Sterically stabilized liposomes with saturated lipid as the major lipid component (DSPC:m-PEGDSPE were applied in DB-67 delivery. The drug retention in vitro and pharmacokinetic properties in vivo were investigated. Liposomal DB-67 was cleared faster from the circulation in the larger liposomes (~180 nm) than in the smaller ones (~120 nm), even though DB-67 was retained longer in smaller size liposomes in vitro. Liposomal DB-67 clearance was increased when cholesterol was present in the liposomal composition (40 mole %). It can be attributable to the faster drug release from cholesterol containing liposomes as compared to liposomes without cholesterol. Cholesterol free liposomes with smaller particle size (~120 nm) were chosen as the optimal formulation. In addition, high lipid doses led to the lower clearance of liposomal DB-67 because the liposomal carriers were retained in the circulation longer. Liposomes of larger particle size were taken up by the liver and spleen to a greater extent than the smaller ones. But cholesterol content and lipid dose did not alter the tissue uptake of liposomes. The area under the DB-67 plasma concentration-time curve (AUC) for liposomal DB-67 was 40-fold higher that for non-liposomal DB-67.

Made available in DSpace on 2015-07-22T20:50:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-08-26 / Obesidade, hipertensão, dislipidemia e diabetes tipo 2 são os principais fatores de risco que caracterizam a síndrome metabólica quando presentes simultaneamente. Com o aumento dos níveis de leptina em quadros de obesidade e a correlação desta patologia com a hipertensão, objetivou-se neste trabalho o estudo das possíveis implicações do hormônio leptina na hipertensão de forma central e periférica e a interação com o principal sistema no controle da pressão arterial (PA), o sistema renina-angiotensina (SRA). Neste trabalho nós mostramos que camundongos com mutação espontânea no gene da leptina, ob/ob, ou no receptor de leptina, db/db apresentam deficiências no controle da PA e ritmo circadiano, alterações no SRA e disfunção autonômica. Em camundongos ob/ob, a atividade da ECA, uma das principais enzimas do SRA, apresentou-se reduzida em condições basais e foi restabelecida após o tratamento agudo com leptina. Cronicamente, a administração de leptina aumentou a atividade dessa enzima e a concentração de fatores que compõem o SRA, como o peptídeo vasoconstritor angiotensina II em camundongos ob/ob. No entanto, não houve aumento da PA. Os camundongos ob/ob apresentaram menor baroreflexo, diminuição da ativação parassimpática e aumento da ativação simpática. Os camundongos db/db também apresentaram o mesmo fenótipo. O tratamento com leptina provocou diminuição do peso e restabeleceu a disfunção autonômica em camundongos ob/ob. Surpreendentemente, o tratamento com enalapril também restabeleceu o tônus autônomo, simpático e parassimpático, assim como o baroreflexo em ob/ob e db/db sugerindo a importância da angiotensina II no controle autônomo concomitante com a ausência na sinalização de leptina. Nossos dados sugerem uma nova interação da via de leptina com o SRA, sendo a angiotensina II um possível fator necessário para a manutenção da ativação autonômica e sobrevivência desses camundongos. / The leptin deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and the renin-angiotensin system (RAS) in the cardiovascular abnormalities observed in obesity using a model lacking leptin. Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here we tried to answer the question whether ACE and leptin could influence blood pressure control being a link between renin-angiotensin system and obesity in ob/ob mice, a model lacking leptin. These mice are obese and diabetic, but have normal 24h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Leptin chronic infusion increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion could restore ACE activity in leptin deficient mice. Moreover, the effect of ACE inhibitor on blood pressure during leptin treatment was not changed in lean, but increased four times in obese mice. In a second part of the study we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril treatment. Autonomic function was assessed pharmacologically. Blood pressure during daytime was slightly higher in the ob/ob compared to control mice while no difference in heart rate was observed. Blood pressure response to trimetaphane and heart rate response to metoprolol were greater in ob/ob mice than in control littermates indicating an activated sympathetic nervous system. Heart rate response to atropine was attenuated. Baroreflex sensitivity and heart rate variability were blunted in ob/ob mice, while low frequency of systolic blood pressure variability was found increased. Chronic leptin replacement reduced blood pressure and reversed the impaired autonomic function observed in ob/ob mice. Inhibition of ACE by enalapril treatment had similar effects prior loss of weight. These findings suggest that the RAS is involved in the autonomic dysfunction caused by the lack of leptin in ob/ob mice. In summary, our findings show that the RAS is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible correlation between RAS and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems and may contribute to clarify the role played by these systems in the pathogenesis of obesity, hypertension, and metabolic syndrome. / TEDE / BV UNIFESP: Teses e dissertações

The 12 March 1938 was not only the beginning of Nazi rule in Austria; it was also the end of a six-year struggle by a significant minority of Austrians to maintain Austrian independence against very considerable odds. This study has sought to refocus attention on the role of the Dollfuß Government 1932–34 in attempting to prevent a Nazi takeover, and to reassess the state of current scholarship on the reasons for its collapse. In this regard, this thesis sets out to re-examine the behaviour and motivations of Dollfuß in particular, and the Christian Socials in general, during the period in question, as well as to document and clarify the key strategies of the Austrian leadership in dealing with the twin threats of Austrian and German National Socialism. Its overall conclusion is that there is a pressing need to modulate the historical narrative of the Dollfuß era to reflect more accurately what actually occurred. This thesis seeks to prove that despite the extreme pressure that it was under from Nazi Germany, the Dollfuß government and its mainstay, the Christian Socials, used all realistic means at their disposal to keep the Nazis from the centres of power while maintaining Austrian independence. It investigates why Dollfuß refused to publicly co-operate with the Social Democrats, but was apparently willing to enter into a deal with the National Socialists, and what this tells us about his anti-Nazi stance. It also considers the question of whether the traditional focus on the breakdown of democracy, as a key cause of the collapse of the Austrian state in 1938, is useful in understanding of the period.

This thesis explores the different scales of sociality (or social interaction) found within the LBK through the lens of a broadly meshwork-based perspective. It evaluates the hypotheses that people in the LBK lived in and recognised multiple levels of 'community', that these different communities overlapped, resulting in negotiation and possibly conflict; and that membership of these communities was potentially open and fluid, varying according to season, task or personal preference. With the help of meshwork-thinking, I explore the social relationships that helped to define the LBK. In doing so, I demonstrate that this dynamic, multi-dimensional approach can offer a new perspective on understanding the degree of homogeneity and variation within the LBK tradition. The core of the thesis is divided into three case studies, each concentrating on a specific scale of analysis. The first case study focuses on social interaction at the household scale and considers the emergence of individual households, household complexes and co-operative groups of households within the Merzbach and Schlangengraben valleys. The second case study explores the inter-play between competing family and clan/lineage identities at the scale of the settlement cluster or micro-region. The third case study zooms out to the regional scale of the Lower Rhine basin, tracing more geographically spread patterns in the material culture as well as interaction with non-LBK groups beyond the loess regions. Calling on these cases studies, I also consider how scale was experienced in the LBK.

Diabetes is closely associated with increased oxidative stress, especially originating from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondria membrane potential by releasing protons across the mitochondria membrane. This phenomenon is referred to as mitochondria uncoupling since oxygen is consumed independently of ATP being produced and can be mediated by Uncoupling Proteins (UCPs). However, increased oxygen consumption is potentially detrimental for the kidney since it can cause tissue hypoxia. Therefore, this thesis aimed to investigate the role of mitochondria uncoupling for development of diabetic nephropathy.      UCP-2 was demonstrated to be the only isoform expressed in the kidney, and localized to tubular segments performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetes in rats increased UCP-2 protein expression and correlated to increased non-transport dependent oxygen consumption in isolated proximal tubular cells. These effects were prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increased mitochondria uncoupling in mitochondria isolated from diabetic kidneys. Mitochondria uncoupling and altered morphology was also evident in kidneys from db/db-mice, a model of type-2 diabetes, together with proteinuria and glomerular hyperfiltration which are both clinical manifestations of diabetic nephropathy. Treatment with the antioxidant coenzyme Q10 prevented mitochondria uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increased mitochondria uncoupling in a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreased mitochondria membrane potential and kidney oxidative stress but did not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension.      The role of increased mitochondria oxygen consumption was investigated by administering the chemical uncoupler dinitrophenol to healthy rats. Importantly, increased mitochondria oxygen consumption resulted in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin, demonstrating a crucial role of increased oxygen consumption per se and the resulting kidney tissue hypoxia for the development of nephropathy.      Taken together, the data presented in this thesis establishes an important role of mitochondria uncoupling for the development of diabetic nephropathy.

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Le tungstène sera soumis à des conditions extrêmes de température et de bombardement de particules en tant que paroi des cibles du divertor dans le réacteur de fusion nucléaire ITER. De hauts flux d’ions légers impacteront la surface du tungstène et sont susceptibles de générer des défauts dans le cristal. Cette étude vise à étudier les premières étapes de la formation des défauts lacunaires dans le cristal de tungstène soumis à un faible flux d’ions de faible énergie afin de comprendre le rôle de l’accumulation de l’hélium, un des produits de la réaction de fusion du deutérium et du tritium. Pour cette étude, une source plasma ICP-RF a été développée et qualifiée afin de réaliser des implantations d’hélium dans des conditions parfaitement contrôlées. Les implantations d’hélium ont été réalisées pour plusieurs conditions de fluence, d’énergie et de température, sur des échantillons de tungstène polycristallins. La spectroscopie d’annihilation des positons a été utilisée pour caractériser les défauts lacunaires, les analyses par réactions nucléaires, pour quantifier l’hélium implanté et la spectrométrie de thermodésorption pour caractériser les interactions de l’hélium dans le cristal. Les résultats montrent que pour une énergie de 320 eV à température ambiante, une fluence incidente limite est atteinte à partir de laquelle une saturation de l’hélium implanté apparaît et la formation de lacunes de grande taille débute. L’étude de l’influence de l’énergie et de la température montre l’importance de la répartition de l’hélium en profondeur et de sa mobilité dans le cristal sur la taille et la diversité des défauts formés. Les implantations sont simulées par dynamique moléculaire. Les résultats obtenus par l’approche numérique sont comparés aux résultats expérimentaux afin de mieux comprendre les mécanismes élémentaires mis en jeu. / Tungsten will be exposed to severe plasma conditions such as high temperature and high particle bombardment as a target of the divertor in the nuclear fusion reactor ITER. High fluxes of light ions will impact its surface and can generate defects in the crystal. This study means to observe the first steps of the vacancy-type defects formation in the tungsten crystal subject to low ion flux of low kinetic energy in order to understand the influence of the accumulation of helium, one of the nuclear reaction products. For the experiments, an ICP-RF plasma source was developed and characterized to perform helium implantations under perfectly controlled conditions. Helium implantations were performed under various conditions of fluence, energy and substrate temperature on polycrystalline tungsten samples. Positron annihilation spectroscopy was used to characterize vacancy-type defects, nuclear reaction analysis to quantify implanted helium and thermal desorption spectrometry to characterize the interactions of helium in the crystal. Results show that, for a kinetic energy of 320 eV and at room temperature, a saturation of the helium implanted quantity is reached for a limit incident fluence and that large vacancy defects starts to form. Study of the kinetic energy and the surface temperature influences show the importance of the depth distribution and the mobility of the helium in the crystal on the size and the diversity of the generated defects. Implantations are performed by molecular dynamic simulations. Results obtained by the numerical approach are compared to experimental ones in order to get a better understanding of the atomic scale mechanisms.

The basis of my work represents a research focused on the problematic of native XML databases. The main goal is to draw comparison between the selected database systems in a sphere of user control and management of XML data. Database products are tested via XMark benchmark test using its XQuery queries and testing XML data. Final comparisons and recommendations for use are based on the concluding evaluation and findings. The results of research may improve orientation in solved problematics. They could help with the selection of a suitable database product to store XML data.

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