Yuji Iwashita

Transgenic expression of human neutrophil peptide‐1 enhances hepatic fibrosis in mice fed a choline‐deficient, L‐amino acid–defined diet

Neutrophils infiltrate the livers of patients with nonalcoholic steatohepatitis (NASH). Human neutrophil peptides (HNPs) induce cytokine and chemokine production under inflammatory conditions, which may contribute to the progression of NASH. In this study, we focused on the effects of HNP‐1 on hepatic steatosis and fibrosis in a mouse model of NASH induced by a choline‐deficient, L‐amino acid–defined (CDAA) diet.

Polyamines mediate glutamine-dependent induction of the intestinal epithelial heat shock response

Heat shock proteins (Hsps) are highly conserved proteins that play a role in cytoprotection and maintaining intestinal homeostasis. Glutamine is essential for the optimal induction of intestinal epithelial Hsp expression, but its mechanisms of action are incompletely understood. Glutamine is a substrate for polyamine synthesis and stimulates the activity of ornithine decarboxylase (ODC), a key enzyme for polyamine synthesis, in intestinal epithelial cells. Thus we investigated whether polyamines (putrescine, spermidine, or spermine) and their precursor ornithine mediate the induction of Hsp expression in IEC-18 rat intestinal epithelial cells. As previously observed, glutamine was required for heat stress induction of Hsp70 and Hsp25, although it had little effect under basal conditions. Under conditions of glutamine depletion, supplementation of ornithine or polyamines restored the heat-induced expression of Hsp70 and Hsp25. When ODC was inhibited by α-difluoromethylornithine (DFMO), an irreversible ODC inhibitor, the heat stress induction of Hsp70 and Hsp25 was decreased significantly, even in the presence of glutamine. Ornithine, polyamines, and DFMO did not modify the nuclear localization of heat shock transcription factor 1 (HSF-1). However, DFMO dramatically reduced glutamine-dependent HSF-1 binding to an oligonucleotide with heat shock elements (HSE), which was increased by glutamine. In addition, exogenous polyamines recovered the DNA-binding activity. These results indicate that polyamines play a critical role in the glutamine-dependent induction of the intestinal epithelial heat shock response through facilitation of HSF-1 binding to HSE.

Invasive carcinoma derived from “flat type” branch duct intraductal papillary mucinous neoplasms of the pancreas: impact of classification according to the height of mural nodule on endoscopic ultrasonography

It has been reported that many branch duct intraductal papillary mucinous neoplasms (BD‐IPMN) with a mural nodule (MN) reveal adenocarcinomas. On the other hand, invasive cancer derived from BD‐IPMN without MN on endoscopic ultrasound (EUS) also exists. The aim of this study was to elucidate the clinicopathological features of invasive cancer derived from BD‐IPMN without MN on EUS.

Human neutrophil peptides induce interleukin-8 in intestinal epithelial cells through the P2 receptor and ERK1/2 signaling pathways

Human neutrophil peptides (HNPs) are antimicrobial peptides produced predominantly by neutrophils. We have previously reported that HNP 1-3 levels are increased in the sera and plasma of patients with active ulcerative colitis. The increased expression of interleukin-8 (IL-8) has also been demonstrated in the colonic mucosa of patients with active ulcerative colitis. HNPs induce IL-8 in lung epithelial cells and monocytes through the P2Y6 signaling pathway. However, the association between HNPs and IL-8 in the intestinal mucosa has not yet been investigated. In the present study, we investigated the effects of HNP-1 on the production of IL-8 by human intestinal epithelial cells and the underlying signaling mechanisms. We observed a significant increase in IL-8 expression in the human colon carcinoma cell line, Caco-2, following treatment with HNP-1. The non-selective P2 receptor antagonists, suramin and pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid) tetrasodium salt hydrate (PPADS), significantly blocked the HNP-1-induced expression of IL-8 in the Caco-2 cells. The P2Y6-specific antagonist, MRS2578, led to a significant but partial decrease in IL-8 expression, suggesting that P2 receptors in addition to P2Y6 are involved in the HNP-1-induced production of IL-8 by Caco-2 cells. In agreement with this finding, HNP-1 also significantly increased IL-8 production in the P2Y6-negative human colon cancer cell line, HT-29, and this increase was blocked by treatment with suramin and PPADS. HNP-1 significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) in the HT-29 cells. However, the HNP-1-induced production of IL-8 was suppressed by the ERK1/2 inhibitor, U0126, but not by the p38 MAPK inhibitor, SB203580. In conclusion, our data demonstrate that HNP-1 induces IL-8 production not only through P2Y6, but also through additional P2 receptors via an ERK1/2-dependent mechanism in intestinal epithelial cells.

Human neutrophil peptide-1 aggravates dextran sulfate sodium-induced colitis.

Background: Human neutrophil peptide (HNP)‐1, HNP‐2, and HNP‐3 (HNP‐1–3) are useful biomarkers for ulcerative colitis (UC). The precise roles of these peptides in UC are poorly understood, however. The aim of this study was to determine whether HNP‐1 affects disease activity in mice with experimental colitis. Methods: Experimental colitis was induced in BALB/c or severe combined immunodeficiency (SCID) mice using dextran sulfate sodium (DSS). Mice were subsequently treated intraperitoneally with HNP‐1 (100 &mgr;g/day) or phosphate‐buffered saline (PBS) from day 4 to day 6. The severity of colitis was evaluated based on a disease activity index, histologic score, and cytokine expression. Results: Body weight and colon length significantly decreased and the disease activity index score, histologic score, and myeloperoxidase activity significantly increased in HNP‐1‐treated BALB/c mice compared with PBS‐treated mice. Interferon‐&ggr; and tumor necrosis factor‐&agr; levels in colon culture supernatants‐derived HNP‐1‐treated mice were also significantly higher, and interleukin (IL)‐1&bgr; levels tended to increase in response to HNP‐1. In addition, treating SCID mice with HNP‐1 aggravated DSS‐induced colitis and IL‐1&bgr; levels in colon culture supernatants from these mice were significantly higher than in cultures obtained from control mice. Furthermore, in both BALB/c and SCID mice increased recruitment of F4/80‐positive macrophages was observed in the inflamed colonic mucosa following HNP‐1 injections. Conclusions: High concentrations of HNP‐1 aggravate DSS‐induced colitis, including upregulated expression of such macrophage‐derived cytokines as IL‐1&bgr;. These results indicate that high concentrations of HNP‐1–3 in patients with UC may exacerbate disease activity via increased cytokine production. (Inflamm Bowel Dis 2011;)

Diagnostic efficacy of liquid-based cytology for solid pancreatic lesion samples obtained with endoscopic ultrasound-guided fine-needle aspiration: Propensity score-matched analysis

There is a paucity of data on the diagnostic efficacy of liquid‐based cytology (LBC) for pancreatic samples obtained by endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA). Using propensity score matching, we retrospectively analyzed the additional diagnostic value of LBC compared to a conventional Papanicolaou smear (CPS) for samples of solid pancreatic lesions obtained by EUS‐FNA.

Risk Factors for Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis and Stent Dysfunction after Preoperative Biliary Drainage in Patients with Malignant Biliary Stricture.

Objective To retrospectively evaluate the risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and stent dysfunction after performing preoperative biliary drainage (BD) in patients with malignant biliary stricture. Methods Between January 2003 and February 2013, 105 consecutive patients who had undergone transpapillary BD before surgery were enrolled in this study. Procedure-related complications, stent dysfunction rates, and their respective risk factors were investigated. PEP was defined according to the consensus guidelines. Results Fifty-five patients had bile duct cancer, 31 had pancreatic cancer, 16 had ampullary cancer, and 3 had gallbladder cancer. Endoscopic biliary stenting (EBS) and nasobiliary drainage (NBD) were performed in 84 patients and 21 patients, respectively. PEP occurred in 10% of the patients, with a significantly higher frequency in those with hilar/upper bile duct stricture (p=0.026) and a normal bilirubin level at admission (p=0.016). Of the 84 patients who underwent initial EBS, stent dysfunction occurred in 13%. The mean number of days from EBS to stent dysfunction was 14±12 days. A multivariate analysis revealed a male gender (p=0.048), a stent diameter ≤8 Fr (p=0.036), and an ERCP procedure time ≥45 minutes (p=0.021) to be risk factors for stent dysfunction. No NBD tube dysfunction was observed. Conclusion Patients with upper/hilar bile duct stricture or a normal bilirubin level are at high risk of developing PEP after preoperative BD. NBD or EBS with a large-bore stent is therefore recommended as preoperative BD.

Jejunal duplication in an adult presenting with hematochezia

A 56-year-old man was admitted to our hospital with appetite loss, palpitations, orthostatic syncope, and hematochezia. Contrast-enhanced abdominal computed tomography (CT) revealed a proximal jejunal diverticulum with contrast extravasation. We immediately performed transoral double balloon enteroscopy (DBE) to treat the bleed in the jejunum, and this revealed a small ulcer with an exposed vessel at the opening of the jejunal diverticulum. Hemostasis was achieved endoscopically with argon plasma coagulation (APC) and hemoclips. During subsequent surgery, the diverticulum was found on the mesenteric side of the jejunum. We performed laparoscopy-assisted partial resection of the jejunum, and pathological examination showed that the diverticulum shared a common proper muscle layer with the jejunum and was covered by jejunal mucosa with no ectopic mucosa. Therefore, we diagnosed jejunal duplication. After hospital discharge, the patient had no recurrence of hematochezia or anemia. We report a rare case of jejunal duplication presenting with hematochezia, which was diagnosed as jejunal diverticular bleeding by CT and DBE before surgery. Pathological analysis confirmed jejunal duplication after surgery. We suggest that intestinal diverticular bleeding, as well as duplication of the gastrointestinal tract, should be considered as part of the differential diagnosis of obscure gastrointestinal bleeding.

A Case of Ampullary Adenoma that Developed to Cancer 7 Years After Initial Diagnosis

Patient: Male, 81 Final Diagnosis: Ampullary cancer Symptoms: Jaundice Medication: — Clinical Procedure: Endoscopy Specialty: Gastroenterology and Hepatology Objective: Unusual clinical course Background: Although ampullary adenomas have been reported to be considered as precancerous lesions, there have been very few reports of cases in which cancer occurred after long-term follow-up. We herein report a case of ampullary adenoma that developed to cancer after long-term observation. Case Report: An 81-year-old man was referred to our hospital due to a tumor at the ampulla of Vater. Histological examination revealed a tubular adenoma. Because the patient refused treatment, follow-up by duodenoscopy, EUS, MRCP, and forceps biopsy was planned. There was no change in the tumor for 6 years. Seven years after the initial diagnosis, he developed from jaundice. Duodenoscopy showed an easy-bleeding, reddish, uneven surface area of the tumor and NBI demonstrated an irregular, non-structured surface pattern. EUS demonstrated invasion of the duodenal muscularis and infiltration into the bile duct. Histological examination revealed a well-differentiated adenocarcinoma. Conclusions: The clinical course of this case provides evidence of the adenoma-carcinoma sequence.