Takehide Imai

Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis

CMCD is a rare congenital disorder characterized by persistent or recurrent skin, nail, and mucosal membrane infections caused by Candida albicans. Heterozygous GOF STAT1 mutations have been shown to confer AD CMCD as a result of impaired dephosphorylation of STAT1. We aimed to identify and characterize STAT1 mutations in CMCD patients and to develop a simple diagnostic assay of CMCD. Genetic analysis of STAT1 was performed in patients and their relatives. The mutations identified were characterized by immunoblot and reporter assay using transient gene expression experiments. Patientsˈ leukocytes are investigated by flow cytometry and immunoblot. Six GOF mutations were identified, three of which are reported for the first time, that affect the CCD and DBD of STAT1 in two sporadic and four multiplex cases in 10 CMCD patients from Japan. Two of the 10 patients presented with clinical symptoms atypical to CMCD, including other fungal and viral infections, and three patients developed bronchiectasis. Immunoblot analyses of patientsˈ leukocytes showed abnormally high levels of pSTAT1 following IFN‐γ stimulation. Based on this finding, we performed a flow cytometry‐based functional analysis of STAT1 GOF alleles using IFN‐γ stimulation and the tyrosine kinase inhibitor, staurosporine. The higher levels of pSTAT1 observed in primary CD14+ cells from patients compared with control cells persisted and were amplified by the presence of staurosporine. We developed a flow cytometry‐based STAT1 functional screening method that would greatly facilitate the diagnosis of CMCD patients with GOF STAT1 mutations.

Possible Synergic Effect of Angiotensin-I Converting Enzyme Gene Insertion/Deletion Polymorphism and Angiotensin-II Type-1 Receptor 1166A/C Gene Polymorphism on Ischemic Heart Disease in Patients with Kawasaki Disease

ACE I/D and AT1R 1166A/C polymorphisms are considered to comprise individual risk factors for the development of coronary disease. We sought to demonstrate that the ACE I/D and AT1R 1166A/C polymorphisms affect coronary artery stenosis in patients with Kawasaki disease (KD). We examined 147 healthy controls and 281 Japanese children with KD. The patients were further divided into group N (n = 246, no ischemia) and group I (n = 35, severe coronary artery stenosis with myocardial ischemia), and we studied the genotype of ACE I/D and AT1R 1166A/C polymorphisms. We also examined ACE activity in patients with acute KD. We did not detect any prevalent genotypes of the ACE and AT1R polymorphisms between controls and KD patients. However, the prevalence of the D allele in the ACE polymorphism and of the C allele in the AT1R polymorphism tended to be higher in group I than in group N (odds ratios, 2.00 and 2.32, respectively). In addition, the presence of the D and/or C alleles significantly increased the relative risk of developing myocardial ischemia (odds ratio, 2.71; p = 0.038). During the convalescent phase of KD, ACE activity was increased despite significant attenuation during the acute phase. These results suggested that the renin-angiotensin system is associated with the formation of severe coronary artery stenosis and myocardial ischemia.

An 8-year-old boy with vertebral artery dissection with cerebellar ataxia featuring suspected vertebral artery hypoplasia

We report an 8-year-old boy with left vertebral artery dissection featuring cerebellar ataxia in which congenital vertebral artery hypoplasia was suspected as a predisposing factor in the dissection. The patient suddenly suffered from vertigo and vomiting while swimming, and he was brought to our department. The initial brain Computed Tomography (CT) demonstrated no abnormalities, and his symptoms disappeared the next morning. However, one month after onset, brain Magnetic Resonance Imaging (MRI) revealed ischemic changes (infarction) in the left cerebellum. Transfemoral angiography showed complete occlusion at the C2 portion of the left vertebral artery, suggesting dissection and diffuse narrowing of the proximal segment of the occlusion site. Three-dimensional CT angiography also revealed diffuse narrowing of the left vertebral artery from the bifurcation of the subclavian artery. He has since been living daily life without any difficulties. The detailed etiology of cerebral artery dissection remains unknown, but arterial anomalies should be considered as a predisposing factor.

Serum KL-6 and surfactant protein D in children with 2009 pandemic H1N1 influenza infection

Background:  A global pandemic influenza A (H1N1) outbreak occurred in 2009. Rapid progress of respiratory distress is one of the characteristic features of pandemic influenza A (H1N1) infection. The physiologic mechanism causing hypoxia in pandemic influenza A (H1N1) infection, however, has not been elucidated.

Normative Data and Predictive Equation of Interrupter Airway Resistance in Preschool Children in Japan

Measurement of interrupter airway resistance (Rint) is a convenient alternative to standard spirometry for assessing respiratory function in uncooperative young children. The aim of the present prospective study was to establish the normative data and predictive equation of Rint in Japanese preschool children. A total of 214 children were enrolled from a single kindergarten; however, 129 were excluded because they met at least 1 of the exclusion criteria, such as wheezing history or recent common cold. Expiratory Rint values were assessed in 85 of the children, but technically unsatisfactory measurements were obtained in 5 of them. Thus, 80 healthy Japanese children (39 boys and 41 girls) without any history or symptoms of respiratory tract diseases were evaluated. Their age, body height, and body weight ranges (median) were 1.67 to 6.42 (4.38) years, 79.8 to 120.9 (102.5) cm, and 10.4 to 24.9 (15.8) kg, respectively. The mean Rint was 0.93±0.25 kPa/L/s (range=0.46-1.49 kPa/L/s). The Rint tended to decrease with increasing age and body height (r=-0.65; P<0.01), but sex played no significant role (P=0.71). The predictive equation based on body height derived by linear regression was expiratory Rint (kPa/L/s) =2.513-0.01567×body height (cm) (multiple correlation coefficient=0.653). Because 79 of the 80 measured Rint values were within 140% of the predictive Rint value, we calculated a 140% cut-off for predicting bronchoconstriction. Our results provide a reference value for evaluating the degree of airway obstruction in young Japanese children.

A Case of Atypical Hodgkin Disease Associated with EB Virus Infection, Presented As a Huge Mediastinal Tumor.

9歳女児。発然, 咳嗽を主訴に近医受診, 胸部単純X線写真で右上縦隔及び右肺門部に腫瘤状陰影を指摘され紹介入院。不明熱発症の8歳時に血液検査で慢性活動性EBウイルス感染症を疑われた。入院時, 顔面の紅斑と肝脾腫を認め, 血液検査では慢性活動性EBウイルス感染症を指摘しえた。胸部CT・MRIでは右上・中・後縦隔に腫瘤性病変がみられた。気管支ファイバースコピーでは気管, 右主気管支, 右中間気管支幹が壁外性に圧迫され扁平化していた。気管支肺胞洗浄液細胞診や気管支粘膜生検で悪性細胞はみられなかった。右鎖骨上リンパ節生検でHodgkin病 (結節硬化型) が強く示唆された。患児は末梢血EBウイルス抗体価の異常高値が発症前から指摘されておりEBウイルスの関与が推測された。胸郭内腫瘍性病変の診断には, 経気管支鏡的検査は侵襲が比較的少なく小児呼吸器疾患領域においても考慮すべき診断方法の一つであると考えられた。

Long-Term Follow-Up of a Pilot Study of Intermittent Intensive Continuation Therapy (HL-3 Protocol) for Childhood Acute Lymphoblastic Leukemia

Although the remission induction of childhood acute lymphoblastic leukemia (ALL) is relatively easy, many patients relapse sometime during their courses. Our past experience (in 1970s) was dismal and we could not attain overall survival of above-50-percent level. To improve the treatment outcome we thought post-remission chemotherapy (“continuation therapy”) is most important. As Skipper showed [1], total leukemic cell kill could be best attained with repeated pulses of sufficiently effective treatment courses. To test this hypothesis and to obtain better treatment outcome, we employed an intermittent intensive continuation therapy. As an interim result from our pilot study of this approach on a small number (n = 20) of patients was satisfactory in attaining over 80 percent relapse free survival at 3 years’ follow-up, we started a group study for childhood ALL in Hiroshima and adjacent areas. Our aim was to obtain near- 100-percent relapse free long-term survival at least in “standard risk” patients. Result of long term follow-up was somewhat disappointing, but proved that the intensive intermittent continuation therapy is one of the useful approaches to improve the treatment outcome of ALL.