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Herein, hydroxylation activities at the 6β-position and 21-position of progesterone mediated by human cytochrome P450 (CYP) 2D6 and its variants and the effects of psychotropic drugs on these hydroxylation activities were compared to clarify whether CYP2D6 polymorphisms and psychotropic drugs impact neurosteroid levels in the brain.Progesterone was incubated with CYP2D6.1, CYP2D6.2 (Arg296Cys, Ser486Thr), CYP2D6.10 (Pro34Ser, Ser486Thr), and CYP2D6.39 (Ser486Thr) in the absence or presence of typical psychotropic drugs (fluvoxamine, fluoxetine, paroxetine, fluphenazine, and milnacipran) and endogenous steroids (testosterone and cortisol). Then, 6β- and 21-hydroxyprogesterone levels were determined by high-performance liquid chromatography.Although the Michaelis-Menten constants (KThese results suggest that CYP2D6 polymorphism can affect the stimulation/inhibition of progesterone 21-hydroxylation.

The Keio Twin Research Center (KoTReC) was established in 2009 at Keio University to combine two longitudinal cohort projects — the Keio Twin Study (KTS) for adolescence and adulthood and the Tokyo Twin Cohort Project (ToTCoP) for infancy and childhood. KoTReC also conducted a two-time panel study of self-control and psychopathology in twin adolescence in 2012 and 2013 and three independent anonymous cross-sectional twin surveys (ToTcross) before 2012 — the ToTCross, the Junior and Senior High School Survey and the High School Survey. This article introduces the recent research designs of KoTReC and its publications.

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04–0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.

Aim We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. Methods Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. Results Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. Conclusion The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

To clarify the impact of blood pressure (BP) management ranges on pregnancy outcomes, we conducted a multicenter retrospective analysis of 215 women with singleton pregnancies diagnosed with essential hypertension either before or within 14 weeks of gestation. Patients were classified according to systolic BP (sBP

Hydroxylation activity at the 6β-position of steroid hormones (testosterone, progesterone, and cortisol) by human cytochromes P450 (CYP) 3A4, polymorphic CYP3A5, and fetal CYP3A7 were compared to understand the catalytic properties of the major forms of human CYP3A subfamily. Testosterone, progesterone, and cortisol 6β-hydroxylation activities of recombinant CYP3A4, CYP3A5, and CYP3A7 were determined by liquid chromatography. Michaelis constants (Km) for CYP3A7-mediated 6β-hydroxylation of testosterone, progesterone, and cortisol were similar to those of CYP3A4 and CYP3A5. The maximal velocity (kcat) and kcat/Km values for CYP3A4 were the highest, followed by CYP3A5 and those for CYP3A7 were the lowest among three CYP3A subfamily members. A decrease in Km values for progesterone 6β-hydroxylation by CYP3A4, CYP3A5, and CYP3A7 in the presence of testosterone was observed, and the kcat values for CYP3A5 gradually increased with increasing testosterone. This indicated that testosterone stimulated progesterone 6β-hydroxylation by all three CYP3A subfamily members. However, progesterone inhibited testosterone 6β-hydroxylation mediated by CYP3A4, CYP3A5, and CYP3A7. In conclusion, the kcat values, rather than Km values, for 6β-hydroxylation of three steroid hormones mediated by CYP3A7 were different from those for CYP3A4 and CYP3A5. In addition, the inhibitory/stimulatory pattern of steroid-steroid interactions would be different among CYP3A subfamily members.

The Keio Twin Research Center has conducted two longitudinal twin cohort projects and has collected three independent and anonymous twin data sets for studies of phenotypes related to psychological, socio-economic, and mental health factors. The Keio Twin Study has examined adolescent and adult cohorts, with a total of over 2,400 pairs of twins and their parents. DNA samples are available for approximately 600 of these twin pairs. The Tokyo Twin Cohort Project has followed a total of 1,600 twin pairs from infancy to early childhood. The large-scale cross-sectional twin study (CROSS) has collected data from over 4,000 twin pairs, from 3 to 26 years of age, and from two high school twin cohorts containing a total of 1,000 pairs of twins. These data sets of anonymous twin studies have mainly targeted academic performance, attitude, and social environment. The present article introduces the research designs and major findings of our center, such as genetic structures of cognitive abilities, personality traits, and academic performances, developmental effects of genes and environment on attitude, socio-cognitive ability and parenting, genes x environment interaction on attitude and conduct problem, and statistical methodological challenges and so on. We discuss the challenges in conducting twin research in Japan.

In a previous Letter to the Editor (Zucker, Bradley, Owen-Anderson, Kibblewhite, & Cantor, 2008), we provided data on the number of referred children and adolescents to a specialized gender identit...

Gender identity and the second-to-fourth finger length ratio (2D : 4D) are discriminative between the sexes. However, the relationship between 2D : 4D and gender identity disorder (GID) is still controversial.The aim of this study is to investigate the relationship between 2D : 4D and score on the Gender Identity Scale (GIS) in female-to-male (FtM) GID subjects.Thirty-seven GID-FtM with testosterone replacement therapy from our clinic were included in this study. As controls, 20 male and 20 female volunteers participated from our institution (medical doctors and nurses). We photocopied left and right hands of the participants and measured the second and fourth finger lengths. Gender identity was measured with the GIS.2D : 4D digit ratio and GIS in male, female, and GID-FtM subjects.The 2D : 4D (mean ± standard deviation) in male, female, and GID-FtM were 0.945 ± 0.029, 0.999 ± 0.035, and 0.955 ± 0.029 in right hand and 0.941 ± 0.024, 0.979 ± 0.040, and 0.954 ± 0.036 in left hand, respectively. The 2D : 4D was significantly lower in male controls in both hands and GID-FtM in the right hand than in female controls (P0.05, analysis of variance). Multiple linear regression analysis revealed that "consistent gender identity" score in the higher domain in GIS and "persistent gender identity" score in the lower domain are statistically significant variables correlating with 2D : 4D in the right hands among biological females.The finger length ratio 2D : 4D in GID-FtM was significantly lower than in female controls in the right hand in this study. 2D : 4D showed a positive correlation with GIS score. Because 2D : 4D influences are assumed to be established in early life and to reflect testosterone exposure, our results suggest a relationship between GID-FtM and perinatal testosterone.

The second to fourth digit ratio has been argued to reflect prenatal hormonal influences and is reportedly associated with various psychological and behavioral traits, such as sexual orientation, cognitive abilities, and personality. We examined genetic and environmental influences on the second to fourth digit ratio (2D:4D) using a Japanese twin sample (N = 300). The genetic analysis showed substantial additive genetic influences for both right and left hand 2D:4D. The rest of the variance was explained mainly by environmental influences not shared within twin pairs. These findings were, in general, in accordance with preceding studies with primarily Caucasian twin samples. The bivariate genetic analysis revealed that the additive genetic influences were largely shared between the right and left hand, while the non-shared environmental influences were largely unique to each hand. Results from a comparison of opposite-sex and same-sex twins were not significant, although they were in the predicted direction according to the prenatal hormone transfer hypothesis. Female monozygotic twin pairs discordant in sexual orientation showed significant within-pair differences in left hand 2D:4D, where non-heterosexual twins had lower (more masculinized) 2D:4D. In addition, we found that non-heterosexual male MZ twins had larger (more feminized) 2D:4D than their heterosexual co-twins. These results suggest the existence of non-shared environmental influences that affect both 2D:4D and sexual orientation.

The present study examined: (1) gender and age differences of mean gender identity disorder (GID) trait scores in Japanese twins; (2) the validity of the prenatal hormone transfer theory, which predicts that, in dizygotic (DZ) twin pairs, twins with an opposite-gender co-twin more frequently exhibit GID traits than twins with a same-gender co-twin; and (3) the magnitude of genetic and environmental influences on GID traits as a function of age and gender. Data from 1450 male twin pairs, 1882 female twin pairs, and 1022 DZ male–female pairs ranging from 3 to 26 years of age were analyzed. To quantify individual variances in GID traits, each participant completed four questionnaire items based on criteria for GID from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Our most important findings were: (1) Japanese females exhibited GID traits more frequently than males and Japanese children exhibited GID traits less frequently than adolescents and adults (among females, the prevalence was 1.6 % in children, 10 % in adolescents, and 12 % in adults; among males, the prevalence was 0.5, 2, and 3 %, respectively); (2) the data did not support the prenatal hormone transfer theory for GID traits; and (3) a large part of the variance for GID traits in children was accounted for by familial factors; however, the magnitude was found to be greater in children than in adolescents or adults, particularly among females. This study suggests that although the prevalence is likely to increase, familial effects are likely to decrease as individuals age.

The present study used event-related brain potentials (ERPs) to investigate allocation of attentional resources to internal and external stimuli in individuals with social anxiety. High and low socially anxious individuals were presented with depictions of various facial expressions or household objects, followed by an internal (vibration presented to the finger) or external probe (the letter “E”). Participants were told that the vibration signals physiological changes and were asked to detect both probes. High socially anxious individuals showed larger front-central N140 amplitudes in response to vibratory internal probes as compared to non-anxious controls. ERPs elicited by picture stimuli and external probes and reaction times in response to both probe types did not differ between high and low social anxiety individuals. Early somatosensory ERPs reveal an attentional bias for internal stimuli that does not appear in overt behavior.

Implicit associations in the fear structure of social anxiety were investigated and their relations with explicit associations were examined in the present study. The Implicit Association Test was used to assess implicit associations. Individuals scoring High ( n = 26) and Low ( n = 18) on Social Anxiety completed two forms of the Implicit Association Test and rated the probability and cost of negative social outcomes. Analyses showed an implicit association between anxiety responses and negative evaluations was more strongly formed in the High Social Anxiety group than in the Low Social Anxiety group. Furthermore, relations between implicit associations and explicit measures were minimal. These findings suggested that the Implicit Association Test is suitable for the assessment of implicit associations in the fear structure of social anxiety, and that implicit associations of social anxiety are relatively independent of explicit associations.

This study investigated the possible effects of genetic and environmental gender differences in effect on individual differences by using the Bem Sex Role Inventory (BSRI) with twins. A sex/gender-limitation analysis, a behavior genetics methodology was used to the following: (a) effects of gender-specific genes, (b) gender differences in quantitative genetic effects, (c) effects of gender-specific shared environment, (d) gender differences of quantitative shared environment, and (e) gender differences of quantitative nonshared environment. Participants were adolescent and adult twins, including 111 identical male pairs, 241 identical female pairs, 36 fraternal male pairs, 65 fraternal female pairs, and 58 opposite-gender pairs. The results indicated that although masculinity and femininity were explained by genetic factors to some extent, there were no significant gender differences in the genetic factors. Moreover, because our data did not support a model which explained gender differences in the effects of specific common environment factors, no evidence was found to support the prenatal hormonal hypothesis or the existence of parenting which encouraged children's gender role personality.

In accordance with the partial amendment of the Law on Mental Health and Welfare for People with Mental Disorders, some mental health and welfare work has been performed under the jurisdiction of cities, towns and villages instead of prefectures since April, 2002. What is the role of prefectural health centres in supporting cities, towns and villages under the partial amendment? To consider this question in the light of transfer of responsibilities from prefectures to the municipalities, we investigated the situation in municipalities in October, 2001.A total of 500 municipalities with populations less than 100,000 were recruited and questionnaire survey was carried out to study the mental health and welfare work, the department in charge and other relevant data.A total of 359 municipalities responded to the questionnaire (the response rate was 71.8%). Mental health and welfare work came under the jurisdiction of 58.5% of the municipalities. The persons in charge were mainly public health nurses and officers and few municipalities had specialists. About 64% of the municipalities had designated a department in charge of the transferred work, but only 16% had designated the number of persons in charge. Although municipalities must provide services for patients living at home as of April, 2002, under the partial amendment, 24.2% of municipalities had already been providing such service previously. About 60% of municipalities had staff who planned to participate in training for care management. For the office work related to the delivery of the health and welfare note for people with mental disorders and public expenditure for hospital expenses, 16.2% of municipalities had designated specialists as persons in charge and 24.2% of municipalities had secured space for privacy. Almost all (98.6%) municipalities pointed to problems in the transfer, which included the shortage of specialists and requested health centres to provide specific information.Although mental health and welfare work comes under the jurisdiction of over half of the municipalities, few have specialists for this purpose. Support services for patients living at home were often provided by the municipalities prior to the partial amendment of the Law going into effect. As municipalities stressed the shortage of specialists and requested specific information, health centres need to support municipalities from the standpoint of their specialized abilities.