Kazumoto Iijima

Tokyo Metropolitan Children's Medical Center, Edo, Tokyo, Japan

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Publications (256)799.11 Total impact

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    ABSTRACT: Most spinal muscular atrophy (SMA) patients lack the survival motor neuron 1 gene (SMN1) in the telomeric region of the SMA locus on chromosome 5q13. On the other hand, the copy number of SMN2, a centromeric homolog of SMN1, is increased in many of these patients.
    No preview · Article · Jan 2016
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    ABSTRACT: Duchene muscular dystrophy (DMD) is a progressive muscle wasting disease, caused by mutations in the dystrophin (DMD) on the X chromosome. One-third of patients are estimated to have de novo mutations. To provide in-depth genetic counseling, the comprehensive identification of mutations is mandatory. However, many DMD patients did not undergo genetic diagnosis because detailed genetic diagnosis was not available or their mutational types were difficult to identify. Here we report the genetic testing of a sporadic DMD boy, who died >20 years previously. Dried umbilical cord preserved for 38 years was the only available source of genomic DNA. Although the genomic DNA was severely degraded, multiplex ligation-dependent probe amplification analysis was performed but no gross mutations found. Sanger sequencing was attempted but not conclusive. Next-generation sequencing (NGS) was performed by controlling the tagmentation during library preparation. A nonsense mutation in DMD (p.Arg2095*) was clearly identified in the proband. Consequently, the identical mutation was detected as an 11% mosaic mutation from his healthy mother. Finally, the proband's sister was diagnosed as a non-carrier of the mutation. Thus using NGS we have identified a pathogenic DMD mutation from degraded DNA and low-level somatic mosaicism, which would have been overlooked using Sanger sequencing.Journal of Human Genetics advance online publication, 7 January 2016; doi:10.1038/jhg.2015.157.
    No preview · Article · Jan 2016 · Journal of Human Genetics
  • Koichi Kamei · Masao Ogura · Mai Sato · Mayumi Sako · Kazumoto Iijima · Shuichi Ito

    No preview · Article · Jan 2016 · Pediatric Nephrology
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    ABSTRACT: Background: To treat children born small for gestational age (SGA) with severe short stature, treatment with growth hormone (GH) has been approved in the United States, Europe, and Japan, however, no population-based studies have reported their prevalence. Our aims were to investigate the prevalence of SGA infants and short children born SGA who qualify for GH treatment at 3 years of age in a Japanese population. Methods: A population-based study was conducted in Kobe, Japan with 27228 infants who were born from 2006-08 and followed until 3 years of age. Prevalence of infants with birth weight (BW) or birth length (BL) ≤-2.0 standard deviation scores (SDS) for gestational age (GA) (the definition of SGA) were calculated. Short children born SGA who qualify for GH treatment at 3 years of age were estimated using the following criteria: BW and BL below the 10th percentile for GA, BW or BL ≤-2.0SDS for GA, and 2.5 SDS below the mean height at their age. Results: The prevalence of SGA infants was 3.5%. The estimated prevalence of short children born SGA who met the criteria for GH treatment was 0.06%. The prevalence in infants born <34 weeks (0.39%) was significantly higher than that in infants born 34-41 weeks GA (0.05%, p=0.02). Conclusions: The prevalence of SGA infants and short children born SGA who qualify for GH treatment is approximately 1 of 30 infants and 1 of 1800 children, respectively. The risk is increased when children are born <34 weeks GA. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Pediatrics International
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    ABSTRACT: Background: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the type IV collagen alpha chain 5 gene (COL4A5). Although many COL4A5 mutations have previously been identified, pathogenic synonymous mutations have not yet been described. Methods: A family with XLAS underwent mutational analyses of COL4A5 by PCR and direct sequencing, as well as transcript analysis of potential splice site mutations. In silico analysis was also conducted to predict the disruption of splicing factor binding sites. Immunohistochemistry (IHC) of kidney biopsies was used to detect α2 and α5 chain expression. Results: We identified a hemizygous point mutation, c.876A>T, in exon 15 of COL4A5 in the proband and his brother, which is predicted to result in a synonymous amino acid change, p.(Gly292Gly). Transcript analysis showed that this mutation potentially altered splicing because it disrupted the splicing factor binding site. The kidney biopsy of the proband showed lamellation of the glomerular basement membrane (GBM), while IHC revealed negative α5(IV) staining in the GBM and Bowman's capsule, which is typical of XLAS. Conclusions: This is the first report of a synonymous COL4A5 substitution being responsible for XLAS. Our findings suggest that transcript analysis should be conducted for the future correct assessment of silent mutations.
    No preview · Article · Nov 2015 · Clinical and Experimental Nephrology
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    ABSTRACT: Background The etiology of Kawasaki disease (KD) is unknown. Reportedly, there is an association between KD and Yersinia pseudotuberculosis (YPT). Steroid therapy for KD patients with high risk of cardiac sequelae (CS) has been reported; however, the number of reports is limited. Methods We conducted a prospective study of 108 patients with newly diagnosed KD in one year to determine how many KD patients have positive anti-YPT antibody titers and/or positive anti-YPT-derived mitogen (YPM) antibody titers. In addition, we tried to identify clinical differences between KD patients in whom YPT infection was or not a contributing factor. We also compared clinical characteristics of patients treated with the protocol of the Randomized controlled trial to Assess Immunoglobulin plus Steroid Efficacy for Kawasaki disease (RAISE) study (RAISE group) and with the conventional Intravenous immunoglobulin (IVIG) protocol (conventional group). Results Eleven patients (10 %) were positive for anti-YPT and/or anti-YPM antibodies (positive group) and 97 (90 %) were negative (negative group). Cardiac sequelae (CS) occurred significantly more frequently in the positive than the negative group (two patients, 18 % vs one patient, 1 %, p = 0.027). Forty patients were in the RAISE group. Two of 40 (5 %) in the RAISE group and one of 68 (1.47 %) in the conventional group had CS (p = 0.55). Conclusions KD patients with YPT infection had CS significantly more frequently and treatment with RAISE protocol did not decrease the frequency of CS in our cohort, nor did YPT infection affect risk scores of no response to IVIG. However, our sample size was overly small to draw such conclusions. Further investigation in a larger cohort is necessary to confirm our findings. Additionally, further research is needed to determine whether early diagnosis of YPT can prevent KD from developing and reduce the incidence of CS.
    Preview · Article · Nov 2015 · BMC Pediatrics
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    ABSTRACT: To date, there have been a very limited number of case reports on combined Alport syndrome (AS) and Klinefelter syndrome (KS). We herein describe the case of a 9-month-old boy diagnosed with concomitant AS and KS. KS was detected on chromosomal analysis of the amniotic fluid, and hematuria/proteinuria was identified in urinary screening at 6 months of age. Renal biopsy indicated AS, with complete deficit of the α5 chain of type IV collagen in the glomerular basement membranes. On genetic analysis for AS, de novo homozygote mutation (c.3605-2a > c) was seen in the gene encoding α5 chain of type IV collagen (COL4A5) on the X chromosomes of maternal origin. This is the first case report of combined AS and KS diagnosed during infancy, and it indicates the need to consider the concurrent existence of these two disorders in infants with urine abnormalities, even in the absence of a family history.
    No preview · Article · Nov 2015 · Pediatrics International
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    ABSTRACT: Neuroblastoma is an aggressive solid tumor that leads to tumor relapse in more than half of high-risk patients. Minimal residual disease (MRD) is primarily responsible for tumor relapses and may be detected in peripheral blood (PB) and bone marrow (BM) samples. To evaluate the disease status and treatment response, a number of MRD detection protocols based on either common or distinct markers for PB and BM samples have been reported. However, the correlation between the expression of MRD markers in PB and BM samples remains elusive in the clinical samples. In the present study, the expression of 11 previously validated MRD markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) was determined in 23 pairs of PB and BM samples collected from seven high-risk neuroblastoma patients at the same time point, and the sample was scored as MRD-positive if one of the MRD markers exceeded the normal range. Although the number of MRD-positive samples was not significantly different between PB and BM samples, the two most sensitive markers for PB samples (CRMP1 and KIF1A) were different from those for BM samples (PHOX2B and DBH). There was no statistically significant correlation between the expression of MRD markers in the PB and BM samples. These results suggest that MRD markers were differentially expressed in PB and BM samples from high-risk neuroblastoma patients.
    Preview · Article · Nov 2015 · Oncology letters
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    ABSTRACT: Recent studies have reported that the absolute lymphocyte count (ALC) during induction therapy is predictive of treatment outcome in de novo acute lymphoblastic leukemia (ALL); however, the significance of ALC on outcomes remains controversial. In the present study, we assessed the significance of ALC at day 29 (ALC-29), the end of induction therapy, on outcomes in our Japanese cohort. The outcomes of 141 patients aged ≤18 years with newly diagnosed ALL who were enrolled on the JACLS ALL-02 at our hospitals were analyzed in terms of ALC-29. Patients with ALC-29 ≥750/μL (n = 81) had a superior 5-year EFS (95.2 ± 2.7 vs 84.3 ± 4.8 %, P = 0.016) and OS (100 vs 87.0 ± 4.7 %, P = 0.0062). A multivariate analysis identified ALC-29 ≥750/μL as a significant predictor of improved EFS and OS after controlling for confounding factors. A multiple linear regression model revealed a significant inverse relationship between the percentage of blasts in bone marrow on day 15 and ALC-29 (P = 0.005). These results indicate that ALC is a simple prognostic factor in childhood ALL, and, thus, has the potential to refine current risk algorithms.
    No preview · Article · Oct 2015 · International journal of hematology
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    ABSTRACT: Background: Vesicoureteral reflux (VUR) is associated with an increased risk of kidney disorders. It is unclear whether VUR is associated with progression from chronic kidney disease (CKD) to end-stage kidney disease (ESKD) in children with congenital anomalies of the kidney and urinary tract (CAKUT). Methods: We conducted a 3-year follow-up survey of a cohort of 447 children with CKD (stage 3-5). Rates of and risk factors for progression to ESKD were determined using the Kaplan-Meier method and Cox regression respectively. Results: Congenital anomaly of the kidney and urinary tract was the primary etiology in 278 out of 447 children; 118 (42.4 %) had a history of VUR at the start of the cohort study. There were significantly more boys than girls with VUR, whereas the proportions were similar in children without VUR. The types of urinary anomalies/complications of the two groups were significantly different. Three-year renal survival rates of the groups were not significantly different, irrespective of CKD stage. Age < 2 years and age after puberty, stage 4 or 5 CKD, and heavy proteinuria, but not history of VUR, were significantly associated with progression to ESKD. Conclusions: History of VUR at the start of follow-up was not associated with the progression of stage 3-5 CKD in children with CAKUT.
    No preview · Article · Sep 2015 · Pediatric Nephrology
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    ABSTRACT: Introduction: Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder that is associated with paraneoplastic diseases. Because OMS can frequently relapse, patients may be inflicted with neurological problems for a long time. Recently, rituximab (RTX) was introduced as a drug to treat OMS. To assess RTX treatment, we studied a patient who experienced recurrence of OMS. Case report: A 2-year-old Japanese boy, who had left adrenal neuroblastoma, suddenly showed OMS symptoms, including ataxia and opsoclonus. Surgical resection of the tumor and subsequent steroid therapy ameliorated his symptoms. When OMS relapsed during the time when prednisolone was reduced, he was treated with full-dose RTX therapy (375mg/m(2)/week) for 4 consecutive weeks. However, 1year later, he presented again with OMS symptoms. This time, we only administered an additional single dose of RTX treatment (375mg/m(2)), allowing remission of OMS symptoms. During 2years after the additional RTX treatment, OMS symptoms did not appear, even when prednisolone was reduced. He had no adverse events associated with RTX during the whole treatment period. Conclusions: An additional single-dose RTX therapy might be effective for relapsed OMS patients who were previously treated with full-dose RTX therapy.
    No preview · Article · Sep 2015 · Brain & development
  • Koichi Kamei · Masao Ogura · Mai Sato · Mayumi Sako · Kazumoto Iijima · Shuichi Ito
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    ABSTRACT: Rituximab (RTX) is known to be effective for the treatment of refractory steroid-dependent nephrotic syndrome (SDNS). However, there are insufficient data on the risk factors for relapse and long-term outcome after RTX treatment. We administered a single dose of RTX to patients with refractory SDNS from November 2007 to December 2013 and continued with immunosuppressants. The risk factors for early relapse and long-term outcome were analyzed. Eighty-one patients were included and the observation period was 13-90 months. Seventy-six patients (94 %) discontinued steroids. Median duration of B-cell depletion was 160 days and 50 % relapse-free survival was 482 days. In multivariate analyses, only a history of steroid-resistant nephrotic syndrome (SRNS) was a statistically significant risk factor (hazard ratio, 2.44; p = 0.048). Fifty percent relapse-free survival in patients without a history of SRNS was 615 days, longer than that of patients with one relapse (393 days; p = 0.005). Fifty-one patients (63 %) received additional RTX treatments for relapses. At last observation, patients using calcineurin inhibitors decreased from 89 % to 23 %, and 12 patients (15 %) discontinued immunosuppressants. Rituximab treatment followed by immunosuppressants is an effective option for patients with SDNS, although a history of SRNS is a risk factor for early relapse.
    No preview · Article · Sep 2015 · Pediatric Nephrology

  • No preview · Article · Sep 2015 · Pediatric Nephrology
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    ABSTRACT: Objectives: To assess the accuracy of transcutaneous bilirubin (TcB) measurements at 5 different body sites in Japanese very low birthweight (VLBW) infants and to determine a cut-off value of TcB to detect total serum/plasma bilirubin (TB) levels ≥10 mg/dL (171 μM). Study design: In a prospective multicenter study, 85 Japanese VLBW infants were enrolled from 5 neonatal intensive care units during the study period. A total of 383 blood samples from infants not receiving phototherapy or ≥24 hours postphototherapy were analyzed. TcB was measured at the forehead, sternum, upper back, lower abdomen, and waist within 1 hour of blood collection. Linear regression analysis and Bland-Altman plots were used to compare TcB values at each site with TB levels. The TcB cut-off value for detecting TB ≥10 mg/dL was determined by receiver operating characteristics curve analysis. Results: TcB significantly correlated with TB, but the coefficient of determination varied among the sites (forehead: 0.5294, sternum: 0.6488, upper back: 0.6321, lower abdomen: 0.5430, waist: 0.7396). At a TcB value ≥8, the sensitivity was 100% at the sternum and upper back, 85% at the waist, 84% at the forehead, and 64% at the lower abdomen to detect TB ≥10 mg/dL. Conclusions: In Japanese VLBW infants, the accuracy of TcB measurements varies according to body site. TcB ≥8 on the sternum or upper back is more reliable than that on the forehead, lower abdomen, or waist to detect TB levels ≥10 mg/dL.
    No preview · Article · Sep 2015 · The Journal of pediatrics
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    ABSTRACT: Glycosylphosphatidylinositol (GPI) anchors tether proteins to the extracellular face of eukaryotic plasma membranes. Defects in the human GPI anchor biosynthetic pathway cause inherited GPI deficiencies (IGDs) characterized by multiple congenital anomalies: dysmorphic faces, developmental delay, hypotonia, and epilepsy. We report the case of a 6-year-old boy with severe psychomotor developmental delay, epilepsy, and decreased granulocyte surface expression of GPI-anchored protein that suggested autosomal recessive GPI deficiency. The case underwent target exome sequencing to screen for IGDs. Target exome sequencing of the proband identified an apparently homozygous c.808T > C (p.Ser270Pro) mutation in PIGN, a gene involved in the GPI anchor biosynthetic pathway. As his parents were expecting another child, genetic carrier screening was conducted for the parents. Direct sequencing of the parents identified a heterozygous c.808T > C PIGN mutation in the father but none in the mother. To identify the mother's mutation, we performed semi-quantitative real-time PCR of the PIGN exons and long PCR, identifying a microdeletion in PIGN (del exons 2-14). The proband had inherited this microdeletion from his mother. Prenatal diagnosis of the fetus revealed that it was a heterozygous carrier of the mother's pathogenic allele. Here, we report a sporadic case of inherited GPI deficiency with a PIGN mutation and the first case of prenatal diagnosis for GPI deficiency. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Sep 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: The nuclear pore complex (NPC) is a huge protein complex embedded in the nuclear envelope. It has central functions in nucleocytoplasmic transport, nuclear framework, and gene regulation. Nucleoporin 107 kDa (NUP107) is a component of the NPC central scaffold and is an essential protein in all eukaryotic cells. Here, we report on biallelic NUP107 mutations in nine affected individuals who are from five unrelated families and show early-onset steroid-resistant nephrotic syndrome (SRNS). These individuals have pathologically focal segmental glomerulosclerosis, a condition that leads to end-stage renal disease with high frequency. NUP107 is ubiquitously expressed, including in glomerular podocytes. Three of four NUP107 mutations detected in the affected individuals hamper NUP107 binding to NUP133 (nucleoporin 133 kDa) and NUP107 incorporation into NPCs in vitro. Zebrafish with nup107 knockdown generated by morpholino oligonucleotides displayed hypoplastic glomerulus structures and abnormal podocyte foot processes, thereby mimicking the pathological changes seen in the kidneys of the SRNS individuals with NUP107 mutations. Considering the unique properties of the podocyte (highly differentiated foot-process architecture and slit membrane and the inability to regenerate), we propose a "podocyte-injury model" as the pathomechanism for SRNS due to biallelic NUP107 mutations.
    No preview · Article · Sep 2015 · The American Journal of Human Genetics
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    ABSTRACT: Autosomal dominant hypocalcemia type 1 (ADH1) is a relatively rare endocrine disorder characterized by hypocalcemia and inadequate parathyroid hormone secretion. ADH is caused by activating mutations in the calcium-sensing receptor (CaSR) gene, CASR. CaSR plays a crucial role in calcium and magnesium homeostasis in the kidney. ADH may be accompanied by hypokalemia and metabolic alkalosis when it is classified as type V Bartter syndrome. However, the mechanism underlying hypokalemia in this disease is unclear. We investigated a 33-year-old woman with hypocalcemia and hypoparathyroidism since childhood, whose mother also had hypocalcemia and hypoparathyroidism, but with no clinical symptoms. Blood examinations showed hypokalemia and metabolic alkalosis in the patient, but not her mother. We conducted mutation analysis and diuretic tests to clarify the patient's and her mother's diagnosis and to investigate the onset mechanism of hypokalemia in ADH1. We also determined the localization of CaSR in the kidney by immunohistochemistry. We detected a known gain-of-function mutation in CASR in both the patient and her mother. Diuretic tests revealed a response to furosemide and no reaction to thiazide in the patient, although the mother responded well to both diuretics. CaSR co-localized with the Na(+)-Cl(-) cotransporter (NCCT) on distal tubular epithelial cells. These results indicate that the NCCT in the distal convoluted tubule was secondarily affected in this patient. We conclude that the main pathogenesis of secondary hypokalemia in ADH1 in this patient was secondary NCCT dysfunction.
    No preview · Article · Sep 2015 · Clinical and Experimental Nephrology
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    ABSTRACT: Newborn screening for urinary cytomegalovirus (CMV) and early introduction of antiviral treatment are expected to improve neurological outcomes in symptomatic congenital CMV-infected infants. This cohort study prospectively evaluated neurological outcomes in symptomatic congenital CMV-infected infants following the introduction of hospital-based newborn urinary CMV screening and antiviral treatment. Following institutional review board approval and written informed consent from their parents, newborns were prospectively screened from 2009 to 2014 for urinary CMV-DNA by PCR within 1week after birth at Kobe University Hospital and affiliated hospitals. CMV-positive newborns were further examined at Kobe University Hospital, and those diagnosed as symptomatic were treated with valganciclovir for 6weeks plus immunoglobulin. Clinical neurological outcomes were evaluated at age ⩾12months and categorized by the presence and severity of neurologic sequelae. Urine samples of 6348 newborns were screened, with 32 (0.50%) positive for CMV. Of these, 16 were diagnosed with symptomatic infection and 12 received antiviral treatment. Four infants developed severe impairment (33%), three developed mild impairment (25%), and five developed normally (42%). This is the first Japanese report of neurological assessments in infants with symptomatic congenital CMV infection who received early diagnosis and antiviral treatment. Urinary screening, resulting in early diagnosis and treatment, may yield better neurological outcomes in symptomatic congenital CMV-infected infants. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
    No preview · Article · Aug 2015 · Brain & development
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    ABSTRACT: Few studies have targeted psychomotor development and associated perinatal risk factors in Japanese very low birth weight (VLBW) infants who are severely small for gestational age (SGA). A single-center study was conducted in 104 Japanese VLBW infants who were born preterm, due to maternal, umbilical cord, or placental abnormalities, between 2000 and 2007. Psychomotor development as a developmental quotient (DQ) was assessed using the Kyoto Scale of Psychological Development at 3years corrected age. Severely SGA was defined as birth weight or length below -2 standard deviation values of the mean values at the same gestation. VLBW infants were divided into 2 subgroups based on gestational age at birth: ⩾28weeks (n=64) and <28weeks (n=40). DQs of infants with severe SGA were compared with those of infants who were appropriate for gestational age (AGA). Factors associated with developmental disabilities in VLBW infants with severe SGA (n=23) were determined. In the group born at ⩾28weeks gestation, infants with severe SGA had normal DQ values and did not significantly differ from those with AGA. However, in the group born at <28weeks gestation, severe SGA infants had significantly lower postural-motor DQ values than AGA infants. Gestational age <28weeks was an independent factor for low postural-motor DQ, regardless of the cause of severe SGA or pregnancy termination. Extremely preterm newborns with severe SGA are at risk of motor developmental disability at age 3years. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
    No preview · Article · Aug 2015 · Brain & development
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    ABSTRACT: Pericatheter leakage is a catheter-related complication of peritoneal dialysis (PD). To prevent pericatheter leakage, a modified technique of PD catheter insertion with fibrin glue was performed in 19 children. At the time of PD catheter insertion, as much fibrin glue as possible was injected into the subcutaneous tissue along the tunneled segment of the catheter and then the skin was compressed. There was no occurrence of pericatheter leakage and full PD could be initiated 1 day (median) after implantation. This technique prevented pericatheter leakage completely even in smaller-weight infants and will enable initiation of full PD with no break-in period. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
    No preview · Article · Aug 2015 · Journal of pediatric urology

Publication Stats

3k Citations
799.11 Total Impact Points


  • 2003-2015
    • Tokyo Metropolitan Children's Medical Center
      Edo, Tokyo, Japan
    • National Defense Medical College
      • Division of Public Health
      Tokorozawa, Saitama, Japan
    • Gunma Children's Medical Center
      Shibukawa, Gunma, Japan
  • 1996-2015
    • Kobe University
      • Division of Pediatrics
      Kōbe, Hyōgo, Japan
  • 2012
    • Aichi Children's Health and Medical Center
      Nagoya, Aichi, Japan
  • 2002-2010
    • National Center for Child Health and Development
      Edo, Tōkyō, Japan
  • 2005-2008
    • Wakayama Medical University
      • Department of Pediatrics
      Wakayama, Wakayama, Japan
  • 1998
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan