Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 127-144).

No description available.

published_or_final_version / Pathology / Master / Master of Philosophy

No description available.

MSc (Med)(Genetic Counselling), Faculty of Health Sciences, University of the Witwatersrand / Autosomal recessive polycystic kidney disease (ARPKD; MIM263200) is a severe recessively inherited disease of the kidneys and biliary tract, with an incidence of approximately 1 in 20000 in non-isolated populations. It has a variable clinical spectrum from neonatal demise (in 30-50%) to survival into adulthood. ARPKD is caused by mutations at a single locus, polycystic kidney and hepatic disease 1 (PKHD1), with over 270 pathogenic mutations described to date. The high rate of compound heterozygosity in affected individuals has made genotype-phenotype correlations difficult. A common missense mutation, p.M627K, in exon 20 of PKHD1 was identified previously on the majority of ARPKD disease associated alleles in the Afrikaans population of South Africa suggesting the presence of a founder effect. The aim of this study was to describe the clinical phenotype of ARPKD in Afrikaans speaking individuals found to be homozygous for the common mutation, and to compare this phenotype to previously described cohorts of patients with ARPKD, known to harbour a spectrum of mutations. This descriptive study used retrospective data collected from records of patients with ARPKD at Johannesburg and Pretoria Academic Hospitals. Twenty seven individuals from 24 families were included in the study. Marked clinical variability was demonstrated within this subject group supporting the limitation of genotype-phenotype correlation described worldwide. ARPKD was diagnosed at a median age of 27 days, older than a North American cohort (NAC) born after 1990 (median age of 1 day). The majority (93%) of subjects in this study were diagnosed with chronic renal v insufficiency (CRI) and hypertension (HT), indicating the renal morbidities to be more common than noted in previous studies, but occurring at a later median age (1.4 years vs 13.5 days in the NAC). This may indicate a trend toward milder expression of renal morbidities in the present study. Portal hypertension was also diagnosed more frequently (81%) than in previous studies but at a younger median age (1.3 years vs 2.8 years), although with similar complication rates. Overall statistical correlation was found between the renal and hepatic related morbidities in this study, indicating that progression of the condition is not organ specific. A survival rate of 89% at one year is comparable to previous studies with similar patient ascertainment. This cohort represents the largest series of patients affected by ARPKD with a common mutation, described to date. The findings will provide for more accurate, specific and informative genetic counselling in families with ARPKD and may present a resource for future studies of modifier genes and environmental influences on the phenotypic expression of ARPKD.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2000. / Restricted until November 2001. Bibliography: leaves 82-97.

Thesis (M.S.)--University of Missouri-Columbia, 2008. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Includes bibliographical references.

Thesis (Ph. D.)--Marshall University, 2004. / Title from document title page. Document formatted into pages; contains p. viii, 210 p. Includes abstract. Includes bibliographical references (p. 179-204).

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Polycystic kidney diseases (PKD) are genetic disorders characterized by fluid filled cysts in the kidney tubules and liver bile ducts. There are two forms of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The focus of the studies in this thesis has been on ADPKD. The disease progresses slowly and the fluid-filled cysts grow in size due to increased rates of cell proliferation and fluid secretion into the cyst lumen. The expanding cysts compromise the normal kidney function and result in a decrease of renal function to the point of end-stage renal failure in midlife. Cyst enlargement is due, at least in part, to chloride secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Currently therapy is limited to renal cyst aspiration, dialysis, and eventually renal transplantation after organ failure, thus it has critical to determine possible drug therapies for the treatment of PKD. Previous studies showed that cyst fluid caused a secretory response in cells lining the cysts. We hypothesized that once the cyst have expanded and become so large that they burst or leak, which could also occur due to renal injury or aging, the cyst fluid may stimulate additional cyst growth. Lysophosphatidic Acid (LPA) was determined to be the active component of human cyst fluid, and we investigated the LPA stimulated signaling pathway. Our data suggest that the LPA stimulates chloride and fluid secretion by a combination of CFTR and Calcium-Activated chloride channels (CaCC) and that the two channels may functionally be linked to each other. The secretion is not occurring through a cAMP stimulated pathway, and it is possible that TMEM16A, a CaCC, plays a larger role than previously expected. Previous studies demonstrated that PPARγ agonists, insulin sensitizing drugs used to treat diabetes, inhibit chloride secretion by the collecting duct principal cells by decreasing CFTR synthesis. It was logical therefore to considered PPARγ agonists as long-term treatment for PKD. The first preclinical studied showed that high (20 mg/kg BW) dose pioglitazone, a PPARγ agonist, inhibited cyst growth in the PCK rat model, a slow progressing model, of PKD. To continue to look at the effects of the PPARγ agonists another preclinical study was completed, which tested if there was a class action of PPARγ agonists and if a lower dose was effective in treating the cystic burden. Using the PCK rat model, and another PPARγ agonist, rosiglitazone, a 24 week study was completed using 3 doses (4, 0.4, and 0.04 mg/kg BW). 4 mg/kg BW rosiglitazone is analogous to 20 mg/kg BW pioglitazone. The data indicated that the rosiglitazone is effective in lowering the cystic burden, and importantly the low dose proved to be effective. An additional rat model, the W-WPK rapidly progressing model was used to determine efficacy across multiple models, and to determine if there was a way to track the progress of the disease in a manner analogous to that used in human patients. The animals were treated with pioglitazone using 2 doses (2 and 20 mg/kg BW), and were imaged using CT scans to track the progress of the disease. The data suggest that pioglitazone was not as effective in the W-WPK rat model as it was the PCK rat model. There was a trend however, that low dose PPARγ agonist was as effective ad high dose. Even more important, the CT scans proved to be an effective way to track the progress of the disease in animal models.