published_or_final_version / Chemistry / Master / Master of Philosophy

This dissertation experimentally explores digital optical computing and optical interconnects with theoretical supports, from the physics of materials and the optimization of devices to system realization. The trend of optical computing is highlighted with the emphasis on the current development of its basic constituent elements, and a couple of algorithms selected to pave the way for utilizing bistable devices for their optical implementations. Optical bistable devices function as "optical transistors" in optical computing. The physics of dispersive optical bistability is briefly described. Bistable ZnS interference filters are discussed in detail regarding their linear and nonlienar characteristics. The optimization of switching characteristics for a bistable ZnS interference filter is discussed, and experimental results are shown. Symbolic substitution which fully takes advantage of regular optical interconnects constitutes two steps: pattern recognition and symbol scription. Two experiments on two digital pattern recognitions and one on a simple but complete symbolic substitution have been demonstrated. The extension of these experiments is an implementation of a binary adder. A one-bit full adder which is a basic block for a computer has been explored experimentally and demonstrated in an all-optical way. The utilization of a bistable device as a nonlinear decision-making element is further demonstrated in an associative memory experiment by incorporating a Vander Lugt matched filter to discriminate two partial fingerprints. The thresholding function of a bistable device enhances the S/N ratio and helps discrimination in associative memory. As the clocking speed of a computer goes higher, e.g. greater than several GHz, the clock signal distribution and packaging become serious problems in VLSI technology. The use of optical interconnects introduces a possible solution. A unique element for holographic optical interconnects, which combines advantages of computer generated hologram and DCG recording material, is discussed. Pattern design of a specific computer generated hologram and a proposed fabrication process are described. Experimental results suggest that this unique element has the capability of being tailored to perform multiple fan-out with resulting uniform tightly-focussed spots, and coupling between devices, e.g. source-to-fiber and fiber-to-waveguides, etc.

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Cytoplasmic 15-hydroxyprostaglandin dehydrogenase from swine kidney was purified to specific activity of 1.2 U per mg protein, by chromatographic techniques. Native molecular weight of enzyme was estimated at 45,000. Enzyme was inhibited by sulfhydryls, diuretics, and various fatty acids. Substrate studies indicated NAD+ specificity and ability to catabolize prostaglandins, except prostaglandin B and thromboxane B. Initial velocity studies gave intersecting plots conforming to a sequential mechanism. 15-keto-prostaglandin exhibited linear noncompetitive production inhibition with respect to either prostaglandin or NAD+; NAD yielded linear competitive production inhibition with respect to NADH. Results, and those of dead-end inhibition and alternated substrate studies, are consistent with an ordered Bi-Bi mechanism: NAD+ is added first, then prostaglandin; then 15-keto-rostaglandin is released, then NADH.

The use of organs from donors after circulatory death (DCD) has been recommended as one strategy to enlarge the donor pool and raise the transplant rate. However, DCD allografts had higher incidence of early post-transplant dysfunction. The general aim of this research project was to develop clinical and experimental strategies to reduce the incidence of early post-transplant dysfunction of kidney and liver allografts from DCD. First the ability of a clinical scoring system based on donor data for identifying DCD kidneys with high-risk of post-transplant dysfunction was evaluated using the Oxford and the UK National DCD kidney transplant cohorts. This works suggest that stratification of DCD kidneys before transplantation might allow early identification of kidneys in which lower graft function and survival could be expected if any additional therapeutic intervention is implemented. Second, as it has been suggested that hypothermic machine perfusion (HMP) may protect DCD kidneys from additional preservation injury and improve their outcome after transplantation, this work explored the benefit of HMP as preservation technique fo DCD kidneys in Oxford and discusses the potential of this technique for reducing the incidence of post-transplant dysfunction in DCD kidneys. The Oxford. Liver Group has provided evidence of the benefit of preservation with normothermic machine perfusion (NMP) on post-transplant function and survival of DCD liver allografts. In this work, the molecular mechanisms associated with this benefit were characterized using micro array technology. This analysis suggests that the beneficial effect ofNMP may be associated with the induction of the ischaemic preconditioning phenomenon and highlights a group of genes with potential for gene therapy. Finally, this works provides the "proof-of-concept" that the use of a non-mammalian viral vector for gene transfer of kidneys and livers during conventional cold preservation is feasible and is not associated with additional tissue injury.

Submitted in fulfillment of the requirements for the degree of Master of Clinical Technology (Nephrology), Durban University of Technology, Durban, South Africa, 2013. / Diabetic nephropathy is a serious complication of diabetes that can lead to end stage renal failure (ESRF). It is now the most common cause of ESRF in patients accepted onto renal replacement therapy (RRT) programmes. Kidney disease is common in South Africa. 60-65% is due to inherited hypertension and 20-25% due to Type 2 diabetes (National Kidney Foundation of South Africa, 2002). The renal replacement therapies include haemodialysis, peritoneal dialysis and transplantation. Successful long-term haemodialysis in patients with end stage renal disease (ESRD) depends to a large extent upon a trouble- free vascular access. Achieving a successful vascular access remains a challenge especially in the diabetic population. Current Kidney Dialysis Outcome Quality Initiative (KDOQI) guidelines encourage placing Arterio-Venous Fistula (AVF) in more haemodialysis patients. While the upper limb is the preferred site for AVF creation, researchers are undecided on which is the ideal location (distal or proximal arm) in the diabetic population. Many new fistulae fail to mature sufficiently to be usable for haemodialysis. Pre-insertion work-up with regard to haemodialysis access is important in maintaining the most appropriate access in the growing diabetic population requiring haemodialysis. Pre-operative vascular mapping to identify suitable vessels has been reported to improve vascular access outcomes . In South Africa, duplex scanning is not routinely done, and a clinical judgement by the surgeon remains in most instances the deciding factor on the site of the AVF. Whilst conducting this research, it has been found that while diabetic patients may have AVF created, the maturation time is of a much extended period, and a challenge to achieve the desired dose of dialysis. This is a prospective, quantitative and qualitative study of 21 diabetic patients. These included patients that were starting on the chronic haemodialysis program and limited to patients that were having first attempt of AVF creation and aims to establish if sonogram testing provides a more accurate measure of the ideal location for the AVF, or if a clinical evaluation alone by the surgeon is sufficient. Surgical techniques are different amongst surgeons and clinical evaluation is more a subjective decision. By limiting the surgeons performing the AVF, a standardized surgical procedure was established. If an ideal AVF access for the patient is created, haemodialysis efficiency is increased and ultimately patient outcome improved. The AVF was created according to the clinical evaluation as is the current process, and the surgeons were not aware of the duplex sonogram results. Failure and success of AVF were analysed according to primary patency and functional success. A primary patency success of the AVF does not guarantee functional success. If an AVF is not able to complete an entire haemodialysis session trouble free at the prescribed dialysis dose, the AVF is considered a failure irrespective of primary patency success. This was evident with 10% of patients who had primary patency but functional success was not achieved. With a 55% functional success in this study with AVF created on clinical evaluation, there was no significance difference (p=0.795) if AVFs were based on duplex sonogram findings. However, there was evidence of increased AVF success in 33% of the failed AVFs when the new AVFs were created at the duplex sonogram site. 95% of patients in this study had commenced haemodialysis with a Central Venous Catheter (CVC). AVF success could be increased if early referral of diabetic patients for permanent access to the surgeon occurred. Maturation rate of AVF differed from KDOQI guidelines with AVF first cannulation only after 17 weeks, and not after the recommended time of 6 weeks. Blood flow rates on dialysis also varied with international standards, with only maximum of 400mls/min reached after one year. With distal arm AVF, diameter of radial artery of less than 2mm and cephalic vein less than 3mm was associated with AVF failure. This research study represents the first of its kind in Kwazulu Natal looking at vascular access sites in diabetic patients with End Stage Renal Disease on haemodialysis. / PDF Full-text unavailable. Please refer to hard copy for Full-text / M

Orientador: Luís Gustavo Modelli de Andrade / Banca: André Luíz Balbi / Banca: Silvana Molina / Banca: Lilian Monteiro Pereira / Banca: Marilda Mazzali / Resumo: Introdução: Os receptores de transplante de órgãos sólidos apresentam elevada incidência de não adesão medicamentosa. Existem poucos estudos de intervenção com abordagens visando o aumento da adesão. Objetivo: Avaliar o impacto da estratégia educacional e comportamental na adesão de transplantados renais no período dos três primeiros meses após o transplante. Métodos: Estudo prospectivo de pacientes incidentes em transplante renal. Os pacientes foram randomizados em dois grupos: Grupo controle de orientações usuais da equipe médica e grupo intervenção de orientações usuais somadas à educação complementar (orientações sobre a importância dos imunossupressores e modificações comportamentais com duração de 30 minutos). A adesão foi avaliada pelo questionário de adesão ITAS ao fim de três meses. Foram avaliadas a função renal aos 3, 6 e 12 meses e a incidência de rejeição. Resultados: A não adesão foi de 46,4% no grupo controle e 14,5% no grupo de tratamento (p=0,001). O razão de chance para não adesão foi 2,59 (IC: 1,38 - 4,88) vezes maior no grupo controle. A análise multivariada mostrou que pertencer ao grupo controle aumentou o risco de não adesão em 5,84 vezes (IC: 1,8 - 18,8, p=0,003). Não houve diferenças na função renal e nas taxas de rejeição entre os grupos. Conclusão: A não adesão é elevada nos três primeiros meses do transplante. A estratégia comportamental e educativa objetivando maior esclarecimento da importância do uso dos imunossupressores aumentou significantemente à adesão a terapia imunossupressora / Abstract: Not available / Doutor

Na rotina clínica de felinos domésticos, algumas modalidades de diagnóstico por imagem, como a ultra-sonografia, radiografia simples e urografia excretora, já são amplamente utilizadas. A cintilografia é uma técnica não invasiva, capaz de oferecer informações funcionais de rins individualmente, porém é considerada uma modalidade menos usual. O objetivo deste estudo foi determinar o tempo de excreção renal de felinos domésticos através da cintilografia, em animais com parâmetros ultra-sonográficos e radiográficos dentro dos limites da normalidade. Foram utilizados 15 animais, 9 machos e 6 fêmeas, e estes foram divididos em grupos de animais não submetidos à anestesia e anestesiados. Foi estabelecido o tempo para o radiofármaco obter acúmulo máximo em cada um dos rins e o tempo para este acúmulo máximo ser reduzido pela metade. Não houve diferença estatística entre os valores dos animais não-anestesiados e anestesiados, nem entre machos e fêmeas, tampouco entre os rins esquerdo e direito. / In internal medicine of domestic cats, imaging modalities, such as ultrasonography, radiography and intravenous pylogram are widely used. Scintigraphy is a non-invasive technique, which provides functional information of each individual kidney; however, it is not widely available or utilized currently in veterinary medicine. The aim of this study was to determine the time of excretion of each kidney in normal domestic cats using nuclear scintigraphy. Fifteen cats (9 males and 6 females) determined to be within normal limits for radiographic and ultrasonographic renal parameters, were divided into two experimental groups (awake and anesthetized cats). Time to maximum radiopharmaceutical activity (T max) and time to decline to half maximum radiopharmaceutical activity (half-time) were determined in each kidney for each cat. No statistical difference was found between groups (awake vs. anesthetized) or sex (males vs. females), or between left and right kidneys.

While the genetic control of ureteric bud (UB) morphogenesis has been extensively studied, the cellular basis of this process remains unclear. The renal organoid system is a novel technique in which embryonic kidneys are dissociated into single cells and then reaggregated, where they reassociate to form organotypic structures. This system may be very beneficial for investigating the cellular basis of ureteric bud development. Here, we first used a fluorescent UB marker, Hoxb7:myrVenus, and time-lapse microscopy to characterize the cellular and tissue-level events during self-organization and UB morphogenesis of E12.5 or E14.5 renal organoids. Briefly, we found that UB structures self-assembled by aggregation of individual cells that sent out long cell processes. The cellular aggregates grew and elongated into epithelial tubes that displayed characteristic ampullae, bifurcated, and appropriately expressed UB tip markers analogous to their in vivo counterparts. We also found that cap mesenchymal cells are attracted to newly formed epithelial structures early in renal organoid development, and were later found in cell clusters surrounding new branches. RET is a trans-membrane tyrosine kinase receptor (RTK), expressed in ureteric bud cells, whose expression is gradually restricted to the tips of the growing ureteric tree. We demonstrate that the renal organoid system can be used, as an alternative to the generation of in vivo chimeric embryos, to study Ret-dependent cell rearrangements previously shown to establish and maintain the UB tip progenitor domain. Chimeric renal organoids that juxtaposed wild-type cells with Sprouty1–/– mutant cells (higher Ret-signaling) or with Ret51/cre (lower Ret-signaling) mutant cells recapitulated the cell sorting pattern observed in similar in vivo chimeras. The cells with higher Ret-signaling preferentially sorted to, and were maintained in, the forming and growing tips of these mosaic ureteric bud structures, out-competing cells with lower Ret-signaling. We then used the mosaic organoid system to ask if fibroblast growth factor receptor 2 (Fgfr2), another RTK expressed in the ureteric bud and important for its development, also mediates individual cell rearrangements that generate and maintain the UB tips. UB cells null for Fgfr2 were largely unable to compete with wild-type cells for occupancy of the UB tips in chimeric renal organoids. Using the innovative MASTR (Mosaic Mutant Analysis with Spatial and Temporal Control of Recombination) technique in vivo, mosaic homozygous deletion of Fgfr2 in newly formed ureteric buds also revealed that mutant cells were slightly deficient in their ability to contribute to Fgfr2 heterozygous UB tips. This demonstrates a novel, cell-autonomous role of Fgfr2 in ureteric bud development. Matrix metalloproteinase 14 (MMP14) is a membrane-bound protein known to participate in a wide variety of cell functions including degradation of the extracellular matrix (ECM), cell signaling, and cell-autonomous cell migration. It is expressed in the UB and was discovered to act downstream of Ret-signaling. Although needed in the ureteric epithelium for ECM degradation and proper UB morphogenesis, its specific function in the UB has not been thoroughly investigated. In generating in vivo chimeras, we discovered that Mmp14 null cells could contribute to wild-type ureteric bud tips at E12.5 and E14.5, demonstrating that, despite its documented role in UB branching, Mmp14 does not have a cell-autonomous role in the cell rearrangements observed during UB morphogenesis.

The critical function of the kidney is to regulate the body’s extracellular fluid volume to maintain homeostasis. When insults to the kidney occur, as in the case of kidney ischemia, the function of the kidney to filter metabolic wastes and reabsorb essential solutes is compromised, leading to a variety of clinical manifestations. Current metrics of kidney function are measured by the rise of a single analyte, the serum creatinine, which implies injury of the kidney tubule and its epithelial cells and is encapsulated by the term Acute Kidney Injury (AKI). Yet, creatinine does not specify the etiology, the cell type, or the molecular pathways that are affected by the acute decreases in kidney excretory function. During my thesis work, I hypothesized that there is a pathogenetic heterogeneity of kidney injury and a specificity of location, timing, and molecular mechanisms, unique to each of these three injury models: kidney ischemia, volume depletion, and urinary tract infection. Using genetic mouse models, RNA-sequencing, and a range of molecular biology techniques, I have found (1) kidney ischemia activates inflammatory responses, signal transduction pathways, and epithelial repair and reprogramming, that are not activated in volume depletion, (2) which in contrast, is a transient metabolic condition, inducing genes regulating energy metabolism that were reversible upon rehydration. Lastly, (3) I have found that urinary tract infection, particularly one that invades the kidney, involves a novel heme transport system in the collecting duct of the kidney, that may contribute to nutritional defenses against bacterial pathogens. Each of these findings is explored in specific aims and experiments, which I detail here in my thesis.