Search

Bone morphogenetic protein (BMP) cytokine is known to regulate ovulation, as BMP-6 null mice exhibit a decrease in the number of ovulatory follicles without effect on either the morphology or the dynamics of follicular development. In the present study, the role of BMP-6 in ovulatory process was investigated using human granulosa-lutein cells (GCs). Granulosa-lutein cells, obtained from in vitro fertilization patients, were cultured with BMP-6 followed by RNA extraction. The neutrophil-chemotactic activity of the supernatant of cultured GC was investigated. Bone morphogenetic protein 6 significantly increased growth-regulated oncogene α (GRO-α) messenger RNA (mRNA) and protein expression in GC. In the neutrophil-chemotaxis assay, the GC supernatant cultured with BMP-6 attracted more neutrophils than control samples, which was negated with anti-GRO-α neutralizing antibody. Bone morphogenetic protein 6 also suppressed the relative expression of the protease inhibitors, secretory leukocyte peptidase inhibitor, and whey acid protein 14 mRNA in GC. Bone morphogenetic protein 6 might play a role in ovulation by increasing the accumulation of neutrophils in the ovulatory follicle and suppressing the effect of protease inhibitors.

Aim: Preoperative autologous blood donation (PAD) has the advantages over allogeneic blood transfusion of theoretically no risk of viral infection and alloimmunization. However, there are some concerns regarding PAD in pregnant women, as they sometimes become anemic and adverse effects such as low blood pressure could be harmful to fetuses. In our hospital, the PAD program was implemented in 2006 and has been used in pregnant women at high risk of massive hemorrhage. In this study, the safety of PAD in pregnant women and its efficacy for avoiding allogeneic blood transfusion were investigated., Methods: The hospital records of pregnant women who delivered at our hospital from January 2009 to June 2012 were reviewed and those who were enrolled in the PAD program for predicted massive hemorrhage were analyzed., Results: Among the total of 3095 deliveries, 69 cases enrolled in the PAD program were analyzed. Blood donation was performed 189 times for the 69 cases. The median donated blood volume was 1200 mL (range, 400-2000). The mean blood loss during delivery was 1976 ± 1654 mL. Autologous blood was transfused in 64 cases. Allogeneic blood transfusion was required in five cases of massive blood loss exceeding 5000 mL. In the other 64 cases, no additional allogeneic blood transfusion was required. No adverse events were observed in either the pregnant women or fetuses., Conclusion: For pregnant women at a high risk of massive hemorrhage, our PAD program was safe and effective for avoiding allogeneic blood transfusion., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

The formation of an individual capillary network in the theca cell layer is required for ovarian folliculogenesis. Although vascular endothelial growth factor (VEGF) is critical for this process, the regulation of VEGF has been unclear. In the present study, the relationship between VEGF and intraovarian cytokine, bone morphogenetic protein 7 (BMP-7) was investigated. Granulosa cells (GC), obtained from in vitro fertilization patients, were cultured with BMP-7 followed by RNA extraction. Human umbilical vein endothelial cells (HUVECs) were also cultured with BMP-7 followed by RNA extraction, tube formation assay, or cell count analysis. The BMP-7 stimulated VEGF messenger RNA (mRNA) and protein expression in GC significantly. In HUVEC, BMP-7 increased an approximately 1.8-fold in the cell number and induced the tube formation significantly compared to control. The BMP-7 also induced a 2-fold increase in VEGF receptor mRNA transcript relative abundance in HUVEC. The BMP-7, a theca cell-derived factor, may stimulate endothelial cell to form vasculature in the follicle via 2 distinct mechanisms, induction of VEGF expression in GC and increased sensitivity of endothelial cells to VEGF.

Aim: Endometriosis is a chronic inflammatory disease. Sirtuin 1 (SIRT1) plays a role in regulation of inflammation. The role of SIRT1 in endometriosis remains unknown. We here addressed the anti-inflammatory effects of SIRT1 on endometriosis., Methods: The expression of SIRT1 in human ovarian endometriomas and eutopic endometria were examined using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Endometriotic stromal cells (ESC) obtained from endometriomas were exposed to either resveratrol or sirtinol, an activator or inhibitor of sirtuins, respectively, and tumor necrosis factor (TNF)-α-induced interleukin (IL)-8 release from the ESC was assessed at mRNA and protein levels., Results: Both immunochemistry and RT-PCR demonstrated that SIRT1 was expressed in ESC and normal endometrial stromal cells. Resveratrol suppressed TNF-α-induced IL-8 release from the ESC in a dose-dependent manner while sirtinol increased IL-8 release., Conclusion: These opposing effects of SIRT1-related agents suggest that IL-8 release from the ESC is modulated through the SIRT1 pathway. Resveratrol may have the potential to ameliorate local inflammation in endometriomas., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Aim: The aim of this study was to identify factors that can predict clinical course among patients hospitalized with pelvic inflammatory disease (PID)., Methods: Ninety-three patients who needed hospitalization with a diagnosis of PID were retrospectively studied. Patients who were discharged within 7 days by conservative treatment were defined as favorable course cases (n = 44). Patients who needed more than 7 days of hospitalization and/or surgery were defined as poor course cases (n = 49). Twenty variables were evaluated by univariate and logistic regression analysis: age, history of pregnancy/delivery, gynecological open/laparoscopic surgery, PID, oral contraceptives/intrauterine device use and intrauterine operation before onset, body temperature, signs of peritoneal irritation, vomiting/diarrhea, abnormal vaginal discharge, endometriosis/fibroid/adenomyosis/any cystic lesion detected by ultrasonography, white blood cell counts/C-reactive protein (CRP) levels . The cut-off value was calculated by receiver-operator curve (ROC) analysis., Results: Factors associated with poor clinical course were advanced age (P < 0.01), history of gynecological open surgery (P < 0.05), any cystic lesion detected by ultrasonography (P < 0.05) and high CRP levels (P < 0.05). High CRP levels and intrauterine operation before onset were independently associated with poor clinical course. The cut-off value for CRP was 4.4 mg/dL., Conclusion: This study identified variables that can predict poor clinical course of PID. These results can assist gynecologists with identifying patients at risk and optimizing the choice of management., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Aim: The purpose of our study was to evaluate the efficacy of laser ablation as a conservative treatment for cervical intraepithelial neoplasia 3 (CIN3) and assess whether the human papillomavirus (HPV) test is useful to predict recurrence after treatment., Materials and Methods: A total of 134 patients who received laser ablation for treatment of CIN3 were enrolled in this study. During the follow-up period, patients were followed with cytological and colposcopic evaluations. Recurrence of CIN3 was regarded as the primary end-point. HPV genotype was tested before and after treatment. Post-treatment cumulative recurrence rates were estimated and comparisons by both patient age and HPV genotype were performed., Results: Overall cumulative recurrence rate of CIN3 in the first year after treatment was 22.6% for all patients. No significant correlation was shown between patient age and recurrence. Patients infected by specific genotypes (16, 18, 31, 33, 52, and 58) frequently failed to clear the infection after treatment. The 1-year recurrence-free survival in those positive after treatment for eight high-risk genotypes (16, 18, 31, 33, 35, 45, 52, and 58) was significantly lower (66.7%), compared to that in those positive for other high-risk types (78.6%). The recurrence-free survival of those who remained HPV-positive after treatment was significantly lower than those who turned negative., Conclusion: Laser ablation should be performed prudently with appropriate patient counseling about recurrence rate. Considering its minimal invasiveness, laser ablation is effective, especially for young patients who are negative for eight high-risk genotypes. With regard to HPV testing, although genotyping has significant value for predicting recurrence, screening for all genotypes warrants further evaluation., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Aim: The aim of this study was to review diagnostic/therapeutic strategies of umbilical endometriosis managed in our department and evaluate the effectiveness of these strategies., Methods: Medical records for patients with diagnosis of endometriosis managed from 1999 through 2011 in the University of Tokyo Hospital were retrospectively reviewed. Cases with diagnosis of umbilical endometriosis were identified. Clinical information of age, gravida, parity, histories of surgery and oral contraceptive (OC), management for the disease prior to the first visit, symptoms, patients' desire for pregnancy, diagnostic/therapeutic methods and prognosis were reviewed and summarized., Results: During the period, 2530 patients with diagnosis of endometriosis were identified. Seven patients had diagnosis of umbilical endometriosis, giving an incidence of 0.29% of all endometriosis cases and 5.6% of extragenital endometriosis cases. A definitive diagnosis was made by histological examination following a biopsy (two cases) or a resection (three cases). A clinical diagnosis was made by empirical treatment with OC (one case) or dienogest (one case). With regard to therapy, three patients chose expectant management and did not require therapeutic intervention. Three patients began OC and symptoms were well controlled in all patients. One patient who wished to conceive chose a wide resection followed by umbilical reconstruction. She became pregnant afterwards and recurrence was not reported., Conclusion: There are various options of diagnostic/therapeutic strategies, such as empirical treatments and OC that can provide individualized management of umbilical endometriosis, congruent with the severity of patient symptoms, age and desire for pregnancy., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Clinical outcome of confined placental mosaicism (CPM) is varied, from normal pregnancy to intrauterine fetal death. It has been suggested that CPM for trisomy 2 is less likely to cause serious adverse effect on pregnancy. We hereby report a case of CPM for trisomy 2, which presented severe fetal growth restriction (FGR) and placental abnormalities. A 30-year-old woman was referred to our hospital at 17⁺² weeks because of marked FGR. Ultrasonography demonstrated prominent placental hypertrophy with multiple focal defects without any fetal structural abnormalities. Amniocentesis at 18⁺³ weeks revealed normal karyotype. Fetal growth rate worsened with gestational weeks, reaching -7 standard deviation at 36 weeks. At 37 weeks, the fetal condition suddenly deteriorated, ending in a stillbirth of a 756-g female baby. Postnatal cytogenetic analysis by array comparative genomic hybridization revealed trisomy 2 of the chorionic villi, and CPM for trisomy 2 was suggested as the cause of FGR and placental abnormalities., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

In human pregnancy, CD14⁺ decidual macrophages (DMs) are the dominant professional antigen-presenting cells in the decidua, comprising 20-30% of the local leukocyte population. Although the relevance of DMs to feto-maternal immune tolerance has been described, the molecular mechanisms underlying these functions have not been fully elucidated. B7-H1, a costimulatory ligand in the B7 family, negatively modulates T cell activity by binding to its corresponding receptor, PD-1. The present study aimed to investigate the functional significance of costimulatory interactions between DMs and T cells, with a particular focus on B7-H1:PD-1 signaling. An analysis of the expression profile of B7 ligands on human DMs revealed that B7-H1 was present on DMs isolated from early but not term pregnancies. B7-H1 was not expressed on the peripheral monocytes (PMs) of pregnant women. In response to IFN-γ, B7-H1 expression was induced on PMs and was enhanced on DMs, suggesting that this cytokine might be a key factor in the control of B7-H1 expression in the decidua. The majority of decidual T cells were noted to exhibit robust expression of PD-1, whereas the expression was limited to a small subpopulation of circulating T cells. Functional assays demonstrated that DMs are able to suppress T cell IFN-γ production via B7-H1:PD-1 interactions. This suppressive property was not observed for PMs, which lack B7-H1. B7-H1 on DMs may function as a key regulator of local IFN-γ production and thereby contribute to the development of appropriate maternal immune responses to the fetus in early pregnancy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Ovarian fibroma can occur in young women of reproductive age. Despite its benign feature, most surgical removals are done in open surgery with oophorectomy. However, an ovarian-sparing tumor resection can be an option, especially for an exophytic type of fibroma, which accounts for more than half of ovarian fibromas. Here we report a case of exophytic ovarian fibroma in a young woman treated by laparoscopic ovarian-sparing surgery. A 27-year-old woman presented with a pelvic mass. Magnetic resonance imaging revealed an 11 cm × 8 cm solid mass connected to the normal-appearing left ovary by a pedicle-like structure. A clinical diagnosis of an exophytic ovarian fibroma was made, and laparoscopic ovarian-sparing surgery with an intraoperative pathological examination was planned. The tumor was resected by cutting the pedicle, morcellated in a pouch and removed. All procedures were performed laparoscopically and the affected ovary was completely preserved. Having confirmation of its benign characteristics by the intraoperative examination, no further excision was performed. The patient conceived 3 months after the surgery and no recurrence was reported. We propose that gynecologists should consider laparoscopic ovarian-sparing surgery for exophytic ovarian fibroma in women of reproductive age., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Objective: To study the recurrence rate and predictive factors for recurrence after surgical excision of ovarian mature cystic teratomas (MCT)., Study Design: Retrospective study of 382 patients who underwent surgical excision of MCT and whose post-surgical follow-up data were available over six months. Patients who underwent concomitant oophorectomy or had a history of oophorectomy were excluded. Medical records were reviewed for evidence of recurrence. The Cox-hazard model was used for the estimation of predictive factors for recurrence. Categorical data were compared using the Chi-square and Fisher's exact tests., Results: There were 16 recurrences within a mean follow-up period of 43.0 months, with a recurrence rate of 4.2%. Young age (<30 years old, Y) (hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.04-8.62, P=0.043), large cyst (≥8 cm in diameter, L) (HR 2.75; 95% CI 1.03-7.37, P=0.044), and bilaterality (B) (HR 2.88; 95% CI 1.07-7.76, P=0.036) were shown to be significant predictive factors. When a patient had all these three factors, the recurrence rate was 21.0%, otherwise 3.4% (P<0.01). Patients with Y+L, Y+B, and B+L also showed significantly higher recurrence rate (21.4%, 15.9%, and 11.4%, respectively)., Conclusion: The long-term recurrence rate after surgical excision of MCT in this study is 4.2%. A patient with young age (<30 years old) or large cyst (≥8 cm in diameter) or bilateral cysts is at high risk of recurrence, which is even higher when a patient has more than one of these factors., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have anti-inflammatory effects. Preterm birth is an important problem in modern obstetrics and one of the main causes is an inflammation. We here showed that abundance of omega-3 fatty acids reduced the incidence of preterm birth induced by LPS with fat-1 mice, capable of converting omega-6 to omega-3 fatty acids. We also indicated that the gene expression of IL-6 and IL-1β in uteruses and the number of cervical infiltrating macrophages were reduced in fat-1 mice. The analyses of lipid metabolomics showed the high level of 18-hydroxyeicosapentaenoate in fat-1 mice, which was derived from EPA and was metabolized to anti-inflammatory product named resolvin E3 (RvE3). We finally showed that the administration of RvE3 to LPS-exposed pregnant wild type mice lowered the incidence of preterm birth. Our data suggest that RvE3 could be a potential new therapeutic for the prevention of preterm birth.

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) play a role in controlling pathological inflammatory reactions. Endometriosis is characterized by the presence of endometrial tissue on the peritoneum and an exaggerated inflammatory environment around ectopic tissues. Here peritoneal endometriosis was reproduced using a mouse model in which murine endometrial fragments were inoculated into the peritoneal cavity of mice. Fat-1 mice, in which omega-6 can be converted to omega-3 PUFAs, or wild type mice, in which it cannot, were used for the endometriosis model to address the actions of omega-3 PUFAs on the development of endometriotic lesions. The number and weight of cystic endometriotic lesions in fat-1 mice two weeks after inoculation were significantly less than half to those of controls. Mediator lipidomics revealed that cystic endometriotic lesions and peritoneal fluids were abundant in 12/15-hydroxyeicosapentaenoic acid (12/15-HEPE), derived from eicosapentaenoic acid (EPA), and their amount in fat-1 mice was significantly larger than that in controls. 12/15-Lipoxygenase (12/15-LOX)-knockout (KO) and control mice with or without EPA administration were assessed for the endometriosis model. EPA administration decreased the number of lesions in controls but not in 12/15-LOX-KO mice. The peritoneal fluids in EPA-fed 12/15-LOX-KO mice contained reduced levels of EPA metabolites such as 12/15-HEPE and EPA-derived resolvin E3 even after EPA administration. cDNA microarrays of endometriotic lesions revealed that Interleukin-6 (IL-6) expression in fat-1 mice was significantly lower than that in controls. These results suggest that both endogenous and exogenous EPA-derived PUFAs protect against the development of endometriosis through their anti-inflammatory effects and, in particular, the 12/15-LOX-pathway products of EPA may be key mediators to suppress endometriosis.

Cyclin D1 is an important regulator of cell cycle progression. Phosphorylation of cyclin D1 at Thr286 by GSK3β triggers its nuclear export and cytoplasmic proteolysis via the 26S proteasome. Cyclin D1 overexpression is a common event in various types of human cancers; however, reports of mutations are extremely rare. We analyzed mutations of the cyclin D1 gene, CCND1, in 88 endometrial cancer tissue specimens and detected mutations in 2 cases (2.3%). Both were unreported mutations with substitution of threonine to isoleucine at codon 286 (T286I). These two tumors harbored coexisting mutations in K-ras, PIK3CA and/or PTEN and showed accumulation of cyclin D1 in the nucleus by immunohistochemistry. Furthermore, we analyzed the functions of mutant cyclin D1 (T286I) by luciferase assays, immunofluorescence, western blotting and clonogenic cell survival assays in HEK-293T cells. We found that exogenous mutant cyclin D1 (T286I) accumulated in the nuclei in HEK-293T cells, and that it inhibited the expression of pRb. Additionally, the number of colonies was increased by introduction of mutant cyclin D1 (T286I) compared to that of wild-type cyclin D1. In conclusion, we identified an unreported CCND1 mutation (T286I) in two endometrial cancers and revealed that the mutation was functional for inducing cell proliferation in human cells.

Laparoendoscopic single-site (LESS) technique has gained popularity in several fields of surgery. Our patient had multiple gallstones and a left ovarian mature cystic teratoma 12 cm in diameter. She underwent concomitant laparoscopic cholecystectomy and adnectomy using LESS technique. Using a transient gasless technique resulted in the extraction of a giant ovarian tumor through the umbilical incision with no leakage into the abdominal cavity. Concomitant LESS surgery is feasible and has many benefits both for patients and doctors - cosmetics, possibly less pain, avoidance of multiple surgeries and cost-effectiveness. LESS technique is also useful for extracting a giant tumor with the transient gasless technique. This novel method might be applied to the removal of a tumor suspicious for malignancy., (© 2013 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.)

Introduction and Hypothesis: The aim of this study was to translate the Pelvic Floor Distress Inventory-Short Form 20 (PFDI-20) into Japanese and test its reliability and validity among Japanese women., Methods: Fifty-nine women with and without pelvic floor disorders (age 55.8 ± 16.8 years, mean ± SD) completed the Japanese PFDI-20 (J-PFDI-20) questionnaire at baseline and 2 weeks later. Intraclass correlation coefficients (ICC) and the Bland and Altman method for test-retest reliability and Cronbach's alpha for internal consistency of the J-PFDI-20 were used. Scores of total and subscales were compared between women with and without pelvic floor disorders for known-groups validity. Spearman's correlation coefficients between the J-PFDI-20 and the severity of pelvic floor disorders and Urinary Incontinence Quality of Life Scale (I-QOL) were used for construct validity., Results: The PFDI-20 was successfully translated from English into Japanese with face validity through rigorous cross-cultural validation. Test-retest reliability of the J-PFDI-20 and three subscales was good to excellent (ICC=0.77-0.90). The Bland and Altman analysis showed that differences between the first and second scores of total J-PFDI-20 and its subscales were not significantly different from 0 and largely fell within the range of 0 ± 1.96 SD. Cronbach's alpha values were 0.52-0.83. Analysis of known-groups validity showed differences in scores of the J-PFDI-20 between women with and without pelvic floor disorders. Acceptable construct validity was found in J-PFDI-20 total and subscale scores with positive correlations to severity of pelvic floor disorders (ρ>0.35) and negative correlations to I-QOL (ρ<-0.39)., Conclusions: The results suggest that the J-PFDI-20 is a reliable and valid condition-specific quality of life instrument for women with pelvic floor disorders.

Purpose: Although studies of serum anti-Müllerian hormone (AMH) in predicting ovarian reserve are numerous, many studies utilized patients under age 40. However, the assessment of ovarian reserve is especially critical in older infertile women. This study evaluates the significance of AMH level in patients over age 40 at the time of their first in vitro fertilization (IVF) treatment., Methods: Forty-nine women over age 40 were studied. Although serum samples were taken prior to their IVF treatments, the data of serum AMH of patients were not taken into consideration to determine the therapy strategy, including follicle induction in which clomiphene citrate and human menopausal gonadotropin were used., Result(s): Twelve out of 49 patients achieved a clinical pregnancy (24.4 %). There was a positive correlation between serum AMH levels and the number of oocytes retrieved (P < 0.0001). The ROC curve analysis for prediction of poor ovarian response, ≤3 retrieved oocytes, showed that the optimum cut-off level was < 1.0 ng/mL for AMH. The lower AMH group (AMH < 1.0 ng/ml) showed less chance of undergoing embryo transfer than the higher AMH group (AMH ≥1.0 ng/ml). There was no difference in pregnancy rate between the two groups. Five out of 12 pregnant women exhibited AMH levels of less than 0.4 ng/ml., Conclusion(s): Assessment of serum AMH concentration in older patients is useful for the prediction of oocytes numbers which may be obtained in IVF. A cut-off level of 1.0 ng/ml AMH can be used to predict poor ovarian response. This cut-off level of AMH of 1.0 ng/ml might be useful to predict whether patients could have an embryo transfer, but had no power to predict achieving pregnancy. On the other hand, our data also showed that patients over age 40 with extreme low levels of AMH still had a chance of pregnancy.

The aim of this study is to examine the regulation of follistatin, an activin-binding protein, in endometriosis. Endometrioma stromal cells (EoSCs) were obtained from 9 patients undergoing laparoscopy of the ovarian endometrioma. In cultured EoSCs, interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α), which could induce activin-A, also induced follistatin messenger RNA (mRNA) and protein. The cystic fluid of endometrioma from 8 patients was obtained to measure the concentration of activin-A and follistatin by enzyme-linked immunosorbent assay (ELISA). Also, activin activity in the fluid was examined by erythroid differentiation assay using mouse erythroleukemia F5-5.fl cells. In the cystic fluid of endometrioma, the mean values of activin-A and follistatin concentration were 36.8 ng/mL and 4.0 ng/mL, respectively. In a bioassay, all 8 samples exhibited activin activity, which was equivalent to recombinant activin-A activity of 12.8 ± 1.4 ng/mL. Although follistatin was present in the cystic fluid of endometrioma, the activity of activin, which is an exacerbation factor of endometriosis, was predominant in vivo.

Problem: The purpose of this study was to evaluate the impact of mechanical stretch caused by uterine contraction and progesterone (P₄) on decidual cells (DC), neutrophil chemokines, and MMP-1 expression., Method of Study: DC were cultured, and cyclic stretch was applied using a computer-operated cell stretch system. Interleukin (IL)-8, growth-regulated oncogene (GRO) α, matrix metalloproteinase (MMP)-1, and mRNA and/or protein expression/activity was measured using RT-PCR and ELISA. Neutrophil chemotactic activity in conditioned media was evaluated using migration assays. The effect of P₄ was also studied., Results: Cyclic mechanical stretch increased IL-8, GROα, mRNA and protein, and MMP-1 production and activity level. Supernatant from stretched cells induced neutrophil chemotactic activity significantly. P₄ suppressed the effect of stretch., Conclusion: The current study demonstrates that cyclic mechanical stretch stimulates the production of neutrophil chemokines and MMP-1 from human decidual cells, and the production was reduced by progesterone. These findings suggest that decidual cells are responding to mechanical and endocrine signals and induce biochemical factors and thereby contribute to the regulation of human labor., (© 2013 John Wiley & Sons A/S.)

Context: Endometriosis is a chronic inflammatory disease in which immune response and production of estrogen in endometriotic tissues are involved in the development of the disease. Prostaglandin E2 (PGE2) stimulates aromatase (P450arom) expression in endometrioma stromal cells (ESCs) and increases the production of estrogens. On the other hand, an accumulating amount of evidence suggests that IL-4, a typical Th2 cytokine, plays important roles in the disease., Objective: The objective of the investigation was to study the effect of IL-4 on the expression of 3β-hydroxysteroid dehydrogenase (HSD3B2), a pivotal enzyme for estrogen production, in ESCs., Design, Patients, and Main Outcome Measures: ESCs were isolated from ovarian endometrioma tissues and cultured with IL-4 and PGE2. CP-690550, a Janus protein tyrosine kinase 3 inhibitor, and HSD3B2 small interfering RNA were added to the culture. Gene expression of HSD3B2 and P450arom was examined by quantitative RT-PCR. Dehydroepiandrosterone (DHEA) was added to the culture, and then the combined enzyme activity of HSD3B2, which converts DHEA to androstenedione, and P450arom, which converts androstenedione to estrone, was examined by measuring estrone concentration in the supernatants with a specific enzyme immunoassay., Results: IL-4 increased the expression of HSD3B2 mRNA in a dose-dependent manner. CP-650550 inhibited the IL-4-induced increase in HSD3B2 mRNA expression. PGE2 also increased the expression of HSD3B2 mRNA, and the combination of IL-4 and PGE2 synergistically increased the expression of HSD3B2 mRNA. IL-4 had no effect on the expression of P450arom mRNA, whereas PGE2 increased the expression of P450arom mRNA. Although PGE2 alone increased the production of estrone from DHEA, the combination of IL-4 and PGE2 significantly augmented the production of estrone from DHEA. The enhanced production of estrone by the combination of IL-4 and PGE2 was inhibited by CP-690550 and HSD3B2 small interfering RNA., Conclusions: IL-4 in combination with PGE2 may enhance estrogen production in endometriotic tissues, implying an elaborate mechanism that Th2 immune response augments inflammation-dependent progression of the disease.

Purpose: To compare the pelvic floor function between women with and without stress urinary incontinence after vaginal delivery., Methods: Seventeen women (age 35.5 ± 3.5) were prospectively studied at about 6 weeks, 3 months, and 6 months after vaginal delivery. Urinary incontinence was assessed by the International Consultation on Incontinence Questionnaire - Short Form. Pelvic floor function was assessed by antero-posterior diameter of the levator hiatus using transperineal ultrasound., Results: Five of 17 women experienced postpartum stress urinary incontinence. The antero-posterior diameter of the levator hiatus at rest was significantly longer in stress urinary incontinent women than in continent women until 3 months after delivery (p < 0.01), though shortening of the antero-posterior diameter of the levator hiatus was not significantly different between continent women and stress urinary incontinent women. Regardless of urinary incontinence, the antero-posterior diameter of the levator hiatus at rest shortened at 6 months postpartum, compared to 6 weeks postpartum (p < 0.001). The antero-posterior diameter of the levator hiatus during contraction had shortened only in continent women by 6 months postpartum (p = 0.02)., Conclusion: The extended pelvic floor may be a cause of stress urinary incontinence in the postpartum period. Therefore, treatment to improve the extended pelvic floor should be developed for the prevention of stress urinary incontinence.

Problem: The aim of this study was to investigate the impact of uterine contraction on the immune environment within the uterus during parturition., Method of Study: Uterine smooth muscle cells (USMC) were isolated from uterine myometrial tissues and cultured. The effects of cyclic stretch on mRNA and/or protein expression of IL-8, Groα, and pro-MMP-1 by USMC were measured using RT-PCR and ELISA. Neutrophil chemotactic activity in conditioned media was evaluated using migration assays. To evaluate the effect of progesterone (P(4) ), USMC were pretreated with P(4) for 24 hr., Results: Cyclic stretch increased IL-8 and Groα mRNA and protein and pro-MMP-1 production significantly. Supernatants from stretched cells induced neutrophil chemotactic activity significantly; these effects were abrogated by anti-IL-8 or Groα neutralizing antibodies. Stretch effects were reduced by P(4) ., Conclusion: These results suggest that uterine contraction may induce neutrophil infiltration and MMP-1 production, which may contribute to cervical ripening and rupture of membrane. The inhibitory effects of P(4) may explain the mechanism by which progestin prevents preterm labor., (© 2012 John Wiley & Sons A/S.)

Introduction: Many patients with endometrial cancer have no children when diagnosed, and thus are reluctant to undergo hysterectomy, hoping to preserve their fertility. Their requirement is met, at least partially, with high-dose medroxyprogesterone acetate that brings good response rate in the treatment of endometrial cancer in the early stage and atypical complex endometrial hyperplasia (EC/ACEH). Actually, a number of successful pregnancies after the conservative treatment have been reported. To conceive, many of them need infertility treatment because of ovulation disorders which might have induced the cancer with unopposed estrogens. However, on the other side, hyperestrogenic status caused by ovulation induction or controlled ovarian stimulation might promote the progression and the recurrence of the disease., Objective: This study aimed to assess the effectiveness and safety of infertility treatment after conservative therapy for EC/ACEH, to confirm the significance of fertility-sparing therapy., Methods: The patients with EC/ACEH who achieved complete response after high-dose medroxyprogesterone acetate were eligible for this retrospective study. Characteristics of the patients, whether they underwent infertility treatment, conceived, or relapsed, and the interval from complete response to conception or recurrence were retrospectively analyzed., Results: The clinical outcomes of 36 patients were investigated. Twenty-six of them desired to conceive soon after complete response. All of them underwent infertility treatment, and 16 women delivered healthy babies. Kaplan-Meyer curve and log-rank test analysis revealed that women who achieved live birth had a significantly lower risk of recurrence than those without live birth. There was not a significant difference between the patients with and without infertility treatment., Conclusions: Use of ovulation induction drugs after conservative treatment of endometrial cancer did not increase the recurrence of the disease. Moreover, resulting pregnancy seems to have an advantageous effect on the oncologic outcome.

A uterine artery pseudoaneurysm (UAP) is a rare but life-threatening complication that can occur after gynecologic surgery. Herein, we present a case of a 38-year-old woman who presented with massive uterine bleeding one month after a laparoscopically assisted myomectomy. Although the bleeding ceased spontaneously, a massive hemorrhage reoccurred three weeks thereafter, and a ruptured perfusion sac at the right uterine artery was identified by computed tomography angiography and ultrasonography. The patient was treated with transfemoral catheter embolization of the right uterine artery, and complete resolution of the UAP was successfully obtained. Our case suggests that a UAP may be a cause of unexplained repetitive metrorrhagia after myomectomy., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Problem: Local adaptive cervical regulatory T cells (Tregs) are the most likely direct suppressors of the immune eradication of cervical intraepithelial lesion (CIN). PD-1 expression on T cells induces Tregs. No studies have quantitatively analyzed the Tregs and PD-1+ cells residing in CIN lesions., Method of Study: Cervical lymphocytes were collected using cytobrushes from CIN patients and analyzed by FACS analysis. Comparisons were made between populations of cervical Tregs and PD-1+ CD4+ T cells in CIN regressors and non-regressors., Results: A median of 11% of cervical CD4+ T cells were Tregs, while a median of 30% were PD-1+ cells. The proportions of cervical CD4+ T cells that were Tregs and/or PD-1+ cells were significantly lower in CIN regressors when compared with non-regressors., Conclusions: The prevalence of cervical tolerogenic T cells correlates inversely with spontaneous regression of CIN. Cervical Tregs may play an important role in HPV-related neoplastic immunoevasion., (© 2012 John Wiley & Sons A/S.)

Although the prognosis of uterine cervical cancer has improved due to the advances of treatment modalities, survival of recurrent or metastatic cervical cancer remains poor. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer is disappointing. Inactivation of tumor suppressors through ubiquitin-mediated degradation by human papillomavirus is known to be a critical step in the carcinogenesis of uterine cervix. Bortezomib, a selective inhibitor of the proteasome, has been shown to inhibit the growth of several solid tumors. To determine the role of bortezomib in cervical cancer as a chemotherapeutic agent, we studied its biological properties. Bortezomib efficiently inhibited the proteasomal activities in cervical cancer cells, and an increased expression of tumor suppressors such as p53, hDlg and hScrib became evident. In addition, sequential or concomitant treatment of bortezomib and cisplatin stimulated the expression of p53, hScrib and p21 and the stimulation was markedly influenced by the order of drugs in HeLa cells. We further confirmed that the concomitant use of bortezomib and cisplatin has synergistic inhibitory effects on the growth of xenograft tumors derived from HeLa cells. Our data establish the possibility that the concomitant use of bortezomib and cisplatin could be an alternative choice in cases resistant to conventional chemotherapy, and sequential effects must be considered for advanced and therapy-resistant cervical cancer patients.

Aim: Platinum is a milestone drug against gynecologic malignancies. The purpose of this retrospective study was to investigate the feasibility of replacing carboplatin with nedaplatin in patients who had developed a hypersensitivity reaction to carboplatin., Material and Methods: Fifteen patients with recurrent gynecologic cancer (12 ovarian, 1 fallopian tube, 1 endometrial and 1 cervical cancer) who had experienced a hypersensitivity reaction to carboplatin and a possible clinical indication for continuing treatment with platinum were treated with nedaplatin (80 mg/m(2) )-containing regimen., Results: The total number of nedaplatin cycles given was 137 (range 1-29). Four (27%) patients developed hypersensitivity reactions on the second, second, fourth, and ninth administration, respectively. The severities of all the hypersensitivity reactions were grade 3 or less. The other 11 patients (73%) had no nedaplatin-associated hypersensitivity reactions. The incidence of hypersensitivity reactions in the paclitaxel and nedaplatin group (three of four, 75%) was more frequent than the docetaxel and nedaplatin group (none of seven, P=0.024). The objective response rate in eleven patients with measurable disease was 36% (complete response at 9% and partial response at 27%), and the disease control rate was 73% (stable disease at 36%)., Conclusion: Nedaplatin-associated hypersensitivity reactions are not rare in patients who developed allergic reactions to carboplatin. Retreatment of carboplatin-allergic patients with nedaplatin cannot be recommended without careful consideration of the potential risks and benefits., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Low-grade endometrial stromal sarcoma (ESS) is a rare neoplasm that is generally estrogen-receptor- and progesterone-receptor-positive and develops in premenopausal women. Although tamoxifen treatment is associated with an increased risk of ESS, the effect of other selective estrogen receptor modulators, including toremifene, on the risk of ESS is not clear. A 61-year-old postmenopausal woman was treated with toremifene as an adjuvant therapy for breast cancer. A cystic mass developed during the treatment, with gradual growth in the uterine myometrium. The patient was treated with hysterectomy and bilateral salpingo-oophorectomy, and the tumor was diagnosed as low-grade ESS (stage IA) with estrogen-receptor and progesterone-receptor. The patient discontinued toremifene and has been progression-free for 21 months. Our data suggest that toremifene might be associated with the development of ESS in certain patients through its estrogen-like effects in the uterus., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease that affects the right side of the heart and causes ventricular arrhythmias. It is considered as the most common cause of sudden cardiac death in young adults. However, risk and optimal management of ARVC during pregnancy and delivery remain unclear due to the small number of reported cases. Here we report a case of successful management of pregnancy and delivery in a patient with ARVC, who had a history of sustained ventricular tachycardia from her previous pregnancy., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Previous studies have shown that the cell polarity regulator hScrib interacts with, and consequently controls, the ERK signaling pathway. This interaction occurs through two well-conserved Kinase Interacting Motifs, which allow hScrib to bind ERK1 directly, resulting in a reduction in the levels of phospho-ERK. This suggests that hScrib might recruit a phosphatase to regulate this signaling pathway. Using a proteomic approach we now show that Protein Phosphatase 1γ (PP1γ) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1γ interaction motif on the hScrib protein, and this interaction appears to be required for hScrib's ability to downregulate ERK phosphorylation. In addition, hScrib also controls the pattern of PP1γ localization, where loss of hScrib enhances the nuclear translocation of PP1γ. Furthermore, we also show that the ability of hScrib to interact with PP1γ is important for the ability of hScrib to suppress oncogene-induced transformation of primary rodent cells. Taken together, these results demonstrate that hScrib acts as a scaffold to integrate the control of the PP1γ and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy.

Uterine arteriovenous fistula (AVF) is a rare entity, but may lead to life-threatening hemorrhage. Although transcatheter embolization, surgical ligation, or hysterectomy would be considered for treatment of uterine AVF, there is poor knowledge as to how gynecologists can manage the uterine AVF with multiple large inflow arteries. Herein we report a uterine AVF successfully treated using multiple-step transcatheter embolization. The patient, a 58-year-old postmenopausal woman with a history of dilation and curettage, had intermittent massive uterine bleeding. Radiologic imaging revealed the presence of a large vasculature mass. The mass occupied the entire pelvis, and the source of hemorrhage was identified as an accompanying AVF. We thought that surgical intervention was contraindicated because of the potential risk of uncontrollable intraoperative bleeding. Multiple-step transcatheter embolization was performed, with complete resolution of the AVF. Thereafter, the patient had no further uterine bleeding. Multiple-step transcatheter embolization might be the most beneficial and efficient treatment option for a uterine AVF with multiple large inflow arteries., (Copyright © 2012 AAGL. Published by Elsevier Inc. All rights reserved.)

Members of the 14-3-3 family are intracellular dimeric phosphoserine-binding proteins that can associate with and modulate the activities of many proteins. In our efforts to isolate the genes regulated by progesterone (P(4)) using suppressive subtractive hybridization, we previously found that 14-3-3τ is one of the genes upregulated by P(4). In this study, we demonstrated by quantitative RT-PCR (qRT-PCR), western blot analyses, and immunohistochemistry that 14-3-3τ mRNA and protein levels were increased in the rat uterus after P(4) treatment. Furthermore, qRT-PCR indicated that P(4) increased 14-3-3τ mRNA levels in human endometrial epithelial cells and endometrial stromal cells (ESCs). Western blot and qRT-PCR analyses revealed that in vitro decidualization using cAMP and medroxyprogesterone 17-acetate increased levels of 14-3-3τ mRNA and protein in ESCs. We have shown by qRT-PCR and western blot analyses that P(4) increased the mRNA and protein levels of 14-3-3τ in Ishikawa cells that stably express P(4) receptor-B (PR-B). Immunocytochemistry revealed that 14-3-3τ colocalizes with PR and translocates from the cytoplasm to the nucleus in response to P(4). Moreover, by luciferase reporter assay, we demonstrated that 14-3-3τ enhances the transcriptional activity of PR-B. Taken together, we propose that 14-3-3τ is a P(4)-responsive gene in uterine cells that modulates P(4) signaling.

Purpose: To assess the utility of transperineal three-dimensional (3D) ultrasound for diagnosing anal sphincter defects and evaluating the function of the anal canal in women with anal incontinence., Methods: The study subjects were 13 women with anal incontinence. Symptoms of fecal incontinence were assessed by Wexner score. The anal canal of each woman was examined ultrasonically with both a convex transperineal 3D scanner and a radial transanal scanner to compare the accuracy of the two approaches for diagnosis of anal sphincter defects. The anorectal angle and the length of the anal canal were also measured by utilizing the functionality of the transperineal 3D ultrasound., Results: The mean age was 58.9 ± 14.9 years (±SD), and the mean Wexner score was 8.4 ± 5.6. In terms of ultrasound diagnosis of anal sphincter defects, the two methods showed consistent results in each woman. The length of the portion where both the internal and external anal sphincters were intact was significantly correlated with the Wexner score, whereas the total length of the anal canal was not., Conclusions: Less invasive transperineal 3D ultrasound provides accurate evaluation of the internal and external anal sphincters in women with anal incontinence, and the method is potentially useful for detection of anal sphincter abnormalities.

Sirtuin 1 (SIRT1), originally found as a class III histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. We examined the role of SIRT1 in the regulation of uterine receptivity using Ishikawa and RL95-2 endometrial carcinoma cell lines. Exogenous expression of SIRT1 significantly enhanced E-cadherin expression, while small interfering RNA-mediated depletion of endogenous SIRT1 resulted in a significant reduction of E-cadherin expression. A SIRT1 activator resveratrol elevated E-cadherin expression in a dose dependent manner, while SIRT1 repressors nicotinamide and sirtinol exhibited a dose dependent reduction of E-cadherin expression. We also showed that both forced expression of SIRT1 and activation of SIRT1 promote E-cadherin-driven reporter gene constructs, and SIRT1 is localized at E-cadherin promoter containing E-box elements in Ishikawa cells. Using an in vitro model of embryo implantation, we demonstrate that exogenous expression of SIRT1 and stimulation of SIRT1 activity resulted in the Ishikawa cell line becoming receptive to JAR cell spheroid attachment. Furthermore, resveratrol enhanced E-cadherin and Glycodelin protein expression at sites of intercellular contact, suggesting an additive role of resveratrol in promoting implantation. The initial step of human reproduction depends on the capacity of an embryo to attach and implant into the endometrial wall, and these results revealed the novel mechanism that activation and increased expression of SIRT1 play an important role in uterine receptivity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The Japanese herbal medicines, Juzen-taiho-to (JTT) and Hochu-ekki-to (HET), have been shown to enhance humoral immune responses to vaccine antigen when used as adjuvants for prophylactic vaccines. However, their adjuvant effect on mucosal cellular immune responses remains unstudied. The precursor lesion of cervical cancer, high-grade CIN that expresses HPV E7 oncoprotein ubiquitously is a target for HPV therapeutic vaccines that elicit mucosal E7-specific type 1 T cell responses. We have demonstrated that oral immunization with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7) is more effective in eliciting mucosal E7-specific IFNγ-producing cells than subcutaneous or intramuscular antigen delivery. Here we report the synergistic effect of an oral Lactobacillus-based vaccine and Japanese herbal medicines on mucosal immune responses. Oral immunization of mice with LacE7 plus either a Japanese herbal medicine (JTT or HET) or a mucosal adjuvant, heated-labile enterotoxin T subunit (LTB), promotes systemic E7-specific type 1 T cell responses but not mucosal responses. Administration of LacE7 plus either Japanese herbal medicine and LTB enhanced mucosal E7-specific type 1 T cell response to levels approximately 3-fold higher than those after administration of LacE7 alone. Furthermore, secretion of IFNγ and IL-2 into the intestinal lumen was observed after oral administration of LacE7 and was enhanced considerably by the addition of Japanese herbal medicines and LTB. Our data indicated that Japanese herbal medicines, in synergy with Lactobacillus and LTB, enhance the mucosal type 1 immune responses to orally immunized antigen. Japanese herbal medicines may be excellent adjuvants for oral Lactobacillus-based vaccines and oral immunization of LacE7, HET and LTB may have the potential to elicit extremely high E7-specific mucosal cytotoxic immune response to HPV-associated neoplastic lesions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Synchronous carcinomas in the endometrium and ovaries can be a single primary tumor with metastasis (SPM) or dual primary tumors (DP). Although the prognosis of DP without any metastases is significantly better than that of SPM, pathological diagnosis is difficult in tumors with similar histological features., Materials and Methods: In 10 tumors from 5 patients with synchronous endometrial and ovarian carcinomas, 250K single nucleotide polymorphism arrays were performed. The patients were genetically diagnosed according to the pattern of copy number alterations (CNAs), in addition to microsatellite status and mutational analysis of PIK3CA, PTEN, K-Ras, and CTNNB1., Results: Of the 5 patients, 3 exhibited identical CNA patterns, including type, loci, and degree of each alteration in the endometrial and ovarian carcinomas. The other 2 exhibited CNAs only in either endometrial or ovarian carcinoma. All 5 tumors had 1 or more genetic mutations in the genes examined. One patient exhibited mutations both in PIK3CA and PTEN at discordant sites between endometrial and ovarian carcinomas, whereas the other 4 exhibited concordant mutations. Overall, 4 of the 5 patients were genetically diagnosed with SPM, and the remaining 1 with DP. The pathological diagnosis was not in agreement with the genetic diagnosis in 4 of the 5 patients., Conclusions: Genome-wide genotyping diagnosis may represent a useful approach for distinguishing between SPM and DP in synchronous endometrial and ovarian carcinomas.

Interstitial pneumonitis after treatment with pegylated liposomal doxorubicin (PLD) has been rarely reported. We describe herein a case of interstitial pneumonitis in a 49-year-old woman with relapsed ovarian carcinoma treated with PLD. Twenty-five days after the second administration of PLD, she presented with fever and dry cough, and chest CT scans revealed bilateral interstitial infiltrates and ground-glass opacities. She was diagnosed to have interstitial pneumonitis induced by PLD. Steroid therapy improved her symptoms.

The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235--a dual PI3K/mTOR inhibitor--and RAD001--an mTOR inhibitor--in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas.

PROBLEM  β(2) glycoprotein1 (β(2) GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-β(2) GP1 antibodies can interact with phosphatidylserine (PS)-bearing CD1d on trophoblast cells and induce local inflammation. METHODS  CD1d-bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross-linking. Cytokine production during co-culture of decidual lymphocytes with CD1d-bearing cells was also examined. RESULTS  Trophoblast surface-expressed CD1d forms a complex with PS-bound β(2) GP1. Anti-β(2) GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-β2GP1 mAb to co-cultures resulted in a three-fold increase in IL12p70 secretion. IFNγ secretion from decidual lymphocytes was also induced during co-culture with anti-β2GP1 mAbs. CONCLUSIONS  β(2) GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism., (© 2011 John Wiley & Sons A/S.)

Cervical cancer is the second largest cause of cancer-related death in women worldwide, and it occurs following persistent infection, sometimes for decades, with a specific subset of human papillomavirus (HPV) types; the approximately 13 oncogenic subtypes. Prophylactic vaccines against HPV infections hold promise for cost-effective reductions in the incidence of cervical cancer, but this may not be enough. Two prophylactic HPV vaccines are presently available and both contain L1 virus-like particles (VLPs) derived from the HPV subtypes most frequently associated with cervical cancer, HPV-16 and -18. Since the L1-VLP vaccines can only effectively prevent infection by the specific HPV subtype against which the vaccine was developed, cervical cancers caused by high-risk HPV subtypes other than HPV-16 and -18 may still occur in recipients of the current HPV vaccines. Furthermore, HPV vaccination coverage for adolescents is insufficient in most countries and therefore even HPV-16 and -18 infections are unlikely to be fully eradicated using the existing strategies. The development of HPV therapeutic vaccines remains essential. Many therapeutic vaccines aimed at clearing HPV-related cervical lesions have been developed and tested in patients with HPV16-positive cervical intraepithelial lesions (CIN) or cervical cancers. To date, definitive clinical efficacy and appropriate immunological responses have never been demonstrated for cervical neoplasia although promising results have been reported in patients with vulvar intraepithelial neoplasia. Here we discuss shortcomings of previous HPV therapeutic vaccine candidates and propose a novel vaccination strategy that leverages newly gained knowledge about mucosal immunity and the induction of mucosal immune responses.

Aim: This study aimed to clarify the factors affecting the outcome of induction of labor (IOL) in a Japanese population and to develop a prediction model to assess the probability of emergent cesarean section (CS)., Material and Methods: By reviewing the medical records of 1029 women who underwent IOL, we compared the emergent CS rate during IOL among subgroups divided by parity and pre-labor risk, such as fetal anomaly and maternal complication. We created a prediction model to predict the CS rate during IOL focusing on 392 cases of nulliparous women with premature rupture of membrane (PROM). Six factors, including Bishop score (BS), gestational age, maternal body mass index (BMI), maternal height (MH) and birth weight (BW) were extracted and multivariable logistic regression analysis followed by cross-validation test were performed., Results: The emergent CS rate was remarkably higher in the nulliparous group than in the multiparous group (17.6% vs 2.0%). In the nulliparous group, the high-risk group demonstrated a higher CS rate than the low-risk group (33.8% vs 15.6%). Multivariate analysis on nulliparous low-risk cases with PROM demonstrated significant odds ratios for emergent CS in BS, MH and BW. Cross-validation test selected these three factors as the best combination of parameters. The prediction formula was determined as follows: probability of CS (%) = (odds/1 + odds) ∗ 100, odds = e(X) and X = 8.18 + 1.23 ∗ BW (kg)- 7.74 ∗ MH (m)- 0.253 ∗ BS., Conclusion: This study is the first to provide a prediction formula targeting an Asian population. Our model, which is specialized for nulliparous low-risk women could enable obstetricians to inform patients of the precise prospect of IOL outcome., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)

Problem: Mucosal T cells are the most likely direct effectors in host anti-human papillomavirus adaptive immunity and regression of cervical intraepithelial neoplasia (CIN) lesions. There are no studies addressing intraepithelial lymphocytes (IELs) in CIN lesions., Method of Study: Cervical lymphocytes were collected using cytobrushes from patients with CIN and analyzed by FACS analysis. Comparisons were made between populations of cervical T cells in CIN regressors and non-regressors., Results: A median of 74% of cervical lymphocytes were CD3(+) T cells. Populations of integrin αEβ7(+) IEL in CIN lesions varied markedly among patients (6-57%). Approximately half of integrin β7(+) T cells were CD45RA-negative memory T cells. The number of integrin αEβ7(+) cells among cervical T cells was significantly higher in CIN regressors when compared to non-regressors., Conclusion: Higher cervical IEL numbers are associated with spontaneous regression of CIN. Accumulation of cervical integrin αEβ7(+) IEL may be necessary for local adaptive effector functions., (© 2011 John Wiley & Sons A/S.)

Background: The bioactive lipid lysophosphatidic acid (LPA) exerts multiple effects in the female reproductive system. Serum/plasma LPA is mainly produced by the lysophospholipase D activity of autotaxin (ATX). Previous studies have suggested that ATX has critical roles in cancer, reproduction, and vascular development. In the present study, we evaluated the usefulness of serum ATX measurements in pregnant women., Methods: We measured the serum ATX antigen levels in 32 normal pregnant women, 15 patients with pregnancy-induced hypertension (PIH), and 7 patients with preterm delivery using a recently developed automated enzyme immunoassay., Results: The serum ATX antigen levels in normal pregnant women were significantly higher than those in non-pregnant women (P<0.001). The serum ATX antigen levels in normal pregnant women were significantly and positively correlated with the gestational week (r=0.809, P<0.001). During the third trimester, the serum ATX antigen levels of the patients with PIH (3.299 ± 1.720 mg/l) were significantly lower than those of the normal pregnant women (4.915 ± 2.323 mg/l) (P=0.04)., Conclusions: The serum ATX antigen level increases with the progression of pregnancy. The serum ATX level may be a serological marker for the prediction of PIH., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Low-grade endometrial stromal sarcoma (ESS) is a rare neoplasm and is generally an indolent tumor with estrogen and progesterone receptors. Objective responses by hormonal treatment with progestin or aromatase inhibitor have been reported, however, long-term management of this disease could be difficult if it becomes refractory to one of these hormonal therapies. A 34-year-old woman was diagnosed with stage I low-grade ESS at the time of hysterectomy for presumed uterine fibroma. Five years later, she recurred with multiple tumors in the lower abdomen. After an optimal surgery, she was free from progression for 6 years with progestin treatment (medroxyprogesterone acetate: MPA, 200-600 mg daily). Thereafter, she recurred twice during the MPA treatment and received debulking surgery each time. MPA was discontinued at age of 53, because another recurrent tumor grew up to 13 cm in diameter. Aromatase inhibitor anastrozole was then given at a daily dose of 1 mg with partial response (the tumor size decreased to 7 cm in diameter) for a duration of 9 months. After complete resection of the recurrent tumor, she remains progression-free for 16 months. Anastrozole was effective to recurrent low-grade ESS even after being refractory to progestin therapy. Aromatase inhibitor treatment may be a useful option as a second-line hormonal treatment to low-grade ESS.

The perinatal mortality rate of vasa previa is high if it is not prenatally diagnosed. In this report, a case of vasa previa diagnosed prenatally is presented. Antepartum hemorrhage at 24 weeks of gestation prompted a close investigation of the uterine cervix, internal os, and placenta. We detected a low-lying bilobed placenta with umbilical cord insertion in the lower uterine segment. Furthermore, one of the connecting vessels of the bilobed placenta passed directly above the internal os. Vasa previa was suspected and confirmed with color Doppler and MRI. The fetus was delivered uneventfully by planned Cesarean section at 38 weeks of gestation. It should be considered that placenta previa (including low-lying placenta), bilobed placenta, and umbilical cord insertion in the lower uterine segment are associated with high risk of vasa previa. Ultrasound screening for cord insertion and placenta around the internal os enables efficient and certain detection of vasa previa.

Hypothermia is believed to suppress cell proliferation by inducing apoptosis/necrosis and phase-specific/nonspecific cell cycle arrest, which are, directly or indirectly, related to a reduced energy supply. Intriguingly, hypothermia is known to improve neurological recovery of animals and humans exposed to focal brain hypoxic-ischemic injury. The underlying mechanism of the neuroprotective effect of hypothermia is unclear, although the prevention of neural cell apoptosis is thought to play a role. Herein we demonstrate that in vitro cell culture of oligodendrocyte precursor cells (OPCs) under conditions of mild hypothermia (31.5°C) results in an increase in cell number relative to cells cultured under normothermic conditions (37°C). Cell cycle analysis, immunoblotting of cyclins, TUNEL assay, and immunocytochemistry of OPC differentiation markers suggest that hypothermia shifts the balance between proliferation and apoptosis/differentiation toward proliferation. A combination of transcriptome analysis, pharmacological intervention, and immunoaffinity-based assays suggests a possible involvement of the Gα13-Rho GTPase Cdc42-ERK1/2 signaling cascade and voltage-dependent anion channel 1 (VDAC1), which associate or dissociate with Gα13 protein at 37°C and 31.5°C, respectively. Immunoelectron microscopy revealed the presence of VDAC1 in the plasma membrane of OPCs. Furthermore, the exogenous addition of impermeable VDAC1 inhibitors enhanced proliferation of OPCs at 37°C. These results may contribute to the elucidation of the mechanism of hypothermic neuroprotection as well as the possible novel role of plasmalemmal VDAC1., (Copyright © 2010 Wiley-Liss, Inc.)

CD1d and CD1d-restricted natural killer T (NKT) cells serve as a natural bridge between innate and adaptive immune responses to microbes. CD1d downregulation is utilized by a variety of microbes to evade immune detection. We demonstrate here that CD1d is downregulated in human papillomavirus (HPV)-positive cells in vivo and in vitro. CD1d immunoreactivity was strong in HPV-negative normal cervical epithelium but absent in HPV16-positive CIN1 and HPV6-positive condyloma lesions. We used two cell lines for in vitro assay; one was stably CD1d-transfected cells established from an HPV-negative cervical cancer cell line, C33A (C33A/CD1d), and the other was normal human vaginal keratinocyte bearing endogenous CD1d (Vag). Flow cytometry revealed that cell surface CD1d was downregulated in both C33A/CD1d and Vag cells stably transfected with HPV6 E5 and HPV16 E5. Although the steady-state levels of CD1d protein decreased in both E5-expressing cell lines compared to empty retrovirus-infected cells, CD1d mRNA levels were not affected. Confocal microscopy demonstrated that residual CD1d was not trafficked to the E5-expressing cell surface but colocalized with E5 near the endoplasmic reticulum (ER). In the ER, E5 interacted with calnexin, an ER chaperone known to mediate folding of CD1d. CD1d protein levels were rescued by the proteasome inhibitor, MG132, indicating a role for proteasome-mediated degradation in HPV-associated CD1d downregulation. Taken together, our data suggest that E5 targets CD1d to the cytosolic proteolytic pathway by inhibiting calnexin-related CD1d trafficking. Finally, CD1d-mediated production of interleukin-12 from the C33A/CD1d cells was abrogated in both E5-expressing cell lines. Decreased CD1d expression in the presence of HPV E5 may help HPV-infected cells evade protective immunological surveillance.

Purpose: To investigate the relationship between displacement of the bladder base and genitohiatal distance during voluntary contractions of pelvic floor muscles in postpartum women., Methods: Twenty women (age 34.7 ± 4.4 years, BMI 21.1 ± 3.2 kg/m(2)) at about 6 weeks after a vaginal delivery were studied. Displacement of the bladder base and genitohiatal distance were measured by transabdominal and transperineal ultrasound, respectively., Results: Displacement of the bladder base was significantly correlated with shortening of genitohiatal distance (r = 0.772, p < 0.001). The intraclass correlation coefficient of the three measurements in each woman was 0.796 for displacement of the bladder base. There was no significant difference in terms of displacement of the bladder base between continent women and incontinent women., Conclusion: This study suggests a strong positive correlation between displacement of the bladder base and shortening of genitohiatal distance during voluntary contractions of pelvic floor muscles in postpartum women. Measurement of displacement of the bladder base by transabdominal ultrasound can be helpful for evaluating pelvic floor function in postpartum women.