Placental dysfunction is implicated in the pathogenesis of preeclampsia. Chemical signals between the placenta and maternal circulation are a suspect cause of endothelial dysfunction and maternal hypertension. This study examined select lipid mediators of inflammation produced by the placenta. Patients were recruited from Virginia Commonwealth University’s pregnancy clinics and placentas were collected at delivery. Forty-eight-hour explant cultures of villous placental tissue were used to model lipid production. Electrospray ionization mass spectrometry was used to quantify concentrations of free lipids in the culture media. Bicinchoninic acid assays were performed to quantify protein in each culture for normalization of lipid data. After analysis, it was found that severity of preeclampsia was correlated with a unique lipid profile. Pro-inflammatory hydroxyeicosatetraenoic acids and sphingolipids were elevated. Aspirin usage in patients who developed preeclampsia was found to attenuate accumulation of isoprostane oxidative stress markers and thromboxane production while preserving omega-3-fatty acid and increasing prostacyclin levels.

Objectives: Adherence to National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer treatment improves patient outcomes. The aim of this study was to assess disparities associated with ovarian cancer treatment in the state of Kentucky and central Appalachia. Methods: Data on patients diagnosed as having ovarian cancer from 2007 through 2011 were extracted from administrative claims-linked Kentucky Cancer Registry data. NCCN compliance was defined by stage, grade, surgical procedure, and chemotherapy. Selection criteria were reviewed carefully to ensure data quality and accuracy. Descriptive analysis, logistic regression, and Cox regression analyses were performed to examine factors associated with guidelines compliance and survival. Results: Most women were age 65 years or older (62.5%), had high grade (65.9%) and advanced stage (61.0%) ovarian cancer. Two-thirds of cases (65.9%) received NCCN-recommended treatment for ovarian cancer. The hazard ratio (HR) of death for women who did not receive NCCN-compliant care was 62% higher compared to the women who did receive NCCN compliant treatment (HR 1.62, 95% CI 1.11-2.35). Results from the logistic regression showed that NCCN-compliant treatment was more likely for: women age 65-74 years compared to age 20-49 (OR=3.32, 95% CI=1.32- 8.32), late stage compared to early stage cancers (OR 0.32, 95% CI 0.20-0.53), receipt of care at tertiary hospitals (OR=1.92, 95% CI=1.10-3.34), and privately insured compared to Medicaid (OR=0.31, 95% CI=0.13-0.77) or Medicare (OR=0.31, 95% CI=0.15-0.66). Conclusions: When the treatment of ovarian cancer did not follow NCCN-recommendations, patients had a significantly higher risk of death. Women were less likely to receive NCCN-compliant care if they were of younger age (20-49 years), had early stage disease, were not privately insured, or had care provided at a non-tertiary hospital.

Thesis (Ph.D. in Nursing) -- University of Colorado, 2006. / Typescript. Includes bibliographical references (leaves 177-185). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

Background: Hypertension during pregnancy is a leading cause of birthing parent mortality and adverse pregnancy outcomes. Since non-metropolitan communities face higher rates of several risk factors for hypertension in pregnancy and shortages in obstetrical services, persons residing in non-metropolitan areas may be at increased risk for adverse outcomes compared to those living in metropolitan areas. Our study objectives were to examine by county of birthing parent residence (1) the prevalence of chronic hypertension (cHTN) and hypertensive disorders of pregnancy (HDP), and (2) the prevalence of adverse birthing parent and neonatal outcomes associated with hypertension. Methods: Using U.S. birth certificate data from 2016 to 2018, we described the prevalence of cHTN and HDP and the association of each with several birthing parent and neonatal outcomes, stratified by non-metropolitan versus metropolitan county of birthing parent residence. Multivariable Poisson regression models were used to calculate adjusted prevalence ratios for birthing parent and neonatal outcomes among individuals with cHTN or HDP who lived in non-metropolitan versus metropolitan U.S. counties. Results: The prevalence of cHTN and HDP for US live births was 2.2% and 7.4%, respectively, among non-metropolitan pregnant individuals and 1.8% and 6.6%, respectively, among metropolitan pregnant individuals. After adjusting for several sociodemographic characteristics among those with HDP, the prevalence ratio for an APGAR score < 7 at 5 minutes (aPR 1.34, 95% CI 1.29-1.38) and neonatal death (aPR 1.36, 95% CI 1.15-1.62) was increased among offspring born to women who resided in non-metropolitan counties. Similar results were seen among those with cHTN. Conclusion: The prevalence of cHTN and HDP is modestly more prevalent in non-metropolitan areas, but most pregnancy outcomes were similar among those residing in non-metropolitan areas compared to metropolitan areas. Further research should investigate the robustness of these findings using alternate definitions of rural and urban areas and the possible link between low APGAR score, low NICU admission, and neonatal death in non-metropolitan counties.

Preeclampsia (PE) is a disorder affecting 2-10% of pregnancies worldwide. Clinical signs include high blood pressure (HBP) and proteinuria in the mother after the 20th week of pregnancy. Currently, the only cure for PE is delivery of the fetus, which is often necessary preterm and thus dangerous for both mother and fetus. Maternal symptoms of PE are caused by excess anti-angiogenic proteins of placental origin called soluble Flt1s (sFlt1s). sFlt1 mRNA isoforms are produced by alternative polyadenylation (APA) of full-length Flt1 (fl-Flt1) pre- mRNA. While fl-Flt1 encodes a transmembrane protein, sFlt1s encode truncated proteins that are soluble. Multiple sFlt1 isoforms exist, and their respective contribution to the pathophysiology of PE is unclear. Furthermore, it is unknown whether there is a genome-wide role for APA in PE. In my thesis research, I developed a polyadenylation site sequencing method, and used this method to simultaneously quantify transcriptome-wide polyadenylation site usage and gene expression levels in normal, early-onset PE, and late-onset PE human placentae. I observed distinct expression profiles amongst the three groups, with differential expression of genes in several functional categories, including angiogenesis. I found that three sFlt1 isoforms account for >94% of all placental FLT1 transcripts, and that increased transcription of the entire FLT1 locus drives upregulation of both fl-Flt1 and sFlt1 in PE. I found that APA does not contribute substantially to PE pathophysiology. I also identified siRNAs that knock down sFlt1 mRNA efficiently in cell lines that pave the way for further development of novel RNAi based therapeutics to alleviate PE.

Prostate and breast cancer are the leading causes of cancer-related death in men and women, respectively, and metastasis is the primary factor underlying the high mortality rates.1 Snail transcription factor is an important molecule that drives prostate and breast cancer metastasis through the process of epithelial mesenchymal transition (EMT). Proteolytic enzymes that promote invasion and metastasis such as the lysosomal cysteine protease cathepsin L (Cat L) have been shown to degrade E-cadherin, promoting the epithelial mesenchymal transition (EMT).2 It has also been shown that silencing Cat L can inhibit transforming growth factor-beta (TGF-β)-mediated EMT by suppressing Snail transcription factor.3 Several recent studies have highlighted an additional unexpected localization and site of action for Cat L within the nucleus in breast, colon and prostate cancer.4 Natural products have been shown to be efficacious in prevention and possible treatment of cancer.5 Specifically, we have been studying Muscadine Grape Skin Extract (MSKE) as a possible candidate to inhibit Snail signaling. MSKE has previously been shown to promote prostate cancer apoptosis.6 We hypothesized that Snail promotes nuclear localization of Cat L, which promotes EMT associated with increased migration and invasion, and that antagonizing Snail-Cat L signaling would lead to mesenchymal epithelial transition (MET). We showed for the first time that MSKE promotes apoptosis through induction of endoplasmic reticulum stress response and autophagy. Additionally, MSKE could inhibit Snail-mediated EMT via scavenging reactive oxygen species. Moreover, Snail could promote nuclear localization of Cat L, which then promoted cleavage of CDP/Cux, increased Snail transcription and decreased E-cadherin transcription by direct promoter binding of cleaved CDP/Cux, leading to EMT associated with increased migration and invasion. Interestingly, Z-FY-CHO, a small molecule specific inhibitor of Cat L, as well as MSKE could antagonize this signaling by promoting nuclear to cytoplasmic re-localization of Cat L. Therefore, we have dissected novel mechanisms of action of Snail and how it can be antagonized by MSKE natural product.

Common, complex disorders are polygenic and multifactorial traits representing interactions between environmental, genetic and epigenetic risk factors. More often than not, contributions of these risk factors have been studied individually and this is especially true for complex reproductive traits where application of genomic technologies has been challenging and slow to progress. This thesis explores the potential of genetic and epigenetic components contributing to a better understanding of the biological pathways underlying disease risk in two specific female complex reproductive traits - polycystic ovary syndrome (PCOS) and preterm premature rupture of membranes (PPROM). The PCOS projects focus on characterization of a gene, DENND1A, whose association to PCOS has been established by Genome Wide Association Studies (GWAS) and is known to contribute to PCOS steroidogenic phenotype. In addition, differential microRNAs expression contributing to DENND1A expression regulation in PCOS theca cells was identified. The studies on PPROM utilize a Whole Exome Sequencing approach to identify rare variants in fetal genes contributing to extracellular matrix composition and synthesis contributing to PPROM risk. The results suggest that fetal contribution to PPROM is polygenic and is driven by a significant genetic burden of potentially damaging rare variants in genes contributing to fetal membrane strength and integrity. Tissue and location specific expression patterns of the Chromosome 21 miRNA cluster (miR-99a, miR-125b, let-7c) in fetal membranes from term pregnancies with spontaneous rupture were investigated. The results suggest that these miRNAs play potential roles in fetal membrane rupture and fetal membrane defects associated with T21.

Stress urinary incontinence is prevalent among women. Pelvic floor muscle exercise has been found to be an effective treatment for management of women with stress urinary incontinence. Women's non-adherence to pelvic floor muscle exercise has been the major obstacle for achieving desirable treatment outcomes. The purpose of this study was to examine the relationships between the severity of stress urinary incontinence, impact of incontinence, self-esteem, and intrinsic motivation among Chinese women with stress urinary incontinence and to examine the implications of these relationships on Chinese women's adherence to pelvic floor muscle exercise. / The model developed from the study explained that Chinese women's adherence to pelvic floor exercise is influenced by the interaction among contextual, intrinsic and extrinsic components. Throughout learning and practicing pelvic floor muscle exercise, women's level of motivation to learn and adhere to exercise can be increased or decreased as these components interacted with each other. Finally, the study also highlights implications for nursing practice including the importance of assessment of women with urinary incontinence, awareness of factors influencing adherence to the exercise, and promoting women's adherence to the exercise by fostering women's exercise competency and commitment to exercise and raising women's awareness of the benefits of exercise. / The phase two findings showed that women's perception of severity of incontinence was influenced by sociocultural factors, self-esteem, and level of knowledge. The findings also indicated that about one-third of women were reluctant to disclose their incontinence problems to their partner. This was partly due to their beliefs of linkage between incontinence and deterioration of sexual function, and their conservative view regarding incontinence as a private matter which should not be discussed with their partner. Furthermore, the findings indicated that women's competency, commitment, perceived benefits of pelvic floor muscle exercise and perceived support from family and health professionals were the factors influencing women's adherence to pelvic floor muscle exercise. Importantly, the study revealed that motivation is dynamic in nature from women's initial learning to maintenance of the exercise. Furthermore, motivation was influenced by beliefs in effectiveness of the exercise, perceived exercise benefits and severity of incontinence. / The study employed a mixed method approach using a quantitative design in phase one and a qualitative design in phase two. The results of phase one of the study showed that the majority of women had low level of severity and impact of incontinence; however, 70% of women had high level of motivation to engage in pelvic floor muscle exercise. The results also demonstrated that women's self-esteem was influenced by the severity of incontinence in terms of consumption of pads, as well as the impact of incontinence on different aspects of life being affected by stress urinary incontinence. In addition, those women who had a higher level of severity in terms of increased wetting in previous year and previous week, as well as increased numbers of activities being affected by incontinence were more likely to have a higher level of motivation to adhere to pelvic floor muscle exercise. Furthermore, women with higher levels of impact of incontinence in terms of being affected on sexual life also demonstrated to have a higher level of motivation to adhere to pelvic floor muscle exercise. / Siu Lai Sheung Katherine. / "August 2006." / Adviser: Sheila Twinn. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1562. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 266-300). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Candida albicans is an opportunistic pathogen that is present in the normal flora in a majority of individuals. One key factor in C. albicans virulence is the ability to change its morphology from yeast to an elongated or hyphal form. The regulation of this morphogenesis relies in part upon quorum sensing (QS) molecules. C. albicans often exists as part of a mixed culture alongside other microbes and is influenced by their presence as well as the presence of QS molecules that they produce. In this study, a library of diploid homozygous transcriptional regulator knockout (TRKO) mutants were screened to identify strains capable of forming hyphae in the presence of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. We identified three strains that showed increased hyphae development compared to wild type C. albicans. The strains identified had deletions of the transcriptional regulating genes Orf19.3928, Orf19.2842 (GZF3), and Orf19.3865 (RFX1). These strains were tested for alterations of filamentation in liquid media, and biofilm formation. All three strains showed increased rates of biofilm formation compared to the wild type. Orf19.3928 showed altered response to farnesol, a marked in biofilm formation and no inhibition of filamentation when farnesol was present in liquid media. The GZF3 deletion strain showed enhanced filamentation with all three bacterial species while the RFX1 deletion strain showed increased filamentation only with E. coli and S. aureus. In spent media, GZF3 showed slight increases in filamentation in E. coli and S. aureus while RFX1 had moderate increases in filamentation in E. coli and S. aureus and slight increases with P. aeruginosa.

This thesis attempts to apply the theory of rational disease dynamics to the human papillomavirus by testing whether HPV vaccinations are prevalence elastic. A prevalence elastic relationship suggests that HPV vaccination rates respond positively to increasing prevalence rates of cervical cancer. Prevalence rates are measured both by incidence rates of cervical cancer and by mortality rates of cervical cancer. Data from the NIS-Teen Survey as well as data from the United States Cancer Statistics branch of the Centers for Disease Controls are used to construct a linear regression that controls for income, education levels, proxies for social culture, and proxies for physician access. Incidence was found to have no statistically significant effect on vaccination rates, while mortality rates were found to have a negative relationship with vaccination rates, suggesting that the rational disease dynamics theory does not apply to human papillomavirus and that vaccination rates for HPV are not prevalence elastic.