MARKERS OF CARDIOVASCULAR DYSFUNCTION AFTER PREGNANCIES COMPLICATED BY PRE-ECLAMPSIA

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy characterized by maternal systemic endothelial dysfunction. While the clinical manifestations resolve soon after delivery, a large body of epidemiological evidence indicates significant long-term maternal risk for cardiovascular disease (CVD) after PE. The mechanisms by which PE and future CVD are associated are unclear, although shared constitutional risk factors likely contribute to the features of endothelial dysfunction characteristic to both. We postulate that PE offers a window of opportunity for the identification of unique markers of dysfunction in the earliest stages of disease that may be used to validate cardiovascular risk screening in the early postpartum period. The studies presented in this thesis provide evidence of changes in circulating factors in women with a recent history of PE. Using blood samples collected within the first year of pregnancy, unique patterns of microRNA expression, enrichment of coagulation system proteins and endothelial progenitor cell dysfunction were described. Many of the described changes appear to be independent of cardiovascular risk. In addition to alterations in circulating factors however, longitudinal postpartum assessments demonstrated that microvascular and cardiac abnormalities were evident in the early periods postpartum after a pre-eclamptic pregnancy. Collectively, the data presented in this thesis reveal that physiological alterations in women with a recent history of PE are not necessarily dependent on clinical parameters of cardiovascular risk, and that resulting dysfunction may be demonstrated within the first year postpartum. Importantly, the biomarkers presented herein are all demonstrated elsewhere in the literature to benefit from lifestyle modification and risk reduction. In closing, the findings of this thesis support a need for cardiovascular risk screening based on obstetrical history, namely after pregnancies complicated by PE.

The type I antifreeze protein gene family in Pleuronectidae

Antifreeze proteins (AFPs) protect marine teleosts from freezing in icy seawater by binding to nascent ice crystals and preventing their growth. It has been suggested that the gene dosage for AFPs in fish reflects the degree of exposure to harsh winter climates. The starry flounder, _Platichthys stellatus_, has been chosen to examine this relationship because it inhabits a range of the Pacific coast from California to the Arctic. This flatfish is presumed to produce type I AFP, which is an alanine-rich, amphipathic alpha-helix. Genomic DNA from four starry flounder was Southern blotted and probed with a cDNA of a winter flounder liver AFP. The hybridization signal was consistent with a gene family of approximately 40 copies. Blots of DNA from other starry flounder indicate that California fish have far fewer gene copies whereas Alaska fish have far more. This analysis is complicated by the fact that there are three different type I AFP isoforms. The first is expressed in the liver and secreted into circulation, the second is a larger hyperactive dimer also thought to be expressed in the liver, and the third is expressed in peripheral tissues. To evaluate the contribution of these latter two isoforms to the overall gene signal on Southern blots, hybridization probes for the three isoforms were isolated from starry flounder DNA by genomic cloning. Two clones revealed linkage of genes for different isoforms, and this was confirmed by genomic Southern blotting, where hybridization patterns indicated that the majority of genes were present in tandem repeats. The sequence and diversity of all three isoforms was sampled in the starry flounder genome by PCR. All coding sequences derived for the skin and liver isoforms were consistent with the proposed structure-function relationships for this AFP, where the flat hydrophobic side of the helix is conserved for ice binding. There was greater sequence diversity in the skin and hyperactive isoforms than in the liver isoform, suggesting that the latter evolved recently from one of the other two. The genomic PCR primers are currently being used to sample isoform diversity in related right-eyed flounders to test this hypothesis.

CARBON MONOXIDE AND PREGNANCY: A SEARCH FOR A POSSIBLE THERAPEUTIC IN THE TREATMENT OF PRE-ECLAMPSIA

Pre-eclampsia (PE) is a pregnancy disorder that affects roughly 5-7% of all pregnancies and is a leading cause of both maternal and fetal/neonatal morbidity and mortality. With no present cure for the disease, researchers are interested in the lower incidence of PE observed among the cigarette smoking pregnant population. However, women who use smokeless tobacco do not experience the same decreased incidence of PE, leading to hypothesis of protection against PE from the largest combustible product of cigarette smoke, carbon monoxide (CO). Studies evaluated levels of CO in PE women and found that they were statistically lower than those of healthy pregnancy. Researchers have found CO to possess many cytoprotective and regulatory properties and specifically within the placenta, it has been found to increase perfusion pressure, decrease oxidative stress, decreases ischemia/reperfusion induced apoptosis and maintain endothelial functioning. The idea for use of CO as a possible therapeutic for PE has thus become a real possibility. This study determined CO levels in pregnant women ± smoking as well as in PE women±smoking, as to discover a possible therapeutic range for future treatments. The best correlated automated CO measurement device with blood CO levels was determined, for use in future clinical studies. This thesis also sought a possible CO delivery concentration, in order to achieve the CO levels observed in the human correlation study. A threshold level of maternal CO exposure in a murine animal model was found, for which fetal and maternal negative toxicities were not observed. The results of this thesis lend a few more pieces to the complicated puzzle involving CO and PE and offer another step toward the possibility of a therapeutic treatment/prevention using this gaseous molecule.

Hope in the Most Unlikely Spaces: Thawra and the Contemporary Arabic Novel

In the early to mid-twentieth century, many novelists in the Arab world championed Arab nationalism in their literary reflections on the social and political struggles of their countries, depicting these struggles primarily in terms of spatial binaries that pitted the Arab world against the West, even as they imported Western literary models of progress and modernity into their own work. The intense experience of national awakening that infused their writing often placed these authors at a literary disadvantage, for in their literature, all too often the depth and diversity of Arabic cultures and the complexity of socio-political struggles across the Arab world were undermined by restrictive spatial discourses that tended to focus only on particular versions of Arab history and on a seemingly unifying national predicament. Between the Arab defeat of 1967 and the present day, however, an increasing number of Arab authors have turned to less restrictive forms of spatial discourse in search of a language that might offer alternative narratives of hope beyond the predictable, and seemingly thwarted, trajectories of nationalism. This study traces the ways in which contemporary Arab authors from Egypt and the Sudan have endeavoured to re-think and re-define the Arab identity in ever-changing spaces where elements of the local and the global, the traditional and the modern, interact both competitively and harmoniously. I examine the spatial language and the tropes used in three Arabic novels, viewing them through the lens of thawra (revolution) in both its socio-political and artistic manifestations. Linking the manifestations of thawra in each text to different scenes of revolution in the Arab world today, in Chapter Two, I consider how, at a stage when the Sudan of the sixties was both still dealing with colonial withdrawal and struggling to establish itself as a nation-state, the geographical and textual landscapes of Tayeb Salih‟s Season of Migration to the North depict the ongoing dilemma of the Sudanese identity. In Chapter Three, I examine Alaa iii al-Aswany‟s The Yacoubian Building in the context of a socially diseased and politically corrupt Egypt of the nineties: social, political, modern, historical, local, and global elements intertwine in a dizzyingly complex spatial network of associations that sheds light on the complicated reasons behind today‟s Egyptian thawra. In Chapter Four, the final chapter, Gamal al-Ghitani‟s approach to his Egypt in Pyramid Texts drifts far away from Salih‟s anguished Sudan and al-Aswany‟s chaotic Cairo to a realm where thawra manifests itself artistically in a sophisticated spatial language that challenges all forms of spatial hegemony and, consequently, old and new forms of social, political, and cultural oppression in the Arab world.