F. Andrei

IL‐23‐mediated regulation of IL‐17 production in Helicobacter pylori‐infected gastric mucosa

Helicobacter pylori (Hp) infection is associated with a marked infiltration of the gastric mucosa by inflammatory cells. The molecular pathways that control Hp‐associated inflammatory reaction are complex, but locally induced cytokines seem to contribute to maintaining the ongoing inflammation. We have previously shown that IL‐17 is over‐produced in Hp‐infected gastric mucosa, and that IL‐17 stimulates the synthesis of IL‐8, the major neutrophil chemoattractant. Factors/mechanisms that regulate IL‐17 expression remain, however, unknown. In this study, we initially expanded our previous data, showing that CD4+ and CD8+ T cells are a source of IL‐17 in Hp‐infected samples. Since IL‐23 enhances T cell‐derived IL‐17 during bacterial infections, we then assessed the role of IL‐23 in controlling IL‐17 expression in Hp‐colonized stomach. Using real‐time PCR and ELISA, IL‐23 was detected in all gastric biopsies, but its expression was more pronounced in Hp‐infected samples in comparison to controls. Treatment of normal gastric lamina propria mononuclear cells (LPMC) with IL‐23 enhanced Stat3 activation and IL‐17 secretion, and pharmacological inhibition of Stat3 prevented IL‐23‐driven IL‐17 synthesis. Consistently, blockade of IL‐23 in cultures of LPMC from Hp‐infected patients reduced Stat3 activation and IL‐17 production. Data show that IL‐23 is overexpressed in Hp‐infected gastric mucosa where it could contribute to sustaining IL‐17 production.

IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis.

Helicobacter pylori (Hp) infection is associated with gastric inflammation and ulceration. The pathways of tissue damage in Hp-infected subjects are complex, but evidence indicates that T cell-derived cytokines enhance the synthesis of matrix metalloproteinases (MMP) that contribute to mucosal ulceration and epithelial damage. In this study, we have examined the role of the T cell cytokine IL-21 in Hp-infected gastric mucosa and evaluated whether IL-21 regulates MMP production by gastric epithelial cells. We show that IL-21 is constitutively expressed in gastric mucosa and is more abundant in biopsy specimens and purified mucosal CD3+ T cells from Hp-infected patients compared with normal patients and disease controls. We also demonstrate that IL-21R is expressed by primary gastric epithelial cells, as well as by the gastric epithelial cell lines AGS and MKN28. Consistently, AGS cells respond to IL-21 by increasing production of MMP-2 and MMP-9, but not MMP-1, MMP-3, MMP-7, or tissue inhibitors of MMP. Analysis of signaling pathways leading to MMP production reveals that IL-21 enhances NF-κB but not MAPK activation, and inhibition of NF-κB activation reduces IL-21-induced MMP-2 and MMP-9 production. Finally, we show that treatment of Hp-infected gastric explants with anti-IL-21 reduces epithelial cell-derived MMP-2 and MMP-9 production. These data indicate that IL-21 is overexpressed in Hp-infected gastric mucosa where it could contribute to increased epithelial gelatinase production.

Ten and eight-day sequential therapy in comparison to standard triple therapy for eradicating Helicobacter pylori infection: a randomized controlled study on efficacy and tolerability.

Background Sequential therapy (SQT) is effective in the eradication of Helicobacter pylori and could become an alternative to standard triple therapy (STT). Aim To compare the efficacy and tolerability of SQT, for either 8 or 10 days, with a 7-day STT. Methods A total of 270 naive H. pylori-positive patients were randomized to receive: SQT for 8 days (SQT-8, n=90) or 10 days (SQT-10, n=90) including esomeprazole 20 mg twice daily (bid) associated with amoxicillin 1000 mg bid (early 4 and 5 d, respectively), followed by esomeprazole 20 mg bid associated with clarithromycin 500 mg bid plus tinidazole 500 mg bid (last 4 and 5 d, respectively); STT (n=90) including esomeprazole 20 mg bid plus amoxicillin 1000 mg bid and clarithromycin 500 mg bid for 7 days. Tolerability was assessed by scoring the severity of symptoms. Results Eradication rates after SQT-8 and SQT-10 were higher than that of after STT at both intention-to-treat (83% and 86% vs. 66%, P<0.02) and per-protocol analysis (90% and 88% vs. 75%, P<0.05), whereas no difference was found between the 2 SQTs. Conclusions This study shows that SQT, for 8 or 10 days, is well tolerated and highly effective in H. pylori eradication and could represent a valid alternative to STT. Further studies, with more power, on larger populations and from other countries are necessary to validate the present findings.

Unsedated transnasal versus transoral sedated upper gastrointestinal endoscopy: a one-series prospective study on safety and patient acceptability.

BACKGROUND While conventional oesophagogastroduodenoscopy is frequently performed under sedation to improve acceptability, transnasal oesophagogastroduodenoscopy would appear to be less invasive. STUDY AIMS To compare diagnostic accuracy, feasibility, acceptability and safety of transnasal oesophagogastroduodenoscopy without sedation versus conventional oesophagogastroduodenoscopy under sedation. PATIENTS Following anxiety assessment, 30 dyspeptic patients underwent transnasal oesophagogastroduodenoscopy under local anaesthesia (lidocaine) and conventional oesophagogastroduodenoscopy under conscious sedation (i.v. midazolam) on two consecutive days. Transnasal oesophagogastroduodenoscopy was performed with an ultrathin and conventional oesophagogastroduodenoscopy with a standard endoscope. METHODS Safety, evaluated by monitoring cardio-respiratory functions. Acceptability, rated according to discomfort and preference between the two examinations. Diagnostic accuracy evaluated taking into account endoscopic patterns and adequacy of biopsy specimens for histology. Feasibility, defined according to endoscopic performance, quality of images and overall opinion of the endoscopist. Only gastric biopsies were evaluated. RESULTS All patients but one who refused conventional oesophagogastroduodenoscopy underwent both transnasal oesophagogastroduodenoscopy and conventional oesophagogastroduodenoscopy. No cardiorespiratory complications occurred during either technique. Majority of patients (87%) preferred transnasal oesophagogastroduodenoscopy. Examinations were completed in all cases, with comparable endoscopic patterns. All biopsy specimens were suitable for histology. CONCLUSIONS Transnasal oesophagogastroduodenoscopy without sedation provides good diagnostic accuracy, is safer and better accepted than conventional oesophagogastroduodenoscopy under sedation and, therefore, represents a valid alternative in routine diagnosis of upper digestive tract diseases.

Bacteria and mucosal immunity

In normal individuals, the intestine is a site of intense immunological activity due to the continuous stimulation by luminal antigens mostly derived from the normal bacterial flora. This is reflected in the huge amount of IgA produced in the gut and the abundant T cells in the lamina propria and epithelium. It is also becoming clear that products of the normal flora may regulate the cytokine environment within the inductive sites of the mucosal immune responses, such as the Peyers patches of the small bowel. Thus normal flora could either negatively or positively regulate specific immune responses by dictating the profile of locally released cytokines. For example, it is known that in Crohns disease the antigens that drive the strongly polarized Th1 tissue-damaging response are derived from the normal bacteria flora. Emerging evidence also indicates that gut microflora can contribute to maintain the mucosal homeostasis by promoting the generation and/or expansion of counter-regulatory mechanisms.

Look out before polypectomy in patients with diverticular disease – a case of a large, inverted diverticulum of the colon resembling a pedunculated polyp

Diverticular disease of the colon may be responsible for abdominal symptoms requiring colonoscopy, which may reveal the presence of concomitant polyps. A polyp found during colonoscopy in patients with colonic diverticular disease may be removed by endoscopic polypectomy with electrosurgical snare, a procedure associated with an incidence of perforation of less than 0.05%. The risk of such a complication may be higher in the event of an inverted colonic diverticulum, which may be misinterpreted as a polypoid lesion at colonoscopy. To date, fewer than 20 cases of inverted colonic diverticula, diagnosed at colonoscopy or following air contrast barium enema, have been reported in the literature. The present report describes a 68-year-old woman who underwent a screening colonoscopy, which revealed a voluminous pedunculated polyp that was recognized to be an inverted giant colonic diverticulum before endoscopic polypectomy.

Large villous adenoma of the appendix: A case treated with sequential endoscopic-minimal surgical technique

Villous adenomas of the appendix are uncommon and arely diagnosed during routine colonoscopy. Less than 60 ases of appendiceal villous adenomas are described worldide and a reported frequency of 0.06% in appendectomy pecimens. There are no specific symptoms for these neolasms and clinical presentation is often acute appendicitis. he malignant potential of appendiceal adenomas is not well ocumented but has been assumed to be the same to those in ther parts of the colon and rectum. Malignant in situ changes re reported in 63% cases [1,2]. A 73-year-old female was admitted for a 10-week hisory of abdominal pain localized in the right and left ypochondrium not responding to NSAID and smooth uscle relaxants. She had no significant medical backround and family history. No abnormal findings were evealed throughout physical examination, laboratory tests nd abdominal ultrasound. The stool was Hemoccult® negaive. Colonoscopy showed the presence of a polypoid lesion n the cecum of 25 mm in diameter (Fig. 1). Polypectomy, perormed using the “piece meal” technique, revealed that the ase of the polyp was located inside the appendix (Fig. 2). istology demonstrated a villous adenoma with high grade ysplasia. In order to completely remove the lesion, the atient underwent appendectomy, with resection of the small rea (30 mm × 20 mm) of the colonic wall at the base of the ppendix. Intraoperative histological examination excluded he presence of atypical cells, thus allowing a limited resecion. Microscopic sections demonstrated a villous adenoma ith high grade dysplasia with no infiltration at the base of the mplant. No neoplastic endoscopic recurrence was detected 2 months after surgery. R

M1065 Sequential Regimens Have Greater Efficacy and Better Tolerability Than Standard Triple Therapy in the Eradication of Helicobacter pylori Infection

Background: Sequential therapy (SQT) has been reported to be effective in the eradication of Helicobacter pylori (HP) infection and, if more largely validated, could become a valid alternative to standard triple therapy (STT). Aim: To evaluate efficacy and tolerability of SQT, with two different durations, in comparison to a 7-day STT. Patients & Methods: A total of 270 naive HP+ patients were randomized to receive STT (n=90), including esomeprazole (ESO) 20 mg bid, plus amoxicillin (AMO) 1000 mg bid, and clarithromycin (CLA) 500 mg bid, for 7 days; SQT for 10 days (SQT-10, n=90), including ESO 20 mg bid, for 10 days, associated with AMO 1000 mg bid for early 5 days, followed by CLA 500 mg bid, plus tinidazole (TNZ) 500 mg bid, both in the last 5 days; SQT for 8 days (SQT-8, n=90), including ESO 20 mg bid, for 8 days, associated with AMO 1000 mg bid for early 4 days, followed by CLA 500 mg bid, plus TNZ 500 mg bid, both in the last 4 days. HP status was established by the agreement of two tests out of three chosen among urea breath test, stool antigen assay, urease rapid test and histology. Tolerability of regimens was assessed by scoring the severity of symptoms reported by patients in a predefined questionnaire. Results: Eradication rates achieved by SQT-10 and SQT-8 were significantly higher than that by STT at both intention-to-treat (86% and 83% vs. 66%, p<0.02) and per-protocol analysis (87% and 90% vs. 75%, p<0.01), while no difference was found among the two SQT therapies. Mean scores of symptoms occurring on SQT-8 were significantly lower than those on SQT10 (nausea: 2.83 ± 1.90 vs. 4.68 ± 4.00, p<0.01; taste perversion: 3.14 ± 1.96 vs. 9.42 ± 6.54, p<0.05) and STT (nausea: 2.83 ± 1.90 vs. 5.08 ± 4.70, p<0.01; diarrhea: 3.14 ± 1.96 vs. 4.11 ± 4.01, p<0.02). Conclusions: SQT for 10 or 8 days are more effective than STT for HP eradication. Among SQT the 8 days regimen appears to be better tolerated than 10 days regimen.