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Background The reliable diagnosis of human T-cell leukemia virus type 1 (HTLV-1) infection is important, particularly as it can be vertically transmitted by breast feeding mothers to their infants. However, current diagnosis in Japan requires a confirmatory western blot (WB) test after screening/primary testing for HTLV-1 antibodies, but this test often gives indeterminate results. Thus, this collaborative study evaluated the reliability of diagnostic assays for HTLV-1 infection, including a WB-based one, along with line immunoassay (LIA) as an alternative to WB for confirmatory testing. Results Using peripheral blood samples from blood donors and pregnant women previously serologically screened and subjected to WB analysis, we analyzed the performances of 10 HTLV-1 antibody assay kits commercially available in Japan. No marked differences in the performances of eight of the screening kits were apparent. However, LIA determined most of the WB-indeterminate samples to be conclusively positive or negative (an 88.0% detection rate). When we also compared the sensitivity to HTLV-1 envelope gp21 with that of other antigens by LIA, the sensitivity to gp21 was the strongest. When we also compared the sensitivity to envelope gp46 by LIA with that of WB, LIA showed stronger sensitivity to gp46 than WB did. These findings indicate that LIA is an alternative confirmatory test to WB analysis without gp21. Therefore, we established a novel diagnostic test algorithm for HTLV-1 infection in Japan, including both the performance of a confirmatory test where LIA replaced WB on primary test-reactive samples and an additional decision based on a standardized nucleic acid detection step (polymerase chain reaction, PCR) on the confirmatory test-indeterminate samples. The final assessment of the clinical usefulness of this algorithm involved performing WB analysis, LIA, and/or PCR in parallel for confirmatory testing of known reactive samples serologically screened at clinical laboratories. Consequently, LIA followed by PCR (LIA/PCR), but neither WB/PCR nor PCR/LIA, was found to be the most reliable diagnostic algorithm. Conclusions Because the above results show that our novel algorithm is clinically useful, we propose that it is recommended for solving the aforementioned WB-associated reliability issues and for providing a more rapid and precise diagnosis of HTLV-1 infection.

Aims/Introduction The role of glucagon abnormality has recently been reported in type 2 diabetes; however, its role in gestational diabetes mellitus (GDM) is still unknown. The glucose intolerance in GDM is heterogeneous, and not all patients require insulin treatment during pregnancy. Here, we investigated whether glucagon abnormality is associated with the requirement for insulin treatment during pregnancy. Materials and Methods A total of 49 pregnant women diagnosed with GDM were enrolled. They underwent a 75‐g oral glucose tolerance test during mid‐gestation, and we measured their plasma glucagon levels (by a new sandwich enzyme‐linked immunosorbent assay) at fasting (0 min), and at 30, 60 and 120 min after glucose load in addition to the levels of plasma glucose and serum insulin. All participants underwent another oral glucose tolerance test at postpartum. Results Of the 49 patients, 15 required insulin treatment (Insulin group) and 34 were treated with diet therapy alone until delivery (Diet group). The early‐phase glucagon secretion after glucose load, as determined by the changes in glucagon from the baseline to 30 min, was paradoxically augmented during mid‐gestation in the Insulin group, but not in the Diet group. The impaired glucagon suppression during mid‐gestation in the Insulin group was not associated with insulin secretory/sensitivity indexes studied, and was ameliorated postpartum, although the plasma glucose levels remained higher in the Insulin group versus the Diet group. Conclusions Impaired early‐phase suppression of glucagon could be associated with the requirement for insulin treatment during pregnancy in patients with GDM., We evaluated the glucagon responses to oral glucose load in patients with gestational diabetes mellitus using a new sandwich enzyme‐linked immunosorbent assay. We investigated whether the glucagon abnormality is associated with the requirement for insulin treatment during pregnancy.

Background: Autoimmune reactions and subsequent inflammation may underlie spermatogenic dysfunction and endometriosis-related infertility.The aim of this study is to identify disease-specific antigens in immune complexes (ICs) in seminal plasma (SP) and in follicular fluid (FF). Methods: Immune complexome analysis, in which nano-liquid chromatography-tandem mass spectrometry is employed to comprehensively identify antigens incorporated into ICs in biological fluids, was performed for specimens collected from infertile couples undergoing assisted reproduction.Forty-two male patients consisting of subjects with oligozoospermia (n=6), asthenozoospermia (n=8), and normal semen analysis (n=28). Fifty-eight female patients consisting of subjects with ovarian endometriosis (n=10) and control women without disease (n=48). Results: Four disease-specific antigens were identified in subjects with oligozoospermia, while five disease-specific antigens were detected in subjects with asthenozoospermia, some of which are involved in sprematogenesis. Eight antigens were detected only in subjects with endometriosis. Conclusion: Functional characteristics of disease-specific antigens were found to correspond to the pathogenesis of male and female infertility. The formation of ICs may contribute to spermatogenic dysfunction and endometriosis-related infertility via loss of function of the related proteins. Immune complexome analysis is expected to be a valuable tool for the investigation of novel diagnostic methods and treatment strategies for infertility., Clinica Chimica Acta, 495, pp.545-551; 2019

Background Surgery for endometriomas may cause detrimental effects on ovarian reserve. In this study, we evaluated the safety of three-step laparoscopic surgery for endometriomas utilizing novel progestin, dienogest in terms of post -surgical ovarian reserve.Methods Twelve women received first look laparoscopy (FLL) with fenestration and drainage. Immediately after the surgery, they took oral dienogest 2mg for three months, then they received second look laparoscopy (SLL) with cystectomy. We compared the effects on ovarian reserve by serum AMH levels between women had three step management with dienogest and another twelve women had conventional one-step surgery without medications. In women had three-step surgery with dienogest, the changes in concentration of proinflammatory cytokines and chemokines (interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1) in peritoneal fluids were evaluated.Results Serum AMH levels were significantly decreased after three months of dienogest following FLL. AMH levels were also significantly decreased 3-6 month both after SLL and after one-step surgery, however, recovery of serum AMH levels at 9-12 months after surgery were evident in women had three-step surgery comparing to those of women had one-step surgery. Proinflammatory cytokines and chemokines in peritoneal fluids were down regulated at the time of SLL comparing to those of FLL.Conclusions Three-step surgery with dienogest may be a beneficial approach to protect ovarian reserve. Dienogest may exert its effects in part by lowering proinflammatory cytokines and chemokines.

Objective Maternal characteristics and neonatal outcomes associated with cell-free DNA (cfDNA) results were analysed retrospectively to assess the details of false-positive and false-negative results after initial blood sampling in non-invasive prenatal testing (NIPT). Study design A multicentre retrospective study was performed for women undergoing NIPT who received discordant cfDNA results between April 2013 and March 2018. The NIPT data obtained using massive parallel sequencing were studied in terms of maternal background, fetal fraction, z-scores, invasive procedure results and neonatal outcomes after birth. Results Of the 56,545 women who participated in this study, 54 false-positive (0.095 %) and three false-negative (0.006 %) cases were found. Seven of the 54 false-positive cases (13.0 %) had vanishing twin on ultrasonography. Among the 18 false-positive cases of trisomy 18, confined placental mosaicism (CPM) was confirmed in three cases (16.7 %), while CPM was present in one of the three false-negative cases of trisomy 21. Conclusion These data suggest that the incidence of women with false-positive or false-negative results is relatively low, that such false results can often be explained, and that vanishing twin and CPM are potential causes of NIPT failure. Genetic counselling with regard to false results is important for clients prior to undergoing NIPT.

Dichorionic diamniotic (DCDA) twin pregnancies after single blastocyst embryo transfer have been reported recently, although a blastocyst ovum is generally believed to divide into monochorionic twin pregnancy. We investigated the incidence of DCDA twin pregnancy after single blastocyst embryo transfer and their zygosity. This prospective cohort study included 655 consecutive twin pregnancies that were managed from 2006 to 2014 at our institution. Chorionicity and amnionicity were determined using first-trimester ultrasonography and/or placental pathology. Zygosity was analyzed if the cases were DCDA twins after single blastocyst embryo transfer. Among 655 twin pregnancies, there were 348 DCDA cases, 295 monochorionic diamniotic (MCDA) cases and 12 monochorionic monoamniotic cases. Single blastocyst embryo transfer was performed in 43 cases. Six out of the 43 (14%) cases involved DCDA twin pregnancies and the other 37 cases involved MCDA twin pregnancies. Three DCDA twins born after single blastocyst embryo transfer, wherein frozen embryo transfer (FET) was performed in the natural cycle, were dizygotic, and the other three cases, wherein FET with hormone replacement therapy was performed, were monozygotic. DCDA twin pregnancy occurred in 14% (7% for monozygotic and 7% for dizygotic) of twin pregnancies after single blastocyst embryo transfer cases.

Background Women who receive negative results from non-invasive prenatal genetic testing (NIPT) may find that they later have mixed or ambivalent feelings, for example, feelings of accepting NIPT and regretting undergoing the test. This study aimed to investigate the factors generating ambivalent feelings among women who gave birth after having received negative results from NIPT. Methods A questionnaire was sent to women who received a negative NIPT result, and a contents analysis was conducted focusing on ambivalent expressions for those 1562 women who responded the questionnaire. The qualitative data gathered from the questionnaire were analyzed using the N-Vivo software package. Results Environmental factors, genetic counseling-related factors, and increased anticipatory anxiety, affected the feeling of ambivalence among pregnant women. Furthermore, pregnant women desired more information regarding the detailed prognosis for individuals with Down syndrome and living with them and/or termination, assuming the possibility that they were positive. Conclusions Three major interrelated factors affected the feeling of ambivalence in women. Highlighting and discussing such factors during genetic counseling may resolve some of these ambivalences, thereby enhancing the quality of decisions made by pregnant women.

The ovaries of women of reproductive age may show specific histological structures that may relate to the maintenance of primordial follicles and the regulation of early follicular development, which are keys to understanding the dynamics of ovarian reserve. The pelvic environment of women is frequently exposed to physiological or pathological inflammatory stimuli. Endometriosis is a disorder that should be viewed as a chronic inflammatory disease manifested by pelvic pain and infertility. Inflammation surrounding the normal ovarian cortex may alter the histological structure which possesses primordial and early growing follicles. Fibrotic changes in histological niches in the nest of primordial follicles may provoke activation of dormant follicles and concomitant atresia. Along with decline in AMH, which is produced by early growing follicles, fibrotic changes may accelerate the demise of primordial follicles which has been described as “burn-out by inflammation”. As a result, women with endome...

AIM The aim of this study was to establish the reference values for circulating pregnancy-associated placental microRNAs in maternal plasma and clarify their clinical significance in patients with hypertensive disorder of pregnancy (HDP). METHODS Blood samples were collected from 145 women with uncomplicated pregnancies (24, 26, 31 and 32 women at 12, 23, 30 and 36 weeks of gestation, respectively, and 32 women 1 day after delivery). Plasma concentrations of pregnancy-associated placental microRNAs (miR-515-3p, miR-517a, miR-517c and miR-518b) were measured by quantitative real-time reverse-transcription polymerase chain reaction. Reference values for each microRNA were determined by the line of best fit and 95% prediction interval and are expressed as logarithmic transformation. To clarify the clinical significance of these reference values, we measured the plasma concentrations of pregnancy-associated microRNAs in a different population comprising 33 pregnant women with HDP and 44 women with uncomplicated pregnancies. RESULTS Reference values for circulating pregnancy-associated placental microRNAs on chromosome 19 miRNA clusters showed an increasing tendency as pregnancy progressed and decreased significantly 1 day after delivery (P < 0.05). The sensitivity and specificity of each reference value were 57.6% and 93.2% for miR-515-3p, 63.6% and 75.0% for miR-517a, 75.8% and 79.5% for miR-517c and 63.6% and 75.0% for miR-518b, respectively. The positive and negative predictive values of each reference value were 86.4% and 74.5% for miR-515-3p, 65.6% and 73.3% for miR-517a, 73.5% and 81.4% for miR-517c and 65.6% and 73.3% for miR-518b, respectively. CONCLUSION Establishing the reference values for circulating pregnancy-associated placental microRNAs in maternal plasma could be useful for the evaluation of HDP.

AIM The study identifies the relevant obstetric factors associated with fetal heart rate (FHR) monitoring for cerebral palsy (CP) in pregnant women with hypertensive disorders of pregnancy (HDP). METHODS The subjects were neonates with CP (birth weight ≥ 2000 g, gestational age ≥ 33 weeks) who were approved for compensation for CP by the Operating Organization of the Japan Obstetric Compensation System between 2009 and 2012. After selection of women with antepartum HDP, obstetric characteristics associated with FHR monitoring were analyzed. RESULTS The subjects included 33 neonates with CP whose mothers suffered from HDP during pregnancy and 450 neonates whose mothers did not develop HDP. The rates of placental abruption (48.5% vs. 20%; P < 0.001) and light-for-gestational age (12.1% vs. 2.2%; P = 0.011) were significantly higher in women with HDP than in those without HDP. Regarding FHR pattern analysis, fetal bradycardia was observed on admission to hospital in 94% of women with placental abruption. In women without placental abruption, FHR was likely to indicate a favorable pattern on admission, but became worse with the progression of labor. CONCLUSION This is first study to clinically demonstrate FHR patterns in CP cases in association with HDP. Although antepartum CP is undetectable, pregnant women with HDP should be placed under strict observation and management to minimize fetal hypoxic conditions during labor.

Endometrioma is one of the main pathologies of endometriosis, though its pathogenesis still remains enigmatic. Ovarian reserve is defined as the number and quality of the follicles left in the ovary at any given time. The cause of infertility in women with endometriosis is multifactorial. Diminished ovarian reserve is major concern in women with endometriosis-associated infertility. Cystectomy for endometriomas could negatively impact on post-operative ovarian reserve. Some women had surgery for endometriomas suffer from poor ovarian response, which directly affects treatment results. In addition, endometriomas themselves may be a cause of diminished ovarian reserve. Destruction of normal histological structure in ovarian cortex may affect dormancy of primordial follicles. Therefore, determination of ovarian reserve may serve as an important role in the management of reproductive health of women with endometriosis. Although the knowledge on the physiology of follicular development and mechanism of maintenance of ovarian reserve are rapidly accumulating, results obtained by ovarian reserve testing after surgery should be carefully evaluated according to the time-points and selected test. Further investigation on this issue is warranted.

Aim The purpose of this study was to report the 3-year experience of a nationwide demonstration project to introduce non-invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan. Methods Tests were conducted to detect aneuploidy in high-risk pregnant women, and adequate genetic counseling was provided. The clinical data, test results, and pregnancy outcomes were recorded. We discuss the problems of NIPT on the basis of published reports and meta-analyses. Results From April 2013 to March 2016, 30 613 tests were conducted at 55 medical sites participating in a multicenter clinical study. Among the 30 613 women tested, 554 were positive (1.81%) and 30 021 were negative (98.1%) for aneuploidy. Of the 289, 128, and 44 women who tested positive for trisomies 21, 18, and 13, respectively, and underwent definitive testing, 279 (96.5%), 106 (82.8%), and 28 (63.6%) were determined to have a true-positive result. For the 13 481 women with negative result and whose progress could be traced, two had a false-negative result (0.02%). The tests were performed on the condition that a standard level of genetic counseling be provided at hospitals. Conclusion Here, we report on the 3-year nationwide experience with NIPT in Japan. It is important to establish a genetic counseling system to enable women to make informed decisions regarding prenatal testing. Moreover, a welfare system is warranted to support women who decide to give birth to and raise children with chromosomal diseases.

Introduction Round ligament varicosities (RLV) are not well-known and they are usually caused by pregnancy. Although the groin swelling of RLV mimics an inguinal hernia, it is difficult to distinguish between them through clinical examination alone, and there have been few published reports on this topic, especially from Asia. Case presentation A 37-year-old Japanese woman complained of left groin swelling for 2 weeks at her 28th week of gestation of her first pregnancy. According to a physical examination, she had a soft, painless swelling in the superficial inguinal ring of the left groin. An inguinal hernia was suspected and she was thus scheduled to undergo herniorrhaphy. However, since she had varicosities in the left labia majora, she first underwent color Doppler ultrasonography and a final diagnosis of round ligament varicosities was this made. Her symptoms resolved after delivery of her baby. Discussion We herein report 10 cases of RLV in pregnant Japanese women who were initially suspected of having an inguinal hernia. All of them were suspected to suffer from inguinal hernias after a clinical examination by their attending gynecologist. All of them were diagnosed using gray scale and color Doppler ultrasonography, treated with conservative management, and the symptoms resolved in all cases after the delivery. Conclusion This is the largest report from Asia regarding RLV. To avoid unnecessary surgery in pregnant women, surgeons must be aware of this entity make an accurate diagnosis based of the findings of Doppler ultrasonography., International Journal of Surgery Case Reports, 36, pp.122-125; 2017

Huge uterine fibroid arising from primary uterine cervical diverticulum: a case report and review of the literatures

Aim To determine whether three-dimensional saline infusion sonohysterography (3D-SISH) is useful for the detection of endometrial polyps and whether it can accurately identify the site of attachment within the uterine cavity. Methods Sixteen women who underwent preoperative magnetic resonance imaging (MRI), 3D-SISH and subsequent hysteroscopic resection or total hysterectomy and who were surgically diagnosed with endometrial polyps were enrolled. The rate of polyp detection and the accuracy of attachment site within the uterine cavity for each test were examined. Results Endometrial polyps could only be identified in 37.5% of women using MRI, but could be identified in all women using 3D-SISH. The accuracy rate of the attachment site of endometrial polyps was 87.5% on 3D-SISH and 18.8% (in all patients) or 50.0% (in polyp-detected patients) on MRI, indicating a higher accuracy rate using 3D-SISH. Conclusion We demonstrated that 3D-SISH is useful for the detection and localization of endometrial polyps and is likely to become the examination method of first choice for the identification of endometrial polyps.

Increased intrauterine microbial colonization by bacteria culture method and occurrence of endometritis have been reported in women with endometriosis. Here we investigated microbial colonization in intrauterine environment and cystic fluid of women with and without endometriosis by molecular approach.This is a case-controlled biological study with a total of 32 women each with and without endometriosis. Among them, 16 each in these two groups of women received treatment with gonadotropin-releasing hormone agonist (GnRHa). Pattern of microbial colonization in endometrial swabs and endometrioma/non-endometrioma cystic fluid was examined using broad-range polymerase-chain reaction (PCR) amplification of bacteria targeting 16S rRNA gene (rDNA). After quantification of index PCR product, 16S rDNA metagenome sequence analysis was done by Illumina Miseq system.A wide proportion (0.01-97.8%) of multiple bacteria was detected in both endometrial swabs and cystic fluid collected from women with and without endometriosis. 16S metagenome assay indicated that proportion of Lactobacillacae was significantly decreased (p0.01) and of Streptococcaceae, Staphylococaceae, Enterobacteriaceae was significantly increased (p0.05 for each) in GnRHa-treated women with endometriosis than in GnRHa-untreated women. While bacteria culture method failed to detect a single colony, 16S metagenome assay could detect significantly higher percentage of Streptococcaceae (p0.01) and Staphylococaceae (p0.05) in the cystic fluid derived from women with ovarian endometrioma comparing to that in cystic fluid collected from non-endometrioma cysts.These findings indicate the occurrence of sub-clinical infection in intrauterine environment and in the cystic fluid of ovarian endometrioma. Additional side effect of GnRHa treatment in promoting silent intrauterine and/or ovarian infection should be considered.

Aim In order to investigate the current status of prenatal testing for genetic disorders, we conducted a multicenter retrospective questionnaire survey. Methods The questionnaire was sent to 105 facilities with genetic counseling systems. The questionnaire consisted of two parts: (i) the number of prenatal tests conducted for genetic disorders from January 2010 to December 2012, whether the laboratory was combined with the counseling facility or separate, the sampling procedure method, the testing results, and the outcomes of the affected fetus in addition to treatment; and (ii) a survey of personal comments regarding prenatal testing for genetic disorders. Results We received responses from 69 of the 105 facilities (65.7%), and genetic testing was performed at 26 of these facilities. Nucleic acid sequential testing was performed on 45 disorders and 252 cases during a three-year period. There were 67 cases of affected fetuses. Six cases continued pregnancy and were treated. The comment survey highlighted difficulties in locating a laboratory to assess prenatal samples, as well as inadequate counseling and preparation for genetic disorders. Conclusions Our study revealed that a number of prenatal testing for genetic disorders are conducted in Japan; however, it is difficult for counselors to locate a laboratory capable of testing for specific genetic disorders. Inadequate counseling and healthcare providers' lack of knowledge is a current problem. A well-established system of prenatal testing for genetic disorders and the further education of general physicians is required.

The human lower genital tract is constantly exposed to various microorganisms, which can infect the upper genital tract through ascending migration. We report on tests of the hypothesis that as normal microbial flora in the vagina, some gram-negative bacteria infect the uterine wall after ascending migration from the vagina, to contaminate menstrual blood, consequently resulting in accumulation of endotoxin in the menstrual/peritoneal fluid and initiation of pelvic inflammation. The aim of the present review is to assess possible intrauterine microbial colonization and to examine the stimulatory effect of E. coli-derived lipopolysaccharide (LPS) on the secretion of various macromolecules by macrophages (Mϕ) known to be involved in endometriosis. We also assess the growth-promoting effect of LPS on endometrial cells and the role of Toll-like receptor 4 (TLR4), a receptor recognizing LPS, in the secretion of macromolecules by Mϕ and growth of endometrial cells. We found higher intrauterine microbial colonization in women with endometriosis than in controls. The ligand from gram-negative bacteria is involved in TLR4-mediated proinflammation in the pelvis as well as growth of endometriosis. Treatment with gonadotropin-releasing hormone agonist (GnRHa) further promotes intrauterine microbial colonization compared with GnRHa-untreated women. Conclusions We propose the bacterial contamination hypothesis as a new concept in endometriosis. Based on our current findings, an estrogen-suppressing agent and an antimicrobial agent may have new therapeutic potential in women with endometriosis.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia-lymphoma (ATL), which is difficult to cure. In Japan, a nationwide HTLV-1 screening test in pregnant women has been recommended since 2011. A 30-year-old woman was diagnosed as being an HTLV-1 carrier in her previous pregnancy. During the current pregnancy, she had persistent fever and cough. Although she had treatment with antibiotics, peripheral white blood cell count remained high, with an abnormal lymphocyte count. Given that she was an HTLV-1 carrier, she was diagnosed with unfavorable chronic ATL (aggressive ATL) at 12 weeks gestation. After pregnancy termination, her ATL status became favorable chronic ATL (indolent ATL). Therefore, watchful waiting was performed until disease progression. This is the first case report of chronic ATL in early pregnancy, in a woman already diagnosed as an HTLV-1 carrier on screening test.

The aim of this study was to clarify the association between placenta previa and circulating levels of cell-free pregnancy-associated placenta-specific microRNAs (miRNAs) in maternal plasma. Twenty singleton pregnancies with placenta previa (placenta previa group) and 26 uncomplicated pregnancies (control group) were recruited. Blood sampling was performed at 32 weeks of gestation, and cesarean delivery in all cases of placenta previa was performed at a mean gestational age of 37 weeks. The maternal plasma concentrations of cell-free pregnancy-associated placenta-specific miRNAs (miR-517a and miR-518b) were measured by absolute quantitative real-time reverse transcription-polymerase chain reaction. Plasma concentrations of cell-free miR-517a were significantly higher in the placenta previa group than that in the control group (P = .011), while the plasma concentration of cell-free miR-518b was significantly lower in the placenta previa group than that in the control group (P = .004). Plasma concentrations of cell-free miR-517a in placenta previa were significantly higher in placenta previa with alert bleeding later group than those in placenta previa without alert bleeding group or control group (P = .030 or .047, respectively) and correlated with the volume of hemorrhage at delivery (R and P value: .512 and .025). Plasma concentrations of cell-free miR-517a and miR-518b at 32 weeks of gestation were altered in pregnant women with placenta previa, and the circulating level of cell-free miR-517a in placenta previa may be a predictive marker for the risks of alert bleeding later and massive hemorrhage at delivery.

Background: As its name indicates, anti-Mullerian hormone (AMH) is primarily found as an inhibitor of the Mullerian duct in male fetus. On the other hand, AMH may act as a mediator of Mullerian duct-derived female tissue, such as endometrium in normal and pathological conditions. However, the role of AMH in the functional regulations of endometriosis is not well understood. It can be hypothesized that AMH in peritoneal fluids may affect the activity of peritoneal endometriosis. In this study, we investigated the levels of AMH in peritoneal fluids (PF) in women with and without endometriosis. Methods: PF were collected during laparoscopy from 90 women diagnosed as having advanced endometriosis (rASRM stage III, n = 30; stage IV, n = 60), and 32 women without endometriosis were served as control. Paired serum samples were also collected before the surgery. AMH in PF and serum were measured by ELISA. Individual clinical information was collected. AMH levels were compared according to the presence of endometriosis. The expression of AMHR2 in peritoneal endometriotic lesions obtained during laparoscopy was examined by immunohistochemistry. Results: AMH levels in PF were positively and significantly correlated with serum AMH levels in both women with and without endometriosis (R2 = 0.17, P < 0.0001; R2 = 0.30, P = 0.001, respectively). Serum AMH levels were inversely and significantly correlated with age in women with endometriosis (R2 = 0.092, P = 0.004) and in control women without statistical significance (R2 = 0.078, P = 0.12). AMH levels in PF were also inversely but not significantly correlated with age in women with and without endometriosis (R2 = 0.029, P = 0.11 and R2 = 0.027, P = 0.37, respectively). Mean age and serum AMH levels were not significantly different between two groups. On the other hand, AMH levels in PF were significantly lower in women with endometriosis compared to those of control women [2.15 ± 2.13 (mean ± SD) vs. 4.40 ± 4.77 ng/mL, P = 0.0001]. AMHR2 are localized at glandular epithelium and stromal cells in the ectopic endometrium of peritoneal endometriosis. Conclusions: Women with endometriosis may present lower PF AMH levels even if they retain serum levels similar to women without disease. As peritoneal endometriosis expresses a specific receptor for AMH, lower AMH levels in PF of women with advanced endometriosis may be involved in the pathophysiology of peritoneal endometriosis., Frontiers in Surgery, 7, art.no.600202; 2020

Objective This study estimated the effects of weekend and off-hour childbirth and the size of perinatal medical care center on the incidence of cerebral palsy. Methods The cases were all children with severe cerebral palsy born in Japan from 2009 to 2012 whose data were stored at the Japan Obstetric Compensation System for Cerebral Palsy database, a nationally representative database. The inclusion criteria were the following: neonates born between January 2009 and December 2012 who had a birth weight of at least 2000 g and gestational age of at least 33 weeks and who had severe disability resulting from cerebral palsy independent of congenital causes or factors during the neonatal period or thereafter. Study participants were restricted to singletons and controls without report of death, scheduled cesarean section, or ambulance transportation. The controls were newborns, randomly selected by year and type of delivery (normal spontaneous delivery without cesarean section and emergency cesarean section) using a 1:10 case to control ratio sampled from the nationwide Japan Society of Obstetrics and Gynecology database. Results A total of 90 cerebral palsy cases and 900 controls having normal spontaneous delivery without cesarean section were selected, as were 92 cerebral palsy cases and 920 controls with emergent cesarean section. A significantly higher risk for cerebral palsy was found among cases that underwent emergent cesarean section on weekends (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.06–2.81) and during the night shift (OR 2.29, 95% CI 1.30–4.02). No significant risk was found among normal spontaneous deliveries on weekends (OR 1.63, 95% CI 0.97–2.73) or during the quasi-night shift (OR 1.26, 95% CI 0.70–2.27). Regional perinatal care centers showed significantly higher risk for cerebral palsy in both emergent cesarean section (OR 2.35, 95% CI 1.47–3.77) and normal spontaneous delivery (OR 2.92, 95% CI 1.76–4.84). Conclusion Labor on weekends, during the night shift, and at regional perinatal medical care centers was associated with significantly elevated risk for cerebral palsy in emergency cesarean section.

As p53-binding protein 1 (53BP1) localizes to the sites of DNA double-strand breaks and rapidly forms nuclear foci (NF), and its presence may be an indicator of endogenous genomic instability (GIN). We previously showed that 53BP1 NF in cervical cells increase with neoplastic progression, indicating the significance of 53BP1 expression for the estimation of malignant potential during cervical carcinogenesis. This study aimed to further elucidate the impact of 53BP1 expression as a biomarker for cervical squamous intraepithelial lesion (SIL). A total of 81 tissue samples, including 17 of normal cervical epithelium, 22 of cervical intraepithelial neoplasia (CIN) 1, 21 of CIN2, and 21 of CIN3, from patients positive for high-risk human papillomavirus (HR-HPV)were used for double-label immunofluorescence of 53BP1 and Ki-67/p16INK4a expression and HR-HPV in situ hybridization. We analyzed associations between 53BP1 expression type with parameters such as CIN grade, HR-HPV infection status, p16INK4a expression, and CIN prognosis. Expression type of 53BP1 was significantly associated with histological grade of CIN and HR-HPV in situ hybridization signal pattern (P < .0001). There was a significant correlation between 53BP1 and p16INK4a expression levels (r ? .73, P < .0001). However, there was no association between 53BP1 expression type and CIN prognosis. We propose that 53BP1 expression type is a valuable biomarker for SIL, which can help estimate the grade and GIN of cervical lesions reflecting replication stress caused by the integration of HR-HPV to the host genome., Cancer control, 27, 1073274819901170; 2020

OBJECTIVE To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (

Systemic lupus erythematosus (SLE) involves multiple organ systems and primarily affects women during their reproductive years. Pregnancy in a woman with SLE may lead to higher rates of disease flares. Little is known regarding which medications are safe to maintain remission and/or treat flares throughout such pregnancies. Here we retrospectively analyzed the efficacy of tacrolimus (TAC) in the pregnancy outcomes of SLE patients. We studied the 54 deliveries of 40 SLE patients over an eight-year period from 2008 to 2016. We used analyses of covariance with adjustments for the propensity score and inverse probability of treatment weights to compare the patient backgrounds between the TAC users and non-TAC users. TAC was administered to the patient in 15 of the 54 (27.8%) pregnancies, and these patients had a significantly higher dose of prednisolone, hypocomplementemia, lower estimated glomerular filtration rate, past history of lupus nephritis, and complication with antiphospholipid syndrome. In the adjusted background of the TAC deliveries, the risks of decreased fetal body weight, low birth weight infant, non-reassuring fetal status (NRFS), and preterm birth were not increased compared to the non-TAC deliveries. Thrombocytopenia and hypertension during the pregnancy were extracted as independent predictive risk factors for decreased fetal body weight and NRFS, respectively. We had anticipated that the maternal and fetal outcomes in the TAC-use deliveries would be poor before the analysis; however, the TAC-use group showed no significant difference in risks contributing to outcomes compared to the non-TAC group, suggesting that adjunct TAC treatment corrected various risk factors during the lupus pregnancies.

Scientific Reports 7: Article number: 46220; published online: 12 April 2017; updated: 22 December 2017. The original version of this Article contained an error in Affiliation 1 which was incorrectly listed as ‘Department of Obstetrics and Gynaecology, Nagasaki University Graduate School of Medicine, Nagasaki, Japan’.

Aim To clarify the association between circulating chromosome 19 miRNA cluster (C19MC) microRNAs in maternal plasma and severe pre-eclampsia. Method Maternal blood samples (7 mL) at 27–34 weeks of gestation were obtained from 20 pregnant women with severe pre-eclampsia (sPE group) and from 20 uncomplicated pregnant women (NP group). Twenty cases of severe pre-eclampsia were classified into late onset (sPELO group; n = 14) and early onset (sPEEO group; n = 6). Plasma concentration of C19MC microRNAs (miR-518b, -1323, -516b, -516a-5p, -525-5p, -515-5p, -520 h, -520a-5p, -519d and -526b) was measured on quantitative real-time reverse transcription–polymerase chain reaction. Results The circulating levels of all 10 C19MC microRNAs in maternal plasma were significantly increased in the sPE group compared with the NP group. Plasma concentration of all 10 C19MC microRNAs tested was significantly increased in the sPEEO group compared with the NP group, while plasma concentration of nine miRNAs, except for miR-519d, was significantly increased in the sPELO group compared with the NP group. Of the 10 C19MC microRNAs measured, plasma concentration of eight miRNAs, except for miR-518b and miR-519d, was significantly increased in the sPEEO group compared with the sPELO group. Conclusions Increased levels of C19MC microRNAs in maternal plasma are a characteristic phenomenon of established severe pre-eclampsia, and it has been shown for the first time that the upregulation of C19MC miRNAs occurred as a consequence of, not in advance of, the onset of pre-eclampsia.

Aim The aim of this study was to provide basic documents applicable to studying the usefulness of administering fibrinogen concentrate to patients with massive post-partum hemorrhage. We investigated the usage of fibrinogen concentrate at training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology. Material and Methods The subjects were women who required fibrinogen concentrate for hemostasis of post-partum hemorrhage during the period between April 2008 and March 2013. The underlying diseases, obstetric disseminated intravascular coagulation scores, blood loss, amount of blood transfusion, dose of fibrinogen concentrate administered, and plasma fibrinogen levels before and after the administration of fibrinogen concentrate were retrospectively investigated. Results Ninety-nine (98.0%) patients survived and two died after taking fibrinogen concentrate. Of the surviving 99 cases, the average amount of blood loss at the time of initial fibrinogen administration and total blood loss was 3559 ± 2103 mL and 4562 ± 3198 mL, respectively. The dose per administration was 3 g, and the plasma fibrinogen level before the initial administration of fibrinogen concentrate was 70.5 mg/dL, thereafter increasing to 187.0 mg/dL. The increase in the fibrinogen level was 32.9 mg/dL/g of fibrinogen concentrate. It was less than 150 mg/dL after the first administration of fibrinogen concentrate only in patients with amniotic fluid embolism and patients with atonic bleeding showed the smallest increase in fibrinogen per gram of fibrinogen concentrate. No adverse events, including thromboembolism, were reported. Conclusion The results indicated the increase in blood fibrinogen levels to, on occasion, be insufficient even with fibrinogen concentrate use; however, this survey may support the safety and usefulness of fibrinogen concentrate for PPH.

Aim To investigate the utility of recombinant activated Factor VII (rFVIIa) for severe post-partum hemorrhage (PPH) in Japan. Methods We studied 69 patients treated with rFVIIa for severe PPH; 44 patients were from the registry of Japan Society of Obstetrical, Gynecological and Neonatal Hematology, and 25 were identified by a survey of the Japan Society of Obstetrics and Gynecology. Results Overall, the mean and median blood loss were 11 835 mL and 8639 mL, respectively. Treatment before rFVIIa included transarterial embolization in 23 patients and hysterectomy in 38. Forty-two patients had a single dose, 17 had two doses, and four had three doses. The mean (± SD) single dose was 81.60 ± 16.25 µg/kg. Sixty-five patients survived, and four died. The cause of PPH in patients who died was uterine rupture plus amniotic fluid embolism in two patients, uterine cervical laceration in one, and placental abruption in one. The amount of blood loss in cases of death was 6428–43 810 mL. This suggested that whether a patient survives or not was more dependent on her general condition before and after rFVIIa treatment than on the amount of blood loss. Four patients had thromboembolic events after rFVIIa treatment (deep vein thrombosis; deep vein thrombosis plus pulmonary embolism; acute myocardial infarction; and pulmonary embolism); all of these patients recovered. Conclusion The present promising results may support the utility of rFVIIa for severe PPH in Japan.

Endometriosis is a multifactorial disease mostly affecting women of reproductive age. An additive effect between inflammation and stress reaction on the growth of endometriosis has been demonstrated. Here we investigated the combined effect between 17β-estradiol (E2) and lipopolysaccharide (LPS) on pelvic inflammation and growth of endometriotic cells. Peritoneal fluid was collected from 46 women with endometriosis and 30 control women during laparoscopy. Peritoneal macrophages (Mφ) and stromal cells from eutopic/ectopic endometrial stromal cells (ESCs) were isolated from 10 women each with and without endometriosis in primary culture. Changes in cytokine secretion (interleukin 6 [IL-6] and tumor necrosis factor α [TNF-α]) by Mφ and proliferation of ESCs in response to single and combined treatment with E2 and LPS were measured by enzyme-linked immunosorbent assay and by bromodeoxyuridine incorporation assay, respectively. A significantly increased secretion of IL-6 and TNF-α in Mφ culture media was found in response to E2 (10(-8) mol/L) compared to nontreated Mφ. This effect of E2 was abrogated after pretreatment of cells with ICI 182720 (10(-6) mol/L; an estrogen receptor [ER] antagonist). Combined treatment with E2 and LPS (10 ng/mL) additively promoted IL-6 and TNF-α secretion by peritoneal Mφ and growth of eutopic/ectopic ESCs. The additive effects of E2 + LPS on cytokine secretion and growth of ESCs were effectively suppressed after combined blocking of ER and Toll-like receptor 4. An additive effect was observed between E2 and LPS on promoting proinflammatory response in pelvis and growth of endometriosis.

Objective A prominent stress reaction in the pelvis of women with endometriosis and the role of human heat shock protein 70 (HSP70) in inflammation and the growth of endometriosis has been recently demonstrated. We report here expression of HSP70 in tissues derived from GnRH agonist (GnRHa)-untreated and -treated women with adenomyosis and uterine myoma. Study design This is a case-controlled biological study. Biopsy specimens were collected from pathological lesions and eutopic endometria/autologous myometria of 30 women with adenomyosis, 35 women with uterine myoma and 15 control women during laparoscopy, laparotomy and hysteroscopy. Fourteen women with adenomyosis and 20 women with uterine myoma were treated with GnRHa for a variable period of 3?6 months before surgery. The immunoexpressions of HSP70 and CD68-positive M? in endometria, lesions/myometria were examined by immunohistochemistry. The immunoreactivity of HSP70 in tissues was analyzed by quantitative-histogram (Q-H) scores. Results Comparing to control women, HSP70 immunoexpression was significantly higher in endometria/myometria and pathological lesions of women with adenomyosis and myoma. A significant positive correlation between Q-H scores of HSP70 and CD68-positive M? numbers was found in the endometria derived from women with adenomyosis (r = 0.388). Treatment with GnRHa significantly decreased Q-H scores of HSP70 in pathological lesions and endometria/myometria of women with adenomyosis and uterine myoma comparing to similar tissues derived from GnRHa-untreated women. Conclusion A variable amount of tissue stress reaction occurred in endometria and pathological lesions of women adenomyosis and uterine myoma that can be effectively suppressed after GnRHa treatment., European Journal of Obstetrics & Gynecology and Reproductive Biology, 187, pp.6-13; 2015

Objective The purpose of this study is to compare the fetal fractions during non-invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP). Study design This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed. Results A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP. Conclusion A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult.

The measurement of human T-cell leukemia virus type 1 (HTLV-1) proviral DNA levels by using polymerase chain reaction has been beneficial for confirming HTLV-1 infection during pregnancy. However, the influence of pregnancy on HTLV-1 infection and proviral DNA levels among pregnant women with HTLV-1 has not been clarified. We prospectively gathered blood samples from 36 pregnant women in whom HTLV-1 carriage was previously diagnosed and sequentially measured their proviral DNA levels. The HTLV-1 proviral DNA levels remained at a plateau during pregnancy but were elevated after delivery. Moreover, flow cytometry and serological analyses revealed that the regulatory T-cell population and soluble interleukin 2 receptor levels were similarly elevated after birth in comparison with those in control pregnant women. This study is the first to provide data on sequential changes in HTLV-1 proviral DNA levels during and after pregnancy. These findings will guide the establishment of a better program to prevent mother-to-child transmission of HTLV-1.

Ovarian cancer is the second leading cause of female-specific cancer death in women over the age of 65 years, and almost half of newly diagnosed cases are in this age group. Many elderly people live with disability and various comorbidities and are vulnerable to stressors. Primary cytoreductive surgery followed by adjuvant chemotherapy is the conventional treatment strategy for advanced ovarian cancer. The increased likelihood of physical comorbidities in elderly patients is thought to be associated with a higher risk of postoperative morbidities and severe side effects from cytotoxic agents. Therefore, elderly patients might be undertreated and miss the opportunity to receive the conventional treatment because of concern about its risks on the part of clinicians. However, guidelines specific for the treatment of elderly patients with ovarian cancer have not been adequately developed. Although treatment strategies for these patients need to be based on relatively limited evidence, appropriate criteria for decision-making regarding treatment have been studied. Appropriate assessments of geriatric patients with cancer to predict the risks of treatment have also been proposed. In this chapter, we outline the current evidence for surgery, chemotherapy, the newer anticancer agents, and comprehensive geriatric assessment to assist gynecologists treating elderly patients with ovarian cancer.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic human retrovirus of adult T-cell leukemia/lymphoma (ATL). The estimated risk for an HTLV-1 carrier to develop ATL is approximately 5%. However, to date, medical treatments for ATL are not effective, and therefore the prognosis for this disease is poor. The vertical transmission of HTLV-1 occurs predominantly through breastfeeding. Therefore, for the prevention of mother-to-child transmission, bottle-feeding is the most effective method to prevent the endemic cycle of HTLV-1. When vertical transmission of HTLV-1 is prevented, the incidence of ATL is significantly reduced in the next generation. In Nagasaki prefecture, which is one of the endemic areas for HTLV-1 in Japan, prefecture-wide screening of pregnant women and advice to refrain from breastfeeding by carrier mothers have been implemented since 1987. HTLV-1-positive women are provided with counseling about methods of feeding, i.e., bottle-feeding, short-term breastfeeding, and freeze-thawing of breast milk, to reduce the risk of HTLV-1 mother-to-child transmission. A recent study of HTLV-1 carriers in Japan showed that the estimated number of HTLV-1 carriers in 2007 was one million and that HTLV-1 carriers have spread to other geographical areas in Japan (prevalence has decreased in endemic areas but increased in metropolitan areas). Therefore, in Japan, since 2011, the nationwide screening of pregnant women for HTLV-1 infection has been recommended to prevent breast milk-borne transmission of HTLV-1. In this chapter, critical points regarding the prevention program for mother-to-child transmission of HTLV-1 are discussed.

Endometriosis is a multifactorial disease mostly affecting women of reproductive age and is associated with chronic pelvic pain and infertility. Even after 300 years, most of the literature claims that pathogenesis and/or pathophysiology of endometriosis is still elusive. Recurrence of pain and lesion continues to occur after effective medical or surgical therapies. Once generated within the pelvis due to retrograde entry of menstrual debris, peritoneal endometriotic lesions time-dependently change their color appearance resulting from certain biochemical change within lesions. A variable pattern of endometriotic lesions within the pelvis can be detected by laparoscopy as visible peritoneal endometriosis. It is generally believed that besides ovarian steroid hormones, the growth of endometriosis can be regulated by the innate immune system in the pelvic microenvironment by their interaction with endometrial cells and immune cells. Even with the careful eyes of an expert surgeon, we may sometimes miss detecting peritoneal lesion within the peritoneal cavity or deep into the peritoneum. In such a case, random collection of normal peritoneum may carry the possibility to identify some hidden endometriotic lesions by microscopy and these lesions can be named as occult (invisible) microscopic endometriosis (OME). Here, we discuss the color appearance of peritoneal lesions and activity of these lesions by analysis of a panel of activity markers. Finally we discuss our recent findings on OME, their biological and clinical significance, and try to make a possible link in the origin between visible endometriosis and OME.

The original publication is available at www.springerlink.com, This questionnaire survey was conducted at 11 hospitals in Japan to determine vaccination coverage against seasonal influenza and the prevalence rate of influenza among pregnant Japanese women. Of 2,808 postpartum women who gave birth at the 11 hospitals during the study period from March 1, 2014, to July 31, 2014, 1,713 (61 %) participated in this study and 876 (51 %) reported having received vaccination against influenza in or after October 2013. Women aged < 25 years had a significantly lower vaccination rate than those aged a parts per thousand yen25 years (31 % vs. 53 %, respectively; p = 0.0000). Eighty-seven (5.1 %) and 1,626 (94.9 %) women did and did not contract influenza, respectively. Although prior birth did not affect overall vaccination coverage (50 % for primiparous vs. 53 % for multiparous), multiparous women had a significantly higher rate of contracting influenza than primiparous women, irrespective of vaccination status (5.6 % vs. 2.2 % [p = 0.0216] and 9.7 % vs. 3.5 % [p = 0.0003] for women with and without vaccination, respectively). The 2013-2014 vaccination program significantly reduced the influenza infection rate by 35 % (3.9 % vs. 6.3 % for women with and without vaccination, respectively; p = 0.0272). Seventy-two (83 %) of the 87 women took antiviral agents for the treatment of influenza and two (2.3 %) required hospitalization. These results suggested that pregnant Japanese women had a high level of concern regarding seasonal influenza. However, campaigns targeting young pregnant Japanese women, as well as multiparous women, for vaccination are needed in order to further reduce the incidence of influenza among pregnant Japanese women.

Objective This study aimed to investigate the effect of labor on plasma concentrations of cell-free, pregnancy-associated, placenta-specific microRNAs (miRNAs) before and after delivery. Method In the non-labor group (32 women), cesarean section (C/S) was performed before the beginning of labor. In the labor group (32 women), C/S was performed after the beginning of labor. Plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs (miR-515-3p, miR-517a, miR-517c, and miR-518b) were measured by real-time quantitative PCR. Each miRNA concentration was compared between the non-labor and labor groups. Results Before C/S, plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs in the labor group were significantly higher than those in the non-labor group (P = 0.001 for 515-3p, P = 0.002 for 517a, P = 0.001 for 517c, and P = 0.003 for 518b). Twenty-four hours after delivery, plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs in the labor group were significantly higher than those in the non-labor group (P = 0.002 for 515-3p, P = 0.017 for 517a, P = 0.043 for 517c, and P = 0.009 for 518b). Conclusion The presence of labor affects cell-free, pregnancy-associated, placenta-specific miRNA levels in maternal plasma. Labor also affects postpartum clearance of these miRNAs 24 h after delivery. © 2014 John Wiley & Sons, Ltd.

One of the important factors influencing the development of uterine cervical cancer is human papillomavirus infection in women. Usually, the infecting papillomavirus is eliminated from individuals; however, some retain the virus and this is believed to lead to the development of uterine cervical cancer. It is possible that virus elimination or persistent infection depends on an individual's genetic background. To identify single nucleotide polymorphisms associated with susceptibility to persistent infection or cervical cancer, a genome-wide association study was performed on 226 cases and 186 controls. Some of the single nucleotide polymorphisms showed a P-value

Objective This study aimed to identify a set of endometrioid endometrial carcinoma EEC-associated microRNAs (miRNAs) in tissue and plasma, and evaluate their clinical significance. Methods A set of EEC-associated miRNAs in tissue and plasma was identified by next-generation sequencing (NGS), which could enable in-depth characterization of the global repertoire of miRNAs. Results NGS identified 11 candidate EEC-associated miRNAs. Quantitative reverse-transcriptase PCR identified 8 EEC-associated miRNAs in tissue (upregulated: miR-499, miR-135b, miR-205, downregulated: miR-10b, miR-195, miR-30a-5p, miR-30a-3p and miR-21). Expression of hsa-miR-499 in International Federation of Gynecology and Obstetrics (FIGO) Stage IA and Grade 1 tissues was significantly lower than in others (FIGO Stage IB or more advanced, and Grade 2 or 3). By receiver operating characteristic (ROC) curve analysis, compared with single EEC-associated miRNA, two miRNA signatures (miR135b/miR195 and miR135b/miR30a-3p) could distinguish between EEC and normal endometrial tissue samples yielding a high area under the curve (AUC) of 0.9835 [95% confidence interval (CI): 0.9677–1.0], and 0.9898 (95% CI: 0.9677–1.0), respectively. As possible non-invasive markers for EEC, four EEC-associated miRNAs (increased level: miR-135b and miR-205, decreased-level: miR-30a-3p and miR-21) in plasma were identified. Circulating levels of three EEC-associated miRNAs (miR-135b, miR-205 and miR-30a-3p) in plasma were significantly decreased after hysterectomy. ROC curves analysis revealed that miR-135b and miR-205 levels in plasma yielded AUCs of 0.9722 (95% CI: 0.913–1.0) and 1.0 (95% CI: 1.0–1.0), respectively. Conclusion Measurement of tissue and plasma EEC-associated miRNAs may be useful for early detection, diagnostic, and follow-up tests for EEC.

Aim To evaluate factors related to the occurrence of Sheehan syndrome. Methods The obstetrical disseminated intravascular coagulation score, total volume of hemorrhage, shock index, level of consciousness at the time of shock occurrence and pituitary magnetic resonance imaging findings were evaluated in nine women who showed massive hemorrhage during delivery. These clinical outcomes were analyzed in all these patients who were prospectively followed-up to identify any possible occurrence of Sheehan syndrome. Results Compared to six women with non-Sheehan syndrome, three women who were diagnosed with Sheehan syndrome showed significant elevation of the obstetrical disseminated intravascular coagulation score, decrease in the level of consciousness during shock and remarkable pituitary gland atrophic change with an empty sella turcica detected by pituitary magnetic resonance imaging. The volume of hemorrhage during delivery and shock index were not significantly different between these two groups of women. Conclusion Careful attention and follow-up should be paid to women with post-partum massive hemorrhage for early detection and management of women with Sheehan syndrome.

Aim To examine clinical and surgical performances of cases with placental polyps in which uterine preservation surgery was conducted. Methods During the period September 2002 to April 2009, we examined eight cases (hysteroscopic resection, six cases; laparotomy, one case; dilatation and curettage, one case) diagnosed with placental polyp that had been treated with polyp extraction surgery. Imaging evaluation was done using magnetic resonance imaging and 2-D ultrasound. Results Three of the eight cases (37.5%) had been first-time pregnancies. Most of our cases experienced minimal surgical manipulation after medical abortion. Among them, six cases (75%) were mid-term medical abortions, one case (12.5%) received no treatment after spontaneous abortion, and one case (12.5%) had postsurgical abortion (dilatation and curettage). All cases showed variable amount of blood flow in the internal mass and myometrium by color Doppler ultrasound. Magnetic resonance imaging angiography showed contrast effects in the intrauterine cavity and myometrium in selected cases. The average duration from diagnosis to surgery was 32 days (range, 11–105). Color Doppler revealed a reduction in blood flow in five cases during the waiting period until surgery with an average blood loss of 10 g (range, 0–20) during surgery. Conclusion Use of color Doppler ultrasound may be useful in diagnosing placental polyp. Although hysteroscopic resection of placental polyp is effective in patients hoping for uterine preservation, delaying timing of surgery may reduce blood loss during operative procedure.

Endometriosis is an estrogen-dependent chronic inflammatory condition associated with variable degrees of pelvic pain and infertility. Studies have showed that the growth and progression of endometriosis continue even in ovariectomized animals. This indicates that besides ovarian steroid hormones, the growth of endometriosis can be regulated by the innate immune system in the pelvic environment. As a component of innate immune system, increased infiltration of macrophages has been described in the intact tissue and peritoneal fluid of women with endometriosis. Different immune cells and dendritic cells express Toll-like receptors (TLR) and exhibit functional activity in response to microbial products. In this review article, we discuss the role of the TLR system in endometrium and endometriosis and outline the involvement of cytokines/endotoxin in causing adverse reproductive outcome. In the first part of this review article, the fundamentals of innate immune system, functional characteristics of TLR and signaling pathways of TLR4 are discussed for easy understanding by the readers.

STUDY QUESTION Is the occurrence of pelvic pain in women with ovarian endometrioma associated with coexisting peritoneal lesions (PLs)? SUMMARY ANSWER Pelvic pain in women with ovarian endometrioma is usually associated with coexisting PLs. An increased tissue inflammatory reaction with elevated prostaglandin (PG) production may be responsible for the generation of pain. WHAT IS KNOWN ALREADY Severe pelvic pain in women with ovarian endometrioma is reported to be associated with deeply infiltrating endometriosis. However, information on pelvic pain in women with ovarian endometriosis with and without coexistent peritoneal superficial lesions is limited. STUDY DESIGN, SIZE AND DURATION Retrospective clinical study with case-controlled biological research using prospectively collected tissue samples derived from women with and without endometriosis and their retrospective evaluation. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a retrospective cohort study conducted in 2988 cases who had laparoscopic surgery for indications of ectopic pregnancy, tubal infertility and other benign gynecologic diseases. We analyzed the occurrence of pelvic pain in the cases with ovarian endometrioma according to the distribution of coexisting PLs and pattern of intrapelvic adhesions. Inflammatory reaction of eutopic and ectopic endometria was measured by immunoreaction to macrophage marker, CD68. The tissue expression of cyclooxygenase (COX) 2 was examined by immunohistochemistry and tissue concentrations of PG F2α were measured by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE Among the 2988 surgical cases, 350 (11.7%) were found to have ovarian endometrioma at laparoscopy. Coexisting PLs were present in 269 of these women and in this group 85.4% of cases experienced pelvic pain and 14.6% had no pain. In contrast, among the 81 women with ovarian endometrioma only, 38.3% cases experienced pelvic pain and 61.7% cases had no pain and the difference between the groups was statistically significant (P < 0.01). The infiltration of CD68-immunoreactive macrophages was significantly higher in the eutopic and ectopic endometria of women with peritoneal endometriosis than in ovarian endometrioma. The tissue expression of COX2 and levels of PGF2α were significantly higher in both the eutopic and ectopic endometria derived from women with peritoneal endometriosis than in similar tissues derived from women with ovarian endometrioma. LIMITATIONS, REASONS FOR CAUTIONS Lack of evaluation in the detection of general or disseminated deeply infiltrating endometriosis in the pelvic cavity could be a bias or limitation in this study. Further multicenter prospective studies are needed to strengthen our current findings. WIDER IMPLICATIONS OF THE FINDINGS Our findings may provide some new insights to understand the physiopathology of pelvic pain in women with ovarian cystic endometriosis and may hint at proper surgical manipulation to prevent the recurrence of pelvic pain in these women. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan. There is no conflict of interest related to this study. TRIAL REGISTRATION NUMBER Not applicable., Human Reproduction, 28(1), pp.109-118; 2013

STUDY QUESTIONCan prostaglandin E2 (PGE2) in menstrual and peritoneal fluid (PF) promote bacterial growth in women with endometriosis?SUMMARY ANSWERPGE2 promotes bacterial growth in women with endometriosis. WHAT IS KNOWN ALREADYMenstrual blood of women with endometriosis is highly contaminated with Escherichia coli (E. coli) compared with that of non-endometriotic women: E. coli-derived lipopolysaccharide (LPS) promotes the growth of endometriosis. STUDY DESIGN, SIZE AND DURATIONCase-controlled biological research with a prospective collection of body fluids and endometrial tissues from women with and without endometriosis with retrospective evaluation. PARTICIPANTS/MATERIALS, SETTING AND METHODSPF and sera were collected from 58 women with endometriosis and 28 women without endometriosis in an academic research laboratory. Menstrual blood was collected from a proportion of these women. Macrophages (Mφ) from PF and stromal cells from eutopic endometria were isolated in primary culture. The exogenous effect of PGE2 on the replication of E. coli was examined in a bacterial culture system. Levels of PGE2 in different body fluids and in the culture media of Mφ and stromal cells were measured by ELISA. The effect of PGE2 on the growth of peripheral blood lymphocytes (PBLs) was examined. MAIN RESULTS AND THE ROLE OF CHANCEThe PGE2 level was 2-3 times higher in the menstrual fluid (MF) than in either sera or in PF. A significantly higher level of PGE2 was found in the MF and PF of women with endometriosis than in control women (P < 0. 05 for each). Exogenous treatment with PGE2 dose dependently increased E. coli colony formation when compared with non-treated bacteria. PGE 2-enriched MF was able to stimulate the growth of E. coli in a dilution-dependent manner; this effect was more significantly enhanced in women with endometriosis than in control women (P < 0. 05). PGE2 levels in the culture media of LPS-treated Mφ/stromal cells were significantly higher in women with endometriosis than in non-endometriosis (P < 0. 05 for each). Direct application of PGE2 and culture media derived from endometrial Mφ or stromal cells significantly suppressed phytohemagglutinin-stimulated growth of PBLs. LIMITATIONS AND REASONS FOR CAUTIONFurther studies are needed to examine the association between PGE 2-stimulated growth of E. coli and endotoxin level and to investigate the possible occurrence of sub-clinical infection within vaginal cavity. WIDER IMPLICATIONS OF THE FINDINGSOur findings may provide some new insights to understand the physiopathology or pathogenesis of the mysterious disease endometriosis and may hold new therapeutic potential. STUDY FUNDING/COMPETING INTEREST(S)This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan. There is no conflict of interest related to this study. TRIAL REGISTRATION NUMBERNot applicable., Human Reproduction, 27(12), pp.3417-3424; 2012

The aim of this study was to clarify the association between circulating pregnancy-associated, placenta-specific microRNAs (miRNAs) in maternal plasma and placental abruption. All samples were obtained after receiving written informed consent, and the study protocol was approved by the institutional review board. Maternal blood samples (7 mL) were obtained at 25 to 40 weeks of gestation from 15 cases of placental abruption (placental abruption group) and from 24 cases of uncomplicated pregnancies (uncomplicated pregnancy group). The plasma concentrations of pregnancy-associated, placenta-specific miRNAs (miR-515-3p, -517a, -517c, and -518b) were measured by quantitative real-time reverse transcription-polymerase chain reaction. There were no significant differences in clinical characteristics between the 2 groups. The median concentration of plasma cell-free miR-517c in the placental abruption group was 21 672.2 copies/mL, whereas that in the uncomplicated pregnancy group was 13 452.0 copies/mL (Mann-Whitney U test, P = .047). Receiver operating characteristic curve analysis revealed that plasma cell-free miR-517c levels discriminated placental abruption from uncomplicated pregnancy with an area under the curve of 0.692. When a cutoff negative/positive value of 15 669.6 copies/mL was selected, the sensitivity and specificity were 73.3% and 62.5%, respectively. In addition, the positive and negative predictive values were 55.0% and 78.9%, respectively. Plasma cell-free miR-517a and miR-517c levels in the large abruption (degree of abruption ≥50% of placenta) group were significantly higher than in the small abruption (

Objective Endometriosis is commonly believed to originate from functionalis endometrium and adenomyosis from basalis endometrium. Due to the lack of enough information, we investigated the biological differences between these two layers of endometrium in women with and without adenomyosis. Study design This was a case-controlled study with 12 control women and 17 women with adenomyosis undergoing hysterectomy. Full thickness (extending from the endometrium to the myometrium) biopsy specimens were obtained after the hysterectomy. Based on the phases of the menstrual cycle, the expression patterns of estrogen receptor (ER), progesterone receptor (PR), Ki-67, and activated Caspase-3 were analyzed by immunohistochemistry in the functionalis and basalis endometria. Apoptotic cells were evaluated by TdT-mediated dUTP-biotin nick end-labeling (TUNEL) assay. Results A similar pattern of ER and PR expression was found in the functionalis and basalis endometria during the proliferative phase. In contrast, a significantly lower ER and PR expression was found in the basalis endometria than in the functionalis endometria during the secretory phase and the menstrual phase. This was equally observed in control women and in women with adenomyosis. Except Ki-67 indices, TUNEL-positive cells, and expression of activated Caspase-3 were significantly lower in the basalis endometria than in the functionalis endometria during the secretory phase. Conclusion A significant biological difference was found between the functionalis and the basalis endometria derived from women with adenomyosis.