published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic inflammation, pain and joint remodeling. Existing RA therapies such analgesics and anti-inflammatories can treat symptoms. More recent strides in disease modifying anti-rheumatic drugs (DMARDs) can slow progression of disease. However, there is still no therapeutic that can reverse disease damage and there is no cure for RA. Resolvin E1 (RvE1) is an endogenous lipid initially identified as a key pro-resolving mediator. By tamping down expression of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), RvE1 is able to down-modulate inflammation and return an inflamed tissue to a homeostatic state. More recently, RvE1 has been shown to act directly to inhibit inflammatory pain through central and peripheral nervous system mechanisms. RvE1 has also been shown to restore bone homeostasis by balancing osteoclast and osteoblast activity. In contrast to current therapeutics that treat symptoms and slow disease progression, a RvE1 pathway agonist has the potential to reverse RA by resolving inflammation, reversing bone remodeling and returning joints to normal homeostasis.

Made available in DSpace on 2014-06-12T15:51:50Z (GMT). No. of bitstreams: 2 arquivo2767_1.pdf: 3278547 bytes, checksum: 342792bf691adceb52843f94ed03bb66 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2011 / A infecção pelo papillomavirus humano (HPV) é o principal agente causal para o desenvolvimento de câncer de colo uterino que é a segunda causa de morte por câncer em mulheres no mundo e o segundo tipo de câncer mais frequente em mulheres na faixa etária de 15 a 44 anos. Além disso, é cada vez mais frequente a infecção por HPV em diferentes locais do corpo humano ocasionando tanto lesões malignas quanto benignas. Dada à importância clínica na saúde pública mundial desta infecção, têm surgido esforços da comunidade científica a fim de desenvolver fármacos que possam inibir e/ou impedir a infecção desse vírus. Neste sentido, a proteína E1 é uma das proteínas virais que têm sido investigadas como um alvo potencial para o desenvolvimento destes fármacos, já que a mesma é uma DNA helicase que participa do processo de replicação viral. O potencial de derivados do ácido bifenilsulfonacético na inibição da atividade ATPase de E1 foi verificado em estudos anteriores. O derivado n° 9 teve maior eficácia na inibição da atividade ATPase da E1 helicase de HPV6 do que na E1 helicase de HPV11. Como não foi encontrado nenhum outro sítio de ligação além do sítio ATPase na E1 de HPV18, esta diferença de inibição observada entre os HPVs estudados foi atribuída a ligação do derivado n° 9 ao aminoácido Y486 de HPV6 que resulta uma mudança conformacional no sítio ATPase e consequentemente impede a ligação do ATP. Assim, o objetivo deste trabalho foi utilizar o docking e a dinâmica molecular a fim de compreender o modo de ligação do derivado nº 9 do ácido bifenilsulfonacético na E1 helicase de HPV, além de determinar a influência dos resíduos de aminoácidos localizados no sítio ATPase na afinidade com o inibidor. Os resultados mostraram que o derivado nº 9 do ácido bifenilsulfonacético e o ATP competem pelo mesmo sítio de ligação e, além disso, as mobilidades observadas no P-loop e nos resíduos de aminoácidos A486, K490, S491 e Y492 do sítio ATPase podem determinar a diferença de afinidade do complexo proteína-inibidor

Desarrolla un método, altamente selectivo y específico, usando el equipo Cromatógrafo Líquido de Ultraperformance con detector Masa – Masa (UPLC – MS – MS) para la determinación de misoprostol éster a través de su metabolito misoprostol ácido en veinte muestras de orina de mujeres gestantes, provenientes de las Divisiones Médico Legales del Perú, que presumiblemente habrían ingerido tabletas de misoprostol. Se ensayan procedimientos de extracción líquido – líquido, cuyos resultados, en el presente estudio; no son reproducibles. Debido a ello se ensayan procedimientos de extracción en fase sólida (SPE) con cartuchos especiales HLB cuyos resultados son reproducibles. Este método logra cuantificar concentraciones hasta partes por billón (ppb), con una concentración promedio de 40,23 y demás valores que están dentro de los límites 11,5 y 81,6 ppb. El método es de gran utilidad para demostrar el uso de misoprostol como abortivo en investigaciones judiciales.

Modern macroeconomic models with a Keynesian flavour usually involve nominal rigidities in wages and commodity prices. A widely used conceptual framework is specifying a wage-setting and a price setting equation, while a more explicit microfoundation recurs to wage bargaining in the labour markets and monopolistic competition in the commodity markets; (Blanchard and Giavazzi, 2001). Characteristic for those approaches is that deregulating the labour markets (i.e. reducing the bargaining power of workers and/or reducing the unemployment benefits) and/or deregulating the commodity markets (i.e. reducing the market power of commodity suppliers) increases equilibrium employment. However, those models are typically static models which do not specify explicitly the economic process in time. In the following paper, we develop a dynamic macroeconomic model in which commodity markets are characterised by monopolistic competition and labour markets by wage bargaining. The number of firms is fixed; the incorporation of firm entry and exit is left for further research. In our analysis the equilibrium solution is a fixed point of the dynamic model which exhibits the usual comparative static properties (deregulating the labour and/or the commodity market increases employment). However, depending upon the parameters the fixed point may loose stability through a Flip-bifurcation giving rise to cyclical solutions. We show analytically that commodity and labour market deregulation may lead to instability; in numerical simulation we even found cases in which deregulation leads to lower average employment. Both results, valid in a dynamic framework, contrast with the usual comparative static properties. / Series: Department of Economics Working Paper Series

Periodontal disease is initiated by bacterial plaque that induces a chronic inflammatory condition with subsequent leukocyte infiltration, osteoclast activation and alveolar bone resorption. The ideal treatment for periodontal disease is the complete regeneration of the lost periodontium. Resolvin E1 (RvE1) is an endogenous anti-inflammatory lipid mediator derived from omega-3 fatty acids. Animal studies showed that topical treatment of periodontitis with RvE1 significantly decreased osteoclast counts, prevented alveolar bone loss, and restored lost periodontal tissues including bone. It is not known if RvE1 directly impacts osteoblast functions and bone formation. The objective of this study was to determine RvE1 mechanism of action on osteoblasts. Results showed that topical RvE1 treatment prevented the progression of ligature-induced periodontitis in mice compared to the vehicle. RvE1 receptor, chemR23, was expressed in murine calvaria osteoblasts and the expression was not changed in the inflammatory environment with or without RvE1 treatment. RvE1 treatment resulted in a significant increase in the ALP activity after 2 and 7 days of treatment compared to the control as well as in the inflammatory milieu. Similarly, RvE1 treatment enhanced murine calvaria osteoblasts mineralization in vitro compared to the inflammatory environment. The proliferation of mouse calvaria osteoblasts was significantly increased with RvE1 treatment after 2 and 10 days of treatment compared to the control. Results for evaluating the impact of RvE1 on OPG/RANKL axis showed that RvE1 treatment markedly elevated OPG production compared to the IL-6/IL-6R treatment and decreased RANKL. Overall, RvE1 increased the OPG/RANKL ratio to favor bone formation. RvE1 treatment resulted in a significant increase in the phosphorylation of AKT, ERK1/2 and ribosomal S6 (rS6) kinase. Those pathways were further confirmed via using specific pharmacological inhibitors which showed a significant reduction in OPG production and in the osteoblast proliferation as well. In conclusion, RvE1 has a positive anabolic impact in ligature-induced periodontitis model via direct actions on osteoblasts. RvE1 increases the OPG/RANKL production ratio favoring the bone formation through a pathway that includes phosphorylation of AKT, ERK1/2 and rS6 kinase. The data suggest that RvE1 stimulates bone formation in inflammatory conditions by directly modulating both the osteoclast and osteoblast functions.

A presente pesquisa consiste em uma análise do edifício administrativo da Escola de Engenharia de São Carlos pertencente à Universidade de São Paulo, do ponto de vista de conforto térmico e iluminação natural. O processo de investigação se dá em algumas etapas: análise projetual enfatizando os aspectos relativos ao conforto ambiental (microclima, partidos arquitetônicos, implantação, materiais, técnicas construtivas, aberturas, envidraçamentos, diagramas e esquemas de estudo); aplicação de questionários aos usuários; e medições in loco de níveis de iluminação e de variáveis ambientais de conforto térmico. Os resultados foram analisados e comparados, para que a partir destes seja possível obter uma avaliação das soluções e técnicas empregadas quanto às questões de térmica e iluminação, contribuindo assim no aperfeiçoamento de técnicas projetuais. Objetiva-se com estas técnicas a obtenção de conforto ambiental e redução no consumo de energia, para edifícios do padrão do estudado, o qual é visto repetir-se incalculavelmente em edifícios administrativos, de escritórios e escolares. / This research is an analysis of the administrative building of the Escola de Engenharia de São Carlos belonging to the Universidade de Sao Paulo, from the point of view of thermal comfort and natural illumination. The process of investigation takes place in some steps: architectural design analysis emphasizing aspects related to environmental comfort (microclimate, architectural parties, implantation, materials, constructive techniques, openings, glassing, diagrams, and study schemes); application of questionnaires to users, and on-site measurements of environmental variables of thermal comfort and levels of illumination. The results were analyzed and compared, so that from the results it\'s possible to evaluate the solutions and applied techniques related to thermal and illumination aspects, thus contributing in the development of design techniques. The objective with these techniques is obtaining environmental comfort and reduction in energy consumption in buildings with the same pattern of use, which is seen to be repeated a lot of times in buildings for administrative use, offices and schools.

A presente pesquisa consiste em uma análise do edifício administrativo da Escola de Engenharia de São Carlos pertencente à Universidade de São Paulo, do ponto de vista de conforto térmico e iluminação natural. O processo de investigação se dá em algumas etapas: análise projetual enfatizando os aspectos relativos ao conforto ambiental (microclima, partidos arquitetônicos, implantação, materiais, técnicas construtivas, aberturas, envidraçamentos, diagramas e esquemas de estudo); aplicação de questionários aos usuários; e medições in loco de níveis de iluminação e de variáveis ambientais de conforto térmico. Os resultados foram analisados e comparados, para que a partir destes seja possível obter uma avaliação das soluções e técnicas empregadas quanto às questões de térmica e iluminação, contribuindo assim no aperfeiçoamento de técnicas projetuais. Objetiva-se com estas técnicas a obtenção de conforto ambiental e redução no consumo de energia, para edifícios do padrão do estudado, o qual é visto repetir-se incalculavelmente em edifícios administrativos, de escritórios e escolares. / This research is an analysis of the administrative building of the Escola de Engenharia de São Carlos belonging to the Universidade de Sao Paulo, from the point of view of thermal comfort and natural illumination. The process of investigation takes place in some steps: architectural design analysis emphasizing aspects related to environmental comfort (microclimate, architectural parties, implantation, materials, constructive techniques, openings, glassing, diagrams, and study schemes); application of questionnaires to users, and on-site measurements of environmental variables of thermal comfort and levels of illumination. The results were analyzed and compared, so that from the results it\'s possible to evaluate the solutions and applied techniques related to thermal and illumination aspects, thus contributing in the development of design techniques. The objective with these techniques is obtaining environmental comfort and reduction in energy consumption in buildings with the same pattern of use, which is seen to be repeated a lot of times in buildings for administrative use, offices and schools.

Modern macroeconomic models with a Keynesian flavour usually involve nominal rigidities in wages and goods prices. A typical model is static and combines wage bargaining in the labour markets and monopolistic competition in the goods markets. As central policy implication it follows that deregulating labour and/or goods markets increases equilibrium employment. We reassess the consequences of deregulation in a dynamic model. It still increases employment at the fixed point, which corresponds to the static equilibrium solution. However, deregulation may also lead to stability loss and endogenous fluctuations. / Series: Working Papers Series "Growth and Employment in Europe: Sustainability and Competitiveness"

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