Heightened maternal inflammation is linked to placental oxidative and nitrosative stress associated with fetal growth restriction in the rat

Deficient trophoblast invasion and spiral artery remodeling are associated with pregnancy complications such as pre-eclampsia (PE) and fetal growth restriction (FGR). Using a model in which pregnant Wistar rats are given daily, low-dose, injections of bacterial lipopolysaccharide (LPS; 10 – 40 µg/kg) on gestational days (GD) 13.5 – 16.5, our group has shown that abnormal maternal inflammation is causally linked to shallow trophoblast invasion, deficient spiral artery remodeling, and altered utero-placental hemodynamics leading to FGR/PE; these alterations were shown to be mediated by TNF-a. The present research evaluated certain consequences of decreased placental perfusion; this was accomplished by examining placental alterations indicative of decreased placental perfusion. Additionally, the role of glyceryl trinitrate (GTN) was determined as a potential therapeutic to prevent the consequences of decreased placental perfusion. Results indicated that dams experiencing heightened maternal inflammation showed significantly greater expression of hypoxia-inducible factor-1a (HIF-1a) and nitrotyrosine, both of which are markers of decreased perfusion and oxidative/nitrosative stress. Contrary to expectations, inflammation did not appear to affect nitric oxide (NO) bioavailability, as revealed by a lack of change in placental or plasma levels of cyclic guanosine monophosphate (cGMP). However, continuous transdermal administration of GTN (25 µg/hr) on GD 12.5 – 16.5 prevented the accumulation of HIF-1a and nitrotyrosine in placentas from LPS-treated rats. These results support the concept that maternal inflammation contributes to placental hypoxia and oxidative/nitrosative stress. Additionally, they indicate that GTN has potential applications in the treatment and/or prevention of pregnancy complications associated with abnormal maternal inflammation.

Mouse Uterine Natural Killer Cell Functions During Early Pregnancy

Early pregnancy is characterized by complex interactions between blood vessels, leukocytes, and conceptus-derived trophoblasts within the gestational uterus. Uterine Natural Killer (uNK) cells become the most abundant leukocyte during decidualization and produce a wide array of angiogenic factors, yet little is known regarding their early pregnancy functions. To characterize the role(s) of uNK cells, whole mount in situ immunohistochemistry of live early implant sites was performed. A timecourse examination of murine early pregnancy (virgin, and gd4.5-9.5) implantation sites was performed. Comparison of Gd6.5, 8.5 and 9.5 implant sites from BALB/c+/+ controls (BALB/c) and BALB/c-Rag2-/-Il2rg-/- (alymphoid) identified anomalies that result from the absence of lymphocytes. In alymphoid decidua basalis, mesometrial angiogenesis was widespread but pruning of nascent vessels within alymphoid decidua basalis was deficient. As early gestation progressed, vessels of alymphoid decidua basalis showed no evidence for remodeling. Alymphoid implantation sites showed ~24h delay in uterine lumen closure and embryonic development. To determine if uNK cells would normalize the anomalies observed in alymphoid implantation sites, adoptive cell transfer of NK+ B- T- marrow to alymphoid mice was performed. All of the above anomalies were reversed by adoptive transfer of NK+B-T- marrow. My results suggest that uNK cells support vascular growth and development which ensures the decidua can support the growing conceptus early in pregnancy prior to formation and function of the placenta. Human decidual NK cells may fill similar roles and be important targets for strategies designed to correct intra-uterine growth restriction.

Self-Management of Chronic Pain: Interventions, Strategies, Barriers, and Facilitators

Background & Purpose: Chronic pain is a prevalent chronic condition for which the best management options rarely provide complete relief. Individuals with chronic pain with neuropathic characteristics (NC) report more severe pain and experience less relief from interventions. Little is known about current self-management practices. The purpose of this dissertation was to inform self-management of chronic pain with and without NC at the individual, health system, and policy levels using the Innovative Care for Chronic Conditions Framework. Methods: The study included a systematic search and review and cross-sectional survey. The review evaluated the evidence for chronic pain self-management interventions and explored the role of health care providers in supporting self-management. The survey was mailed to 8,000 randomly selected Canadians in November 2011, and non-respondents were followed-up in May 2012. Screening questions were included for both chronic pain and NC. The questionnaire captured pain descriptions, self-management strategies, and self-management barriers, and facilitators. Results: Findings of the review suggested that self-management interventions are effective in improving pain and health outcomes. Health care professionals provided self-management advice and referred individuals to self-management interventions. The questionnaire was completed by 1,520 Canadians. Those with chronic pain (n=710) identified primary care physicians as the most helpful pain management professional. Overall, use of non-pharmaceutical medical self-management strategies was low. While use positive emotional self-management strategies was high, individuals with NC were more likely to use negative emotional self-management strategies compared to those without NC. Multiple self-management barriers and facilitators were identified, however those with NC were more likely than those without NC to experience low self-efficacy, depression and severe pain which may impair the ability to self-management. Conclusions: Health care professionals have the opportunity to improve chronic pain outcomes by providing self-management advice, referring to self-management interventions, and addressing self-management barriers and facilitators. Individuals with NC may require additional health services to address their greater self-management challenges, and further research is needed to identify non-pharmaceutical interventions effective in relieving chronic pain with NC. Public policy is needed to facilitate health systems in providing long-term self-management support for individuals with chronic pain.