Infections of Reoviridae consisting of a double-stranded RNA (dsRNA) genome and the biliary innate immune response to dsRNA are implicated in the aetiopathogenesis of biliary atresia (BA). Epithelial-mesenchymal transition (EMT) has recently been proposed as a mechanism behind the sclerosing cholangitis in BA. We hypothesized that the innate immune response to dsRNA in biliary epithelial cells plays an important role in peribiliary fibrosis via biliary EMT. Experiments using cultured human biliary epithelial cells revealed that stimulation with poly(I : C) (a synthetic analogue of viral dsRNA) increased the expression of basic fibroblast growth factor (bFGF, an EMT-inducer), S100A4 (a mesenchymal marker) and Snail (a transcriptional factor), and decreased that of epithelial markers (biliary-type cytokeratin 19 and E-cadherin) and Bambi (TGF-beta1 pseudoreceptor). The expression of TGF-beta1 (EMT-inducer) and vimentin (a mesenchymal marker) was not affected by poly(I : C). Both EMT-inducers, bFGF and TGF-beta1, evoked a decrease and increase in the expression of the epithelial markers and of vimentin respectively, and the expression of Bambi was down-regulated on stimulation with bFGF. Combined treatment with bFGF and TGF-beta1 quickly and completely induced a transformation of morphology as well as change from epithelial to mesenchymal features in cultured biliary epithelial cells. Immunohistochemistry revealed that biliary epithelial cells lining extrahepatic bile ducts and peribiliary glands in BA frequently show a lack of epithelial markers and an aberrant expression of vimentin. Moreover, the biliary epithelium showing sclerosing cholangitis expressed bFGF accompanied by bFGF-positive mononuclear cells. In conclusion, the EMT may contribute to the histogenesis of sclerosing cholangiopathy, and the biliary innate immune response to dsRNA viruses induces biliary epithelial cells to undergo EMT via the production of bFGF and the increased susceptibility to TGF-beta1 caused by the down-regulation of Bambi expression.

Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.

A 5-year-old male presented with scrotal migration of the catheter from a ventriculoperitoneal shunt manifesting as left scrotal swelling 4 months after implantation. Surgical obliteration of the patent peritoneal processus vaginalis that forms a corridor from the peritoneum to the scrotum was performed to avoid shunt malfunction. Review of the 26 reported cases including the present case revealed that most patients were up to 18 months old. Our patient was the oldest. Migration tended to occur within 6 months after implantation (mean 3.8 months, median 1.0 month). Involvement of the right side of the scrotum was prevalent (23 of 26 cases). Patent processus vaginalis and small peritoneal cavity probably contribute to scrotal catheter migration.

Alpha-fetoprotein (AFP) is an important tumor marker for yolk sac tumor and hepatoblastoma in childhood. We have been using the graph of the normal range of serum AFP made by Tsuchida et al, when we evaluate the serum AFP levels in early infancy. We measured the serum AFP levels by an immunoradiometric assay in 163 normal infants under 2 years of age, in order to make a more precise graph. Our normal range was a little wider than that of Tsuchida et al. According to our graph, false-positive cases would be fewer. Referring to the half-lives of serum AFP levels in normal infancy is also useful, when it is difficult to evaluate the AFP level.

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