Yuri Etani

A blocking peptide for transforming growth factor-β1 activation prevents hepatic fibrosis in vivo

BACKGROUND/AIMS Thrombospondin-1 is a major activator of transforming growth factor-beta1 (TGF-beta1), and a peptide derived from the latency-associated peptide, Leu-Ser-Lys-Leu (LSKL), inhibits the activation of TGF-beta1. In this study, the effects of LSKL on the hepatocyte damage and fibrogenesis in dimethylnitrosamine (DMN)-induced rat liver fibrosis were examined. METHODS Animals were given an intraperitoneal (i.p.) injection of DMN or saline three times per week for 4 weeks, and treated with LSKL, a control peptide, or saline i.p. daily. RESULTS Liver atrophy caused by DMN-injection was significantly inhibited in the DMN+LSKL group. The degrees of necrosis/degeneration and fibrosis scores were significantly lower in the DMN+LSKL group than in the control groups. The hydroxyproline content was significantly higher in the control groups than in the DMN+LSKL group. The amount of active TGF-beta1 was less in the DMN+LSKL group than in the control groups, and the active/total TGF-beta1 ratio in the DMN+LSKL group was suppressed in the control groups. Phosphorylation of Smad 2 in the liver was significantly decreased in the DMN+LSKL group. CONCLUSIONS The LSKL peptide prevented the progression of hepatic damage and fibrosis through the inhibition of TGF-beta1 activation and its signal transduction in vivo.

Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter

Thyroid hormones are known to be essential for growth, development, and metabolism. Recently, the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter, and MCT8 mutations have been associated with Allan-Herndon-Dudley syndrome, an X linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. Here we describe in detail the clinical and biochemical features and the response to thyroid hormone (L-thyroxine (LT4)) administration in a boy with an MCT8 mutation (c.1649delA) that truncates the protein in the twelfth transmembrane domain. It is of note that brain magnetic resonance imaging (MRI) revealed delayed myelination from infancy. Endocrine functions other than thyroid hormone regulation and metabolism were intact, resulting in normal hypothalamic/pituitary function tests. While LT4 administration suppressed thyrotropin (TSH) secretion, no significant changes in thyroid hormone values or clinical symptoms were observed. Conclusion: the characteristic thyroid hormone function tests and brain MRI findings may allow screening of high-risk populations for a better understanding of MCT8 pathophysiology.

Favorable response to lymphoblastoid interferon-alpha in children with chronic hepatitis C.

BACKGROUND/AIMS We investigated the efficacy of interferon therapy for the treatment of children with chronic hepatitis C virus infection. METHODS Twenty-four out of 26 children completed the 6-month treatment with lymphoblastoid interferon-alpha and were followed for 12 months or longer. Response to interferon therapy was defined by assaying for circulating HCV-RNA, using a nested PCR, at 6-month intervals after the end of the therapy. RESULTS At the end of treatment circulating HCV-RNA was undetectable in 18/24 patients and at 6 months in 12/24. Ten of these 12 primary responders have remained virus free for more than 2 years. One patient remained negative at 12 months. The remaining patient relapsed at 12 months. At 24 months 10 of 18 patients tested negative for HCV-RNA. Serum alanine aminotransferase was normal in 11/24 patients at the end of treatment, at 6 months 12/24 were normal, and at 12 months 11/12 were normal. In eight children with sustained response, repeated liver biopsies revealed a reduction in Knodells scores for inflammation in the hepatic lobules and in the portal areas. In three of them neither plus nor minus strand of HCV-RNA was detectable in the liver tissue. Responders had a significantly lower level of viremia than non-responders. Side effects of interferon including fever, hair loss, neutropenia, and thrombocytopenia were not serious enough to warrant cessation of interferon treatment. CONCLUSIONS Interferon therapy in children with chronic hepatitis C may be beneficial as evaluated by sustained loss of viremia as well as by primary response.

Genes for members of the GATA-binding protein family (GATA-GT1 and GATA-GT2) together with H+/K(+)-ATPase are specifically transcribed in gastric parietal cells.

mRNAs for novel DNA‐binding proteins (GATA‐GT1 and GATA‐GT2) recognizing the (G/C)PuPu(G/C)NGAT(A/T)PuPy sequence and H+/K+‐ATPase (proton pump) α subunit were detected in parietal cells of the rat gastric body mucosa by in situ hybridization. These results suggest that GATA‐GT1 and GATA‐GT2 together with H+K+‐ATPase are transcribed specifically in gastric parietal cells and that the two DNA‐binding proteins may have important roles in cell specific gene regulation. Furthermore, we could detect parietal cells in different states of gene expression.

Efficacy and Safety of Azathioprine and 6-Mercaptopurine in Japanese Pediatric Patients with Ulcerative Colitis: A Survey of the Japanese Society for Pediatric Inflammatory Bowel Disease

Background and Aims: Azathioprine (AZA) and 6-mercaptopurine (6-MP) have recently been used in Japanese pediatric patients with ulcerative colitis. The aims of this study were to evaluate both the therapeutic efficacy and safety of AZA/6-MP in this group of patients. Methods: Fourteen members of the Japanese Society for Pediatric Inflammatory Bowel Disease reported 35 retrospective cases that received AZA/6-MP and were evaluated for adverse drug effects. In those who tolerated AZA/6-MP, disease activity and corticosteroid doses before and during the first 6 months of therapy were assessed. Results: AZA or 6-MP was safely used in 21 of 35 patients (60%) without adverse drug effects. The disease activity began to decrease from the first month of therapy and the maximum effect was achieved after 3 months. The mean daily prednisolone dose was decreased from 26.9 to 11.6 mg and dose reduction was achieved in 58% of patients after 6 months of therapy. Fourteen of the 35 patients (40%) experienced adverse drug effects, including leukopenia (n = 11), aplastic anemia (n = 1), pancreatitis (n = 1) and liver dysfunction (n = 1). Conclusions: The majority of Japanese children with ulcerative colitis tolerated AZA/6-MP and experienced favorable effects. However, 40% experienced adverse drug effects, mainly myelosuppression.

Three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine

We present here three paediatric patients with primary sclerosing cholangitis. In case 1, the serum γ‐glutamyl transpeptidase was decreased only temporarily by ursodeoxycholic acid (UDCA) treatment and 34 months later, sulphasalazine was added because of microscopic colitis. The enzyme level decreased with dual therapy. Similarly, in case 3, first diagnosed as autoimmune hepatitis, the transpeptidase levels remained elevated for 18 months during treatment with UDCA, prednisolone and mizoribin. The enzyme decreased only after a diagnosis of primary sclerosing cholangitis complicated with ulcerative colitis was established and sulphasalazine was introduced. Case 2 also had Crohns colitis and was put on UDCA and sulphasalazine from the start. The enzyme level was normalized within 1 month and has remained normal for the following 5 years. Liver biopsies were analysed repeatedly in these three patients. In case 1, periductal fibrosis remained unchanged while being treated by UDCA. There appeared to be no progression in liver cirrhosis in case 3 while being treated by UDCA, prednisolone, and mizoribin. In case 2, who has been treated with both UDCA and sulphasalazine from the start, periductal fibrosis and portal fibrosis were remarkably improved 45 months later. We suggest that sulphasalazine in addition to UDCA might be a viable treatment for children with primary sclerosing cholangitis.

Three Cases with TT Virus Infection and Idiopathic Neonatal Hepatitis

We present three cases of infants with idiopathic neonatal hepatitis showing diffuse intrahepatic fatty degeneration. Prolonged cholestasis has improved immediately upon intravenous administration of a high-dose gammaglobulin treatment in all three patients. The TT virus (TTV) genome was detectable in the serum of two patients, in the duodenal fluid of one and in the liver of all three. By analyzing sequence homology, we observed that the respective TTV isolated from serum, duodenal fluid and liver tissue were completely identical in cases 2 and 3. These findings suggest that TTV infection was one of the contributing factors for neonatal cholestasis in these patients. TTV was isolated from the serum of two out of the three mothers. The viruses were either completely or almost identical in sequence to those isolated from their respective infants, suggesting that they had been transmitted from mother to infant in these 2 cases. The patients presented here, whose livers were infected with the TTV and showed a favorable response to gammaglobulin therapy, may represent a subset of idiopathic neonatal hepatitis patients.

Peginterferon alpha-2b and ribavirin for the treatment of chronic hepatitis C in Japanese pediatric and young adult patients: a survey of the Japan Society of Pediatric Hepatology

Objectives Only a few studies on the treatment with peginterferon-2b and ribavirin are available in children with chronic hepatitis C virus (HCV). The aim of this study was to evaluate both the efficacy and the safety of the treatment in Japanese children and young adults. Methods Twenty-two of 41 members of the Japan Society of Pediatric Hepatology reported on 37 cases who were treated with peginterferon and ribavirin. Results Of the 37 patients, 29 have completed the treatment and all of them cleared the HCV virus. Three patients are still being treated, whereas the remaining five failed to complete the treatment. Cessation of the treatment was because of the nonresponsiveness (n=3), the expense of the treatment (n = 1), or lethargy (n=1). After excluding the three patients, who were continuing the treatment and one who has not completed the 24-week follow-up period, from the 37 patients, 33 were available for sustained virologic response (SVR) analysis. After 4 weeks of follow-up, one of the 33 relapsed. An intention-to-treat analysis showed that 27 of the 33 (81.8%) achieved a SVR. The only factor significantly associated with SVR was their virologic response status at week 4. Conclusion The results showed that the present patients infected with HCV and treated with peginterferon-2b and ribavirin achieved a remarkably high SVR rate. In addition, most of the patients achieved a SVR once they showed a virologic response at week 4. The combination of peginterferon-&agr; with ribavirin may be considered as a standard therapy for children and young adults.

Successful stenting for renal artery stenosis in a patient with Alagille syndrome.

A 12-year-old girl with Alagille syndrome manifested severe hypertension caused by renal artery stenosis in a solitary functioning kidney. Percutaneous transluminal angioplasty (PTA) and stenting was performed, but the hypertension persisted. On the next day, acute renal failure occurred with the administration of angiotensin-converting enzyme inhibitor, and migration of the stent was confirmed by angiography. Thus, a second stent was placed with success. Since then, the hypertension has been controlled with anti-hypertensive medication, and the renal function has recovered to normal range.

Interferon treatment on glomerulonephritis associated with hepatitis C virus

Abstract We report on a 10-year-old girl with glomerulonephritis associated with hepatitis C virus infection, who was treated with interferon-α. On the first renal biopsy at 8 years of age, mild mesangial hypercellularity in a segmental to semiglobal pattern was present in all glomeruli. After 6 months interferon-α therapy, proteinuria diminished completely. However, mesangial proliferation was advanced on the second biopsy at 10 years of age. We concluded that the interferon-α was effective in the treatment of proteinuria despite the lack of pathological improvement.