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No description available.

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No description available.

Sepsis is a life-threatening condition characterized by overwhelming inflammation, resulting in organ system damage, leading to a high mortality rate. Care in the clinical setting is supportive, and there are no approved sepsis-specific treatments. In septic mice, activation of the cholinergic anti-inflammatory pathway decreases cytokine secretion by leukocytes and improves survival. The cholinergic anti-inflammatory pathway is a reflex of the parasympathetic nervous system, converging on the α7 nicotinic acetylcholine (α7nAChR) at the surface of macrophages. Signaling through the receptor blocks NF-kB activation, thus cytokine secretion. Receptor activation has other effects on macrophages, including modulating their migration to target tissues during inflammation. The goal of this study was to describe the contribution of α7nAChR to macrophage migration during sepsis, using both activation with agonist PNU-282987 and α7nAChR-/- mice. We showed that α7nAChR-deficiency impedes migration to inflamed tissues, and that α7nAChR activation promotes macrophage accumulation in tissues, an effect mediated through altered expression of integrin aMb2.

<p>We are all born germ-free. Soon after birth, microbes colonize our body’s surfaces, with the intestine housing the highest density of microbes on earth. Most of us remain blissfully unaware of this co-existence because inflammatory responses to the indigenous microbes are normally not triggered. Nonetheless, intestinal microbes are true educators of our immune system, which is exemplified by the immature immune system observed in germ-free animals. Accumulating evidence suggests that microbial exposure and/or composition impacts on immune regulation. As an example, isotype switch to immunoglobulin E (IgE) is normally very tightly regulated such that in healthy individuals and mice, serum levels are maintained at very low levels. In contrast, total serum IgE levels are elevated in germ-free mice, indicating that in the absence of microbes the regulatory pathway that maintains IgE at basal levels is disrupted. We hypothesize that in the absence of stimuli from the resident intestinal bacteria the immune system does not receive adequate educational signals. We showed that in germ-free mice class switch recombination (CSR) to IgE occurred at intestinal mucosal lymphoid sites a few weeks after birth. IgE levels then remained at elevated levels throughout life, even when intestinal bacteria were introduced after weaning. In the first part of this thesis, the mechanisms involved in this hygiene-induced IgE were investigateted. In a second part, the immunoregulatory role of commensal bacteria was extended to a model of autoimmunity.</p> <p>Collectively these results demonstrate a new dimension of the impact of intestinal symbionts on the immune system: they dictate baseline immune system regulation. Elucidating the mechanisms whereby microbes induce immunoregulatory pathways may give insights into the increasing prevalence of allergic- and autoimmune diseases.</p> / Doctor of Philosophy (PhD)

<p>This thesis examines patterns in poliomyelitis mortality in Wentworth and York Counties of southern Ontario, Canada, from 1900 to 1937. This period marked polio’s shift from endemic to epidemic status. It was also a time of shifting social, cultural, demographic, and economic patterns. Contemporaries struggled to understand polio’s epidemiology, and even today, with the poliovirus on the verge of global eradication, models to explain its changing patterns and impact continue to be revised.</p> <p>This thesis uses both qualitative and quantitative data collected from a variety of archival sources, including death, birth, and marriage registrations, census records, and newspaper articles, among other records. This information was used to build a geodatabase which forms the basis for analyses of mortality patterns in relation to age and sex, illness duration, seasonality, nativity, birthplace, ethnicity, and religion. Further analyses included family size, birth order, socioeconomic status, and place of residence patterns.</p> <p>Examined in the context of Wentworth and York Counties in the early 20^th century, the results both reveal a local pattern to polio’s epidemic emergence and provide a means to test broader hypotheses regarding polio’s epidemiological patterns. Specifically, results from this study were compared to the expectations of the intensive-exposure and cross-sex transmission hypotheses proposed by Nielsen and colleagues. Among the most important contributions of this thesis are the results showing a pattern of change over the study period, with two distinct stages. Stage One (1910 to 1927) is characterized by an equal sex ratio and a median known family size of four. Stage Two (1928 to 1937) is characterized by excess male deaths and a median known family size of two. These results link polio mortality patterns to demographic and ecological shifts in the early 20^th century and confirm that there is still much to learn from the history of this disease.</p> / Doctor of Philosophy (PhD)

<p>Modelling and analysis of recurrent infectious disease epidemics often depends on the reconstruction of a time-varying transmission rate from historical reports of cases or deaths. Statistically rigorous estimation methods for time-varying transmission rates exist but are too computationally demanding to apply to a time series longer than a few decades. We present a computationally ecient estimation method that is suitable for very long data sets. Our method, which uses a discrete-time approximation to the SIR model for infectious diseases, is easy to implement and outperforms the classic Fine and Clarkson estimation method.</p> / Master of Science (MSc)