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Thesis (M.Sc.)--University of Alberta, 2010. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Department of Physiology. Title from pdf file main screen (viewed on March 20, 2010). Includes bibliographical references.

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published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics / Doctoral / Doctor of Philosophy

The convoluted (CPT) and straight (SPT) portions of the renal proximal tubule are susceptible to injury by a wide variety of chemical agents. These agents often affect the CPT or SPT selectively by proposed mechanisms usually attributed to tubular concentration, blood flow delivery patterns and tubuloglomerular feedback responses within the intact kidney. The innate cellular responses to chemical exposures remain virtually unexplored. Hence, the basic goal of this research was to develop an in vitro system that was conducive to examining the innate cellular differences in susceptibility between the CPT and SPT following in vitro exposure to mercuric chloride (HgCl₂), potassium dichromate (K₂Cr₂O₇)$ or hypoxic conditions. A renal cortical slicing technique was developed for these studies to position the CPT and SPT within discrete regions of slices made perpendicular to the cortical-papillary axis. An incubation vessel that could maintain the morophological and biochemical viability of slices for at least 12 hr was also developed. The selective necrosis of CPT induced by K₂Cr₂O₇ or hypoxic exposure, and SPT induced by HgCl₂, observed in vivo was reproduced in renal cortical slices exposed in vitro. Innate cellular uptake mechanisms were then investigated since the tissue distribution of each metal was found to be most concentrated within their respective injured cell type. The transport of PAH, TEA, phosphate, sulfate, glutathione and cysteine were examined as potential mechanisms for selective accumulation of these metals. K₂Cr₂O₇ caused a dose-dependent reduction in the uptake rate of sulfate by cortical slices, while phosphate, PAH, and TEA uptake were unaffected. Although HgCl₂ has a high affinity for sulfhydryl groups its uptake as a complex to glutathione or cysteine was not enhanced. HgCl₂ also had no affect on the uptake rate of PAH or TEA even though both HgCl₂ and K₂Cr₂O₇ were able to reduce the steady state accumulation of these organic substrates.

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The rising incidence of small, asymptomatic renal tumours discovered usmg abdominal imaging during the investigation of unrelated symptoms has fuelled the desire for new therapies which avoid surgical excision. Extracorporeal High Intensity Focused Ultrasound (HIFU) was proposed as one of these modalities but so far clinical research has been ,~." inconclusive. The present work was designed to improve these clii teal outcomes through the conduct of further clinical trials, laboratory based research and the translation of new technology into existing HIFU devices. A Phase II clinical trial of patients (n=13) with newly diagnosed <4cm renal tumours (clinical stage T1a) was designed, peer reviewed and received ethical approval (Ox REC 09/H0606104). Ten of 13 patients underwent renal HIFU using a clinical HIFU device (Model JCIJC200, HAIFU, China). One patient could not be treated due to poor tumour visualisation after anaesthesia and two patients could not be treated as they became unwell before or during anaesthesia. Histological evidence of HIFU ablation in either tumour or normal renal parenchyma was seen in all ten patients. Evidence of sub-total tumour ablation was seen in 8/10 of patients. Grade 1 «50%), 2 (50-90%) & 3 (90-99%) ablation was achieved in 4/10, 3/1 0 & 3/1 0 patients respectively but complete (100%) tumour ablation was not possible. HIFU treatment caused minimal morbidity - no Grade III- V (Clavien-Dindo) complications related to HIFU treatment occurred. Grade I skin pain and induration was seen in 9/1 0 patients; Grade II skin pain occurred in a single patient. Patient demographics, imaging and tumour characteristics were used to design parameters to improve patient selection for renal HIFU. The tumour location, thickness of peri-nephric fat and renal nephrometry score were useful predictors of successful screening for treatment. Page /ii Dr R. W Ritchie Nutiield Department of Surgical Sciences - TT 2012 Abstract Diligent use of these factors could limit unnecessary treatments and Improve ablation outcomes. , It is well known that ultrasound imaging of small renal masses can be challenging. Ultrasound imaging often deteriorates further during HIFU as the abdominal wall and fat tissues swell and cause increased attenuation. This loss of imaging quality was clearly demonstrated in this clinical trial and resulted in the early termination of treatment, before ,#,J' ... ~ .•.. endpoints were reached, in a number of cases. The current clinical method for monitoring the success of HIFU ablation using hyperecho analysis of B-mode ultrasound images is also questionable. Laboratory based studies using ex-vivo bovine liver subjected to HIFU confirmed that hyperecho monitoring had low sensitivity, predictive values and overall accuracy. A novel method of HIFU monitoring - passive mapping of the emissions received from acoustic cavitation activity and other sources of non-linearity during HIFU treatment - is believed to represent a significant opportunity to improve feedback. This technique uses the passively received signature of cavity activity which, when time-reversed, gives high- resolution images of the precise location of the activity. Laboratory-based ex-vivo work, using a commercially available ultrasound system (z.one, Zonare, USA), demonstrates its superiority over hyperecho monitoring. Indeed, thresholds could be applied to successfully predict HIFU ablation with high sensitivity and specificity. This technique was successfully translated into the clinical setting through the design of a Passive Acoustic Mapping (P AM) device. Custom-built receiving elements were applied without limiting the function of the existing HIFU devices. Both pre-clinical and ethically- Page [iii Dr R. W Ritchie Nuffield Department of Surgical Sciences - TT 2012 Abstract approved clinical studies demonstrated its safe integration without significant impact on the device energy output or treatment accuracy. Using similar passive beamfonning algorithms, acoustic cavitation activity was successfully mapped and corresponded with the location of thermal ablation in both ex-vivo tissue phantoms and during clinical HIFU therapy. ,~-' It is believed that the development of new patient selection paral~~tel's will elimil?ate target those patients who are most suitable for renal HIFU - small tumours, minimal peri-nephric fat & low nephrometry score .. The use of P AM will lead to a significant improvement in the efficacy of treatment. It can be successfully applied to existing devices and predicts the location and extent ofHIFU ablation with greater accuracy that existing techniques.

Call number: LD2668 .T4 1958 F43 / Master of Science

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Master of Science in the School of Molecular and Cell Biology. Johannesburg, 2016. / Telomeres play significant roles in maintaining genome stability, regulating cell proliferation and apoptosis. The role of telomere biology and telomerase reactivation has been studied extensively in cancers. Telomerase has been previously associated with driving chronic kidney disease (CKD) advancement and most frequently due to HIV infection. However, the mechanism by which telomerase activation contributes towards disease progression beyond its canonical function of telomere maintenance is poorly understood. Telomerase is a ribonucleoprotein whose main function is telomere maintenance. Telomerase activity is dependent on expression of the rate-limiting human telomerase reverse transcriptase (hTERT) component. In addition to telomere maintenance, hTERT is implicated in other non-telomere related functions that promote cellular proliferation. Expression of hTERT is predominantly regulated at the transcription level where variation in promoter and minisatellite (MNS16A) sequences alter its expression. This variation has been implicated to confer susceptibility to diseases such as cancer and ageing disorders in non-African populations. Data on variation and pathogenicity of telomere-associated genes in African populations is limited and warrants further research. Thus bioinformatics analysis was performed to elucidate variation within the human TERT gene and promoter in different populations. The promoter, MNS16A and relative telomere length (RTL) were also evaluated in 159 African study participants with and without CKD. TERT common variants are equally distributed across populations with limited data on connection to the effects of the variants in African populations. Further bioinformatics analyses revealed significant difference (p<0.0001) in distribution of promoter variant rs2853669 between African and non-African populations. No common promoter mutations were identified in our study population. Interestingly, the long MNS16A variant suggested to increase TERT expression was significantly overrepresented in individuals with CKD regardless of HIV status. For the first time, a strong association of the long MNS16A variant with CKD regardless of HIV status is reported, implicating MNS16A as a potential risk factor in CKD.