published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

Bioethics has been central to living donor liver transplantation (LDLT), which mandates a high recipient benefit and an acceptably low donor risk. The double equipoise imposes the contextual features of this already technically complex treatment. This research aimed at looking into key bioethical issues of LDLT in the light of the contemporary practice standards. In adult LDLT, in order to provide a partial graft of adequate size, donor right hepatectomy is often required. This procedure pioneered by The University of Hong Kong is now being performed at many centers and by many surgeons. Through close guidance and gradual granting of surgical privilege, newer surgeons can now perform this operation safely with low blood loss (400 mL) and low complication rates ( 30%). Analysis of our series also showed that right liver donors with a smaller remnant left liver had higher peak bilirubin level and longer peak prothrombin time after the operation. Severe complications were associated with hyperbilirubinemia (p=0.031) while prolonged hospital stay was associated with prolonged prothrombin time (p=0.011) and smaller remnant left liver (p=0.036). Facts need to be known to potential right liver donors before operation. Donor left hepatectomy, which carries a lower donor risk, is more feasible for donors with a larger left liver and recipients with a smaller body size. Lowering the graft size requirement also allows more LDLTs being done using left livers. The percentages of left liver LDLTs feasible with a graft to standard liver volume (G/SLV) ≥ 40%, ≥ 35%, ≥ 30%, and ≥ 25% were 5.8%, 12.5%, 29.1%, and 62.3% respectively. For every 5% decrease in G/SLV ratio, twice as many left liver LDLTs could be performed. The 5-year survival rate was 85.7% for liver transplantation recipients with hepatocellular carcinoma (HCC) within the Up-to-7 criteria, unaffected by the presence of microvascular invasion (88.2% vs. 85.1%, p=0.652). This is comparable with that of liver resection patients with HCC without microvascular invasion (81.2%, p=0.227) but far superior to that of liver resection patients with lesions with microvascular invasion (50.0%, p<0.0001). Primary liver transplantation for HCC with microvascular invasion and within the Up-to-7 criteria in fact doubled the chance of cure as compared with liver resection. LDLT has been criticized of fast-tracking patients with more aggressive HCC for transplant. Waiting does select out patients with better survival to undergo transplantation. With careful selection though without waiting, LDLT nevertheless does not confer poorer survival. Progressive liver failure following a major hepatectomy for HCC is a known and uncommon cause of mortality. Proceeding to LDLT is an ethical challenge because of the possibility of coercion. Tumor status as confirmed by histopathological examination of resected specimens can demonstrate features of more aggressive cancer, which warns against a rescue transplantation for the increase in chance of tumor recurrence. In order to overcome ABO blood group incompatibility, paired donor interchange (between two pairs: A to B and B to A) has been practiced for the liver. The extension to matching with one pair of universal donor (O) and universal recipient (AB) was also performed at our center. The obvious biological advantage of this treatment modality has to be weighed against the potential increase in risks to patients involved. Media coverage of advances and successes in liver transplantation stimulates deceased donor organ donation (DDOD). The relation between widely reported key events and DDOD can be recognized as celebrity hero influence, medical success, or emotional response. An accountable liver transplant service answerable to the public is vital to a region where the DDOD rate is low. Selective disclosure of patient information to the media for public interest in promoting organ donation can be justified. LDLT now has a two-decade history of clinical practice. Basic and clinical research has provided a clearer picture of the efficacy and fallibility of LDLT. We can now be more accurate in defining and interpreting the applicability of LDLT for a wider spectrum of disease indications. / published_or_final_version / Medicine / Master / Doctor of Medicine

Implantation is a critical step in reproduction. It is complicated and well-coordinated consisting of apposition, attachment and invasion of embryo into the endometrium. The mechanism of implantation is unclear. Our previous proteomic study showed an increase of annexin A2 in the endometrium during the implantation window of mice, consistent with the increased annexin A2 expression in the receptive human endometrium. The hypothesis of this project was that annexin A2 mediatedthe embryo-endometrium attachment. The first objective was to study the spatio-temporal expression of endometrial annexin A2 immunoreactivities in humans and mice. The cyclical change in annexin A2 expression in the mouse and human reproductive cycle suggested the involvement of a steroid regulatory mechanism. Interestingly, annexinA2 was transiently expressed on the membrane between the mouse uterine luminal epithelium and the implanting embryos from Day 4 (pre-implantation) to Day 5 (post-implantation) of pregnancy. No such signal change was observed at the inter-implantation sites, showing that the implanting embryos partially regulated annexin A2 expression. These observations and the high expression of the molecule in the luminal epithelium of human endometrium in the mid-and late luteal phase were consistent with a role of annexin A2 in implantation. The second objective was to verify the action of steroids on annexin A2 expression. It was found that a combination of 6675 pmol/L of estrogen and 429.8nmol/L of progesterone increased the total and apical surface expression of annexin A2. In mice, estrogen but not progesterone, increased annexin A2 expression in the uterine luminal epithelium of ovariectomized mice. The third objective was to study the function of annexin A2 in embryo-endometrium attachment using an Ishikawa (endometrial epithelial cells)-JEG-3 trophoblast spheroids (embryo surrogate) coculture model. Knockdown of the expression of annexin A2 in either or both cell lines significantly decreased the attachment rate of the spheroids onto the endometrial cells. The suppressive action on the two cell lines was additive. The attachment was also suppressed in the presence of anti-annexin A2 antibody during coculture. Annexin A2 was also involved in mouse implantation as demonstrated by a significant decrease in implantation sites after injection of anti-annexin A2 antibody into the mouse uterine horn. The final objective was to study the action of annexin A2 as an adhesive molecule in embryo attachment. It was found that loss of P11, the binding partner of annexin A2, reduced the attachment rate of the JEG-3 spheroids probably by decreasing the translocation of annexin A2 to the surface of the endometrial cells. Recombinant P11 and annexin A2 protein failed to bind significantly to the Ishikawa cells and the JEG-3 cells. In summary, this study demonstrates the involvement of annexin A2 as an adherent molecule in the embryo-endometrium interaction. / published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

abstract / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Not available / text

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medicine / Master / Doctor of Medicine

No description available.

Therapies that promote tolerance will improve outcomes in solid organ transplantation by eliminating the need for long-term immunosuppression. This thesis investigates two possible tolerance induction mechanisms: rapamycin induced expression of regulatory T cells and re-education of the immune system using syngeneic hematopoietic stem cell transplantation. Fibrinogen-like protein 2, a effector molecule of regulatory T cells, was also determined as a key mediator in the tolerance induction pathway as depletion of fibrinogen-like protein 2 lead to allograft rejection. The feasibility of using syngeneic hematopoietic stem cells for inducing allograft tolerance was studied by setting up a murine heart and bone marrow transplant model. Syngeneic T-depleted bone marrow transplantation resulted in a slight prolongation of the graft survival time compared to the animals reconstituted with total bone marrow cells. We provide compelling evidence to suggest that fibrinogen-like protein 2 and syngeneic hematopoietic stem cells can possibly be used to induce transplantation tolerance.