Altered quality control in the endoplasmic reticulum causes cortical dysplasia in knock-in mice expressing a mutant BiP.

Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) molecular chaperone that is central to ER function. We examined knock-in mice expressing a mutant BiP in order to elucidate physiological processes that are sensitive to BiP functions during development and adulthood. The mutant BiP lacked the retrieval sequence that normally functions to return BiP to the ER from the secretory pathway. This allowed us to examine the effects of a defect in ER function without completely eliminating BiP function. The homozygous mutant BiP neonates died after birth due to respiratory failure. Besides that, the mutant BiP mice displayed disordered layer formation in the cerebral cortex and cerebellum, a neurological phenotype of reeler mutant-like malformation. Consistent with the phenotype, Cajal-Retzius (CR) cells did not secrete reelin, and the expression of reelin was markedly reduced posttranscriptionally. Furthermore, the reduction in the size of the whole brain and the apparent scattering of CR cells throughout the cortex, which were distinct from the reeler phenotype, were also seen. These findings suggest that the maturation and secretion of reelin in CR cells and other factors related to neural migration may be sensitive to aberrant ER quality control, which may cause various neurological disorders.

Clinicopathological features in patients with hepatic graft-versus-host disease.

BACKGROUND/AIMS: Hepatic graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation and often results in a fatal outcome. However, hepatic manifestation of chronic GVHD accompanied by unresolved acute GVHD has not been clarified so far. The present study was intended to examine clinicopathological features in patients in which acute GVHD appeared to progress gradually into chronic GVHD. METHODOLOGY: We evaluated laboratory data, pathological features and response to immunosuppression in 11 patients whose diseases were diagnosed as hepatic GVHD, retrospectively. The patients were classified into 3 groups: acute GVHD group (n=3), non-progressive chronic GVHD group (n=5) and progressive chronic GVHD group (n=3), which means continuous liver dysfunction beyond day 100 post-transplant. RESULTS: Patients with progressive chronic GVHD showed higher peaks of aminotransferase and biliary tract enzyme levels than patients with acute GVHD and non-progressive chronic GVHD. Their biopsy specimens demonstrated severer changes in lobular parenchyma, portal area and small interlobular bile ducts. They also showed marked loss of bile ducts. Despite administration of prednisolone or dose escalation of cyclosporin A, their liver function tests did not return to normal within one year. CONCLUSIONS: In cases of liver dysfunction that emerges within 100 days after transplantation, liver biopsy appears to be important to confirm diagnosis. Patients with acute hepatic GVHD need strong immunosuppression to prevent progression to chronic GVHD.

Fatal chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis.

We report a 22-year-old female who presented with pyrexia, pancytopenia and liver dysfunction. The patient showed mild liver dysfunction with low-grade fever and mild hepatosplenomegaly 6 years previously, and autoimmune hepatitis (AIH) was diagnosed based on the examination of the laboratory data and liver biopsy. On admission, both markers of Epstein-Barr virus (EBV) and in-situ hybridisation from a liver biopsy specimen indicated chronic active EBV infection (CAEBV). The patient was administered an immunosuppressive agent and antiviral drug added to steroid therapy, but ultimately died from liver failure and virus-associated haemophagocytosis 10 months after the definite diagnosis. Retrospective examination of the serum at the diagnosis of AIH revealed extremely high titres of antibody to EBV, and EBV-DNA was also detectable by polymerase chain reaction. These results suggest the possibility that the patient may already have suffered from CAEBV at the initial diagnosis. We presume that hepatic involvement of CAEBV should be considered as differential diagnosis in cases showing liver dysfunction with clinical and biochemical features observed in AIH.

Successful clearance of hepatitis B virus after allogeneic stem cell transplantation: beneficial combination of adoptive immunity transfer and lamivudine.

We report a 38-yr-old male with acute lymphocytic leukemia (ALL), whose serological tests for the hepatitis B virus (HBV) before transplantation showed a chronic carrier status, and a liver biopsy specimen revealed chronic liver injury because of HBV. The patient underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his sibling who was hepatitis B surface antibody (HBsAb) positive. He had received lamivudine treatment for the prophylaxis of HBV reactivation during cytotoxic chemotherapy, and lamivudine administration continued after transplantation. Successful engraftment was documented 3 wk after PBSCT, and clearance of the hepatitis B surface antigen (HBsAg) was observed 2 months after PBSCT. Liver function tests transiently showed a mild elevation of aminotransferases on day 25, although this returned to normal after the dose escalation of the immunosuppressive agent. We presume that the combination of adoptive immunity transfer by bone marrow transplantation (BMT) from an HBsAb-positive donor and antiviral drugs such as lamivudine is beneficial in clearing HBV in chronic carriers.

Clinical utility of doppler ultrasonography in evaluation of early therapeutic efficacy after transcatheter arterial embolization in patients with hepatocellular carcinoma.

This study was undertaken to determine the value of Doppler ultrasonography in the early evaluation of therapeutic efficacy of hepatocellular carcinoma after transcatheter arterial embolization (TAE). Fifty-two nodules in which tumor vascularity had been detected by Doppler ultrasonography before TAE were examined in 41 patients. Doppler signals were evaluated 1 week after TAE, and the results were compared with tumor vascularity as determined by dynamic magnetic resonance imaging (dynamic MRI), which was used as the gold standard. The sonographic signal disappeared in 41 (79%) of the 52 nodules and remained in 11 (21%). All nodules in which intratumor vascularity had been detected showed positive stain to dynamic MRI. Four of 41 nodules in which the sonographic signal disappeard showed positive stain on dynamic MRI. The Sensitivity of Doppler ultrasonography was 73%; specificity, 100%; and accuracy, 92%. Flow signal in deeply (≥5 cm) located small (<3 cm) nodules tended to be more difficult to detect. We conclude that Doppler ultrasonography warrants use after TAE in the early evaluation as a specific and noninvasive imaging technique.