Made available in DSpace on 2016-06-02T19:05:56Z (GMT). No. of bitstreams: 1 4310.pdf: 3265738 bytes, checksum: 6650fb70eee9b096860bcac6b5ed596c (MD5) Previous issue date: 2012-02-24 / Currently in the medical field there is a large amount of unstructured information (i.e., in textual format). Regarding the large volume of data, it makes it impossible for doctors and specialists to analyze manually all the relevant literature, which requires techniques for automatically analyze the documents. In order to identify relevant information, as well as to structure and store them into a database and to enable future discovery of significant relationships, in this paper we propose a paragraph-based process to extract treatments from scientific papers in the biomedical domain. The hypothesis is that the initial search for sentences that have terms of complication improves the identification and extraction of terms of treatment. This happens because treatments mainly occur in the same sentence of a complication, or in nearby sentences in the same paragraph. Our methodology employs three approaches for information extraction: machine learning-based approach, for classifying sentences of interest that will have terms to be extracted; dictionary-based approach, which uses terms validated by an expert in the field; and rule-based approach. The methodology was validated as proof of concept, using papers from the biomedical domain, specifically, papers related to Sickle Cell Anemia disease. The proof of concept was performed in the classification of sentences and identification of relevant terms. The value obtained in the classification accuracy of sentences was 79% for the classifier of complication and 71% for the classifier of treatment. These values are consistent with the results obtained from the combination of the machine learning algorithm Support Vector Machine with the filter Noise Removal and Balancing of Classes. In the identification of relevant terms, the results of our methodology showed higher F-measure percentage (42%) compared to the manual classification (31%) and to the partial process, i.e., without using the classifier of complication (36%). Even with low percentage of recall, there was no impact observed on the extraction process, and, in addition, we were able to validate the hypothesis considered in this work. In other words, it was possible to obtain 100% of recall for different terms, thus not impacting the extraction process, and further the working hypothesis of this study was proven. / Atualmente na área médica existe uma grande quantidade de informações não estruturadas (i.e., em formato textual) sendo produzidas na literatura médica. Com o grande volume de dados, torna-se impossível que os médicos e especialistas da área analisem toda a literatura de forma manual, exigindo técnicas para automatizar a análise destes documentos. Com o intuito de identificar as informações relevantes, estruturar e armazenar estas informações em um banco de dados, para posteriormente identificar relacionamentos interessantes entre as informações extraídas, nesta dissertação é proposto um processo baseado em parágrafos para a extração de tratamentos de artigos científicos do domínio biomédico. A hipótese é que a busca inicial de sentenças que possuem termos de complicação melhora a eficiência na identificação e na extração de termos de tratamento. Isso acontece porque tratamentos ocorrem principalmente na mesma sentença de complicação ou em sentenças próximas no mesmo parágrafo. Esta metodologia utiliza três abordagens de extração de informação encontradas na literatura: abordagem baseada em aprendizado de máquina para classificar as sentenças de interesse; abordagem baseada em dicionário com termos validados pelo especialista da área e abordagem baseada em regras. A metodologia foi validada como prova de conceito, utilizando artigos do domínio biomédico, mais especificamente da doença Anemia Falciforme. A prova de conceito foi realizada na classificação de sentenças e identificação de termos relevantes. O valor da acurácia obtida na classificação de sentenças foi de 79% para o classificador de complicação e 71% para o classificador de tratamento. Estes valores condizem com os resultados obtidos com a combinação do algoritmo de aprendizado de máquina Support Vector Machine juntamente com a aplicação do filtro Remoção de Ruído e Balanceamento das Classes. Na identificação de termos relevantes, os resultados da metodologia proposta obteve percentual superior de 42% de medida-F comparado à classificação manual (31%) e comparado ao processo parcial, ou seja, sem utilizar o classificador de complicação (36%). Mesmo com a baixa revocação, foi possível obter 100% de revocação para os termos distintos de tratamento, não impactando o processo de extração, e portanto a hipótese considerada neste trabalho foi comprovada.

Made available in DSpace on 2016-06-02T19:06:20Z (GMT). No. of bitstreams: 1 6477.pdf: 3193803 bytes, checksum: 2bf85c80b2865f8b7efd9d6eeb6aa172 (MD5) Previous issue date: 2013-11-28 / Financiadora de Estudos e Projetos / Recently, there is an enormous amount of scientific material written in textual format and published in electronic ways (paper on proceedings and articles on journals). In the biomedical field, researchers need to analyse a vast amount of information in order to update their knowledges, in order to get more precise diagnostics and propose more modern and effective treatments. The task of getting knowledge is extremely onerous and the manual process to annotate relationships and to propose novel hypothesis for treatments becomes very slow and error-prone. In this sense, as a result of this master s research it is proposed a method to extract cause and effect semantic relationships in sentences of scientific papers of the biomedical domain. The goal of this work is to propose and implements a solution for: (1) to extract terms from the biomedical domain (genes, proteins, chemical components, structures and anatomical processes, cell components and strutures, and treatmens), (2) to identify existing relationships on the texts, from the extracted terms, and (3) to suggest a knowledge network based on the relations of cause and effect . Over the approach using textual patterns, our proposed method had extracted semantic relations with a precision of 94,83 %, recall of 98,10 %, F-measure of 96,43 %. / Atualmente, existe uma enorme quantidade de material científico escrito em formato textual e publicado em meios eletrônicos (artigos em anais de eventos e periódicos). Na área biomédica, pesquisadores necessitam assimilar uma grande parte deste conteúdo com a finalidade de se atualizarem e, por conseguinte realizarem diagnosticos mais precisos e aplicar tratamentos mais modernos e eficazes. A tarefa de obtenção de conhecimento é bastante onerosa e o processo manual para anotar relacionamentos e propor novas hipóteses de tratamentos torna-se muito lento. Neste sentido, como resultado desta pesquisa de mestrado, foi proposto um método para a extração de relacionamentos semânticos do tipo causa e efeito em artigos científicos do domínio biomédico. Mais especificamente, o objetivo deste trabalho é propor e implementar uma solução para (1) extrair termos do domínio biomédico de documentos científicos (genes, componentes químicos, proteínas, estruturas e processos anatômicos, componentes e estruturas celulares e tratamentos), (2) identificar relacionamentos existentes nos textos, com base nos termos extraídos, e (3) sugerir uma rede de conhecimento baseada nos relacionamentos extraídos. Através de uma abordagem utilizando regras e padrões textuais, o método proposto extraiu relacionamentos semânticos com uma precisão de 94,83 %, cobertura de 98,10 % e Medida-F de 96,43 %.

Introdução: A doença falciforme (DF) é a afecção hematológica hereditária de maior prevalência no mundo, sendo que a anemia falciforme (AF) é a forma mais grave com elevada morbidade e mortalidade. Alterações cardíacas são reconhecidamente associadas à AF, como aumento cavitário, hipertensão arterial pulmonar e disfunção diastólica do ventrículo esquerdo. No entanto, ainda não existe consenso quanto à função sistólica ventricular nesses pacientes. O objetivo deste estudo foi o de investigar a função ventricular de pacientes com anemia falciforme utilizando o strain e o twist ventricular obtidos pelo speckle tracking bidimensional, e reconhecer os indivíduos sob maior risco cardiovascular, em que a instituição precoce de tratamento específico poderá beneficiar essa população. Métodos: Foram recrutados 40 pacientes com anemia falciforme (23,5 ± 9,3 anos; 24 homens) e 40 controles saudáveis pareados por sexo e idade, submetidos à entrevista estruturada, ecocardiograma transtorácico, cintilografia pulmonar ventilação perfusão e coleta de amostras de sangue. Todos os indivíduos foram submetidos à avaliação ecocardiográfica convencional padrão e subsequente avaliação offline do strain sistólico biventricular e estudo rotacional do ventrículo esquerdo utilizando speckle-tracking ecocardiográfico. Resultados: Os pacientes com AF apresentaram volume do VE indexado, massa do VE indexado, pressão arterial pulmonar e E/E\' médio superiores aos controles. As medidas de FE do VE, excursão sistólica do plano da tricúspide (TAPSE), Strain Global do VE (longitudinal, circunferencial, radial) e Strain Global do VD (longitudinal) não evidenciaram diferenças entre os grupos. Twist VE se mostrou reduzido em comparação aos controles (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) e Tempo de pico de rotação apical prolongado (366,7 ± 26,1ms vs 344,6 ± 11,7ms , P <0,0001 ). Algumas variáveis se mostraram fortemente relacionadas ao twist VE, como índice de gravidade clínico (Rho= - 0,97, Z value= - 6,05, P < 0,0001), relação E/E\' médio (r = 0,94, F valor= 156.9, p<0,0001), IVDFVE (índice do volume diastólico final do ventrículo esquerdo)(r = 0,81 e p<0,0001) e pressão sistólica arterial pulmonar (r = 0,72 e p<0,0001). Conclusões: Os resultados deste trabalho indicam que o twist ventricular esquerdo derivado do speckle tracking bidimensional encontra-se alterado em pacientes com anemia falciforme e função sistólica ventricular preservada, avaliada pela metodologia convencional, e existe forte correlação entre o twist ventricular esquerdo e o índice clínico de gravidade, relação E/E\', índice do volume diastólico final do ventrículo esquerdo e pressão sistólica arterial pulmonar. / Background: Sickle cell disease (SCD) is the most prevalent hematological condition in the world, with sickle cell anemia (SCA) being its most serious form, displaying a high level of morbidity and mortality. Cardiac changes are known to be associated with SCA, including an increase in cardiac chamber size, pulmonary hypertension and left ventricle diastolic dysfunction. However, there is still no consensus regarding the ventricular systolic function in these patients. The purpose of this study is to investigate the ventricular function of patients with sickle cell anemia utilizing the strain and ventricular twist, obtained by two-dimensional speckle tracking, as well as to identify individuals with higher cardiovascular risk, in which early application of specific treatment could benefit this group of people. Methods: 40 patients were recruited with sickle cell anemia (ages 23.5 ± 9.3 years; 24 males) and 40 healthy control individuals paired by gender and age, submitted to structured interviews, transthoracic echocardiogram, pulmonary scintigraphy and collection of blood samples. All individuals were submitted to a standard echocardiographic evaluation and subsequent off line evaluation of the biventricular systolic strain and rotational study of the left ventricle using echocardiographic speckle-tracking. Results: Patients with SCA presented LV volume indices, LV mass Indices, pulmonary arterial pressure and E/ E\' ratios statistically higher than the control individuals. Measurements of Ejection Fraction (EF) of the left ventricle, tricuspid annular plane systolic excursion (TAPSE), Overall LV Strain (Longitudinal, Circumferential, and Radial) and Overall RV Strain (Longitudinal) did not present differences between the groups. LV twist was significantly lower in relation to the control group (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) and prolonged time to peak apical rotation (366.7 ± 26.1ms vs 344.6 ± 11.7ms , P <0.0001 ). In addition, some variables showed themselves to be strongly related to LV twist such as the clinical severity index ( Rho= - 0.97, Z value= - 6.05, P < 0.0001), E/E\' Ratio (r = 0.94, F value=156.9 e p<0.0001) ), left ventricle end diastolic volume index (LVEDV index) (r = 0,81, p<0,0001) and pulmonary systolic arterial pressure (r = 0.72 e p<0.0001). Conclusions: The results of this study indicate that the left ventricular twist derived from two-dimensional speckle tracking is altered in patients with sickle cell anemia and a preserved ventricular systolic function, evaluated using conventional methodology and that there is a strong correlation between left ventricular twist and the clinical severity index, E/E\' ratio, left ventricle end diastolic volume index and the pulmonary systolic arterial pressure.

La drépanocytose est la maladie moléculaire et héréditaire (transmission mendélienne récessive et autosomique) la plus répandue au monde. Elle est un problème de santé publique par sa gravité et ses implications socio-économiques dans de nombreux pays. Seuls les sujets homozygotes (SS) ou hétérozygotes composites (SC) sont malades, les hétérozygotes (AS) ne sont que des transmetteurs du gène S. Elle est la première cause d’OstéoNécrose de la Tête Fémorale (ONTF), douloureuse évoluant vers l’arthrose, en l’absence de traitement chez un patient jeune.<p>La Guadeloupe compte 450.000 habitants, dont 12% sont porteurs de l’hémoglobine S. Le nombre des drépanocytaires est estimé à 1.200 dont les 3/4 sont suivis au Centre Caribéen de la Drépanocytose (CCD), créé en 1990. Le centre assure la prise en charge médicale des enfants dès leur naissance et des adultes malades. Nos activités au CHU de Pointe-à-Pitre, au CCD et à l’Unité INSERM-UMR S458 depuis juillet 1992 nous ont permis d’étudier:<p>- le diagnostic de l’ONTF;<p>- l’évaluation de l’hyperpression osseuse dans l’ONTF et l’évaluation du traitement par forage simple;<p>- l’étude de l’impact de la prise en charge orthopédique précoce sur la survenue et l’évolution de l’ONTF.<p>Notre étude concerne les patients drépanocytaires adultes homozygotes (SS) et double hétérozygotes (SC):<p>- une série rétrospective de 1993-1994 [E-1994] portant sur 115 patients (58 SS, 57 SC) identifiés en 1984,<p>sans suivi médical ni orthopédique;<p>- une série prospective de 1995 à 2008 [E-2008] portant sur 215 patients (94 SS, 121 SC) avec prise en<p>charge médicale et orthopédique.<p>L’IRM est l’examen de référence pour le diagnostic de l’ONTF comme dans la nécrose idiopathique. En absence d’imagerie moderne, la radiographie traditionnelle réalisée de façon complète (profil et, surtout, faux profil), permet le diagnostic avant toute déformation. Seules les lésions cliniquement symptomatiques et évolutives (examen clinique itératif, contrôle radiologique, tomographie, TDM ou IRM) ont une indication opératoire.<p>L’hyperpression intra osseuse, dans l’ONTF drépanocytaire, est significativement liée à la douleur (que les patients soient homozygotes ou hétérozygotes). Sa diminution a un effet antalgique objectif, observée après forage. Elle permet de confirmer le diagnostic d’ostéonécrose au stade précoce, dans les régions où l’IRM est inexistante.<p>Un forage réalisé aux stades précoces de l’ONTF permet un arrêt rapide de l’évolution des lésions vers une arthrose, avec une efficacité certaine pour les stades I et II. Il garde une efficacité limitée pour le stade III. En plus de l’indolence apportée par la décompression, le bénéfice du forage se manifeste par l’allongement du délai avant arthroplastie (de 7,4 ± 2,7 ans). La technique est réalisable dans les régions sous équipées, où la drépanocytose est fréquente.<p>La description histologique aux différents stades radiologiques de l’ONTF montre toujours des lésions de nécrose médullaire et osseuse. A l’inverse des lésions idiopathiques, les lésions drépanocytaires sont caractérisées par la présence d’une inflammation, en dehors de tout processus infectieux.<p>Dans la littérature, la fréquente de l’ONTF drépanocytaire chez l’adulte est voisine de 40%, proche de celle observée dans [E-1994], notre population non suivie (36,5%). En comparant les études [E-1994] et [E-2008], la fréquence de l’ONTF passe de 36,5% à 14,4%. L’officialisation en 1992 d’une prise en charge médicale et d’un suivi orthopédique régulier au CCD et au CHU de Pointe-à-Pitre, a permis la réduction de la fréquence de l’ONTF et d’autres morbidités.<p>Le rappel sur la drépanocytose révèle la complexité de la maladie, la variabilité de son expression clinique et de ses complications. L’amélioration de vie des patients nécessite une prévention primaire, secondaire et tertiaire, en l’absence d’un traitement spécifique de la maladie.<p>La prise en charge médicale, complétée par une prévention et un traitement précoce (orthopédique ou chirurgical) telle que réalisés au CCD en Guadeloupe, a permis une réduction significative de la survenue de la nécrose de hanche et de ses complications. Pour une prévention tertiaire des complications ostéo-articulaires, nous suggérons:<p>- une prise en charge médicale régulière des enfants et des adultes afin de réduire les crises vaso-occlusives;<p>- une éducation des patients à la recherche de signes d’appel de l'ONTF et, aussi, d’autres articulations;<p>- un examen clinique ostéo-articulaire lors des bilans annuels et après toute crise vaso-occlusive;<p>- une attention particulière à l’adolescence (passage enfant-adulte), après une grossesse;<p>- une prise en charge précoce, orthopédique ou chirurgicale conservatrice (forage ou ostéotomie) face à une<p>nécrose, afin de réduire les complications invalidantes de l’ONTF.<p><p>Sickle-cell anemia is the most widespread hereditary (autosomal recessive Mendelian transmission) molecular pathology in the world. It is a public health issue in many countries, due to its severity and socio-economic impact. Only homozygous (SS) and double heterozygous (SC) subjects are affected, heterozygous (AS) subjects merely transmitting the gene S. Sickle-cell anemia is the most frequent cause of osteonecrosis of the femoral head (ONFH), a painful condition which evolves towards osteoarthritis if not treated at an early age.<p>Guadeloupe has a population of 450,000, 12% of whom are carriers of hemoglobin S. There are estimated to be 1,200 sickle-cell anemia sufferers, three-quarters of whom are followed in the Caribbean Sickle-Cell Center (Centre Caribéen de la Drépanocytose: CCD), which was set up in 1990. The Center provides medical care for adult patients and for children as of birth. Work has been ongoing since July 1992, in the Pointe-à-Pitre University Hospital, the CCD and the INSERM-UMR S458 research unit, focusing on:<p>- diagnosis of ONFH;<p>- bone hyperpressure measurement in ONFH and assessment of simple drilling treatment;<p>- the impact of early orthopedic treatment on the onset and evolution of ONFH.<p>The present study involved homozygous (SS) and double heterozygous (SC) adult sickle-cell anemia patients:<p>- a retrospective series, from 1993 to 1994 [S-1994], including 115 patients (58 SS, 57 SC) identified in 1984,<p>who had no medical or orthopedic care;<p>- a prospective series, from 1995 to 2008 [S-2008], including 215 patients (94 SS, 121 SC), with medical and orthopedic care.<p>MRI is the diagnostic gold-standard in ONFH, as in idiopathic necrosis. Where such modern imaging is not available, complete standard X-ray (lateral and especially false lateral) enables diagnosis to be made before deformity sets in. Surgery is indicated only for clinically symptomatic evolutive lesions on iterative clinical check-up, X-ray control, tomography, CT or MRI.<p>Intraosseous hyperpressure in sickle-cell ONFH shows a significant correlation with pain, in both homozygous and heterozygous patients. Pressure reduction is objectively pain-relieving, as seen after drilling, and can confirm diagnosis of ONFH at an early stage, in places where MRI is not available.<p>Drilling performed in the early stages of ONFH quickly arrests evolution towards osteoarthritis, with proven efficacy in grades I and II, and a certain degree of effectiveness in grade III. Over and above the pain-relief provided by decompression, drilling also enables hip replacement to be postponed, by 7.4±2.7 years. Moreover, the technique is feasible in those under-equipped regions in which sickle-cell disease is widespread.<p>Histologic description of radiologic ONFH stages consistently finds medullary and bone necrosis. In contrast to idiopathic lesions, sickle-cell related lesions show inflammation without any associated infection.<p>In the literature, the frequency of adult sickle-cell ONFH is reported to be nearly 40%, close to the 36.5% found in the S-1994 study of a non-treated population. In the S-2008 study of a population with medical and orthopedic care, ONFH frequency fell to 14.4%. The official provision of medical care and regular orthopedic follow-up in the CCD and Pointe-à-Pitre Hospital has reduced the frequency of ONFH and other morbidities.<p>A review of sickle-cell disease reveals its complexity: the variability of its clinical expression and associated complications. Improving patients’ quality of life requires primary, secondary and tertiary prevention, in the absence of specific treatment.<p>Medical care, supplemented by early prevention and treatment (orthopedic or surgical), as practiced in the Guadeloupe CCD, has significantly reduced the rates of ONFH and associated complications. We recommend the following CCD protocol for tertiary prevention of osteoarticular complications:<p>- regular medical care for children and adults, to reduce the incidence of vaso-occlusive crises;<p>- patient education in alarm signs of osteonecrosis of the femoral head and of other joints;<p>- systematic osteoarticular assessment at yearly check-up and after all vaso-occlusive crises;<p>- special focus on adolescence (child-to-adult transition) and following pregnancy;<p>- early care, both orthopedic and by conservative surgery (drilling or osteotomy), in case of necrosis, to reduce the rate of disabling complications of ONFH / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Sickle cell anemia (SCA) is the result of a mutation in the beta globin chain gene, resulting in the production of an abnormal hemoglobin, Hb S. Losing oxygen, Hb S decreases its solubility, suffering aggregation and polymerization, which hardens and distorts the erythrocytes causing occlusion of small blood vessels. The venocclusive phenomena characteristic of AF may occur in any organ, including the heart and lung. These complications are among the leading causes of morbidity and mortality related to this disease. Objectives: To evaluate cardiopulmonary involvement of children, adolescents and young adults with sickle cell anemia and investigate the correlations between left ventricular hypertrophy (LVH) and restrictive lung pattern variables, as well as any associations. Method: Cross-sectional study in which were consecutively included patients with SCA, attending the Pediatric Hematology, University Hospital, Federal University of Sergipe. Demographic, clinical and laboratory data have been collected and ecocadiograma and spirometry were performed. Results: 153 patients have been studied, with a mean age of 14.9 years. LVH was identified in 40% of patients, without systolic or diastolic dysfunction. Patients with LVH had lower hemoglobin levels, higher albumin/creatinine ratio and AST (p=0.03, 0.02 and 0.03 respectively). Impairment in pulmonary function has been found in 60.9 % of patients, of which 46.9% had pulmonary restrictive pattern. These had higher mean of age (p=0.04) and showed higher mean corpuscular volume, AST and creatinine clearance (p=0.03, 0.03 and 0.02, respectively). There was not statistic between LVH and restrictive lung pattern (p=0.49). suggesting that they are events with different natural histories. The findings of the study indicate the need for investigation of cardiopulmonary alterations in patients with sickle cell anemia. Spirometry and echocardiography should be performed independently. / A anemia falciforme (AF) é o resultado de uma mutação no gene da cadeia globínica beta resultando na produção de uma hemoglobina anormal, a hemoglobina S (HbS). Ao perder oxigênio, a Hb S diminui sua solubilidade, sofrendo agregação e polimerização, que enrijece e distorce o eritrócito causando oclusão de pequenos vasos sanguíneos. Os fenômenos vaso-oclusivos característicos da AF podem ocorrer em qualquer órgão, incluindo o coração e os pulmões. As complicações cardiopulmonares estão entre as principais causas de morbidade e mortalidade desta doença. Objetivos: Avaliar o comprometimento cardiopulmonar de crianças, adolescentes e adultos jovens portadores de anemia falciforme e determinar variáveis relacionadas a hipertrofia do ventrículo esquerdo (HVE) e ao padrão restritivo pulmonar, bem como eventuais associações. Método: Estudo transversal no qual foram incluídos de forma consecutiva pacientes portadores de AF, atendidos no Serviço de Hematologia Pediátrica do Hospital Universitário da Universidade Federal de Sergipe. Foram coletados dados demográficos, clínicos e laboratoriais, e realizados ecocadiograma e espirometria. Resultados: Foram estudados 153 pacientes com média de idade de 14,9 anos. HVE foi encontrada em 40% dos pacientes, sem disfunção sistólica ou diastólica. Pacientes com HVE apresentaram valores menores de hemoglobina, maior relação albumina/creatinina e aminotransferase aaminotransferase a aminotransferase a aminotransferase a aminotransferase a aminotransferase aaminotransferase aaminotransferase aaminotransferase asparatosparato sparato sparato (AST) (AST)(AST) (p= 0,03; 0,02 e 0,03 respectivamente). Alterações na função pulmonar foram encontradas em 60,9% dos pacientes, dos quais 46,9% apresentaram padrão restritivo pulmonar. Estes possuíam média de idade mais elevada (p=0,04) e apresentaram valores maiores de volume corpuscular médio, AST e clearance de creatinina (p=0,03; 0,03 e 0,02 respectivamente). A comparação entre os pacientes não evidenciou associação entre HVE e padrão restritivo pulmonar (p=0,49), sugerindo serem eventos com diferentes histórias naturais. Os achados do estudo indicam a necessidade de investigação de alterações cardiopulmonares nos pacientes com anemia falciforme. Espirometria e ecocardiograma devem ser realizados de forma independente.

L’hémolyse post transfusionnelle retardée (HPTR) est une complication potentiellement mortelle de la transfusion dans la drépanocytose. Sa fréquence est sous-estimée et aucun facteur prédictif de sa survenue n'a encore été identifié. Nous avons mené une étude observationnelle prospective monocentrique pendant 30 mois. Nous avons inclus 694 épisodes transfusionnels (ET) chez 311 patients adultes drépanocytaires, divisés en ET ponctuels (ETP = 360) et en ET chronique dans le cadre d’un programme (ETC = 334). Au cours de ce suivi, 15 HPTR ont été enregistrées, exclusivement après un ETP. L'incidence cumulative d’HPTR sur 30 mois était de 4,2 % par ETP (IC 95 % [2,6 ; 6,9]) ou 6,8 % par drépanocytaires transfusés (IC 95 % [4,2 ; 11,3]). Le taux d’incidence était de 16,4 HPTR pour 1000 ETP-Année (IC 95 % [10,1 ; 27,2]) ou 27,1 HPTR pour 1000 Personne-Année (IC 95% [16,7 ; 45,0]). Nous avons étudié 11 HPTR supplémentaires afin de construire un score prédictif. Les variables retenues étaient un antécédent d’HPTR, le nombre d’unités précédemment transfusées et l’état d’immunisation pré transfusionnelle. L’adéquation du score était excellente (Hosmer-Lemeshow = 1,40, p = 0,71), sa capacité discriminante très satisfaisante (aire sous la courbe ROC = 0,85 ; p < 0,0001), une valeur prédictive négative de 98,4 % et une valeur prédictive positive de 50,0 %. La validité interne du score, réalisée par Bootstrap, montre une très bonne performance. Nous rapportons, pour la première fois, l'incidence de l’HPTR et montrons qu’elle survient uniquement suite à un ETP. Nous décrivons également un score simple de prédiction d’une HPTR avant un ETP afin de mieux prendre en charge cette transfusion. / Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication of transfusion in sickle cell disease (SCD). The frequency of DHTR is underestimated and no predictive fac-tors for identifying patients likely to develop DHTR have yet been defined. We conducted a prospective single-center observational study over 30 months. We included 694 transfusion epi-sodes (TE) in 311 adult patients, divided into occasional TE (OTE: 360) and TE during a chronic program (CTE: 334). During follow-up, 15 cases of DHTR were recorded, exclusively after OTEs. DHTR cumulative incidence durin the 30 months was 4.2% per OTE (95% CI [2.6, 6.9]) or 66.8% per patient (95% CI [4.2, 11.3]). The incidence rate was 16.4 DHTR per 1000 OTE-Year (95% CI [10.1, 27.2]) or 27.1 DHTR per 1000 Person-Year (95% CI [16.7 ; 45.0]). We studied 11 additional DHTR cases to construct a score for predicting DHTR after OTE. Fifteen % of the 26 DHTR patients died. The variables retained in the multivariate model were history of DHTR, number of units previously transfused and immunization status before transfusion. The score adequacy was excellent (Hosmer-Lemeshow = 1.40, p = 0.71), very satisfactory dis-criminant capacity (area under ROC curve = 0.85, p <0.0001), negative-predictive value of 98.4% and a positive-predictive value of 50%. The internal validity of the score, realized by Bootstrap, shows a very good performance.We report, for the first time, the incidence of DHTR and we show that DHTR developed only in OTE. We also describe a simple score for predicting DHTR in patients undergoing occasional transfusion, to facilitate the management of blood transfusion in SCD patients.

Sickle cell disease (SCD) is one of the most difficult and stressful chronic diseases for parents of afflicted children to manage. Managing SCD can be traumatic for parents particularly if they have no specific coping strategies for managing the disease or ensuring the child visits the doctor as scheduled. The use of certain coping strategies may affect the parents' and patients' perceptions of the illness and influence their decisions regarding treatment, which can have a lasting impact on their lives. Effective parental strategies such as positive thinking can aid in disease management, but there is limited research on the coping strategies used by parents of children with SCD specifically. The purpose of this phenomenological study, which was guided by Thompson and Gustafson's transactional stress and coping model, was to describe parents' coping strategies in managing their young child's SCD as it relates to use of health services. Data collection included one-to-one, open-ended interviews with 10 parents of children with SCD. Colaizzi's method of phenomenological data analysis was used to identify themes. Five themes emerged from data analysis and they are: parental methods of coping with SCD, participants' understanding of SCD, SCD family and support, managing SCD with hydration and medication, and experience accessing healthcare. These results indicated the participants' coping strategies varied according to their individual situations. Insight from this study could lead to positive social change by helping to identify specific coping strategies parents can use to better manage their child's disease and effectively access available health services.

Die Infektion mit dem Erreger der Malaria tropica, Plasmodium falciparum, verläuft individuell unterschiedlich. Während manche der Infizierten rasch an einer komplizierten Malaria versterben, zeigen andere keinerlei Symptomatik, obwohl jahrelang eine Parasitämie besteht. Was diese Individuen voneinanderen unterscheidet, ist weitgehend unbekannt. Morbidität und Mortalität der Erkrankung sind von der Auseinandersetzung zwischen Wirt und Parasit abhängig, die von exogenen und endogenen Faktoren beeinflußt wird. Unter den endogenen Faktoren spielen die genetischen Determinanten, die sowohl an angeborenen als auch an erworbenen Resistenz- und Immunmechanismen beteiligt sind, eine besondere Rolle. In den hier zusammengefaßten Arbeiten wurden als Determinanten der angeborenen Resistenz gegenüber Malaria die Sichelzellanämie, Alpha-Thalassämie, G6PD-Mangel und der HLA-Klasse-II-Polymorphismus und als genetische Einflußfaktoren von erworbenen Immunmechanismen Varianten des TNF-Promotors, von ICAM-1 und iNOS untersucht. Die Arbeiten unterstützen die Hypothese, daß die Interaktion von Mensch und Plasmodien zu einer ständigen gegenseitigen Beeinflussung und Anpassung geführt hat. Die koevolutonäre Veränderung der Genome der beiden Organismen ist wahrscheinlich mitverantwortlich für die unterschiedliche geographische Verteilung von Genvarianten sowohl des Menschen als auch der Plasmodien und scheint auch heute noch Teil einer komplexen und dynamischen Anpassung von Wirt und Parasit zu sein. / The manifestation of an infection with Plasmodium falciparum, the pathogen of malaria, is individually different. Some indiviuals have a high risk of developing severe malaria, whereas others remain asymptomatic despite a long-lasting parasitemia. The basis of these differences is unknown. Morbidity and mortality of malaria are dependent on the interaction between the host and the parasite which is influenced by exogenic and endogenic factors. The latter are determined by genetic elements involved in innate and acquired mechanisms of resistance and immunity. The studies summerized here address genetic determinants of innate resistance against malaria (sickle cell trait, alpha-thalassemia, G6PD deficiency, blood groups and HLA class II alleles) and those of acquired immunity (variants of the TNF promoter, ICAM-1, and iNOS). The results support the view that the interaction between humans and plasmodia has led to continuous mutual influences and adaptations. Probably, the co-evolution of the genomes of both organisms is jointly responsible for the different geographical distribution of parasitic and human gene variants. This process seems to be part of an ongoing complex and dynamic adaptation of the host and the parasite.

Os eicosanoides, produtos do metabolismo do ácido araquidônico, apresentam papel importante na homeostasia e na patogênese de diversas doenças humanas. A biossíntese desses compostos pode ser estimulada por agentes farmacológicos como ionóforos e inibidores da Ca2+-ATPase, e também por agonistas naturais como o formil-metionil-leucil-fenialanina (fMLP). Considerando os interesses em avaliar e comparar o perfil de mediadores lipídicos, como os leucotrienos (LTs), as prostaglandinas (PGs), os ácidos epoxieicosatrienoicos (EETs), os ácidos dihidroxitetraenoicos (DiHETEs) e os ácidos hidroxieicosatetraenoicos (HETEs), na saúde e na doença, o objetivo deste trabalho foi padronizar um método analítico para determinar do perfil de eicosanoides em plasma humano após estimulação do sangue total, e assim observar diferenças entre indivíduos saudáveis e doentes. Dessa forma, um método por cromatografia líquida de alta eficiência acoplada à espectrometria de massas sequencial (HPLC-MS/MS) foi validado para quantificação de 22 eicosanoides em plasma de indivíduos saudáveis. A análise por HPLCMS/ MS foi realizada em modo negativo pelo modo de varredura por monitoramento de reações múltiplas (MRM). A linearidade do método apresentou coeficiente de correlação (r) maior que 0,98 para todos os eicosanoides analisados. A precisão e exatidão intra e inter-ensaios tiveram desvio padrão e erro relativo menores que 15%, exceto para o limite inferior de quantificação cujos valores foram menores que 20%. Para estimulação das células do sangue total, quatro estímulos (fMLP, ionomicina, A23187 e tapsigargina) foram utilizados. A análise estatística mostrou que o A23187 e a tapsigargina foram os estímulos mais potentes na indução da produção de eicosanoides. Em seguida, comparamos o perfil de eicosanoides em amostras de plasma de indivíduos saudáveis com pacientes com anemia falciforme (AF), em tratamento com hidroxiureia (HU) ou transfusão sanguínea crônica. Os resultados demonstraram que o método é preciso para determinação de diferenças entre os pacientes e indivíduos saudáveis quanto à produção dos mediadores lipídicos 5-HETE, 12-HETE, LTB4, LTE4, TXB2 e PGE2. Portanto, nosso método analítico é sensível, específico e reprodutível para identificar e quantificar diferenças no perfil de eicosanoides em amostras de sangue estimuladas in vitro, e poderá contribuir para o estabelecimento do perfil de mediadores lipídicos em diferentes doenças inflamatórias e infecciosas. / Eicosanoids, products from arachidonic acid metabolism, play an important role in the homeostasis and in the pathogenesis of various human diseases. Pharmacological agents such as Ca2+ ionophores and Ca2+-ATPase inhibitors, as well as natural agonists such as fMet-leu-Phe (fMLP) can stimulate eicosanoid biosynthesis. Considering the interests in evaluate and compare the profile of lipid mediators, as leukotriens (LTs), prostaglandins (PGs), epoxyeicosatrienoic acids (EETs), dihydroxytetraenoic acids (DiHETEs) and hydroxyeicosatetraenoic acids (HETEs), in healthy and disease, the aim of this work was to standardize a method to determine the eicosanoid profile of human plasma samples after whole blood stimulation, and to assess differences between healthy and sick individuals. For this purpose, a liquid chromatographytandem mass spectrometry (LC-MS/MS) method was validated for the quantification of 22 eicosanoids using human plasma from healthy volunteers. In addition, we optimized a method for the stimulation of eicosanoids in human whole blood. LC-MS/MS analyses were performed by negative electrospray ionization and multiple reaction monitoring. An assumption of linearity resulted in a regression coefficient > 0.98 for all eicosanoids tested. The mean intra-assay and inter-assay accuracy and precision values had relative standard deviations and relative errors of < 15%, except for the lower limit of quantification, where these values were < 20%. For whole blood stimulation, four stimuli (fMLP, ionomycin, A23187, and thapsigargin) were used. Results of the statistical analysis showed that A23187 and thapsigargin were potent stimuli to induce the production of eicosanoids. We next compared the eicosanoid profiles of healthy volunteers to those of patients with sickle cell anemia (SCA) under treatment with hydroxyurea (HU) or after chronic red blood cell (RBC) transfusion. The results indicate that the method was sufficient to find a difference between lipid mediators released in whole blood of SCA patients compared to healthy subjects for 5-HETE, 12-HETE, LTB4, LTE4, TXB2, and PGE2. In conclusion, our analytical method is sensitive, specific and reproducible for indentify and quantify changes in eicosanoid profiles in whole blood stimulated in vitro, which can contribute to establishing the eicosanoid profiles associated with different inflammatory and infectious diseases.

Il existe une grande variabilité dans la réponse aux chimiothérapies anticancéreuses. Ses sources sont diverses: génétiques, physiologiques, comorbidités, médicaments associés, etc. La marge thérapeutique de ces médicaments étant généralement étroite, une telle variabilité peut avoir de graves conséquences: toxicités graves ou absence d'effet thérapeutique. Plusieurs approches pour adapter individuellement les posologies ont été proposées: a priori (basées sur l'information génétique, la taille corporelle, les fonctions d'élimination, etc.) et a posteriori (sur les informations de mesures d'exposition au médicament et/ou effets). La modélisation à effets-mixtes de la pharmacocinétique et de la pharmacodynamie (PK-PD), combinée avec une estimation bayésienne des effets individuels, est la meilleure méthode pour individualiser des schémas posologiques a posteriori. Dans cette thèse, une nouvelle approche pour ajuster les doses sur la base des prédictions données par un modèle pour les observations catégorielles de toxicité a été développée et explorée par simulation. Les aspects plus techniques concernant l'estimation des paramètres individuels ont été analysés pour déterminer les facteurs de bonne performance de la méthode. Ces travaux étaient basés sur l'exemple du syndrome mains-pieds induit par la capécitabine dans le traitement du cancer colorectal. Une revue des modèles pharmacodynamiques de données discrètes (catégorielles, de comptage, de survie) a été effectuée. Enfin, des analyses PK-PD de l'hydroxyurée dans le traitement de la drépanocytose ont été réalisées pour comparer des différentes posologies et déterminer les modalités optimales de suivi du traitement / There is high variability in response to cancer chemotherapies among patients. Its sources are diverse: genetic, physiologic, comorbidities, concomitant medications, environment, compliance, etc. As the therapeutic window of anticancer drugs is usually narrow, such variability may have serious consequences: severe (even life-threatening) toxicities or lack of therapeutic effect. Therefore, various approaches to individually tailor treatments and dosing regimens have been developed: a priori (based on genetic information, body size, drug elimination functions, etc.) and a posteriori (that is using information of measurements of drug exposure and/or effects). Mixed-effects modelling of pharmacokinetics and pharmacodynamics (PK-PD), combined with Bayesian maximum a posteriori probability estimation of individual effects, is the method of choice for a posteriori adjustments of dosing regimens. In this thesis, a novel approach to adjust the doses on the basis of predictions, given by a model for ordered categorical observations of toxicity, was developed and investigated by computer simulations. More technical aspects concerning the estimation of individual parameters were analysed to determine the factors of good performance of the method. These works were based on the example of capecitabine-induced hand-and-foot syndrome in the treatment of colorectal cancer. Moreover, a review of pharmacodynamic models for discrete data (categorical, count, time-to-event) was performed. Finally, PK-PD analyses of hydroxyurea in the treatment of sickle cell anemia were performed and used to compare different dosing regimens and determine the optimal measures for monitoring the treatment