AI-assisted capsule endoscopy reading in suspected small bowel bleeding: a multicentre prospective study.

BACKGROUND: Capsule endoscopy reading is time consuming, and readers are required to maintain attention so as not to miss significant findings. Deep convolutional neural networks can recognise relevant findings, possibly exceeding human performances and reducing the reading time of capsule endoscopy. Our primary aim was to assess the non-inferiority of artificial intelligence (AI)-assisted reading versus standard reading for potentially small bowel bleeding lesions (high P2, moderate P1; Saurin classification) at per-patient analysis. The mean reading time in both reading modalities was evaluated among the secondary endpoints. METHODS: Patients aged 18 years or older with suspected small bowel bleeding (with anaemia with or without melena or haematochezia, and negative bidirectional endoscopy) were prospectively enrolled at 14 European centres. Patients underwent small bowel capsule endoscopy with the Navicam SB system (Ankon, China), which is provided with a deep neural network-based AI system (ProScan) for automatic detection of lesions. Initial reading was performed in standard reading mode. Second blinded reading was performed with AI assistance (the AI operated a first-automated reading, and only AI-selected images were assessed by human readers). The primary endpoint was to assess the non-inferiority of AI-assisted reading versus standard reading in the detection (diagnostic yield) of potentially small bowel bleeding P1 and P2 lesions in a per-patient analysis. This study is registered with ClinicalTrials.gov, NCT04821349. FINDINGS: From Feb 17, 2021 to Dec 29, 2021, 137 patients were prospectively enrolled. 133 patients were included in the final analysis (73 [55%] female, mean age 66·5 years [SD 14·4]; 112 [84%] completed capsule endoscopy). At per-patient analysis, the diagnostic yield of P1 and P2 lesions in AI-assisted reading (98 [73·7%] of 133 lesions) was non-inferior (p<0·0001) and superior (p=0·0213) to standard reading (82 [62·4%] of 133; 95% CI 3·6-19·0). Mean small bowel reading time was 33·7 min (SD 22·9) in standard reading and 3·8 min (3·3) in AI-assisted reading (p<0·0001). INTERPRETATION: AI-assisted reading might provide more accurate and faster detection of clinically relevant small bowel bleeding lesions than standard reading. FUNDING: ANKON Technologies, China and AnX Robotica, USA provided the NaviCam SB system.

Dental evaluation is helpful in the differentiation of functional heartburn and gastroesophageal reflux disease.

BACKGROUND: Heartburn is identically the key symptom of both, gastroesophageal reflux disease (GERD) and functional heartburn (FHB), making the differential diagnosis resource-intensive. Oral manifestations of GERD can be easily examined; therefore, their exploration might be a cheap, widely available, and useful tool in the differentiation of GERD and FHB. AIM: To evaluate the prevalence of dental erosions (DE) and periodontal diseases (PD) in patients with heartburn and their association with GERD and FHB. METHODS: A total of 116 [M/F: 51/65, mean age: 54 (17-80) years] consecutive patients with heartburn were enrolled for detailed esophageal function and orodental examinations. RESULTS: Dental disorders were detected in 89% (103/116). Patients with PD + DE had significantly more often pathologic reflux (90.0% vs 27.8%; P < 0.05), higher esophagitis scores (1.8 vs 0.9; P < 0.05), and a significantly different mean impedance curve (P = 0.04) than those without any dental diseases. The opposite approach established that patients with GERD had significantly higher prevalence of DE and PD, especially if both were present (28.9% vs 2.0%; P < 0.01), more severe PD (1.5 vs 1.0; P < 0.01), and longer history of heartburn (15 years vs 9 years; P < 0.01) than those with FHB. CONCLUSION: The dental evaluation of patients with heartburn seems to be useful in the differential diagnosis of GERD and FHB. Among the studied parameters, the co-appearance of DE and PD seems to be the best predictor of GERD, whereas the absence of dental disorders was mostly observed in FHB.

Surgical treatment of gastroesophageal reflux disease and Barrett's esophagus / A gastro-oesophagealis refluxbetegség és a Barrett-nyelocso sebészi kezelése

For the centenary of the Department of Surgery, University of Szeged we have investigated and summarized the results and outcomes of 779 anti-reflux surgery cases between 1. January 2000 ­ 31. May 2021. The indication for surgery was made in close collaboration with the internal medicine workgroup depending on the results of endoscopy and functional tests. The primer indication for surgery was medical therapy-resistant reflux disease. Based on our clinical practice we performed laparoscopic Nissen fundoplication in 98,2% of the cases. Besides the long- and short-term postoperative complications, we investigated the long-term effect of anti-reflux surgery on acid and bile reflux, and the improvement of the patients' quality of life using the Visick score, and modified GERD-HRLQ score. Our investigations have proven the effect of acid and bile reflux in the pathogenesis of Barrett's esophagus and furthermore we have confirmed that laparoscopic anti-reflux surgery restores the function of the lower esophageal sphincter and eliminates acid and bile reflux, so in certain cases Barrett's esophagus regression can be achieved. But due to the heterogeneity of GERD and Barrett's esophagus long-term and regular endoscopic control is necessary.

[Minimally invasive surgery for motility disorders of the oesophagus]. / A nyelocso motilitási betegségeinek minimálisan invazív sebészete

Introduction and aims. We present our experience with minimally invasive surgery for pharyngoesophageal (Zenker) diverticulums, epiphrenic diverticulums and achalasia cardiae focusing on the perioperative features and patients' quality of life. Patients and methods. Between 1 January 2003 and 31 December 2020, patients were selected with a symptom-causing Zenker diverticulum, epiphrenic diverticulum and achalasia cardiae. In 17 cases, transoral stapler diverticulostomy, in 23 cases transcervical diverticulectomy and cricomyotomy were done because of Zenker diverticulum, in 14 cases, laparoscopic transhiatal surgery was performed because of epiphrenic diverticula, while in 63 cases, laparoscopic Heller­Dor operation were carried out because of achalasia cardiae. Perioperative results, the quality of life outcomes of various surgeries were evaluated in mid- and long-term. Results/conclusions. The surgeries were performed with minimal blood loss, zero mortality and low morbidity. According to our result, the two different surgical approaches in the therapy of Zenker's diverticulum, the laparoscopic Heller­Dor procedure applied in the management of epiphrenic diverticulas and achalasia cardiae are safe and effective operations. In the long term, the symptom control in patients after minimally invasive surgeries is sufficient and only a small percentage of the patients may require additional medication therapy and/or reintervention due to persistent complaints.

First prospective European study for the feasibility and safety of magnetically controlled capsule endoscopy in gastric mucosal abnormalities.

BACKGROUND: While capsule endoscopy (CE) is the gold standard diagnostic method of detecting small bowel (SB) diseases and disorders, a novel magnetically controlled capsule endoscopy (MCCE) system provides non-invasive evaluation of the gastric mucosal surface, which can be performed without sedation or discomfort. During standard SBCE, passive movement of the CE may cause areas of the complex anatomy of the gastric mucosa to remain unexplored, whereas the precision of MCCE capsule movements inside the stomach promises better visualization of the entire mucosa. AIM: To evaluate the Ankon MCCE system's feasibility, safety, and diagnostic yield in patients with gastric or SB disorders. METHODS: Of outpatients who were referred for SBCE, 284 (male/female: 149/135) were prospectively enrolled and evaluated by MCCE. The stomach was examined in the supine, left, and right lateral decubitus positions without sedation. Next, all patients underwent a complete SBCE study protocol. The gastric mucosa was explored with the Ankon MCCE system with active magnetic control of the capsule endoscope in the stomach, applying three standardized pre-programmed computerized algorithms in combination with manual control of the magnetic movements. RESULTS: The urea breath test revealed Helicobacter pylori positivity in 32.7% of patients. The mean gastric and SB transit times with MCCE were 0 h 47 min 40 s and 3 h 46 min 22 s, respectively. The average total time of upper gastrointestinal MCCE examination was 5 h 48 min 35 s. Active magnetic movement of the Ankon capsule through the pylorus was successful in 41.9% of patients. Overall diagnostic yield for detecting abnormalities in the stomach and SB was 81.9% (68.6% minor; 13.3% major pathologies); 25.8% of abnormalities were in the SB; 74.2% were in the stomach. The diagnostic yield for stomach/SB was 55.9%/12.7% for minor and 4.9%/8.4% for major pathologies. CONCLUSION: MCCE is a feasible, safe diagnostic method for evaluating gastric mucosal lesions and is a promising non-invasive screening tool to decrease morbidity and mortality in upper gastro-intestinal diseases.

Prevalence of reflux-related symptoms in South-Hungarian blood donor volunteers.

BACKGROUND/AIM: Population-based studies on the prevalence of GERD-related symptoms are still missing in Eastern Europe, therefore, we aimed to obtain such data in South-East Hungarian subjects. METHODS: A total of 2,002 apparently healthy blood donor volunteers were consecutively enrolled and completed detailed questionnaires related to general factors, demographic data, socioeconomical factors, and the presence and frequency of typical and atypical GERD-related symptoms. RESULTS: Among 2,002 study participants, 56.5% were completely asymptomatic. The prevalence of typical GERD symptoms appearing at least monthly or weekly was 16.5% and 6.8%, respectively. Two-thirds (209/330) of the patients experienced at least monthly occurring typical GERD symptoms and also had associated atypical symptoms and this was even more pronounced when comparing subgroups with higher symptom frequencies. Significant correlations were found between monthly GERD-related complaints and height, body mass index (BMI), coffee consumption, and smoking. Positive family history was another significant factor in all the symptom-frequency categories. GERD-related symptom frequency showed a linear association with sex (R2 = 0.75, P = 0.0049). Typical and atypical GERD symptoms were significantly more common in those with chronic diseases than those without. Heartburn was observed in 12.5% and 4.4% (P<0.05) and acid regurgitation was seen in 6.9% and 1.8% (P<0.05), respectively. CONCLUSION: The prevalence of GERD-related symptoms in South Hungary was significantly lower than that in Western countries and was closer to Eastern values. The presence of mild, non-exclusionary chronic diseases significantly increased the prevalence of GERD-related symptoms, as well as positive family history of GERD, height, BMI, coffee consumption, and smoking.

COVID-19-associated diarrhea.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as a highly virulent respiratory pathogen that is known as the causative agent of coronavirus disease 2019 (COVID-19). Diarrhea is a common early symptom in a significant proportion of patients with SARS-CoV-2 infection. SARS-CoV-2 can infect and replicate in esophageal cells and enterocytes, leading to direct damage to the intestinal epithelium. The infection decreases the level of angiotensin-converting enzyme 2 receptors, thereby altering the composition of the gut microbiota. SARS-CoV-2 elicits a cytokine storm, which contributes to gastrointestinal inflammation. The direct cytopathic effects of SARS-CoV-2, gut dysbiosis, and aberrant immune response result in increased intestinal permeability, which may exacerbate existing symptoms and worsen the prognosis. By exploring the elements of pathogenesis, several therapeutic options have emerged for the treatment of COVID-19 patients, such as biologics and biotherapeutic agents. However, the presence of SARS-CoV-2 in the feces may facilitate the spread of COVID-19 through fecal-oral transmission and contaminate the environment. Thus gastrointestinal SARS-CoV-2 infection has important epidemiological significance. The development of new therapeutic and preventive options is necessary to treat and restrict the spread of this severe and widespread infection more effectively. Therefore, we summarize the key elements involved in the pathogenesis and the epidemiology of COVID-19-associated diarrhea.

Surgical Treatment of Esophageal Achalasia in the Era of Minimally Invasive Surgery.

INTRODUCTION: We have analyzed the short- and long-term results of various surgical therapies for achalasia, especially changes in postoperative esophageal function. PATIENTS AND METHODS: Between January 1, 2008 and December 31, 2017, 54 patients with esophageal achalasia were treated in our institution. Patients scheduled for surgery underwent a comprehensive gastroenterological assessment pre- and post-surgery. Forty-eight of the elective cases involved a laparoscopic cardiomyotomy with Dor's semifundoplication, while two cases entailed an esophageal resection with an intrathoracic gastric replacement for end-stage achalasia. Torek's operation was performed on two patients for iatrogenic esophageal perforation, and two others underwent primary suture repair with Heller-Dor surgery as an emergency procedure. The results of the different surgical treatments, as well as changes in the patients' pre- and post-operative complaints were evaluated. RESULTS: No intra-operative complications were observed, and no mortalities resulted. During the 12 to 24-month follow-up period, recurrent dysphagia was observed mostly in the spastic group (TIII: 33%; diffuse esophageal spasm: 60%), while its occurrence in the TI type did not change significantly (14.5%-20.8%). As a result of the follow-up of more than two years, good symptom control was achieved in 93.7% of the patients, with only four patients (8.3%) developing postoperative reflux. CONCLUSIONS: The laparoscopic Heller-Dor procedure provides satisfactory long-term results with low morbidity. In emergency and advanced cases, traditional surgical procedures are still the recommended therapy.

Epidemiologic characteristics of Helicobacter pylori infection in southeast Hungary.

BACKGROUND: Epidemiologic studies have revealed a decrease in the prevalence of Helicobacter pylori (H. pylori) infection in Western Europe. AIM: To obtain data regarding the prevalence of H. pylori in Csongrád and Békés Counties in Hungary, evaluate the differences in its prevalence between urban and rural areas, and establish factors associated with positive seroprevalence. METHODS: One-thousand and one healthy blood donors [male/female: 501/500, mean age: 40 (19-65) years] were enrolled in this study. Subjects were tested for H. pylori IgG antibody positivity via enzyme-linked immunosorbent assay. Subgroup analysis by age, gender, smoking habits, alcohol consumption, and urban vs non-urban residence was also performed. RESULTS: The overall seropositivity of H. pylori was 32%. It was higher in males (34.93% vs 29.2%, P = 0.0521) and in rural areas (36.2% vs 27.94%, P = 0.0051). Agricultural/industrial workers were more likely to be positive for infection than office workers (38.35% vs 30.11%, P = 0.0095) and rural subjects in Békés County than those in Csongrád County (43.36% vs 33.33%, P = 0.0015). CONCLUSION: Although the prevalence of H. pylori infection decreased in recent decades in Southeast Hungary, it remains high in middle-aged rural populations. Generally accepted risk factors for H. pylori positivity appeared to be valid for the studied population.

Laparoscopic Surgery for Epiphrenic Esophageal Diverticulum.

BACKGROUND AND OBJECTIVES: We wanted to assess our surgical results focusing on the patients' quality of life. We present our experience with laparoscopic surgery for epiphrenic esophageal diverticulum. Short- and long-term results of surgical therapy were analyzed. METHODS: Eight patients were examined with a symptom-causing epiphrenic diverticulum. Patients underwent complex gastroenterologic examinations before and after surgery. Laparoscopic transhiatal epiphrenic diverticulectomy, Heller cardiomyotomy, and Dor anterior partial fundoplication were performed on 7 patients. One patient underwent only diverticulectomy, where no motility disorder was present. Results from surgical treatments and changes in patients' pre- and postoperative complaints were evaluated. RESULTS: In all cases except 1, the preoperative examination showed dysmotility of the esophagus. The average duration of the surgeries was 165 (130-195) minutes; blood loss was minimal. One patient developed bleeding in the early postoperative period, and a second laparoscopy was required. No other intraoperative complication was detected, and no mortality occurred. In one case, a staple line leak developed (1/8 [12.5%]), which was resolved with conservative therapy. Functional check-ups confirmed adequate esophageal function. The total symptom score for the patients was 6.3 points before surgery, and it decreased to 1.6 (P < .001) after surgery, an average of 74% subjective improvement. During the follow-up period (mean, 60 months; 10-138 months), proton pump inhibitor therapy was started in 4 patients to treat gastroesophageal reflux. In 3 cases, drug therapy was successful; in one case, Nissen antireflux surgery was performed. CONCLUSION: Laparoscopic transhiatal diverticulectomy and Heller-Dor surgery are effective interventions with low morbidity. Patient quality of life significantly improves in the long term, but gastroesophageal reflux disease may occur.

Matrix metalloproteinase (MMP)-7 in Barrett's esophagus and esophageal adenocarcinoma: expression, metabolism, and functional significance.

Matrix metalloproteinase (MMP)-7, unlike many MMPs, is typically expressed in epithelial cells. It has been linked to epithelial responses to infection, injury, and tissue remodeling including the progression of a number of cancers. We have now examined how MMP-7 expression changes in the progression to esophageal adenocarcinoma (EAC), and have studied mechanisms regulating its expression and its functional significance. Immunohistochemistry revealed that MMP-7 was weakly expressed in normal squamous epithelium adjacent to EAC but was abundant in epithelial cells in both preneoplastic lesions of Barrett's esophagus and EAC particularly at the invasive front. In the stroma, putative myofibroblasts expressing MMP-7 were abundant at the invasive front but were scarce or absent in adjacent tissue. Western blot and ELISA revealed high constitutive secretion of proMMP-7 in an EAC cell line (OE33) that was inhibited by the phosphatidylinositol (PI) 3-kinase inhibitor LY294002 but not by inhibitors of protein kinase C, or MAP kinase activation. There was detectable proMMP-7 in cultured esophageal myofibroblasts but it was undetectable in media. Possible metabolism of MMP-7 by myofibroblasts studied by proteomic analysis indicated degradation via extensive endopeptidase, followed by amino- and carboxpeptidase, cleavages. Myofibroblasts exhibited increased migration and invasion in response to conditioned media from OE33 cells that was reduced by MMP-7 knockdown and immunoneutralization. Thus, MMP-7 expression increases at the invasive front in EAC which may be partly attributable to activation of PI 3-kinase. Secreted MMP-7 may modify the tumor microenvironment by stimulating stromal cell migration and invasion.

Modeling Esophagitis Using Human Three-Dimensional Organotypic Culture System.

Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems. Three-dimensional organotypic tissue culture (OTC) is an innovative three-dimensional multicellular in vitro platform that recapitulates normal esophageal epithelial stratification and differentiation. We hypothesized that this platform can be used to model esophagitis to better understand the interactions between immune cells and the esophageal epithelium. We found that human immune cells remain viable and respond to cytokines when cultured under OTC conditions. The acute inflammatory environment induced in the OTC significantly affected the overlying epithelium, inducing a regenerative response marked by increased cell proliferation and epithelial hyperplasia. Moreover, oxidative stress from the acute inflammation induced DNA damage and strand breaks in epithelial cells, which could be reversed by antioxidant treatment. These findings support the importance of immune cell-mediated esophageal injury in esophagitis and confirms the utility of the OTC platform to characterize the underlying molecular events in esophagitis.

Role of ion transporters in the bile acid-induced esophageal injury.

Barrett's esophagus (BE) is considered to be the most severe complication of gastro-esophageal reflux disease (GERD), in which the prolonged, repetitive episodes of combined acidic and biliary reflux result in the replacement of the squamous esophageal lining by columnar epithelium. Therefore, the acid-extruding mechanisms of esophageal epithelial cells (EECs) may play an important role in the defense. Our aim was to identify the presence of acid/base transporters on EECs and to investigate the effect of bile acids on their expressions and functions. Human EEC lines (CP-A and CP-D) were acutely exposed to bile acid cocktail (BAC) and the changes in intracellular pH (pHi) and Ca(2+) concentration ([Ca(2+)]i) were measured by microfluorometry. mRNA and protein expression of ion transporters was investigated by RT-PCR, Western blot, and immunohistochemistry. We have identified the presence of a Na(+)/H(+) exchanger (NHE), Na(+)/HCO3 (-) cotransporter (NBC), and a Cl(-)-dependent HCO3 (-) secretory mechanism in CP-A and CP-D cells. Acute administration of BAC stimulated HCO3 (-) secretion in both cell lines and the NHE activity in CP-D cells by an inositol triphosphate-dependent calcium release. Chronic administration of BAC to EECs increased the expression of ion transporters compared with nontreated cells. A similar expression pattern was observed in biopsy samples from BE compared with normal epithelium. We have shown that acute administration of bile acids differently alters ion transport mechanisms of EECs, whereas chronic exposure to bile acids increases the expression of acid/base transporters. We speculate that these adaptive processes of EECs represent an important mucosal defense against the bile acid-induced epithelial injury.

A pilot study on faecal MMP-9: a new noninvasive diagnostic marker of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading malignancies worldwide, therefore cheap noninvasive screening methods are of great importance. Matrix-metalloproteinase-9 (MMP-9) has a role in the progression of CRC, and its level is elevated in tumour biopsies. Faecal MMP-9 levels are increased in active ulcerative colitis patients, but in CRC patients, they have never been measured. We aimed to assess the faecal MMP-9 levels in patients undergoing total colonoscopy according to endoscopic and histological diagnosis. METHODS: One hundred and nine patients provided faecal samples for MMP-9 analysis. A total colonoscopy was performed; suspicious lesions were evaluated by histology. Faecal MMP-9 levels were measured by ELISA. RESULTS: The number of patients allocated to different groups were: negative/diverticulosis: 34 (referred to as controls); hyperplastic polyps: 15; adenomas: 32 (22 at high risk); and CRC: 28. Faecal MMP-9 was significantly increased in CRC compared with all other groups (P<0.001). Faecal MMP-9 was suitable to distinguish CRC patients from controls (sensitivity: 89.3%; specificity: 91.2%). By means of a lower cutoff level, faecal MMP-9 identified high-risk adenomas besides CRC (sensitivity: 76%; specificity: 85.3%). This lower cutoff level screened 59% of high-risk adenomas. CONCLUSIONS: Faecal MMP-9 may be a promising new noninvasive marker in CRC.

[New trends and novel possibilities in the diagnosis of esophageal tumors]. / Újdonságok és új lehetoségek a nyelocsodaganatok diagnosztikájában.

The diagnosis of esophageal malignancies remains to be a significant challenge. The lack of symptoms and widely applicable, predictive screening tests make their early recognition difficult, however this would be essential for the successful treatment, cost-effective management and the improvement of survival. In this manuscript the author discusses the diagnostic tools available at present and in the near future.

[Comparison of surgical patients with gastroesophageal reflux disease and Barrett's esophagus]. / Refluxbetegség és Barrett-nyelocso miatt mutétre kerülo betegek összehasonlító vizsgálata.

INTRODUCTION: Barrett's esophagus (BE) is the only known precursor of adenocarcinoma occuring in the lower third of the esophagus. According to statistics, severity and elapsed time of gastroesophageal reflux disease (GERD) are major pathogenetic factors in the development of Barrett's esophagus. PATIENTS AND METHODS: In a retrospective study between 2001 and 2008, we compared the preoperative results (signs and sympthoms, 24 hour pH manometry, esophageal manometry, Bilitec) and treatment efficacy of 176 GERD patients and 78 BE patients, who have undergone laparoscopic Nissen procedure for reflux disease. RESULTS: The two groups of patients had similar demographic features, and elapsed time of reflux sympthoms were also equal. Both groups were admitted for surgery after a median time of 1.5 years (19.87 vs. 19.20 months) of ineffective medical (proton pump inhibitors) treatment. Preoperative functional tests showed a more severe presence of acid reflux in the BE group (DeMeester score 18.9 versus 41.9, p < 0.001). On the other hand, mano-metry - despite confirming lower esophageal sphincter (LES) damage - did not show difference between the two groups (12.10 vs. 12.57 mmHg, p = 0.892). We did not experience any mortality cases with laparoscopic antireflux procedures, although in two cases we had to convert during the operation (1 due to extensive adhesions, and 1 due to injury to the spleen). 3 months after the procedure - according to Visick score - both groups experienced a significant decrease, or lapse in reflux complaints (group I: 73%, group II: 81% of patients), LES functions improved (17.58 vs.18.70 mmHg), and the frequency and exposition of acid reflux decreased (DeMeester score 7.73 vs. 12.72). CONCLUSION: The severity of abnormal acid reflux occuring parallel with the incompetent function of the damaged LES triggers not only inflammation in the gastroesophageal junction (GEJ), but also metaplastic process, and the development of Barrett's esophagus. Laparoscopic Nissen procedure for reflux disease can further improve outcome among patients with GERD not responding to conservative therapy.

Role of antispasmodics in the treatment of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT1A receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS.

Intraductal acidosis in acute biliary pancreatitis.

Acute pancreatitis recently became the most common cause for hospitalization among gastrointestinal diseases. There is no specific therapy against the disease due to insufficient understanding of pathogenesis. Animal and in vitro models indicated that reduced pancreatic ductal bicarbonate secretion and consequent intraductal acidosis is an early event in acute pancreatitis, but human data are lacking. Therefore, our aim was to determine the luminal pH in the main pancreatic duct during acute pancreatitis in humans. Intraductal pH was measured in patients with acute biliary pancreatitis (n = 6) during endoscopic retrograde cholangio-pancreatography. Patients with common bile stones without pancreatitis (n = 5) and a patient with an adenoma of the papilla of Vater served as controls. The luminal pH was significantly lower in the group of acute biliary pancreatitis vs. controls (6.97 ± 0.13 vs. 7.79 ± 0.20). Our brief report shows for the first time that there is marked intraductal acidosis in acute biliary pancreatitis, which seems to worsen with time. Further clinical trials are needed to determine the exact roles of reduced intraductal pH in ABP.

Luminal cysteine-proteases degrade colonic tight junction structure and are responsible for abdominal pain in constipation-predominant IBS.

OBJECTIVES: Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBS patients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies. METHODS: Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN. RESULTS: We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-D patients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant human occludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64. CONCLUSIONS: These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS.

Fecal MMP-9: a new noninvasive differential diagnostic and activity marker in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is characterized by frequent relapses, with the presence of colorectal inflammation and mucosal lesions. Matrix-metalloprotease 9 (MMP-9) is elevated in colonic biopsies, urine, and blood plasma of UC patients. MMP-9 has been suggested as a predictor of UC in the urine of children; however, 20% of the controls tested positive. So far, fecal MMP-9 levels have never been measured. Our aims were: 1) to compare fecal MMP-9 levels in UC patients to control subjects and a functional gastrointestinal disorder characterized by diarrhea (IBS-D); 2) to test the correlation between UC disease activity and fecal levels of MMP-9; and 3) to correlate fecal MMP-9 levels with a known fecal marker of UC activity, calprotectin. METHODS: UC (n = 47), IBS-D (n = 23) patients, and control subjects (n = 24) provided fecal samples for MMP-9 analysis. In UC patients, disease severity was evaluated by the Mayo score. Fecal MMP-9 and calprotectin levels were measured by enzyme-linked immunosorbent assay and lateral flow assay, respectively. RESULTS: MMP-9 was undetectable or ≤0.22 ng/mL in the feces of all controls and IBS-D patients. In UC patients, fecal MMP-9 levels significantly correlated with the overall Mayo score (P < 0.001), the endoscopic score (P < 0.001), and the serum C-reactive protein levels (P = 0.002). Additionally, in UC patients fecal MMP-9 levels showed a significant correlation with a known disease activity marker, fecal calprotectin (P = 0.014). CONCLUSIONS: These results highlight fecal MMP-9 as a useful tool in the differential diagnosis of diarrheic disorders and in the noninvasive evaluation of disease activity and mucosal healing in UC.