A tuberculose (TB) é uma doença infecciosa bacteriana causada por Mycobacterium tuberculosis (Mtb), acomete seres humanos em todo mundo, e é considerada uma das principais causas de morbidade e mortalidade dentre as doenças infecciosas. Nesse cenário, a TB ainda é vista como um grande desafio para a ciência e para medicina. Com o estudo de novos alvos moleculares para terapia e diagnóstico, por exemplo, a sinalização Notch tem sido descrita como uma via importante para a manutenção da resposta imunológica durante a infecção por Mtb. Assim, o objetivo deste trabalho foi avaliar a participação da via Notch na modulação da resposta imune durante a infecção por Mtb em humanos. Neste trabalho foram incluidos 13 pacientes com tuberculose ativa e 13 indivíduos saudáveis. Células mononucleares de sangue periférico (PBMCs) foram isoladas e avaliadas quanto à expressão de receptores Notch 1 - 2 em células T e ligantes Notch, DLL1 - 4 em subpopulações de monócitos por citometria de fluxo e expressão de genes relacionados à via Notch e resposta imune. Além disso, o plasma foi utilizado para avaliar níveis de citocinas, CD14s e CD163s. Ainda, avaliamos a função celular dependente da ativação da via Notch durante a infecção de células mononucleares de sangue periférico de indivíduos saudáveis com Mtb H37Rv in vitro. Observamos que pacientes com TB ativa apresentaram aumento na expressão de DLL4 em monócitos intermediários e não-clássicos e diminuição na expressão de Notch 2 em células T CD8+. In vitro, observamos nas culturas de PBMCs, aumento da expressão de DLL4 em monócitos intermediários e Notch 2 em células T CD4+. A expressão do ligante DLL4 em monócitos intermediários e a expressão do Notch 1 em células T CD4+ em pacientes com TB ativa se correlacionaram positivamente com o grau de lesão pulmonar. Além disso, pacientes com quadros de lesão pulmonar moderado e avançado têm maior expressão de Notch 1 em células T CD4+ quando comparados a pacientes com grau mínimo de lesão pulmonar. Pacientes com TB ativa apresentam aumento significativo nos níveis plasmáticos de IL-6, IP- 10, CD14s e CD163s e diminuição nos níveis de IFN-?, IL-17A, IL-4, IL-2, IL-1? e RANTES. Os níveis plasmáticos de IFN-?, TNF-?, IL-17A, IL-4, IL-2, IL-12, IL-1?, RANTES e IL-10 se correlacionaram positivamente com o maior grau de lesão pulmonar.Além disso, demonstramos que os níveis de IFN-?, IL-17A, IL-1?, IL-4 e IL-2 se relacionam com maior expressão do receptor Notch 1 em células T CD4+ , enquanto níveis plasmáticos de IP-10, CD163s e de procalcitonina se correlacionam com maior expressão de Notch 1 em células T CD8+. Evidenciamos maior tendência na expressão de HES1 em pacientes com TB ativa e células infectadas in vitro, indicando que a via Notch está sendo ativada durante a infecção por Mtb. De forma interessante, in vitro as culturas de PBMCs tratadas com inibidor farmacológico da via Notch (GSI), reduziram a produção de IL-17A, IL-2 e IL-10 e aumentaram IL-8, enquanto o tratamento com anti-hDLL4 promoveu o aumento significativo nos níveis de TNF-? e atividade fagocítica de monócitos. Em conclusão, a expressão de receptores e ligantes Notch é alterada durante a TB, em especial o ligante DLL4 em subpopulações de monócitos. Além disso, a via Notch parece ser importante na modulação de respostas pró e anti-inflamatórias. Nesse trabalho, sugerimos que a expressão de Notch 1 em células T e DLL4 em subpopulações de monócitos estão associados com a gravidade da TB. Assim, a detecção desses constituintes da via Notch em PBMCs de pacientes com TB ativa são potenciais biomarcadores para avaliar a progressão da doença. / Tuberculosis (TB) is a bacterial infectious disease caused by Mycobacterium tuberculosis (Mtb), affects humans worldwide, and is considered a major cause of morbidity and mortality among infectious diseases. In this scenario, TB is still seen as a major challenge for science and medicine. With the study of new molecular targets for therapy and diagnosis, for example, Notch signaling has been described as an important pathway for the maintenance of immune response during Mtb infection. Thus, the objective of this work was to evaluate the participation of the Notch pathway in the modulation of the immune response during Mtb infection in humans. In this study, 13 patients with active tuberculosis and 13 healthy individuals were included. Peripheral blood mononuclear cells (PBMCs) were isolated and evaluated for Notch 1 - 2 receptor expression in T cells and Notch, DLL1 - 4 ligands in monocyte subpopulations by flow cytometry and expression of Notch - pathway related genes and immune response. In addition, plasma was used to assess levels of cytokines, CD14s and CD163s. Furthermore, we evaluated the cellular function dependent on the activation of the Notch pathway during the infection of peripheral blood mononuclear cells of healthy subjects with Mtb H37Rv in vitro. We observed that patients with active TB had increased DLL4 expression in intermediate and nonclassic monocytes and decreased expression of Notch 2 in CD8+ T cells. In vitro, we observed in the cultures of PBMCs, increased expression of DLL4 in intermediate monocytes and Notch 2 in CD4+ T cells. The expression of the DLL4 linker in intermediate monocytes and the expression of Notch 1 in CD4+ T cells in patients with active TB correlated positively with the degree of lung injury. In addition, patients with moderate and advanced lung injury have higher Notch 1 expression in CD4+ T cells when compared to patients with a minimal degree of lung injury. Patients with active TB showed a significant increase in plasma levels of IL-6, IP-10, CD14s and CD163s, and decreased levels of IFN-?, IL-17A, IL-4, IL-2, IL-1? and RANTES. The plasma levels of IFN-?, TNF-?, IL-17A, IL-4, IL-2, IL-12, IL-1?, RANTES and IL-10 correlated positively with the highest degree of lung injury. In addition, we demonstrated that levels of IFN-?, IL-17A, IL-1?, IL-4 and IL-2 are related to higher Notch 1 receptor expression in CD4+ T cells, whereas plasma levels of IP-10,CD163s and procalcitonin correlate with increased Notch 1 expression in CD8+ T cells. We have shown a greater trend in HES1 expression in patients with active TB and in vitro infected cells, indicating that the Notch pathway is being activated during Mtb infection. Interestingly, in vitro cultures of PBMCs treated with the Notch pharmacological inhibitor (GSI), reduced IL-17A, IL-2 and IL-10 production and increased IL-8, while anti-hDLL4 treatment promoted the significant increase in TNF-? levels and monocyte phagocytic activity. In conclusion, the expression of Notch receptors and ligands is altered during TB, especially the DLL4 linker in monocyte subpopulations. In addition, the Notch pathway appears to be important in modulating pro and anti-inflammatory responses. In this work, we suggest that Notch 1 expression in T cells and DLL4 in monocyte subpopulations is associated with TB severity. Thus, detection of these constituents of the Notch pathway in PBMCs of patients with active TB are potential biomarkers to assess disease progression.

This thesis explores the relationship between sexual orientation and gender identity (SOGI) and career progression (CP) by applying a performative, post-structuralist, and queer theory influenced approach to career theory. It analyses how, that is to say in what ways and by what means, homosexual and transgender difference is produced through the processes associated with CP. It is based on 36 interviews with individuals of diverse ages and occupations who identify as Lesbian, Gay, Bisexual or Transgender (LGBT) and are based in the south-west of England. Hitherto career theory has based its understanding of CP on individual differences and/or category based explanations. The contribution of this thesis comes from using an anti-categorical understanding of difference to show how SOGI and CP are interacting disciplinary regimes. SOGI not only affects CP through assumptions about capability and suitability, but difference is constituted through CP – as the associated acts and interactions shape the way we think of ourselves, our possibilities, our becoming. Responsibility for achieving SOGI and CP is devolved to the individual, who is then often forced to prioritise one or the other. The findings show some shared patterns (which are argued to be based on situational, performative, embodied experiences not identity categories), such as minimising or compensating for difference, femininity as a locus for limiting discourse and self-employment as a mode of exclusion. Trajectories, choices and aspirations are affected, though not necessarily disadvantageously, leading to the conceptualisation of careers as queered by homosexual and transgender difference. This research contributes by arguing that rather than consider CP in terms of category based ceilings, CP and the production of difference can be understood as multiplicitous, emergent, and co-productive processes. This thesis forms a timely contribution to understanding LGBT experience during a period of intense change in social recognition, which includes discourses of normalisation, by suggesting that we still need to recognise the often subtle internal and external reiterations of heteronormative discourse that produce difference.

Introdução: A demência devido à Doença de Alzheimer (DDA) é uma alteração neurodegenerativa primária, progressiva, que se manifesta por deterioração cognitiva, particularmente a memória. O número de pessoas no mundo acima de 60 anos com diagnóstico de DDA foi estimado em 35 milhões em 2010. Essa doença apresenta atrofia predominantemente da região do hipocampo e outras regiões corticais. A maioria dos estudos avaliam os estágios pré-clínicos e iniciais da doença por meio de avaliação clínica correlacionada aos biomarcadores. Contudo, os biomarcadores não são usualmente avaliados para a doença moderada à grave, sendo sustentado apenas de forma hipotética. Objetivos: Avaliar a morfometria cerebral de controles e portadores de DDA em todos os estágios. Encontrar o perfil de neurodegeneração estrutural para todas as fases da DDA. Casuística e métodos: Foram selecionados idosos acima de 60 anos portadores de DDA (n=44) acompanhados no serviço de Geriatria do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP) e como grupo controle idosos cognitivamente saudáveis (n=16), provenientes dos diversos serviços do HCFMRP e da comunidade com idades semelhantes às do grupo de pacientes. Sujeitos com critério de demência vascular ou outras demências foram excluídos. Imagens de todo os indivíduos foram adquiridas no equipamento de Ressonância Magnética (RM) de 3T do HCFMRP por meio da sequência de imagem Gradiente Eco 3D ponderada em T1, sem agente de contraste. Dados quantitativos de volumetria e espessura cortical foram obtidos para regiões cerebrais definidas pelos atlas de subdivisões Desikan e Deutriox. Foi realizada segmentação automática com o programa Freesurfer® sem modificação. A volumetria de cada região foi normalizada pela volumetria cerebral total para minimizar o efeito de atrofia com a idade. Resultados: Como já reportadas em estudo prévios nos estágios iniciais na DDA, as regiões acometidas também apresentaram atrofia nos estágios mais avançados da doença. Não foi observada correlação significativa entre volumetria, idade e anos de escolaridade. Por outro lado, apresentou correlação significativa com o índice de avaliação cognitiva Clinical Dementia Rating (CDR) e mini-exame do estado mental (MEEM). Observamos redução da espessura cortical para a região do giro parahipocampal em todas as fases da progressão da DDA em concordância com a literatura que, no entanto, avaliaram somente as fases iniciais. Para demais regiões descritas, como assinatura cortical, lobo temporal, parietal e frontal observamos redução somente nos estágios moderados e avançados da DDA. Discussão e Conclusão: Concluímos que as regiões cerebrais mais afetadas pela DDA atrofiam linearmente com a progressão da doença, até as fases mais avançadas. Ao contrário de modelos hipotéticos que consideravam maior atrofia volumétrica nas fases iniciais e um platô nas fases avançadas. Essas regiões estão muito relacionadas à perda neuronal e gliose já descrita há 40 anos e ao dano patológico da doença. Enfim, os resultados de morfometria por RM indicam a atrofia como biomarcador mesmo nas fases avançadas da DDA. Esses achados possibilitam maior compreensão do processo fisiopatológico e o acompanhamento de potenciais drogas modificadoras da doença mesmo nas fases mais avançadas. Palavras-chave: Doença de Alzheimer, Idosos, Volumetria, Progressão da doença de Alzheimer / Background: Dementia due to Alzheimer\'s disease (DAD) is a primary neurodegenerative disorder, progressive, manifested by cognitive impairment, particularly memory. The number of people worldwide over age 60 diagnosed with DAD has been estimated at 35 million in 2010. This disease has predominantly atrophy of the hippocampus and other cortical regions. Most studies evaluate the preclinical and early stages of the disease through clinical evaluation correlated the biomarkers. However, it is not often evaluated biomarkers for moderate to severe disease, being sustained only hypothetically. Objective: To evaluate the brain morphometry of controls and patients with DAD at all stages. Finding the structural neurodegeneration profile for all stages of Alzheimer\'s disease. Methods: We selected DAD patients (n = 44), over 60 years, followed at the Geriatric Service HCFMRP and individuals cognitively healthy for control group (n = 16) with age paired, from the different departments of HCFMRP. Subjects with vascular dementia criteria or other dementias were excluded. Images were acquired of all individuals in 3T equipment at HCFMRP by the sequence of 3D image weighted Gradient Echo T1 without contrast agent. Quantitative data of volumetry and cortical thickness were obtained for brain regions defined by Desikan and Deutriox subdivisions atlas. Automatic segmentation was performed with Freesurfer® program without modification. The volumetry of each region was normalized by the total volumetric brain to minimize the effect of atrophy with age. Results: The regions affected in DAD in the early stages, as reported in previous study, also showed atrophy in the later stages of the disease. There was no significant correlation between volumes, age and years of schooling. On the other hand, showed a significant correlation with cognitive evaluation indexes MMSE and CDR. We observed a reduction of the cortical thickness for the parahippocampal gyrus for all stages of the progression of DAD in agreement with the literature have evaluated the early stages only. For other regions described as cortical signature, temporal lobe, parietal and frontal observed reduction only in moderate and advanced stages of the DDA. Discussion and Conclusion: We conclude that the brain regions most affected on DDA atrophy linearly with disease progression until more advanced stages. Unlike hypothetical models considered higher volumetric atrophy in the early stages and a plateau in the advanced stages. These regions are closely related to neuronal loss and gliosis already described 40 years ago and the pathological damage of the disease. Anyway, the results of morphometry MRI indicate atrophy biomarker even in advanced stages of the DDA. These findings enable greater understanding of the pathophysiological process and monitoring of potential disease-modifying drugs even in the later stages

Extreme sport participation has traditionally been conceptualized as a psychological disorder and something to be avoided (Cashmore, 2002). Viewed in this way, these individuals are thought to be enacting an unhealthy psychology (Ogilvie, 1997; Slanger & Rudestam, 1997). Other research has described participants in extreme sports as sensation seekers under-stimulated by their normal surroundings and out of control (Zuckerman, 1979). Using Brymer's (2005) focused definition of extreme sports, "activities where a mismanaged mistake or accident would most likely result in death, as opposed to injury" (p. 5), this study utilized a phenomenological method to analyze semi-structured interviews with 16 free-solo climbers (n =16). The participants described their motivations in terms of overwhelming enjoyment, heightened focus, and personal progress. These results support more recent research describing extreme sport experiences as opportunities for positive transformation with outcomes including gains in courage, humility, eco-centrism, and emotional engagement (Brymer, 2009; Willig, 2008). These findings challenge the traditional, stereotypical notions of extreme sports participants as young and male (Wheaton & Beal, 2003), sensation-seeking (Zuckerman, 1979), and psychologically unwell (Ogilvie, 1997; Slanger & Rudestam, 1997). Answering Brymer's (2005) call to investigate all extreme sports individually, this study focused on the specific extreme sport of free-solo climbing and found the experience of the free-solo climber is a powerful undertaking enjoyed by young, old, male, and female.

Par nature, le théâtre a partie liée avec le temps. Dans les sept pièces conservées de Sophocle, χρόνος est au cœur du discours des personnages, comme sujet de leur réflexion sur l’existence, mais aussi comme agent de la progression du drame. Au premier niveau, son action est destructrice, car l’homme de Sophocle, « homme d’un jour » (Aj.399 et Ant. 790), éprouve durement sa nature brutale, faite de revirements arbitraires, auxquels il résiste autant qu’il peut, à moins qu’il ne s’en joue. Mais au second niveau, celui de la dynamique de l’action, le temps est aussi constructeur de l’effet tragique. En atteste le lexique, important et varié, capable de rendre visible la fatalité en marche au sein de la tragédie. Ainsi, le temps, non représentable puisqu’il échappe à la mimèsis, peut servir de révélateur à la tension latente, qu’on appelle communément le tragique, concept flou et jamais véritablement défini par les textes, et qui va trouver ici une consistance poétique et une définition nouvelle dans l’observation des choix d’écriture du dramaturge. Ce faisant, c’est la démarche créatrice de Sophocle que l’on interroge. L’analyse du vocabulaire dans des passages choisis dément sa réputation d’auteur peu spectaculaire : retard, hâte, revirements, hasard, opportunité…sont mis en valeur au cœur des vers comme des indicateurs majeurs de la marche du drame vers sa fin. Et si l’on croise ensuite les données lexicales avec les marques de l’énonciation et les éléments des rites civiques qui affleurent dans les textes, on distingue alors la concaténation assurant la cohésion des ensembles et forgeant la temporalité propre à chaque pièce. Du rapport contraint entre le temps dramatique et le temps scénique, Sophocle a tiré des effets originaux qui forment sa poétique. Comme l’aède-démiurge d’Homère, le dramaturge construit ses tragédies en charpentier de l’effet tragique. Il fabrique un présent dramatique parsemé de signes indiciels marquant le passage de χρόνος. Ce présent, troublé par le passé qui s’y déploie encore, est celui de l’inadaptation du héros, tout à la fois temps de l’urgence, du retard, de l’immobilité qu’il faut conjurer pour que la perspective d’un futur puisse prendre forme. La tragédie sophocléenne s’avère finalement très consciente d’elle-même, développant un langage performatif qui entraîne à l’action, disant le rapport sensible de l’homme au temps et tout à la fois sa propre relation au temps qui la compose.MOTS-CLÉS : tragédie-effet tragique-deixis-temps-temporalité / By nature, theatre and time are linked. In Sophocles’ seven remaining tragedies, χρόνος is in the heart of the characters’ speeches, as a subject of their thought about human life, but first of all, as an agent of the progressing plot. On the first level, his action is destructive, because Sophocles’ hero, “a man of one day” (Aj. 399 and Ant.790), is afflicted by the brutal nature of time, made of arbitrary reversals to which he tries to resist to, as much he can, unless he makes light of them. But, on the second level, action in progress, time is also constructive of the tragic effect. This is attested by many and diverse words, showing fate going through the tragedy. So, time, that is impossible to represent on stage, because it is outside of the mimesis, reveals the hidden tension, commonly named the tragic, a woolly concept, never really defined by the texts, which will find here a poetic consistency and a new definition by the observation of the playwright’s choices. Thus, it is Sophocles’ creative reasoning that is analysed. According to the vocabulary in some passages selected, his reputation of not being a very spectacular author is belied: delay, haste, reversals, luck, opportunity… are highlighted in the texts, as major indicators of the action progressing to its end. And then, by crossing the lexical data, the enunciation marks and elements of civic rituals showed on the surface of the texts, we can then clearly distinguish the logical sequences of events making the tragedies’ coherence and the own temporality of each work. Sophocles builds his tragedies like a “carpenter” of the tragic effect. He makes up a dramatic present scattered with a plenty of signs showing χρόνος going through. At the end, Sophoclean tragedies are conscious of their own structure, because they develop a performative language to speak about the sensitive relation between man and time, and also, about their relation with time making of their poetic organization.KEYWORDS: tragedy-tragic effect-deixis-time-temporality

This study seeks to answer the question of what significant barriers are present for women managers in the organisational structure of hotels in Australia and New Zealand that impedes their progress to top management positions. Women seem to be under-represented at senior management levels in hotel companies and this exploratory research endeavoured to find out why this is the case.The research was carried out in conjunction with a major international group represented by more than 30 hotels in both countries. It consisted of an online survey sent to the hotel group's female supervisors and managers and a series of 18 follow up interviews. There was a high response rate to the survey and from respondents wishing to be interviewed. Issues arising from the research included organisational culture, the Old Boy Network, geographical mobility, role models, and the pathway to General Manager.The research concluded that for female managers aspiring to proceed up the career ladder in Australian or New Zealand hotels, it would be difficult for them to combine family life and career in the same manner as their male colleagues. There were also negative aspects of hotel culture and organisational practices that disadvantaged women at various stages of their career life cycle. If hotels companies wish to retain more women, they need to review whether their organisations consist of 'opportunity 'structures' (Scully 2003) or 'inequality regimes' (Acker 2006) for women.

Les tissus de verre imprégnés d'une matrice de type époxyde constituent le matériau de base des circuits imprimés. Après imprégnation du tissu par la résine, des défauts (striations, absence locale de résine, dryness, ...), rédhibitoires pour la fiabilité diélectrique et structurale, peuvent être observés. Ces défauts sont attribués en général à un « mauvais mouillage » du tissu, sans que l'on sache précisément le définir.<br />La mouillabilité du tissu, au sens thermodynamique du terme, est-elle réellement en cause? <br />Pour apporter des éléments de réponse à cette question, nous avons cherché à caractériser les propriétés de surfaces des tissus aux échelles microscopique et macroscopique.<br />La caractérisation microscopique a permis d'apprécier l'homogénéité des traitements des tissus et d'identifier les fonctions chimiques présentes.<br />La caractérisation macroscopique, fondée sur le suivi de la progression capillaire dans un tissu, a représenté l'essentiel de ce travail. L'approche suivie repose sur une évolution du modèle de Washburn initialement adapté aux milieux poreux isotropes. Il a été complété pour prendre en compte les spécificités du milieu poreux hiérarchisé anisotrope qu'est le tissu de verre : existence de deux populations de canaux (macro- et micro-canaux correspondant respectivement à l'espace entre les fils et à l'espace entre les filaments), grande surface d'échange (rôle de l'évaporation du liquide imprégnant), couplages dans le mouillage des fils de directions orthogonales (existence d'un double front de progression capillaire).<br />A l'issue de ce travail, un protocole de caractérisation, permettant la mesure des rayons capillaires au sein des structures tissées, mais aussi de la composante dispersive de l'énergie de surface et du caractère acide/base des tissus de verre, a été défini et validé. La connaissance de ces caractéristiques, couplée à l'analyse des résines d'imprégnation, permet de progresser dans l'estimation de la compatibilité renfort/matrice.

Nous étudions la répartition des zéros non triviaux de la fonction Zêta de Riemann. Plus précisément, nous montrons qu'il n'y en a pas dans une région à gauche de l'axe $\Re s =1$ de la forme : \Re s \ge 1- \frac1(R_0 \log (|\Im s|+2)), où R_0=5.70175. Les méthodes élaborées dans ce cas se généralisent alors à celui des fonctions de Dirichlet et nous établissons que les fonctions L associées à un module q fixé ne s'annulent jamais dans la région~: \Re s \ge 1- \frac1(R_1 \log(q\max(1,|\Im s|))) où R_1=6.4355, à l'exception d'au plus une d'entre elles qui correspondrait alors à un caractère réel et qui aurait au plus un zéro réel dans cette zone (qu'on appelle zéro de Siegel). De plus, nous précisons que chaque fonction associée à un caractère donné possède au plus quatre zéros très proches de l'axe réel dans la région \Re s \ge 1- \frac1(R_4 \log(q\max(1,|\Im s|))) où R_4=2.58208. Enfin, nous appliquons nos résultats à la répartition des nombres premiers dans une progression arithmétique de la forme (a+nq). Nous établissons ainsi que le plus petit d'entre eux (qu'on notera P(a,q)) vérifie P(a,q) \le \exp\big(\alpha(\log q)^2\big) où \alpha=6.95015 pour q\ge10^6.

Der Beitrag fasst die Ergebnisse einer Forschungsarbeit zur Verbalflexion in Lehrplänen und Lehrwerken für den Französischunterricht an allgemeinbildenden Gymnasien der Bundesrepublik Deutschland zusammen. Im Mittelpunkt steht ein Problem, das bereits in der frühesten fächerübergreifenden Methodik des modernen Fremdsprachenunterrichts aufgeworfen wurde. (Seidelmann, Christian Friedrich: Tractatus philosophico-philologicus de methodo recte tractandi linguas exoticas speciatim gallicam, italicam et anglicam (1724). Faksimiliert, übersetzt und herausgegeben von Franz Josef Zapp und Konrad Schröder, Augsburg 1984.) Seidelmann hat schon vor mehr als 250 Jahren darauf hingewiesen, daß für den Fremdsprachenunterricht ungeeignete Grammatiken zur Verfügung stehen. Sie weisen einerseits Lücken auf und enthalten andererseits unnötigen Ballast: 'Ne quisquam sibi persuadeat, Grammaticas, maximam partem hodiernas, esse compendia, in quibus Linguarum fundamenta sive prima principio contineantur .... ' ('Niemand darf der Meinung sein, daß die Grammatiken, und erst recht die derzeitigen, Zusammenfassungen sind, die die Grundlagen oder die wichtigsten Elemente der Sprachen enthalten.') Seidelmann 1724; zitiert nach der zweisprachigen Ausgabe von Zapp und Schröder, Augsburg 1984, S. 81. <br /> <br /> Vor bald 100 Jahren betonte Viëtor im Zusammenhang mit der Diskussion um die 'Überbürdung' der Schüler die Notwendigkeit, die Verbalflexion gewissermaßen 'auszumisten'. Wie meine Arbeit u.a. zeigt, reichen ganze 42 Verbparadigmen aus, um das Lernziel der kommunikativen Kompetenz zu realisieren. Das heißt, man kann auf über die Hälfte der bis zu 90 Verbalparadigmen, die in Lehrwerken für den Französischunterricht vermittelt werden, verzichten. Die 42 Konjugationsmuster können als Teil eines nach kohärenten Prinzipien konstituierten und in diesem Sinne genormten sprachlichen Grundstocks für unterschiedliche Lehrgangstypen betrachtet werden. Dieser Grundstock läßt sich schulartübergreifend und adressatenunabhängig, d.h. in Lehrmaterialien für allgemeinbildende und berufsbildende Schulen, verwenden. Außerdem wird noch ein Vorschlag für die Progression der Lehrinhalte der Verbalflexion über vier bzw. zweieinhalb Schuljahre unterbreitet.

Prostate cancer constitutes the most common malignancy and the most common cause of cancer‐related death in Swedish men. A large body of evidence suggests that inherited genetic variants contribute to both development and progression of prostate cancer. The aim of this thesis is to identify genetic variants that alter prostate cancer risk and progression. All papers included in this thesis are based on a Swedish population‐based case‐control study (CAPS) comprising 2,965 incident prostate cancer cases and 1,823 controls. In paper I, we investigated if genetic variants in the E‐cadherin gene altered prostate cancer risk. Seven haplotype tagging SNPs(tagSNPs) were selected and genotyped in CAPS and families with hereditary prostate cancer. We confirmed association of a promoter SNP rs16260 previously reported to increase risk of hereditary prostate cancer (OR: 2.6; 95% CI: 1.6‐4.3) for homozygous ‘A’ carriers. In paper II, we assessed 46 polymorphisms earlier reported to be associated with prostate cancer risk. Six polymorphisms in five different genes were replicated. Interestingly, three of these genes were involved in the androgen biosynthesis. In paper III, we followed up on the results from paper II by genotyping 23 tagSNPs located in the hormone regulating genes AR, CYP17 and SRD5A2. Multiple SNPs and haplotypes were associated with prostate cancer risk, especially in the AR gene. Combining risk alleles from all genes revealed a substantial risk increase for each additional allele carried (OR: 1.12; 95% CI: 1.1‐1.2, P=0.00009). In paper IV, we collected information about cause of death for all case patients in CAPS. At time of follow‐up 300 study subjects were deceased from prostate cancer. We assessed AR, CYP17 and SRD5A2 variants for association with lethal prostate cancer and found overall no association. However, one AR promoter SNP was associated with an increased risk of dying from prostate cancer amongst men who received palliative hormonal therapy as primary treatment. In paper V, we assessed common genetic variation at the ERG locus for association between prostate cancer risk and survival. ERG is recognized as a protooncogene frequently overexpressed in prostate cancer. A total of 21 tagSNPs in the 5’ region of ERG were genotyped. There was no correlation between ERG SNPs and prostate cancer risk but common genetic variation located approximately 100,000 basepairs upstream of ERG was significantly associated with prostate cancer specific survival. In summary, our results suggest that common genetic variation in Ecadherin alters prostate cancer risk in Swedish men with a positive family history of prostate cancer. Moreover, common genetic variation in the androgen‐related genes AR, CYP17 and SRD5A2 affects the risk of developing prostate cancer but is unlikely to alter prostate cancer progression. However, genetic variants in AR may affect hormonal therapy response. Finally, ERG polymorphisms are associated with prostate cancer‐specific death but are not likely to play a role in prostate cancer development.