A number of questions about the hepatic mechanisms of tissue-type plasminogen activator (t-PA) clearance still remain unanswered. Although certain liver endothelial cell receptors have been implicated, the parenchymal cell system, which is responsible for most clearance, still remains a mystery. The aim of this project, in the most simple terms, was to solve this mystery. The foundation upon which this project was built was that t-PA is cleared, by a hepatic receptor, in complex with its primary inhibitor, plasminogen activator inhibitor type 1 (PAI-1). The affinity of binding was estimated to be 0.8-1.0 nM and the number of binding sites per cell, 35 000-70 000. Affinity chromatography and chemical cross-linking resulted in a band of A?70 kDa which was presumed to be the receptor. This project was designed to characterize this hepatic receptor for t-PA-PAI-1 and determine whether plasmin-2-antiplasmin (PAP) is recognised by the same receptor. Characterizing the receptor was attempted initially by employing cell binding assays using the human hepatoma cell line, Hep G2. This methodology required the formation and characterization of pure pre-formed ligands which was achieved by overcoming preliminary problems. The binding assays showed that competition between t-PA-PAI-1 and PAP was occurring but that high non-specific binding and error between duplicate samples suggested that this system was not suitable for characterization of the receptor. The data accumulated in this study suggested that LRP was primarily responsible for hepatic uptake of t-PA and that proteases were recognised preferentially in complex with their inhibitors.

No description available.

Thesis (M.Ph.)--Chinese University of Hong Kong. / Bibliography: leaves 66-78.

by Ho King Wah Stephen. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (leaves 251-304). / Title Page --- p.1 / Table of Contents --- p.2 / Summary --- p.3 / Glossary of abbreviations used in the thesis --- p.10 / List of Figures --- p.12 / List of Tables --- p.20 / Acknowledgments --- p.24 / Chapter Chapter 1 --- Hepatic Cancer - Review of the Medical Literature --- p.25 / Chapter Chapter 2 --- Selective Internal Radiation Therapy - Review of the Medical Literature --- p.47 / Chapter Chapter 3 --- The Background In Physics --- p.76 / Chapter Chapter 4 --- Hypothesis and Testing the Hypothesis --- p.88 / Chapter Chapter 5 --- Parameters Required in the Partition Model --- p.98 / Chapter Chapter 6 --- Prediction of Radiation Dose and Verification of the Partition Model --- p.143 / Chapter Chapter 7 --- Clinical Evaluation of the Partition Model --- p.181 / Chapter Chapter 8 --- Conclusions and Future Development --- p.248 / References --- p.251

Primary hepatocytes maintained in culture progressively down regulate liver-specific genes and lose their characteristic function and morphology. This process, termed dedifferentiation, is a hindrance to in vitro modelling of systems such as xenobiotic metabolism, liver disease and regeneration. However the results presented here demonstrate that dedifferentiated hapatocytes spontaneously induce expression of ductal genes, and therefore represent a useful model of cell reprogramming.

Among NAFLD patients without known diabetes or high fasting plasma glucose at or above 7.0 mmol/I, 21% had undiagnosed diabetes and 29% had impaired glucose tolerance. In this population, post-challenge hyperglycemia was associated with NASH and liver fibrosis. Oral glucose tolerance test should be considered in the evaluation of NAFLD patients. / NAFLD is closely related to metabolic syndrome. Using the ethnic-specific IDF criteria, 70% of NAFLD patients had metabolic syndrome, compared to 7% of the general population. A significant proportion of NAFLD patients had body mass index between 23 and 25 kg/m2. The diagnosis of NAFLD may predate the development of different components of metabolic syndrome. / NAFLD patients have lower serum adiponectin level than healthy controls. NASH patients have higher serum tumor necrosis factor alpha (TNF-alpha) level than those with simple steatosis. The differences in adipokines remained significant after adjustment for traditional metabolic risk factors. These suggest that abnormalities in adipokines may be involved in the pathogenesis of NAFLD and NASH. On the other hand, genetic polymorphisms of the adiponectin and TNF-alpha genes are not associated with histological severity. / Since advanced fibrosis is less common in Chinese NAFLD patients, performing liver biopsies on every NAFLD patient for disease staging does not appear to be essential or cost-effective. Recently, the NAFLD fibrosis score is developed using 6 clinical parameters including age, BMI, impaired fasting glucose or diabetes, AST/ALT ratio, platelet count and albumin. The score had high negative predictive value of 91% in excluding advanced fibrosis in Chinese NAFLD patients. It may also reduce the burden of liver biopsies in the majority of cases. / Through a series of clinical studies in Chinese nonalcoholic fatty liver disease (NAFLD) patients in Hong Kong, we demonstrated that nonalcoholic steatohepatitis (NASH) and advanced fibrosis do occur in Chinese, with around 10% of NAFLD patients having advanced fibrosis, and 80% having necroinflammation. Importantly, up to half of the patients had progression of liver fibrosis upon long-term follow-up. / by Wong Wai Sun. / Adviser: Lik Yuen Henry Chan. / Source: Dissertation Abstracts International, Volume: 70-09, Section: B, page: . / Thesis submitted in: May 2008. / Thesis (M.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 219-263). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Concerning potential immunological reaction in patients receiving multiple bioartificial liver treatments (with porcine hepatocytes bioreactor), the beneficial effect of sequential plasmapheresis-hemoadsorption-bio-liver treatment protocol was studied. The hypothesis was tested in a trichosanthin-induced anaphylaxis rat model. Fatal anaphylactic response upon antigen challenge was reduced in a previously trichosanthin sensitized rat prior with cross circulation. It was suggested that circulating antibodies responsible for immunological response were removed by the non cell-based treatment. The potential risk of hypersensitivity reaction of subsequent cell-based treatment was reduced. In the design of HBLSS, the sequential plasmapheresis-hemofiltration-bio-liver treatment was suggested to alleviate potential immunological consequences and allow multiple uses in single patient. / In addition to artificial liver research, pharmacological therapies are sought to treat ALF. Recent studies suggested that the local renin-angiotensin system (RAS) in the liver regulate the fibrogenic response. The possible involvement of RAS in acute liver injury was investigated in the present study. In the D-galactosamine induced rat liver failure model, angiotensin II type 1 receptors (AT1R) were detected by immunohistochemical staining in the centrilobular region after induction of acute liver injury which was not evident in normal liver. There were associated elevation of total bilirubin, alanine aminotransferase and tissue inhibitor of metalloproteinase type 1 (TIMP-1). Losartan treatment was able to reduce all these parameters. TIMP-1 protein was reduced by 1.5 fold (p<0.05) on day 1 and 1.56 fold (p<0.05) on day 3 in the losartan treatment group relative to the GalN group. The survival rate of the losartan treatment group was significantly higher than that without treatment (5-day survival, 85% vs 42.5%, p<0.05). This finding suggested the local renin-angiotensin system plays a role in the pathophysiological mechanism of acute liver injury. / In summary, the presence study addressed two approaches in treating liver failure. The HBLSS treatment protocol improved survival of acute-on-chronic liver failure patients. The protective effect of losartan in liver injury suggests AT1R blockade is a potential therapeutic strategy in acute liver injury. / The mainstay treatment of acute liver failure (ALF) is conservative medical therapy. In patients having acute liver insufficiency, the only proven life-saving procedure is liver transplantation. The concept of supportive care in liver failure is to optimize patient's clinical condition by replacing some of the essential functions of liver and allowing liver regeneration in order to compensate the loss of hepatocellular functions. / There was increasing evidence suggesting a role of artificial liver (extracorporeal system) in the treatment of liver failure. A retrospective study was performed in a group of acute-on-chronic liver failure (AoCLF) patients treated with hybrid bioartificial liver support system (HBLSS). From 2001-2004, there were 40 chronic liver disease patients presented with acute deterioration. Patients were treated either with conventional medical therapy (n=21) or integrated with HBLSS treatment (n=19). The 60-day survival rate was 30% and 68.5% respectively (P<0.05 log-rank test). Integration of hybrid bioartificial liver support system (HBLSS) in treating acute-on-chronic liver failure (AoCLF) patients improved the survival outcome. Univariate analysis of admission blood parameters revealed creatinine appeared to predict mortality in AoCLF patients with HBLSS treatment. / Chan Hoi Ming Herman. / "June 2006." / Adviser: Siu-cheung Michael Tam. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1547. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 104-116). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Chronic Liver Disease (CLD) and Acute Liver Failure (ALF) are serious medical syndromes. Current therapeutic options consist of managing complications, and liver transplant. Even if liver transplantation is thought to be suitable for CLD or ALF patients, there are not enough organs available and thus increasingly more deaths occur on the transplant waiting list. Therefore, there is a pressing need to develop additional therapies. This thesis firstly systematically reviews trials in autologous cell therapies as possible treatments for patients with cirrhosis. The published literature is imperfect and the difference in trial design means it has not been possible to conduct a meta-analysis. Regardless of these shortcomings, cell therapy is a potentially positive prospect. In ALF and CLD monocyte-macrophages have diverse roles within the liver. Monocyte and immune cell changes in ALF are investigated and it is demonstrated for the first time that patients with paracetamol induced ALF have a significantly altered blood compartment and that these changes correlate with patient outcome. It is possible that these results may help stratify which patients may spontaneously survive and which patients may require an emergency liver transplant. Furthermore, modulation of these changes may improve outcomes for patients. The thesis also examines monocyte-macrophages in cirrhotic patients and demonstrates the feasibility of differentiating cirrhotic patients’ monocytes into functional macrophages, comparable to healthy volunteers in a Good Manufacturing Practice (GMP) environment. A first in-man trial using macrophages infused to patients with cirrhosis as a potential new treatment is also detailed. Finally, this thesis outlines developmental work for cell therapy in patients with cirrhosis in the multi-centre REALISTIC trial. Patients were randomly assigned to receive; standard medical care, Granulocyte Stimulating Factor (GCSF) injections alone or GCSF combined with repeated stem cell infusion.

archives@tulane.edu / 0 / Anna Smith

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.