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Autoimmune and thyroid conditions account for a substantial proportion of the morbidity and mortality experienced in the United States, affecting >40 million Americans combined. Co-occurrence of both an autoimmune and thyroid condition is also likely, particularly among women. Epidemiologic studies on both sets of conditions have examined many risk factors, including demographic, lifestyle, genetic, and environmental risk factors. However, one area which has been neglected is the effect of early life exposures on the development of autoimmune and thyroid conditions. To investigate the potential association between an individual’s birth weight (by category;in uteroand early childhood, extending the hypothesis to include thyroid conditions.

In the current studies the effects of administration of 0.1 to 1000 ppb of aldicarb, a carbamate pesticide, on the immune system of C3H mice were investigated. It was observed that aldicarb caused significant immunomodulation of macrophage functions analyzed in a variety of different systems. Initially, it was found that aldicarb decreased the stimulatory functions of the macrophages as studied by decreased capacity to stimulate normal autoreactive TF cells in the SMLR. This decreased stimulatory activity of the macrophages was found not to be due decrease in the expression of class II MHC-antigens (la molecules) nor was it due to the generation of any suppressor macrophages acting to down-regulate the immune response. Further investigations revealed that the decreased stimulatory activity of the macrophages correlated with decreased IL-1 production/signal to the T cells by the macrophages. It was also evident that aldicarb did not affect the T cell functions directly. Thus, T cells from aldicarb-treated mice when studied in the SMLR and AlloMLR or when stimulated with ConA or anti-CD3 mAbs, in the presence of normal macrophages, demonstrated normal responses. In contrast, normal T cells exhibited decreased responsiveness in the presence of aldicarb-treated macrophages. The fact that aldicarb did not affect the T cell functions directly was also evident by the fact that aidicarb-treated T cells could respond normally to stimulation with PMA + Ca²⁺ ionophore, a response which is independent of accessory cells. The aldicarb-treated macrophages also exhibited decreased capacity to process and present the antigen, conalbumin, to the T helper cell clone D10.G4. When the mechanism of aldicarb induced defect was investigated, it was observed that aldicarb-treated macrophages produced decreased amounts of IL-1 which was also confirmed by complete reconstitution of the response following addition of exogenous IL-1. With this in mind, macrophage functions in a number of other systems were examined and demonstrated that aldicarb-treatment also suppressed the macrophage-mediated cytotoxicity of tumor cells, but failed to inhibit the NK cell-mediated cytotoxicity of tumor cells. Together, these studies suggest that aldicarb selectively affects the macrophage but not NK or T ceil functions directly. However, since macrophages play an important role as accessory cells in T cell-mediated responses, it is likely that aldicarb indirectly will also affect the T cell responses. / Master of Science

"Multi-Agent systems" is a topic for a lot of research, especially research involving strategy, evolution and cooperation among various agents. Various learning algorithm schemes have been proposed such as reinforcement learning and evolutionary computing. In this thesis two solutions to a multi-agent herding problem are presented. One solution is based on Q-learning algorithm, while the other is based on modeling of artificial immune system. Q-learning solution for the herding problem is developed, using region-based local learning for each individual agent. Individual and batch processing reinforcement algorithms are implemented for non-cooperative agents. Agents in this formulation do not share any information or knowledge. Issues such as computational requirements, and convergence are discussed. An idiotopic artificial immune network is proposed that includes individual B-cell model for agents and T-cell model for controlling the interaction among these agents. Two network models are proposed--one for evolving group behavior/strategy arbitration and the other for individual action selection. A comparative study of the Q-learning solution and the immune network solution is done on important aspects such as computation requirements, predictability, and convergence. / Master of Science

No / Triple-negative breast cancers (TNBC) are clinically heterogeneous, an aggressive form of breast cancer with poor diagnosis and highly therapeutic resistant. It is urgently needed for identifying novel biomarkers with increased sensitivity and specificity for early detection and personalised therapeutic intervention. Microarray profiling offered significant advances in molecular classification but sample scarcity and cohort heterogeneity remains challenging areas. Here, we investigated diagnostics signatures derived from human triple-negative tissue. We applied REMARK criteria for the selection of relevant studies and compared the signatures gene lists directly as well as assessed their classification performance in predicting diagnosis using leave-one-out cross-validation. The cross-validation results shows excellent classification accuracy ratios using all data sets. A subset signature (17-gene) extracted from the convergence of eligible signatures have also achieved excellent classification accuracy of 89.37% across all data sets. We also applied gene ontology functional enrichment analysis to extract potentially biological process, pathways and network involved in TNBC disease progression. Through functional analysis, we recognized that these independent signatures have displayed commonalities in functional pathways of cell signaling, which play important role in the development and progression of TNBC. We have also identified five unique TNBC pathways genes (SYNCRIP, NFIB, RGS4, UGCG, LOX and NNMT), which could be important for therapeutic interventions as indicated by their close association with known drivers of TNBC and previously published experimental studies. / Yorkshire Cancer Research for the Supplementary ort of CWS (BPP049 and B209PG)

This final year thesis introduces the principles and properties of the artificial immune systems to the reader, then abstracts the principles from this knowledge and applies the real artificial immune systems on them. It provides a view at the practical applications that use and extend given ideas.

Attempts to assess psychological stress rely heavily upon subjective techniques which measure changes in perceived mental loading and situational awareness (Hart and Staveland 1988, Reid and Nygren 1988, Lemyre and Tessier 2003, 1998). Although quantitative methodologies do exist, for example monitoring changes in the cardiopulmonary system (Gelfand et al. 2004, Harada et al. 2006), such parameters are subject to influence by factors other than stress. Psychological stress is known to influence the effectiveness of the innate immune system, leading to an increased risk of infection and immune-related disease (Dhabhar et al. 1996, Boscarino et al. 1999, Altemus et al. 2006). Leukocytes, primarily neutrophils have been identified as an essential component of this mechanism - periods of increased psychological stress have been shown to stimulate neutrophils to release reactive oxygen species into surrounding healthy tissues (Mian et al. 2003). The exact biochemical pathways by which this occurs have not yet been fully elucidated. However, this mechanism has become the basis for a novel in vitro technique (McLaren et al. 2003) which has the potential and sensitivity to rapidly quantify and discriminate between changes in psychological stress, resulting from exposure to short-term low-level everyday life-stressors. Aims The overall aim of this research was to further explore the relationship between short-term psychological stress and altered immune responsiveness. Leukocyte coping capacity (LCC) is a luminol-dependent chemiluminescent technique for the assay of reactive oxygen species production in whole blood samples. The feasibility of applying this test as an objective, quantitative, diagnostic measure of altered mental workload (mental stress), in the assessment of ergonomics within automotive research and development was examined. Methods Leukocyte activity was determined from whole blood, using a luminol-dependent, in vitro, chemiluminescent technique referred to as Leukocyte Coping Capacity (LCC). 2 The technique measures reactive oxygen species production following phorbol 12-myristate 13-acetate (PMA) stimulation. Subjective psychological measures, including likert scales and the NASA task load index were employed to assess perceived stress and altered mental workload. Other traditional physiological parameters including heart rate, systolic and diastolic blood pressure and core body temperature were also measured. The ability of each parameter to detect and discriminate between related short-term stressors was investigated, and results were correlated with post-test changes in leukocyte activity. To investigate the mechanism of stress induced leukocyte activation, standard ELISA was used to assess post-stressor plasma concentration changes in nine mediators including Adrenaline, Noradrenaline, Cortisol, E-Selectin, L-Selectin, Interleukin-1β, Interleukin-6, Endothelin-1, and Tumour Necrosis Factor-α. All 5 studies involved the use of mental stressors that were associated with either driving or the ergonomics of driving. Participants were moderately fit and healthy, aged between 20 and 65 years. Study one assessed the ability of the LCC technique to objectively discriminate between two closely related stressors (performing a simple manoeuvre in two different vehicles). Study two investigated leukocyte sensitivity, by testing whether a quantifiable response was elicited following exposure to a low-level stressor lasting seconds. The third study was used to explore the mechanism of leukocyte activation following short-term low-level stress. In addition to testing the viability of leukocyte responsiveness as an objective quantitative ergonomic assay for use within the motor industry, study four investigated how the magnitude of leukocyte responsiveness changed following repeated exposure to the same stressor. The final study used leukocyte reactivity to investigate how mental loading was affected during the interaction with three different motor vehicle control interfaces, whilst simultaneously maintaining lane discipline within a simulated driving environment.

The intestinal tract of salmonids provides a dynamic interface that not only mediates nutrient uptake but also functions as the first line of defence against ingested pathogens. Exposure of the immune system to beneficial microorganisms and different dietary immunostimulants via the intestine has been shown to prime the immune system and help in the development of immune competence. Furthermore, the morphology and function of teleostean intestines are known to respond to feed components and to ingested and resident bacterial communities. Histological appraisal is still generally considered to be the gold standard for sensitive assessment of the effects of such dietary modulation. The aim of the present study was to improve understanding of salmonid intestinal function, structure and dynamics and to use the knowledge gained to develop a model for analysis, which would allow intestinal health to be assessed with respect to different intestinal communities and feed components. Virtual histology, the process of assessing digital images of histological slides, is gaining momentum as an approach to supplement traditional histological evaluation methodologies and at the same time, image analysis of digitised histological sections provides a practical means for quantifiable assessment of structural and functional changes in tissues, being both objective and reproducible. This project focused on the development of a rapid, practical analytical methodology based on advanced image analysis, that was able to measure and characterise a range of features of the intestinal histology of Atlantic salmon in a quantitative manner. In the first research chapter, the development of a novel histological assessment system based upon advanced image analysis was described, this being developed with the help of a soybean feed model known to induce enteropathy in Atlantic salmon. This tool targeted the evaluation of the extent of morphological changes occurring in the distal intestine of Atlantic salmon following dietary modulation. The final analytical methodology arrived at, could be conducted with minimal user-interaction, allowing rapid and objective assessment of 12 continuous variables per histological frame analysed. The processing time required for each histological frame was roughly 20-25 min, which greatly improved the efficiency of conducting such a quantitative assessment with respect to the time taken for a subjective semi-quantitative alternative approach. Significant agreement between the fully automated and the manual morphometric image segmentation was achieved, however, the strength of this quantitative approach was enhanced by the employment of interactive procedures, which enabled the operator / observer to rectify preceding automated segmentation steps, and account for the specimen’s variations. Results indicated that image analysis provided a viable alternative to a pathologist’s manual scoring, being more practical and time-efficient. In the second research chapter, feeding Atlantic salmon a high inclusion level of unrefined SBM (25 %) produced an inflammatory response in the distal intestine as previously described by other authors. The model feed trial successfully generated differentiable states, although these were not, for the most part, systemically differentiable through the majority of standard immunological procedures used, being only detectable morphologically. Quantitation of morphometric parameters associated with histological sections using the newly developed image analysis tool successfully allowed identification of major morphological changes. Image analysis was thus shown to provide a powerful tool for describing the histomorphological structure of Atlantic salmon distal intestine. In turn, the semi-automated image analysis methods were able to distinguish normal intestinal mucosa from those affected by enteritis. While individual parameters were less discriminatory, use of multivariate techniques allowed better discrimination of states and is likely to prove the most productive approach in further studies. Work described in the third research chapter sought to validate the semi-automated image analysis system to establish that it was measuring the parameters it was purported to be measuring, and to provide reassurance that it could reliably measure pre-determined features. This study, using the same sections for semi-quantitative and quantitative analyses, demonstrated that the quantitative indices performed well when compared to analogous semi-quantitative descriptive parameters of assessment for enteritis prognosis. The excellent reproducibility and accuracy performance levels indicated that the image analysis system was a useful and reliable morphometric method for the quantification of SB-induced enteritis in salmon. Other characteristics such as rapidity, simplicity and adaptability favour this method for image analysis, and are particularly useful where less experienced interpreters are performing the analysis. The work described in the fourth research chapter characterised changes in the morphology of the intestinal epithelial cells occurring as a result of dietary modulation and aspects of inflammatory infiltration, using a selected panel of enzyme and IHC markers. To accomplish this, image analysis techniques were used to evaluate and systematically optimise a quantitative immunolabelling assessment protocol. Digital computer-assisted quantification of labelling for cell proliferation and regeneration; programmed cell death or apoptosis; EGCs and t-cell like infiltrates; mobilisation of stress-related protein regenerative processes and facilitation of nutrient uptake and ion transport provided encouraging results. Through the description of the intestinal cellular responses at a molecular level, such IHC expression profiling further characterised the inflammatory reaction generated by the enteropathic diet. In addition, a number of potential diagnostic parameters were described for fish intestinal health e.g. the relative levels of antigenicity and the spatial distribution of antigens in tissues. Work described in the final research chapter focused on detailed characterisation of intestinal MCs / EGCs in order to try to elucidate their functional role in the intestinal immune responses. Through an understanding of their distribution, composition and ultrastructure, the intention was to better characterise these cells and their functional properties. The general morphology, histochemical characteristics and tissue distribution of these cells were explored in detail using histochemical, IHC and immunogold staining / labelling, visualised using light, confocal and TEM microscopy. Despite these extensive investigations, their physiological function and the content of their granules still remain somewhat obscure, although a role as immunodulatory cells reacting to various exogeneous signals through a finely regulated process and comparable to that causing the degranulation of mammalian MCs is suggested. The histochemical staining properties demonstrated for salmonid MCs / EGCs seem to resemble those of mammalian mucosal mast cells, with both acidophilic and basophilic components in their granules, and a granule content containing neuromodulator / neurotransmitter-peptides such as serotonin, met-enkephalin and substance-p. Consequently, distinguishable bio-chromogenic markers have been identified that are of utility in generating a discriminatory profile for image analysis of such cells.

Thesis (PhD (Pathology. Medical Microbiology))--University of Stellenbosch, 2005. / There has recently been a significant transformation in the medical world, in particular regarding the relation between the mind/health and mind/illnesses. The changes are briefly a revolution whereby the new approach sees the development of an illness as an interaction between the psychological, biochemical and physiological factors. Music, which is used as a clinical intervention, is perceived first through the brain, affirms this interaction between the body systems, as well as having the capacity to modify the mind and thus the biochemistry of the body. The aim of this study was essentially to supply empirical data by measuring selective parameters while the patients were receiving music intervention during the physiotherapeutic treatment for pneumonia and bronchitis. Forty adult patients who were divided into an experimental and control group, according to a random scale, participated in the research. The dependant variables that had shown significant changes amongst the experimental group after three days of physiotherapeutic treatment were as follows: the cortisol, the cortisol: DHEA ratio plasma levels, the POMS scale (that measures different moods), the peak flow measurements of the lung functions and the immune parameters, namely, CD4+ : CD8+ ratio and B-cells. The results showed that the experimental group that was exposed to the acoustic stimuli of the Magnificat in D, BWV 243 of JS Bach, experienced a more positive mood and lower cortisol levels, while the immune markers as well as the peak flow of the lungs had improved. The results of the control group showed significant implications, in that its cortisol levels increased and the POMS subscale of anger and depression showed no significant change, while the tension decreased significantly. This research provided sufficient scientific evidence to confirm the concept of a bidirectional communication between the brain and the immune system. It also showed clearly that music had the capacity to modify emotional conditions, which again influenced the endocrine and autonomic nervous system and modulated the immune systems.