Bien qu’évoluant dans un cadre national dépourvu d’institutions étatiques, le Hamas exerce bel et bien une politique étrangère qui s’explique bien plus par les intérêts que par l’idéologie. L’analyse des processus de décision internes au mouvement le confirme. Agissant comme des filtrent des intérêts et des propositions idéologiques, ces processus, plus ou moins inclusifs en fonction du contexte et de la nature des décisions, illustrent l’importance des intérêts et la marginalité du rôle de l’idéologie. Seule la trêve conclue en juin 2008 avec Israël a donné lieu à des divergences idéologiques et à conduit au départ de certains membres de la branche armée du mouvement qui ont alors choisi de rejoindre des groupes salafistes. Au-delà de ces divergences, les intérêts des différents acteurs au sein du Hamas convergent au moins parce qu’ils cherchent tous à garantir la prépondérance politique de leur mouvement. La politique étrangère leur permet de réaliser un certain nombre d’intérêts à la fois extérieurs et intérieurs: obtenir la reconnaissance diplomatique et symbolique, rechercher des ressources matérielles, assurer leur domination sur la bande de Gaza et enfin concurrencer leurs adversaires nationalistes et islamistes. Les propositions idéologiques sont constamment adaptées pour accompagner la défense de ces différents intérêts. / The present thesis argues that the Palestinian movement Hamas pursues its own foreign policy even though it may be considered a non state actor, or a semi-state actor at best. The key independent variables determining this foreign policy are internal decision-making processes and various types of interests that in the vast majority of cases prevail upon ideological considerations. Decision making processes vary from period to period and sometimes from case to case. Sometimes their output reflects a compromise of competing interests, even though these compromises are always biased in favour of the stronger groups or factions within the movement. Only the 2008 truce with Israel gave rise to substantial ideological debates which left their trace in the run-up to this event and subsequent cleavages and defections, in particular to the al-Qassam brigades. In spite of various diverging interests, the leaders and members of Hamas share a basic objective which is to guarantee the political supremacy of their movement in Palestine. Its foreign policy enables Hamas to pursue a number of interests both external and internal: to obtain diplomatic and symbolic recognition, mobilize material and symbolical ressources, secure its domination over the Gaza strip, and compete with its nationalist and islamist opponents. Ideological propositions are constantly adapted to these different interests.

Research suggests that the construction industry plays a crucial role in the fight against climate change and global warming. In 2010, the building sector answered for 30% of the global CO2 emissions and 32% of the total energy use. By adopting life-cycle assessments (LCA), the construction companies have a chance to improve indicators for economic, social and environmental sustainability. The Swedish government is in the process of making climate declarations of buildings, through LCA, a requirement to steer the industry towards more sustainable development.This study aims to show what barriers there are for wide adoption of LCA in the Swedish construction sector today and how these barriers are related to the rate of adoption. Furthermore, the study aims to investigate if there are differences in barriers between big and small actors in the industry. The study is guided by the theory “Diffusion of Innovations” by Everett Rodgers. The main method for data collection has been semi-structured interviews with people in the Swedish construction industry.The main barriers identified were lack of demand and lack of regulation. The study shows that the relative advantage of LCA is not perceived as high enough for it to be widely adopted without an increase in demand. It is also shown that high demand on a wide front is unlikely to happen without regulation. Furthermore, this study shows that the barriers are the same for actors of different sizes. The difference is the ability to deal with the barriers. Much of that ability can be ascribed to how much resources are available within the company. / Forskning tyder på att byggbranschen spelar en avgörande roll i kampen mot klimatförändringar och global uppvärmning. Byggnadsbranschen svarade 2010 för 30% av de globala koldioxidutsläppen och 32% av den totala energianvändningen. Genom att anta livscykelanalyser (LCA) har byggföretagen möjlighet att förbättra indikatorerna för ekonomisk, social och miljömässig hållbarhet. Den svenska regeringen håller på att göra klimatdeklarationer av byggnader, genom LCA, till ett krav för att styra industrin mot en mer hållbar utveckling.Denna studie syftar till att visa vilka hinder det finns för bred implementering av LCA i den svenska byggbranschen idag, och hur dessa hinder är relaterade till upptagandet. Vidare syftar studien till att undersöka om det finns skillnader i hinder mellan stora och små aktörer i branschen. Studien guidas av teorin "Diffusion of Innovations" av Everett Rodgers. Huvudmetoden för datainsamling har varit semi-strukturerade intervjuer med utvalda personer i den svenska byggbranschen.De viktigaste hindren som identifierades är brist på efterfrågan och brist på reglering. Studien visar att den relativa fördelen av LCA inte uppfattas som tillräckligt hög för att den ska vidtas allmänt utan att efterfrågan ökar. Det visas också att hög efterfrågan på en bred front sannolikt inte kommer att ske utan reglering. Vidare visar denna studie att hindren är desamma för aktörer av olika storlekar. Skillnaden är förmågan att hantera barriärerna. Mycket av den förmågan kan hänföras till hur mycket resurser som finns inom företaget.

Syftet med undersökningen var att undersöka skillnader i elitidrottssatsande gymnasieungdomars attributionsstil vid motgång jämfört med framgång. I studien undersöktes skillnader mellan individuella- jämfört med lagidrotter samt skillnader mellan kvinnor och män. Totalt deltog 209 idrottare (76 kvinnor och 133 män), varav 85 individuella idrottare och 124 lagidrottare. Metoden bestod av en digital enkät uppbyggd på två situationer; en period av motgång och en period av framgång. För de båda situationerna mättes intern attribution, stabil attribution och upplevd påverkansgrad. Resultatet visade signifikanta skillnader mellan situationerna, där orsaksförklaringen vid framgång i högre grad beskrevs bero på utövaren själv (intern attribution) än vid motgång. Även graden av stabil attribution var högre vid framgång, alltså att orsaksförklaringen ansågs komma att bestå framöver. Vidare visade resultatet att män i högre utsträckning gör interna attributioner än vad kvinnor gör. Och slutligen påvisades att individuella idrottare i högre utsträckning använde sig av interna attributioner jämfört med lagidrottare och även att individuella idrottare upplever en högre grad av påverkan. / The aim of the study was to investigate differences in the attribution style of high school youth participating in elite sports in the event of adversity compared to success. The study examined differences between individual versus team sports as well as differences between women and men. A total of 209 athletes participated (76 women and 133 men), of which 85 were individual athletes and 124 were team athletes. The method consisted of a digital survey built on two situations; a period of adversity and a period of success. For both situations, internal attribution, stable attribution and perceived degree of influence were measured. The result showed significant differences between the situations, where the causal explanation in the case of success was described to a greater degree as being due to the practitioner himself (internal attribution) than in the case of failure. The degree of stable attribution was also higher in the case of success, meaning that the causal explanation was considered to persist in the future. Furthermore, the results showed that men more often use internal attributions, than woman do. And finally, it was shown that individual athletes used internal attributions to a greater extent compared to team athletes and also that individual athletes experience a higher degree of influence the situation.

The thesis is focused on construction of Czech national identity in press (MF DNES January - June 2010). It describes this complex problem in the way of discourse analysis. Therefore, there is not used special or particular research method, because the subject of matter is approached and thought by ontological and epistemological assumptions behind it. The objective of the work is find system, which characterizes construction of Czech national identity, Czech patriotism and Czech character. There must be emphasized that it is not providing absolute answers to the specific problem, but enable us to understand the conditions behind it. First of all, there is shown thinking about Czech national identity from the historical point of view. There are described presumptions of Czech identity and character from the times of Karel Čapek and Tomáš G. Masaryk. Secondly, there is shown contemporary discourse through the study of different levels of the media text, the concepts of Teun van Dijk or Jack Lule are involved.

This paper is about usage of accounting information in financial analysis. In the first part financial statements under Czech Accounting Standards and under International Financial Reporting Standards are described. The most important differences are discussed. In the second part methods of financial analysis are explained. In the third part practical financial analyses are done for the companies Vodafone Czech Republic, a.s. (reports under CAS) and Telefónica O2 Czech Republic, a.s. (reports under IFRS). Main differences in financial analysis which rise from different accounting standards are discussed.

Les ARN non-codants exercent des rôles essentiels au sein de nombreux processus biologiques, allant de la régulation de l’expression génique à l’activité enzymatique. Afin de remplir leurs fonctions cellulaires, ces ARN doivent adopter des structures tridimensionnelles spécifiques, et mieux comprendre ces structures et leur dynamique est crucial pour élucider leur mécanisme d’action et créer des ARN possédant de nouvelles fonctions. Afin de mieux comprendre la structure, la dynamique et l’ingénierie des ARN, notre laboratoire étudie le ribozyme VS de Neurospora, un petit ARN (~160 nucléotides) possédant une activité catalytique. Le ribozyme VS a été découvert il y a une trentaine d’années chez certains isolats naturels du champignon microscopique Neurospora. Ce ribozyme a fait l’objet d’études approfondies et est considéré comme étant un système modèle idéal pour étudier la structure et la fonction de l’ARN in vitro, en raison de sa taille relativement petite, de sa structure tridimensionnelle complexe et de son activité enzymatique facilement détectable. Comme plusieurs autres ribozymes de sa famille, le ribozyme VS catalyse des réactions de clivage et de ligation d’une liaison phosphodiester spécifique. Toutefois, il a la capacité unique de reconnaître et de cliver un substrat isolé, replié sous forme de tige-boucle, par l’entremise d’une interaction boucle-boucle extrêmement stable, une caractéristique intéressante d’un point de vue de l’ingénierie de l’ARN. Des structures cristallines récentes ont fourni de l’information importante à propos de l’état fermé du ribozyme, qui comprend un site actif pré-catalytique. Toutefois, des études récentes ont plutôt démontré que le ribozyme VS adopte un état ouvert en solution et il n’existe que très peu d’information structurale sur cet état et sur les mécanismes de transition menant à la forme fermée. Afin de caractériser la structure du ribozyme en solution, une stratégie modulaire de divide-and-conquer a été entreprise et des structures RMN à haute résolution de chacun des sous-domaines structuraux clés ont été déterminées. Cette thèse vise à caractériser la structure du ribozyme VS complet en solution et à explorer sa capacité à cliver une molécule d’intérêt différente de son substrat naturel. Dans un premier temps, une étude d’ingénierie a été entreprise afin de créer des variants du ribozyme VS capables de reconnaître une tige-boucle d’ARN dérivée de l’Élément de Réponse de Transactivation du virus d’immunodéficience humaine (VIH). Ainsi, des variants hautement actifs du ribozyme ont été identifiés par sélection in vitro et une étude complémentaire de dynamique moléculaire a démontré que l’interaction boucle-boucle agit à titre de charnière dynamique et facilite la formation de l’état fermé du ribozyme. L’approche structurale de divide-and-conquer a ensuite été complétée en combinant des études de RMN et de diffusion des rayons-X aux petits angles (SAXS). Ainsi, des structures à haute résolution du domaine catalytique minimal et d’un complexe formé entre un ribozyme VS plus étendu et un substrat non-clivable ont alors été obtenus. En comparant ces structures aux structures cristallines, nous avons découvert un réarrangement structural important associé à la formation du site actif. Dans l’ensemble, ces travaux offrent une meilleure compréhension de l’architecture globale du ribozyme VS et de son mécanisme d’action qui comprend un échange dynamique de multiples états conformationnels. Plus généralement, les leçons apprises ici permettront de mieux guider les expériences d’ingénierie du ribozyme VS et d’autres ARN fonctionnels. / Non-coding RNAs play essential roles in many biological processes, ranging from the regulation of gene expression to enzymatic activity. To perform their cellular functions, RNAs must adopt specific three-dimensional structures, and understanding how these structures fold is crucial to elucidate their mechanism of action. However, our fundamental understanding of the structure and dynamics of RNA at atomic resolution remains rather limited. To better understand the structure, dynamics and engineering of RNA, our laboratory is investigating the Neurospora VS ribozyme, a small RNA (~160 nucleotides) with catalytic activity. The VS ribozyme was originally found 30 years ago in natural isolates of Neurospora fungi. It has been thoroughly investigated as an ideal model system to study the structure and function of RNA in vitro, due to its small size, its complex three-dimensional structure and easily detectable activity. Like other small nucleolytic ribozymes, the VS ribozyme catalyzes the cleavage and ligation reactions of a specific phosphodiester bond. However, it has the unique ability to recognize and cleave an isolated hairpin substrate through the formation of a highly stable kissing-loop interaction, which is of great interest for RNA engineering purposes. Recent crystal structures have provided useful information on the closed state of the ribozyme, in which the active site is formed. However, the VS ribozyme is also known to adopt an open state in solution and there is still very little structural information regarding this state and how it is converted into the active closed state. In order to characterize the solution structure of the ribozyme and its dynamics, an NMR-based divide-and-conquer approach was previously undertaken in which high-resolution structures of each of the key structural subdomains were determined. The work presented in this thesis aims to characterize the structure of the complete VS ribozyme in solution and to explore its ability to cleave an RNA hairpin of interest, different from its natural substrate. First, an engineering study was undertaken to create VS ribozyme variants capable of recognizing an RNA stem-loop derived from the HIV-1 Trans-Activation Response Element RNA. Using in vitro selection, highly active ribozyme variants were identified, and their sequence analysis suggests that the improved activity observed in some variants depends on increased conformational sampling of the kissing-loop interaction. Complementary molecular dynamics studies indicate that the kissing-loop interaction acts as a dynamic hinge to facilitate the formation of the closed state of the ribozyme. Next, the divide-and-conquer approach for structural investigation of the VS ribozyme was completed by combining NMR and small-angle X-ray scattering (SAXS) data. High-resolution structures were determined for both a minimal catalytic domain and a complex between a more extended trans ribozyme and a non-cleavable substrate. By comparing these solution structures to the previously reported crystal structures, we uncovered an important structural rearrangement associated with the formation of the active site. Overall, this work provides a better understanding of the global architecture of the VS ribozyme and how it fulfills its function by dynamic exchange of many conformational states. More generally, the structural and dynamic knowledge generated from this work will help to guide future engineering studies of the VS ribozyme and other functional RNAs.

A aplicação da digestão anaeróbia aparece como opção para processamento da vinhaça, visto que por meio deste processo é possível aliar a recuperação de energia (hidrogênio e metano) ao enquadramento ambiental deste resíduo sem interferir em suas qualidades como biofertilizante. Nesse sentido, este trabalho avaliou a aplicação da digestão anaeróbia da vinhaça em sistema combinado acidogênico e metanogênico. Inicialmente, avaliou-se a influência de materiais suportes (argila expandida, carvão vegetal, cerâmica porosa e polietileno de baixa densidade) na produção de hidrogênio, em reatores de leito empacotado (APBR) operados em condição mesofílica (25°C) (Etapa 1). De uma forma geral, apenas traços de hidrogênio foram observados nos reatores preenchidos com partículas de carvão vegetal e cerâmica porosa (2 - 7,9 mL-H2.d-1.L-1 reator). Por outro lado, os valores para a produção volumétrica de hidrogênio (PVH) nos reatores com argila expandida e polietileno de baixa densidade foram dez vezes superior (74,3 - 84,2 mL-H2.d-1.L-1 reator), todavia, estatisticamente iguais. O critério de seleção do material suporte ocorreu com base em relatos na literatura que indicaram rebaixamento do leito e entupimento da saída de reatores APBR preenchidos com argila expandida. Portanto, o polietileno de baixa densidade foi escolhido como melhor opção dentre os suportes avaliados. Não obstante, a baixa relação C/N da vinhaça associada à microaeração do sistema (presença de microrganismos anóxicos) afetou severamente os reatores APBR com diferentes materiais suportes, levando-os à falência. Na segunda etapa, adotou-se a operação dos APBR preenchidos com polietileno de baixa densidade, em condição termofílica (55°C) a fim de diminuir o rendimento da biomassa acidogênica e a solubilidade do oxigênio. Adicionalmente, foi avaliada influência da Carga Orgânica Volumétrica aplicada (COVa - 36,4 - 108,6 kg- DQO.m-3.d-1), por meio da variação do Tempo de Detenção Hidráulica (TDH - 8 - 24 h). Produção contínua de hidrogênio foi observada em todos os reatores operados em condição termofílica (Etapa 2). Nessa etapa, estabeleceu-se a condição ótima de operação com COVa de 84,2 kg-DQO.m-3.d-1 e TDH de 10 h, resultando em PVH de valor 575,3 mL-H2.d-1.L-1 reator e rendimento de hidrogênio (Y1H2) de 1,4 mol-H2.mol-1 carboidratos totais. Na Etapa III, essas condições foram impostas na operação do APBR, resultando em aumento de 18,2% e 14,2% nos valores de PVH e Y1H2, respectivamente, em relação aos dados obtidos na Etapa II. Em paralelo, foram operados dois reatores metanogênicos do tipo manta de lodo (UASB), compondo um sistema único (UASB) e um sistema combinado (APBR/UASB). A produção de energia no sistema combinado foi 25,7% superior ao observado no sistema único. A eficiência de remoção da matéria orgânica total e solúvel aumentou de 60,7 ± 0,3% e 72,6% ± 1,2% no sistema único e 74,6 ± 0,3% e 96,1 ± 1,7% no sistema combinado, respectivamente, sob COVa de 25 kg-DQO.m-3.d-1 (calculada para os sistemas metanogênicos). / Anaerobic digestion application appears as an option for sugar cane vinasse processing, since via this process it is possible to combine the energy recovery (hydrogen and methane) to the environmental framework of this residue without interfering in their qualities as biofertilizer. In this sense, this study evaluated the application of anaerobic digestion of vinasse in two-stage system (acidogenic and methanogenic). Initially, it was evaluated the influence of support material (expanded clay, charcoal, porous ceramics, and low-density polyethylene) on hydrogen production in acidogenic packed bed reactors (APBR) operated under mesophilic condition (25°C) (Phase 1). In general, only traces of hydrogen were observed in APBR filled with charcoal and porous ceramics particles (2 - 7.9 mL-H2.d-1.L-1 reactor). On the other hand, in APBR with expanded clay and low-density polyethylene as support, the values for volumetric hydrogen production (VHP) were ten times higher (74.3 - 84.2 mL-H2.d-1.L-1 reactor), however, statistically equal. The selection criteria of support material was based on reports in the literature that indicated bed lowering and clogging in APBR outlet with expanded clay as support. Therefore, the low-density polyethylene was chosen as the best support among those evaluated. Nevertheless, the low C/N ratio of vinasse associated to microaeration condition in the systems (presence of microorganisms anoxic) severely affected the APBR with different support materials, leading them to bankruptcy. In the second phase, it was adopted the operation of APBR filled with low density polyethylene in thermophilic conditions (55°C) in order to reduce the acidogenic biomass yield and oxygen solubility. Moreover, it was evaluated the influence of organic loading rate (OLR - 36.4 to 108.6 kg-COD.m-3.d-1) by hydraulic retention time varying (HRT - 8 - 24 h). Continuous hydrogen production was observed in all reactors operated at 55°C (Phase 2). In this phase, it was established the optimum condition of operation, OLR of 84.2 kg-COD.m-3.d-1 and HRT of 10 h, resulting in values for PVH and hydrogen yield (Y1H2) of 575.3 mL-H2.d-1.L-1 reactor and 1.4 mol-H2.mol-1 total carbohydrates, respectively. In Phase III, these conditions were imposed on the operation of the APBR, resulting in an increase of 18.2% and 14.2% in the values of PVH and Y1H2, respectively, compared to the data obtained in Phase II. In parallel, two methanogenic reactors were operated (Up-flow Anaerobic Sludge Blanket UASB type), which composed a single stage system (UASB) and a two-stage system (APBR/UASB). The energy production in the two-stage system was 25.7% higher compared to the single stage system. The values for total and soluble organic matter removal were 60.7 ± 0.3% and 72.6 ± 1.2% to single stage system and 74.6 ± 0.3% and 96.1 ± 1.7% to two-stage system, respectively, at OLR of 25 kg-COD.m-3.d-1 (calculated for the methanogenic reactors).

Au Cameroun, l'enchaînement des reformes en matière de santé a renforcé le flottement idéologique entre deux courants opposés : un socio-universel qui promeut l'équité, et l'autre néolibéral, qui milite pour une plus grande efficacité économique des systèmes en place. Articulant deux préoccupations que sont l'aggravation des inégalités de santé comme conséquence des choix politiques portés sur l'efficacité des services sans prise en compte des facteurs qui soutiennent la demande, et les formes d'organisation de la santé qui découlent d'une traduction imparfaite des grands principes internationaux, cette thèse a pour objectif de contribuer à une réflexion critique sur le processus de fabrication, la mise en œuvre et les résultats produits par ces politiques de santé. Pour cerner la spécificité camerounaise, nous les inscrivons dans un triple champ théorique. Le courant économique néo-institutionnaliste pour saisir l'importance de l'histoire économique du pays et son influence sur l'évolution du système de santé, ce qui permet de comprendre les conditions de changement politique. Le modèle de référentiel de politique publique pour appréhender les fondements de la nouvelle politique publique, notamment la façon dont les idées et les intérêts sont formatés par les institutions. Un essai de décodage du jeu d'acteurs est entrepris en s'appuyant sur la médiation, mettant à l'épreuve les hypothèses de « l'ajustement par le haut ». Enfin, les théories de la justice sont sollicitées pour argumenter en faveur de l'existence d'un déséquilibre entre l'offre et la demande qui agit sur les résultats sanitaires et qui renforce le conflit efficacité versus équité. En effet, notre travail ambitionne d'apporter des éléments de réponses à trois questions principales : (i) Pourquoi (déclencheurs) et comment (dynamique) les politiques publiques de santé sont-elles transformées dans leur construction et leur mise en œuvre par les politiques économiques ? (ii) Quels sont les effets du changement induit par le référentiel global sur le référentiel sectoriel qui exige une distribution de l'accès aux services de santé plus équitable ? (iii) Quels enseignements peut-on tirer de la connaissance des interrelations entre la dynamique de réduction de la pauvreté et l'inaccessibilité persistante dans l'accès aux soins de santé pour une amélioration de l'évaluation des politiques publiques ? A partir d'un nombre d'indicateurs quantitatifs et qualitatifs, la robustesse de la nouvelle politique est questionnée suivant les perspectives de distribution et d'accessibilité. Dès lors, nous soulignons la difficulté à atteindre des résultats satisfaisants que ce soit en termes d'efficacité ou d'équité à cause du système institutionnel et organisationnel dans lequel elle se conçoit et se met en œuvre. Trois communautés épistémiques plus ou moins forts qui agissent de façon peu structurée sont repérées et analysées à travers un matériau qualitatif riche qui permet d'appréhender l'existence d'un conflit paradigmatique né de la façon dont les groupes se positionnent et arrivent à mettre en cohérence le référentiel sectoriel de la santé avec le référentiel global de marché qui revêt plutôt un caractère spontané et impératif. Un travail statistique et économétrique permettant de mesurer plus finement les inégalités et les déterminants d'accès et de recours aux soins par les populations soutient l'idée d'un creusement des inégalités de santé par ces politiques soutenues par des mécanismes de financement fortement régressifs. L'analyse des déterminants de survenue des dépenses catastrophiques vient également confirmer ce positionnement. Nous apprécions par la suite l'efficacité allocative et l'efficience des dépenses publiques de santé ainsi que leur impact sur l'utilisation des services et les bénéfices révélés de leur utilisation. / In Cameroon, the sequence of reforms in the health sector has reinforced an ideological wavering between two opposing currents: a socio-universal that promotes equity, and a neoliberal, which militates for greater economic efficiency of existing systems. Articulating two concerns which are, the worsening of health inequalities as consequence of policy choices made on the efficacy of services without taking into account factors that support the demand, and the form of organization of the health system arising from an imperfect translation of major international principles, this thesis aims to contributing to a critical reflection on the process, the implementation and the results produced by these health policies. To determine Cameroonian specificity, we inscribe them in a triple theoretical field. The neo-institutionalist approach, mobilize to grasp the importance of the economic history and its influence on the evolution of the health system, which allows understanding the conditions for policy change. The “referentials” approach to policy analysis in order to apprehend the foundations of the new public policy, including the understanding of how interests and ideas are formatted by institutions. An effort to illuminate the policy game is undertaken to appraise the mediation of political entrepreneurs, thereby testing empirically the “top-down hypothesis”. Finally, the theories of justice help to argue for the existence of an imbalance between health supply and demand which undermines health outcomes, and reinforces the conflict efficacy versus equity. Indeed, our work aims to provide some answers to three main questions: (i) Why (triggers) and how (dynamic) health public policies are influenced in their construction and implementation by economic policies? (ii) What are the outcomes of induced changes by the global referential (macroeconomic framework) on sectoral referential that requires a more equitable distribution and access to health services? (iii) What lessons can we learn from the knowledge of the interrelationships between the dynamics of poverty reduction and the persistence of inaccessibility to health care in order to improve the evaluation of public policies? From a number of quantitative and qualitative indicators, the robustness of the new policy is questioned following prospects regarding health distribution and accessibility. Therefore, we emphasize the difficulty of the public policy to achieve satisfactory results both in terms of efficacy or equity due to the institutional and organizational system in which it is designed and implemented. Three epistemic communities acting on a nonstructural basis are identified and analyzed through a robust qualitative material that enables us to grasp the existence of a paradigmatic conflict emerged from how different groups are positioning themselves and interpret reality in order to put in coherence the sectorial referential and the global market-based one which appears to be rather spontaneous and mandatory. Statistical and econometric works to measure more precisely the inequalities and determinants of access and use of health services by the population supports the idea of a widening of inequalities by the health policies maintained by strong regressive mechanisms. The analysis of the determinants of occurrence of catastrophic health expenditures also confirms this. We mobilize thereafter an additional material to assess the allocative efficiency and efficacy of public spending on health as well as their impact on the use of services and benefits revealed from their use.

Genetische Polymorphismen in den Enzymen CYP2D6, CYP2C19 und CYP2C9 beeinflussen die Pharmakokinetik medizinisch bedeutsamer Arzneimittel wie Antidepressiva, oraler Antidiabetika und nichtsteroidaler Antiphlogistika in erheblichem Ausmaß. In der Zukunft kann die Bestimmung genetischer Varianten bei Patienten zur Verbesserung der Arzneitherapie genutzt werden, jedoch nur dann, wenn klinische Konsequenzen wie konkrete Therapieempfehlungen aus den genetischen Daten abgeleitet werden können. An gesunden Probanden wurde die die Bedeutung der beiden Aminosäurevarianten des Enzyms CYP2C9, Arg144Cys (CYP2C9*2) und Leu359Ile (CYP2C9*3) für die Pharmakokinetik von Tolbutamid, Glibenclamid, Nateglinid, Diclofenac, Ibuprofen, Celecoxib und Fluvastatin untersucht. Die Analyse der pharmakokinetischen Parameter ergab eine erheblich erniedrigte Clearance für diese Substrate bei homozygoten Trägern der Allelvariante CYP2C9*3, wie sie etwa 1% in der Bevölkerung tragen. Um bioäquivalente Konzentrationsverläufe zu erreichen, müssten diese Patienten deutlich niedrigere Dosierungen (unter 50%) der meisten der untersuchten CYP2C9-Substrate erhalten. Hingegen zeigte die CYP2C9*2-Variante nur einen geringen Einfluss auf die Pharmakokinetik der untersuchten Medikamente. Für den Bereich der Therapie mit Antidepressiva und Antipsychotika sollte untersucht werden, inwieweit umfassende pharmakogenetisch begründete Therapieempfehlungen gegeben werden können. Eine systematische Analyse aller bisher publizierten Daten zum Einfluss von Polymorphismen von CYP2D6, CYP2C19 und CYP2C9 ergab, dass für die meisten gängigen Antidepressiva bereits Studien zur Bedeutung von Cytochrom-P450-Polymorphismen durchgeführt wurden. Für die beiden in Deutschland sehr häufig verwendeten Trizyklika Trimipramin und Doxepin dagegen lagen keine ausreichenden Daten vor. Beide Medikamente wurden deshalb bei Probanden getestet, die jeweils Träger eines oder zweier Allele mit defizienter oder herabgesetzter Enzymaktivität von CYP2D6, CYP2C19 oder CYP2C9 waren. Es ergab sich ein deutlicher Einfluss des CYP2D6-Genotyps, ein schwächerer von CYP2C19 und des Genotyps CYP2C9*3/*3. Eine Dosisreduktion für Langsam-Metabolisierer von CYP2D6 und etwas moderater für Langsam-Metabolisierer von CYP2C19, sowie für Träger des Genotyps CYP2C9*3/* erscheint für diese beiden Antidepressiva sinnvoll. Die eigenen Daten und die Daten für andere Antidepressiva aus der Literatur wurden dazu verwendet, eine Methode zur Ableitung von pharmakogenetisch basierten Dosierungsempfehlungen zu entwickeln. Auf dem Prinzip der Bioäquivalenz basierend wurden Dosierungsanpassungen für unterschiedliche Genotypen je nach Unterschieden in der Clearance von Substanzen errechnet. Durch diese Dosierungsanpassungen können zumindest theoretisch die durch herabgesetzte Enzymaktivität verursachten Unterschiede in den Plasmakonzentrationsverläufen von Medikamenten ausgeglichen werden. Dabei wurden aktive an der Arzneimittelwirkung teilhabende Metaboliten mit berücksichtigt. Auf Seiten der Pharmakodynamik wurden die vielen Studien zu genetischen Polymorphismen in Serotonin-, Dopaminrezeptoren und Transportern und auch zu anderen Kandidatengenen für die Antidepressiva-, und Antipsychotikawirkung analysiert. Jedoch lassen sich aus den teilweise geringen Einflüssen einzelner Genotypen auf die Arzneimittelwirkung derzeit noch keine pharmakodynamisch begründeten Therapieempfehlungen ableiten. Zusammenfassend lassen sich also bereits heute pharmakogenetisch basierte Dosierungsempfehlungen für viele Medikamente berechnen. Derartige Empfehlungen müssen prospektiv überprüft, validiert und angepasst werden. Auf Seiten der Zielmoleküle der Arzneimittelwirkung ist eine Ableitung genetisch basierter Therapieempfehlungen schwieriger. Das Ziel, konkrete Therapieempfehlungen aus genetischen Daten abzuleiten, ist eine notwendige Bedingung, um Pharmakogenetik in die klinische Praxis der Arzneitherapie einzuführen. / Genetic polymorphisms of the cytochrome P450 enzymes CYP2D6, CYP2C19 and CYP2C9 largely influence pharmacokinetics of clinically important drugs such as antidepressants, oral antidiabetics and nonsteroidal antiphlogistic drugs. Pharmacogenetic diagnostics is ready to be used for optimization of drug treatment in the future if concise recommendations for clinical decisions can be derived from the genetic data. Panel studies in healthy volunteers served to characterize the impact of the amino acid variants Arg144Cys (CYP2C9*2) and Leu359Ile (CYP2C9*3) in cytochrome P450 2C9 on pharmacokinetics of the oral antidiabetics tolbutamide, glyburide and nateglinide, of the nonsteroidal analgetic drugs diclofenac, ibuprofen, celecoxib, and of fluvastatin. Analysis of pharmacokinetic parameters revealed largely reduced oral clearances in homozygous carriers of the CYP2C9*3 allele for most of the substrates studied. About 1% in the general population are carriers of this genotype and patients should get about 50% lower doses of most of the CYP2C9 substrates in order to achieve similar plasma concentration versus time courses. In contrast, the CYP2C9*2 variant had little influence on pharmacokinetics of the CYP2C9 substrates. For antidepressant and antipsychotic drug therapy, the aim was to derive detailed dose recommendations from the large amount of data existing. Thus, a systematic analysis of all published data on the clinical influence of genetic polymorphisms in CYP2D6, CYP2C19 and CYP2C9 was performed and dose recommendations were given for many antidepressants. For two substances, the tricyclics doxepin and trimipramine, no pharmacogenetic data have been found, and therefore own clinical studies were performed. Healthy volunteers who were heterozygous and homozygous carriers of alleles with deficient activity of CYP2D6, CYP2C19 or CYP2C9 were tested for differences in metabolism and elimination of doxepin and trimipramine and compared to carriers of the wildtype. A significant influence of the CYP2D6 genotype was detected whereas CYP2C19 and the genotype CYP2C9*3/*3 had smaller influences. A significant dose reduction for CYP2D6 poor metabolizers and a smaller reduction for CYP2C19 poor metabolizers would be predicted from these data. According the principles of bioequivalence, calculation methods for pharmacogenetic based dose recommendations from clearance or drug concentration data were developed. Using all published data and the own study results, we developed dose adjustments for each genotype. These dose adjustments would allow to compensate for lower drug clearance caused by genetic variants. Active metabolites which contribute to overall drug effects were considered as well. With regard to target molecules of antidepressant and antipsychotic drug action, many studies have been performed on genetic polymorphisms in serotonin-, and dopamine receptors and in transporter molecules but as well in other candidate genes. However, it is not yet possible to derive therapeutic consequences based on these data. In conclusion, on the pharmacokinetic side of drug action, we are already able to give pharmacogenetic based therapeutic recommendations by adjusting the doses according to genotype. However, the benefit of pharmacogenetic dose adjustments has to be studied prospectively. With regard to the pharmacodynamic side of drug action, the situation is much more complex and we are not yet ready to give pharmacogenetics based therapeutic guidelines. However, this has to be a major goal in order to introduce pharmacogenetic diagnostic into clinical practice.

No experimento I, objetivou-se avaliar os efeitos de aditivos microbianos e tempo de armazenamento na qualidade de silagens de milho. A cultura do milho foi ensilada sem aditivos (Controle) ou com inoculantes contendo bactérias láticas homofermentativas (Lactobacillus plantarum + Enterococcus faecium + Pediococcus acidilactici) + enzimas celulolíticas e hemiceluloliticas ou heterofermentativas (Lactobacillus buchneri) aplicados na dose 1 × 105 ufc/g. As silagens foram armazenadas em silos experimentais durante 3, 7, 15, 30, 60, 210, 390, 480 ou 570 dias. Foram avaliados: composição químico-bromatológica, produtos de fermentação, perfil microbiológico, perdas fermentativas, estabilidade aeróbia e degradabilidade ruminal in situ. Os inoculantes não afetaram a maior parte das variáveis estudadas. Entretanto, L. buchneri aumentou a concentração de ácido acético das silagens e diminuiu a deterioração aeróbia, confirmada pelo menor acúmulo térmico durante o ensaio de estabilidade aeróbia. O teor de carboidratos solúveis diminuiu ao longo do tempo de armazenamento, reflexo do metabolismo dos açúcares em produtos de fermentação. As concentrações da prolamina como esperado diminuíram e as concentrações de nitrogênio amoniacal e proteína solúvel aumentaram com os tempos de armazenagem prolongados, reflexo da ocorrência de proteólise na silagem de milho. O pH da silagem diminuiu rapidamente nos primeiros sete dias de armazenamentos mantendo-se estável para os demais tempos de estocagem, diferente do ocorrido para a concentração de ácido acético, que aumentou com o tempo de armazenamento. Verificou-se diminuição na contagem de bactérias láticas e leveduras ao longo do armazenamento. A produção de gás e a perda de matéria seca aumentaram com o tempo de armazenamento. O tempo de armazenamento aumentou todas as variáveis de EA. Os ganhos mais significativos para a EA se deram até aproximadamente 60 dias de armazenamento. A degradação ruminal de amido e, consequentemente de MS, foi incrementada ao longo do armazenamento. No experimento II, objetivou-se avaliar o desempenho de vacas leiteiras em função da estratégia de descarregamento da silagem de milho em silo do tipo trincheira: silagem de milho oriunda da metade superior do silo (topo) ou silagem de milho oriunda da metade inferior do silo (base). Foram utilizadas 24 vacas alocadas em 12 blocos casualisados, com arranjo de reversão simples com períodos de 21 dias. Os animais foram alojados em confinamento tie-stall. As dietas foram iso-protéicas (16,5%) e iso-amiláceas (17,0%), com 60% de silagem de milho (% MS). O consumo de matéria seca, produção e composição do leite foram determinados entre os dias 15 e 21 de cada período experimental. Apesar da silagem oriunda da base do silo levar à maior digestibilidade da dieta e menor concentração de nitrogênio ureico do leite (8,95 e 11,35 mg/dL) não houve efeito da dieta no consumo de matéria seca nem na produção de leite. Sob condições ótimas de manejo, a estratégia de descarregamento da silagem de milho não afeta o desempenho de vacas leiteiras. / In the experiment I, the aim was to evaluate the effects of microbial additives and length of storage on the quality of corn silage. Whole-corn plants were ensiled without or with inoculants containing homofermentative (Lactobacillus plantarum + Enterococcus faecium + Pediococcus acidilactici + cellulolytic and hemicellulolytic enzymes) or heterofermentative lactic acid bacteria (Lactobacillus buchneri) applied at 1 × 105 cfu/g. Treated forages were packed and stored in experimental silos for 3, 7, 15, 30, 60, 210, 390, 480, and 570 days. Samples were evaluated for chemical composition, fermentation end-products, microbial counts, fermentation losses, aerobic stability, and ruminal degradability in situ. Inoculants did not affect most of the variables studied. However, L. buchneri increased acetic acid concentration and decreased aerobic deterioration of silages, as indicated by the lower heat accumulation during the exposure to air. Soluble carbohydrates decreased across the storage period, reflecting the conversion of soluble sugars to fermentation end-products. Concentrations of prolamin decreased, whereas ammonia and soluble protein concentrations increased over the storage period, indicating the proteolysis. The silage pH declined rapidly in the first seven days of storage and remained stable for the remaining storage period, unlike for acetic acid concentration that increased with storage period. On the other hand, counts of lactic acid bacteria and yeasts decreased during the storage. Gas production and dry matter loss increased with the length of storage. The storage period increased all variables stability aerobic. Most of significant improvements in stability aerobic were observed during the first 60 days of storage. Ruminal degradability of starch and, consequently, dry matter increased along the storage. In the experiment II, the aim was to evaluate the influence of strategy of silage unload on the performance of dairy cows. Corn silage from a bunker silo was separated at unloading as silage from the upper half of the silo (top) or from the lower half of the silo (bottom) and used to compose total mixed rations fed to 24 lactating cows allocated in 12 randomized blocks, arranged in a cross-over design with 21 periods. Cows were housed in a tie-stall barn. All diets contained 60% of corn silage and were iso-nitrogen (16.5% CP) and iso-starch (17.0% of starch). Dry matter intake, milk yield and composition were determined from day 15 to 21 in each period. Although silage from bottom led to higher total tract DM digestibility and lower milk urea nitrogen concentration (8.95 vs. 11.35 mg/dL), most of evaluated variables were not affected by treatments. Under optimal silo management, the strategy used to unload corn silage does not affect the performance of dairy cows.