Takafumi Honda

Tokyo Women's Medical University, Edo, Tōkyō, Japan

Are you Takafumi Honda?

Claim your profile

Publications (21)87.5 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 Ca2+/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca2+ release activated Ca2+ (CRAC) channel mediating store-operated Ca2+ 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 Ca2+/NFAT pathway in the pathogenesis of this disorder.
    Preview · Article · Jan 2016 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A 4-year-old boy with no history or family history of related disease came to our hospital with cardiopulmonary arrest. He had fainted after running to the entrance of his home. After 30 minutes of cardiovascular resuscitation, circulation returned spontaneously. Polymorphic ventricular tachycardia and fibrillation were often seen and were suppressed by β-blockers, suggesting catecholaminergic polymorphic ventricular tachycardia (CPVT). No finding was made from resting electrocardiogram, except sinus bradycardia. Exercise electrocardiography was difficult for him because of his age. Two single nucleotide polymorphisms (SNPs) in calsequestrin 2 (CASQ2) confirmed the diagnosis.
    Preview · Article · Jan 2015 · Nihon Shuchu Chiryo Igakukai zasshi

  • No preview · Article · Jan 2014 · Nihon Shuchu Chiryo Igakukai zasshi
  • [Show abstract] [Hide abstract]
    ABSTRACT: Polyomaviruses (PyVs) WU and KI are reportedly associated with respiratory tract disease (RTD) worldwide. However, their incidence is unclear in Japan. In a two-year prospective study, WU/KIPyV were detected in 48 (13.9%) and 5 (1.4%) of 345 children hospitalized with lower RTD. The seasonal distribution was observed in spring and early summer. Other respiratory viruses were co-detected in 51% of PyV positive patients, but 8 (2.3%) WUPyV-positive patients were negative for other known pathogens.
    No preview · Article · May 2013 · Pediatrics International
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The genetic background of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been extensively investigated for the last decade in Western countries, but it remains unstudied in the Asian population. Methods and results: In 50 Japanese probands from unrelated families who satisfied clinical criteria for CPVT, genetic testing was conducted in all exons on 3 CPVT-related genes: cardiac ryanodine receptor 2 (RYR2), calsequestrin 2 (CASQ2) and inward rectifier potassium channel 2 (KCNJ2), and the clinical features between RYR2-genotyped and -non-genotyped patient groups were compared. Genetic and clinical evaluation was also done in 46 family members. In the genetic screening, 28 (18 novel) RYR2 (56.0%), 1 compound heterozygous CASQ2 (2.0%) and 1 KCNJ2 (2.0%) mutation carriers were identified. In the RYR2 mutation-positive group, the frequency of bidirectional ventricular tachycardia and the use of β-blockers were significantly higher than in the mutation-negative group. In contrast, there was no significant difference in supraventricular arrhythmias between the 2 groups. With regard to disease penetrance, the number of family members of RYR2-genotyped probands with a clinical diagnosis of CPVT was high. Conclusions: Thirty gene mutation carriers were found for 3 genes in 50 probands clinically diagnosed as having CPVT. The penetrance of CPVT phenotype was significantly higher in RYR2 mutation carriers, thus RYR2 gene screening in CPVT patients would be indispensable to prevent unexpected cardiac sudden death of young family members.
    No preview · Article · Apr 2013 · Circulation Journal
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Kawasaki disease (KD) is an acute systemic vasculitis occurring in medium-sized arteries, especially coronary arteries. Patients with KD who fail to respond to standard therapy with intravenous immunoglobulin (IVIG) face a higher risk of developing coronary artery lesions. Cyclosporin A (CsA) is one treatment option for IVIG-resistant KD. However, the mechanism of its suppression of inflammation in patients with KD remains unknown. Methods and results: We analyzed time-line profiles of multiple inflammatory cytokines in sera of 19 patients treated with CsA (4 mg/kg/day, p.o., 14 days) after additional IVIG. Trough concentration of CsA in blood was maintained between 60 and 200 ng/ml. We examined serum samples before, on day 7, and at the end (day 14) of CsA treatment. Assays were conducted using a Milliplex kit®. Fourteen patients responded to CsA and became afebrile within 5 days (Responders), although five patients were regarded as Non-responders. Serum transitional levels of IL-6 (p<0.001), sIL-2R (p<0.001), sTNFRII (p<0.001), and G-CSF (p<0.001) reflect disease severity. In Non-responders, average levels of IL-6 at day 7 (43.5 vs. 13.8 pg/ml, p<0.001) and average levels of sIL-2R at day 14 (21.3 vs. 3.31 pg/ml, p=0.014) were significantly higher than those in Responders. Conclusion: CsA treatment effectively reduced the persisting serum inflammatory cytokines in most of the IVIG-resistant KD patients. Soluble IL-2R suppression implies a mechanism explaining the effects of CsA.
    No preview · Article · Aug 2012 · Cytokine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.
    Full-text · Article · Mar 2012 · Nature Genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: There are still no definite treatments for refractory Kawasaki disease (KD). In this pilot study, we evaluated the use of cyclosporin A (CyA) treatment in patients with refractory KD. We prospectively collected clinical data of CyA treatment (4-8 mg/kg/d, oral administration) for refractory KD patients using the same protocol among several hospitals. Refractory KD is defined as the persistence or recurrence of fever (37.5°C or more of an axillary temperature) at the end of the second intravenous immunoglobulin (2 g/kg) following the initial one. Subjects were enrolled out of 329 KD patients who were admitted to our 8 hospitals between January 2008 and June 2010. Among a total of 28 patients of refractory KD treated with CyA, 18 (64.3%) responded promptly to be afebrile within 3 days and had decreased C-reactive protein levels, the other 4 became afebrile within 4 to 5 days. However, 6 patients (21.4%) failed to become afebrile within 5 days after the start of CyA and/or high fever returned after becoming afebrile within 5 days. Although hyperkalemia developed in 9 patients at 3 to 7 days after the start of CyA treatment, there were no serious adverse effects such as arrhythmias. Four patients (1.2%), 2 before and the other 2 after the start of CyA treatment, developed coronary arterial lesions. CyA treatment is considered safe and well tolerated, and a promising option for patients with refractory KD. Further investigations will be needed to clarify optimal dose, safety, and timing of CyA treatment.
    No preview · Article · May 2011 · The Pediatric Infectious Disease Journal
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A novel influenza A (2009 H1N1) virus has led to a worldwide pandemic. A significant number of patients with pneumonia have been reported, although its pathogenesis remains to be elucidated. To determine its pathogenesis, we evaluated serum interleukin (IL)-5 and peripheral eosinophil counts in patients with acute pneumonia caused by the 2009 H1N1 virus. During the period from October to December 2009, 40 patients with laboratory-confirmed 2009 H1N1 pneumonia were under investigation. Their mean age at presentation was 6.8 years. The most characteristic finding was the early development of hypoxemic respiratory distress in the first 24 hr after the onset of fever. Bronchial mucous plugs included eosinophils in addition to neutrophils, even in patients without allergies. Serum IL-5 levels were elevated in 20 out of 24 patients (83%) whose samples were obtained in the first 24 hr after the onset of fever (26.5 ± 20.1 pg/mL), independent of the presence of underlying allergies. In contrast, induction of IL-5 was not documented in sera from eight patients with laboratory-confirmed 2009 H1N1 virus who developed neurological complications, but without lower respiratory infection (2.1 ± 0.7 pg/mL, P < 0.001 vs acute pneumonia). Peripheral eosinophilia was characteristic in acute pneumonia, but not in patients without a lower respiratory infection. There was a marked difference in the induction of IL-5 in 2009 H1N1 patients who developed acute pneumonia, compared with those without a lower respiratory infection. IL-5 may play a role in the early phase of acute pneumonia caused by the 2009 H1N1 virus in Japanese children.
    Preview · Article · Feb 2011 · Microbiology and Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small-and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5′ untranslated region of CASP3 (rs72689236; P = 4.2 × 10-8 in the Japanese and P = 3.7 × 10-3 in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggestthat altered CASP3 expression in immune effecter cells influences susceptibility to KD. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] /* */
    Full-text · Article · Jul 2010 · Human Molecular Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical characteristics of human bocavirus (HBoV) infection have been studied worldwide, but their importance of those characteristics remains unknown. We investigated distinctive clinical features of HBoV-positive children with lower respiratory tract infection (LRTI). During April 2007-July 2009, for 402 hospitalized children younger than 2 years with LRTI, we prospectively examined virus genomes in nasopharyngeal swabs for HBoV, respiratory syncytial virus (RSV), rhinovirus, metapneumovirus, parainfluenzavirus, and adenovirus. The HBoV genomes were identified in 34 patients (8.5%). Clinical and laboratory data of HBoV-positive and other virus/bacteria-negative patients (n = 18) were analyzed and compared with data of RSV-single positive patients (n = 99). The seasonal distribution of HBoV exhibits a concentration of cases during March-September, with most RSV cases occurring during winter in Japan. The minimum age of HBoV-positive patients was 5 months, although 44 patients (44%) with RSV were younger than 6 months. The main clinical features were respiratory distress and hypoxia. Hypoxia advances within 3 days after onset. The mean oxygen saturation on arrival was 92.8%, which was significantly lower than that in patients with RSV (p < 0.001). White blood cell counts were similar among groups. However, the percentage of neutrophils in white blood cells were significantly higher in HBoV-positive patients (62 vs. 45%, p < 0.001). Their prognoses were good. Their hospital stays were 6.6 days. HBoV-single positive patients show several clinical characteristics, such as seasonality, age, hypoxia, and neutrophilia, which differ from those with RSV infection.
    Full-text · Article · Apr 2010 · European Journal of Pediatrics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Remarkable amounts of neovascularization develop in patients with cyanotic congenital heart disease who have low pulmonary blood flow and systemic cyanosis, but the factors functionally responsible for angiogenesis in cyanotic congenital heart disease have not been determined. To investigate the functional angiogenic molecules in serum from these patients, serum angiogenic activity was studied in 21 patients (systemic oxygen saturation: 82+/-1.9%) and in 17 healthy controls. Patient serum was more active in stimulating the tube formation of human umbilical vein endothelial cells (HUVECs) into capillary-like structures than control serum (150% vs 104% of internal control; p<0.001). This increased serum angiogenic activity normalized after total cardiac repair (p<0.001). The migration activity of HUVECs was also accelerated in patient serum (p=0.007). To identify the molecules in patient serum affecting tube formation of HUVECs, we examined the effects of an inhibitor or a neutralizing antibody against various angiogenic molecules on in vitro angiogenesis. Both the soluble vascular endothelial growth factor (VEGF) receptor 1 and the VEGF receptor 2 tyrosine kinase inhibitor SU5416 reduced the basal serum angiogenic activity of patients and this was reversed by a supplement of recombinant human VEGF. Our results indicate that serum VEGF functionally contributes to vascular endothelial cell kinetics in patients with cyanotic congenital heart disease.
    No preview · Article · Sep 2007 · International journal of cardiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The inflammatory mediators play an important role in the progression of coronary vasculitis in Kawasaki disease (KD), but effects of KD serum including inflammatory mediators on endothelial cells remain unknown. We hypothesized that serum activity to stimulate in vitro human umbilical vein endothelial cells (HUVEC) tube formation might be impaired in KD. Serum from patients with coronary aneurysms was less active in stimulating HUVEC tube formation than serum from patients without coronary aneurysms or febrile controls. In patients with coronary aneurysms, the reduction in the serum angiogenic activity was documented already before KD treatment (p=0.03 vs healthy controls, p=0.08 vs febrile controls) and enhanced after intravenous immune globulin plus aspirin (p<0.001 vs healthy controls, p=0.002 vs febrile controls); both drugs did not affect the assay studied. This reduction was greater in patients who later developed giant aneurysms >8 mm compared with those who developed small to moderate aneurysms (p=0.01). The reduced serum angiogenic activity was partly caused by the reduction in the serum activity of stimulating HUVEC proliferation. Serum activity to stimulate HUVEC tube formation was impaired in KD patients who later developed larger coronary aneurysms, which may be associated with the severity of vascular injury.
    No preview · Article · Aug 2007 · Circulation Journal
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report successful selective local intra-arterial thrombolytic therapy for thromboembolic occlusion of right middle cerebral artery in a patient with asplenia syndrome and unrepaired cyanotic congenital heart disease.
    No preview · Article · Dec 2006 · Congenital Heart Disease
  • Hiromichi Hamada · Masaru Terai · Takafumi Honda · Yoichi Kohno
    [Show abstract] [Hide abstract]
    ABSTRACT: No abstract is available for this article.
    No preview · Article · Mar 2005 · Pediatrics International
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We studied the effects of a new regimen consisting of intravenous immune globulin (IVIG) combined with dexamethasone (DEX) on clinical outcome and serum levels of vascular endothelial growth factor (VEGF) in the initial treatment of Kawasaki disease (KD). A total of 46 KD patients received 0.3 mg/kg per day DEX plus heparin i.v. for 3 consecutive days, together with 2 g/kg IVIG over 4 to 5 days (DEX group). Low-dose acetylsalicylic acid was started after completion of DEX therapy. The control group consisted of 46 KD patients retrospectively treated earlier with 2 g/kg IVIG over 4 to 5 days plus higher dose acetylsalicylic acid (CONTROL group). No serious adverse effect was noted in either group. There were no differences in baseline and post-treatment laboratory data except for C-reactive protein between the groups. Post-treatment C-reactive protein in the DEX group (median 0.9 mg/dl, range 0.0 to 24.7 mg/dl) was lower than that (1.2 mg/dl, range 0.2 to 19.5 mg/dl) in the CONTROL group ( P=0.033 by Mann-Whitney U test). In addition, the mean duration of fever after the first IVIG infusion was 2.2 days (median 1 day, range 1 to 12 days) in the DEX group and 2.8 days (2 days, 1 to 16 days) in the CONTROL group ( P=0.015 by Mann-Whitney U test). The new regimen did not reduce VEGF levels. Two patients in each group developed small- or medium-sized coronary artery aneurysms. CONCLUSION: Although this regimen did not affect coronary outcome, intravenous immune globulin therapy combined with dexamethasone for the initial treatment of Kawasaki disease was safe and may accelerate the resolution of systemic inflammation.
    Full-text · Article · May 2004 · European Journal of Pediatrics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Increased microvascular permeability is an initial step of Kawasaki disease (KD). We reported that vascular endothelial growth factor (VEGF) might play a role in the vascular leakage of KD. In fatal KD, plasma leakage was extensively documented at VEGF-positive microvessels. Increases in vascular leakage cause hypoalbuminemia and noncardiogenic edema. However, the prognostic impact of vascular leakage in KD remains unclear. We compared 76 patients who became afebrile within 5 days after starting intravenous gamma globulin (IVGG) (2 g/kg over 5 days) (IVGG-responsive) with 27 patients who did not respond (IVGG-resistant). Baseline levels of serum VEGF and albumin were similar between the groups. After IVGG, VEGF levels increased (P<0.0001) and albumin levels decreased (P<0.00001) in both groups. However, the IVGG-resistant group had higher VEGF levels (P=0.029) and severe hypoalbuminemia (P<0.00001) compared with the IVGG-responsive group. Coronary aneurysms were documented in 12 patients from the IVGG-resistant group but not in the IVGG-responsive group. Then IVGG-resistant patients were divided into 2 subgroups according to the presence (n=12) or absence (n=15) of coronary aneurysms. There was no difference between subgroups in age, sex, laboratory data including albumin, and retreated doses of IVGG. However, body weight gain after IVGG was documented in patients who subsequently developed coronary aneurysms (P=0.003) but not in those who did not (P=0.967). These results suggest that vascular leakage may be a key feature of KD pathophysiology. The present study may provide better insights into the pathogenesis and treatment of patients resistant to IVGG in acute KD.
    Preview · Article · Jul 2003 · Circulation
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: We previously reported the short-term efficacy of heparin and exercise (HE) therapy on the alleviation of myocardial ischemia in the collateral-dependent area after Kawasaki Disease (KD). Purpose: We studied mid-term efficacy o f this therapy for KD patients. Methods: Six patients, aged 9 to 20 years, who received HE therapy between 1997 and 1999 were studied. All patients had total obstruction in left or right coronary artery system. Dipyridamole-loading 99m technetiu m-tetrofos min single photon emission computed tomography (SPECT) had documented improved myocardial perfusion in all patients within 1 week after HE therapy. Two of the 6 patients received additional HE therapy within 1 year because they still had high SPECT defect scores after initial HE therapy. In all patients, dipyridamole-loading SPECT was performed at 1.5 year after initial HE therapy. Follow-up coronary angiography was performed in 3 of the 6 patients. All patients have been maintained on anti-p latelet therapy. Results: None developed anginal attack during follow-up. Follow-up dipyridamole-loading SPECT documented that total defect scores remained unchanged (n=1) or decreased (n=5) compared with those at baseline, and also remained unc h anged (n=1), increased (n=1) or decreased (n=4) compared with those within 1 week after initial HE therapy. Coronary angiography documented the development of collateral vessels in 2 of 3 patients studied. Conclusions: The present study sugges t ed that the HE therapy might have a favorable mid-term effect on alleviation of myocardial ischemia in patients with total coronary obstruction.
    Full-text · Article · Jan 2003 · Pediatric Research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kawasaki disease (KD) is believed to have an infective etiology. However, the agent is not determined. Most KD patients receive drug(s) such as antibiotics just after fever onset. Drug-related vasculitis includes rash, edema and eosinophilia. However, little is known about effects of drugs on KD. We studied peripheral blood eosinophilia (>5%) in 131 patients with acute KD. Eosinophilia was documented in 61 patients (47%), mostly in the first or second week of illness, but not in the age-matched controls (p<0.0001). Importantly, circulating levels of interleukin-5 was elevated in almost patients studied, suggesting eosinophil activation. Furthermore, KD microvascular lesions had 20 percent of eosinophils in all fatal KD cardiac tissues studied. Then, we studied effects of antibiotics on child mice immunized with Bacillus Calmette-Guerin (BCG), because BCG potently induces cell-mediated immune reactions. Surprisingly, antibiotics caused hypersensitive symptoms in child mice with BCG, but rarely in those without BCG (p<0.0001). Subsequently, coronary vascular mononuclear cell infiltrates with eosinophils were also developed in child mice after antibiotic exposure. Monocyte chemoattractant protein-1 was also expressed in the vascular lesions, mostly in macrophages. These findings suggest that antibiotics may cause coronary vasculitis in susceptible mice. BCG may be a susceptible factor for drug-induced hypersensitivity. Epidemiological survey is urgently necessitated to confirm the association of drugs including antibiotics with the development of KD vasculitis.
    Full-text · Article · Jan 2003 · Pediatric Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early stage Kawasaki disease (KD) histopathology includes perivasculitis and vasculitis of the microvessels. The lesions then extend to larger vessels. Therefore the analysis of microvessel lesions is important to better understand the initial pathogenesis of KD vasculitis. We studied epicardial microvessel lesions (<50 microm) and aneurysm lesions of paraffin-embedded cardiac tissues from 4 Japanese patients who died 7 to 22 days after KD onset. The cellular composition in the microvessel lesions was different from that in coronary aneurysm lesions; eosinophils were preferentially accumulated in the microvessel lesions. The average population of eosinophils was 16% of total infiltrated cells in the microvessel lesions, whereas it was 3% in the intima of aneurysm walls. We examined peripheral blood eosinophil cell counts in 95 KD patients and 95 febrile age-matched controls. Baseline eosinophil cell counts in KD patients were higher than those in febrile control patients (361 +/- 441 65 +/- 133; < 0.0001). Eosinophilia (>350 cells/microl) before therapy was documented in 36% of KD patients, but in only 4% of febrile controls ( < 0.0001). Sixty-six KD patients (69%) developed eosinophilia within 2 weeks of illness. Because the numbers of circulating eosinophils in the body are tightly regulated, eosinophil accumulation in blood or tissues may reflect the host's immune response against KD related antigen(s).
    No preview · Article · Aug 2002 · The Pediatric Infectious Disease Journal

Publication Stats

325 Citations
87.50 Total Impact Points

Institutions

  • 2010-2013
    • Tokyo Women's Medical University
      • Department of Pediatrics
      Edo, Tōkyō, Japan
  • 1995-2007
    • Chiba University
      • • Department of Pediatrics
      • • Graduate School of Medicine
      Chiba-shi, Chiba-ken, Japan