O objetivo deste trabalho é provar um Closing Lema Parcial para variedades bidimensionais compactas, orientáveis ou não--orientáveis. Para enunciá--lo, considere um campo vetorial \\linebreak $X\\in\\mathfrak^r(M)$, $r\\ge 2$, de classe $C^r$ em uma variedade bidimensional compacta $M$, e seja $\\Sigma$ um segmento transversal a $X$ passando por um ponto recorrente não--trivial $p$ de $X$. Seja $P:\\Sigma\\to\\Sigma$ a correspondente transformação de primeiro retorno. O primeiro resultado deste trabalho consiste em mostrar que se $P$ tem a propriedade de que para todo $n\\ge N$ e $x\\in{m dom}\\,(P^n)$, $\\vert DP^n(x)\\vert<\\lambda$, onde $N\\in\\N$ e $0<\\lambda<1$, então existe um campo vetorial $Y$ arbitrariamente próximo de $X$ na topologia $C^r$ tendo uma trajetória periódica passando por $p$. O segundo resultado consiste em apresentar condições, sobre os expoentes de Lyapunov de $P$, para que $\\vert DP^n\\vert<\\lambda$ para todo $n\\ge N$. Nesta tese, também incluímos um resultado sobre a estabilidade assintótica no infinito de campos planares diferenciáveis, mas não necessariamente de classe $C^1$. / The aim of this work is to provide a Partial $C^r$ Closing Lemma for compact surfaces, orientable or non--orientable. To state it, let $X\\in\\mathfrak^r(M)$, $r\\ge 2$, be a $C^r$ vector field on a compact surface $M$ and let $\\Sigma$ be a transverse segment to $X$ passing through a non--trivial recurrent point $p$ of $X$. Let $P:\\Sigma\\to\\Sigma$ be the corresponding first return map. The first result of this work consists in showing that if $P^n$ has the property that for all $n\\ge N$ and $x\\in{m dom}\\,(P^n)$, $\\vert DP^n(x)\\vert<\\lambda$, where $N\\in\\N$ e $0<\\lambda<1$, then there exists a vector field $Y$ arbitrarily close to $X$ in the $C^r$ topology such that $p$ is a periodic point of $Y$. The second result consists in presenting sufficient conditions, upon the Lyapunov exponents of $P$, so that $\\vert DP^n\\vert<\\lambda$ for all $n\\ge N$. In this thesis, we also include a result concerning the asymptotic stability at infinity of planar differentiable vector fields, not necessarily of class $C^1$.

Introdução: A papilomatose recorrente respiratória (PRR) é uma doença benigna de enorme morbidade, com manifestações clínicas muito distintas, causada pelo papiloma vírus humano (HPV) dos tipos 6 e 11. Objetivo: Identificar os diferentes tipos de HPV e suas variantes relacionados com a PRR e estabelecer possível correlação clínica entre o tipo / variante viral e a agressividade da doença. Casuística e Métodos: Estudo prospectivo, realizado com 41 pacientes atendidos no Ambulatório de Laringologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, entre os anos de 2008 e 2015, que apresentaram quadro de PRR. Foi realizada genotipagem viral das biopsias laríngeas e os vírus presentes foram relacionados com a evolução clínica de cada paciente e a agressividade da doença, pelo escore de Derkay, número de cirurgias e traqueostomia. Resultados: Dos 41 pacientes avaliados, a maioria era do sexo masculino (68,29%), e maiores de 12 anos (63,41%). Os menores de 12 anos apresentaram número de cirurgias e escore de Derkay significativamente maiores do que os pacientes mais velhos. Foram identificados somente os HPV dos tipos 6 e 11, na frequência de 73,17% e 26,83%, respectivamente. A agressividade da doença não mostrou relação com o tipo ou a variante do vírus, mas sim com a idade de apresentação clínica da doença. Conclusão: Os tipos de HPV e as suas variantes não apresentaram comportamento clínico mais agressivo na PRR no grupo estudado. Em contrapartida, a idade foi determinante para a agressividade da doença. / Introduction: Recurrent respiratory papillomatosis (RRP) is a benign disease of enormous morbidity that presents very distincts clinical manifestations. It is usually caused by the human papillomavirus (HPV), mostly types 6 and 11. Purpose: To identify the different HPV types and variants related to RRP and to establish a possible correlation between HPV type/variant and viral disease aggressiveness. Casuistic and Methods: This prospective study included 41 patients followed at the Outpatient Clinic of Laryngology of the Medical School of Ribeirão Preto, University of São Paulo, between 2008 to 2015, due to RRP. Virus genotyping was performed on laryngeal biopsies by PCR, and this information was associated to each patient\'s data regarding aggressiveness of the disease and clinical evolution, by Derkay\'s score, number of surgeries and tracheostomy. Results: Most patients were male (68.29%) and older than 12 years-old (63.41%). Patients younger than 12 years had a significantly higher number of surgeries and Derkay score than older patients. In all samples, only HPV 6 and HPV 11 were detected, in a prevalence of 73.17% and 26.83%, respectively. The aggressiveness of the disease was not related to the type or variant of the virus, but to the age of patient when the clinical presentation of the disease occurred. Conclusions: HPV types and variant of HPV showed no more aggressive clinical behavior in recurrent respiratory papillomatosis in the studied group. In contrast, age was crucial to the aggressiveness of the disease.

Diante da indicação do tratamento da Classe II subdivisão com extrações dentárias, existe a alternativa de extrair três ou quatro pré-molares. Estes protocolos atuam diferentemente na relação molar porque o tratamento com três extrações mantém a relação molar de Classe II em um dos lados e a de Classe I no outro e o tratamento com quatro extrações busca atingir uma relação molar de Classe I bilateral, corrigindo a relação molar de Classe II presente no início do tratamento. Considerando-se que o sucesso do tratamento ortodôntico está relacionado com a manutenção das alterações promovidas, em longo prazo, e que alguns autores questionam a estabilidade do término com relação molar de Classe II, julgou-se pertinente comparar a estabilidade dos resultados promovidos por estes dois protocolos. Para tanto, foram selecionados 162 pares de modelos de gesso de 52 pacientes Classe II subdivisão, correspondentes a três estágios distintos: pré-tratamento (T1), pós-tratamento (T2) e de observação pós-tratamento (T3), ou seja, confeccionados 6,9 anos, em média, após o término do tratamento. O grupo 1 foi composto pelos modelos de gesso de 24 pacientes tratados com três extrações e com idade média de 13,54 anos (9,50 a 21,06) no pré-tratamento, de 17,03 anos (14,42 a 25,11) no pós-tratamento e de 23,45 anos (18,33 a 29,87) no estágio de observação pós-tratamento e o grupo 2 compreendeu os modelos de gesso de 28 pacientes tratados com quatro extrações e com idade média de 13,33 anos (10,51 a 15,68) no pré-tratamento, de 16,31 anos (14,01 a 20,86) no pós-tratamento e de 23,70 anos (17,18 a 35,16) no estágio de observação pós-tratamento. Calculou-se os valores dos índices oclusais PAR e IPT para todos os pares de modelos de gesso e, a partir deles, calculou-se as alterações do tratamento e pós-tratamento. O teste t independente foi empregado para a comparação entre os grupos das idades e dos valores dos índices oclusais PAR e IPT nos três estágios de avaliação, dos tempos de tratamento e de observação pós-tratamento, bem como das alterações ocorridas durante o tratamento e no período pós-tratamento, dos percentuais de melhora e de recidiva. A avaliação da estabilidade foi realizada pela subtração dos valores dos índices PAR e IPT pós-tratamento dos valores do estágio de observação pós- tratamento (PAR3-PAR2 e IPT3-IPT2), sendo que quanto maior a diferença, maior foi a recidiva. Os resultados não apontaram diferenças entre os grupos em nenhuma das variáveis estudadas. Desta forma, verificou-se que a estabilidade dos resultados do tratamento da Classe II subdivisão realizado com três ou quatro extrações é semelhante. / If Class II subdivision treatment with extractions is the best treatment alternative, it can comprise 3- or 4- premolar extractions. The main difference between these two protocols is their accomplishment to the posttreatment molar relationship because the first achieve a Class II molar relationship in one side and a Class I in the other and the second attain a bilateral Class I molar relationship. Considering that long-term stability is an important item of treatment success evaluation and stability of Class II molar relationship that is kept unchanged in some protocols is considered to be suspicious by some authors, the purpose of this study was to compare the occlusal stability of Class II subdivision malocclusion treatment with 3- and 4- premolar extractions. The sample comprised 162 pairs of dental casts obtained at T1 (pretreatment), T2 (posttreatment) and T3 (long-term posttreatment), that match to a mean of 6.9 years after treatment conclusion of 52 Class II subdivision patients. Group 1 comprised the dental casts of 24 patients treated with 3 premolar extractions and with a mean age of 13.54 years (range, 9.50 to 21.06) at pretreatment, 17.03 years (range 14.42 to 25.11) at posttreatment and 23.45 years (range, 18.33 to 29.87) at long-term posttreatment and group 2 included 28 patients\' dental casts treated with four premolar extractions and with a mean age of 13.33 years (range, 10.51 to 15.68) at pretreatment, 16.31 years (range, 14.01 to 20.86) at posttreatment and 23.70 years (range, 17.18 to 35.16) at long-term posttreatment. The PAR and TPI occlusal indexes were calculated for all the dental casts and they were used to calculate the treatment and long-term posttreatment changes. T tests were used to compare the groups´ ages and the indexes values at T1, T2 and T3, the treatment time, the long-term posttreatment time, the amount of treatment and long-term posttreatment changes and the percentages of reduction and relapse. Stability evaluation was calculated by subtracting the posttreatment from the long-term posttreatment index values (PAR3-PAR2 and TPI3-TPI2). The greater the difference, the greater the relapse. There were not significant differences between the groups\' variables considered in this study and it was concluded that treatment of Class II subdivision malocclusion with 3- and 4- premolar extractions have a similar long-term posttreatment stability.

O tumor odontogênico queratocístico (TOQ) é uma neoplasia cística benigna, que apresenta controvérsias no seu diagnóstico e no tratamento. Propôs-se analisar 24 TOQs, correlacionando seus aspectos clínico-imaginológicos, histopatológicos e cirúrgicos, para aplicação no diagnóstico, prognóstico e tratamento racional. As análises foram submetidas ao teste do qui-quadrado (2) de Yates, com nível de significância de 5%. O abaulamento lingual foi presente em 100% dos casos no ramo mandibular. O padrão radiográfico unilocular e o deslocamento dental tiveram prevalências de 79,2% e 70%, respectivamente. A ocorrência de fluido queratinóide foi de 50% e mostrou correlação significativa com a síndrome do carcinoma nevóide de células basais (SCNCB). Nos demais fluidos (translúcido, citrino, sanguinolento e turvo), 63,6% apresentaram precipitado queratinóide. Fenestrações ósseas chegaram a 80% no ramo mandibular e 100% na tuberosidade maxilar. Inflamação ocorreu em 85,7% dos casos, com alterações epiteliais em 88,9% deles. A prevalência de microcistos satélites foi de 66,6%, com maior freqüência na SCNCB, no contorno festonado e no padrão multilocular. Dois casos submetidos à excisão tegumentar evidenciaram microcistos na mucosa. Num período médio de 25,5 meses, apenas um caso (4,2%) recorreu. A exérese por curetagem ocorreu em 17,4% dos casos, sem nenhuma correlação com infecção secundária, atrofia epitelial e inflamação. Todos os casos marsupializados apresentaram microcistos na lesão residual. As deiscências relacionadas à solução de Carnoy ocorreram em 75% dos casos marsupializados e em 11,1% dos demais. Parestesias relacionadas à aplicação da substância na área posterior da mandíbula ocorreram em 30,8%, com diferença significativa nos casos com e sem exposição nervosa. Conclui-se que: 1) o abaulamento lingual é característico no ramo mandibular; 2) a unilocularidade e o deslocamento dental são freqüentes; 3) o fluido queratinóide é freqüente na SCNCB e o precipitado é aplicável no diagnóstico diferencial; 4) as fenestrações corticais são prevalentes na tuberosidade maxilar e no ramo mandibular; 5) a inflamação interfere no diagnóstico histopatológico; 6) os microcistos satélites são prevalentes na SCNCB, relacionados à multilocularidade e presentes nos tecidos moles; 7) a curetagem é determinada por fatores técnicos; 8) a exérese é recomendável depois da marsupialização; 9) as deiscências são influenciadas pela marsupialização; e 10) as parestesias dependem do contato da solução de Carnoy com o epineuro. / The keratocystic odontogenic tumor (KOT) is a cystic benign neoplasm, which presents controversies about its diagnosis and treatment. It was proposed to analyze 24 KOTs, correlating their clinical, image, histological and surgical aspects with application to diagnosis, prognosis and rational treatment. The data were submitted to the chi-square test (2) from Yates, with significance level of 5%. The lingual cortical expansion was present in 100% of the cases in the mandibular ramus. The unilocular radiograph pattern and the dental displacement had prevalence of 79.2% and 70%, respectively. The occurrence of keratin-like fluid was 50% and this was significantly correlated with the nevoid basal cell carcinoma syndrome (NBSCS). For the other fluids (translucid, citrin, bloody and cloudy), 63.6% presented keratin-like precipitation. Bone fenestrations achieved 80% of the mandibular ramus and 100% at the maxillary tuberosity. Inflammation occurred in 85.7% of the cases, with epithelial alterations in 89% of them. The satellite microcysts prevalence was 66.6%, with higher frequency in the NBSCS, at the fenestrated contour and at the multilocular pattern. Two cases submitted to tegument excision showed microcysts in the mucosa. In a mean period of 25.5 months, only one case (4.2%) recurred. The excision by curettage occurred in 17.4% of cases, without any specific correlation to the secondary infection, epithelial atrophy or inflammation. All marsupialized cases displayed microcysts in the residual lesion. The dehiscence related to the use of Carnoy solution occurred in 75% of the marsupialized cases and 11.1% of the others. Paresthesia related to the use of this solution in the posterior region of the mandible occurred in 30.8% of the cases, with significant difference among cases with and without nerve exposure. It can be concluded that: 1) the lingual cortical expansion is characteristic in the mandibular ramus; 2) the unilocular aspect and dental displacement are frequent; 3) the keratin-like fluid is frequent in the NBSCS and the precipitation in appliable for differential diagnosis; 4) the cortical fenestrations are prevalent in the maxillary tuberosity and at the mandibular ramus; 5) the inflammation interferes in the histopathologic diagnosis; 6) the satellite microcysts are prevalent in the NBSCS, related to multilocular aspect and present in soft tissues; 7) the curettage is determined by technical facts; 8) the exeresis is recommended after marsupialization; 9) the dehiscence is influenced by marsupialization; and 10) the paresthesia depends of the contact of Carnoy solution with the epineurium.

Objectifs: Notre travail avait pour objectif la prédiction du risque de récidive du cancer de prostate localisé à partir d’une caractérisation multimodale de ce cancer comprenant des facteurs anatomopathologiques, des biomarqueurs tissulaires et des paramètres quantitatifs originaux issus de l’IRM pré-thérapeutique, ainsi que l'élaboration d'une méthodologie pour l'évaluation des corrélations existantes entre ces différents facteurs. Matériel et méthodes : La valeur pronostique de la nouvelle classification ISUP, de l'infiltration lympho-vasculaire, de l'expression des marqueurs Ki67, Survivin et Caveolin-1 a été évaluée sur de larges cohortes multicentriques de patients avec cancer de prostate traité par prostatectomie radicale, en analyse multivariée avec calcul des C-index correspondants. L'intérêt, notamment pronostique, de la radiomique, correspondant à l'extraction et l'étude de caractéristiques quantitatives d'imagerie, a été évalué dans le cancer de prostate par une revue systématique de la littérature. L'intérêt de descripteurs texturaux issus de l'IRM pour la prédiction du risque de récidive biologique a été évalué dans une cohorte monocentrique de patients traités par radiothérapie externe. Dans une étude préliminaire basée sur 8 patients, une méthodologie a été proposée pour la reconstruction 3D de la pièce de prostatectomie et son recalage avec l'imagerie pré-opératoire. Ce travail a alors permis une mise en correspondance des données biologiques tumorales et les données quantitatives de l'imagerie. Des classifieurs pour l'identification et la caractérisation tumorale ont été construits et validés. Résultats : Nos travaux ont confirmé que la nouvelle classification ISUP, l'infiltration lymphovasculaire, et l'expression de Ki-67, Survivin, et Caveolin-1 sur la pièce de prostatectomie étaient associées à des caractéristiques pathologiques défavorables dans le CaP et au risque de récidive biologique après prostatectomie radicale. Cependant, leurs valeurs pronostiques sont limitées comparé aux facteurs pronostiques standards. La radiomique est un domaine prometteur pour l'identification et la caractérisation tumorale dans le CaP mais son intérêt pronostique reste à démontrer. Nos travaux confirment sa valeur pronostique pour les patients traités par radiothérapie externe. Avec une erreur moyenne de recalage de 5 mm, notre méthodologie de recalage nous a ensuite permis de proposer une mise en correspondance des données biologiques tumorales basées sur le score de Gleason et l'expression de marqueurs tissulaires. Cette mise en correspondance a permis l'élaboration de classifieurs permettant de prédire la présence de tumeurs et estimer leur score de Gleason avec des résultats satisfaisants. L'évaluation de l'expression immunohistochimique de marqueurs tissulaires reste limitée. Conclusion : Ces travaux confirment la valeur pronostique de marqueurs issus de l'étude quantitative de l'imagerie pré-opératoire, ainsi que de l'analyse anatomopathologique et immunohistochimique de la pièce de prostatectomie. Une méthodologie de mise en correspondance et de corrélation de ces différents marqueurs a été proposée avec des résultats préliminaires justifiant la poursuite des travaux sur une cohorte de patients plus importante. / Objective: The aim of this work was the prediction of prostate cancer recurrence based on a multimodal characterization of this cancer including pathological markers, tissue biomarkers, and quantitative parameters from Magnetic Resonance Imaging (MRI), and to propose a method to assess correlations between these factors. Material and methods: The prognostic values of the new ISUP groups, the lymphovascular invasion, the expressions of Ki67, Survivin et Caveolin-1 were assessed in large multicentric and international cohorts of patients with prostate cancer treated with radical prostatectomy. A review of the literature investigated the use and the performance of radiomics and texture analysis to predict prostate cancer recurrence. The prognostic value of MRI features including Haralick’s texture features to predict biochemical recurrence after prostate cancer radiotherapy was assessed in a retrospective cohort of 83 patients. In a preliminary study including eight patients, a method to correlate in-vivo observations from pre-operative imaging with biological findings from radical prostatectomy using quantitative analysis was proposed. Résultats: Our studies confirmed the new ISUP groups, the lymphovascular invasion, the expressions of Ki67, Survivin and Caveolin-1 were associated with adverse pathologic features and prostate cancer recurrence after radical prostatectomy. However, these factors did not add clinically relevant information to established models. Our review of the literature revealed radiomics was promising for tumor identification and characterization but that few studies assessed its prognostic value. We demonstrated T2-w Haralick’s features were predictors of biochemical recurrence after prostate cancer radiotherapy. With a mean error of 4.90mm, our method to register prostate whole mount histology to in-vivo MRI resulted in the construction of classifiers to predict the presence of tumor, Gleason score, and Ki67 expression. Conclusion : Our work confirm the prognostic value of different markers from tissue, pathological pre-operative imaging analyses. Our method of registration and correlation of these markers leads to promising preliminary results that justify further evaluation with larger cohorts of patients.

Toxoplasma gondii est un parasite intracellulaire obligatoire qui infecte plus du tiers de la population mondiale. La toxoplasmose oculaire (TO), qu’elle soit d’origine acquise ou congénitale, est une infection fréquente et redoutable où le pronostic visuel est fortement engagé. La présence du parasite dans le tissu rétinien, ainsi que la réponse immunitaire de l’hôte, qu’il génère participent au développement des lésions. Cependant, les mécanismes physiopathologiques aboutissant à la destruction de la rétine et ceux conduisant à la latence et à la réactivation parasitaires ne sont toujours pas clairement identifiés. De plus, des améliorations des traitements actuels semblent nécessaires afin de traiter au mieux l’ensemble des patients et d’agir également sur la forme latente du parasite et les récidives qui en découlent. Nos travaux sur des modèles murins de la phase aiguë de la TO démontrent que le facteur de virulence parasitaire ROP16 est responsable de l’augmentation de la charge parasitaire et des réponses inflammatoires oculaires Th1 et Th17. De plus, lorsque cette protéine se trouve dans un génotype parasitaire différent de celui d’origine, la pathologie oculaire en est exacerbée. Nous avons également démontré que la cytokine IL-23 participe à la destruction de la rétine et à la multiplication parasitaire. Notre modèle murin de réactivation de la TO met en évidence le rôle protecteur de la voie Th1 à travers l’IFN-γ et celui fortement délétère de la cytokine IL-6. La neutralisation de cette cytokine dans notre modèle diminue la charge parasitaire oculaire ainsi que l’ensemble de la réponse inflammatoire et n’altère en rien la structure rétinienne. Il serait donc très intéressant d’utiliser une thérapie ciblant le récepteur de l’IL-6 afin de contrecarrer les effets des récurrences de la TO. / The obligate intracellular parasite Toxoplasma gondii infects more than one third of the world population. Ocular toxoplasmosis (OT), whether acquired or congenital, is a common and frightening infection which can strongly impair the visual function. OT is considered as a major cause of posterior uveitis and retinochoroiditis is its most common manifestation. The presence of the parasite in the retina as well as the immune response it generates in the host are two factors involved in the development of ocular lesions. However, up to now, the pathophysiological mechanisms leading to the destruction of the retina and those implied in the parasite latency and reactivation have not been clearly identified. Morever, improvements of current treatments are necessary in order to give all patients a better care but also to fight the parasite latent form and relapses they may cause. Our mouse models of OT acute phase have demonstrated that the parasite virulence factor ROP16 is responsible for the parasite load increase and the Th1 and Th17 ocular inflammatory responses. When this protein is in a different genotype than its original one – this has been made possible by recombining strains – the ocular pathology is more severe. We also showed that the IL-23 cytokine was involved in the destruction of the retina and in parasite multiplication. Our mouse model of OT reactivation highlighted the protective role of the Th1 pathway through IFN-γ as well as the highly deleterious IL-6 cytokine. By neutralizing this cytokine in our model, we reduced the ocular parasite load and the global inflammatory response without modifying the retinal structure. It would be very interesting to elaborate a therapy targeting the IL-6 receptor in order to counter the effects of OT recurrences.

Multilayered metallo-dielectric nanoparticles are increasingly considered in various applications to control the spatial and temporal behavior of electromagnetic fields. In particular, the surface mode excitation by photons or electrons in metal nanorings finds significant applications because of the implied field distribution and electromagnetic energy confinement. However, most solid nanorings that are multilayered and/or embedded in a medium have non-simply connected geometry resulting in surface modes which are not linearly independent. That is, unlike particle plasmon eigenmodes in other geometries, the amplitudes of the eigenmodes of tori exhibit a distinct forward and backward coupling. We investigate the surface modes of such toroidal nano-structures and obtain the canonical plasmon dispersion relations and resonance modes for arbitrarily layered nanorings. When seeking the nonretarded surface modes for a stratified solid torus, we obtain a three-term difference equation which plays an important role in obtaining the needed dispersion relations. The obtained dispersion relations are investigated in depth in terms of the involved matrix continued fractions and their convergence properties including their determinant forms for computing the plasmon eigenmodes. The numerical solutions of the dispersion relations in case of a solid ring are presented for comparison and the resonance frequencies for the first few dominant modes of a ring composed of plasmon supporting materials such as gold, silver, and aluminum are provided and compared to those for a silicon ring. The mode complementarity and hybridization in multilayered toroidal structures is discussed and different ring configurations are simulated in the quasistatic limit by selecting number of layers modeled by their local dielectric functions. A generalized Green’s function with derivation intricacies addressed for multilayer tori is obtained from which one may calculate and study the scattering behavior of any of the modes that may exist in the many layer system. In particular, the electric potential distribution corresponding to individual poloidal and toroidal modes in response to an arbitrarily polarized external field and the field of electrons is obtained. The results are applied to obtain the local density of states and decay rate of a dipole near the center of the torus. Finally, two new types of toroidal particles in the form of janus nanorings are introduced.

Abstract Intracerebral hemorrhage (ICH) is the most pernicious form of stroke, with high mortality. Warfarin-associated ICH (WA-ICH) carries an even higher mortality rate. The major reason for the high mortality is explained by early hematoma growth. Warfarin use has rapidly increased with the aging of the population. We investigated temporal trends in the incidence and outcome of WA-ICHs. We found that although the proportion of warfarin users almost quadrupled in our population, the annual incidence and case fatality of WA-ICHs decreased. Management of ICH is mostly supportive. Prevention of associated complications is the issue in improving outcome. Hypertension is the most important modifiable risk factor for primary ICH, but little is known of the effect of preceding hypertension on outcome. Aggressive lowering of blood pressure is suggested to be a feasible treatment option. Reversal of warfarin anticoagulation with prothrombin complex concentrate (PCC) has been implemented as an acute treatment option for patients with WA-ICH. We found that the survival of WA-ICH subjects among our population improved after implementation of reversal of warfarin anticoagulation with PCC, likely because of the introduction of PCC. Because high mean arterial blood pressure (BP) at admission is an independent predictor of early death in patients with ICH, we explored its role in survival and poor outcome separately in normotensive subjects and subjects with treated and untreated hypertension. We found that despite their higher BP values at admission, subjects with untreated hypertension showed better survival and more often a favorable outcome after BP-lowering therapy than other patients. Studies on recurrent ICH are scarce. Underlying comorbidities, prior strokes, and drug-induced impaired platelet function may increase the risk for primary ICH (PICH). A lobar location of primary ICH may predict recurrent ICH. We investigated whether these factors predicted recurrence of PICH. In our study the annual incidence of recurrent ICH was 1.67%. Cumulative 5- and 10-year incidences were 9.6% and 14.2%. In multivariable analyses, prior ischemic stroke and diabetes proved to be independent predictors for recurrence. Moreover, diabetes was an independent risk factor for fatal recurrent PICH. Use of aspirin and serotonergic drugs did not significantly contribute to the risk. / Tiivistelmä Aivoverenvuoto (ICH) on aivoverenkiertohäiriöistä vakavin. Sille on tyypillistä korkea kuolleisuus erityisesti varfariinihoitoon liittyen, ja eloonjääneetkin vammautuvat usein vakavasti. Verenvuodon koon kasvu alkuvaiheessa selittänee korkean kuolleisuuden. Väestön ikääntymisen myötä varfariinin käyttö on lisääntynyt nopeasti. Aivoverenvuodon hoito perustuu pitkälti ennusteen parantamiseen komplikaatioita estämällä. Verenpaine on tärkein hoidettavissa oleva riskitekijä, mutta tutkimustieto akuutin vaiheen verenpainetason merkityksestä ennusteeseen on vähäistä. Tehokasta verenpaineen alentamista alkuvaiheessa pidetään lupaavana hoitomenetelmänä. Vuodon koon kasvua pyritään rajoittamaan kumoamalla varfariinin antikoaguloiva vaikutus protrombiinikompleksi-konsentraatilla (PCC). Väitöstyössäni selvitän varfariinin käyttöön liittyvien aivoverenvuotojen (WA-ICH) esiintymistiheyttä ja ennustetta ajan myötä. Tutkin myös vuodon koon kasvun rajoittamista ja alkuvaiheen korkean verenpaineen alentamista hoitomenetelminä sekä selvitän, mitkä tekijät johtavat ICH:n uusiutumiseen. Totesimme WA-ICH:n ilmaantuvuuden ja tapauskuolleisuuden pienentyneen, vaikka varfariinin käyttö miltei nelinkertaistui väestössämme. Toisaalta WA-ICH -potilaiden kuolleisuus pieneni PCC-hoidon aloittamisen jälkeen, mahdollisesti sen ansiosta. Tutkiessamme riippumattomasti varhaista kuolemaa ennustavan korkean tulovaiheen verenpaineen roolia normaaliverenpaineisilla, hoidettua ja hoitamatonta verenpainetautia sairastavilla totesimme hoitamattomien hypertonia-potilaiden selvinneen akuutin vaiheen lääkehoidon myötä muita useammin hengissä ja hyväkuntoisina korkeista tulovaiheen verenpainearvoista huolimatta. Aivoverenvuodon uusiutumiseen vaikuttavista tekijöistä on vähän tutkimustietoa. Muu sairastavuus, aiemmat aivoverenkiertohäiriöt ja trombosyyttien toimintaan vaikuttavat lääkkeet saattavat lisätä ICH:n uusiutumisriskiä. Totesimme vuosittaisen uuden ICH:n esiintymistiheyden olevan 1,67&#160;%. Aikaisempi aivoinfarkti ja diabetes osoittautuivat riippumattomiksi uusiutumista ennustaviksi riskitekijöiksi, minkä lisäksi diabetes ennusti kuolemaan johtavaa uutta ICH:a. Asetyylisalisyylihapon ja selektiivisten serotoniinin takaisinoton estäjien käyttäminen ei vaikuttanut merkittävästi uusiutumisriskiin.

Background Many risk factors for stroke are well characterized and might, at least to some extent, be similar for first-ever stroke and for recurrent stroke events. However, previous studies have shown heterogeneous results on predictors and rates of stroke recurrence. Patients who survive spontaneous intracerebral hemorrhage (ICH) often have compelling indications for antithrombotic (AT) treatment (antiplatelet (AP) and/or anticoagulant (AC) treatment), but due to controversy of the decision to treat, a large proportion of these patients are untreated. In the absence of evidence from randomized controlled trials (RCTs), there is need for more high- quality observational data on the clinical impact of, and optimal timing of AT in ICH survivors. The aims of this thesis were to assess time trends in stroke recurrence, to determine the factors associated with an increased risk of stroke recurrence – including socioeconomic factors – and to determine to what extent ICH survivors with and without atrial fibrillation (AF) receive AT treatment and to determine the optimal timing (if any) of such treatment.  Methods The population-based Monitoring Trends and Determinants of Cardiovascular Disease (MONICA) stroke incidence register was used to assess the epidemiology and predictors of stroke recurrence after ischemic stroke (IS) and ICH from 1995 to 2008 in northern Sweden. Riksstroke, the Swedish stroke register, linked with the National Patient Register and the Swedish Dispensed Drug Register, made it possible to identify survivors of first-ever ICH from 2005 to 2012 with and without concomitant AF to investigate to what extent these patients were prescribed AP and AC therapy. The optimal timing of initiating treatment following ICH in patients with AF 2005–2012 was described through separate cumulative incidence functions for severe thrombotic and hemorrhagic events and for the combined endpoint “vascular death or non-fatal stroke”. Riksstroke data on first-ever stroke patients from 2001 to 2012 was linked to the Longitudinal Integration Database for Health Insurance and Labour market studies to add information on education and income to investigate the relationship between socioeconomic status and risk of recurrence. Results Comparison between the cohorts of 1995–1998 and 2004–2008 showed declining risk of stroke recurrence (hazard ratio: 0.64, 95% confidence interval (CI): 0.52-0.78) in northern Sweden. Significant factors associated with an increased risk of stroke recurrence were age and diabetes. Following ICH, a majority (62%) of recurrent stroke events were ischemic.  The nationwide Riksstroke study confirmed the declining incidence, and it further concluded that low income, primary school as highest attained level of education, and living alone were associated with a higher risk of recurrence beyond the acute phase. The inverse effects of socioeconomic status on risk of recurrence did not differ between men and women and persisted over the study period. Of Swedish ICH-survivors with AF, 8.5% were prescribed AC and 36.6% AP treatment, within 6 months of ICH. In patients with AF, predictors of AC treatment were less severe ICH, younger age, previous anticoagulation, valvular disease and previous IS. High CHA2DS2-VASc scores did not seem to correlate with AC treatment. We observed both an increasing proportion of AC treatment at time of the initial ICH (8.1% in 2006 compared with 14.6% in 2012) and a secular trend of increasing AC use one year after discharge (8.3% in 2006 versus 17.2% in 2011) (p&lt;0.001 assuming linear trends). In patients with high cardiovascular event risk, AC treatment was associated with a reduced risk of vascular death and non-fatal stroke with no significantly increased risk of severe hemorrhage. The benefit appeared to be greatest when treatment was started 7–8 weeks after ICH. For high-risk women, the total risk of vascular death or stroke recurrence within three years was 17.0% when AC treatment was initiated eight weeks after ICH and 28.6% without any antithrombotic treatment (95% CI for difference: 1.4% to 21.8%). For high-risk men, the corresponding risks were 14.3% vs. 23.6% (95% CI for difference: 0.4% to 18.2%). Conclusion Stroke recurrence is declining in Sweden, but it is still common among stroke survivors and has a severe impact on patient morbidity and mortality. Age, diabetes and low socioeconomic status are predictors of stroke recurrence. Regarding ICH survivors with concomitant AF, physicians face the clinical dilemma of balancing the risks of thrombosis and bleeding. In awaiting evidence from RCTs, our results show that AC treatment in ICH survivors with AF was initiated more frequently over the study period, which seems beneficial, particularly in high-risk patients. The optimal timing of anticoagulation following ICH in AF patients seems to be around 7–8 weeks following the hemorrhage.

The ancient Chinese I Ching, the Book of Changes, and the philosophy of the German philosopher Friedrich Nietzsche (1844-1900) both assert that the universe exists in a state of change. The I Ching, originally a book of divination, illustrates the changing phenomena of the natural world in terms of sixty-four hexagrams, which are figures composed of six lines  yielding and firm lines, representing actual conditions and relationships existing in the world and caused by the interplay between two primordial forces, yin and yang. The I Ching shows that on the macro level the Tao works in the universe, in heaven and on earth, and on the micro level it applies to man. The I Ching teaches harmony with Tao and its power (natural law and moral law), so that its reader may take appropriate action in any given situation with reference to the hexagrams and their appended judgments as revealed by the oracle. Nietzsche, however, regards the world as the Will to Power, ‘a monster of energy’, like a storming and flooding ocean eternally changing, where harmony and order seems impossible. His mouthpiece, Zarathustra, who teaches the Übermensch, encourages a war-like attitude towards life. Zarathustra’s second metamorphosis of an evolving spirit, the warrior lion, marks the difference between the Nietzschean Übermensch and the Chinese sage who attains harmony and balance within and without, a mysterious union with heaven. Zarathustra’s third metamorphosis, a playing child, creates itself as its own ‘bridge’ through a process of self-overcoming, whereas the I Ching indicates order to be the ‘bridge’ over chaos, the order of the human world being expressed in the five cardinal relationships. Whereas the I Ching advises its reader to follow their own nature and fate in order to lead a harmonious moral life, Nietzsche’s Übermensch is ‘the annihilator of morality’ and paradoxically ‘the designation of a type of supreme achievement’ (EH Books 1). With his idea of the Übermensch, Nietzsche indicates that morality is a pose (BGE 216). He seeks to make us become aware that we should invent our own virtue and create our own way in order to become what we are. He criticizes Christian morality, calling himself ‘the first immoralist’. His shocking approach attempts to make us become aware of the possibility that a ‘noble morality’ and ‘higher moralities’ ought to be possible. His Übermensch represents such a higher mode of existence. Zarathustra also teaches the doctrine of eternal recurrence, implying that moment is eternity, changelessness within change. Multifarious manifestations are the expression of the Tao. Everything is interconnected and interdependent. Whereas ordinary men see the continuity of phenomena as real, enlightened beings are aware of the transitory and illusive nature of the self and all things. The Nietzschean Übermensch embodies the characteristics of an enlightened being, a Buddha or Bodhisattva in Buddhist terms, characteristics such as wisdom and compassion. Therefore, the practice of the Bodhisattva is explored as a feasible way for actualizing the Nietzschean hypothetical Übermensch. / Thesis (DPhil)--University of Pretoria, 2009. / Philosophy / unrestricted