O cloridrato de tramadol, analgésico sintético de ação central, possui dois centros quirais: o isômero cis é ativo e o isômero trans é uma impureza de processo. Ambos os enantiômeros do cloridrato de cis-tramadol contribuem para o efeito analgésico, mas através de mecanismos diferentes, complementares e interativos farmacologicamente. Os dois isômeros do cis-tramadol apresentam efeitos terapêuticos, e a presença de impurezas, incluindo os isômeros trans - decorrentes do processo de síntese ou devido à decomposição - podem comprometer a qualidade do produto comercializado. Assim, este trabalho teve como objetivo desenvolver e validar metodologia estereosseletiva para análise do cloridrato de cis-tramadol e das possíveis impurezas quirais ou não na matéria-prima e formulações farmacêuticas. Para a separação e quantificação dos enantiômeros do cloridrato de cis-tramadol e das impurezas trans-tramadol, 1,2-olefina e 1,6-olefina, foi utilizada a coluna Chiralcel® OD-H, fase móvel constituída por hexano (60% e 100% de n-hexano, 1:1, v/v):isopropanol:dietilamina:ácido trifluoracético (99,5:0,5:0,3:0,1, v/v/v/v), na vazão de 0,7 mL min-1 e detecção em 274 nm. A coluna Chiralpak® AD fase móvel constituída por hexano (60% de n-hexano):etanol absoluto:dietilamina (95:5:0,1, v/v/v), na vazão de 1,0 mL min-1 e o comprimento de onda para detecção dos compostos foi de 228 nm foi utilizada para a separação e quantificação das impurezas O-desmetiltramadol, N-desmetiltramadol e tramadol N-óxido. Os métodos desenvolvidos foram devidamente validados através dos parâmetros seletividade, linearidade, precisão, exatidão, intervalo, limite de detecção e limite de quantificação. Os resultados obtidos na validação mostraram que os métodos são adequados para a determinação do cis-tramadol e de suas impurezas na matéria prima e na formulação farmacêutica. / Tramadol hydrochloride is a centrally acting analgesic with two chiral centers; the cis isomer is the active drug and the trans isomer is a process impurity. Both enantiomers of cis-tramadol hydrochloride contribute to the analgesic effect through different, but complementary and interactive pharmacological mechanisms. Although both isomers of cis-tramadol hydrochloride show therapeutic effects, the presence of impurities, originated from the synthesis process or due to degradation, can compromise the quality of the marketed product. The aim of this present work was the development and validation of a stereosselective methodology for the analysis of the drug cis-tramadol hydrochloride and the possible chiral or non-chiral impurities in raw materials and pharmaceutical formulations. The separation and quantitation of cis-tramadol enantiomers and the impurities trans-tramadol, 1,2-olefin and 1,6-olefin were carried out using a Chiralcel® OD-H column, mobile phase of hexane (60% and 100% of n-hexane, 1:1, v/v):2-propanol:diethylamine:trifluoroacetic acid (99,5:0,5:0,3:0,1, v/v/v/v) at a flow rate of 0,7 mL min-1 and detection at 274 nm. For the separation and quantitation of the impurities O-desmethyltramadol, N-desmethyltramadol and tramadol N-oxide, a Chiralpak® AD column was used with a mobile phase of hexane (60% of n-hexane):ethanol absolute: diethylamine (95:5:0,1, v/v/v) at a flow rate of 1,0 mL min-1 and detection at 228 nm. The methods were validated using the parameters selectivity, linearity, precision, accuracy, range, detection limit and quantitation limit. The results obtained show that the methods are suitable for the analysis of cis-tramadol and its impurities in raw material and pharmaceutical formulation.

Neste trabalho foi avaliada a possibilidade do emprego de caldo de cana-de-açúcar (Saccharum officinarum) como matéria-prima para obtenção de 2,3-butanodiol por fermentação, utilizando a bactéria Klebsiella pneumoniae NRRL B199. A pesquisa compreendeu o teste de diferentes nutrientes para a composição de um meio de fermentação eficiente com o caldo de cana e experimentos em que a influência da concentração inicial de sacarose (S0) sobre o processo em regime descontínuo foi estudada. Ensaios realizados em frascos agitados, com S0 entre 140 e 150 g/L, mostraram que a fermentação de caldo de cana clarificado não suplementado com nutrientes não é viável. Por outro lado, a adição de 5,0 a 10,0 g/L de fosfato de amônio ao caldo levou a concentrações finais de 2,3-butanodiol de até 64 g/L e rendimentos, em relação ao máximo teórico, da ordem de 81% em cerca de 38 horas. Estes resultados se aproximam daqueles alcançados na fermentação do caldo enriquecido com vários nutrientes, usado como referência, na qual foram produzidos 66,7 g/L de diol com um rendimento de 85,6%. A utilização de concentrações de fosfato de amônio de até 4,0 g/L resultou em fermentações incompletas. A cinética da fermentação foi estudada com o caldo diluído a, aproximadamente, 180 g/L de sacarose e suplementado com 8,0 g/L de fosfato de amônio e, também, com o meio rico, em regime descontínuo em fermentador de bancada. Foram obtidos, nestes ensaios, concentrações de butanodiol de 71,7 e 71,1 g/L, rendimentos de 78,0 e 74,1 %, produtividades de 2,1 e 2,0 g/Lh e tempos de fermentação de 34,5 e 35,7 horas, respectivamente. A principal diferença foi observada na concentração de biomassa que atingiu 9,1 g/L, no meio com fosfato, e 11,8 g/L no meio rico. As máximas velocidades específicas de crescimento (µx, m), 0,61 e 0,45 h-1, observadas com oxigênio dissolvido acima de zero, indicam que o crescimento celular, no meio rico, foi inibido pela alta concentração de nutrientes. Na seqüência das fermentações, com concentrações nulas de oxigênio dissolvido, a produção de diol foi iniciada e as máximas velocidades específicas de formação de produto (µP,m), 0,53 h-1 com fosfato de amônio e 0,45 h-1 com o meio rico, foram atingidas, sugerindo que altas concentrações de nutrientes afetam, também, a formação de produto. Nos dois ensaios foi observada a ocorrência de uma fase estacionária de crescimento que, no caso do meio contendo fosfato de amônio, teve uma duração 12 horas mais longa devido a um insuficiente suprimento de oxigênio ou do esgotamento de algum nutriente. Neste ponto, foi verificada uma queda das velocidades específicas de formação de produto (µP). Com o caldo diluído a cerca de 20 g/L de sacarose e 8,0 g/L de fosfato de amônio, a fermentação transcorreu em um tempo muito longo (23,5 horas) para a baixa concentração de sacarose empregada. Com S0 semelhante e o meio rico, o tempo de processo foi de apenas 6,5 h, o que demonstra que, no primeiro caso, ocorreu uma diluição excessiva dos nutrientes naturalmente presentes no caldo. O estudo do efeito da concentração inicial de sacarose sobre a fermentação, conduzido em fermentador de bancada e com o meio rico em nutrientes, mostrou que este parâmetro influencia fortemente o crescimento celular e a produção de 2,3-butanodiol. O aumento de S0 levou a valores decrescentes dos fatores de conversão de substrato em células, enquanto os rendimentos em diol aumentaram com S0 até 152 g/L. Valores crescentes de S0 provocaram uma inibição do crescimento celular, evidenciada pela diminuição de µx,m de 0,91 a 0,45 h-1, com S0 entre 24 e 181 g/L. Valores aproximadamente constantes de µP,m (0,62 a 0,68 h-1) foram observados com S0 até 152 g/L, enquanto uma queda acentuada foi verificada com S0=181 g/L (µP,m=0,45 h-1). As máximas produtividades (3,2 g/Lh) foram obtidas com valores de S0 de 105 e 152 g/L. Os dados gerados neste trabalho permitem concluir que caldo de cana-de-açúcar é uma matéria-prima adequada para a produção de 2,3-butanodiol por Klebsiella pneumoniae. / The use of sugar cane (Saccharum officinarum) juice, as raw material for the fermentative production of 2,3-butanediol by Klebsiella pneumoniae NRRL B199, was evaluated in this work. The research was focused on testing different nutrients to formulate an efficient fermentation medium with the juice and some experiments to study the effect of the initial sucrose concentration (S0) on the batch process. Shaker flasks experiments with S0 between 140 and 150 g/L have shown that the fermentation of sugar cane juice without added nutrients is not viable. On the other hand, the addition of 5.0 to 10.0 g/L ammonium phosphate to the juice led, after 38 hours, to final 2,3-butanediol concentrations of 64 g/L, with yields of 81% of the theoretical maximum. These results are similar to those found in the fermentation of a reference medium composed of juice enriched with several nutrients in which 66.7 g/L butanediol and a yield of 85.6% were obtained. Ammonium phosphate concentrations up to 4.0 g/L resulted in incomplete fermentations. The fermentation kinetics was studied in a laboratory scale fermentor, with the sugar cane juice diluted to ca. 180 g/L sucrose. Both ammonium phosphate (8.0 g/L) and reference media were tested. In these experiments, after process times close to 35 hours, butanediol concentrations of 71.7 and 71.1 g/L, yields of 78.0 and 74.1 % , and productivities of 2.1 and 2.0 g/Lh, respectively, were obtained. The most important difference was the final biomass concentration that reached 9.1 g/L with the ammonium phosphate medium and 11.8 g/L with the rich medium. The maximum specific growth rates (µx,m=0.61 and 0.45 h-1), measured with dissolved oxygen concentrations above zero, have indicated that cell growth in the rich medium was inhibited by high nutrient concentration. In the sequence, when the oxygen concentration was zero, butanediol production started and maximum specific production rates (µP,m of 0.53 h-1 with the ammonium phosphate medium and 0.45 h-1 with the rich medium were reached. These values suggest that nutrient concentration in the rich medium also affects product formation. ln both runs, a stationary growth phase was noticed. In the experiment with the ammonium phosphate medium, the stationary phase was 12 hours longer due to the insufficient oxygen supply rate or the shortage of some nutrient. At that moment, decreasing specific product formation rates (7#181;P) were observed. With the sugar cane juice diluted to approximately 20 g/L and 8.0 g/L ammonium phosphate, fermentation time was 23.5 hours, too long to such sucrose concentration. With similar S0 and the rich medium, fermentation time was reduced to 6.5 hours. That shows that, in the first case, natural nutrients of the juice were excessively diluted. The study on the effect of the initial sucrose concentration on the process, performed in a laboratory fermentor with the rich medium, has shown that this parameter strongly affects both cell growth and 2,3-butanediol production. Increasing S0 led to decreasing cell yields and, for S0 up to 152 g/L, diol yields increased. Cell growth inhibition was stronger as higher sucrose concentrations were used. This is evidenced by the values of µx,m that decreased from 0.91 to 0.45 h-1 as S0 was augmented from 24 to 181 g/L. Approximately constant µP,m (0.62 to 0.68 h-1) were observed with S0 up to 152 g/L. With S0=181 g/L, µP,m is reduced to 0.45 h-1 . The maximum productivities (3.2 g/Lh) were obtained with S0 between 105 and 152 g/L. From the results of this work, one can conclude that sugar cane juice is a suitable raw material for the production of 2,3-butanediol by Klebsiella pneumoniae.

國內大多數之公司皆為中小企業，其相較於大公司資源有限，並無一套有系統的策略形成與管理工具。此工具一直是管理階層重視之議題，然而從過去之文獻發現，策略形成的方法紛呈，最為著名的是Porter(1980)競爭策略，但此類文獻大部分皆為國外學者所著，因而本研究針對國內吳思華(2000)的策略九說，以個案實作之方式，闡明其亦能有效協助公司形成策略。 依據過往文獻發現，策略形成工具協助公司形成策略後，往往就不了了之，並無明確說明如何執行已形成之策略。本研究依據Kaplan and Norton(1992)提出之平衡計分卡概念，以吳安妮(2002)(2003)提出策略執行系統4.7.4為架構與策略診斷性系統分析，協助公司執行已形成之策略及分析公司有無水平或垂直缺口，以免導致公司擁有策略後，卻因執行的後繼無力，而無法展現成效。 最後，以免公司內部單位各自為政，造成資源浪費，因而依據Niven(2002)與吳安妮(2002)提供之觀念，使總公司、SBU與SSU三者之策略能有效連結，形成綜效。 關鍵字：中小企業、策略九說、策略形成與執行系統、策略診斷性分析、綜效。 / Most domestic companies are all small and medium enterprises. The limitations in resources for small and medium enterprises are much greater, causing them to not have a systematic strategy formation and management tools. These management tools have been important management issues, however, the literature only found ways to form strategies, the most famous being the Porter (1980) competitive strategy, but most of these documents were all written by foreign scholars. One famous document written by domestic scholars by Wu Se-hwa (2000) strategy nine, wrote a case by case implementation of management tools can also effectively help companies clarify their strategy. Based on previous literature found about the formation of strategic tools to assist companies to form policy, there is often no clear description of how the strategy has been formed. The study, based on Kaplan and Norton (1992) proposed the concept of the Balanced Scorecard, to Miss Anne (2002) (2003) proposed strategies for the implementation of the system 4.7.4 system architecture and analysis of diagnostic strategies to help companies execute strategy and has formed the analysis of the company to see whether they have horizontal or vertical gaps, so as not to cause the company to have a strategy, with the inability to perform follow-ups, and can not show results. Finally, in order to avoid fragmented units within the company, resulting in waste of resources, which according to Niven (2002) and Anne Wu (2002) provided, thus allowing the head office, SBU and SSU's strategy to effectively link the three to form a synergy. Keywords: SMEs, strategy nine, strategic formulation and implementation, analysis of diagnostic strategies, synergy.

Cette théese est basée sur la représentation Eulerienne-Lagrangiene de la vitesse, qui nous appelons la transformation de Weber-Clebsch.<br />Constantin a construit en 2002 une extension de la description de Weber-Clebsch des fluides parfaits aux fluides visqueux. La nécessité de réinitialiser périodiquement les coordonnées Lagrangiennes à été interprété par Constantin comme un diagnostique de la reconnexion de la <br />vorticité. Le système de Constantin est contenu dans notre formulation, qui est plus générale, dans une limite singulière.<br /><br />Pour comparer les résultats obtenus en utilisant notre formulation généralisée à ceux qui sont obtenus dans la formulation de <br />Constantin nous avons procédé à des simulations numériques d'un certain nombre d'écoulements obéissants aux équations de Navier<br />Stokes.<br /><br />Des extensions à la magnéto hydrodynamique et aux fluides compressibles sont également proposées et validées numériquement.

Ce travail de Thèse traite des problèmes directs et inverses de la magnétoencéphalographie (MEG) et de l'électroencéphalographie (EEG). Trois thématiques y sont abordées. Le problème direct est traité à l'aide des méthodes d'éléments frontière. Une nouvelle formulation, dite formulation symétrique, est proposée. Cette nouvelle formulation est ensuite appliquée au problème de la tomographie par impédance électrique pour lequel deux algorithmes d'estimation de conductivité sont proposés. Le problème inverse est traité dans le cadre des méthodes image. Des techniques de régularisation d'image par processus de diffusion sont transposées au problème inverse pour contraindre la reconstruction de sources distribuées. Plusieurs algorithmes sont proposés dont un calculant la solution inverse de variation totale minimale.

La quantification sur le cône de lumière est une méthode de quantification opérant dans la Front Form de Dirac et nécessitant une procédure de traitement des contraintes dynamiques. Elle est abordée dans le cas de deux théories scalaires. La théorie phi4 (1+1) est examinée à l'aide d'une formulation continue du développement de Haag des champs et des modes zéros (CLCQ). Ceci permet une résolution originale des équations du mouvement et des contraintes ainsi qu'une renormalisation consistante des divergences infrarouges et ultraviolettes. L'analyse de la transition de phase fait apparaître au deuxième ordre un couplage critique non perturbatif de valeur analogue aux résultats du quatrième ordre des méthodes conventionnelles. L'étude comparée du commutateur de Pauli-Jordan dans les formulations discrètes et continues montre que la violation de causalité n'est qu'un pur effet de taille finie associé à la soustraction du mode zéro dans les sommes discrètes. L'étude de la théorie phi4 (3+1) O(N) est amorcée par le calcul des champs et des modes zéros à l'ordre 3 du développement en 1/sqrt(N) qui permet de retrouver jusqu'à l'ordre 1/N^3 les fonctions de corrélation conventionnelles obtenues par intégrales de chemin.

On présente ici deux types de modélisations, ainsi que de nombreuses données expérimentales, portant sur les déformations des bétons et en particulier celles des bétons à hautes performances. La première a pour but de prévoir les amplitudes des déformations instantanées, de retrait endogène et de fluage propre, en fonction de la formulation. On utilise pour cela une approche par homogénéisation, en adaptant le modèle bisphère de Hashin au calcul du module du béton. La démarche de modélisation, fondée sur la prise en compte de la compacité réelle du squelette granulaire, aboutit à une géométrie trisphère. On fait le choix, après l'avoir justifié, de fixer les coefficients de Poisson à un cinquième. Puis, on applique le modèle trisphère au calcul des amplitudes de fluage propre et de retrait endogène. Les paramètres principaux de formulation (rapports eau sur ciment, fumée de silice sur ciment, proportion granulaire, classe du ciment) sont pris en compte. L'approche appliquée au fluage est confortée par un calcul viscoélastique linéaire. Dans la deuxième approche, on propose un modèle simplifié, de type réglementaire, pour le calcul des déformations des bétons à hautes performances en fonction du temps, et d'un nombre Limité de paramètres. Les apports principaux de la modélisation concernent la prise en compte de l'autodessiccation, de la maturité et de la résistance du matériau au moment du chargement. Le modèle a été validé d'après de nombreuses données, et pour des bétons de maturités très variables au chargement, variant de seize heures à plus de deux ans. Elaboré dans le cadre de l'Association Française pour le Recherche et l'Etude des Matériaux et des Structures (AFREM), le modèle est proposé comme annexe au règlement français de béton précontraint (BPEL), pour les bétons couvrant la gamme B40-B80.

In this study, teaching is seen as a complex decision-making situation, where different factors that influence the teaching and learning process are interwoven and connected with each other. To describe and analyse the complexity of teaching literature in a foreign language instruction setting is the aim of the study. The study was conducted with one teacher participant and her group of 16–17 years old pupils in a Swedish upper secondary school, while they read a German youth novel. Data on the teacher decisions in the planning phase was collected by interviewing the teacher before the actual teaching of the novel and between lessons, while the implementation of the teacher decisions was observed during the lessons. In the interviews, four decision areas showed to be central to the teacher: teaching goals, choice of text, task formulation, and the role of freedom and control as central concepts of learner autonomy. In the analysis chapters, the decisions within these different areas are described, commented on, and contextualized within the teacher’s own teaching concepts, and within current research and theory on foreign language reading, learning, and teaching. Factors critical to the decision-making situation are identified. The findings of the study show that teaching literature employs a decision-making process of great complexity because of the subjective character of the reading process. The complexity of the process is increased by the fact that a foreign language was being taught. Even for an experienced teacher (as the teacher who was observed in the study is) teaching decisions are characterized by a complexity which her many years of teaching experience can only partly compensate for. The main goal for the teaching of the novel was formulated by the teacher as ‘reading pleasure’, a concept grounded on a previous teaching experience. Since the teacher saw tasks as an obstacle for a reading experience, the task formulation constituted a conflict for her. In the study, the structure of the conflict is described by investigating different understandings of the concepts ‘reading pleasure’ and ‘task’. A crucial question was raised: What was considered to be the most important activity of the lesson: the reading or the tasks? When the task is secondary to the reading, there is an opportunity for the learner to focus on the reading experience; an important condition for reading pleasure. When the task is considered to be the primary activity, the student’s focus is on solving the task, and the reading activity thus looses its importance when the task is fulfilled. The interpretation of teaching concepts like ‘task’ is therefore a crucial factor that influences the teacher’s decisions about the teaching. A second concept that is central to the teacher’s teaching activities is ‘learner autonomy’. Since it is a central concept in the Swedish school curriculum, learner autonomy is held in very high esteem, whilst teacher control is consequently held in very low esteem. The idealization of learner autonomy, along with insufficient explanation of its impact on the distribution of the responsibility for the learning process between teachers and pupils are seen as factors that lead to an increased complexity in the decision-making process about how to manage situations where pupils are not prepared to take on the responsibility that is given to them.

In der vorliegenden Dissertation wird auf der Grundlage einer kontinuumsmechanischen Herangehensweise die Formulierung eines mechanischen Modells in Verbindung mit der Umsetzung in ein Schalenelement im Rahmen der Finite-Element-Methode zur Simulation des Tragverhaltens geschichteter Flächentragwerksstrukturen unter Berücksichtigung der Schädigungsart Delamination vorgestellt. Grundlage des Mehrschichten-Modells ist die Entwicklung einer geometrisch nichtlinearen oberflächenorientierten Schalentheorie mit schub- und dickenelastischem Verhalten ausgehend von der vollständigen Kinematik einer Multidirektor-Theorie. Der Oberflächenbezug gewährleistet eine auf Kontaktprobleme angepasste mechanische Modellbildung. Innerhalb der Schichten wurde ein Materialgesetz für linear elastisches, orthotropes Material verwendet, dessen Dreidimensionalität durch die Schalenformulierung nicht eingeschränkt wird. Das Hauptaugenmerk der Arbeit liegt auf der Entwicklung eines auf verschiedene Materialien anpassbaren Schichten-Verbundmodells. Das Versagen des Schichtenverbundes – Delamination genannt – wurde durch ein einfaches Spannungskriterium beschrieben. Die Delamination wird durch Modifikation der kinematischen Bedingungen diskret berücksichtigt. Zur Beschreibung des Tragverhaltens nach Ausbildung der Delamination wurde ein als „innerer Kontakt“ bezeichnetes Kontakt-Modell entwickelt, durch das Adhäsion zwischen den Schichten berücksichtigt werden kann. Das vorliegende Schalenmodell kann bei Berücksichtigung von Delamination auf Probleme, in denen kleine Relativverschiebungen zu erwarten sind, für beliebige elastische Materialien angewendet werden. Der Rahmen, in dem diese Arbeit entstand, gab den hauptsächlichen Einsatzbereich, die Simulation von Flächentragwerksstrukturen mit einer Verstärkungsschicht aus textilbewehrtem Feinbeton, vor. / This publication introduces, in a continuum-mechanical approach, the formulation of a mechanical model in connection with the transformation into a shell element using the finite element method for the simulation of the load-bearing behaviour of laminated shell structures thereby considering delamination as a type of damage. This multi-layer model is based upon the development of a geometrically nonlinear surface-related shell theory with shear-elastic behaviour and variable thickness, beginning with the complete kinematics of a multi-director theory. The surface relationship ensures a mechanical modelling which is adaptable for contact problems. A linear-elastic orthotropic material law, whose three-dimensionality is not restricted by the shell formulation, applies within the layers. The main focus of the thesis is on the development of a layer-bond model that can be adjusted for different materials. The debonding of layers – called delamination – is described by a simple stress criterion. Delamination is discretely taken into account by modifying the kinematic conditions. A contact model, called „inner contact“, that can be used to account for adhesion between layers, has been developed to describe the load-bearing behaviour after delamination has occurred. The present shell model is restricted to elastic material behaviour and can preferably be applied to such problems where small relative displacements are expected. The environment, in which this research has been conducted, established the primary of application area, which is the simulation of shell structures within a strengthening layer comprised of textile-reinforced concrete.

Ce mémoire se propose d'examiner le comportement asymptotique en temps long des fluides visqueux bidimensionnels, homogènes ou faiblement inhomogènes. On y examine souvent la dynamique des écoulements en fonction de l'évolution de la densité et, plutôt que de la vitesse, du vecteur de rotation instantanée appelé tourbillon ou vorticité. Les travaux de Thierry Gallay et C. Eugene Wayne ont mis en relief le rôle primordial d'une famille de solutions auto-similaires --- les tourbillons d'Oseen ou vortex --- pour décrire l'asymptotique des écoulements à densité constante. Toute solution de l'équation de Navier-Stokes, ayant une mesure finie comme tourbillon initial et de circulation non nulle, est asymptotique en temps long à un tourbillon d'Oseen. Le résultat de Gallay et Wayne ne présente que l'inconvénient de ne pas être explicite, la première tâche de ce mémoire est de l'expliciter, ce qui fournit ainsi une borne sur le temps de vie de la turbulence bidimensionnelle. On montre ensuite que les tourbillons d'Oseen sont asymptotiquement stables en tant que fluides à densité variable, retrouvant également, par là-même, le résultat de Gallay et Wayne pour des écoulements incompressibles faiblement inhomogènes et lents. Quant aux fluides compressibles faiblement inhomogènes, on établit qu'ils se comportent essentiellement comme des fluides à densité constante dès lors que l'on considère des écoulements lents et de circulation nulle.