Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Master of Science in the School of Informatics, Indiana University May 2003 / Alzheimer's disease is a progressive, age-related, degenerative brain disorder, which is one of the most serious diseases in old people. The patients' memory is lost and their personality and behavior are changed gradually; furthermore, this process is irreversible until the patients die [1]. Alzheimer's disease first attacks the entorhinal cortex; then to the hippocampus, which help to control short-term memory; then to other regions, especially the cerebral cortex, which is very important in using language and reasoning [1 , 2]. After its attack, the neurons degenerate and lose synapses and eventually die [1 , 2]. According to the age of having this disease, Alzheimer's disease can be divided to early-onset (usually at age 30 to 60) and late-onset (at age of 65 or older) [1]. About 5% to 10% of Alzheimer's disease cases are early onset [1 ]. Another way to describe Alzheimer's disease is according to the inheritance pattern. In this way, Alzheimer's disease also can be divided to: sporadic Alzheimer's disease, which has no certain inheritance pattern; and familial Alzheimer's disease (FAD), which has certain inheritance pattern [1]. All FAD are early onset [1 ]. Alzheimer's disease is a progressive disease and the progression of symptoms can be divided into mild, moderate and severe phases [2, 3]. The symptoms of mild Alzheimer's disease include loss of memory, disorientation, and difficulty of performing routine tasks. [2]. Patients in this phase can live independently [3]. The moderate symptoms include having great difficulty in daily living, wandering, personality changes, agitation and anxiety [2]. Patients in this phase should be cared by other people. People in severe phase lose all communication functions, almost cannot think, and need total care [2].

Chronic respiratory disease (CRD), comprised mainly of asthma and chronic obstructive lung disease (COPD), is responsible for significant morbidity and mortality worldwide. Although asthma and COPD cannot be cured, they can be controlled using appropriate medications. Poorly controlled CRD is associated with significantly poorer quality of life and mortality for patients, an increased burden on the healthcare system, and a negative economic impact due to loss of productivity. CRD is underdiagnosed, undertreated and poorly controlled, especially in low- and middle-income countries. Improving control of CRD would result in improved quality of life for patients and a reduced burden on the healthcare system and economy. Despite the increase in burden of CRD globally, limited data are available on the burden of CRD in South Africa. Such data are essential if appropriate measures are to be put in place to address these needs. In this mini-dissertation, I aimed to describe the symptomatic burden of disease and levels of treatment in adults with CRD attending primary healthcare facilities in the Western Cape. Additionally, I aimed to identify predictors of both the quality of life and receipt of treatment in this population. This study was a secondary analysis of the baseline data collected during the Primary Care 101 (PC101) trial, a large pragmatic cluster randomised controlled trial conducted in 38 primary healthcare clinics in the Eden and Overberg districts of the Western Cape between 2011 and 2012. The study population for the current study was limited to the 1 157 participants enrolled in the CRD cohort of the PC101 trial. Part A of this mini-dissertation comprises the research protocol which was submitted to, and approved by, the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee. Part B comprises the literature review, which outlines the prevalence and increasing burden of CRD both globally and in South Africa. As demonstrated in many studies from a wide variety of countries, the literature supports that CRD is underdiagnosed, undertreated, and has a significant impact both on affected individuals as well as healthcare systems and economies. Part C includes the journal-ready manuscript. Findings confirm a high burden of symptoms and activity limitation, indicating a poor quality of life amongst this population. Findings also suggest undertreatment, with 40% of patients not receiving treatment for CRD despite being symptomatic. More respiratory symptoms were associated with male sex, a positive screen for depression, previous tuberculosis, previous smoking, more activity limitation and current receipt of treatment for CRD. Greater activity limitation was associated with unemployment, diabetes, a positive screen for depression, more respiratory symptoms, recent hospital admission and receiving treatment for CRD. Participants were more likely to be on treatment if they were older, more symptomatic or had greater activity limitation due to their respiratory condition. Treatment was less likely in participants who screened positive for depression, were current smokers, had increased recent clinic visits or a recent hospital admission. In summary, we found a high burden of symptoms and activity limitation, and of undertreatment, possibly contributed to by under-recognition of respiratory disease among patients attending primary care clinics in the Western Cape. Depression, a history of previous tuberculosis and unemployment are common features in such patients. Potential interventions are to introduce a systematic approach to CRD diagnosis in primary care clinics that includes screening for depression, improving availability of essential drugs for the management of CRD, and preventive strategies such as more effective tuberculosis control, and support and pharmacotherapy to assist smokers to quit.

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Peripheral neuropathies, affect approximately 20 million people in the United States and are often a complication of conditions such as diabetes that can result in amputation of affected areas such as the feet and toes. In vitro methodologies to facilitate the understanding and treatment of these disorders often lack the cellular and functional complexity required to accurately model peripheral neuropathies. In particular, they are often 2-D and functional readouts, such as electrical activity, are limited to cell bodies thereby limiting the understanding of axonopathy which often characterizes these disorders. We have developed a functional 3-D model of peripheral nerves using a capillary alginate gel (Capgel™), as a scaffold. We hypothesize that: 1) The unique microcapillary structure of Capgel™ allows for the modeling of the 3-D microstructure of the peripheral nerve, and 2) That axon bundling in the capillary allows for the detection of axonal electrical activity. In our initial studies, we demonstrate that culturing embryonic dorsal root ganglia (DRG) within the Capgel™ environment allows for the separation of cell bodies from axons and recreates many of the features of an in vivo peripheral nerve fascicle including myelinated axons and the formation of a rudimentary perineurium. To develop functionality for this model we have integrated the DRG Capgel™ culture with a microelectrode array to examine spontaneous activity in axon bundles, which we find demonstrates superiority to other widely used 2-D models of the same tissue. Furthermore, by analyzing the activity on individual electrodes, we were able to record action potentials from multiple axons within the same bundle indicating a functional complexity comparable to that observed in fascicles in vivo. This 3D model of the peripheral nerve can be used to study the functional complexities of peripheral neuropathies and nerve regeneration as well as being utilized in the development of novel therapeutics.

The gastrointestinal tract forms the body’s largest interface with the external environment and is exposed to a vast amount of foreign material, including pathogenic and commensal bacteria, as well as food antigens. The gastrointestinal tract has multiple functions that are performed through complex interactions by its different components. It must be able to degrade food, absorb nutrients and eliminate waste, while at the same time maintain a balance between immune tolerance and protection against pathogenic and antigenic material. This concept of mucosally-induced tolerance is a key feature of the gut immune system, whereby a state of local and systemic unresponsiveness to food protein or systemic ignorance of commensal bacteria is maintained under homeostatic conditions through interactions between the host, dietary factors, and the intestinal microbiota. Dysfunctional interactions can lead to a breakdown in tolerance to otherwise innocuous antigens. One of the best characterized food sensitivities is celiac disease (CD). CD is a chronic immune-mediated disease triggered by the ingestion of gluten, the water insoluble protein fraction in wheat, rye and barley, in patients who are HLA/DQ2 or DQ8 positive. Celiac patients can experience a loss of oral tolerance to gluten any time throughout life. The clinical presentation of CD is variable and is often associated with extra-intestinal autoimmune diseases, such as type 1 diabetes (T1D). The increasing incidence of CD and the observation that only a small proportion of genetically susceptible individuals go on to develop active inflammation suggest a role for additional environmental factors in disease pathogenesis. The current treatment for CD is a strict, life-long adherence to a gluten-free diet (GFD), which is very demanding. Frequent gluten contamination can lead to persistent mucosal damage and symptoms, which have a negative effect on quality of life. Understanding the environmental and host factors that contribute to gluten tolerance is critical for the development of adjuvant therapies to the GFD. Therefore, the overall aim of my thesis is to characterize a humanized mouse model of gluten sensitivity in order to study factors that influence host-responses to gluten and to investigate potential therapeutic strategies. In chapter 3 of this thesis I characterized host responses to gluten using transgenic non-obese diabetic (NOD)/DQ8 mice. I found that gluten sensitization in NOD/DQ8 mice induced barrier dysfunction with a moderate degree of enteropathy and the development of anti-gliadin and anti-tissue-transglutaminase antibodies. I also explored the potential role of gluten in the development of T1D and found that gluten-induced barrier dysfunction was not sufficient to induce insulitis; a partial depletion of regulatory T cells (Tregs) plus gluten sensitization was required. In chapter 4, I utilized this model to demonstrate that the microbiota can modulate host responses to gluten. I found that both the presence and absence of a microbiota, as well as the composition of the microbiota influenced host responses to gluten in NOD/DQ8 mice. Finally, Chapters 5 and 6 of this thesis utilized transgenic DQ8 mice to explore two different adjuvant therapies for CD. In chapter 5, I showed that administration of a gluten binding polymer, P(HEMA-co-SS, to gluten-sensitive HLA/DQ8 mice reduced short-term and long-term gluten-induced barrier dysfunction and inflammation. In chapter 6, I discovered that elafin, a human anti-protease, was decreased in patients with active CD and in vitro, it inhibited the deamidation of gliadin peptides, a key step in the pathogenesis of CD. I showed that administration of elafin prevented gluten-induced barrier dysfunction and intraepithelial lymphocytosis. Together these results, (a) provide an in depth characterization of a humanized animal model for studying gluten-induced intestinal and extra-intestinal immune responses, (b) demonstrate the role of the microbiota as an environmental modulator of gluten-induced immune responses, (c) support the preclinical potential of two novel adjuvant therapies to the GFD. These findings emphasize the translational value of using relevant animal models to study the complex interactions between environmental and host factors that contribute to intestinal health and disease. / Thesis / Doctor of Philosophy (Medical Science)

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