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The objective of this study was to explore the factors associated symptoms of depression among pregnant women with gestational diabetes mellitus (GDM) in Japan. This cross-sectional study was conducted at a hospital in Toyota, Japan, from January 2015 to June 2016. Pregnant women who visited the hospital and were diagnosed with GDM in the second trimester were enrolled. We analyzed depression symptoms using the Centers for Epidemiological Studies Depression Scale (CES-D) and considered related factors of depression symptoms, such as dietary intake and daily walking. Dietary intake during the past month was assessed using a brief self-administered diet history questionnaire, and daily walking was assessed using an accelerometer. The prevalence rate for GDM was 8.8%, and 25 pregnant women with GDM were analyzed. The CES-D was not significantly correlated with pre-pregnancy BMI, postprandial plasma glucose, hemoglobin A1c, and the number of steps walked. In contrast, a significant negative correlation was observed between the CES-D score and intake of fish with bones, simmered fish, pickles, green leaves, mushrooms, and green tea. Furthermore, a significant positive correlation was found between Coke® and CES-D scores. For nutrient intake, a significant negative correlation was found between the CES-D score and vitamin K, folate, and β-carotene levels. The present study suggests that depression symptoms among pregnant women with GDM in the second trimester may be associated with diet.

Introduction Sexual function and frequency can change between couples during pregnancy and postpartum, with a decline in sexual function in women. Aim To investigate sexual function in couples during pregnancy and postpartum. Methods This questionnaire-based cross-sectional descriptive study solicited data from 551 couples, 127 (23%) of whom responded: 15 during the first trimester; 26 during the second trimester; and 21, 22, 21, and 22 at 1, 3, 6, and 12 months postpartum, respectively. The Female Sexual Function Index (FSFI) and International Index for Erectile Function (IIEF) questionnaires were used for female and male participants, respectively, and included questions about delivery, breastfeeding, partner’s contribution to housework, and desire to have more children for women, and about aspects of their partner’s pregnancy and postpartum life for men. Data about maternal/paternal age, parity, body mass index, and mode of delivery were also collected. Main Outcome Measure FSFI and IIEF total and subcategory scores with attributable factors. Results The total and subcategory scores related to female and male sexual functions were lowest at 1 and 3 months postpartum, with 79 women reporting female sexual dysfunction (score Conclusion Sexual function decreased around the time of delivery for men and women, but did not correlate with the sexual satisfaction of men. Type of delivery, breastfeeding, intimacy, and partner’s contribution to housework did not affect sexual dysfunction.

Purpose To analyze the usefulness of intravaginal insemination (IVI) for the infertility treatment in couples with sexual dysfunction before applying assisted reproductive technology (ART). Methods Among 208 couples who presented sexual dysfunction, 144 couples underwent IVI procedures. The profiles of pregnant and non‐pregnant patients were compared. Results Of 144 patients, 58 women conceived successfully (40.3% pregnancy rate). Between the pregnant and non‐pregnant cases, the husband's age and infertility period were significantly higher (P = .0104) and longer (P = .0027) in the unsuccessful cases than the successful ones. The husbands who could not impregnate had a significantly higher ratio of sperm abnormalities (P = .0048). Among the 57 successful cases who underwent IVI treatment, 38 (66.7%) patients became pregnant within 3 times of the procedure, while 48 (84.2%) patients conceived within 6 times. Conclusion The authors can propose the following inclusion IVI criteria for couples with sexual dysfunction: (a) younger husband (36 years old or less) which may be most important, (b) infertility duration of 3 years or less, (c) normal sperm condition, and (d) IVI trial for 3 times (maximum of 6 times). Since IVI appears to be a simple, noninvasive, and inexpensive way for couples with sexual dysfunction, it can be attempted before ART application., Intravaginal insemination (IVI) is a useful method for the infertility treatment in couples with sexual dysfunction before ART application. The following inclusion criteria can be proposed; (a) younger husband (36 years old or less), (b) infertility duration of 3 years or less, (c) normal sperm condition, and (d) IVI trial up to 3 times (maximum of 6 times).

Given the possible medical complications, risks, and the need for informed decision making, pregnancy after kidney transplantation is a serious and difficult issue. In this article, we summarize aspects related to pregnancy counselling for kidney transplant recipients based on past research. Kidney transplant recipients tend to have overall higher rates of preterm deliveries, low-birthweight babies, and caesarean section than the general population. There have been instances of maternal complications such as preeclampsia, allograft loss, and urinary tract infections during pregnancy; in particular, hypertension is a common problem among kidney transplant recipients. Pregnancy counselling should start when a recipient chooses renal replacement therapy, and the counselling program should be tailored to the recipient's life cycle and treatment period. It is necessary to explain the essential conditions for pregnancy, such as the need to change to a safe drug, ensure stable kidney function, and wait one to two years after transplantation before conception. Medical staff should be informed about menstrual recovery after transplantation, contraception, and unexpected pregnancy. When a recipient becomes pregnant, it is necessary to convey information about the mode of delivery and breastfeeding. The contents of pregnancy counselling must be modified according to recipient needs, and detailed discussions are needed between medical staff and transplant recipients. Medical staff should support recipients and their family during the decision-making process before conception. It is essential for kidney transplant recipients to discuss the topic of pregnancy with transplantation physicians, so as to give birth safely and maintain their health with a donated kidney.

AIM This study evaluated the usefulness of daily walking for gestational diabetes mellitus (GDM) management by analyzing the relationship between daily walking and glucose tolerance in pregnant women with GDM who were in the second trimester. METHODS This longitudinal study was conducted at TOYOTA Memorial Hospital in Toyota, Japan, from January 2015 to June 2016. Pregnant women with GDM wore accelerometers on the waist for 7-12 weeks. RESULTS Seventy-three women with GDM were included in the present study; data collected from 24 women were analyzed. The estimated number of steps walked daily showed a significant positive correlation (r = 0.798, P = 0.000) with energy expenditure related to physical activity. There was a significant negative correlation (r = -0.603, P = 0.014) between the post- to pre-research casual glucose level (CGL) ratio and the number of steps walked daily. No significant correlation (r = -0.004, P = 0.986) was detected between the ratio of hemoglobin A1c and the number of steps taken. When the study was completed, the 11 participants who walked ≥6000 steps/day showed significantly lower CGL (95 + 10 mg/dL [mean + SD]) than the 13 participants in the

Background In recent years, uterus transplantation (UTx) has been applied as the treatment for patients with uterine factor infertility worldwide. Thus, the clinical application of UTx in Japan should be considered through both the history of UTx technology development in the world and future prospects. Methods Recent information on UTx was collected via a literature survey and the Internet. Results Basic research using various animals has been done mainly since 2000. In 2014, the world's first UTx baby was born in Sweden. In total, 24 UTx procedures have been performed at 10 institutes in nine countries and five births were obtained (as of May, 2017). In Japan, the “Project Team for Uterus Transplantation” initiated UTx experiments in 2008 and the “Japan Society for Uterus Transplantation” was organized in March, 2014. In the rest of the world, the “International Society for Uterus Transplantation” was established in January, 2016. Conclusion Uterus transplantation is still under development as a reproductive medicine tool and organ transplant procedure. A collaborative system that is not limited by facilities and specialties should strive to build an “all-Japan” team.

Background: For individuals who have undergone organ transplants, pregnancy counseling is necessary to avoid high-risk or unwanted pregnancies. This study investigated kidney transplant recipients’ pregnancy outcomes and their requests for pregnancy information, to present future directions for pregnancy counseling. Methods: Data were collected from 65 Japanese kidney transplant recipients from 21 hospitals who had given birth after transplant. Data for 83 fetal outcomes were collected via a questionnaire and then evaluated. Pregnancy-related data were collected on factors including the provision of pregnancy information by medical staff, when the participants hoped to have a child, and request for pregnancy information. Results: Mean age at the time of transplant was 28.3 ± 4.6 years. Maternal age was 33.8 ± 3.9 years, with gestation duration of 35.3 ± 3.3 weeks and baby birth weight of 2303.8 ± 592.5 grams. A total of 83 fetal outcomes were evaluated. More than 80% of the recipients and 54% of the recipients’ partners received information from health professionals before and after kidney transplant. Drug effects on the fetus represented the pregnancy information most requested by recipients. Conclusion: Recipients requested more detailed pregnancy information even after provision of information by medical staff. Recipients indicated low satisfaction with the counseling and anxiety during pregnancy. It is especially important to explain the influence of medicines on the mother's body and the fetus. The contents of pregnancy counseling must be modified according to recipient needs, and detailed discussions are needed between medical staff and transplant recipients. Keywords: Kidney Transplant Recipient, Pregnancy, Nursing, Counseling

Background For mothers who experience transplants, pregnancy and childcare can have significant consequences on their quality of life. This study aims to investigate the childcare-related suffering faced by women who gave birth following kidney transplantation. Methods Data were collected from 65 Japanese kidney transplant recipients from 21 hospitals who had given birth after transplant. The questionnaire included questions concerning the childcare-related suffering of the female kidney transplant recipients. The data were analyzed using KH Coder for the qualitative text mining analysis. Results The results of the co-occurrence network of words and hierarchical cluster analysis revealed 6 categories that were identified regarding the difficulties in childcare experienced by mothers who gave birth after kidney transplantation: comparing themselves with healthy mothers, parenting priorities, getting tired, not being able to take medicine on time, carefully giving the child a hug, being unable to give breast milk, having regular doctor checkups, and having to leave the child. Conclusion Recipients experience suffering related to the lifestyle changes that occur as a matter of course during childcare. Recipients are exhausted because of how busy they are with childcare, and they sometimes forget to take their medicine. It is necessary to confirm the living situations of recipients after birth and provide support for their self-management based on their new lifestyles.

Yuki Yoshikawa,1,2 Junji Uchida,3 Chiharu Akazawa,4 Nobuhiko Suganuma2 1Faculty of Medicine, Osaka City University, Osaka, Japan; 2Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; 3Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan; 4Faculty of Nursing, Osaka Medical College, Osaka, Japan Purpose: Health-related quality of life (HRQOL) among kidney transplant recipients is associated with physical and psychosocial characteristics. Furthermore, pregnancy and childcare may be particularly challenging for women. The aim of this study was to assess the relationship between patients’ psychosocial characteristics and HRQOL, specifically for recipients who have given birth after their kidney transplant.Patients and methods: This was a cross-sectional study. Participants were 59 kidney transplant recipients who had given birth after transplantation. The tools used were the Medical Outcomes Scale, the Kidney Transplantation Self-Management Scale, the Multidimensional Scale of Perceived Social Support (MSPSS), and The Maternal Consciousness Scale.Results: Mean age was 42.3±7.2 years, and the mean age at the time of transplant was 28.2±4.6 years. A total of 82 fetal outcomes were evaluated. Maternal age was 33.6±4.1 years, duration of gestational period was 35.3±3.3 weeks, and birth weight was 2,303.8±592.5 g. HRQOL results were nearly the same as stratified national norms. The physical component summary was positively correlated with the MSPSS (p=0.025), and self-care behavior was positively correlated with the mental component score (p=0.029) and MSPSS (p=0.016). A structural equation model revealed that self-care behavior and the patient–health professions partnership indirectly affected physical health through social support.Conclusion: Self-management indirectly affects physical health through social support. To create a supportive environment through monitoring and consultation with patient families, child-rearing kidney transplant recipients should be encouraged to improve their self-management skills to improve their quality of life. Social support for self-management may contribute to improve HRQOL for women who experience pregnancy and child-rearing after transplantation. Keywords: kidney transplant, quality of life, pregnancy, child-rearing, social support&nbsp

Objective: Kampo education has been part of the curriculum in medical universities and colleges since 2001. However, it has not been the part of nursing university/college curriculum. The purpose of this study is to identify and follow the trend of Kampo education in Japanese nursing universities and colleges. We also gathered the opinion of beneficiaries of Kampo education, i.e. nursing students and teachers. Subjects and methods: The implementation status of Kampo education was investigated at departments of nursing in 90 schools of all Japanese public universities and colleges (n=90) in 2012 and 2016 using mail and web surveys. The recovery rate indicated 100%. In addition, questionnaire surveys concerning Kampo education were conducted among nursing students (n=208) and nursing teachers (n=365). Results: Although number of performing Kampo education increased from 27 in 2012 to 38 in 2016 significantly (p=0.04), it was smaller portion compared with medical courses (100%). In the consciousness survey on Kampo education, 75.5% of the nursing students and 88.8% of the nursing teachers responded that Kampo education was necessary. Conclusions: The present results indicated the necessity of Kampo education to nursing students. Because Kampo education was introduced into the nursing curriculum by the Japanese government recently, educational program should be arranged in the near future.

Background striae gravidarum affects the quality of life (QOL) of Japanese pregnant women. Many pregnant women use skin moisturisers to prevent striae gravidarum. However, the relationship between these preventive steps and QOL remains unclear. Objective to evaluate the moisturising effect and QOL of pregnant women in an urban prefecture in central Japan with preventive steps against striae gravidarum. Design and method cross-sectional study. Pregnant women at 36 weeks of gestation were recruited at antenatal examinations. Setting four private clinics in an urban prefecture in central Japan. Participants 156 pregnant women consisting of 83 primiparae and 73 multiparae were analysed. Measurements a self-administered questionnaire, the severity of striae gravidarum assessed by Davey's score and the dermatology-specific QOL were assessed by Skindex29. The water content in the stratum corneum of each woman's abdomen was measured with a Moisture checker. The Ethical Committee of Osaka University Medical School approved the study. Findings the prevalence of striae gravidarum was 37.8% and 121 (77.6%), including 76 (91.6%) primiparae and 45 (61.6%) multiparae, said they used a cream and/or lotion in an attempt to prevent striae gravidarum. The water content in the stratum corneum of the abdominal wall increased significantly after using cream and/or lotion ( p =0.001). The severity and presence of striae gravidarum were not correlated with the preventive steps or water content in the stratum corneum of the abdominal wall ( p =0.330 and p =0.835). Pregnant women who took the preventive steps showed higher scores for emotion on Skindex29 than those who did not ( p =0.002). Although pregnant women with striae gravidarum showed a lower QOL for emotion than those without striae gravidarum ( p =0.045), those who took the preventive steps maintained a similar level of QOL for emotion regardless of striae gravidarum. There have been few trials evaluating the QOL of pregnant women with striae gravidarum so a comparison of results among studies and determination of an appropriate sample size could not be conducted. Key conclusions and implications for practice preventive steps increase the amount of water content in the stratum corneum but this does not prevent striae gravidarum. Although pregnant women with striae gravidarum showed a lower QOL for emotion, the preventive steps were correlated with the level of QOL for emotion in pregnant women with striae gravidarum. Midwives need to absorb such information and recommend moisturising skin care for pregnant women.

Assisted reproductive technology has improved markedly in recent years, and many infertile patients have had children with the use of this technology. However, women with infertility due to an absent or nonfunctional uterus currently have no option of having a genetically linked child other than gestational surrogacy. Uterus transplantation (UTx) is now a possible approach for women with uterine-factor infertility to deliver a child. UTx studies have been performed in many animals, and accumulation of data from these studies has brought UTx within reach of clinical application. This has led to performance of UTx in humans in Saudi Arabia, Turkey, and Sweden. However, there has yet to be a delivery after allogeneic UTx in primates. More basic studies in primates are needed, and data from research in primates can provide important information for establishment of UTx in humans. In this review, we summarize the literature on UTx studies, with a focus on primates, both human and nonhuman.

Aim Uterine transplantation (UTx) is a potential option for child-bearing in women with uterine infertility. Recovery of uterine function after allogeneic UTx in non-human primates has not been reported. The objective of this study is to establish the functional uterine transplant model in non-human primates. Methods Uteri of two cynomolgus monkeys were simultaneously removed, cooled at 4°C and perfused with heparin saline. The uteri were interchanged with each other and then orthotopically transplanted. Immunosuppressive protocols included use of three agents (tacrolimus, mycophenolate mofetil and methylprednisolone) in case 1 and two agents (tacrolimus and methylprednisolone) in case 2. Transabdominal ultrasonography, vaginoscopy and biopsy of the transplanted uterine cervix were routinely conducted to monitor rejection after surgery. Results The blood concentration of tacrolimus decreased 11 days after surgery and evidence of rejection was found in biopsy of the uterine cervix in both cases. The suspected rejection disappeared 23 days after surgery in case 1 and temporary menstruation resumed at 3 months after surgery. In case 2, blood flow to the uterine artery gradually decreased and the uterus resulted in atrophy due to ischemia, which has been triggered by rejection. Conclusion Allogeneic UTx in the cynomolgus monkeys resulted in temporary recovery of menstruation with three immunosuppressants and uterine atrophy with two immunosuppressants. This preliminary experience suggests that recovery of uterine function after allogeneic UTx in non-human primates is possible but more experiments are required.

Objective To clarify the current status of uterus transplantation (UT) and the medical, ethical, and social problems surrounding UT. Design Systematic review. Setting Not applicable. Patient(s) Mainly nonhuman primates and humans. Intervention(s) Not applicable. Main Outcome Measure(s) A systematic search of Pubmed with the terms "uterus/uterine transplantation" was performed for English-language articles to review the current status of UT and issues associated with its clinical application, with a focus on nonhuman primate and human studies on UT. Result(s) The first UT procedure in humans was conducted for a patient with absolute uterine infertility in Saudi Arabia in 2000. The transplanted uterus was removed after 99 days owing to prolapse and necrosis. That attempt led to a greater focus on basic UT experiments in animal models, including nonhuman primates. The subsequent accumulation of basic data has led to performance of UT in humans by groups in Turkey and Sweden. However, there has yet to be a pregnancy or delivery after allo-UT in primates. Moreover, there are many medical, ethical, and social problems that require examination before clinical application. Conclusion(s) Clinical application of UT has just begun, but more basic data are needed and medical, ethical, and social problems require thorough discussion before clinical application.

This study compared the nutritional status before pregnancy, as well as dietary profiles and biomarkers during first trimester, between never-smokers and antenatal quitters among Japanese women. One hundred fifty pregnant women (79 never-smokers and 71 antenatal quitters) from two obstetrics and gynecology clinics were recruited in Japan. Subjects' prepregnancy nutritional status was indicated by their body mass index (BMI). In the first trimester, their dietary profiles were assessed by the Brief Diet-History Questionnaire (BDHQ) and pregnancy outcomes were screened by biomarker tests. Generalized linear regression was used to examine the differences of energy-adjusted dietary intakes and biomarker results between the two smoking groups, with adjustment of maternal age, BMI, gestation week, and parity. The results showed that antenatal quitters were more likely to have a prepregnancy underweight status than never-smokers. During the first trimester, antenatal quitters had significantly higher intakes of unsaturated fatty acids and antioxidants (vegetable lipids and isoflavone), and lower intakes of total cholesterol than never-smokers. Moreover, antenatal quitters had a significantly higher level of serum homocysteine (6.36 nmol/mL vs 4.88 nmol/mL) than never-smokers. In conclusion, antenatal quitters are more likely to have a poor nutritional status before pregnancy than never-smokers. Quitting smoking before pregnancy and having a good nutritional profile during the trimester may not sufficiently reverse the adverse effects of former smoking behaviors on pregnancy outcomes.

Gestational diabetes mellitus (GDM) is one of the perinatal complications. This disorder affects women not only during pregnancy but also after delivery. It is necessary for pregnant women to be cognizant of both their diet and physical activity. Although recommendation for dietetic treatment for GDM was represented, a consensus on diet treatment for GDM has not been obtained yet. Effectiveness of physical activity interventions on preventing GDM was demonstrated, however, scientific evidences related to non-exercise activity thermogenesis are still lacking. More researches concerning nutrition and physical activity during pregnancy should be performed to establish the better management protocol for prevention and treatment of GDM.

Understanding the causes of congenital anomalies is of prime importance to develop management and/or prevention strategies. It is widely accepted that the occurrence of congenital malformations in fetuses and neonates is heavily correlated with maternal genetic makeup and lifestyle. However, very few epidemiologic analyses have been conducted on the embryonic developmental period because of the rarity of data available. Instigated in 1961, the Kyoto Collection of Human Embryos comprises approximately 45,000 specimens of embryos and fetuses. The collection's most unique feature is that most specimens were added to the collection along with epidemiologic information on the respective mothers. This is the first report on the digitization of data from the collection. A total of 22,262 embryonic specimens were selected on the basis of data integrity. Data related to the embryos were then classified according to the following criteria: developmental stage, sampling period, geographical area, maternal determinant, and external malformation. Results indicate that 7.8% of the embryos exhibit external anomalies and 92.2% are without anomalies. The three most common anomalies were nuchal bleb, holoprosencephaly and spina bifida. A special emphasis was placed on the potential association between maternal determinants and embryonic external anomalies, allowing for statistical analyses. The present study provides further evidence that this collection represents a unique source of information to conduct epidemiological analyses, not only to further the understanding of congenital anomalies but also to help establish preventive health guidelines for pregnant women.

background: Uterus transplantation may be the only theoretical option for some women, for example, those with congenital uterine infertility or who have undergone hysterectomy. In this study, we evaluated the intra- and post-operative blood flow conditions of vascular anastomosed regions and the blood-perfused area of the transplanted uterus in a cynomolgus macaque model of uterus autotransplantation. methods: Female cynomolgus monkeys (n ¼ 6) underwent surgery: the first two animals were used to study the pelvic vascular anatomy and the remaining four animals were used for uterus autotransplantation. We used indocyanine green (ICG) fluorescent angiography during surgery to assess blood perfusion in the vascular anastomosed region and uterine area. After surgery, the uterine size, presence or absence of the endometrium and blood flow rates in the uterine artery and vein were evaluated using Doppler ultrasonography. results: Uterine arterial and venous anastomoses succeeded in all four animals that underwent autotransplantation. Intraoperative ICG fluorescence angiography showed favorable blood flow in the vascular anastomosed regions and the entire uterus received a sufficient blood supply from a single uterine artery. Favorable blood flow in the uterine artery and vein immediately after surgery was shown by Doppler ultrasonography. Ultimately, three out of four animals died within 3 months following surgery because of reduced feeding and loss of body strength. conclusions: ICG fluorescence angiography can be used for simple evaluation of real-time blood flow conditions in the anastomosed uterine artery, vein and uterine area and can facilitate the success rate of uterus transplantation.

Cervical mucus plays an important role in host defense mechanisms and is involved in the ascendance of sperm. To determine the change of neutrophil mediators contained in cervical mucus, we measured total neutrophil elastase (NE) levels throughout the menstrual cycle.Cervical NE concentrations in 31 healthy women having regular ovulatory cycles were measured during the follicular, ovulatory and luteal phases.The cervical NE levels during the follicular, ovulatory and luteal phases were 0.73 ± 0.57 (mean ± SD), 0.29 ± 0.33 and 1.32 ± 1.24 μg/ml, respectively. The NE concentrations during the ovulatory phase were significantly lower than the other phases.The decrease in total cervical NE level during the ovulatory phase suggests that neutrophil activity in cervical mucus is depressed around ovulation. The decreased cervical NE levels and the depressed neutrophil activity in cervical mucus at ovulation may be suitable for sperm passage through the cervical canal.

Women who undergo hysterectomy due to uterine malignancy, benign disease or postpartum hemorrhage and those with congenital uterine infertility due to a uterine or vaginal defect (Rokitansky syndrome) cannot have a child in Japan because surrogate conception is not permitted. This may be a serious impediment to their marriage, relationship and quality of life. To restore fertility, uterine implantation has been proposed as assisted reproductive technology (ART), as a successor to surrogate conception without the associated ethical problems, and fundamental studies are ongoing. The attitudes toward surrogacy and uterine implantation were investigated by analysis of comments of maternity nurse students, who are likely to play a leading role in maternal management. The results showed that many students answered "I cannot say yes or no" to the question "Would you want to have a child by a surrogate mother or uterine implantation?". Only 1 (7.7%) and 5 (38.5%) of 13 student nurses answered positively to wanting a child by a surrogate mother and by uterine implantation, respectively. In this article, we evaluate the responses of the Japanese maternal nurse students and discuss the current status and restrictions on surrogacy in Japan.

Objective To determine whether the concentration of hCG in cervical fluid can predict miscarriage during early pregnancy. Design Prospective clinical study. Setting University hospital. Patient(s) Ninety-nine women with singleton pregnancies, 17 of whom suffered a miscarriage. Intervention(s) None. Main Outcome Measure(s) Miscarriage and the cervical fluid/serum hCG concentration ratio. Result(s) With a cutoff value of 1.0, the sensitivity, specificity, and positive and negative predictive values of the cervical fluid/serum hCG concentration ratio for predicting miscarriage were 88.2%, 94.9%, 83.3%, and 96.6%, respectively. Conclusion(s) The cervical fluid/serum hCG concentration ratio might be a useful predictor of miscarriage during early pregnancy.

BACKGROUND: To create a more effective selection standard for early embryos, we developed a new grading system consisting of conventional morphological evaluation in combination with analysis of blastomere nuclei. METHODS: A total of 744 embryos used during 459 cycles of embryo transfer on day 2 and blastocyst transfer were subjected to retrospective analysis. The overall implantation rate was 15.5% (115/744). Morphological evaluation of the embryos was performed on day 2 by referring to both the size of blastomere and fragmentation (conventional method) and the nucleic features of the blastomeres-either multinucleated or anucleic (nuclei counting method). The implantation rate for every transferred embryo and blastocyst was examined. RESULTS: Although a high implantation rate was observed with the highest quality embryos as judged by either the conventional method (24.1%; 57/237) or the nuclei counting method (26.1%; 104/399), the nuclei counting method predicted implantation rate better than the conventional method. The embryos that were considered to be high quality according to the conventional method, but low quality according to the nuclei counting method, had a limited implantation success rate of 6.3% (4/66). Also, after blastocyst transfer, implantation occurred most often when high quality embryos evaluated by the nuclei counting method were used (25.5%; 25/98), while the blastocysts from low quality embryos seldom implanted (3.2%; 2/63). CONCLUSIONS: When choosing which embryo to transfer, the normality of blastomere nuclei may be a more important index of quality than standard fragmentation features and/or blastomere uniformity analysis. When choosing among embryos, if nucleic status is identical, then embryos with the least fragmentation should be chosen. Moreover, in blastocyst transfer, a blastocyst whose nuclei were judged normal on day 2 should be selected on day 5 over any other blastocysts.

Plasma cells play a pivotal role in the immune system and are responsible for the synthesis and release of immunoglobulins. Numerous in vitro culture experiments on the yolk sac demonstrated the generation of mature cells of the myeloid and lymphoid lineages under appropriate culture conditions. However, there are no reports describing the development of mature lymphoid cells in the yolk sac so far. For this reason, we undertook this study to investigate the development of antibody-containing plasma cells during early yolk sac haematopoiesis. Immunohistochemistry and immunoelectron microscopy were employed in the study. Results of this work demonstrated very weak immune staining for the intracytoplasmic IgA, IgG, and IgM at days 10 and 11 of embryonic life, while dark staining was obtained at 12 days. Positive staining was localized to the endodermal cell layer. Electron microscopic examinations revealed the existence of cells with the typical characteristics of plasma cells inside the endodermal cell layer, which may suggest their endodermal origin. To further verify the nature of these cells, intracytoplasmic immunoglobulins were demonstrated by immunoelectron microscopy. The present study demonstrated emergence of mature functioning plasma cells in early rat yolk sac. In a previous work we hypothesized the possibility of endodermal origin of yolk sac macrophages. This study adds additional evidence to support that hypothesis. The possible role of plasma cells in the yolk sac is discussed.

hCG, LH, FSH, and TSH are a family of heterodimeric glycoprotein hormones that contain a common alpha-subunit, but differ in their hormone-specific beta-subunits. The alpha-subunit has two N-glycosylation sites at Asn52 and Asn78. To obtain more information on the relationship between the structure and function of the alpha-subunit, we introduced a novel N-glycosylation site in the N-terminal region by mutating Asp3 and Gln5 into Asn and Thr, respectively. Glycosylation mutants were expressed alone or with hCGbeta-subunit in Chinese hamster ovary cells. New N-linked oligosaccharides were efficiently added to the wild-type and mutant alpha-subunits lacking N-glycan at Asn52 (alpha deltaAsn1), Asn78 (alpha deltaAsn2), and both (alpha deltaAsn(1 + 2)). The new sugar chain did not affect secretion and assembly except that 1) it increased the intracellular degradation of alpha deltaAsn(1 + 2), and 2) it augmented the assembly of alpha deltaAsn1 with hCGbeta-subunit. Amino acid changes generated the attachment of O-glycosylation in free alpha-subunit but not in assembled form. These data indicate that the newly introduced N-glycosylation consensus sequence is functional, and that the N-terminal region of the alpha-subunit is flexible and can be modified without affecting the intracellular function. Furthermore, amino acid sequences in the N-terminus are involved in the O-glycosylation in free alpha-subunit.

To analyze the effects of treatments with GH and cyclic estrogen/progesterone (E/P) replacement on bone mineralization in patients with Turner's syndrome (TS), bone mineral density (BMD) was measured longitudinally. BMDs of the whole body and the lumbar spine in 16 adult female patients with TS (17-38 year old; 0-20 years by length of E/P treatment) were assessed using dual energy X-ray absorptiometry one to 5 times over a treatment period of up to 7 years maximum. GH treatment was performed in 9 cases (GH group), but not in the remaining 7 (non-GH group). E/P replacement therapy was initiated in all patients after they finished GH administration. The BMDs of both the whole body and the lumbar spine in the patients with TS were significantly less than those in age-matched normal subjects, and did not improve with E/P treatment. Although there were no differences in final body height and age at the beginning of E/P administration between the GH and non-GH groups, whole body BMD in the GH group was significantly lower than that in the non-GH group. These results indicate that GH administration in childhood and adolescence and E/P treatment in adulthood did not increase bone mineralization in the TS patients. Therefore, we can conclude that the optimal protocol of hormonal replacement therapy with GH and E/P during childhood and adolescence should be established as soon as possible.

Human chorionic gonadotropin (hCG) is a member of a family of heterodimeric glycoprotein hormones that contain a common alpha-subunit but differ in their hormone-specific beta-subunits. Both subunits have five and six disulfide bonds, respectively, which consist of cystine knot structure. It is evident from numerous studies that the structure of beta-subunits is rigid, whereas that of alpha-subunit is flexible and can be molded by a beta-subunit. Previously, we reported that secreted forms of a mutants where either cysteine residue in the disulfide bond 7-31 or 59-87 was converted to alanine contained a disulfide-linked homodimer in addition to a monomer. To study whether the hCGbeta-subunit affects the conformations of alpha mutants, alpha-subunits lacking either the 7-31 or 59-87 disulfide bond were expressed with wild-type (WT) hCGbeta in Chinese hamster ovary cells, and homodimer formation and glycosylation of dimerized alpha-subunit were assessed by continuous labeling with [35S]methionine/cysteine, immunoprecipitation with anti-alpha or -hCGbeta serum, digestion with endoglycosidase-H or -F, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis in a non-reducing condition. Our data showed that a homodimer was not observed in the half-Cys mutants except one, where cysteine at position 7 was converted to alanine, in the presence of beta-subunit. This finding indicated that hCGbeta-subunit rescued the a half-Cys mutants from the formation of intermolecular disulfide-linked homodimer by preferentially combining with the alpha mutants. In both free WT and all mutants treated with endoglycosidase-H, no or faint bands were recognized as the same migration as seen in endoglycosidase-F treatment. Even in the endoglycosidase-H sensitive cases, the amount of sensitive alpha-subunits was less than 5% of total alpha-subunits. In contrast to free alpha-subunits, distinct endoglycosidase-H sensitive bands were seen in both WT and mutants, although the ratio was various. We concluded that hCGbeta-subunit affects the folding and glycosylation of the alpha-subunit mutants.

OBJECTIVE: Previously we reported on the abundant existence of hepatocyte growth factor in amniotic fluid. This study was conducted to clarify the effects of hepatocyte growth factor in amniotic fluid on fetal intestinal epithelial cells. STUDY DESIGN: Amniotic fluid samples were obtained from 22 cases at various gestational ages. The effects of amniotic fluid and recombinant human hepatocyte growth factor on proliferation, migration, and morphogenesis of intestine 407 cells (a cell line derived from fetal intestinal epithelial cells) were investigated. RESULTS: The mobility of intestine 407 cells was stimulated by amniotic fluid in proportion to the concentration of hepatocyte growth factor in amniotic fluid with the same effect observed with recombinant human hepatocyte growth factor. This activity was neutralized by addition of antihuman hepatocyte growth factor antibody. Neither increased deoxyribonucleic acid synthesis nor morphogenesis in response to amniotic fluid was identified under the conditions used. CONCLUSIONS: Amniotic fluid stimulates intestinal epithelial cell migration by way of hepatocyte growth factor in amniotic fluid during development of the fetal intestine. (Am J Obstet Gynecol 1998;178:175-9.)

To investigate the relation between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in malignant ovarian tumor, MMP and TIMP activities in conditioned media of 16 malignant ovarian tumor tissues and six normal ovaries were detected by zymography and reverse zymography, respectively and were quantitated with a densitometer. TIMP-1 and TIMP-2 were detected in all normal and malignant ovarian tumor tissues by reverse zymography. In normal ovaries, the intensity of TIMP-2 bands was stronger than TIMP-1, but in malignant tumor tissues those of TIMP-1 were stronger. The ratios of TIMP-1 to TIMP-2 and MMP-9 to MMP-2 were significantly higher in malignant tumor tissues than in normal ovaries (P0.001). TIMP activity consisting of TIMP-1 and TIMP-2 correlated significantly to MMP activity of MMP-2 and MMP-9 (r = 0.67, P0.005). There was a significant correlation between TIMP-1 activity and MMP activity (r = 0.72, P0.001), but no correlation was observed between TIMP-2 activity and MMP activity. The high level of TIMP-1 appeared to be related to malignant phenotype in ovaries as well as the high level of MMP-9.

Objective: To analyze the effects of gonadotropin and ovarian steroid hormones on the gene expression of c-mos in mouse oocytes. Methods: The changes of c-mos messenger RNA (mRNA) levels in oocytes were examined after the administration of pregnant mare's serum gonadotropin (PMSG) in vivo, or after incubation with estrogen and/or progesterone in vitro. Five IU PMSG was injected intraperitoneally to female immature mice, and human chorionic gonadotropin was also injected intraperitoneally 48 hours after the PMSG injection, with or without mating with male mice. The oocytes were collected from follicles or oviducts at 24, 30, 36, 42, 48, 60, 72, and 84 hours after the injection. The RNAs were extracted from 5 oocytes at each time point, and a reverse-transcription polymerase chain reaction using specific primers to c-mos DNA was performed to measure the relative amount of c-mos mRNA. Results: The c-mos mRNA in oocytes at 36 hours after the injection was 2.7 times higher than that at 24 hours. The c-mos mRNA level gradually decreased thereafter, and after ovulation the level was only 1/10 of the peak level. When the oocytes that were retrieved 24 hours after PMSG injection were incubated with 800 ng/ml estradiol 17-β or 600 ng/ml progesterone for 120 minutes, the c-mos gene expression was significantly suppressed or stimulated, respectively, in comparison with the absence of these substances. Conclusion: Although the regulatory mechanism of c-mos gene expression in oocytes is still unclear because the result obtained from the in vitro study, that estrogen suppressed the c-mos gene expression directly, was inconsistent with the result of the in vivo study, that increases of both c-mos mRNA and estrogen occurred simultaneously with PMSG stimulation in the early phase of preovulatory oocytes, our present study revealed that gonadotropin and steroid hormones might affect c-mos gene expression in mouse oocytes indirectly and/or directly.

Objective There have been few studies concerning the clinical pathology of squamous cell carcinoma arising from ovarian mature cystic teratoma. Thus, the objective of this study is to determine clinicopathologic factors affecting survival in this rare tumor. Methods From September 1979 to June 1996, 37 patients with squamous cell carcinoma arising from ovarian mature cystic teratoma were treated by the Tokai Ovarian Tumor Study Group. A retrospective clinicopathologic and survival analysis of these patients was performed. The mode of infiltration was classified into expansive, moderately diffused, and diffused patterns. Results Although the 5-year survival rate was 94.7% and 80.0% for stage I and II patients, respectively, 12 of 13 patients with stage III died within 20 months (P = .0001). A significant difference was also observed between the survival of the groups with and without residual tumor at surgery (P = .0001). Pathologic features, grade, mode of infiltration, and vascular involvement were significant factors by univariate analysis. Multivariate analysis showed significant differences in survival related to grade (P = .0154) and mode of infiltration (P = .0053). The preoperative squamous cell carcinoma antigen level was significantly higher in the patients with squamous cell carcinoma arising from mature cystic teratoma than in patients with mature cystic teratoma (P Conclusion This study suggests that pathologic factors, grade, and mode of infiltration can provide valuable information for predicting the survival of patients with squamous cell carcinoma arising from mature cystic teratoma. In addition, squamous cell carcinoma antigen may be a useful marker to detect this disease preoperatively.

Disrupting disulfide loops in the human chorionic gonadotropin beta subunit (CGbeta) inhibits combination with the alpha subunit. Because the bioactivity requires a heterodimer, studies on the role of disulfide bonds on receptor binding/signal transduction have previously been precluded. To address this problem, we bypassed the assembly step and genetically fused CGbeta subunits bearing paired cysteine mutations to a wild-type alpha (WTalpha) subunit. The changes altered secretion of the single-chain mutants which parallel that seen for the CGbeta monomeric subunit. Despite conformational changes in CG disulfide bond mutants (assayed by gel electrophoresis and conformationally sensitive monoclonal antibodies), the variants bind to the lutropin/CG receptor and activated adenylate cyclase in vitro. The data show that the structural requirements for secretion and bioactivity are not the same. The results also suggest that the extensive native subunit interactions determined by the cystine bonds are not required for signal transduction. Moreover, these studies demonstrate that the single-chain model is an effective approach to structure-activity relationships of residues and structural domains associated with assembly of multisubunit ligands.

We investigated hyaluronidase activity in gynaecological normal and malignant tissues. Hyaluronidase activity in culture medium of tissue specimens was detected by hyaluronic acid zymography and quantified by densitometry. Hyaluronidase activity was shown as one dominant band (molecular weight 65 kDa) at pH 3.5. Hyaluronidase activity was significantly higher in normal ovary (P < 0.05) and normal endometrium (P< 0.05) than in normal cervix. One dominant 65-kDa hyaluronidase was expressed in 100% (14 out of 14) of ovarian cancer tissues and in 91% (10 out of 11) of endometrial cancer tissues. However, hyaluronidase activity was not observed in cervical cancer tissues. Hyaluronidase activity was significantly higher in ovarian (P < 0.001) and endometrial (P < 0.01) cancer tissues than in cervical cancer tissue and was significantly higher in ovarian cancer tissue than in endometrial cancer tissue (P < 0.05). These facts suggest that the cancer cells make use of the original characteristic of the organ to invade and metastasize. Moreover, these results reflect the difference in metastatic forms and are suggestive of a strong relationship between hyaluronidase activity and invasion and metastasis of ovarian and endometrial cancers compared with cervical cancer. Images Figure 1 Figure 3 Figure 4 Figure 5

The human chorionic gonadotropin β-subunit (hCGβ) is a glycoprotein in which 12 cysteine residues pair to form six intramolecular disulfide bonds. In order to elucidate the effect of each disulfide bond on glycosylation of the molecule, we analysed structures of asparagine-linked oligosaccharides of various recombinant hCGβ produced in Chinese hamster ovary (CHO) cells: wild-type hCGβ (βWT) and mutants in which any one of the six intramolecular disulfide bonds had been disrupted by site-directed mutagenesis. SDS-PAGE analysis of βWT and these mutants before and after digestion with endoglycosidase F and H revealed structural changes in the oligosaccharide moieties of some mutants. In addition, structural analysis of oligosaccharides obtained from metabolically labeled βWT and a mutant showed that the mutant contained additional high mannose type oligosaccharides. These results suggest that elimination of a specific disulfide bond, resulting in a change in the protein conformation, disturbs the normal assembly of the mature complex type oligosaccharides in the hCGβ molecule. Abbreviations: hCGβ, human chorionic gonadotropin β-subunit; βWT, wild type hCGβ; CHO, Chinese hamster ovary; Endo-H, endoglycosidase H; Endo-F, endoglycosidase F

Ovarian cancer cells disseminate by attachment to the peritoneal mesothelial cell surface of the abdominal cavity. We therefore investigated the influence of conditioned medium (CM) from human peritoneal tissues and mesothelial cells on the secretion of matrix metalloproteinases (MMPs) by ovarian cancer cells. The molecular weights of MMPs stimulating factors derived from human peritoneal tissues and mesothelial cells were estimated using microconcentrators with various cut-off membranes. Human peritoneal tissues were obtained from 12 surgical patients, and mesothelial cells were isolated from three peritoneal specimens. Exposure to CM from peritoneal tissue caused a concentration-dependent increase of the MMP-2 and MMP-9 bands in CM from NOM1 ovarian cancer cells, as shown by zymography. There was a significant difference in the increase of MMP-2 and MMP-9 (2.46-fold and 7.14-fold, respectively, at 0.4mg/ml protein; P < 0.005). CM from mesothelial cells also significantly increased the secretion of MMP-9 by NOM1 cells. The molecular size of possible MMP-9-stimulating factors secreted by peritoneal tissues and mesothelial cells was above M 100000. Further, CM of peritoneal tissues and mesothelial cells also induced the invasiveness of NOM1 cells. These findings suggest that mesothelial cells may secrete some factors which predominantly induce the MMP-9 production and increase invading cell numbers.

To clarify the significance of the Fas antigen (Ag) in gynecologic tumors, its expression in gynecologic cancer cell lines was examined. The Fas Ag was expressed in 6 of 15 cell lines. Five of 8 ovarian cancer cell lines but none of 4 choriocarcinoma cell lines expressed the Fas Ag. In drug-resistant cell lines derived from one of the Fas-positive cells, its expression was not lost after development of resistance to cisplatin, SN-38 or etoposide, but its expression was absent in the cell line resistant to Adriamycin. The effect of the anti-Fas antibody (Ab) was then studied. Apoptosis was induced in 7 of 9 Fas-positive cell lines, whereas the remaining two cell lines were unaffected. Furthermore, the combination effect of the anti-Fas Ab and drugs was examined in an ovarian cancer cell line and its drug-resistant variants, and a synergistic effect was observed. These results suggest important roles of the Fas Ag in ovarian cancer and the potential for overcoming drug resistance by a combination of the anti-Fas Ab and various drugs.

Uterine transplantation (UTx) is a potential option for child-bearing in women with uterine infertility. Recovery of uterine function after allogeneic UTx in non-human primates has not been reported. The objective of this study is to establish the functional uterine transplant model in non-human primates.Uteri of two cynomolgus monkeys were simultaneously removed, cooled at 4°C and perfused with heparin saline. The uteri were interchanged with each other and then orthotopically transplanted. Immunosuppressive protocols included use of three agents (tacrolimus, mycophenolate mofetil and methylprednisolone) in case 1 and two agents (tacrolimus and methylprednisolone) in case 2. Transabdominal ultrasonography, vaginoscopy and biopsy of the transplanted uterine cervix were routinely conducted to monitor rejection after surgery.The blood concentration of tacrolimus decreased 11 days after surgery and evidence of rejection was found in biopsy of the uterine cervix in both cases. The suspected rejection disappeared 23 days after surgery in case 1 and temporary menstruation resumed at 3 months after surgery. In case 2, blood flow to the uterine artery gradually decreased and the uterus resulted in atrophy due to ischemia, which has been triggered by rejection.Allogeneic UTx in the cynomolgus monkeys resulted in temporary recovery of menstruation with three immunosuppressants and uterine atrophy with two immunosuppressants. This preliminary experience suggests that recovery of uterine function after allogeneic UTx in non-human primates is possible but more experiments are required.

Uterus transplantation (UTx) is an alternative to gestational surrogacy and adoption for patients with absolute uterine infertility. Studies have been conducted in animals, and UTx is now within the reach of clinical application in humans. Procedures in humans have been published, but many medical, ethical, and social problems and risks of UTx require discussion prior to widespread clinical application, from the perspectives of donors, recipients, families, and newborns. In this article, we summarize the burdens and risks of UTx, with a focus on donors who provide the uterus.

To study how clinical factors such as embryo quality, cell stage of embryo at cryopreservation, and synchronization of developmental stages between embryo and endometrium at thawing affect the implantation rate after cryopreserved-thawed embryo transfer (ET), these factors were examined in 106 cryopreserved-thawed ETs including 204 embryos.In 86 embryos graded as high quality before transfer by morphological evaluation, 31 implantations were successful, while the other, low-quality embryos did not implant at all. High-quality embryos received less cryoinjury during cryopreservation compared to the injuries sustained by embryos in moderate and poor quality. When cyopreservation was performed at the 1-, 2-, and 3-day cell stages, pregnancies were similiarly achieved among most of the embryos at all cell stages. At thawed ETs in natural ovulation cycles, there were some differences among the developmental stages between thawed embryo and endometrium that received the thawed transferred embryos. Although the transfer timelag ranged a day or more, asynchronism of endometrium growth to the cell stage did not reduce pregnancy rates.These results indicated that embryo quality evaluated morphologically was the most important clinical factor for successful implantation of cryopreserved-thawed ET.

The mutations (Trp8 --Arg and Ile15 --Thr) in the human LHbeta -subunit caused by nucleotide point mutations in the LHbeta gene were reported in women with immunologically anomalous LH and menstrual disorders. To estimate the effects of the mutations on LH bioactivity in vitro and in vivo, we constructed a LHbeta gene containing this nucleotide mutation in each site or in both sites by site- directed mutagenesis and analyzed the bioactivities of the mutant LH expressed in Chinese hamster ovary cells. Although no alterations were noted in the receptor-binding activity of LH due to the mutations, the LHs containing the mutations at Trp8 --Arg and at both sites in the beta-subunit showed a higher biopotency of progesterone production in vitro. The clearance rate from the circulation was faster in vivo in all mutant LHs, which were induced primarily by the mutation at Trp8 --Arg. However, the mutations did not affect the ability of LH to induce ovulation in vivo. These results indicate that LH consisting of the mutant beta-subunit exhibits hyperbioactivity on steroidogenesis and has a short turnover rate. This may affect the endocrine pathway among women with the mutant LH and lead to menstrual disorders.

To analyze how the synthesis and release of glycosylated PRL (G-PRL) is regulated, we transfected human PRL complementary deoxyribonucleic acid (cDNA) into three different cell lines consisting of GH3 cells that originated in rat pituitary tissue, Chinese hamster ovary cells, and COS-1 cells generated from monkey renal tissue. 35S-labeled PRLs produced by the cells were immunoprecipitated with anti-human PRL antiserum, and the ratios of G-PRL to total PRL were compared. PRLs of 23 kDa and 25 kDa were detected in the cell lysate and medium. The 25-kDa PRL was confirmed to be a glycosylated form by endoglycosidase treatments. The ratios of G-PRL/total PRL were 0.17-0.33, which were similar in lysates and media and among different cell lines. Pulse-chase experiments revealed that the autonomaous secretion rates of G-PRL and non-glycosylated PRL were almost identical. These results indicate that synthesis and secretion kinetics of human PRL may not be affected by its glycosylation in the cells transfected with PRL cDNA.

Since the incidence of mucinous carcinoma of the ovary is relatively low, with only small numbers of cases at any institution, detailed clinicopathologic studies on the prognosis and the care of patie