Mechanisms of CYP3A induction by glucocorticoids in human fetal liver cells.

Human fetal liver (HFL) cells express major drug metabolic enzymes CYP3A4, CYP3A5 and CYP3A7. In the fetal hepatocytes, betamethasone and dexamethasone (DEX) markedly enhanced the expression levels of CYP3A4 and CYP3A7 mRNAs and slightly increased the expression level of CYP3A5 mRNA. Interestingly, a high correlation between the CYP3A induction ability and the intensity of anti-inflammatory effect was observed. Human glucocorticoid receptor (GR)-small interfering RNA clearly attenuated the expression level of GR mRNA, and diminished the DEX-stimulated CYP3A4, CYP3A5 and CYP3A7 expression in HFL cells. These findings indicate that GR mediates the induction of CYP3A4 and CYP3A7 expression in human fetal hepatocytes as well as the CYP3A5.

Endoscopic band ligation with a water-jet scope for the treatment of colonic diverticular hemorrhage.

Although lower gastrointestinal bleeding generally has a less severe course and stops spontaneously in most cases without therapeutic intervention, some patients require endoscopic, surgical, or angiographic treatment depending on the nature of the bleeding. We applied endoscopic band ligation (EBL) with a water-jet scope to bleeding colonic diverticula and evaluated the efficacy and safety of EBL retrospectively. Five consecutive patients were diagnosed as having colonic diverticular hemorrhage, and were treated with EBL at St Luke's International Hospital in Tokyo from June 2009 to August 2009. Comorbid diseases, usage of anti-platelet agents, hemoglobin level on admission, procedural time, complications such as perforation and abscess formation, and rebleeding after EBL were retrospectively evaluated. In all cases, EBL achieved successful immediate hemostasis without any procedural complications. In four of five cases, bleeding colonic diverticula were everted after EBL. The mean length of hospital stay after EBL was 5 days (range 4-8 days). No patient exhibited clinical evidence of further bleeding during the mean follow-up period of 3 months (range 2-4 months), and no further intervention was needed after EBL. EBL with a water-jet scope is considered to be a safe and effective endoscopic treatment for colonic diverticular hemorrhage.

Endoscopic submucosal dissection and preoperative assessment with endoscopic ultrasonography for the treatment of rectal carcinoid tumors.

BACKGROUND: Rectal carcinoid tumors 10 mm in diameter or smaller located within the submucosal layer can be cured by local excision including endoscopic treatment. But complete resection of these tumors with endoscopic polypectomy is difficult. This study aimed to evaluate the usefulness of endoscopic submucosal dissection (ESD) and endoscopic ultrasonography (EUS) for the treatment of rectal carcinoid tumors. METHODS: In this study, 22 rectal carcinoid tumors in 21 patients were evaluated with EUS and treated using ESD from January 2004 to December 2008. RESULTS: The mean size of the resected tumors was 6.1 mm (range, 2.0-10 mm) on histopathologic evaluations. When the sizes of the tumors shown by EUS and histopathologic evaluation were compared, the mean values were not significantly different. All the tumors were located within the submucosal layer, and the accuracy of the preoperative depth determination with EUS was 100% (22/22). The mean duration of the ESD procedure was 37 min (range, 20-71 min). The overall rate of en bloc resection with ESD was 100% (22/22). Although postoperative bleeding occurred in two cases (9%), both cases were successfully managed by endoscopic hemostasis. No perforation or recurrence was observed during the mean follow-up period of 30 months (range, 7-66 months). CONCLUSIONS: Endoscopic submucosal dissection and preoperative assessment with EUS are effective for treating rectal carcinoid tumors and enabling en bloc resection.

Endoscopic submucosal dissection with a combination of small-caliber-tip transparent hood and flex knife is a safe and effective treatment for superficial esophageal neoplasias.

BACKGROUND: Superficial esophageal neoplasias resected in piecemeal manner with endoscopic mucosal resection (EMR) sometimes recur locally, and additional treatments need to be developed. Efficacy and safety of endoscopic submucosal dissection (ESD) for esophageal neoplasias are not sufficiently demonstrated, so we conducted a retrospective study to evaluate the efficacy and safety of ESD for superficial esophageal neoplasias. METHODS: Thirty-seven superficial esophageal neoplasias consisted of 34 squamous cell neoplasias and 3 columnar neoplasias in 35 patients were treated with ESD from May 2006 to July 2008. Patients were regularly followed up with endoscopy every 6 months, and with echoendoscope and computed tomography every year. Therapeutic efficacy, complications, and follow-up results were evaluated. RESULTS: The mean size of the resected neoplasias and that of the resected specimens were 22 mm (range 10-83 mm) and 41 mm (range 18-90 mm), respectively. The mean duration of the ESD procedures was 117 min (range 40-235 min). The overall rates of en bloc resection and of free margin resection were 100% (37/37) and 95% (35/37), respectively. The mean follow-up period of 19 months (range 7-32 months) revealed no local or distant recurrence. There were no complications such as bleeding or perforation in any case. In all nine cases, the strictures were successfully managed with prophylactic endoscopic balloon dilation. CONCLUSIONS: ESD with a combination of small-caliber-tip transparent hood and flex knife is a safe endoscopic treatment for superficial esophageal neoplasias and enables large en bloc resection.

Comparison of basal gene expression and induction of CYP3As in HepG2 and human fetal liver cells.

Human fetal liver (HFL) cell culture was initiated from a pool of six normal human liver tissues. The proliferation and viability of HFL cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay, and the cells increased by more than 100-fold by culture for 15 d. The levels of expression of albumin (ALB), hepatocyte nuclear factor 4alpha, hepatocyte growth factor, CYP3A4, CYP3A5, and CYP3A7 mRNAs in HFL cells increased with culture period, while that of alpha-fetoprotein (AFP) mRNA decreased gradually. In HepG2 cells, however, the expression levels of ALB and AFP mRNAs were not changed, and the levels of expression of CYP3A4, CYP3A5, and CYP3A7 mRNAs decreased gradually. The mRNA expression of major CYP isoforms including CYP3As, i.e., CYP1A2, CYP2A6, CYP2B6, CYP2C (2C9 and 2C19), CYP2D6, and CYP2E1, could be detected in HepG2 cells. With the exception of CYP1A2, all of the CYP mRNAs expressed in HepG2 cells were detected in HFL cells. In HFL cells, CYP3A4 and CYP3A7 mRNA expression levels were markedly up-regulated by dexamethasone (DEX), but not by rifampicin (RIF). CYP3A5 mRNA expression was increased to a level 3-fold greater than control by DEX. On the other hand, CYP3A4, CYP3A5, and CYP3A7 mRNA expression levels in HepG2 cells were increased from 2- to 3-fold by treatment with DEX and RIF. Pregnane X receptor mRNA was expressed in HepG2 cells, but not HFL cells. These results indicate that the character of HFL cells with regard to CYP expression was different from that of HepG2 cells.

Expression and induction of CYP3As in human fetal hepatocytes.

CYP3A4 and CYP3A7 mRNA expression levels were markedly up-regulated by dexamethasone (DEX), but not by rifampicin (RIF). CYP3A5 mRNA level was not increased significantly by DEX, RIF, or phenobarbital. Testosterone 6beta-hydroxylase activity was induced to about 2-fold of control by DEX. However, concomitant treatment with RIF did not alter DEX-mediated induction of CYP3A mRNA expression and testosterone 6beta-hydroxylase activity. DEX-mediated induction of CYP3A mRNA was suppressed in a dose-dependent manner by RU486, a glucocorticoid receptor (GR) antagonist. At 5microM RU486, DEX-mediated induction of CYP3A4, CYP3A5, and CYP3A7 mRNA expression was inhibited almost completely. These results suggest that, in human fetal hepatocytes, PXR is not involved in DEX-mediated induction of CYP3A4 and CYP3A7, and that the induction is mediated directly by GR.

[CT evaluation of infectious colitis].

Computed tomography (CT) is useful for evaluating the diagnosis of gastrointestinal disease, such as infectious colitis, in patients with severe pain and bloody diarrhea. During the 7 years between November 1993 and October 2000, 34 patients with infectious colitis (18 male, 16 female; mean age 42 +/- 19 yrs), received emergency CT and colonoscopy because of severe abdominal pain and dysentery. The following organisms were isolated: pathogenic Escherichia coli (12), 6 of which were O157:H7 (O-157), Salmonella species (11), Campylobacter species (5), Vibrio parahaemolyticus (3), Yersinia enterocolotica (2) and Shigella species (1). Thickening of the intestinal wall greater than 10 mm was seen in the ascending colon in the 6 cases with E. coli O 157, in 5/11 cases with Salmonella, 4/5 with Campylobacter and 1/6 with non-O157 pathogenic E. Coli. Marked intestinal wall thickening, greater than 20 mm, was seen in the ascending colon of the 4 of the patients with an O-157 infection. In all patients with O-157 colitis, slight ascites was noted in the pelvic space. In additions, ascites was also seen in 3/13 patients with Salmonella and 1/5 patients with Campylobacter colitis. The CT findings, in the patients with infectious colitis, are non-specific but knowledge and recognition of the findings will help in patient evaluation and proper treatment.