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BACKGROUND Changes in blood flow impedance of the uterine artery (UA) and uterine radial artery (RA) which is in the lower-extremity of the UA were examined during early pregnancy. METHODS Blood flow impedance was assessed by transvaginal color-pulsed-Doppler-ultrasonography in 72 women from weeks 4–16 of pregnancy and expressed as a resistance index (RI). RESULTS RA-RI remained at the late-luteal phase level until the 5th week of pregnancy, decreased until the 7th week, and remained low until the 10th week. UA-RI remained at the late-luteal phase level until the 10th week, and then gradually decreased until the 16th week. In nine women with spontaneous abortion, five out of six women with impaired growth of the gestational sac showed high RA-RI at the 6th week of pregnancy, whereas all three women with loss of fetal heart beat at the 8th week showed normal changes in RA-RI. CONCLUSIONS Our results show different changes in blood flow impedance between the UA and RA during early pregnancy. A significant decrease of RA-RI after the 5th week may reflect vascular remodeling in the maternal–fetal interface at placentation, whereas a significant decrease of UA-RI after the 10th week may reflect changes of the whole uterine blood flow associated with uterine growth. [ABSTRACT FROM AUTHOR]

Competing Interests: Declarations. Conflict of interest: Hiroyuki Yamamoto and Hiraku Kumamaru are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo. The department is a social collaboration department supported by grants from the National Clinical Database, Johnson & Johnson K.K., Nipro Corporation and Intuitive Surgical Sàrl.

We herein report a rare case of acute myeloid leukemia (AML) with t(11;12)(p15;q13) and NUP98::RARG, which seems to be involved in the development of AML. The morphological features were similar to those of classic acute promyelocytic leukemia (APL), but unlike classic APL, this leukemia was resistant to treatment with all-trans retinoic acid (ATRA). We decided to use standard chemotherapy for AML with monitoring of minimal residual disease (MRD) by qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for NUP98::RARG mRNA. Although MRD disappeared after induction chemotherapy, it later reappeared, and hematological relapse occurred during subsequent chemotherapies. The patient received haploidentical hematopoietic stem cell transplantation while not in remission and achieved a second molecular remission. However, relapse occurred 4 months after transplantation. The specific mechanism of ATRA resistance in this unique case of AML remains unclear, and no standard treatment has been determined. This is the first case report of AML with NUP98::RARG rearrangement in Japan. Qualitative RT-PCR analysis for NUP98::RARG mRNA was helpful for the accurate diagnosis and evaluation of MRD to choose an adequate treatment for this type of AML., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest in association with the present study., (© 2024. Japanese Society of Hematology.)

The transplantation of human mesenchymal stromal/stem cells (hMSCs) has potential as a curative and permanent therapy for congenital skeletal diseases. However, the self-renewal and differentiation capacities of hMSCs markedly vary. Therefore, cell proliferation and trilineage differentiation capacities were tested in vitro to characterize hMSCs before their clinical use. However, it remains unclear whether the ability of hMSCs in vitro accurately predicts that in living animals. The xenograft model is an alternative method for validating clinical MSCs. Nevertheless, the protocol still needs refinement, and it has yet to be established whether hMSCs, which are expanded in culture for clinical use, retain the ability to engraft and differentiate into adipogenic, osteogenic, and chondrogenic lineage cells in transplantation settings. In the present study, to establish a robust xenograft model of MSCs, we examined the delivery routes of hMSCs and the immunological state of recipients. The intra-arterial injection of hMSCs into X-ray-irradiated (IR) NOG, a severely immunodeficient mouse, achieved the highest engraftment but failed to sustain long-term engraftment. We demonstrated that graft cells localized to a collagenase-released fraction (CR), in which endogenous colony-forming cells reside. We also showed that Pdgfrα + Sca1 + MSCs (PαS), which reside in the CR fraction, resisted IR. These results show that our protocol enables hMSCs to fulfill a high level of engraftment in mouse bone marrow in the short term. In contrast, long-term reconstitution was restricted, at least partially, because of IR-resistant endogenous MSCs., (© 2024. The Author(s).)

Aim: Dose-dense paclitaxel /carboplatin (ddTC) therapy was shown to be more effective against ovarian cancer than conventional tri-weekly TC in the JGOG3016 study. However, two phase III studies performed after JGOG3016 did not show the same positive results. Because we have been using ddTC in the frontline or first platinum-sensitive relapse of ovarian cancer, we investigated the clinical outcome of the patients treated with ddTC., Methods: We retrospectively examined the response rate (RR), progression free survival (PFS) and adverse events of the patients who were treated with ddTC for stage III and IV epithelial ovarian, tubal and peritoneal cancer from January 2012 to December 2018., Results: We analyzed 50 patients for frontline treatment and 11 patients for first platinum-sensitive relapse treatment, excluding those receiving maintenance therapy. Among the patients that received frontline ddTC treatment, RR was 82.9% for those in a neo-adjuvant chemotherapy (NACT) setting and 85.0% for those in an adjuvant setting. The median progression-free survival (PFS) was 20 months after initial therapy. Among 31 cases that achieved remission by frontline surgery and the following ddTC, 22 had a platinum-sensitive relapse. RR of 11 patients treated with ddTC therapy alone for the first platinum-sensitive relapse was 81.8%, and the median PFS of these patients was 22 months after the first recurrence., Conclusions: ddTC therapy for advanced ovarian cancer achieved high response rates in all settings (NACT, adjuvant or platinum-sensitive relapse). ddTC therapy was effective for improving the prognosis of patients with stages III and IV of ovarian cancer., (© 2024 Japan Society of Obstetrics and Gynecology.)

Hyperekplexia is a rare neurological disorder that is characterized by an excessive startle response to unexpected stimuli. Recently, heterogeneous causative genes have been identified. Most cases are diagnosed during the neonatal period from hypertonia or stiffness. Adult cases are relatively rare and can cause severe head injury, but they are often misdiagnosed, typically as epilepsy or psychiatric disorders, due to the rarity of the pathology. This report describes a genetically confirmed case of hyperekplexia in an adult with head trauma, highlighting the features of head trauma and discussing potential pitfalls in the diagnosis of adult patients with hyperekplexia., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Japan Neurosurgical Society.)

Short stature with IGF-1 receptor (IGF1R) gene alteration is known as small-for-gestational-age (SGA) short stature with elevated serum IGF1 levels. Its prevalence and clinical characteristics remain unclear. No adapted treatment is available for short stature related to IGF1R gene alteration in Japan, and genetic testing is not yet widely accessible. We investigated short stature with IGF1R gene alterations and analyzed the clinical data of 13 patients using the results of questionnaires issued to the Japanese Society for Pediatric Endocrinology. Four cases were caused by a deletion of chromosome 15q26.3, and eight were caused by heterozygous pathogenic variants in the IGF1R gene. Cases with deletions showed a more severe degree of growth impairment (-4.5 ± 0.43 SD) than those caused by pathological variants (-2.71 ± 0.15 SD) and were accompanied by neurodevelopmental delay. However, cases caused by pathological variants lacked distinctive features. Only three of the 12 cases demonstrated serum IGF1 values exceeding +2 SD, and the other three had values below 0 SD. Four patients did not meet the criteria for SGA at birth. Six patients received GH therapy for SGA short stature and showed improvement in growth rate without any side effects or elevated serum IGF1 levels during treatment. Elevated IGF1 levels (over +2 SD) after GH treatment should be considered a suspicious finding. Owing to the lack of distinctive features, there was a possibility of undiagnosed cases of this condition. Promoting genetic testing and clinical trials on GH administration for this condition is recommended.

Decidualization of the human endometrium is critical for establishing pregnancy and is entailed by differentiation of endometrial stromal cells (ESCs) into decidual cells. During decidualization, the actin cytoskeleton is dynamically reorganized for the ESCs' morphological and functional changes. Although actin dynamically alters its polymerized state upon external stimuli not only in the cytoplasm, but also in the nucleus, nuclear actin dynamics during decidualization have not been elucidated. Here, we show that nuclear actin was specifically assembled during decidualization of human ESCs. This decidualization-specific formation of nuclear actin filaments was disassembled following the withdrawal of the decidualization stimulus, suggesting its reversible process. Mechanistically, RNA-seq analyses revealed that the forced disassembly of nuclear actin resulted in the suppression of decidualization, accompanied with the abnormal upregulation of cell proliferation genes, leading to incomplete cell cycle arrest. CCAAT/enhancer-binding protein beta (C/EBPβ), an important regulator for decidualization, was responsible for downregulation of the nuclear actin exporter, thus accelerating nuclear actin accumulation and its assembly for decidualization. Taken together, we demonstrate that decidualization-specific nuclear actin assembly induces cell cycle arrest for establishing the decidualized state of ESCs. We propose that not only the cytoplasmic actin, but also nuclear actin dynamics profoundly affect decidualization process in humans for ensuring pregnancy., (© 2024. The Author(s).)

Background: The effect of coronary artery bypass grafting (CABG) on cardiac function improvement remains controversial. Furthermore, recent evidence suggests that improvement in cardiac function after CABG does not improve life expectancy. This study aimed to examine whether CABG improved cardiac function and how this improvement influenced all-cause mortality and to compare patient prognosis according to preoperative cardiac function., Methods: This retrospective study included patients with a left ventricular ejection fraction (LVEF) of ≤35% who underwent CABG between January 1994 and December 2022. We compared patients with and without cardiac function improvement, defined as an increase in LVEF of ≥10%, to identify associated factors and assess the impact on all-cause mortality. We also compared outcomes according to the degree of preoperative LV dysfunction., Results: Among the 166 patients included, 102 and 64 had a preoperative LVEF of 25%-35% and ≤25%, respectively. The mean follow-up duration was 79.9 ± 72.3 months. We observed significant LVEF improvement, from 28% (range, 23.3%-35%) preoperatively to 39% (range, 31%-46%) at 13.1 months postoperatively. The 7-year survival rates were similar in the ejection fraction ≤25% and 25%-35% groups (80.2% vs 73.8%, P  = .11). However, patients with an LVEF improvement of ≥10% exhibited a markedly better prognosis than those without LVEF improvement at 7 years (85.9% vs 63.5%, P =.001)., Conclusions: Our findings suggest that CABG may enhance cardiac function in more than half of patients with ischemic cardiomyopathy, with a correlation to improved all-cause mortality. Moreover, LVEF improvement after CABG is associated with an improved prognosis., (© 2024 The Authors.)

Decidualization can be induced by culturing human endometrial stromal cells (ESCs) with several decidualization stimuli, such as cAMP, medroxyprogesterone acetate (MPA) or Estradiol (E 2 ). However, it has been unclear how decidualized cells induced by different stimuli are different. We compared transcriptomes and cellular functions of decidualized ESCs induced by different stimuli (MPA, E 2  + MPA, cAMP, and cAMP + MPA). We also investigated which decidualization stimulus induces a closer in vivo decidualization. Differentially expressed genes (DEGs) and altered cellular functions by each decidualization stimuli were identified by RNA-sequence and gene-ontology analysis. DEGs was about two times higher for stimuli that use cAMP (cAMP and cAMP + MPA) than for stimuli that did not use cAMP (MPA and E 2  + MPA). cAMP-using stimuli altered the cellular functions including angiogenesis, inflammation, immune system, and embryo implantation whereas MPA-using stimuli (MPA, E 2  + MPA, and cAMP + MPA) altered the cellular functions associated with insulin signaling. A public single-cell RNA-sequence data of the human endometrium was utilized to analyze in vivo decidualization. The altered cellular functions by in vivo decidualization were close to those observed by cAMP + MPA-induced decidualization. In conclusion, decidualized cells induced by different stimuli have different transcriptome and cellular functions. cAMP + MPA may induce a decidualization most closely to in vivo decidualization., (© 2024. The Author(s).)

Purpose: We investigated the interactions between mural granulosa cells (MGCs) and cumulus granulosa cells (CGCs) during ovulation after the LH surge., Methods: We performed clustering, pseudotime, and interactome analyses utilizing reported single-cell RNA sequencing data of mouse ovary at 6 h after eCG-hCG injection., Results: Clustering analysis classified granulosa cells into two distinct populations, MGCs and CGCs. Pseudotime analysis divided granulosa cells into before and after the LH surge, and further divided them into two branches, the ovulatory MGCs and the ovulatory CGCs. Interactome analysis was performed to identify the interactions between MGCs and CGCs. Twenty-six interactions were acting from CGCs toward MGCs, involving ovulation and steroidogenesis. Thirty-six interactions were acting from MGCs toward CGCs, involving hyaluronan synthesis. There were 25 bidirectional interactions, involving the EGFR pathway. In addition, we found three novel interactions: Ephrins-Ephs pathway and Wnt-Lrp6 pathway from CGCs to MGCs, associated with steroidogenesis and lipid transport, respectively, and TGF-β-TGFBR1 pathway from MGCs to CGCs, associated with hyaluronan synthesis., Conclusions: MGCs and CGCs interact with each other in the preovulatory follicle after the LH surge, and their interactions have roles in corpus luteum formation, oocyte maturation, and follicle rupture., Competing Interests: Norihiro Sugino is Editor‐in‐Chief of the Reproductive Medicine and Biology and co‐author of this article. He was excluded from the peer‐review process and all editorial decisions related to the acceptance and publication of this article. Peer review was handled independently by Editors‐in‐Associate Chief Tasuku Harada to minimize bias., (© 2024 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Japanese spotted fever (JSF) is a tick-transmitted infection caused by  Rickettsia japonica  ( R. japonica ), which is indigenous to Japan. Patients with JSF typically present with fever and spotted erythema on the palms and/or soles, and most of them have site(s) of tick bites. The prognosis is good, but some cases have a fatal course. Kawasaki disease (KD) is a systemic vasculitis with an unknown cause that is characterized by symptoms such as fever, conjunctival injection, oral findings, amorphous rash, rigid edema, and nonsuppurative cervical lymphadenopathy. Although the symptoms of JSF are partially similar to those of KD, case reports of JSF overlapping KD have never been internationally published. Herein, we report a boy with JSF and KD symptoms. A five-year-old boy presented with fever and rash after he had been on a mountain inhabited by  R. japonica . On the fifth day, erythema was spotted mainly on his bilateral palms, bilateral cervical lymphadenopathy, rigid edema of his lower feet, and mild conjunctival injection appeared. Intravenous immunoglobulin (IVIG) therapy was performed because these symptoms satisfied five out of the six diagnostic criteria for KD. However, on the sixth day, the fever persisted, and then we readministered IVIG in addition to tosufloxacin and azithromycin since we found a tick-bite eschar, which suggested a complication of JSF. His symptoms resolved soon after this treatment. Coronary artery lesions were never observed. This case indicates that the R. japonica  infection overlaps clinically with KD. Tosufloxacin and azithromycin should be considered to avoid the use of minocycline in younger patients with JSF., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Sasaki et al.)

Purpose: To test the theory that invaginated ovarian surface epithelium and endometrial implants on the ovary form ovarian endometriomas., Methods: Adhesion sites of ovarian endometrioma on the peritoneum and consecutive ovarian endometrioma cyst wall, called non-adhesion sites, were histologically examined. DNA methylomes of the adhesion sites, non-adhesion sites, and blueberry spots were compared with those of ovary, endometrium, and peritoneum., Results: The non-adhesion sites showed an ovarian surface epithelium-like structure near the adhesion site, which continued to a columnar epithelium-like structure. Calretinin staining was strong in the ovarian surface epithelium-like structure but weak in the columnar epithelium-like structure. Estrogen receptors were absent in the ovarian surface epithelium-like structure, but present in the columnar epithelium-like structure. The adhesion sites had endometrial gland-like structures that expressed estrogen receptors. Analyses of DNA methylomes classified the non-adhesion sites and ovaries into the same group, suggesting that ovarian endometriomas originate from the ovarian surface epithelium. The adhesion sites, blueberry spots and peritoneum were classified in the same group, suggesting that the adhesion sites and blueberry spots originate from the peritoneum., Conclusions: The present results support the invagination theory. Ovarian endometriomas consist of invaginated ovarian surface epithelium with celomic metaplasia and endometrium implants on the peritoneum., Competing Interests: Norihiro Sugino and Isao Tamura are Editorial Board members of Reproductive Medicine and Biology and co‐authors of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication., (© 2023 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one of the most common maternally inherited mitochondrial diseases accompanied by neuronal damage due to defects in the oxidative phosphorylation system. There is no established treatment. Our previous study reported a superior restoration of mitochondrial function and bioenergetics in mitochondria-deficient cells using highly purified mesenchymal stem cells (RECs). However, whether such exogenous mitochondrial donation occurs in mitochondrial disease models and whether it plays a role in the recovery of pathological neuronal functions is unknown. Here, utilizing induced pluripotent stem cells (iPSC), we differentiated neurons with impaired mitochondrial function from patients with MELAS. MELAS neurons and RECs/mesenchymal stem cells (MSCs) were cultured under contact or non-contact conditions. Both RECs and MSCs can donate mitochondria to MELAS neurons, but RECs are more excellent than MSCs for mitochondrial transfer in both systems. In addition, REC-mediated mitochondrial transfer significantly restored mitochondrial function, including mitochondrial membrane potential, ATP/ROS production, intracellular calcium storage, and oxygen consumption rate. Moreover, mitochondrial function was maintained for at least three weeks. Thus, REC-donated exogenous mitochondria might offer a potential therapeutic strategy for treating neurological dysfunction in MELAS.

Background and Aims: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis., Methods: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system., Results: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed., Interpretation: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations., (© 2023 Peripheral Nerve Society.)