大口 昭英

Objective: We compared the frequency of peripheral blood Treg cells in women with pre-eclampsia (PE) and in those without, and investigated whether the frequency of Treg cells in women with high-risk factor for PE changed during pregnancy. Methods: We examined the frequency of CD4(+)FoxP3(+) Treg cells in the peripheral blood using flow cytometry. Eleven women with PE and 10 women without PE (controls) were included. Every control had any risk factors for PE, such as high blood pressure, bilateral notching or a past history of PE or gestational hypertension. Blood sampling was conducted 1-3 times in the controls. Results: No significant differences were observed in the frequency of Treg cells between women with PE and the controls [mean +/- SE (%): 5.74 +/- 0.91 versus 5.48 +/- 0.94, p=0.843]. In five controls with serial sampling, the frequency of Treg cells significantly decreased from 5.83 +/- 1.20 to 2.99 +/- 0.54 (p=0.046) (week of the first sampling to that of the last sampling [mean +/- SD]: 21.5 +/- 1.6 weeks to 31.2 +/- 2.5 weeks). Conclusion: The frequency of Treg cells in women with PE was almost identical to that in the controls. The frequency of Treg cells in the controls was reduced by half from the second trimester to the third trimester. These results suggested that the levels of Treg cells in a high-risk pregnant cohort were decreased to those in women with PE in the third trimester irrespective of the occurrence of PE.

Background/Aims: The placenta is a vital organ for pregnancy. Many in vitro placental experiments are conducted under 21% O-2; however, O-2 tension could influence cellular functions, including cytokine secretion. We investigated the effects of oxygen tension between moderate hypoxia (5% O-2) and normoxia (21% O-2) by testing the hypothesis that moderate hypoxia regulates cellular phenotypes differently from normoxia in human trophoblast cells. Methods and Results: Sw.71 trophoblast cells were incubated under normoxic or moderately hypoxic conditions. Cells were also treated with lipopolysaccharide (LPS) as a Toll-like receptor 4 (TLR4) ligand inducing inflammation. Interleukin-6 (IL-6) as an inflammatory cytokine was determined, and TLR4, hypoxia-induced factor-1 alpha (HIF1 alpha), and reactive oxygen species (ROS) production were detected. Moderate hypoxia increased HIF1 alpha expression and cell proliferation and acted by two different mechanisms to decrease IL-6 secretion compared with normoxia: it limits the TLR4 expression and ROS production. Treatment with cobalt chloride as an HIF1 activator inhibited IL-6 secretion and TLR4 expression; this effect was reversed on treatment with PX-12 as an HIF1 suppressor. Conclusion: IL-6 secretion, TLR4 expression, and ROS production, classical markers of inflammation, are down-regulated by moderate hypoxia, and HIF1 alpha and ROS have a potential to regulate these responses in human trophoblast cells. Copyright (C) 2015 S. Karger AG, Basel

Although recent studies have demonstrated that microRNAs (miRNAs or miRs) regulate fundamental natural killer (NK) cellular processes, including cytotoxicity and cytokine production, little is known about the miRNA-gene regulatory relationships in maternal peripheral blood NK (pNK) cells during pregnancy. In the present study, to determine the roles of miRNAs within gene regulatory networks of maternal pNK cells, we performed comprehensive miRNA and gene expression profiling of maternal pNK cells using a combination of reverse transcription quantitative PCR (RT-qPCR)-based miRNA array and DNA microarray analyses and analyzed the differential expression levels between first-and third-trimester pNK cells. Furthermore, we constructed regulatory networks for miRNA-mediated gene expression in pNK cells during pregnancy by Ingenuity Pathway Analysis (IPA). PCR-based array analysis revealed that the placenta-derived miRNAs [chromosome 19 miRNA cluster (C19MC) miRNAs] were detected in pNK cells during pregnancy. Twenty-five miRNAs, including six C19MC miRNAs, were significantly upregulated in the third-compared to first-trimester pNK cells. The rapid clearance of C19MC miRNAs also occurred in the pNK cells following delivery. Nine miRNAs, including eight C19MC miRNAs, were significantly downregulated in the post-delivery pNK cells compared to those of the third-trimester. DNA microarray analysis identified 69 NK cell function-related genes that were differentially expressed between the first-and third-trimester pNK cells. On pathway and network analysis, the observed gene expression changes of pNK cells likely contribute to the increase in the cytotoxicity, as well as the cell cycle progression of third-compared to first-trimester pNK cells. Thirteen of the 69 NK cell function-related genes were significantly downregulated between the first-and third-trimester pNK cells. Nine of the 13 downregulated NK-function-associated genes were in silico target candidates of 12 upregulated miRNAs, including C19MC miRNA miR-512-3p. The results of this study suggest that the transfer of placental C19MC miRNAs into maternal pNK cells occurs during pregnancy. The present study provides new insight into maternal NK cell functions.

To construct a model to calculating probability of requiring allogeneic blood transfusion on cesarean section (CS) for placenta previa (PP). A retrospective cohort study involving all 205 patients with PP who underwent CS in our institute. We determined the relationship between allogeneic blood transfusion and nine preoperative factors: (1) maternal age, (2) parity, (3) uterine myoma, (4) previous CS, (5) the placenta covering the previous CS scar (referred to as "scar covering"), (6) degree of previa, (7) ultrasound finding of lacunae, (8) preoperative anemia, and (9) preparation of autologous blood. Independent risk factors of allogeneic blood transfusion were identified by multivariate logistic regression analysis. These significant factors were included in the final model, and, the probability of allogeneic blood transfusion was calculated. Independent risk factors of allogeneic blood transfusion were scar covering, previous CS without scar covering, and lacunae. These three factors were used to create a predictive model. The model revealed that patients with scar covering and lacunae had the highest probability (0.73), while those with no risk factors had the lowest probability (0.02). This simple model may be useful to calculate probability of requiring allogeneic blood transfusion on CS for placenta previa.

Despite the increasing commercial use of nanoparticles, little is known about their effects on placental inflammation and pregnancy complications. In this study, nanosilica (NS) particles upregulated the inflammasome component nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) and induced placental inflammation and reactive oxygen species (ROS) generation, resulting in pregnancy complications. Furthermore, NS-induced pregnancy complications were markedly improved in N mice but not in component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-deficient (Asc) mice, indicating the independence of NLRP3 inflammasomes. Pregnancy complications in Nlrp3(-/-) and Asc(-/-) mice phenotypes were dependent on the balance between interleukin (IL)-1 a and IL-10. NS-induced pregnancy complications were completely prevented by either inhibition of ROS generation or forced expression of IL-10. Our findings provide important information about NS-induced placental inflammation and pregnancy complications and the novel pathophysiological roles of NLRP3 and ASC in pregnancy.

Background: Type I interferons (IFNs), including IFN-alpha (IFNA) and IFN-beta (IFNB), have anti-inflammatory properties and are used to treat patients with autoimmune and inflammatory disorders. However, little is known of the role of IFN-tau (IFNT), a type I IFN produced by ruminant animals for inflammation. Because IFNB has recently been shown to inhibit nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome activation and subsequent secretion of the potent inflammatory cytokine interleukin (IL)-1 beta, we examined the effects of ruminant IFNT on NLRP3 inflammasome-mediated IL-1 beta secretion in human THP-1 macrophages. Methods and Results: IFNT dose-dependently inhibited IL-1 beta secretion induced by nano-silica, a well-known activators of NLRP3 inflammasomes, in human macrophages primed with lipopolysaccharide (LPS, TLR4 agonist) and Pam3CSK4 (TLR1/2 agonist). IFNT also suppressed phagocytosis of nano-silica and reactive oxygen species (ROS) generation. Western blot analysis showed that IFNT inhibited both pro-IL-1 beta and mature IL-1 beta. In addition, real-time RT-PCR analysis showed that IFNT suppressed IL-1 beta mRNA expression induced by LPS and Pam3CSK4. Although nano-silica particles did not induce IL-10 secretion, IFNT induced IL-10 secretion in a dose-dependent manner. Furthermore, IFNT-suppressed IL-1 beta secretion was restored by anti-IL-10 neutralizing antibody. Conclusions: Ruminant IFNT inhibits NLRP3 inflammasome-driven IL-1 beta secretion in human macrophages via multiple pathways, including the uptake of nano-silica particles, generation of ROS, and IL-10-mediated inhibition of pro-IL-1 beta induction. It may be a therapeutic alternative to IFNA and IFNB.

During pregnancy, human placenta-associated microRNAs (miRNAs) derived from the miRNA cluster in human chromosome 19 are expressed in villous trophoblasts and secreted into maternal circulation via exosomes; however, little is known about whether circulating placenta-associated miRNAs are transferred into maternal immune cells via exosomes, and modulate expression of target genes in the recipient cells. We employed an in vitro model of trophoblast-immune cell communication using BeWo cells (a human trophoblast cell line) and Jurkat cells (a human leukemic T-cell line) and investigated whether BeWo exosomal placenta-associated miRNAs can suppress expression of target genes in the recipient Jurkat cells. Using this system, we identified PRKG1 as a target gene of placenta-associated miRNA miR-517a-3p. Moreover, we demonstrated that BeWo exosomal miR-517a-3p was internalized into Jurkat cells and subsequently suppressed the expression of PRKG1 in recipient Jurkat cells. Furthermore, using peripheral blood natural killer (NK) cells in vivo, we confirmed that circulating miR-517a-3p was delivered into maternal NK cells as it was into Jurkat cells in vitro. Placenta-associated miR-517a-3p was incorporated into maternal NK cells in the third trimester, and it was rapidly cleared after delivery. Expression levels of miR-517a-3p and its target mRNA PRKG1 were inversely correlated in NK cells before and after delivery. These in vitro and in vivo results suggest that exosome-mediated transfer of placenta-associated miRNAs and subsequent modulation of their target genes occur in maternal NK cells. The present study provides novel insight into our understanding of placentamaternal communication.

To describe a naturally conceived woman with ovary hyperstimulation syndrome (OHSS) accompanying molar pregnancy and review the literature on this condition. We report a 31-year-old 2 parous naturally conceived woman with OHSS accompanying partial molar pregnancy. Dilatation and evacuation (D&E) were performed at 10 weeks of gestation. The signs and symptoms of OHSS were the severest on day 8 after D&E, when hCG had already decreased. This case is reported in detail. We also review the literature. A literature search yielded seven cases of this condition. Any type of molar pregnancy, i.e., complete, partial, or invasive, can accompany OHSS. The initial manifestation of OHSS occurred at a median of the 12th week of gestation (range 7-16), which may be later compared with OHSS caused by ovulation induction. In all cases, OHSS aggravated after D&E. We must be aware that OHSS can occur during molar pregnancy, and can be exacerbated after D&E.

Uterine artery pseudoaneurysm (UAP) is considered a rare disorder after traumatic delivery or traumatic pregnancy termination such as cesarean section or dilatation and curettage, initially manifesting as genital hemorrhage. Our clinical impression contradicts these three assumptions; after traumatic delivery/termination, hemorrhage, and its rarity. Thus, we attempted to clarify these three issues. We retrospectively analyzed 22 UAP cases treated at our institute over a 6-year period. Uterine artery pseudoaneurysm occurred in 2-3/1,000 deliveries. Of 22 cases, half occurred after non-traumatic deliveries or non-traumatic pregnancy termination. Fifty-five percent (12/22) showed no hemorrhage; ultrasound or color Doppler revealed UAP. Thus, half of UAP occurred after non-traumatic deliveries or non-traumatic pregnancy termination and showed no hemorrhage at the time of their diagnoses. All patients received transarterial embolization, which stopped blood flow into UAP or achieved hemostasis. We must be aware that UAP may not be so rare and it may be present in patients after non-traumatic deliveries/pregnancy termination and without postpartum or postabortal hemorrhage.

Context: Jichi Medical University (JMU) is the only medical school in Japan that is devoted solely to producing rural and remote doctors. To support research activities of its graduates, mainly young graduates under obligatory rural service, JMU established a voluntary team, Clinical Research Support Team (CRST)-Jichi. Issues: CRST-Jichi consists of current and past JMU faculty members; all of them are specialists of certain medical fields and many are also graduates of JMU who have completed rural service. A client who asks the CRST for advice on study design or editing a paper emails the CRST to ask for support in conducting a study. Then, core members of the CRST assign the job to a registered specialist of the corresponding topic, who becomes a 'responsible supporter' and continues to support the client until a paper has been published. During the 3 years from July 2010, 12 English papers have been published in international peer-review journals, two Japanese papers in domestic journals, and 13 studies are in progress. Ninety-one percent of clients were satisfied with the service, and eighty-two percent considered their papers would not have been published if they had not used the service. Sense of commitment, existence of JMU-graduated specialists, and quick response were reported by clients as major strengths of CRST-Jichi. Lessons learned: The experience of CRST-Jichi can potentially be transferred to not only other Japanese medical schools with rural doctor production programs, which are now rapidly increasing as part of a national policy, but also rural medical education systems in other countries.

Objective: We evaluated the biological interaction among mean blood pressure (MBP), uterine artery Doppler (UAD), and the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio for preeclampsia (PE) risk. Study design: A prospective cohort study. Main outcome measures: In 1239 pregnant women, MBP and UAD were measured at 16-23 weeks of gestation, and plasma levels of the sFlt-1/PlGF ratio at 19-25 weeks and 26-31 weeks. A Cox proportional hazard model was used. Women with a low sFlt-1/PlGF ratio and either low BP or normal UAD were set as controls. The relative excess risk due to biological interaction (RERI) was calculated using the following equation: RERI = hazard ratio (HR) in women with high sFlt-1/PlGF and both high BP and abnormal UAD (group 3) - HR in women with both high BP and abnormal UAD alone (group 1) - HR in women with high sFlt-1/PlGF alone (group 2) + 1. RERI >= 10 was considered to be strong. Results: At 19-25 weeks, the HR and 95% confidence intervals (CI) in group 1, group 2, and group 3 were 7.4 (3.1-17.4), 15.3 (4.5-52.2), and 107.0 (41.0-279), respectively, and the RERI for PE was 85.3. At 26-31 weeks, the HR and 95% CI in each group were 8.3 (2.9-23.2), 7.5 (0.97-57.8), and 69.0 (18.5-256), respectively; the RERI for PE was 54.2. Conclusions: We found a trio of risk factors for the onset of PE in the second and early third trimesters: high BP, abnormal UAD, and high sFlt-1/PlGF ratio. (C) 2014 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.

Although massive haemorrhage at caesarean section (CS) for placenta praevia is a serious concern, effective treatment is not yet determined. We performed a new uterine sandwich to achieve haemostasis at CS for total placenta praevia in five consecutive cases in whom the placenta reached up to >5cm from the internal cervical os in all directions of an uterine wall. A Matsubara-Yano (MY) uterine compression suture was placed, followed by placement of an intrauterine balloon. Haemostasis was achieved in all five cases with median blood loss of 1618mL. No short-term adverse events were observed. The MY sandwich can be used to achieve haemostasis at CS for placenta praevia.

The Clinical Guidelines for Obstetrical Practice, 2011 edition' were revised and published as a 2014 edition (in Japanese) in April 2014 by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction of burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. The number of Clinical Questions and Answers items increased from 87 in the 2011 edition to 104 in the 2014 edition. The Japanese 2014 version included a Discussion, a List of References, and some Tables and Figures following the Answers to the 104 Clinical Questions; these additional sections covered common problems and questions encountered in obstetrical practice, helping Japanese readers to achieve a comprehensive understanding. Each answer with a recommendation level of A, B or C was prepared based principally on evidence' or a consensus among Japanese obstetricians in situations where evidence' was weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 104 Clinical Questions and Answers items, with the omission of the Discussion, List of References, and Tables and Figures, are presented herein to promote a better understanding among English readers of the current standard care practices for pregnant women in Japan.

Our aim was to develop a novel screening method to detect the imminent onset of preeclampsia (PE) within 4 weeks after blood sampling. We prospectively collected data regarding past history of PE/gestational hypertension (GH), blood pressure levels at 16-23 weeks and plasma levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) twice at 19-31 weeks, which were measured using an automated electrochemiluminescence immunoassay. We found that a three-step approach by sequential selection using maternal factors, including a past history of PE/GH or blood pressure levels >= 120/80mmHg at 16-23 weeks (first step), followed by plasma levels of PlGF in the < 5th percentile (second step) and plasma levels of sFlt-1 in the >= 95th percentile (third step) yielded both high sensitivity and specificity. The imminent onset of PE occurred in 2 of 1199 (0.2%) women recruited at 19-25 weeks and in 6 of 798 (0.8%) women recruited at 26-31 weeks. The sensitivity, specificity, positive likelihood ratio (95% confidence interval), negative likelihood ratio (95% confidence interval), positive predictive value and negative predictive value of the three-step approach for predicting the imminent onset of PE at 19-25 weeks were 100%, 99.8%, 599 (150-2390), 0%, 50% and 100%, respectively; and those at 26-31 weeks were 83%, 99.1%, 94 (42-214), 0.17 (0.03-1.01), 42% and 99.9%, respectively. In conclusion, the three-step approach is a highly sensitive and specific screening method for detecting the imminent onset of PE within 4 weeks after blood sampling at 19-31 weeks of gestation.

A disintegrin and metalloproteinases (ADAMs) are members of the metzincin family of zinc-dependent metalloproteinases that play pivotal roles in the proteolytic degradation of the extracellular matrix for cell invasion. Few studies have investigated the ADAM subtypes that are expressed in first trimester trophoblast cells. The purpose of this study was to elucidate the differential expression profiles of ADAMs between first trimester villous trophoblast cells (VTs) and extravillous trophoblast cells (EVTs). We isolated EVTs from explanted human first trimester chorionic villi and investigated the mRNA expression levels of five members of the ADAM family (ADAMTS1, ADAMTS2, ADAM10, ADAM12, and ADAM17) using real-time PCR. Chorionic villous tips were defined as first trimester VTs. Of the differentially expressed ADAM genes between first trimester VTs and EVTs, ADAMTS1 was expressed at a significantly higher level in EVTs than in VTs. In contrast, both ADAM10 and ADAM12 were expressed at significantly higher levels in VTs than in EVTs. No differences were found in the mRNA levels of ADAMTS2 and ADAM17 between the two cell types. Moreover, we demonstrated that in VTs, the expression level of ADAM12 was significantly downregulated in the late first trimester (10-13 gestational weeks) compared to the middle first trimester (7-8 weeks). These results suggest that first trimester trophoblast cells express ADAM genes in cell type- and gestational age-dependent manners. Our data provide additional insight into the functions of ADAMs in the human placenta.

AimOur aim was to establish measurements of subcutaneous fat area ratio (SFAR) and visceral fat area ratio (VFAR) in the early second trimester using magnetic resonance imaging (MRI) in an obese pregnant cohort. MethodsObesity was defined as pre-pregnancy body mass index of 25.0 or more. One hundred and twelve obese pregnant women with a singleton pregnancy gave written informed consent between April 2007 and April 2010. For determining the most suitable MRI slice level, four women lacking MRI slices at the level of L2-3 or L3-4, and two women upon whom MRI was performed at 14 and 19 weeks were excluded, and the remaining 106 women were analyzed. We developed a novel method for calculating SFAR and VFAR at 15-18 weeks using a T-1-weighted spin echo sequence with fluid-attenuated inversion recovery for MRI where fat shows high signal intensity. ResultsMRI slices just above the uterine fundus at 15-18 weeks of gestation never included either the fundus or liver, but the other three slices always included either the liver or the uterus. In addition, the mean value of VFAR just above the uterine fundus was significantly larger than those at L2-3, L3-4 and navel position (47.31.1% vs 37.3 +/- 1.0%, 45.1 +/- 1.2%, 45.6 +/- 1.2%, respectively [P<0.001]). ConclusionThe most suitable MRI slice level for calculating SFAR and VFAR may be just above the uterine fundus in pregnant women at 15-18 weeks of gestation. The evaluation of clinical significance of visceral adiposity for gestational diabetes mellitus is warranted.

AimIn placenta previa (PP), anterior placentation, compared with posterior placentation, is reported to more frequently cause massive hemorrhage during cesarean section (CS). Whether this is due to the high incidence of placenta accreta, previous CS, or a transplacental approach in anterior placenta is unclear. We attempted to clarify this issue. Material and MethodsWe retrospectively analyzed the relation between the bleeding amount during CS for PP and various factors that may cause massive hemorrhage (>2400mL) (n=205) in a tertiary center. If the preoperatively ultrasound-measured distance from the internal cervical ostium to the placental edge was longer in the uterine anterior wall than in the posterior wall, we defined it as anterior previa, and vice versa. ResultsPatients with accreta, previous CS, total previa, and anterior placentation bled significantly more than their counterparts. Multivariate logistic regression analysis showed that accreta (odds ratio [OR] 12.6), previous CS (OR 4.7), total previa (OR 4.1), and anterior placentation (OR 3.5) were independent risk factors of massive hemorrhage. ConclusionsAnterior placentation, namely, the placenta with a longer os-placental edge distance in the anterior wall than in the posterior wall, was a risk of massive hemorrhage during CS for PP.

Various fetal or placental disorders cause Ballantyne's (mirror) syndrome. For the first time, we report a maternal manifestation of Ballantyne's syndrome occurring concomitantly with the development of fetal congenital mesoblastic nephroma (CMN). In a pregnant woman with a CMN fetus, lung edema, hypertension, hyperthyroidism, and high serum human chorionic gonadotrophin level occurred, all of which characterize maternal manifestation of Ballantyne's syndrome. The fetus and placenta were devoid of edema', lacking triple edema', and thus this condition was not diagnosed as Ballantyne's syndrome; however, we considered this condition as the maternal manifestation of Ballantyne's syndrome. We performed emergent cesarean section at 28 weeks. Delivery acutely ameliorated maternal symptoms. Tumor was resected and was confirmed as CMN. Maternal manifestations of Ballantyne's syndrome, such as lung edema and hypertension, can occur in a mother with fetal CMN even without fetal and/or placental edema. The clinical course of this patient may suggest an etiology of Ballantyne's syndrome.

A recent report indicated that vascular endothelial growth factor (VEGF)-D, regulating cell proliferation and/or differentiation, may be associated with the development of placental mesenchymal dysplasia (PMD), a disorder characterized by cell proliferation/differentiation. In PMD placenta, we examined the expression of five cell-proliferation/differentiation-associated genes, namely, Wnt3a, Wnt5a, -catenin, VEGF-D and Dickkopf-1 (DKK-1). In PMD, expressions of Wnt3a, Wnt5a and -catenin were decreased, whereas those of VEGF-D and DKK-1 were increased. These abnormal expressions suggest a relationship between these genes and PMD pathogenesis/pathophysiology.

Introduction Extravillous trophoblast (EVT) cell invasion plays a crucial role in establishment of successful pregnancy. CD44, a cell-surface receptor for hyaluronic acid (HA), plays a key role in HA-mediated remodeling and degradation that triggers cancer cell invasion. However, few studies have reported on the expression or functions of CD44 in human EVT cells. We hypothesized that CD44-HA interaction was involved in invasion by EVT cells. Methods To test our hypothesis, we conducted in situ examinations of CD44 and HA expression in the human first-trimester placenta. We also assessed the methylation status of CD44 promoter and exon 1 regions in EVT cells. Finally, we conducted transwell cell invasion assays using EVT cell lines and EVT cells isolated from first-trimester human villous explant cultures. Results and discussion EVT cells, but not villous trophoblast cells, in the first-trimester placenta expressed CD44. HA was strongly expressed in adventitia surrounding the spiral uterine arterial walls of the decidua. The extent of demethylation of CD44 promoter and exon 1 CpG islands was increased in EVT cells compared to those of first-trimester chorionic villi (including villous trophoblast cells), suggesting that CD44 expression was, at least in part, associated with methylation status. Data from transwell cell invasion assay with siRNA knockdown of CD44 revealed that CD44 expression significantly promoted invasion by EVT cells in an HA-dependent manner. Conclusions The discovery of a CD44-HA interaction between EVT cells and the extracellular matrix contributes to our understanding of the mechanism underlying invasion by EVT cells. © 2014 Elsevier Ltd. All rights reserved.

Background: Japan experienced two rubella outbreaks in the past decade (2004 and 2012 - 2013), resulting in 10 and 20 infants with congenital rubella syndrome (CRS), respectively. This study was performed to determine whether the seronegative rate was lower in multiparous women than in primiparous women in Japan. Methods: Hemagglutination inhibition (HI) test results during pregnancy were analyzed retrospectively in 11048 primiparous and 9315 multiparous women who gave birth at six hospitals in northern Japan in the 5-year study period (January 2008 through December 2012). Women with HI titer < 1: 8 were defined as susceptible to rubella. Results: The seronegative rate was significantly lower in multiparous than primiparous women aged 30 - 31 years (2.3% [22/967] vs. 4.5% [66/1454], P = 0.0036), 36 - 37 years (3.4% [55/1601] vs. 5.7% [79/1389], P = 0.0030), and overall women (3.8% [350/9315] aged 34.7 +/- 5.2 vs. 5.4% [597/11048] for 33.2 +/- 5.9, P < 0.001). The susceptible fraction size did not differ largely according to hospital, ranging from 3.5% to 6.3%. Those for each year did not change markedly; 4.5% [150/3369], 5.2% [221/4268], 4.4% [195/4412], 4.6% [186/4056], and 4.6% [195/4258] for 2008, 2009, 2010, 2011, and 2012, respectively. Those for teenagers were consistently high: 22.7% [5/22], 20.7% [6/29], 20.6% [7/34], 13.0% [3/23], and 23.5% [4/17] for 2008, 2009, 2010, 2011, and 2012, respectively. Conclusions: The seronegative rate was significantly lower in multiparous than primiparous women. However, Japanese rubella vaccination programs were insufficient to eliminate CRS.

Recently, transient inferior vena cava (IVC) filters have been employed to protect against pulmonary embolism (PE) in pregnant women with deep vein thrombosis. A 34-year-old primiparous Japanese woman with a history of myomectomy was diagnosed with deep vein thrombosis by ultrasound at 27 weeks of gestation. Unfractionated heparin was administered, which soon ameliorated swelling in the right thigh. A transient IVC filter was implanted just before cesarean section. An enhanced computed tomography scan 2 days after cesarean section revealed a wide thrombus just distal to the filter. We performed catheter thrombus fragmentation with fibrinolysis just before the removal of the IVC filter, resulting in re-canalization of blood flow. No significant PE occurred. Although a transient IVC filter may work well for the prophylaxis of PE during labor and delivery, catheter fragmentation with fibrinolysis may become necessary at removal of the filter.

Dilatation and curettage (D&C) sometimes causes uterine perforation, which usually does not cause a serious problem. Here, we report uterine perforation caused by D&C, in which the small intestine prolapsed from the uterus, requiring intestinal resection. D&C was performed for missed abortion at 9 weeks. After dilating the cervix, forceps grasped tissue that, upon being pulled, resulted in the intestine being prolapsed into the vagina. Laparotomy revealed a perforation at the low anterior uterine wall, through which the ileum had prolapsed. The mesentery of the prolapsed ileum was completely detached and the ileum was necrotic, which was resected. The uterus and the intestine were reconstructed. Although intestinal prolapse is considered to be caused by "unsafe" D&C performed by inexperienced persons or even by nonphysicians in developing countries, this occurred in a tertiary center of a developed country. We must be aware that adverse events such as uterine perforation with intestinal prolapse can occur even during routine D&C.

It has not been clarified whether high mean blood pressure (HBP) of >= 90 mm Hg and bilateral notching (BN) on uterine artery Doppler additively affect the subsequent circulating levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng). Serum levels of PlGF, sFlt-1 and sEng at 17-25 weeks and 26-32 weeks were measured in all women with HBP+BN- (n=272), HBP-BN+ (n=130) and HBP+BN+ (n=60) in 1239 eligible women, and 338 consecutive women with HBP-BN- were selected from the remaining 777 women. Only data before the onset of preeclampsia were evaluated. The cutoff value of an abnormal decrease of PlGF was set at the 5th percentile, and those of an abnormal increase of sFlt-1, sFlt-1/PlGF and sEng were set at the 95th percentile. The frequency of HBP in those with BN- was almost the same as that in those with BN+ (25.9% vs. 26.7%). In women with HBP-BN-, HBP-BN+, HBP+BN- and HBP+BN+, the frequency of abnormal sFlt-1/PlGF ratio at 26-32 weeks was 6.6%, 9.2%, 14.4% and 22.8%, respectively; and the frequency of abnormal sFlt-1/PlGF ratio at 26-32 weeks in those with HBP+BN+ was significantly increased than in HBP-BN-. Similarly, in the four groups, the frequency of abnormal sEng at 26-32 weeks was 5.4%, 2.5%, 12.2% and 19.0%, respectively; and the frequency in those with HBP+BN+ was significantly increased than in HBP-BN-. In conclusion, high BP levels and abnormal uterine artery Doppler may be additively implicated in circulating abnormalities of angiogenesis-related factors.

Our aim was to evaluate the onset threshold of plasma levels of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio for predicting the imminent onset of preeclampsia (PE) within 4 weeks after blood sampling. We prospectively measured the plasma levels of sFlt-1 and PlGF by an automated electrochemiluminescence immunoassay at 19-25 weeks of gestation in 1199 women and at 26-31 weeks of gestation in 798 women. The onset threshold of the sFlt-1/PlGF ratio was determined as the 2.5th percentile of the 95th confidence interval (CI) of a regression line between the onset gestational weeks of PE and the standard deviation score of log 10 (sFlt-1/PlGF), using 25 samples taken within 1 week after the onset of PE. The imminent onset of PE was identified in 2 (0.2%) women recruited at 19-25 weeks and in 6 (0.8%) women recruited at 26-31 weeks. The onset threshold of plasma levels of the sFlt-1/PlGF ratio at 19-25 weeks showed a sensitivity (SE) of 1.00, a specificity (SP) of 1.00, a positive likelihood ratio (LR+) of ∞ and a positive predictive value (PPV) of 1.00 the onset threshold of plasma levels of the sFlt-1/PlGF ratio at 26-31 weeks showed a SE of 0.83, a SP of 0.994, a LR+ of 132 (95% CI: 51-339) and a PPV of 0.50. In conclusion, the onset threshold of plasma levels of the sFlt-1/PlGF ratio was shown to be a highly sensitive and a highly specific screening method for detecting the imminent onset of PE within 4 weeks after blood sampling at 19-31 weeks. © 2013 The Japanese Society of Hypertension All rights reserved.

Aggravated hypertriglyceridemia with a serum triglyceride of more than 1000mg/dL is a risk of acute pancreatitis during pregnancy. However, there have been few reports on the administration of an eicosapentaenoic acid (EPA) agent for aggravated hypertriglyceridemia during pregnancy. A 29-year-old multiparous Japanese woman was transferred to our hospital at 29+0 weeks of gestation due to hypertriglyceridemia of 898mg/dL. Because diet control was not enough, we decided to use an EPA agent, resulting in a reduction in triglyceride levels to 550mg/dL. A male infant, weighing 2667g, was born at 37+2 weeks transabdominally, and was complicated with respiratory distress syndrome. The final diagnosis was type III hyperlipoproteinemia with the apolipoprotein E3/2 phenotype and a broad -migrating lipoprotein on polyacrylamide gel electrophoresis of serum lipoproteins. In conclusion, an EPA agent may be a possible therapeutic approach for aggravated hypertriglyceridemia during pregnancy, although it may increase a risk of respiratory distress syndrome.

Objectives: We evaluated the biological interaction between blood pressure (BP) and uterine artery Doppler (UAD) in the second trimester for early-onset preeclampsia (EO-PE) risk. Study design: A prospective cohort study. Main outcome measures: In 2410 pregnant women, mean pulsatility index (mPI) and mean notch depth index (mNDI) were examined by UAD at 16-23 weeks' gestation. We defined EO-PE as PE with onset at <34 weeks, abnormal UAD as coexistence of mPI >= 90th percentile and mNDI >= 90th percentile, and high BP as systolic BP/diastolic BP >= 120/80 mmHg. Abnormal UAD and high BP were combined as a series of dummy variables, and were entered into a logistic regression model. The relative excess risk due to biological interaction (RERI) was calculated using the following equation: RERI = odds ratio (OR) in women with both high BP and abnormal UAD - OR in women with high BP alone - OR in women with abnormal UAD alone + 1. RERI >= 10 was considered as strong. Results: EO-PE and late-onset PE (LO-PE) occurred in 1.1% and 1.2%, respectively. Adjusted odds ratio (95% CI) in women with abnormal UAD alone, high BP alone, and both high BP and abnormal UAD for predicting EO-PE was 4.3 (0.37-49), 12 (2.6-55) and 85 (17-422), respectively; and that for predicting LO-PE was 6.3 (1.5-27), 6.1 (2.1-17) and 15 (3.6-61), respectively. The RERI for EO-PE and LO-PE was 70 and 3.3, respectively. Conclusion: High BP and abnormal UAD may have a strong biological interaction for the occurrence of EO-PE. (C) 2013 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.

Uterine artery pseudoaneurysm can occur after cesarean section or traumatic delivery, usually manifesting as postpartum hemorrhage. Pregnant women after adenomyomectomy sometimes suffer some adverse events, among which uterine rupture has been widely acknowledged. We describe a post-abortive woman who had uterine artery pseudoaneurysm occupying the entire uterine cavity. She underwent adenomyomectomy and became pregnant. She experienced a missed abortion and underwent evacuation and curettage, which caused bleeding. Several days later, ultrasound revealed an intrauterine mass with marked blood flow. Angiography revealed the un-ruptured left uterine artery pseudoaneurysm, with arterial embolization stopping the flow within the pseudoaneurysm. Adenomyomectomy with subsequent curettage was considered to have caused the pseudoaneurysm. We must be cautious that pseudoaneurysm may occur in post-abortive women after adenomyomectomy.

For cesarean hysterectomy with placenta previa accreta, "universally achievable" measures are required. We propose eight measures: (i) placement of intra-iliac arterial occlusion balloon catheters (ii) placement of ureter stents (iii) "holding the cervix" to identify the site to be transected (iv) uterine fundal incision (v) avoidance of uterotonics (vi) "M cross double ligation" for ligating the ovarian ligament (vii) "filling the bladder" to identify the bladder separation site and "opening the bladder" for placenta previa accreta with bladder invasion and (viii) to continue to clamp the medial side of the parametrium or the cervix or employment of the "double edge pick-up" to ligate it. These eight measures are simple, easy, effective, and thus "universally achievable". © 2013 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.

In 1997, B-Lynch pioneered the use of uterine compression sutures for postpartum hemorrhage. Since then, some researchers, including ourselves, have devised various uterine compression sutures. High-level evidence has not been demonstrated as to whether compression sutures achieve better and safer hemostasis for postpartum hemorrhage than other methods, and, if they do, whether one suture is more efficient and safer than another. However, generally speaking, uterine compression sutures have achieved hemostasis while preserving fertility in many women and thus their efficacy and safety have been time-tested. Each suture has both merits and drawbacks: obstetricians must be aware of the fundamental characteristics of various sutures. In this review, we summarize the technical procedures, efficacy, safety and complications of various uterine compression sutures. We add our own experiences and opinions where necessary.

This is the report of the Committee on cerebrovascular disorders, including eclampsia and emergency medical services, of the Japan Society for the Study of Hypertension in Pregnancy (JSSHP). Based on blood pressure (BP) analyses of eclamptic patients, it was concluded that BP variability was important for the onset of eclampsia. Furthermore, the Committee established guidelines for antihypertensive treatment that recommend a sliding scale of antihypertensive drug administration for hypertensive emergencies during both antepartum and postpartum periods.

Mean blood pressure (MBP), bilateral notching (BN) in the uterine artery and increased circulating levels of soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio are predictors of preeclampsia (PE). Recently, we disclosed that reducing the plasma level of hydroxysteroid (17-beta) dehydrogenase 1 (HSD17B1), which is a steroidogenetic enzyme catalyzing the conversion of estrone to 17 beta-estradiol, is a potential prognostic factor for PE. Our aim was to evaluate whether HSD17B1 is an independent risk factor for predicting PE after adjusting for the effects of MBP, BN and the plasma level of the sFlt-1/PlGF ratio in the second trimester. One hundred and twenty-eight consecutive normal pregnant women without gestational hypertension (GH) or PE and 30 women with PE were selected from 1724 pregnant women. Multivariate logistic regression with a forward stepwise procedure was used to construct a prediction model. A past history of GH/PE, a family history of hypertension, pre-pregnancy body mass index, MBP, BN, plasma levels of sFlt-1/PlGF ratio and plasma levels of HSD17B1 were significantly associated with the occurrence of PE; however, only MBP (OR (95% confidence interval), 1.08 (1.03-1.14)), BN (7.5 (1.9-30)), sFlt-1/PlGF (21 (2.7-163)) and HSD17B1 (0.43 (0.22-0.85)) were independent risk factors for PE. The area under the receiver-operating-characteristic curve for the combination model was 0.89, yielding a sensitivity of 0.84, a specificity of 0.88 and a positive likelihood ratio of 7.2 (4.0-13). In conclusion, HSD17B1 is an independent risk factor for PE, and the combination of several risk factors including HSD17B1 in the second trimester may improve the prediction of PE. Hypertension Research (2012) 35, 1152-1158; doi:10.1038/hr.2012.109; published online 12 July 2012

Aim: Our aim was to determine the reference values of indices of impedance to flow in uterine arteries at 16-23 weeks, and to evaluate the effects of these indices for predicting early-onset pre-eclampsia (EO-PE), which was defined as PE with onset at <32 weeks. Methods: During 2004 to 2008, 1536 women with a singleton pregnancy were recruited into a prospective cohort study at 16-23 weeks. The mean notch depth index (mNDI), mean pulsatility index (mPI) and mean resistance index (mRI) were calculated. Results: Early-onset pre-eclampsia occurred in 16 (1.0%). The 80th, 90th, 95th and 97.5th percentiles of the mNDI at 16-23 weeks were determined. Normal reference ranges of the mPI and mRI were constructed, and individual standard deviation scores (SDS) of the mPI and mRI were calculated. The area under the receiver-operating characteristics curves (AROC) of the mNDI, mPI, mRI and bilateral notching (BN) for predicting EO-PE were 0.807, 0.809, 0.782 and 0.798, respectively. For predicting EO-PE, a mNDI of the 90th percentile, mPI-SDS of 1.383, mRI-SDS of 0.975 and BN yielded sensitivities (specificities) of 0.688 (0.886), 0.750 (0.889), 0.813 (0.809) and 0.750 (0.845) with positive likelihood ratios and 95% confidence intervals of 6.0 (4.2-8.6), 6.8 (4.9-9.3), 4.3 (3.3-5.5) and 4.9 (3.6-6.6), respectively. Conclusions: We established the reference values for mNDI, mRI and mPI at 16-23 weeks. The positive likelihood ratios of mNDI and mPI for predicting EO-PE showed moderate screening performances, indicating mNDI or mPI in the second trimester could assist to find high risk women with the subsequent onset of EO-PE.

Our aims were to elucidate the factors that affected vancomycin (VCM) serum trough levels and to find the optimal initial dose based on creatinine clearance (CrCl) and body weight (BW) to minimize inadequate trough levels in a retrospective observational study among Japanese adults. One hundred and six inpatients, in whom VCM trough levels were measured after completing the third dosing, were consecutively recruited into our study in a tertiary hospital. We considered the frequency of < 30% as low. In the generalized linear model, initial VCM total daily dose, CrCl, and BW were independent risk factors of VCM trough levels. In patients with CrCl a parts per thousand yen30 and < 50 mL/min, 1 g/day yielded low frequencies of a trough level of a parts per thousand yen20 mcg/mL, regardless of BW. In patients with CrCl a parts per thousand yen50 mL/min, 2 g/day yielded low frequencies of a trough level of < 10 mcg/mL in patients weighing < 55 kg, but not in patients weighing a parts per thousand yen55 kg. Optimal VCM initial total daily dose may be 1 g/day in patients with CrCl a parts per thousand yen30 and < 50 mL/min regardless of BW and 2 g/day in patients weighing < 55 kg with CrCl a parts per thousand yen50 mL/min among Japanese adults.