Magnifying endoscopy with narrow-band imaging in the differential diagnosis of gastric adenoma and carcinoma and identification of a simple indicator.

BACKGROUND AND AIMS: Discrimination of gastric adenomas from adenocarcinomas by conventional endoscopy is difficult. Therefore, we evaluated the usefulness of magnifying endoscopy combined with narrow-band imaging for this differential diagnosis. METHODS: Forty-nine consecutive gastric lesions were diagnosed as adenomas by conventional endoscopy with forceps biopsy and finally resected by endoscopic submucosal dissection. The findings from magnifying endoscopy with narrow-band imaging were retrospectively classified into five types according to the marginal crypt epithelium and microvascular pattern: Types I and II (clear marginal crypt epithelium combined with regular or unclear microvascular pattern) and Types III, IV, and V (unclear marginal crypt epithelium combined with regular, irregular, or unclear microvascular pattern). RESULTS: Conventional endoscopy showed 39 flat elevated-type lesions (0-IIa) and 10 flat elevated-type lesions with depression (0-IIa+IIc). The patterns on magnifying endoscopy with narrow-band imaging were Type I (n = 8), Type II (n = 8), Type III (n = 2), Type IV (n = 30), and Type V (n = 1). The final histological diagnoses after endoscopic submucosal dissection were adenoma (n = 20), adenocarcinoma in adenoma (n = 22), and adenocarcinoma (n = 7). The cancer-bearing rates were Type I (0%), Type II (0%), Type III (100%), Type IV (89.7%), and Type V (100%). Among the expert endoscopists, intra- and interobserver κ values for each type were 0.85 each, with 92.0% and 88.0% consensus of diagnoses, respectively. CONCLUSIONS: Magnifying endoscopy with narrow-band imaging is a powerful tool for diagnosing gastric borderline lesions.

Prognostic factors for colectomy in refractory ulcerative colitis treated with calcineurin inhibitors.

Calcineurin inhibitors (CNIs) such as cyclosporin A (CSA) and tacrolimus (FK506) are efficacious in patients with steroid-refractory or steroid-dependent ulcerative colitis (UC). We retrospectively investigated patients with refractory UC treated with CNIs to elucidate the prognostic factors for a colectomy. Data from 59 patients (35 men and 24 women) were analyzed. CSA and FK506 were administered by intravenous infusion and peroral administration, respectively. The efficacy of the CNIs was assessed using Seo's complex integrated disease activity index. Categorical data analyses were also conducted. The results revealed that the response rates for CSA and FK506 were similar (CSA, 66.6%; FK506, 63.6%). However, oral FK506 had a slower onset of action than intravenous CSA. The risk factors for CNI non-responsiveness were: i) more than 10,000 mg of prednisolone used prior to CNI treatment; and ii) positivity for cytomegalovirus antigenemia (C7-HRP). The factors affecting the rate of colectomy were: i) CNI non-responsiveness; ii) more than 10,000 mg of prednisolone used prior to the initiation of CNI treatment; and iii) positivity for C7-HRP. The addition of azathioprine (AZA) following CNI treatment significantly reduced the incidence of colectomy. Our results revealed the prognostic factors affecting the efficacy of CNI therapy and the need for colectomy in patients with refractory UC. Importantly, some of these factors may be obtained prior to or shortly following the start of CNI treatment. Furthermore, AZA is an important agent for averting colectomy once a patient responds to CNIs.

Magnified endoscopy combined with narrow band imaging of minimal superficial esophageal neoplasia-indicators to differentiate intraepithelial neoplasias.

PURPOSE: Clinical application of narrow band imaging facilitates diagnosis of esophageal neoplasia. However, no previous investigation has been conducted on magnifying endoscopy combined with narrow band imaging in detection of minimal superficial esophageal neoplasia, which is defined as neoplasia <10 mm in diameter. The aim of this retrospective study was to evaluate the usefulness of this combined technique in the differential diagnosis of minimal superficial esophageal neoplasia. METHODS: Between January 2005 and November 2011, 53 minimal superficial esophageal neoplasias in 40 patients were diagnosed by screening upper gastrointestinal endoscopy with narrow band imaging at our hospital. We investigated findings including brownish dots, brownish epithelium, and demarcation line of minimal superficial esophageal neoplasia diagnosed histopathologically as low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and squamous cell carcinoma. RESULTS: Significantly more brownish dots (P < 0.05) and brownish epithelium (P < 0.005) were observed in intraepithelial papillary capillary loops in high-grade neoplasia compared with low-grade neoplasia. When minimal superficial esophageal neoplasia was diagnosed as high-grade intraepithelial neoplasia or squamous cell carcinoma, sensitivity, specificity, positive predictive value, and negative predictive value were 88.9, 42.9, 44.4, and 88.2%, respectively, for brownish dots; 94.4, 51.4, 50.0, and 94.7%, respectively, for brownish epithelium; and 66.7, 62.9, 48.0, and 78.6%, respectively, for demarcation line. CONCLUSIONS: The combined technique was useful in the differential diagnosis of minimal superficial esophageal neoplasia.

The severity of dextran sodium sulfate-induced colitis can differ between dextran sodium sulfate preparations of the same molecular weight range.

BACKGROUND: We hypothesized that the severity of dextran sodium sulfate (DSS)-induced colitis could differ between DSS preparations of the same molecular weight, and that this difference may be affected by the sulfur content. To test this, we used three DSS preparations of similar molecular weights but with different sulfur contents. METHODS: Three DSS preparations with molecular weights of 40,000 to 50,000 were tested: MP Biomedicals (MP Bio), USB (USB), and The Lab Depot (The Lab). Epithelial cell lines were used to assess the levels of poly (ADP-ribose) polymerase (PARP) in the presence of 2.0% DSS in vitro. Eight-week-old female C57/B6 mice were fed 2.0% DSS in water for 1 week, and then sacrificed to investigate the effects of the DSS preparations in vivo. RESULTS: In vitro experiments using CaCo-2 and CMT-93 cells revealed decreased PARP levels from all DSS preparations. Notably, the PARP level was significantly decreased in CaCo-2 cells treated with DSS from USB as compared to The Lab Mice treated with The Lab DSS had significantly decreased body weight losses on day 7 as compared to mice receiving DSS from MP Bio and USB. This result was supported by their DAI score, colon weight/length ratio, and histological scores. CONCLUSION: The severity of colitis can differ between similar DSS preparations of the same molecular weight range. This difference in colitogenic properties may be affected by the total sulfur content of each DSS preparation.

The DPP-IV inhibitor ER-319711 has a proliferative effect on the colonic epithelium and a minimal effect in the amelioration of colitis.

Dipeptidyl-peptidase IV (DPP-IV) inhibitors are expected to prolong the half-life of Glucagon-like peptide (GLP-2) as well as GLP-1, and may result in the promotion of epithelial cell proliferation and regeneration. The aim of this study was to investigate whether a DPP-IV inhibitor can promote epithelial proliferation and attenuate dextran sodium sulfate (DSS)-induced colitis. Nine-week-old female C57/B6 mice were given a single dose of ER-319711 to assess the changes in plasma GLP-2 concentrations. Ten mice were divided into two groups: a vehicle group and an ER-319711 group. ER-319711 was administered orally for 7 days. The mice were then given bromodeoxyuridine (BrdU) intraperitoneally 2 h before sacrifice on day 7. Twenty-six mice were divided into three groups: a vehicle group, a DSS-induced colitis group and a DSS-induced colitis treated with ER-319711 group. The mice were given DSS for 5 days and sacrificed on day 14. Plasma GLP-2 levels were elevated in response to ER-319711. The ER-319711 group had a significantly decreased body weight from days 1 to 3. The number of BrdU positive cells per crypt and the crypt height were increased in the ER-319711 group. The DSS + ER-319711 group had a decreased body weight transition. The disease activity index and colon length showed an amelioration of colitis in the DSS + ER-319711 group. DPP-IV inhibitors are thought to promote the proliferation of the intestinal epithelium. However, the amelioration of DSS-induced colitis was only partial.

Butyrate stimulates IL-32alpha expression in human intestinal epithelial cell lines.

AIM: To investigate the effects of butyrate on interleukin (IL)-32alpha expression in epithelial cell lines. METHODS: The human intestinal epithelial cell lines HT-29, SW480, and T84 were used. Intracellular IL-32alpha was determined by Western blotting analyses. IL-32alpha mRNA expression was analyzed by real-time polymerase chain reaction. RESULTS: Acetate and propionate had no effects on IL-32alpha mRNA expression. Butyrate significantly enhanced IL-32alpha expression in all cell lines. Butyrate also up-regulated IL-1beta-induced IL-32alpha mRNA expression. Butyrate did not modulate the activation of phosphatidylinositol 3-kinase (PI3K), a mediator of IL-32alpha expression. Like butyrate, trichostatin A, a histone deacetylase inhibitor, also enhanced IL-1beta-induced IL-32alpha mRNA expression. CONCLUSION: Butyrate stimulated IL-32alpha expression in epithelial cell lines. An epigenetic mechanism, such as histone hyperacetylation, might be involved in the action of butyrate on IL-32alpha expression.

The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease.

BACKGROUND: Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients. METHODS: Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses. RESULTS: Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with theMRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype(P = 0.049). Of the 15 patients who experienced leucopenia (<3 x 109/l), 7 patients carried the MRP4 variant.The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03­10.57, P = 0.036). CONCLUSIONS: These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.

Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis.

BACKGROUND: Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 has been shown to elicit a Th2-like cytokine response in immune cells. In this study, we investigated IL-33 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-33 expression in human colonic subepithelial myofibroblasts (SEMFs). METHODS: IL-33 mRNA expression was determined by real-time polymerase chain reaction (PCR). IL-33 expression in the IBD mucosa was evaluated by immunohistochemical methods. RESULTS: IL-33 mRNA expression was significantly elevated in active lesions from patients with ulcerative colitis (UC), but was not detected in inactive lesions from UC patients or in lesions from patients with either active or inactive Crohn's disease. Colonic SEMFs were identified as a major source of IL-33 in the mucosa. IL-1ß and tumor necrosis factor-α (TNF-α) significantly enhanced IL-33 mRNA and protein expression in isolated colonic SEMFs. IL-1ß and TNF-α did not affect IL-33 expression in intestinal epithelial cell lines (HT-29 and Caco-2 cells). This IL-1ß- and TNF-α-induced IL-33 mRNA expression was mediated by p42/44 mitogen activated protein kinase (MAPK) pathway-dependent activation of nuclear factor (NF)-κB and activator protein (AP)-1. CONCLUSIONS: IL-33, derived from colonic SEMFs, may play an important role in the pathophysiology of UC.

Cellobiose Prevents the Development of Dextran Sulfate Sodium (DSS)-Induced Experimental Colitis.

Cellobiose is produced from cellulose using specific bacterial enzymes, and is hydrolyzed into glucose by the enzymes cellobiosidase and cellulase. In this study, we examined the effects of cellobiose on colonic mucosal damage in a dextran sulfate sodium (DSS) colitis model. BALB/c mice were divided into two groups. In the first group, the mice were fed 3.5% DSS mixed with normal chow. In the second group, the mice were fed 3.5% DSS plus 6.0 or 9.0% (weight/weight) cellobiose mixed with normal chow. The development of colitis was assessed on day 21. Mucosal cytokine expression was analyzed by RT-PCR. Body weight loss was significantly attenuated in the 9.0% cellobiose-fed DSS mice as compared to the DSS mice. Colonic weight/length ratio, a maker of tissue edema, was significantly higher in the DSS mice than in the 9.0% cellobiose-fed DSS mice. The disease activity index and histological colitis score were also significantly higher in the DSS mice than in the 9.0% cellobiose-fed DSS mice. Mucosal mRNA expression for IL-1beta, TNF-alpha, IL-17 and IP-10 were markedly reduced in the 9.0% cellobiose-fed DSS mice. In conclusion, a preventive effect of cellobiose against DSS colitis suggests its clinical use for inflammatory bowel diseases patients.