Les fractures de l'os temporal constituent une pathologie fréquente insuffisamment étudiée sur le plan biomécanique, et mal prise en charge sur le plan thérapeutique. Leur complexité biomécanique et leur polymorphisme clinique ont donc été analysés dans cette étude. Ainsi une base de données prospectives de patients pris en charge pour fractures temporales a été initiée afin d'évaluer les séquelles et leur impact sur la qualité de vie. Une étude expérimentale de traumatismes temporaux a été réalisée afin d'apporter des données dans la caractérisation biomécanique de l'os temporal. En complément, un modèle éléments finis d'os temporal a été developpé, et un traumatisme temporal a été simulé. La régénération du nerf facial traumatisé a été étudiée, et un effet thérapeutique de la vitamine D3 a été recherché par une étude expérimentale animale. Nos résultats montrent qu'une amélioration de la prévention des fractures temporales est nécessaire surtout par adaptation et utilisation des casques dans le cadre de la pratique du vélo. Cette prévention doit se reposer sur la caractérisation biomécanique des traumatismes temporaux par une double approche, expérimentale et numérique. La vitamine D3 augmente significativement la récupération fonctionnelle et la myélinisation dans un modèle animal de traumatisme du nerf facial. Cette étude ouvre la perspective d'essais cliniques. La fréquence des séquelles cochléo-vestibulaires invalidantes après fractures temporales et leur impact sur la qualité de vie montrent la nécessité d'un suivi des patients dans un cadre multidisciplinaire. / Temporal bone fracture is a frequent pathology insufficiently studied on terms of biomechanical, and poorly managed on terms of therapeutic. The biomechanical complexity and the clinical polymorphism of temporal bone trauma were analysed in this study. Our dynamic was to zoom from patient with temporal bone trauma to lesional process of temporal bone fracture. A prospective database of patients with temporal bone fracture was initiated to analyse sequelae and their impact on quality of life. An experimental study of temporal bone trauma was conducted to bring data in biomechanical characterization of temporal bone. In addition, a finite element model of the temporal bone was designed, and a lateral impact was simulated. The regeneration of traumatized facial nerve was studied, and a therapeutic effect of vitamin D3 (cholécalciférol) was evaluated with animal experimental study. Our results showed that an improvement of temporal fracture prevention is necessary by promoting the use of helmets and improvements in helmet design as part of cycling practice. This prevention must base on biomechanical characterization of temporal bone trauma with experimental and numerical approach. Vitamin D3 increases significantly functional recovery and myelination in an animal model of facial nerve trauma. It paves further the way for clinical trials. The frequency of cochleovestibular sequelae after temporal bone fracture and their impact on quality of life demonstrate the importance of, and the need for, on-going follow up with a multidisciplinary management.

Contexte : De nos jours, la survie à 5 ans des enfants atteints d’un cancer dépasse les 80% en France, ce qui correspond à plus de 50 000 adultes guéris d’un cancer pédiatrique, mais la prévalence des complications à long terme dépasse 60% après un suivi de 30 ans. Dans cette thèse, nous nous sommes intéressés à deux problème de santé distincts : l’un grave et mortel, qui est le risque de cancer secondaire du sein – l’autre, morbide, altérant la qualité de vie et multifactoriel, qui est le risque d’une petite taille à l’âge adulte. Méthodes : L’approche fut différente, essentiellement descriptive avec une analyse de terrain, puis interventionnelle avec la mise en place d’un programme national de dépistage dans une population ciblée pour le cancer du sein secondaire – et analytique avec élaboration d’un modèle de prédiction du risque pour le risque d’une petite taille à l’âge adulte. La population étudiée fut en majeure partie celle de la cohorte française FCCSS, qui sont des adultes guéris d’un cancer pédiatrique solide et traités avant 2000, à laquelle se sont associés quelques centres pour la partie sur le cancer du sein.Résultats : Peu de femmes guéries d’un cancer dans l’enfance et dont le traitement comportait entre autres de la radiothérapie bénéficiaient d’un dépistage (21,2% et 15,4% avec des examens radiologiques). Une proportion importante de carcinomes infiltrants étaient agressifs avec 29% de tumeurs triple négatives. Sur un plan interventionnel, le programme DeNaCaPST a débuté il y a 18 mois et a été confronté au problème du suivi, et de la transition de ces adultes guéris. Concernant le risque de petite taille adulte, nous avons pu préciser que de faibles doses de radiothérapie reçues par l’hypophyse étaient un facteur de risque significatif, que ce risque augmentait avec la dose, qu’un grand champ sur la colonne était également un paramètre important. Etre petit et être jeune au diagnostic du cancer pédiatrique étaient deux facteurs de risque supplémentaires. Par ailleurs, nous avons découvert l’impact de deux molécules de chimiothérapie de la famille des alkylants : le busulfan et la lomustine. Conclusion : Les cancers du sein secondaires rappellent ceux survenant chez les femmes ayant une mutation constitutionnelle BRCA (âge de survenue, incidence cumulée à 50 ans, agressivité des cancers, taux de bilatéralité), ce qui a justifié l’élaboration d’un programme national, inspiré de celui pour les femmes à haut risque du fait d’une mutation génétique pour que « à risque égale, un dépistage égal ». Le réseau de prise en charge nécessaire se met progressivement en place, nécessitant plusieurs amendements au programme. Concernant le risque de petite taille à l’âge adulte, d’autres études sont nécessaires pour confirmer nos découvertes. / Background: Today, the five-year survival rate of children with cancer in France is over 80%, which corresponds to more than 50,000 adults cured of pediatric cancer, but the prevalence of long-term complications exceeds 60% after a 30-year follow-up. In this thesis, we focused on two distinct health problems: one serious and fatal, which is the risk of secondary breast cancer - the other morbid, affecting quality of life and multifactorial, which is the risk of a small height in adulthood. Methods: The approach was different, essentially descriptive with field analysis, followed by intervention with the implementation of a national screening program in a targeted population for secondary breast cancer - and analytical with the development of a risk prediction model for small height risk in adulthood. The population studied was mainly that of the French FCCSS cohort, which are adults cured of childhood solid cancer and treated before 2000, with which some centres have joined for the breast cancer part. Results: Few women cured of childhood cancer and whose treatment included radiotherapy were screened (21.2% and 15.4% with radiological examinations). A significant proportion of infiltrating carcinomas were aggressive with 29% of triple negative tumors. On an intervention level, the DeNaCaPST program began 18 months ago and faced the problem of follow-up and transition of these survivors.Concerning the risk of small adult size, we were able to specify that low doses of radiotherapy received by the pituitary gland were a significant risk factor that this risk increased with the dose, that a large field on the spine was also an important parameter. Being small and being young at diagnostic of childhood cancer were two additional risk factors. In addition, we discovered the impact of two chemotherapy molecules from the alkylant family: busulfan and lomustine. Conclusion: Secondary breast cancers are reminiscent of those occurring in women with a BRCA constitutional mutation (age of onset, cumulative incidence at 50 years, aggressiveness of cancers, bilaterality rate), which justified the development of a national program, inspired by that for women at high risk due to a genetic mutation so that "equal risk, equal screening". The necessary care network is gradually being set up, requiring several amendments to the program. Regarding the risk of small height in adulthood, further studies are needed to confirm our findings.

5 SUMMARY Context: Acute methanol poisoning is a life-threatening condition. Methanol is metabolized in the organism to formaldehyde and than to formic acid, which inhibits cytochrome c oxidase in mitochondria and thus contributes to the development of oxidative stress. Aim: To study the role of oxidative stress in the pathogenesis of acute neuronal damage to the central nervous system (CNS), in the development of long-term sequelae of methanol poisoning and chronic neurodegenerative processes in the years following acute methanol exposure. Material and Methods: Methanol intoxication was confirmed analytically in 55 patients included in he d ; hei age a he ime f i ning a 46.7 3.6 ea (9 female and 46 male ). All a ien , together with 41 control subjects, were examined in a prospective longitudinal cohort study. At admission, during hospitalisation, and at regular intervals after discharge during the follow-up, the patients were sampled for serum concentrations of lipid oxidative damage markers 4-hydroxy-trans-2- hexenal (HHE), 4-hydroxynonenal (HNE), malondialdehyde (MDA), and 8-isoprostane, for nucleic acids oxidative damage markers 8-hydroxy-2 -deoxyguanosine (8-OHdG), 8-hydroxyguanosine (8- OHG), 5- (hydroxymethyl) uracil (5-OHMU), for proteins oxidative damage markers ortho-tyrosine (o- Tyr),...

Background: Post COVID-19 Condition (PCC, also known as long COVID and post-acute sequelae of COVID-19) is a major public health concern with severe and pervasive impacts on physical and mental health. PCC is highly heterogeneous and may manifest as different clusters of symptoms of varying intensity and duration. The etiology of PCC remains uncertain, though several underlying pathophysiological mechanisms, such as cellular damage, inflammatory cytokines, and a hypercoagulable state, are thought to contribute to PCC inception and trajectory. Examination of potential serological markers of PCC, accounting for clinical covariates, may yield emergent pathophysiological insights. Objectives: Primary objectives of this thesis are to 1) Identify key clinical and potential serological predictors of PCC; 2) Acquire clinical and serological data in a large-scale prospective observational study; 3) Assess relationships between PCC and serological markers, accounting for clinical covariates; 4) Systematically review evidence to date on primary observational studies comparing serological response between people with and without persistent symptoms post COVID-19 recovery; 5) Discuss persisting gaps in knowledge and data quality, and propose strategies for resolve. Methods: This thesis is framed around three core efforts: 1) The design of survey questions and study materials, recruitment of participants, and data collection in a large-scale prospective cohort study launched in 2020; 2) The assessment of relationships between pre-defined serological predictors and PCC, accounting for clinical covariates; and 3) A robust rapid review of PCC onset and phenotype as functions of serological markers. Expert opinion was sought to define serological predictors. Clinical predictors were defined a priori based on systematic reviews meeting AMSTAR 2 guidelines. Conclusions: To address objectives, we described efforts to collect clinical and serological data from a large-scale prospective cohort study; identify PCC-cases and infected-controls; assess associations between pre-defined serological predictors (IgG titres targeting SARS-CoV-2 spike (S), nucleocapsid (N), and receiver binding domain (RBD) antigens, and efficient neutralization) and PCC; and synthesized findings from an extensive rapid review on PCC as a function of serological markers. Our multivariate analysis using Stop the Spread Ottawa data is, to our knowledge, the first Canadian study to report the direction and magnitude of association between selected serological predictors (anti-IgG response to S, N, and RBD SARS-CoV-2 antigens, and neutralizing efficiency) and PCC status and impact on quality of life. Finally, we described five potential strategies which may improve the accessibility, quality, and amalgamation of data pertaining to PCC: 1) Fostering comparability between studies to enable synthesis of multiple datasets; 2) Advancing the characterization and consensus on PCC phenotypes; 3) Employing innovative modelling strategies that could potentially yield novel insights; 4) Promoting robust collaboration and knowledge sharing among research teams; and 5) Engaging people with lived experience at all stages of research.

Un nombre alarmant de personnes signalent une maladie persistante appelée COVID longue après leur infection par le virus SRAS-CoV-2. Il y a 650 million de cas de COVID-19 dans le monde, dont 10% de ces personnes développent des symptômes persistants. Parmi les symptômes observés, on remarque une fatigue profonde, de la myalgie, des troubles cognitifs, etc. Ces symptômes sont étonnamment similaires à ceux de l'encéphalomyélite myalgique (EM), une maladie chronique débilitante. L’EM est une maladie complexe souvent caractérisée par une fatigue profonde et le malaise après-effort. Environ 70% des patients atteints d'EM décrivent des épisodes d'infections virales comme élément déclencheur. Une autre maladie qui partage des symptômes similaires à l’EM est la fibromyalgie (FM). La FM est une autre maladie chronique et débilitante qui se caractérise par une douleur musculosquelettique et une sensibilisation centrale. Il n’existe toujours pas de traitement ni de test diagnostic à ce jour. Auparavant, nous avons découvert et validé onze microARN en tant que premier panel diagnostic pour l'EM et la FM. La majorité de ces petits ARN non codants participent à la régulation de gène, l'immunité et l'inflammation. Ce projet consiste à déterminer les trajectoires cliniques des personnes atteintes de la COVID longue à l’aide d’un nouveau test pronostic constitué de 11 miARN circulants permettant de différencier les diverses séquelles de la COVID longue. Par la suite, une recherche pan-génomique a permis d’établir une signature moléculaire plus précise pour chacun des six sous-groupes COVID longue. Nous proposons que les effets du virus SRAS-CoV-2 sur les microARN de l'hôte pourraient déclencher la persistance des symptômes de la COVID longue et que l’expression différentielle de certains microARN puissent contribuer au développement de différentes séquelles à long terme. Nous avons recruté des participants âgés de plus de 18 ans ayant été infectés par le virus SRAS- CoV-2, non-hospitalisés et présentant une COVID longue de plus de six mois et des sujets sains (groupe pré-pandemie) n’ayant pas reportés d’infection. L’analyse des symptômes a été réalisée à l’aide de trois questionnaires (SF-36, MFI-20, DSQ) complétés par tous les participants. Les niveaux d’expression de 11 microARN, précédemment identifiée dans l’EM, ont été mesurés par RT-qPCR dans des échantillons de plasma et la détermination des différentes trajectoires associées à des séquelles à long terme a été réalisée par analyse des composantes principales et validée par Random Forest Model (RFM). En stratifiant les patients selon leur signature de 11 miARN, nous avons évalué l’expression globale des 2549 miARN pour chaque séquelle et identifié de nouveaux miRNA spécifiques pour chacun des groupes à l’aide de la technologie microRNA array Agilent, une biopuce de la société Agilent. Nos données préliminaires nous ont permis d’identifier une signature moléculaire spécifique à chacune des séquelles de la COVID longue. Ces résultats nous permettrons de développer un nouveau test diagnostic basé sur les miRNA afin de prédire les conséquences à la suite de l’infection par le virus SRAS-CoV-2. / An alarming number of people are reporting a persistent illness called long COVID after their infection with the SARS-CoV-2 virus. There are an estimated 650 million cases of COVID-19 worldwide, with 10% of these people developing persistent symptoms. Among the symptoms observed, we notice profound fatigue, myalgia, cognitive disorders, etc. These symptoms are strikingly similar to those of myalgic encephalomyelitis (ME), a debilitating chronic disease. ME is a complex disease often characterized by profound fatigue and post-exertional malaise. Approximately 70% of ME patients describe episodes of viral infections as a trigger. Another disease that shares similar symptoms to ME is fibromyalgia (FM). FM is another chronic and debilitating disease that is characterized by musculoskeletal pain and central sensitization. There is still no treatment or diagnostic test to date. Previously, we discovered and validated eleven microRNAs as the first diagnostic panel for ME. Most of these small non-coding RNAs participate in gene regulation, immunity and inflammation. The objective of this project was to build a new diagnostic test to differentiate the various after-effects of long COVID using miRNAs. This project consists of determining the clinical trajectories of people with long COVID using a new prognostic test made up of 11 circulating miRNAs making it possible to differentiate the various after-effects of long COVID. Subsequently, a pan-genomic search made it possible to establish a more precise molecular signature for each of the six long COVID subgroups. We recruited participants aged over 18 years who had been infected with the SARS-CoV-2 virus, who were not hospitalized and had symptoms of long COVID for more than six months and healthy subjects (pre-pandemic group) who had not reported infection. The analysis of symptoms was carried out using three questionnaires (SF-36, MFI-20, DSQ) completed by all participants. The expression levels of 11 microRNAs previously identified in EM, from plasma samples were measured by RT-qPCR and the determination of the different trajectories associated with long-term sequelae was carried out by principal component analysis (PCA) and validated by Random Forest Model (RFM). By stratifying patients according to their signature of 11 miRNAs, we evaluated the overall expression of the 2549 miRNAs for each sequelae and identified new miRNAs specific for each of the groups using the Agilent microRNA array technology, a biochip from the company Agilent. Our preliminary data allowed us to identify a molecular signature specific to each of the after-effects of long COVID. These results will allow us to develop a new diagnostic test based on miRNAs in order to predict the consequences following infection by SARS-CoV-2 viruses.

Made available in DSpace on 2014-07-29T15:28:53Z (GMT). No. of bitstreams: 1 Tese de Doutorado- Lilian de Fatima Guedes de Amorim.pdf: 270685 bytes, checksum: 1597019ea89b336fa3fd7d7f3038c027 (MD5) Previous issue date: 2010-05-14 / Aim: Determine the prevalence of dental injuries (TDI) in primary teeth and the influence of predisposing clinical factors on their occurrence and analyze the prevalence of developmental sequelae in permanent teeth and determine the association between these sequelae and age, gender, injury type, injury recurrence and sequelae in primary teeth, in children under 7 years old who sought treatment at a private pediatric dental clinic in Goiânia, Goiás, over a period of 15 years. Methodology: A retrospective study which analyzed 2725 dental records. Three hundred and eight dental records with 412 traumatized primary teeth were selected. This constituted the sample used to determine the prevalence of injuries in primary teeth and their association with predisposing clinical factors (Article 1); of these, 241 primary teeth (148 dental records) were followed up until the eruption of the permanent successor teeth. This was the sample for the study of sequelae in primary and permanent teeth (Article 2). All the data were statistically analyzed using the frequency distribution, chi-square test and logistic regression analysis. The level of significance was 5%. Results: The prevalence of dental injuries was 11.3%, with the greatest frequency in the 13-36 month age group. There was no statistical difference between genders. The most frequently affected teeth were the maxillary central incisors (83.3%). The main location of inuries was the home (43.5%), with falls the most frequent cause. The prevalence of dental TDI was similar in all months of the year. The most common type of TDI was subluxation (35.1%). Clinical factors overjet > 3 mm and negative overbite showed a significant difference between the trauma and no-trauma groups. In 46.5% of the cases, treatment was sought in the first 24 hours after the trauma. The most prevalent type of treatment was follow-up (51.0%). Color alteration of crown (26.0%) was the most frequent sequelae for primary teeth. The sequelae found in permanent teeth were enamel discoloration and/or hypoplasia (74.1%) and eruption disorder (25.9%). No significant relation was found between sequelae in permanent teeth and sequelae in primary teeth, type of trauma, gender or TDI recurrence. The only statistical difference was found in relation to the child s age at the moment of trauma. Conclusion: Immediate treatment of the child with a TDI, associated with the efficient diagnosis and long-term follow-up are decisive for the success of treatment. New research to help establish an effective protocol for the treatment of TDIs in primary teeth and the implementation of strategies that prepare professionals to treat TDIs and to educate the public about prevention and treatment of these lesions is necessary.. / Objetivo: Determinar a prevalência dos traumatismos em dentes decíduos,verificar a existência de associação entre os mesmos e os fatores predisponentes bucais e averiguar a ocorrência de sequelas nos dentes decíduos e nos dentes permanentes sucessores em crianças de 0 a 6 anos que buscaram atendimento numa clínica privada de odontopediatria da cidade de Goiânia-Go, Brasil, num período de 15 anos. Metodologia: Estudo retrospectivo analisando 2725 prontuários, tendo sido selecionados 308 prontuários com 412 dentes decíduos traumatizados, que constituiram a amostra utilizada para determinar a prevalência dos traumatismos em dentes decíduos e sua associação com fatores predisponentes bucais (Artigo 1); destes, 241 dentes decíduos (148 prontuários) foram acompanhados até a erupção do dente permanente sucessor representando a amostra para estudo das sequelas em dentes decíduos e permanentes (Artigo 2). A análise estatística dos dados foi realizada por distribuição de frequências, teste de qui-quadrado e análise de regressão logística. Resultados: A prevalência dos traumatismos foi de 11,3%, com maior freqüência na faixa etária de 13 36 meses (P = 0,001). Não houve diferença estatística entre os gêneros (P = 0,03). Os dentes mais frequentemente afetados foram os incisivos centrais superiores (83,3%). O domicílio foi o principal local de ocorrência (43,5%), sendo a queda causa mais comum (50,3%). A prevalência dos traumatismos dentários ao longo do ano mostrou-se semelhante em todos os meses. O tipo de traumatismo mais comum foi a subluxação (35.1%). Em relação aos fatores bucais, o overjet > 3 mm e o overbite negativo mostraram diferença significante entre os grupos com e sem traumatismo. Em 46,5% dos casos, a procura por atendimento ocorreu nas primeiras 24 horas. O tipo de tratamento mais prevalente foi o acompanhamento (51,0%). A alteração de cor da coroa (26,0%) foi a sequela mais observada para o dente decíduo. As sequelas observadas nos dentes permanentes foram a descoloração do esmalte e/ou hipoplasia (74,1%) e o distúrbio de erupção (25,9%). Não foi encontrada relação de significância entre as sequelas nos dentes permanentes e as sequelas nos dentes decíduos, os tipos de traumatismo, o gênero e a recorrência de TDI. Diferença estatística foi observada apenas em relação à idade da criança no momento do traumatismo. Conclusão: O atendimento imediato da criança com TDI, associado ao diagnóstico correto e acompanhamento eficiente a longo prazo são decisivos para o sucesso do tratamento. São necessários maiores esforços na realização de novas pesquisas que auxiliem no estabelecimento de protocolo eficaz de tratamento das TDIs em dentes decíduos e na implementação de estratégias que preparem os profissionais para atender as TDIs e eduquem a população para prevenção e procura de atendimento destas lesões.

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Background: Methanol poisoning is a life-threatening condition which induces acute toxic optic neuropathy with possible long-term visual sequelae in survivors. Aim: To study the prevalence, character, dynamics, and key determinants of chronic morphological and functional visual pathway changes during 4 years after methanol-induced optic neuropathy. Methods: A total of 55 patients with confirmed methanol poisoning with mean age 46.7 ± 3.6 years (46 males and 9 females), and 41 controls were included in this prospective longitudinal cohort study. The patients were examined 4.9 ± 0.6, 25.0 ± 0.6, and 49.9 ± 0.5 months after discharge. The following tests were performed: visual evoked potential (VEP), optical coherence tomography with retinal nerve fiber layer (RNFL) measurement, brain magnetic resonance imaging (MRI), complete ocular examination, biochemical tests, and apolipoprotein E (ApoE) genotyping. Results: Of 42/55 patients with all three consecutive examinations, abnormal RNFL thickness was registered in 13 (31%) and chronic axonal loss during the observation period was found in 10 (24%) patients. The risk estimate of chronic global RNFL loss for arterial blood pH<7.3 at admission was: 11.65 (1.91-71.12; 95% CI) after adjusting for age and sex. The patients with chronic axonal degeneration demonstrated...

No description available.