Search

Objectives: The purpose is to investigate how umbilical arterial blood flow changes by an intraamniotic distilled water infusion and to determine whether the changes in umbilical circulation have any relationship with fetal cardiovascular status and osmolality in amniotic fluid and fetal plasma. Methods: Eleven chronically catheterized pregnant sheep were used in this study. After a 1-hour control period, 1.5 L of warmed sterile distilled water was injected over 10 minutes into the amniotic cavity. Fetal heart rate and carotid arterial pressure, blood flow of the umbilical and fetal carotid arteries were continuously measured. Fetal arterial blood sampled twice during the control period and then at 30, 60, 90, 120, 180, 240, 300, and 360 minutes after the start of the infusion, was analyzed for blood gases, pH, plasma electrolytes, and osmolality. Results: Data obtained from seven sheep with normoxemic fetuses were studied statistically. Umbilical arterial blood flow decreased significantly from 229.5 ± 3.83 mL/min in the control to 167.4 ± 11.1 mL/min at 30 minutes after water infusion (P <.001). Umbilical arterial vascular resistance increased rapidly and reached its peak at approximately 60 minutes after infusion and then showed a gradual recovery to the control level (P <.001). Amniotic fluid osmolality had a high degree of correlation with umbilical arterial blood flow and vascular resistance, while fetal arterial blood pressure and heart rate had only little correlation with umbilical blood flow. Conclusion: A distilled water infusion into the amniotic cavity in near-term pregnant sheep led to an acute drop in umbilical arterial blood flow. The changes in umbilical flow were closely correlated with those in amniotic fluid osmolality. Hemolysis in the capillary networks in the fetal membranes seems to be one of the main causes of umbilical vasoconstriction. It is speculated that the fetal membranes, including capillary networks, intramembranous pathway, and amnion epithelial cells, sense the changes in amniotic fluid osmolality, which leads to a fetal adaptation to the hypotonic environment. [Copyright &y& Elsevier]

Objective: A fractal is a shape made of parts similar to the whole in some way. The objective of this study was to determine whether surface growth patterns in endometrioid endometrial adenocarcinoma are fractal, and the mean fractal dimension differs according to histologic grades and depth of myometrial invasion. Methods: After the images of photographs of 120 resected uteri with endometrial cancers were digitized, the fractal dimensions of surface of tumors were measured using a fractal analysis software. Results: The mean fractal dimensions of surface growth patterns in G1, G2, and G3 adenocarcinoma were 2.318, 2.303, and 2.383, respectively. These values were significantly greater than the topological dimension of a surface (= 2). The value was significantly higher in G3 than in G2 (p = 0.03). And although not statistically significant, the value of G3 was greater than G1 (p = 0.10) and than (G1 and G2) group (p = 0.06). No significant difference nor tendency was found in the fractal dimension of the surface of the tumor according to depth of invasion. Conclusion: This study shows that the surface of endometrioid endometrial adenocarcinoma has a fractal structure, and the mean fractal dimension may differ according to histologic grades. Our report proposes a new way of looking at endometrial cancer pathology. We believe that fractal geometry gives insights into tumor morphology and becomes a useful tool for analyzing complex and irregular tumor growth patterns mathematically. [ABSTRACT FROM AUTHOR]

Objective. The objective of this study was to determine whether sonographically depicted ovarian tumor growth is fractal, and the mean fractal dimension differs according to stages of the disease and histologic types.Methods. The fractal dimensions of outlines of sonographically depicted solid components in 160 ovarian tumors were measured using a box-counting method.Results. The mean fractal dimensions of the surface of intracystic solid components in serous, mucinous, endometrioid, and clear cell adenocarcinoma were 1.259, 1.243, 1.238, and 1.182, respectively. These values were significantly greater than the topological dimension of a line (=1). The value was significantly higher in stage I or II (1.381) than stage III or IV (1.205) in serous carcinoma (P = 0.02), but not significantly different in clear cell carcinoma (1.187 and 1.172, respectively). In stage I or II, the value of serous carcinoma (1.381) was significantly higher than that of clear cell carcinoma (1.187) (P = 0.03). The value of mucinous cystadenoma of low malignant potential was 1.337, which was also significantly greater than 1. The mean fractal dimensions of outlines of solid tumors in cases with dysgerminoma and thecoma-fibroma were 1.036 and 1.023, respectively. These values were not significantly different from 1.Conclusion. This study shows that the surface of solid components in cystic epithelial ovarian cancers has a fractal structure, and the mean fractal dimension may differ according to stages of the disease and histologic types. Fractal geometry, a vocabulary of irregular shapes, can be useful for describing the pathological architecture of ovarian tumors and for yielding insights into the mechanisms of tumor growth. [Copyright &y& Elsevier]

Abstract The purpose of this study was to investigate whether an actigraph can be a tool for measuring fetal movements in sheep. Actiwatches™ were placed on a fetal forelimb and the maternal uterine wall in near-term pregnant sheep. No significant correlation was found between fetal and maternal activity counts for periods of 1 min. The patterns of fetal activity counts were characterized by ultradian rhythms, with bursts of activity every 20–30 min; however, there was no evidence of diurnal changes in fetal activity counts. The results suggest that fetal movements can be measured by using an actigraph in chronically prepared fetal sheep. [ABSTRACT FROM AUTHOR]

The article reports on the call of the new editor-in-chief of the "Journal of Obstetrics and Gynaecology Research" for submissions from researchers within and beyond the Asia Pacific region on experimental and clinical investigation related to gynecology and obstetrics. It states that the acceptance criteria for these research papers are quality, originality and significance to readership. It adds that quality certification will be provided by the peer-review system for published papers.

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. [ABSTRACT FROM AUTHOR]

Abstract: Glutamate-induced excitotoxicity has been implicated in the pathogenesis of various neurological damages and disorders. In the brain damage of immature animals such as neonatal hypoxic-ischemic brain injury, the excitotoxicity appears to be more intimately involved through apoptosis. Bax, a member of the Bcl-2 family proteins, plays a key role in the promotion of apoptosis by translocation from the cytosol to the mitochondria and the release of apoptogenic factors such as cytochrome c. Recently, Bax-inhibiting peptide (BIP), a novel membrane-permeable peptide which can bind Bax in the cytosol and inhibit its translocation to the mitochondria, was developed. To investigate the possibility of a new neuroprotection strategy targeting Bax translocation in glutamate-induced neuronal cell death, cerebellar granule neurons (CGNs) were exposed to glutamate with or without BIP. Pretreatment of CGNs with BIP elicited a dose-dependent reduction of glutamate-induced neuronal cell death as measured by MTT assay. BIP significantly suppressed both the number of TUNEL-positive cells and the increase in caspases 3 and 9 activities induced by glutamate. In addition, immunoblotting after subcellular fractionation revealed that BIP prevented the glutamate-induced Bax translocation to the mitochondria and the release of cytochrome c from the mitochondria. These results suggest that agents capable of inhibiting Bax activity such as BIP might lead to new drugs for glutamate-related diseases in the future. [Copyright &y& Elsevier]

Background: Detrended fluctuation analysis (DFA) has recently been validated as an excellent method by which to analyze heart rate variability and distinguish healthy subjects from patients with various types of the cardiac nervous system dysfunction. Methods: One hundred and nineteen fetal heart rate (FHR) recordings obtained from healthy normal fetuses and 68 recordings obtained from small-for-gestational-age (SGA) fetuses were analyzed by DFA to examine gestational and pathologic changes of the scaling exponent, α. Results: In normal fetuses, a significant increase was observed in both the short-term (≤30 s) α1 and long-term (>30 s) α2 scaling exponents according to gestational age. The α1 values of SGA fetuses were not significantly different from those of healthy normal fetuses; however, the α2 values of the former group (0.955 ± 0.152) were significantly higher than those of normal subjects (0.887 ± 0.128; p = 0.001). Conclusion: The α2 exponent appears to be a sensitive probe for detecting subtle, and possibly important, changes that occur in fetuses with intrauterine growth restriction, and may be helpful in the early and noninvasive detection of placental insufficiency or incipient intrauterine growth restriction. The use of DFA techniques offers great promise for understanding FHR behavior. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Problem: Our previous studies have demonstrated that a subclass of soluble human leukocyte antigen-G1 protein (sub-sHLA-G1), that has α1 to α3 extra-cellular portion but lacks C-terminus of authentic soluble HLA-G1 secreted by trophoblasts, fine-tunes the release of cytokines from peripheral blood mononuclear cells (PBMCs) chiefly by counterbalancing membrane-bound HLA-G1 (mHLA-G1), and thereby may play a role in maintaining pregnancy. In this study, we investigated whether the presence of sHLA-G1 protein altered the release of cytokines from decidual mononuclear cells (DMCs) which are localized at the interface of feto–maternal interaction and whose cell population is completely different from PBMCs. Method of study: We cultured peripheral DMCs with either HLA-A and -B lacking B lymphoblast cell line (721.221 cells) or the cells transfected with mHLA-G1 (721.221-G1 cells) with or without sub-sHLA-G1. Cytokines concentrations in the culture media were determined by an enzyme-linked immunosorbent assay. Results: Regardless of the presence of mHLA-G1 expressing cells, the addition of the recombinant sub-sHLA-G1 protein in the DMC culture media decreased the amounts of tumor necrosis factor (TNF)-α and interferon (IFN)-γ, with the release of IL-4 from DMCs being unchanged. Conclusion: The sub-sHLA-G1 protein modulates the release of cytokines from DMCs additively to mHLA-G1 expressing cells. In view of the distinct fetomaternal interaction during implantation, it appears that sHLA-G1 might play a role in the establishment of pregnancy by regulating cytokine release in concert with mHLA-G1. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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 m L (range, 400-2000). The mean blood loss during delivery was 1976 ± 1654 m L. Autologous blood was transfused in 64 cases. Allogeneic blood transfusion was required in five cases of massive blood loss exceeding 5000 m L. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 m RNA 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

Abstract: 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 (≥8cm 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 (≥8cm 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 &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 ( P4), USMC were pretreated with P4 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 P4. 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 P4 may explain the mechanism by which progestin prevents preterm labor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2)-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. [ABSTRACT FROM AUTHOR]

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 PP1c and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

Abstract: 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 &y& Elsevier]

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 NVPBEZ235- 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. [ABSTRACT FROM AUTHOR]

Citation Iwasawa Y, Kawana K, Fujii T, Schust DJ, Nagamatsu T, Kawana Y, Sayama S, Miura S, Matsumoto J, Adachi K, Hyodo H, Yamashita T, Kozuma S, Taketani Y. A possible coagulation-independent mechanism for pregnancy loss involving β2glycoprotein 1-dependent antiphospholipid antibodies and CD1d. Am J Reprod Immunol 2012; 67: 54-65 Problem β2glycoprotein1 (β2GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-β2GP1 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 β2GP1. Anti-β2GP1 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 β2GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism. [ABSTRACT FROM AUTHOR]

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 = eX 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. [ABSTRACT FROM AUTHOR]

Citation Kojima S, Kawana K, Fujii T, Yokoyama T, Miura S, Tomio K, Tomio A, Yamashita A, Adachi K, Sato H, Nagamatsu T, Schust DJ, Kozuma S, Taketani Y. Characterization of gut-derived intraepithelial lymphocyte (IEL) residing in human papillomavirus (HPV)-infected intraepithelial neoplastic lesions.Am J Reprod Immunol 2011; 66: 435-443 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. [ABSTRACT FROM AUTHOR]

Abstract: 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±1.720mg/l) were significantly lower than those of the normal pregnant women (4.915±2.323mg/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 &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

The article presents guidelines on the determination and treatment of intrapartum fetal heart rate (FHR) patterns. The authors adopted a five-tier system to classify the FHR patterns and modified the color-coded classification. They propose a standardized management protocol according to FHR pattern, level for both doctors and midwives.

Abstract: Although many clinical trials on human papillomavirus (HPV) therapeutic vaccines have been performed, clinical responses have not been consistent. We have addressed mucosal cytotoxic cellular immune responses to HPV16 E7 after oral immunization of mice with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7). C57BL/6 mice were orally exposed to 0.1–100mg/head of attenuated LacE7 or vehicle (Lac) vaccines at weeks 1, 2, 4, and 8. Responses to subcutaneous or intramuscular injection of an HPV16 E7 fusion protein using the same timing protocol were used for comparison. Oral immunization with LacE7 elicited E7-specific IFNγ-producing cells (T cells with E7-type1 immune responses) among integrin α4β7+ mucosal lymphocytes collected from gut mucosa. An induction of E7-specific granzyme B-producing cells (E7-CTL) exhibiting killer responses toward HPV16 E7-positive cells was also observed. The induction of T cells with specific mucosal E7-type1 immune responses was greater after oral immunization with LacE7 when compared to subcutaneous or intramuscular antigen delivery. Oral immunization with Lactobacillus-based vaccines was also able to induce mucosal cytotoxic cellular immune responses. This novel approach at a therapeutic HPV vaccine may achieve more effective clinical responses through its induction of mucosal E7-specific CTL. [Copyright &y& Elsevier]

Problem Lysophosphatidic acid (LPA) is a bioactive lipid mediator and thought to play an important role in pregnancy. Plasma LPA is produced by autotaxin (ATX), and ATX activity in plasma increases during pregnancy paralleled with gestational weeks and decreases to near the non-pregnant level soon after delivery. However, the source of increased ATX during pregnancy is still uncertain. We hypothesized that the source of increased ATX might be placenta. Method of study We investigated the protein and mRNA expression of ATX in human placenta using immunohistochemistry and RT-PCR, respectively. Results At all 3 gestational trimesters, immunohistochemical staining for placenta tissues revealed the most marked positive staining of ATX protein in trophoblasts. Real-time PCR revealed that mRNA amounts of ATX in placenta tissues paralleled with gestational weeks, i.e. ATX level in plasma. Conclusion These findings suggest that trophoblasts might produce ATX and its bioactive resultant substance, LPA, paralleled with gestational weeks. [ABSTRACT FROM AUTHOR]

Problem Among class Ib human leukocyte antigen (HLA) molecules, HLA-E is known to be a major ligand of CD94/NKG2 receptor on natural killer (NK) cells, and to play a pivotal role in recognition of extravillous trophoblasts (EVTs) by maternal immune cells. However, it is scarcely known how HLA-E expression is regulated in EVTs. Method of study In this study, we investigated whether progesterone, an essential hormone in maintaining pregnancy, regulated HLA-E expression in EVT-like cell line, JEG-3. HLA-E mRNA amount in cultured JEG-3 cells was assessed by real-time PCR and cell-surface HLA-E protein was analyzed by flowcytometry. Results Real-time PCR showed 3.5-fold increase 1 hour after the addition of 1000 ng/ml progesterone. This response was dimished by the addition of RU486, an antagonist for progesterone receptor. Flowcytometry indicated that 1000 ng/ml progesterone slightly enhanced HLA-E expression on the surface of JEG-3. Conclusion These results suggest that progesterone up-regulates HLA-E expression in JEG-3 cells through the pathway mediated by progesterone receptor. Our findings might give a new insight into immunomodulatory function of progesterone at fetomaternal interface. [ABSTRACT FROM AUTHOR]

Background: Recently, multifractal analysis based on generalized concepts of fractals has been applied to biological tissues composed of complex structures. Methods: Using digitized images of the maternal surface of 278 placentas, multifractal parameters were measured with a fractal analysis software. Results: The values of αmin, α(0), αmax and the degree of multifractality given by the αmax – αmin difference calculated from 278 placentas were 1.840 ± 0.068, 2.089 ± 0.034, 2.856 ± 0.128 and 1.017 ± 0.136, respectively. A significant decrease of αmin and as a consequence a significant increase in the degree of multifractality were observed according to gestational age. The α(0) value of the placenta complicated by pregnancy-induced hypertension (PIH) was significantly higher than that without PIH. The αmin and α(0) values of the placenta having intrauterine growth restriction (IUGR) were significantly higher than those without IUGR. On the other hand, the presence of chorioamnionitis did not change multifractal properties of the maternal surface of the placenta. Conclusion: The multifractal parameters may be objective indices of the heterogeneity or complexity of the macroscopic morphology of the maternal surface of the placenta. Multifractal analysis holds a promise for quantitatively evaluating physiological and pathological development of the placenta. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: CD1d is a specific ligand for the invariant Vα24Vβ11-natural killer T (iNKT) cells that play an important role in placental development during early human pregnancy. The localization and regulation of placental CD1d expression remain unclear. Immunohistochemistry of human early gestational placentas revealed CD1d was present in villous and extravillous trophoblast (EVT) but not in syncytiotrophoblast or decidual cells. CD1d immunoreactivity in EVT cells decreased with EVT differentiation. Flow cytometry of primary cultured human trophoblast cells confirmed cell-surface expression of CD1d decreased with time in culture. These changes in CD1d expression occur at the level of transcription. TGF-β1 secreted from the cultured EVT cells accumulated with time in culture and directly suppressed CD1d expression, as evidenced by monoclonal antibody neutralization of TGF-β1 effects. Thus, trophoblast differentiation is characterized by TGF-β1-mediated decreases in trophoblast cell CD1d expression. This effect may support appropriate activation of decidual iNKT cells at the maternal-fetal interface. [Copyright &y& Elsevier]

Problem To get insight into the basis for the empirical usage of herbal medicines, such as Tokishakuyaku-san (Toki) and Sairei-to (Sai) in the treatment of recurrent abortion and intrauterine growth restriction, we examined whether these medicines modulate the production of granulocyte–macrophage colony-stimulating factor (GM-CSF), a cytokine working as an important mediator for intercellular communication in the embryonic development, in decidual stromal cells (DSCs). Method of study Human DSCs were cultured with either Toki or Sai at several different concentrations. The effect on cell proliferation was assessed by WST-8 assay. GM-CSF released into culture medium was analyzed using enzyme-linked immunosorbent assay, and semi-quantitative polymerase chain reaction was carried out to see GM-CSF mRNA expression in DSCs. Results Sai inhibited the proliferation of cultured DSCs, while no interference was observed in the presence of Toki. Both Toki and Sai enhanced the release of GM-CSF into culture medium. The amount of GM-CSF mRNA in cultured DSCs was as well increased by either Toki or Sai. Conclusion Considering the significance of GM-CSF in embryonic development, clinical benefit of these herbal medicines in the treatment of recurrent abortion might be based on the shown pharmacological reaction related to GM-CSF. [ABSTRACT FROM AUTHOR]

Problem Human leukocyte antigen (HLA)-F together with other class 1b HLAs may play a pivotal role in immunological interaction at feto-maternal interface. However, it is not elucidated whether HLA-F is expressed on cell surface of extra-villous trophoblasts (EVTs). Method of study The localization of HLA-F in placenta of each trimester was investigated by immunohistochemistry. The expression modality of HLA-F molecule was compared with that of HLA-G in cultured EVTs using flowcytometry. Results and conclusion In immunohistochemical study, remarkable staining for HLA-F was confirmed in EVTs throughout gestation. HLA-F expression was restricted to be intracellular in cultured EVTs. HLA-F expression was increased with time in culture, which was accompanied by the increase of cell surface HLA-G. Consequently, HLA-F lacking in cell surface expression on EVTs may not contribute to the direct cell-to-cell immune reaction but might work supportively modifying the function of HLA-G. [ABSTRACT FROM AUTHOR]

Abstract: The balance of inhibitory and activating natural killer (NK) receptors on maternal decidual NK cells, most of which are CD56bright, is thought to be crucial for the proper growth of trophoblasts in placenta. A lectin-like NK receptor, CD94/NKG2, is the receptor for human leukocyte antigen (HLA)-E, which is expressed on trophoblasts. To clarify the mechanism regulating the activity of decidual NK cells during pregnancy, we investigated the expression patterns of inhibitory NK receptor, CD94/NKG2A, and activating receptor, CD94/NKG2C, on decidual NK cells in an early stage of normal pregnancy and compared them with those on peripheral NK cells, most of which are CD56dim. The rate of NKG2A-positive cells was significantly higher for decidual CD56bright NK cells than for peripheral CD56dim NK cells, but the rates of NKG2C-positive cells were comparable between the two cell types. Interestingly, peripheral CD56dim NK cells reciprocally expressed inhibitory NKG2A and activating NKG2C, but decidual CD56bright NK cells that expressed activating NKG2C simultaneously expressed inhibitory NKG2A. The co-expression of inhibitory and activating NKG2 receptors may fine-tune the immunoregulatory functions of the decidual NK cells to control the trophoblast invasion in constructing placenta. [Copyright &y& Elsevier]

Abstract: Background: Many studies on the physiology of the cardiovascular system reported that nonlinear chaotic dynamics may govern the generation of the heart rate signal. Objective: To examine whether the heart rate dynamics of an intrauterine growth restricted (IUGR) fetus is different from a healthy normal fetus by nonlinear methods of time series analysis. Design of the study: One hundred nineteen fetal heart rate (FHR) recordings from healthy normal fetuses, and 69 recordings from IUGR fetuses were analyzed. Nonlinear analyses included attractor reconstruction, calculation of the largest Lyapunov exponents using the Wolf algorithm, and estimation of correlation dimension. The largest Lyapunov exponents from normal fetuses were checked by means of surrogate-data test. Results: Abnormal FHR patterns of IUGR fetuses such as decreased variability and repetitive late decelerations presented a remarkably different structure in the reconstructed attractor. Surrogate data suggest that the FHR of healthy normal fetuses has unique nonlinear characteristics. The largest Lyapunov exponents were positive for all of 119 healthy normal fetuses, indicating that the FHR control system is sensitive to initial conditions. The values of IUGR fetuses were significantly lower than those of normal subjects. In normal fetuses, significant changes of correlation dimension according to gestational age were observed. In IUGR fetuses, however, such changes were not found. Conclusions: The heart rate dynamics of IUGR fetuses is less chaotic than that of normal fetuses. Decreased system complexity suggested by correlation dimension may limit the IUGR fetuses'' ability to maintain cardiovascular integrity, and therefore, to adapt to the variety of internal and external cardiovascular stresses. [Copyright &y& Elsevier]

Background: Decelerations of fetal heart rate (FHR) are the results of many pathophysiological factors that modulate the intrinsic rate of the heart. FHR change is a complex phenomenon and can be viewed as a type of nonlinear dynamic system. This paper presents a qualitative model of FHR decelerations based on catastrophe theory, especially to account for abrupt heart rate changes seen in variable decelerations. Methods: One of the elementary catastrophes, the cusp catastrophe, was used to model FHR changes seen in variable, late, and early decelerations. Results: Catastrophe theory describes typical variable decelerations as an abrupt response to a slowly changing force of attack (uterine contraction) and physiological defense. Because of its three-dimensionality and topological features, the cusp catastrophe model provides a qualitatively satisfying description of FHR decelerations. Conclusion: The organized complexity of living systems offers the best hope for the application of catastrophe theory. The nature of the elementary catastrophes will be essential knowledge in the mathematical analysis of biology. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]