Impact of Diagnosis and Treatment of Chronic Endometritis on Outcomes Before Starting Assisted Reproductive Technology: A Retrospective Study.

This study aimed to investigate the effect of diagnosis and treatment of chronic endometritis (CE) on the outcome of assisted reproductive technology (ART) with or without repeated implantation failure (RIF). This retrospective analysis included patients who underwent pathological examination for diagnosis of CE at Yamagata University Hospital. The examination was performed for all patients planned for ART with or without RIF. Patients who were examined within 6 months of the first oocyte retrieval or embryo transfer were included. We counted the number of CD138-positive cells within the endometrial stroma in patients' specimens and analyzed the patients' clinical information. Clinical rates of pregnancy and implantation were determined. A total of 80 women met the inclusion criteria: 13 CE-negative patients (17.3%) and 67 CE-positive patients (83.7%). A significant decrease was noted in the CD138-positive cell count between the first biopsy and second biopsy after CE treatment (p < 0.001). In addition, no significant differences were noted in ongoing pregnancy rates between the CE-negative patients and those who underwent CE treatment. The CD138-positive cell counts at first biopsy tended to be lower in each pregnancy group than in the non-pregnancy group. For patients planned to undergo ART, examination for diagnosis of CE with or without RIF could be considered. Pathological CD138-positive cell counts were considered useful for CE diagnosis and treatment decision-making. The study findings suggest the efficacy of antimicrobial agents in CE treatment, contributing to improved pregnancy outcomes.

Septal Rupture During Early Pregnancy and Successful Delivery in Monozygotic Dichorionic Diamniotic Twin After a Single Blastocyst Transfer.

The frequency of twins resulting from a single embryo transfer has been reported to be 1.56%, with the majority being monochorionic. We present a case of septal rupture at 8 weeks of gestation and successful delivery at 36 weeks of gestation of a monozygotic dichorionic diamniotic twin after a single blastocyst transfer. This report could partially clarify the pathogenesis of monozygotic twins and septal disruption. A 37-year-old woman with 9 months of primary infertility was referred to our department. After seven cycles of artificial insemination, she underwent her first in vitro fertilization. Ten cumulous-oocyte complexes were retrieved, of which three were fertilized, and three blastocysts were cryopreserved. The first single blastocyst transfer in a hormone replacement cycle resulted in a dichorionic diamniotic twin pregnancy. Transvaginal ultrasound at 7 weeks and 4 days gestation revealed a size difference in the gestational sacs and a disruption of the inter-amniotic membrane between the two gestational sacs at 8 weeks and 6 days. Both fetuses were seen in the larger gestational sac; however, the umbilical cord of the migrated fetus was from the original gestational sac. Both fetuses developed without discordancy or obvious anomalies. At 36 weeks and 6 days of gestation, the patient underwent cesarean delivery, resulting in the birth of two viable male infants without any congenital anomalies (weighing 2256 g and 2456 g). Two amniotic cavities existed; however, no chorionic villi were present. There have been many reports on septal disruption in monochorionic diamniotic twins; however, only two cases of dichorionic diamniotic twins have been reported. Furthermore, the onsets in both reports were after the second trimester of pregnancy. This report presents the first case of septal disruption in dichorionic diamniotic twins during the first trimester.

Evaluation of the efficacy and safety of an integrated telerehabilitation platform for home-based cardiac REHABilitation in patients with heart failure (E-REHAB): protocol for a randomised controlled trial.

INTRODUCTION: Cardiac rehabilitation (CR) is strongly recommended as a medical treatment to improve the prognosis and quality of life of patients with heart failure (HF); however, participation rates in CR are low compared with other evidence-based treatments. One reason for this is the geographical distance between patients' homes and hospitals. To address this issue, we developed an integrated telerehabilitation platform, RH-01, for home-based CR. We hypothesised that using the RH-01 platform for home-based CR would demonstrate non-inferiority compared with traditional centre-based CR. METHODS AND ANALYSIS: The E-REHAB trial aims to evaluate the efficacy and safety of RH-01 for home-based CR compared with traditional centre-based CR for patients with HF. This clinical trial will be conducted under a prospective, randomised, controlled and non-inferiority design with a primary focus on HF patients. Further, to assess the generalisability of the results in HF to other cardiovascular disease (CVD), the study will also include patients with other CVDs. The trial will enrol 108 patients with HF and 20 patients with other CVD. Eligible HF patients will be randomly assigned to either traditional centre-based CR or home-based CR in a 1:1 fashion. Patients with other CVDs will not be randomised, as safety assessment will be the primary focus. The intervention group will receive a 12-week programme conducted two or three times per week consisting of a remotely supervised home-based CR programme using RH-01, while the control group will receive a traditional centre-based CR programme. The primary endpoint of this trial is change in 6 min walk distance. ETHICS AND DISSEMINATION: The conduct of the study has been approved by an institutional review board at each participating site, and all patients will provide written informed consent before entry. The report of the study will be disseminated via scientific fora, including peer-reviewed publications and presentations at conferences. TRIAL REGISTRATION NUMBER: jRCT:2052200064.

Ventricular Septal Rupture Caused by Myocardial Infarction With Nonobstructive Coronary Arteries.

Myocardial infarction with nonobstructive coronary arteries (MINOCA) has poor long-term cardiovascular outcomes, similar to myocardial infarction with conventional atherogenic coronary artery disease. However, MINOCA-related mechanical complications are rarely reported. We report a case of an octogenarian woman diagnosed with MINOCA-related ventricular septal rupture assessed by multimodal images, including autopsy findings. (Level of Difficulty: Intermediate.).

Effects of localisation of uterine adenomyosis on outcome of in vitro fertilisation/intracytoplasmic sperm injection fresh and frozen-thawed embryo transfer cycles: a multicentre retrospective cohort study.

BACKGROUND: Uterine adenomyosis is a benign disease, common among women in their 40 and 50 s, characterised by ectopic endometrial tissue in the uterine myometrial layer. Adenomyosis causes infertility and has a negative effect on the outcomes of in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) embryo transfer (ET) cycles. It has also been reported to have different characteristics depending on the adenomyotic lesion localisation. The effect of its localisation on IVF/ICSI-ET outcomes is unclear. This study aimed to investigate whether adenomyotic lesion localisation, assessed using magnetic resonance imaging (MRI), was associated with outcomes of IVF/ICSI-ET cycles. METHODS: This multicentre, joint, retrospective cohort study analysed the medical records of 67 infertile patients with adenomyosis who underwent IVF/ICSI with fresh and frozen-thawed ET at five participating facilities from January 2012 to December 2016 and for whom MRI data were available. Fifteen patients were excluded; therefore, the MRI data of 52 patients were evaluated by two radiologists. We assessed the localisation of and classified adenomyotic lesions into advanced (invades the full thickness of the uterine myometrium), extrinsic (localised on the serosal side), and intrinsic (localised on the endometrial side) subtypes. RESULTS: There were 40 advanced, nine extrinsic, and three intrinsic cases, and the outcomes of 100, 27, and nine ET cycles, respectively, were analysed. Pregnancy loss/clinical pregnancy and live birth rates of the advanced, extrinsic, and intrinsic groups were 64 % (16/25) and 9 % (9/100), 33.3 % (3/9) and 22.2 % (6/27), and 50 % (1/2) and 11.1 % (1/9), respectively. A logistic regression analysis adjusted for age, prior miscarriage, and body mass index showed that the extrinsic group had fewer pregnancy losses (odds ratio 0.06; 95 % confidence interval [CI]: 0.00-0.54, p = 0.026) and more live births (odds ratio 6.05; 95 % CI: 1.41-29.65, p = 0.018) than the advanced group. CONCLUSIONS: Adenomyotic lesions exert different effects on IVF/ICSI-ET outcomes. Thus, MRI assessments of adenomyosis in infertile patients are beneficial. Establishment of treatment plans based on adenomyotic lesion localisation should be considered.

Impact of endoplasmic reticulum stress on oocyte aging mechanisms.

Endoplasmic reticulum (ER) stress is associated with several aging-related diseases; however, the mechanism underlying age-related deterioration of oocyte quality is unclear. Here, we used post-ovulatory, in vivo aged mouse oocytes as a model. Super-ovulated oocytes harvested from the oviduct at 14 h and 20 h post-hCG injection were designated as 'fresh' and 'aged', respectively. Embryo development following IVF was compared between fresh, aged and ER stress-induced oocytes. Expression of the ER stress marker GRP78 was examined at each stage. To evaluate the effect of salubrinal, an ER stress suppressor, on embryo development following IVF, expression levels of GRP78 and phospho-eukaryotic initiation factor 2 alpha were compared between aged and salubrinal-treated aged oocytes. Embryo transfer of salubrinal-treated aged oocytes was performed to examine the safety of salubrinal. Similar to aged oocytes, ER stress-induced oocytes showed lower fertilization rates and poor embryo development. Following IVF, expression of GRP78 decreased with embryo development. GRP78 expression was significantly higher in aged oocytes than in fresh oocytes. Salubrinal lowered GRP78 levels and improved embryo development. No adverse effect of salubrinal treatment was found on the birth weight of pups or on organogenesis in mice. The limitation of this study was that protein kinase-like ER kinase was the only ER stress pathway examined; the role of IRE1 and ATF6 pathways was not considered. Nevertheless, salubrinal can significantly improve embryo development in in vivo aged oocytes undergoing ER stress. Hence, regulation of ER stress might represent a promising therapeutic strategy to overcome poor oocyte quality.

Successful laparoscopic resection of virilizing ovarian steroid cell tumor, not otherwise specified, in a 22-year-old woman: a case report and evaluation of the steroidogenic pathway.

OBJECTIVE: Ovarian steroid cell tumor (SCT) is a rare tumor with steroid-producing ability. We report a 22-year-old woman with secondary amenorrhea and hirsutism caused by an ovarian SCT-not otherwise specified (NOS), who underwent successfully laparoscopic resection of the tumor. CASE REPORT: A 22-year-old null gravida woman presented to a hospital, having amenorrhea for 18 months and increasing facial hair. Physical examination revealed obesity (body mass index, 37.3 kg/m2) with evident facial and trunk hair. Total and free serum testosterone, and dehydroepiandrosterone sulfate levels were found to be elevated. Levels of serum adrenocorticotropic hormone, gonadotropins, cortisol, aldosterone, and ovarian steroids were observed to be within reference intervals. Although polycystic ovaries were not found, a hyperechogenic solid tumor (3 cm) was detected on transvaginal ultrasonography. Laparoscopic resection of the tumor was performed. One month post-surgery, total and free testosterone levels were observed to have decreased, and menstruation resumed two months thereafter. The patient was histologically diagnosed with ovarian SCT-NOS. Expression of ovarian steroidogenic enzymes, which are related to hyperandrogenism, was observed. No disease recurrence has been reported for more than 5 years post-surgery.

Brachial-to-ankle pulse wave velocity as an independent prognostic factor for ovulatory response to clomiphene citrate in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) has a risk for cardiovascular disease. Increased arterial stiffness has been observed in women with PCOS. The purpose of the present study was to investigate whether the brachial-to-ankle pulse wave velocity (baPWV) is a prognostic factor for ovulatory response to clomiphene citrate (CC) in women with PCOS. METHODS: This study was a retrospective cohort study of 62 women with PCOS conducted from January 2009 to December 2012 at the university hospital, Yamagata, Japan. We analyzed 62 infertile PCOS patients who received CC. Ovulation was induced by 100 mg CC for 5 days. CC non-responder was defined as failure to ovulate for at least 2 consecutive CC-treatment cycles. The endocrine, metabolic, and cardiovascular parameters between CC responder (38 patients) and non-responder (24 patients) groups were analyzed. RESULTS: In univariate analysis, waist-to-hip ratio, level of free testosterone, percentages of patients with dyslipidemia, impaired glucose tolerance, and diabetes mellitus, blood glucose and insulin levels at 60 min and 120 min, the area under the curve of glucose and insulin after 75-g oral glucose intolerance test, and baPWV were significantly higher in CC non-responders compared with responders. In multivariate logistic regression analysis, both waist-to-hip ratio (odds ratio, 1.77; 95% confidence interval, 2.2-14.1; P=0.04) and baPWV (odds ratio, 1.71; 95% confidence interval, 1.1-2.8; P=0.03) were independent predictors of ovulation induction by CC in PCOS patients. The predictive values of waist-to-hip ratio and baPWV for the CC resistance in PCOS patients were determined by the receiver operating characteristic curves. The area under the curves for waist-to-hip ratio and baPWV were 0.76 and 0.77, respectively. Setting the threshold at 0.83 for waist-to-hip ratio offered the best compromise between specificity (0.65) and sensitivity (0.84), while the setting the threshold at 1,182 cm/s for baPWV offered the best compromise between specificity (0.80) and sensitivity (0.71). CONCLUSIONS: Both metabolic and cardiovascular parameters were predictive for CC resistance in PCOS patients. The measurement of baPWV may be a useful tool to predict ovulation in PCOS patients who receive CC.

Effects of different trehalose concentrations in a warming medium on embryo survival and clinical outcomes in vitrified human embryos.

BACKGROUND/AIMS: In the present study, we examined the effects of different concentrations of trehalose in a warming medium on both embryo survival and clinical outcomes in vitrified-warmed embryo transfer cycles. METHODS: We retrospectively analyzed a total of 209 vitrified-warmed cycles from 177 patients who underwent in vitro fertilization or intracytoplasmic sperm injection and embryo transfer. Embryos were cryopreserved by the vitrification method and warmed in solutions containing either 0.5 or 1.0 M trehalose. We compared the 0.5 and 1.0 M trehalose warming solution groups with respect to the embryo survival rate after warming and clinical outcomes. RESULTS: The embryo survival rate in the 1.0 M trehalose group (96.5%) was significantly higher than that in the 0.5 M trehalose group (57.0%). The percentage of embryo transfers after warming in the 1.0 M trehalose group (94.3%) was significantly higher than that in the 0.5 M trehalose group (83.7%). The clinical pregnancy rate in the 1.0 M trehalose group (25.0%) was significantly higher than that in the 0.5 M trehalose group (11.1%). CONCLUSION: Embryo survival and clinical pregnancy rates were higher when a 1.0 M trehalose solution was used than when a 0.5 M trehalose solution was used during the embryo warming process.

Pioglitazone counteracts the tumor necrosis factor-α inhibition of follicle-stimulating hormone-induced follicular development and estradiol production in an in vitro mouse preantral follicle culture system.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age and is characterized by chronic anovulation. Insulin resistance may be a key component of the pathogenesis of this disorder. Pioglitazone is a thiazolidinedione derivative that acts by improving insulin resistance via the peroxisome proliferator-activated receptor-γ (PPAR-γ) pathway. Reportedly, pioglitazone improves the anovulation status in patients with PCOS. In the present study, we examined whether pioglitazone directly affects ovarian follicular development and steroidogenesis using in vitro mouse preantral follicle culture system. METHODS: An isolated individual in vitro mouse preantral follicle culture was used to test the effects of pioglitazone on the follicle development and steroidogenesis. Tumor necrosis factor-α (TNF-α), which plays a role in insulin resistance, has been reported to inhibit the follicle stimulating hormone (FSH)-induced follicular development and steroidogenesis in an in vitro mouse preantral follicle culture system. Therefore, we examined whether pioglitazone counteracts these effects by TNF-α. We assessed the follicle diameter and follicle survival and antral-like cavity formation rates, the 17ß-estradiol (E2) levels in the culture medium, and the ovulation rate using the in vitro preantral follicle culture. RESULTS: Pioglitazone treatment counteracted the inhibition of TNF-α in FSH-induced follicle development in a dose-dependent manner. Pioglitazone, at a concentration of 5 µM, which was the minimum effective concentration, significantly counteracted the inhibition of TNF-α in FSH-induced follicle survival (29 versus 56%, P < 0.05), antral-like cavity formation (29 versus 48%, P < 0.05), E2 concentration in the culture medium (mean ± SEM = 21 ± 1 versus mean ± SEM = 27 ± 1 pg/mL, P < 0.05), and human chorionic gonadotropin-induced ovulation rate (9 versus 28%, P < 0.05). CONCLUSIONS: Pioglitazone counteracted the inhibition by TNF-α on FSH-induced follicle development and steroidogenesis in the in vitro mouse preantral follicle culture. The results suggest that pioglitazone may directly affect the follicular development and steroidogenesis.

Molecular mechanism of poor embryo development in postovulatory aged oocytes: mini review.

Oocyte quality is a key factor in determining embryo development; however, we have a poor understanding of what constitutes oocyte quality or the mechanisms governing it. Postovulatory aging of oocytes that have not been fertilized for a prolonged time after ovulation is known to significantly impair oocyte quality and subsequent embryo development after fertilization. Embryos derived from postovulatory-aged oocytes are prone to undergo apoptosis due to the decreased Bcl-2 expression. Postovulatory aging of oocytes changes the patterns of Ca(2+) oscillations at fertilization as a result of impaired Ca(2+) regulation in the endoplasmic reticulum. Moreover, postovulatory aging of oocytes impairs mitochondrial adenosine triphosphate production as a result of increasing oxidative stresses. Oxidative stresses also affect intracellular Ca(2+) regulation and impair embryo development after fertilization. Collectively, the mechanism of postovulatory oocyte aging might be involved in reactive oxygen species-induced mitochondrial injury followed by abnormal intracellular Ca(2+) regulation in the endoplasmic reticulum.

Hepatocyte growth factor prevents peritoneal fibrosis in an animal model of encapsulating peritoneal sclerosis.

BACKGROUND: Ultrafiltration failure associated with peritoneal fibrosis can lead patients to discontinue continuous ambulatory peritoneal dialysis (CAPD). It has been reported that the reciprocal imbalance between transforming growth factor-beta1 (TGF-beta1) and hepatocyte growth factor (HGF) is closely involved in the progression of tissue fibrosis. We previously showed that exogenous HGF restores the growth of human peritoneal mesothelial cells suppressed by a high concentration of D-glucose or TGF-beta1. In this study, we examined whether constitutive exposure to HGF prevents peritoneal fibrosis in an animal model of encapsulating peritoneal sclerosis (EPS). METHODS: To establish the model, a daily intraperitoneal injection of 0.1% chlorhexidine gluconate was given to male Wister rats for 35 days. Rat peritoneal mesothelial cells (RPMCs) transfected with full-length human HGF cDNA in an expression vector (pUCSRalpha/HGF) were injected into the peritoneal cavity of the rats. Thereafter, pathological changes to the peritoneal membrane were observed, and the effect on peritoneal ultrafiltration volume was examined. RESULTS: In the model, microscopic examination revealed a progressive thickening of the submesothelial layer, and an increase in the number of capillary vessels. Peritoneal ultrafiltration volume was decreased. Interestingly, the pathological changes to the peritoneal membrane were reversed by the intraperitoneal injection of pUCSRalpha/HGF-transfected RPMCs. Furthermore, peritoneal ultrafiltration volume was increased. CONCLUSIONS: The constitutive production of HGF by UCSRalpha/HGF-transfected RPMCs can improve peritoneal fibrosis resulting in an increase in peritoneal ultrafiltration volume. This approach may have clinical application.

Possible effects of hepatocyte growth factor for the prevention of peritoneal fibrosis.

OBJECTIVE: Some patients who had carried out long-term continuous ambulatory peritoneal dialysis discontinued the treatment because of progressive peritoneal fibrosis. It has been previously reported that transforming growth factor-beta1 (TGF-beta1) is one of the factors that induces peritoneal fibrosis. Also, hepatocyte growth factor (HGF) plays a role in the prevention of fibrosis and in inhibiting TGF-beta1 production. In this study, we examined the effects of HGF on peritoneal fibrosis by TGF-beta1 induced by high concentrations of D-glucose. DESIGN: We transfected a full-length human HGF cDNA in an expression vector into human peritoneal mesothelial cells (HPMCs) using the calcium phosphate method. Transfected HPMCs were cultured with high concentrations of D-glucose solution and co-cultured with fibroblasts using a transwell system. Cell proliferation was determined using the Tetra Color One method. TGF-beta1 and HGF protein were measured by enzyme-linked immunosorbent assay. RESULTS: In addition to recombinant HGF, the growth inhibition of HPMCs by high concentration D-glucose or TGF-beta1 was significant. By transfecting HGF cDNA into HPMCs, growth inhibition by high concentration D-glucose was completely restored. Furthermore, the production of TGF-beta1 was also significantly decreased. CONCLUSION: These results suggested that exogenous HGF could possibly prevent peritoneal fibrosis.

Mutant type glutathione S-transferase theta 1 gene homologue to mTOR in myelodysplastic syndrome: possible clinical application of rapamycin.

In this study, we observed the expression of the GSTT-1 gene in patients with myelodysplastic syndrome (MDS) at the messenger RNA level. Reverse transcription-polymerase chain reaction (RT-PCR) for GSTT-1 was performed with a pair of primers complementary to the 5' coding section and the 3' coding section of the GSTT-1 cDNA for amplifying the 623-bp band. Among 20 patients with MDS, 8 patients showed the expected 623-bp band on RT-PCR, and 12 patients showed a 500-bp band on RT-PCR, indicating that a 123-bp sequence was deleted as a mutant of the GSTT-1 gene. Furthermore, a BLAST DNA search showed that the deletion of a 123 bp sequence creates a sequence that is 63% homologous to human FKBP-rapamycin associated protein (FRAP); this protein has been termed a mammalian target of rapamycin (mTOR). We respectively transfected the wild type and the mutant type GSTT-1 gene in an expression vector to two cell lines (K562 and HL-60). The stable transformants for the wild type and the mutant type GSTT-1 genes were made by G418 selection. Interestingly, rapamycin could induce significant growth inhibition of the stable transformants for mutant type GSTT-1, which was indicative of apoptosis, but not that of those for wild type GSTT-1. These results suggest that rapamycin could be included in the therapeutic modality for the patients with MDS who have the mTOR sequences in GSTT-1 gene.

Involvement of TGF-beta signal for peritoneal sclerosing in continuous ambulatory peritoneal dialysis.

BACKGROUND: Functional failure of the peritoneal membrane is the most serious problem in long-term continuous ambulatory peritoneal dialysis (CAPD). Transforming growth factor-beta (TGF-ss) is one of the key mediators of fibrosis in some organs, and is thought to be involved in peritoneal alterations. In this study, we examined the role of TGF-beta1/TGF-ss receptors for human peritoneal mesothelial cells (HPMCs) and fibroblasts, and their interactions in CAPD patients. METHODS: HPMCs were cultured for 48 h in a medium containing normal- dose glucose (7 mM), high-dose glucose (30 mM) and mannitol as an osmotic agent, equal to 30 mM glucose. Cell proliferation was observed using the Tetra Color One assay. The concentration of TGF-beta1 in culture supernatants was measured by enzyme-linked immunosorbent assay (ELISA). The expression of TGF-ss receptor types I and II was observed by flow cytometry. HPMCs and fibroblasts were co-cultured and assayed using transwell inserts in order to identify the effects of the high-concentration glucose solution. RESULTS: HPMC proliferation was inhibited by the high concentration of glucose but not by mannitol. The inhibition was abrogated by the neutralizing antibody for TGF-beta1. TGF-beta1 was induced by a high concentration of glucose but not by mannitol. The expression of both TGF-ss receptors was augmented in culture with the high concentration of glucose but not with mannitol. In the co-culture assay, the number of HPMCs was decreased and fibroblasts were significantly increased in culture with the high concentration of glucose. CONCLUSIONS: A high concentration of glucose induced a large amount of TGF-beta1 and enhanced the expression of TGF-ss receptors. HPMCs were sensitive to TGF-beta1 in response to a high concentration of glucose. These data suggest that TGF-beta1 from HPMCs exposed to a high concentration of glucose down-regulates the proliferation of HPMCs and accelerates peritoneal fibrosis.