La prévalence de l’obésité et du diabète de type 2 évolue de façon épidémique. Ces pathologies sont caractérisées par un état inflammatoire à bas bruit dont l’origine moléculaire est inconnue. L’une des pistes qui émerge concerne le microbiote intestinal et plus particulièrement des molécules pro-inflammatoires présentes à la surface des bactéries Gram(-) : les lipopolysaccharides (LPS). Nous avons récemment montré que ces LPS augmentent les taux circulants de glucagon-like peptide 1 (GLP-1), une hormone connue pour stimuler la sécrétion d'insuline. Par ailleurs, un lien existerait entre qualité nutritionnelle de l’alimentation et taux de LPS sanguins. Ainsi, alimentation, LPS et GLP-1 pourraient être liés. Ces travaux de thèse portent sur i) les mécanismes moléculaires reliant LPS et GLP-1 et ii) les conséquences physiopathologiques d’une endotoxémie expérimentale lors d’un régime obésogène. Nous montrons, in vitro, ex vivo et in vivo, que les LPS stimulent la sécrétion de GLP-1 par les cellules entéroendocrines via un mécanisme TLR4-dépendant. Les LPS présents dans l’intestin déclenchent cette sécrétion lors de situations pathologiques de dégradation de la muqueuse, faisant du GLP-1 un potentiel marqueur précoce d’altération de la barrière intestinale. Chez des souris sauvages, une endotoxémie expérimentale n’aggrave pas les conséquences métaboliques généralement observées lors d’un régime obésogène, certains paramètres sont même améliorés. Enfin, des souris présentant un défaut de détoxification des LPS nourries avec un régime obésogène prennent plus de masse corporelle que les souris contrôles. Les origines moléculaires de ces différences sont également recherchées. / Obesity and type 2 diabetes are metabolic diseases which have reached epidemic proportions worldwide. These metabolic disorders are related to a low grade inflammation whose molecular origin is still unknown. Previous studies have highlighted the involvement of the gut microbiota and especially components of the cell wall of Gram(-) bacteria: lipopolysaccharides (LPS). We have recently shown that LPS enhance glucagon-like peptide 1 (GLP-1) plasma levels, a hormone which is known to stimulate insulin secretion. Moreover there would be a link between the nutritional qualities of food and LPS plasma levels. Thus diet, LPS and GLP-1 may be closely related. The present work focuses on i) the molecular mechanisms linking LPS to GLP-1 and ii) the pathophysiological consequences of an experimental endotoxemia under obesogenic diet conditions. In vitro, ex vivo and in vivo experiments highlight LPS as potent secretagogues of GLP-1. They are able to induce GLP-1 secretion from enteroendocrine cells through a direct TLR4-dependent mechanism. Luminal LPS trigger GLP-1 secretion only under pathological conditions leading to intestinal mucosal damages. Therefore GLP-1 could be a promising early biomarker for diagnosing gut barrier injuries. Experimentally-induced endotoxemia in wild-type mice does not worsen the usually observed metabolic consequences of an obesogenic diet but rather seems to improve some of them. In addition, under high-fat diet, genetically-engineered mice with a defective LPS detoxification process gain more weight than control mice. The purpose of this thesis is also to disentangle the molecular explanation behind this difference.

Le tractus gastro-intestinal, interface initiale pour la détection, la digestion et l'absorption des nutriments, joue un rôle critique dans la régulation de l'homéostasie énergétique. Les signaux qui proviennent du tractus gastro-intestinal sont nécessaires au contrôle de la fonction intestinale et de la régulation de la prise alimentaire. Les neurones afférents vagaux (NAV) sont une voie importante via laquelle les informations sur les nutriments ingérés atteignent le système nerveux central pour influencer ces deux fonctions. Les NAVs expriment les récepteurs pour la plupart des peptides régulateurs libérés par l'intestin impliqués dans la régulation de la prise alimentaire et du poids corporel. Cette thèse porte sur le rôle de deux peptides de l'intestin, la leptine et le glucagon-like peptide-1 (GLP-1), qui agissent au niveau des NAVs pour inhiber la prise alimentaire. Tout d'abord, nous expliquons le mécanisme d'action du GLP-1 sur les NAVs. La satiété induite par le GLP-1 nécessite un état post-prandial ; les données confirment que le statut nutritionnel régule la localisation du GLP-1R du cytoplasme vers la membrane des cellules neuronales. De plus, la ghréline et son récepteur GHSR1, exprimés par les NAVs, sont impliqués dans la régulation de la translocation du GLP-1R. Deuxièmement, ’utilisation de souris knockout pour le recepteur a la leptine sur les NAVs nous a permis de montrer l’importance de ce recepteur dans la physiopathologie de l’obésité et de l’hyperhagie. En effet, ces souris KO présentent un phénotype obésogène. L'obésité et ses conséquences sur la santé sont des problèmes majeurs de santé dans le monde entier. Les traitements efficaces de prévention ou de l'obésité sont limités. Nos résultats ont apporté des connaissances sur le mécanisme du GLP-1 et sur la signalisation de la leptine au niveau es NAVs. Comprendre la physiologie de la régulation de la prise alimentation est impératif dans le développement des traitements non-invasifs contre l’obésité. / As the initial interface for nutrient sensing, digestion and absorption, the gastrointestinal (GI) tract plays a critical role in the regulation of energy homeostasis. Information that arises from the GI tract is key to normal physiological responses controlling gut function and regulating food intake. Vagal afferent neurons (VAN) are a major pathway by which information about ingested nutrients reaches the central nervous system to influence GI function and food intake behavior. VAN express receptors for many of the regulatory peptides released from the gut that are involved in regulation of food intake and body weight. This dissertation addresses the role of two gut peptides, leptin and glucagon-like peptide-1, acting at the level of VAN, to inhibit food intake. First, the mechanism of action of glucagon-like peptide-1 (GLP-1) on VAN is addressed. GLP-1-induced satiation requires a postprandial state; the data support that feeding changes the localization of GLP-1Rs from the cytoplasm to the neuronal cell membrane. Further, ghrelin and its receptor GHSR1 expressed by VAN is involved in regulating GLP-1 receptor translocation. Second, the importance of leptin receptor expression by VAN in the development of hyperphagia and obesity was demonstrated by selective knockout of the leptin receptor (LepR) in VAN; mice express an obesogenic phenotype. Obesity and its resultant health consequences are a major worldwide health problem. Effective or preventative treatments for obesity are limited. Our findings have filled the gap in our knowledge of the mechanism of GLP-1 and leptin signaling on VAN. Understanding the physiology regulating feeding behavior is imperative in developing non-invasive anti-obesity treatments.

Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability. This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition. A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test. NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms. Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle. Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.

The syndrome known as Gastric Dilation Air Sacculitis (GDAS) has recently been described by Lumsden et al. (2002) for Chinook salmon (Oncorhynchus tshawytscha, Walbaum), in seawater (SW) culture in New Zealand. The syndrome is characterised by distended abdomens, gastric dilation and air sacculitis, increased feed conversion ratios (FCR) and mortality. Consequently, financial returns on affected stocks are greatly reduced. A study into the epidemiology and physiology of the syndrome was initiated, working with the major aquaculture company, The New Zealand King Salmon Company (NZKS). The study revealed causative factors of GDAS. GDAS was experimentally induced only in saltwater by feeding a commercially manufactured low-cohesion pelleted diet. Control groups were fed a different diet with high physical cohesion. Low-cohesion pellets have previously been associated with a high incidence of GDAS in commercial sea cages. These data implicated osmoregulatory stress and physical properties of the feed in GDAS development. In addition, gastrointestinal (GI) physiology in GDAS -affected and -control fish was characterised. The process of GDAS development in O. tshawytscha is characterised by a loss of smooth muscle tone of the stomach as it distends. Laplace's law (P= 2T/r, where P is the distending pressure, T is the tension in the wall and r is the radius of the cylinder) predicts that unless muscle mass increases, the ability of the stomach wall to contract will be lost and consequently a loss of GI motor function will result. Therefore, GI circular smooth muscle integrity in terms of (1) stimulated and maximal contractility, (2) osmoregulatory ability of the intestine and the (3) control of the GI system was studied in pathologically affected (+ve) and unaffected (-ve) smolt. Affected fish showed changes in GI circular smooth muscle function and osmoregulatory dysfunction. Feeding different diets induced distinct gastric evacuation patterns. The intestinal brake hypothesis is presented and argued to be the probable mechanism for GDAS development. GDAS (+ve) serum showed the presence of factors capable of contracting gut smooth muscle. In addition, potential humoral mediators of the intestinal brake in fish were investigated.

Diabetes Mellitus (DM) is a metabolic disorder in which the body fails to achieve glucose homeostasis, due to either insulin resistance or reduced insulin secretion or both. This inadequate glucose control leads to hyperglycemia which, if left unchecked, leads to secondary complications like nephropathy, neuropathy, retinal degeneration and other serious conditions. In non-disease state, normal glucose level in the blood is maintained by pancreatic β-cells, which secrete insulin. However, during diabetes development, there is loss of β-cell mass and function; resulting in decreased insulin secretion which is the ultimate cause of hyperglycemia. The ability to non-invasively monitor changes in the β-cell mass during the development or treatment of diabetes would be a significant advance in diabetes management. However, a primary limitation for analysis of β-cell mass and developing dysfunction is the lack of specificity of β-cell targeting agents. Our novel approach for achieving the required specificity for a usable β-cell targeted contrast agent is to target a set of receptors on the cell surface that, as a combination, are unique to that cell. Through genetic screening, Glucagon Like Peptide-1 Receptor (GLP-1R) and α2Adrenergic Receptor (α2AR) were chosen as a potential molecular barcode for β-cells since their combination expression is relatively unique to the β-cells. GLP-1R and α2AR are both G-protein couple receptors (GPCRs) that, apart from being a β-cell specific combination, play an important role in regulating fundamental downstream signaling pathways in β-cells. To target these receptors effectively, we synthesized a multivalent ligand composed of Yohimbine (Yhb), an α2 adrenergic receptor (α2AR) antagonist, linked to an active Glucagon-like Peptide 1 analog (GLP-1₇₋₃₆). In this manuscript, I describe the synthesis and characterization of binding selectivity and signaling ability of GLP-1/Yhb at the cellular level. Using high throughput binding assays, we observed high affinity binding of GLP-1/Yhb to βTC3 cells, a β-cell mimetic line expressing both receptors, at a Kd of ~3 nM. Using microscopy, we observed significant Cy5-tagged GLP-1/Yhb binding and rapid internalization in cells expressing the complementary receptor pair at low concentrations, as low as 1 nM and 5 nM. When one of the receptors was made inaccessible due to presence of saturating quantities of a single unlabeled monomer, GLP-1/Yhb-Cy5 failed to bind to the cells at low concentrations (<10 nM). Similarly, in cells where either GLP-1R or α2AR were knocked down (using shRNA), binding of GLP-1/Yhb was significantly reduced (≤half of cells with both receptors), indicating strong selectivity of the ligand to cells expressing the combination of receptors. We also observed that GLP-1/Yhb construct modulates downstream signaling inβ TC3 cells resulting in enhanced Glucose Stimulated Insulin Secretion (GSIS). In presence of stimulatory glucose, GLP-1/Yhb significantly potentiated GSIS with a half-maximal effective dose of 2.6 nM. Compared to GLP-1₇₋₃₆ alone or GLP-1₇₋₃₆ and Yhb monomers added together, only GLP-1/Yhb could significantly potentiate GSIS at 1 nM, demonstrating that GLP-1/Yhb could translate high affinity binding to increased efficacy for GSIS potentiation. Unlike for insulin secretion, high affinity divalent binding did not translate to increased cAMP production at low concentrations, with significant increases above baseline seen only at 10 nM and higher. Nevertheless, these data show that GLP-1/Yhb binds selectively to β-cells and affects signaling, demonstrating its potential for targeted β-cell imaging and therapy. Overall, our work indicates that synthetic heterobivalent ligands, such as GLP-1/Yhb can be developed to increase cellular specificity and sensitivity making them a strong candidate for both noninvasive imaging and targeted therapy.

O setor de Gás Liquefeito de Petróleo (GLP), produto considerado de primeira necessidade para a população brasileira, está inserido em um ambiente altamente competitivo devido a poucas barreiras de entrada, ao aumento da atratividade e à baixa diferenciação do produto. Nesse cenário, os sistemas de distribuição propiciam um componente de grande importância no que se refere à diferenciação e ao desenvolvimento de vantagens competitivas no varejo. Assim, o presente estudo tem como objetivo geral analisar os principais aspectos a serem levados em consideração na tomada de decisão sobre os canais de distribuição no segmento domiciliar de GLP, referente ao primeiro elo da cadeia (distribuidora para revenda de GLP). Como objetivos específicos, se destacam a verificação da relevância das variáveis encontradas na literatura para o mercado domiciliar de GLP e a verificação de uma tendência para o setor. Para isso, serão abordados referenciais teóricos sob a ótica da Organização Industrial (OI), da Nova Economia Institucional (NEI) e de Canais de Marketing. Buscando atingir os objetivos propostos, além da revisão teórica, foi realizado um levantamento histórico sobre o GLP e as principais distribuidoras brasileiras, o qual trouxe à tona fatos políticos e econômicos que influenciam até hoje as decisões dos agentes econômicos do setor. O método utilizado foi uma pesquisa qualitativa, por meio de um estudo de caso na maior empresa brasileira de distribuição de GLP, a Cia. Ultragaz S/A. Foram desenvolvidos e aplicados questionários semiestruturados, por meio de entrevistas com os executivos da alta direção da empresa e com um executivo da direção do Sindicato Nacional das Empresas Distribuidoras do Gás Liquefeito do Petróleo (SINDIGÁS), trazendo assim uma visão mais global do segmento. Após a aplicação do estudo de caso, foram encontrados resultados relevantes para a academia, dos quais pode ser citada a constatação de que não existe uma relação direta entre as variáreis \"ativos específicos\" e \"incerteza interna/comportamental\" com a escolha dos canais de distribuição. Outros resultados importantes provindos da análise dos dados foram: a ordenação dos fatores que determinam a escolha dos canais indiretos e a influência das relações de poder na tomada de decisão em canais de distribuição. Por fim, analisando a tendência do setor, o mercado de GLP não deve findar nos próximos 50 anos e, se isso ocorresse, as empresas atuais buscariam novos mercados fora do setor de energia. Dessa forma, apesar das limitações, as quais serão apresentadas ao final da presente dissertação, muitos estudos acadêmicos ainda podem ser desenvolvidos dentro desse setor de expressiva relevância econômica e social para o País. / The Liquefied Petroleum Gas (LPG) sector, a product deemed basic needs for the Brazilian population is placed in a highly competitive environment due to a few barriers to entry, the increase in attractiveness and low product differentiation. In this scenario, the distribution systems provide a component of great importance regarding differentiation and development of competitive advantages in the retail market. Thus, this study aims to conduct an analysis on the main aspects to be taken into consideration when deciding on the distribution channels in the LPG household segment, referring to the first link in the chain (LPG distributor for dealer). The specific objectives are: verifying the relevance of the variables found in the literature for the LPG residential market and verifying the trend for the sector. For this purpose theoretical perspectives will be discussed using Industrial Organization, New Institutional Economics and Marketing Channels. In order to reach the proposed aims, a survey was conducted on the LPG history and major Brazilian distributors besides the theoretical review, which brought up political and economic facts that influence present decisions of economic agents in the industry. The method used was a qualitative research by means of a case study in the largest Brazilian LPG distributor, Cia. Ultragaz S/A. Semi-structured questionnaires were developed and applied by means of interviews with executives from company top management and with an executive director of the National Association of Liquefied Petroleum Gas Distributors (SINDIGÁS), bringing out a global view of the segment. After the application of the case study, relevant results were found to the academy, which may be due to the fact that there is not a direct relationship between the variables \"specific assets\" and \"internal behavioral/uncertainty\" with the choice of the distribution channels. Other important results obtained from the data analysis were: the hierarchical ordering of factors that determine the choice of indirect channels and the influence of power relations in decision making on distribution channels. Finally, by analyzing the industry´s trends, the LPG market should not end in the next 50 years and, if it that happened, current companies would look for new markets outside the energy sector. Thus, despite the limitations, which will be presented at the end of this study, many academic studies can still be developed in a sector which presents economic and social relevancy for the country.

O presente trabalho objetiva identificar e analisar as dimensões de excelência logística, desenvolvidas como forma de se obter vantagens competitivas, buscando analisar a influência do trabalho organizado em equipes na excelência logística de uma organização do mercado de Gás Liquefeito de Petróleo. O trabalho foi realizado através de uma revisão bibliográfica sobre os temas excelência logística nas organizações e trabalho organizado em equipes. Como metodologia foi proposto um construto teórico de excelência logística e trabalho em equipe, realizado através de uma revisão bibliográfica sobre os temas, com a apresentação de um estudo de caso em uma empresa líder do mercado em que atua, de forma a ilustrar a aplicação dos conceitos propostos. Como resultado, o trabalho conclui que a organização do trabalho em equipes se mostra grande apoiadora das práticas de excelência logística nessa organização, integrando e possibilitando o desenvolvimento das diferentes dimensões de excelência logística. / This paper aims to identify and analyze the dimensions of logistics excellence, developed as a way to gain competitive advantage, seeking to analyze the influence of teamwork in the logistics excellence of a Liquefied Petroleum Gas organization. The study was conducted through a literature review on the issues logistics excellence in organizations and teamwork. The methodology has been proposed a theoretical construct of logistics excellence and teamwork, accomplished through a literature review on the issues, with the presentation of a case study in a leading company in the market it operates, in order to illustrate the application of concepts proposed. As a result, the paper concludes that the organization of teamwork is a strong supporter of logistics best practices in this organization, integrating and enabling the development of the different dimensions of logistics excellence.

Submitted by PPG Biologia Celular e Molecular (bcm@pucrs.br) on 2017-07-18T12:45:18Z No. of bitstreams: 1 FERNANDA_CRISTINA_DE_MESQUITA_TES.pdf: 3705815 bytes, checksum: d4984b596a690199bbc567a00b9a5f63 (MD5) / Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-07-28T18:46:03Z (GMT) No. of bitstreams: 1 FERNANDA_CRISTINA_DE_MESQUITA_TES.pdf: 3705815 bytes, checksum: d4984b596a690199bbc567a00b9a5f63 (MD5) / Made available in DSpace on 2017-07-28T18:54:15Z (GMT). No. of bitstreams: 1 FERNANDA_CRISTINA_DE_MESQUITA_TES.pdf: 3705815 bytes, checksum: d4984b596a690199bbc567a00b9a5f63 (MD5) Previous issue date: 2017-03-17 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Liver fibrosis is the wound healing response to repeated injury of the liver. This process begins with the damage of the parenchymal cells and subsequent inflammation, characterized by the rupture of the hepatic architecture associated to the increase of the expression of the components of the extracellular matrix. The development of hepatic fibrosis is based on the activation of hepatic stellate cells (HSC) that undergo phenotypic changes and are characterized by loss of vitamin A deposition and increased cell proliferation, triggering hepatic microcirculatory dysfunction and fibrogenesis in patients with chronic liver disease (CLD). Liraglutide is a GLP-1 agonist (glucagon-like peptide 1) well established as an antidiabetic drug, but also has anti-inflammatory properties, in addition to the effectiveness for NAFLD (non-alcoholic fatty liver disease). Therefore, the aim of this study was to evaluate the effects of liraglutide on the HSC phenotype and liver microvascular function using diverse pre-clinical models of CLD. The results obtained demonstrate that Liraglutide de-activated human and rat HSC phenotype through a GLP1-Rindependent mechanism. Liraglutide did not affect the HSC viability but decreased cell proliferation. CLD-rats receiving liraglutide exhibited significantly lower portal pressure (-20%) with a consequent reduction in intrahepatic vascular resistance. There was also a marked improvements in hepatic vascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue. In conclusion, this study demonstrates for the first time that liraglutide improves hepatic sinusoidal endothelium in clinically relevant experimental models of cirrhosis, which leads to improvement in fibrosis and portal hypertension, and therefore is valid in the treatment of advanced chronic liver disease. / A fibrose hep?tica ? a resposta cicatricial do f?gado ? les?es repetidas. Este processo inicia com o dano das c?lulas parenquimatosas e consecutiva inflama??o, caracterizado pelo rompimento da arquitetura hep?tica associada ao aumento da express?o dos componentes da matriz extracelular. O desenvolvimento da fibrose hep?tica ? baseado na ativa??o das c?lulas hep?ticas estreladas (HSC) que sofrem mudan?as fenot?picas e se caracterizam pela perda do dep?sito de vitamina A e aumento da prolifera??o celular, desencadeando disfun??o microcirculat?ria hep?tica e fibrog?nese nos pacientes com doen?a hep?tica cr?nica (CLD). A liraglutida ? um an?lago do GLP-1 (glucagon-like peptide 1) bem estabelecido como f?rmaco antidiab?tico, mas que tamb?m possui propriedades antinflamat?rias, al?m da efetividade para NAFLD (doen?a hep?tica gordurosa n?o alco?lica). Por essa raz?o, o objetivo deste estudo foi avaliar os efeitos da liraglutida sobre o fen?tipo das HSC e a fun??o microvascular hep?tica utilizando diversos modelos pr?-cl?nicos de CLD. Os resultados obtidos demonstram que a liraglutida desativou o fen?tipo das HSC humanas e de ratos atrav?s de um mecanismo independente do receptor GLP1. A liraglutida n?o afetou a viabilidade das HSC mas diminuiu a prolifera??o celular. Os ratos com CLD que receberam liraglutida apresentaram press?o portal significativamente menor (-20%) com consequente redu??o da resist?ncia vascular intra-hep?tica. Houve tamb?m uma acentuada melhoria na fun??o vascular hep?tica, fibrose, fen?tipo das HSC e fen?tipo endotelial sinusoidal. Os efeitos anti-fibr?ticos da liraglutida tamb?m foram confirmados em tecido hep?tico humano. Como conclus?o, este estudo demonstra pela primeira vez que a liraglutida melhora o endotelio sinusoidal hep?tico em modelos experimentais clinicamente relevantes de cirrose, o que leva a melhora no quadro fibr?tico e na hipertens?o portal e, portanto, pode ser v?lido no tratamento da doen?a hep?tica cr?nica avan?ada.

Made available in DSpace on 2014-06-12T17:38:44Z (GMT). No. of bitstreams: 2 arquivo509_1.pdf: 2632583 bytes, checksum: 534eb9b0779ed97c63f7a6d3f31123ae (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2011 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O transporte por oleodutos é considerado o transporte mais seguro de substâncias a longas distâncias, o GLP pode ser transportado na sua forma líquida por dutovias, mas a sua construção oferece um risco às comunidades circunvizinhas a faixa de duto, pois o GLP ao ser lançado na atmosfera e à temperatura ambiente torna-se um produto gasoso, inflamável, inodoro e asfixiante em altas concentrações. A Análise Quantitativa de Riscos (AQR) permite quantificar esses riscos, de forma a contribuir para a tomada de decisão quanto às ações para redução dos mesmos. Neste sentido, o presente trabalho desenvolveu e aplicou uma metodologia de AQR em dutovia de GLP, quando foram identificados seis cenários acidentais, dos quais três apresentaram alto grau de severidade. Foi realizado um estudo em que foi comprovada a inexistência de padronização dos níveis de tolerabilidade dos riscos, nos manuais de análise de riscos nos estados brasileiros analisados. Foram obtidos os alcances dos efeitos fiscos e da vulnerabilidade dos cenários selecionados através do software EFFECTS 8.1, o de maior alcance foi de 219,1 metros, para a tipologia acidental de incêndio em nuvem, para o cenário 05 que corresponde à grande liberação de GLP, no período noturno, correspondendo a 100% de fatalidade. Foram estimadas as freqüências de ocorrência e calculados os riscos através do software RiskCurves 7.6 e avaliados através da comparação dos limites de tolerabilidade para dutovias, todos os riscos estiveram na zona de aceitabilidade

Muito se têm noticiado sobre as possibilidades de expansão do uso do gás combustível como energético no âmbito comercial e residencial, porém entende-se que tal promessa deveria ser precedida de uma vasta e ampla discussão estratégica sobre os mecanismos necessários a serem desenvolvidos pelos agentes da sociedade para que tal expansão possa se concretizar. Dentro desse enfoque, entende-se como preocupante o desconhecimento a respeito das características de produtos e serviços utilizados, bem como o baixo grau de capacitação da indústria de prestação de serviços de instalações, andando de mãos dadas com a própria indústria da construção civil. Sem produtos ou serviços adequados é difícil prever a possibilidade concreta da expansão do gás no segmento residencial. Obviamente existem as abordagens sobre mudanças culturais a respeito da utilização do gás como energético, disponibilidade de aparelhos adequados para sua utilização, fatores econômicos envolvendo o preço do gás e uma centena de outros temas complementares. Todos esses tópicos podem ser considerados estratégicos. A dissertação pretende focar o problema da conformidade e da conseqüente disponibilização de produtos e serviços ao mercado. O trabalho explora as estratégias utilizadas para provocar melhoria e capacitação de segmentos de mercado, atrelando-os à resultados de competência e competitividade, através de monitoramento da sua conformidade com requisitos de produtos e serviços previamente estabelecidos. Discorre-se sobre as estratégias passíveis de serem utilizadas para fomento do desenvolvimento deste segmento de mercado e aborda-se os modelos válidos de avaliação de conformidade existentes atualmente no Brasil, discutindo propostas para o caso específico do monitoramento da infra-estrutura de distribuição de gás combustível no país. Utilizando-se, então, de um arcabouço de estruturas teóricas, apresenta-se um caso real do ponto de vista do mercado consumidor, particularizando a atuação da Comgás no Estado de São Paulo, discorrendo sobre as preocupações da empresa com relação à conformidade no mercado e estabelecendo paralelos entre tais iniciativas, as premissas teóricas e lacunas existentes no processo. O trabalho levanta o histórico técnico sobre modelos de avaliação de conformidade, apresentando um exercício de reflexão a respeito de propostas a serem potencialmente adotadas pelo segmento de mercado no caso de construção da infra-estrutura para condução e distribuição de gás combustível aos consumidores finais. / It has been noticed about the possibilities of gas uses expansion in commercial and residential scope, however it understands that such promise would have to be preceded of a great strategic discussion concerning the necessary ways to be developed for the society agents so that such expansion can be materialize. Looking for this approach, its worry about the unfamiliarity regarding the products and services characteristics, as well as the low degree of services installations industry qualification, walking together with the building construction industry. Without adequate products or services it is difficult to foresee the concrete possibility of the gas expansion in the residential segment. Obviously its necessary to consider the aspects on cultural changes regarding the gas uses, availability of gas appliances, economic factors involving the gas price and a hundred of other complementary subjects. All these topics can be considered like strategic. The paper intends to focus the problem of the conformity and the consequent availability of products and service to the market. The work explores the strategies used to improve qualification of market segments, connecting them with the results of ability and competitiveness, through inspection of its conformity with requirements of products and services previously established. It is discoursed on the strategies to be used for promotion this market segment development and currently approaches the valid conformity evaluation models existing of conformity in Brazil, arguing proposals for the specific case of the combustible gas distribution infrastructure inspection in the country. Using the theoretical structures, it presents a real case of the consuming market point of view, distinguishing the performance of the Comgás in the São Paulo State, discoursing on the concerns of the company with regard to conformity in the market and establishing parallel between such initiatives, the theoretical premises and existing gaps in the process. The paper raises the description technician on conformity models evaluation, presenting an exercise of reflection regarding proposals to be potentially adopted for the market segment in case of infrastructure construction for gas conduction and distribution to the end consumers.