Kandai Nozu

Kobe University, Kōbe, Hyōgo, Japan

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Publications (84)305.26 Total impact

  • The Lancet 01/2015; · 39.21 Impact Factor
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    ABSTRACT: Although a 2-year combination therapy is effective for severe childhood immunoglobulin A (IgA) nephropathy, proteinuria persists in some patients even after the treatment. Seventy-nine patients aged <18 years with IgA nephropathy in which >80 % of glomeruli showed mesangial proliferation were enrolled in the study. Risk factors for persistent proteinuria after combination therapy were investigated using multivariate logistic regression analysis. Proteinuria (≥0.2 g/1.73 m(2)/day) persisted in 27 patients (34 %) after the combination therapy. Twenty-four-hour urinary protein excretion, rate of glomeruli with crescents, rate of glomeruli with segmental sclerosis and rate of glomeruli with global sclerosis at diagnosis were higher in patients with persistent proteinuria than those without. In the multivariate analysis, 24-h urinary protein excretion [odds ratio (OR) 6.9; 95 % confidence interval (CI) 2.1-27.8; p = 0.001] and rate of glomeruli with crescents (OR 3.8; 95 % CI 1.1-13.9; p = 0.03) were independent risk factors for persistent proteinuria. Analysis of the receiver operating characteristic curve demonstrated that the most accurate cut-off values to detect persistent proteinuria were a urinary protein excretion of 1.32 g/1.73 m(2)/day and a 14 % rate of glomeruli with crescents. In our cohort, urinary protein excretion and rate of glomeruli with crescents at diagnosis were independent risk factors for persistent proteinuria after the combination therapy.
    Pediatric Nephrology 12/2014; · 2.88 Impact Factor
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    ABSTRACT: Background Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity. Methods We did a multicentre, double-blind, randomised, placebo-controlled trial at nine centres in Japan. We screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1–18 years. Patients with complicated FRNS or SDNS who met all other criteria were eligible for inclusion after remission of the relapse at screening. We used a computer-generated sequence to randomly assign patients (1:1) to receive rituximab (375 mg/m2) or placebo once weekly for 4 weeks, with age, institution, treatment history, and the intervals between the previous three relapses as adjustment factors. Patients, guardians, caregivers, physicians, and individuals assessing outcomes were masked to assignments. All patients received standard steroid treatment for the relapse at screening and stopped taking immunosuppressive agents by 169 days after randomisation. Patients were followed up for 1 year. The primary endpoint was the relapse-free period. Safety endpoints were frequency and severity of adverse events. Patients who received their assigned intervention were included in analyses. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000001405. Findings Patients were centrally registered between Nov 13, 2008, and May 19, 2010. Of 52 patients who underwent randomisation, 48 received the assigned intervention (24 were given rituximab and 24 placebo). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223–374) than in the placebo group (101 days, 70–155; hazard ratio: 0·27, 0·14–0·53; p<0·0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p=0·36). Interpretation Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS. Funding Japanese Ministry of Health, Labour and Welfare.
    The Lancet 10/2014; · 39.21 Impact Factor
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    ABSTRACT: Microdeletion of 16q12 is a rare chromosomal abnormality. We present the cases of two Japanese patients with developmental and renal symptoms of differing clinical severity. Both patients had 16q12 interstitial microdeletions that included the entire SALL1 gene. Patient 1 was a 15-year-old Japanese boy clinically diagnosed with branchio-oto-renal syndrome with mild developmental delay, but with no imperforate anus or polydactyly. Array comparative genome hybridization (aCGH) indicated a 5.2 Mb deletion in 16q12, which included SALL1. Patient 2 was a 13-year-old Japanese boy diagnosed with Townes–Brocks syndrome and severe developmental delay, epilepsy, and renal insufficiency requiring renal replacement therapy. Fluorescence in situ hybridization indicated deletion of the entire SALL1 gene. Subsequent aCGH showed a 6 Mb deletion in 16q12q13, which included SALL1. Precise analysis of the present two cases will give us some clues to elucidate the pathogenic mechanisms of 16q12 microdeletion syndrome.
    Pediatrics International 10/2014; 56(5). · 0.73 Impact Factor
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    ABSTRACT: X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.
    Clinical Journal of the American Society of Nephrology 09/2014; · 5.25 Impact Factor
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    ABSTRACT: The criterion for performing a renal biopsy in children with idiopathic nephrotic syndrome (NS) showing microscopic hematuria at onset remains controversial.
    Pediatric nephrology (Berlin, Germany). 08/2014;
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    ABSTRACT: In this multicenter, open-label, randomized controlled trial, we determined whether 2-month prednisolone therapy for steroid-sensitive nephrotic syndrome was inferior or not to 6-month therapy despite significantly less steroid exposure. The primary end point was time from start of initial treatment to start of frequently relapsing nephrotic syndrome. The pre-specified non-inferiority margin was a hazard ratio of 1.3 with one-sided significance of 5%. We randomly assigned 255 children with an initial episode of steroid-sensitive nephrotic syndrome to either 2 - or 6-month treatment of which 246 were eligible for final analysis. The total prednisolone exposure counted both initial and relapse prednisolone treatment administered over 24 months. Median follow-up in months was 36.7 in the 2-month and 38.2 in the 6-month treatment group. Time to frequent relaps was similar in both groups; however, the median was reached only in the 6-month group (799 days). The hazard ratio was 0.86 (90% confidence interval, 0.64-1.16) and met the non-inferior margin. Time to first relapse was also similar in both groups: median day 242 (2-month) and 243 (6-month). Frequency and severity of adverse events were similar in both groups. Most adverse events were transient and occurred during initial or relapse therapy. Thus, 2 months of initial prednisolone therapy for steroid-sensitive nephrotic syndrome, despite less prednisolone exposure, is not inferior to 6 months of initial therapy in terms of time to onset of frequently relapsing nephrotic syndrome.Kidney International advance online publication, 23 July 2014; doi:10.1038/ki.2014.260.
    Kidney International 07/2014; · 8.52 Impact Factor
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    ABSTRACT: Although the Oxford classification of IgA nephropathy appears valid, we found crescents were significantly related to renal outcome in our cohort, whereas segmental glomerulosclerosis (S) was not. The timing of renal biopsy may significantly affect the variables in the Oxford classification.
    Pediatric Nephrology 06/2014; · 2.88 Impact Factor
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    ABSTRACT: Mutation-induced activation of splice sites in intronic repetitive sequences has contributed significantly to the evolution of exon–intron structure and genetic disease. Such events have been associated with mutations within transposable elements, most frequently in mutation hot-spots of Alus. Here, we report a case of Alu exonization resulting from a 367-nt genomic COL4A5 deletion that did not encompass any recognizable transposed element, leading to the Alport syndrome. The deletion brought to proximity the 5′ splice site of COL4A5 exon 33 and a cryptic 3′ splice site in an antisense AluY copy in intron 32. The fusion exon was depleted of purines and purine-rich splicing enhancers, but had low levels of intramolecular secondary structure, was flanked by short introns and had strong 5′ and Alu-derived 3′ splice sites, apparently compensating poor composition and context of the new exon. This case demonstrates that Alu splice sites can be activated by outlying deletions, highlighting Alu versatility in shaping the exon–intron organization and expanding the spectrum of mutational mechanisms that introduce repetitive sequences in mRNAs.
    Molecular Genetics & Genomic Medicine. 05/2014;
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    ABSTRACT: Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchiogenic malformation, hearing loss and renal anomalies. The prevalence of BOR syndrome is 1/40,000 in Western countries, and nationwide surveillance in 2009–2010revealed that there were approximately 250 BOR patients in Japan. Three causative genes for BOR syndrome have been reported thus far:EYA1, SIX1, and SIX5.However, the causative genes for approximately half of all BOR patients remain unknown. This review article discusses the epidemiology, clinical symptoms, genetic background and management of BOR syndrome.
    Pediatrics International 04/2014; · 0.73 Impact Factor
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    ABSTRACT: Autosomal recessive Alport syndrome (ARAS) is a rare hereditary disease caused by homozygous or compound heterozygous mutations in either the COL4A3 or COL4A4 genes. Failure to diagnose ARAS cases is common, even if detailed clinical and pathological examinations are carried out. As the mutation detection rate for ARAS is unsatisfactory, we sought to develop more reliable diagnostic methods and provide a better description of the clinicopathological characteristics of this disorder. A retrospective analysis of 30 genetically diagnosed patients with ARAS in 24 pedigrees was conducted. The mutation detection strategy comprised three steps: (1) genomic DNA analysis using polymerase chain reaction (PCR) and direct sequencing; (2) mRNA analysis using reverse transcription (RT)-PCR to detect RNA processing abnormalities; (3) semi-quantitative PCR using capillary electrophoresis to detect large heterozygous deletions. Using the three-step analysis, we identified homozygous or compound heterozygous mutations in all patients. Interestingly, 20 % of our ARAS patients showed normal expression of α5 in kidney tissue. The median age of developing end-stage renal disease was 21 years. The strategy described in this study improves the diagnosis for ARAS families. Although immunohistochemical analysis of α5 can provide diagnostic information, normal distribution does not exclude the diagnosis of ARAS.
    Pediatric Nephrology 03/2014; · 2.88 Impact Factor
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    ABSTRACT: X-linked Alport syndrome is caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain (α5(IV)). Complete absence of α5(IV) in the renal basal membrane is considered a pathological characteristic in male patients; however, positive α5(IV) staining has been found in over 20% of patients. We retrospectively studied 52 genetically diagnosed male X-linked Alport syndrome patients to evaluate differences in clinical characteristics and renal outcomes between 15 α5(IV)-positive and 37 α5(IV)-negative patients. Thirteen patients in the α5(IV)-positive group had non-truncating mutations consisting of nine missense mutations, three in-frame deletions, and one splice-site mutation resulting in small in-frame deletions of transcripts. The remaining two showed somatic mutations with mosaicism. Missense mutations in the α5(IV)-positive group were more likely to be located before exon 25 compared with missense mutations in the α5(IV)-negative group. Furthermore, urinary protein levels were significantly lower and the age at onset of end-stage renal disease was significantly higher in the positive group than in the negative group. These results help to clarify the milder clinical manifestations and molecular characteristics of male X-linked Alport syndrome patients expressing the α5(IV) chain.Kidney International advance online publication, 4 December 2013; doi:10.1038/ki.2013.479.
    Kidney International 12/2013; · 8.52 Impact Factor
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    ABSTRACT: An open-label, multicenter, randomized phase II trial was conducted from July 1, 2005 to March 29, 2011 to compare two protocols for treating children with frequently relapsing nephrotic syndrome using microemulsified cyclosporine. Ninety-three children with frequently relapsing nephrotic syndrome were randomly assigned to group A (n=46) or group B (n=47). In both groups, the 2-hour postdose cyclosporine level was monitored. For group A, the cyclosporine target was set to 600-700 ng/ml for the first 6 months and 450-550 ng/ml for the next 18 months; for group B, it was set to 450-550 ng/ml for the first 6 months and 300-400 ng/ml for the next 18 months. The primary end point was the sustained remission rate. At the end of the study, if there was no difference in safety profile between the two groups and the sustained remission rate in group A was superior to group B with a decision threshold of 8%, then the regimen for group A would be determined the better treatment. Eight children from an ineligible institution, where cyclosporine levels were not measured, were excluded from all analyses. At 24 months, the sustained remission rate was nonsignificantly higher in group A (n=43) than group B (n=42; 64.4% versus 50.0%; hazard ratio, 0.57; 95% confidence interval, 0.29 to 1.11; P=0.09), and the progression-free survival rate was significantly higher (88.1% versus 68.4%; hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.94; P=0.03). The relapse rate was significantly lower in group A than group B (0.41 versus 0.95 times/person-year; hazard ratio, 0.43; 95% confidence interval, 0.19 to 0.84; P=0.02). The rate and severity of adverse events were similar in both treatment groups. The sustained remission rate was not significantly different between the two treatment groups, but the regimen with the higher 2-hour postdose cyclosporine level target improved progression-free survival and reduced the relapse rate.
    Clinical Journal of the American Society of Nephrology 11/2013; · 5.07 Impact Factor
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    ABSTRACT: Background/Aims: Exercise-induced acute renal failure [exercise-induced acute kidney injury (EI-AKI)] is defined as AKI due to heavy anaerobic exercise. Although hypouricemia is known to be a risk factor for the onset of EI-AKI, a direct causal link between EI-AKI and serum uric acid has not been established. This study aimed to analyze urate transporter genes in patients with EI-AKI and its molecular mechanism. Methods: Genomic DNA and total RNA were isolated from peripheral blood leukocytes of patients with a history of EI-AKI. Mutations were analyzed by PCR and a direct sequencing method. We first analyzed the SLC22A12 gene, and then the SLC2A9 gene if no mutations were found in SLC22A12. Results: Seventeen patients were enrolled in this study and 16 had mutations: 15 in SLC22A12 and 1 in SLC2A9. Fourteen (82.4%) patients showed hypouricemia, and all of the patients with hypouricemia had either homozygous or compound heterozygous mutations in SLC22A12 or SLC2A9, which confirmed that all of them had renal hypouricemia. Two patients had heterozygous mutations of SLC22A12, and they were not accompanied by hypouricemia. One patient was found to have no mutations in SLC22A12 or SLC2A9. Conclusion: We were able to determine the genetic background of urate transporter genes in patients with EI-AKI. Decreased function of urate transporters, rather than decreased serum uric acid levels, may be of great importance for the onset of EI-AKI. © 2013 S. Karger AG, Basel.
    American Journal of Nephrology 10/2013; 38(4):316-320. · 2.65 Impact Factor
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    ABSTRACT: Multicystic dysplastic kidney (MCDK) is one of the most common congenital abnormalities of the kidney and urinary tract (CAKUT), although its pathophysiology remains unknown. Familial occurrence of MCDK suggests that mutations in genes associated with nephrogenesis are involved in the pathogenesis in at least some cases. Hepatocyte nuclear factor 1β (HNF1β) is a member of the homeodomain-containing super family of transcription factors, and is known to regulate tissue-specific gene expression in a number of organs including the kidneys, pancreas and liver. It has been recently postulated to be associated with CAKUT, including MCDK. We recently encountered a family with a deletion mutant of HNF1β, of which the 2nd son, the proband, developed bilateral MCDK resulting in renal loss of function in infancy while the 1st son developed unilateral MCDK. Their father has two normal kidneys. This family confirmed that mutations in the HNF1β gene are strongly associated with the development of MCDK. Furthermore, the fact that no clear phenotype-genotype correlation exists suggests that gene(s) other than HNF1β are also involved in nephrogenesis and the development of MCDK.
    Clinical nephrology 06/2013; 79(6):484-487. · 1.23 Impact Factor
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    ABSTRACT: BACKGROUND: A possible mechanism of cyclosporine (CsA) nephrotoxicity is tubular apoptosis. Endoplasmic reticulum (ER) stress has been shown to be an apoptosis activator. Glucose-regulated proteins 78 and 94 (GRP78, GRP94, respectively) are ER stress-induced chaperones. Eukaryotic translation initiation factor 2α (EIF2α) attenuates protein synthesis. If stress is prolonged, cells undergo apoptosis, inducing the production of GADD153, a transcription factor, which in turn downregulates anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). METHODS: Endoplasmic reticulum stress-related molecules were evaluated by real-time polymerase chain reaction (PCR) using renal biopsy tissues from 17 children with frequently relapsing nephrotic syndrome before and after 2 years of CsA therapy. RESULTS: GRP78, GRP94, eIF2α, and Bcl-2 were significantly upregulated in renal biopsy tissues from children 2 years post-CsA treatment. However, there was almost no change in GADD153. Mean ratios of post- to pre-CsA expression of GRP78, GRP94, eIF2α and Bcl-2 were 2.53, 1.80, 2.38 and 1.92, respectively. Post-CsA administration, GRP78 and eIF2α were upregulated by up to sixfold, and GRP94 and Bcl-2 were upregulated by up to fourfold compared with the respective pre-CsA levels. There were significant correlations between GRP78, GRP94, eIF2α, and Bcl-2 levels. These findings suggest that CsA induced an unfolded protein response due to ER stress, but did not cause apoptosis. CONCLUSIONS: An unfolded protein response due to ER stress induced by CsA may function in a defensive manner, with less apoptosis occurring under low-dose conditions. This finding is important for the rationale for CsA administration.
    Pediatric Nephrology 01/2013; · 2.88 Impact Factor
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    ABSTRACT: We analyzed the SLC26A3 gene in patients with a clinical diagnosis of Bartter and Gitelman syndromes in whom genetic diagnoses could not be determined. We also examined the genetic and clinical characteristics of patients for whom genetic proof could not be obtained. The present study included 10 patients. With regard to genetic characteristics, 1 patient harbored a heterozygous mutation in the SLC12A3 gene (c.2573T>A, p.L858H), which was also reported in a previous report. With regard to clinical characteristics, 3 patients had abnormalities that were identified incidentally during medical examinations and other illnesses and 1 patient had polyhydramnios. One case of nephrocalcinosis was also noted. Eight patients were of below average height. Although we analyzed the SLC26A3 gene in these 10 patients, none were found to have pathological mutations. Investigation of the outcomes of these cases showed that examination findings had normalized and medication was no longer necessary for 3 patients, whereas hypokalemia and metabolic alkalosis were observed in another patient only in the presence of acute disease. We concluded that few patients develop illnesses because of SLC26A3 mutations. Other disease-related genes may also be involved. Although hypokalemia and metabolic alkalosis are clinical characteristics of Bartter and Gitelman syndromes, many other conditions also present such symptoms, and thus, differential diagnosis is of paramount importance.
    The Kobe journal of medical sciences 01/2013; 59(2):E36-43.
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    ABSTRACT: BACKGROUND: Some patients with IgA nephropathy (IgAN) achieve spontaneous remission even when not receiving medication. However, details on such remissions remain unknown. The aim of our study was to clarify this information in the clinical setting of childhood IgAN with minor glomerular abnormalities or focal mesangial proliferation (MGA/FMP). METHODS: This study was a retrospective analysis of 96 children with MGA/FMP who did not receive medication from among the 555 patients with newly diagnosed childhood IgAN treated between January 1972 and December 2000. The Kaplan-Meier method and Cox proportional hazard model were used for the analysis. RESULTS: Of the 96 pediatric patients who did not receive medication, 57 (59.4 %) achieved spontaneous remission. The cumulative spontaneous remission rates among these patients were 57.5 and 77.4 % at 5 and 10 years, respectively, from onset. The mean time from onset to remission was 5.9 ± 0.4 years. Clinical and histological findings were similar between the remission and non-remission groups. Of the 57 patients with spontaneous remissions, ten (17.5 %) also developed a recurrence of urinary abnormalities. The cumulative recurrence-free rates were 79.9 and 67.9 % at 5 and 10 years, respectively, after remission. CONCLUSIONS: The spontaneous remission rate in childhood IgAN with MGA/FMP was higher than expected. Our results suggest that physicians should consider the potential for spontaneous remission and refrain from very aggressive treatment in IgAN patients with MGA/FMP.
    Pediatric Nephrology 09/2012; · 2.88 Impact Factor
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    ABSTRACT: The renal prognosis of patients with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation syndrome (WAGR) is poor. However, the renal histology and its mechanisms are not well understood. We performed renal biopsies in 3 patients with WAGR syndrome who had heavy proteinuria. The complete deletion of one WT1 allele was detected in each patient by constitutional chromosomal deletion at 11p13 using G-banding, high-resolution G-banding, and fluorescence in situ hybridization. The patients exhibited proteinuria at the ages of 6, 10, and 6 years and were diagnosed as having focal segmental glomerulosclerosis (FSGS) at the ages of 7, 16 and 19 years, respectively. They exhibited normal or mildly declined renal function at the time of biopsy. Re-examination of a nephrectomized kidney from 1 patient revealed that some glomeruli showed segmental sclerosis, although he did not have proteinuria at the time of nephrectomy. The other 2 patients did not develop Wilms' tumor and thus did not undergo nephrectomy, chemotherapy, or radiotherapy, thereby eliminating any effect of these therapies on the renal histology. In conclusion, complete deletion of one WT1 allele may induce the development of FSGS. Our findings suggest that haploinsufficiency of the WT1 could be responsible for the development of FSGS.
    PEDIATRICS 05/2012; 129(6):e1621-5. · 5.30 Impact Factor
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    ABSTRACT: Atypical membranoproliferative glomerulonephritis (MPGN) is considered to progress to typical MPGN, and it is believed that it can be treated with corticosteroids. However, consensus that atypical MPGN is a continuum of morphologic manifestations of typical MPGN cannot be reached. Herein, we report two cases of atypical MPGN with opposite clinical course. Case 1 was a 4-year-old boy with macrohematuria and proteinuria with no prodromal symptoms. His serum C3 level had abruptly dropped, and renal biopsy confirmed a diagnosis of atypical MPGN. After performing kidney biopsy, his urinary abnormality improved and his C3 level had normalized 1 year after onset without medication. At the most recent follow-up, neither proteinuria nor hematuria was detected. Case 2 was a 7-year-old girl with microhematuria and proteinuria at her school urinary screening. Her first biopsy finding was similar to dense deposit disease, and the second biopsy showed atypical MPGN. Oral corticosteroids were started from this point, but heavy proteinuria and hypocomplementemia could not be improved sufficiently. We immediately performed third kidney biopsy and diagnosed typical MPGN. These findings suggest that the indication of therapy for atypical MPGN should be re-examined. Aggressive therapy such as steroid administration is not necessarily essential and effective for therapeutic intervention of all atypical MPGN. Moreover, atypical MPGN may involve different etiologic and pathogenetic factors, rather than a continuum of morphologic manifestations of MPGN.
    CEN Case Reports. 05/2012; 1(1).

Publication Stats

693 Citations
305.26 Total Impact Points


  • 2002–2014
    • Kobe University
      • Division of Pediatrics
      Kōbe, Hyōgo, Japan
  • 2008–2013
    • Kansai Medical University
      • Department of Paediatrics
      Moriguchi, Ōsaka, Japan
    • Tokyo Metropolitan Children's Medical Center
      Edo, Tōkyō, Japan
  • 2006–2011
    • Wakayama Medical University
      • Department of Pediatrics
      Wakayama, Wakayama, Japan
  • 2009
    • National Center for Child Health and Development
      Edo, Tōkyō, Japan