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A novel organo sulfur and selenium-controlled emission behavior in discrete copper(I) clusters has been demonstrated for the first time. The pentanuclear [Cu 5 Br 5 ( L 1 ) 2 ] ( 1 ), trinuclear [Cu 3 Br 3 ( L 2 ) 2 ] ( 2 ), dinuclear [Cu 2 I 2 ( L 1 ) 2 ] ( 3 ), and tetranuclear [Cu 4 I 4 ( L 2 ) 2 CH 3 CN] ( 4 ) copper(I) discrete clusters have been synthesized from the reaction between L 1 [ L 1 = 1-isopropyl-3-(pyridin-2-yl)-imidazol-2-thione] or L 2 [ L 2 = 1-isopropyl-3-(pyridin-2-yl)-imidazol-2-selone] chelating ligands and corresponding copper(I) halide salts. These new clusters have been characterized by FT-IR, UV-visible, thermogravimetric analysis, and fluorescence spectroscopy techniques. Single-crystal X-ray diffraction studies reveal that 1-4 consists of abundant d 10 -d 10 interactions. The structural and bonding features of clusters have been investigated using density functional theory calculations. Notably, the L 2 -ligated 2 and 4 are poorly emissive, while L 1 -ligated 1 and 3 showed strong emission in the orange and green regions, respectively. The time-dependent density functional theory natural transition orbital calculations of 1 and 3 reveal the nature of the transitions contributed by 3 MLCT/ 3 LLCT/ 3 ILCT. Photoluminescence quantum yields of 1 and 3 are 19 and 11%, with average lifetimes of 21.55 and 6.57 μs, respectively. 1 and 3 were coated on prototype LED bulbs for light-emitting performance.

Micro-sized chiral-nematic liquid crystal (N* LC) polymer particles have attracted considerable interest as versatile reflective colorants with selective circularly polarized light (CPL) properties. However, challenges in achieving the desired size distribution of N* LC particles have led to an incomplete understanding of their reflective characteristics. In this study, we successfully synthesized N* LC particles via dispersion polymerization, enabling precise control over size polydispersity by manipulating the composition of the polymerization solvent. Our investigation revealed that monodisperse N* LC particles displayed distinct reflection bands with high CPL selectivity, while polydisperse particles exhibited broader reflection with lower CPL selectivity. These findings underscore the potential to synthesize N* LC particles with tailored reflective properties using identical monomeric compounds. Furthermore, we demonstrated the production of multifunctional reflective colorants by blending N* LC particles with varying reflection colors. These discoveries hold significant promise for advancing the development of reflective colorants and anti-counterfeiting printing techniques utilizing micro-sized N* LC particles.

Hexaazatriphenylene (HAT) derivatives have attracted wide attention because of their electron-deficient nature and unique self-assembly properties. In this work, a facile synthesis method for obtaining HAT derivatives with alternating electron-withdrawing nitrile and electron-donating alkoxy groups (HATCNOCn) is proposed. Crystal structure analysis indicated that HATCNOCn forms a one-dimensional columnar structure via strong π-π interactions. Density functional theory calculations revealed that the edge of HATCNOCn is divided into positively and negatively charged sites owing to the presence of alternating nitrile and alkoxy groups, which would induce strong π-π interactions. Thermal analysis and polarizing optical microscopy revealed that HATCNOCn exhibits columnar liquid-crystal phases. Time-resolved microwave conductivity measurements further demonstrated the photoconductive nature of HATCNOCn. The proposed strategy could provide a new strategy for the design of novel organic semiconductive materials., (© 2022 Wiley-VCH GmbH.)

Heterocyclic compounds with effective solid-state luminescence offer a wide range of uses. It has been observed that combining pyrimidine and indole moieties in a single molecule can enhance material behavior dramatically. Here, different heterocyclic compounds with indole and pyrimidine moieties have been synthesized effectively, and their structures have been validated using NMR, IR, and mass spectroscopy. The photoluminescence behavior of two substances was investigated in powder form and solutions of varying concentrations. After aggregation, one molecule displayed a redshifted luminescence spectrum, whereas another homolog showed a blueshift. Thus, density functional theory calculations were carried out to establish that introducing a terminal group allows modifying of the luminescence behavior by altering the molecular packing. Because of the non-planarity, intermolecular interactions, and tiny intermolecular distances within the dimers, the materials demonstrated a good emission quantum yield (Φ em ) in the solid state (ex. 25.6%). At high temperatures, the compounds also demonstrated a stable emission characteristic., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Purpose: Our aim is to make an ideal embryo culture medium close to human oviduct fluid (HOF) components, and to evaluate the quality of this medium with embryo quality and clinical outcomes in assisted reproductive technology (ART) by a prospective randomized controlled trial (RCT)., Methods: Study I: HOF was collected laparoscopically from patients ( n  = 28) with normal pelvic findings. According to HOF analysis results, the new medium "HiGROW OVIT ® " (OVIT) was designed. Study II: Embryos (2 pronuclei (2PN) = 9633) were assigned from 1435 patients. The blastulation rate (BR), good BR (gBR), utilized (transferred/cryo-preserved) BR (uBR), pregnancy rate (PR), and miscarriage rate (MR) were compared between the OVIT and control groups by RCT., Results: The novel medium 'OVIT' was produced according to 31 HOF components. The concentrations of essential amino acids (e-AAs) were lower in OVIT than in current media, yet the opposite was true for ne-AA concentrations. gBR and uBR were higher in the OVIT group than in the control group. In the older female group, gBT and uBR were significantly higher in the OVIT group., Conclusions: The novel medium 'OVIT' was produced according to HOF data. The OVIT had significantly better embryo quality and clinical outcomes than the current media., Competing Interests: Takafumi Utsunomiya has nothing to disclose. The remaining authors have nothing to disclose., (© 2022 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Gold(I) complexes, enabling to form linear coordination geometry, are promising materials for manifesting both aggregation-induced emission (AIE) behavior due to strong intermolecular Au-Au (aurophilic) interactions and liquid crystalline (LC) nature depending on molecular geometry. In this study, we synthesized several gold(I) complexes with rod-like molecular skeletons where we employed a mesogenic biphenylethynyl ligand and an isocyanide ligand with flexible alkoxyl or alkyl chains. The AIE behavior and LC nature were investigated experimentally and computationally. All synthesized gold(I) complexes exhibited AIE properties and, in crystal, room-temperature phosphorescence (RTP) with a relatively high quantum yields of greater than 23% even in air. We have demonstrated that such strong RTP are drastically changed depending on the crystal-size and/or crystal growth process that changes quality of crystals as well as the aggregate structure, of e.g., Au-Au distance. Moreover, the complex with longer flexible chains showed LC nature where RTP can be observed. We expect these rod-like gold(I) complexes to have great potential in AIE-active LC phosphorescent applications such as linearly/circularly polarizing phosphorescence materials.

A mesoionic N-heterocyclic carbene-gold(I) complex with a unique Au⋯H-C(methine) intramolecular hydrogen bonding interaction has been investigated in the solid state. The structure of this new neutral gold(I)-carbene was characterized by FT-IR and NMR spectroscopy, TGA, and X-ray diffraction techniques. Density functional theory (DFT) and atoms-in-molecule (AIM) analysis revealed that the gold-hydrogen bonding situation is more favored. Besides, the photophysical properties of the gold(I) complex were also investigated.

Chiral nematic (N*) liquid crystal elastomers (LCEs) are suitable for fabricating stimuli-responsive materials. As crosslinkers considerably affect the N*LCE network, we investigated the effects of crosslinking units on the physical properties of N*LCEs. The N*LCEs were synthesized with different types of crosslinkers, and the relationship between the N*LC polymeric system and the crosslinking unit was investigated. The N*LCEs emit color by selective reflection, in which the color changes in response to mechanical deformation. The LC-type crosslinker decreases the helical twisting power of the N*LCE by increasing the total molar ratio of the mesogenic compound. The N*LCE exhibits mechano-responsive color changes by coupling the N*LC orientation and the polymer network, where the N*LCEs exhibit different degrees of pitch variation depending on the crosslinker. Moreover, the LC-type crosslinker increases the Young's modulus of N*LCEs, and the long methylene chains increase the breaking strain. An analysis of experimental results verified the effect of the crosslinkers, providing a design rationale for N*LCE materials in mechano-optical sensor applications.

Purpose: This study was conducted to investigate how the COVID-19 pandemic has impacted reproductive medical providers' behaviors and considerations, including their concerns regarding the necessity of fertility treatments., Methods: A web-based questionnaire was distributed to Japan Society of Fertilization and Implantation (JSFI) members from May 18 through May 31, 2020 to survey their professional behaviors and concerns during the COVID-19 pandemic., Results: Most survey participants reported a decrease in the number of patients and a decrease in their workload. Most also believe that the use of fertility treatments will return to the pre-pandemic levels after the COVID-19 pandemic ends. Additionally, more than half of the participants reported that they consider fertility treatment neither necessary nor unnecessary during the COVID-19 pandemic., Conclusions: At the institute where reproductive medical providers worked in Japan, the number of outpatients and the working time tended to decrease during the COVID-19 pandemic. However, amid fears of infection during the COVID-19 pandemic, the reproductive medical providers working at fertility institutes in Japan have remained engaged in their work with a sense of mission and hope., Competing Interests: Kuniaki Ota, Osamu Tsutsumi, Tasuku Mitani, Yoshiharu Morimoto, Atsushi Tanaka, Yutaka Osuga, Toshifumi Takahashi, and Yoshihiko Hosoi declare that they have no conflict of interest. Human rights statements and informed consent: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from all participants included in the study. The Institutional Review Board of HORAC Grand Front Osaka Clinic approved this study (Number:2020‐31). Animal rights: This report does not contain any studies performed by any of the authors that included animal participants., (© 2021 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

The synthesis and the luminescence features of three gold(I)-N-heterocyclic carbene (NHC) complexes are presented to study how the n-alkyl group can influence the luminescence properties in the crystalline state. The mononuclear gold(I)-NHC complexes, [(L 1 )Au(Cl)] (1), [(L 2 )Au(Cl)] (2), and [(L 3 )Au(Cl)] (3) were isolated from the reactions between [(tht)AuCl] and corresponding NHC ligand precursors, [N-(9-acridinyl)-N'-(n-butyl)-imidazolium chloride, (L 1 .HCl)], [N-(9-acridinyl)-N'-(n-pentyl)-imidazolium chloride, (L 2 .HCl)] and [N-(9-acridinyl)-N'-(n-hexyl)-imidazolium chloride, (L 3 .HCl)]. Their single-crystal X-ray analysis reveals the influence of the n-alkyl groups on solid-state packing. A comparison of the luminescence features of 1-3 with n-alkyl substituents is explored. The molecules 1-3 depicted blue emission in the solution state, while the yellow emission (for 1), greenish-yellow emission (for 2), and blue emission (for 3) in the crystalline phase. This paradigm emission shift arises from n-butyl to n-pentyl and n-hexyl in the crystalline state due to the carbon-carbon rotation of the n-alkyl group, which tends to promote unusual solid packing. Hence n-alkyl group adds a novel emission property in the crystalline state. Density Functional Theory and Time-Dependent Density Functional Theory calculations were carried out for monomeric complex, N-(9-acridinyl)-N'-(n-heptyl)imidazole-2-ylidene gold(I) chloride and dimeric complex, N-(9-acridinyl)-N'-(n-heptyl)imidazole-2-ylidene gold(I) chloride to understand the structural and electronic properties., (© 2021 Wiley-VCH GmbH.)

Biocompatible luminogens with aggregation-induced emission (AIE) have several applications in the biology field, such as in detecting biomacromolecules bioprobes and in bio-imaging. Due to their bioactivities and light-emitting properties, many heterocyclic compounds are good candidates for such applications. However, heterocyclic π-conjugated systems with AIE behavior remain rare as strong intermolecular π-π interactions usually quench their emission. In this work, new thienopyrimidine heterocyclic compounds were synthesized and their structures were verified by elemental analysis and Fourier transform infrared (FT-IR), 1 H nuclear magnetic resonance (NMR), and 13 C NMR spectra. The photophysical properties of some compounds were investigated in the solution and solid states. Density functional theory calculations were also performed to confirm the observed photophysical properties of the compounds. The studied dyes displayed AIE properties with spectral shapes related to the aggregate structure and a quantum yield up to 10.8%. The emission efficiency of the powder is attributed to the incorporation of multiply rotatable and twisted aryl groups to the fused heterocyclic moieties. The dyes also showed high thermal stability and potent antimicrobial activities against numerous bacterial and fungal strains. Additionally, the cytotoxicity of the new compounds was evaluated against the Caco-2 cell line, and molecular docking was used to investigate the binding conformation of the most effective compound with the MNK2 enzyme. Therefore, the presented structures may potentially be used for bioapplications., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.)

The aggregation behaviour of Au(I) complexes in condensed phases can affect their emission properties. Herein, aggregation-induced room-temperature phosphorescence (RTP) is observed from the crystals of trinuclear Au(I) complexes. The RTP is highly sensitive to the crystal structure, with a slight difference in the alkyl side chains causing not only a change in the crystal structure but also a shift in the RTP maximum. Furthermore, in nanocrystals, reversible RTP colour changes are induced by phase transitions between crystal polymorphs during crystal growth from solution or the pulverisation of bulk crystals. The colour change mechanism is discussed in terms of intermolecular interactions in the crystal structure of the luminescent aggregates. The results suggest that the behaviour in nanocrystals may differ from that in bulk crystals. These insights will advance the fundamental understanding of crystallisation mechanisms and may aid in the discovery of new materials properties for solids with nano- to micrometre sizes., (© 2020. The Author(s).)

Purpose: The purpose of this study was to investigate the effectiveness of intrauterine administration of platelet-rich plasma (PRP) in frozen embryo transfer (FET) cycle in Japanese patients with a thin endometrium., Method: A prospective single-arm self-controlled trial was conducted in Japan. PRP administration was performed in 36 of the 39 eligible patients with a thin endometrium (≤7 mm). Hormone replacement therapy (HRT) with estrogen was performed for 2 menstrual cycles, and PRP was administrated on the 10th and 12th days of the second HRT cycle. The endometrial thickness was evaluated on transvaginal ultrasonography by two physicians at every visit, one an attending physician and the other a specialist physician blinded to the date and timing of the sonography. FET was performed during the second HRT cycle after PRP administration., Results: After PRP administration, the mean (SD) endometrial thickness on the 14th day was significantly increased by 1.27 mm ( P  < .001) and 0.72 mm ( P  = .001) on the basis of the unblinded and blinded measurements, respectively. Of the 36 patients, 32 (88.9%) underwent FET. The clinical pregnancy rate was 15.6%. No adverse events occurred., Conclusions: PRP therapy was safe and effective in increasing endometrial thickness improving possibly pregnancy rate., Competing Interests: Maki Kusumi, Tatsuji Ihana, Takako Kurosawa, Yasuo Ohashi, and Osamu Tsutsumi declare that they have no conflict of interest., (© 2020 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Highly efficient (≈75% quantum yield), aggregation-induced phosphorescence is reported. The phosphorescence is emitted at room temperature and in the presence of air from crystals of trinuclear Au(I) complexes, accompanied by an extremely large Stokes shift of 2.2 × 10 4 cm -1 (450 nm). The mechanism of the aggregation-induced room-temperature phosphorescence from the Au complex crystals was investigated in terms of the crystal packing structure and the primary structure of the molecules. It was found that two kinds of intermolecular interactions occurred in the crystals, and that these multiple dual-mode intermolecular interactions in the crystals play a crucial role in the in-air room-temperature phosphorescence of the trinuclear Au(I) complexes.

The synthesis and photophysical properties of macrocyclic Zn(ii) selone molecule have been reported. The structural property of Zn(ii) selone was elucidated using single crystal X-ray diffraction study. The solid-state structure of zinc(ii) selone molecule exhibits a perfect zinc(ii) selone 28 membered ring system with tetra coordination geometry around zinc(ii) center. The zinc(ii) selone ring system can be considered as the largest zinc(ii) ring system known without any non-interacting centered guest moiety. Detailed trends in photophysical as well as thermal properties were probed. In photoluminescence study, the solid-state sample of zinc(ii) selone ring system emits the bluish-yellow color with considerable quantum yields, while the solution state sample of zinc(ii) selone ring system in DMSO emits bluish-yellow. The luminescence lifetime of zinc(ii) selone was measured using standard time-correlated single photon counting (TCSPC) technique., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Herein, the photophysical properties of an acridine derivative of a bis-N-heterocyclic carbene silver complex were investigated. The HOMO and LUMO energy differences between 9-[( N -methyl imidazol-2-ylidene)]acridine and 4,5-bis[( N -methyl-imidazol-2-ylidene)methyl]acridine were theoretically compared. Based on the calculation, the 4,5-bis N-heterocyclic carbene-tethered acridine type of ligand was found to be a potential source for tuning the fluorescent nature of the resultant metal derivatives. Thus, a 4,5-bis N-heterocyclic carbene (NHC)-tethered acridine silver(i) salt was synthesized, and its photophysical properties were investigated. The 4,5-bis[( N -isopropylimidazol-2-ylidene)methyl]acridine silver(i) hexafluorophosphate complex was obtained from the reaction between [4,5-bis{( N -isopropylimidazolium)methyl}acridine] hexafluorophosphate and Ag 2 O in very good yield; this molecule was characterized by elemental analysis and FTIR, multinuclear ( 1 H and 13 C) NMR, UV-Vis, and fluorescence spectroscopic techniques. The molecular structure has been confirmed by single-crystal X-ray diffraction analysis, which has revealed that the complex is a homoleptic mononuclear silver(i) cationic solid. The charge of the Ag(i)-NHC cation is balanced by the hexafluorophosphate anion. The cationic moieties are closely packed in the chair and inverted chair forms where silver(i) possesses a quasi-linear geometry. Moreover, the silver complex provided blue emission from all the three excitations with good fluorescence quantum yield. The fluorescence lifetime of the silver(i) complex has been determined using the time-correlated single photon counting technique. Interestingly, the fluorescence decay pattern and the fluorescence lifetimes of the silver complex are largely different from those of the parent ligand acridine imidazolium salt. Moreover, the theoretical predictions have been found to be in good agreement with the experimental results., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The epigenetic status of the genome changes dynamically from fertilization to implantation. In addition, the physiological environment during the process of gametogenesis, including parental age, may affect the epigenome of the embryo after fertilization. It is important to clarify the influence of parental age on gene expression in the embryo in terms of transgenerational epigenetics to improve the techniques currently used in assisted reproductive medicine. Here, we performed single-embryo RNA-seq analysis on human blastocysts fertilized by intracytoplasmic sperm injection, including from relatively elderly mothers, to elucidate the effects of parental age on the embryonic gene expression profile. We identified a number of genes in which the expression levels were decreased with increasing maternal age. Among these genes, several are considered to be important for meiotic chromosomal segregation, such as PTTG1, AURKC, SMC1B and MEIKIN. Furthermore, the expression levels of certain genes critical for autophagy and embryonic growth, specifically GABARAPL1 and GABARAPL3, were negatively correlated with advanced paternal age. In addition, levels of transcripts derived from major satellite repeats also decreased as the maternal age increased. These results suggest that epigenetic modifications of the oocyte genome may change with parental age and be transmitted to the next generation.

Mesogenic Au complexes with a biphenyl core were synthesized as new AIEgens, and their thermodynamic and photophysical properties were discussed. Similar to Au complexes with a phenyl core which have been reported previously, the complexes with a short alkoxy chain formed dimers in the crystal form. However, the complexes with a long alkoxy chain formed two-dimensional layer structures through multiple intermolecular interactions in both the crystalline and liquid-crystalline (LC) phases. The present Au complexes showed a high thermochemical stability against thermal decomposition and a high thermodynamic stability of the LC phase. Moreover, these materials exhibited intensive phosphorescence with a large quantum yield (∼66%) in the crystals. In the crystal and LC phase with a layer structure, the phosphorescence intensity was enhanced only on aggregation. Thus, these mesogenic Au complexes can be expected to be useful as phosphorescent AIEgens.

A series of new cyclic trinuclear Au(I) complexes with alkoxy side chains of various lengths were synthesized as photoluminescence materials. None of the complexes emitted luminescence in solution; however, some showed photoluminescence in the crystalline phase. Single crystal X-ray structural analyses revealed that an intermolecular interaction between two Au atoms (aurophilic interaction) existed only in the emissive complexes, which formed molecular aggregates in the crystal. Because isolated molecules show no luminescence in the present system, we conclude that only molecules aggregated via aurophilic interactions can luminesce. We demonstrated that luminescence properties, such as colour and intensity, were very sensitive to the aggregated structure of the molecules. We also found that such luminescence properties can be controlled by a change in the aggregated structure induced by external stimuli, such as heat, solvent, and mechanical stress.

Purpose: To compare the embryo outcomes of in vitro fertilization/intra-cytoplasmic sperm injection with a gonadotropin-releasing hormone (GnRH) antagonist protocol with follicle stimulating hormone (FSH) and with human menopausal gonadotropin (hMG)., Methods: We performed a retrospective cohort study in 465 patients. Stimulation was started by daily FSH injection, and either FSH was continued (FSH alone group) or hMG was administrated (FSH-hMG group) after administration of a GnRH antagonist. Primary outcomes were the embryo profile (number of retrieved, mature, and fertilized eggs, and morphologically good embryos on day 3) and endocrine profile. Secondary outcomes were the doses and durations of gonadotropin. Data were stratified by the patients' age into two groups: <35 years and ≥35 years., Results: In patients aged <35 years, the number of retrieved oocytes in the FSH alone group was significantly increased than that in the FSH-hMG group (13.7 vs 9.2, P  = 0.04), while there was no difference at other age groups. The FSH-hMG group required a significantly greater amount of gonadotropins at any age (all ages, P  < 0.001; <35 years, P  = 0.013; ≥35 years, P  < 0.001)., Conclusions: Exogenous FSH alone is probably sufficient for follicular development and hMG may not improve the embryo profile in a GnRH antagonist protocol across all age.

Background: Previous studies have found that the decision-making process for stored unused frozen embryos involves much emotional burden influenced by socio-cultural factors. This study aims to ascertain how Japanese patients make a decision on the fate of their frozen embryos: whether to continue storage discard or donate to research., Methods: Ten Japanese women who continued storage, 5 who discarded and 16 who donated to research were recruited from our infertility clinic. Tape-recorded interviews were transcribed and analyzed for emergent themes., Results: A model of patients' decision-making processes for the fate of frozen embryos was developed, with a common emergent theme, "coming to terms with infertility" resulting in either acceptance or postponing acceptance of their infertility. The model consisted of 5 steps: 1) the embryo-transfer moratorium was sustained, 2) the "Mottainai"- embryo and having another child were considered; 3) cost reasonability was taken into account; 4) partner's opinion was confirmed to finally decide whether to continue or discontinue storage. Those discontinuing, then contemplated 5): the effect of donation. Great emotional conflict was expressed in the theme, steps 2, 4, and 5., Conclusions: Patients' 5 step decision-making process for the fate of frozen embryos was profoundly affected by various Japanese cultural values and moral standards. At the end of their decision, patients used culturally inherent values and standards to come to terms with their infertility. While there is much philosophical discussion on the moral status of the embryo worldwide, this study, with actual views of patients who own them, will make a significant contribution to empirical ethics from the practical viewpoint.

To investigate the effect of cadmium (Cd) contamination on endometrial function, human endometrial stromal cells were isolated and cultured with E(2) plus P in the presence of Cd, a major contaminant in cigarette smoke, and assayed for PRL concentrations and its messenger RNA expression. Cd significantly increased PRL concentrations in the culture media and significantly up-regulated PRL messenger RNA expression of the endometrial stromal cells, suggesting that Cd stimulates decidualization of the endometrium and may disrupt endometrial environment, causing early decidualization.

Background: Vasopressin is often used locally to reduce blood loss during surgery. The use of a local infiltration of a low concentration of vasopressin, less than 0.05-0.3 units/mL, has been considered to be safe. The use of low-dose vasopressin is not free of side effects, and it can also sometimes cause lethal complications., Case: In a healthy woman with multiple uterine myomas, we experienced a case of sudden cardiac arrest immediately after the intramyometrial injection of vasopressin at a total dose of 11 units (0.2 units/mL). The patient was successfully resuscitated., Conclusion: Local intramyometrial infiltration of low-dose vasopressin may cause lethal cardiopulmonary complications.

IL-1, secreted by human embryos and trophoblast cells, is important for successful implantation and pregnancy. We previously reported that IL-1beta induced IL-8 production in human endometrial stromal cells (ESCs) and that induction was regulated by substances implicated in implantation. In the present study using human primary cells in culture, we measured IL-1beta-induced production of IL-8 from endometrial epithelial cells (EECs) and ESCs and examined effects of the endometrium-derived IL-8 on migration and number of first-trimester villous cytotrophoblast cells (vCTs). Both basal and IL-1beta-induced IL-8 levels of cell supernatants were much higher in EECs than ESCs. Addition of IL-1beta to EECs increased the chemotactic activity of the supernatants to vCTs, and this effect was suppressed by immunoneutralization with anti-IL-8 antibody. Supernatants of IL-1beta-stimulated EECs yielded significantly higher number of vCTs compared with those of untreated EECs, and the effect was inhibited by IL-8 antibody. These findings suggest that IL-1 promotes implantation by stimulating EECs to produce IL-8, which subsequently induces migration of vCTs and contributes to survival of vCTs.

Cholesterol sulfate (CS) is a component of cell membranes that plays a role in stabilizing the cell membrane. We previously reported that CS increased in the endometrium during implantation, suggesting that CS plays an important role in reproduction. It has been reported that CS regulates progesterone and pregnenolone production in the placenta, adrenal glands and ovary. The regulatory mechanisms of steroid hormone production by CS, however, are still unknown. In the present study, we investigated the effect of CS on the expression of progesterone production-related genes in KGN cells, derived from human granulosa-like tumor. KGN cells were cultured with CS (10 muM) or cholesterol (10 muM) in the presence of 8-bromo-cAMP (1 mM). Progesterone levels in the culture media were measured by enzyme linked fluorescent assay at 24 h after treatment of CS and cAMP. Total RNAs were extracted for quantitative real time RT-PCR with specific primer of StAR protein, P450scc, HSD3B2, ferredoxin and ferredoxin reductase. Whole cell lysates were extracted for western blot analysis with antibody for StAR protein. Progesterone concentration in the culture medium increased to 38-fold by treatment of cAMP. CS significantly reduced progesterone concentration by 30% compared with those of cAMP treatment (p<0.05), while cholesterol did not change the progesterone concentration. CS treatment down-regulated the expression of StAR mRNA and P450scc mRNA was to 54% and 60%, respectively (p<0.05). Western blot analysis revealed that the amount of StAR protein was also reduced by CS treatment. The expression of HSD3B2 mRNA was up-regulated to 3.4-fold by treatment of cAMP. The expression of ferredoxin and ferredoxin reductase mRNA was not affected by CS treatment. These data implied that CS has an inhibitory effect on progesterone production by regulating the expression of StAR and P450scc gene expression.

Objectives: To investigate the insulin response to glucose loading and to determine which method is best in order to evaluate insulin resistance in women with polycystic ovary syndrome (PCOS)., Methods: In order to eliminate the influence of obesity on the variables, all subjects were non-obese. Standard oral glucose tolerance tests were performed in 23 normal women and 21 patients with PCOS. Insulin resistance was evaluated by the homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment for beta-cell function (HOMA-%B), the quantitative insulin-sensitivity check index (QUICKI) and area under the curve for glucose (AUC(glucose)) and insulin (AUC(insulin))., Results: The mean values of HOMA-IR, AUC(insulin) and AUC(glucose) in the PCOS group were significantly higher than in the BMI-matched normal control group (p < 0.05, p < 0.01 and p < 0.01, respectively). There were significant positive correlations between AUC(insulin) and AUC(glucose) and androgens or luteinizing hormone in all subjects (p < 0.001). However, HOMA-IR and fasting insulin were significantly correlated only with total testosterone (p < 0.05). AUC(insulin) and AUC(glucose) values were elevated in more than 50% of PCOS patients with normal values of HOMA indices., Conclusion: In the PCOS group, the abnormal response of insulin to glucose loading was suggested. AUC(insulin) may be a better index than others to evaluate insulin resistance in non-obese PCOS patients.

Periostin/OSF2 is a ligand for alphavbeta3 and alphavbeta5 integrins and activates the Akt/PKB pathway. Recent reports of periostin/OSF2 gene disrupted mice indicate that periostin/OSF-2 plays an important role in implantation. Quantitative RT-PCR revealed that the expression of periostin/OSF-2 mRNA in rat uteri was reduced to approximately 10% at 12 h after 17beta-estradiol (E2) injection, but was not changed after progesterone (P) injection. RT-PCR revealed the expression of periostin/OSF-2 in human endometrium, cultured human endometrial stromal cells (ESCs), and cultured human endometrial epithelial cells. In ESCs, the expression of periostin/OSF-2 mRNA was reduced to approximately 50% at 6 h after E2 treatment. The amount of periostin/OSF2 mRNA in human endometrium significantly increased during mid-proliferative and early secretory phases of menstrual cycle, and decreased during late-proliferative, mid-secretory and late secretory phases. The expression of periostin/OSF2 mRNA significantly decreased in ESCs decidualized by treatment with E2 and P for 7 and 11 days. By immunohistochemistry, the expression of periostin/OSF-2 was strongly detected in endometrial stromal cells during early proliferative, mid-proliferative and early secretory phases, and was strongly detected in endometrial epithelial cells during late secretory phase. This study demonstrated that the expression of periostin/OSF-2 is regulated by ovarian steroid hormones in rat uterus and human endometrium.

The endometrium is one of the target tissues of the ovarian steroid hormones, estrogen and progesterone. In order to elucidate the mechanism of gene regulation in the endometrium, suppressive subtraction hybridization was performed to isolate the candidate genes controlled by progesterone in rat uterus. Alcohol dehydrogenase (ADH) class I gene was one of the candidate genes. Here we investigated the expression and regulation of ADH class I gene in rat uterus. The mRNA of ADH class I was detected in uterus by RT-PCR using specific primers. Using specific probe for ADH class I, in situ hybridization was performed to investigate localization in rat uterus. Positive signals were detected in the endometrial stromal cells of rat uterus by in situ hybridization and were not detected in endometrial epithelial cells and myometrium in rat uterus. Ovariectomized rats were treated with 17-beta estradiol and progesterone and the uteri of these rats were used for Northern blot analysis and assay of the ADH activity. Northern blot analysis revealed that the expression of ADH class I mRNA in rat uteri was up-regulated approximately two-fold after progesterone treatment, but not estrogen. Likewise, ADH activity was approximately two-fold higher in progesterone-treated rat uteri compared with controls. This study demonstrated that ADH class I gene is progesterone-responsive in the uterus. This implies that progesterone might be involved with retinoic acid synthesis in the uterus, since ADH is the key enzyme for retinoic acid synthesis.

Problem: Ovarian follicles undergo a dynamic change to provide a mature ovum, and the process involves angiogenesis, follicular cell proliferation and leukocyte recruitment. Midkine (MK) is a heparin-binding growth factor that has angiogenic, mitogenic, and chemotactic activities. In the present study, we investigated the presence of MK and its possible role in human ovarian follicles., Method of Study: Follicular fluid (FF) and luteinized granulosa cells (LGC) were collected from women undergoing in vitro fertilization and embryo transfer. Expression of MK protein in FF was examined by Western blotting. Concentrations of MK, estradiol and oxygen in FF were measured. 5-bromo-2'-deoxyuridine (BrdU) incorporation assay was performed in LGC. Normal ovarian tissues were obtained surgically and used in in-situ hybridization of MK mRNA., Results: The presence of MK protein was verified in FF. MK mRNA was expressed in both granulosa cells and theca cells of large follicles. There is a significant negative correlation between the concentrations of MK and oxygen in FF, and a significant positive correlation between the concentrations of MK and estradiol. MK promoted BrdU uptake in LGC., Conclusion: The present findings imply that hypoxic condition, a characteristic of growing follicles, associates with the production of MK. Given that MK is involved in granulosa cell proliferation and estradiol production in developing follicles, MK may play a role as a local regulator in the human ovary.

Aim:  Hysterosalpingography (HSG) is one of the most commonly used methods in order to evaluate the condition of fallopian tubes in infertility clinics. In the present paper, we retrospectively compared the findings of HSG and laparoscopy to elucidate the relationship between tubal dysfunction and background factors, such as Chlamydia trachomatis infection, endometriosis and previous surgery. Methods:  We retrospectively reviewed clinical records of 314 patients who were examined by both HSG and laparoscopy between 1996 and 2001 in the Department of Obstetrics and Gynecology, University of Tokyo. Results:  When HSG findings were evaluated in reference to those of laparoscopy, sensitivity and specificity for tubal patency were 0.63 and 0.79, respectively, whereas those for peri-tubal adhesion were 0.65 and 0.61, respectively. We compared the percentage of existence of background factors between the patients who were diagnosed as normal by both HSG and laparoscopy (Group L[+]) and those whose fallopian tubes were observed as patent by HSG, but were not patent by chromopertubation under laparoscopy (Group L[-]). The percentage of patients with positive chlamydial antibodies in Group L(-) (42.9%, 15/35) was significantly higher than that of patients with positive chlamydial antibodies in Group L(+) (22.8%, 44/193, P  < 0.05). Conclusions:  These finding suggested that even if HSG showed normally patent tubes in a patient with positive Chlamydia trachomatis antibodies, the possibility of tubal occulusion still remains high and further examination by laparoscopy is recommended. (Reprod Med Biol 2007; 6 : 39-43).

Background: Secretion of growth hormone (GH) is known to be suppressed in women with polycystic ovary syndrome (PCOS). The suppression may be implicated in the pathogenesis of PCOS., Objective: To investigate the cause of suppressive GH secretion in PCOS., Methods: In order to eliminate the influence of obesity on the variables, all subjects were non-obese. Standard oral glucose tolerance tests (OGTT) were performed in 13 normal women and 15 patients with PCOS., Results: The serum GH level decreased progressively during the OGTT, and the mean area under the curve (AUC) for the GH response was significantly smaller in the PCOS group than in the normal group. A reduction in the level of serum free fatty acids (FFAs) was observed during OGTT, but only the fasting level of FFAs was significantly higher in the PCOS group than in the normal group. The mean AUCs for glucose, insulin and FFA responses in the PCOS group were significantly greater than those in the normal group. There was a significant negative correlation only between AUC(GH) and testosterone (r = -0.4557, p = 0.012)., Conclusion: Our findings suggest that the cause of susceptibility for GH secretion to be suppressed after glucose loading in non-obese PCOS patients may be hyperandrogenemia.

IFN-gamma secreted by a human embryo and trophoblast cells during implantation is suggested to play an important role in implantation and pregnancy. In the present study, we explored expression and possible functions of CXCL11, a CXC chemokine strongly induced by IFN-gamma, and its receptor CXCR3 in the human endometrium. Secreted CXCL11 protein was not detected in cultured endometrial stromal cells (ESC) but was detected in cultured endometrial epithelial cells (EEC). IFN-gamma stimulated the protein levels of CXCL11 in a dose-dependent manner in EEC and ESC. CXCL11 secreted from EEC with 100 ng/ml IFN-gamma was 220-fold of the control, and 100-fold as compared with that secreted from ESC with the same dose of IFN-gamma. CXCR3 was expressed in EEC, ESC, and trophoblast cells. Addition of IFN-gamma to EEC increased the chemotactic activity of its culture medium to trophoblast cells and T cells, and the effect was suppressed by immunoneutralization with Abs of three CXCR3 ligands, including anti-CXCL11 Ab. CXCL11 significantly increased BrdU incorporation of ESC, which was inhibited by a p42/44 MAPK pathway inhibitor PD98059. In contrast, CXCL11 significantly decreased BrdU incorporation and increased the release of lactate dehydrogenase and the positive staining of annexin V in EEC. These findings suggest that IFN-gamma promotes implantation by stimulating EEC to produce CXCL11, which induces migration of trophoblast cells and T cells, proliferation of ESC, and apoptosis of EEC.

Novel liquid-crystalline polymers (LCPs) containing a long azotolane moiety were synthesized, and the relationship between the chemical structures and the photoresponsive behavior was investigated. All homogeneously aligned LCP films exhibited extremely high values of birefringence (Deltan) in the wide wavelength range. Specifically, the azotolane LCP with two azobenzene units showed the most efficient change in the alignment of the azotolane moiety with a huge change in Deltan (>/=0.65). This means that the high value of Deltan in the homogeneously aligned state can be converted to the change in Deltan effectively.

In various cells including endometriotic cells, p38 mitogen-activated protein kinase (MAPK) plays essential roles for inflammation, an etiological factor for endometriosis. We evaluated the effect of FR 167653, a p38 MAPK inhibitor, on the development of endometriosis using a murine model. As an endometriosis model, estradiol-treated ovariectomized BALB/c mice were injected intraperitoneally with endometrial fragments of the syngenic donor mice. The animals were injected with either 30mg/kg FR 167653 or only vehicle (control) s.c. twice a day, starting 2 days before endometrial injection. Three weeks later, the peritoneal fluids and the developed endometriotic lesions were collected. Both the weight of all the endometriotic lesions per mouse and the concentrations of interleukin-6 and monocyte chemoattractant protein-1 in the peritoneal fluid were significantly lower in the FR 167653-treated mice than in the control mice. These findings suggest that FR 167653 may inhibit the development of endometriosis possibly by suppressing peritoneal inflammatory status.

This study was performed to investigate the effect of androgen on the metabolism of bisphenol A (BPA), an endocrine disruptor, in order to clarify the mechanism of the higher levels of serum BPA in men and hyperandrogenemic women compared with normal women. Castrated female rats (OVX) were subcutaneously injected with testosterone propionate (TP) (0.01, 0.1, and 1 mg) every day for 2 weeks. Serum BPA concentrations in OVX rats showed a TP dose-dependent increase and were significantly higher at 0.1 and 1.0 mg of TP. The enzyme reaction of BPA glucuronidation in the rat liver microsomes showed that the ratio of glucuronide in the OVX rats was significantly reduced in a TP dose-dependent manner. Analysis of the mRNA expression of UDP-glucuronosyltransferase 2B1 (UGT2B1) by real-time quantitative RT-PCR revealed that the relative expression level of UGT2B1 mRNA showed a TP dose-dependent decrease. The results of enzyme analyses demonstrated that the ratio of BPA glucuronidation and the expression level of UGT2B1 mRNA were significantly lower under the hyperandrogenemic conditions. The clearance of BPA may be slowed in a TP dose-dependent manner, resulting in an increase of serum BPA concentration under hyperandrogenemic conditions.

Background:  Studies in several countries have reported a decline in human sperm quality similar to that observed in wild animals. To quantify whether the number of sperm in humans has decreased and whether humans are affected by similar environmental influences, we compared the number of spermatogonia and Sertoli cells in human fetal and neonatal testes autopsied at two institutions in Tokyo between 1958-1964 (term A) and 1989-1998 (term B), with special attention to chronological changes during gestation. Methods:  We used an immunohistochemical method with antibody against neuron-specific enolase to determine the percentage of seminiferous tubules containing spermatogonia in the formalin-fixed tissue samples, and a morphometrical method using a dissector to count the number of spermatogonia. Results:  There were no significant statistical differences between the two time periods in the regression parameters compared for the number of spermatogonia and Sertoli cells, nor was there a remarkable difference in the estimated number of Leydig cells. Conclusion:  The results indicate that even if there has been a deterioration in human semen quality, it is not necessarily caused by endocrine disruption of fetal testicular development. (Reprod Med Biol 2006; 5 : 65-70).

Background: Inflammation has been proposed to play essential roles in the pathophysiology of endometriosis, in which neutrophils and mast cells have been suggested to be involved. We studied whether the protease-activated receptor 2 (PAR2), which is activated by enzymes from neutrophils and mast cells, in endometriotic stromal cells (ESC) has any implication in the development of the disease., Methods: Cultured ESC were stimulated with various concentrations of a specific PAR2 agonist peptide. Proliferating activity of the cells was determined using immunostaining of proliferating cell nuclear antigen (a cell proliferation marker), 5-bromo-2'-deoxyuridine incorporation into DNA and cell count. The concentrations of interleukin (IL)-6 and IL-8 were measured using specific enzyme-linked immunosorbent assay kits. The phosphorylation of three mitogen-activated protein kinases (MAPK), i.e. p38 MAPK, p42/44 MAPK and stress-activated protein Kinase/c-jun N terminal Kinase, in ESC was examined with Western blot analysis., Results: Activation of PAR2 stimulated the proliferation of ESC and the secretion of IL-6 and IL-8 from ESC in a dose-dependent manner. Activation of PAR2 stimulated the phosphorylation of all three MAPK, and inhibitors of each MAPK suppressed the PAR2 activation-induced proliferation of ESC., Conclusions: The activation of PAR2 in ESC may be involved in the pathophysiology of endometriosis by inducing the growth and inflammation of endometriotic lesions.

The goal of this study was to investigate fetal exposure to phytoestrogens, estrogenic compounds derived from plants, by measuring serum concentrations of phytoestrogens in maternal and cord blood. This study included 51 mothers scheduled for cesarean section (C-section), to obtain the serum of mother and fetus at almost the same time. Serum concentrations of phytoestrogens, including genistein (Gen), daidzein (Dai), coumestrol (Cou), equol (Equ; a metabolite of Dai), and sulfate-conjugated Gen, were measured in maternal and cord blood samples by LC-MS/MS and HPLC. It was found that phytoestrogens were transferred from mother to fetus. The detection rates of Gen, Dai, Equ, and Cou in cord serum were 100%, 80%, 35%, and 0%, respectively. Levels of Gen and Dai were higher in cord than in maternal serum (mean=19.4 ng/ml vs.7.2 ng/ml and 4.3 ng/ml vs.1.8 ng/ml for Gen and Dai, respectively). However, a reverse pattern was seen for Equ (cord mean=0.9 ng/ml, maternal mean=2.0 ng/ml). The correlations were significant between the concentration levels of Gen and Dai, Gen and Equ, and Gen and Dai plus Equ in cord serum. However, in maternal serum, the correlations were weak. Also, in 8 of 10 cord serum samples, sulfate-conjugated Gen was detected (mean=5.2 ng/ml, standard deviation=4.7), but it was detected from only one maternal serum (8.7 ng/ml). This study demonstrates placental transfer of phytoestrogens from mother to fetus. It is suggested that the metabolic and/or excretion rates of phytoestrogens are different between mother and fetus and once phytoestrogens are transferred to the fetus, they tend to stay in the fetal side longer than in the maternal side. While the implications for the health and development of the newborn are not known, these data suggest that the effects of fetal exposure to phytoestrogens should be studied further.

Background: Aiming at improving an animal model of endometriosis, we developed a homologous mouse model using 'green mice' that ubiquitously express green fluorescent protein., Methods: Endometrial fragment obtained from estradiol (E2)-supplemented ovariectomized 'green mice' was minced and injected into the peritoneal cavity of ovariectomized wild-type mice. The recipient wild mice were raised with or without E2 supplementation for 2 weeks, and then were euthanized. Endometriotic lesions that developed in the abdomen were examined both macroscopically and microscopically under fluorescence, and weight of the lesions was measured., Results: The endometriotic lesions were more clearly detected under fluorescence imaging than by conventional macroscopic examination. Histologically, endometriotic lesions deriving from 'green mice' were sharply distinguished from surrounding host tissues under fluorescence microscopy. More lesions developed in E2-supplemented than control recipient mice. The measured fluorescence intensity of endometriotic lesions showed significant positive correlation with their weight (R=0.844, P<0.0001), and was significantly higher in E2-supplemented mice than in vehicle-supplemented mice (P=0.0062)., Conclusion: The present endometriosis model using 'green mice' would be useful for expeditious identification and quantitative evaluation of endometriotic lesions.

Endometriosis is known to be associated with local inflammatory reactions. Given the emerging concept of thrombin and its specific receptor, protease-activated receptor 1 (PAR1), as important players in inflammation and cell proliferation, we investigated whether thrombin and PAR1 might be involved in the pathophysiology of the disease, using a primary cell culture system of endometriotic tissues. PAR1 mRNA was expressed in primary endometriotic stromal cells (ESCs). Thrombin and SFLLRN (Ser-Phe-Leu-Leu-Arg-Asp), a PAR1 agonist peptide, increased the mRNA expression of IL-8, monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) and the protein secretion of IL-8 nd MCP-1 in ESCs. The addition of thrombin inhibitor d-phenylalanyl-l-prolyl-l arginine chloromethyl ketone (PPACK) together with thrombin inhibited the thrombin-induced secretion of IL-8 and MCP-1. Thrombin, but not SFLLRN, activated matrix metalloproteinase-2 in ESCs, and the effect was inhibited by PPACK. Thrombin and SFLLRN increased proliferating cell nuclear antigen-positive ratio of ESCs, indicating their cell proliferation-stimulating effects. The thrombin-induced increase in proliferating cell nuclear antigen-positive ratio was diminished by PPACK. These findings imply that the thrombin system might be involved in the pathophysiology of endometriosis, stimulating inflammatory responses of endometriotic cells and their mitogenic activity.

Objective: To investigate the role of interleukin (IL)-16 in peritoneal fluid in the pathogenesis of endometriosis., Design: Comparative and laboratory study., Setting: University of Tokyo Hospital., Patient(s): Peritoneal fluids (PFs) were collected from women without endometriosis (n = 34) and with endometriosis (stages I/II, n = 30; stages III/IV, n = 58). Peritoneal fluid mononuclear cells (PFMCs) were collected from six women., Intervention(s): The PFs were collected; PFMCs were isolated and cultured with or without recombinant human (rh) IL-16., Main Outcome Measure(s): Concentrations of IL-16 in PFs were measured by enzyme-linked immunosorbent assay (ELISA). Concentrations of IL-6, tumor necrosis factor-alpha (TNF-alpha), and IL-1beta in culture media of PFMCs were determined by ELISA., Result(s): The IL-16 concentrations in the PF of women with advanced endometriosis (stages III/IV) (330 pg/mL, 231-501; median, interquartile range) were significantly higher (P=.0016) than those without endometriosis (229 pg/mL, 174-311). The PFMCs cultured with rhIL-16 released an increased amount of IL-6, TNF-alpha and IL-1beta, which was a 1.17-, 1.33-, and 1.54-fold increase, respectively, over that in the control culture., Conclusion(s): The present study indicates that IL-16 in PF may play a role in the pathogenesis of endometriosis by initiating or sustaining inflammatory responses in the peritoneal cavity.

Background: The present study was conducted to assess whether midkine (MK), a multifunctional molecule known to stimulate tumor growth, may be involved in the development of endometriosis., Methods: The mitogenic activity of MK on cultured endometriotic stromal cells was examined by measuring 5-bromo-2'-deoxyuridine (BrdU) incorporation. Concentrations of MK in the peritoneal fluid (PF) of women without or with endometriosis and those under GnRH agonist treatment were measured using a specific enzyme immunoassay. The expression of MK mRNA in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues was evaluated by RT-PCR., Results: MK significantly increased BrdU incorporation into the DNA of cultured endometriotic stromal cells. The MK concentrations in the PF of the women with advanced endometriosis (stages II, III and IV) Median: 1.21 ng/ml; interquartile range 0.80-2.27 were significantly higher than those of the women without endometriosis and with stage I endometriosis (0.06 ng/ml, 0.67-1.26, P < 0.05). As for the menstrual phase, the MK concentration in PF in the inteal phase (1.32 ng/ml. 0.72-2.21) were significantly higher than those in the follicular phase (0.95 ng/ml, 0.68-1.24, P < 0.05). In addition, women with adnexal adhesions had higher concentrations of MK in PF than those without adhesions (P < 0.05). The MK concentrations of the women under GnRH agonist treatment were significantly lower than those of the other groups (P < 0.001). The expression of MK mRNA was detected in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues., Conclusions: The present findings suggest that MK may play roles, such as stimulation of endometriotic cell proliferation, in the development of endometriosis.