Yoichi Kohno

Publications (137)331.11 Total impact

• Article: The expression of CD203c on basophils as a marker of IgE-mediated L-asparaginase allergy.

  Moeko Hino, Naoki Shimojo, Hidemasa Ochiai, Yuzaburo Inoue, Kumiko Ando, Koji Chikaraishi, Setsuo Ota, Yuri Okimoto, Shosuke Sunami, Ryosuke Nakamura, Reiko Teshima, Yasunori Sato, Yoichi Kohno
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  ABSTRACT: ABSTRACT Immediate allergy to L-asparaginase (ASP) is a major obstacle in treating lymphoid malignancies. ASP-specific IgG (ASP-IgG) has been used as a surrogate marker. Recently, the CD203c-basophil activation test (BAT) was found to be useful in diagnosing IgE-mediated allergies. We compared the diagnostic utility of the CD203c-BAT to that of ASP- IgG levels in determining ASP allergies in children. Eight ASP allergic reactions occurred over 75 ASP treatment courses. The sensitivity, specificity and area under the receiver operating characteristic curve of CD203c-BAT were similar to the ASP-IgG levels (0.75 vs. 0.85, 0.82 vs. 0.78, and 0.81 vs. 0.85, respectively). Positive skin prick test results in ASP allergy patients with suggested that ASP-IgE was one of the key players in ASP allergy. A combination of the BAT with the ASP-IgG level had the highest specificity (0.95) and positive predictive value (0.62), which permitted us to identify ASP allergy more effectively.
  Leukemia & lymphoma 04/2013; · 2.40 Impact Factor
• Article: Visual analogue scale as a predictor of GINA-defined asthma control. The SACRA study in Japan.

  Ken Ohta, Philippe-Jean Bousquet, Kazuo Akiyama, Mitsuru Adachi, Masakazu Ichinose, Motohiro Ebisawa, Gen Tamura, Atsushi Nagai, Sankei Nishima, Takeshi Fukuda, Akihiro Morikawa, Yoshitaka Okamoto, Yoichi Kohno, Hirohisa Saito, Hiroshi Takenaka, Larry Grouse, Jean Bousquet
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  ABSTRACT: Abstract Objective: The assessment of asthma control is pivotal to treatment decisions. A questionnaire that assesses the Global Initiative for Asthma (GINA)-defined control requires four questions. A visual analogue scale (VAS) to evaluate asthma control can be simply marked, but its correlation with GINA-defined control has been insufficiently evaluated. The purpose of this study is to evaluate whether VAS levels can predict GINA-defined asthma control with particular emphasis on the distinctions between "partly controlled" and "uncontrolled" and between "partly controlled" and "controlled" asthma. Methods: A cross-sectional multicenter study was carried out throughout Japan (SACRA) from March to August 2009 among patients with a diagnosis and treatment of asthma. Asthma control was studied using the GINA questionnaire and a VAS measurement of asthma severity. Pulmonary function testing was not carried out. Results: 1,910 physicians enrolled 29,518 patients with asthma. 15,051 (51.0%) questionnaires were administered by physicians; patients filled out 14,076 (47.7%) questionnaires themselves. 28,225 (95.6%) of the patients were evaluable. VAS measurement of asthma symptoms was useful in predicting levels of GINA-defined control categories (the area under the ROC curve ranging from 0.704 to 0.837). Patients with "controlled", "partly controlled" and "uncontrolled" asthma were discriminated by VAS levels (1.50, 4.79, 7.19). Similar results have been obtained with self- and physician's administered questionnaires showing the validity of results. Conclusion: Measurement of VAS levels is able to discriminate between patients with "controlled", "partly controlled" and "uncontrolled" asthma. The VAS score could be a simple guide in clinical situations requiring daily or regular evaluation of asthma control.
  Journal of Asthma 03/2013; · 1.52 Impact Factor
• Article: Isoniazid- and streptomycin-resistant miliary tuberculosis complicated by intracranial tuberculoma in a Japanese infant.

  Naruhiko Ishiwada, Osamu Tokunaga, Koo Nagasawa, Keiko Ichimoto, Kaori Kinoshita, Haruka Hishiki, Yoichi Kohno
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  ABSTRACT: In Japan, the incidence of severe pediatric tuberculosis (TB) has decreased dramatically in recent years. However, children in Japan can still have considerable opportunities to contract TB infection from adult TB patients living nearby, and infants infected with TB may develop severe disseminated disease. A 3-month-old girl was admitted to our hospital with dyspnea and poor feeding. After admission, miliary TB and multiple brain tuberculomas were diagnosed. Anti-tuberculous therapy was initiated with streptomycin (SM), isoniazid (INH), rifampicin and pyrazinamide. Symptoms persisted after starting the initial treatment and mycobacterial cultures of gastric fluid remained positive. Drug sensitivity testing revealed the TB strain isolated on admission as completely resistant to INH and SM. Treatments with INH and SM were therefore stopped, and treatment with ethambutol and ethionamide was started in addition to rifampicin and pyrazinamide. After this change to the treatment regimen, symptoms and laboratory data gradually improved. The patient was treated with these four drugs for 18 months, and then pyrazinamide was stopped. After another 2 months, ethambutol was stopped. Treatment of tuberculosis was completed in 24 months. No adverse effects of these anti-TB drugs were observed. The patient achieved a full recovery without any sequelae. On the other hand, the infectious source for this patient remained unidentified, despite the extensive contact investigations. The incidence of drug-resistant TB is increasing in many areas of the world. Continuous monitoring for pediatric patients with drug-resistant TB is therefore needed.
  The Tohoku Journal of Experimental Medicine 01/2013; 229(3):221-5. · 1.24 Impact Factor
• Article: Milk allergy in the neonatal intensive care unit: comparison between premature and full-term neonates.

  Yoshinori Morita, Hideo Iwakura, Harumi Ohtsuka, Yoichi Kohno, Naoki Shimojo
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  ABSTRACT: There have been several reports on neonates with milk allergy in a neonatal ward. This type of allergy is mostly categorized as a non-IgE-mediated food allergy. Although most cases of milk allergy occur in the first few months of life, the differences in clinical characteristics between premature and full-term neonates are still unclear. This study aimed to clarify the differences in clinical characteristics of milk allergy between premature and full-term neonates. We retrospectively evaluated 2,116 neonates admitted to the Department of Neonatology, Chiba Kaihin Municipal Hospital, between 2001 and 2007. We identified 24 neonates strongly suspected of having milk allergy because of symptoms, such as bloody stools, repeated vomiting, diminished sucking and abdominal distension, as well as objective laboratory findings of eosinophilia in stool cytology and/or positive results for a rectal milk challenge test. Twelve of these 24 neonates were premature (median gestational age, 31 ± 3 weeks; median birth weight, 1,656 ± 592 g) and the other 12 were full-term (median gestational age, 38 ± 1 weeks; median birth weight, 2,760 ± 560 g). There were no differences in symptoms and time to start of feeding between premature and full-term neonates, but there was a significant difference in the median postnatal age at onset (premature neonates: 23 days; vs. full-term neonates: 3.5 days; p < 0.01). All premature neonates developed a milk allergy after 32 weeks of corrected gestational age, suggesting that the development of milk allergy requires a certain degree of immunological maturation.
  Asia Pacific allergy. 01/2013; 3(1):35-41.
• Article: Cytokine Biomarker Candidates in Breast Milk Associated with the Development of Atopic Dermatitis in 6-Month-Old Infants.

  Shingo Ochiai, Naoki Shimojo, Yoshinori Morita, Minako Tomiita, Takayasu Arima, Yuzaburo Inoue, Mayuko Nakaya, Naoki Uehara, Yasunori Sato, Chisato Mori, Yoichi Suzuki, Yoichi Kohno
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  ABSTRACT: Background: A few studies have reported that the quantity of selected cytokines/chemokines in breast milk might be associated with atopic dermatitis (AD). Using the multiplex cytokine assay system, we examined cytokines/chemokines in human milk in order to identify new biomarkers related to AD. Methods: We recruited 49 infants with or without AD who participated in a birth cohort and measured the concentrations of cytokines/chemokines in the colostrum (collected within 4-5 days after birth) and mature milk (collected at 1 month postpartum) received by the infants. Results: There were significant differences in the concentrations of interleukin (IL)-1β and IL-12p40 in the colostrum, and in those of IL-4, eotaxin, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α2 and MIP-1α in the mature milk between the milk received by infants who developed AD at the age of 6 months and that received by the control infants. There was weak to moderate correlation between those 6 cytokines/chemokines in mature milk. Atopic history and IgE levels of mothers were not related to cytokine/chemokine concentrations in breast milk. Logistic regression analyses showed that high levels of eotaxin in the mature milk were a risk for the development of AD at 6 months of age. Conclusion: These results suggest that several cytokines/chemokines, especially eotaxin, are potential biomarkers for development of AD in early infancy.
  International Archives of Allergy and Immunology 11/2012; 160(4):401-408. · 2.40 Impact Factor
• Article: Association Study of Matrix Metalloproteinase-12 Gene Polymorphisms and Asthma in a Japanese Population.

  Fumiya Yamaide, Siizkhuu Undarmaa, Yoichi Mashimo, Naoki Shimojo, Takayasu Arima, Yoshinori Morita, Tomomitsu Hirota, Kimie Fujita, Akihiko Miyatake, Satoru Doi, [......], Hiroko Watanabe, Akira Hoshioka, Minako Tomiita, Akiko Yamaide, Misa Watanabe, Yoshitaka Okamoto, Yoichi Kohno, Mayumi Tamari, Akira Hata, Yoichi Suzuki
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  ABSTRACT: Background: Matrix metalloproteinase 12 gene (MMP12) has been shown to be associated with asthma in a Caucasian population. In this study, we investigate whether single-nucleotide polymorphisms (SNPs) of MMP12 are associated with a risk for asthma in a Japanese population. Methods: We tested for an association between SNPs in MMP12 and asthma, including its severity, in a Japanese population (630 pediatric and 417 adult patients with atopic asthma and 336 children and 632 adults as controls). The rs652438 A and G variants (N357S) were generated by site-directed mutagenesis and an assay with artificial peptide substrates was used to compare two types of MMP12 activity. The effect of MMP12 inhibition with MMP12-specific small interfering RNA (siRNA) on chemokine secretion from airway epithelial cells was also tested in vitro. Results: N357S showed a p value <0.05 for childhood and combined (adult plus childhood) asthma in the dominant model [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.00-2.56, p = 0.047; OR 1.40, 95% CI 1.04-1.89, p = 0.028, respectively]. This risk variant is associated with asthma severity in adult patients. In the functional assay, the minor-allele enzyme showed significantly lower activity than the major-allele enzyme. MMP12-specific siRNA suppressed IP-10 secretion from airway epithelial cells upon stimulation with IFN-β. Conclusions: Our results suggest that MMP12 confers susceptibility to asthma and is associated with asthma severity in a Japanese population. MMP12 may be associated with asthma through inappropriate attraction of leukocytes to the inflamed tissue.
  International Archives of Allergy and Immunology 10/2012; 160(3):287-296. · 2.40 Impact Factor
• Article: 14-3-3 Proteins, particularly of the epsilon isoform, are detectable in cerebrospinal fluids of cerebellar diseases in children.

  Katsunori Fujii, Hideki Uchikawa, Yuzo Tanabe, Taku Omata, Ikuya Nonaka, Yoichi Kohno
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  ABSTRACT: Background: Detection of 14-3-3 proteins in cerebrospinal fluid (CSF) is a powerful tool for elucidating the mechanisms of neurological disorders. There have been useful studies on 14-3-3 CSF protein detection in Creutzfeldt-Jakob disease and other neurological disorders, but none on cerebellar diseases. Objective: To elucidate whether 14-3-3 CSF proteins are a sensitive biomarker of cerebellar disruption in children. Materials and Methods: We examined 14-3-3 CSF proteins by immunoblotting in seven patients with cerebellar disorders: two with acute cerebellitis, two with acute cerebellar ataxia, and three with cerebellar atrophy. We also investigated 14-3-3 CSF proteins in four cases of febrile seizure and three of influenza-related encephalopathy. Isoforms of 14-3-3 proteins were also identified using isoform-specific antibodies. Results: 14-3-3 proteins were detected in CSF of six patients with cerebellar disorders, the exception being one with acute cerebellar ataxia caused by viral infection. Interestingly, only the 14-3-3 ε isoform was detected in two tested patients with cerebellar involvement. Moreover, longitudinal analysis of 14-3-3 CSF proteins in one patient with infantile neuroaxonal dystrophy showed that the 14-3-3 band density proportionally decreased when the cerebellar atrophy gradually progressed. Another CSF derived from a case of febrile seizure showed no 14-3-3 proteins, whereas all those derived from influenza-related encephalopathy demonstrated 14-3-3 CSF proteins with six isoforms. Conclusions: This is the first report on 14-3-3 CSF proteins as a significant biomarker of cerebellar disruption, as well as other brain diseases. Since 14-3-3 ε is localized in the molecular layer of cerebellum, the unique detection of 14-3-3 ε may indicate cerebellar involvement in the brain.
  Brain & development 10/2012; · 1.74 Impact Factor
• Article: Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccine.

  Katsunori Fujii, Maiko Suyama, Koki Chiba, Tomoko Okunushi, Junko Oikawa, Yoichi Kohno
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  ABSTRACT: Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the central nervous system. We describe a previously healthy 2-year-old boy with ADEM, who exhibited high fever, lethargy, and recurrent seizures at 25 days after H1N1 influenza vaccination. To our knowledge, there has been only one report of ADEM following the 2009 H1N1 influenza vaccine, although such vaccination is accompanied with optic neuritis apart from this case. Thus, this is the first case of ADEM without optic neuritis, following the 2009 H1N1 influenza vaccination. Although vaccine-associated ADEM remains rare, the increasing number of influenza vaccinations might increase the incidence of ADEM. We still need to pay attention to the occurrence of ADEM and treat patients with steroid therapy.
  Pediatrics International 08/2012; 54(4):539-41. · 0.63 Impact Factor
• Article: The Use of Complementary and Alternative Medicine by Pediatric Food-Allergic Patients in Japan.

  Taiji Nakano, Naoki Shimojo, Yoshitaka Okamoto, Motohiro Ebisawa, Kazuyuki Kurihara, Akira Hoshioka, Koichi Yamaguchi, Komei Ito, Takao Fujisawa, Makoto Kameda, Yutaka Suehiro, Hideo Ogura, Rumiko Shibata, Shuichi Suzuki, Yutaka Takahashi, Masanori Ikeda, Yoichi Kohno
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  ABSTRACT: Background: In developed countries, increasing food allergy prevalence and concern regarding food allergies have been reported. Although the use of complementary and alternative medicine (CAM) for the treatment of allergic diseases has increased in some Western countries, the actual proportion and patterns of CAM use for pediatric food allergies in Japan are still unknown. Methods: Fourteen allergy centers in Japan participated in the study using a questionnaire survey regarding the use of CAM by pediatric patients. A diagnosis of food allergy was made at each hospital by pediatric allergists. Results: Surveys were completed by parents/guardians, and data were collected for a total of 962 pediatric food-allergic patients. Overall, 8.4% of the participants used CAM to treat a food allergy. The major CAM therapies used were herbal teas (22.2%), including several Japanese herbal teas, Chinese herbal medicine (18.5%) and lactic acid bacteria (16%). Among the participants using CAM to treat food allergy, 13.6% thought that the CAM being used was very effective, while 11.1% of participants thought that CAM caused some type of side effect. Conclusions: Our study is the first large-scale national survey regarding the use of CAM in pediatric patients with food allergies in Japan. Unlike in the USA, which has a higher rate of CAM use (17%), approximately 8.4% of food-allergic patients used CAM in Japan. Interestingly, the major types of CAM used in Japan differed from those used in the USA. Cultural differences and food customs may affect the use of CAM.
  International Archives of Allergy and Immunology 07/2012; 159(4):410-415. · 2.40 Impact Factor
• Article: A case of infantile Takayasu arteritis with a p.D382E NOD2 mutation: an unusual phenotype of Blau syndrome/early-onset sarcoidosis?

  Yuzaburo Inoue, Yasushi Kawaguchi, Naoki Shimojo, Kenichi Yamaguchi, Yoshinori Morita, Taiji Nakano, Takayasu Arima, Minako Tomiita, Yoichi Kohno
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  ABSTRACT: Blau syndrome/early-onset sarcoidosis (Blau/EOS) is an autoinflammatory disease characterized by granulomatous arthritis, uveitis, and skin rash. It has been shown that gain-of-function NOD2 mutations cause Blau/EOS. In this paper, we describe a patient with a gain-of-function NOD2 mutation who developed infantile Takayasu arteritis, which is rare in Blau/EOS, but who has not yet had significant granulomatous changes in joints, eyes, or skin. We suspect that this case is an unusual phenotype of Blau/EOS.
  Modern Rheumatology 07/2012; · 1.58 Impact Factor
• Article: Phrenic nerve palsy associated with birth trauma - Case reports and a literature review.

  Tadashi Shiohama, Katsunori Fujii, Masaharu Hayashi, Tomoro Hishiki, Maiko Suyama, Hiromi Mizuochi, Hideki Uchikawa, Shigetoshi Yoshida, Hideo Yoshida, Yoichi Kohno
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  ABSTRACT: Phrenic nerve palsy is a peripheral nerve disorder caused by excessive cervical extension due to birth trauma or cardiac surgery. We describe two new patients with phrenic nerve palsy associated with birth trauma. Both patients exhibited profound dyspnea and general hypotonia immediately after birth. A chest roentgenogram and fluoroscopy revealed elevation of the diaphragm, leading to a diagnosis of phrenic nerve palsy associated with birth trauma. Since they had intermittently exhibited dyspnea and recurrent infection, we performed video-assisted thoracoscopic surgery (VATS) plication in both cases, at an early and a late stage, respectively. Both patients subsequently exhibited a dramatic improvement in dyspnea and recurrent respiratory infection. Interestingly, the late stage operated infant exhibited spontaneous recovery at 7months with cessation of mechanical ventilation once. However, this recovery was transient and subsequently led to an increased ventilation volume demand, finally resulting in surgical treatment at 15months. Histological examination of the diaphragm at this time showed grouped muscle atrophy caused by phrenic nerve degeneration. To our knowledge, this is the first pathologically proven report of grouped muscle atrophy of the diaphragm due to phrenic nerve degeneration, suggesting that partial impairment of phrenic nerves resulted in respiratory dysfunction with incomplete recovery. We conclude that recently developed VATS plication is a safe and effective treatment for infants with phrenic nerve palsy, and should be considered as a surgical treatment at an early period.
  Brain & development 06/2012; · 1.74 Impact Factor
• Article: Food allergy after cord blood stem cell transplantation with tacrolimus therapy in two patients who developed veno-occlusive disease.

  Yuzaburo Inoue, Hidemasa Ochiai, Tomoro Hishiki, Naoki Shimojo, Hideo Yoshida, Yoichi Kohno
  Allergology International 06/2012; 61(3):497-9.
• Article: The onset of allergic rhinitis in Japanese atopic children: a preliminary prospective study.

  Syuji Yonekura, Yoshitaka Okamoto, Naoki Shimojo, Heizaburo Yamamoto, Daiju Sakurai, Shigetoshi Horiguchi, Toyoyuki Hanazawa, Yuzaburo Inoue, Takayasu Arima, Minako Tomiita, Yoichi Kohno
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  ABSTRACT: This preliminary prospective study suggests that background factors may differ among allergic diseases. The beneficial interventions for reducing development of allergic rhinitis (AR) are also effective for the prevention of subsequent onset of bronchial asthma (BA). To determine the risk factors associated with onset of AR in atopic children in a prospective study. All patients with atopic dermatitis (AD) or food allergy with or without BA who visited the Pediatric Unit of Chiba University Hospital from 2005 to 2006 were enrolled in the study and received allergy examinations every 3-6 months. A total of 100 patients were followed up for more than 2 years. Among the 60 patients without BA at entry to the study, 12 developed BA during the follow-up period. Development of AR preceded BA in 10 of the 12 patients (83.3%). In the background factors at the entry, positive sensitization to house dust mite (HDM) was significantly related to development of BA. Among the 48 patients without AR, 20 developed AR. High titers of serum HDM-specific IgE and high eosinophil counts in blood, and detection of eosinophils in nasal smears at the entry were significantly related to development of AR.
  Acta oto-laryngologica 04/2012; 132(9):981-7. · 0.98 Impact Factor
• Article: Reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage.

  Yuko Kazato, Katsunori Fujii, Hiroshi Oba, Moeko Hino, Hidemasa Ochiai, Hideki Uchikawa, Yoichi Kohno
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  ABSTRACT: We described a 7-year-old girl with reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. She initially presented with high fever and pancytopenia, leading to a diagnosis of most severe type aplastic anemia. We treated her with cyclosporine, methylprednisolone and anti-thymocyte globulin. Thereafter she recurrently complained of a very severe headache called as thunderclap, and finally exhibited loss of consciousness. Brain imaging revealed massive parenchymal hemorrhage between the left occipital and parietal lobes on computed tomography, and diffuse cerebral vasoconstriction on magnetic resonance angiography. The cerebral vasoconstriction resolved within two months, and thus we diagnosed her as having reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. This syndrome has been frequently reported in adult females, but rarely in children. However, even in children, a so called thunderclap headache may become a clue for the diagnosis of reversible cerebral vasoconstriction syndrome, especially in cases taking immunosuppressive agents. Immediate magnetic resonance angiography is essential to diagnose this syndrome, and a prompt application of calcium channel inhibitors should be considered to resolve constriction of the vessels and to prevent subsequent brain damage.
  Brain & development 02/2012; 34(8):696-9. · 1.74 Impact Factor
• Article: Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma.

  Mamiko Endo, Katsunori Fujii, Katsuo Sugita, Kayoko Saito, Yoichi Kohno, Toshiyuki Miyashita
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  ABSTRACT: Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by developmental defects and tumorigenesis. The clinical manifestations of NBCCS have been reported in large epidemiological studies from the United States, the United Kingdom, and Australia, but not from an Asian country. We conducted a nationwide survey and identified 311 NBCCS patients in Japan. We investigated the detailed clinical manifestations of 157 patients ranging in age from 9 months to 77 years old (mean: 33.1 years). We then compared the frequency and age of onset for various tumors developed in Japanese NBCCS patients with patients from the three countries listed above in which NBCCS studies were previously conducted. Our most significant finding was the low frequency of basal cell carcinoma (BCC) in Japanese patients. Frequency of BCC in patients over 20 years of age was 51.4%, a much lower rate compared to the United States, Australia, and the United Kingdom (91%, 85%, and 73%, respectively). The mean age of BCC onset was 37.4 years of age, a much older age compared to the above-mentioned countries. These findings suggest that differences in ethnicity and/or environmental factors affect the incidence of BCC. Because the age of BCC onset is generally higher in Japanese NBCCS patients, careful skin examination over a prolonged period of time is warranted.
  American Journal of Medical Genetics Part A 02/2012; 158A(2):351-7. · 2.39 Impact Factor
• Article: Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis.

  Hiroki Inoue, Yoichi Mashimo, Makiko Funamizu, Shuji Yonekura, Shigetoshi Horiguchi, Naoki Shimojo, Yoichi Kohno, Yoshitaka Okamoto, Akira Hata, Yoichi Suzuki
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  ABSTRACT: Matrix metalloproteinase 9 (MMP9) gene has been shown to be involved in the pathogenesis of allergic rhinitis (AR) and asthma. Previous studies suggested that single-nucleotide polymorphisms (SNPs) of the MMP9 gene conferred a risk for childhood asthma. However, whether the SNPs confer a risk for AR has not been previously investigated. The objective of this study was to investigate whether SNPs of the MMP9 gene are associated with risk of seasonal AR (pollinosis), perennial AR and allergen sensitization. A total of 670 school children were recruited in Japan and genotyped for functional polymorphism in the promoter (-1590C/T: rs3918242) and three amino-acid substitutions (R297Q: rs17576; P574R: rs2250889; R668Q: rs17577). Serum levels of total and specific IgE were determined. Disease status and other clinical characteristics of the subjects were investigated using a questionnaire. Associations between the MMP9 SNPs and both AR and serum IgE levels were evaluated. -1590C/T showed significant association with cedar pollinosis (corrected P (Pcor)=0.039). R668Q was in strong linkage disequilibrium (LD) with -1590C/T and showed significant association with cedar pollinosis (Pcor=0.023) and serum cedar pollen-specific IgE level (Pcor=0.022). A haplotype associated with -1590T and 668Q showed a significant association with cedar pollinosis, orchard grass pollinosis and cedar pollen-specific IgE (Pcor=0.0012, Pcor=0.0059 and Pcor=0.0041, respectively). R297Q and P574R were in weak LD with the rest of the SNPs and did not show significant association with disease. Compared with wild-type MMP9 protein (279R-574P-668R), a variant enzyme (279R-574P-668Q) that showed association with pollinosis had lower activity. However, lower enzyme activity was not associated with disease risk because another variant (279Q-574R-668R) showed lower enzyme activity but was not associated with pollinosis. The -1590T allele and its corresponding haplotype was associated with higher promoter activity and with pollen-specific IgE levels and pollinosis, suggesting that -1590C/T may have more impact on sensitization and disease development than R668Q. Our results suggest that the MMP9 gene confers susceptibility to cedar pollinosis in Japanese children. The MMP9 gene may be associated with pollinosis through sensitization processes.
  Journal of Human Genetics 01/2012; 57(3):176-83. · 2.57 Impact Factor
• Article: Higher dose of methimazole causes frequent adverse effects in the management of Graves' disease in children and adolescents.

  Hirokazu Sato, Nozomu Sasaki, Kanshi Minamitani, Masanori Minagawa, Itsuro Kazukawa, Shigetaka Sugihara, Kunio Wataki, Susumu Konda, Hiroaki Inomata, Kazunori Sanayama, Yoichi Kohno
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  ABSTRACT: Abstract Objective: Methimazole (MMI) is used as a first-line antithyroid drug in children and adolescents with Graves' disease (GD). The aim of this study was to evaluate the correlation between the initial dose of MMI and the clinical course of GD after treatment. Design: Retrospective and collaborative study. Setting: Nine facilities in Chiba prefecture, Japan. Patients: Sixty-four children and adolescents with GD were analyzed. The subjects were divided into three groups by the initial daily dose of MMI: group A, 0.4±0.1 mg/kg (mean±SD, n=11); group B, 0.7±0.2 (n=37); group C, 0.9±0.2 (n=16). Main outcome measures: The duration of time required for normalization of serum free T4 on initial treatment and the incidence of adverse effects for 1 year after the start of MMI were compared. Outcomes were compared among patients who were followed more than 3 years (group A, n=7; group B, n=24; group C, n=12). Results: Mean duration of times for normalization of T4 was 1.9±1.5 months in group A, 1.6±0.9 in group B and 1.9±1.5 in group C (NS). No major adverse reactions were observed. Minor adverse effects occurred in 9.1% of cases in group A, 13.5% in group B and 62.0% in group C (p<0.01). Remission rates did not differ among the three groups. Conclusions: Higher doses of MMI are harmful for initial use in children and adolescents with GD.
  Journal of pediatric endocrinology & metabolism: JPEM 01/2012; 25(9-10):863-7. · 0.88 Impact Factor
• Article: Coenzyme A contained in mothers' milk is associated with the potential to induce atopic dermatitis.

  Takehiro Higashi, Naoki Shimojo, Shuichi Suzuki, Mayuko Nakaya, Rie Takagi, Kumiko Hashimoto, Kazuyuki Nakagome, Koichiro Nakamura, Yoichi Kohno, Sho Matsushita
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  ABSTRACT: T(h)2 adjuvant activity can be qualitatively and quantitatively evaluated using a mixed lymphocyte reaction and by changes in the intracellular cyclic adenosine 3',5'-monophosphate concentration, using human dendritic cells in vitro. The current study shows that mothers, whose children (n = 55) developed atopic dermatitis (AD) within 6 months after birth, often demonstrate a higher T(h)2 adjuvant activity in their milk, in comparison to those whose children did not develop such symptoms. Such an activity was recovered in a liquid phase of mothers' milk and was eluted as a single fraction by reversed-phase HPLC. Further analysis of this fraction by mass spectrometry showed that signals originating from a factor with a molecular weight of 767.53 are observed, exclusively in milk with a high T(h)2 adjuvant activity. The mass is exactly that of Coenzyme A (CoA), and indeed, a low concentration of CoA exhibited T(h)2 adjuvant activity both in vitro and in vivo. Moreover, mesenteric lymph node non-T cells obtained from mice that were orally treated with CoA led allogeneic naive CD4(+) T cells to differentiate into T(h)2. Furthermore, the oral administration of CoA induced rough skin, hyperplasia of the epidermis, hypergranulosis in the spinous layer and the thickening of the stratum in mice. These data collectively indicate that some of the patients with AD were exposed to mothers' milk carrying high T(h)2 adjuvant activity right after birth, which may be attributable to presence of CoA contained in the milk.
  International Immunology 12/2011; 23(12):741-9. · 3.41 Impact Factor
• Article: Establishment of diagnosis by bisulfite-treated methylation-specific PCR method and analysis of clinical characteristics of pseudohypoparathyroidism type 1b.

  Kaori Kinoshita, Masanori Minagawa, Tomozumi Takatani, Rieko Takatani, Mika Ohashi, Yoichi Kohno
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  ABSTRACT: Pathogenesis of pseudohypoparathyroidism type 1b (PHP-1b) is related to the loss of methylation at the GNAS exon A/B region, which is combined with epigenetic defects at other differentially methylated GNAS regions in most sporadic cases. In this study, we established a method for evaluating the methylation status of a CpG island in exon A/B using a methylation-specific polymerase chain reaction (MSPCR). We designed two primer pairs specific for the methylated and unmethylated alleles and evaluated the methylation status of GNAS exon A/B in samples from PHP-1b patients and normal controls. We examined 20 Japanese patients and 20 normal controls, and one primer set was found to be appropriate for diagnosis. Furthermore, we evaluated the clinical data of patients. Weight and height of patients were not significantly different from the normal population. Short stature (adult height ≤ 2SD) was observed in one patient and short metacarpals in two. Obesity was observed in six patients, and no patient showed ectopic subcutaneous calcification. Seven patients showed subclinical hypothyroidism because of resistance to thyroid stimulating hormone, but no patient had an abnormally low free thyroxine level, and none received oral thyroid hormone replacement. For diagnosis of PHP-1b, only clinical data is not sufficient because a few PHP-1b patients show clinical features similar to PHP-1a, and hence, molecular biology techniques are required for correct diagnosis. We concluded that MSPCR is applicable for rapid molecular diagnosis of PHP-1b.
  Endocrine Journal 08/2011; 58(10):879-87. · 2.03 Impact Factor
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  Available from: Tomomitsu Hirota

  Article: Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.

  Emiko Noguchi, Hiromi Sakamoto, Tomomitsu Hirota, Kaori Ochiai, Yoshimasa Imoto, Masafumi Sakashita, Fumitake Kurosaka, Akira Akasawa, Shigemi Yoshihara, Noriko Kanno, [......], Nobuyuki Hizawa, Toru Sakamoto, Hironori Masuko, Yusuke Nakamura, Ichiro Nomura, Mayumi Tamari, Tadao Arinami, Teruhiko Yoshida, Hirohisa Saito, Kenji Matsumoto
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  ABSTRACT: Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10(-8)) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P(combined) = 2.3×10(-10), odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10(-10), OR = 1.52, and DPB1*0901: P = 2.0×10(-7), OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.
  PLoS Genetics 07/2011; 7(7):e1002170. · 8.69 Impact Factor