The purpose of this study was to use retrograde tracing techniques to examine hepatic neuroanatomy in the rat model, with special emphasis upon the identification of previously undiscovered intrahepatic parasympathetic ganglia. Retrograde analysis was performed using Fluoro-Gold (FG) tracer injections of both male and female Sprague-Dawley rats. To accurately examine the neural connectivity of both the vasculature and the parenchyma, the FG-labelled livers were divided into two groups. In the first, vessel trees were extracted via dissection and whole-mounted for bright field and confocal visualization. Left lateral lobes taken from the male and female liver that constituted the second group were sectioned, and slices from various layers of tissue were fixed to slides and visualized. The results indicated the presence of several large, fluorescent structures bearing a strong resemblance to parasympathetic ganglia. However, the images were not detailed enough to properly differentiate true ganglia from similar paraganglia. Regardless, the importance of this experiment lies in its attempt to revisit an understudied field in neuroscience, and the findings of this study could potentially provide a starting point for further inquiry.

Introdução – O tratamento da hipertensão portal continua sendo um desafio e muitos desses pacientes necessitam até transplante de fígado, como tratamento definitivo. Nesse contexto a derivação porto-sistêmica intra-hepática transjugular (Transjugular Intrahepatic Portosystemic Shunt – TIPS) surgiu como uma alternativa atraente para esta complicação da doença hepática crônica, sobretudo por não requerer laparotomia e efetivamente reduzir a pressão portal. O conhecimento da distância entre as veias hepáticas e os ramos portais e outros dados anatômicos, no fígado cirrótico, são requisitos importantes no planejamento e execução desse procedimento. Objetivos - Determinar as distâncias e diâmetros das veias hepáticas direita e média para os ramos portais e para a bifurcação da veia porta, no fígado cirrótico humano, com vistas à construção do TIPS. Tipo de estudo – Estudo anatômico descritivo e macroscópico em moldes vasculares de resina obtidos por corrosão de fígados humanos isolados e cirróticos. Material e método – O estudo foi autorizado pelo Comitê de Ética em Pesquisa do HUOC/Procape-UPE e todos os pacientes, ou seus representantes legais, assinaram Termo de Consentimento Livre e Esclarecido. Foram obtidos 21 moldes de resina acrílica dos ramos portais e veias hepáticas de fígados cirróticos, de pacientes transplantados, dos hospitais Jayme da Fonte e Universitário Oswaldo Cruz, do Recife/PE. Após a completa corrosão do parênquima, foram medidas as distâncias e diâmetros das veias hepáticas e ramos da veia porta. Para testar a hipótese de diferença da média estimada em relação a um valor de referência, foi aplicado o teste t-Student para uma amostra. Resultados - A distância média da veia hepática direita para o ramo direito da veia porta e para a sua bifurcação foram, respectivamente, de 33 (±6,4) e 36 (±7,4) mm, ambos significativamente menores (p<0,0001 e p<0,0002) que os resultados encontrados na literatura, em fígados normais. A distância média da veia hepática média para o ramo direito e para o ramo esquerdo da veia porta foi, respectivamente, de 36 (±6,8) e 26 (±8,8) mm . Conclusão – As distâncias entre a veia hepática direita e o ramo direito da veia porta ou a bifurcação da mesma, em fígados cirróticos, foram significativamente menores que as anteriormente relatadas em fígados normais. A veia hepática média é confirmada como uma via alternativa adequada. / Introduction - The treatment of portal hypertension remains a challenge and many of these patients need liver transplantation as definitive treatment. In this context the Transjugular Intrahepatic Portosystemic Shunt (TIPS) has emerged as an attractive alternative to this complication of chronic liver disease, especially for not requiring laparotomy and effectively reducing the portal pressure. Knowing the distance between the hepatic veins and portal branches and other anatomical data in the cirrhotic liver, they are important requirements in the planning and execution of this procedure. Purpose: To determine spatial arrangements and diameters of right and middle hepatic veins relative to portal vein branches in cirrhotic human livers, gaining strategic insight to percutaneous procedures as transjugular intrahepatic portosystemic shunt. (TIPS). Materials and Methods: This study was authorized by an area Research Ethics Committee, and each study subject or legal representative granted signed informed consent. Acrylic corrosion casts of 21 resected cirrhotic livers were generated. Diameters of hepatic veins and portal branches and pertinent intervening distances were measured. To assess differences in estimated average (relative to reference values), Student's t-test for one sample was applied. Results: Mean distances from right hepatic vein to right portal branch and to portal vein bifurcation were 33±6.4 mm and 36±7.4 mm, respectively, both significantly shorter than published reference values in healthy human livers (p<0.0001 and p<0.0002, respectively). Mean distances from middle hepatic vein to right and left branches of portal vein were 36±6.8 mm and 26±8.8 mm, respectively. Conclusion: Distances separating right hepatic vein and portal vein (right branch and bifurcation) are diminished in cirrhotic livers compared to healthy ones. The middle hepatic vein is confirmed as a suitable alternative route.

Introduction. Alors qu’elle constitue le seul traitement curatif du cholangiocarcinome intrahépatique (CCIH), la résection reste associée à un taux de récidive supérieur à 60% et un taux de survie réelle à 5 ans inférieur à 20%. Une estimation fiable du pronostic ainsi qu’une meilleure compréhension de la biologie tumorale est essentielle pour améliorer le pronostic.Méthodes. A l’appui des données clinico-biologiques de deux larges cohortes de patients avec CCIH réséqué (MSKCC, n=189 et AFC, n=522), trois objectifs ont été explorés. Tout d’abord, définir quel modèle pronostique publié est le plus performant. Ensuite, définir la fiabilité de l’évaluation pronostique préopératoire à partir de, respectivement, l’imagerie, des microARN (miR) circulants diagnostiques et du profil génomique tumoral. Enfin, évaluer l’impact pronostique de la survenue d’événements périopératoires tels que transfusion et morbidité.Résultats. Premièrement, les nomogrammes apportaient une meilleure estimation pronostique en comparaison à la classification AJCC 7ème édition. Deuxièmement, la taille et la multifocalité tumorale sur l’imagerie préopératoire permettaient de différencier deux groupes de patients de pronostic clairement distincts (p<0,001). L’existence d’une mutation d’un gène de remodelage de la chromatine (BAP1, ARID1A, PBRM1) tendait à être associé à une survie sans récidive plus favorable qu’en l’absence de mutation (p=0,09). Alors qu’ayant un potentiel comme marqueur diagnostique circulant, miR21 et miR221 n’étaient pas associé à la survie. Troisièmement, la transfusion peropératoire n’impactait pas la survie à long terme alors que la survenue d’une complication sévère (grade Dindo-Clavien > 2) était indépendamment associée à une survie globale plus courte (p=0,002).Conclusion. Alors que les nomogrammes postopératoires apportent une meilleure estimation pronostique, le développement de modèles pronostiques préopératoires est faisable notamment à partir de l’imagerie et de marqueurs biologiques tumoraux complémentaires. / Introduction. Complete resection stands as the only curative option for intrahepatic cholangiocarcinoma (IHCC). Still, prognosis remains poor after resection due to a recurrence rate over 60% leading to actual 5-year survival rates below 20%. Reliable prognostic estimation and better understanding of tumor biology would be of interest for improving IHCC prognosis.Methods. Using clinical and biological data from two large cohort of resected IHCC (MSKCC, n=189 and AFC, n=522), three objectives have been explored. First, assessing the performances of different published prognostic models. Second, defining the reliability of preoperative prognostic estimation using imaging, tumoral genomic profiling and circulating tumoral microRNA (miR). Third, evaluating the prognostic impact of perioperative events such as blood transfusion and morbidity.Results. First, nomograms displayed better prognostic accuracy over the AJCC 7th edition staging system. Second, tumor size and multifocality on preoperative imaging allowed patient stratification in groups statistically different regarding prognosis (p<0.001). Further, the presence of chromatine remodeling gene mutations (BAP1, ARID1A, PBRM1) tended towards longer recurrence-free survical (p=0,09). Some diagnostic circulating miR such as miR21 and miR221 were not associated with survival. Third, in contrast with intraoperative transfusion, the occurrence of severe morbidity (Dindo-Clavien grade > 2) was independently associated with shorter overall survival (p=0.002).Conclusion. Nomograms outperform conventional staging sytem. Preoperative prognostic estimation is feasible and reliable using imaging. Identifying new prognostic biomarkers would help refining preoperative prognostic estimation.

No description available.

Introdução – O tratamento da hipertensão portal continua sendo um desafio e muitos desses pacientes necessitam até transplante de fígado, como tratamento definitivo. Nesse contexto a derivação porto-sistêmica intra-hepática transjugular (Transjugular Intrahepatic Portosystemic Shunt – TIPS) surgiu como uma alternativa atraente para esta complicação da doença hepática crônica, sobretudo por não requerer laparotomia e efetivamente reduzir a pressão portal. O conhecimento da distância entre as veias hepáticas e os ramos portais e outros dados anatômicos, no fígado cirrótico, são requisitos importantes no planejamento e execução desse procedimento. Objetivos - Determinar as distâncias e diâmetros das veias hepáticas direita e média para os ramos portais e para a bifurcação da veia porta, no fígado cirrótico humano, com vistas à construção do TIPS. Tipo de estudo – Estudo anatômico descritivo e macroscópico em moldes vasculares de resina obtidos por corrosão de fígados humanos isolados e cirróticos. Material e método – O estudo foi autorizado pelo Comitê de Ética em Pesquisa do HUOC/Procape-UPE e todos os pacientes, ou seus representantes legais, assinaram Termo de Consentimento Livre e Esclarecido. Foram obtidos 21 moldes de resina acrílica dos ramos portais e veias hepáticas de fígados cirróticos, de pacientes transplantados, dos hospitais Jayme da Fonte e Universitário Oswaldo Cruz, do Recife/PE. Após a completa corrosão do parênquima, foram medidas as distâncias e diâmetros das veias hepáticas e ramos da veia porta. Para testar a hipótese de diferença da média estimada em relação a um valor de referência, foi aplicado o teste t-Student para uma amostra. Resultados - A distância média da veia hepática direita para o ramo direito da veia porta e para a sua bifurcação foram, respectivamente, de 33 (±6,4) e 36 (±7,4) mm, ambos significativamente menores (p<0,0001 e p<0,0002) que os resultados encontrados na literatura, em fígados normais. A distância média da veia hepática média para o ramo direito e para o ramo esquerdo da veia porta foi, respectivamente, de 36 (±6,8) e 26 (±8,8) mm . Conclusão – As distâncias entre a veia hepática direita e o ramo direito da veia porta ou a bifurcação da mesma, em fígados cirróticos, foram significativamente menores que as anteriormente relatadas em fígados normais. A veia hepática média é confirmada como uma via alternativa adequada. / Introduction - The treatment of portal hypertension remains a challenge and many of these patients need liver transplantation as definitive treatment. In this context the Transjugular Intrahepatic Portosystemic Shunt (TIPS) has emerged as an attractive alternative to this complication of chronic liver disease, especially for not requiring laparotomy and effectively reducing the portal pressure. Knowing the distance between the hepatic veins and portal branches and other anatomical data in the cirrhotic liver, they are important requirements in the planning and execution of this procedure. Purpose: To determine spatial arrangements and diameters of right and middle hepatic veins relative to portal vein branches in cirrhotic human livers, gaining strategic insight to percutaneous procedures as transjugular intrahepatic portosystemic shunt. (TIPS). Materials and Methods: This study was authorized by an area Research Ethics Committee, and each study subject or legal representative granted signed informed consent. Acrylic corrosion casts of 21 resected cirrhotic livers were generated. Diameters of hepatic veins and portal branches and pertinent intervening distances were measured. To assess differences in estimated average (relative to reference values), Student's t-test for one sample was applied. Results: Mean distances from right hepatic vein to right portal branch and to portal vein bifurcation were 33±6.4 mm and 36±7.4 mm, respectively, both significantly shorter than published reference values in healthy human livers (p<0.0001 and p<0.0002, respectively). Mean distances from middle hepatic vein to right and left branches of portal vein were 36±6.8 mm and 26±8.8 mm, respectively. Conclusion: Distances separating right hepatic vein and portal vein (right branch and bifurcation) are diminished in cirrhotic livers compared to healthy ones. The middle hepatic vein is confirmed as a suitable alternative route.

L'infection par le virus de l'hépatite C implique des processus d'interaction complexe entre l'hôte et le virus. Plusieurs facteurs de l'hôte incluant des polymorphismes génétiques et les réponses immunitaires influent sur l'infection et les réponses au traitement. Aussi, il est important d'identifier en amont les facteurs pour prédire la réponse au traitement. L'objectif de la thèse est d'étudier l'influence de certains polymorphismes génétiques de l'hôte sur la réponse à la bithérapie et sur le statut immunitaire du foie dans l'infection chronique par le VHC. L'étude a porté sur les polymorphismes des gènes de l'interféron lambda 3 et 4, l'interféron gamma, l'interleukine 10, et l'interleukine 17, conjointement à la réponse au traitement avec le peg-IFNα et la RBV et aux réponses immunitaires du foie chez les patients. Nous avons établi une méthode PCR-RFLP simple et fiable pour le typage de deux polymorphismes de l'IFNL3. En utilisant les enzymes de restriction BstUI et BrsDI permet le génotypage de deux variantes de IFNL3 (rs12979860 C/T et rs8099917 T/G, respectivement). Les résultats indiquent que cette méthode PCR-RFLP donne des résultats similaires à ceux des méthodes standard et présente un intérêt pour des analyses de routine en laboratoire clinique car elle est peu coûteuse. Nous avons analysé l'association des polymorphismes avec la réponse au traitement antiviral sur une cohorte de 108 patients infectés par le VHC de génotype 1 traités par la bithérapie. Nous avons ainsi démontré que le génotype de l'IFNL4 TT/TT de ss469415590 et une réponse virologique rapide sont des facteurs prédictifs indépendants pour atteindre un taux de réponse virologique soutenue (OR = 3,93, p = 0,004 et OR = 6,74, p = 0,021). D'autre part, une charge virale initiale haute est associée à l'échec au traitement (OR = 0,34, p = 0,023). Ainsi, ces paramètres sont utiles pour la définition d'un traitement personnalisé. Pour expliquer l'influence de ces polymorphismes dans l'infection chronique par le VHC, nous avons étudié l'association des polymorphismes IFNL3 et 4 avec la réponse immunitaire du foie chez les patients atteints d'une infection chronique par le VHC. En utilisant l'expression de CD107a comme marqueur de l'activité sécrétoires des lymphocytes, nous avons observé une activité de dégranulation des lymphocytes du foie plus importante les patients porteurs des génotypes de IFNL4 favorables en comparaison avec les patients porteurs de l'allèle défavorable. En utilisant des analyses de régression, les taux d'ALT sont en corrélation avec la fréquence des cellules NKT CD107a+ dans le foie. Enfin, chez les patients traités par la bithérapie, une forte activité de dégranulation est observée chez les patients avec les génotypes favorables IFNL3 et 4. Nous suggérons que les polymorphismes des gènes de l'interféron lambda sont associés à l'activité de la dégranulation des lymphocytes intra-hépatiques et contribuent à un mécanisme de clairance du VHC sous la bithérapie. Nous avons également étudié l'impact de plusieurs polymorphismes génétiques sur la gravité de l'hépatite C chronique. Les résultats montrent une association significative observée entre le polymorphisme de l'IFN-γ et la gravité de l'hépatite C chronique. Pour l'analyse de régression logistique, l'allèle T et la présence d'une stéatose sont des facteurs prédictifs indépendants de la sévérité de la maladie hépatique chronique associée au VHC. L'utilisation du génotypage de l'IFN-γ pourrait être utile dans la prise en charge des patients. En conclusion, nous avons montré que les polymorphismes des gènes des IFNL3 et 4 et de l'IFN-γ de l'hôte jouent un rôle important dans l'efficacité du traitement et les réponses immunitaires hépatiques. Ces résultats aident à définir un traitement personnalisé pour le contrôle de l'infection chronique par le VHC, en particulier dans les régions aux ressources limitées où les nouveaux traitements ne sont pas accessibles. / Hepatitis C virus (HCV) infection is a complex interaction process between the host and viral factors. The host immune responses and genetic polymorphisms have been shown to be associated with the outcome of HCV infections and the responses to treatments. Thus, it is very important to identify pre-treament factors to predict treatment outcomes. The overall aim of the thesis study is to investigate the role of host genetic polymorphisms on response to combination therapy and immune response in the liver in chronic HCV infection. The study has focused on polymorphisms in the interferon lambda (IFNL) genes, interferon gamma, interleukin 10, and interleukin 17 in relation to response to therapy with peg-IFNα and Ribavirin (RBV) and liver immune responses in patients with chronic HCV infection.First, we have established a simple and reliable method for genotyping of the IFNL3 polymorphisms. We designed primers and selected restriction enzymes BstUI and BrsDI for genotyping 2 variants rs12979860 C/T and rs8099917 T/G, respectively. The results indicate that this PCR-RFLP method yields to identical data than standard sequencing method and commercial kit. We suggest that PCR-RFLP method could be used routinely in conventionally clinical laboratory for genotyping of IFNL3 polymorphisms. Next, we analysed the association of these variants with response in combination therapy of peg-IFNα and RBV. Among 108 treated patients infected with HCV genotype 1, by using logistic regression model analyses, we showed that patients who had favorable IFNL4 genotype (genotype TT/TT of ss469415590) and presented a rapid virological response (RVR) were independent predictors of achieving sustained virological response rate (OR = 3.93, CI = 1.53 -10.08, p = 0.004 and OR = 6.74, CI = 1.33 - 34.06, p= 0.021), whereas patients with high baseline viral load level were associated with failure to treatment (OR = 0.34, CI = 0.13 - 0.87, p = 0.023). We suggest that patients had favorable IFNL4 genotype and achieved RVR should benefit an individualized treatment of combination therapy of peg-IFNα and RBV. To explain the influence of these polymorphisms in chronic HCV infection, we investigated the association of IFNL4 polymorphisms with immune response in the liver in patients with chronic HCV infection. By using marker CD107a, a marker expressing degranulation activity of cytotoxic lymphocytes, we indicated that degranulation process was found in liver lymphocytes in patients carrying favourable IFNL4 genotypes compared with patients with unfavourable genotypes. By using multiple regression analyses, we demonstrated that ALT levels correlate with frequency of CD107a+ NKT cells in the liver. Finally, in patients treated by peg-IFNα and RBV, high degranulation activity observed in patients with favourable genotypes of IFNL3 and IFNL4 (CC of rs12979860 and TT/TT of ss469415590). We suggest that polymorphisms in the interferon lambda genes associated with intrahepatic lymphocyte degranulation activity and contribute to clearance mechanism of HCV under combination treatment of peg-IFNα and RBV.We investigated the impact of several genetic polymorphisms on the severity of chronic hepatitis C. We showed a significant association observed between polymorphism of IFN-γ and the severity of chronic hepatitis C. By using logistic regression analysis, T allele of IFN-γ and the presence of steatosis are independent predictive factors of severity of HCV-1 - related liver disease. This suggests we can use genetic variant of IFN-γ in classification and management of chronic hepatitis C. In conclusion, we indicated that host genetic polymorphisms play critical roles both in responses to treatment and in the immunopathogenesis of chronic HCV infection. This study can help to reach a closer step to individualized medicine for the control of chronic HCV infection in resource-limited regions when new treatment regimens are not available.

Introdução – O tratamento da hipertensão portal continua sendo um desafio e muitos desses pacientes necessitam até transplante de fígado, como tratamento definitivo. Nesse contexto a derivação porto-sistêmica intra-hepática transjugular (Transjugular Intrahepatic Portosystemic Shunt – TIPS) surgiu como uma alternativa atraente para esta complicação da doença hepática crônica, sobretudo por não requerer laparotomia e efetivamente reduzir a pressão portal. O conhecimento da distância entre as veias hepáticas e os ramos portais e outros dados anatômicos, no fígado cirrótico, são requisitos importantes no planejamento e execução desse procedimento. Objetivos - Determinar as distâncias e diâmetros das veias hepáticas direita e média para os ramos portais e para a bifurcação da veia porta, no fígado cirrótico humano, com vistas à construção do TIPS. Tipo de estudo – Estudo anatômico descritivo e macroscópico em moldes vasculares de resina obtidos por corrosão de fígados humanos isolados e cirróticos. Material e método – O estudo foi autorizado pelo Comitê de Ética em Pesquisa do HUOC/Procape-UPE e todos os pacientes, ou seus representantes legais, assinaram Termo de Consentimento Livre e Esclarecido. Foram obtidos 21 moldes de resina acrílica dos ramos portais e veias hepáticas de fígados cirróticos, de pacientes transplantados, dos hospitais Jayme da Fonte e Universitário Oswaldo Cruz, do Recife/PE. Após a completa corrosão do parênquima, foram medidas as distâncias e diâmetros das veias hepáticas e ramos da veia porta. Para testar a hipótese de diferença da média estimada em relação a um valor de referência, foi aplicado o teste t-Student para uma amostra. Resultados - A distância média da veia hepática direita para o ramo direito da veia porta e para a sua bifurcação foram, respectivamente, de 33 (±6,4) e 36 (±7,4) mm, ambos significativamente menores (p<0,0001 e p<0,0002) que os resultados encontrados na literatura, em fígados normais. A distância média da veia hepática média para o ramo direito e para o ramo esquerdo da veia porta foi, respectivamente, de 36 (±6,8) e 26 (±8,8) mm . Conclusão – As distâncias entre a veia hepática direita e o ramo direito da veia porta ou a bifurcação da mesma, em fígados cirróticos, foram significativamente menores que as anteriormente relatadas em fígados normais. A veia hepática média é confirmada como uma via alternativa adequada. / Introduction - The treatment of portal hypertension remains a challenge and many of these patients need liver transplantation as definitive treatment. In this context the Transjugular Intrahepatic Portosystemic Shunt (TIPS) has emerged as an attractive alternative to this complication of chronic liver disease, especially for not requiring laparotomy and effectively reducing the portal pressure. Knowing the distance between the hepatic veins and portal branches and other anatomical data in the cirrhotic liver, they are important requirements in the planning and execution of this procedure. Purpose: To determine spatial arrangements and diameters of right and middle hepatic veins relative to portal vein branches in cirrhotic human livers, gaining strategic insight to percutaneous procedures as transjugular intrahepatic portosystemic shunt. (TIPS). Materials and Methods: This study was authorized by an area Research Ethics Committee, and each study subject or legal representative granted signed informed consent. Acrylic corrosion casts of 21 resected cirrhotic livers were generated. Diameters of hepatic veins and portal branches and pertinent intervening distances were measured. To assess differences in estimated average (relative to reference values), Student's t-test for one sample was applied. Results: Mean distances from right hepatic vein to right portal branch and to portal vein bifurcation were 33±6.4 mm and 36±7.4 mm, respectively, both significantly shorter than published reference values in healthy human livers (p<0.0001 and p<0.0002, respectively). Mean distances from middle hepatic vein to right and left branches of portal vein were 36±6.8 mm and 26±8.8 mm, respectively. Conclusion: Distances separating right hepatic vein and portal vein (right branch and bifurcation) are diminished in cirrhotic livers compared to healthy ones. The middle hepatic vein is confirmed as a suitable alternative route.

Introduction Estrogen-induced cholestasis is a disease characterized by a failure of bile flow and bile production. It can develop in women after oral contraceptives use, hormone replacement therapy or during pregnancy. The estrogen metabolism is a complex process leading to formation of metabolites with different biological activities. It takes place primarily in the liver (Phase I and Phase II including hydroxylation, methylation, sulfation and glucuronidation). The enzymes from UDP-glucuronosyltransferases family , abbreviated UGT, are responsible for the glucuronidation of estrogens. Aims The objective of my work is to define estrogen metabolism and gene expression of UGT1A1, CYP1A2 and SULT1A1 and characterize cholestatic liver damage in the UGT1A1 deficient rat strain (Gunn rats) compared to rats with normal enzyme activity and try to define possible mechanisms responsible for the liver damage. Methods Adult female Gunn and corresponding heterozygous rats were treated with ethinylestradiol (EE, 5 mg/kg body weight SC) for 5 days, while control rats received propanediol (vehicle). Day six, the animals were sacrificed and plasma and liver tissue were collected for analysis. Markers of cholestasis and liver damage ALP, AST, ALT and bilirubin were determined using an automatic analyzer, total...

Made available in DSpace on 2016-01-26T12:51:45Z (GMT). No. of bitstreams: 1 fernandaribeirofunes_dissert.pdf: 809143 bytes, checksum: b26631e59407a8a29bb4194e0fc73690 (MD5) Previous issue date: 2011-12-15 / Introduction: The transjugular intrahepatic portosystemic shunt (TIPS) is a non-surgical treatment option with low morbidity and mortality, can be realized in patients with severe hepatic dysfunction, minimally invasive surgery that aims to decompress the portal system treating or reducing the complications portal hypertension. Objective: To analyze survival, and overall early mortality related to the etiology of the disease, characterization of the procedure in the emergency or elective and Child-Pugh and MELD classification and analyze the complications presented by patients. Methods: A retrospective study in the database of medical records of patients with cirrhosis who underwent TIPS for treatment of gastrointestinal bleeding due to portal hypertension who have not responded to medical treatment and endoscopic treatment from 1998 to 2010 in the Department of Liver Transplantation, Hospital de Base and Faculty Medicine of Sao Jose do Rio Preto. To check the rate of mortality, survival and complications were excluded patients who have failed the technical procedure and the others were followed until the closure of the study, performing a liver transplant or death occurred. The study was approved by the Ethics and Research Committee. Results: The sample consisted of 72 (84.7%) patients who were successful in the procedure of which 57 (79.2%) were male, mean age 47.4 years (between 16 and 85 years, SD=13), 21(29.2%) patients had a cause excessive consumption of alcohol, 21(29.2%) to contamination by hepatitis virus, 16(22.2%) excessive alcohol consumption associated with virus and 14(19.4%) patients had other causes. Procedure was performed on an emergency basis in 37(51.4%) and electively in 35(48.6%). The initial classification, 14 (20%) had Child-Pugh A, 33 (47.1%) Child-Pugh B and 23 (32.9%) Child-Pugh C. MELD was initially obtained in 68 patients, 37 (54.4%) with more than 15 points, while 31 (45.6%) up to 15 points. Early death occurred in 19 (26.4%). Overall mortality occurred in 41(60.3%). Conclusion: There was no difference regarding the etiology of early mortality, mortality and survival and overall mortality rate of patients undergoing emergency TIPS in characterization compared with elective TIPS. Difference was observed between the groups of patients undergoing emergency TIPS in characterizing compared to elective TIPS in early mortality rate, death is higher in emergency TIPS. Regarding the classification of Child-Pugh and MELD higher overall mortality was observed in patients early and Child-Pugh class C and MELD> 15, and shorter survival in this group of patients. Complications were similar to those described in the literature, but the percentage of occurrence of stent dysfunction (26,4%) was lower than in most studies the incidence of encephalopathy (58,3%) was higher. / Introdução: A derivação portossistêmica transjugular intra-hepática (TIPS) é uma opção de tratamento não cirúrgica com baixo índice de morbimortalidade e com possibilidade de realização em pacientes com disfunção hepática grave, por ser minimamente invasiva e que visa descomprimir o sistema porta tratando ou reduzindo as complicações da hipertensão portal. Objetivo: Analisar a sobrevida, mortalidade precoce e global relacionada à etiologia da doença, caracterização do procedimento em urgência ou eletiva e classificações de Child-Pugh e MELD e analisar as complicações apresentadas pelos pacientes. Casuística e Métodos: Estudo retrospectivo baseado no banco de dados dos prontuários dos pacientes cirróticos submetidos a TIPS para tratamento da hemorragia digestiva por hipertensão portal que não responderam ao tratamento clínico endoscópico e atendidos no período de 1998 a 2010 no Serviço de Transplante de Fígado do Hospital de Base e Faculdade de Medicina São José do Rio Preto. Para verificação da taxa de mortalidade, sobrevida e complicações os pacientes seguidos até o fechamento do estudo, realização de transplante de fígado ou ocorrência de óbito. O estudo foi aprovado pelo Comitê de Ética e Pesquisa. Resultados: A amostra foi composta de 72(84,7%) pacientes que obtiveram êxito no procedimento sendo 57(79,2%) do sexo masculino, idade média de 47,4 anos (entre 16 e 85 anos e DP=13), 21(29,2%) pacientes apresentaram como causa o consumo excessivo de álcool; 21(29,2%) a contaminação por vírus da hepatite, 16 (22,2%) o consumo excessivo de álcool associado a vírus e 14 (19,4%) pacientes apresentaram outras causas. Procedimento foi realizado em caráter de urgência em 37(51,4%) e de forma eletiva em 35 (48,6%). Quanto à classificação inicial, 14(20%) tinham Child-Pugh A, 33(47,1%) Child-Pugh B e 23(32,9%) Child-Pugh C. MELD inicial foi obtido em 68 pacientes sendo 37 (54,4%) com mais de 15 pontos, enquanto 31(45,6%) tiveram até 15 pontos. Óbito precoce ocorreu em 19(26,4%). Mortalidade global ocorreu em 41 (60,3%). Conclusão: Não houve diferença da etiologia com relação à mortalidade precoce, mortalidade global e sobrevida e na taxa de mortalidade global dos pacientes submetidos a TIPS de urgência comparados a TIPS eletivo. Observou-se diferença entre os grupos de pacientes submetidos a TIPS de urgência comparados a TIPS eletivo na taxa de mortalidade precoce, sendo o óbito maior no TIPS de urgência. Com relação as classificações de Child-Pugh e MELD foi observado maior mortalidade global e precoce nos pacientes Child-Pugh classe C e MELD >15, e menor sobrevida nesse grupo de pacientes. As complicações encontradas foram semelhantes às descritas na literatura, porém a porcentagem da ocorrência de disfunção do stent (26,4%) foi menor que na maioria dos estudos e a incidência de encefalopatia (58,3%) foi superior.

The global epidemic of obesity is rapidly becoming a major public health problem in many parts of the world. Unhealthy diets and physical inactivity are two modifiable risk factors for prevention of obesity and its associated chronic diseases. Their influence on muscle energy metabolism and fat mass is not completely elucidated. A decreased capacity for fatty acid oxidation (FAO) may be a metabolic risk factor for weight gain and is found to be depressed in obese individuals; and exercise training may promote an increased capacity for FAO. In addition to the interest in whole-body FAO, the role of site specific lipid accumulation including visceral adipose tissue (VAT), intrahepatic lipids (IHL) and intramyocellular lipids (IMCL) has become a focus of interest because of their reported association with insulin resistance (IR), a key metabolic defect associated with obesity and type 2 diabetes mellitus (T2DM). However, ambiguity persists regarding the importance of IMCL as a metabolic substrate for energy production in obesity. A better understanding of the factors regulating FAO, body fat distribution and IMCL mobilisation is important for the development of interventions allowing effective treatment of conditions in which these are disturbed. The study of individuals with metabolic myopathies can give more information about the energy metabolism of muscle. McArdle disease (MD) affects glucose availability to muscle for energy production. Investigations into IMCL storage and mobilisation in MD have not been reported. The aims of this thesis are to investigate 1) the effects of weight-loss via dietary restriction plus modest but clinically-relevant exercise training on FAO, body fat distribution and mobilisation of IMCL during exercise in obese non-diabetic adults; 2) the effect of an exercise training intervention on IMCL storage and mobilisation in a subject with MD. All obese subjects underwent a 4 month lifestyle intervention with weekly meetings with a dietitian and an exercise physiologist. Of the 92 subjects, 73 completed the intervention. They showed significant decreases in body weight (8%), fat mass (14%) and total cholesterol (5%). The exercise prescription of 1500 kcal.week-1 resulted in variable compliance with the prescription (1224 ± 1085 kcal.week-1) measured by heart rate monitor. Those who did most exercise and also those who had less weekly variability in their exercise, had greater reductions in body weight and fat mass. The total activity energy expenditure measured by accelerometry did not change post-intervention but there was a reduction in low intensity activity and an increase in moderate and high intensity activity. A submaximal treadmill test and resting metabolic rate (RMR) using indirect calorimetry was measured before and after the intervention to investigate factors regulating FAO and energy expenditure. Subjects showed increases in FAO without change in energy expenditure for the same walking speed post intervention, but the volume of exercise completed during the intervention was not associated with these changes. To investigate body fat distribution in obesity, VAT, IHL and soleus muscle IMCL was measured in a sub-group of 18 males by magnetic resonance imaging (MRI) and spectroscopy (MRS) along with measurement of maximal aerobic capacity. Fitness increased significantly with significant decreases in VAT (29%) and IHL (54%), without significant change in IMCL. Subjects who had the greatest decrease in VAT were those who exercised for longer durations during the intervention. IHL was the only measure of excess lipid that correlated with IR. The measurement of IMCL before and after 1-hour of cycle ergometer exercise showed no significant mobilisation of IMCL either at baseline or after the lifestyle intervention. The intensity of the acute exercise was adjusted to correspond to each individual’s maximal fatty acid oxidation (MFAO) which increased by over 60% post intervention. In the subject with MD, an 8 week exercise training intervention without dietary intervention increased IMCL stores by 27%, but there was no marked change in IMCL with acute exercise at both time points. The findings of this thesis demonstrate that a clinically relevant and achievable lifestyle intervention incorporating weight loss through diet and objectively measured exercise can achieve improvements in blood lipid profile, body composition and FAO. The differential effects of the intervention on the various fat depots and their associations to metabolic markers suggest that individualised strategies may be required dependent upon body fat distribution. The non detection of mobilisation of IMCL by MRS suggests that these lipids may not be present as a substrate source in this population but rather an ectopic lipid depot related to increased energy consumption in diet. The relatively low capacity for FAO in both the obese and MD subjects may have affected the results. This thesis discusses implications for clinical practice, discusses novel findings related to the energy metabolism in obesity and MD and informs clinical and basic science about important future directions.