Publications by authors named "Hidetoshi Takada"

158 Publications

Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.

J Allergy Clin Immunol 2021 Jan 30. Epub 2021 Jan 30.

Department of Pediatrics, Kyoto University, Kyoto, Japan.

Background: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear.

Objectives: This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis.

Methods: Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases.

Results: Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation.

Conclusions: Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.
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http://dx.doi.org/10.1016/j.jaci.2021.01.018DOI Listing
January 2021

Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3.

Am J Med Genet A 2021 Jan 27. Epub 2021 Jan 27.

Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.
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http://dx.doi.org/10.1002/ajmg.a.62084DOI Listing
January 2021

Effectiveness of Water Jelly Ingestion for Both Rehabilitation and Prevention of Aspiration Pneumonia in Elderly Patients With Moderate to Severe Dysphagia.

J Clin Gastroenterol 2021 Jan 19. Epub 2021 Jan 19.

Digestive Disease Center, Showa Inan General Hospital, Komagane Department of Pediatrics, University of Tsukuba Hospital Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Background And Aims: We evaluated the effectiveness of water jelly ingestion for both rehabilitation and the prevention of aspiration pneumonia in a retrospective analysis of elderly patients with moderate to severe dysphagia.

Patients And Methods: Study 1: consecutive patients with borderline ingestion in an endoscopic swallowing evaluation were enrolled (n=36, 18 men and 18 women: mean age 82±9 y) and categorized into a group with water jelly (50 to 100 mL) ingestion training 3×/day or an untrained control group. Their food intake levels were then compared using a Food Intake Level Scale. Study 2: consecutive patients who were hospitalized because of aspiration pneumonia were enrolled (n=64, 35 men and 29 women: mean age 81±9 y) and categorized into a group with cyclic ingestion of water jelly immediately after each meal or a control group. The incidence of aspiration pneumonia that was newly developed during hospitalization was compared between the groups.

Results: In study 1, 36 patients with a Hyodo-Komagane score of 8 were enrolled. Three of the 12 (25%) patients who underwent water jelly ingestion training were able to eat a pureed diet (level 5, 2 patients; level 6, 1 patient) while none of the 24 patients (0%) who did not undergo this training were able to eat any form of diet (levels 5 and 6, no patients) (P=0.011). In study 2, 64 patients were enrolled. No newly developed aspiration pneumonia was observed in the 34 patients (0%) who received cyclic water jelly ingestion, whereas 17% (5/30) of patients not receiving water jelly after meals newly developed aspiration pneumonia during hospitalization (P=0.031).

Conclusions: Water jelly ingestion was effective for both rehabilitation and the prevention of aspiration pneumonia in elderly patients with moderate to severe dysphagia.
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http://dx.doi.org/10.1097/MCG.0000000000001493DOI Listing
January 2021

Pneumococcal Serotype-specific Opsonophagocytic Activity in Interleukin-1 Receptor-associated Kinase 4-deficient Patients.

Pediatr Infect Dis J 2021 Jan 19. Epub 2021 Jan 19.

From the Department of Pediatrics, Naha City Hospital, Naha; Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo; Toyama Institute of Health, Toyama; Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki; Department of Neurology; Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai; Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Background: The antibody response after pneumococcal vaccines and their effectiveness against invasive pneumococcal disease (IPD) in patients with interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency have not been fully evaluated. Here, we evaluated pneumococcal serotype-specific opsonophagocytic activity (OPA) in IRAK4-deficient patients along with their clinical course.

Methods: We investigated 6 IRAK4-deficient patients in Japan, whose attending physicians could be contacted. We performed OPA measurements using stored and more recent serum samples obtained from these patients.

Results: All patients had received pneumococcal vaccination. Among the 3 patients who had IPD, 2 had an episode of pneumococcal meningitis and the other developed pneumococcal bacteremia 3 years after the occurrence of pneumococcal meningitis. Only one episode of invasive bacterial infection was caused by a Streptococcus pneumoniae vaccine-type strain. An increased opsonization index was found in the sera after vaccination for all IRAK-deficient patients, including when the 23-valent pneumococcal polysaccharide vaccine was used.

Conclusions: A significant increase in levels of OPA against most of the pneumococcal vaccine antigens was observed for all IRAK4-deficient patients. However, IPD could not be prevented by pneumococcal vaccination alone. Therefore, adequate prophylaxis should be provided with antibiotics at least until 8 years of age, along with regular immunoglobulin therapy, particularly during the infantile period.
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http://dx.doi.org/10.1097/INF.0000000000003060DOI Listing
January 2021

Utilization of a novel Sendai virus vector in ex vivo gene therapy for hemophilia A.

Int J Hematol 2021 Jan 1. Epub 2021 Jan 1.

Department of Pediatrics, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki, 305-8576, Japan.

Sendai virus (SeV) vectors are being recognized as a superior tool for gene transfer. Here, we report the transfection efficacy of a novel, high-performance, replication-defective, and persistent Sendai virus (SeVdp) vector in cultured cells and in mice using a near-infrared fluorescent protein (iRFP)-mediated in vivo imaging system. The novel SeVdp vector established persistent infection, and strong expression of inserted genes was sustained indefinitely in vitro. Analysis of iRFP-expressing cells transplanted subcutaneously into NOG, nude, and ICR mice suggests that innate immunity was involved in the exclusion of the transplanted cells. We also evaluated the feasibility of this novel SeVdp vector for hemophilia A gene therapy. This system enabled insertion of full-length FVIII genes, and transduced cells secreted FVIII into the culture medium. Transient FVIII activity was detected in the plasma of mice after intraperitoneal transplantation of these FVIII-secreting cells. Further improvement in methods to evade immunity, such as simultaneous expression of immunomodulatory genes, would make this novel vector a very useful tool in regenerative medicine.
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http://dx.doi.org/10.1007/s12185-020-03059-6DOI Listing
January 2021

Successful trans-maternal nadolol pharmacotherapy in a fetus presenting with long QT syndrome type 2 complicated by torsade de pointes.

J Cardiol Cases 2020 Dec 25;22(6):265-268. Epub 2020 Jul 25.

Department of Child Health, University of Tsukuba, Tsukuba, Japan.

Fetuses with congenital long QT syndrome (LQTS) may experience life-threatening arrhythmias, such as torsade de pointes (TdP), and/or functional atrioventricular block. However, trans-maternal pharmacotherapy for these cases is rarely reported and management practices have yet to be established. The fetus of a mother with genetically-confirmed LQTS type 2 (LQT2) presented with complex arrhythmias, diagnosed via magnetocardiography as ventricular arrhythmias (including TdP), at 28 weeks of gestation. After initiation of trans-maternal nadolol administration at 15 mg/d initial dosage and 30 mg/d subsequent dosage, the frequency of fetal ventricular arrhythmias decreased and almost disappeared within several days. The mother gave birth to the baby at full term without significant complications in either the mother or fetus. This is the first report that demonstrates the efficacy and safety of trans-maternal administration of nadolol for treatment of symptomatic LQT2 fetuses with TdP. < Prenatal diagnosis of congenital long QT syndrome (LQTS) is challenging, but characteristic arrhythmias, including sinus bradycardia, intermittent atrioventricular block and torsade de pointes (TdP), as well as family history of LQTS, can be clues to the diagnosis. If TdP is diagnosed in the fetus, trans-maternal administration of anti-arrhythmic drugs, such as beta-blockers, sodium channel blockers, and magnesium, could be effective to restore sinus rhythm and avoid intrauterine fetal death.>.
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http://dx.doi.org/10.1016/j.jccase.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718506PMC
December 2020

Cognitive Functions of Pediatric Brain Tumor Survivors Treated With Proton Beam Therapy: A Case Series.

J Pediatr Hematol Oncol 2020 Nov 23. Epub 2020 Nov 23.

Departments of Child Health.

Pediatric brain tumor survivors who received proton beam therapy at the University of Tsukuba Hospital from 2004 to 2011 were retrospectively evaluated for cognitive function. Five patients were included. The median age of diagnosis was 5.4 years (range: 1.5 to 12.5 y) and the median follow-up time was 5.8 years (range: 3.1 to 8.1 y). IQ scores at follow-up were decreased in 2 of 5 patients; 1 underwent whole-brain irradiation and the other was examined just after surgical removal of recurrent tumors. Local proton beam therapy may preserve cognitive function in survivors of pediatric brain tumors.
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http://dx.doi.org/10.1097/MPH.0000000000002011DOI Listing
November 2020

Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency.

Brain Dev 2021 Mar 21;43(3):475-481. Epub 2020 Nov 21.

Department of Pediatrics, University of Tsukuba Hospital, Japan; Department of Child Health, Faculty of Medicine, University of Tsukuba, Japan.

Peroxisomal acyl-CoA oxidase (ACOX1) deficiency is a rare autosomal recessive single enzyme deficiency characterized by hypotonia, seizures, failure to thrive, developmental delay, and neurological regression starting from approximately 3 years of age. Here, we report two siblings with ACOX1 deficiency born to non-consanguineous Japanese parents. They showed mild global developmental delay from infancy and began to regress at 5 years 10 months and 5 years 6 months of age respectively. They gradually manifested with cerebellar ataxia, dysarthria, pyramidal signs, and dysphasia. Brain MRI revealed T2 high-intensity areas in the cerebellar white matter, bilateral middle cerebellar peduncle, and transverse tracts of the pons, followed by progressive atrophy of these areas. Intriguingly, the ratios of C24:0, C25:0, and C26:0 to C22:0 in plasma, which usually increase in ACOX1 deficiency were within normal ranges in both patients. On the other hand, whole exome sequencing revealed novel compound heterozygous variants in ACOX1: a frameshift variant (c.160delC:p.Leu54Serfs*18) and a missense variant (c.1259 T > C:p.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C24:0, C25:0, and C26:0) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C24:0 β-oxidation activity was dramatically reduced. Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient's fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.
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http://dx.doi.org/10.1016/j.braindev.2020.10.011DOI Listing
March 2021

IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation.

J Clin Immunol 2021 Jan 20;41(1):125-135. Epub 2020 Oct 20.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, 1-2-3 Kasumi, Minami-Ku, Hiroshima-Shi, Hiroshima, 734-8551, Japan.

IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.
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http://dx.doi.org/10.1007/s10875-020-00885-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846526PMC
January 2021

Nationwide survey of late-onset hemolysis in very low birthweight infants.

Pediatr Int 2021 Feb 6;63(2):172-176. Epub 2021 Feb 6.

Departments of, Department of, Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Background: In Japan, some cases of late-onset acute hemolysis in very low birthweight (VLBW) infants have been reported. These cases had common features but the cause of hemolysis was unknown. The incidence and prognosis of this disease are also unknown. However, there are only few reports of such hemolytic episodes in countries other than Japan. Thus, this study aimed to examine the incidence and clinical course of late-onset acute hemolysis and to establish it as a new disease concept.

Methods: A nationwide prospective survey was conducted from 2011 to 2015 as a rare disease surveillance project of the Japan Society for Neonatal Health and Development.

Results: Twenty-four cases were confirmed. The median (range) gestational age, birthweight, and onset of hemolytic episodes were 26 weeks and 2 days (23 weeks and 4 days-31 weeks and 2 days), 898 g (627-1,416 g), and 19 days after birth (9-33 days), respectively. Phototherapy, blood transfusion, and exchange transfusion were required in 22 (96%), 24 (100%), and 7 (29%) cases, respectively. During the observation period, no recurrence of the hemolytic episode occurred. All patients survived; however, one case developed kernicterus and suffered severe neurological sequelae.

Conclusions: In this study, at least 1 out of 1,259 VLBW infants developed hemolysis at 9-33 days after birth in Japan. Owing to the risk of kernicterus, this disease should be recognized as among the important pathological conditions of VLBW infants, suggesting the need to manage jaundice and anemia until 5 weeks after birth.
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http://dx.doi.org/10.1111/ped.14493DOI Listing
February 2021

A case of cardiac tamponade without cardiac tumor in pediatric lymphoma.

Pediatr Int 2020 Oct 25;62(10):1201-1202. Epub 2020 Sep 25.

Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.

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http://dx.doi.org/10.1111/ped.14280DOI Listing
October 2020

Poststreptococcal acute glomerulonephritis in a girl with renal cell carcinoma: possible pathophysiological association.

CEN Case Rep 2021 Feb 20;10(1):139-144. Epub 2020 Sep 20.

Department of Pediatrics, University of Tsukuba, 2-1-1 Amakubo, Tsukuba, Ibaraki, 305-8576, Japan.

The severity of the poststreptococcal acute glomerulonephritis is considered to be modulated by the immune response of each individual, although there had been few reports regarding specific factors. Renal cell carcinoma is a cancer frequently associated with paraneoplastic syndrome, characterized by fever, leukocytosis, elevated cytokines, and elevated hormone levels. All of these symptoms resolve after tumor resection. A girl with renal cell carcinoma developed renal failure rapidly, which resolved promptly right after nephrectomy for the carcinoma. She was diagnosed as having poststreptococcal acute glomerulonephritis according to the results of pathological and serological examinations. In addition, elevated serum interleukin-6 level before the surgery was detected. Six and a half years after the diagnosis, the patient's renal function was within normal range and she was tumor free. Because of the quick resolution of her renal dysfunction after the nephrectomy, paraneoplastic syndrome induced by renal cell carcinoma seemed to play a key role in the accentuation of poststreptococcal acute glomerulonephritis.
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http://dx.doi.org/10.1007/s13730-020-00526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829280PMC
February 2021

A Family with Gitelman Syndrome with Asymptomatic Phenotypes while Carrying Reported SLC12A3 Mutations.

Case Rep Nephrol Dial 2020 May-Aug;10(2):71-78. Epub 2020 Jul 13.

Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Gitelman syndrome (GS) is an autosomal recessive disorder characterized by alkalosis, hypokalemia, and hypomagnesemia. Although hundreds of genetic variants associated with GS have been reported, many of them are categorized as of uncertain significance in ClinVar. Here, we describe a pediatric GS patient from a three-generation family whose mother and maternal grandmother were asymptomatic. The proband was a 16-year-old Japanese girl with muscle weakness and continuous hypokalemic metabolic alkalosis. The patient, her mother, and her maternal grandmother were compound heterozygous for, and each expressing a different combination of, previously reported variants in GS patients. The mother and the maternal grandmother had no symptoms related to GS, and blood gas tests showed that the blood potassium levels and venous pH were within normal limits; however, the venous blood HCO3- levels were slightly elevated. The phenotypic effect of missense mutations is difficult to evaluate, and accumulation of genotypic data with accurate phenotyping, including those of "healthy" and "asymptomatic" individuals in various ethnic populations, will improve the genetic diagnosis of GS.
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http://dx.doi.org/10.1159/000507845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443650PMC
July 2020

A Follow-Up Report of an Infant Born to a Mother Receiving Tamoxifen.

Case Rep Pediatr 2020 26;2020:2056756. Epub 2020 Jul 26.

Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.

Tamoxifen, an estrogen receptor antagonist, is contraindicated in pregnant women due to its teratogenic activity. In the present study, we report the case of an infant whose mother received tamoxifen for breast cancer while unaware of the pregnancy. The infant, born at 29 weeks and 6 days of gestational age with a birth weight of 1664 g, had no congenital anomalies. This case presents detailed information on the development of an infant with placental transfer of tamoxifen. The infant has grown and developed normally throughout a 5-year follow-up period, but long-term vigilance continues.
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http://dx.doi.org/10.1155/2020/2056756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399775PMC
July 2020

Novel mutation identified in infantile spasm syndrome patient.

Hum Genome Var 2020 31;7. Epub 2020 Mar 31.

2Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.

We report a 7-year-old boy with infantile spasms caused by a novel mutation in the () gene. He showed infantile spasms and hypsarrhythmia on electroencephalogram from early infancy. Brain MRI did not reveal severe malformation of the brain except mild hypoplasia of the corpus callosum. Two-fold adrenocorticotropic hormone (ACTH) therapy failed to control the seizures, and ketogenic diet therapy and multi-antiepileptic drug therapy were required as he showed intractable daily tonic-clonic seizures. Exome sequencing identified a hemizygous mutation in the gene, NG_008281.1(ARX_v001):c.1448 + 1 G > A, chrX: 25025227 C > T (GRCh37). To our knowledge, this mutation has not been reported previously.
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http://dx.doi.org/10.1038/s41439-020-0094-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109071PMC
March 2020

Quantitative assessment of fine motor skills in children using magnetic sensors.

Brain Dev 2020 Jun 3;42(6):421-430. Epub 2020 Apr 3.

Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan; Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Aim: We aimed to establish objective and quantitative data on fine motor development in typically developing children using magnetic sensors.

Methods: The study included 110 Japanese elementary school children volunteers (57 boys, 53 girls). The participants were instructed to tap their thumbs and index fingers together repetitively for 10 s. After attaching coils to the participants' right and left thumbs and index fingers, participants executed "in-phase" and "anti-phase" tapping. We used two-way analysis of variance to analyze the influences of age and sex on fine motor development.

Results: The "number of taps" significantly increased with age, while the "standard deviation (SD) of tapping interval" significantly decreased. More than half of the "acceleration" parameters significantly increased with age. Boys performed significantly faster than girls in some parameters of "velocity" and "acceleration," while girls had significantly lower "SD of local maximum velocity in opening motion" and "SD of local minimum velocity in closing motion."

Discussion: We established both objective and quantitative reference data on fine motor development in typically developing Japanese children aged between 7 and 12 years using magnetic sensors. We revealed that this system can monitor real-time details of the parameters involved in the finger-tapping movement in children without complications. This device could be useful for obtaining objective and quantitative data on fine motor skills in the clinical assessment of developmental coordination disorder, assessments of educational intervention, or rehabilitation and discovery of new therapeutic agents.
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http://dx.doi.org/10.1016/j.braindev.2020.03.004DOI Listing
June 2020

Outcomes of paediatric out-of-hospital cardiac arrest according to hospital characteristic defined by the annual number of paediatric patients with invasive mechanical ventilation: A nationwide study in Japan.

Resuscitation 2020 03 10;148:49-56. Epub 2020 Jan 10.

Department of Health Services Research, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Health Services Research and Development Center, University of Tsukuba, Ibaraki, Japan.

Aim: We examined whether outcomes of paediatric out-of-hospital cardiac arrest (OHCA) are associated with a hospital characteristic defined by the annual number of invasive mechanical ventilation cases, suggesting hospitals' experience in caring for severely ill paediatric patients.

Method: We analysed the Japanese Diagnosis Procedure Combination database from 2010 to 2017. We identified children (<18 years) with OHCA and post-resuscitation intensive care (defined as invasive mechanical ventilation and/or catecholamine infusion). Hospitals were divided into four groups by mean annual number of paediatric cases involving invasive mechanical ventilation. The primary outcome was in-hospital mortality, and the secondary outcome was unfavourable outcomes (death or medical care dependency at discharge). Multivariable logistic regression analyses were conducted to examine the relationship between hospitals' experience and outcomes.

Results: We included 2540 paediatric OHCA patients from 385 institutions. Overall in-hospital mortality was 62.4%, with rates of 69.6%, 61.3%, 61.8%, and 57.0% in hospitals with low (≤48 cases/year), low-intermediate (48-110), high-intermediate (110-164), and high (>164) experience levels (P < .001), respectively. Compared to hospitals with low experience, adjusted odds ratios (95% confidence interval) for hospitals with low-intermediate, high-intermediate, and high experience were as follows: primary outcome: 0.64 (0.40-1.01), 0.67 (0.42-1.05), and 0.46 (0.31-0.70), respectively; secondary outcome: 0.93 (0.55-1.57), 0.95 (0.63-1.43), and 0.67 (0.46-0.96), respectively.

Conclusion: Japanese hospitals with higher experience in caring for severely ill paediatric patients showed lower mortality for paediatric OHCA. This fact should be considered by the Emergency Medical Systems when deciding transport strategy.
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http://dx.doi.org/10.1016/j.resuscitation.2019.12.020DOI Listing
March 2020

A case of autism spectrum disorder with cleft lip and palate carrying a mutation in exon 8 of .

Clin Case Rep 2019 Nov 24;7(11):2059-2063. Epub 2019 Sep 24.

Department of Pediatrics, Faculty of Medicine University of Tsukuba Tsukuba Japan.

We report a patient with autism and cleft lip and palate carrying a de novo heterozygous mutation, c.1464_1467del ACTC (p.Tyr488*). Although the causal relationship between cleft lip and palate and this mutation is unclear, this case report may expand the clinical phenotype of AUTS2 syndrome.
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http://dx.doi.org/10.1002/ccr3.2377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878208PMC
November 2019

Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease.

Cardiovasc Res 2021 Jan;117(1):96-108

Kawasaki Disease Center, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Higashi-ku, Fukuoka 813-0017, Japan.

Aims: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD.

Methods And Results: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls.

Conclusion: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD.
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http://dx.doi.org/10.1093/cvr/cvz305DOI Listing
January 2021

Urgent Proton Beam Therapy With Interinstitutional Transfer for Patients With Intracranial Rhabdomyosarcoma: Report of 3 Cases.

J Pediatr Hematol Oncol 2020 01;42(1):e12-e17

Departments of Pediatrics.

A number of cases have been reported in recent years regarding the use of proton beam therapy to mitigate adverse events affecting important cranial organs in cases of rhabdomyosarcoma at parameningeal sites. However, few reports have described the use of proton beam therapy as urgent radiotherapy for parameningeal rhabdomyosarcoma with intracranial extension. We treated 3 patients diagnosed with parameningeal rhabdomyosarcoma extending into the cranium who were assessed at other hospitals as suitable for urgent radiotherapy and transferred to our hospital for proton beam therapy. These patients comprised 2 boys and 1 girl 6 to 12 years of age at diagnosis, and proton beam therapy was started on days 5, 11, and 23 after diagnosis, respectively. Patients with parameningeal rhabdomyosarcoma extending into the cranium can be transferred to institutions equipped to perform proton beam therapy. To minimize the interval to starting therapy, medical information should be shared with institutions capable of providing such therapy as soon as the possibility of intracranial soft-tissue sarcoma is recognized. Proton beam therapy is 1 option for radiotherapy in cases of intracranial rhabdomyosarcoma.
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http://dx.doi.org/10.1097/MPH.0000000000001620DOI Listing
January 2020

Patient Transfer to Receive Proton Beam Therapy During Intensive Multimodal Therapy is Safe and Feasible for Patients With Newly Diagnosed High-risk Neuroblastoma.

J Pediatr Hematol Oncol 2020 01;42(1):e18-e24

Departments of Pediatrics.

Neuroblastoma (NB) predominantly presents as high-risk disease, requiring intensive multimodal therapy. Proton beam therpy (PBT) is a promising option for many childhood cancers, but is not widely available. Patients with NB hoping to receive PBT may therefore need to be transferred between institutions during intensive multimodal therapy, risking undesirable effects. We evaluated patients with high-risk NB who received PBT at our institute as part of first-line therapy, mainly focusing on the safety and feasibility of mid-treatment patient transfer. Eighteen patients with newly diagnosed high-risk NB who received PBT between April 2010 and June 2016 were retrospectively analyzed for local control, outcomes, and toxicity. Survival (3-y overall survival 71%±11%; 3-y event-free survival 44%±12%) and local control rate (100%) were comparable with previous studies. Few acute adverse events were recorded, and all patients completed PBT without treatment delay. PBT for high-risk NB was safe and feasible for patients requiring mid-treatment interinstitutional transfer.
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http://dx.doi.org/10.1097/MPH.0000000000001570DOI Listing
January 2020

Decision-making dilemmas of paediatricians: a qualitative study in Japan.

BMJ Open 2019 08 19;9(8):e026579. Epub 2019 Aug 19.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: To delineate the critical decision-making processes that paediatricians apply when treating children with life-threatening conditions and the psychosocial experience of paediatricians involved in such care.

Design: We conducted semistructured, individual face-to-face interviews for each participant from 2014 to 2015. The content of each interview was subjected to a comprehensive qualitative analysis. The categories of dilemma were extracted from a second-round content analysis.

Participants: Participants were board-certified paediatricians with sufficient experience in making decisions in relation to children with severe illnesses or disabilities. We repeated purposive sampling and analyses until we reached saturation of the category data.

Results: We performed interviews with 15 paediatricians. They each reported both unique and overlapping categories of dilemmas that they encountered when making critical decisions. The dilemmas included five types of causal elements: (1) paediatricians' convictions; (2) the quest for the best interests of patients; (3) the quest for medically appropriate plans; (4) confronting parents and families and (5) socioenvironmental issues. Dilemmas occurred and developed as conflicting interactions among these five elements. We further categorised these five elements into three principal domains: the decision-maker (decider); consensus making among families, colleagues and society (process) and the consequential output of the decision (consequence).

Conclusions: This is the first qualitative study to demonstrate the framework of paediatricians' decision-making processes and the complex structures of dilemmas they face. Our data indicate the necessity of establishing and implementing an effective support system for paediatricians, such as structured professional education and arguments for creating social consensus that assist them to reach the best plan for the management of severely ill children.
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http://dx.doi.org/10.1136/bmjopen-2018-026579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707677PMC
August 2019

Neonatal outcomes of very low birthweight infants born to mothers with hyperglycaemia in pregnancy: a retrospective cohort study in Japan.

BMJ Paediatr Open 2019 16;3(1):e000491. Epub 2019 Jul 16.

Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.

Objective: To examine the mortality and morbidities of very low birthweight (VLBW, <1500 g) infants of mothers with hyperglycaemia in pregnancy.

Design And Setting: We conducted a retrospective cohort study using data from the Neonatal Research Network of Japan, a nationwide registry of VLBW infants (2003-2012).

Patients: We studied 29 626 infants born at 23 to 32 weeks without major congenital anomalies, of which 682 (2.3%) infants were from pregnancies affected by maternal hyperglycaemia.

Main Outcome Measures: The primary outcome was hospital mortality. Secondary outcomes were neonatal morbidities and their anthropometric values. Associations between maternal hyperglycaemia and each outcome were observed for the overall period, and statistical tests for interaction were conducted to assess whether they differed before or after the adoption of the International Association of Diabetes in Pregnancy Study Group (IADPSG) guidelines in 2010 for the diagnosis of gestational diabetes mellitus.

Results: Overall, hospital mortality (4.1% vs 5.2%), composite outcomes of mortality and severe morbidity (54.2% vs 60%), and anthropometric values were not significantly different between infants of mothers with or without hyperglycaemia in pregnancy. However, the incidence of respiratory distress syndrome (RDS) in VLBW infants from mothers with hyperglycaemia was significantly higher than those from mothers without it only before (relative risk (RR) 1.09, 95% CI 1.00 to 1.19) and not after (RR 0.97, 95% CI 0.83 to 1.11) the adoption of the IADPSG guidelines.

Conclusion: VLBW infants born to mothers with hyperglycaemia in pregnancy do not seem to be at higher risk of mortality and morbidities, except for RDS only before the adoption of the IADPSG guidelines.
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http://dx.doi.org/10.1136/bmjpo-2019-000491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668750PMC
July 2019

Inflammation in the neonatal period and intrauterine growth restriction aggravate bronchopulmonary dysplasia.

Pediatr Neonatol 2019 10 25;60(5):496-503. Epub 2018 Nov 25.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: To investigate the hematological features of infants with bronchopulmonary dysplasia (BPD) and their relationships with clinical severity.

Methods: This prospective observational study enrolled 73 BPD patients from a total of 331 infants with a birth weight of <1500 g from 2005 to 2013. The clinical severity of BPD was defined by the duration of oxygen supplementation and positive pressure ventilation (PPV) in line with the diagnostic criteria of BPD. The hematological status and cytokine levels were surveyed from blood samples at birth and at 2 and 4 weeks of life.

Results: Thirty-four (46.6%) cases were classified as "moderate-to-severe" BPD. Small-for-gestational-age (SGA) was associated with the severity of BPD (OR: 5.05; 95% CI: 1.45 to 17.2). The CRP level at 2 weeks (partial regression coefficient [rc]: 21.8; 4.01 to 39.7) and the neutrophil count at 4 weeks (0.005; 0.001 to 0.007) were positively correlated with the oxygenation period. The PPV period was found to be correlated with the CRP level at 2 weeks (27.2; 14.9 to 39.5), and the neutrophil count (0.003; 0.001 to 0.004) at 4 weeks.

Conclusion: The aggravation of BPD was associated with both SGA at birth and inflammation during neonatal period.
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http://dx.doi.org/10.1016/j.pedneo.2018.11.007DOI Listing
October 2019

Tracheal Size and Morphology on the Reconstructed CT Imaging.

Pediatr Crit Care Med 2019 08;20(8):e366-e371

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objectives: To characterize the real size and morphology of tracheas in childhood for the optimal selection of endotracheal tube.

Design: A retrospective cohort study of pediatric patients who received CT scan of the cervical spine from July 2011 to March 2018. Cross-sectional CT images vertical to trachea were reconstructed and the accurate tracheal diameters were measured. The validity of the traditional age-based formula for predicting the endotracheal tube size was assessed for the best fit to trachea.

Setting: Tertiary Emergency and Critical Care Center of Kyushu University Hospital.

Patients: Children, who are 1 month to 15 years old, received CT scan of the cervical spine.

Interventions: None.

Measurements And Main Results: We enrolled 86 children with median age of 53 months. The cross-sectional shape of pediatric trachea was circular at the cricoid level and elliptical at the infraglottic level. The narrowest part of pediatric trachea was the transverse diameter at the infraglottic level at any age. Significant positive correlation between age and the narrowest diameter was observed. When compared the transverse diameter at the infraglottic level with the outer diameter of endotracheal tubes, uncuffed endotracheal tubes selection based on the traditional age-based formula ran a significant risk of oversized endotracheal intubation until 10 years old compared with cuffed endotracheal tubes selection (60.0% vs 23.8%; p < 0.05).

Conclusions: These findings indicate the safety and efficacy of cuffed endotracheal tubes in infants and children and the reconsideration for the airway management in pediatric anesthesia and intensive care.
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http://dx.doi.org/10.1097/PCC.0000000000001996DOI Listing
August 2019

A novel missense mutation identified in a patient with macrocephaly and developmental delay.

Hum Genome Var 2019 23;6:25. Epub 2019 May 23.

1Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.

Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/autism syndrome harboring a novel missense heterozygous mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation.
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http://dx.doi.org/10.1038/s41439-019-0056-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531540PMC
May 2019

MOB1 regulates thymocyte egress and T-cell survival in mice in a YAP1-independent manner.

Genes Cells 2019 Jul 24;24(7):485-495. Epub 2019 May 24.

Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan.

Mammalian STE20-like protein kinase 1/2 (MST1/2) and nuclear Dbf2-related kinase 1/2 (NDR1/2) are core components of Hippo signaling that are also known to be important regulators of lymphocyte trafficking. However, little is understood about the roles of other Hippo pathway molecules in these cells. Here, we present the first analysis of the function of Mps one binder kinase activator-1 (MOB1) in T lymphocytes in vivo. T-cell-specific double knockout (DKO) of MOB1A/B in mice [tMob1 DKO mice] reduces the number of naïve T cells in both the circulation and secondary lymphoid organs, but leads to an accumulation of CD4 CD8 and CD4 CD8 single-positive (SP) cells in the thymus. In vitro, naïve MOB1A/B-deficient T cells show increased apoptosis and display impaired trafficking capacity in response to the chemokine CCL19. These defects are linked to suppression of the activation of MST and NDR kinases, but are independent of the downstream transcriptional co-activator Yes-associated protein 1 (YAP1). Thus, MOB1 proteins play an important role in thymic egress and T-cell survival that is mediated by a pathway other than conventional Hippo-YAP1 signaling.
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http://dx.doi.org/10.1111/gtc.12704DOI Listing
July 2019

Establishment of immunity against Epstein-Barr virus infection in a patient with CHARGE/complete DiGeorge syndrome after peripheral blood lymphocyte transfusion.

Pediatr Transplant 2019 06 29;23(4):e13424. Epub 2019 Apr 29.

Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan.

CHARGE syndrome is a rare congenital malformation syndrome which may share symptoms with DiGeorge syndrome. Complete DiGeorge syndrome (cDGS) is a severe form of DiGeorge syndrome, characterized by a CD3+ T-cell count of <50/mm due to athymia, and is fatal without immunologic intervention. We performed peripheral blood lymphocyte transfusion (PBLT) from an HLA-identical sibling without pretransplant conditioning in a CHARGE/cDGS patient with a novel CHD7 splice site mutation. Cyclosporine and short-term methotrexate were used for graft versus host disease (GVHD) prophylaxis, and neither acute nor chronic GVHD was observed. After PBLT, T-cell proliferative response to phytohemagglutinin and concanavalin A recovered, and intractable diarrhea improved. EBV infection, evidenced by a gradual increase in the viral genome copy number to a maximum of 2861 copies/μgDNA on day 42 after PBLT, resolved spontaneously. HLA A2402 restricted, EBV-specific CTLs were detected from peripheral blood on day 148, and EBV seroconversion was observed on day 181. Thus, EBV-specific immunity was successfully established by PBLT. Our results indicate that PBLT is a simple and effective therapy to reconstitute immune systems in CHARGE/DiGeorge syndrome.
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http://dx.doi.org/10.1111/petr.13424DOI Listing
June 2019

Epstein-Barr Virus-Associated γδ T-Cell Lymphoproliferative Disorder Associated With Hypomorphic Mutation.

Front Pediatr 2019 4;7:15. Epub 2019 Feb 4.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an EBV-associated lymphoproliferative disease characterized by repeated or sustainable infectious mononucleosis (IM)-like symptoms. EBV is usually detected in B cells in patients who have IM or Burkitt's lymphoma and even in patients with X-linked lymphoproliferative syndrome, which is confirmed to have vulnerability to EBV infection. In contrast, EBV infects T cells (CD4 T, CD8 T, and γδT) or NK cells mono- or oligoclonally in CAEBV patients. It is known that the CAEBV phenotypes differ depending on which cells are infected with EBV. CAEBV is postulated to be associated with a genetic immunological abnormality, although its cause remains undefined. Here we describe a case of EBV-related γδT-cell proliferation with underlying hypomorphic mutation. The immunological phenotype consisted of γδT-cell proliferation in the peripheral blood. A presence of EBV-infected B cells and γδT cells mimicked γδT-cell-type CAEBV. Although the patient had normal expression of CD132 (common γ chain), the phosphorylation of STAT was partially defective, indicating impaired activation of the downstream signal of the JAK/STAT pathway. Although the patient was not diagnosed as having CAEBV, this observation shows that CAEBV might be associated with immunological abnormality.
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http://dx.doi.org/10.3389/fped.2019.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369201PMC
February 2019