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In early pregnancy, human extravillous trophoblasts (EVTs) invade and remodel maternal arteries. We have previously demonstrated that CCR1 is expressed on perivascular/endovascular trophoblasts and that CCR1 ligands promote EVT migration. In this study, we examined the physiologic roles of platelet-derived chemoattractants on EVT invasion. By immunohistochemistry, maternal platelets were localized among endovascular trophoblasts within the lumen of spiral arteries. Extracellular matrices (ECMs) were also detected among endovascular trophoblasts and platelets, suggesting that the platelets in these arteries were activated by ECMs. In vitro, platelets attached to EVTs isolated from human villous explant cultures and expressed P-selectin on the cell surface. Platelets significantly enhanced migration of EVTs without affecting proliferation of EVTs or secretion of MMP-2 or MMP-9. The invasion-enhancing effect of platelet-derived culture medium on EVTs was neutralized by anti-CCR1 antibody. Heat treatment completely abrogated the invasion-promoting effects of platelet-derived culture medium, but charcoal stripping did not. Platelets also induced endovascular trophoblast-like morphologic changes and integrin α1 expression in EVTs during 48-hour culture. These findings suggest that maternal platelets activated in the spiral arteries can regulate trophoblastic vascular infiltration and differentiation by releasing various soluble factors.

In early pregnancy, human extravillous trophoblasts (EVTs) invade and remodel maternal arteries. We have previously demonstrated that CCR1 is expressed on perivascular/endovascular trophoblasts and that CCR1 ligands promote EVT migration. In this study, we examined the physiologic roles of platelet-derived chemoattractants on EVT invasion. By immunohistochemistry, maternal platelets were localized among endovascular trophoblasts within the lumen of spiral arteries. Extracellular matrices (ECMs) were also detected among endovascular trophoblasts and platelets, suggesting that the platelets in these arteries were activated by ECMs. In vitro, platelets attached to EVTs isolated from human villous explant cultures and expressed P-selectin on the cell surface. Platelets significantly enhanced migration of EVTs without affecting proliferation of EVTs or secretion of MMP-2 or MMP-9. The invasion-enhancing effect of platelet-derived culture medium on EVTs was neutralized by anti-CCR1 antibody. Heat treatment completely abrogated the invasion-promoting effects of platelet-derived culture medium, but charcoal stripping did not. Platelets also induced endovascular trophoblast-like morphologic changes and integrin α1 expression in EVTs during 48-hour culture. These findings suggest that maternal platelets activated in the spiral arteries can regulate trophoblastic vascular infiltration and differentiation by releasing various soluble factors.

A clinical case that suggested the involvement of blood coagulation cascades in the inflammation reaction induced by leakage of ovarian endometriotic cysts was encountered. Here, a rapid elevation in plasma D-dimer level (119.6 micro g/ml) was observed within 5 h after onset of ovarian cyst rupture. By contrast, the plasma fibrinogen level fell below normal range (105 mg/dl). During the following few days, the plasma D-dimer level fell acutely to approximately normal, while the fibrinogen level gradually increased to a high value (590 mg/dl). In addition, the anti-thrombin III level was slightly reduced on the day after rupture, though the concentration of blood platelets remained unchanged. Three days later, laparoscopic surgery showed the surface of the posterior wall of the uterus and peritoneum of the pelvic wall to be extensively covered with the leaked content of a right ovarian endometriotic cyst. Pathological examination confirmed the diagnosis of endometriotic cyst. In the endometrial stromal region, deposit of D-dimer was detected by immunohistochemical staining. These findings suggest that fibrin-derived degradation products in endometriotic cysts can affect coagulation cascades when they leak into the peritoneal cavity; they may also induce local inflammatory reactions, causing pelvic pain and/or extension of the endometriotic lesion.

Previously, it was reported that T-lymphocytes derived from non-pregnant mice promote murine embryo implantation. In order to examine the immunological regulation of endometrial receptivity in humans, the effects of peripheral blood mononuclear cells (PBMCs) on endometrial epithelial cell (EEC) function were monitored by a newly developed attachment assay using primary human EEC culture and BeWo cell-derived spheroids.

During the establishment of the maternal blood circulation around the implanting human embryo, maternal peripheral blood mononuclear cells (PBMC) directly contact trophoblasts. To determine the physiological significance of this interaction, the effects of PBMC obtained from pregnant women on the proliferative and invasive properties of a human choriocarcinoma cell line, BeWo cells, were examined.

Indoleamine 2,3-dioxygenase (IDO) is expressed in trophoblasts and defends the conceptus against rejection by reducing the tryptophan level and suppressing the T cell activity. We isolated a cDNA for tryptophan 2,3-dioxygenase (TDO), another key catabolizing enzyme of tryptophan, from a mouse uterus cDNA library enriched with pregnancy-induced genes. Northern blot and in situ hybridization analyses demonstrated that the TDO mRNA was induced in the decidualized stromal cells around the implanted embryo at the time of implantation. The expression was then upregulated and primarily localized at the mesometrial decidua. TDO mRNA was induced by deciduoma formation as well as embryo transfer but not by ovarian steroid hormones. These findings demonstrated that TDO is induced in the endometrial stromal cells concomitant with decidualization and suggested its involvement in the implantation process by regulating the tryptophan level at the implantation site.

PURPOSE: The effects of transcatheter intraarterial infusion of anticancer drugs on the prognosis of cervical cancer were retrospectively studied. MATERIALS AND METHODS: Two or three sessions of transcatheter arterial infusion therapy were performed in 97 patients with primary uterine cervical cancer. The number of patients in stage I, II, III, or IV were 15, 37, 34, and 11, respectively. The drugs infused were cisplatin (60-70 mg/m^2), doxorubicin hydrochloride (30-40 mg/m^2), mitomycin (15 mg/m^2), and 5-fluorouracil (500 mg/body). They were infused via the bilateral internal iliac arteries. Seventyfive patients of the 97 (78%) underwent radical hysterectomy after arterial infusion: stage I (14 of 15), stage II (31 of 37), stage III (25 of 34), and stage IV (5 of 11). Three stage II and nine stage III patients received radical radiation therapy. The other 10 patients (one with stage I, three with stage II, and six with stage IV) did not receive an operation and radiation therapy after arterial infusion because of their distant metastases at the time of operation. Thirty-eight patients of 75 (51%) received postoperative radiation therapy. RESULTS: The complete histologic response rates (no active cancer cells) after arterial infusion were four of 14, four of 31, six of 25, and one of five for stages I, II, III, and IV. The histologic response rates, which showed no parametrial invasion after arterial infusion, were 12 of 14, 24 of 31, and 15 of 25 for stages I, II, and III. The histologic response rates, which demonstrated no lymph node metastases after arterial infusion, were 12 of 14, 24 of 31, and 19 of 25 for stages I, II, and III. The overall 5-year survival rates of the patients with stages I, II, and III were 93.3%, 58.7%, and 69.7%, respectively. The 5-year survival rates of the operated patients with stages I, II, and III were 100%, 60.5%, and 63.6%, respectively. The 5-year survival rates of the irradiated patients with stage III was 87.5%. Leukocytopenia and thrombocytopenia occurred as an acute complication in 75% and 79% of the patients, respectively. As a late complication, ileus occurred in 7%. CONCLUSIONS: Arterial infusion may improve the prognosis of patients with cervical cancer without increasing the incidence of late complications.

We previously reported that integrin α6 is expressed on granulosa cells in the inner layers of the human and porcine ovarian follicles, where granulosa cells have no direct contact with basal lamina. In this study, we examined the physiological role of integrin α6 on follicular growth with an immature superovulated mice model using the anti-integrin α6 monoclonal antibody, GoH3. In the ovaries of 9- to 20-day-old mice, integrin α6 was detected on all the layers of granulosa cells in the primordial, primary, and secondary follicles by immunohistochemistry. The 13-day-old female mice were superovulated by pregnant mare serum gonadotropin and human chorionic gonadotropin with the treatment of intraperitoneal administration of GoH3, or a control antibody, or PBS. In the group of GoH3 treatment, successful ovulation was observed in 57±25.7% of the animals, whereas no ovulation was observed in the control groups (p<0.01). These findings indicate that integrin α6 is involved in gonadotropin-induced follicular growth.

N‐acetylaspartate (NAA) is found exclusively in neurons and their processes in the adult brain. Since the regional distribution of NAA may be imaged using magnetic resonance spectroscopic imaging (1H‐MRSI), a regional measure of neuronal density may be noninvasively obtained. The technique may be particularly useful in the diagnosis of diseases where neurons are selectively injured, since these diseases do not result in definitive changes on conventional imaging studies. The goal of this study was to determine whether 1H‐MRSI measurement of NAA detects neuronal loss following global ischemia. 1H‐MRSI was performed in rats 24 h after global ischemia was induced by bilateral carotid occlusion plus hypotension. 1H‐MRSI showed that NAA was decreased by 29–74% in vulnerable regions, including the cortex, striatum, hippocampus, and, to a lesser extent, the thalamus. No change was observed in the brain stem or cerebellum. Regions where 1H‐MRSI observed NAA was decreased also had histological evidence of selective neuronal necrosis and showed marked increase of lactate and alanine. These results show that 1H‐MRSI detected loss of NAA in brain regions with selective neuronal loss, suggesting that 1H‐MRSI measurements of NAA could detect neuronal loss in a variety of disease states where there is selective neuronal necrosis.

To investigate the expression of messenger RNA (mRNA) for gonadal steroid hormone receptors in the human pelvic peritoneum.

Mutation within the Mitfgene causes, in microphthalmic MitfMi/mitfMi(mi/mi) mice, multiple defects, including white coat color and functional defects in macrophages and osteoclasts. Our previous mating experiments have demonstrated that the mi mutation reduces the numbers of newborns and induces uterine inversion at delivery. The present study was designed to determine the causes of these pregnancy defects. The histology and number of F4/80-positive macrophages were not different between the ovaries of 23-day-old mi/miand +/+ mice given eCG 48 h earlier. When ovulation was induced in these mice by hCG, the number of ovulated ova was significantly smaller in mi/mimice than in wild-type (+/+) mice (p< 0.05). When bone marrow cells from +/+ mice were transplanted i.p. into 42 mi/mifemale newborns, successful transplantation was observed in 16 of them at 20 days after birth. In one of these, the upper incisors had erupted. The mean number of tubal ova in mi/mimice significantly increased after transplantation (p < 0.05) and was almost equal to that of +/+ mice. No uterine inversion occurred at 6 deliveries in 5 mi/mifemales after bone marrow transplantation, while it occurred at 4 of 5 deliveries in mi/mifemales during the same observation period (p< 0.05). These results indicate that bone marrow-derived cells, defective in mi/mimice, are necessary for normal ovulation and delivery; the findings are consistent with the notion that macrophages play major roles in ovulation.

Protein tyrosine phosphorylation is thought to play an important role in the regulation of neural function. To elucidate the role that protein tyrosine phosphatases (PTPs) may play in the postischemic brain, PTPs expressed in regions of the rat brain vulnerable to transient forebrain ischemia were examined. With the reverse-transcriptase polymerase chain reaction using degenerate primers, three PTPs, STEP, PTPS, and SH-PTP2, were identified. They were expressed in the hippocampus 12 h after transient ischemia for 20 min. During the reperfusion period, the mRNA levels of these PTPs were not different from those in sham-operated rats. In contrast, a fourfold increase in the mRNA level of CL100 (3CH134), a PTP that is inducible by oxidative stress, was detected by Northern blotting in the hippocampus and cerebral cortex 1 h after the onset of reperfusion. In situ hybridization histochemistry showed a slight increase in the level of CL100 mRNA in neuronal cells in the hippocampus and cortex of postischemic rats compared to control rats. These findings suggest that PTPs play a role in the normal function of the hippocampus and cerebral cortex and demonstrate that ischemia induced CL100 expression.

Vav is a signal transducing molecule containing SH2 and SH3 domains and a guanine nucleotide releasing factor-like domain. Its expression is thought to be highly specific for hematopoietic cells. Here we describe the expression of vavtranscripts in human nonhematopoietic trophoblasts. By northern blotting, expression of 2.8-kb vavmRNA was detected in human decidual, placental, and chorionic villous tissues and in a choriocarcinoma cell line BeWo. By in situ hybridization, vavmRNA was found to be expressed in the cytotrophoblast shell and columns and in the extravillous trophoblasts in the maternal decidua from the first through third trimesters. VavmRNA was also detected in villous syncytiotrophoblasts during the second and third, but not the first, trimesters. When 1 μM oligodeoxynucleotide antisense to the vavmRNA was added to the medium, growth of BeWo cells was significantly inhibited. These results suggest that vavplays an important role for successful implantation and placental development by regulating development of trophoblasts.

Using an electron-transfer stopped-flow method, the triphenylamine cation radical was generated in acetonitrile via the electron transfer between TPA and the tris(p-bromophenyl)amine cation radical and the changes in the absorption spectra were observed. The well-known decay process of was observed in the absence of TPA, reflecting the dimerization reaction of and the consecutive electron-transfer reactions of the dimer compound, tetraphenylbenzidine (TPB). When was mixed with a large excess amount of TPA, new absorption peaks appeared around 400 and 850 nm. No time changes were observed for these peaks, while the decrease in and the increase in were observed overlapping on these peaks. The new absorption spectrum can be assigned to that of or, more presumably, Although has not been recognized as an intermediate in the electrochemical oxidation of TPA, it has been ascertained that is electrochemically generated under certain conditions, e.g., during the initial stage of the oxidation of TPA in a stirred solution containing a sufficient amount of TPA. (c) 2001 The Electrochemical Society. All rights reserved.

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Leukaemia inhibitory factor (LIF) is a cytokine that displays multiple activities in various tissues and is essential for blastocyst implantation in mice. In the human uterus, LIF is expressed in endometrial tissue and the decidua. To elucidate the role it plays, the mRNA levels for two LIF receptor (R) subunits, LIF-R and gp130, were examined in human endometrium, placenta and decidua by Northern blot hybridization. The expression of LIF-R gene was detected in the chorionic villus during the first trimester, in term placenta, and at lower levels in the decidua. The expression of LIF-R gene was not detectable in non-pregnant endometrium. The expression of the gp130 gene was detected in all tissues examined. During pregnancy, there was no significant change in the mRNA concentration of LIF-R in the placenta, while that of gp130 increased after the second trimester. The human choriocarcinoma cell line, BeWo, was found to express LIF-R and gp130. LIF inhibited forskolin-induced human chorionic gonadotrophin (HCG)-B production by BeWo in a dose-dependent manner, and it ameliorated forskolin-induced growth suppression. These findings suggest that LIF plays a regulatory role in trophoblast growth and differentiation during pregnancy in human placenta.