Potent and rapid activation of tropomyosin-receptor kinase A in endometrial stromal fibroblasts by seminal plasma.

Seminal plasma (SP), the liquid fraction of semen, is not mandatory for conception, but clinical studies suggest that SP improves implantation rates. Prior in vitro studies examining the effects of SP on the endometrium, the site of implantation, surprisingly revealed that SP induces transcriptional profiles associated with neurogenesis. We investigated the presence and activity of neurogenesis pathways in the endometrium, focusing on TrkA, one of the canonical receptors associated with neurotrophic signaling. We demonstrate that TrkA is expressed in the endometrium. To determine if SP activates TrkA signaling, we isolated the two most abundant endometrial cell types-endometrial epithelial cells (eEC) and endometrial stromal fibroblasts (eSF)-and examined TrkA activity in these cells after SP exposure. While SP only moderately activated TrkA in eEC, it potently and rapidly activated TrkA in eSF. This activation occurred in both non-decidualized and decidualized eSF. Blocking this pathway resulted in dysregulation of SP-induced cytokine production by eSF. Surprisingly, while the canonical TrkA agonist nerve growth factor was detected in SP, TrkA activation was principally induced by a 30-100-kDa protein whose identity remains to be established. Our results show that TrkA signaling is highly active in eSF and is rapidly induced by SP.

Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2-related factor 2 signaling in trophoblast cells.

AIM: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator against oxidative stress through the induction of antioxidant and cytoprotective genes, such as heme oxygenase 1 (HO-1), glutamyl cysteine ligase catalytic (GCLC), and glutamyl cysteine ligase modulatory (GCLM). Nrf2 signaling is disrupted in pre-eclamptic placentas, although increased oxidative stress is implicated in pre-eclampsia. The aims of the study were: (i) to investigate the mechanism that underlies the impaired Nrf2 signaling in pre-eclamptic placentas, and (ii) to examine the potential therapeutic role of statin for pre-eclampsia. MATERIAL AND METHODS: Human choriocarcinoma JAR cells were cultured under normoxia (20% O2 ) or hypoxia (1% O2 ). Small-interfering ribonucleic acids were used to knockdown Nrf2. Real-time quantitative reverse transcriptase polymerase chain reaction and Western blotting were used to evaluate the influence of oxidative stress (H2O2 100 µM) and simvastatin (50 µM) on Nrf2 and its target genes. Reactive oxygen species levels were analyzed by flow cytometry in immortalized human trophoblast TCL1 cells treated with or without H2O2 (100 µM) ± simvastatin (50 µM). RESULTS: Nuclear factor erythroid 2-related factor 2 activation was significantly suppressed under hypoxic conditions. Nrf2 knockdown resulted in insufficient enhancement of HO-1, GCLC and GCLM expression under oxidative stress. In contrast, Nrf2 signaling was augmented by simvastatin, which suppressed the induction of oxidative stress in trophoblasts. CONCLUSION: Hypoxia is one of the important negative regulators of Nrf2 activation, and simvastatin inhibits oxidative stress through the activation of Nrf2 signaling in trophoblasts, indicating the potential therapeutic role of statin for pre-eclampsia.

Complement split product C4d deposition in placenta in systemic lupus erythematosus and pregnancy-induced hypertension.

Systemic lupus erythematosus (SLE) and pregnancy-induced hypertension (PIH) are related to premature delivery and intrauterine growth restriction (IUGR), and share histological findings of the placenta. Association with complement dysregulation has been reported in pregnancy for both disorders. The purpose of this study was to investigate the utility of C4d immunohistochemistry for placentas with SLE- and PIH-associated pregnancy. C4d staining was performed on paraffin-embedded tissue of placentas from 26 patients with SLE, 26 with PIH, and 25 control cases. We used the H-score with a range of 0-300 for the evaluation of C4d immunoreactivity. Placentas of SLE and PIH cases showed a higher H-score than control cases (average, SLE, 38.3 (P < 0.05); PIH, 17.8; control, 1.68), with linear staining on the membrane of syncytiotrophoblast. C4d-high groups comprised 50% (12/26) of SLE and 35% (9/26) of PIH cases, with H-scores ranging 14-270 and 15-170. C4d-high groups were significantly associated with low-placental weights and low birth weight in both SLE and PIH (P < 0.05), and lower gestational age (P < 0.05) in PIH cases. These results suggest that C4d might be utilized as a biomarker evaluating the subsequent risk for IUGR and disease control during the gestation period in these patients.

Pyomayoma during pregnancy: a case report and review of the literature.

Pyomyoma (suppurative leiomyoma) is a rare but serious complication of uterine leiomyomas. Although the management of leiomyomas during pregnancy is usually expectant, prompt surgical intervention is mandatory for pyomyoma. We present a case of pyomyoma with peritonitis that necessitated myomectomy at 21 weeks of gestation in a 28-year-old nullipara in which the pregnancy continued to successful delivery at 37 weeks of gestation. Perinatal and neonatal outcomes in pregnancies complicated with pyomyoma may be improved by prompt surgical intervention even in the early second trimester. A brief review of the literature regarding pyomyoma associated with pregnancy is also described.

Serial magnetic resonance imaging of placenta percreta with bladder involvement during pregnancy and postpartum: a case report.

Whether to manage placenta previa percreta surgically or conservatively has been a controversial issue. A 30-year-old woman with placenta percreta with bladder involvement was treated conservatively. A planned cesarean section was performed at 33 weeks' gestation. A 1768-g female infant was delivered through a transverse fundal uterine incision with the placenta left inside the uterus. The following morning, a massive postpartum hemorrhage occurred, and was successfully treated with transarterial embolization. The placenta was never expelled and spontaneously disappeared 4 months after surgery. We demonstrate serial magnetic resonance imaging of the placenta percreta during pregnancy and the postpartum period.

Uterine rupture successfully treated with a damage-control strategy of hysterectomy and resuscitative endovascular balloon occlusion of the aorta-assisted cardiopulmonary resuscitation.

Background: Uterine rupture is a major cause of postpartum hemorrhage (PPH) that requires surgery. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is also helpful for PPH. However, the effectiveness of REBOA in PPH with cardiac arrest is unknown. Case Presentation: A 40-year-old woman developed hemorrhagic shock due to uterine rupture after an induced delivery. She developed cardiac arrest, but was rescued by cardiopulmonary resuscitation (CPR), REBOA, a hysterectomy, and pelvic gauze packing. The hemodynamics were too unstable to move to the operating room. Then we initiated the CPR assisted with REBOA and decided to activate massive transfusion and perform laparotomy in the emergency room. She was finally discharged home without neurological sequelae. Conclusion: Our damage control strategy, including REBOA-assisted CPR, contributed to saving the life of a patient with a life-threatening PPH.

Deciduosis can cause remarkable leukocytosis and obscure abdominal pain.

Remarkable leukocytosis with obscure abdominal pain during pregnancy is clinically challenging for obstetricians. A 31-year-old pregnant woman developed persistently elevated white blood cell (approximately 30 000/µL) and C-reactive protein (3.0 mg/dL) with occasional moderate abdominal pain. At 29 gestational weeks, she underwent emergency cesarean section due to suspected abruptio placentae. Hemoperitoneum was observed with extensive hemorrhagic nodules on the peritoneal and omental surfaces. White blood cells rose 87200/µL, and C-reactive protein peaked at 44.9mg/dL after surgery. Pathologically, biopsies showed deciduosis, and decidual cells on the omental surface showed immunohistochemical staining for granulocyte colony-stimulating factor (G-CSF). Serum G-CSF concentration was 339 pg/mL at 28 weeks, and that of ascites was 312 000 pg/mL at cesarean section. G-CSF-producing deciduosis can induce leukocytosis as well as abdominal pain during pregnancy and postpartum.

Lower systolic blood pressure levels in early pregnancy are associated with a decreased risk of early-onset superimposed preeclampsia in women with chronic hypertension: a multicenter retrospective study.

To clarify the impact of blood pressure (BP) management ranges on pregnancy outcomes, we conducted a multicenter retrospective analysis of 215 women with singleton pregnancies diagnosed with essential hypertension either before or within 14 weeks of gestation. Patients were classified according to systolic BP (sBP; <130, 130-139, 140-159, and ≥160 mmHg) or diastolic BP (dBP; <80, 80-89, 90-109, and ≥110 mmHg) at 8-11, 12-15, and 16-19 weeks of gestation. The risk of early-onset superimposed preeclampsia and small-for-gestational-age neonates was assessed in each BP group. Moreover, a subgroup analysis was performed in 144 eligible patients whose BP was measured at both 12-13 and 14-15 weeks of gestation. At 16-19 weeks of gestation, higher sBP significantly increased the incidence of early-onset superimposed preeclampsia (13.3%, 24.6%, 32.2% and 75.0%, respectively) and small-for-gestational-age neonates (6.0%, 13.1%, 16.9% and 50.0%, respectively). Multivariate logistic regression analyses showed that women with sBP < 130 mmHg at 16-19 weeks of gestation had a significantly lower risk of early-onset superimposed preeclampsia than women with sBP of 140-159 mmHg. Subgroup analyses also showed that even at 14-15 weeks of gestation, sBP < 130 mmHg was associated with a significantly lower risk of early-onset superimposed preeclampsia than an sBP of 140-159 mmHg. In conclusion, sBP < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed preeclampsia in women with chronic hypertension.

Disseminated intravascular coagulation as the presenting sign of gastric cancer during pregnancy.

Gastric cancer during pregnancy is rare and the outcome is generally poor. A 36-year-old woman in the 28th week of gestation was complicated with disseminated intravascular coagulation (DIC), and she was diagnosed with gastric cancer with bone marrow metastasis. Cesarean delivery followed by sequential methotrexate (100 mg/m2) and 5-fluorouracil (600 mg/m2) chemotherapy was conducted. DIC was successfully managed with blood transfusion and chemotherapy. She has received chemotherapy in the outpatient clinic. This report is the second case of a pregnant woman with DIC as the initial manifestation of advanced gastric cancer. Prompt diagnosis and chemotherapy increases the chances of a relatively favorable outcome even in advanced gastric cancer presenting with DIC due to bone marrow involvement.

Secondary postpartum hemorrhage due to uterine artery pseudoaneurysm rupture in von Willebrand disease.

We here report a case of a 33-year-old woman who experienced secondary postpartum hemorrhage (PPH) due to uterine artery pseudoaneurysm rupture. She had intrauterine balloon tamponade for unexplained primary PPH after spontaneous vaginal delivery, and subsequent angiography showed no abnormal contrast extravasation. However, profuse vaginal bleeding occurred 22 days postpartum. Color Doppler ultrasonography demonstrated an anechoic mass with turbulent flow in the lower uterine segment, corresponding to uterine artery pseudoaneurysm. She was successfully treated with selective uterine arterial embolization. Decreased levels of von Willebrand factor and factor VIII led to the diagnosis of von Willebrand disease. When it is determined that a patient has unexplained PPH or uterine artery pseudoaneurysm, a high index of suspicion and further investigation for underlying bleeding disorders is warranted.

Management of retained products of conception with marked vascularity.

Cases of retained products of conception (RPOC) with marked vascularity present a clinical challenge because simple dilation and curettage (D&C) can lead to life-threatening hemorrhage. We describe here two cases of hypervascular RPOC that were successfully managed with two different approaches. Case 1: A 26-year-old woman with history of 3 D&Cs was transported to the emergency room for heavy vaginal bleeding 45 days after a spontaneous abortion. Diagnosis of RPOC with aneurysm-like structure was considered and uterine artery embolization was performed. Four days after the uterine artery embolization, reduction of the vascularity of RPOC was confirmed on color Doppler ultrasonography and D&C was successfully carried out. Case 2: A 37-year-old woman with history of one cesarean section became pregnant after the regular menses. She underwent D&C for missed abortion at 8 weeks' gestation. Seven days after the D&C, sonographically heterogenous mass emerged in the vicinity of the previous cesarean scar. Thereafter, the mass gradually grew larger and diagnosis of hypervascular placental polyp was considered. As the amount of vaginal bleeding was small, expectant management was instituted. Sixty-one days after the first D&C, reduction of the vascularity of RPOC was confirmed on color Doppler ultrasonography and D&C was successfully completed.

Prenatal findings in congenital leukemia: a case report.

We here describe a case of congenital leukemia that ended in intrauterine fetal demise at 30 weeks of gestation. Acute enlargement of the fetal trunk, elevated pulsatility index of the umbilical artery with concomitant decline of pulsatility index of the middle cerebral artery, pleural effusion, and polyhydramnios preceded the fetal death. Diagnosis of congenital myeloid leukemia was suggested by microscopic examination of the placental tissue, revealing immature myeloid precursors filling the lumina of fetal vessels in the umbilical cord and chorionic villi. Extensive vascular involvement of the placenta by leukemic cells was considered to be a primary cause of the fetal death.

Thioredoxin binding protein-2 inhibits excessive fetal hypoglycemia during maternal starvation by suppressing insulin secretion in mice.

Glucose is a major fuel for fetal development. Fetal blood glucose level is mainly dependent on maternal blood glucose concentration, though it is also regulated by fetal insulin level. Thioredoxin binding protein-2 (TBP-2), which is identical to vitamin D3 up-regulated protein (VDUP1) and thioredoxin interacting protein (Txnip), was recently reported to be a key transcriptional factor controlling glucose metabolism. Here, we elucidated the functions of TBP-2 in maintaining blood glucose homeostasis during the fetal period. TBP-2(+/-) female mice were mated with TBP-2(+/-) male mice; beginning 16.5-d post coitum, pregnant mice were fed or fasted for 24 h. Under conditions of maternal starvation, the blood glucose levels of TBP-2(-/-) fetuses were significantly lower than those of TBP-2(+/+) fetuses, corresponding to the elevated plasma insulin levels of TBP-2(-/-) fetuses compared with those of TBP-2(+/+) fetuses. There was no difference between TBP-2(+/+) and TBP-2(-/-) fetuses in terms of their pancreatic beta-cell masses or the expression of placental glucose transporters under conditions of either maternal feeding or fasting. Thus, during maternal fasting, fetal TBP-2 suppresses excessive insulin secretion to maintain the fetus's glucose levels, implying that TBP-2 is a critical molecule in mediating fetal glucose homeostasis depending on nutrient availability.

Middle cerebral artery-peak systolic velocity in dizygotic twins with anti-E alloimmunization.

Middle cerebral artery-peak systolic velocity (MCA-PSV) has been reported to predict fetal anemia with similar accuracy as amniotic ΔOD450 assay. Alloimmunized dizygotic twin pregnancy allows us to compare anemic and non-anemic twins in the same intrauterine environment. We herein present a case of Rh (E)-incompatible dizygotic twin pregnancy, where MCA-PSV could precisely detect the anemia in one of the twins. A 36-year-old woman, whose previous child required exchange transfusion due to hemolytic anemia of newborn (HFDN), conceived twins after in vitro fertilization-embryo transfer. At 24 weeks' gestation, MCA-PSV of twin A and twin B were 23.9 cm/s (0.8 multiples of median; MoM) and 30.7 cm/s (1.0 MoM), respectively. At 31 weeks' gestation, MCA-PSV values of both twins were sharply elevated to nearly 1.4 MoM. Thereafter, MCA-PSV of twin A fell to 1.0 MoM, whereas MCA-PSV of twin B exceeded 1.5 MoM at 34 weeks' gestation. Development of fetal anemia was suspected and emergency cesarean section was performed. Twin B showed moderate anemia with positive direct Coombs' test and was diagnosed as HFDN due to anti-E alloimmunization. Twin B required phototherapy and red cell transfusion, but exchange transfusion was safely obviated.

Pseudo-Meigs Syndrome Caused by a Giant Uterine Leiomyoma with Cystic Degeneration: A Case Report.

Pseudo-Meigs syndrome is defined as secondary accumulation of ascites and hydrothorax associated with a pelvic tumor other than benign ovarian tumors such as fibroma, which usually resolve after surgical removal of the tumor. Here we report a case of pseudo-Meigs syndrome caused by a giant uterine leiomyoma, which was initially suspected to be ovarian cancer. A 37-year-old nulliparous woman presented with a 5-month history of abdominal distension and anorexia. Abdominal ultrasonography revealed a giant cystic lesion and solid mass in the peritoneal cavity, along with plentiful ascites. Chest X-ray images showed a small pleural effusion on the right side. The patient was referred to our hospital for treatment of suspected ovarian cancer and peritonitis carcinomatosis. Although serum CA125 level was elevated (up to 331.8 U/mL), magnetic resonance imaging showed a giant sub-serosal uterine leiomyoma with cystic degeneration (27 × 15 × 13 cm). A small dermoid cyst was also detected in the right ovary. Ascites was drained and the patient underwent myomectomy and ovarian cystectomy. The patient had a degenerated leiomyoma with no pathological evidence of malignancy. Because symptoms disappeared postoperatively and serum CA125 returned to normal, without recurrence of ascites, pseudo-Meigs syndrome was diagnosed.

Stress affects uterine receptivity through an ovarian-independent pathway.

BACKGROUND: Although stress is known to disturb natural fertility through the inhibition of the hypothalamic-pituitary-gonadal (HPG) axis, the impact of stress on infertile women who receive exogenous gonadal hormones is not well defined. This is probably due to lack of experimental models for evaluating the impacts of stress through an ovarian-independent pathway. The objective of this study was to investigate the possible impact of stress on uterine receptivity, independent of HPG axis dysfunction, using a mouse implantation model maintained with hormone supplementation. METHODS: Blastocysts from donor mice were transferred into the uterine lumen of ovariectomized (OVX) Balb/c female recipient mice following supplementation with estradiol and progesterone. The recipients were divided into two groups: those exposed (stress group) or not exposed (control group) to intermittent sonic exposure prior to embryo transfer (ET). The number of implantation sites (IS) was compared between these groups. Microarray analysis was performed to elucidate stress-induced molecular alterations in uteri during the implantation period. Sequential gene expression of leukemia inhibitory factor (Lif), an estradiol-inducible gene, was also analyzed using real-time PCR. RESULTS: A non-mating OVX model with satisfactory implantation rates was established. The number of IS in the stress group (n = 20) was significantly less than that in the control group (n = 18) (Mann-Whitney test, P = 0.0375). Implantation-related genes and ovarian-hormone-responsive genes were repressed in the stress group despite ovarian hormone supplementation. The expression of Lif was suppressed in the stress group. CONCLUSIONS: Stress can cause decreased uterine receptivity through an ovarian-independent pathway.

A Software Level Calibration Based on Bayesian Regression for a Successive Stochastic Approximation Analog-to-Digital Converter System.

Recently, a novel low-power high-precision analog-to-digital converter (ADC) called the successive stochastic approximation ADC has been proposed which has two kinds of outputs from different modes, and which requires a software-level error correction method of combining them into a high-precision total output. From the practical viewpoint, we propose an error correction method based on the Bayesian regression with an incremental learning, in which additional data are successively selected according to the uncertainty of the corresponding predictive total output, and the uncertainty is approximately estimated by evaluating the upper bound of the standard deviations of the Bayesian predictive distributions of the outputs in each block of a partition of the all data set. Through numerical experiments, we verify the performance of the proposed method.

Regulation of human extravillous trophoblast function by membrane-bound peptidases.

During human placentation, the invasion of extravillous trophoblasts (EVTs) into maternal decidual tissues, especially toward maternal spiral arteries, is considered an essential process for subsequent normal fetal development. However, the precise regulatory mechanisms to induce EVT invasion toward arteries and/or to protect EVTs from further invasion have not been well understood. Recently, we found that two cell surface peptidases, dipeptidyl peptidase IV (DPPIV) and carboxypeptidase-M (CP-M,) are differentially expressed on EVTs. DPPIV expression was mainly observed on EVTs that had already ceased invasion. CP-M was detected on migrating EVTs including endovascular trophoblasts in the maternal arteries. The enzymatic inhibition of these peptidases affected the invasive property of choriocarcinoma-derived cell lines, BeWo and JEG3 cells. In addition, a chemokine, RANTES, that is one of the substrates for DPPIV, enhanced invasion of EVTs isolated from primary villous explant culture and its receptor, CCR1, was specifically expressed on migrating EVTs toward maternal arteries. Furthermore, a novel membrane-bound cell surface peptidase, named laeverin, was found to be specifically expressed on EVTs that had almost ceased invasion. These findings suggest that membrane-bound peptidases are important factors regulating EVT invasion during early placentation in humans.

Spontaneous regression of congenital cystic adenomatoid malformation of the lung: longitudinal examinations by magnetic resonance imaging.

We report a case of large cystic adenomatoid malformation of the lung (CCAM), which occupied almost the entire left lung with a prominent mediastinal shift at 24 weeks of gestation. The volume of the lesion, determined by magnetic resonance imaging (MRI), was 27.0 cm3. Subsequent MRI and ultrasound examinations revealed a spontaneous resolution of the lesion at 32 and 36 weeks of gestation without a mediastinal shift, when the lesion volume was 12.8 cm3 and 5.6 cm3, respectively. At 37 weeks of gestation, a mature male baby weighing 2638 g with an Apgar score of 7 was delivered by elective cesarean section. A lobectomy of the left upper lobe of the lung was carried out at 3 days of age, due to an enlargement of the CCAM after birth.

New regulatory mechanisms for human extravillous trophoblast invasion.

Human extravillous trophoblasts (EVT) invade maternal deciduas and reconstructed maternal spiral arteries during early placentation. However, the precise regulatory mechanisms to induce EVT invasion toward arteries and/or to protect EVT from further invasion have not been well understood. Recently, it was found that EVT that had already ceased their invasion, specifically expressed cluster of differentiation (CD9) and dipeptidyl peptidase IV (DPPIV) on their cell surface. In addition, EVT migrating to maternal spiral arteries expressed CC chemokine receptor type-1 (CCR-1), which is a chemokine receptor for regulated on activation normal T cell expressed and secreted (RANTES) and so on. CD9 is associated with integrin molecules on the cell surface and is considered to modulate integrin function. In contrast, DPPIV is a cell surface peptidase that can metabolize RANTES at extracellular sites before its accessing to the chemokine receptors. In vitro functional assay showed that CD9, DPPIV and RANTES are involved in the regulation for EVT invasion. From these findings, it can be proposed that CD9 and DPPIV, including chemokines, are new regulatory factors for human extravillous trophoblasts. (Reprod Med Biol 2005; 4: 189-195).