La leishmaniose viscérale (LV) à Leishmania infantum est une zoonose qui sévit notamment autour du bassin méditerranéen. Elle atteint principalement le chien, qui représente le réservoir de l’infection. Chez l’homme, si la forme patente est rare, il existe de nombreux sujets porteurs asymptomatiques dans les zones d’endémies. Au cours de ce travail, nous avons abordé 3 problématiques importantes concernant la LV. La première problématique à porté sur l’importance du portage asymptotique humain à L. infantum au niveau mondial et de ses conséquences. Notre étude montre que la fréquence de porteurs asymptomatiques dépend des tests de détection utilisés et des populations étudiées et qu'elle peut atteindre jusqu'à 70% dans certaines zones d’endémies. Elle montre également que la transmission du parasite par don de sang est peu probable et que le rôle du portage asymptomatique comme réservoir n’est pas encore démontré. Elle souligne également la nécessité de détecter le portage asymptotique chez le donneur et le receveur de greffe et le risque de développement de la forme patente chez l’asymptomatique déprimé. La deuxième problématique porte sur le développement de procédés vaccinaux contre L. infantum par voie endonasale chez la souris BALB/c. Nos résultats montrent que la vaccination par voie nasale induit de manière reproductible une immunité systémique, cellulaire et humorale et que la protection dépend de paramètres tels que la nature et la dose des antigènes utilisées et la présence d’adjuvant tels que le CNF et le MPL. Enfin, la sélection d’une infection intradermique permet d’améliorer significativement la protection.La troisième partie porte sur la mise au point de modèles expérimentaux d’infection basés sur l’utilisation de parasites recombinants exprimant le gène de la luciférase. Nos travaux montrent que l’utilisation de tels outils permet de suivre l’infection à L. infantum in vitro, ex vivo et in vivo chez la souris BALB/c et de ce fait sont utiles pour le criblage de médicaments comme la miltéfosine et potentiellement pour tester des préparations vaccinales. Cet outil nous a permis en outre de révéler un nouveau site de prolifération parasitaire. / Visceral leishmaniasis (VL) caused by L. infantum is a zoonotic disease present in the Mediterranean basin (LVM). Dogs represent the reservoir and the main victim of the disease. In man, besides a limited number of cases of patent VL, a great number of infection remains asymptomatic. In this report, three different aspects of VL have been studied.First, the prevalence and the consequences of asymptomatic carriers of L. infantum was evaluated worldwide. The prevalence of asymptomatic carriers depends on the selected detection tests and the studied population and can reach 70% in some endemic zones. Our study also shows that the role of asymptomatic carriers as reservoirs remains to be established. However, in immunocompromised asymptomatic carriers such as HIV positive individuals, infection can be reactivated.Second, we developed vaccine trials against L. infantum in the BALB/c mouse model using the nasal route. Nasal immunization with Leishmania antigens induces cellular and humoral systemic immunity. Protection depends on various parameters including the nature of antigens, the dose and the presence of adjuvants such as CNF or MPL. Protection was improved when mice were challenged by ID route.Third, we set up experimental models of infection based on the use of recombinant parasites expressing the luciferase gene. These tools allow us to trace the infection in vitro, ex vivo and in vivo and therefore are useful to evaluate the efficiency of drugs and potentially to assess vaccine preparations. Bioluminescence imaging was also useful to evidence a new potential site of parasite proliferation.

Made available in DSpace on 2015-07-22T20:49:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-12-31. Added 1 bitstream(s) on 2015-08-11T03:25:33Z : No. of bitstreams: 1 Publico-0144.pdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A cirurgia dos tumores selares é tradicionalmente um campo de atuação dos neurocirurgiões. Contudo, desde a retomada da abordagem transeptaltransesfenoidal para acessar a sela túrcica, na década de sessenta do século passado, os otorrinolaringologistas têm exercido importante parceria neste procedimento. A divulgação da cirurgia endoscópica nasossinusal na otorrinolaringologia criou o interesse pela sua aplicação na cirurgia da região selar. a uso do endoscópio permitiu acesso transnasal direto ao seio esfenoidal sem a necessidade de descolamento do septo nasal, com menor desconforto para o paciente, além de morbidade pós-operatória inferior aos métodos tradicionais. Objetivo: O objetivo deste trabalho foi verificar as dificuldades técnicas, intercorrências e complicações pós-operatórias, no manejo otorrinolaringológico do acesso transnasal endoscópico à sela túrcica. Método: Foram analisados retrospectivamente os prontuários e imagens de arquivo de 159 pacientes submetidos à cirurgia da região selar entre março de 2001 e dezembro de 2005, na Universidade Federal de São Paulo / Escola Paulista de Medicina. Foram incluídos neste estudo 91 pacientes submetidos a um total de 95 procedimentos por via transnasal endoscópica. Resultados: Foi possível a realização da técnica endoscópica transnasal em todos os pacientes estudados, independente de idade, presença de variações anatômicas, características e etiologia do tumor, e antecedente de cirurgia prévia. Não houve necessidade de remoção da concha média ou correção de desvios septais para realização do procedimento cirúrgico em nenhum dos casos. A principal intercorrência foi a abertura do diafragma selar durante a remoção de tumores, causando fístula liquórica intra-operatória em 13,68 por cento dos casos. As complicações pós-operatórias encontradas foram: sangramento nasal (8,42 por cento), fístula liquórica (8,42 por cento), e meningite (2,19 por cento). Conclusão: O acesso endoscópico transnasal aos tumores selares pôde ser realizado de forma minimamente invasiva, preservando-se as estruturas nasais nos 95 procedimentos estudados, independente da idade do paciente, características e etiologia do tumor. / Sellar tumor surgery is traditionally a neurosurgeon´s field. However, since the renewed interest in the transseptal-transsphenoidal approach to access the sellar region in the sixties, otolarynngologists have played an important partnership in this procedure. Divulging of endoscopic sinus surgery in otolaryngology created an interest in its application in sellar region surgery. The use of endoscopes allowed a direct transnasal approach to the sphenoidal sinus without need of dissection of the septal mucosa, with less post-operative discomfort and morbidity inferior to that of traditional methods. Objective: The objective of this work was to verify the technical difficulties, intercurrences and post-operative complications in the otolaryngological handling of the endoscopic transnasal approach to the sellar region. Method: The analisys comprised both the files and archive images of 159 patients submitted to sellar region surgery between march 2001 and December 2005, at Universidade Federal de São Paulo / Escola Paulista de Medicina. 91 patients submitted to a total of 95 endoscopic transnasal procedures were included in this study. Results: It was possible to apply the endoscopic transnasal tecnique in all studied patients, independent of age, anatomical variations, tumor characteristics and etyology, and previous surgery history. There was no need of middle turbinate removal, or septal deviations corrections for the surgical procedure in any of the cases. The main intercurrence was the opening of the sellar diaphragm during the removal of the the tumors, causing intra-operative CSF leak in 13.68% of the cases. The post-operative complications encountered were: nasal bleeding (8.42%), CSF leak (8,42%), and meningitis (2.19%). Conclusion: Transnasal endoscopic approach to sellar tumors was done in a minimally invasive form, preserving the nasal structures in the 95 studied procedures, independently of patient age, tumor characteristics and etyology. / TEDE / BV UNIFESP: Teses e dissertações

Das vom endonasalen Neuroepithel der Rima olfactoria entstandenen Aesthesioneuroblastom gehört zu den seltenen malignen Tumoren der Rhinobasis. Eine generelle Therapieempfehlung für die Behandlung dieses Tumors gibt es nicht, da bis heute etablierte, durch umfassende onkologische Studien untermauerte diagnostische und therapeutische Standards fehlen und der klinische Verlauf oft unberechenbar ist. Die Aufgabe der vorliegenden Arbeit bestand in der Überprüfung des chirurgischen Konzeptes bei der Therapie von Aesthesioneuroblastomen und in der erstmaligen molekularzytogenetischen Charakterisierung von Aesthesioneuroblastomen. Dazu wurden 18 Patienten mit Aesthesioneuroblastomen, die im Zeitraum zwischen 1988 und 2001 in der HNO-Klinik (17 Patienten) sowie in der Neurochirurgischen Klinik des Klinikums Fulda operiert wurden, untersucht. Die daraus resultierenden 22 Aesthesioneuroblastome wurden alle mit Hilfe der Vergleichenden Genomischen Hybridisierung (CGH) analysiert. Nach derzeitigem Kenntnisstand besteht die optimale Therapie der Aesthesioneuroblastome in der chirurgischen Resektion des Tumors mit nachfolgender stereotaktischer Bestrahlung. Für die operative Sanierung der Aesthesioneuroblastome und auch anderer Malignome der vorderen Schädelbasis ist das nachfolgende neue Fuldaer Konzept empfehlenswert: 1) Endonasale Resektion, wenn keine intrakranielle bzw. orbitale Tumorinfiltration vorliegt; 2) Subfrontaler Zugang, bei Infiltration des Gehirns; 3) Midfacial degloving, bei weit lateraler Tumorausbreitung; 4) Laterale Rhinotomie nur bei der Notwendigkeit der simultanen Exenteratio orbitae (bei orbitaler Tumorinfiltration). Aesthesioneuroblastomen sind durch ein typisches genetisches Muster charakterisiert, das Deletionen im Bereich der chromosomalen Arme 1p, 2q, 3p/q, 4p/q, 5p/q, 6q, 8p/q, 9p, 10p/q, 11p, 12q, 13q, 18q und 21q sowie Amplifikationen der Chromosomen 1p, 7q, 9q, 11q, 14q, 16p/q, 17p/q, 19p/q, 20p/q und 22p/q umfasst. Die beim Aesthesioneuroblastom häufigen DNA-Verluste im Bereich der chromosomalen Banden 1p21-p31 scheinen mit der Prognose dieser Tumoren assoziiert zu sein. Die Tumoren aller in der vorliegenden Studie am Malignom verstorbenen Patienten zeigten eine Kombination aus 1p21-p31-Deletion, dem Vorliegen des klinischen Stadiums C oder D sowie gleichzeitig einer schlechten Differenzierung (Grad III oder IV). Vermittels der CGH ist es möglich, eine klonale Zuordnung von Metastasen bzw. auch Rezidiven zu ihren primären Aesthesioneuroblastomen vorzunehmen. Die vorliegende Arbeit zeigt nicht nur neue Ansätze in der chirurgischen Therapie von Aesthesioneuroblastomen sondern auch die erste umfassende molekularzytogenetische Analyse dieser Tumorentität, auf dem Weg, das biologische Verhalten dieser Malignome genauer charakterisieren zu können. / Esthesioneuroblastoma (ENB) is a very rare malignant neoplasm arising from the olfactory epithelium which is recognized for its propensity for local recurrence and distant dissemination. Therapeutic management approaches for this neoplasm lack uniformity. The present study describes therapeutic management in ENB: Complete surgical resection combined with adjuvant stereotactic radiation therapy. Thereby, a new surgical concept is recommended: 1) Endonasal approach in cases without tumor infiltration of the orbit and/or the brain; 2) Subfrontal approach in cases with extended tumor infiltration of the intradural space or of the brain; 3) Midfacial degloving in cases with far lateral tumor spread, particularly fossa pterygoidea or pterygopalatina; 3) Lateral rhinotomy in all cases where an exenteratio orbitae is needed. Secondarily, the study characterizes the specific chromosomal alterations of ENB analyzed using Comparative Genomic Hybridization (CGH). ENB show frequently deletions of chromosoms 1p, 2q, 3p/q, 4p/q, 5p/q, 6q, 8p/q, 9p, 10p/q, 11p, 12q, 13q, 18q and 21q as well as DNA gains of chromosoms 1p, 7q, 9q, 11q, 14q, 16p/q, 17p/q, 19p/q, 20p/q and 22p/q. Deletions of the chromosomal region 1p21-p31 could be associated with bad prognosis since the tumors of all patients who died were of stage C or D and grade III or IV, and showed 1p21-p31 deletions. The analysis of primary ENB and their corresponding metastases shows clonality by a high concordance of alterations between the tumor pairs. For the first time, this study presents the specific chromosomal alterations of ENB pathogenesis and progression.