive use of any other substance, including opioids, was identified. It was verified that the pattern for substance use was not influenced by exposure to substances or the presence of non-psychotic psychiatric disorders. Conclusion: More studies are needed to reinforce these findings, but they suggested that the use of opioid analgesics for the management of SCD painful crises is safe and do not induces substance abuse.

Introdução: a doença falciforme é uma alteração hereditária, que causa malformação nas hemácias com consequências vaso-oclusivas de potencial dano auditivo. Os estudos que tratam da relação entre alteração auditiva e doença falciforme apresentam grande disparidade de resultados. Em todos os trabalhos consultados, não foram encontrados artigos sobre o potencial evocado auditivo com estímulo de fala nesta população. Objetivo: analisar as respostas obtidas pelos potenciais evocados auditivos em crianças, adolescentes e jovens com a doença falciforme. Métodos: trata-se de um estudo observacional, transversal, com amostra de sujeitos com diagnóstico de doença falciforme, advindos de um ambulatório de hemoglobinopatia de um hospital público, localizado no sul do país. A avaliação audiológica ocorreu após liberação médica e foi realizada por meio dos seguintes procedimentos: anamnese, audiometria tonal liminar, audiometria tonal de altas frequências, timpanometria, emissão otoacústica evocada transiente, potencial evocado auditivo de tronco encefálico com estímulo clique (PEATE) e com estímulo de fala (PEATE-f). Resultados: a amostra foi constituída de 54 sujeitos, com idade entre seis e 24 anos. Em relação ao PEATE, verificou-se alteração em 88,9% da amostra, com diferença estatisticamente significativa no aumento da latência absoluta da onda V (p=0,009) e no interpico I-III (p=0,004), no grupo do sexo masculino (p=0,028). A faixa etária em que a alteração mais se evidenciou foi a dos adolescentes (12 a 18 anos) (p=0,017). Quanto ao PEATE-f, 98,1% da amostra apresentaram alguma alteração, mas não houve diferença estatisticamente significativa entre os gêneros. A latência da onda A foi mais tardiamente detectada na orelha esquerda, na faixa etária da adolescência (p=0,021). Conclusões: verificou-se que a maior parte dos sujeitos da amostra apresentou alterações no PEATE e PEATE-f, apesar de possuir limiares auditivos, medidas de imitância acústica e emissões otoacústicas evocadas transientes normais. É recomendável, portanto, que a avaliação auditiva dos indivíduos com a doença falciforme inclua a pesquisa de potenciais evocados auditivos, visando ao diagnóstico e ao encaminhamento para tratamento específico, tendo em vista a adequada capacidade de compreensão de fala e a prevenção de distúrbios linguísticos, biopsicoemocionais e sociais. / Introduction: sickle cell disease is a hereditary disorder that causes malformation in the red blood cells with vaso-occlusive consequences of potential hearing damage. Studies that deal with the relationship between auditory alteration and sickle cell disease present a great disparity of results. In all the studies consulted, no articles on the auditory evoked potential with speech stimulus in this population were found. Objective: to analyze the responses obtained by evoked auditory brainstem response in children, adolescents and young people with sickle cell disease. Methods: it is an observational, cross-sectional study with a sample of subjects with sickle cell disease diagnosed from a hemoglobinopathy outpatient clinic located in the south of the country. The audiological evaluation occurred after medical release and was performed through the following procedures: anamnesis, tonal threshold audiometry, high frequency tone audiometry, tympanometry, transient evoked otoacoustic emission, evoked auditory brainstem response (ABR) and peech-evoked auditory brainstem response (cABR). Results: the sample consisted of 54 subjects, from six to 24 years old. In relation to ABR, there was change in 88,9% of the sample, with a statistically significant difference in the increase of the absolute latency of the V wave (p = 0.009) and in the interpeak I-III (p = 0.004) in the male group (p = 0.028). The age group in which the change was most evident was the adolescent (12 to 18 years) (p = 0.017). Concerning cABR, 98,1% of the sample had some alteration, but there was no statistically significant difference between the genders. The latency of wave A was later detected in the left ear in the adolescence age group (p = 0.021). Conclusions: It was verified that most of the subjects of the sample presented alterations in ABR and cABR, despite having auditory thresholds, acoustic immitance measures and normal transient evoked otoacoustic emissions. It is recommended, therefore, that the auditory evaluation of individuals with sickle cell disease should include the search for auditory evoked potentials, aiming at diagnosis and referral for specific treatment, in view of the adequate ability to understand speech and the prevention of language disorders, biopsychological and social.

Sickle cell anaemia is a genetic haematologic disease, causing small vessels obstructions and haemolytic anaemia due to blood red cells sickling. In Brazil (mostly in Northeast region), is the most prevalent hereditary disease and constitutes a public health problem, affecting 1/1000 live born children. Affected individuals are particularly at risk for under-nutrition, and frequently have short stature and bone and sexual delayed maturation, which may be related to nutritional deficits. This study aimed to evaluate nutritional status of sickle cell disease patients. We evaluated 108 individuals, both genders, aging from 2 to 30 years. Food consumption (macro and micronutrients) was assessed using three 24h inventory. Anthropometric data measured were: weight, height, mid upper arm circumference, triceps skin fold thickness, and bone age through radiological study. Energy consumption figures were close to normal requirements calculated using Estimate Energy Requirement but when compared to Body Mass Index (BMI), large number of individuals, mostly adolescents (25%) and adults (27%), were underweighted. Bone age delay was common and half of adolescents were below the height/age 15th percentile, probably related to calcium, phosphorus and magnesium insufficient intake. Overall, 74% of patients were considered to have mid arm muscle mass depleted (below 5th percentile), in association with insufficient intake of zinc, calcium and magnesium. Macronutrients distribution was considered adequate, when compared to total caloric consumption, but 25% of adolescents had carbohydrate overconsumption and 30% of children and 28% of adolescents were below normal lipids consumption. Iron intake was probably adequate, but folate intake was below the Estimated Medium Requirement within all age groups. Our findings suggest that sickle cell patients have inadequate energetic consumption, as well as of micronutrients, affecting growth. / A anemia falciforme é uma doença hematológica genética, caracterizada por complicações vaso-oclusivas e anemia hemolítica causada pela falcização das hemácias. Originária do continente africano, no Brasil é a doença hereditária mais comum, sendo um problema de saúde pública especialmente na região nordeste, com estimativa de 1/1000 nascidos vivos. Devido ao alto catabolismo os pacientes são considerados relativamente subnutridos, têm baixa estatura e retardo na maturação óssea e sexual, fatores estes que podem estar relacionados às deficiências nutricionais. Objetivando avaliar o estado nutricional de pacientes com anemia falciforme, foram estudados 108 indivíduos de ambos os gêneros, entre dois e 30 anos. Foi avaliado o consumo alimentar de macro e micronutrientes através de três recordatórios de 24h. Os dados antropométricos utilizados foram: peso, altura, perímetro braquial, prega cutânea do tríceps e a idade óssea através de estudo radiológico. O consumo energético mostrou-se próximo às necessidades calculadas através das equações das Necessidades Energéticas Estimadas, porém pelo Índice de Massa Corporal constatou-se que parcela considerável dessa população, principalmente adolescentes (25%) e adultos (27%), se encontrava com baixo peso. Observou-se atraso na idade óssea, e que 50% dos adolescentes estavam abaixo do 15º. percentil para o índice altura/idade, em associação a consumo insuficiente de cálcio, fósforo e magnésio. Os resultados sugerem que o consumo energético mostrou-se provavelmente inadequado na amostra estudada. Observou-se também inadequação no consumo de micronutrientes, em associação ao comprometimento do crescimento.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-09-29T14:58:08Z No. of bitstreams: 1 francianevilelarechedamotta.pdf: 2971466 bytes, checksum: 8f4dcfb1c0a5f4667c81331b8b79fbe1 (MD5) / Rejected by Adriana Oliveira (adriana.oliveira@ufjf.edu.br), reason: doença falciforme minúsculo on 2017-10-09T19:42:11Z (GMT) / Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-10-09T19:48:06Z No. of bitstreams: 1 francianevilelarechedamotta.pdf: 2971466 bytes, checksum: 8f4dcfb1c0a5f4667c81331b8b79fbe1 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-10-09T20:04:41Z (GMT) No. of bitstreams: 1 francianevilelarechedamotta.pdf: 2971466 bytes, checksum: 8f4dcfb1c0a5f4667c81331b8b79fbe1 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-10-09T20:05:38Z (GMT) No. of bitstreams: 1 francianevilelarechedamotta.pdf: 2971466 bytes, checksum: 8f4dcfb1c0a5f4667c81331b8b79fbe1 (MD5) / Made available in DSpace on 2017-10-09T20:05:38Z (GMT). No. of bitstreams: 1 francianevilelarechedamotta.pdf: 2971466 bytes, checksum: 8f4dcfb1c0a5f4667c81331b8b79fbe1 (MD5) Previous issue date: 2017-08-17 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Objetivou-se desvelar o vivido das hospitalizações pelos adolescentes com Doença Falciforme e compreender como se constitui o núcleo de cuidado familiar desses indivíduos. Utilizou-se um método de investigação de abordagem Qualitativa fundamentado na Fenomenologia de Martin Heidegger. A pesquisa foi desenvolvida no Hemocentro Regional (Hemominas) localizado na região central de um município da Zona da Mata Mineira. Os participantes foram 10 adolescentes com Doença Falciforme, em tratamento no respectivo Hemocentro. Para alcançarmos os objetivos do estudo foi utilizada a entrevista fenomenológica, através da técnica de entrevista aberta e uma entrevista para a construção de um Genograma, confeccionado junto com o adolescente. Emergiram, então, as estruturas essenciais constituindo seis Unidades de Significados. A compreensão vaga e mediana dos significados permitiu a construção do fio condutor que conduziu à Hermenêutica. O modo do ser-adolescente-com-Doença Falciforme foi desvelado quando os participantes revelaram o impacto das hospitalizações em suas atividades cotidianas, indicando sentirem medo, tristeza e solidão e, ainda, ao falarem das complicações decorrentes da patologia. No tempo fenomenológico, as hospitalizações não foram apenas vividas, mas vivenciadas, uma vez que muitos deles ainda sofrem com as consequências causadas por esses períodos, como as reprovações escolares. A dor também é vivência que permeia a sua existência desde muito cedo. Os participantes falaram sobre a importância de ser-com: ser-com a família, ser-com os amigos e ser-com os profissionais. Emergiu a figura do profissional ocupado, mas também daquele profissional atento e afetuoso, que realiza um cuidado pré-ocupado. Nos Genogramas confeccionados com os adolescentes foi possível evidenciar a dimensão do cuidado dispensado pela família. O Genograma mostrou-se como instrumento viável e enriquecedor para a pesquisa e para o conhecimento acerca do núcleo familiar, facilitando a apreensão das informações e atingindo o objetivo proposto com a obtenção de resultados satisfatórios de forma prática e relativamente rápida. / This work aimed to unveil the hospitalization experiences of adolescents suffering from Sickle Cell Disease (SCD) and to understand how the nucleus of family care of these individuals is constituted. A qualitative approach method based on Martin Heidegger's Phenomenology was used. The research was developed in the hospital Hemocentro Regional (Hemominas), which is located in the central region of Zona da Mata Mineira. The subjects were 10 adolescents with Sickle Cell Disease, who were receiving treatment in Hemominas. In order to achieve the aims of the study, it was conducted a phenomenological interview using a technique of open interview. It was also conducted an interview to raise a Genogram. Six Units of Meaning constituted the essential structures. The vague and medium understanding allowed the construction of a common thread that led to Hermeneutics. The mode being-adolescent-with-sickle-cell-disease was unveiled when the participants told about the impact of hospitalizations on their daily activities, indicating fear, sadness and loneliness. That was also noticed when they talked about complications arising from the pathology. In phenomenological time, hospitalizations were not only experienced, but they are currently experienced, since many of them still suffer from the consequences of such periods, such as school failures. Pain is also an experience that permeates their lives since early age. The adolescents also expressed the importance of being-with: being-with-family, being-with-friends and being-with-professionals. The figure of the busy professional was also unveiled. At the same time, it was noticed the figure of an attentive and affectionate professional, who performs a pre-occupied care. In the Genograms constructed with the adolescents it was possible to show the dimension of the care provided by the family. Genogram proved to be a viable and enriching instrument for research and knowledge about the family nucleus. It facilitated the apprehension of information and reached the proposed aim of this study, with achievement of satisfactory results in a practical and relatively fast way.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2018-08-14T12:06:37Z No. of bitstreams: 1 camilamessiasramos.pdf: 2300883 bytes, checksum: 713f56e17a7da5eb4cca7859a9d6b689 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-09-03T16:31:38Z (GMT) No. of bitstreams: 1 camilamessiasramos.pdf: 2300883 bytes, checksum: 713f56e17a7da5eb4cca7859a9d6b689 (MD5) / Made available in DSpace on 2018-09-03T16:31:38Z (GMT). No. of bitstreams: 1 camilamessiasramos.pdf: 2300883 bytes, checksum: 713f56e17a7da5eb4cca7859a9d6b689 (MD5) Previous issue date: 2018-07-19 / Objetivou-se com este estudo desvelar o sentido do vivido de mães cujos filhos foram acometidos por Acidente Vascular Encefálico devido a Doença Falciforme. Utilizou-se como método de investigação a abordagem qualitativa optando pela fenomenologia, embasado no referencial teórico filosófico de Martin Heidegger. A pesquisa foi realizada de setembro de 2017 a março de 2018, com 10 mães de filhos acometidos por Acidente Vascular Encefálico devido a Doença Falciforme, e que fazem parte da Associação de Pessoas com Doença Falciforme de uma cidade da Zona da Mata Mineira. Para alcançar o objetivo do estudo foi utilizada uma entrevista fenomenológica, por meio da técnica de entrevista aberta e, para a captação das participantes utilizamos a técnica de snowball sampling (“bola de neve”). Ao indagarmos o ente, imerso na sua cotidianidade, fomos construindo as unidades de significação, nas quais vieram à tona significados comuns e diferentes da vivência destas mães frente aos questionamentos que eram apresentados. A compreensão vaga e mediana permitiu a elaboração do fio condutor indo em direção a hermenêutica. Para a mulher o vivido do cuidado com o filho significou relembrar o momento da revelação do diagnóstico da doença, o que lhes causou grande impacto. Sua participação como principal cuidadora exigiu tempo, dedicação e predisposição para prestar o cuidado, o que gerou cansaço. A fé em Deus deu-lhes força para que continuassem a cuidar dos filhos e se mostrou uma estratégia de enfrentamento dos problemas que surgiram, em que Deus não permite que falte nada pois tudo vem Dele, sem o qual não conseguem viver. As sequelas do Acidente Vascular Encefálico foram motivos de tristeza, sofrimento e dificuldade em aceitar e lidar com esta nova realidade. Relataram contar com o apoio da família e dos amigos nos cuidados com o filho, e no enfrentamento desta situação. Nesse vivido apareceu o relato de terem buscado educar os filhos de tal modo a terem uma vida mais próxima do normal possível. / The objective of this study was to reveal the lived experience of mothers whose chil- dren were affected by stroke due to sickle cell disease. The qualitative approach opting for phenomenology, based on the theoretical philosophical reference of Martin Heide- gger, was used as research method. The research was carried out from September 2017 to March 2018, with 10 mothers of children suffering from SCD due to Sickle Cell Disease, and who are part of the Association of People with Sickle Cell Disease in a city in the Zona da Mata Mineira. In order to reach the objective of the study, a pheno- menological interview was used, through the technique of open interview, and for the capture of the participants we used the technique of snowball sampling ("snowball"). When we inquired about the entity, immersed in its daily life, we were constructing the units of signification, in which common and different meanings of the experience of these mothers came to light on the questions that were presented. The vague and median understanding allowed the elaboration of the guiding thread towards herme- neutics. For the woman, the experience of caring for the child meant reminding the moment when the diagnosis of the disease was revealed, which caused them great impact. Her participation as the main caregiver required time, dedication and predis- position to provide care, which generated fatigue. Faith in God gave them strength to continue to care for their children and was a strategy to deal with the problems that have arisen, in which God does not allow anything to be lacking because everything comes from Him, without which they can not live. The sequelae of the Stroke were reasons for sadness, suffering and difficulty in accepting and dealing with this new reality. They reported having the support of family and friends in caring for their child, and in coping with this situation. In this lived appeared the report of having sought to educate the children in such a way to have a life closer to the normal possible.

Orientadores: Nicola Amanda Conran Zorzetto, Fernando Ferreira Costa / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T23:15:59Z (GMT). No. of bitstreams: 1 Santos_AlissonFernandesdos_D.pdf: 3501020 bytes, checksum: 082754f565197f1a75d8da113de08ea3 (MD5) Previous issue date: 2014 / Resumo: A anemia falciforme (AF) é uma doença genética causada pela substituição de um ácido glutâmico por uma valina na posição 6 da cadeia globina 'beta'. A mutação de ponto origina a hemoglobina S (HbS), que sob condições de deoxigenação se polimeriza tornando os eritrócitos mais propensos à falcização. A fisiopatologia da AF resulta em processos recorrentes de vaso-oclusão e hemólise, causando numerosas complicações clínicas, incluindo a danificação dos rins e problemas cardiovasculares. A angiotensina II (Ang II), um peptídeo vasoconstritor derivado do sistema renina-angiotensina (SRA), controla a pressão arterial e o equilíbrio dos fluidos. A Ang II também participa na geração de espécies reativas de oxigênio, diminuindo a biodisponibilidade do óxido nítrico (NO), um gás vasodilatador, podendo contribuir para alterações no endotélio. A hidroxiureia (HU), agente quimioterápico importante no tratamento dos indivíduos portadores de AF, exerce seu efeito benéfico por meio do aumento de hemoglobina fetal (HbF), reduzindo a falcização dos eritrócitos, diminuindo o número de leucócitos, além de possuir a capacidade de gerar NO. O objetivo deste estudo foi verificar se a produção e expressão das proteínas do SRA estão alteradas na AF e os efeitos da terapia com HU nestes parâmetros. Para analisar a atividade do SRA na AF e um possível papel para a Ang II no processo inflamatório, foram quantificadas as concentrações plasmáticas de Ang II, enzima conversora de angiotensina (ACE), molécula de adesão vascular-1, molécula de adesão intercelular-1, endotelina-1 (ET-1), metabólitos de NO, guanosina monofosfato cíclico (GMPc), interleucina-6, interleucina-8, fator de necrose tumoral-'alfa' e inibidor do ativador do plasminogênio-1 nas amostras de sangue dos indivíduos portadores de AF e indivíduos sadios controles. A produção de Ang II e expressão de algumas proteínas do SRA também foram estudadas em um modelo animal de AF. Adicionalmente, camundongos com AF foram tratados com a HU (50 e 75 mg/kg/dia) por 4 semanas. Não foram encontradas diferenças significativas nos níveis plasmáticos de Ang II nos indivíduos portadores de AF e indivíduos controles, porém a Ang II mostrou correlação positiva com níveis plasmáticos de HbF e ET-1. Uma correlação negativa entre níveis da Ang II e GMPc também foi encontrada no plasma. As concentrações plasmáticas de ACE foram encontradas significantemente menores em indivíduos portadores de AF em comparação aos indivíduos controle. Em camundongos com AF, as concentrações plasmáticas de Ang II estão significativamente diminuídas quando comparadas aos camundongos controles. O tratamento de camundongos AF com HU (75 mg/kg/dia) aumentou significativamente os níveis de Ang II. Diferenças significativas nas expressões dos genes AT1R e ACE1 (que codificam o receptor de angiotensina II tipo 1 e a enzima ACE, respectivamente) foram detectadas em camundongos com AF sem tratamento de HU quando comparados aos camundongos controles, sendo que as expressões dos genes foram menores nos rins e maiores no fígado. Os dados obtidos no estudo sugerem que pode haver alterações no SRA em indivíduos portadores de AF, apesar de não encontrar associações entre alterações em Ang II com parâmetros inflamatórios. Futuros estudos poderiam indicar se alterações na expressão das proteínas do SRA contribuem para algumas manifestações da AF ou refletem danos teciduais nestes indivíduos / Abstract: Sickle cell disease (SCD) is caused by a point mutation that results in the substitution of glutamic acid for valine at the sixth position of the 'beta'-globin chain, leading to the production of hemoglobin S (HbS). HbS polymerizes under conditions of low oxygen concentration, causing the erythrocyte to adopt a sickled shape. The pathophysiology of SCD results in recurrent vaso-oclusion and hemolysis, causing clinicals complications, including kidney damage and cardiovascular problems. Angiotensin II (Ang II), a peptide and vasoconstrictor derived from the action of the renin-angiotensin system (RAS), controls blood pressure and fluid balance. Ang II also participates in the generation of reactive oxygen species, decreasing the bioavailability of the vasodilatory gas nitric oxide (NO), and potentially causing endothelial alterations. Hydroxyurea (HU), an important chemotherapeutic drug employed in the treatment of SCD, has numerous benefits that include augmentation of fetal hemoglobin, reduction of erythrocyte sickling and decreased leukocyte numbers; furthermore, HU also generates NO in vivo. The aim of this study was to investigate whether the production and expression of proteins of the RAS are altered in SCD and the effects of HU therapy on these parameters. To analyse alterations in Ang II and possible associations with inflamatory processes in sickle cell anemia (SCA), the following were quantified in the plasma of SCA patients on and off HU and in healthy control individuals; Ang II, angiotensin converting enzyme (ACE), vascular adhesion molecule-1, intercellular adhesion molecule-1 and endothelin-1 (ET-1), NO metabolites, cyclic guanylate monophosphate (cGMP), interleucin-6, interleucin-8, tumor necrosis factor-'alfa' and plasminogen activator inhibitor-1. The production of Ang II and the expressions of some RAS proteins were also studied in an animal model of SCD. In addition, SCD mice were treated, or not, with hydroxyurea (50 and 75 mg/kg/day) for 4 weeks. Plasma levels of Ang II of SCA patients did not differ from those of controls; however, Ang II demonstrated positive correlations with fetal hemoglobin and ET-1; and a negative correlation with plasma cGMP. Plasma levels of ACE were significantly lower in SCA individuals compared with control individuals. In SCD mice, plasma levels of Ang II were significantly decreased when compared to control mice. Treatment with HU (75 mg/kg/day) in the SCD mice increased levels of Ang II significantly. Significant differences in the gene expressions of AT1R and ACE1 (encoding the angiotensin II receptor type 1 and ACE) were detected in SCD mice not treated with HU, when compared to control mice, where these gene expressions were lower in the kidneys and higher in the liver. These results suggest that some alterations in the RAS may occur in SCD individuals. Although we found no association between plasma Ang II levels with inflammatory parameters in patients, further studies should indicate whether alterations in the RAS may contribute to some of the manifestations of SCD or reflect tissue damage in these individuals / Doutorado / Clinica Medica / Doutor em Clínica Médica

Nous avons étudié les marqueurs hémorhéologiques, hématologiques et biochimiques chez des sujets drépanocytaires homozygotes SS (HbS/HbS) et hétérozygotes composites SC (HbS/HbC) dans deux cohortes, pédiatriques et adultes, de patients drépanocytaires, et ce, à travers 7 complications récurrentes de la drépanocytose : 2 appartenant au profil hémolytique (l’ulcère de jambes et la glomérulopathie) et 5 appartenant au phénotype visqueux/vaso-occlusif (l’hypertension artérielle, le syndrome thoracique aigu (STA), la crise vaso-occlusive (CVO), la rétinopathie et l’ostéonécrose). Nous avons montré que : 1) une viscosité sanguine et une déformabilité érythrocytaire élevées sont des facteurs de risques de CVO chez les enfants homozygotes ; 2) Une viscosité sanguine élevée est associée à une hypertension artérielle systémique relative chez des adultes SS ; 3) les enfants SC présente une fonction vasculaire mieux préservée que les enfants SS pour faire face à une augmentation de la viscosité sanguine ; 4) les patients adultes SS avec une ostéonécrose présentent une déformabilité érythrocytaire plus élevée que les patients sans ostéonécrose ; 5) une viscosité sanguine élevée est associée à la présence d’une rétinopathie chez les adultes SC mais pas chez les SS ; 6) les patients adultes SS présentant une glomérulopathie ont un taux d’hémolyse élevé, une déformabilité érythrocytaire réduite et des agrégats érythrocytaires très robustes ; 7) les patients adultes SS avec des ulcères de jambes récurrents ont un taux d’hémolyse accru et une déformabilité érythrocytaire réduite. De plus, nos travaux confirment que l’-thalassémie module les propriétés de déformabilité érythrocytaire, mais montrent pour la première fois qu’elle module aussi les propriétés d’agrégation érythrocytaire, et notamment la force des agrégats érythrocytaires. En conclusion, ces travaux permettent de préciser le rôle de la rhéologie sanguine dans un certain nombre de complications de la drépanocytose et d’enrichir le modèle préexistant divisant les complications de la drépanocytose selon 2 phénotypes : hémolytique versus visqueux/vaso-occlusif. Nous montrons pour la première fois que le phénotype hémolytique est caractérisé aussi par des anomalies de la rhéologie du globule rouge : rigidité accrue et agrégats érythrocytaire robustes. / Hemorheological, hemathological, and biochemical marquers of patients with sickle cell anemia (SS) and patients with sickle cell SC disease (SC) were studied in 2 cohorts: children and adults. We focused on 7 recurrent complications: 5 belonging to the viscosity/vaso-occlusion phenotype (systemic hypertension, acute chest syndrome (ACS), vaso-occlusive crisis (VOC), retinopathy and osteonecrosis) and 2 belonging to the hemolytic phenotype (leg ulcer and glomerulopathy). Our results show that 1) high viscosity is associated with increased risk for VOC in SS children; 2) blood viscosity is increased in SS adults with systemic relative hypertension; 3) SC children have preserved vascular function compared to SS children; 4) SS adults with osteonecrosis are characterized by higher red blood cell (RBC) deformability than SS adults without osteonecrosis; 5) high blood viscosity is associated with retinopathy in SC adults but not in SS adults; 6) SS adults affected by glomerulopathy have high hemolytic rate, low RBC deformability and increased RBC aggregates strenght; 7) SS adults with recurrent leg ulcers have high hemolytic rate and reduced RBC deformability. Moreover, our studies shows that alpha-thalassemia modulate RBC deformability and RBC aggregation properties. In conclusion, this work shows for the first time that the hemolytic phenotype is characterized by an abnormal RBC rheology which may play a role in several sickle cell complications.

Cette thèse cherche à optimiser l’utilisation du génotypage et des scores de gravité dans la drépanocytose. L’aspect diagnostic génétique ne nous semblait pas poser problème jusqu’à ce que nous rencontrions un cas très atypique d’hétérozygotie A/S avec délétion en mosaïque du gène β-globine qui nous a conduits à réfléchir sur une nouvelle forme génétique potentielle de syndrome drépanocytaire majeur. Pour ce qui est des gènes modificateurs de drépanocytose, nous avons voulu faciliter leur l’accès en proposant, pour deux d’entre eux (haplotypes β-globine et G6PD), une méthode de génotypage rapide par HRM et/ou FRET. Notre travail a consisté ensuite en la validation d’un score de sévérité pédiatrique décrit initialement par Van den Tweel. De façon inattendue, les résultats nous ont amenés à nous interroger sur le rôle exact du génotype α-globine dans la drépanocytose avec un possible effet âge-dépendant. Enfin, nous avons étudié les fréquences alléliques des principaux polymorphismes influant sur l’activité des opiacés: une résistance pharmacologique (gènes OPRM1 et COMT) est apparue peu probable mais une proportion non négligeable de drépanocytaires pourrait avoir des génotypes ABCB1 et UGT2B7 défavorables à la biodisponibilité des opiacés / This work is submitted for a PhD thesis in the field of red cell haematology. Sickle cell disease (SCD) is a monogenic disorder under polygenic and environmental control. The aim of this work was to integrate genotyping results from patients' DNA into the determination of the disease severity scores. Through a large population of SCD patients, we have discovered an atypical case of βA / βS heterozygosity namely, a mosaicism deletion of the beta-globin gene. This represents a new SCD complex situation for molecular diagnosis. Further investigations have led to set up a new genotyping method by using HRM and/or FRET for the determination of two SCD modifiers (beta-globin haplotypes and G6PD deficiency). By using a paediatric severity score of the disease proposed by Van den Tweel, our results show that there is a possible age-dependent effect of the alpha-globin gene in the severity of SCD. Finally, we studied the allelic frequencies of the main opiate-related polymorphisms: a pharmacological resistance (OPRM1 and COMT genes) seemed unlikely but a quite important proportion of patients could have both an ABCB1 and a UGT2B7 genotype unfavorable for opiates bioavailability

Introduction : La majorité des enfants ayant l’anémie falciforme (AF) sont déficients en vitamine D. Cette déficience causerait ou exacerberait possiblement les complications de l’AF telles que les crises de douleur et les complications osseuses. Nous avons récemment publié que près de 70% des enfants suivis à notre clinique d’AF étaient déficients en vitamine D (<50 nmol/L), que ceux-ci avaient de faibles apports alimentaires en vitamine D et prenaient peu de suppléments. Cliniquement, les enfants déficients en vitamine D avaient un moins bon profil hématologique que les enfants suffisants en vitamine D. Ces résultats nous ont amené à proposer une intervention pour résoudre ces problèmes. Objectifs : Primaires : Évaluer la faisabilité, l’acceptabilité et la sécurité d’un bolus oral de 300 000 UI de vitamine D3, chez les enfants ayant l’AF, combiné à une supplémentation quotidienne de 1 000 UI de vitamine D3 pour 3 mois. Secondaires : Évaluer le changement des taux sériques de 25(OH)D après 3 mois ainsi que les impacts cliniques d’une telle supplémentation. Méthode : Des enfants avec AF (5 à 17 ans, tous les génotypes) ont été randomisés à un bolus oral de vitamine D3 (300 000 UI) ou à un placebo. Tous les enfants ont également reçu une prescription pour des comprimés de 1 000 UI vitamine D3 à prendre quotidiennement. La 25(OH)D sérique a été mesurée au début de l’étude et 3 mois post-bolus (efficacité de l’intervention). Les autres paramètres mesurés lors de l’étude étaient le ratio calcium/créatinine urinaire et le calcium sérique (sécurité), la douleur musculosquelettique, la qualité de vie, l’hématologie et les marqueurs osseux (paramètres cliniques exploratoires). Résultats : Trente-huit enfants ont participé à l’étude (âge moyen de 10,1 +/- 3,6 ans; 63% HbSS, 29% HbSC et 8% S/β thal+) : 18 ont reçu le bolus de vitamine D et 20 le placebo. Au début de l’étude, les niveaux moyens de 25(OH)D étaient de 75 +/- 27 nmol/L et 50% des enfants étaient insuffisants en vitamine D (<75 nmol/L). Chez les enfants ayant pris le bolus, les taux de 25(OH)D se sont élevés à 94 nmol/L après 3 mois et le taux d’insuffisance en vitamine D est descendu à 17%, alors que pour le placebo, les taux de 25(OH)D post 3 mois étaient de 74 +/- 19 nmol/L et le taux d’insuffisance en vitamine D était de 45% (p=0,001). Aucun épisode d’hypercalcémie, d’hypercalciurie ou d’hypervitaminose D (>250 nmol/L) n’a eu lieu durant l’étude, mais les enfants du groupe bolus ont expérimenté plus de symptômes gastro-intestinaux dans le premier mois suivant l’ingestion du bolus, comparativement au groupe placebo. Le décompte de réticulocytes était plus faible à la fin de l’étude pour les enfants du groupe bolus. Aucun autre effet clinique de l’intervention n’a été observé. Conclusion : L’utilisation d’un bolus de vitamine D à haute dose combiné à une supplémentation quotidienne en vitamine D chez des enfants ayant l’AF était plus efficace à élever les taux de 25(OH)D à des taux supérieurs à 75 nmol/L que la supplémentation quotidienne seule. Des études multicentriques à plus grande échelle et de plus longue durée sont nécessaires afin d’évaluer les effets cliniques d’une telle supplémentation. / Background: Most children with sickle cell disease (SCD) are vitamin D deficient. This deficiency could possibly cause or exacerbate SCD complications such as pain crisis and bone complications. We previously showed that nearly 70% of children followed in our SCD Clinic were vitamin D deficient (<50 nmol/L) with low vitamin intake and poor use of supplements. Clinically, worse hematological profile was seen in vitamin D-deficient children compared to vitamin D-sufficient children. This study was designed to overcome these issues. Objectives: Primary objectives were to assess feasibility, acceptability, and safety of a single oral bolus of 300,000 IU of vitamin D3 combined to daily 1,000 IU vitamin D3 for 3 months in children with SCD. Secondary objectives were to asses the mean change in serum 25(OH)D from baseline to 3 months post-bolus and its clinical impact. Procedure: A randomized controlled trial was carried out in children with SCD (5-17 years, all genotypes). Children were randomized to a single bolus of vitamin D3 (300,000 IU) or placebo and also received prescription for daily 1,000 IU vitamin D3. Serum 25OHD (efficacity outcome) was measured at baseline and 3 months post-bolus. Other outcomes measured were urinary calcium/creatinine ratio and serum calcium (safety), musculoskeletal pain, quality of life as well as hematology and bone markers (exploratory outcomes). Results: Thirty-eight children were randomized to received the vitamin D bolus (n=18) or the placebo (n=20) (mean age 10.1 +/- 3.6 years; 63% HbSS, 29% HbSC and 8% S/β thal+). At baseline, 50% of the children were vitamin D insufficient (<75 nmol/L) and mean serum 25(OH)D levels were 75 +/- 27 nmol/L. In the vitamin D bolus group, insufficiency dropped to 17% post 3 months and mean 25(OH)D levels raised to 94 nmol/L. In children who took the placebo, rates of vitamin D insufficiency were 45% and mean 25(OH)D levels were 74 +/-19 nmol/L post 3 months (p=0.001). The vitamin D bolus caused no hypercalcemia, hypercalciuria nor hypervitaminosis D (>250 nmol/L). However compared to the placebo group, more children in the bolus group experienced gastro-intestinal symptoms within the first month following the vitamin D bolus. As for the hematology parameters, only a slight difference in reticulocytes counts was observed with lower reticulocytes count the end of the study in children from the bolus group. No other clinical effects of the intervention were observed. Conclusions: High-dose vitamin D bolus combined to daily supplementation in children with SCD is more efficient than daily supplementation alone to raise 25(OH)D levels ≥75 nmol/L. Large-scale multicenter studies of longer duration are needed to assess whether this intervention can improve clinical outcomes of children with SCD.