Cheung King Ho. / "August 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 140-158). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Introduction: Gene therapy is currently being developed for people with cystic fibrosis (CF), a life-threatening condition for which there is no cure. The UK CF Gene Therapy Consortium are preparing for a multi-dose gene therapy trial of sufficient duration that clinical benefit may be seen. Aims: The current study aimed to explore the expectations and beliefs of cystic fibrosis (CF) patients involved in the preparatory phase of the gene therapy trial (the Run-in study), from which participants will be selected for the multi-dose actual gene therapy trial. Method: Twelve participants (six with mild and six with moderate CF) were interviewed using a semi-structured interview. Interviews were recorded, transcribed verbatim and then analysed using a Constructivist Grounded Theory approach. Results: Since entering the Run-in study, half of the patients had increased their expectations of gene therapy being an effective future treatment. Most of the participants hoped to derive clinical benefit from the trial itself though half were unsure of what to expect. Whilst half of the participants expressed the hope of a future cure for CF, the remainder saw gene therapy only in terms of an improved treatment. Participants used several strategies to manage their expectations including not thinking too far ahead and trusting the research team. Discussion: The findings indicate that participants in the Run-in trial are generally eager to be involved in the gene therapy trial and have developed a strong sense of trust in the research team conducting the trials. The levels of optimism expressed for personal benefit from trial were higher than those from earlier studies. Some of the positive expectations were unlikely to be met by the gene therapy trial and participants risk disappointment. However other patients participated with apparently realistic expectations and it seems likely that some patients would have participated even without prospect for personal benefit. Possible areas of psychological support are discussed e.g. a standard clinical interview for all those not accepted for the gene therapy trial; screening for anxiety pre-, during and post-participation.

Galectin-3, a unique member of the growing family of β-galactoside binding lectins, contains a single carbohydrate recognition domain and a glycine rich N-terminal domain through which it can form oligomers and functions to cross-link both carbohydrate and non-carbohydrate ligands. Galectin-3 is widely expressed in adult tissues, particularly on and secreted by activated macrophages and monocytes. Galectin-3 has been implicated in many facets of the inflammatory response including neutrophil and macrophage activation and function. In this thesis I have examined the role of galectin-3 during fibrosis, alternative activation of macrophages and pneumonia. Galectin-3 expression is upregulated in established human fibrotic liver disease and in a mouse model of liver fibrosis induced by carbon tetrachloride. Galectin-3 expression is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis in this model. In addition, disruption of the galectin-3 gene markedly attenuates liver and kidney fibrosis, induced by unilateral ureteric obstruction, with reduced collagen deposition and myofibroblast activation. Results suggest that galectin-3 may promote fibrosis by stimulating myofibroblast activation by a transforming growth factor-β (TGF-β)-independent mechanism. Recent reports suggest that alternative macrophage activation is one of the key steps toward the progression of fibrosis. Disruption of the galectin-3 gene specifically restrains interleukin-4 (IL-4)/IL-13-induced alternative macrophage activation in vitro. My results suggest that the key mechanism required for activation of an alternative macrophage phenotype is an IL-4-stimulated galectin-3 feed back loop which directly activates CD98 causing sustained phosphatidylinositol 3-kinase (PI3-K) activation. The gram-positive Streptococcus pneumoniae (S. pn) is the leading cause of community acquired pneumonia worldwide, resulting in high mortality. Galectin-3-/- mice demonstrate a clearance defect of S. pn with increased septicaemia and a greater extent of lung damage compared to wild type mice. This phenotype is markedly reduced in pneumonia induced by the gram-negative Escherichia coli (E.coli). I have shown that presence of galectin-3 reduces the severity of pneumonia induced by S. pn and this is achieved through a number of processes: 1) Galectin-3 has bactericidal properties towards S. pn in vitro. 2) Galectin-3-/- macrophages show reduced production of nitrite following incubation with both S. pn and E. coli and hence a reduction in bacterial killing. 3) Galectin-3 activates neutrophils to produce reactive oxygen species which enhances the bactericidal activity of neutrophils. 4) Activation of neutrophils by galectin-3 augments phagocytosis of bacteria. 5) Finally, initial data suggests that galectin-3-/- neutrophils apoptose more readily than wild type neutrophils in vitro and galectin-3-/- macrophages phagocytose apoptotic neutrophils less efficiently compared to wild type. In vivo this would result in an accumulation of dying cells in the lung. The damage these apoptotic cells would have on the lung tissue may enable the bacteria to enter the blood stream resulting in sepsis. In summary, in response to chronic tissue injury, persistant upregulation of galectin-3 causes myofibroblast and alternative macrophage activation, thus enhancing collagen deposition and scarring. However during an acute S. pn infection, galectin-3 plays a benefitial role to aid the clearance of bacteria through a variety of processes. Therefore, galectin-3 plays a critical role in a variety of inflammatory disorders.

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published_or_final_version / abstract / Medicine / Master / Master of Philosophy

published_or_final_version / abstract / Biological Sciences / Master / Master of Philosophy

The grief experienced by mothers and fathers when their child is diagnosed with a life threatening chronic-illness was investigated in order to validate the presence of grief in these parents and look at the factors that influence it. More specifically, I was interested in whether the grief experience differed for mothers and fathers and the impact that perceptions and coping have on both these gender differences in grief and on grief in general. The particular population investigated in this study were parents of children with Cystic Fibrosis. Participants were recruited through questionnaires randomly sent out by the National Cystic Fibrosis Association. In all, 37 mothers and 15 fathers took part. Results not only confirmed presence of grief in these parents but also indicated that this grief differs for mothers and fathers, with mothers reporting significantly higher levels of physical distress. In line with the literature no gender differences were found in regards to perception of impact parents felt their child's chronic-illness had had on their lives. Contrary to what was expected, however, no differences were found amongst the coping strategies used by mothers and fathers. In regards to the question of which factors have the greatest impact on the grief experienced by mothers and fathers combined, the coping strategy of self-blame was found to be the most important, followed closely by negative perceptions. The significance of these findings and their implications for parents and the people who work with them was discussed.

No description available.

No description available.

No description available.