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PubMed | Funabashi Municipal Medical Center, Hidaka General Hospital, Asahi General Hospital, Chiba Childrens Hospital and 23 more.
Type: Journal Article | Journal: PloS one | Year: 2016

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.


PubMed | Center for Clinical Research and Development, Tokyo Women's Medical University, Fukushima Medical University, Nagoya University and 10 more.
Type: Journal Article | Journal: Clinical and experimental nephrology | Year: 2016

Transition of adolescent and young adult (AYA) patients with childhood-onset chronic kidney diseases (C-CKD) from pediatric to adult renal services has received increasing attention. However, information on transition of Japanese patients with C-CKD is limited.The Transition Medicine Working Group, in collaboration with the Japanese Society for Nephrology, the Japanese Society for Pediatric Nephrology and the Japanese Society of Pediatric Urology, conducted a retrospective cross-sectional study in 2014 on issues concerning the transition of Japanese patients with C-CKD.Few institutions in Japan had transition programs and/or transition coordinators for patients with C-CKD. Refusal to transfer by patients or their families, lack of concern about transition and inability to decide on transfer were common reasons for non-transfer of patients still followed by pediatric renal services. Around 25% of patients who had ended or interrupted follow-up by pediatric renal services presented to adult renal services because of symptoms associated with C-CKD. Patients with various types of childhood-onset nephrourological diseases were transferred from pediatric to adult renal services. IgA nephropathy, minimal change nephrotic syndrome and congenital anomalies of the kidney and urinary tract were the most frequent primary kidney diseases in adult patients with C-CKD.These survey results indicate the need for introduction of transitional care for Japanese AYA patients with C-CKD. Consensus guidelines for the optimal clinical management of AYA patients with C-CKD are required to ensure the continuity of care from child to adult renal services.


PubMed | Center for Clinical Research and Development, Tokyo Women's Medical University, Japan National Research Institute of Fisheries Science, Kansai Medical University and 5 more.
Type: Journal Article | Journal: American journal of human genetics | Year: 2015

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 107kDa (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 133kDa) and NUP107 incorporation into NPCs invitro. 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 ofthe 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.


PubMed | Japan Atomic Energy Agency, Hamamatsu University, Chinese University of Hong Kong, Tokyo Electron and 7 more.
Type: | Journal: Lancet (London, England) | Year: 2016

Evidence is accumulating that early consumption is more beneficial than is delayed introduction as a strategy for primary prevention of food allergy. However, allergic reactions caused by early introduction of such solid foods have been a problematic issue. We investigated whether or not early stepwise introduction of eggs to infants with eczema combined with optimal eczema treatment would prevent egg allergy at 1 year of age.In this randomised, double-blind, placebo-controlled trial, we enrolled infants 4-5 months of age with eczema from two centres in Japan. Exclusion criteria were being born before 37 weeks of gestational age, experience of ingestion of hens eggs or egg products, history of immediate allergic reaction to hens eggs, history of non-immediate allergic reaction to a particular type of food, and complications of any severe disease. Infants were randomly assigned (block size of four; stratified by institution and sex) to early introduction of egg or placebo (1:1). Participants in the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age. We aggressively treated participants eczema at entry and maintained control without exacerbations throughout the intervention period. Participants and physicians were masked to assignment, and allocation was concealed. The primary outcome was the proportion of participants with hens egg allergy confirmed by open oral food challenges at 12 months of age, assessed blindly by standardised methods, in all randomly allocated participants who received the intervention. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000008673.Between Sept 18, 2012, and Feb 13, 2015, we randomly allocated 147 participants (73 [50%] to the egg group and 74 [50%] to the placebo group). This trial was terminated on the basis of the results of the scheduled interim analysis of 100 participants, which showed a significant difference between the two groups (four [9%] of 47 participants had an egg allergy in the egg group vs 18 [38%] of 47 in the placebo group; risk ratio 0222 [95% CI 0081-0607]; p=00012). In the primary analysis population, five (8%) of 60 participants had an egg allergy in the egg group compared with 23 (38%) of 61 in the placebo group (risk ratio 0221 [0090-0543]; p=00001). The only difference in adverse events between groups was admissions to hospital (six [10%] of 60 in the egg group vs none in the placebo group; p=0022). 19 acute events occurred in nine (15%) participants in the egg group versus 14 events in 11 (18%) participants in the placebo group after intake of the trial powder.Introduction of heated egg in a stepwise manner along with aggressive eczema treatment is a safe and efficacious way to prevent hens egg allergy in high-risk infants. In this study, we developed a practical approach to overcome the second wave of the allergic epidemic caused by food allergy.Ministry of Health, Labour and Welfare, and National Centre for Child Health and Development, Japan.


PubMed | University of Miyazaki, Center for Clinical Research and Development, National Hospital Organization Chiba East National Hospital, Okayama University of Science and Kanazawa Medical University
Type: Journal Article | Journal: Clinical and experimental nephrology | Year: 2016

The clinical presentation of Henoch-Schnlein purpura nephritis (HSPN) has not been thoroughly investigated among patients of different ages. We therefore compared the features of HSPN and IgA nephropathy (IgAN) based on data from the Japan Renal Biopsy Registry (J-RBR).This cross-sectional study analyzed data from patients who were registered in the J-RBR between 2007 and 2012. Clinico-pathological findings at diagnosis were compared among children (aged 18years), adult (aged 19-64years) and elderly (aged 65years) patients with HSPN (n=513) and IgAN (n=5679).The age at diagnosis considerably differed between HSPN and IgAN; HSPN peaked at 1-19 and at 60-69years, whereas IgAN peaked at 30-39years. The clinical features were significantly more severe for HSPN than IgAN, especially proteinuria (children, 1.28 vs. 0.57; adult, 1.95 vs. 1.05; elderly patients, 2.71 vs. 1.64g/day), and low albumin levels (children, 3.72 vs. 4.13; adults, 3.62 vs. 3.99; elderly patients, 3.07 vs. 3.57g/dL). The rate (%) of histologically classified endocapillary proliferative or crescentic glomerulonephritis was higher in patients with HSPN than with IgAN. Multiple regression analysis revealed that low albumin level and high BP were independent factors associated with decreased estimated glomerular filtration rates in adult and elderly patients with HSPN.Age at HSPN diagnosis was bimodally distributed, and the clinical features of HSPN were more severe than those of IgAN across all age groups.


Funaki T.,National Center for Child Health and Development | Inoue E.,Center for Clinical Research and Development | Miyairi I.,National Center for Child Health and Development
BMC Infectious Diseases | Year: 2016

Background: Invasive diseases due to Moraxella catarrhalis are rare in children, even in immunocompromised hosts. Therefore, data regarding clinical characteristics and risk factors of such patients are limited. The aim of this study is to compare the clinical characteristics of patients with bacteremia due to Moraxella catarrhalis against those with bacteremia due to Streptococcus pneumoniae and Haemophilus influenzae. Methods: We performed a retrospective case-control study to compare patients younger than 18years of age with positive blood cultures for the three pathogens between June 2008 and May2014 at our institution. Data regarding patients' demographics and clinical course were collected from their medical records. Three group comparisons, with M. catarrhalis as reference, were made by the Fisher's exact test and Wilcoxon rank sum test for discrete and continuous variables, respectively. Results: There were eight cases of M. catarrhalis, 110 cases of S. pneumoniae (105 patients) and 22 cases of H. influenzae. The M. catarrhalis group consisted of six females (75%) with a mean age of 16months. The majority of patients (7/8, 88%) had underlying diseases; however, only one was immunocompromised. Characteristically, six patients (75%) had medical devices including trans-nasal devices (5/8, 63%). Univariate analysis revealed that underlying conditions (P=0.005), trans-nasal devices (P<0.001), and lower body weight (P=0.016) and low white blood cell count (P=0.011) at the onset of illness were associated with the M. catarrhalis group compared to the S. pneumoniae group. Meanwhile, the higher rates of the patients with underlying conditions and trans-nasal devices were associated with the M. catarrhalis group compared to the H. influenzae group (P=0.039, P<0.001, respectively). Conclusions: The presence of underlying conditions, particularly in those with trans-nasal devices, were characteristic features of patients with bacteremia due to M. catarrhalis. © 2016 Funaki et al.


Iijima K.,Kobe University | Sako M.,Center for Clinical Research and Development | Nozu K.,Kobe University
Clinical and Experimental Nephrology | Year: 2016

Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. At least 20 % of children with this syndrome show frequent relapses and/or steroid dependence during or after immunosuppressive therapies, a condition defined as complicated frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). Approximately 1–3 % of children with idiopathic nephrotic syndrome are resistant to steroids and all immunosuppressive agents, a condition defined as refractory steroid-resistant nephrotic syndrome (SRNS); these SRNS children have a high risk of end-stage renal failure. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective for patients with complicated FRNS/SDNS and refractory SRNS. This review describes the recent results of rituximab treatment applied to pediatric nephrotic syndrome, as well as those of our recent study, a multicenter, double-blind, randomized, placebo-controlled trial of rituximab for childhood-onset complicated FRNS/SDNS (RCRNS01). The overall efficacy and safety of rituximab for this disease are discussed. © 2016 The Author(s)


PubMed | Center for Clinical Research and Development
Type: Clinical Trial | Journal: Brain and nerve = Shinkei kenkyu no shinpo | Year: 2015

Following the first period of the multicenter, open-label, single-armed N01223 trial, the second period of the N01223 trial was conducted to evaluate long-term safety, along with the efficacy of adjunctive levetiracetam treatment (individualized dose range, 20-60 mg/kg/day or 1,000-3,000 mg/day) in Japanese pediatric patients with uncontrolled partial-onset seizures (POS). Of the 62 children who completed the first period, 55 children [age: 10.4 3.4 years (mean standard deviation)] were elected to enter the second period for a maximum of 39 months. Twenty children were withdrawn during this second period. Frequencies of treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs) were 98.2% (54/55 cases) and 27.3% (15/55 cases), respectively. The most common TEAEs were nasopharyngitis (76.4%), influenza (36.4%) and pyrexia (25.5%). The only frequent ADR (>2%) was somnolence (3.6%). Although serious TEAEs and death were reported in 8 cases and 1 case (drowning), respectively, a serious ADR was only reported in 1 case (vomiting). The median percentage reduction and 50% response rate for POS were 43.32% and 41.8%, respectively. One child showed a maximum seizure-free period of 163 days. In conclusion, levetiracetam demonstrated long-term safety and good tolerance with beneficial efficacy as an adjunctive therapy in Japanese children with uncontrolled POS. (Received June 30, 2015; Accepted July 14, 2015: Published November 1, 2015).


PubMed | Center for Clinical Research and Development and Kobe University
Type: | Journal: Clinical and experimental nephrology | Year: 2016

Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. At least 20% of children with this syndrome show frequent relapses and/or steroid dependence during or after immunosuppressive therapies, a condition defined as complicated frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). Approximately 1-3% of children with idiopathic nephrotic syndrome are resistant to steroids and all immunosuppressive agents, a condition defined as refractory steroid-resistant nephrotic syndrome (SRNS); these SRNS children have a high risk of end-stage renal failure. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective for patients with complicated FRNS/SDNS and refractory SRNS. This review describes the recent results of rituximab treatment applied to pediatric nephrotic syndrome, as well as those of our recent study, a multicenter, double-blind, randomized, placebo-controlled trial of rituximab for childhood-onset complicated FRNS/SDNS (RCRNS01). The overall efficacy and safety of rituximab for this disease are discussed.

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