Influence of fetal tissue transplant on the morphology of the neuromuscular junctions of tibialis anterior and medial gastrocnemius following spinal transection in the rat

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Dysregulation of placental cystathionine-β-synthase promotes fetal growth restriction

Fetal growth restriction (FGR) is characterized by the birth weight and body mass below the tenth percentile for gestational age. FGR is a major cause of perinatal morbidity and mortality and babies born with FGR are prone to develop cardiovascular diseases later in life. The underlying pathology of FGR is inadequate placental transfer of nutrients from mother to fetus, which can be caused by placental insufficiency. Hydrogen sulfide (H2S), a gaseous messenger is produced endogenously by cystathionine-lyase (Cth), cystathionine-β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), which are present in human placenta. Recently, we demonstrated that the dysregulation of H2S/Cth pathway is associated with preeclampsia and blockade of CSE activity induces preeclampsia-like condition in pregnant mice. We hypothesized that defect in H2S pathways promote FGR and H2S donor restores fetal growth in mice where CBS or CSE activity has been compromised. Western blotting and qPCR revealed that placental CBS expressions were significantly reduced in women with FGR. ELISA analysis showed reduced placental growth factor production (PlGF) from first trimester (8–12 weeks gestation) human placental explants following inhibition of CBS activity by aminooxyacetic acid (AOA). Administration of AOA to pregnant mice had no effects on blood pressure, but caused fetal growth restriction. This was associated with reduced PlGF production. Histological analysis revealed a reduction in the placental junction zone, within which trophoblast giant cells and glycogen cells were less prominent in CBS inhibitor treated mice. These results imply that placental CBS is required for placental development and that dysregulation of CBS activity may contribute to the pathogenesis of FGR but not preeclampsia.

The impact of statin use on fetal development:a meta-analysis

INTRODUCTION: Statin use inadvertently during pregnancy and proposed use of statins for the treatment of preeclampsia, led us to question the evidence behind their current contraindicated status. Several studies have evaluated the relationship between statin use in pregnancy with fetal outcome but their results have not been quantitatively assessed by meta-analysis. Our objective was to undertake a systematic review of all published clinical evidence to assess the effects of statin use in pregnancy on subsequent fetal wellbeing. METHODS: A comprehensive search strategy was performed of all electronic databases and the Merck reporting database for studies published from 1966 to 2014. Two reviewers independently screened citations and undertook study quality assessment and data extraction. We obtained summary estimates of adverse fetal events that were classified as potentially fatal, clinically significant morbidity or minor adverse event. We identified 602 titles and reviewed 30 articles for inclusion and exclusion criteria. Meta-analysis was performed on seven studies (3 cohort, 3 case-series and 1 case-control). RESULTS: Of the 922 cases of statin exposure in pregnancy, 27 exposures were associated with lethal or clinically significant fetal morbidity and 10 with minor adverse events. Statin exposure was limited to the first trimester in all but two cases. The pooled rate of lethal or clinically significant fetal abnormalities in pregnant women exposed to statins was 0.01 (95% CI 0.00-0.04), less than the European rate of 0.026 (95% CI 2.54- 2.57)EUROCAT. The rate of fetal abnormality for simvastatin was 0.03 (95% CI 0.00-0.08), atorvostatin 0.11 (95% CI 0.00-0.52), pravastatin 0.01 (95% CI 0.00-0.2) and lovastatin use 0.04 (95% CI 0.00-0.28). Systems based anomalies were also calculated, congenital heart disease was 0.8 (95% CI 0.02-0.12) compared with the background rate of 0.79 (95% CI 0.78- 0.80). CONCLUSIONS: The published data suggests that statins may not be teratogenic when given inadvertently during pregnancy and prospective studies such as The StAmP Trial may provide more data

Dysregulation of placental cystathionine-β-synthase impact on fetal growth restriction

INTRODUCTION: Fetal growth restriction (FGR), which causes perinatal morbidity and mortality, is characterized by birth weight and body mass being below 10th percentile for gestational age. FGR babies are prone to develop cardiovascular diseases later in life. Inadequate placental transfer of nutrients from mother to fetus due to placental insufficiency is considered the underlying cause of FGR. Recently, we demonstrated that blockade of cystathionine-γ-lyase (CSE) activity induces preeclampsia-like condition in pregnant mice. We hypothesized that defect in cystathionine-β-synthase (CBS) / H2S pathway may promote FGR. METHODS: Placental CBS expressions were determined in women with FGR (n=9) and normal controls (n=14) by Western blotting and real-time qPCR. ELISA was used to determine angiogenic factors levels in plasma and first-trimester (8–12 weeks gestation) human placental explants. Time pregnant mice were treated with CBS inhibitor, aminooxyacetic acid (AOA). Mean arterial blood pressure (MBP), histological assessments of placenta and embryos were performed. RESULTS: Placental CBS expressions were significantly reduced in women with FGR. Inhibition of CBS activity by AOA reduced PlGF production from first-trimester human placental explants, Administration of AOA to pregnant mice had no effects on blood pressure, but caused fetal growth restriction, which was associated with reduced placental PlGF production. Histological analysis revealed a reduction in the placental junction zone, within which trophoblast giant cells and glycogen cells were less prominent in CBS inhibitor-treated animals. Furthermore, H2S donor GYY4137 treatment restored fetal growth in pregnant mice exposed to high level of sFlt-1. CONCLUSIONS: These results imply that placental CBS is required for placental development and that dysregulation of CBS activity may contribute to the pathogenesis of FGR but not preeclampsia opening up the therapeutic potentials of H2S therapy in this condition.

The impact of gestational age and fetal weight on the risk of failure of spinal anesthesia for cesarean delivery.

BACKGROUND: There are limited data about spinal dosing for cesarean delivery in preterm parturients. We investigated the hypothesis that preterm gestation is associated with an increased incidence of inadequate spinal anesthesia for cesarean delivery compared with term gestation. METHODS: We searched our perioperative database for women who underwent cesarean delivery under spinal or combined spinal-epidural anesthesia with hyperbaric bupivacaine ⩾10.5mg. The primary outcome was the incidence of inadequate surgical anesthesia needing conversion to general anesthesia or repetition or supplementation of the block. We divided patients into four categories: <28, 28 to <32, 32 to <37 and ⩾37weeks of gestation. The chi-square test was used to compare failure rates and a multivariable regression analysis was performed to investigate potential confounders of the relationship between gestational age and failure. RESULTS: A total of 5015 patients (3387 term and 1628 preterm) were included. There were 278 failures (5.5%). The incidence of failure was higher in preterm versus term patients (6.4% vs. 5.1%, P=0.02). Failure rates were 10.8%, 7.7%, 5.3% and 5% for <28, 28 to <32, 32 to <37 and ⩾37weeks of gestation, respectively. In the multivariable model, low birth weight (P<0.0001), gestational age (P=0.03), ethnicity (P=0.02) and use of combined spinal-epidural anesthesia (P<0.0001) were significantly associated with failure. CONCLUSIONS: At standard spinal doses of hyperbaric bupivacaine used in our practice (⩾10.5mg), there were higher odds of inadequate surgical anesthesia in preterm parturients. When adjusting for potential confounders, low birth weight was the main factor associated with failure.

Morphology of soleus and EDL neuromuscular junctions in the transected rat model following fetal tissue transplant

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Influence of fetal tissue transplant on the morphology of the neuromuscular junctions of tibialis anterior and medial gastrocnemius following spinal transection in the rat

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Maternal-Fetal Attachment and Health Behaviors among Women with HIV/AIDS

Background: Mothers with HIV often face personal and environmental risks for poor maternal health behaviors and infant neglect, even when HIV transmission to the infant was prevented. Maternal-fetal attachment (MFA), the pre-birth relationship of a woman with her fetus, may be the precursor to maternal caregiving. Using the strengths perspective in social work, which embeds MFA within a socio-ecological conceptual framework, it is hypothesized that high levels of maternal-fetal attachment may protect mothers and infants against poor maternal health behaviors. Objective: To assess whether MFA together with history of substance use, living marital status, planned pregnancy status, and timing of HIV diagnosis predict three desirable maternal health behaviors (pregnancy care, adherence to prenatal antiretroviral therapy–ART, and infant’s screening clinic care) among pregnant women with HIV/AIDS. Method: Prospective observation and hypothesis-testing multivariate analyses. Over 17 consecutive months, all eligible English- or Spanish-speaking pregnant women with HIV ( n = 110) were approached in the principal obstetric and screening clinics in Miami-Dade County, Florida at 24 weeks’ gestation; 82 agreed to enroll. During three data collection periods from enrollment until 16 weeks after childbirth (range: 16 to 32 weeks), participants reported on socio-demographic and predictor variables, MFA, and pregnancy care. Measures of adherence to ART and infant care were extracted from medical records. Findings: Sociodemographic, pregnancy, and HIV disease characteristics in this sample suggest changes in the makeup of HIV-infected pregnant women parallel to the evolution of the HIV epidemic in the USA over the past two decades. The MFA model predicted maternal health behaviors for pregnancy care (R2 = .37), with MFA, marital living status, and planned pregnancy status independently contributing ( = .50, = .28, = .23, respectively). It did not predict adherence to ART medication or infant care. Relevance: These findings provide the first focused evidence of the protective role of MFA against poor maternal health behaviors among pregnant women with HIV, in the presence of adverse life circumstances. Social desirability biases in some self-report measures may limit the findings. Suggestions are made for orienting future inquiry on maternal health behaviors during childbirth toward relationship and protection.

Fetal Development

The chapter explains fetal development fro embryo to fetus and the factors which impact on fetal development

Fetal Movements in late Pregnancy : Categorization, Self-assessment, and Prenatal Attachment in relation to women’s experiences

Aim: To explore how pregnant women experience fetal movements in late pregnancy. Specific aims were:  to study women’s experiences during the time prior to receiving news that their unborn baby had died in utero (I), to investigate women’s descriptions of fetal movements (II), investigate the association between the magnitude of fetal movements and level of prenatal attachment (III), and to study women’s experiences using two different self-assessment methods (IV). Methods: Interviews, questionnaires, and observations were used. Results: Premonition that something had happened to their unborn baby, based on a lack of fetal movements, was experienced by the participants. The overall theme “something is wrong” describes the women’s insight that the baby’s life was threatened (I). Fetal movements that were sorted into the domain “powerful movements” were perceived in late pregnancy by 96 % of the participants (II). Perceiving frequent fetal movements on at least three occasions per 24 hours was associated with higher scores of prenatal attachment in all the three subscales on PAI-R. The majority (55%) of the 456 participants reported average occasions of frequent fetal movements, 26% several occasions and 18% reported few occasions of frequent fetal movements, during the current gestational week.  (III). Only one of the 40 participants did not find at least one method for monitoring fetal movements suitable. Fifteen of the 39 participants reported a preference for the mindfetalness method and five for the count-to-ten method. The women described the observation of the movements as a safe and reassuring moment for communication with their unborn baby (IV). Conclusion:  In full-term and uncomplicated pregnancies, women usually perceive fetal movements as powerful. Furthermore, women in late pregnancy who reported frequent fetal movements on several occasions during a 24-hour period seem to have a high level of prenatal attachment. Women who used self-assessment methods for monitoring fetal movements felt calm and relaxed when observing the movements of their babies. They had a high compliance for both self-assessment methods. Women that had experienced a stillbirth in late pregnancy described that they had a premonition before they were told that their baby had died in utero. 

AN ECONOMIC ANALYSIS OF THE ADDITION OF BEVACIZUMAB TO STANDARD CHEMOTHERAPY IN PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA

Thesis (Master's)--University of Washington, 2016-08

Fetal Alcohol Spectrum Disorder Primary Prevention through FASD Diagnosis: Identification of High-Risk Birth Mothers through the Diagnosis of their Children. Follow-up Study

Thesis (Master's)--University of Washington, 2016-08

Human Fetal Progenitor Tenocytes for Regenerative Medicine.

Tendon injuries are very frequent and affect a wide and heterogeneous population. Unfortunately, the healing process is long with outcomes that are not often satisfactory due to fibrotic tissue appearance, which leads to scar and adhesion development. Tissue engineering and cell therapies emerge as interesting alternatives to classical treatments. In this study, we evaluated human fetal progenitor tenocytes (hFPTs) as a potential cell source for treatment of tendon afflictions, as fetal cells are known to promote healing in a scarless regenerative process. hFPTs presented a rapid and stable growth up to passage 9, allowing to create a large cell bank for off-the-shelf availability. hFPTs showed a strong tenogenic phenotype with an excellent stability, even when placed in conditions normally inducing cells to differentiate. The karyotype also indicated a good stability up to passage 12, which is far beyond that necessary for clinical application (passage 6). When placed in coculture, hFPTs had the capacity to stimulate human adult tenocytes (hATs), which are responsible for the deposition of a new extracellular matrix during tendon healing. Finally, it was possible to distribute cells in porous or gel scaffolds with an excellent survival, thus permitting a large variety of applications (from simple injections to grafts acting as filling material). All of these results are encouraging in the development of an off-the-shelf cell source capable of stimulating tendon regeneration for the treatment of tendon injuries.

Imaging of activated complement using ultrasmall superparamagnetic iron oxide particles (USPIO) - conjugated vectors: an in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development.

In the current study, we have developed a magnetic resonance imaging-based method for non-invasive detection of complement activation in placenta and foetal brain in vivo in utero. Using this method, we found that anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles bind within the inflamed placenta and foetal brain cortical tissue, causing a shortening of the T2* relaxation time. We used two mouse models of pregnancy complications: a mouse model of obstetrics antiphospholipid syndrome (APS) and a mouse model of preterm birth (PTB). We found that detection of C3 deposition in the placenta in the APS model was associated with placental insufficiency characterised by increased oxidative stress, decreased vascular endothelial growth factor and placental growth factor levels and intrauterine growth restriction. We also found that foetal brain C3 deposition was associated with cortical axonal cytoarchitecture disruption and increased neurodegeneration in the mouse model of APS and in the PTB model. In the APS model, foetuses that showed increased C3 in their brains additionally expressed anxiety-related behaviour after birth. Importantly, USPIO did not affect pregnancy outcomes and liver function in the mother and the offspring, suggesting that this method may be useful for detecting complement activation in vivo in utero and predicting placental insufficiency and abnormal foetal neurodevelopment that leads to neuropsychiatric disorders.