Eitaro Hiejima

Kyoto University, Kioto, Kyōto, Japan

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Publications (16)35.33 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.European Journal of Human Genetics advance online publication, 10 June 2015; doi:10.1038/ejhg.2015.119.
    European journal of human genetics: EJHG 06/2015; DOI:10.1038/ejhg.2015.119 · 4.35 Impact Factor
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    ABSTRACT: Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in the homeostasis of mucosal immunity; however, their role in inflammatory bowel disease (IBD) is unclear. Flow cytometry was used to enumerate peripheral blood MAIT cells in 88 patients with ulcerative colitis (UC), 68 with Crohn's disease (CD), and in 57 healthy controls. Immunohistochemistry identified MAIT cells in intestinal tissue samples from patients with UC (n = 5) and CD (n = 10), and in control colon (n = 5) and small intestine (n = 9) samples. In addition, expression of activated caspases by MAIT cells in the peripheral blood of 14 patients with UC and 15 patients with CD, and 16 healthy controls was examined. Peripheral blood analysis revealed that patients with IBD had significantly fewer MAIT cells than healthy controls (P < 0.0001). The number of MAIT cells in the inflamed intestinal mucosae of patients with UC and CD was also lower than that in control mucosae (P = 0.0079 and 0.041, respectively). The number of activated caspase-expressing MAIT cells in the peripheral blood of patients with UC and CD was higher than that in healthy controls (P = 0.0061 and 0.0075, respectively), suggesting that the reduced MAIT cell numbers in IBD are associated with an increased level of apoptosis among these cells. The number of MAIT cells in the peripheral blood and inflamed mucosae of patients with UC and CD was lower than that in non-IBD controls. Also, MAIT cells from patients with IBD exhibited proapoptotic features. These data suggest the pathological involvement and the potential for therapeutic manipulation of these cells in patients with IBD.
    Inflammatory Bowel Diseases 05/2015; 21(7). DOI:10.1097/MIB.0000000000000397 · 4.46 Impact Factor
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    ABSTRACT: Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of immune dysregulation and is classified as primary or secondary according to the underlying aetiology. The treatment strategies recommended for these two groups differ substantially; however, it is thought to be impossible to predict the underlying causes of HLH using conventional laboratory tests. Recent studies show that serum levels of soluble interleukin-2 receptor (sIL2R) and ferritin are useful for differentiating some forms of HLH. The present study reports that combinations of common laboratory parameters, such as the percentage of total lymphocytes within the peripheral blood leucocyte population, serum levels of lactate dehydrogenase and the sIL2R/ferritin ratio, are useful for identifying patients with familial haemophagocytic lymphohistiocytosis and for differentiating the underlying aetiology of paediatric HLH during the early course of the disease. These findings suggest that the pathogenesis of HLH differs greatly in terms of innate and adaptive immunity depending on the aetiology and may provide a new approach to unravelling the complex pathophysiology underlying this syndrome. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; 170(4). DOI:10.1111/bjh.13461 · 4.71 Impact Factor
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    ABSTRACT: Wilson's disease (WD) is an autosomal recessive defect in cellular copper transportation. Although acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy, only two cases of ALL associated with WD have been reported to date. One patient died of relapse and infection, and the other died of neutropenic sepsis during the treatment. We here describe the case of a 10-year-old girl with WD and ALL. Adverse events of chemotherapy, including liver toxicity and severe myelosuppression, necessitated adjustments in the chemotherapy doses. After completion of the treatment, the patient has remained in remission from ALL without progression of liver damage for 2 years. Severe treatment-related toxicity should be considered in chemotherapy for patients with WD.
    Pediatrics International 08/2014; 56(4). DOI:10.1111/ped.12313 · 0.73 Impact Factor
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    ABSTRACT: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed as a diagnostic procedure for two pediatric patients with intra-abdominal tumors. Case 1 was an 8-year-old boy with a huge tumor in the portal-hepatic region. Case 2 was a 17-year-old girl with a history of diabetes and recurrent relapse of Burkitt lymphoma, who had a newly developing tumor in the pancreatic body. In both cases, EUS-FNA was performed as a less invasive diagnostic procedure than open biopsy or total resection of the tumor. Tumor cells were determined to be of the B cell lineage by flow cytometric and immunostaining analyses. Both cases were diagnosed as having Burkitt lymphoma based on detection of IgH/C-MYC translocation by FISH. The aspiration was successfully conducted without severe complications, and both patients were immediately given chemotherapy. EUS-FNA is a safe and minimally invasive procedure with high diagnostic value for pediatric cases with intra-abdominal tumors.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 07/2013; 54(7):653-7.
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    ABSTRACT: Plasma mannose is suggested to be largely generated from liver glycogen-oriented glucose-6-phosphate. This study examined plasma mannose in glycogen storage disease type Ia (GSD Ia) lacking conversion of glucose-6-phosphate to glucose in the liver. We initially examined fasting-and postprandial 2 h-plasma mannose and other blood carbohydrates and lipids for seven GSD Ia children receiving dietary interventions using cornstarch and six healthy age-matched children. Next, one-day successive intra-individual parameter changes were examined for six affected and two control children. Although there were no significant differences in fasting-and postprandial 2 h-glucose and insulin levels, the mannose level of the affected group was invariably much higher than that of the control group (p < 0.001): the fasting level of the affected group was about two-fold that of the control group; the postprandial-2 h level remained almost unchanged in the affected group, although it was one-half of the fasting level in the control group. Inter-individual analyses revealed that the GSD Ia group mannose level was significantly and positively correlated with lactate and triglycerides levels at both time points (p < 0.01). In each control, mannose levels fluctuated greatly, maintaining strong and significant negative correlations with glucose and insulin levels (p < 0.001). Correlations were lower or nonexistent in GSD Ia children. In individuals with high lactate and triglycerides levels, strikingly high mannose levels never changed against glucose and insulin fluctuations. Plasma mannose is less sensitive to blood glucose and insulin in GSD Ia children. Its basal level and the fluctuation pattern differ by their metabolic activity.
    Journal of Inherited Metabolic Disease 09/2012; 36(1). DOI:10.1007/s10545-012-9514-x · 3.37 Impact Factor
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    ABSTRACT: Background: The mechanisms of liver damage and steatosis in Wilson's disease (WD) presenting accumulation of copper generating oxidants remain unclear. Recent studies have shown that peroxisome proliferator-activated receptors (PPARs), in particular PPARs α and γ, regulate fat content of the liver together with the anti-oxidant and anti-inflammation systems. However, such PPARs have never been studied in WD. Methods: We examined PPARs along with the liver damage and steatosis of WD using liver specimens from affected patients exhibiting mild liver damage (group I, n = 5), moderate or greater liver damage (group II, n = 10) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (group H, n = 4). Results: PPAR α expression was increased over the control levels in groups H and I but was decreased in groups II and III in parallel with the progression of liver damage (group H = I>II>III). PPAR γ expression was inversely increased (group H<I<II<III). Mn-dependent superoxide dismutase (Mn-SOD), CuZn-SOD, and catalase activities were decreased in the affected three groups, and were increased in group H. Among group II exhibiting substantial inter-individual variances in parameters, the severity of steatosis showed a significant positive correlation with PPAR γ expression (p<0.001) but not PPAR α expression. CuZn-SOD activity was positively correlated with PPARα expression (p<0.05) but not PPAR γ expression. Conclusion: These results suggest that changes of PPARs γ and α are associated with the steatosis and the impairment of anti-oxidant system in the liver of WD.
    Molecular Genetics and Metabolism 08/2012; 107(3). DOI:10.1016/j.ymgme.2012.08.004 · 2.63 Impact Factor
  • Rheumatology (Oxford, England) 05/2012; 51(11):2107-9. DOI:10.1093/rheumatology/kes101 · 4.48 Impact Factor
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    Eitaro Hiejima · Hiroshi Nakase · Shinji Uemoto · Toshio Heike
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    ABSTRACT: The patient was an 8-month-old boy with a 2-month history of stridor. Initially, he had been diagnosed with bronchitis and/or asthma and treated with antibiotics, a β-antagonist and a leukotriene antagonist, but his symptoms were not relieved. An enhanced computed tomography scan showed a gas filled mass and tracheal compression above the level of the aortic arch, and barium swallow revealed an approximately 3 cm mass with irregular surface. Endoscopic examination showed a yellow foreign body (FB) with surrounding granulation tissue. The FB was removed surgically. Postoperative bronchoscopy showed improvement of tracheal compression. The patient had an uneventful recovery with disappearance of his stridor.
    Clinical Journal of Gastroenterology 04/2012; 5(2). DOI:10.1007/s12328-012-0283-8
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    ABSTRACT: Acute liver failure (ALF) with macrophage activation syndrome (MAS) is well known as a complication of systemic-onset juvenile idiopathic arthritis (S-JIA). However, liver failure without overt MAS is rare in S-JIA. We encountered two Japanese children with S-JIA in whom ALF developed during the remission of clinical manifestations. ALF without MAS was improved with plasma exchange and cyclosporine A combined with pulse methylprednisolone.
    Journal of Paediatrics and Child Health 11/2011; 48(3):E122-5. DOI:10.1111/j.1440-1754.2011.02213.x · 1.15 Impact Factor
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    ABSTRACT: Recently, the prevalence of genotype A in patients with acute hepatitis B virus (HBV) infection has markedly increased in Japan. We encountered a 1-year-old infant who was infected with HBV genotype A and became an HBV carrier. His grandfather was identified as an HBV carrier; however, the grandfather was not aware of chronic HBV infection. This was a case of intrafamilial transmission. In addition, the child's father developed acute hepatitis B within 1 month of the infant's diagnosis. Molecular analysis revealed that the HBV isolates from the grandfather, the infant, and the father had identical sequences that belonged to genotypes A2/Ae. Compared with other HBV genotypes, genotype A has a significant association with chronic outcome. Therefore, prolonging hepatitis can increase the risk of transmitting the virus without realizing. The at-risk strategy of hepatitis B vaccination, which has been adopted in Japan, cannot prevent such intrafamilial transmission. Universal vaccination in childhood is only one way to prevent young children from unexpected HBV infection.
    Journal of Infection and Chemotherapy 04/2011; 17(2):272-7. DOI:10.1007/s10156-010-0107-z · 1.49 Impact Factor
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    ABSTRACT: Although the diagnostic scoring system of autoimmune hepatitis (AIH) has been used, these criteria are intended mainly as research tools and are complicated to apply. To resolve these difficulties and allow quick diagnosis, a simplified scoring system was proposed in 2007. We retrospectively compared the simplified AIH scoring system with the 1999 revised original AIH scoring system in children. Twenty children (boys/girls 10/10, age 1-15 years, mean age ± SD 8.4 ± 4.4 years) who were diagnosed with AIH based on clinical, biochemical, immunological, and histological data were enrolled in this study. In addition, 36 children with non-AIH liver diseases (boys/girls 22/14, age 1-16 years, mean age ± SD 7.8 ± 4.4 years) were available for evaluation of both the simplified and the 1999 revised scoring system. The sensitivity and specificity of the 1999 revised scoring system were 100% and 81%, respectively. In contrast, the sensitivity and specificity of the simplified scoring system were 55% and 86%, respectively. Of the 20 children with AIH, 9 (45%) were classified as not having AIH using the simplified scoring system. Of the 9 children, 2 and 7 were classified as having definite AIH and probable AIH using the 1999 revised scoring system, respectively. All 5 children with primary sclerosing cholangitis were graded as having AIH using the simplified AIH criteria and the 1999 revised criteria. Although the simplified AIH scoring system has low sensitivity for the diagnosis of AIH in children, the specificity of the simplified AIH scoring system is high. However, the simplified AIH scoring system could not differentiate between AIH and primary sclerosing cholangitis. Therefore, the simplified AIH scoring system does not seem to be a reliable diagnostic tool in children.
    Journal of pediatric gastroenterology and nutrition 03/2011; 52(4):470-3. DOI:10.1097/MPG.0b013e3181fc1e0b · 2.63 Impact Factor
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    ABSTRACT: The administration of hepatitis B immunoglobulin followed by hepatitis B vaccine can result in a protective efficacy of almost 90% in mother-to-child transmission of hepatitis B virus (HBV). However, little is known about immunity against HBV infection in children after immunoprophylactic treatment. We tried to assess the association between T-cell responses and viremia in children after successful prophylactic treatment. Thirteen children and their 8 HBV carrier mothers (8 families), who were positive for human leukocyte antigen (HLA)-A24, were enrolled in this study. All of the 13 children received immunoprophylactic treatment and became negative for hepatitis B surface antigen (HBsAg) after birth. HBV-specific cytotoxic T lymphocyte (CTL) responses were evaluated using IFNgamma - enzyme-linked immunosorbent spot (ELISPOT) and major histocompatibility complex class I peptide pentamer assays. Serum HBV DNA was measured by real-time PCR. Significant HBV-specific T-cell responses were detected in 2 (15%) of the 13 children by ELISPOT. However, the frequency of HLA-A24-HBV-specific CTLs was very low in both HBV carrier mothers and children using pentamers. Of the 13 children, 4 (31%) were positive for serum HBV DNA. However, the levels of serum HBV DNA were 100 copies/ml or less. One of the 2 children in whom significant HBV-specific CTL responses were detectable was positive for serum HBV DNA. HBV core and polymerase-specific T-cell responses were detected and a low-dose viremia was observed in children after successful immunoprophylaxis treatment. Although the presence of viremia was not related to HBV-specific T-cell responses, CTLs might play a role in the control of HBV infection in children born to HBsAg-positive mothers after immunoprophylactic treatment.
    BMC Infectious Diseases 04/2010; 10(1):103. DOI:10.1186/1471-2334-10-103 · 2.61 Impact Factor
  • Kanzo 01/2010; 51(8):457-459. DOI:10.2957/kanzo.51.457
  • Kanzo 01/2010; 51(10):582-585. DOI:10.2957/kanzo.51.582
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    ABSTRACT: Aim: In order to clarify the sources of chronic HBV (hepatitis B virus) infection in children after the implementation of an “at-risk” strategy in Japan, chronically infected children were assessed. In addition, chronically infected children born to HBsAg-negative mothers and their family members were assessed to identify the sources of HBV transmission. Methods: Fifty-seven children who tested HBsAg-positive after the initiation of a mother-to-child transmission prevention program were enrolled in this study. The full-genome HBV DNA sequence was analyzed to confirm the transmission sources. Results: Of the 57 patients, 37 (65%) were born to HBV carrier mothers. The remaining 20 (35%) patients were born to HBsAg-negative mothers. Fourteen of these patients had HBV carrier fathers, and 2 patients, who were siblings, did not have an HBV carrier father. The remaining 4 patients had no family members with HBV infection. Phylogenetic tree analysis confirmed that father-to-child transmission and sibling-to-sibling transmission occurred in 3 families and 1 family, respectively. Conclusion: Although vaccine failure of mother-to-child transmission was the major cause of chronic HBV infection in children, father-to-child transmission was the second most common mode of transmission. In addition, sibling-to-sibling transmission was found. Unless at-risk individuals and groups can be accurately identified to prevent horizontal transmission, the introduction of universal vaccination is essential for achieving the elimination of HBV infection in Japan.
    Hepatology Research 03/2009; 39(6):569-76. DOI:10.1111/j.1872-034X.2009.00496.x · 2.74 Impact Factor