Response of negative ion beamlet width and axis deflection to RF field in beam extraction region.

Beam-divergence characteristics of single negative ion beamlet have been experimentally investigated with a superimposition of a controlled perturbation of a radio frequency wave (RF) field in a filament-arc discharge negative ion source. Oscillations of a negative-ion beamlet width and axis responding to the RF perturbation were observed, which may be a cause of the larger beam divergence angle of the RF negative ion source for ITER. It is pointed out that the oscillation of the beamlet width depends on the perveance and on an RF frequency such that the oscillation is suppressed at perveance-matched conditions and at low RF frequency.

Adult Height in Girls with Central Precocious Puberty with Onset after 6 Years: Effects of Gonadotropin-Releasing Hormone Analog Therapy.

Introduction: Precocious puberty (PP), which is sometimes divided into gonadotropin-dependent or gonadotropin-independent PP, is a pathological condition characterized by premature secretion of gonadal steroids resulting in the early development of secondary sexual characteristics. Girls younger than 6 years with idiopathic gonadotropin-dependent PP (referred to as central PP or CPP) who receive gonadotropin-releasing hormone analog (GnRHa) therapy experience an increase in their adult height (AH) in contrast to girls who are aged 6 years or more, who show no consistent pattern of increase even with GnRHa therapy.

Methods: In total, 133 girls aged 6 years or more who visited any one of the seven study centers between April 2000 and March 2020 and who met the diagnostic criteria for PP in Japan were retrospectively examined.

Clinical and molecular analyses of isolated central congenital hypothyroidism based on a survey conducted in Japan.

Central congenital hypothyroidism (CH) can occur as an isolated deficiency or as part of combined pituitary hormone deficiency. Unlike primary CH, central CH cannot be detected by newborn screening (NBS) using dry filter paper blood TSH levels, and early diagnosis remains challenging. In this study, the clinical and genetic backgrounds of patients with isolated central CH were determined through a questionnaire-based survey among members of the Japanese Society for Pediatric Endocrinology.

DHX37 Variant is One of Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome / Partial Gonadal Dysgenesis without Müllerian Derivatives.

Introduction: The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. The clinical phenotype of TRS often overlaps with that of partial gonadal dysgenesis (PGD). Previous studies have demonstrated a causal association between TRS/PGD and heterozygous missense variants of DHX37.

Incidence and Risk Factors for Adrenal Crisis in Pediatric-onset Adrenal Insufficiency: A Prospective Study.

Context: Adrenal crisis (AC) is a life-threatening complication that occurs during follow-up of patients with adrenal insufficiency (AI). No prospective study has thoroughly investigated AC in children with primary and secondary AI.

Objective: This work aimed to determine the incidence and risk factors for AC in patients with pediatric-onset AI.

A case of hyperphosphatemic familial tumoral calcinosis due to maternal uniparental disomy of a variant.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, inherited autosomal recessive disorder caused by fibroblast growth factor-23 (), N-acetylgalactosaminyltransferase 3 (), or Klotho () gene variants. Here, we report the case of a Japanese boy who presented with a mass in his left elbow at the age of three. Laboratory test results of the patient revealed normocalcemia (10.

Transport and Golgi organization 2 deficiency with a prominent elevation of C14:1 during a metabolic crisis: A case report.

Mutations in transport and Golgi organization 2 homolog () have recently been described as a cause of an autosomal recessive syndrome characterized by episodes of metabolic crisis associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration. Herein, we report a case of a one-and-a-half-year-old Japanese girl, born to nonconsanguineous parents, who presented with metabolic crisis characterized by hypoglycemia with hypoketonemia, rhabdomyolysis, lactic acidosis, and prolonged corrected QT interval (QTc) at the age of 6 months. Acylcarnitine analysis during the episode of crisis showed prominent elevation of C14:1, suggesting very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.

Various phenotypes of short stature with heterozygous () mutations.

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in normal fetal and postnatal growth. Over 30 pathogenic variants of have been identified in patients with short stature. Yet, 20 years after the first report, a variety of phenotypes remain poorly defined.

Clinical Features of 57 Patients with Lipoid Congenital Adrenal Hyperplasia: Criteria for Nonclassic Form Revisited.

Context: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. Classic (CLCAH) and nonclassic (NCLCAH) forms were reported as total and partial deficiencies, respectively, of adrenal and gonadal steroid hormones. The rarity of LCAH has precluded large-scale epidemiological and clinical investigations.

Optimization of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines to generate a highly selective PI3Kδ inhibitor.

Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model.

Optimization and in vivo evaluation of pyrazolopyridines as a potent and selective PI3Kδ inhibitor.

Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.

Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kδ inhibitors.

Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks.

Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism.

Background: Congenital hypogonadotropic hypogonadism (CHH) is classified as Kallmann syndrome (KS) with anosmia/hyposmia or normosmic (n)CHH. Here, we investigated the genetic causes and phenotype-genotype correlations in Japanese patients with CHH.

Methods: We enrolled 22 Japanese patients with CHH from 21 families (18 patients with KS and 4 with nCHH) and analyzed 27 genes implicated in CHH by next-generation and Sanger sequencing.

Enhancement of lipid peroxidation and its amelioration by vitamin E in a subject with mutations in the SBP2 gene.

Selenocysteine (Sec) insertion sequence-binding protein 2 (SBP2) is essential for the biosynthesis of Sec-containing proteins, termed selenoproteins. Subjects with mutations in the SBP2 gene have decreased levels of several selenoproteins, resulting in a complex phenotype. Selenoproteins play a significant role in antioxidative defense, and deficiencies in these proteins can lead to increased oxidative stress.

Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature.

Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals.

Heterozygous nonsense mutations near the C-terminal region of IGF1R in two patients with small-for-gestational-age-related short stature.

Objective: The type I insulin-like growth factor I receptor (IGF1R) plays an important role in growth. We aimed to evaluate the detailed mechanism underlying the effect of IGF1R on human growth.

Patients And Methods: We have performed sequence analysis of IGF1R in 55 patients with SGA short stature in Japan, since 2004, and identified novel heterozygous nonsense mutations in 2 patients: an 8-year-old Japanese boy (case 1), with a birthweight of 2228 g (-3·3 SDS) and height of 46 cm (-2·1 SDS), and a 3-year-old Japanese girl (case 2), with a birthweight of 2110 g (-3·0 SDS) and height of 44·3 cm (-2·8 SDS).

Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients.

Study Question: What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) in the genome?

Summary Answer: Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation.

What Is Known Already: Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias.

Pseudodominant inheritance in a family with nonautoimmune hypothyroidism due to biallelic DUOX2 mutations.

Objectives: Mutations in the dual oxidase 2 gene (DUOX2) is the most common genetic cause of congenital hypothyroidism (CH) in Japan. All previously described DUOX2 mutation-carrying families have followed autosomal recessive inheritance. We report a nonconsanguineous Japanese family harbouring biallelic DUOX2 mutations, which presented an apparently dominant inheritance of nonautoimmune hypothyroidism.