Investigation of the effect of intrauterine inflammation and infection on fetal brain injury using human and animal models

In recent years, increased focus has been placed on the role of intrauterine infection and inflammation in the pathogenesis of fetal brain injury leading to neurodevelopmental disorders such as cerebral palsy. At present, the mechanisms by which inflammatory processes during pregnancy cause this effect on the fetus are poorly understood. Our previous work has indicated an association between experimentally-induced intrauterine infection, increased proinflammatory cytokines, and increased white matter injury in the guinea pig fetus. In order to further elucidate the pathways by which inflammation in the maternal system or the fetal membranes leads to fetal impairment, a number of studies investigating aspects of the disease process have been performed. These studies represent a body of work encompassing novel research and results in a number of human and animal studies. Using a guinea pig model of inflammation, increased amniotic fluid proinflammatory cytokines and fetal brain injury were found after a maternal inflammatory response was initiated using endotoxin. In order to more closely monitor the fetal response to chorioamnionitis, a model using the chronically catheterized fetal ovine was carried out. This study demonstrated the adverse effects on fetal white matter after intrauterine exposure to bacterial inoculation, though the physiological parameters of the fetus were relatively stable throughout the experimental protocol, even when challenged with intermittent hypoxic episodes. The placenta is an important mediator between mother and fetus during gestation, though its role in the inflammatory process is largely undefined. Studies on the placental role in the inflammatory process were undertaken, and the limited ability of proinflammatory cytokines and endotoxin to cross the placenta are detailed herein. Neurodevelopmental disorders can be monitored in animal models in order to determine effective disease models for characterization of injury and use in therapeutic strategies. Our characterizations of postnatal behaviour in the guinea pig model using motility monitoring and spatial memory testing have shown small but significant differences in pups exposed to inflammatory processes in utero. The data presented herein contributes a breadth of knowledge to the ongoing elucidation of the pathways by which fetal brain injury occurs. Determining the pathway of damage will lead to discovery of diagnostic criteria, while determining the vulnerabilities of the developing fetus is essential in formulating therapeutic options.

AUSTRALIA’S STRATEGIC CULTURE: An investigation of the concept of strategic culture and its application to the Australian case

The notion that each state in the international system approaches matters of war and peace somewhat differently because they each possess a unique strategic culture is not a new or obscure one – but it nevertheless remains controversial. While some scholars dismiss the utility or practicality of examining states’ cultures when seeking to explain or predict those states’ patterns of strategic decision-making, even amongst those who accept that we should pay attention to cultural differences between states when carrying out strategic analysis there remains a frustratingly eclectic range of offerings from scholars regarding how best to do so. In short, significant uncertainty remains regarding both whether strategic culture should be used as an analytical tool and, if it is so utilized, how one should go about doing so. This thesis therefore explores the concept of strategic culture in great detail, both theoretical and empirical. The opening three chapters examine why the more traditional rationalist/materialistic theories should not exclusively dominate strategic analysis, then the various existing strategic cultural offerings are considered and critiqued and, finally, a new conceptual model for strategic cultural analysis is proposed which draws from the hitherto largely neglected psychological and sociological literature. Both of these fields, it is submitted in Chapter 3, have spent more time and effort developing ways of understanding and analyzing culture than the field of IR has to date, and therefore the models and methods debated and developed in these fields should, it is argued, be ‘imported’ into IR to drive further strategic cultural research. The thesis then moves in the following six chapters to consider Australia’s strategic culture. The purpose of this part of the thesis is two-fold: first, it illustrates how the model offered in Chapter 3 works and, by implication, suggests how scholars may go about applying it to other cases. Second, and perhaps more importantly, the latter six chapters explore the twists and turns of Australia’s substantive strategic decision-making over the course of the last century or more, thereby explaining how Australia’s strategic history can be understood from a cultural perspective.

The Genetics of Postglacial Colonization and Peripherality in Northwestern Populations of the Spring Peeper, Pseudacris crucifer

Glaciation over the Pleistocene induced dramatic range fluctuations for species across North America such that postglacial recolonization by southern refugial lineages has characterized the genetic structure of northern North American species. Based on the leading edge model of postglacial range expansion, dispersal and rapid population growth in these northern taxa is expected to produce vast areas of genetic homogeneity. Previous work on the widely distributed spring peeper (Pseudacris crucifer) revealed six distinct mitochondrial lineages that diverged between 3-11 mya, expanding and contracting with glacial cycles. Beginning 16,000 yBP, receding glaciers permitted Eastern lineage refugia residing in the southern Appalachians to migrate northward into the St. Lawrence Valley then westward through most of central Canada. Peripheral populations at the northwestern range limit of P. crucifer in central Manitoba are likely descended from this westward expanding Eastern lineage. According to the central-marginal hypothesis, founder effects from colonization as well as limited gene flow is expected to reveal genetic differentiation and lower genetic diversity in peripheral populations. The goal of my study is to further our understanding of peripheral range dynamics in peripheral Manitoba populations of P. crucifer by determining their genetic affinity and diversity relative to more central populations in Ontario and Minnesota. In this study I amplified and aligned cytochrome b sequences from sample sites across central Manitoba to reconstruct a Bayesian phylogeny for P. crucifer; additionally, microsatellite loci were genotyped to estimate genetic diversity. Results from this study affirmed Eastern lineage descent for peripheral Manitoba sites by aligning with Ontario. Initial colonization by the Interior lineage between glacial retreat and the appearance of arid vicariance events may explain the apparent introgression of non-Eastern lineages in Manitoba. However, genetic diversity measured in expected heterozygosity (H¬e) was not found to be significantly different in Manitoba genotypes. Greater isolation by distance and inbreeding relative to Ontario and Minnesota is likely the primary driver of genetic variation in these sites. Further sampling is necessary to generate a more complete genetic population structure for P. crucifer.