Although attention has focused on the chemopreventive action of retinoic acid (RA) in hepatocarcinogenesis, the functional role of RA in the liver has yet to be clarified. To explore the role of RA in the liver, we developed transgenic mice expressing RA receptor (RAR) ␣-dominant negative form in hepatocytes using albumin promoter and enhancer. At 4 months of age, the RAR ␣-dominant negative form transgenic mice developed microvesicular steatosis and spotty focal necrosis. Mitochondrial ␤-oxidation activity of fatty acids and expression of its related enzymes, including VLCAD, LCAD, and HCD, were down-regulated; on the other hand, peroxisomal ␤-oxidation and its related enzymes, including AOX and BFE, were up-regulated. Expression of cytochrome p4504a10, cytochrome p4504a12, and cytochrome p4504a14 was increased, suggesting that -oxidation of fatty acids in microsomes was accelerated. In addition, formation of H 2 O 2 and 8-hydroxy-2-deoxyguanosine was increased. After 12 months of age, these mice developed hepatocellular carcinoma and adenoma of the liver. The incidence of tumor formation increased with age. Expression of ␤-catenin and cyclin D1 was enhanced and the TCF-4/␤-catenin complex was increased, whereas the RAR ␣/ ␤-catenin complex was decreased. Feeding on a high-RA diet reversed histological and biochemical abnormalities and inhibited the occurrence of liver tumors. These results suggest that hepatic loss of RA function leads to the development of steatohepatitis and liver tumors. In conclusion, RA plays an important role in preventing hepatocarcinogenesis in association with fatty acid metabolism and Wnt signaling. (HEPATOLOGY 2004;40:366-375.)

This observational study investigated the influence of febrile neutropenia on the emergency of ARC for the first time. ARC was strongly associated with VCM pharmacokinetics, and two-thirds of the ARC patients had subtherapeutic VCM concentrations. In patients with ARC, individualized dosing regimens are required to achieve the target trough concentration.

We determined polymorphism in the serotonin (5-HT) transporter gene-linked polymorphic region (5-HTTLPR) in 501 healthy Japanese, individuals, using the polymerase chain reaction of Lesch et al., with minor modifications. The distribution of allele frequencies was determined and found to differ from that in Caucasians. We also investigated the relationship of polymorphism in 5-HTTLPR to anxiety traits, by having 189 of the 501 subjects complete a self-rating questionnaire for anxiety and depression. Subjects with the short/short (s/s) genotype had significantly higher anxiety scores than those with the long/long (l/l) or l/s genotype. It is suggested that populations with the s/s genotype of 5-HTTLPR have stronger anxiety-related personality traits than those with the 1 allele.

Human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) are expected to be an excellent source of cells for transplantation. In addition, the stem cell plasticity of human UCBMSCs, which can transdifferentiate into hepatocytes, has been reported. However, the mechanisms involved remain to be clarified. To identify the genes and/or signals that are important in specifying the hepatic fate of human UCBMSCs, we analyzed gene expression profiles during the hepatic differentiation of UCBMSCs with human telomerase reverse transcriptase, UCBMSCs immortalized by infection with a retrovirus carrying telomerase reverse transcriptase, but whose differentiation potential remains unchanged. Efficient differentiation was induced by 5-azacytidine (5-aza)/hepatocyte growth factor (HGF)/oncostatin M (OSM)/fibroblast growth factor 2 (FGF2) treatment in terms of function as well as protein expression: 2.5-fold increase in albumin, 4-fold increase in CCAAT enhancer-binding protein α, 1.5-fold increase in cytochrome p450 1A1/2, and 8-fold increase in periodic acid-Schiff staining. Consequently, we found that the expression of Wnt/β-catenin-related genes downregulated, and the translocation of β-catenin was observed along the cell membrane and in the cytoplasm, although some β-catenin was still in the nucleus. Downregulation of Wnt/β-catenin signals in the cells by Fz8-small interference RNA treatment, which was analyzed with a Tcf4 promoter-luciferase assay, resulted in similar hepatic differentiation to that observed with 5-azacytidine/HGF/OSM/FGF2. In addition, the subcellular distribution of β-catenin was similar to that of cells treated with 5-azacytidine/HGF/OSM/FGF2. In conclusion, the suppression of Wnt/β-catenin signaling induced the hepatic differentiation of UCBMSCs, suggesting that Wnt/β-catenin signals play an important role in the hepatic fate specification of human UCBMSCs.

This polymorphism does not appear to be involved in a genetic predisposition to the disease but may affect the frequency of attacks in patients with migraine. These findings may contribute to our understanding of factors that influence the clinical severity of migraine.

Superoxide dismutase (SOD) is a radical-scavenging enzyme. We determined Cu, Zn-SOD concentrations and activities in platelets from subjects with migraine and tension-type headaches. Thirty migraine without aura (MWoA) patients, 9 migraine with aura (MWA) patients, and 53 tension-type headache patients were selected for study. Thirty healthy volunteers composed the control group. Concentrations of platelet SOD were determined using enzyme-linked immunosorbent assay techniques. The activity of platelet SOD was determined by measuring reductivity of nitroblue tetrazolium. Low concentrations of platelet SOD were found in patients with MWA and MWoA. Platelet SOD activity decreased in MWA patients but not in patients with MWoA or tension-type headaches. These findings suggest vulnerability to oxidative stress in patients with migraine. It is suggested that low platelet SOD levels may play an important role in the etiology of migraine.

Nitric oxide (NO) is a candidate as a causative molecule in migraine. We determined nitrite, total nitrate/nitrite, and cyclic guanosine 3',5'-monophosphate (cGMP) concentrations in platelets from 30 migraine without aura (MwoA) patients and 17 migraine with aura (MwA) patients. All migraine patients were studied during their migraine attacks. The control group consisted of 28 healthy volunteers. Concentrations of platelet nitrite and total nitrate/nitrite were determined using simple and sensitive nitrate/nitrite fluorometric assay techniques. High concentrations of platelet nitrite and total nitrate/nitrite were found in patients with MwoA and MwA when compared with healthy controls. High concentrations of platelet cGMP were also found in patients with MwoA and MwA. The levels of platelet total nitrate/nitrite significantly decreased in headache-free periods after treatment with oral propranolol. These findings suggest that NO is produced in platelets during migraine attacks. It may also be related to the migrainous pain and the changes in cerebral blood flow experienced during migraine attacks. These data may provide new strategies for the treatment of migraine.

The present study suggests that aFGF/bFGF/HGF/type IV collagen coating is the efficient condition for hepatic differentiation of UE7T-13 cells, and that WISP1 and WISP2 play an important role in hepatic transdifferentiation of these cells.