Sirtuin 7 Inhibitor Attenuates Colonic Mucosal Immune Activation in Mice-Potential Therapeutic Target in Inflammatory Bowel Disease.

Accumulating evidence has shown that sirtuin 7 (SIRT7), a mediator of various cellular activities, plays an important role in the pathogenesis of various immune-mediated inflammatory disorders. However, information remains limited regarding the role of SIRT7 in intestinal inflammation. We used a murine colitis model to investigate the role of SIRT7 in intestinal immunity and whether SIRT7 inhibitors could attenuate the intestinal inflammatory response. Mice were divided into three groups: control, colitis-induced, and SIRT7-inhibitor-treated. A colitis mouse model was established by intraperitoneal injection and nasal challenge with ovalbumin, as in our previous study. Quantitative analyses of inflammatory cytokines and SIRT7 levels in the colonic mucosa were performed to compare the changes in inflammatory responses between the three groups. The colitis group showed increased levels of inflammatory cytokines and SIRT7 in the colonic mucosa. The inflammatory reaction was suppressed in colitis-induced mice administered the SIRT7 inhibitor. The qRT-PCR results showed normalization of inflammatory cytokines in the SIRT7 inhibitor-treated group. Histologic study revealed a decrease in the extent of inflammation after SIRT7 treatment. We also observed that the degree of clinical inflammation was improved in SIRT7-treated mice. Our study demonstrated that SIRT7 inhibition attenuated the inflammatory response in the colon of mice, suggesting a possible role for SIRT7 in the pathogenesis of immune-mediated intestinal inflammation.

Colonic Mucosal Immune Activation in Mice with Ovalbumin-Induced Allergic Airway Disease: Association between Allergic Airway Disease and Irritable Bowel Syndrome.

Recent studies on the pathophysiology of irritable bowel syndrome (IBS) have focused on the role of mast cells (MCs) in intestinal mucosal immunity. A link between allergic airway diseases (AADs) and IBS has been suggested because both diseases have similar pathophysiology. We aimed to investigate whether the induction of AAD in mice could lead to inflammation of the colonic mucosa, similar to IBS. We also evaluated whether this inflammatory response could be suppressed by administering a therapeutic agent. Mice were divided into three groups: control, AAD-induced, and salbutamol-treated. An AAD mouse model was established by intraperitoneal injection and nasal challenge with ovalbumin. Mice with AAD were intranasally administered salbutamol. Analyses of cytokine levels, MC count, and tryptase levels in the intestinal mucosa were performed to compare the changes in inflammatory responses among the three groups. Inflammation was observed in the intestinal mucosa of mice in the AAD group. This inflammation in AAD mice was suppressed after salbutamol treatment. Our study demonstrates that AAD induces an inflammatory response similar to that in IBS, suggesting a possible association between IBS and AADs. In patients with IBS with such allergic components, salbutamol may have the potential to alleviate the inflammatory response.

Endoscopic en bloc resection of an exophytic gastrointestinal stromal tumor with suction excavation technique.

Here, we report the first successful endoscopic resection of an exophytic gastrointestinal stromal tumor (GIST) using a novel perforation-free suction excavation technique. A 49-year-old woman presented for further management of a gastric subepithelial tumor on the lesser curvature of the lower body, originally detected via routine upper gastrointestinal endoscopy. Abdominal computed tomography and endoscopic ultrasound showed a 4-cm extraluminally protruding mass originating from the muscularis propria layer. The patient firmly refused surgical resection owing to potential cardiac problems, and informed consent was obtained for endoscopic removal. Careful dissection and suction of the tumor was repeated until successful extraction was achieved without serosal injury. We named this procedure the suction excavation technique. The tumor's dimensions were 3.5 cm × 2.8 cm × 2.5 cm. The tumor was positive for C-KIT and CD34 by immunohistochemical staining. The mitotic count was 6/50 high-power fields. The patient was followed for 5 years without tumor recurrence. This case demonstrated the use of endoscopic resection of an exophytic GIST using the suction excavation technique as a potential therapy without surgical resection.

The effect of polaprezinc on gastric mucosal protection in rats with ethanol-induced gastric mucosal damage: comparison study with rebamipide.

AIMS: Polaprezinc (PZ), which consists of l-carnosine and zinc, is widely used to treat gastric ulcers. We compared the effects of PZ with those of rebamipide (RM) on the expression of inflammatory cytokines, antioxidants, growth factors, and heat shock proteins (HSP) in a rat model. MAIN METHODS: Seventy Sprague-Dawley rats were randomly assigned to test groups according to the dose of PZ at 5, 10, or 30 mg/kg or RM at 10, 30, or 100 mg/kg. Next, we obtained ulcer indices from rats with ethanol-induced gastric mucosal damage. Western blot analysis was used to evaluate the expression of various target proteins. KEY FINDINGS: Pathological ulcer indices in the PZ and RM groups were significantly lower than those in the control group. The levels of inflammatory cytokines (interleukin 1ß [IL-1ß], IL-6, IL-8, and tumor necrosis factor α) decreased, whereas the levels of platelet-derived growth factor-B, vascular endothelial growth factor, and nerve growth factor significantly increased after PZ administration. Furthermore, the expression of antioxidants (superoxide dismutase 1 [SOD-1], SOD-2, heme oxygenase-1, glutathione S-transferase, peroxidredoxin-1, and peroxidredoxin-5) was significantly higher in the PZ group, and the levels of HSP 90, 70, 60, 47, 27, and 10 significantly increased with an increase in PZ dose. SIGNIFICANCE: In a rat model of ethanol-induced gastric mucosal damage, PZ administration ameliorated ethanol-induced mucosal injury and showed protective effects on the mucosa by reducing the levels of inflammatory cytokines and increasing the expression of antioxidant enzymes and growth factors. Furthermore, PZ showed cytoprotective effects by increasing the HSP levels.

The efficacy of transdermal fentanyl for pain relief after endoscopic submucosal dissection: a prospective, randomised controlled trial.

OBJECTIVE: Epigastric pain management following endoscopic submucosal dissection is an important consideration. This study aimed to investigate the utility and safety of fentanyl patches for pain relief after the procedure. METHODS: Patients who were scheduled to undergo endoscopic submucosal dissection were prospectively randomised to either a transdermal fentanyl patch group or a placebo control group. An additional pethidine was intravenously administered when pain developed and a numerical rating scale was used to evaluate both pre- and post-procedural pain. RESULTS: One hundred and ten patients were randomly assigned to receive either a 12 mcg/h fentanyl patch or a control patch on the night before the procedure. The fentanyl patch group had significantly lower pain scores immediately following the procedure (mean, 5.17 vs. 4.26, p=0.030). Maximal pain scores during the first 24 h (5.43 vs. 4.46, p=0.038) and pain scores on the day after the procedure (2.98 vs. 1.20, p<0.001) were also lower in the fentanyl patch group. In addition, the fentanyl patch group required a significantly lower dose of pethidine for pain management (24.54 vs. 11.25, p=0.004). CONCLUSIONS: The application of a transdermal fentanyl patch is an effective, convenient, and safe method to control epigastric pain after endoscopic submucosal dissection.

Comparison of sequential and 7-, 10-, 14-d triple therapy for Helicobacter pylori infection.

AIM: To compare the effectiveness of sequential therapy for Helicobacter pylori (H. pylori) infection with that of triple therapy of varying durations. METHODS: The 460 patients enrolled in this study had H. pylori-associated gastritis or a gastric or duodenal ulcer. After screening, H. pylori-infected patients were randomly assigned to receive either conventional triple therapy for 7, 10 or 14 d, or a new 10-d sequential therapy. Each of the 4 treatment groups included 115 patients. The outcomes of eradication therapy were assessed 4 wk after treatment by the urea breath test and histology. RESULTS: The overall eradication rate was 81.0%, and eradication rates were 75.7% for 7-d conventional triple therapy, 81.9% for 10-d conventional triple therapy, 84.4% for 14-d conventional triple therapy, and 82.0% for 10-d sequential therapy. Neither intention-to-treat analysis nor per protocol analysis showed significant differences in eradication rates using sequential therapy or the standard triple therapy (P = 0.416 and P = 0.405, respectively). CONCLUSION: There are no significant differences between 10-d sequential eradication therapy for H. pylori and any duration of standard triple treatment in Korean patients.

Is intercellular space different among layers in normal esophageal mucosa? An electron microscopic study.

BACKGROUND/INTRODUCTION: Dilatation of intercellular space (IS) of esophageal epithelial cells is described as a sensitive early marker for epithelial damage by refluxate. Esophageal epithelia are morphologically subdivided into three layers according to the shape of the cells and nuclei. Meanwhile, ten transmission electron microscopy (TEM) photographs and ten randomly selected measurements per photo from gastroesophageal reflux disease (GERD) patients have been widely accepted without any theoretical criticism. We assumed that the IS differs among each layer and thus studied IS according to subdivided layers of normal esophageal epithelium. We also evaluated an optimal number of IS measurements per photograph. MATERIALS AND METHODS: Esophagogastroduodenoscopy was performed in 15 healthy adults without any symptom of GERD, taking biopsies from mucosa above 5 cm from the squamo-columnar junction. Tissues were handled and prepared for TEM, verifying three layers of esophageal mucosa, i.e., squamous cell layer, prickle cell layer, and basal layer. Ten digital photomicrographs were taken from each three layers by TEM, and ISs were measured with a computerized image analysis program. For the method of measuring IS, 5, 10, 20, 30, and 40 measurements per photomicrograph were respectively performed by four different examiners. Mean value and intraclass correlation coefficient (ICC) was also yielded. RESULTS: Mean IS of lower esophagus irrelevant to three epithelial layers were 0.39 ± 0.30 µm. When subdivided into three layers, however, mean IS of squamous cell layer was 0.62 ± 0.23 µm, prickle cell layer 0.23 ± 0.19 µm, and basal layer 0.55 ± 0.36 µm, with their difference statistically significant (p < 0.05). On the other hand, ICC of 5, 10, 20, 30, and 40 measurements were 0.688, 0.917, 0.837, 0.790, and 0.765, respectively. CONCLUSIONS: Mean IS values of each three layers of esophageal epithelium in normal subjects were significantly different, and reconsideration of the standard measurement method is needed. Ten measurements per photo had an adequate inter-observer agreement.

Electron microscopic study of intercellular space: correlation analysis of bronchial asthma and gastroesophageal reflux disease.

BACKGROUND AND AIMS: Bronchial asthma (BA) is considered an extra-esophageal syndrome of gastroesophageal reflux disease (GERD) with poor pathophysiological background. We analyzed the correlation between GERD and BA, examining esophageal epithelium with transmission electron microscopy (TEM), along with clinical findings. METHODS: BA patients of controlled and partly-controlled levels were enrolled in the study. A pulmonary and gastrointestinal (GI) questionnaire was given. Patients with no symptoms joined the control group. Esophageal mucosal tissue was taken by esophagogastroduodenoscopy from both groups and processed for TEM. Intercellular space (IS) was measured with an image analyzing program, 100 times for each patient. RESULTS: The control (n=20) and BA (n=20) groups revealed no significant differences in baseline characteristics. All BA patients were using corticosteroid inhalers, with seven patients having a recent history of acute exacerbation. Patients with at least one GI symptom made up 70% (14/20) of the BA group, and heartburn and/or regurgitation were detected in 40% of patients. Endoscopic findings of GERD were mucosal breaks (n=3). The IS of the control group was 0.389±0.297 um, while the BA group was 0.806±0.556 um (P=0.001). The presence of GERD symptoms (P=0.306) and a history of recent asthma attacks (P=0.710) did not show significant differences. CONCLUSIONS: The BA group showed a significant difference in the dilatation of IS compared to the control group, suggesting a higher prevalence of GERD in BA patients and a close pathophysiological correlation.

How good is cola for dissolution of gastric phytobezoars?

AIM: To evaluate the efficacy of cola treatment for gastric phytobezoars, including diospyrobezoars. METHODS: A total of 17 patients (range: 48 to 78 years) with symptomatic gastric phytobezoars treated with cola and adjuvant endoscopic therapy were reviewed. Three liters of cola lavage (10 cases) or drink (7 cases) were initially used, and then endoscopic fragmentation was done for the remnant bezoars by using a lithotripsy basket or a polypectomy snare. The overall success of dissolving a gastric phytobezoars with using three liters of cola and the clinical and endoscopic findings were compared retrospectively between four cases of complete dissolution by using only cola and 13 cases of partial dissolution with cola. RESULTS: After 3 L of cola lavage or drinking, a complete dissolution of bezoars was achieved in four patients (23.5%), while 13 cases (76.5%) were only partially dissolved. Phytobezoars (4 of 6 cases) were observed more frequently than diospyrobezoars (0 of 11) in the group that underwent complete dissolution (P = 0.006). Gender, symptom duration, size of bezoar and method of cola administration were not significantly different between the two groups. Twelve of 13 patients with residual bezoars were completely treated with a combination of cola and endoscopic fragmentation. CONCLUSION: The rate of complete dissolution with three liters of cola was 23.5%, but no case of diospyrobezoar was completely dissolved using this method. However, pretreatment with cola may be helpful and facilitate endoscopic fragmentation of gastric phytobezoars.

An adequate level of training for technical competence in screening and diagnostic colonoscopy: a prospective multicenter evaluation of the learning curve.

BACKGROUND: Various training programs in colonoscopy recommend that trainees should perform at least 100 to 200 procedures to be considered technically competent at diagnostic colonoscopy. OBJECTIVE: Our purpose was to determine the adequate level of training for technical competence in screening and diagnostic colonoscopy. DESIGN: A prospective multicenter trial. SETTING: Fifteen tertiary care academic medical centers. PATIENTS: Over 8 months we prospectively evaluated the procedures of 24 first-year GI fellows in 15 tertiary care academic medical centers. A total of 4351 colonoscopies were assessed prospectively with variable clinical factors. INTERVENTION: Cecal intubation was documented by photographing the identified cecal landmarks, including the appendiceal orifice and the ileocecal valve. MAIN OUTCOME MEASUREMENTS: Acquisition of competence (success rate) was evaluated for colonoscopic training on the basis of 2 objective criteria: (1) adjusted completion rate (>90%) and (2) cecal intubation time (<20 minutes). RESULTS: The overall success rate was 83.5% (3635/4351). The mean cecal intubation time was 9.23 +/- 4.63 minutes. The success rate significantly improved and reached the requisite standard of competence after 150 procedures (71.5%, 82.6%, 91.3%, 94.4%, 98.4%, and 98.7%, respectively, for every 50 consecutive blocks). The polyp detection rate did not improve significantly during the 8 months and was not correlated with the learning curve. In addition, mean time to cecal intubation decreased significantly, from 11.16 to 8.39 minutes, after 150 procedures. Logistic regression analysis found that prolonged cecal intubation was caused by the following factors: elderly patients, female sex, low body mass index, poor bowel preparation, poor American Society of Anesthesiologists status, abdominal pain as an indication, instructor's supervision, and low case volume. LIMITATIONS: We did not record final pathologic reports of detected polyps and withdrawal time. CONCLUSIONS: Competence in technically efficient screening and diagnostic colonoscopy generally requires experience with more than 150 cases. Also, factors associated with prolonged cecal intubation for typical trainees did not differ from those for experienced colonoscopists.

Stretching Causes Extensive Changes of Gastric Submucosa: Is It Acceptable to Define 500 microm as the Safe Margin?

BACKGROUND/AIMS: Endoscopic mucosal resection can cure early gastric cancer. The risk of lymphatic metastasis is related to the depth of submucosal invasion by the mucosal malignancy, with a resection depth of 500 microm generally accepted as a safe cut-off. However, excessive thinning induced by stretching of the resected tissue sometimes preventing a precise diagnosis. We studied the effects of stretching on different layers and sites of gastric tissue. METHODS: Porcine stomachs were cut into 2.0x2.0 cm pieces, and pieces from body were stretched to 2.5, 3.0, and 3.5 cm. Pieces from the cardia, body, and antrum were also stretched to 3.0 cm. The thickness of each layer was measured and analyzed statistically. RESULTS: Whole gastric wall and submucosal layers showed gradual thinning, with stretching to 3.5 cm tearing the tissues and resulting in imperfect extension. The submucosa was thinner in body tissue than in cardia and antrum tissues. Stretching to 3.0 cm induced a consistent decrease in submucosal thickness (30-70%). The change in thickness varied widely between individual samples. CONCLUSIONS: A resection margin of 500 microm might be insufficient for the complete removal of malignancy. Moreover, the thickness of the submucosal layer differs with the gastric site and between individuals. Future studies are needed to confirm the findings in human tissue.

Comparison of postpolypectomy bleeding between epinephrine and saline submucosal injection for large colon polyps by conventional polypectomy: a prospective randomized, multicenter study.

AIM: To evaluate and compare the clinical outcomes of prophylactic submucosal saline-epinephrine injection and saline injection alone for large colon polyps by conventional polypectomy. METHODS: A prospective study was conducted from July 2003 to July 2004 at 11 tertiary endoscopic centers. Large colon polyps (> 10 mm in diameter) were randomized to undergo endoscopic polypectomy with submucosal saline-epinephrine injection (epinephrine group) or normal saline injection (saline group). Endoscopic polypectomy was performed by the conventional snare method, and early (< 12 h) and late bleeding complications (12 h-30 d) were observed. RESULTS: A total of 561 polyps in 486 patients were resected by endoscopic polypectomy. Overall, bleeding complications occurred in 7.6% (37/486) of the patients, including 4.9% (12/244) in the epinephrine group, and 10.3% (25/242) in the saline group. Early and late postpolypectomy bleeding (PPB) occurred in 6.6% (32/486) and 1% (5/486) of the patients, respectively, including 4.5% (11/244), 0.4% (1/244) in the epinephrine group, and 8.7% (21/242), 1.7% (4/242) in the saline group. No significant differences in the rates of overall, early and late PPB were observed between the 2 groups. Multivariate stepwise logistic regression analysis revealed that large size (> 2 cm) and neoplastic polyps were independently and significantly associated with the presence of PPB. CONCLUSION: The prophylactic submucosal injection of diluted epinephrine does not appear to provide an additional advantage over the saline injection alone for the prevention of PPB.

Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial.

BACKGROUND & AIMS: We assessed the relationship between antibodies to infliximab (ATI) and the loss of response postinfliximab, infusion reactions and, in a randomized trial, investigated whether intravenous hydrocortisone premedication can reduce ATI. METHODS: Initially, we prospectively evaluated clinical response, adverse events, and ATI levels in 53 consecutive patients with Crohn's disease who received 199 infliximab (5 mg/kg) infusions. Subsequently, 80 patients with Crohn's disease were randomized to intravenous hydrocortisone 200 mg or placebo immediately before their first and subsequent infliximab infusions. The primary endpoint was reduction in median ATI levels at week 16. Analysis was by intention to treat. RESULTS: Nineteen of our initial 53 patients (36%) developed ATI, including all 7 patients with serious infusion reactions (median ATI level, 19.6 microg/mL). Eleven of 15 patients (73%) who lost their initial response were ATI positive compared with none of 21 continuous responders, (8.9 vs. 0.7 microg/mL, P < 0.0001). Administering a second infusion within 8 weeks of the first (OR, 0.13; 95% CI, 0.03-0.5; P = 0.0007) or concurrent immunosuppressants (OR, 0.19; 95% CI, 0.04-1.03; P = 0.007) significantly reduced ATI formation. In the placebo-controlled trial, ATI levels were lower at week 16 among hydrocortisone-treated patients (1.6 vs. 3.4 microg/mL, P = 0.02), and 26% of hydrocortisone-treated patients developed ATI compared with 42% of placebo-treated patients, P = 0.06. CONCLUSIONS: Loss of initial response and infusion reactions post-infliximab is strongly related to ATI formation and level. Administering a second infusion within 8 weeks of the first and concurrent immunosuppressant therapy significantly reduce ATI formation. Intravenous hydrocortisone premedication significantly reduces ATI levels but does not eliminate ATI formation or infusion reactions.