Plasma adiponectin concentrations and placental adiponectin expression in pre-eclamptic women.

This study was conducted to compare maternal plasma adiponectin concentrations and adiponectin expression in term placentas between normotensive pregnant women and pre-eclamptic women. Plasma adiponectin concentrations were assessed by a sandwich enzyme-linked immunosorbent assay in 81 normotensive pregnant women, 27 pre-eclamptic women and 15 non-pregnant healthy women. The expression of adiponectin in the placentas was assessed by immunohistochemistry. Plasma adiponectin concentrations in normotensive pregnant women did not show a significant change during pregnancy and postpartum compared with non-pregnant women. However, plasma adiponectin concentrations in pre-eclamptic women were significantly (p < 0.05) lower than in non-pregnant and normotensive pregnant women. No immunoreactive adiponectin was detected in the term placentas of normotensive pregnant women, whereas a positive immunostaining for adiponectin was observed in endothelial cells of chorionic vessels in pre-eclamptic women. Our data suggest that decreased plasma adiponectin concentrations may contribute to the pathophysiology of pre-eclampsia and that adiponectin localized in chorionic vessels may play a role in the restoring of endothelial damage in the feto-maternal units of pre-eclampsia.

Caffeine induces apoptosis of human umbilical vein endothelial cells through the caspase-9 pathway.

Caffeine is known to modulate placental and fetal umbilical circulation. It is demonstrated that apoptosis of human umbilical vein endothelial cells (HUVECs) is associated with placental umbilical vascular diseases. The present study was conducted to investigate the effects of caffeine on apoptosis of HUVECs. Isolated HUVECs were cultured under serum-free conditions for 24 h, and then treated with graded concentrations of caffeine (30, 100 and 300 microM) for additional 24 h and 48 h. The number of viable HUVECs was determined by cell counting. Apoptotic HUVECs were assessed by Hoechst33342 dye staining. The expression of caspase-9, caspase-8, caspase-3 and poly(ADP-ribose) polymerase (PARP) was assessed by Western blot analysis. Caffeine induced a dose- and time-dependent decrease in the number of viable HUVECs. Caffeine at concentrations higher than 100 microM significantly increased the percentage of apoptotic HUVECs. Caffeine at concentrations higher than 100 microM significantly increased cleaved caspase-9, caspase-3 and PARP expression in HUVECs at 24-h treatment compared with untreated cultures, whereas 30 microM caffeine significantly increased only caspase-3 expression at 24 h. Caffeine did not affect cleaved caspase-8 expression at 48 h. These results suggest that high concentrations of caffeine inhibit cell growth of HUVECs and induce apoptosis through the caspase-9 pathway.

A central role for ceramide in the age-related acceleration of apoptosis in the female germline.

An age-dependent acceleration of apoptosis occurs in female germ cells (oocytes), and this requires communication between the oocyte and its surrounding somatic (cumulus) cells. Here we show in aged mice that ceramide is translocated from cumulus cells into the adjacent oocyte and induces germ cell apoptosis that can be prevented by sphingosine-1-phosphate. Trafficking of ceramide requires gap junction-dependent communication between the cumulus cells and the oocyte as well as intact lipid rafts. Further, the occurrence of the elevated incidence of apoptosis in oocytes of aged females is concomitant with an enhanced sensitivity of the oocyte to a spike in cytosolic ceramide levels, as well as increased bax mRNA and Bax protein levels. Thus, the force driving the age-related increase in female germ cell death is multifactorial, but changes in the intercellular trafficking of ceramide, along with hypersensitivity of oocytes to ceramide, are key factors in this process.

Noncompaction of the left ventricular myocardium diagnosed in pregnant woman and neonate.

Noncompaction of the left ventricular myocardium (NCLV) is an uncommon congenital cardiomyopathy with poor prognosis. We describe a case of NCLV that developed in a pregnant woman and her neonate. A nulliparous woman was referred at 24 weeks' gestation due to dyspnea and fetal hydrops. Maternal echocardiography demonstrated NCLV with characteristic findings of prominent and excessive ventricular trabeculations and deep intertrabecular recesses in the left ventricle. An M-mode echocardiography suggested depressed left ventricular systolic function. A fetal echocardiography at 24 weeks' gestation demonstrated cardiomegaly, but morphologic findings were not definitive for NCLV. An emergency cesarean section was performed due to maternal heart failure. A neonatal echocardiography diagnosed NCLV with depressed left ventricular systolic function. The neonate died of cardiac failure on the second day of life. Autopsy confirmed the echocardiographic findings. Since patients with NCLV may develop heart failure, multidisciplinary management is mandatory. In addition, awareness of familial occurrence of NCLV should be kept in mind for early diagnosis in the fetus and neonate.

Changes in the expression and cytological localization of betacellulin and its receptors (ErbB-1 and ErbB-4) in the trophoblasts in human placenta over the course of pregnancy.

OBJECTIVE: Betacellulin (BTC), purified and cloned from mouse beta cell tumor (BTC-JC10), is regarded as a new member of the epidermal growth factor family. The present study was conducted to clarify the expression of BTC and its receptors, ErbB-1 and ErbB-4, in the trophoblasts in the human placenta over the course of pregnancy. DESIGN AND METHODS: Human placental tissues were obtained from 4 pregnant women at the 4th to 5th week of pregnancy (very early placentas), 10 women at the 6th to 12th week (early placentas), 5 women at the 18th to 21st week (mid placentas) and 8 women at the 38th and 40th week (term placentas). The mRNA expressions of BTC, erbB-1 and erbB-4 were evaluated by quantitative RT-PCR with Southern blotting and the expression of the soluble form of BTC was determined by western immunoblot with a specific antibody to BTC protein. Immunohistochemical staining of BTC, ErbB-1 and ErbB-4 was also performed. RESULTS: The levels of BTC mRNA expression in early and mid placentas were significantly higher than those in term placentas. The soluble form of BTC protein with an estimated molecular mass of 9.5 kDa was expressed in early and mid placentas, whereas the soluble form was not detected in term placentas. BTC from very early placentas until mid placentas was immunolocalized in syncytiotrophoblasts (S-cells), and was most abundant in early placentas. In contrast, BTC was immunolocalized in extravillous trophoblasts (EVTs), but not in villous trophoblasts in term placentas. The levels of erbB-1 mRNA in the early and mid placentas were significantly higher than those in term placentas, whereas the levels of erbB-4 mRNA in early placentas were significantly lower than those in mid and term placentas. ErbB-1 was immunolocalized in cytotrophoblasts in very early placentas, whereas it was immunolocalized in S-cells from early until term placentas. ErbB-4 from very early placentas until mid placentas was immunolocalized in S-cells, whereas ErbB-4 in the term placentas was detected in EVTs, but not in villous trophoblasts. CONCLUSIONS: These findings provide evidence for changes in expression and cytological localization of BTC and its receptors in the trophoblasts in human placenta over the course of pregnancy. BTC may play a pivotal role as a local growth factor in promoting the differentiated villous trophoblastic function via ErbB-1 in early placentas and in contributing to placental growth through the maintenance of EVT cell function via ErbB-4 in term placentas.

Minireview: Up-date management of non responder to clomiphene citrate in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder in which chronic anovulation is a common feature despite the presence of multiple micro- structures in the ovaries. A growing body of evidence has suggested that serum hyperinsulinemia contributes to the excess ovarian androgen secretion observed in women with PCOS. The standard therapy for anovulatory women with PCOS is oral administration of clomiphene citrate (CC). However, a significant proportion of women with PCOS fail to ovulate with the use of standard dosage of CC and are called CC-resistant PCOS. The recent introduction of the insulin-sensitizing agents as adjuvants to clomiphene citrate and gonadotropins has changed the treatment strategy. This is a comprehensive review of the literature, with an emphasis on the role of hyperinsulinemia in the pathogenesis of PCOS and on randomized controlled trials of the medical and surgical treatment options for women with CC-resistant PCOS. Although both standard and novel treatments were addressed in the present review, special attention was paid to the evidence in support of the recent introduction of insulin-sensitizing agents in the management of anovulatory woman with CC-resistant PCOS.

Prenatal imaging of congenital cerebral primitive neuroectodermal tumor.

A case of fetal brain tumor, which appeared after 32 weeks' gestation, is presented. Prenatal ultrasonography and magnetic resonance imaging demonstrated a large heterogeneous mass in the right supratentorial region and left enlarged ventricle. A male fetus weighing 2,616 g was delivered at 34 weeks' gestation by cesarean section and died on the 37th day of life due to rapid growth of the tumor. Following autopsy, the pathohistological examination revealed primitive neuroectodermal tumor. Magnetic resonance imaging in the prenatal management of the congenital brain tumor is efficient in evaluating the expansion and margin of the tumor and intratumoral bleeding, which are not demonstrated by ultrasonography.

Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells.

We recently reported that a targeted disruption of the gene encoding the aromatic hydrocarbon receptor (AHR) in mice reduces fetal oocyte apoptosis, leading to a 2-fold increase in the number of primordial follicles endowed at birth. Although the identity of the natural ligand(s) for the AHR remains to be unequivocally established, these findings indicate that the level of AHR function is an important physiological determinant of how many oocytes will succumb to apoptosis during development of the fetal ovaries. Furthermore, the AHR is a well established receptor for polycyclic aromatic hydrocarbons (PAHs), a class of ubiquitous environmental chemicals known to cause the death of female germ cells in fetal life. Given the possibility that the AHR serves as a key mediator of fetal oocyte death under both physiological and pathological situations, this study was conducted to more fully examine the impact of PAH-AHR interaction on fetal ovarian germ cells. In addition, experiments were designed to begin identification of the mechanism(s) by which ligand activation of the AHR induces prenatal oocyte depletion after transplacental exposure of fetuses to PAHs in vivo. Embryonic d 13.5 murine fetal ovaries cultured in the presence of PAHs exhibited a high level of germ cell loss via apoptosis that was prevented by the selective AHR antagonist, alpha-napthoflavone (ANF). Immunohistochemical analysis revealed an accumulation of Bax protein in germ cells of fetal ovaries exposed to PAHs before the onset of apoptosis, whereas cotreatment with ANF inhibited the induction of Bax expression. The functional importance of increased Bax expression to the cytotoxic response was confirmed by findings that fetal ovarian germ cell loss caused by in utero exposure of wild-type female fetuses to PAHs was not observed in Bax-deficient female fetuses exposed in parallel. We conclude that a central role exists for the AHR in transducing the actions of PAHs in fetal ovarian germ cells, and that the proapoptotic Bcl-2 family member, Bax, is a required mediator of PAH-induced oocyte loss in female fetuses exposed to PAHs in utero.