Search

The genetic regulation of ovarian development remains largely unclear. Indeed, in most cases of impaired ovarian development—such as 46,XX disorders of sex development (DSD) without SRY, and premature ovarian insufficiency (POI)—the genetic causes have not been identified, and the vast majority of disease-associated sequence variants could lie within non-coding regulatory sequences. In this study, we aimed to identify enhancers of five ovarian genes known to play key roles in early ovarian development, basing our analysis on the expression of enhancer derived transcripts (eRNAs), which are considered to characterize active enhancers. Temporal expression profile changes in mouse WT1-positive ovarian cells were obtained from cap analysis of gene expression at E13.5, E16.5 and P0. We compared the chronological expression profiles of ovarian-specific eRNA with expression profiles for each of the ovarian-specific genes, yielding two candidate sequences for enhancers of Wnt4 and Rspo1. Both sequences are conserved between mouse and human, and we confirmed their enhancer activities using transient expression assays in murine granulosa cells. Furthermore, by sequencing the region in patients with impaired ovarian development in 24 patients, such as POI, gonadal dysgenesis and 46,XX DSD, we identified rare single nucleotide variants in both sequences. Our results demonstrate that combined analysis of the temporal expression profiles of eRNA and mRNA of target genes presents a powerful tool for locating cis-element enhancers, and a means of identifying disease-associated sequence variants that lie within non-coding regulatory sequences, thus advancing an important unmet need in forward human genetics.

In Kawasaki disease (KD), convulsions are rare and mostly attributed to latent and coexisting encephalitis/encephalopathy due to KD itself. Therefore, we retrospectively investigated concomitant viral infections in patients with KD. Between January 2012 and December 2020, among 523 patients with KD, 7 (1.53%), 1 (0.19%), 6 and 1 (1.15% and 0.19%) were positive for adenovirus (AdV-Ag), respiratory syncytial virus (RSV-Ag), and influenza A or B (Flu A-Ag or Flu B-Ag) antigens, respectively. Among them, two were positive for both AdV-Ag and FluA-Ag. Seven patients with KD (1.3%) presented febrile convulsions, and only one was diagnosed with encephalitis/encephalopathy. Between January 2021 and August 2022, 57 patients with KD were newly diagnosed among whom FilmArray® respiratory panel (FARP) was applied on 24 patients, and 14 (58.3%) were positive for at least one virus. During the same period, 32 out of 45 patients (71.1%) with febrile convulsions examined using the FARP were positive for at least one virus. The trend of viruses in patients with KD and febrile convulsion reflected the regional epidemic viral infection. Respiratory virus detected at a much higher rate using the FARP suggests that most convulsions in patients with KD might be related to concomitant viral infection. The possible involvement and association of concomitant respiratory viral infections in patients with KD with prognosis or encephalopathy/encephalitis remain to be investigated.

In Japan, since the introduction of newborn screening for congenital adrenal hyperplasia in 1989, most patients with 21-hydroxylase deficiency (21OHD) have been treated with glucocorticoid from the neonatal period (1, 2). Although early initiation of glucocorticoid therapy from the neonatal period remarkably improved the outcomes of final height, the average final height in 21OHD patients is below the standard height observed in normal healthy adults by approximately –1 standard deviation (SD) (3, 4), and optimization of glucocorticoid therapy remains challenging (5,6,7, 8). Glucocorticoids have a strong potential for reducing linear growth, whereas undertreatment with glucocorticoids leads to androgen excess, precipitating pubertal development (5,6,7). Recent studies have revealed that the final height positively correlates with height at two years of age (9), and the lowest possible hydrocortisone (HC) dose for maintenance treatment during the first two years of life considered crucial for maximizing the final height of 21OHD patients. For maintenance therapy, 15–25 mg/m2 HC therapy is widely accepted (10). In contrast to maintenance HC therapy, the optimal HC dose for initial treatment has not been established. The consensus statement on 21OHD by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology (ESPE) suggests an HC dose of up to 25 mg/m2 for treatment initiation (11). Conversely, the Japanese Society for Pediatric Endocrinology (JSPE) recommended a considerably higher HC dose of HC (100–200 mg/m2) for the initial treatment (12), and in the revised guideline published in 2014, the recommended dose was lowered to 25–100 mg/m2, which is still higher than that recommended by the ESPE (13). A high initial HC dose may help normalize the elevated adrenal androgen levels during the neonatal and early infantile periods, followed by sufficient control by a lower maintenance dose. Our previous study has revealed that the height at two years of age in patients with 21OHD treated with a higher HC dose during initial therapy could be compared with those receiving lower HC doses (14). However, detailed differences between patients with 21OHD treated with higher and lower doses during initial HC therapy have not been assessed. In the present study, we aimed to evaluate the effects of initial HC treatments on clinical profiles during infancy and early childhood in patients with 21OHD.

BACKGROUND One of the major purposes of newborn screening for 21-hydroxylase deficiency (21OHD) is preventing life-threatening adrenal crisis. However, the details of adrenal crisis in newborns are not precisely documented. AIM We aimed to clarify the clinical details of salt-wasting in newborn 21OHD patients. METHODS Based on the follow-up survey of the screening in Tokyo from 1989 to 2017, we retrospectively analysed the conditions of classical 21OHD neonates before the initiation of therapy. RESULTS One hundred classical 21OHD patients (55 male, 45 female) were analysed. The age at the first hospital visit was 0-20 days with sex difference (male: 9.0 ± 3.5 days; female: 6.2 ± 3.9 days). Thirty-seven (37.4%) patients exhibited severe salt-wasting (SSW), that is, Na 7 mEq/L or Na/K ratio 7 mEq/L and Na/K

Background Child abuse is a risk factor for mood disorders, and linked to decreased DNA methylation (DNAm) of FKBP5 intron 7 through interactions with the single nucleotide polymorphism (SNP) rs1360780. However, no study has investigated which specific subtypes of child abuse are related to decreased DNAm of FKBP5 intron 7 in mood disorders. We therefore aimed to examine the relationship among various subtypes of child abuse, rs1360780, and the DNAm level of FKBP5 intron 7. Methods A total of 190 subjects (87 patients with major depressive disorder [MDD], 61 patients with bipolar disorder [BD], and 42 healthy controls) participated. The Child Abuse and Trauma Scale (CATS) was used to evaluate child abuse. Whole blood was processed for genotyping, and pyrosequencing was conducted to assess the DNAm level of FKBP5 intron 7. A multiple regression analysis was used to analyze the DNAm level as a dependent variable, and the CATS subtypes and rs1360780 were used as independent variables. Results Emotional abuse/neglect, one of the specific subtypes of child abuse, was related to lower DNAm of FKBP5 intron 7 interacting with rs1360780 in the BD patients. There were no significant results in the MDD patients or the controls. Limitations Since the study was limited to Japanese individuals, particularly those with MDD and BD, the findings are not generalizable. Furthermore, as child abuse was measured retrospectively, there may be recall bias. Conclusions This finding indicates that a specific subtype of child abuse may play an important role in the development of BD.

Background The most severe forms of congenital hyperinsulinism (CHI) are caused by inactivating mutations of two KATP channel genes, KCNJ11 and ABCC8. Unresponsiveness to diazoxide and need for subtotal pancreatectomy can usually be predicted by genetic form, particularly biallelic mutations in KATP channel genes. A few reports indicated marked clinical heterogeneity in siblings with identical biallelic mutations in ABCC8. The clinical heterogeneity in biallelic KATP CHI was speculated to be caused by epigenetic and environmental factors or related to differences in splicing factor machinery. Objective To elucidate the clinical pathophysiology, especially heterogeneity, among three cases with CHI caused by a homogenous novel mutation. Patients and methods We report a case series that includes two siblings and one unrelated individual with CHI caused by a homogenous 1-bp deletion around the splice acceptor site at the exon 35 mutation of ABCC8, which exhibited markedly distinct phenotypes. To assess the effect of the mutation on splicing, we performed digital droplet polymerase chain reaction (ddPCR) on normal pancreas tissue and a patient's lymphocytes. Results ddPCR of ABCC8 cDNA revealed that expression of exon 35 and its upstream and downstream regions did not differ. These data suggested that clinical heterogeneity may not be caused by differences in splicing factor machinery. Conclusion The phenotypic variation in homozygotes could not be explained by splicing abnormalities. Though early genetic diagnosis of KATP CHI could contribute to selecting appropriate therapeutic options, more deliberate selection of therapeutic options in diffuse CHI due to biallelic ABCC8 mutations may be required.

This paper examines the herd behavior of regional banks during financial fluctuations using loan data on Japanese banks from the 1980s to the 1990s. We use the herding measure developed by Lakonishok, Shleifer, and Vishny (1992) and Uchida and Nakagawa (2007) to detect evidence of herding and its inefficiency. The findings are threefold. First, herding and its inefficiency was consistently observed, regardless of financial fluctuations. Second, the magnitude of herding was not related with bank sizes. Finally, the herding magnitude was positively related with bank's financial health.

In addition to malignant diseases, hematopoietic stem cell transplantation (HSCT) is also a vital option as a curative therapy for non-malignant diseases, such as immunodeficiency, and other hematological disorders. Not only for malignant diseases, but for non-malignant diseases, cytotoxic therapy of conditioning regimens are associated with high risks of adverse effects; however, clinical details regarding the long term outcomes of cytotoxic therapy for non-malignant diseases are not documented yet. To clarify the endocrinological consequences of pediatric HSCT for non-malignant disease patients, we conducted a retrospective analysis. From 1983 to 2014, 75 patients that underwent HSCT for non-malignant diseases were selected for this study. Of these, 23 patients (19 men, 4 women) were continuously followed up in our institute, with regular health check-ups for late effects. Based on a multiple linear regression analysis, the glucocorticoid treatment duration for chronic graft-versus-host disease (cGVHD) and the conditioning regimen were found to be independent predictors of growth retardation. All four female patients developed hypogonadism, and required hormone replacement therapy. The conditioning regimen for the four female patients with hypogonadism was based on the use of alkylating agents, and two female patients were treated with a reduced-intensity conditioning (RIC) regimen. Our study revealed that even the RIC regimen was toxic for the gonads in female patients, and that the survivors of both non-malignant and malignant diseases should be followed up carefully after pediatric HSCT.

Background Acute encephalitis/encephalopathy (AE/E) is a rare and severe complication of common childhood infections; however, a treatment strategy based on clinical and pathological evidence has not been established. Methods The clinical data and aetiological results using a rapid and comprehensive virological detection system of 62 Japanese children diagnosed with AE/E from 2010 to 2014 were collected. We assessed clinical differences between causes and effectiveness of our multiplex PCR system to establish a pathogen-based treatment strategy for AE/E. Results Suspected causes were detected in 84% of patients, and our multiplex PCR system contributed to diagnosing 38% of the patients. Furthermore, a negative virus PCR might be important for inferring underlying disease. Most cases were triggered by human herpes virus (HHV) 6/7 (32%) and influenza virus (24%). The causes of AE/E depended on age (p = 0.00089) but not on sex (p = 0.94). The median age of HHV6/7-associated AE/E was 2.3 years, which is lower than the median ages of AE/E associated with other viruses. Major initial treatments were pulse steroid therapy (83.9%) and acyclovir (71%). Most of the patients in this study had good prognoses: 77% recovered without neurological sequalae. Conclusions Our virological detection system was useful for detecting the cause of AE/E, and may also contribute to construction of pathogen-based treatment strategies for AE/E. Our data indicated the possibility that early intervention with pulse steroid therapy could be effective for treating AE/E. Further investigation for selection of antiepileptic drugs and additional therapies might be required to prevent progression of AE/E.

Daurichromenic acid (DCA) synthase catalyzes the oxidative cyclization of grifolic acid to produce DCA, an anti-HIV meroterpenoid isolated from Rhododendron dauricum. We identified a novel cDNA encoding DCA synthase by transcriptome-based screening from young leaves of R. dauricum. The gene coded for a 533-amino acid polypeptide with moderate homologies to flavin adenine dinucleotide oxidases from other plants. The primary structure contained an amino-terminal signal peptide and conserved amino acid residues to form bicovalent linkage to the flavin adenine dinucleotide isoalloxazine ring at histidine-112 and cysteine-175. In addition, the recombinant DCA synthase, purified from the culture supernatant of transgenic Pichia pastoris, exhibited structural and functional properties as a flavoprotein. The reaction mechanism of DCA synthase characterized herein partly shares a similarity with those of cannabinoid synthases from Cannabis sativa, whereas DCA synthase catalyzes a novel cyclization reaction of the farnesyl moiety of a meroterpenoid natural product of plant origin. Moreover, in this study, we present evidence that DCA is biosynthesized and accumulated specifically in the glandular scales, on the surface of R. dauricum plants, based on various analytical studies at the chemical, biochemical, and molecular levels. The extracellular localization of DCA also was confirmed by a confocal microscopic analysis of its autofluorescence. These data highlight the unique feature of DCA: the final step of biosynthesis is completed in apoplastic space, and it is highly accumulated outside the scale cells.

Hyperglycemia in extremely low-birth weight infants (ELBWIs) is frequently observed during the acute perinatal phase, (i.e., first 1–2 weeks postnatal period); however it can occasionally persists for >2 weeks, extending to the post-acute phase. Since such prolonged hyperglycemia (PH) is not typical for ELBWIs, the aim of the present study was to further understand the clinical details of PH. Twenty-five hyperglycemic ELBWIs born before 28 weeks of gestation from 2015 to 2018 were included in the study. Based on the duration of hyperglycemia, we separated the subjects into two groups: non-prolonged hyperglycemia (NPH) who achieved remission within ≤2 weeks [n = 18, median 3.0 (range, 2.0–4.0) days], and PH, whose hyperglycemia persisted for >2 weeks [n = 7, median 50.0 (range, 33.5–66.0) days]. Compared to the NPH group, glucose metabolism of the PH group was more deteriorate. The peak blood glucose level was significantly higher in the PH group [PH: median 472 mg/dL, NPH: median 275 mg/dL, p

Background We previously reported that child abuse indirectly predicts the diagnosis of major depressive disorder (MDD) or bipolar disorder (BP) based on higher scores of affective temperaments; however, the subtypes of child abuse have not been examined sufficiently. Therefore, in the present study, we used the reclassified version of the Child Abuse and Trauma Scale (CATS) to determine how the subtypes of child abuse affect affective temperaments. Methods A total of 502 participants (212 healthy controls, 163 patients with MDD and 127 patients with BP) were administered the Japanese version of the CATS; the Japanese version of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire; and the Japanese version of the Patient Health Questionnaire-9. Data were analyzed by exploratory and confirmatory factor analyses, as well as by univariate and multivariate analyses. Results A five-factor structure was appropriate for the CATS. The MDD group scored significantly higher on all subtypes of the reclassified CATS than did the control group. Among the subscales of the reclassified CATS, physical abuse and loneliness/psychological stress were significant predictors of affective temperaments, although all subscales were significantly associated with affective temperaments compared to the original CATS. Limitations Since child abuse was assessed retrospectively, there might be recall bias. Furthermore, as the study was limited to Japanese individuals, particularly those with mood disorders, the findings might not be generalizable. Conclusions This study revealed that the subtypes of child abuse (especially physical abuse and loneliness/psychological stress) might be associated with MDD and BP.

Schimmelpenning syndrome is a rare neurocutaneous disorder categorized as a mosaic RASopathy due to postzygotic HRAS or KRAS mutations. We report a 6-year-old girl diagnosed with Schimmelpenning syndrome due to a postzygotic KRAS G12D mutation. The patient had three atypical symptoms of Schimmelpenning syndrome: renovascular hypertension, congenital lipomatosis, and diabetes mellitus. The first two symptoms may overlap with phenotypes of other neurocutaneous syndromes or congenital lipomatous overgrowth syndrome due to mosaic RASopathies or other somatic mosaic mutations. We propose that impaired glucose tolerance was caused by KRAS mutation and a novel clinical phenotype of Schimmelpenning syndrome. Our study indicated that clinical diagnosis of Schimmelpenning syndrome or related conditions should be reorganized with genetic diagnosis of postzygotic mutation. Moreover, further accumulation of genetically proven cases with mosaic RASopathies should be used to more accurately characterize phenotypic presentations of this syndrome and develop a future therapeutic strategy, such as molecular-targeted therapy.

This paper investigates whether inefficient herd behavior of Japanese financial institutions in the domestic loan market affected the real economy during the period between 1975 and 1999. By using Japanese loan data, arranged by geographical area, we show that loans stemming from inefficient herd behavior of Japanese financial institutions tended to have destabilizing effects on the GDP and land prices in the following years, while ordinary loans of those financial institutions had a more positive impact. Our results indicate that the deterioration of the real economy in the 1990s may have been attributable partly to the inefficient herd behavior in the Japanese loan market during the period of the economic bubble in the late 1980s.

This paper investigates whether Japanese banks followed herd behaviour during the 1980s and 1990s. The results indicate the existence of herding during the sample period, while the inefficiency of herding is concentrated in the early to mid 1980s, the period immediately after financial deregulation began. Evidence for the inefficient herding is observed in the behaviour of banks that made loans to new borrowers, and in the behaviour of banks that followed the type of banks that were more informed on lending to new borrowers. On the other hand, inefficient herd behaviour is rarely observed in the 1990s.

This paper empirically investigates whether the responsiveness of aggregate demand to the nominal interest rate, or the slope of a New Keynesian IS curve, changed in Japan in the 1990s. Our model shows that given the constant intertemporal elasticity of substitution, this responsiveness can reduce as a result of deterioration in the financial market's efficiency. Using the data of the Japanese financial market since the 1980s, our results suggest that the efficiency of the Japanese financial market deteriorated significantly in the 1990s, which led to a reduction in the responsiveness of aggregate demand to the nominal interest rate.

This paper empirically investigates whether Japanese banks followed herd behavior as a result of financial deregulation in the 1980s, and whether any observed herd behavior brought about inefficiencies that could have caused macroeconomic fluctuations. Using loan-portfolio data, the paper examines Granger-causalities in lending behavior by different types of banks. We find that Japanese banks inefficiently herd from the early through mid-1980s, the period immediately after financial deregulation began. However, contrary to anecdotal evidence, inefficient herd behavior is rarely observed in the 1990s. The herd behavior in the 1980s was more frequently observed in lending to new borrowers than to traditional borrowers. In addition, other banks were inclined to follow those banks that were considered more informed in lending to a specific industry, or that were large enough to adjust more effectively to the environment created by deregulation. These results are consistent with theoretical predictions in the literature and suggest the possibility that the herd behavior contributed to the asset price bubble in the late 1980s., JEL Classifications: G11, G14, G21, E44

This paper investigates whether Japanese banks had been following herd behavior in the domestic loan market from 1975 through 2000. Applying the technique developed by Lakonishok, Shleifer, and Vishny [Lakonishok, J., Shleifer, A., Vishny, R.V., 1992. The impact of institutional trading on stock prices, J. Finan. Econ. 32, 23–43] to the data from loans outstanding to different types of borrowers, we obtain evidence indicative of the existence of herding. City banks in Japan had been following a cyclical pattern of herding with one of the peaks around the bubble period in the late 1980s. Adjusting further for herding resulting from rational behavior, evidence indicative of the existence of irrational herding was observed only in the bubble period. Our estimate indicates that a total of some 5 trillion yen of loan increase by city banks during the period of 1987–1989 can be attributed to irrational herd behavior. The results imply that irrational bank behavior in the late 1980s might have contributed to the problems Japanese banks had with non-performing loans. We also obtained evidence for herding among regional banks and among geographically proximate banks.

This paper investigates the learnability of the equilibrium under adaptive learning with heterogeneous and misspecified models. Agents have imperfect and mutually different information sets of economic variables,so they form heterogeneous expectations under learning rules that are differently underparameterized. Under heterogeneous learning,the economy converges to a type of restricted perceptions equilibrium,which here is called a Heterogeneous Misspecification Equilibrium (HME). The paper finds that the HME is more learnable than the equilibrium under homogeneous and correctly specified learning rules that corresponds to a rational expectations equilibrium(REE); in other words,the stability conditions of the HME are less stringent than those of the REE. In a basic NK model with a Taylor-type monetary policy rule, for example, the central bank is allowed to choose a wider range of values of policy parameters to ensure the learnability of the HME than that permitted to ensure the learnability of the REE, that is, the Taylor principle.In addition, if the correlation between demand and supply shocks is low, the stability conditions of the HME become further less stringent so that the central bank might not have to address the learnability of the equilibrium., Canadian Economics Association 44th Annual Conference (Quebee City, Canada, May 28, 2010), Japanese Economic Association 2010 Semiannual Meeting (Chiba, Japan, June 6, 2010), Western Economic Association International 85th Annual Conference (Portland, Oregon, USA, July 2, 2010), Grants-in-Aid for Scientific Research No.20730139

Why is the rational expectations equilibrium locally indeterminate if the central bank raises the nominal interest rate too actively in response to a rise in expected inflation? This is because although the bank succeeds in stabilizing the expectations of the future economy, it allows the current economy to arbitrarily fluctuate. This indeterminacy expands in dimension as the forecast horizon of the rule becomes long.

This paper investigates the impact of a financial market imperfection on the conditions that monetary policy rules must satisfy for the determinacy of a rational-expectations equilibrium. A financial market imperfection can disturb intertemporal substitution in certain cases. If a financial market is sufficiently imperfect, this imperfection can cause the real interest rate elasticity of aggregate demand to become positive. In this case, the Taylor principle is not the unique necessary and sufficient condition for monetary policy rules to ensure determinacy. If the central bank responds to current inflation, then the Taylor principle is a sufficient, but not a necessary, condition. Moreover, if the bank responds to expected inflation, the Taylor principle is neither a necessary nor a sufficient condition. Our calibration results suggest that it may be dangerous for a central bank to adhere solely to the Taylor principle when real financial markets are immature or bankrupt, as was the case for the Japanese market during the 1990s.

This paper investigates whether Japanese banks had been following herd behavior in the domestic loan market from 1975 through 2002. Applying the technique developed by Lakonishok, Shleifer, and Vishny (LSV) (1992, J. of Fin. Econ.) to the data of loans outstanding to different types of borrowers, we obtain evidence indicative of the existence of herding. Consistent herding during the entire sample period is observed among regional banks, whereas city banks had been following a cyclical herd behavior with one peak around the bubble period in the late 1980s. Even after adjusting for herding resulting from rational or institutional factors, we still observe herding for regional banks in the entire period, whereas herding only in the bubble period remains for city banks. The results would indicate that regional banks had been consistently following irrational herd behavior, while city banks were frantic enough to herd only in the bubble period in the late 1980s

The oscillation from a linear relation in the 20 vs. sin2ψ diagram has been a most important problem in X-ray stress measurement. There are, therefore, a number of papers concerned with the X-ray elastic constant, lattice strains under stresses and evaluation of stresses of textured materials.The purpose of the present study is to analyze the three-dimensional orientation distribution of steel sheets by means of the Vector method proposed by Ruer and Baro, and to calculate the elastic modulus of textured sheets by means of a finite element method (FEM) using the three-dimensional orientation distribution, and then to calculate the strain/stress ratios vs. the directions defined by the angles between the specimen normal and the normal to the diffracting planes.

The melting rate of iron oxide pellets into iron melt and the reduction rate of pellets by carbon in iron melt were obtained by measuring the evolution rate of CO gas. The pellets were made from iron oxide powder by pressing and sintering and were not crushed into pieces when added onto the iron melt. The effects of the iron oxide phase, the oxide additives in pellets, and the temperature and the carbon content of iron melts on the melting and the reduction rates were investigated. The following results were obtained:(1)It has been found that the heat transfer was not the rate-determining step for the two rates. It is considered that the carbon diffusion in a boundary layer on the iron melt surface could be the rate-determining step.(2) The total reduction rate was constant for reduction degrees from about 20% to about 70%, where solid iron oxides were reduced by carbon dissolved in iron melt.(3) The apparent activation energy of the melting of pellets into the carbon saturated iron melt was 35 for Fe2O3; 18 and 41 for Fe3O4 above and below 1470°C, respectively; 44 and 79kcal/mol for FeO above and below 1470°C, respectively.(4) The melting rate of Fe2O3, Fe3O4 and FeO pellets into the iron melt at 1570°C was proportional to C0.57, C0.45 and C0.42 respectively, where C denotes the weight percentage of carbon in an iron melt. The minimum amount of CO gas evolved was obtained at about 2%C.