Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/cvr/cvz305

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DOI： 10.1096/fj.202001113R

Language：English   Publishing type：Research paper (scientific journal)  

De Novo Truncating Mutation of TRIM8 Causes Early-Onset Epileptic Encephalopathy.
BACKGROUND: Early-onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile-onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants. CASE REPORT AND METHODS: We present a 10-year-old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole-exome sequencing and array-comparative genome hybridization were performed to search for de novo variations. Two-week-old C57Bl/6 mice were used for immunofluorescence studies. RESULTS: This case had a paternally inherited, 0.2-Mb duplication at chromosome 22q11.22. The whole-exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy-associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain. CONCLUSION: This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE-associated genes.

DOI： 10.1111/ahg.12157

Language：English   Publishing type：Research paper (scientific journal)  

Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice.
Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8-10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6-8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.

DOI： 10.1038/srep22991

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1126/scitranslmed.3002166

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1074/jbc.M110566200

Language：English   Publisher：Brain and Development  

Background: Previous national studies of acute encephalopathy in Japan were conducted in 2007–2010 and 2014–2017. In this third study (April 1, 2020–October 31, 2023), spanning the coronavirus disease 2019 (COVID-19) outbreak, we compared results to assess trends in pediatric viral infections and therapeutic practices. Methods: Questionnaires were sent to 430 hospitals of the Japanese Pediatric Society, yielding 241 responses and 1197 cases. A secondary survey to 151 facilities received 110 responses (72.8 %), identifying 622 eligible patients (604 for treatment, 544 for outcome analysis). Data on patient background, syndrome classification, causative virus, treatment, and prognosis were collected. Results: Among 622 cases (54.6 % boys), the highest incidence was in 1-year-olds, with case numbers peaking during COVID-19 and influenza outbreaks. The frequency of clinical syndromes was: acute encephalopathy with biphasic seizures and late reduced diffusion, 35.1 %; clinically mild encephalitis/encephalopathy with a reversible splenial lesion, 17.8 %; hemorrhagic shock and encephalopathy syndrome (HSES), 6.9 %; acute encephalitis with refractory, repetitive partial seizures, 3.7 %; acute fulminant cerebral edema (AFCE), 2.2 %; acute necrotizing encephalopathy, 1.6 %; and unclassifiable, 31.4 %. Notably, the combined HSES/AFCE rate increased from 1.9 % in the 2014–2017 survey to 9.1 %, likely due to enhanced diagnosis and COVID-19 impact. Pathogens were exanthem subitum (16.1 %), severe acute respiratory syndrome coronavirus 2 (15.9 %), and influenza (7.7 %). Treatments included steroid pulse therapy (68.9 %), mitochondrial cocktails (42.5 %), and targeted temperature management (31.0 %). Conclusion: This study provides a comprehensive overview of pediatric acute encephalopathy during COVID-19 outbreaks, shows increases in the incidence of HSES/AFCE, and presents current treatment.

DOI： 10.1016/j.braindev.2025.104387

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DOI： 10.3171/CASE2576

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Language：English   Publisher：Pediatric Blood and Cancer  

DOI： 10.1002/pbc.31694

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Publisher：Diseases of the Colon and Rectum  

BACKGROUND: Data registries lack a definitive classification system that distinguishes different locations of colon cancer from one another. OBJECTIVE: To establish an international consensus on the definition of primary colon cancer segment locations. DESIGN: Between December 2022 and June 2023, the Delphi survey study was conducted to seek opinions from relevant international experts and eventually develop a consensus definition of each colon cancer segment. SETTING: Three-round online-based Delphi survey study. INTERVENTIONS: The online survey included 17 questions. In the first 2 rounds, participating experts were asked to rank each statement on a scale of 1 (least relevant) to 9 (most relevant). Consensus statements and definitions were revised according to the results for statements obtaining a consensus score of 7 to 9. During the third round and online meeting, definitions and statements that reached a moderate or high consensus (above 4 for more than 70% of participants) were included. MAIN OUTCOME MEASURES: The primary goal of our project was focused on precisely localizing the specific segment affected by primary colon cancer rather than identifying surgical treatment or type of resection needed for a particular segment. RESULTS: The first round included 331 experts; 301 (91%) completed the second round and 295 (98%) completed the final round. Experts strongly supported the use of a “10-cm rule” to describe colon cancer sites at the flexures and anatomical landmarks for other segments. Regarding the definition of rectosigmoid cancer, experts from United States and Europe reached a high consensus that the term rectosigmoid as a colon cancer location must be abolished in contrast to experts from Asia. The description of overlapping segments of cancers achieved a consensus of 64%. LIMITATIONS: Subjective decisions are based on individual expert clinical experience. CONCLUSIONS: This Delphi survey, the first internationally conducted consensus study, achieved a remarkable level of consensus among a panel of global experts. Ambiguity still exists regarding overlapping lesions. See Video Abstract.

DOI： 10.1097/DCR.0000000000003739

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DOI： 10.1177/03009858251349124

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DOI： 10.1093/jjco/hyaf102

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> The precise pathogenesis of Kawasaki disease (KD) remains unclear, but immune dysregulation involving damage-associated molecular patterns (DAMPs), such as oxidized low-density lipoprotein (LDL) and high mobility group box 1 (HMGB1), has been implicated. We investigated the roles of 2 anti-DAMPs antibodies in KD and their associations with inflammatory and oxidative stress markers.</p><p><b><i>Methods and Results:</i></b> Serum levels of anti-oxidized LDL and anti-HMGB1 antibodies were measured by enzyme-linked immunosorbent assay in patients with KD and in febrile disease controls (DC). Correlations with inflammatory (C-reactive protein [CRP]) and oxidative stress (red blood cell distribution width [RDW]) markers were evaluated. Serum anti-oxidized LDL antibody levels increased significantly after intravenous immunoglobulin (IVIG) therapy in KD patients, suggesting a protective role of anti-oxidized LDL antibodies against vascular inflammation. Conversely, anti-HMGB1 antibody levels showed a decreasing trend post-IVIG. A significant correlation between antibody levels and CRP was observed in DC but not in KD patients. Furthermore, a weak inverse trend between anti-oxidized LDL antibodies and RDW-coefficient of variation was noted in KD patients.</p><p><b><i>Conclusions:</i></b> This study highlighted the distinct roles of anti-oxidized LDL and anti-HMGB1 antibodies during the acute phase of KD. The increase in anti-oxidized LDL antibodies following IVIG treatment suggests a protective effect, while the transient nature of anti-HMGB1 antibodies warrants further exploration.</p>

DOI： 10.1253/circrep.cr-25-0018

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Language：English   Publisher：International Journal of Urology  

Objectives: To report outcomes of active surveillance (AS) for prostate cancer in men with intermediate-risk features of International Society of Urological Pathology (ISUP) grade group 2 and/or clinical stage T2 compared with ISUP grade group 1 and clinical stage T1 in the PRIAS-JAPAN study. Methods: Patients with prostate cancer diagnosed between January 2010 and February 2024 were included in this study. PSA test, rectal examination, and re-biopsy were performed regularly. We calculated the pathological reclassification rate, program persistence rate, and subsequent treatment. Results: Data from 1302 participants were collected. After excluding patients who did not fit inclusion criteria (n = 28) or follow-up of less than 1 year (n = 208), 1066 patients were included in this analysis. The median follow-up was 42.4 months (interquartile range 17.0–72.1). There were no statistical differences in the pathological reclassification, persistence rates, and subsequent therapy between low- and intermediate-risk features. Conclusion: This preliminary study demonstrated medium-term outcomes of AS in prostate cancer with intermediate-risk features in Japan, suggesting no significant difference in the pathological reclassification, persistence rate, and subsequent therapy between low- and intermediate-risk features.

DOI： 10.1111/iju.70063

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Language：English   Publisher：Neonatology  

Introduction: Infants born extremely preterm are at high risk for neurodevelopmental problems. However, their neurodevelopment exhibits a variety of trajectories. This study aimed to investigate the association between changes in neurodevelopmental outcomes and clinical characteristics among extremely preterm infants. Methods: This is a retrospective study of surviving children born at gestational age 22–28 weeks in Kyushu University Hospital between 2010 and 2020. We collected perinatal and post-discharge data and investigated the association between clinical characteristics and changes in developmental quotient (DQ) scores between 1.5 and 3 years of corrected age. Results: Out of the 179 eligible extremely preterm infants, 115 (64%) underwent neurological evaluations at 1.5 and 3 years of corrected age. Among them, 33 (29%) showed improvement in their DQ scores (+10 or more), 62 (54%) showed no change (−9 to +9), and 20 (17%) showed a decline (−10 or less). Gestational age, birth weight, and perinatal complications during the NICU stay did not affect individual changes in DQ scores. Multivariable analysis revealed that greater growth in height until age 3 years was a significant predictor of increasing DQ scores, while male sex and having siblings had a negative effect on changes in the DQ scores. Conclusion: We first demonstrate clinical data conceptualizing that growth in height, sex, and sibling status, rather than perinatal complications, are biologically linked with favorable or unfavorable neurodevelopmental changes of extremely preterm infants during the first 3 years of life.

DOI： 10.1159/000541129

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Language：English   Publisher：BMC Pediatrics  

Background: Methylmalonic acidemia is a rare autosomal recessive disorder of propionate catabolism characterized by the accumulation of propionic acid and methylmalonic acid caused by methylmalonyl-CoA mutase deficiency. Clinical presentations range from acute deterioration in the neonatal period to later onset with a heterogeneous clinical course. Metabolite accumulation results in systemic involvement, affecting the nervous, gastrointestinal, and renal system functions and causing cardiomyopathy. Bone marrow dysfunction manifesting as neutropenia and anemia is a common hematological finding. Although rare, three cases of secondary hemophagocytosis were documented. Case presentation: An 18-year-old male patient diagnosed with methylmalonic acidemia presented with vomiting and altered mental status. He had a medical history of presumably hemophagocytic lymphohistiocytosis (HLH) at the age of 17 months. Physical examination, laboratory tests, and bone marrow aspiration results met the HLH-2004 diagnostic criteria, confirming a recurrent HLH. Although he recovered after intensive treatment, his cognitive function declined. Retrospective analysis revealed higher serum levels of ferritin during acute decompensations compared with nonattack periods. Correlation analysis revealed a strong relationship between serum ferritin and propionylcarnitine, one of the major propionyl-CoA-derived metabolites. Conclusions: HLH is a rare and underrecognized hematologic emergency in methylmalonic acidemia, and its early diagnosis and treatment are critical. Serum ferritin may be a useful clinical biomarker in the diagnosis of HLH-associated attacks in methylmalonic acidemia.

DOI： 10.1186/s12887-025-05613-9

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Language：English   Publisher：Journal of Clinical Investigation  

Mycobacterium tuberculosis causes human tuberculosis (TB). As mycobacteria are protected by a thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, the antigenicity of most adjuvantic lipids is unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activated human T cells bearing a unique αβ T cell receptor (αβTCR). This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA-Seq using newly established CD1b-TMM tetramers revealed that TMM-specific T cells were present as CD4+ effector memory T cells in the periphery of uninfected donors but expressed IFN-γ, TNF, and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells were detected in cord blood and PBMCs of donors without bacillus Calmette-Guérin vaccination but were expanded in patients with active TB. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively charged CDR3α, and long CDR3β regions. These results indicate that humans have a commonly shared and preformed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.

DOI： 10.1172/JCI185443

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：Microbiology and Immunology  

Yersinia pseudotuberculosis (Ypt) is a gram-negative bacterium that infects both humans and animals primarily through fecal‒oral transmission. While Ypt causes acute gastroenteritis in humans, an association with Kawasaki disease (KD), a disease that primarily affects infants and young children and causes multisystemic vasculitis, has also been suspected. Although KD represents a significant health concern worldwide, the highest annual incidence rate is reported in Japan. Previously, a geographical origin-dependent population structure of Ypt comprising the Asian, transitional, and European clades was proposed. However, genomic data on KD-associated Ypt strains is currently unavailable. In this study, to analyze the phylogenetic and genomic features of KD-associated strains, we determined the whole-genome sequences of 35 Japanese Ypt strains, including 11 KD-associated strains, and constructed a genome set (n = 204) representing the global population of Ypt by adding publicly available Ypt genomes. In a phylogenetic analysis, all sequenced Japanese strains, including the KD-associated strains, belonged to the Asian clade, which appeared to be the ancestral clade of Ypt, and the KD-associated strains belonged to multiple lineages in this clade. Strains from patients with Far East scarlet-like fever (FESLF), a KD-related disease, also belonged to the Asian clade. Moreover, no KD strain-specific genes were identified in pan-genome-wide association study analyses. Notably, however, the gene encoding a superantigen called Yersinia pseudotuberculosis-derived mitogen (YPM) showed a distribution pattern highly biased to the Asian clade. Although further studies are needed, our results suggest that Asian clade strains may have a greater potential to trigger KD.

DOI： 10.1111/1348-0421.13199

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Language：English   Publisher：Pediatric Blood and Cancer  

Programs allowing access to investigational drugs and off-label drug use for serious diseases have often been applied to pediatric cancers. A clinical study conducted under the Japanese “Patient-Proposed Healthcare Services” evaluated the efficacy and safety of dabrafenib plus trametinib in children with BRAF V600 mutant glioma (jRCTs071210071). This study successfully provided unapproved and off-label medications to four enrolled patients, two with low-grade glioma and two with high-grade glioma (median age: 10.5 years), until regulatory approval. The timeframe and data collection from such access programs need to be optimized for pediatric patients in accordance with the healthcare system of each nation.

DOI： 10.1002/pbc.31510

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Language：English   Publisher：Scientific Reports  

Very-low-birth-weight infants (VLBWIs) are at high risk for neurodevelopmental problems after age 3 years. We investigated the association between the developmental quotient (DQ) of VLBWIs and their growth profiles during 6 years after birth. Participants were VLBWIs born at Kokura Medical Center (the first cohort) and Kyushu University Hospital (the second cohort) between 2012 and 2017. Recorded charts were used to collect growth profiles and developmental quotients (DQ) of the participants until age 6 years. In the first cohort (n = 64), the DQ values at age 6 years were correlated with those at age 3 years. VLBWIs with DQ ≥ 85 at age 6 years had a higher body weight and height at age 3 years than those with DQ < 85. The second cohort (n = 69) validated these findings. A comparative analysis of the two cohorts revealed that the DQ of VLBWIs was dissociated from their growth profiles after age 3 years. Clustering analyses indicated that DQ values at age 3 years predicted better the prognosis of VLBWIs with DQ ≥ 85 at age 6 years than their growth profiles. This study demonstrates that VLBWIs gain divergent profiles in growth, development, and growth-and-development correlation during postnatal 6 years.

DOI： 10.1038/s41598-025-88721-x

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Language：English   Publisher：Asian Journal of Endoscopic Surgery  

Introduction: Global warming poses an urgent challenge, with the healthcare sector being a significant contributor to greenhouse gas (GHG) emissions. The rise in minimally invasive surgery, which often depends on energy-intensive technologies and single-use devices, further exacerbates this environmental burden. The concept of “Green Surgery” aims to reduce the environmental footprint while maintaining patient care standards. Yet awareness and attitudes of surgeons in Japan regarding these practices are largely unknown. Methods: The Japanese Society for Endoscopic Surgery (JSES)'s Working Group on Environmental Issues conducted an online survey with 21 questions exploring knowledge of Green Surgery and perspectives on sustainable practices. The survey was distributed to all JSES members, with anonymous responses collected between October 18 and November 12, 2024. Results: A total of 1601 participants (10.1%) responded. Awareness of Green Surgery was limited, with only 5% demonstrating a well-developed understanding, though 67% expressed concerns about GHG emissions and operating room waste. Environmentally friendly practices were reported by only 14% of respondents' facilities, with perceived cost increases (55%) and workflow changes (39%) as key barriers. Nonetheless, 82% were willing to adopt sustainable practices, preferring reusable instruments (74%) and remanufactured single-use devices (66%). Conclusion: This survey highlights the challenges and opportunities in promoting Green Surgery in Japan. Despite limited awareness, there is considerable interest in adopting sustainable practices. These findings support the JSES in spearheading initiatives to integrate sustainability into surgical practices, thereby aiding in achieving global climate goals.

DOI： 10.1111/ases.70087

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Language：Japanese   Publisher：(一社)日本小児神経学会  

Hyperventilation-induced high-amplitude rhythmic slowing with altered awareness(HIHARSAA)は,過呼吸負荷時に脳波上で高振幅かつ律動的な徐波化を生じ,意識変容を呈する現象であり,年齢依存性の非てんかん性生理現象と考えられている.今回我々は,脳波ビデオ同時記録検査でHIHARSAAと診断した4歳女児例を経験したので報告する.症例は,啼泣後の過呼吸時に一過性の意識減損を認め,精査目的に当院を受診した.来院時,意識清明で神経学的異常所見を認めず,頭部MRI・MRAで脳動脈主幹部の狭窄などの有意な異常所見を認めなかった.脳波検査では,発作間欠期に異常を認めなかったが,過呼吸負荷時に律動的な3～3.5Hz全般性高振幅徐波が突発的に出現し,脳波異常が出現する間,意識が朦朧となり,口をもぐもぐさせ,手を動かし,そわそわと落ち着かない様子を認めた.発作症状は定型欠神発作との鑑別が困難であったが,発作時脳波が棘波を伴わない律動性高振幅徐波であったことからHIHARSAAと診断し,無投薬で経過観察とした.HIHARSAAは稀な現象であるが,定型欠神発作と類似しており,両者の鑑別には脳波ビデオ同時記録が有用と考えられる.(著者抄録)

Language：Japanese   Publisher：The Japanese Society of Child Neurology  

DOI： 10.11251/ojjscn.57.91

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Language：Japanese   Publisher：The Japanese Society of Child Neurology  

<p>  Hyperventilation-induced high-amplitude rhythmic slowing with altered awareness (HIHARSAA) is an age-dependent nonepileptic physiological phenomenon induced by hyperventilation, in which rhythmic high-amplitude slow-wave activity appears on electroencephalogram (EEG) and transiently alters the consciousness. Here, we report the case of a 4-year-old girl who was diagnosed with HIHARSAA by EEG video recording. She showed transient loss of consciousness during hyperventilation followed by crying and was subsequently admitted to our hospital for detailed examination. She was alert and had no neurological abnormalities. Head MRI and MRA showed no significant abnormal findings such as stenosis of the main cerebral arteries. Electroencephalography showed no abnormalities during the interictal period. During hyperventilation, a sudden occurrence of rhythmic high-amplitude 3-3.5 Hz slow-wave activity was observed on EEG, and she became dazed, started to mumble, moved her hands, and began to fidget, consistent with the appearance of EEG abnormalities. Although it was difficult to differentiate the seizures from typical absence seizures, the patient was diagnosed with HIHARSAA because the ictal EEG was a rhythmic high-amplitude slow wave without spikes. Hence, she was followed up without medication. Although HIHARSAA is a rare phenomenon, it should be differentiated from typical absence seizure by means of EEG video recording.</p>

DOI： 10.11251/ojjscn.57.45

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Language：English   Publisher：Dentomaxillofacial Radiology  

Objectives: The purpose of this study was to compare the image quality of ultra-high-resolution CT (U-HRCT) with that of conventional multidetector row CT (convCT) and demonstrate its usefulness in the dentomaxillofacial region. Methods: Phantoms were helically scanned with U-HRCT and convCT scanners using clinical protocols. In U-HRCT, phantoms were scanned in super-high-resolution (SHR) mode, and hybrid iterative reconstruction (HIR) and filtered-back projection (FBP) techniques were performed using a bone kernel (FC81). The FBP technique was performed using the same kernel as in convCT (reference). Two observers independently evaluated the 54 resulting images using a 5-point scale (5 = excellent diagnostic image quality; 4 = above average; 3 = average; 2 = subdiagnostic; and 1 = unacceptable). The system performance function (SPF) was calculated for a comprehensive evaluation of the image quality using the task transfer function and noise power spectrum. Statistical analysis using the Kruskal-Wallis test was performed to compare the image quality among the 3 protocols. Results: The observers assigned higher scores to images acquired with the SHRHIR and SHRFBP protocols than to those acquired with the reference (P < 0.0001 and P < 0.0001, respectively). The relative SPF value at 1.0 cycles/mm in SHRHIR and SHRFBP compared to the reference protocol were 151.5% and 45.6%, respectively. Conclusions: Through phantom experiments, this study demonstrated that U-HRCT can provide superior-quality images compared to conventional CT in the dentomaxillofacial region. The development of a better image reconstruction method is required to improve image quality and optimize the radiation dose.

DOI： 10.1093/dmfr/twae068

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Language：English   Publisher：Neuroradiology Journal  

Hypomyelination of early myelinating structures (HEMS) has recently been defined as a new genetic disorder accompanied by clinical and MR imaging characteristics. However, no studies have focused on diffusion-weighted imaging (DWI) findings of HEMS. We would like to propose a “sheep sign,” which is formed by DWI hyperintensity in the medial medullary lamina along with alternating high-low-high (HLH) intensity stripes in the posterior limb of the internal capsule. We believe the presence of the “sheep sign” on DWI in combination with alternating HLH intensity stripes may be a valuable tool for diagnosing HEMS.

DOI： 10.1177/19714009231224419

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

BACKGROUND AND OBJECTIVES: All 4 previous nationwide surveys of multiple sclerosis (MS) in Japan were conducted before the discovery of anti-aquaporin-4 (AQP4) antibodies; thus, neuromyelitis optica spectrum disorder (NMOSD) was included in MS, as optic-spinal MS. We aimed to clarify the epidemiologic features and trends of MS and NMOSD in Japan separately using a fifth nationwide survey. METHODS: The primary survey, in which a questionnaire was sent to 3,799 selected departments (including neurology/internal medicine, pediatrics, and ophthalmology), explored the estimated number and prevalence of patients with MS or NMOSD in 2017, and the secondary survey collected detailed characteristics of the patients using a second questionnaire. RESULTS: The response rates for the primary and secondary surveys were 60.1% and 53.9%, respectively. The estimated total number of patients with MS or NMOSD was 24,800, 2.5-fold higher than that in the fourth survey in 2003. The crude prevalence was 19.6 per 100,000 patients (14.2 for MS and 5.4 for NMOSD), compared with 7.7 per 100,000 patients in the fourth survey. Patients with MS showed milder disability (median Expanded Disability Status Scale [EDSS] score: 2.0 [interquartile range 1.0-4.5] vs 2.5 [1.0-6.0]), decreased secondary progression (8.5% vs 15.2%), and increased usage of disease-modifying drugs (63.7% vs 37.2%) compared with those with conventional MS in the fourth survey. The proportions of oligoclonal bands and Barkhof criteria fulfillment on MRI, which are features of classical MS, increased with advancing year of birth. Patients with NMOSD also showed less disability and shorter disease duration than patients with optic-spinal MS in the fourth survey (EDSS score: 3.5 [2.0-5.5] vs 3.8 [2.0-6.0]; disease duration: 8.0 [3.9-14.8] vs 10.0 [5.0-16.0]). Among patients with NMOSD, disability was exacerbated by a history of longitudinally extensive spinal cord lesions and anti-AQP4 antibody positivity, which both decreased with advancing year of birth. DISCUSSION: The prevalences of MS (particularly with classical features) and NMOSD have been increasing in Japan, suggesting the contribution of environmental factors. However, disabilities in patients with MS and NMOSD have been mitigated. Extensive usage of various disease-modifying drugs could be a factor contributing to this disability mitigation in MS.

DOI： 10.1212/wnl.0000000000209992

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Neurology and Neurosurgery  

Dural arteriovenous fistula (DAVF) represents a pathological group of intracranial shunts arising from the dural artery to venous sinus and veins. Childhood-onset DAVF is generally considered to be poor in prognosis, whereas only limited information is available for the onset and long-term outcomes. We herein report a Japanese girl with trisomy 21, large ventricular septal defects, and pulmonary vein stenosis, for which a transcatheter stent had been placed after birth. At age 6 years, she developed bacterial meningitis due to S. pneumoniae, leading to the diagnosis of venous sinus thrombosis and multiple intracranial shunts. Cerebral angiography identified multiple shunts arising from the middle meningeal arteries to the superior sagittal sinus and a concurrent reflux to cortical vein. Endovascular embolization successfully occluded the shunts without neurovascular complications over 24 months. This report first demonstrates the favorable outcome of DAVF in a pediatric patient with trisomy 21 after the catheter intervention. For children at a risk for intracranial thrombosis, preemptive neurovascular evaluation and transcatheter intervention provide a chance of early diagnosis of DAVF to improve their survival and neurologic outcome.

DOI： 10.1016/j.clineuro.2024.108540

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publisher：Asian Journal of Endoscopic Surgery  

DOI： 10.1111/ases.13364

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Microbiology Immunology and Infection  

BACKGROUND/PURPOSE: Recent large-scale epidemiological studies have revealed significant temporal associations between certain viral infections and the subsequent development of Kawasaki disease (KD). Despite these associations, definitive laboratory evidence linking acute or recent viral infections to KD cases remains elusive. The objective of this study is to employ a molecular epidemiological approach to investigate the temporal association between viral infections and the development of KD. METHODS: We analyzed 2460 patients who underwent the FilmArray® Respiratory Panel test between April 2020 and September 2021. RESULTS: Following the application of inclusion criteria, 2402 patients were categorized into KD (n = 148), respiratory tract infection (n = 1524), and control groups (n = 730). The KD group exhibited higher positive rates for respiratory syncytial virus (RSV), human rhinovirus/enterovirus (hRV/EV), parainfluenza virus (PIV) 3, and adenovirus (AdV) compared to the control group. Additionally, coinfections involving two or more viruses were significantly more prevalent in the KD group. Notably, RSV-positive, hRV/EV-positive, and PIV3-positive KD patients exhibited a one-month delay in peak occurrence compared to non-KD patients positive for corresponding viruses. In contrast, AdV-positive KD cases did not show a one-month delay in peak occurrence. Moreover, anti-RSV, anti-PIV3, and anti-AdV antibody-positive rates or antibody titers were higher in RSV-, PIV3-, and AdV-positive KD cases, respectively, compared to non-KD cases with the same viral infections. CONCLUSION: Recent infection with RSV, PIV3, or AdV, occasionally in conjunction with other viruses, may contribute to the pathogenesis of KD as infrequent complications.

DOI： 10.1016/j.jmii.2024.07.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

An autism‐associated gene Shank3 encodes multiple splicing isoforms, Shank3a‐f. We have recently reported that Shank3a/b‐knockout mice were more susceptible to kainic acid‐induced seizures than wild‐type mice at 4 weeks of age. Little is known, however, about how the N‐terminal and ankyrin repeat domains (NT‐Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry‐based proteomic search for proteins interacting with GFP‐tagged NT‐Ank. In this study, NT‐Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA‐binding (n = 102), spliceosome (n = 22), and ribosome‐associated molecules (n = 9) were significantly enriched. Among them, an X‐linked intellectual disability‐associated protein, Nono, was identified as a NT‐Ank‐binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b‐knockout mice aberrantly expressed splicing isoforms of autism‐associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA‐binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism‐associated genes after birth.

DOI： 10.1111/gtc.13142

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Language：Japanese   Publisher：慶應義塾大学出版会(株)  

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Language：English   Publisher：Elsevier B.V.  

症例は生後2ヵ月の乳児で、生後1ヵ月で筋力低下を認め、遺伝子スクリーニングでSMN1エクソン7のホモ接合性欠失およびSMN2コピー数2を有し、脊髄性筋萎縮症(SMA)I型と診断された。抗AAV9抗体が陽性であったため、ヌシネルセンやオナセムノゲンアベパルボベク(OA)は使用せず、代替として経口リスジプラムを導入した。抗体価は徐々に低下し、生後7ヵ月で1:25未満となったため、OA(1.1×10^14 vector genome/kg)を投与した。投与前日より経口プレドニゾロン1mg/kg/日を開始した。OA投与5日後にAST 100U/L、ALT 39U/Lと軽度の肝酵素上昇を認めたが自然軽快した。投与46日後にRSウイルス感染による呼吸困難が出現し、51日後には人工呼吸管理が必要となった。52日後に急性肝不全を発症し、AST 24297U/L、ALT 6128U/L、LDH 21659U/L、凝固異常を認めた。ヒドロコルチゾン7mg/kg静注とメチルプレドニゾロン4mg/kg/日で加療し、呼吸状態と肝機能は改善した。

Publisher：診断と治療社  

DOI： 10.34433/pp.0000001150

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Language：English   Publisher：Clinical Journal of Gastroenterology  

Multiple endocrine neoplasia type 2B is a rare autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, Marfan-like fatigue, a peculiar face with thickening of the lips, mucosal neuromas on the lips and tongue, and gastrointestinal phenomena. Most patients harbor pathological variants of the RET gene. Herein, we present the first case of a 14 year-old boy who experienced small intestinal volvulus along with a megacolon, and he was diagnosed with multiple endocrine neoplasia type 2B. The patient complained of constipation since he was 2 years old and slowly progressive abdominal distension at school age. At 14 years of age, he presented with remarkable megacolon mimicking Hirschsprung’s disease and complicated with small intestinal volvulus. The volvulus was successfully repaired, and the particularly dilated transverse colon was resected following a rectal biopsy. Histopathological evaluation of the resected transverse colon revealed to be compatible with ganglioneuromatosis. After emergency surgery, the patient was diagnosed with multiple endocrine neoplasia type 2B with medullary thyroid carcinoma, and a de novo variant of RET was confirmed. Gastroenterologists should consider it when treating patients with constipation, especially those with megacolon. Therefore, timely diagnosis may lead to appropriate treatment of medullary thyroid carcinoma and improve mortality.

DOI： 10.1007/s12328-024-01979-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient’s iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy.

DOI： 10.1038/s41598-024-68062-x

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Other Link： https://www.nature.com/articles/s41598-024-68062-x

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Experimental Immunology  

The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2-47 years, 12 males) and 22 controls (age 4-40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, P = 0.00731) and oxidative phosphorylation (hsa00190, P = 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.

DOI： 10.1093/cei/uxae048

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Dmm Disease Models and Mechanisms  

Pathogenic variants in ATP1A3, the α3 subunit of the Na+/K+-ATPase-encoding gene, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerating symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as EIF4G, PABPC1 and FMRP. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C-variant ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 and increased susceptibility to heat stress. In agreement with these findings, iPSCs from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient's iPSCs showed lower calcium influxes in responses to stimulation with ATP than controls. These data indicated that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes of patients with the p.R756C variant among a variety of ATP1A3-related disorders.

DOI： 10.1242/dmm.050574

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Publisher：Physical Review B  

Perovskites with Bi or Pb on the A site host a number of interesting and yet to be understood phenomena such as negative thermal expansion in BiNiO3. We employ hard x-ray photoemission spectroscopy of Ni 2p core level as well as valence band to probe the electronic structure of BiNiO3 and PbNiO3. The experimental results supported by theoretical calculations using dynamical mean-field theory reveal essentially identical electronic structure of the Ni-O subsystem typical of Ni2+ charge-transfer insulators. The two materials are distinguished by filling of the Bi(Pb)-O antibonding states in the vicinity of the Fermi level, which is responsible for the Bi disproportionation in BiNiO3 at ambient pressure and absence of similar behavior in PbNiO3. The present experiments provide evidence for this conclusion by revealing the presence/absence of Bi/Pb 6s states at the top of the valence band in the two materials.

DOI： 10.1103/PhysRevB.109.205131

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Language：English   Publisher：(一社)日本血液学会  

家族性血球貪食性リンパ組織球症(FHLH)に対する根治的造血細胞移植(HCT)を確立するため、九州の地域治療ネットワークにおける骨髄非破壊的造血幹細胞移植の治療成績を検討した。2011年から2022年までにフローサイトメトリースクリーニングにより診断されたFHLH患児13例(FHLH2;11例、FHLH3;2例)を対象とした。新規PRF1バリアントの1例はスクリーニングから漏れたが、FHLH2の全例が診断に至り、そのうち8例は生後3ヵ月と9ヵ月までにHCTを受けた。最も早いHCTは生後65日目に行われた。移植前の死亡例は診断時に肝不全であった新生児の3例であった。移植後の患児10例は無病状態を維持しており、そのうち7例には神経学的病変を認めなかった。最初のエトポシド点滴静注からHCTまでの期間は、中枢神経系疾患や出血のない患児の方が、それらの因子を有する患児よりも短かった。加えて、血縁関係のない患児9例中6例にPRF1 c.1090_1091delCTバリアントが認められた。

Language：English   Publisher：International Journal of Hematology  

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50–81] vs. 122 [89–209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

DOI： 10.1007/s12185-024-03721-3

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：English   Publisher：Stem Cell Research and Therapy  

Background: The detection rate of superficial non-ampullary duodenal epithelial tumors (SNADETs) has recently been increasing. Large tumors may contain malignant lesions and early therapeutic intervention is recommended. Endoscopic mucosal dissection (ESD) is considered a feasible treatment modality, however, the anatomical and physiological characteristics of the duodenum create a risk of postoperative perforation after ESD. Methods: To explore whether myoblast sheet transplantation could prevent delayed perforation after ESD, a first-in-human (FIH) clinical trial of laparoscopic autologous myoblast sheet transplantation after duodenal ESD was launched. Autologous myoblast sheets fabricated from muscle tissue obtained seven weeks before ESD were transplanted laparoscopically onto the serous side of the ESD. The primary endpoints were the onset of peritonitis due to delayed perforation within three days after surgery and all adverse events during the follow-up period. Results: Three patients with SNADETs ≥ 20 mm in size underwent transplantation of a myoblast sheet onto the serous side of the duodenum after ESD. In case 1, The patient’s postoperative course was uneventful. Endoscopy and abdominal computed tomography revealed no signs of delayed perforation. Despite incomplete mucosal closure in case 2, and multiple micro perforations during ESD in case 3, cell sheet transplantation could prevent the postoperative massive perforation after ESD, and endoscopy on day 49 after transplantation revealed no stenosis. Conclusions: This clinical trial showed the safety, efficacy, and procedural operability of this novel regenerative medicine approach involving transplanting an autologous myoblast sheet laparoscopically onto the serosa after ESD in cases with a high risk of delayed perforation. This result indicates the potential application of cell sheet medicine in treating various abdominal organs and conditions with minimal invasiveness in the future. Trial registration: jRCT, jRCT2073210094. Registered November 8 2021, https://jrct.niph.go.jp/latest-detail/jRCT2073210094.

DOI： 10.1186/s13287-024-03730-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular Genetics and Genomic Medicine  

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

DOI： 10.1002/mgg3.2427

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Language：English   Publisher：Pediatric Infectious Disease Journal  

Background: In Japan, the incidence of subacute sclerosing panencephalitis (SSPE) has reduced; however, the medical conditions and factors associated with disease progression remain unclear. Methods: A nationwide survey of SSPE was conducted using a questionnaire in 2022. We conducted a descriptive analysis of the patients with SSPE in 2022 and Cox proportional hazards analyses for disease progression. We compared the patients with SSPE with those in a 2007 survey. Results: A total of 37 surviving patients with SSPE were enrolled [median age: 32 years (range: 16-52 years)]. No new cases have been identified since 2017 in the survey. Jabbour stage IV was the most common stage (66.7%). The hazard ratios (95% confidence intervals) of male sex and age at the time of measles infection (years) were 2.56 (1.13-5.76) and 0.57 (0.34-0.93), respectively. Compared with those in 2007, the proportion of patients in hospitals decreased from 13.7% to 2.7%, whereas that of patients in nursing facilities increased from 17.6% to 29.7%. The proportions of patients prescribed inosine pranobex, interferon and ribavirin at the time of the survey decreased from 96.1% to 79.4%, 74.8% to 14.3% and 25.3% to 0%, respectively. The proportions of patients with gastrostomy, tracheostomy and ventilator use increased from 5.9% to 69.7%, 23.3% to 60.0% and 10.8% to 32.4%, respectively. Conclusions: Decreased measles cases in Japan reduced new SSPE cases. However, surviving patients in 2022 had advanced disease stages and needed medical care. Male sex and early measles infection were significantly associated with disease progression.

DOI： 10.1097/INF.0000000000004234

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Publisher：Molecular Psychiatry  

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) “OCD vs. healthy controls” (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) “unmedicated OCD vs. healthy controls” (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) “medicated OCD vs. unmedicated OCD” (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6–79.1 in adults; 35.9–63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

DOI： 10.1038/s41380-023-02392-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Blood and Cancer  

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144 days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/μL naïve T cells with balanced repertoire 1 month post transplant, and survived more than 12 months with home care. Twelve patients including the index cases received HCT at a median 106 days after birth (range: 70-195 days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p = .02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

DOI： 10.1002/pbc.30809

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Language：English   Publisher：International Journal of Molecular Sciences  

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

DOI： 10.3390/ijms25052820

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Language：English   Publisher：Annals of Gastroenterological Surgery  

Aim: The aim of this study was to verify the clinical feasibility of tele-proctoring using our ultra-low latency communication system with shared internet access. Methods: Connections between two multiple remote locations at various distances were established through the TELEPRO® tele-proctoring system. The server records the latency between the two locations for tele-proctoring using the annotations. Questionnaires were administered to the surgeons, assistants, and medical staff. Respondents rated the quickness and quality of communication in terms of latency and disturbances in the audio, video, and usefulness of the live telestrations with annotation. Results: Seven hospitals tele-proctored with Sapporo Medical University between January 2021 and September 2022. The median latency of annotation between the two locations ranged from 24.5 to 48.5 ms. No major technological problems occurred, such as streaming interruption, loss of video or audio, poor resolution. The video encoding time was 10 ms, and its decoding time was 0.8 ms. The total latency positively correlated with the distance between two locations (R = 0.55, p < 0.01). The quality of communication regarding latency, disturbance, and surgical education with intraoperative annotative instructions showed similar trends, with perfectly fine being the most common response. No significant differences in surgical quality, educational effect, or social impact were observed between the latency ≥30 and <30 ms groups for whether the size of latency affects surgical education. Conclusion: The feasibility of the tele-proctoring system is expected to be a sustainable approach to help education for young surgeons and surgical supports in rural areas, thereby reducing disparities in health care.

DOI： 10.1002/ags3.12750

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Language：English   Publisher：Pediatric Neurology  

Background: Area postrema syndrome (APS), a rare childhood condition, manifests as intractable nausea and hiccups. APS has high diagnostic significance in neuromyelitis optica syndrome spectrum disorders (NMOSD) and can be the initial presentation of other critical diseases, including brainstem glioma. Methods: We described two representative cases of unrelated Japanese patients with APS. An etiologic evaluation, including a detailed intracranial neuroradiological examination and autoantibodies assessment, was performed. We also reviewed the literature focusing on the prognosis of pediatric APS symptoms. Results: A 14-year-old girl with aquaporin-4 antibody-positive NMOSD showed a good prognosis with immunotherapy, whereas another nine-year-old girl with irresectable medullary low-grade glioma had persistent symptoms for more than 10 years. All reported children aged >12 years were diagnosed with NMOSD, and patients aged <13 years showed heterogeneous etiologies. Conclusions: Distinctive time courses and neuroimaging features were key clinical findings for the diagnostic and therapeutic processes in these patients. This literature review highlights the wide spectrum and prognosis of pediatric-onset APS.

DOI： 10.1016/j.pediatrneurol.2023.12.010

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Language：English   Publisher：Journal of the Neurological Sciences  

Objective: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sometimes triggers acute encephalopathy as a serious neurological complication in children. We previously reported the clinico-radiological findings of SARS-CoV-2-associated encephalopathy. The advent of the SARS-CoV-2 omicron variant led to a marked increase in pediatric patients with coronavirus disease 2019 (COVID-19); however, epidemiological changes with acute encephalopathy according to the emergence of SARS-CoV-2 have not yet been documented. Therefore, the present study investigated epidemiological differences in SARS-CoV-2-associated encephalopathy during the BA.1/BA.2 and BA.5 predominant periods and also between SARS-CoV-2-associated and non-SARS-CoV-2-associated encephalopathy. Methods: We conducted a nationwide survey of SARS-CoV-2-associated encephalopathy in Japanese children between June and November 2022. We compared the present results during the BA.5 predominant period and previous findings during the BA.1/BA.2 predominant period. We also compared the clinico-radiological syndromes of encephalopathy between SARS-CoV-2-associated and non-SARS-CoV-2-associated encephalopathy. Results: Although many patients with SARS-CoV-2-associated encephalopathy in the BA.5 predominant period had seizures as their initial symptoms, no significant differences were observed in the clinical features. Patients with SARS-CoV-2-associated encephalopathy had worse outcomes than those with non-SARS-CoV-2-associated encephalopathy (p-value = 0.003). Among 103 patients with SARS-CoV-2-associated encephalopathy, 14 (13.6%) had severe types of acute encephalopathy, namely, encephalopathy with acute fulminant cerebral edema (AFCE) and hemorrhagic shock and encephalopathy syndrome (HSES). Also, 28 (27.2%) patients with SARS-CoV-2-associated encephalopathy had poor outcome: severe neurological sequelae or death. Ninety-five patients (92.2%) were not vaccinated against SARS-CoV-2. Conclusions: In SARS-CoV-2-associated encephalopathy, high percentages of AFCE and HSES can result in poor outcomes.

DOI： 10.1016/j.jns.2024.122867

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Publisher：Journal of Membrane Science  

Erythrocyte-mimetic perfluorooctylbromide (PFOB)/polydimethylsiloxane (PDMS) thermoplastic elastomer core-shell microparticles were fabricated (for the first time) via Shirasu porous glass membrane emulsification (SPG ME) with evaporation-induced phase separation (EIPS). The resulting micro-sized core-shell particles showed a spontaneously concave shape without a subsequent deformation process such as organic solvent immersion or temperature variations. It replicated the healthy human erythrocyte morphology. In addition, their sizes and morphologies could be controlled by varying the pore size and dispersed-phase composition of the SPG membrane. The diameters of the precisely controlled particles were similar to those of human blood cells (9.6 ± 1.9 μm). The microcompression test revealed a high deformability of the particles owing to both softness of the PDMS-TPE shell and their core-shell structure. The PDMS-based materials displayed a high oxygen permeability, and PFOB displayed a high oxygen solubility. Finally, the oxygen transportation function was evaluated using oxygen tension-responsive HeLa cells (hr-HeLa) under hypoxic conditions (5% O<inf>2</inf>). This demonstrated the effectiveness of PFOB/PDMS-TPE microparticles as artificial oxygen carriers in various biomedical applications such as tissue engineering.

DOI： 10.1016/j.memsci.2023.122119

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC Neurology  

BACKGROUND: The systemic manifestations of coronavirus disease 2019 (COVID-19) include hyperinflammatory reactions in various organs. Recent studies showed evidence for the frequent involvement of central nervous system in affected patients; however, little is known about clinical features of cerebrovascular diseases in childhood-onset COVID-19. CASE PRESENTATION: A 10-year-old boy recovered from SARS-CoV-2 infection without complication. On 14 days after infection, he presented with loss of consciousness. A head computed tomography detected a ruptured cerebral aneurysm at the left posterior cerebral artery accompanying subarachnoid hemorrhage (SAH). Immediate surgical intervention did not rescue the patient, resulting in the demise 7 days after admission. Serological and genetic tests excluded the diagnosis of vasculitis and connective tissue disorders. Retrospective analysis showed markedly higher levels of interleukin (IL)-1β, IL-6 and IL-8 in the cerebrospinal fluid than the serum sample concurrently obtained. A review of literature indicated that adult patients with COVID-19 have a risk for the later development of SAH during the convalescent phase of COVID-19. CONCLUSIONS: SAH is a severe complication of COVID-19 in children and adults who have asymptomatic cerebrovascular aneurysms. The markedly high levels of cytokines detected in the cerebrospinal fluid suggested that intracranial hyperinflammatory condition might be one of the possible mechanisms involved in the rupture of a preexisting cerebrovascular aneurysms.

DOI： 10.1186/s12883-023-03493-z

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Language：English   Publisher：Journal of Clinical Investigation  

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

DOI： 10.1172/JCI171235

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01232&link_issn=&doc_id=20231229160001&doc_link_id=10.11251%2Fojjscn.56.5&url=https%3A%2F%2Fdoi.org%2F10.11251%2Fojjscn.56.5&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Translational Immunology  

OBJECTIVES: The objectives of this study were to investigate the pathophysiology of Kawasaki disease (KD) from immunological and oxidative stress perspectives, and to identify real-time biomarkers linked to innate immunity and oxidative stress in KD. METHODS: We prospectively enrolled 85 patients with KD and 135 patients with diverse conditions including immune, infectious and non-infectious diseases for this investigation. Flow cytometry was used to analyse the surface expression of CD14, CD38 and CD62L on monocytes, along with a quantitative assessment of CD14 down-modulation. Additionally, oxidative stress levels were evaluated using derivatives of reactive oxygen metabolites (d-ROMs) and antioxidant capacity measured by a free radical elective evaluator system. RESULTS: During the acute phase of KD, we observed a prominent CD14 down-modulation on monocytes, reflecting the indirect detection of circulating innate immune molecular patterns. Moreover, patients with KD showed a significantly higher CD14 down-modulation compared with infectious and non-infectious disease controls. Notably, the surface expression of CD14 on monocytes was restored concurrently with responses to intravenous immunoglobulin and infliximab treatment in KD. Furthermore, d-ROM levels in patients with KD were significantly elevated compared with patients with infectious and non-infectious diseases. Following intravenous immunoglobulin treatment, oxidative stress levels decreased in patients with KD. CONCLUSION: Monitoring CD14 down-modulation on monocytes in real-time is a valuable strategy for assessing treatment response, distinguishing KD relapse from concomitant infections and selecting second-line therapy after IVIG treatment in KD patients. The interplay between inflammation and oxidative stress likely plays a crucial role in the development of KD.

DOI： 10.1002/cti2.1482

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Language：Japanese   Publisher：The Japanese Society of Child Neurology  

<p>  Recent progress in genetic analysis and therapeutics provide patients and families with a hope for the cure of intractable diseases. The current age also enforces pediatricians to think over the complex and diverse decision-making processes and therapeutic options for each patient. Presumably, this situation will become more complex within the range of legal and ethical consensus for therapeutic options that pediatricians must consider as advocates for ill children. We cannot simplify or streamline the process for how they support the interests of children and what they should protect. When standing at the critical point of decision-making for a life-threatening condition, pediatricians need to develop agreement with their patients and families through persistent discussions without setting up a goal for agreement among them. Thus, translational research in pediatrics may represent the search for essence deeply embedded in bioethics, which may possibly lead us to untangling the conundrums in clinical practice.</p>

DOI： 10.11251/ojjscn.56.5

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DOI： 10.1080/00219592.2023.2204899

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Medical Genetics  

INTRODUCTION: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoproteins. Neurocognitive dysfunctions have been documented in patients with CDDG1; however, deteriorating phenotypes of affected individuals remain elusive. CASE PRESENTATION: A Japanese boy with delayed psychomotor development showed ataxic movements from age 5 years and myoclonic seizures from age 12 years. Appetite loss, motor and cognitive decline became evident at age 12 years. Electrophysiological studies identified paroxysmal discharges on myoclonic seizure and a giant somatosensory evoked potential. Perampanel was effective for controlling myoclonic seizures. Exome sequencing revealed that the patient carried compound heterozygous variants in NGLY1, NM_018297.4: c.857G > A and c.-17_12del, which were inherited from mother and father, respectively. A literature review confirmed that myoclonic seizures were observed in 28.5% of patients with epilepsy. No other patients had progressive myoclonic epilepsy or cognitive decline in association with loss-of-function variations in NGLY1. CONCLUSION: Our data provides evidence that a group of patients with CDDG1 manifest slowly progressive myoclonic epilepsy and cognitive decline during the long-term clinical course.

DOI： 10.1016/j.ejmg.2023.104895

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Language：English   Publisher：Biomaterials Advances  

Subcutaneous transplantation aims to enhance the growth and functionality of transplanted cells for therapeutic outcomes in tissue engineering. However, the limited subcutaneous vascular network poses a challenge. Conventional methods involve co-transplantation with endothelial cells or angiogenic scaffold implantation, but they have drawbacks like tissue inflammation, compromised endothelial cell functionality, and the risk of repeated scaffold transplantation. Effective techniques are needed to overcome these challenges. This study explores the potential of G/O-NGD, a gel-in-oil nanogel dispersion, as a transdermal carrier of proliferative factors to promote angiogenesis in subcutaneous graft beds before cell transplantation. We observed robust subcutaneous angiogenesis by delivering varying amounts of bFGF using the G/O-NGD emulsion. Quantitative analysis of several parameters confirmed the efficacy of this method for building a subcutaneous vascular network. G/O-NGD is a biodegradable material that facilitates localized transdermal delivery of bFGF while maintaining its activity. The findings of this study have significant implications in both medical and industrial fields.

DOI： 10.1016/j.bioadv.2023.213628

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DOI： 10.1016/j.isci.2023.107900

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FASEB Bioadvances  

<jats:title>Abstract</jats:title><jats:p>Mutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca<jats:sup>2+</jats:sup> permeable nonselective cation channel, cause TRPV4‐related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4‐mediated Ca<jats:sup>2+</jats:sup> deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain‐of‐function TRPV4 mutation, c.1855C &gt; T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca<jats:sup>2+</jats:sup> augmented AKT‐mediated α‐synuclein (α‐syn) induction, resulting in mitochondrial Ca<jats:sup>2+</jats:sup> accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α‐syn knockdown, normalizes the mitochondrial Ca<jats:sup>2+</jats:sup> levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca<jats:sup>2+</jats:sup>/AKT‐induced α‐syn in mitochondrial Ca<jats:sup>2+</jats:sup> accumulation. Folic acid was effective in normalizing mitochondrial Ca<jats:sup>2+</jats:sup> levels via the transcriptional repression of α‐syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4‐related disorders and related therapeutic strategies.</jats:p>

DOI： 10.1096/fba.2023-00057

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Language：English   Publisher：Molecular Psychiatry  

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen’s d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen’s d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

DOI： 10.1038/s41380-023-02077-0

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Language：English   Publisher：Molecular Psychiatry  

Correction to: Molecular Psychiatry, published online 2 May 2023 In this article Honami Arai, Irene Bollettini, Rosa Calvo Escalona, Ana Coelho, Federica Colombo, Leila Darwich, Martine Fontaine, Toshikazu Ikuta, Jonathan C. Ipser, Asier Juaneda-Seguí, Hitomi Kitagawa, Gerd Kvale, Mafalda Machado-Sousa, Astrid Morer, Takashi Nakamae, Jin Narumoto, Joseph O’Neill, Sho Okawa, Eva Real, Veit Roessner, Joao R. Sato, Cinto Segalàs, Roseli G. Shavitt, Dick J. Veltman, Kei Yamada were missing from the author list indexed under the ENIGMA-OCD Working Group. Additionally, there was an error regarding Tokiko Yoshida’s name, where the first name and last name were written in the wrong order. The original article has been corrected.

DOI： 10.1038/s41380-023-02211-y

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Language：English   Publisher：Biochemical and Biophysical Research Communications  

Cancer incidence is increasing annually, and the invasion of cancer into the stroma significantly affects cancer metastasis. The stroma primarily comprises an abundant extracellular matrix (ECM) that interacts closely with cancer cells. Cancer cells use the ECM as a scaffold to migrate from a tumor via mechanical actions such as pushing and pulling the fibers. The purpose of this study is to clarify the effects of elastic modulus differences on cell migration behavior based on the same ECM fiber structure. We observe temporal changes in the morphology of cancer cells and the surrounding ECM to elucidate the relationship between changes in the mechanical properties of the ECM and the invasive behavior of cancer cells. We analyze the shape and migration distance of cancer cells and the displacement field of the ECM by varying the fiber elastic modulus but fixing the ECM density. Increasing the elastic modulus results in a protruding cell shape, which indicates the maximum displacement of the ECM around the cell. Additionally, differences in cell migration speed and dispersion based on the elastic modulus are observed. The behavior of cells with increasing elasticity is classified via cluster analysis. Owing to the chemical cross-linking of the fibers, some cells cannot deform the surrounding tissue. This is attributable to the gel state of the ECM and microscopic fluctuations in the fiber density around the cells. We successfully assessed the effect of changes in the ECM modulus on cell mortality and morphology to reveal the mechanism of cancer invasion.

DOI： 10.1016/j.bbrc.2023.06.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Angiogenic factors associated with Moyamoya disease (MMD) are overexpressed in M2 polarized microglia in ischemic stroke, suggesting that microglia may be involved in the pathophysiology of MMD; however, existing approaches are not applicable to explore this hypothesis. Herein we applied blood induced microglial-like (iMG) cells. We recruited 25 adult patients with MMD and 24 healthy volunteers. Patients with MMD were subdivided into progressive (N = 7) or stable (N = 18) group whether novel symptoms or radiographic advancement of Suzuki stage within 1 year was observed or not. We produced 3 types of iMG cells; resting, M1-, and M2-induced cells from monocytes, then RNA sequencing followed by GO and KEGG pathway enrichment analysis and qPCR assay were performed. RNA sequencing of M2-induced iMG cells revealed that 600 genes were significantly upregulated (338) or downregulated (262) in patients with MMD. Inflammation and immune-related factors and angiogenesis-related factors were specifically associated with MMD in GO analysis. qPCR for MMP9, VEGFA, and TGFB1 expression validated these findings. This study is the first to demonstrate that M2 microglia may be involved in the angiogenic process of MMD. The iMG technique provides a promising approach to explore the bioactivity of microglia in cerebrovascular diseases.

DOI： 10.1038/s41598-023-41456-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Biochemical and Biophysical Research Communications  

Melatonin entrainment of suprachiasmatic nucleus-regulating circadian rhythms is mediated by MT1 and MT2 receptors. Melatonin also has neuroprotective and mitochondrial activating effects, suggesting it may affect neurodevelopment. We studied melatonin's pharmacological effects on autism spectrum disorder (ASD) neuropathology. Deciduous tooth-derived stem cells from children with ASD were used to model neurodevelopmental defects and differentiated into dopaminergic neurons (ASD-DNs) with or without melatonin. Without melatonin, ASD-DNs had reduced neurite outgrowth, mitochondrial dysfunction, lower mitochondrial Ca²⁺ levels, and Ca²⁺ accumulation in the endoplasmic reticulum (ER) compared to control DNs from typically developing children-derived stem cells. Melatonin enhanced IP3-dependent Ca²⁺ release from ER to mitochondria, improving mitochondrial function and neurite outgrowth in ASD-DNs. Luzindole, an MT1/MT2 antagonist, blocked these effects. Thus, melatonin supplementation may improve dopaminergic system development in ASD by modulating mitochondrial Ca²⁺ homeostasis via MT1/MT2 receptors.

DOI： 10.1016/j.bbrc.2023.09.050

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Early Human Development  

INTRODUCTION: To establish actionable neonatal screening during the first month of life, we investigated critical diseases in seemingly healthy newborns discharged from birth hospitals. METHODS: This retrospective study enrolled previously healthy full-term infants who visited our hospital, a tertiary hospital in Japan, from home between 5 and 28 days after birth from 2009 to 2018. Infants with known perinatal or congenital diseases, positive newborn screening results, or accidental injuries were excluded. Data were collected from electronic medical records, including principal diagnosis, clinical details, and prognosis at 18 months of age. RESULTS: Ninety-seven (58 %) of 168 eligible neonates were admitted to the hospital, and 71 (42 %) were not. The median admission rate in patients with disease onset at ≤14 days after birth (80 %) was significantly higher than that in patients with disease onset at ≥15 days (42 %). Among 45 patients who received intensive medical care, 5 died and 10 developed neurodevelopmental sequelae. Four of 5 patients died by 100 days. Among 25 diseases treated in intensive care unit, 17 (68 %) diseases had a prevalence of <1 per 2000 live births. The commonly used diagnostic methods were imaging (n = 58, 35 %) and physical examination (n = 34, 20 %). CONCLUSION: Critical diseases due to rare and heterogeneous causes in ostensibly healthy newborns occurred predominantly in the first two weeks of life. Optimal newborn screening and health check-up protocols may benefit from the wide spectrum of life-threatening diseases occurring in home after birth.

DOI： 10.1016/j.earlhumdev.2023.105869

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Language：English   Publisher：Microscopy  

Soft magnetic materials have low coercive fields and high permeability. Recently, nanocrystalline alloys obtained using annealing amorphous alloys have attracted much interest since nanocrystalline alloys with small grain sizes of tens of nanometers exhibit low coercive fields comparable to that of amorphous alloys. Since nanocrystalline soft magnetic materials attain remarkable soft magnetic properties by controlling the grain size, the crystal grains' microstructure has a substantial influence on the soft magnetic properties. In this research, we examined the magnetic properties of Fe-Si-B-P-Cu nanocrystalline soft magnetic alloys obtained by annealing amorphous alloys. During crystallization, the observation findings reveal the correlation between the generated microstructures and soft magnetic properties.

DOI： 10.1093/jmicro/dfac042

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Language：English   Publisher：Radiography  

Introduction: No study has investigated scan parameters in head and neck dual layer dual-energy computed tomography (DL-DECT). This study aimed to select the appropriate scan parameters in head and neck imaging by evaluating the scan parameter effects on the accuracies of CT numbers and conduct iodine quantification in DL-DECT. Methods: A multi-energy phantom was scanned using a dual layer CT (DLCT) scanner. Reference materials of iodine, blood, calcium, and adipose were used. A helical scan was performed by using reference and several protocols. Iodine density and virtual monochromatic images (VMIs) at the energy of 50, 70, and 100 keV were reconstructed. The iodine concentrations and CT numbers in each protocol were measured. Moreover, the absolute percentage errors (APEs) of iodine quantifications and CT numbers (reference vs. each protocol) were compared. Equivalence was observed when APEs between reference and each protocol was within 5%. Statistical analysis was performed using appropriate software. Results: The APEs between the high-tube-voltage and reference protocol were 23.7, 14.0, 8.8, and 8.1% for iodine reference materials with concentrations equal to 2, 5, 10, and 15 mg/ml, respectively. At 50 keV, APEs between the high-tube-voltage and reference protocols were greater than 5% except for calcium and adipose. At 100 keV, APEs between the high-tube-voltage and reference protocols were greater than 5% except for blood and calcium. Conclusions: The high-tube-voltage protocol improved the accuracies of the measurement for iodine quantification and CT numbers. Additionally, the scanning parameters except for tube voltage had no effect on accuracies of iodine quantitation and CT numbers in the DLCT scanner. Implications for practice: The use of the high-tube-voltage protocol will be recommended for more accurate material decomposition in head and neck DL-DECT.

DOI： 10.1016/j.radi.2023.06.003

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Language：English   Publisher：エルゼビア・ジャパン(株)  

マウスの生後早期の視床機能の発達におけるShank3a/bアイソフォームの役割について検討した。WTマウスとShank3a/bノックアウトを使用した。評価項目は脳の各領域における定量PCR、カイニン酸治療、免疫蛍光染色、ウェスタンブロット法などとした。その結果、マウスShank3スプライシングアイソフォームShank3a/bは視床核で特異的に発現し、生後2～4週間でピークに達することが示された。また、Shank3a/bノックアウトマウスでは視床核のパルブアルブミンが低かった。一貫して、Shank3a/bノックアウトマウスは、カイニン酸処理後、WTマウスと比較して全般発作を起こしやすいことが示された。以上から、Shank3a/bのNT-Ankドメインは、マウス生後早期において、視床皮質ニューロンを過剰興奮から守る分子経路を制御していることが示された。

Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publisher：Frontiers in Plant Science  

Climate change due to global warming is now affecting agricultural production worldwide. In rice, one of the most important crops, water limitation due to irregular rainfall in rainfed lowlands during crop growth limits yield. Dry direct-sowing has been proposed as a water-efficient approach to cope with water stress during rice growth, but poor seedling establishment due to drought during germination and emergence is a problem. Here, we germinated indica rice cultivars Rc348 (drought tolerant) and Rc10 (drought sensitive) under osmotic stress induced by PEG to elucidate mechanisms of germination under drought. Rc348 had higher germination rate and germination index under severe osmotic stress of −1.5 MPa, above those of Rc10. Rc348 showed up-regulated GA biosynthesis, down-regulated ABA catabolism, and up-regulated α-amylase gene expression in imbibed seeds under PEG treatment compared to that of Rc10. During germination, reactive oxygen species (ROS) play important roles in antagonism between gibberellic acid (GA) and abscisic acid (ABA). Embryo of Rc348 treated with PEG had significantly greater expression of NADPH oxidase genes and higher endogenous ROS levels, together with significantly increased endogenous GA<inf>1</inf>, GA<inf>4</inf> and ABA contents compared to that of Rc10. In aleurone layers treated with exogenous GA, expression of α-amylase genes was higher in Rc348 than in Rc10, and expression of NADPH oxidase genes was enhanced with significantly higher ROS content in Rc348, suggesting higher sensitivity of GA to ROS production and starch degradation in aleurone cells of Rc348. These results suggest that the osmotic stress tolerance of Rc348 is due to enhancement of ROS production, GA biosynthesis, and GA sensitivity, resulting in a higher germination rate under osmotic stress.

DOI： 10.3389/fpls.2023.1186960

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DOI： 10.6009/jjrt.2023-1289

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Blood and Cancer  

DOI： 10.1002/pbc.30047

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Language：Japanese   Publisher：(一社)日本小児神経外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Human Genetics  

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

DOI： 10.1038/s41431-023-01335-7

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Language：Japanese   Publisher：(一社)長野県理学療法士会  

外来心臓リハビリテーションで心肺運動負荷試験(CPX)と身体機能評価を行った心疾患患者40例(平均年齢61.2±11.4歳)を対象に、5回立ち上がり検査(5STS)と運動耐容能の関連性を明確にし、運動耐容能評価としての5STSの有用性について検討した。CPXから得られた最高酸素摂取量(Peak VO2)とPeak METs、身体機能評価として膝伸展筋力、握力、片脚立位時間、5STS、10m歩行の最大および快適速度を調査し、Peak VO2と各指標との相関を算出した。その結果、Peak VO2と有意な相関を認めた身体機能評価項目は年齢、5STS、10m最大歩行速度と片脚立位時間であった。運動耐容能を推定する上で最も優れた身体機能評価項目は5STSであり、5METs以上の運動耐容能を有する5STSのカットオフ値は7.28秒(感度80.9%、特異度78.9%)であった。

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Language：English   Publisher：Frontiers in Neuroscience  

Background and objectives: To clarify whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection cause acute encephalopathy in children and which are the most common syndromes that cause them and what are the outcomes. Methods: A nationwide web-based survey among all members of the Japanese Society of Child Neurology to identify pediatric patients aged < 18 years who developed acute encephalopathy in Japan between 1 January 2020 and 31 May 2022 associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction or antigen tests using pharyngeal swabs. Acute encephalopathy was defined as acute onset of impaired consciousness lasting > 24 h or an altered mental state; neurological symptoms arising within 2 weeks of onset of COVID-19 or multisystem inflammatory syndrome in children (MIS-C)/pediatric inflammatory multisystem syndrome (PIMS); evidence of SARS-CoV-2 infection; and reasonable exclusion of other diseases. Patients were divided into the known clinico-radiological acute encephalopathy syndrome group and unexplained or unclassifiable acute encephalopathy group. Outcomes were assessed by pediatric cerebral performance category (PCPC) score at hospital discharge. Results: Of the 3,802 society members, 217 representing institutions responded, and 39 patients with suspected acute encephalopathy were reported, of which 31 met inclusion criteria. Of these patients, 14 were diagnosed with known clinico-radiological acute encephalopathy syndromes, with acute encephalopathy with biphasic seizures and late reduced diffusion (five patients) being the most common. Five developed acute encephalopathy associated with MIS-C/PIMS. Among 31 patients, 9 (29.0%) had severe sequelae or died (PCPC ≥ 4). Two of three patients with encephalopathy with acute fulminant cerebral edema and two with hemorrhagic shock and encephalopathy syndrome died. The PCPC scores were higher in the known clinico-radiological acute encephalopathy syndrome group than in the unexplained or unclassifiable acute encephalopathy group (P < 0.01). Discussion: Acute encephalopathy related to SARS-CoV-2 infection was demonstrated to be more severe than that caused by other viruses in Japan. Acute encephalopathy syndromes characterized by specific neuroradiological findings was associated with poor clinical outcomes.

DOI： 10.3389/fnins.2023.1085082

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Publisher：Progress of Theoretical and Experimental Physics  

KAGRA, the underground and cryogenic gravitational-wave detector, was operated for its solo observation from February 25 to March 10, 2020, and its first joint observation with the GEO 600 detector from April 7 to April 21, 2020 (O3GK). This study presents an overview of the input optics systems of the KAGRA detector, which consist of various optical systems, such as a laser source, its intensity and frequency stabilization systems, modulators, a Faraday isolator, mode-matching telescopes, and a high-power beam dump. These optics were successfully delivered to the KAGRA interferometer and operated stably during the observations. The laser frequency noise was observed to limit the detector sensitivity above a few kilohertz, whereas the laser intensity did not significantly limit the detector sensitivity.

DOI： 10.1093/ptep/ptac166

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatrics International  

DOI： 10.1111/ped.15503

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

症例は9ヵ月齢男児。Down症候群とFallot四徴症に罹患していた。右室流出路閉塞は比較的軽症であり、出生以降、チアノーゼまたは無酸素発作のエピソードはみられていなかった。9ヵ月齢になってから点頭発作を伴う強直性攣縮がみられ始めた。脳波検査でヒプスアリスミアが示されたことからWest症候群と確定診断され、副腎皮質刺激ホルモン(ACTH)治療を行うため当院へ入院となった。入院6日目にACTH治療を開始したが、同治療6日目の哺乳後に徐脈(心拍数60bpm)とチアノーゼを発症した。心エコー法では右室流出路閉塞の悪化と肺血流量の減少が示された。無酸素発作を疑い、体位をchest-knee positionとしたところ、容量輸液を行わずとも約30分後に発作は回復した。以降も徐脈がみられ無酸素発作を間欠的に4回発症したことからACTH治療は中止した。その中止から2日後の心拍数は110bpmまで回復し、無酸素発作はもはやみられなくなっていた。ACTH中止後はトピラマートを使用した。以降も無酸素発作または攣縮発作はみられず退院した。14ヵ月齢時に心内修復術が施行され、術後経過に問題はみられず、6ヵ月間の経過観察中にもてんかん性攣縮は再発しなかった。

Language：English   Publisher：Journal of Affective Disorders  

Background: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. Methods: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6–65) was divided into six successive 6–10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. Results: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6–13 and adults aged 50–65 with OCD taking SRIs (Cohen's d = −0.24 to −0.74). Volumes of putamen, pallidum (d = 0.18–0.40), and ventricles (d = 0.31–0.66) were greater in patients aged 20–29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = −0.27 to −1.31). Conclusions: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20–29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

DOI： 10.1016/j.jad.2022.08.084

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC Neurology  

BACKGROUND: Intracranial aneurysms (ICA) rarely occur in children under 3 years of age. Little is known for neuroimaging parameters that predict survival and clinical outcomes of patients with ICA in early childhood. CASE PRESENTATION: A 2-year-old girl showed intracranial hemorrhage due to a rupture of aneurysm at the middle cerebral artery. Quantitative measurements of ischemic damages on the head computed tomography (CT) marked an extremely low score of 2 points with modified Alberta Stroke Program Early CT Score (mASPECTS). She died 15 days after admission. In publications from 2021 to 2022, we found 21 children who were under 3 years of age at onset of ICA. None of them died, but two of three patients who had mASPECTS scores 0-8 showed developmental delay and/or epilepsy as neurological complications. CONCLUSION: Early CT findings are applicable for predicting survival and neurological outcomes of young children with intracranial hemorrhage.

DOI： 10.1186/s12883-022-03022-4

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Publisher：BMC Bioinformatics  

Background: Kinetic modeling is a powerful tool for understanding the dynamic behavior of biochemical systems. For kinetic modeling, determination of a number of kinetic parameters, such as the Michaelis constant (K<inf>m</inf>), is necessary, and global optimization algorithms have long been used for parameter estimation. However, the conventional global optimization approach has three problems: (i) It is computationally demanding. (ii) It often yields unrealistic parameter values because it simply seeks a better model fitting to experimentally observed behaviors. (iii) It has difficulty in identifying a unique solution because multiple parameter sets can allow a kinetic model to fit experimental data equally well (the non-identifiability problem). Results: To solve these problems, we propose the Machine Learning-Aided Global Optimization (MLAGO) method for K<inf>m</inf> estimation of kinetic modeling. First, we use a machine learning-based K<inf>m</inf> predictor based only on three factors: EC number, KEGG Compound ID, and Organism ID, then conduct a constrained global optimization-based parameter estimation by using the machine learning-predicted K<inf>m</inf> values as the reference values. The machine learning model achieved relatively good prediction scores: RMSE = 0.795 and R² = 0.536, making the subsequent global optimization easy and practical. The MLAGO approach reduced the error between simulation and experimental data while keeping K<inf>m</inf> values close to the machine learning-predicted values. As a result, the MLAGO approach successfully estimated K<inf>m</inf> values with less computational cost than the conventional method. Moreover, the MLAGO approach uniquely estimated K<inf>m</inf> values, which were close to the measured values. Conclusions: MLAGO overcomes the major problems in parameter estimation, accelerates kinetic modeling, and thus ultimately leads to better understanding of complex cellular systems. The web application for our machine learning-based K<inf>m</inf> predictor is accessible at https://sites.google.com/view/kazuhiro-maeda/software-tools-web-apps, which helps modelers perform MLAGO on their own parameter estimation tasks.

DOI： 10.1186/s12859-022-05009-x

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Language：English   Publisher：Genetics in Medicine  

Purpose: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. Methods: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. Results: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA–S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. Conclusion: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

DOI： 10.1016/j.gim.2022.08.007

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Language：English   Publisher：Plant Molecular Biology  

Key message: Alterations in DNA methylation levels of ROS, GA and ABA related gene promoters cause transcriptional changes upon imbibition to induce seed germination in barley seeds exposed to heat stress during grain filling. Abstract: Environmental changes, especially changes in temperature, during seed development affect germination in several plant species. We have previously shown that heat stress during rice grain filling alters DNA methylation, an epigenetic mark important for gene silencing, regulates transcript levels of phytohormone metabolism genes, and delays seed germination. However, whether this phenomenon is present in other plant species remained to be elucidated. In this study, we compared seeds germination of barley (Hordeum vulgare L.) plants grown at 15 °C (control) or 25 °C (heat stress) during grain filling. Heat stress during grain filling significantly promoted seed germination in comparison with the control. The phytohormone gibberellic acid (GA) and reactive oxygen species produced by NADPH oxidases promote seed germination, whereas phytohormone abscisic acid (ABA) suppresses seed germination. We found that in heat-stressed seeds, genes related to ABA biosynthesis (HvNCED1 and 2) were significantly suppressed, whereas genes related to ABA catabolism (HvABA8’OH) and GA biosynthesis (HvHA20ox, HvGA3ox), and NADPH oxidase (HvRboh) genes were significantly upregulated after imbibition. Using MeDIP-qPCR, we showed that the promoters of HvNCED were hyper-methylated, and those of HvABA8’OH1, HvABA8’OH3, HvGA3ox2, and HvRbohF2 were hypo-methylated in heat treated seeds. Taken together, our data suggest that heat stress during grain filling affects DNA methylation of germination-related genes and promotes seed germination in barley.

DOI： 10.1007/s11103-022-01278-5

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Publisher：医歯薬出版  

DOI： 10.32118/ayu28303217

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：English   Publisher：Oral Radiology  

Objectives: This study aimed to investigate the impact of a deep learning-based reconstruction (DLR) technique on image quality and reduction of radiation exposure, and to propose a low-dose multidetector-row computed tomography (MDCT) scan protocol for preoperative imaging for dental implant surgery. Methods: The PB-1 phantom and a Catphan phantom 600 were scanned using volumetric scanning with a 320-row MDCT scanner. All scans were performed with a tube voltage of 120 kV, and the tube current varied from 120 to 60 to 40 to 30 mA. Images of the mandible were reconstructed using DLR. Additionally, images acquired with the 120-mA protocol were reconstructed using filtered back projection as a reference. Two observers independently graded the image quality of the mandible images using a 4-point scale (4, superior to reference; 1, unacceptable). The system performance function (SPF) was calculated to comprehensively evaluate image quality. The Wilcoxon signed-rank test was employed for statistical analysis, with statistical significance set at p value < 0.05. Results: There was no significant difference between the image quality acquired with the 40-mA tube current and reconstructed with the DLR technique (40DLR), and that acquired with the reference protocol (3.00, 3.00, p = 1.00). The SPF at 1.0 cycles/mm acquired with 40DLR was improved by 156.7% compared to that acquired with the reference protocol. Conclusions: Our proposed protocol, which achieves a two-thirds reduction in radiation dose, can provide a minimally invasive MDCT scan of acceptable image quality for dental implant surgery.

DOI： 10.1007/s11282-021-00584-w

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Publisher：Frontiers in Pharmacology  

The liver metabolizes a variety of substances that sometimes interact and regulate each other. The modeling of a single cell or a single metabolic pathway does not represent the complexity of the organ, including metabolic zonation (heterogeneity of functions) along with liver sinusoids. Here, we integrated multiple metabolic pathways into a single numerical liver zonation model, including drug and glucose metabolism. The model simulated the time-course of metabolite concentrations by the combination of dynamic simulation and metabolic flux analysis and successfully reproduced metabolic zonation and localized hepatotoxicity induced by acetaminophen (APAP). Drug metabolism was affected by nutritional status as the glucuronidation reaction rate changed. Moreover, sensitivity analysis suggested that the reported metabolic characteristics of obese adults and healthy infants in glucose metabolism could be associated with the metabolic features of those in drug metabolism. High activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate phosphatase in obese adults led to increased APAP oxidation by cytochrome P450 2E1. In contrast, the high activity of glycogen synthase and low activities of PEPCK and glycogen phosphorylase in healthy infants led to low glucuronidation and high sulfation rates of APAP. In summary, this model showed the effects of glucose metabolism on drug metabolism by integrating multiple pathways into a single liver metabolic zonation model.

DOI： 10.3389/fphar.2022.995597

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Language：English   Publisher：Plos One  

Objective To study the updated prevalence and clinical features of myasthenia gravis (MG) in Japan during 2017. Methods We sent survey sheets to the randomly selected medical departments (number = 7,545). First, we asked the number of MG patients who visited medical departments from January 1, 2017, to December 31, 2017. Then, we sent the second survey sheet to the medical departments that answered the first survey to obtain the clinical information of patients who received MG diagnosis between January 1, 2015, and December 31, 2017. Results The received answer to the first survey were 2,708 (recovery rate: 35.9%). After all, the prevalence of the 100,000 population was estimated as 23.1 (95%CI: 20.5-25.6). As a result of the second survey, we obtained 1,464 case records. After checking the duplications and lacking data, we utilized 1,195 data for further analysis. The median [interquartile range (IQR)] from the onset age of total patients was 59 (43-70) years old. The male-female ratio was 1: 1.15. The onset age [median (IQR)] for female patients was 58 (40-72) years old, and that for male patients was 60 (49-69) years old (Wilcoxon-Mann-Whitney test, p = 0.0299). We divided patients into four categories: 1) anti-acetylcholine receptor antibody (AChRAb) (+) thymoma (Tm) (-), 2) AChRAb(+)Tm(+), 3) anti-muscle-specific kinase antibody (MuSKAb) (+), and AChRAb(-)MuSKAb(-) (double negative; DN). The onset age [median (IQR)] of AChRAb(+)Tm(-) was 64 (48-73) years old, and AChRb(+)Tm(+) was 55 (45-66), MuSKAb(+) was 49 (36-64), DN was 47 (35-60) year old. The multivariate logistic regression analysis using sex, initial symptoms, repetitive nerve stimulation test (RNST), and edrophonium test revealed that sex, ocular symptoms, bulbar symptoms, and RNST were factors to distinguish each category. The myasthenia gravis activities of daily living profile at the severest state were significantly higher in MuSKAb(+). MuSKAb(+) frequently received prednisolone, tacrolimus plasmapheresis, and intravenous immunoglobulin; however, they received less acetylcholine esterase inhibitor. 99.2% of AChRAb(+)Tm(+) and 15.4% of AChRAb(+)Tm(-) received thymectomy. MuSKAb(+) did not receive thymectomy, and only 5.7% of DN received thymectomy. The prognosis was favorable in all categories. Conclusion Our result revealed that the prevalence of Japanese MG doubled from the previous study using the same survey method in 2006. We also found that the onset age shifted to the elderly, and the male-female ratio reached almost even. Classification in four categories; AChRAb(+)Tm(-), AChRAb(+)Tm(+), MuSKAb(+), and DN, well describe the specific clinical features of each category and differences in therapeutic approaches.

DOI： 10.1371/journal.pone.0274161

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Language：English   Publisher：BMJ Neurology Open  

Background: There was no nationwide epidemiological study of Lambert-Eaton myasthenic syndrome (LEMS) in Japan; therefore, we conducted a nationwide survey. Methods: For the first survey, we sent survey sheets to randomly selected medical departments (n=7545) to obtain the number of LEMS who visited medical departments between 1 January 2017 and 31 December 2017. For the second survey, we sent survey sheets to the corresponding medical departments to obtain clinical information on LEMS. Results: We received 2708 responses (recovery rate: 35.9%) to the first survey. We estimated the number of LEMS as 348 (95% CI 247 to 449). The prevalence was 2.7 (95% CI 1.9 to 3.5) in 1 000 000 population. As a result of the second survey, we obtained 30 case records of 16 men and 14 women. Fourteen patients (46.7%) had a tumour, and 10 out of 14 tumours were small-cell lung carcinoma (71.4%). There was a predominance of men in the LEMS with tumour (paraneoplastic LEMS, P-LEMS) (n=11, 78.6%) and women in the LEMS without tumour (a primary autoimmune form of LEMS, AI-LEMS) (n=11, 68.8%) (p=0.0136). The onset age (mean (SD)) for the P-LEMS was 67.1 (9.0), and that for AI-LEMS was 57.8 (11.2) years old (p=0.0103). The disease duration (median) for P-LEMS was 2 years, and for AI-LEMS was 7.5 years (p=0.0134). Conclusions: The prevalence of LEMS in Japan is similar to that in other countries. There are predominances of men in P-LEMS and women in AI-LEMS.

DOI： 10.1136/bmjno-2022-000291

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Publisher：Algorithmica  

The similarity between a pair of time series, i.e., sequences of indexed values in time order, is often estimated by the dynamic time warping (DTW) distance, instead of any in the well-studied family of measures including the longest common subsequence (LCS) length and the edit distance. Although it may seem as if the DTW and the LCS(-like) measures are essentially different, we reveal that the DTW distance can be represented by the longest increasing subsequence (LIS) length of a sequence of integers, which is the LCS length between the integer sequence and itself sorted. For a given pair of time series of length n such that the dissimilarity between any elements is an integer between zero and c, we propose an integer sequence that represents any substring-substring DTW distance as its band-substring LIS length. The length of the produced integer sequence is O(cn²) , which can be translated to O(n²) for constant dissimilarity functions. To demonstrate that techniques developed under the LCS(-like) measures are directly applicable to analysis of time series via our reduction of DTW to LIS, we present time-efficient algorithms for DTW-related problems utilizing the semi-local sequence comparison technique developed for LCS-related problems.

DOI： 10.1007/s00453-022-00968-2

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Language：English   Publisher：Japanese Journal of Radiology  

Purpose: We investigated the effects of the heart rate (HR) on the motion artifact in coronary computed tomography angiography (CCTA) with ultra-high-resolution-CT (U-HRCT), and we clarified the upper limit of optimal HR in CCTA with U-HRCT in a comparison with conventional-resolution-CT (CRCT) on a cardiac phantom and in patients with CCTA. Materials and methods: A pulsating cardiac phantom equipped with coronary models was scanned at static and HR simulations of 40–90 beats/min (bpm) at 10-bpm intervals using U-HRCT and CRCT, respectively. The sharpness and lumen diameter of the coronary model were quantitatively compared between U-HRCT and CRCT stratified by HR in the phantom study. We also assessed the visual inspections of clinical images in CCTA with U-HRCT. Results: At the HRs ≤ 60 bpm, the error of the lumen diameter of the U-HRCT tended to be smaller than that of the CRCT. However, at the HRs > 60 bpm, the inverse was shown. For the image sharpness, the U-HRCT was significantly superior to the CRCT (p < 0.05). In the visual assessment, the scores were negatively correlated with HRs in patients (Spearman r = − 0.71, p < 0.01). A receiver-operating characteristic analysis revealed the HR of 61 bpm as the optimal cutoff of the non-diagnostic image quality, with an area under the curve of 0.87, 95% sensitivity, and 71% specificity. Conclusion: At HRs ≤ 60 bpm, U-HRCT was more accurate in the imaging of coronary arteries than CRCT. The upper limit of the optimal HR in CCTA with U-HRCT was approx. 60 bpm.

DOI： 10.1007/s11604-022-01265-2

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Language：English   Publisher：Pediatric Research  

Abstract: Phelan–McDermid syndrome (PMS) is a rare genetic disorder presenting with developmental delay, epilepsy, and autism spectrum disorder (ASD). The segmental deletion of chromosome 22q13.3 affects the copy number of SHANK3, the gene encoding a scaffolding protein at the postsynaptic density. Biological studies indicate that SHANK3 plays crucial roles in the development of synaptic functions in the postnatal brain. Notably, induced pluripotent stem (iPS) cells have enabled researchers to develop brain organoids and microglia from patients and to explore the pathophysiology of neurodevelopmental disorders in human cells. Single-cell RNA sequencing of these cells revealed that human-specific genes are uniquely expressed during cortical development. Thus, patient-derived disease models are expected to identify as-yet-unidentified functions of SHANK3 in the development of human brain. These efforts may help establish a new style of translational research in pediatrics, which is expected to provide therapeutic insight for children with PMS and broader categories of disease. Impact: Phelan–McDermid syndrome is a prototypic model for molecular studies of autism spectrum disorder.Brain organoids are expected to provide therapeutic insight.Single-cell RNA sequencing of microglia may uncover the functional roles of human-specific genes.

DOI： 10.1038/s41390-021-01806-x

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Language：Japanese   Publisher：(一社)日本てんかん学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Antioxidants  

Mitochondrial fission factor (MFF) is an adapter that targets dynamin-related protein 1 from the cytosol to the mitochondria for fission. Loss-of-function MFF mutations cause encephalopathy due to defective mitochondrial and peroxisomal fission 2 (EMPF2). To elucidate the molecular mechanisms that were involved, we analyzed the functional effects of MFF depletion in deciduous teeth-derived dental pulp stem cells differentiating into dopaminergic neurons (DNs). When treated with MFF-targeting small interfering RNA, DNs showed impaired neurite outgrowth and reduced mitochondrial signals in neurites harboring elongated mitochondria. MFF silencing also caused mitochondrial Ca2+ accumulation through accelerated Ca2+ influx from the endoplasmic reticulum (ER) via the inositol 1,4,5-trisphosphate receptor. Mitochondrial Ca2+ overload led DNs to produce excessive reactive oxygen species (ROS), and downregulated peroxisome proliferator-activated receptor-gamma co-activator-1 alpha (PGC-1α). MFF was co-immunoprecipitated with voltage-dependent anion channel 1, an essential component of the ER-mitochondrial Ca2+ transport system. Folic acid supplementation normalized ROS levels, PGC-1α mediated mitochondrial biogenesis, and neurite outgrowth in MFF depleted DNs, without affecting their mitochondrial morphology or Ca2+ levels. We propose that MFF negatively regulates the mitochondrial Ca2+ influx from the ER. MFF-insufficiency recapitulated the EMPF2 neuropathology with increased oxidative stress and suppressed mitochondrial biogenesis. ROS and mitochondrial biogenesis might be potential therapeutic targets for EMPF2.

DOI： 10.3390/antiox11071361

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Early Human Development  

INTRODUCTION: Infants with congenital diaphragmatic hernia (CDH) are at risk of neurodevelopmental disabilities. This study aimed to investigate the association between lung to thorax transverse area ratio (LTR) and neurodevelopmental outcomes at 3 years of age in fetuses with CDH. METHODS: We performed a retrospective study of infants with prenatally diagnosed isolated left-sided CDH born in Kyushu University Hospital between 2008 and 2016. We examined the association between prenatal ultrasound findings including LTR and development quotient (DQ) at 36 to 42 months of chronological age. RESULTS: We identified 34 live-born fetuses with isolated left-sided CDH, of which 30 survived and four died before discharge. The median LTR in the survivors was higher than in the non-survivors (p < 0.01). Among the survivors, 26 had available data on LTR (median 0.12, range 0.08-0.18) and overall DQ at 3 years of age (93, 61-112). Their median gestational age and birth weight were 37.6 (range 34.4-39.1) weeks and 2716 (2.256-3494) grams, respectively. There was no significant difference in overall DQ scores between the two groups divided according to the median LTR values (p = 0.62). LTR values were not associated with overall DQ scores after adjusting for gestational age (p = 0.39). In addition, no association was observed between LTR values and any subscale DQ scores. CONCLUSION: In fetuses with isolated left-sided CDH, prenatal LTR predicts the mortality but not neurodevelopmental outcomes at 3 years of age.

DOI： 10.1016/j.earlhumdev.2022.105598

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Publisher：Plos One  

The heartwood color of a major plantation tree Cryptomeria japonica shows high variability among clones and cultivars, and brighter heartwood has higher value in the usage of non-laminated wood such as in traditional construction, which makes heartwood color an important trait in breeding of this species. However, the genetic basis of the interactions between genetics and the environment on heartwood color has been understudied while these are necessary for effective breeding programs in multiple environmental condition. The objectives of the present study were to evaluate the effects of genetics and environments on heartwood color and how they interact in contrasting environments, and to identify genomic regions controlling heartwood color in C. japonica across multiple environments. Heartwood color in terms of L*a*b* color space and spectral reflectance was measured in common gardens established in three contrasting sites. Quantitative trait loci (QTL) that affect heartwood color were identified using previously constructed highly saturated linkage maps. Results found that heartwood color was largely genetically controlled, and genotype-by-environment interaction explained one-third of the total genetic variance of heartwood color. The effect of the environment was small compared to the effect of genetics, whereas environmental effects largely varied among heartwood color traits. QTL analysis identified a large number of QTLs with small to moderate effects (phenotypic variation explained of 6.6% on average). Some of these QTLs were stably expressed in multiple environments or had pleiotropic effects on heartwood color and moisture content. These results indicated that genetic variation in phenotypic plasticity plays an important role in regulating heartwood color and that the identified QTLs would maximize the breeding efficiency of heartwood color in C. japonica in heterogeneous environments.

DOI： 10.1371/journal.pone.0270522

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FASEB Bioadvances  

Down syndrome (DS) is one of the common genetic disorders caused by the trisomy of human chromosome 21 (HSA21). Mitochondrial dysfunction and redox imbalance play important roles in DS pathology, and altered dopaminergic regulation has been demonstrated in the brain of individuals with DS. However, the pathological association of these elements is not yet fully understood. In this study, we analyzed dopaminergic neurons (DNs) differentiated from deciduous teeth-derived stem cells of children with DS or healthy control children. As previously observed in the analysis of a single case of DS, compared to controls, patient-derived DNs (DS-DNs) displayed shorter neurite outgrowth and fewer branches, as well as downregulated vesicular monoamine transporter 2 and upregulated dopamine transporter 1, both of which are key regulators of dopamine homeostasis in DNs. In agreement with these expression profiles, DS-DNs accumulated dopamine intracellularly and had increased levels of cellular and mitochondrial reactive oxygen species (ROS). DS-DNs showed downregulation of non-canonical Notch ligand, delta-like 1, which may contribute to dopamine accumulation and increased ROS levels through DAT1 upregulation. Furthermore, DS-DNs showed mitochondrial dysfunction in consistent with lower expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and upregulation of a HSA21-encoded negative regulator of PGC-1α, nuclear receptor-interacting protein 1. These results suggest that dysregulated dopamine homeostasis may participate in oxidative stress and mitochondrial dysfunction of the dopaminergic system in DS.

DOI： 10.1096/fba.2021-00086

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Clinical Nutrition  

Vitamin deficiencies are an emerging concern in the management of children with autism spectrum disorder (ASD). Particular attention is required for recognizing the variable signs caused by unbalanced food intakes. We herein report two patients with multiple vitamin deficiencies who needed critical care showing different prognoses. Patient 1 with 'Shoshin' beriberi presenting with cardiac arrest had thiamine deficiency developed severe neurological sequelae despite rapid vitamin supplementation. Patient 2, who had leg pain and a limping gait, showed a rapid recovery with intravenous infusion and tube feeding after being diagnosed with scurvy. A literature search revealed several children with ASD with critically ill thiamine deficiency, but few reports documented a life-threatening condition in the form of cardiac arrest at the onset. Considering the high observation rate of food selectivity in children with ASD, early intervention is required to prevent the exacerbation of vitamin deficiencies to severe neurological disabilities.

DOI： 10.1038/s41430-022-01170-x

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Language：English   Publisher：Journal of Gastroenterology  

Background: Human chemically induced liver progenitors (hCLiP) induced by small molecules produced by mature hepatocytes can potentially overcome issues related to hepatocyte transplantation, such as graft rejection or donor shortage. However, to our knowledge, no studies have explored the induction of hCLiP from mature hepatocytes (MHs) in damaged liver, indicated for liver transplantation. Methods: Liver tissues were collected from surgically resected livers, including damaged livers, of 86 patients at our department, and hepatocytes were isolated using the collagenase perfusion method. Hepatocytes isolated from 33 of these 86 donors were cultured in YAC medium containing Y-27632 (ROCK inhibitor), A-83-01 (TGF-β type I receptor inhibitor), and CHIR99021 (GSK-3 inhibitor) to induce hCLiP, and their functions were assessed. Results: Hepatocytes were isolated regardless of the liver fibrosis classifications (viability: F0,1: 87.2 ± 13.2%; F2,3: 87.8 ± 13.1%; and F4: 86.3 ± 4.2%). Most hepatocytes cultured in the YAC medium acquired the liver progenitor cell (LPC) gene. The expression of MH markers (ALB, HNF4α, G6PC, and CYP1A2) was lower in hCLiP than in MHs before reprogramming. Reverse transcription-polymerase chain reaction revealed that hCLiP markers (e.g., EpCAM, SOX9, CK19, and CD133) exhibited higher expression in LPCs than in MHs. Furthermore, hCLiPs had the ability to differentiate into hepatocytes, and were engrafted on the liver surface as mature hepatocytes. Conclusion: Hepatocytes could be isolated from damaged liver. Furthermore, hCLiP may be obtained from hepatocytes isolated from damaged liver and may differentiate into MHs in vitro. Autologous hCLiP can potentially be transplanted without tumorigenesis and remodel damaged liver.

DOI： 10.1007/s00535-022-01869-5

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：English   Publisher：Gels  

Researchers have long awaited the technology to develop an in vitro kidney model. Here, we establish a rapid fabricating technique for kidney-like tissues (cysts) using a combination of an organ-derived extracellular matrix (ECM) gel format culture system and a renal stem cell line (CHK-Q cells). CHK-Q cells, which are spontaneously immortalized from the renal stem cells of the Chinese hamster, formed renal cyst-like structures in a type-I collagen gel sandwich culture on day 1 of culture. The cysts fused together and expanded while maintaining three-dimensional structures. The expression of genes related to kidney development and maturation was increased compared with that in a traditional monolayer. Under the kidney-derived ECM (K-ECM) gel format culture system, cyst formation and maturation were induced rapidly. Gene expressions involved in cell polarities, especially for important material transporters (typical markers Slc5a1 and Kcnj1), were restored. K-ECM composition was an important trigger for CHK-Q cells to promote kidney-like tissue formation and maturation. We have established a renal cyst model which rapidly expressed mature kidney features via the combination of K-ECM gel format culture system and CHK-Q cells.

DOI： 10.3390/gels8050312

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PubMed

Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：Japanese   Publisher：(一社)日本小児神経学会  

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Language：English   Publisher：Biodiversity Data Journal  

Background Although the Japanese species of Urostylididae are of interest to not only heteropteran taxonomists, but also to the public, an illustrated key for all species of the family from the country is lacking. To date, the urostylidid species Urostylis hubeiensis Ren, 1997, has been known to occur in China and Korea, but not in Japan. New information Urostylis hubeiensis is recorded from Japan for the first time and represents the easternmost occurrence of this species. In Japan, it inhabits the broad-leaved forest of Tsushima Island and was found on Quercus acutissima Carruth. (Fagaceae). An illustrated key to the species of Urostylididae occurring in Japan is provided.

DOI： 10.3897/BDJ.10.e83656

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatrics and Neonatology  

DOI： 10.1016/j.pedneo.2022.01.006

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Publisher：Advanced Materials Technologies  

Human red blood cells (hRBCs) possess a unique biconcave structure with a highly deformable cell membrane and condensed cytosol hemoglobin for oxygen delivery. Inspired by hRBCs, novel deformable core-shell particles are developed as perfluorocarbon-based oxygen carriers (OCs), called “cDFCs” (concave-shaped deformable PFC-based OCs), using the Shirasu porous glass (SPG) membrane emulsification technique. cDFCs have a perfluorooctyl bromide core of high oxygen solubility and poly(lactide-co-caprolactone) shell, which is thin and highly deformable. They have an optical equivalent diameter of 7.9 ± 2.5 µm and a unique concave shape. Owing to their low Young's modulus (93 kPa) and their diameter and shape, they successfully pass through a 4.5-µm-gap silicon microchannel as a blood capillary model. Enhanced oxygen supply to multiple layered cells is demonstrated under hypoxic conditions, indicating their efficiency as OCs. cDFCs are new potential OCs in tissue engineering and blood substitution in the future.

DOI： 10.1002/admt.202100573

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Publisher：Geoderma  

Geographic information on soil organic carbon (SOC) is important for climate change research and understanding the global carbon cycle. At present, this information is limited for forest soils in mountainous regions that have complex topographies and are affected by tephra deposition. This study predicted the SOC concentration (OC), bulk density (BD), apparent rock coarse fraction (CF), and SOC stock (OCS) at 0–5, 5–15, and 15–30 cm in the soil horizon for the forested areas (ca. 230 000 km²) of Japan. This was carried out with a 10 m grid resolution using a digital soil mapping (DSM) approach. To determine the appropriate spatial prediction model, we evaluated the accuracy of a two dimensional approach for ordinary kriging (OK) and regression kriging (RK), and a three dimensional approach for random forest model (RF). The RF was based on topography, climate and vegetation factors (RF<inf>env</inf>), distance and direction from 152 volcanos (RF<inf>env+vol</inf>), distance from survey points (RF<inf>env+sp</inf>); these factors were also combined (RF<inf>all</inf>) as explanatory attributes. The results demonstrated an improvement in the average root mean square errors (RMSEs) of RF<inf>env+vol</inf>, RF<inf>env+sp</inf>, and RF<inf>all</inf> by approximately 12%, 14%, 5%, and 21% for OC, BD, CF, and OCS using 10-fold cross-validation on a site-by-site basis, respectively, compared with OK. Based on the relatively small difference in improvement among RF<inf>env+vol</inf>, RF<inf>env+sp</inf>, and RF<inf>all</inf> (<0.5%), and the considerably high computational cost of RF<inf>env+sp</inf> and RF<inf>all</inf>, RF<inf>env+vol</inf> was considered as the appropriate model for the area. The R² of RF<inf>env+vol</inf> was calculated at 0.59, 0.44, 0.30, and 0.38 in OC, BD, CF, and OCS, respectively, using 10-fold cross validation on a site-by-site basis. The predicted map by RF<inf>env+vol</inf> accurately reproduced the large spatial variation in OCS at small watershed, regional, and national scales; this have been derived from the effect of microtopography, tephra deposition, and the gradient of temperature with latitude, respectively. A larger OCS was predicted to accumulate on the ridges, highland slopes, near volcanos, and higher latitudes than at other areas. The mean OCS was estimated to be 7.6 kg·m⁻² for a soil depth of 0–30 cm in Japanese forests. The results also suggest that the fine-scale three dimensional random forest approach using the distances from volcanoes showed promise for regional-scale OCS prediction. This approach was considered particularly effective in hills and mountainous areas that are strongly exposed to tephra deposition, this includes the Pacific Rim regions and other volcanic countries.

DOI： 10.1016/j.geoderma.2021.115534

Scopus

Publisher：Chemistry of Materials  

The B-site-ordered double-perovskite Pb2NiMoO6 was prepared at high pressure and high temperature. The structural analysis of synchrotron powder X-ray diffraction data shows that Pb2NiMoO6 crystallizes into monoclinic symmetry with the space group Pc (no. 7), where the Ni and Mo ions are ordered in a rock-salt-type manner. The magnetic and specific heat characterizations reveal unusual two-step antiferromagnetic (AFM) transitions at 18 and 26 K for Pb2NiMoO6. The X-ray absorption spectra at the Ni-L2,3 edge and the Mo-L3 edge and the high-resolution partial fluorescence yield at the Pb-L3 edge indicate Pb2+2Ni2+Mo6+O6 valence states. Although in A2NiMoO6 (A = Sr2+, Pb2+, and Ba2+), the size of the A cation increases gradually from Sr2+ (1.44 Å) to Pb2+ (1.49 Å) to Ba2+ (1.61 Å), Pb2NiMoO6 exhibits much lower symmetry structure and AFM transition temperature, TN, compared with Sr2NiMoO6 (I4/m, TN = 81 K) and Ba2NiMoO6 (Fm3¯ m, TN = 64 K), which is attributed to the large distortion of NiO6 and MoO6 octahedra induced by the lone pair electron effect of Pb2+ with a 6s2 electronic configuration. Moreover, symmetry-breaking phase transition from a high-temperature centrosymmetric, cubic Fm3¯ m phase to a low-temperature non-centrosymmetric, monoclinic Pc phase was observed at 393-413 K in Pb2NiMoO6.

DOI： 10.1021/acs.chemmater.1c02826

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Language：English   Publisher：British Journal of Radiology  

Objectives: To demonstrate the effect of an improved deep learning-based reconstruction (DLR) algorithm on Ultra-High-Resolution Computed Tomography (U-HRCT) scanners. Methods: Clinical and phantom studies were conducted. Thirty patients who underwent contrast-enhanced CT examination during the follow-up period were enrolled. Images were reconstructed using improved DLR [termed, New DLR, i.e., Advanced Intelligent Clear-IQ Engine (AiCE) Body Sharp] and conventional DLR (Conv DLR, AiCE Body) algorithms. Two radiologists assessed the overall image quality using a 5-point scale (5 = excellent; 1 = unacceptable). The noise power spectra (NPSs) were calculated to assess the frequency characteristics of the image noise, and the square root of area under the curve (√AUC NPS) between 0.05 and 0.50 cycle/ mm was calculated as an indicator of the image noise. Dunnett’s test was used for statistical analysis of the visual evaluation score, with statistical significance set at p < 0.05. Results: The overall image quality of New DLR was better than that of the Conv DLR (4.2 ± 0.4 and 3.3 ± 0.4, respectively; p < 0.0001). All New DLR images had an overall image quality score above the average or excellent. The √AUC<inf>NPS</inf> value of New DLR was lower than that of Conv DLR (13.8 and 14.2, respectively). The median values of reconstruction time required with New DLR and Conv DLR were 5.0 and 7.8 min, respectively. Conclusions: The new DLR algorithm improved the image quality within a practical reconstruction time. Advances in knowledge: The new DLR enables us to choose whether to improve image quality or reduce the dose.

DOI： 10.1259/bjr.20220731

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatrics International  

Background: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan. Methods: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene. Results: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT. Conclusions: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction.

DOI： 10.1111/ped.15286

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Publisher：Human Brain Mapping  

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive–compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

DOI： 10.1002/hbm.24972

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Language：English   Publisher：British Journal of Radiology  

Objectives The lung nodule volume determined by CT is used for nodule diagnoses and monitoring tumor responses to therapy. Increased image noise on low-dose CT degrades the measurement accuracy of the lung nodule volume. We compared the volumetric accuracy among deep-learning reconstruction (DLR), model-based iterative reconstruction (MBIR), and hybrid iterative reconstruction (HIR) at an ultra-low-dose setting. Methods Artificial ground-glass nodules (6 mm and 10 mm diameters, −660 HU) placed at the lung-apex and the middle-lung field in chest phantom were scanned by 320-row CT with the ultra-low-dose setting of 6.3 mAs. Each scan data set was reconstructed by DLR, MBIR, and HIR. The volumes of nodules were measured semi-automatically, and the absolute percent volumetric error (APEvol) was calculated. The APEvol provided by each reconstruction were compared by the Tukey-Kramer method. Inter- and intraobserver variabilities were evaluated by a Bland-Altman analysis with limits of agreements. Results DLR provided a lower APEvol compared to MBIR and HIR. The APEvol of DLR (1.36%) was significantly lower than those of the HIR (8.01%, p = 0.0022) and MBIR (7.30%, p = 0.0053) on a 10-mm-diameter middle-lung nodule. DLR showed narrower limits of agreement compared to MBIR and HIR in the inter- and intraobserver agreement of the volumetric measurement. Conclusions DLR showed higher accuracy compared to MBIR and HIR for the volumetric measurement of artificial ground-glass nodules by ultra-low-dose CT. Advances in knowledge DLR with ultra-low-dose setting allows a reduction of dose exposure, maintaining accuracy for the volumetry of lung nodule, especially in patients which deserve a long-term follow-up.

DOI： 10.1259/bjr.20210915

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

新生児スクリーニングで同定された日本人初の小児発症Pompe病症例および新生児スクリーニング以前に診断された別症例を対象として、早期酵素補充療法を速やかに開始することの問題点について検討した。症例1は女児で、妊娠36週4日に帝王切開により娩出された。6日目に実施された新生児スクリーニングで酸性アルファグルコシダーゼ(GAA)低値であったため、28日目に当院に紹介された。新生児スクリーニング結果および臨床所見から乳児発症Pompe病が疑われた。GAA遺伝子の次世代シーケンシングの結果、新規アウトフレーム変異(p.F181Dfs*6)および既知変異(p.R600C)が同定され、乳児発症Pompe病と診断された。58日目にERTが開始された。生後58日目にクレアチンキナーゼ血清中濃度が上昇し、心筋肥大がみられたため、酵素補充療法が開始された。その後、臨床的・生化学的マーカーは速やかに改善した。生後14ヵ月で発達遅滞もなく、健常であった。症例2は12歳男児で、NBS時代の前に生後5ヵ月齢で乳児発症Pompe病と診断されていた。GAAホモ接合性変異(p.R608X)が同定された。12年間にわたる酵素補充療法により、心筋肥大は克服された。

Language：Japanese   Publisher：The Japanese Society of Child Neurology  

DOI： 10.11251/ojjscn.54.214

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cei.13662

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DOI： 10.1016/j.clineuro.2021.106922

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DOI： 10.1016/j.ymgmr.2021.100778

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DOI： 10.1016/j.jneuroim.2021.577656

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DOI： 10.1016/j.eplepsyres.2021.106647

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DOI： 10.1136/bmjopen-2020-043202

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DOI： 10.1016/j.braindev.2021.07.001

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DOI： 10.5772/intechopen.98817

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DOI： 10.1016/j.braindev.2021.01.008

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-021-91628-y

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DOI： 10.1002/pbc.29122

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DOI： 10.1016/j.braindev.2020.12.006

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DOI： 10.1016/j.nut.2021.111275

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DOI： 10.1001/jamanetworkopen.2021.4475

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DOI： 10.1126/sciadv.abd2368

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DOI： 10.1002/npr2.12144

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DOI： 10.1016/j.jns.2020.117047

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DOI： 10.1093/ofid/ofaa288

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DOI： 10.1111/dmcn.14403

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DOI： 10.1002/mgg3.1175

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DOI： 10.1186/s12881-020-01019-9

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DOI： 10.1016/j.ejmg.2019.103825

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DOI： 10.1186/s12887-020-1923-7

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DOI： 10.1007/s12185-019-02738-3

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DOI： 10.1038/s41372-019-0494-7

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DOI： 10.1016/j.jpeds.2019.05.033

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DOI： 10.1136/bmjopen-2018-026579

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DOI： 10.1002/ana.25481

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DOI： 10.1038/s41467-019-10482-9

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DOI： 10.1016/j.bbrc.2019.04.084

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DOI： 10.4274/jcrpe.galenos.2018.2018.0169

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DOI： 10.1093/cid/ciy816

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DOI： 10.1186/s12879-019-4082-4

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DOI： 10.1016/j.braindev.2018.10.012

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DOI： 10.1177/1550059418786381

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DOI： 10.1002/ppul.24200

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DOI： 10.1016/j.jns.2018.10.007

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DOI： 10.1542/peds.2017-4286

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DOI： 10.1016/j.bbrep.2018.09.004

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DOI： 10.1016/j.braindev.2018.05.016

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DOI： 10.1136/jclinpath-2017-204962

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DOI： 10.1016/j.jns.2018.07.006

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DOI： 10.1016/j.ejmg.2018.03.003

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DOI： 10.1007/s12185-018-2424-4

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DOI： 10.1007/s12185-018-2493-4

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DOI： 10.1016/j.seizure.2018.06.012

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DOI： 10.1016/j.eplepsyres.2018.04.006

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DOI： 10.1097/MPH.0000000000001111

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DOI： 10.1038/s41598-018-25890-y

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DOI： 10.1016/j.bbrc.2018.03.077

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DOI： 10.1002/ppul.23944

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DOI： 10.1002/epi4.12085

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DOI： 10.1016/j.celrep.2017.12.074

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DOI： 10.1186/s12881-017-0477-5

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DOI： 10.1111/cei.13002

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DOI： 10.1038/s41598-017-14440-7

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DOI： 10.1016/j.pedneo.2017.05.001

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DOI： 10.1186/s12941-017-0240-y

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DOI： 10.1016/j.braindev.2017.03.023

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DOI： 10.1002/humu.23200

Language：English   Publishing type：Research paper (scientific journal)  

A nationwide survey of pediatric acquired demyelinating syndromes in Japan.

DOI： 10.1212/WNL.0000000000003318

Language：English   Publishing type：Research paper (scientific journal)  

Involuntary movements and coma as the prognostic marker for acute encephalopathy with biphasic seizures and late reduced diffusion.
Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) occurs in children associated with infection. It is characterized by a prolonged febrile seizure in the first phase, and a cluster of seizures, deterioration of consciousness and the white matter lesions with reduced diffusion in the second phase. The patients often have severe neurological sequelae, but the prognostic indicators remain unknown. The present study aimed to clarify the characteristics of AESD patients who subsequently exhibited severe neurological sequelae. We retrospectively analyzed the clinical and laboratory findings along with the brain imaging in patients who had severe (n=8) and non-severe neurodevelopmental outcomes (n=12). Severe group more frequently showed coma (p=0.014) or involuntary movements including dystonia and oral dyskinesia (p=0.018) before the second phase than non-severe group. Severe group exhibited higher levels of serum alanine aminotransferase than non-severe group (p=0.001). Quantitatively assessed MRI in the second phase revealed that severe group had more extensive lesions than non-severe group, in the anterior (p=0.015) and posterior parts (p=0.011) of the cerebrum and basal ganglia (p=0.020). Early appearing involuntary movements or coma might account for the extension of acute brain lesions and the poor neurological outcomes in AESD patients.

DOI： 10.1016/j.jns.2016.09.018

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1177/1550059415579767

Language：English   Publishing type：Research paper (scientific journal)  

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis.
BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder that manifests recurrent attacks of hemiplegia, oculogyric, and choreoathetotic involuntary movements. De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes. It remains to be determined whether or not a rare mutation in ATP1A3 may cause atypical phenotypes. CASE PRESENTATION: A 7-year-old boy presented with recurrent symptoms of generalized paralysis since 1 year and 5 months of age. Hypotonia, dystonia, and choreoathetosis persisted with exacerbation under febrile conditions, but no cerebellar ataxia had ever evolved in 6 years. Whole-exome sequencing (WES) was performed to determine his genetic background, and mutations were validated by the Sanger method. Crude protein extracts were prepared from the cultured cells, and expression of the wild-type or mutant ATP1A3 proteins were analyzed by Western blotting. WES identified a de novo pathogenic mutation in ATP1A3 (c.2266C > T:p.R756C) for this patient. A literature overview of two reported cases with p.R756C and p.R756H mutations showed both overlapping and distinct phenotypes when compared with those of the present case. The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins. CONCLUSIONS: This study confirmed that p.R756C mutation of ATP1A3 cause atypical forms of AHC-associated disorders. The wide spectra of neurological phenotypes in AHC are linked to as-yet-unknown deficits in the functions of mutant ATP1A3.

DOI： 10.1186/s12883-016-0680-6

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/srep27164

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/jhg.2016.1

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DOI： 10.1002/aur.1559

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DOI： 10.1038/jhg.2015.163

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DOI： 10.4049/jimmunol.1500295

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DOI： 10.1038/ejhg.2015.92

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Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells.
Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.

DOI： 10.1038/srep13191

Language：English   Publishing type：Research paper (scientific journal)  

A case of pontine tegmental cap dysplasia with comorbidity of oculoauriculovertebral spectrum.

DOI： 10.1016/j.braindev.2014.02.007

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0113054

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DOI： 10.1016/j.pscychresns.2014.04.012

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/1755-8794-7-19

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DOI： 10.1016/j.braindev.2013.05.009

Language：English   Publishing type：Research paper (scientific journal)  

Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus.

DOI： 10.1016/j.ejmg.2013.06.009

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1442-200X.2011.03331.x

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DOI： 10.1093/hmg/ddr243

Language：English   Publishing type：Research paper (scientific journal)  

Parental ages and the growth and development of children: a study from check-ups.

DOI： 10.1111/j.1442-200X.2011.03331.x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00439-009-0781-z

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.braindev.2009.09.018

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1528-1167.2008.01861.x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/13550280802298120

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neures.2007.06.1480

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00109-006-0053-5

Language：English   Publishing type：Research paper (scientific journal)  

A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome.

DOI： 10.1016/j.braindev.2005.10.002

Language：English   Publishing type：Research paper (scientific journal)  

Benign convulsion with mild gastroenteritis and benign familial infantile seizure.

DOI： 10.1016/j.eplepsyres.2006.01.004

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jbiotec.2005.08.020

Language：English   Publishing type：Research paper (scientific journal)  

Genetic susceptibility to simple febrile seizures: interleukin-1beta promoter polymorphisms are associated with sporadic cases.

DOI： 10.1016/j.neulet.2005.04.097

Language：English   Publishing type：Research paper (scientific journal)  

Gene expression profiles in peripheral blood mononuclear cells from patients with subacute sclerosing panencephalitis using oligonucleotide microarrays.

DOI： 10.1080/13550280590953825

Language：English   Publishing type：Research paper (scientific journal)  

Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates.

DOI： 10.1074/jbc.M402393200

Language：English   Publishing type：Research paper (scientific journal)  

Functional MxA promoter polymorphism associated with subacute sclerosing panencephalitis.

Language：English   Publishing type：Research paper (scientific journal)  

An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress.

DOI： 10.1074/jbc.M306201200

Language：English   Publishing type：Research paper (scientific journal)  

Founder effect of the C9 R95X mutation in Orientals.

DOI： 10.1007/s00439-002-0870-8

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S0022-2836(02)00163-8

Language：English   Publishing type：Research paper (scientific journal)  

Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen.
In human cells APE1 is the major AP endonuclease and it has been reported to have no functional mitochondrial targeting sequence (MTS). We found that APE2 protein possesses a putative MTS. When its N-terminal 15 amino acid residues were fused to the N-terminus of green fluorescent protein and transiently expressed in HeLa cells the fusion protein was localized in the mitochondria. By electron microscopic immunocytochemistry we detected authentic APE2 protein in mitochondria from HeLa cells. Western blotting of the subcellular fraction of HeLa cells revealed most of the APE2 protein to be localized in the nuclei. We found a putative proliferating cell nuclear antigen (PCNA)-binding motif in the C-terminal region of APE2 and showed this motif to be functional by immunoprecipitation and in vitro pull-down binding assays. Laser scanning immunofluorescence microscopy of HeLa cells demonstrated both APE2 and PCNA to form foci in the nucleus and also to be co-localized in some of the foci. The incubation of HeLa cells in HAT medium containing deoxyuridine significantly increased the number of foci in which both molecules were co-localized. Our results suggest that APE2 participates in both nuclear and mitochondrial BER and also that nuclear APE2 functions in the PCNA-dependent BER pathway.

DOI： 10.1093/nar/29.11.2349

Language：English   Publishing type：Research paper (scientific journal)  

Intracellular distribution of the antimutagenic enzyme MTH1 in the liver, kidney and testis of F344 rats and its modulation by cadmium
Cellular distribution of the antimutagenic MTH1 protein in the liver, kidney, and testis of Fischer rat was evaluated using the immunohistochemical staining with anti-MTH1 polyclonal antibody. The present investigation revealed a non-uniform distribution of MTH1 among cells and among the cytoplasmic, nuclear, and membranal structures of cells within a given tissue. A particularly strong expression of MTH1 was observed for the first time in the perinuclear acrosomic bodies of spermatocytes and in the acrosomic vesicles of sperm heads. Treatment of rats with a single sc dose of 20 μmol Cd(II)/kg body wt. produced histopathologic changes in these organs accompanied by redistribution of the cellular MTH1 protein between the cytoplasm and nuclei. The acute phase of Cd(II) toxicity, that in the liver and especially in the testes (but not in kidneys) led to cell necrosis, was accompanied by a characteristic decrease in the abundance of MTH1-expressing nuclei. Chronic toxicity without necrosis, persisting in the kidney over the entire 14-day study, as well as the survival and proliferation of cells, observed in the liver and testis after the necrotizing phase, were signified by increased number of nuclei expressing MTH1. Thus, unlike previous biochemical studies, immunohistochemistry managed to reveal alterations in the patterns of inter- and intracellular distribution of MTH1, associated apparently with the conditional changes in the dynamics of synthesis of nucleic acids, assisted by this protein.

DOI： 10.1078/0940-2993-00201

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S0165-4608(99)00087-4

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/00043426-199807000-00013

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

【目的】全エクソーム・シーケンス(WES)法にもとづき、点変異およびコピー数変異(CNV)を同時に分析することは、難解な症例の遺伝的背景を明らかにする上で重要である。今回、乳児期早期にてんかんを発症し、重度の発達障害を示した男児の遺伝的背景を決定し、その分子病態を検討した。【方法】症例は8歳男児。両親は健常。胎児発育遅延と出生時体重児（1,198g、アプガー7/9）のため当院NICUに１か月入院。退院後、体重増加および哺乳良好であったが、2か月時より群発する半身強直間代けいれんを発症。小頭症、眼瞼斜上を含む特徴的な顔貌を認めたが、Gバンドは46, XY。その他検査成績に異常なし。有意な神経画像所見なし。7歳時に両親と本児の全血由来DNAを用いて、CNV（Baylor MGL; 0.1Mb exonic array）およびWES解析を行った。CNV確定のため、定量PCRはサイバーグリーン法(ddCT)を用いた。胎生16.5日-生後2週齢の野生型C57Bl/6マウスを用いて、免疫蛍光染色を行った。4週齢のマウス脳抽出液を用いて、免疫共沈降およびRNA免疫沈降法(RIP)を行った。【結果】アレイCGHの結果、父由来の22q11.22重複、WES解析ではTRIM8遺伝子のコーディング領域にデ・ノボ一塩基挿入を認めた。野生型マウス脳抽出液を用いた免疫共沈降法では両者の複合体は検出できなかったが、FMRP-TOP3B-RNA複合体にTrim8 mRNAが有意に濃縮されていた。【考察】乳児期早期発症の焦点性てんかんおよび重度発達遅滞を示した男児に、WES解析を行い、まれな点変異およびCNVを見いだした。同一個体内に存在する複数の遺伝的バリエーションは、互いに機能的な修飾因子として作用する可能性が示唆された。

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

【はじめに】MAGEL2遺伝子は、染色体15q11.2領域に存在する母系インプリンティング遺伝子の一つである。最近、MAGEL2のトランケーション型点変異によってプラダー・ウィリー症候群(PWS)が発症することが報告された(Schaaf CP, Nat Genet 2013)。今回、乳児期に点頭てんかんを発症した成人女性にエクソーム・シーケンス解析を行った結果、MAGEL2およびNF1遺伝子に変異を有することが判明した。【方法】症例は44歳女性。3か月時に眼球上転、首をかくんとさせる症状に気づかれ、点頭てんかんと診断。内服治療のため外来通院を継続。難治性てんかんと発達の遅れのため、1歳4か月時に当科紹介。初診時、皮膚にカフェオレ斑を多数認められ、神経線維腫症I型と診断されたが、てんかんとの関連性は不明であった。各種代謝スクリーニング異常なし。脳波所見の詳細不明。29歳時のMRIでは、大脳白質にびまん性高信号病変あり。これまでの発達は独歩不可、有意語なし。低身長、肥満あり、丸く大きな眼裂、厚い口唇、巨舌などの特徴的な顔貌は、PWSの臨床像に矛盾なし。【結果】エクソーム・シーケンスの結果、本症例はMAGEL2コーディング領域に1塩基欠失(NM019066.2:c.219delC)、およびNF1スプライシング部位に1塩基置換(NM001042492.2:c.4835+1G＞T)を認め、いずれも両親とのトリオ解析およびサンガーシーケンスの結果、de novo変異であることが判明した。【考察】MAGEL2変異を有するPWS症例でのてんかん形質は、これまで報告されていない。また本症例の乳児期発症の難治性てんかんや重篤な発達障害は、MAGEL2およびNF1各遺伝子のいずれの単独変異でも説明できない。両者が併存することで重篤な神経症状を示した可能性が考えられ、今後異なる遺伝子間の機能的相互作用に関する生物学的検討が必要である。

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