Yokohama-shi, Japan
Yokohama-shi, Japan

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Nagasaka H.,Chiba Childrens Hospital | Yorifuji T.,Kyoto University | Kobayashi K.,Sapporo Hokuyu Hospital | Takikawa H.,Teikyo University | And 7 more authors.
Molecular Genetics and Metabolism | Year: 2010

4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate. © 2010 Elsevier Inc. All rights reserved.


Komatsu H.,Yokohama Eastern Hospital | Komatsu H.,Toho University | Inui A.,Yokohama Eastern Hospital | Sogo T.,Yokohama Eastern Hospital | And 4 more authors.
BMC Infectious Diseases | Year: 2010

Background: 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.Methods: 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 IFNγ - enzyme-linked immunosorbent spot (ELISPOT) and major histocompatibility complex class I peptide pentamer assays. Serum HBV DNA was measured by real-time PCR.Results: 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.Conclusions: 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. © 2010 Komatsu et al; licensee BioMed Central Ltd.


Aomatsu T.,Osaka Medical College | Komatsu H.,Yokohama Eastern Hospital | Yoden A.,Osaka Medical College | Hosomi A.,Saiseikai Suita Hospital | And 5 more authors.
European Journal of Pediatrics | Year: 2010

Hepatitis B virus (HBV) reactivation after chemotherapy has been investigated, but little is known about the risk of horizontal transmission from an immunocompromised host with HBV reactivation. We treated two children with fulminant hepatitis B and acute hepatitis B, respectively, whose grandmother, an HBV carrier, had been undergoing rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R+CHOP) therapy for lymphoma. The grandmother was also suffering from fulminant hepatitis when both children became ill. The complete HBV DNA sequences of the three family members were identical. The full genome sequence analysis of HBV provided strong evidence of intrafamilial transmission of HBV. Treatments that cause immunosuppression, such as R+CHOP therapy for lymphoma, can increase the levels of serum HBV DNA and the risk of intrafamilial HBV infection when given to HBV carriers. In conclusion, specific antiviral prophylaxis is indispensable for preventing horizontal transmission as well as reactivation of HBV in chemotherapy-treated HBV carriers. © Springer-Verlag 2009.


Tsunoda T.,Yokohama Eastern Hospital | Inui A.,Yokohama Eastern Hospital | Etani Y.,Research Institute for Maternal and Child Health | Kiyohara Y.,Osaka University | And 6 more authors.
Hepatology Research | Year: 2011

Aim: There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN-α2a monotherapy for children infected by chronic hepatitis C virus (HCV). Methods: From 2004-2006, we conducted a prospective, open-label, multicenter study of 22 patients aged 4-18years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN-α2a at a dose of 3μg/kg once a week for 48weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24weeks after the cessation of treatment. Results: SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN-α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500IU/L) during treatment. Conclusion: The efficacy of PEG IFN-α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults. © 2011 The Japan Society of Hepatology.

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