"Welcome to OBGYN World!" A novel recruitment event for medical students organized by the Japan Society of Obstetrics and Gynecology.

"Welcome to OBGYN World!" A novel recruitment event for medical students organized by the Japan Society of Obstetrics and Gynecology. Since 2012, the number of doctors in Japan who specialize in obstetrics and gynecology has shown a decreasing trend. To increase the number of doctors majoring in obstetrics and gynecology, the Japanese Trainees in Obstetrics and Gynecology subcommittee developed a new recruitment event called Welcome to OBGYN World! (WOW!); the aim of this event was to focus on lower grades of medical students. The present report describes the content of WOW! and the results of a post-event questionnaire administered to participating students and tutors. WOW! was held online in order to avoid the risk of Coronavirus Disease 2019 infection for participants. Sixty of the 82 medical schools nationwide (73.2%) participated in this event. Overall, there were 285 participating students, ranging from first to fourth grade in medical school, and 106 tutors were involved to teach material at the event. In the post-event questionnaire survey, 97.6% (248/254) and 100% of the participants stated they now had a high degree of interest in obstetrics and gynecology and found the specialty attractive, respectively. Furthermore, 93.6% (90/94) of the tutors stated that WOW! had helped recruitment activities in their universities. Based on this outcome, members of the Japanese Trainees of Obstetrics and Gynecology subcommittee will now try to increase the number of doctors specializing in obstetrics and gynecology by holding WOW! annually.

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.

CD4+ T cell heterogeneity in gestational age and preeclampsia using single-cell RNA sequencing.

A balance between pro-inflammatory decidual CD4+ T cells and FOXP3+ regulatory T cells (FOXP3+ Tregs) is important for maintaining fetomaternal tolerance. Using single-cell RNA-sequencing and T cell receptor repertoire analysis, we determined that diversity and clonality of decidual CD4+ T cell subsets depend on gestational age. Th1/Th2 intermediate and Th1 subsets of CD4+ T cells were clonally expanded in both early and late gestation, whereas FOXP3+ Tregs were clonally expanded in late gestation. Th1/Th2 intermediate and FOXP3+ Treg subsets showed altered gene expression in preeclampsia (PE) compared to healthy late gestation. The Th1/Th2 intermediate subset exhibited elevated levels of cytotoxicity-related gene expression in PE. Moreover, increased Treg exhaustion was observed in the PE group, and FOXP3+ Treg subcluster analysis revealed that the effector Treg like subset drove the Treg exhaustion signatures in PE. The Th1/Th2 intermediate and effector Treg like subsets are possible inflammation-driving subsets in PE.

Immunological regulation and the role of autophagy in preeclampsia.

Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous trophoblasts invade the decidua and uterine myometrium, facing maternal immune cells, which participate in the immune suppression of paternal and fetal antigens. Regulatory T cells will likely increase in response to a specific antigen before and during early pregnancy. Insufficient expansion of antigen-specific Treg cells, which possess the same T cell receptor, is associated with the pathophysiology of preeclampsia, suggesting sterile systemic inflammation. Autophagy is involved in reducing inflammation through the degradation of inflammasomes and in the differentiation and function of regulatory T cells. Autophagy dysregulation induces protein aggregation in trophoblasts, resulting in placental dysfunction. In this review, we discuss the role of regulatory T cells in normal pregnancies. In addition, we discuss the association between autophagy and regulatory T cells in the development of preeclampsia based on reports on the role of autophagy in autoimmune diseases.

Dynamics of neuropilin1 (Nrp1)-positive thymus-derived and Nrp1-negative peripherally induced paternal antigen specific regulatory T cells in the uterus and spleen during pregnancy in mice.

Paternal antigen-specific regulatory T (PA-Treg) cells suppress the immune response against the fetus. Naturally occurring Treg (nTreg) cells derived from the thymus and peripherally induced Treg (iTreg) cells are functional for sustaining pregnancy. This study aimed to compare the variation in PA-Treg cells between the feto-maternal interface and the spleen and to elucidate the dynamics of nTreg and iTreg cells during the gestational period. PA-Treg cells, defined as Treg cells with paternally derived Mls-1a antigen-specific T cell receptors Vß6, from allogeneic pregnant mice on days 3.5, 5.5, 11.5, and 18.5 post-coitum (pc) were evaluated by flow cytometry. The percentage of Vß6+ Ki67+ PA-Treg cells activated by the paternal antigen increased on day 11.5 pc in the decidua (p < 0.05) compared to non-pregnant mice. On day 18.5 pc, this percentage in the decidua parietalis decreased to the level of the non-pregnant state but was significantly higher (p < 0.05) in the decidua basalis. No changes were observed in the spleens. We used two nTreg cell markers, neuropilin1 (Nrp1) and Helios, to distinguish between nTreg cells and iTreg cells. Nrp1+ PA-Treg cell levels decreased in late pregnancy compared to those observed in early pregnancy (day 3.5 pc: 57.14 ± 6.16% vs. day 18.5 pc: 30.43 ± 3.09%; p < 0.05), whereas Helios+ cell levels did not change. In conclusion, PA immune tolerance is induced by Nrp1+ nTreg cells in early pregnancy and Nrp1-negative Treg cells in late pregnancy.

PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy.

Dyslipidemia including the accumulation of cholesteryl esters (CEs) in the brain is associated with neurological disorders, although the underlying mechanism has been unclear. PDZD8, a Rab7 effector protein, transfers lipids between endoplasmic reticulum (ER) and Rab7-positive organelles and thereby promotes endolysosome maturation and contributes to the maintenance of neuronal integrity. Here we show that CEs accumulate in the brain of PDZD8-deficient mice as a result of impaired lipophagy. This CE accumulation was not affected by diet, implicating a defect in intracellular lipid metabolism. Whereas cholesterol synthesis appeared normal, degradation of lipid droplets (LDs) was defective, in the brain of PDZD8-deficient mice. PDZD8 may mediate the exchange of cholesterol and phosphatidylserine between ER and Rab7-positive organelles to promote the fusion of CE-containing LDs with lysosomes for their degradation. Our results thus suggest that PDZD8 promotes clearance of CEs from the brain by lipophagy, with this role of PDZD8 likely contributing to brain function.

The role of decidual regulatory T cells in the induction and maintenance of fetal antigen-specific tolerance: Imbalance between regulatory and cytotoxic T cells in pregnancy complications.

Fetal antigen-specific tolerance is important for maintaining allogeneic pregnancies. Maternal conventional T cells recognize fetal antigens; however, regulatory T (Treg) cells suppress immune reactions against the fetus. Fetal antigen-specific Treg cells are induced in the decidua upon contact with antigen-presenting cells and extravillous trophoblasts (EVTs). Functional alteration of cytotoxic T cells (CTLs) in the decidua also contributes to maintaining the pregnancy. Reduced, dysfunctional, and imbalanced Treg cell distribution likely contributes to the pathogenesis of pregnancy complications, such as miscarriage and preeclampsia. Recent studies have revealed differences in Treg cell characteristics during preeclampsia and miscarriage. Treg cell reduction in the decidua is likely associated with miscarriage. Insufficient expansion of fetal antigen-specific Treg cells in the decidua probably plays a role in preeclampsia pathogenesis. In addition, the balance between Treg cell-mediated tolerance and functional alteration of CTLs is important. Further investigations of functional molecules in Treg cells will contribute to the development of immunotherapy for pregnancy complications.

Analysis of TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8+ T Cells Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia.

CD8+ T cells, the most abundant T cell subset in the decidua, play a critical role in the maintenance of pregnancy. The majority of decidual CD8+ T cells have an effector memory phenotype, while those in the peripheral blood display a naive phenotype. An increased amount of highly differentiated CD8+ T cells in the decidua indicates local antigen stimulation and expansion, albeit these CD8+ T cells are suppressed. In decidual CD8+ T cells, co-inhibitory molecules such as PD-1, TIM-3, LAG-3, and CTLA-4 are upregulated, reflecting the suppression of cytotoxicity. Previous studies established the importance of the PD-1/PD-L1 interaction for feto-maternal tolerance. CD8+ T cells could directly recognize fetal-specific antigens, such as HLA-C, expressed by trophoblasts. However, although fetal-specific CD8+ T cells have been reported, their TCR repertoires have not been identified. In this study, we analyzed the TCR repertoires of effector memory CD8+ T cells (CD8+ EM cells) and naive CD8+ T cells (CD8+ N cells) in the decidua and peripheral blood of women with normal or complicated pregnancy and examined PD-1 expression at a single-cell level to verify whether antigen-specific CD8+ T cells accumulate in the decidua and to identify immunological differences related to the suppression of antigen-specific CD8+ T cells between normal pregnancy, miscarriage, and preeclampsia. We observed that some TCRß repertoires, which might recognize fetal or placental antigens, were clonally expanded. The population size of clonally expanded CD8+ EM cells was higher in the decidua than in the peripheral blood. CD8+ EM cells began to express PD-1 during the course of normal pregnancy. We found that the total proportion of decidual CD8+ EM cells not expressing PD-1 was increased both in miscarriage and in preeclampsia cases, although a different mechanism was responsible for this increase. The amount of cytotoxic CD8+ EM cells increased in cases of miscarriage, whereas the expression of PD-1 in clonally expanded CD8+ EM cells was downregulated in preeclampsia cases. These results demonstrated that decidual CD8+ EM cells were able to recognize fetal-specific antigens at the feto-maternal interface and could easily induce fetal rejection.

Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation.

Endosome maturation depends on membrane contact sites (MCSs) formed between endoplasmic reticulum (ER) and endolysosomes (LyLEs). The mechanism underlying lipid supply for this process and its pathophysiological relevance remains unclear, however. Here, we identify PDZD8-the mammalian ortholog of a yeast ERMES subunit-as a protein that interacts with protrudin, which is located at ER-LyLE MCSs. Protrudin and PDZD8 promote the formation of ER-LyLE MCSs, and PDZD8 shows the ability to extract various lipids from the ER. Overexpression of both protrudin and PDZD8 in HeLa cells, as well as their depletion in mouse primary neurons, impairs endosomal homeostasis by inducing the formation of abnormal large vacuoles reminiscent of those apparent in spastin- or REEP1-deficient neurons. The protrudin-PDZD8 system is also essential for the establishment of neuronal polarity. Our results suggest that protrudin and PDZD8 cooperatively promote endosome maturation by mediating ER-LyLE tethering and lipid extraction at MCSs, thereby maintaining neuronal polarity and integrity.

Effects of aripiprazole on insight and subjective experience in individuals with an at-risk mental state.

INTRODUCTION: Although medication with antipsychotic for the psychosis prodrome has often caused some ethical issues, recent studies have shown that some novel antipsychotics are safer and more tolerable for young people. This study aimed to investigate whether the administration of aripiprazole would not only relieve the prodromal symptoms but also be tolerable for prodromal subjects and to evaluate the effect of medication on improvements in insight and subjective well-being. METHODS: The Structured Interview for Prodromal Syndromes was performed for patients identified as having the psychosis prodrome. Psychiatric measures included the Scale of Prodromal Symptoms. Clinical insight was measured using the Scale to Assess Unawareness of Mental Disorder, and changes in subjective experience were assessed using the Subjective Well-being Under Neuroleptics, Short version. The time frame was the first 8 weeks after beginning study medication. RESULTS: Thirty-six treatment-seeking prodromal patients (men, 42%; mean [SD] age, 23.4 [5.6] years) were enrolled. At the 12-week follow-up point, 30 participants (83%) remained in the trial. Improvements on the Scale of Prodromal Symptoms and Scale to Assess Unawareness of Mental Disorder scores were statistically significant at end point. Although the Subjective Well-being Under Neuroleptics, Short version total scores improved significantly at 4 weeks, however, they did not change significantly from baseline at 8 weeks. CONCLUSIONS: This trial suggests that aripiprazole not only produces a clinical benefit in prodromal subjects but also results in a high adherence to medication with immediate improvements in insight and subjective well-being. Although further placebo-controlled studies are needed, aripiprazole might be a first-line treatment for individuals at imminent risk for psychosis.

Chromosomal instability in human mesenchymal stem cells immortalized with human papilloma virus E6, E7, and hTERT genes.

Human mesenchymal stem cells (hMSCs) are expected to be an enormous potential source for future cell therapy, because of their self-renewing divisions and also because of their multiple-lineage differentiation. The finite lifespan of these cells, however, is a hurdle for clinical application. Recently, several hMSC lines have been established by immortalized human telomerase reverse transcriptase gene (hTERT) alone or with hTERT in combination with human papillomavirus type 16 E6/E7 genes (E6/E7) and human proto-oncogene, Bmi-1, but have not so much been characterized their karyotypic stability in detail during extended lifespan under in vitro conditions. In this report, the cells immortalized with the hTERT gene alone exhibited little change in karyotype, whereas the cells immortalized with E6/E7 plus hTERT genes or Bmi-1, E6 plus hTERT genes were unstable regarding chromosome numbers, which altered markedly during prolonged culture. Interestingly, one unique chromosomal alteration was the preferential loss of chromosome 13 in three cell lines, observed by fluorescence in situ hybridization (FISH) and comparative-genomic hybridization (CGH) analysis. The four cell lines all maintained the ability to differentiate into both osteogenic and adipogenic lineages, and two cell lines underwent neuroblastic differentiation. Thus, our results were able to provide a step forward toward fulfilling the need for a sufficient number of cells for new therapeutic applications, and substantiate that these cell lines are a useful model for understanding the mechanisms of chromosomal instability and differentiation of hMSCs.

The genetic differences between gallbladder and bile duct cancer cell lines.

Biliary tract cancers carry dismal prognoses. It is commonly understood that chromosomal aberrations in cancer cells have prognostic and therapeutic implications. However, in biliary tract cancers the genetic changes have not yet been sufficiently studied. The aim of this study was to clarify the presence of mutations in specific chromosomal regions that are likely to harbor previously unknown genes with a significant role in the genesis of biliary tract cancer. The recently developed bacterial artificial chromosome (BAC) array comparative genomic hybridization (CGH) can facilitate detail analysis with high resolution and sensitivity. We applied this to 12 cancer cell lines of the gallbladder (GBC) and the bile duct (BDC) using a genome-wide scanning array. Cell line DNA was labeled with green colored Cy5 and reference DNA derived from normal human leucocytes was labeled with red colored Cy3. GBC, as well as BDC cell lines, have shown DNA copy number abnormalities (gain or loss). In each of the seven GBC cell lines, the DNA copy number was gained on 6p21.32 and was lost on 3p22.3, 3p14.2, 3p14.3, 4q13.1, 22q11.21, 22q11.23, respectively. In five BDC cell lines, there were DNA copy number gains on 7p21.1, 7p21.2, 17q23.2, 20q13.2 and losses were on 1p36.21, 4q25, 6q16.1, 18q21.31, 18q21.33, respectively. The largest region of gain was observed on 13q14.3-q21.32 ( approximately 11 Mb) and of loss on 18q12.2-q21.1 ( approximately 15 Mb), respectively. Both GBC and BDC cell lines have DNA copy number abnormalities of gains and/or losses on every chromosome. We were able to determine the genetic differences between gallbladder and bile duct cancer cell lines. BAC array CGH has a powerful potential application in the screening for DNA copy number abnormalities in cancer cell lines and tumors.

Unusual gamma heavy chain disease protein in a patient with splenic marginal-zone lymphoma.

We conducted an electrophoretic analysis of monoclonal gamma-globulin found in the serum of a patient with splenic marginal-zone lymphoma. This monoclonal protein showed electrophoretic mobility to the gamma region and reacted with anti-immunoglobulin (IgG) antiserum but not with anti-kappa or anti-lambda light chain antisera. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting of the monoclonal protein-rich gamma-globulin fraction extracted from the sliced gel revealed the presence of two types of abnormal IgG molecule, low- and high-molecular-weight IgG, neither of which reacted with anti-kappa or anti-lambda light chain antisera. Additionally, an abnormal high-molecular-weight gamma heavy chain was identified by reducing SDS-PAGE. These findings suggest that this monoclonal protein is composed only of gamma heavy chains of normal and larger size. The presence of abnormal serum immunoglobulin composed of only gamma heavy chain has been known as a fundamental feature of gamma heavy chain disease (HCD). However, the unique composition of monoclonal gamma-globulin makes our case distinct from typical gammaHCD, which is characterized by an abnormal truncated low-molecular-weight gamma heavy chain. Thus, the unusual monoclonal protein may have been produced by a somatic mutation of IgH gene associated with splenic marginal-zone lymphoma.

A longitudinal study investigating sub-threshold symptoms and white matter changes in individuals with an 'at risk mental state' (ARMS).

BACKGROUND: Evidence supports disruption in white matter (WM) connectivity in established schizophrenia, however, it is unclear when these abnormalities occur during the course of illness and if they are progressive. Here we investigated whether WM abnormalities predate illness onset by examining a group of individuals with an 'at risk mental state' (ARMS) and assess whether there is evidence of progressive change. We hypothesized that WM abnormalities are associated with symptom change. METHODS: Sixteen healthy controls and 41 ARMS subjects at baseline underwent Diffusion Tensor Imaging (DTI). Sub-threshold positive symptoms were measured using the Scale of Prodromal Symptoms (SOPS). Imaging and symptoms were re-administered in the ARMS group after one year (52weeks). Fractional anisotropy (FA) value differences between ARMS and control groups at baseline were localized using the method of Tract-Based Spatial Statistics (TBSS). RESULTS: At baseline, FA was significantly reduced in a sub-region of the corpus callosum (CC) in the ARMS group as a whole compared to controls. This reduction was also found in the 34 individuals who did not transition (ARMS-N) during the one-year follow-up. However, the ARMS-N group showed a significant improvement in sub-threshold positive symptoms at follow-up, which was correlated with an increase in FA in the same CC region (r=-0.664, p<0.001). DISCUSSION: There was a significant FA reduction in the CC in individuals at high risk for psychosis regardless of transition status at one year. This suggests that WM abnormalities in the CC may represent a biological vulnerability to psychosis. Improvement in sub-threshold positive symptoms was associated with improvement in measures of WM integrity in the CC. This may suggest that neurobiological 'resilience' is associated with improved outcomes, although this notion requires future study.

Gamma heavy chain disease screening showing a discrepancy between electrophoretic and nephelometric determinations of serum gamma globulin concentration.

A 75-year-old woman with rheumatoid arthritis showed a discrepancy between the reduced level of serum gamma globulin on cellulose acetate electrophoresis and the normal level of serum IgG determined by laser nephelometry. Although no M-peak was detectable on cellulose acetate electrophoresis, immunoelectrophoresis of the patient's serum revealed a monoclonal protein reacting with anti-IgG antiserum but not with anti-kappa or anti-lambda light chain antiserum. Western blotting of the patient's serum showed abnormal low-molecular-weight gamma chains. Thus, the patient was diagnosed with gamma heavy chain disease. A comparison of gamma globulin levels determined by different methods may be useful when screening for this disease.

The discrepancy between electrophoretic and nephelometric determinations of serum gamma-globulin level.

We studied the significance of discrepancies in correlation between serum gamma-globulin levels electrophoretically estimated and immunoglobulin levels nephelometrically determined. Discrepancies appeared in cases with IgA myeloma, macroglobulinemia, and rare types of dysgammaglobulinemia frequently overlooked in serum electrophoresis, IgD myeloma and gamma-heavy chain disease. It is suggested that comparison of the gamma-globulin levels by the different methods is a simple and useful method of detecting these dysgammaglobulinemias.

Evaluation of improved safety management program for outpatient drug dispensing in terms of effect on potential adverse drug events.

Dispensing errors may cause serious health damage. To eradicate dispensing errors, we implemented new safety management strategies, including the development of a dispensing-support system with a computerized check function. We previously evaluated and reported the usefulness of these new strategies for safety management by comparing the incidence of potential adverse drug events (PADEs) before and after the implementation of these strategies. In the present study, we compared the incidence of PADEs from outpatient prescriptions in the late phase 5 years after the start of the new safety management program with that before the implementation. The incidence of PADEs from outpatient prescriptions after the start of these strategies (late phase) was significantly lower than that before their introduction (p<0.001), similar to the results in the early phase. When examining PADEs with respect to category, the incidence of PADEs related to the dispensing of a wrong drug, such as those related to errors in the drug name or standard/dosage form of the same drug, in the late phase was significantly lower than that before the new program began (p<0.05), as was also the case in the early phase. The incidence of PADEs related to errors in counting tablets/capsules was also significantly lower (p<0.01, p<0.05). With respect to the level of influence on patients (level 0 to 3a), the incidence of level-0 PADEs, which represents potential errors that were prevented, in the late phase was significantly lower than that before implementation (p<0.01), as was also demonstrated in the early phase. The incidence of level-1 PADEs in the late phase was significantly lower than that before implementation (p<0.05), but not in the early phase. No level-2 or higher PADE occurred in the early or late phases after the start of the new safety program. When the PADEs were examined with respect to possible contributing factors, the incidences of PADEs associated with the presence of multiple standards in the early and late phases were significantly lower than that before (p<0.05). These results suggest the long-term usefulness of this series of newly introduced strategies for safety management.

Poor outcome associated with symptomatic deterioration among help-seeking individuals at risk for psychosis: a naturalistic follow-up study.

AIMS: It remains debatable whether early intervention for psychosis is capable of meeting the needs of at-risk subjects. The aims of this study were to describe the actual impact of interventions on subjective difficulties and to explore the factors that may be associated with a poor outcome. METHODS: Participants were help-seeking outpatients at a university hospital who met the Criteria of Prodromal Syndromes. Changes in the symptoms, subjective experience and current insight were assessed using the Scales of Prodromal Symptoms, the Subjective Well-being under Neuroleptics, and the Scale to Assess Unawareness of Mental Disorder, respectively. Global functioning, social functioning and subjective quality of life were evaluated using the Global Assessment of Functioning Scale, the Social Functioning Scale, and the WHO-Quality of Life 26, respectively. These measures were assessed both at baseline and after 1 year. RESULTS: Forty-six patients agreed to participate. Of the 27 patients who completed the reassessment at the follow-up point, 13 patients (48%) showed little improvement in their positive/negative symptoms, subjective well-being or awareness of their symptoms. Additionally, less severe negative symptoms, more severe general symptoms and lower subjective well-being at baseline significantly predicted a deterioration of positive/negative symptoms after 1 year. CONCLUSION: Our findings suggest that the current strategy for reducing psychosis risk based on positive symptoms should be reappraised.