bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distribution of Immunocompetent Cells in Decidua of Controlled and Uncontrolled (Choriocarcinoma/Hydatidiform mole) Trophoblast Invasion
Authors: Knoeller S. , Lim E. , Aleta L. , Hertwig K. , Dudenhausen J. W. , Arck P. C. 
Published: June 2003

Problem:  Pregnancy has been considered as a model of successfully controlled tissue invasion where trophoblast cells infiltrate the maternal decidua without being rejected or without destroying the tissue. In choriocarcinoma (CC) and hydatidiform mole (HM), a dysregulation of invasive (malignant/benign) trophoblast cells is present. Immunocompetent cells (IC) are known to be involved in rejection pathways of malignant cells and can also be identified in early pregnancy decidua. The aim of the present study was to identify the phenotype of IC in decidua of women with normal pregnancy (NP), CC and HM.Methods:  Immunocompetent cells were detected by immunohistochemistry in decidual tissue from first trimester NP (n = 10), CC (n = 12) and HM (n = 11) using antibodies against CD8+, CD3+, CD56+, CD68+ cell surface markers and mast cell tryptase (MCT). A scaled eye piece was used for cell counting to obtain semiquantitative results. Statistical analysis was performed using Wilcoxon rank/Mann–Whitney tests.Results:  We observed a significantly increased number of lymphocytes positive for CD8, CD3 and MCT positive granulocytes in CC and HM compared with the samples from NP (all P ≤ 0.001). Lymphocytes positive for natural killer (NK) cell marker CD56 were significantly decreased in CC and HM versus NP (P ≤ 0.001). The number of CD68 positive cells (macrophages) were not significantly different among the tissue pools.Conclusion:  The increase of CD8/CD3 T cells and mast cells in CC and HM and the decrease of CD56 cells, compared with NP, suggests the necessity of a balance between T and NK cells in controlling trophoblast invasion.
Heme Oxygenases in Pregnancy II: HO‐2 is Downregulated in Human Pathologic Pregnancies
Authors: Zenclussen A. C. , Lim E. , Knoeller S. , Knackstedt M. , Hertwig K. , Hagen E. , Klapp B. F. , Arck P. C. 
Published: June 2003

Problem:  We previously reported a diminished expression of the heme‐degrading enzymes heme oxygenases (HO)‐1 and HO‐2 in decidua and placenta from mice undergoing Th1‐mediated abortion, strongly indicating the protective effect of HO in murine pregnancy maintenance. Here we investigated whether the expression of HO‐1 and HO‐2 is also reduced at the feto‐maternal interface of pathologic human pregnancies.Method of Study:  Immunohistochemistry was used to detect HOs expression in placental and decidual first‐trimester tissue from patients with: spontaneous abortion (n = 14), choriocarcinoma (n = 14), hydatidiform mole (H‐mole) (n = 12), compared with normally progressing pregnancies (n = 15). Further, we investigated early third‐trimester decidual and placental tissue from patients with pre‐eclampsia (n = 13) compared with fetal growth retardation (n = 14) as age‐matched controls.Results:  In first trimester tissue, we observed a significant reduction of HO‐2 expression in invasive trophoblast cells, endothelial cells, and syncytiotrophoblasts in samples from patients with spontaneous abortion compared with normal pregnancy. H‐mole samples showed a diminished expression of HO‐2 in invasive trophoblast cells and endothelial cells in comparison with NP, whereas choriocarcinoma samples showed no significant differences compared with the control. In third trimester tissue, HO‐2 was also reduced in syncytiotrophoblasts and invasive trophoblast cells from pre‐eclampsia compared with samples from fetal growth retardation. HO‐1 expression was diminished in all pathologies investigated; however, the differences did not reach levels of significance.Conclusions:  Our data indicate that HOs play a crucial role in pregnancy and low expression of HO‐2, as observed in pathologic pregnancies, may lead to enhanced levels of free heme at the feto‐maternal interface, with subsequent upregulation of adhesion molecules, allowing enhanced inflammatory cells migration to the feto‐maternal interface.
Antinuclear Autoantibodies, Complement Level, Hypergammaglobulinemia and Spontaneous Intrauterine Hematoma in Pregnant Women
Authors: Alijotas Jaume , Izquierdo Maximo , Serra Bernat , Cusido Ma Teresa , Ribera Miquel , Carrera Josep Ma 
Published: June 2003

Problem: To examine the associative relationship among autoantibodies, C4 levels and intrauterine hematomas (IUH) in more detail than in the studies published earlier.Method Of Study: We performed a retrospective study of 54 women with poor obstetric outcomes. Sera were screened for antinuclear antibodies (ANA), anti‐DNA antibodies, antiphospholipid antibodies (aPL), and antithyroid antibodies. C4‐complement and gammaglobulin levels were also monitored. We compared the main variables in IUH complicated pregnancy group with the risk pregnancy group without IUH. We also compared these variables in the IUH cases before and during IUH.Results: Eight IUH were detected. The average number of spontaneous losses for these eight women was 3.3 ± 2.1 (range: 1–8). aPL was present in 100% of cases. ANAs and hypergammaglobulinemia were present in 50% of cases and low C4 in 87.5% of cases. After comparing these variables apart from C4 before and during IUH, we found no statistical differences. However, C4 was low in four patients before IUH and in seven patients during IUH (OR: 7.0; 95% CI: 0.57–86.33). When we compared autoantibodies apart from lupus anticoagulant (LAC) between the two groups, no differences were observed. However, seven of the eight (87.5%) patients with IUH were LAC positive whereas only 24 of the 46 patients (52.1%) were positive in the non‐IUH group (OR: 6.42; 95% CI: 0.73–56.41). Rapid plasma reagin was present in 8/46 in the non‐IUH group (16.7%) and 5/8 in the IUH group (62.5%) P < 0.015).Conclusions: In women with poor obstetric histories, autoantibodies, especially antiphospholid antibodies, may play a role in the IUH development especially if low C4 and/or hypergammaglobulinemia are present.
Stimulatory Effect of the Herbal Medicine Keishi‐bukuryo‐gan on a Cytokine‐induced Neutrophil Chemoattractant, in Rat Ovarian Cell Culture
Authors: Yasui Toshiyuki , Matsuzaki Toshiya , Ushigoe Kenjiro , Kuwahara Akira , Maegawa Masahiko , Furumoto Hiroyuki , Aono Toshihiro , Irahara Minoru 
Published: June 2003

Problem and Method of Study:  We investigated the effects of Keishi‐bukuryo‐gan, a Japanese herbal medicine, and its crude ingredients in relation to the production of cytokine‐induced neutrophil chemoattractant (CINC/gro), interleukin 1β (IL‐1β) and tumor necrosis factor α (TNFα), which are known to stimulate the secretion of CINC/gro in the ovulatory process, and the effects of Keishi‐bukuryo‐gan with those of Toki‐shakuyaku‐san, which has been shown to have an effect on the ovary. We cultured whole ovarian dispersates from immature (3‐week‐old) female rats with Keishi‐bukuryo‐gan, Toki‐shakuyaku‐san and crude ingredients of Keishi‐bukuryo‐gan. The contents of CINC/gro, IL‐1β and TNFα in the cultured media were determined by enzyme‐linked immunosorbent assay (ELISA).Results:  Keishi‐bukuryo‐gan stimulated the secretion of CINC/gro in a dose‐dependent manner, and the secretion of CINC/gro into the culture medium increased significantly at concentrations of Keishi‐bukuryo‐gan of 10 and 100 μg/mL (P < 0.001). The stimulatory effect of Keishi‐bukuryo‐gan on the production of CINC/gro is significantly (P < 0.001) stronger than that of Toki‐shakuyaku‐san at the same concentrations of 100 μg/mL. In addition, Keishi‐bukuryo‐gan stimulated the secretion of IL‐1β in a dose‐dependent manner, while it did not stimulate the secretion of TNFα even at a concentration of 100 μg/mL. Moutan Cortex, Paeoniae Radix and Persicae Semen, which are crude ingredients of Keishi‐bukuryo‐gan, enhanced the secretion of CINC/gro significantly (P < 0.01) in cultured whole ovarian dispersates.Conclusions:  These results show that Keishi‐bukuryo‐gan can stimulate the secretion of CINC/gro as well as the production of IL‐1β and that this stimulatory effect of Keishi‐bukuryo‐gan was significantly stronger than that of Toki‐shakuyaku‐san in immature rat ovarian cell culture.
Possible Modulators of IL‐8 and GRO‐α Production by Granulosa Cells
Authors: Zeineh Kosay , Kawano Yasushi , Fukuda Junichiro , Nasu Kaei , Narahara Hisashi , Miyakawa Isao 
Published: June 2003

Problem:  Interleukin‐8 (IL‐8) and growth‐regulated oncogene‐α (GRO‐α) have been proved to be important modulators of leukocyte chemotaxis in the mechanism of human ovulation. This study investigated the possible effects of IL‐1α, tumor necrosis factor‐α (TNF‐α), protein kinase C (PKC) activators (TPA), and db‐cyclic adenosine monophosphate (cAMP) on IL‐8 and GRO‐α production by immortalized GC1a and granulosa‐lutein cells.Method of Study:  Confluent granulosa‐lutein cells were placed in serum‐free medium before incubated for 8 hr with the above‐mentioned test agents. Finally, we measured IL‐8 and GRO‐α levels in the culture media using an enzyme‐linked immunosorbent assay (ELISA).Results:  Treatment of granulosa‐lutein cells with of IL‐1α (1 nM), TNF‐α (1 nM), TPA (1 nM) and db‐cAMP (100 μM) produced higher levels of IL‐8 than untreated cells by 8 hr (2274.7 ± 146.3, 1489.8 ± 190.1, 1452.9 ± 152.7, 1313.6.6 ± 48.4 pg/mL, respectively; control = 457.7 ± 38.2 pg/mL; P < 0.001). Treatment of granulosa‐lutein cells with 1 nM of IL‐1α, TNFα, TPA, and db‐cAMP (100 μM) resulted in higher levels of GRO‐α than untreated cells by 8 hr (993.7 ± 9.5, 171.4 ± 6.5, 147.5 ± 6.7, 472.4 ± 16.2 pg/mL respectively; control = 73.8 ± 8.2 pg/mL; P < 0.001).Conclusions:  Our data strongly suggests roles for IL‐1α, TNFα, and PKC activators in the inflammation–like mechanism of human ovulation. Furthermore, our study suggests a positive, but still debatable, role for cAMP in the same mechanism.
Deficient Expression of Tumor Necrosis Factor Receptor Type 2 in the Endometrium of Women with Endometriosis
Authors: Kharfi Abdelaziz , Labelle Yves , Mailloux Jacques , Akoum Ali 
Published: June 2003

Problem: Tumor necrosis factor‐α (TNF‐α) is secreted mainly during the menstrual phase and has been suggested to play a role in induction of apoptosis in endometrial cells and menstrual shedding. TNF‐α receptor type 2 (TNF‐RII) is believed to play a central role in TNFα‐mediated cytotoxic, mitogenic, anti‐proliferative and apoptotic effects. The aim of this study was to assess whether TNF‐RII maybe expressed differentially in the endometrium of women with different degrees of endometriosis.Method of study: TNF‐RII expression in the endometrial tissue of women with and without endometriosis was investigated by immunohistochemical techniques and in situ hybridization.Results: In histological sections, we observed TNF‐RII mRNA and the corresponding protein localized mainly in endometrial glandular cells, with only very faint immunostaining in the surrounding stromal cells. Statistical analysis of our data showed a significant decrease in protein and mRNA expression of TNF‐RII in endometrial glandular cells of patients with stages I and II endometriosis compared to normal subjects. TNF‐RII expression was also found to decrease significantly in the secretory phase of the menstrual cycle in women with early endometriosis stages (I and II).Conclusions: In view of the relevant role of TNF‐RII in the modulation of the inflammatory and the proapoptotic effects of TNFα, deficient expression of TNF‐RII mRNA in the endometrium of women at the earliest stages of endometriosis may play a significant role in the pathophysiology of this disease.
Expression of Allograft Inflammatory Factor‐1 in Mouse Uterus and Poly (I:C)‐induced Fetal Resorption
Authors: Shimada Shigeki , Iwabuchi Kazuya , Watano Keiko , Shimizu Hidemi , Yamada Hideto , Minakami Hisanori , Onoé Kazunori 
Published: June 2003

Problem: To investigate whether the allograft inflammatory factor‐1 (AIF‐1) is expressed and plays a role in the reproductive system.Method of study: AIF‐1 expression was examined in uteri of non‐pregnant and pregnant mice by Northern blot analysis, RT‐PCR and immunohistochemistry.Results: The expression of AIF‐1 varied during the estrous cycle with a peak at estrus. After the insemination, the expression of AIF‐1 mRNA diminished gradually and again increased in the pre‐implantation or implantation period in allogeneic or syngeneic pregnancy, respectively. Enhanced expressions of AIF‐1, tumor necrosis factor‐α (TNF‐α) and nitric oxide synthase 2 (NOS2) mRNA were observed in the embryos of resorption‐prone pregnancy injected with poly(I:C).Conclusions:  This study demonstrated for the first time that AIF‐1 was expressed in uterus. The expression level was associated with the population size of macrophage and varied during the estrous cycle and the pregnancy period. The augmented expression of AIF‐1 with concomitant expressions of TNF‐α and NOS2 mRNA in poly(I:C)‐injected mice suggests a correlation between AIF‐1 production and fetal resorption.
Relationships between Chlamydia trachomatis Antibody Titers and Tubal Pathology Assessed using Transvaginal Hydrolaparoscopy in Infertile Women
Authors: Shibahara Hiroaki , Takamizawa Satoru , Hirano Yuki , Ayustawati  , Takei Yuji , Fujiwara Hiroyuki , Tamada Saori , Sato Ikuo 
Published: June 2003

Problem: Since transvaginal hydrolaparoscopy (THL) was introduced as the first‐line procedure in the early stages of the exploration of the adnexal structures in infertile women, it has been shown that THL is a less traumatic and a more suitable outpatient procedure than diagnostic laparoscopy. This study was performed to investigate the relationships between Chlamydia trachomatis antibody titers and tubal pathology assessed using THL in infertile women.Methods: The C. trachomatis antibody titers (IgG and IgA) were evaluated by ELISA. The posterior of the uterus and the tubo‐ovarian structures were carefully observed, and tubal passage using indigocarmine was confirmed using THL. THL was carried out in 32 infertile women having C. trachomatis antibody in their sera between May 1999 and October 2001. Unilateral salpingectomy had been performed on two of the 32 patients.Results: Tubal occlusion was confirmed in 20 (32.3%) of the 62 tubes, while peritubal adhesion was diagnosed in 37 (59.7%) of the 62 tubes. Using receiver operating characteristics curves, the cut‐off value of C. trachomatis IgG antibody titer to predict tubal occlusion was determined to be 3.55. Tubal occlusion was observed in 16 (51.6%) of the 31 tubes in patients with the C. trachomatis IgG antibody titer of more than 3.55, which was significantly higher in four (12.9%) of the 31 tubes having the antibody titer less than 3.55 (P = 0.004). However, there was no correlation between C. trachomatis IgG antibody titer and peritubal adhesion. As for C. trachomatis IgA antibody titer, there was no correlation between antibody titer and tubal occlusion or peritubal adhesion.Conclusions: These results suggest that C. trachomatis infection is significantly associated with tubal pathology. Although the cut‐off value of C. trachomatis IgG antibody titer to predict the existence of tubal occlusion was shown to be 3.55, we would suggest that THL or standard laparoscopy is performed to consider appropriate treatments in patients with past C. trachomatis infection because of the high prevalence of peritubal adhesion.
An Immunohistochemical Study of the Secretory Immune System in Human Fetal Membranes and Decidua of the First Trimester of Pregnancy
Authors: Gurevich Pavel , Elhayany Asher , Ben‐Hur Herzl , Moldavsky Moisey , Szvalb Sergio , Zandbank Judit , Shperling Isai , Zusman Itshak 
Published: June 2003

Problem: We analyzed the presence and distribution of components of the secretory immune system (SIS) in human fetal membranes (amnion, yolk sac, chorion) and decidua from the first trimester of pregnancy.Materials and methods: Specimens from 17 embryos (4–8 weeks of pregnancy) and nine fetuses (9–12 weeks) were divided into those that had not been exposed to massive foreign antigenic effects (Group I, n = 18) and those that had suffered acute chorioamnionitis (Group II, n = 8).Results: Positive immunostaining for secretory component (SC), joining (J) chain, IgG, IgA, and macrophages was seen from 4 to 5 weeks of development and then during the whole first trimester of pregnancy in the syncytio‐and cytotrophoblasts, the amniotic epithelium, the yolk sac endoderm and decidual cells. Macrophages with J chain, IgG and IgA were found in embryonic tissues on week 4, whereas lymphocytes, including those synthesizing IgA and IgM, appeared only at the end of the first trimester of pregnancy. In the decidua, lymphocytes and macrophages were recognized during the whole period of study. In cases with chorioamnionitis (Group II), reactivity of IgG and IgA in the mentioned cells of fetuses decreased sharply while the rate of immunoreactivity of SC and J chain as well as the number of T and B lymphocytes did not change. In the decidua, the number of immune reactive cells sharply increased with the appearance of plasma cells.Conclusions: In the fetal membranes and decidua all the SIS components are present. We suggest that two SIS, maternal and fetal, participate in the formation of the barrier between a mother and the fetus. Both these systems have different origin and cellular content as well as different immune reactions.
SB‐656104‐A, a novel selective 5‐HT7 receptor antagonist, modulates REM sleep in rats
Authors: Thomas David R , Melotto Sergio , Massagrande Mario , Gribble Andrew D , Jeffrey Phillip , Stevens Alexander J , Deeks Nigel J , Eddershaw Peter J , Fenwick Susan H , Riley Graham , Stean Tania , Scott Claire M , Hill Matthew J , Middlemiss Derek N , Hagan Jim J , Price Gary W , Forbes Ian T 
Published: June 2003

(6‐((R)‐2‐{2‐[4‐(4‐Chloro‐phenoxy)‐piperidin‐1‐yl]‐ethyl}‐pyrrolidine‐1‐sulphonyl)‐1H‐indole hydrochloride) (SB‐656104‐A), a novel 5‐hydroxytryptamine (5‐HT7) receptor antagonist, potently inhibited [3H]‐SB‐269970 binding to the human cloned 5‐HT7(a) (pKi 8.7±0.1) and 5‐HT7(b) (pKi 8.5±0.2) receptor variants and the rat native receptor (pKi 8.8±0.2). The compound displayed at least 30‐fold selectivity for the human 5‐HT7(a) receptor versus other human cloned 5‐HT receptors apart from the 5‐HT1D receptor (∼10‐fold selective).
SB‐656104‐A antagonised competitively the 5‐carboxamidotryptamine (5‐CT)‐induced accumulation of cyclic AMP in h5‐HT7(a)/HEK293 cells with a pA2 of 8.5.
Following a constant rate iv infusion to steady state in rats, SB‐656104 had a blood clearance (CLb) of 58±6 ml min−1 kg−1 and was CNS penetrant with a steady‐state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg−1), the compound displayed a t1/2 of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 μM, respectively.
SB‐656104‐A produced a significant reversal of the 5‐CT‐induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5‐HT7 receptor interaction in vivo (ED50 2 mg kg−1).
SB‐656104‐A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg−1 i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg−1 i.p. with no significant effect on the latency to, or amount of, non‐REM sleep. SB‐269970‐A produced qualitatively similar effects in the same study.
In summary, SB‐656104‐A is a novel 5‐HT7 receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5‐HT7 receptors in the modulation of REM sleep.

British Journal of Pharmacology (2003) 139, 705–714. doi:10.1038/sj.bjp.0705290
Effects of heparin and related molecules upon neutrophil aggregation and elastase release in vitro
Authors: Brown Rachel A , Lever Rebecca , Jones Neil A , Page Clive P 
Published: June 2003

Neutrophil‐derived elastase is an enzyme implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Heparin inhibits the enzymatic activity of elastase and here we provide evidence for the first time that heparin can inhibit the release of elastase from human neutrophils.
Unfractionated and low molecular weight heparins (UH and LMWH, 0.01–1000 U ml−1) and corresponding concentrations (0.06–6000 μg ml−1) of nonanticoagulant O‐desulphated heparin (ODH), dextran sulphate (DS) and nonsulphated poly‐L‐glutamic acid (PGA) were compared for their effects on both elastase release from and aggregation of neutrophils.
UH, ODH and LMWH inhibited (P<0.05) the homotypic aggregation of neutrophils, in response to both N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP, 10−6 M) and platelet‐activating factor (PAF, 10−6 M), as well as elastase release in response to these stimuli, in the absence and presence of the priming agent tumour necrosis factor‐alpha (TNF‐α, 100 U ml−1).
DS inhibited elastase release under all the conditions of cellular activation tested (P<0.05) but had no effect on aggregation. PGA lacked efficacy in either assay, suggesting general sulphation to be important in both effects of heparin on neutrophil function and specific patterns of sulphation to be required for inhibition of aggregation.
Further investigation of the structural requirements for inhibition of elastase release confirmed the nonsulphated GAG hyaluronic acid and neutral dextran, respectively, to be without effect, whereas the IP3 receptor antagonist 2‐aminoethoxydiphenylborate (2‐APB) mimicked the effects of heparin, itself an established IP3 receptor antagonist, suggesting this to be a possible mechanism of action.

British Journal of Pharmacology (2003) 139, 845–853. doi:10.1038/sj.bjp.0705291
Calcium dobesilate potentiates endothelium‐derived hyperpolarizing factor‐mediated relaxation of human penile resistance arteries
Authors: Angulo Javier , Cuevas Pedro , Fernández Argentina , Gabancho Sonia , Videla Sebastián , Tejada Iñigo Sáenz de 
Published: June 2003

We have evaluated the participation of endothelium‐derived hyperpolarizing factor (EDHF) in the endothelium‐dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium‐dependent relaxation of these tissues was investigated.
Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium‐dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium‐dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K+ (35 mM) or by blocking Ca2+‐activated K+ channels, with apamin (APA; 100 nM) and charybdotoxin (CTX; 100 nM), suggesting the involvement of EDHF in these responses.
Endothelium‐dependent relaxation to ACh was markedly enhanced by DOBE (10 μM) in HPRA but not in HCC. The potentiating effects of DOBE on ACh‐induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mM) and were abolished by high K+ or a combination of APA and CTX.
In vivo, DOBE (10 mg kg−1 i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats.
EDHF plays an important role in the endothelium‐dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium‐dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED.

British Journal of Pharmacology (2003) 139, 854–862. doi:10.1038/sj.bjp.0705293