Résumé : Depuis 2002, une augmentation des taux d’issues défavorables de l’infection à Clostridium difficile (ICD) a été attribuable à l’émergence de la souche NAP1/BI/R027. Il est indispensable d’identifier les facteurs de risque de développer des complications (ICDc) et des récidives (ICDr), et de pouvoir les prédire lors du diagnostic afin d’optimiser le traitement. Le projet de recherche a comme objectifs: i) l’identification des facteurs de risque pour le développement d’ICDc et ICDr et ii) le développement et la validation d’un outil de prédiction à partir de variables mesurées dans les 48h du diagnostic d’une ICD. Méthode: Une cohorte multicentrique prospective de patients adultes hospitalisés pour une ICD. Les données suivantes ont été recueillies: i) démographiques; ii) comorbidités; iii) traitements et procédures reçus dans les 2 mois avant le diagnostic; iv) paramètres cliniques, vi) biochimiques, hématologiques et vii) microbiologiques (ribotypage). Un suivi à 30 et 90 jours a été effectué. Les facteurs de risque ont été identifiés par des modèles multivariés de régression logistique et d'analyse de survie. La méthode de validation croisée a été utilisée pour la dérivation et la validation interne. Différents modèles ont été comparés selon l’aire sous la courbe ROC (ASC), l’erreur de prédiction (EP) et les paramètres de performance. Un score prédictif a été dérivé à partir du modèle optimal. Résultats: Au total, 1380 patients ont été inclus dont 96% suivis 90 jours. Une ICDc a été observée chez 8% et une ICDr chez 26%. La souche R027 représentait 52% des souches caractérisées. Les ICDc sont associées à un âge ≥80 ans, un rythme cardiaque >90/min, un rythme respiratoire >20/min, globules blancs (GB) <4 et ≥20×10[indice supérieur 9]/L, albumine sérique <25 g/L, urée sérique >7 mmol/L, et CRP ≥150 mg/L. Les ICDr sont associés à l'âge ≥ 65 ans, à l’exposition à des macrolides et/ou clindamycine, CRP ≥150 mg/L, R027, et une hospitalisation ≥14 jours suivant l'ICD. Un sous-groupe de 1038 cas complets a été utilisé pour la modélisation prédictive. Le modèle optimal contenait l’âge ≥80 ans, GB ≥12×10[indice supérieur 9]/L, albumine sérique <26 g/L et urée sérique >7 mmol/L, avec une ASC de 0,84 et une EP de 6%. Un score variant entre 0 et 17 points a été construit. En validation, un score >10 points présentait une sensibilité de 50% (IC[indice inférieur 95]% = 28-72), une spécificité de 85% (81-89), une valeur prédictive positive de 17% (7-27) et une valeur prédictive négative de 96% (94-99). Conclusions: En utilisant une large cohorte prospective multicentrique et plusieurs étapes de modélisation prédictive et de validation interne, nous avons identifié les facteurs associés aux ICDc et ICDr et dérivé un score prédictif des ICDc ayant une performance acceptable. Au moment du diagnostic de l’ICD, ces facteurs sont à considérer pour envisager le traitement le plus optimal afin de prévenir ces issues. / Abstract : A significant increase in Clostridium difficile infection (CDI) unfavourable outcomes was observed since 2002 and was associated with the emergence of the strain NAP1/BI/R027. Identifying patients at high risk of developing complications (cCDI) and recurrences (rCDI), and predicting these outcomes early in the course of illness could improve clinical decision-making. The main objectives of this research were to: i) identify risk factors for cCDI and rCDI, and ii) develop and validate a clinical prediction rule for cCDI using predictors measured within 48h of CDI diagnosis. Methods: Adult in patients with confirmed CDI diagnosis in 10 acute care hospitals, were enrolled in a prospective cohort. Data at enrolment were collected : demographics, underlying illnesses, past medical and drug history (two months prior to CDI), clinical signs, blood tests, and C. difficile strain type. A follow-up was completed on day 30 and 90 after enrolment. Risk factors were identified by multivariate logistic regression and survival analyses. Split-sample technique was used for training and validation sets. Several predictive models were derived and assessed in both sets by AUC/ROC, prediction error (PE), and performance parameters. A predictive score was built using the optimal predictive model. Results: A total of 1380 patients were enrolled and 96% had 90 days follow -up. cCDI was observed in 8% and rCDI in 26%. R027 was identified in 52% of patients. Age ≥80 years, heart rate >90/min, respiratory rate >20/ min, white cell count <4 or ≥20 × 109/L, albumin <25 g/L, blood urea nitrogen >7 mmol/L, and C-reactive protein (CRP) ≥150 mg/L were independently associated with cCDI. Age ≥65 years, increased CRP, expos ure to macrolides/clindamycin, R 027, and prolonged hospital stay were associated with rCDI. A sub-group of 1038 complete cases was used for predictive modelling. In the training set, the optimal model with 6% PE and AUC 0.84 included age≥80, WBC≥12x10 [superscript 9]/L, BUN>7 mmol/L, and serum albumin <26 g/L. A predictive score was built with minimum 0 and maximum 17 points. A score >10 points showed 50% sensitivity (95%CI, 28-72), 85% specificity (81-89), 17% (7-27) positive predictive value, and 96% (94-99) negative predictive value. Conclusion: Through a large multicenter prospective cohort and multiple modelling approached, independent risk factors of complications and recurrence of CDI were identified. We derived a predictive score that included easily available meas ures at the bedside and showed acceptable performance. At time of CDI diagnosis, these predictors could be used by clinicians to identify patients at higher risk and adjust for the most optimal treatment that could prevent unfavourable outcomes.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Medulloblastomas are the most frequent malignant childhood brain tumors, arising in the posterior fossa of children. The overall 5-year survival is 70%, although children often suffer severe long-term side effects from standard medical care. To improve progression-free survival and quality of life for these children, finding new therapeutic targets in medulloblastoma is imperative. Medulloblastoma is divided in to four molecular subgroups (WNT, SHH, Group 3 and Group 4) based on key developmental pathways essential for the initiation and maintenance of tumor development. The MYC family of proto-oncogenes regulates cell proliferation and differentiation in normal brain. Aberrant expression of MYC proteins occurs commonly in medulloblastoma. Our studies on Group 3 medulloblastoma identify the transcription factor SOX9 as a novel target for the E3 ubiquitin ligase FBW7, and show that increased stability of SOX9 confers an increased metastatic potential in medulloblastoma. Moreover, SOX9-positive cells drive distant recurrences in medulloblastoma when combining two regulatable TetON/OFF systems. MYCN depletion leads to increased SOX9 expression in Group 3 medulloblastoma cells, and the recurring tumor cells are more migratory in vitro and in vivo. Segueing to treatment of medulloblastoma, we show that BET bromodomain inhibition specifically targets MYC-amplified medulloblastoma cells by downregulating MYC and MYC-transcriptional targets, and that combining BET bromodomain- and cyclin-dependent kinase- inhibition improves survival in mice compared to single therapy. Combination treatment results in decreased MYC levels and increased apoptosis, and RNA-seq confirms upregulation of apoptotic markers along with downregulated MYC target genes in medulloblastoma cells. This thesis addresses novel findings in transcription factor biology, recurrence and treatment in Group 3 medulloblastoma, the most malignant subgroup of the disease.

The work presented in this dissertation contributes to the field of programming lan- guage design and implementation for stream processing applications. There is a fast-expanding domain of stream processing applications which demand processing high-volume streams quickly and often in real time. Examples include analysis and synthesis of audio, video and other digital media, sensor array signals, real-time phys- ical simulation etc. High performance is crucial in this domain. When choosing between available programming methods, the programmer often chooses one that maximizes performance while sacrificing ease of programming, code comprehension, maintainability and reusability. This work contributes towards improving the state of the art by jointly maximizing these aspects. High-volume streams are often most naturally represented as multi-dimensional arrays with one infinite dimension representing time. Algorithms working with such streams are typically defined mathematically using recurrence equations. A pro- gramming language is presented in this dissertation which enables an almost literal translation of such mathematical definitions to computer programs. The language also supports powerful facilities for abstraction and code reuse such as polymorphic and higher-order functions. Together, these features enable a more natural expression of algorithms and improve code modularity and reusability. A major contribution of this dissertation is the compilation of the proposed lan- guage in the polyhedral framework, specifically targeting general-purpose multi-core processors. This framework provides powerful means of analysis and transformations of computations on multi-dimensional arrays, which enables data-locality optimiza- tions essential for high performance on general-purpose processors with deep memory hierarchies. The benefit of this framework for computations on finite arrays has been extensively explored. However, this dissertation presents essential extensions that enable the application of state-of-the-art optimizations in this framework on infinite arrays representing streams. / Graduate

Orientador: José Carlos Bruni / Banca: Clélia Aparecida Martins / Banca: Franklin Leopoldo e Silva / Resumo: Esta pesquisa tem como objetivo analisar a construção filosófica de Friedrich Nietzsche acerca do sentido de sabedoria trágica, desde sua formulação no estudo sobre a tragédia até os escritos finais no que concerne ao trágico. Nesse intuito, busca-se aprofundar o estudo dos elementos tratados por Nietzsche ao longo de sua produção filosófica, passando pelos conceitos apolíneo e dionisíaco, a partir dos quais tratará do nascimento da arte trágica e do enfrentamento do pessimismo, e retratando as modificações sofridas por seu pensamento ao distanciar-se da concepção metafísica de arte e voltar-se a um projeto pelo qual enaltece a força dionisíaca em oposição ao conhecimento moral e metafísico. Desse modo, serão analisados os caminhos percorridos por esta filosofia trágica, que encontrará sua máxima na concepção do eterno retorno e na força dionisíaca de afirmação da existência / Abstract: This research aims to analyse the philosophical construction of Friedrich Nietzsche specifically the tragic wisdom's meaning, since when it was formulates in the study of the tragedy until the final writings in regard to the tragic. To this end, the focus was to analyse with details the study of elements that are used by Nietzsche throughout his philosophical production, through with the apollonian and dionysian's concepts, from which will deal with the begin of the tragic art and the confront of the pessimism, and reflecting the changes suffered from his thought that is to be distant from the metaphysical conception of art and to be with a project that extols the dionysian force in opposition to the moral and metaphysical knowledge. Thus, it will be analysed the paths that are taken by this tragic's philosophy, and that will find its maximum in the conception of eternal recurrence and Dionysian's power of life's affirmation / Mestre

Rädsla för recidiv är vanligt förekommande bland patienter som genomgått cancersjukdom. Det är viktigt att sjuksköterskan har kunskaper om hur rädslan för recidiv kan påverka hälsan för att kunna stödja dessa patienter på ett tillfredsställande sätt. Syftet med litteraturstudien var att beskriva patienters upplevelser av rädslan för recidiv efter genomgången cancersjukdom. Tio resultatartiklar som motsvarade studiens syfte granskades och sammanställdes. Genom att kondensera innehållet framkom i databearbetningen tre kategorier som bildade resultatet: Rädsla för recidiv underhålls av återkommande påminnelser, Rädsla för recidiv skapar emotionell och existentiell sårbarhet och Rädsla för recidiv påverkar livskvalitén. I litteraturstudiens resultat identifierades flera faktorer som utlöste patienters rädsla för recidiv. Dessa faktorer var uppföljningsbesök, media, historier om andras cancersjukdom och kroppsliga förändringar. I resultatet framkom också patienters tankar och känslor som gav dem en emotionell och existentiell sårbarhet. Rädslan för recidiv påverkade i hög utsträckning patienternas livskvalité och hade negativ inverkan på deras hälsa. Det är av stor vikt att sjuksköterskan uppmärksammar faktorer hos patienter som kan associeras med rädsla för recidiv och mer forskning krävs om hur sjuksköterskan kan stödja dessa patienter på ett adekvat sätt. / Fear of recurrence is a common issue among patients who have had cancer. It is important that the nurse has knowledge of how the fear of recurrence can affect healthin order to be able to support these patients in a satisfactory manner. The purpose of the literature study was to describe patients' experiences of the fear of recurrence after having cancer.Ten articles that matched the purpose of the study were reviewed and compiled. By condensing the content, the data processing revealed three categories that formed the result: Fear of recurrence is maintained by recurring reminders, fear of recurrence creates emotional and existential vulnerability andfear of recurrence affects the quality of life. In the results of the literature study, several factors were identified that triggered patients' fear of recurrence. These factors were follow-up visits, media, stories of other people's cancer and bodily changes. The result also showed patients' thoughts and feelings that gave them an emotional and existential vulnerability. The fear of recurrence greatly affected the patients' quality of life and had a negative impact on their health. It is of great importance that the nurse draws attention to factors in patients who can be associated with fear of recurrence and more research is needed on how the nurse can adequately support these patients.

Dans ce travail, nous étudions les propriétés statistiques de certains systèmes dynamiques déterministes et stochastiques. Nous nous intéressons particulièrement aux valeurs extrêmes et à la récurrence. Nous montrons l’existence de Lois pour les Valeurs Extrêmes(LVE) et pour les Statistiques des Temps d’Entrée (STE) et des Temps de Retour (STR) pour des systèmes avec décroissance des corrélations rapide. Nous étudions aussi la convergence du Processus Ponctuel d’Evènements Rares (PPER).Dans la première partie, nous nous intéressons aux systèmes dynamiques déterministes, et nous caractérisons complètement les propriétés précédentes dans le cas des systèmes dilatants. Nous montrons l’existence d’un Indice Extrême (IE) strictement plus petit que 1 autour des points périodiques, et qui vaut 1 dans le cas non-périodique, mettant ainsi en évidence une dichotomie dans la dynamique caractérisée par l’indice extrême. Dans un contexte plus général, nous montrons que le PPER converge soit vers une distribution de Poisson pour des points non-périodiques, soit vers une distribution de Poisson mélangée avec une distribution multiple de type géométrique pour des points périodiques. De plus, nous déterminons explicitement la limite des PPER autour des points de discontinuité et nous obtenons des distributions de Poisson mélangées avec des distributions multiples différentes de la distribution géométrique habituelle. Dans la deuxième partie, nous considérons des systèmes dynamiques stochastiques obtenus en perturbant de manière aléatoire un système déterministe donné. Nous élaborons deux méthodes nous permettant d’obtenir des lois pour les Valeurs Extrêmes et les statistiques de la récurrence en présence de bruits aléatoires. La première approche est de nature probabiliste tandis que la seconde nécessite des outils d’analyse spectrale. Indépendamment du point choisi, nous montrons que l’IE est constamment égal à 1 et que le PPER converge vers la distribution de Poisson standard. / In this work, we study the statistical properties of deterministic and stochastic dynamical systems. We are particularly interested in extreme values and recurrence. We prove the existence of Extreme Value Laws (EVLs) and Hitting Time Statistics (HTS)/ ReturnTime Statistics (RTS) for systems with decay of correlations against L1 observables. We also carry out the study of the convergence of Rare Event Point Processes (REPP). In the first part, we investigate the problem for deterministic dynamics and completely characterise the extremal behaviour of expanding systems by giving a dichotomy relying on the existence of an Extremal Index (EI). Namely, we show that the EI is strictly less than 1 for periodic centres and is equal to 1 for non-periodic ones. In a more general setting, we prove that the REPP converges to a standard Poisson if the centre is non-periodic, and to a compound Poisson with a geometric multiplicity distribution for the periodic case. Moreover, we perform an analysis of the convergence of the REPP at discontinuity points which gives the convergence to a compound Poisson with a multiplicity distribution different than the usual geometric one.In the second part, we consider stochastic dynamics by randomly perturbing a deterministic system with additive noise. We present two complementary methods which allow us to obtain EVLs and statistics of recurrence in the presence of noise. The first approach is more probabilistically oriented while the second one uses spectral theory. We conclude that, regardless of the centre chosen, the EI is always equal to 1 and the REPP converges to the standard Poisson. / Neste trabalho, estudamos as propriedades estatısticas de sistemas dinâmicos deterministicos e estocasticos. Estamos particularmente interessados em valores extremos e recorrência. Provamos a existência de Leis de Valores Extremos (LVE) e Estatısticas doTempo de Entrada (ETE) / Estatısticas de Tempo de Retorno (ETR) para sistemas comdecaimento de correlaçoes contra observaveis em L1. Também realizamos o estudo daconvergência dos Processos Pontuais de Acontecimentos Raros (PPAR). Na primeira parte, investigamos o problema para dinâmica determinıstica e caracterizamos completamente o comportamento extremal de sistemas expansores. Mostramos que ha uma dicotomia quanto 00E0 existência de um Indice de Extrema (IE). Nomeadamente, provamos que o IE é estritamente menor do que 1 em torno de pontos periodicos e é igual a 1 para pontos aperiodicos. Num contexto mais geral, mostramos que os PPAR convergem para um processo de Poisson simples ou um processo de Poisson composto, em que a distribuiçao de multiplicidade é geométrica, dependendo se o centro é um ponto aperiodico ou periodico, respectivamente. Além disso, realizamos uma analise da convergência dos PPAR em pontos de descontinuidade, o que conduziu à descoberta de convergência para um processo de Poisson composto com uma distribuiçao de multiplicidade diferente da usual distribuiçao geométrica. Na segunda parte, consideramos dinâmica estocastica obtida por perturbaçao aleatoria de um sistema determinıstico por inclusao de um ruıdo aditivo. Apresentamos duas técnicas complementares que nos permitem obter LVE e as ETE na presen¸ca deste tipo de ruıdo. A primeira abordagem é mais probabilıstica enquanto que a outra usa sobretudo teoria espectral. Conclui-se que, independentemente do centro escolhido, o IE é sempre igual a 1 e os PPAR convergem para o processo de Poisson simples.

A busca por uma terapia não-cirúrgica para o tratamento da fissura anal crônica resulta de que a esfincterotomia, a despeito de eficaz para a cura da fissura anal, pode levar a graus variáveis de incontinência fecal. Poucos estudos comparativos contemplando o emprego de bloqueadores de canais de cálcio podem ser identificados. Associadamente, a evidência científica acerca da eficácia do cloreto de betanecol para o tratamento da fissura anal crônica é pouco robusta na literatura mundial e nula em nosso meio. O objetivo do presente estudo foi analisar comparativamente os resultados de eficácia, segurança e recidiva associados ao emprego de duas modalidades de tratamento farmacológico tópico: o cloridrato de diltiazem e o cloreto de betanecol. Trata-se de estudo retrospectivo e uni-institucional. Entre janeiro de 2001 e abril de 2005 foram avaliados os prontuários médicos relativos a 332 pacientes com diagnóstico de fissura anal crônica. Dos 332 pacientes cujos prontuários médicos foram revisados, 30 pacientes submetidos a tratamento com diltiazem gel 2% (grupo D) e 30 submetidos a tratamento com betanecol gel 0,1% (grupo B) foram selecionados. Uma vez indicado o tratamento clínico da fissura anal crônica, este tinha duração de oito semanas para os grupos D e B. Todos os pacientes eram orientados para realizar a aplicação tópica do gel contendo o princípio ativo após higiene local e na freqüência de duas vezes ao dia. Os pacientes eram entrevistados após uma e oito semanas do início do tratamento. Sucesso do tratamento no presente estudo foi definido como a ausência de sintomas ao final do tratamento com ou sem a cicatrização da fissura anal. A recidiva foi definida no presente estudo como a presença de sintomas após ter sido diagnosticado sucesso do tratamento. Com relação ao sexo, no grupo D haviam 13 (43,3%) pacientes do sexo masculino e no grupo B, 11 (36,7%) p=0,598 . Com relação à idade, a mediana no grupo D foi de 36 (19-76) anos e no grupo B foi de 39 (20-75) anos p=0,937. No que se refere à duração dos sintomas conforme o grupo de estudo, o grupo D apresentou mediana de 11 (2 82) meses e o grupo B, de 12 (2 276) meses - p=0,958. Com relação à distribuição da casuística conforme a localização da fissura anal, no grupo D, ela estava localizada na região posterior em 22 (73,4%) pacientes; na região anterior, em seis (20%); em posição lateral, em um (3,3%) caso; e havia uma fissura anterior e outra posterior em outro (3,3%) caso. No grupo B, havia 17 (56,7%) pacientes com fissura posterior e 13 (43,3%) com fissura na localização anterior p=0,899. No que se refere à distribuição da casuística conforme a presença de sintomas e cicatrização da fissura analisadas sete dias após o início do tratamento, no grupo D foram observados seis (35,3%) pacientes com sintomas; no grupo B, esses eram 11 (68,8%) p=0,055. No que se refere à cicatrização da fissura anal após sete dias de tratamento, no grupo D foram observados três (17,6%) pacientes com fissura cicatrizada; no grupo B foram identificados quatro (25%) pacientes p=0,688. Ao final de dois meses de tratamento, nos grupos D e B, 11 (36,7%) pacientes ainda apresentavam sintomas enquanto 19 (63,3%) pacientes se encontravam sem sintomas. Com relação à cicatrização da fissura ao final do tratamento, no grupo D, 16 (53,3%) pacientes evoluíram com cicatrização e no grupo B, 15 (50%) pacientes apresentaram cicatrização p=0,796. Ao final do tratamento, ambos os grupos apresentavam 19 (63,3%) pacientes com sucesso. Com relação à necessidade de tratamento cirúrgico durante o tempo de acompanhamento do estudo, no grupo D, nove (30%) pacientes foram operados e no grupo B, 11 (36,7%) pacientes foram submetidos a tratamento cirúrgico p=0,584. Com relação à ocorrência de complicações associadas ao tratamento, três (10%) dos pacientes no grupo D apresentaram complicações. No grupo B, complicações ocorreram em somente um caso (3,3%) p=0,612. A recidiva sintomática ocorreu em 4 (21%) de 19 pacientes submetidos ao tratamento com sucesso com o emprego do diltiazem e foi a mesma (21%) para os pacientes tratados por betanecol. A mediana do intervalo de tempo (meses) até o diagnóstico da recidiva no grupo D foi de 16 (10-24) meses. No grupo B, o intervalo médio até o diagnóstico de recidiva foi de 7,5 (2-15) meses p=0,147. As conclusões do presente estudo sobre o emprego do diltiazem e do betanecol tópicos para o tratamento clínico da fissura anal foram: 1. é possível que o emprego do diltiazem no tratamento clínico da fissura anal esteja associado a resposta clínica mais precoce; 2. ao final do tratamento clínico de mesma duração, diltiazem e betanecol são igualmente eficazes; 3. diltiazem e betanecol têm perfil de utilização seguro e estão ambos associados a baixa ocorrência de complicações e efeitos colaterais; 4. a ocorrência de recidiva após sucesso do tratamento clínico parece similar; entretanto, o diltiazem pode estar associado a maior sustentação da resposta clínica de sucesso. / Surgical treatment of chronic anal fissure is effective but is associated to some risk of fecal continence impairment in the early or late postoperative period. Few clinical trials comprising calcium channel blockers are available. Moreover, solid scientific evidence regarding bethanechol use for chronic anal fissure is lacking. The present study aims to comparatively analyze safe and effectiveness of two topical pharmacological agents for treatment of chronic anal fissure: diltiazem and bethanechol. This was a retrospective study and was performed in a single institution. Between January 2001 and April 2005, the medical records of 332 patients with chronic anal fissure were reviewed. Of these patients, it was possible to evaluate outcomes of thirty patients treated with diltiazem 2% gel (group D) which were compared to thirty patients who underwent clinical management with bethanechol 0.1% gel (group B). The treatment duration was 8 weeks. All patients in both groups were asked to apply a small gel amount to the anus twice a day, and they were interviewed after seven days and at the end of the treatment (8 weeks). Treatment success was defined as symptoms absence associated or not to fissure healing. Recurrence was defined as symptom recurrence after successful treatment. There were 13 (43.3%) men in group D and 11 (36.7%) in group D p=0.598. Median age was 36 (19-76) for patients in group D, and 39 (20-75) in group B p=0.937. Regarding symptoms duration, its median value in group D was 11 (2-82) months, and 12 (2-276) in group B p=0.958. The anal fissure had the following location in group D: posterior in 22 (73.4%) patients; anterior in six (20%) patients, lateral in one (3.3%) patient, and there was an anterior and a posterior fissure in another (3.3%) case; in group B, it was located in the posterior wall in 17 (56.7%) patients, and in the anterior wall in 13 (43.3%) p=0.899. Seven days after the beginning of treatment, in group D, six (35.3%) were still symptomatic; in group B, 11 (68.8%) were symptomatic p=0.055. Regarding healing of the fissures after seven days, in group D it occurred in three (17.6%) cases, and in group B, it was observed in 4 (25%) cases p=0.688. At the completion of treatment (8 weeks), in both groups, 11 (36.7%) patients were still symptomatic. Regarding fissure healing at the end of treatment, it occurred for 16 (53.3%) patients in group D, and for 15 (50%) patients in group B - p=0.796. Success at treatment completion was the same for both grous: 19 (63.3%) patients. In group D, 9 (30%) patients were operated on while in group B, 11 (36.7%) required surgery p=0.584. In group D, 3 (10%) patients had treatment-related complications; in group B, they occurred in only one (3.3%) patient p=0.612. Symptomatic recurrence was observed in 4 (21%) out of 19 patients with successful initial treatment in group D. Recurrence was the same after successful treatment with bethanechol. Mean time interval to recurrence diagnosis in group D was 16 (10-24) months; this interval was 7.5 (2-15) in group B p=0.147. The conclusions of the present study regarding medical management of chronic anal fissure with diltiazem and bethanechol are the following: 1. there is evidence to suggest that topical diltiazem treatment is associated to an earlier clinical response; 2. after eightweek topical treatment, diltiazem and bethanechol are equally efficient; 3. both are safe and associated to a low complication rate; 4. recurrence rates after successful treatment seem to be similar although clinical success may be more lasting after diltiazem treatment.

A hepatite auto-imune (HAI) é doença necroinflamatória crônica do fígado que provoca destruição progressiva do parênquima e, na ausência de tratamento imunossupressor, evolui para óbito. Estudos prévios demonstraram algumas particularidades clínicas e genéticas dessa doença no Brasil. O objetivo desse trabalho foi avaliar aspectos clínicos, laboratoriais, histológicos, evolução da gestação e a resposta ao tratamento de 268 pacientes com diagnóstico provável ou definitivo de HAI atendidos no período de 20 anos, com tempo médio de seguimento de 6,2 anos. A relação sexo F:M foi de 5,7:1, a idade média ao diagnóstico de 29,1 anos, 28,4% apresentaram doença auto-imune extra-hepática concomitante, a mais freqüente foi tireoidiana. A forma de apresentação da doença foi aguda em 56%. Antes do tratamento 81,4% tinham diagnóstico definitivo de HAI. 78,4% tinham HAI tipo 1, 7,1% tipo 2, 9% HAI sem marcador e 5,6% HAI com antimitocôndria. 80,6% submeteram-se à biópsia hepática inicial, 56% com cirrose hepática (45,1% da casuística). O tratamento inicial foi azatioprina e prednisona em 70,9%, com 57,5% de efeitos colaterais e necessidade de troca do esquema terapêutico em 33%. O efeito colateral documentado mais freqüente foi desmineralização óssea. 51,5% dos pacientes atingiram remissão bioquímica e apenas 36,2% remissão histológica em tempo médio de cinco anos; em 22% foi necessário o uso do ácido ursodesoxicólico como tentativa de normalização bioquímica. As doses médias de corticóide e azatioprina usadas para remissão histológica foram 8,3mg/dia e 84,3mg/dia. A recidiva após suspensão do tratamento ocorreu em 58,7%, 75,7% nos primeiros seis meses. A sobrevida em cinco anos foi de 91,4%, 9,7% necessitaram de transplante hepático, com 26,9% de recidiva da HAI em seguimento médio de quatro anos após o transplante. A principal etiologia de mortalidade foi infecção. Para avaliação da gestação foram consideradas 54 gestações ocorridas em 39 patientes (71,8% com HAI tipo 1, 15,4% tipo 2 e 12,8% formas variantes), com idade média à gestação de 24 anos e 68,4% de cirrose hepática. 48,1% usavam azatioprina e prednisona na concepção e início da gestação e 48,1% tomaram prednisona 20mg/d após o seu diagnóstico. A taxa de perda fetal foi de 29,4%, a de abortos espontâneos 24%, de prematuridade 11,8%. Ocorreram 3,9% malformações fetais e uma gestação ectópica. Aparentemente não houve relação entre o uso de azatioprina e eventos gestacionais desfavoráveis. Embora em quatro gestações houvesse complicações maternas, não se observaram óbitos. Em 55% das gestações ocorreram aumentos das enzimas hepáticas, mas recidiva da HAI ocorreu em 31,4%, apenas no período puerperal. Concluímos que a HAI no Brasil é doença mais grave, com idade mais precoce de início, maior porcentagem de cirrose hepática à apresentação. Há necessidade de maiores doses de medicação para remissão e menores taxas de resposta completa e recidiva após a suspensão do tratamento. A gestação na HAI é geralmente segura, com necessidade de monitorização rigorosa principalmente no puerpério e o uso de azatioprina é aparentemente desprovido de complicações. / Autoimmune hepatitis (AIH) is a chronic liver disease in which there is a progressive destruction of the hepatic parenchyma, leading to cirrhosis without treatment. Previous publications reported some regional and racial differences in clinical, laboratorial, histologic features and treatment response of this disease, probably related to genetic backgrounds and environmental factors. The aim of this study was to analyze clinical, laboratorial and histologic features, pregnancy outcomes and treatment response of 268 patients with definite or probable diagnosis of AIH followed-up for 20y (median time - 6.2y). Women were more affected than men; gender ratio of 5.7:1. Median age at diagnosis was 29.1y. 28.4% had a concomitant autoimmune extra-hepatic disease, more frequently a thyroid disease. Clinical presentation was acute in 56% of patients. Before treatment, 81.4% had a definite diagnosis of AIH, 78.4% type 1, 7.1% type 2, 9% seronegative and 5.6% with antimitochondrial antibodies. 80.6% had initial histologic evaluation, 56% of them with liver cirrhosis. Initial treatment included azathioprine and prednisone in 70.9% of patients; 57.5% had side effects and 33% of them needed to change the medication regimen. The most frequent documented side effect was bone disease. 51.5% of patients entered biochemical remission but only 36.2% had a complete response in 5 years. In 22% of patients ursodeoxycholic acid was added to improve biochemical remission. Median doses of azathioprine and prednisone for histological remission were 84.3mg/day and 8.3mg/day respectively. Relapses after treatment withdrawal occurred in 58.7%, mostly in the first six months. Five-year survival was 91.4%, 9.7% of patients underwent liver transplantation and 26.9% had AIH recurrence in 4-year follow-up. The main cause of death was infection. We analyzed 54 pregnancies of 39 patients with AIH (71.8% type 1, 15.4% type 2 and 12.8% variant forms). Median age at pregnancy was 24 years, 68.4% of patients had liver cirrhosis. In 48.1% of pregnancies, patients were taking azathioprine and prednisone at conception and early pregnancy. In 48.1% of pregnancies 20mg/day prednisone was administered alone, after the diagnosis of gestation. The fetal loss rate was 29.4%, spontaneous abortions occurred in 24% and premature labors in 11.8%. There were 3.9% of congenital malformation and one ectopic pregnancy. Apparently there was no relationship between adverse pregnancy outcomes and azathioprine use. In 4 pregnancies there were maternal complications, but no mortalities. In 55% of pregnancies there were elevation of aminotransferase levels, 31.4% had a relapse of AIH, only in the postpartum period. We concluded that AIH in Brazil occurred in a younger age, had more cirrhosis at presentation and medication doses for histologic remission were higher than those previously reported. Patients had lower rates of complete response and of relapse after drug withdrawal. Pregnancy is safe, but a close monitoring is important especially in the postpartum period. Azathioprine administration during pregnancy apparently had no toxic effects.

O principal objetivo de nossa tese foi examinar de que maneira a doutrina do eterno retorno do mesmo se relaciona com o projeto de transvaloração dos valores e com a noção nietzschiana de trágico. Para efetivar nosso intento, realizamos, primeiramente, uma investigação acerca da esfera cosmológica da doutrina do eterno retorno. Em segundo lugar, promovemos a relação entre esse âmbito cosmológico do eterno retorno e o projeto de transvaloração dos valores. Essa relação deu ensejo a duas problemáticas para as quais tentamos dar resposta nas duas últimas partes de nossa tese. Nesse sentido, tentamos responder à primeira problemática que chamamos de o problema do determinismo no eterno retorno esclarecendo a noção nietzschiana de trágico e tentando mostrar de que forma ela está relacionada com a doutrina do eterno retorno e com o projeto de transvaloração dos valores. Por fim, propomos uma resposta à segunda problemática, a saber, a incompatibilidade entre o perspectivismo e a cosmologia do eterno retorno do mesmo. / The main aim of this thesis is to examine how the doctrine of the eternal recurrence of the same is related to the project of transvaluation of values and to the Nietzschean notion of tragic. To accomplish this purpose, first we examined the cosmological sphere of the doctrine. Secondly, we promote the relationship between this cosmological context and the project of transvaluation of values. Two problems have emerged from this relationship to which we tried answering in the last two parts of the thesis. We tried answering the first problem that we called the problem of determinism in the eternal return clarifying the Nietzschean notion of tragic and showing how it is related to the doctrine of the eternal return and to the project of transvaluation of values. Finally, we propose an answer to the second problem, namely the incompatibility between perspectivism and cosmology of the eternal return of the same.