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Patients with portal hypertension who have bled from oesophageal varices have a mortality of approximately 30&37 . It is a therapeutic paradox that life-saving resuscitation following haemorrhagic shock may be detrimental by causing variceal rebleeding or continued haemorrhage and by inducing gastric erosions. This thesis addresses the hypotheses: i) secondary bleeding from varices in portal hypertension (PHT) is precipitated by blood volume restitution resulting from increased portal pressure, an increase which can be prevented by the somatostatin analogue, SMS 201-995 (Octreotide); ii) erosive gastritis found in patients with varices results from increased susceptibility to mucosal injury, is exacerbated by reperfusion, and is mediated by oxygen-derived free radicals. The three principal approaches employed were initially to establish prehepatic portal hypertension in a rat model by graded portal vein ligation (PVL). Acute PHT (3 days post-PVL) was characterised by high portal pressure and little portasystemic shunting, while chronic PHT (14 days post-PVL) was characterised by lower portal pressure and increased shunting. In anaesthetised hypovolaemic animals, arterial pressure was reduced below 35mmHg for 30 minutes. Following reperfusion, portal pressure increased by up to 34&37 above baseline values. In acute PHT, this was mediated by increased portal venous inflow, whereas in chronic PHT, outflow resistance increased. The rise in portal pressure was prevented by SMS 201-995 (dose-related). Secondly, studies of the gastric mucosa in PHT demonstrated that; it was not more susceptible to injury; injury was dependent on gastric luminal acidity; a gradient of injury existed, and there was no correlation between injury and portal pressure or shunting.

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No description available.

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Hepatocellular carcinoma (HCQ is one of the commonest cancers worldwide. There is, however, a marked geographical variation in incidence and it has been suggested that the pathogenesis may vary in different parts of the world. A retrospective analysis of 110 HCC patients was initially undertaken which confirmed that only 29% of British patients had markers of hepatitis B infection, suggesting a possible role for other environmental agents in the pathogenesis, and that 80% of patients had underlying cirrhosis. The nature of the strong relationship between HCC and cirrhosis has not been established but it has been postulated that increased hepatocyte turnover in the cirrhotic liver may predispose to DNA damage by environmental mutagens. Cell proliferation is required to express the strongly promutagenic DNA base lesion 0'-methylguanine, produced by alkylating agents, as a mutation. &- methylguanine is repaired by the DNA repair enzyme 06-methylguanine-DNA methyltTansferase (06-MT). A microassay was developed which could reliably measure 06-MT levels in liver biopsy samples. Using this approach 06-MT levels were found to be significantly lower in cirrhotic liver when compared to non-cirrhotic and normal liver tissue. No correlation was found between lymphocyte and liver levels from individual patients with liver disease indicating that the deficiency in DNA repair is disease-a nd tissue-specific. Three polyclonal antibodies were subsequently raised to 06-MT peptides and characterised by immunoblotting in an attempt to establish the tissue distribution of the enzyme in liver. Although none of the antisera were able to detect &-MT in tissue sections they were used to analyse structural differences in the enzyme between cirrhotic and non-cirrhotic liver using SDS-PAGE followed by immunoblotting and fluorography. A band of M, 24,000r,e presentingn ative enzyme, was visualised by fluorography in all liver extracts. Densitometry of these bands correlated with the enzyme activity determined by the direct enzyme assay, validating the assay findings. Other small molecular weight bands were seen in all liver extracts and comparison with immunoblots suggested that these bands represent C-terminal truncated enzyme. The spectrum of smaller molecular weight enzyme forms was similar in cirrhotic and non-cirrhotic liver. It was, thus, concluded that although 06-MT levels were lower in'cirrhosis this was not accounted for by structural differences in the enzyme. DNA mutations (G to A) produced by the failure to repair 06-methylguanine are known to activate oncogenes and turnour suppressor genes such as p53. However only 5/55 (9%) of HCC expressed mutant p53. Other factors potentially involved in hepatocarcinogenesis include the growth factor TGF-a and a growth factor receptor encoded by the c-erb B-2 proto-oncogene. Expression of TGF-a and the C-erbB -2 oncoprotein were seen in 8/28 (28%) and 2/26 (8%) of HCC respectively, findings which differ from those observed in HCC from the Far East. Deficient DNA repair by &-MT provides one possible reason why cirrhosis is an important risk factor for the development of HCC. However, failure to repair 06-mothylguanine does not result in mutations within the p53 gene in British HCC. Furthermore, the finding of low expression of mutant p53, TGF-a and the c-erb B-2 oncoprotein in HCC from Britain compared to HCC from the Far East and Africa suggests geographical differences in the molecular mechanisms involved in hepatocarcinogenesis between areas of high and low HCC prevalence.

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vi, 237 leaves : photos., tables, graphs ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Human Physiology and Pharmacology, 1979

Thesis (M. Phil.)--University of Hong Kong, 2007. / Also available online.

Thesis (M.S.)--Auburn University, 2007. / Abstract. Vita. Includes bibliographic references (ℓ. 54-58)