Kazumoto Iijima

Kobe University, Kōbe, Hyōgo, Japan

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Publications (196)593.44 Total impact

  • [Show abstract] [Hide abstract]
    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 : CJASN. 09/2014;
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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: Abstract Aims: Neurological outcomes differ considerably between symptomatic and asymptomatic infants with congenital cytomegalovirus (CMV) infection. Our objective was to characterize laboratory markers in symptomatic newborns in comparison with asymptomatic newborns with congenital CMV infection. Methods: Ten newborns with symptomatic and 13 newborns with asymptomatic congenital CMV infection were included in this 3-year prospective cohort study. Total immunoglobulin M (IgM), CMV-IgM, CMV antigenemia, and CMV-DNA in blood and urine were measured and their positive rates and quantitative values compared between the symptomatic and asymptomatic groups. Results: Fifty percent of newborns in the symptomatic group were positive based on total IgM; this was significantly lower than in the asymptomatic group (100%). Quantitative total IgM values were significantly lower, and there were significantly more copies of CMV-DNA in the blood of symptomatic newborns than in asymptomatic newborns (median values for total IgM: 14 vs. 43 mg/dL and blood CMV-DNA: 3.2×102 vs. 3.5×101 copies/106 white blood cells). CMV-IgM, CMV antigenemia, and urine CMV-DNA did not differ significantly between groups. Conclusion: Low total IgM values and high blood CMV loads were associated with the presence of symptoms in newborns with congenital CMV infection.
    Journal of perinatal medicine. 06/2014;
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    ABSTRACT: Bartter syndrome (BS) is a disorder with normotensive hypokalemic alkalosis and hyperreninemic hyperaldosteronemia. BS affects infants or early childhood. Patients with BS type 3 harbor mutation in CLCNKB, Cl channel Kb. Gitelman syndrome (GS) is a disorder in childhood, with mutation in SLC12A3. Isolated adrenocorticotropin deficiency (IAD) causes secondary adrenal insufficiency. Neither elderly cases, nor cases with IAD were previously reported in BS. A 72-year-old man was admitted with acute adrenal crisis. He had been treated for IAD for 19 years. He had no trouble during perinatal period, delivery, and growth. After the recovery from adrenal crisis, laboratory tests revealed hypokalemia; 3.0 mEq/L (normal: 3.5-4.5), impaired renal function: eGFR; 37.6 mL/min/1.73m(2), normomagnesemia; 2.1 mg/dL (1.7-2.3), hyperreninemia; 59.4 ng/mL/h (0.2-2.7), hyperaldosteronemia; 23.5 ng/dL (3.0-15.9), and normal urinary ratio of calcium/creatinine. In diuretic tests, he showed a fine response to furosemide, and a mild response to thiazide. In genetic tests, no mutation of SLC12A3 was found and homozygous mutation: c.1830 G>A in CLCNKB was shown. Thus he was diagnosed as BS type 3. Current case presented with unusual features as BS type 3, 1) his late and mild clinical manifestation suggested GS rather than BS, 2) laboratory data and diuretics tests did not show typical features as BS, and 3) IAD and chronic renal failure altered electrolyte metabolism. In conclusion, current case implies that BS type 3 should be considered even in elderly cases with normotensive hypokalemia, and highlights importance of endocrinological and genetic examinations.
    Endocrine journal. 06/2014;
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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 (Berlin, Germany). 06/2014;
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    ABSTRACT: TAFRO syndrome is a unique clinicopathologic variant of multicentric Castleman's disease that has recently been identified in Japan. It is characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, reticulin Fibrosis of the bone marrow, Renal dysfunction and Organomegaly (TAFRO). Previous reports have shown that affected patients usually respond to immunosuppressive therapy, but the disease sometimes has a fatal course. TAFRO syndrome occurs in the middle-aged and elderly and there are no prior reports of the disease in adolescents. Here we report the first adolescent case, successfully treated with anti-IL-6 receptor antibody (tocilizumab, TCZ) and monitored with serial cytokine profiles.
    BMC Pediatrics 06/2014; 14(1):139. · 1.98 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disease, is mostly caused by exon deletion mutations in the DMD gene. The reading frame rule explains that out-of-frame deletions lead to muscle dystrophin deficiency in DMD. In outliers to this rule, deletion junction sequences have never previously been explored as splicing modulators. In a Japanese case, we identified a single exon 45 deletion in the patient's DMD gene, indicating out-of-frame mutation. However, immunohistochemical examination disclosed weak dystrophin signals in his muscle. Reverse transcription-PCR amplification of DMD exons 42 to 47 revealed a major normally spliced product with exon 45 deletion and an additional in-frame product with deletion of both exons 44 and 45, indicating upstream exon 44 skipping. We considered the latter to underlie the observed dystrophin expression. Remarkably, the junction sequence cloned by PCR walking abolished the splicing enhancer activity of the upstream intron in a chimeric doublesex gene pre-mRNA in vitro splicing. Furthermore, antisense oligonucleotides directed against the junction site counteracted this effect. These indicated that the junction sequence was a splicing silencer that induced upstream exon 44 skipping. It was strongly suggested that creation of splicing regulator is a modifier of dystrophinopathy.Journal of Human Genetics advance online publication, 29 May 2014; doi:10.1038/jhg.2014.36.
    Journal of human genetics. 05/2014;
  • No to hattatsu. Brain and development 05/2014; 46(3):227-8.
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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;
  • Naoya Morisada, Kandai Nozu, Kazumoto Iijima
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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; · 0.88 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; · 2.94 Impact Factor
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    ABSTRACT: Few studies have reported the characterization of postnatal serum concentrations of endogenous free fatty acids (FFAs) in high-risk newborns and their effects on unbound bilirubin (UB). Serum concentrations of FFA, albumin (Alb), UB and total bilirubin (TB) were measured in 713 samples obtained within 5 days after birth from 439 newborns without intravenous lipid supplementation admitted to the neonatal intensive care unit (NICU). Serum FFA was reported as the day-specific percentile-based curve. Serum FFA and FFA/Alb ratios were compared in term and preterm patients. To assess the impact of FFA on UB, daily changes in FFA/Alb and UB/TB ratios were compared in term patients without receiving phototherapy or any drugs, and linear regression analysis was performed between FFA/Alb ratio and serum UB concentration or UB/TB ratio using 140 sera with hyperbilirubinemia of term and preterm patients. A percentile-based curve showed that serum FFA peaked at 1 day of age and progressively decreased. Serum FFA and the FFA/Alb ratio were significantly higher in term than in preterm patients at birth and 1 and 3 days of age. FFA/Alb ratio significantly changed over 5 days after birth, but UB/TB ratio remained constant. FFA/Alb ratio did not correlate with serum UB concentration or UB/TB ratio in sera with hyperbilirubinemia. We assessed postnatal concentrations of serum FFA in a large number of high-risk newborns admitted to the NICU. The concentration of endogenous FFAs in newborns admitted to the NICU was not rising until it influenced UB.
    Annals of Clinical Biochemistry 03/2014; · 1.92 Impact Factor
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    ABSTRACT: Calcineurin inhibitors (CIs) with/without intravenous methylprednisolone pulse therapy (MPT) constitute the standard treatment for childhood-onset, steroid-resistant nephrotic syndrome (SRNS). However, some patients fail to achieve remission. We treated SRNS patients resistant to CIs and MPT with additional rituximab combined with MPT and immunosuppressive agents. Ten patients (aged 2-14 years) with CI- and MPT-resistant SRNS were enrolled. Patients were administered rituximab (1-4 doses; 375 mg/m(2)) followed by MPT (30 mg/kg/day of methylprednisolone for 3 consecutive days) once every 2-4 weeks until complete remission (CR). We analyzed clinical outcome and safety. Six patients received a single dose of rituximab, 2 received two doses, and 2 received four doses. Seven patients achieved CR, 1 achieved partial remission, and 2 showed no response. Although 2 patients with no response progressed to end-stage renal failure, 7 patients with CR preserved normal renal function without proteinuria at the last observation. There were two serious adverse events. Additional rituximab combined with conventional MPT and immunosuppressive agents is a promising option for overcoming refractory SRNS. Aggressive B cell suppression by rituximab may ameliorate resistance to conventional treatments and a cocktail of other immunosuppressive agents, such as CIs, MMF, mizoribine, may be beneficial. However, as intense immunosuppression may cause serious adverse events, further evaluation is necessary.
    Pediatric Nephrology 02/2014; · 2.94 Impact Factor
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    ABSTRACT: The importance of the transition from pediatric to adult healthcare has recently been recognized. In patients with steroid-sensitive nephrotic syndrome (SSNS), the shift in steroid dose during the transition period is a big problem. Thus, change in treatment methods during this transition need to be clarified. Questionnaires were sent to all councilors of the Japanese Society for Pediatric Nephrology who managed SSNS in children. The questionnaires asked about steroid dose, informed consent, and transition programs. Councilors in 50 of 57 (87.7 %) institutes responded within 2 weeks. About one-third of pediatric nephrologists (PNs) did not transfer patients to adult units, and half of PNs followed patients after they reached adulthood (i.e., age >20 years). The dose of steroids after puberty varied between doctors, but 74 % of PNs provided short-term daily therapy. 72 % of PNs informed the patients of the shift in steroid dose, but 26 % of PNs did not. About two-thirds of PNs did not consult with adult nephrologists before the transition from pediatric to adult care. No institute had a transition program for SSNS and 2 institutes had transition coordinators. Transition programs are needed in Japan. But the difference in the steroid regimen between pediatric and adult patients with SSNS is a barrier to transition. This difference needs to be discussed.
    Clinical and Experimental Nephrology 02/2014; · 1.25 Impact Factor
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    ABSTRACT: To reduce the incidence of infants with congenital infections, women should be aware of and know prevention measures against maternal infection with mother-to-child infections during pregnancy. Our objective was to assess the awareness of and knowledge about mother-to-child infections in Japanese pregnant women. A survey of 343 Japanese pregnant women was completed. Awareness of 13 pathogens capable of mother-to-child transmission was surveyed. Knowledge about the transmission route, the most susceptible time of infection that may cause severe fetal disease during pregnancy, and methods to prevent maternal infection were investigated for four major pathogens (cytomegalovirus, rubella virus, Toxoplasma gondii, and parvovirus B19) and results were compared between these pathogens. The proportion of women aware of pathogens concerning TORCH syndrome was the following: rubella virus 76%, Treponema pallidum 69%, Toxoplasma gondii 58%, parvovirus B19 28%, herpes simplex virus 27%, and cytomegalovirus 18%. Only 8% knew how cytomegalovirus is transmitted, and only 12% knew how parvovirus B19 is transmitted; both were significantly lower than those who knew transmission routes for rubella virus or Toxoplasma gondii. The proportion of women who knew the most susceptible time for severe fetal infection by maternal acquisition of cytomegalovirus, Toxoplasma gondii, or parvovirus B19 was significantly lower than that for rubella virus. The vast majority of surveyed women were not aware of methods to prevent maternal infection with cytomegalovirus or parvovirus B19. In conclusion, current awareness of and knowledge about cytomegalovirus and parvovirus B19 infection are low in Japanese pregnant women.
    Congenital Anomalies 02/2014; 54(1):35-40.
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    ABSTRACT: Abstract Objective: To determine whether dried umbilical cords (UCs) are useful for retrospective diagnosis of intrauterine enterovirus (EV) infection. Methods: Dried UCs in two patients with neonatal EV sepsis and 10 neonates without infectious signs were enrolled. Viral RNA was extracted from their dried UCs, and nested RT-PCR was performed. Results: Infection routes estimated by the clinical course were intrauterine infection in Case 1 and postnatal horizontal infection in Case 2. EV-RNA was detected from dried UC in Case 1, but not in Case 2 and 10 neonates. Conclusions: This report showed the potential use of dried UCs for retrospective diagnosis of intrauterine EV infection.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 01/2014; · 1.36 Impact Factor
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    ABSTRACT: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.
    Neurology 01/2014; · 8.25 Impact Factor
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    ABSTRACT: Background: Menkes disease is a lethal disorder associated with copper metabolism. Although early treatment with copper-histidine injections can improve outcomes, early diagnosis is difficult because the clinical features of Menkes disease are subtle or do not manifest in affected neonates. Previous report stated that the low activity of dopamine β-hydroxylase, a copper-dependent enzyme, leads to increases in the urine homovanillic acid/vanillylmandelic acid (HVA/VMA) ratios in patients with Menkes disease, and indicated that a urine HVA/VMA ratio cut-off value of >4 is useful in screening for Menkes disease. Methods: We examined the standard values of the urine HVA/VMA ratio in unaffected neonates and assessed its use as a screening parameter for Menkes disease among neonates. In total, 112 neonates, aged between 1 and 6 days, were enrolled in the study and were classified into 2 groups based on their urine HVA/VMA ratios: high (>4) and low (⩽4). Results: Multivariate logistic analysis revealed that mechanical ventilation was an independent risk factor for a high urine HVA/VMA ratio (odds ratio: 21.94; 95% confidence interval: 2.82–247.03; p = 0.004). The mean urine HVA/VMA ratio was 2.47 ± 0.67 among 92 neonates who did not receive mechanical ventilation. Conclusion: This study established standard values for the urine HVA/VMA ratio in newborn babies that could be useful in screening for Menkes disease among neonates.
    Brain & development 01/2014; · 1.74 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.
    Lancet. 01/2014;

Publication Stats

2k Citations
593.44 Total Impact Points


  • 2000–2014
    • Kobe University
      • Division of Pediatrics
      Kōbe, Hyōgo, Japan
  • 2013
    • Seirei Hamamatsu General Hospital
      Hamamatu, Shizuoka, Japan
    • Kansai Medical University
      • Department of Paediatrics
      Moriguchi, Ōsaka, Japan
  • 2003–2013
    • Tokyo Metropolitan Children's Medical Center
      Edo, Tōkyō, Japan
  • 2002–2013
    • National Center for Child Health and Development
      Edo, Tōkyō, Japan
  • 2001–2013
    • Wakayama Medical University
      • Department of Pediatrics
      Wakayama, Wakayama, Japan
  • 2012
    • Numazu City Hospital
      Sizuoka, Shizuoka, Japan
    • Aichi Children's Health and Medical Center
      Nagoya, Aichi, Japan
  • 2001–2003
    • Hyogo University of Health Sciences
      Kōbe, Hyōgo, Japan
  • 1998–1999
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan