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Toshiro Hara

Publications and source records attributed to Toshiro Hara.

At least 19 recordsLinked to original sources
PubMed2007

PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children.

Interaction between Programmed cell death-1 (PD-1), a member of costimulatory molecules, and its receptors Programmed cell Death-1 Ligand 1 (PD-L1) and Programmed cell Death-1 Ligand 2 (PD-L2), play an important role in the negative regulation of immune reactions. It was shown that a polymorphism in a regulatory site of the PD-1 gene was associated with susceptibility to several autoimmune diseases in various ethnic groups, whereas the contribution of the PD-1 gene or its ligand genes to the onset of type 1 diabetes (T1D) mellitus in the Japanese population remains unknown. We first screened PD-1, PD-L1, and PD-L2 genes for polymorphisms in the Japanese population, and then investigated the frequencies of polymorphisms in patients with T1D mellitus in comparison with healthy controls. In total, we identified 26 polymorphic sites within these genes, and then 23 polymorphisms with minor allele frequencies greater than 5% were intensively analyzed for genotyping in the patients and the controls. As a result, allele and genotype frequencies of the polymorphism numbers 2, 3, 4, 5, 6, and 8 in the PD-1 gene were different to some extent between the patients and the controls with P < 0.05, which did not reach statistical significance after the correction of multiple comparisons. Allele or genotype frequencies of any SNPs in the PD-L1 or PD-L2 gene did not show differences between the patients and the controls. The frequencies of the estimated haplotypes, those of which consisted of polymorphism numbers 2, 3, 4, 5, 6, and 8 in the PD-1, were significantly different between the patients and the controls (P = 0.00095). The in vitro assessment for a transcription activity of each haplotype of the PD-1 gene by luciferase assay did not demonstrate a functional difference between the haplotypes. In conclusion, the genetic evaluation by association study demonstrated that the PD-1 gene was a predisposing gene to the development of T1D mellitus in the Japanese population.

Adolescent↗
PubMed2007

Successful self-infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor.

Regular self-infusion of an activated prothrombin complex concentrate (APCC) has been successfully introduced to a 14-year-old boy with hemophilia A. The child was diagnosed as a neonate, and at age 7 years, developed a high titer (127 BU/mL) factor VIII inhibitor coincident with a protracted ankle joint bleeding. From age 7-10 years, he received on-demand therapy using a prothrombin complex concentrate (PCC), PROPLEX-ST. From age 10-14 years, he received prophylaxis with PROPLEX-ST, initiated after an intracranial hemorrhage and coincident anamnestic inhibitor response. Throughout 7-year period of PCC treatment, he experienced recurrent bleeding episodes. Self-prophylaxis with APCC, FEIBA VH [Anti-inhibitor Coagulant Complex] (50 U/kg/dose three times per week) using infusion pump was initiated at 14 years of age and has continued for 2 years. There were no bleeding, thrombotic events or other adverse events after initiation of this prophylaxis, and inhibitor levels decreased to 1 BU/mL. His quality of life was improved, particularly with respect to school. Our long observation proposes a well-disciplined home-based FEIBA prophylaxis in inhibitor-positive hemophiliacs.

Adolescent↗
PubMed2006

Serum levels of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in subacute sclerosing panencephalitis.

We determined the relationship between the serum concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) in 33 patients with subacute sclerosing panencephalitis (SSPE) to investigate the function of the blood-brain-barrier (BBB) in SSPE. Serum MMP-9 and TIMP-1 levels were measured by ELISA. Serum MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients in Papua New Guinea (n = 24), and those in Japan (n = 9) were significantly higher than the each control (MMP-9, p = 0.0390, and p = 0.0023, respectively; MMP-9/TIMP-1, p = 0.0319, and p = 0.0009, respectively). Serum MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients with Jabbour stage III (n = 13) were significantly higher than those with Jabbour stage II (n = 18) (p = 0.003, and p = 0.0412, respectively). There were no significant differences of serum TIMP-1 levels between the SSPE patients and controls. High serum MMP-9 and MMP-9/TIMP-1 levels will promote brain invasion through the BBB by immunocompetent cells in the blood. Our findings suggest that the balance of serum MMP-9 and TIMP-1 levels modulate the inflammatory cascade of SSPE.

Adolescent↗
PubMed2006

Long-term outcome of infants with twin-to-twin transfusion syndrome.

OBJECTIVE: To clarify the long-term neurodevelopmental outcome of twin-to-twin transfusion syndrome (TTTS) survivors. METHODS: From January 1994 to December 2003, 33 newborns with TTTS who were derived from 18 monochorionic twin gestations were enrolled for the study. The development and growth at 3 or 6 years of age were compared between TTTS survivors and weight-matched singleton controls. RESULTS: The mortality in TTTS (8/33: 24%) was significantly higher than that of the controls (7/80: 9%). Of all 12 TTTS patients who were diagnosed before 25 weeks and born before 28 weeks of gestation, in 10 (83%) it led to neonatal or intrauterine death. The morbidity of cerebral palsy, epilepsy, and mental retardation did not differ between TTTS and control patients. The morbidity and severity of neurological deficits at school age were similar in both groups. No growth parameters at 3 or 6 years of age differed between TTTS and controls. CONCLUSIONS: Morbidity, growth and development of TTTS survivors attained comparable levels of weight-matched controls, despite the higher neonatal mortality. These results suggest that the early management of TTTS is critical for refining the total outcome of the affected twins.

Child Development↗
PubMed2006

CSF cytokine and chemokine profiles in acute disseminated encephalomyelitis.

We simultaneously measured 16 cytokines/chemokines in cerebrospinal fluid (CSF) from 14 patients with acute disseminated encephalomyelitis (ADEM) and 20 controls using a fluorescent bead-based immunoassay. A variety of cytokines, such as IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, G-CSF and MIP-1beta, were significantly elevated in ADEM. In particular, G-CSF showed a marked 38-fold increase compared to the control mean. Significant positive correlations with inflammatory parameters in CSF, such as cell counts and protein levels, were found for IFN-gamma, IL-6 and IL-8. In contrast, IL-17 produced by activated CD4(+) memory T cells was not increased. The results suggested that various cytokines related to activation of macrophages/microglias and Th(1) and Th(2) cells are upregulated in CSF in ADEM.

Chemokines↗
PubMed2006

The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal.

Human MTH1 protein hydrolyzes oxidized purine nucleotides 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP), 2-OH-dATP or their ribo-forms to their monophosphates, thus minimizing replicational and transcriptional errors both in the nuclei and mitochondria. MTH1 suppresses mitochondrial dysfunction and cell death caused by H(2)O(2). Furthermore, MTH1 suppresses the transient increase in 8-oxoguanine in mitochondrial DNA in the dopaminergic nerve terminals in mouse striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, and it protects the nerve terminals. We previously reported that a novel MTH1 allele with a single nucleotide polymorphism (SNP) in its exon 2c segment encodes the fourth MTH1 isoform, namely, MTH1a (p26), in addition to the three known isoforms, MTH1b (p22), c (p21), and d (p18). Another SNP located in exon 4 of the MTH1 gene, which is closely linked to the SNP in exon 2c, substitutes the Val83 residue in MTH1d with Met83. We herein show that all MTH1 isoforms efficiently hydrolyzed 2-OH-dATP and 8-oxo-dGTP. The amino terminal region of MTH1a functioned as a mitochondrial targeting signal when it was expressed in the HeLa cells as a fusion protein with enhanced green fluorescent protein. The cellular fractionation revealed that MTH1a(Met83) was localized in the mitochondria to the same extent as was MTH1d(Val83). However, the mitochondrial translocation of MTH1d(Met83) was less efficient than that of MTH1d(Val83).

Adenosine Triphosphate↗
PubMed2006

Benign convulsion with mild gastroenteritis and benign familial infantile seizure.

The authors present Japanese siblings of a 6-year-old girl and a 4-year-old boy, who concurrently experienced convulsions with mild gastroenteritis. These siblings, their father and paternal grandfather had afebrile seizures that intermittently occurred without symptoms of gastroenteritis and terminated within a few days at their infancy. An underlying genetic factor might not only cause benign familial infantile seizures but it might also confer the susceptibility to the convulsions with mild gastroenteritis in these siblings.

Anticonvulsants↗
PubMed2006

A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome.

The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (MIM 238970) is an autosomal recessive metabolic disorder caused by a deficiency of the mitochondrial ornithine transporter, one of the urea cycle components. Mutations in the SLC25A15 gene have been coupled to the HHH syndrome. We describe a Japanese female patient with the HHH syndrome due to a novel homozygous R275X SLC25A15 mutation and male sibling who presumably carried the same mutation. He exhibited slowly progressive deterioration with seizures, a gait disturbance due to polyneuropathy, episodic confusion, and died of acute encephalopathy at 34 years of age while the proband exhibited moderate mental retardation, seizures, mild spastic paraplegia, and deafness without neurological deterioration for more than 20 years. The clinical features of previously documented patients with the homozygous SLC25A15 mutation demonstrated that genotype did not simply correlate with clinical severity. The phenotypic variability might depend on other factors, such as dietary and other genetic ones.

Adult↗
PubMed2006

Prolonged severe pancytopenia preceding the cutaneous lesions of juvenile xanthogranuloma.

We report a case of juvenile xanthogranuloma (JXG) having progressive pancytopenia for 6 months until the proliferating skin lesions. A 2-month-old infant presented recurrent fever, anemia, and hepatosplenomegaly mimicking hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML). At 8 months of age, the biopsy of a growing papule on the elbow made the diagnosis. Bone marrow (BM) specimens showed clustering foamy cells including hemophagocytosis by histiocytes. Treatment with etoposide followed by vinblastine plus prednisolone (PSL) therapy improved the disease. Although JXG is a benign non-Langerhans cell histiocytosis, the multisystem-visceral form should be considered as a potential aggressive disease when associated with BM failure in early infancy.

Blood Coagulation Disorders↗
PubMed2006

Epstein-Barr virus-associated bronchial leiomyoma in a boy with cellular immunodeficiency.

Bronchial leiomyoma is a rare disease in children. Recently, the association of leiomyoma and HIV infection was reported. We describe a boy with a cellular immunodeficiency, who had endobronchial leiomyoma. The tumor cells were positive for Epstein-Barr virus-encoded RNA-1 (EBER-1) and Epstein-Barr virus-determined nuclear antigen-2, suggesting a role of Epstein-Barr virus in the pathogenesis of leiomyoma.

Bronchial Neoplasms↗
PubMed2006

Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.

Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

Adolescent↗
PubMed2006

Delayed separation of the umbilical cord in two siblings with Interleukin-1 receptor-associated kinase 4 deficiency: rapid screening by flow cytometer.

We describe 2 siblings who had interleukin-1 receptor-associated kinase 4 deficiency with a novel mutation in exon 2. They had delayed separation of the umbilical cord. The flow cytometric analysis of monocytic intracellular tumor necrosis factor-alpha production in response to lipopolysaccharide may be a useful method to screen for the disease.

Biomarkers↗
PubMed2006

Clinical characteristics and outcome of Wilms tumors with a favorable histology in Japan: a report from the Study Group for Pediatric Solid Malignant Tumors in the Kyushu Area, Japan.

BACKGROUND/PURPOSE: Since 1996, the standard treatment of Wilms tumors in Japan has been based on the regimen of the Japanese Wilms Tumor Study. However, in Japan, there have been no reports about Wilms tumors that analyzed the clinical features and patient outcome in a large series until now. This study aims to assess the clinical characteristics of patients with Wilms tumor with a favorable histology from a retrospective standpoint in the Kyushu area in Japan and, furthermore, to analyze the historical changes of clinical features and outcome from the 1980s to the 1990s. METHODS: Between 1982 and 1996, 90 cases of Wilms tumors with a favorable histology were registered in the Kyushu area. Regarding the clinical feature and outcome, they were divided into 2 groups (group A, 1982-1989, n = 50; group B, 1990-1996, n = 40). The outcome was analyzed based on the 5-year overall survival rate. RESULTS: The clinical features (age, sex, initial symptom, location, stage) demonstrated no definite differences between group A and group B. Regarding the operation, the rate of an initial complete resection in the early stages was significantly higher in group B than in group A. All stage V cases in group B undewent a bilateral tumor biopsy instead of a radical nephrectomy as the initial operation. The 5-year overall survival rate throughout the whole period was 87.8%, whereas the rates were 84.0% for group A and 90.0% for group B (P = NS), respectively. Of particular note, the outcome of patients with stage I and stage V in group B substantially improved in comparison to that in group A. However, in advanced cases, no significant improvement in the outcome was noted. CONCLUSIONS: This is the first report about the clinical features and outcome for Wilms tumors with a favorable histology in Japan from the 1980s to the 1990s. The present study suggested that in the early-stage cases, an initially complete resection followed by standard postoperative chemotherapy substantially improved the outcome of the patients in group B. In the stage V cases, the performance of renal salvage surgery may have positively contributed to the improvement in the outcome in group B. However, in the advanced stage cases, no definite improvement was noted. In the future, an improved efficacy of the treatments for Wilms tumors based on the standard protocol established by the Japanese Wilms Tumor Study in 1996 is expected in Japan.

Child, Preschool↗
PubMed2006

Nonimmune hydrops fetalis due to generalized lymphatic dysplasia in an infant with Robertsonian trisomy 21.

We report the first case of generalized lymphatic dysplasia and trisomy 21 presenting with nonimmune hydrops fetalis. This infant showed intractable chylothorax, chylous ascites, and periodic bouts of edema. A karyotype analysis revealed Robertsonian trisomy 21: 46,XY,t(14q21q)(q10;q10) +21. This patient died of multiple organ failure at 400 days of life, despite the management of chylous effusions. The lymphoscintigraphy and histopathological findings led to the final diagnosis of generalized lymphatic dysplasia, which might also contribute to the development of hydrops. Refractory chylothorax in trisomy 21 patients may emphasize the need for intensive scrutiny of lymphatic disorders.

Adult↗
PubMed2006

Rheumatic fever-mimicking carditis as a first presentation of chronic active Epstein-Barr virus infection.

UNLABELLED: A 7-y-old girl presented with prolonged fever, arrhythmia and cardiomegaly during the treatment course of group A beta-haemolytic streptococcal pharyngitis. The isolated rheumatogenic strain M1 suggested the diagnosis of rheumatic fever. However, serous pericardial effusion contained high levels of Epstein-Barr virus (EBV) DNA. Clonally proliferating EBV+ T cells were determined in the circulation. The atypical carditis without valvitis was then complicated by coronary artery dilatations. Four months after the start of prednisolone plus antiviral/bacterial therapy, EBV+ T-cell lymphoma developed in the thigh. CONCLUSION: Atypical carditis may be a notable and life-threatening presentation of chronic active EBV infection to be differentiated from rheumatic fever.

Child↗
PubMed2006

Identification of novel genes with prognostic value in childhood leukemia using cDNA microarray and quantitative RT-PCR.

The aim of this study was to identify genes distinctively expressed or suppressed in childhood leukemia with different prognoses, using cDNA microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR). The expression levels of the selected genes by cDNA microarray were quantified in primary leukemic blasts from 44 patients (acute lymphoblastic leukemia, 28; acute myelogenous leukemia (AML), 13; transient myeloproliferative disorder, 3). The expression levels of CDKN2C, CRADD, and IGFBP-2 genes were significantly associated with the event-free survival of the patients in AML. The present results suggest that a combination of cDNA microarray and quantitative RT-PCR may be useful to identify novel genes with prognostic value in childhood AML.

Adaptor Proteins, Signal Transducing↗