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Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 106-122).

Without doubt a well-developed financial sector is related to efficient resource allocation and growth, but there is modest consensus on the direction of that link, on the notion of what is meant by "well developed", on which subset of the financial market is crucial and thus which organisational set-up provides optimal returns for both architects and market participants alike. With sluggish growth, torn down market barriers and systemic change in the EU accession countries the direction, magnitude, sustainability, institutional set-up of the finance-growth nexus (and which), becomes one of the core issues of both macroeconomic theory and practice. This paper reviews the economic theory available, provides a well structured overview of 54 empirical studies conducted since 1964, sets the stage for constructing a data base encompassing the major three segments of financial markets (stock, bond and bank credit) and provides the methodological background for combining cross-country production function and time-series approaches in order to answer the following questions: (1) What is the direction of the finance-growth nexus, (2) which segment of the financial sector drives whatever nexus there is, and (3) what are the features of a growth supportive financial architecture. / Series: EI Working Papers / Europainstitut

O sulindaco é um antiinflamatório não esteroidal (AINE) classificado quimicamente como ácido carboxílico, da classe dos acetatos, que inibe de forma não seletiva a cicloxigenase 1 e 2. Terapeuticamente, é utilizado como agente analgésico e antiinflamatório para o tratamento de sintomas da artrite reumatóide aguda e crônica, osteoartrite e espondilite anquilosante, no entanto, seu uso não está restringido somente a estas patologias, pois apresenta atividade quimiopreventiva, sendo atualmente também utilizado para este fim, apesar de inúmeros relatos de toxicidade gastrointestinal e hepática terem sido relatados na literatura. Ele é ingerido como um pró-fármaco, e por reações de biotransformação hepática origina um metabólito reduzido (sulindaco sulfeto, ativo farmacologicamente) e outro oxidado (sulindaco sulfona, inativo). Para avaliar os efeitos do sulindaco e seus metabólitos, foram realizados estudos in vitro em mitocôndrias isoladas de fígado de rato, para explorar aspectos mecanísticos de toxicidade mitocondrial, e ensaios com linhagem celular de hepatoma humano HepG2, para avaliar seus efeitos após metabolização, uma vez que estas células mantém enzimas responsáveis pelas reações de biotransformação de fase I e II. Nossos resultados demonstram que o sulindaco sulfeto estimula a respiração de estado 4 e promove a liberação de cálcio pré-acumulado pela organela de maneira concentração-dependente, sendo evidente o efeito desacoplador sobre a fosforilação oxidativa, refletidos na diminuição da viabilidade celular em associação com a diminuição do conteúdo de ATP, provocado pela dissipação do potencial de membrana mitocondrial, sugerindo um mecanismo protonoforético de desacoplamento, responsável pela toxicidade deste antiinflamatório. Além disso, foi observado o inchamento das mitocôndrias em meio energizado, condição que ocorre independente de cálcio presente no meio reacional. Este evento foi parcialmente sensível a ciclosporina A e Mg2+, teve prevenção total com a adição de BHT e insensibilidade a outros moduladores, como ADP, ATP, DTT e NEM. Os resultados não condizem com a transição de permeabilidade mitocondrial clássica, uma vez que é dependente de cálcio, e o mecanismo de prevenção deste efeito obtida com a adição de BHT é desconhecido, pois não foi observada a indução de formação de radicais livres nos dois modelos experimentais utilizados. No entanto, a indução de intumescimento mitocondrial pode contribuir para seus efeitos tóxicos. O sulindaco e o sulindaco sulfona não apresentaram quaisquer efeitos descritos para o sulindaco sulfeto, indicando que somente o metabólito farmacologicamente ativo é responsável pelos efeitos tóxicos observados. A biotransformação por reações de Fase I e II podem contribuir para a toxicidade in vivo, por originarem o metabólito reduzido, e como o sulindaco é utilizado em terapias que envolvem uso por tempo prolongado, é prudente realizar um monitoramento da função hepática antes e durante o período de tratamento, no sentido de prevenir complicações do uso na terapia convencional / Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) known to inhibit non-selectively ciclooxygenases (COX) 1 and 2. Sulindac is therapeutically used as anti-inflammatory and analgesic in the symptomatic treatment of acute and chronic rheumatoid arthritis, osteoarthritis, and ankylosing spondylits. In addition to this property, a role in the prevention/regression of colonic carcinogenesis, has been described for both sulindac and metabolites. Nevertheless, its therapeutic use has been limited because of its toxicity to the gastrointestinal tract and liver, reported in the literature. Sulindac is a prodrug that is ?in vivo? metabolized to its pharmacological active metabolite, sulindac sulfide and its pharmacological inactive one, sulindac sulfone. In order to assess the effects of sulindac and its metabolites, we used ?in vitro? studies with isolated rat liver mitochondria, to evaluate the aspects of its toxicity in mitochondria; and studies with human hepatoma cell line (HepG2), to evaluate its affects after biotransformation. The present study shows that sulindac sulfide, but not sulindac sulfone or sulindac itself, cause mitochondrial uncoupling, releasing pre-accumulated Ca2+ from the organelle, and decrease Hep-G2 cell viability in an apparent association with cellular ATP depletion resulted from mitochondrial uncoupling-associated membrane potential dissipation. We therefore propose mitochondrial uncoupling by sulindac sulfide as a potential mechanism for the well established toxicity of sulindac, at least to the liver in humans. It was also observed a mitochondrial swelling in energized media that can occur without dependence on the calcium present in the media. This event was partial inhibited by CsA and Mg2+, and completely inhibited with the addition of BHT. It did not show any inhibition with the addition of ADP, ATP, DTT or NEM. These results can not be associated to the classical mitochondrial permeability transition that is dependent to calcium, and the mechanism of inhibition observed with BHT is not known, since it was not observed any production of free radicals in our models, but the swelling observed can also contribute to the toxic effects observed. The sulindac itself and the sulfone metabolite did not show any toxic effect observed for the sulfide form, indicating that just the pharmacological active metabolite is responsible for the toxic effects. The biotransformation (phase I and II reactions) can contribute to sulindac toxicity, because they generate the reduced form. Sulindac is also used in long term treatment, so it is necessary the monitoring of the hepatic function is necessary before and during the treatment, in order to prevent any further complication.

Le théorème central de cette thèse est une construction de métriques quaternion-kählériennes sur des variétés de dimension 8 modelées sur l'espace symétrique de type non-compact G2/SO(4). Cette construction s'inscrit dans la lignée des constructions de LeBrun (1989) et de Biquard (2000) pour lesquelles d'un côté les variétés quaternion-kählériennes construites possèdent un modèle homogène qui est un espace symétrique de type non-compact G/K, et d'un autre côté, les données initiales peuvent s'interpréter comme étant des déformations d'un bord de Furstenberg G/P où P est un sous-groupe parabolique de G. Ces constructions nous amènent ainsi à penser qu'il existe une correspondance générale entre des déformations de bords de Furstenberg G/P et des variétés quaternion-kählériennes.Ces déformations d'espaces G/P sont des variétés munies de géométries paraboliques. Après une présentation de la théorie des géométries paraboliques donnée dans la première partie, nous nous consacrerons, dans la deuxième partie à la correspondance précédemment supposée. En observant la construction de LeBrun (1989), nous réduirons les candidats pour une généralisation de cette construction à deux cas dont celui de l'espace G2/SO(4) et du parabolique P fixant une droite isotrope de R^{3,4}. Dans la dernière partie, nous donnerons justement la construction des métriques quaternion-kählériennes dont les données initiales sont des géométries paraboliques de type (G2,P). Cette construction passe par la construction d'espaces des twisteurs dans lesquels nous déformons des courbes doubles. Les variétés quaternion-kählériennes construites sont des ouverts des espaces de déformation de ces courbes. / The main theorem of this thesis is a construction of quaternionic Kählerian metrics over a 8-manifolds modelled on the non-compact Riemannian symmetric space G2/SO(4). This construction is in line with LeBrun?s construction (1989) and Biquard?s construction (2000) for which, on one side, the quaternionic Kählerian manifolds constructed have a homogeneous model which is a non-compact Riemannian symmetric space G/K , and in the other side, the initial data can be seen as deformations of a Furstenberg boundary G/P with P a parabolic sub-group of G. These constructions lead us to think about a general correspondence between the deformations of Furstenberg boundaries and quaternionic Kählerian manifolds. Those deformation of G/P space are manifolds with parabolic geometries. After a presentation of the theory of parabolic geometries given in the first part, we will focus on the previous supposed correspondence in the second part. Observing LeBrun?s construction (1989), we will reduce the candidates for a generalisation of this construction to two cases among which the one of the space G2/SO(4) with the parabolic sub-group P stabilizing an isotropic line in R^{3,4}. In the last part, we will precisely give the construction of quaternionic Kählerian metrics with initial data some parabolic geometries of type (G2,P). This construction begins with the construction of twistor spaces where we will deform some double curve named ribbon. The quaternionic Kählerian manifolds constructed will be some open set in the space of deformation of these curves.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23382号 / 医博第4751号 / 新制||医||1052(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊藤 貴浩, 教授 滝田 順子, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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<p>The aim of this work has been to characterize the effects of conditioned medium (CM) on insect cell productivity and physiology in order to get a better understanding about the mechanisms that regulate productivity in serum-free media. Two cell lines have been investigated, Spodoptera frugiperda (Sf9) and Trichoplusia ni (T. ni, BTI-Tn-5B1-4). The baculovirus expression vector system (BEVS) was used for protein expression, using the ligand-binding domain of the human glucocorticoid receptor as a model protein. Addition of CM at inoculation led to a shorter lag phase and that the cells reached the maximum cell density faster than cells in fresh medium for both Sf9 and T. ni cells. Sf9 cells passed a switch in growth kinetics after 30-40 passages. At this point, CM lost its stimulating effect on proliferation. CM also affected the cell size and cell cycle progression. Sf9 and T. ni cells became smaller when CM was added at inoculation because they had a minor arrest in the cell cycle after inoculation and therefore started to divide earlier than cells in fresh medium. For Sf9 cells, this was illustrated by a smaller arrest in G2/M in the beginning of culture and the cells were consequently less synchronized. For T. ni cells, the initial decrease in the S phase population was followed by an earlier increase of the S phase population for the cells with CM than for the cells in fresh medium.</p><p>Addition of 20 % CM or CM filtrated with a 10 kDa cut-off filter to Sf9 cultures had a negative effect on the specific productivity. However, addition of CM to Sf9 cells that had passed the switch in growth kinetics had no negative effect on productivity. This indicates that CM not affects the protein production per se, but rather through its effects on cell physiology. Instead, the degree of cells synchronized in G2/M is important for high productivity and the gradually decreasing degree of synchronization during the course of a culture might be the explanation behind the cell density dependent decrease in productivity for Sf9 cells. This was further supported by the positive effects on productivity achieved by synchronizing Sf9 cells in G2/M by yeastolate limitation, which counteracted the cell density-dependent drop in productivity and hence a higher volumetric yield was achieved. Addition of 20 % CM to T. ni cultures had a positive effect on productivity. The specific productivity was maintained at a high level longer than for cells in 100 % fresh medium. The product concentration was 34 % higher and the maximum product concentration was obtained 24 hours earlier for the cells with the addition of CM. These results show that the effects of CM on productivity are not the same for the two cell lines and that the mechanism regulating productivity are quite complex.</p>

Iron is an essential trace element for almost all living organisms. Iron overload in cells and tissues, however, leads to their disruption. Most oftenly damaged are parenchymatic organs such as the liver, pancreas and heart. The aim of this thesis was to create cellular in vitro models for the investigation of effects of excess iron on hepatocytes and pancreatic beta cells and on these models to investigate cellular processes which lead to cellular damage during iron overload. We focused on examining the presence of oxidative and endoplasmic reticulum stress and the activation of apoptotic cell death. For our experiments, we used HEP-G2 cell line which represents human hepatocytes and NES2Y cell line which represents human pancreatic beta cells. To study the mechanisms of cellular damage during iron overload, we used two approaches by which we observed both acute and long-term effects of high levels of iron on damage of the tested cell lines. When studying the acute effect of excess iron on the cells, we applied high doses of iron (using 15 mM ferric citrate in medium) that led to the activation of cell death in hours. Long-term effects of iron overload were tested on cells regularly cultivated in the presence of 50 μM and 100 μM ferric citrate over a period of several months. Iron concentrations...