Primordial follicles remaining in young cancer survivors who received chemotherapy.

AIM: Ovarian tissue cryopreservation (OTC) is performed for fertility preservation in cancer patients undergoing chemotherapy. Although anti-Müllerian hormone is used as a marker for ovarian reserve, serum levels do not always correlate with the number of follicles. Additionally, the follicle development stage most affected by chemotherapy is unclear. We examined the association between serum anti-Müllerian hormone levels and the number of remaining primordial follicles after chemotherapy, as well as which follicle stage is most affected by chemotherapy before ovarian cryopreservation. METHODS: Thirty-three patients who underwent OTC were divided into the chemotherapy (n = 22) and non-chemotherapy (n = 11) groups; their ovarian tissues underwent histological examination. Pathological ovarian damage induced by chemotherapy was assessed. Ovarian volumes were estimated from weights. We compared the number of follicles at each developmental stage as a percentage of primordial follicles between the groups. The relationship between serum anti-Müllerian hormone level and primordial follicle density was analyzed. RESULTS: The chemotherapy group had a significantly lower serum anti-Müllerian hormone level, ovarian volume, and density of developing follicles than the non-chemotherapy group. Serum anti-Müllerian hormone levels correlated with primordial follicle density only in the non-chemotherapy group. The chemotherapy group had significantly lower numbers of primary and secondary follicles. CONCLUSIONS: Chemotherapy induces ovarian damage and follicle loss. However, serum anti-Müllerian hormone level does not always reflect the number of primordial follicles after chemotherapy, and chemotherapy more significantly affects primary and secondary follicles than primordial follicles. Many primordial follicles remain in the ovary after chemotherapy, supporting OTC for fertility preservation.

Impact of awake mapping on overall survival and extent of resection in patients with adult diffuse gliomas within or near eloquent areas: a retrospective propensity score-matched analysis of awake craniotomy vs. general anesthesia.

PURPOSE: Awake craniotomy (AC) with intraoperative mapping is the best approach to preserve neurological function for glioma surgery in eloquent or near eloquent areas, but whether AC improves the extent of resection (EOR) and overall survival (OS) is controversial. This study aimed to compare the long-term clinical outcomes of glioma resection under AC with those under general anesthesia (GA). METHODS: Data of 335 patients who underwent surgery with intraoperative magnetic resonance imaging for newly diagnosed gliomas of World Health Organization (WHO) grades II-IV between 2000 and 2013 were reviewed. EOR and OS were quantitatively compared between the AC and GA groups after 1:1 propensity score matching. The two groups were matched for age, preoperative Karnofsky performance status (KPS), tumor location, and pathology. RESULTS: After propensity score matching, 91 pairs were obtained. The median EOR was 96.1% (interquartile range [IQR] 7.3) and 97.4% (IQR 14.4) in the AC and GA groups, respectively (p = 0.31). Median KPS score 3 months after surgery was 90 (IQR 20) in both groups (p = 0.384). The median survival times were 163.3 months (95% confidence interval [CI] 77.9-248.7) and 143.5 months (95% CI 94.4-192.7) in the AC and GA groups, respectively (p = 0.585). CONCLUSION: Even if the glioma was within or close to the eloquent area, AC was comparable with GA in terms of EOR and OS. In case of difficulties in randomizing patients with eloquent or near eloquent glioma, our propensity score-matched analysis provides retrospective evidence that AC can obtain EOR and OS equivalent to removing glioma under GA.

Sex difference in anti-sperm antibodies.

Background: Some diseases have sex differences. There have been no reports on the relationship between anti-sperm antibodies (ASA) and sex differences. Methods: ASA are detected by sperm-immobilization test using patients' sera in women. In men, the ASA testing is generally performed by direct-immunobead test. Main findings: Sperm-immobilizing antibodies in women inhibit sperm migration in their genital tract and exert inhibitory effects on fertilization. ASA bound to sperm surface in men also show inhibitory effect on sperm passage through cervical mucus. The fertilization rate of IVF significantly decreased when sperm were coated with higher numbers of ASA. For women with the antibodies, it is important to assess individual patients' SI50 titers. In patients with continuously high SI50 titers, pregnancy can be obtained only by IVF. For men with abnormal fertilizing ability by ASA, it is necessary to select intracytoplasmic sperm injection. Production of sperm-immobilizing antibodies is likely to occur in women with particular HLA after exposure to sperm. The risk factors for ASA production in men are still controversial. Conclusion: Attention to sex differences in specimens, test methods and the diagnosis of ASA should be paid. For patients with ASA, treatment strategies have been established by considering sex difference for each.

Evaluation of NKp46 expression and cytokine production of decidual NK cells in women with recurrent pregnancy loss.

Purpose: NKp46, a receptor on NK cells, is involved in cytotoxicity and cytokine production. The authors aimed to evaluate the effect of NKp46 on decidual NK (dNK) cells during pregnancy and whether it can be a marker for immunological abnormalities in women with recurrent pregnancy loss (RPL). Methods: Flow-cytometric analysis was made to assess NKp46 expression and intracellular cytokine production of dNK cells. The proportion of NKp46+ dNK cells was analyzed among RPL patients who aborted karyotypically normal pregnancies and those who either aborted karyotypically abnormal pregnancies or without genetic studies, and controls who were going through the induced abortion. Results: The %NKp46+ and %NKp46bright dNK cells were significantly lower in the RPL women who aborted karyotypically normal pregnancies than in the control group. The %NKp46bright dNK cells were significantly correlated with the NK1/NK2 ratio of dNK cells. The %NKp46+ dNK cell cutoff for RPL with immunological abnormalities was determined by the ROC curve analysis. In women with the low %NKp46+ dNK, NK1/NK2 ratios were significantly higher than those with the high. Conclusion: RPL patients with an immunological abnormality have decreased NKp46 expression and NK1 shift in dNK cells. NKp46 expression could be a marker for RPL of immunological abnormalities.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Focal Hand Dystonia: A Pilot Study.

BACKGROUND: The efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for the treatment of focal hand dystonia (FHD) is not well known. OBJECTIVE: We aimed to prospectively investigate the efficacy of MRgFUS thalamotomy for the treatment of FHD. METHODS: We performed MRgFUS thalamotomy of the ventro-oral (Vo) nucleus in 10 patients with FHD. We evaluated the scores of the Writer's Cramp Rating Scale (WCRS, 0-30; higher scores indicating greater severity), Tubiana Musician's Dystonia Scale (TMDS, 0-5; lower scores indicating greater severity), and Arm Dystonia Disability Scale (ADDS, 0%-100%; lower scores indicating greater disability) at baseline and 3 and 12 months post-treatment. RESULTS: WCRS, TMDS, and ADDS scores significantly improved from 6.3 ± 2.7, 1.4 ± 0.5, and 58.7% ± 14.3% at baseline to 1.6 ± 3.1 (P = 0.011), 5.0 ± 0 (P = 0.0001), and 81.6% ± 22.9% (P = 0.0229) at 12 months, respectively. There was one prolonged case of dysarthria at 12 months. CONCLUSION: We show that MRgFUS Vo-thalamotomy significantly improved FHD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mucosal thickening of the maxillary sinus is frequently associated with diffuse glioma patients and correlates with poor survival prognosis of GBM patients: comparative analysis to meningioma patients.

Glioma patients were frequently associated with mucosal thickening of the maxillary sinus (MTMS), which reflects mucosal inflammation. We suspected that MTMS is associated with impaired mucosal immune response and correlated with dysfunction in the anti-tumor immune response in diffuse glioma patients. Therefore, the aim of this study was to determine whether the occurrence of diffuse glioma is correlated with MTMS compared to meningioma and control groups. Furthermore, we investigated whether MTMS is associated with overall survival (OS) in glioblastoma (GBM) patients. This study included 343 patients with newly diagnosed diffuse gliomas and 218 patients with meningioma treated at our institution between 2015 and 2018. As control, 201 patients with headache who did not have an intracranial organic lesion were included. Using three-axis MR images, we evaluated the incidence of MTMS in all patients. Additionally, we investigated the relationship between MTMS and OS. The incidence of MTMS in patients with diffuse glioma was significantly higher than that in the meningioma (p < .0001) and control groups (p < .0001). In 128 patients with GBM, MTMS status correlated significantly with OS (p = .0064). We revealed that the incidence of MTMS is significantly associated with patients with diffuse glioma. This suggests that MTMS is indirectly involved in the occurrence of diffuse gliomas. Furthermore, the presence of MTMS correlated significantly with shorter OS in GBM patients, indicating that MTMS is involved in suppression of anti-tumor immune response. Preoperative recognition of MTMS might be useful for improving the clinical management of GBM patients.

Treatment with Laevo (L)-carnitine reverses the mitochondrial function of human embryos.

PURPOSE: Laevo (l)-carnitine plays important roles in reducing the cytotoxic effects of free fatty acids by forming acyl-carnitine and promoting beta-oxidation, leading to alleviation of cell damage. Recently, the mitochondrial functions in morula has been shown to decrease with the maternal age. Here, we assessed the effect of l-carnitine on mitochondrial function in human embryos and embryo development. METHODS: To examine the effect of L-carnitine on mitochondrial function in morulae, 38 vitrified-thawed embryos at the 6-11-cell stage on day 3 after ICSI were donated from 19 couples. Each couple donated two embryos. Two siblings from each couple were divided randomly into two groups and were cultured in medium with or without 1 mM L-carnitine. The oxygen consumption rates (OCRs) were measured at morula stage. The development of 1029 zygotes cultured in medium with or without L-carnitine was prospectively analyzed. RESULTS: Addition of L-carnitine to the culture medium significantly increased the OCRs of morulae and improved the morphologically-good blastocyst formation rate per zygote compared with sibling embryos. Twenty healthy babies were born from embryos cultured in L-carnitine-supplemented medium after single embryo transfers. CONCLUSION(S): L-carnitine is a promising culture medium supplement that might be able to counteract the decreased mitochondrial function in human morula stage embryos.

Sperm immobilization test and quantitative sperm immobilization test using frozen-thawed sperm preparation applied with computer-aided sperm analysis.

PURPOSE: In a previous study, a new method was described using the sperm immobilization test (SIT) with computer-aided sperm analysis (CASA). However, obtaining high-quality sperm as needed was a known issue. Here, we compared the results of using frozen-thawed sperm and fresh sperm for the SIT using the CASA method. METHODS: For the frozen-thawed preparation, 500 µL of condensed semen and 500 µL of Sperm Freeze were mixed in a cryovial and cryopreserved in liquid nitrogen. Density gradient centrifugation was used for the collection of motile sperm in both the fresh and frozen-thawed sperm preparations. A total of 50 serum samples were prepared for both the fresh and frozen-thawed sperm with each sample tested containing 10 µL of serum, 1 µL of either fresh or frozen motile sperm suspension, and 2 µL of complement. Sperm motilities were measured using CASA after a 1-hour incubation period for both fresh and frozen-thawed sperm. RESULTS: Both fresh and frozen-thawed sperm reacted similarly when exposed to serum containing sperm-immobilizing antibodies asserting the use of frozen-thawed sperm for the diagnosis of immunological infertility. CONCLUSION: These results suggest the possibility of using cryopreserved sperm for the SIT when fresh sperm is unavailable.

Influence of wide opening of the lateral ventricle on survival for supratentorial glioblastoma patients with radiotherapy and concomitant temozolomide-based chemotherapy.

The prognosis for glioblastoma (GBM) varies among patients. Ventricular opening during surgery has been reported as a prognostic factor for GBM patients, but the influence of ventricular opening itself on patient prognosis remains controversial. We presumed that the degree of ventricular opening would correlate with the degree of subventricular zone (SVZ) resection and with prognosis in GBM patients. This study therefore investigated whether the degree of ventricular opening correlates with prognosis in GBM patients treated with the standard protocol of chemo-radiotherapy. Participants comprised 111 patients with newly diagnosed GBM who underwent surgery and received postoperative radiotherapy and temozolomide-based chemotherapy from 2005 to 2018. We classified 111 patients into "No ventricular opening (NVO)", "Ventricular opening, small (VOS; distance < 23.2 mm)", and "Ventricular opening, wide (VOW; distance ≥ 23.2 mm)" groups. We evaluated the relationship between degree of ventricular opening and prognosis using survival analyses that included other clinicopathological factors. Log-rank testing revealed age, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) status, isocitrate dehydrogenase (IDH)1 mutation, and degree of ventricular opening correlated significantly with overall survival. Multivariate analysis identified the degree of ventricular opening (small vs. wide) as the most significant prognostic factor (hazard ratio = 3.674; p < 0.0001). We demonstrated that wide opening of the lateral ventricle (LV) contributes to longer survival compared with small opening among GBM patients. Our results indicate that wide opening of the LV may correlate with the removal of a larger proportion of tumor stem cells from the SVZ.

Mitochondrial oxygen consumption rate of human embryos declines with maternal age.

PURPOSE: The fertility of women decreases with age because of factors such as an increased incidence of aneuploidies and-possibly-decreased mitochondrial activity in oocytes. However, the relationship between maternal aging and mitochondrial function of their embryos remains unknown. Here, we assessed the relationship between maternal age and mitochondrial functions in their oocytes and embryos METHODS: The relationships between maternal age and oxygen consumption rates (OCRs), mitochondrial DNA (mtDNA) copy numbers, or blastocyst development was investigated using 81 embryos donated from 63 infertility couples. The developmental rates from morulae to blastocysts were retrospectively analyzed using data of 105 patients. RESULTS: The OCRs of morulae decreased with maternal age (r2 = 0.48, P < 0.05) although there were no relationships between maternal age and mtDNA copy number in any stages. The more oxygen consumed at the morula stage, the shorter time was required for embryo development to the mid-stage blastocyst (r2 = 0.236, P < 0.05). According to the clinical data analysis, the developmental rate from morulae to blastocysts decreased with maternal age (P < 0.05, < 37 years, 81.1%, vs. ≥ 37 years, 64.1%). CONCLUSIONS: The data of the present study revealed that mitochondrial function at the morula stage of human embryos decreased with their maternal age and a decrease of mitochondrial function led to slow-paced development and impaired developmental rate from morulae to blastocysts.

Resuscitative hysterotomy in a patient with peripartum cardiomyopathy.

Resuscitative hysterotomy (RH) is a resuscitation technique, allowing the restoration of a pregnant patient's heartbeat. Here, we reported a case of RH performed in a patient with cardiac arrest as a complication of a peripartum cardiomyopathy. A 29-year-old woman with suspected hemolysis, elevated liver enzymes, low platelet syndrome was admitted to the hospital. Cardiopulmonary resuscitation and RH were initiated at 30 weeks of gestation. The infant was successfully delivered 2 min after the mother's cardiac arrest, weighting 1388 g. At the first minute, the Apgar score was 3 and the 5th minute was 6. After delivery, defibrillation was performed on the mother and restoration of spontaneous circulation was observed. However, she was hemodynamically unstable and approximately 2 months later she died. After cardiac arrest, it is possible that RH could improve the hemodynamic status. The opportunity of performing a RH is rare; however, it is necessary to be familiarized with the technique as a resuscitation method.

Risk Factors and Outcomes of Recurrent Pregnancy Loss in Japan.

AIM: To clarify the risk factors and pregnancy outcomes for each risk factor of recurrent pregnancy loss (RPL) in Japan. METHODS: Using a prospective RPL database collected from 16 facilities in Japan, the prevalence of risk factors for RPL, their treatments and pregnancy outcomes were examined. RESULTS: Of 6663 patients registered in our database, 5708 patients had RPL. All examinations for risk factors were performed for 1340 patients (23.5%). The prevalences of positive antiphospholipid antibodies (aPL), malformation of the uterus, thyroid dysfunction, parental karyotype abnormality, factor XII deficiency, protein S deficiency and unknown risk factors were 8.7%, 7.9%, 9.5%, 3.7%, 7.6%, 4.3% and 65.1%, respectively. Although factor XII deficiency and protein S deficiency are not recognized as risk factors for RPL in general, low-dose aspirin (LDA) or unfractionated heparin + LDA therapy improved live birth rates. In transiently aPL-positive patients, the live birth rate with LDA therapy was similar to that with heparin + LDA. For unknown risk factors of RPL, the live birth rate in normal fetal karyotype in the none treatment group was similar to that in all other treatments group (81.3% vs 86.0%). Of 5708 RPL patients, pregnancy outcomes were known for 2261 patients and 1697 patients (75.1%) had at least one live birth. CONCLUSION: The risk factors and pregnancy outcomes for each risk factor of RPL are useful for clinicians and patients. Factor XII deficiency and protein S deficiency may be risk factors of RPL.

Fertility preservation and pregnancy outcomes in adolescent and young adult male patients with cancer.

PURPOSE: Sperm cryopreservation is the gold standard for maintaining fertility in male survivors of cancer. In order to help increase the future success of fertility preservation in these patients, the present state of sperm cryopreservation was examined at the current institution and its challenges were discussed. METHODS: Between January, 2004 and February, 2017, 31 male patients with cancer were introduced to the center for fertility preservation. The ages and semen characteristics of these patients were examined and compared between those whose sperm were cryopreserved before (the pretreatment group) and after (the post-treatment group) cancer treatment. RESULTS: The mean sperm concentration of the pretreatment group was significantly higher than that of the post-treatment group. Normozoospermia was found in eight and three patients in the pretreatment and the post-treatment groups, respectively, albeit this difference was not significant. In contrast, the prevalence of azoospermia was higher in the post-treatment group (five patients) than in the pretreatment group (one patient). CONCLUSION: As many patients possibly suffer from infertility following chemotherapy, it is necessary to provide fertility preservation opportunities to young male patients with cancer prior to the commencement of cancer treatment.

Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss.

AIM: Natural cytotoxicity receptors (NCR) are unique markers that regulate natural killer (NK) cell cytotoxicity and cytokine production. In this study, we investigated the expression of NCR (NKp46, NKp44, and NKp30) and cytokine production in NK cells derived from the uterine endometrium of women with recurrent pregnancy loss (RPL). We also investigated the expression of NCR in peripheral blood NK cells in pregnant women with and without a history of RPL. METHODS: The expression of NCR (NKp46, NKp44, and NKp30) in NK cells (CD56dim and CD56bright ) in the uterine endometrium was analyzed using 3-color flow cytometry. Cytokine (tumor necrosis factor-α and interferon-γ) production was also analyzed. NK cells from the mid-secretory endometrium of 28 women with RPL, 34 women with implantation failure, and 74 controls were collected and mechanically dispersed using a tissue grinder. The expression of NCR in peripheral blood NK cells from pregnant women with (n = 17) and without (n = 91) a history of RPL was analyzed. RESULTS: The percentages of NKp46+ NK cells were significantly lower in both women with RPL and pregnant women with a history of RPL. The percentages of tumor necrosis factor-α- and/or interferon-γ-producing uterine endometrial NK cells were significantly lower in women with RPL compared with controls. CONCLUSION: The changes in NCR expression and cytokine production, especially decreased NKp46 expression in endometrial NK cells, suggests the presence of abnormal NK cell regulation in women with reproductive failures.

1,25-Dihydroxy-vitamin D3 regulates NK-cell cytotoxicity, cytokine secretion, and degranulation in women with recurrent pregnancy losses.

Vitamin D has a pivotal role in regulating immune responses by promoting Th2 immune responses and suppressing Th1 responses. Propensities to a Th1 immune response and increased NK-cell levels and cytotoxicity have been reported in women with recurrent pregnancy losses (RPL). In women with RPL, vitamin D deficiency is prevalent; however, the effect of vitamin D on NK cells is largely unknown. In this study, we demonstrated that CD69(+) activating receptor expression on NK cells was significantly decreased by incubation with 1,25(OH)2 D3 in a dose-dependent manner, while CD158a and CD158b inhibitory receptor expression was upregulated. The degranulation marker CD107a was significantly downregulated on NK cells following incubation with 1,25(OH)2 D3 . NK-cell conjugation with K562 target cells was not affected by 1,25(OH)2 D3 ; however, depolarization of perforin granules in conjugated NK cells was significantly increased. TLR4 expression on NK cells was significantly decreased and TNF-α and IFN-γ production was significantly reduced by 1,25(OH)2 D3 through interference with NF-κB. Our results suggest 1,25(OH)2 D3 has immune regulatory effects on NK cell cytotoxicity, cytokine secretion and degranulation process as well as TLR4 expression. Potential therapeutic application of 1,25(OH)2 D3 for dysregulated NK-cell immunity should be explored in the future.

Development of a new clinically applicable device for embryo evaluation which measures embryo oxygen consumption.

STUDY QUESTION: Does a new system-the chip-sensing embryo respiration monitoring system (CERMs)-enable evaluation of embryo viability for potential application in a clinical IVF setting? SUMMARY ANSWER: The system enabled the oxygen consumption rate of spheroids, bovine embryos and frozen-thawed human embryos to be measured, and this rate corresponded to the developmental potential of embryos. WHAT IS ALREADY KNOWN: To date, no reliable and clinically suitable objective evaluation methods for embryos are available, which circumvent the differences in inter-observer subjective view. Existing systems such as the scanning electrochemical microscopy (SECM) technique, which enables the measurement of oxygen consumption rate in embryos, need improvement in usability before they can be applied to a clinical setting. STUDY DESIGN, SIZE, DURATION: This is a prospective original research study. The feasibility of measuring the oxygen consumption rate was assessed using CERMs for 9 spheroids, 9 bovine embryos and 30 redundant frozen-thawed human embryos. The endpoints for the study were whether CERMs could detect a dissolved oxygen gradient with high sensitivity, had comparable accuracy to the SECM measuring system with improved usability, and could predict the development of an embryo to a blastocyst by measuring the oxygen consumption rate. The relationship between the oxygen consumption rate and standard morphological evaluation was also examined. PARTICIPANTS/MATERIALS, SETTING, METHODS: We developed a new CERMs, which enables the oxygen consumption rate to be measured automatically using an electrochemical method. The device was initially used for measuring a dissolved oxygen concentration gradient in order to calculate oxygen consumption rate using nine spheroids. Next, we evaluated data correlation between the CERMs and the SECM measuring systems using nine bovine embryos. Finally, the oxygen consumption rates of 30 human embryos, which were frozen-thawed on 2nd day after fertilization, were measured by CERMs at 6, 24, 48, 72 and 96 h after thawing with standard morphological evaluation. Furthermore, the developed blastocysts were scored using the blastocyst quality score (BQS), and the correlation with oxygen consumption rate was also assessed. MAIN RESULTS AND THE ROLE OF CHANCE: The device enabled the oxygen consumption rate of an embryo to be measured automatically within a minute. The oxygen concentration gradient profile showed excellent linearity in a distance-dependent change. A close correlation in the oxygen consumption rates of bovine embryos was observed between the SECM measuring system and CERMs, with a determination coefficient of 0.8203 (P = 0.0008). Oxygen consumption rates of human embryos that have reached the blastocyst stage were significantly higher than those of arrested embryos at 48, 72 and 96 h after thawing (P = 0.039, 0.004 and 0.049, respectively). Thus, in vitro development of frozen-thawed human embryos to the blastocyst stage would be predicted at 48 h after thawing (day 4) by measuring the oxygen consumption using CERMs. Although a positive linear relationship between BQS and the oxygen consumption rate was observed [the determination coefficient was R(2) = 0.6537 (P = 0.008)], two blastocysts exhibited low oxygen consumption rates considering their relatively high BQS. This suggests that morphology and metabolism in human embryos might not correlate consistently. LIMITATIONS, REASONS FOR CAUTION: Transfer of the embryo and pregnancy evaluation was not performed. Thus, a correlation between oxygen consumption and the in vivo viability of embryos remains unknown. Clinical trials, including embryo transfer, would be desirable to determine a threshold value to elect clinically relevant, quality embryos for transfer. We utilized frozen-thawed human embryos in this study. The effect of these manipulations on the respiratory activity of the embryo is also unknown. WIDER IMPLICATIONS OF THE FINDINGS: Selection of quality embryos, especially in a single embryo transfer cycle, by CERMs may have an impact on obtaining better clinical outcomes, albeit with clinical trials being required. Furthermore, the early determination of quality embryos by CERMs may enable the omission of long-term in vitro embryo culture to the blastocyst stage. CERMs is scalable technology that can be integrated into incubators and/or other embryo evaluation systems, such as the time-lapse systems, due to its chip-based architecture. Thus, CERMS would enable automatic measurement of oxygen consumption, under 5% CO2, in the near future, in order to reduce oxidative stress from exposure to atmospheric air. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from the Health and Labor Sciences Research Grant (H24-Hisaichiiki-Shitei-016). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Expression of retinoid-related orphan receptor (ROR)γt on NK22 cells in the peripheral blood and uterine endometrium of women with unexplained recurrent pregnancy loss and unexplained infertility.

AIM: Recently, NK22 cells, a subset of interleukin (IL)-22-producing natural killer (NK) cells, were identified. We have previously reported the higher percentage of NK22 cells in women suffering recurrent pregnancy loss (RPL). Moreover, we have also reported lower expression of NKp46, a kind of natural cytotoxicity receptor (NCR), on NK cells and the changes of NK cell producing cytokines in women who experience RPL. NK22 cells express NCRs, such as NKp44 or NKp46. Retinoid-related orphan receptor γt (RORγt) is known as a regulator of NK22 cells; however, in NK22 cells of peripheral blood (PB) and the uterine endometrium (UE), the relationship between NCRs and RORγt is unclear. We investigate RORγt expression NK22 cells in the PB and UE of women with unexplained infertility (uI) or unexplained RPL (uRPL). METHODS: Lymphocytes were extracted from PB and UE, derived from women with uI or uRPL. Expression of RORγt and NCRs in NK cells and NK cell-produced cytokines were analyzed by flow cytometry. RESULTS: CD56+ /NKp46+ /RORγt+ cells were positively correlated with CD56+ /IL-22+ cells in both PB and UE. CD56bright /NKp46bright /RORγt+ cells were significantly higher in uRPL than in uI, and endometrial CD56bright /NKp46bright /RORγt+ cells were positively correlated with PB. In UE, CD56bright /RORγt+ cells were negatively correlated with CD56bright /interferon-γ+ and CD56bright /tumor necrosis factor-α+ cells of uRPL. CONCLUSION: RORγt may be associated with NK22 cells in reproduction. Particularly, higher expression of RORγt may be associated with elevated NK22 cells in uRPL.

NK cell abnormality and its treatment in women with reproductive failures such as recurrent pregnancy loss, implantation failures, preeclampsia, and pelvic endometriosis.

The regulation of uterine and peripheral blood natural killer (NK) cells has been associated with problems related to reproductive immunology such as recurrent pregnancy loss (RPL), implantation failure or preeclampsia. NKp46, one of the natural cytotoxicity receptors (NCRs), is a unique marker that functions in NK cell cytotoxicity and cytokine production. Expression of NKp46 on NK cells is lower in women with recurrent pregnancy loss and pregnancy-induced hypertension. Moreover, expression of NKp46 on peritoneal fluid NK cells is lower in women with pelvic endometriosis. Therefore, evaluation of NKp46 on peripheral blood NK cells may provide a means of screening for reproductive abnormalities. Recently, a new type of NK cell, the NK22 cell, has been reported. This cell may be a regulator not only of the mucosal barrier but also of reproduction. For women with RPL showing abnormal uterine and/or peripheral blood NK cells, both intravenous immunoglobulin treatment and intralipid treatment have been reported. The effects of these treatments are still controversial, and further studies are needed in order to clarify their true impact. The present review examines variations in the expression of NCRs on NK cells, the participation of NK22 cells in reproduction, and the possible use of intravenous immunoglobulin or intralipid treatment for women with recurrent pregnancy loss and NK cell abnormality.