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Preeclampsia (PE) is a serious complication of pregnancy with a pathogenesis that is not fully understood, though it involves the impaired invasion of extravillous trophoblasts (EVTs) into the decidual layer during implantation. Because the risk of PE is actually decreased by cigarette smoking, we considered the possibility that nicotine, a critical component of tobacco smoke, might protect against PE by modifying the content of exosomes from EVTs. We investigated the effects of nicotine on our PE model mouse and evaluated blood pressure. Next, exosomes were extracted from nicotine-treated extravillous trophoblasts (HTR-8/SVneo), and the peptide samples were evaluated by DIA (Data Independent Acquisition) proteomic analysis following nano LC-MS/MS. Hub proteins were identified using bioinformatic analysis. We found that nicotine significantly reduced blood pressure in a PE mouse model. Furthermore, we identified many proteins whose abundance in exosomes was modified by nicotine treatment of EVTs, and we used bioinformatic annotation and network analysis to select five key hub proteins with potential roles in the pathogenesis or prevention of PE. EVT-derived exosomes might influence the pathogenesis of PE because the cargo delivered by exosomes can signal to and modify the receiving cells and their environment. [ABSTRACT FROM AUTHOR]

Objective: High-mobility group A1 (HMGA1) protein is known to express in trophoblast; however, the role of migration has not been reported to date. In this study, we investigated the role of HMGA1 on the pathogenesis of preeclampsia using immortalized human trophoblast cell (HTR-8/SVneo). Materials and Methods: We investigated HMGA1 expression in cytotrophoblasts derived from our preeclampsia model mouse, the CD40L mouse, using immunofluorescence. Wound healing and transwell migration assays were also performed using HTR-8/SVneo (extravillous trophoblast) cells transfected with DNA or siRNA of HMGA1. The effect of extranuclear translocation of HMGA1 on the migration of extravillous trophoblastic cells was evaluated using deoxycholic acid (DCA). Results: HMGA1 was expressed exclusively in the nuclei of trophoblasts derived from control mice; cytoplasmic expression was observed only in CD40L mice with preeclampsia. Furthermore, overexpression of HMGA1 in the nuclei of HTR-8/SVneo cells stimulated cell proliferation and migration. Translocation of nuclear HMGA1 to cytoplasm treated with DCA reduced cell migration. Conclusions: Collectively, these findings demonstrate that proper subcellular localization of HMGA1 is important for its function in trophoblast cells, and suggest that aberrant cytoplasmic expression of HMGA1 contributes to the pathogenesis of preeclampsia through impairment of trophoblast migration. [ABSTRACT FROM AUTHOR]

Aim: Preeclampsia is characterized by a disruption of general vascular dilatation, which is mainly mediated by nitric oxide (NO) and disturbed by reactive oxygen species (ROS). The present study investigated the roles of NO and ROS in the pathogenesis of preeclampsia. Methods: Serum samples were obtained prospectively. Serum levels of NO2/NO3 (NOx) and creatol (CTL), the oxidized metabolite of creatine, and flow-mediated dilatation (FMD) of brachial artery were measured in normal pregnant women and preeclamptic patients. To evaluate the effect of circulating factors that control vascular function NO synthase (NOS) and NAD(P)H oxidase mRNA expression was evaluated in cultured human umbilical vein endothelial cells using reverse transcriptase polymerase chain reaction. Results: Serum NOx concentration was decreased and CTL concentration was increased in preeclamptic patients relative to healthy controls during the first trimester of pregnancy. Further, preeclamptic patients exhibited disrupted FMD, which was regulated in part by NO. Immunohistochemistry demonstrated strong expression of nitrotyrosine in the vasculature of preeclamptic placentas. Treatment with sera derived from preeclamptic patients increased endothelial expression of inducible NOS (iNOS) mRNA, and this increase was inhibited by angiotensin II (Ang II) receptor type 2 (AT2) blocker. Endothelial NAD(P)H oxidase subunit gp91 phox expression was increased by treatment with sera from preeclamptic patients and this increase was attenuated by Ang II receptor type 1 (AT1) blocker. Conclusion: The present findings suggest that NO and ROS play important roles in the pathogenesis of preeclampsia and that these roles involve Ang II. [ABSTRACT FROM AUTHOR]

In normal pregnancy, trophoblast (TR) invasion plays a crucial role in remodeling the spiral arteries to develop uteroplacental circulation. Disruption of this invasion is associated with deficient uteroplacental circulation, which can lead to the development of preeclampsia (PE) through abnormal expression of adhesion molecules in the placenta and high serum causative factors such as cytokines. We aimed to evaluate whether serum factors in PE influence intercellular adhesion molecule-1 (ICAM-1) expression of TRs. ICAM-1 expression of TRs was measured using flow cytometry and immunohistochemistry was performed to examine the localization of tumor necrosis factor-α (TNFα) and ICAM-1 in placentas derived from women with normal pregnancies and women with PE. Sera from PE patients significantly increased ICAM-1 expression on TRs compared to sera from normal pregnant women; this increase was blocked with an antibody to TNFα. TNFα also enhanced ICAM-1 expression on TRs through nuclear factor-κB activation. We conclude that ICAM-1 expressed on TRs is involved in PE pathogenesis and is regulated by cytokines. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Problem Endothelial progenitor cell (EPC), which mediates neovascularization of uterine endometrium may be involved in the neovascularization in the utero-placental circulation. We evaluated whether EPC proliferation in pre-eclampsia (PE) differed from that in normal pregnancy. Method of study EPC number in peripheral blood (20 non-pregnancy, 36 normal pregnancy, 10 PE) was measured using flow cytometry. Peripheral blood mononuclear cell was cultured for 7 days and EPC proliferation was assessed based on detection of the uptake of acetylated low-density lipoprotein and lectin. Furthermore, the proliferative activity induced by angiotensin II (Ang II) and tumor necrosis factor- α (TNF- α) was measured by BrdU assay. Results EPC number in peripheral blood did not differ significantly between PE and normal pregnancy; however, EPC proliferation was significantly increased in PE. Furthermore, Ang II and TNF- α induced the proliferation of EPC derived from patients with PE. Conclusions In PE, some factors including Ang II and TNF- α stimulated EPC proliferation; however, the impairment of EPC mobilization into systemic circulation by serum factors may contribute to insufficient regeneration of EC in disturbed utero-placental circulation of PE. [ABSTRACT FROM AUTHOR]

Objective. Our purpose was to elucidate the role of adhesion molecules in the pathogenesis of pregnancy-induced hypertension (PIH). Methods. Sera, peripheral lymphocytes, and polymorphonuclear cells (PMN) from PIH patients, normal pregnant women, and nonpregnant women were collected. Soluble intercellular adhesion molecule-1 (sICAM-1) in sera was measured by ELISA. ICAM-1 expression on endothelial cells (EC) incubated with sera was analyzed by flow cytometry and RT-PCR. CD11a, CD11b, and CD18 expression on lymphocytes and PMN were also measured by flow cytometory. Results. CD11a and CD18 expression levels on PMN and lymphocytes of PIH patients were significantly higher than those of normal pregnant women (p < 0.05). The expression of CD11b was significantly increased in normal pregnancy compared with that in nonpregnant women (p < 0.05). Serum sICAM-1 in PIH patients was higher than that in normal pregnant women (p < 0.05). ICAM-1 expression level on EC incubated with PIH serum for 24 hr was significantly higher than that with normal pregnant serum (p < 0.0005). ICAM-1 mRNA expression after 12 hr incubation with PIH serum was also significantly increased compared with serum from normal pregnant women (p < 0.05). Conclusion. Adhesion molecules may play an important role in the pathogenesis of PIH. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a serious disease that can be fatal for the mother and fetus. The two-stage theory has been proposed as its cause, with the first stage comprising poor placentation associated with the failure of fertilized egg implantation. Successful implantation and placentation require maternal immunotolerance of the fertilized egg as a semi-allograft and appropriate extravillous trophoblast (EVT) invasion of the decidua and myometrium. The disturbance of EVT invasion during implantation in PE results in impaired spiral artery remodeling. PE is thought to be caused by hypoxia during remodeling failure–derived poor placentation, which results in chronic inflammation. High-mobility group protein A (HMGA) is involved in the growth and invasion of cancer cells and likely in the growth and invasion of trophoblasts. Its mechanism of action is associated with immunotolerance. Thus, HMGA is thought to play a pivotal role in successful pregnancy, and its dysfunction may be related to the pathogenesis of PE. The evaluation of HMGA function and its changes in PE might confirm that it is a reliable biomarker of PE and provide prospects for PE treatment through the induction of EVT proliferation and invasion during the implantation. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to compare the efficacy of intravenous immunoglobulin (IVIG) therapy for obstetric antiphospholipid syndrome (APS) refractory to conventional treatment. Methods: We conducted a single-arm, open-label multicentre clinical intervention trial. The enrolled criteria were patients with refractory APS who had a history of still or premature birth before 30 weeks of gestational age, even though they had been treated with conventional treatment, i.e. heparin and low-dose aspirin. After confirming the foetal heartbeats, a single course of IVIG (0.4 g/kg body weight daily for 5 days) was added to conventional treatment. The primary outcome was a live birth ratio of >30 weeks of gestational period, and the secondary outcome included improving pregnancy outcomes compared to previous pregnancy. Results: Twenty-five per cent of patients (2 of 8 cases) achieved a live birth after the 30th week of pregnancy by IVIG-only add-on treatment, which is the same prevalence as the historical control. However, by adding other second-line therapy to IVIG and conventional treatment, further three patients (37.5%) achieved improvements in pregnancy outcome compared to previous treatments. In total, five patients (62.5%) were able to achieve preferable pregnancy outcomes through combination treatment including IVIG. Conclusions: This clinical trial could not demonstrate the efficacy of IVIG-only add-on therapy at improving the pregnancy outcomes of patients with obstetric APS refractory to conventional treatment. However, the combination of IVIG with rituximab or statins adding to conventional treatment improved pregnancy outcomes and resulted in more live births. Further studies are needed to investigate the efficacy of multi-targeted therapy to treat obstetric refractory APS. [ABSTRACT FROM AUTHOR]

The pathogenesis of preeclampsia begins when a fertilized egg infiltrates the decidua, resulting in implantation failure (e.g., due to extravillous trophoblast infiltration disturbance and abnormal spiral artery remodeling). Thereafter, large amounts of serum factors (e.g., soluble fms-like tyrosine kinase 1 and soluble endoglin) are released into the blood from the hypoplastic placenta, and preeclampsia characterized by multiorgan disorder caused by vascular disorders develops. Successful implantation and placentation require immune tolerance to the fertilized egg as a semi-allograft and the stimulation of extravillous trophoblast infiltration. Recently, exosomes with diameters of 50–100 nm have been recognized to be involved in cell–cell communication. Exosomes affect cell functions in autocrine and paracrine manners via their encapsulating microRNA/DNA and membrane-bound proteins. The microRNA profiles of blood exosomes have been demonstrated to be useful for the evaluation of preeclampsia pathophysiology and prediction of the disease. In addition, exosomes derived from mesenchymal stem cells have been found to have cancer-suppressing effects. These exosomes may repair the pathophysiology of preeclampsia through the suppression of extravillous trophoblast apoptosis and promotion of these cells' invasive ability. Exosomes secreted by various cells have received much recent attention and may be involved in the maintenance of pregnancy and pathogenesis of preeclampsia. [ABSTRACT FROM AUTHOR]

Background: Globally, 2.6 million stillbirths occur every year. Of these, 98% occur in developing countries. According to the United Nations Children's Fund, the neonatal mortality rate in Zambia in 2014 was 2.4%. In 2016, the World Health Organization released the International Classification of Diseases - Perinatal Mortality (ICD-PM) as a globally applicable and comparable system for the classification of the causes of perinatal deaths. However, data for developing countries are scarce. The aim of this study was to evaluate the rates and causes of stillbirths and neonatal deaths at a local hospital in Zimba, Zambia to identify opportunities for preventive interventions.Methods: All cases of stillbirths and neonatal deaths at Zimba Mission Hospital in Zambia in 2017 were included in this study. Outborn neonates who were transferred to the hospital and later died were also included in the study. Causes of stillbirths and neonatal deaths were analyzed and classified according to ICD-PM.Results: In total, 1754 babies were born via 1704 deliveries at the hospital, and 28 neonates were transferred to the hospital after birth. The total number of perinatal deaths was 75 (4.2%), with 7 deaths in the antepartum, 25 deaths in the intrapartum, and 43 deaths in the neonatal period. Most antepartum deaths (n = 5; 71.4%) were classified as fetal deaths of unspecified causes. Intrapartum deaths were due to acute intrapartum events (n = 21; 84.0%) or malformations, deformations, or chromosomal abnormalities (n = 4; 16.0%). Neonatal deaths were related primarily to complications from intrapartum events (n = 19; 44.2%); low birth weight or prematurity (n = 16; 37.2%); or infection (n = 3; 7.0%).Conclusions: Perinatal deaths were associated with acute intrapartum events and considered preventable in 40 cases (53.3%). Effective interventions to prevent perinatal deaths are needed. [ABSTRACT FROM AUTHOR]

Reports on an investigation into the relation between serum samples from pre-eclamptic pregnant patients and endothelial cell Ca++. Disturbance in uteroplacental circulation as a cause of pre-eclampsia; The role of Ca++ in cell proliferation and expression of cellular function; Interpretations of the study.

Aim: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high‐risk pregnant women. Methods: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age‐specific PPV and NPV were estimated. Results: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78–99.96), 99.12% (95% CI: 96.83–99.76), and 100% (95% CI: 88.30–100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age‐specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. Conclusion: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high‐risk pregnant women, and maternal age‐specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan. [ABSTRACT FROM AUTHOR]

Objectives: To establish the reference values for PAPP-A and total hCG between 11 and 13 weeks of gestation for the use of risk assessment of fetal aneuploidy in Japanese pregnant women.Methods: A multicenter prospective study was conducted. The subjects included only Japanese pregnant women with viable singleton who requested the first trimester combined (nuchal translucency and maternal serum marker) screening for fetal aneuploidy. Reference values of PAPP-A and total hCG in Japanese population were made and compared with them in Caucasian.Results: Overall 1,751 Japanese pregnant women were analyzed. Median vales of maternal serum concentration in Japanese pregnant women from 11 + 0-13 + 6 weeks' gestation were ranged from 3.01 to 9.51 mIU/mL for PAPP-A and from 70.2 to 58.3 IU/mL for total-hCG, respectively. Regression curve of median maternal serum PAPP-A and total-hCG concentration against gestational days are significantly higher in Japanese comparing with Caucasian. At most distant values, Japanese serum concentration indicated 1.45 MoM for total-hCG and 1.70 MoM for PAPP-A based on Caucasian regression curves.Conclusion: A modification of the equations by specific reference values is necessary for Japanese pregnant women at the risk assessment of chromosomal abnormalities using the first trimester maternal serum marker. [ABSTRACT FROM AUTHOR]

The aim was to evaluate whether natural killer (NK) cells and regulatory T (Treg) cells were involved in mechanisms underlying beneficial effects of a high dose of intravenous immunoglobulin (IVIG) on recurrent pregnancy losses (RPL) of unexplained etiology. In a double-blind, randomized, placebo-controlled trial of IVIG (400 mg/kg, for 5 days in 4–6 weeks of gestation) in women with RPL, blood samples were collected pre-infusion, one week after infusion (1 w), and eight weeks of gestation/when miscarried (8 w). Levels of NK and Treg cells in peripheral blood were compared between women with IVIG (n = 50) and placebo (n = 49), and between women with IVIG who gave live birth (n = 29) and those who had miscarriage with normal chromosome (n = 12). Effector Treg cell percentages in IVIG group at 1 w (mean 1.43 % vs. 1.03 %) and at 8 w (1.91 % vs. 1.18 %) were higher than those in placebo group (p < 0.01). Total Treg cell percentages in IVIG group at 1 w (4.75 % vs. 4.08 %) and at 8 w (5.55 % vs. 4.47 %) were higher than those in placebo group (p < 0.05). In women with live birth, total Treg cell percentages increased at 8 w (5.52 %, p < 0.001) compared with pre-infusion (4.54 %) and 1 w (4.47 %), while NK cell activity decreased at 1 w (20.18 %, p < 0.001) compared with pre-infusion (26.59 %). IVIG increased Treg cell percentages and suppressed NK cell activity very early in pregnancy, and these were associated with subsequent live birth. Stimulation of Treg cells and suppression of NK cell activity very early in pregnancy may be a mechanism of pharmacological effects of high dose IVIG. • In a RCT involving severe cases of primary RPL, a high dose of IVIG very early in pregnancy increased peripheral Treg cells, and the increase in Treg cells was associated with subsequent live birth outcomes. • A high dose of IVIG in women with RPL suppressed peripheral NK cell activity, and the decrease in NK cell activity was associated with subsequent live birth outcomes. • Stimulation of Treg cells and suppression of NK cell activity very early in pregnancy may be a mechanism of pharmacological effects of high dose IVIG. [ABSTRACT FROM AUTHOR]

The introduction of laparoscopic surgery has also been beneficial for patients with gynecological malignancies. In this respect, surgeons should receive related training in the context of human resource development. Hands-on training was introduced using Thiel-embalmed human cadavers (THCs) in 2014. To determine the usefulness of THCs, they were evaluated in terms of tissue color, consistency and operative tactility, among others, compared with in vivo laparoscopic training for gynecological malignancies. Hands-on training sessions using THCs were held for a total of 11 times at Ehime University Graduate School of Medicine between March 2014 and October 2017. Training on THCs included advanced laparoscopic procedures for radical hysterectomy type III. At the end of each training session, data were collected using a standardized, anonymous questionnaire termed the Likert scale. THCs ensured flexibility and plasticity of tissues and organs; therefore, the working space was similar to that in the living body under pneumoperitoneum. After analyzing the quality and consistency of tissue and organ color compared with in vivo conditions, most of the participants agreed or strongly agreed regarding the uterus, adnexa and ureter, but not regarding the large blood vessels. The highest scores were observed in the authenticity of the anatomical condition of each organ. Most participants strongly agreed that training using THCs would help improve their laparoscopic skills with a high level of satisfaction. Furthermore, most participants reported that they would recommend this training to other obstetrician-gynecologists. Laparoscopic training for gynecological malignancies using THCs was comparable to the in vivo conditions in terms of surgical view and operative tactility. Therefore, THCs may be an excellent training tool for improving laparoscopic surgical skills for gynecological malignancies. [ABSTRACT FROM AUTHOR]

Supernumerary ovaries are extremely rare. Herein is reported a case of supernumerary ovary detected in a 31-year-old woman who complained of lower abdominal pain on her left side. Ultrasonography indicated a cystic mass in the pelvis, the size of which fluctuated periodically. A laparotomy was performed and indicated two normal ovaries in addition to a cystic mass in the cul-de-sac. Histology of the mass confirmed the presence of both normal ovarian tissue and cystic corpus luteal tissue consistent with the presence of a supernumerary ovary. Examination of the patient's medical history suggested that the supernumerary ovary was likely to be of embryonic origin, and not caused by surgical treatment or inflammation. This is the first report of a supernumerary ovary that was associated with periodic episodes of pain and changes in size, and a giant corpus luteal cyst near the rectum. [ABSTRACT FROM AUTHOR]