Medical advancements and research initiatives in the last two decades have changed the experience of growing up with a chronic illness. Young people living with Cystic Fibrosis (CF), a chronic, life-threatening, life-limiting, genetic disease, have benefitted from these advances and are living fuller, healthier, longer lives than previously thought possible. Literature exploring the experiences of young people living with CF has traditionally relied on information from caregivers and health care practitioners. It does not reflect the diverse experiences of young people today, or explore the subjective meanings constructed from experiences. Using a social constructionist and narrative inspired methodology, this study explores illness narratives and identity constructions among three young women living with CF. Their narratives are broad and diverse. Shared elements include; making meaning of their illness, and constructing a multi-faceted, relational, layered and flexible sense of self. The layered experiences of CF are one of many important factors influencing their unfolding identity. Relational processes and socially constructed norms and expectations of illness, health, and gender also influence participants’ unfolding sense of self. This study demonstrates the value of rich conversations exploring identity construction and illness narratives, and the complexities and nuances within individual experiences. / Graduate / 0758

The objective of this study was to investigate the extent to which vitamin D and K are associated with bone health in pediatric cystic fibrosis (CF) patients. We hypothesized that: (1) the prevalence of vitamin D and K deficiencies would be high despite routine vitamin therapy, (2) bone health would be reduced and (3) vitamin K and D status would be associated with bone health. / Our results showed poor bone mineral mass in these CF children despite mild disease and good nutritional status. Neither vitamin K nor D was a predictor of bone health but weight and height Z-scores, fat-free mass, physical activity and lung function were all consistent predictors. / These results indicate that nutritional status as well as physical activity are key determinants of bone health in CF children and offer a unique opportunity in the prevention of CF-related bone disease. Further vitamin intervention research needs to be done in this population.

Genetic studies of lung disease in Cystic Fibrosis are faced with the challenge of identifying a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. This thesis uses data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies (CGS), Johns Hopkins University Twins and Siblings Study (TSS), and University of North Carolina/Case Western Reserve University Gene Modifier Study (GMS)), to calculate two novel phenotypes using age-specific CF percentile values of FEV1 (Forced Expiratory Volume in 1 second), with adjustment for CF age-specific mortality. The normalized residual, mortality adjusted (NoRMA) was designed for population based samples, while KNoRMA, using Kulich percentiles, is robust to sample ascertainment; both account for the effects of age-related disease progression and mortality attrition. NoRMA was computed for 2122 patients representing the Canadian CF population. KNoRMA was computed for these 2122 patients and also 1137 extreme phenotype patients in the GMS study and 1323 patients from multiple CF sib families in the TSS study. Phenotype was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype was highly correlated with the previously recommended mixed model phenotype1; 2, but computationally much easier and suited to studies with limited follow up time. As an example of its use, KNoRMA was used to test the association between locus variants in a previously published candidate gene, Transforming Growth Factor β1(TGFβ1), and lung function in CF, in an attempt to provide insight into discrepant results in the literature. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible interpolation distortions.

Misfolding of membrane proteins as a result of mutations that disrupt their functions in substrate transport across the membrane or signal transduction is the cause of many significant human diseases. Yet, we still have a limited understanding of the direct consequences of these mutations on folding and function - a necessary step toward the rational design of corrective therapeutics. This thesis addresses the gap in understanding the residue-specific implications for folding through a series of experiments that utilize the cystic fibrosis transmembrane conductance regulator (CFTR) as a model in various contexts. We first examined the thermodynamic implications of mutations in the soluble nucleotide binding domain 1 (NBD1) of CFTR. We found that mutations can have a significant effect on thermodynamic stability that is masked in non-physiological conditions. Our studies were then focussed on a membrane-embedded hairpin CFTR fragment comprised of transmembrane segments 3 (TM3) and 4 (TM4) to evaluate the direct effects of mutations on folding in a systematic manner. It was found that the translocon-mediated membrane insertion of helices closely parallels a basic hydrophobic-aqueous partitioning event. This study was then extended to determine residue-specific effects on helix-helix association. We found that this process is not solely dependent on hydropathy, but there is a context dependence of these results with regard to residue position within the helix. Overall, these findings constitute a key step in relating mutation-derived effects on membrane protein folding to the underlying basis of human disease such as cystic fibrosis.

Erratum inserted on front fly leaf. / Bibliography: p. 283-315. / xiv, 315 p., [3] leaves of plates : ill. (one col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / To establish whether altered sulphation in cystic fibrosis could be demonstrated in different experimental systems, by focusing on glycosaminoglycans. The second aim was to establish the molecular basis for such a phenomenon. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1995

"16th September 2002." / Accompanying CD contains 2 MPEG clips with accompanying text, and a copy in PDF format of: Recovery of airway cystic fibrosis transmembrane conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer / M. Limberis ... [et al.], published in Human gene therapy vol. 13 (2002). / Bibliography: leaves xxix-li. / xxvii, 213, li leaves : ill., plates (some col.) ; 30 cm. + 1 CD-ROM (4 3/4 in.) / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis focuses on modulating the physical barriers of the airway epithelium with mild detergents, so as to enhance gene transfer by a HIV-1 based lentivirus vector in vivo. The efficiency of the gene transfer was evaluated in the nasal airway of C57B1/6 mice using the Lac Z marker gene. This demonstration of lentivirus-mediated in vivo recovery of CFTR function in CF airway epithelium illustrated the potential of combining a pre-conditioning of the airway surface with a simple and brief HIV-1 based gene transfer vector exposure to produce therapeutic gene expression in the intact airway. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2003

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: pp. 219-243.

Thesis (Ph.D. in Immunology) -- University of Colorado at Denver and Health Sciences Center, 2006. / Typescript. Includes bibliographical references (leaves 182-208). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains xxiii, 337 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 289-296).

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains ix, 64 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 35-43).