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ObjectiveA considerable proportion of patients with irritable bowel syndrome (IBS) may be wheat-sensitive and respond to a gluten-free diet (GFD) although they do not have coeliac disease. However, a diagnostic test for wheat sensitivity (WS) is missing. Our study evaluated the diagnostic accuracy (sensitivity and specificity) of confocal laser endomicroscopy (CLE) for the identification of WS as primary outcome.DesignIn this prospective, double-blind diagnostic study 147 non-coeliac patients fulfilling the Rome III criteria for IBS were tested by CLE for duodenal changes after wheat (index test), soy, yeast or milk exposure. Patients with IBS responding to 2 months of GFD were classified as having WS (reference test) using response criteria recommended by regulatory bodies for pharmaceutical trials of patients with IBS. After 2 months, CLE results were unblinded and patients were advised to exclude those food components that had led to a positive CLE reaction. The clinical response was assessed at follow-up after 6 and 12 months.ResultsOf 130 patients who completed the study per protocol, 74 (56.9%) responded to GFD and were classified as WS after 2 months, and 38 of these 74 patients were correctly identified by CLE (sensitivity 51.4%; 97.5% CI: 38.7% to 63.9%). A total of 38 of 56 patients without WS were correctly identified by CLE (specificity 67.9%; 97.5% CI: 52.9% to 79.9%). At 6 months follow-up, CLE correctly identified 49 of 59 food-sensitive patients (sensitivity 83.1%; 97.5% CI: 69.9% to 91.3%) but specificity was only 32% (97.5% CI: 15.7% to 54.3%).ConclusionIn light of the high proportion of patients with IBS responding to GFD, the diagnostic accuracy of CLE is too low to recommend widespread use of this invasive procedure.Trail registration numberThis study was registered as clinical trial in the German Registry for Clinical Studies (DRKS00010123).

Background A recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting. Methods In this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application. Results 111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88–99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59–91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation. Conclusions PuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery.

In the two inflammatory bowel diseases, ulcerative colitis (UC) and Crohn’s disease (CD), altered expression of tight junction (TJ) proteins leads to an impaired epithelial barrier including increased uptake of luminal antigens supporting the inflammation. Here we focused on regulation of tricellulin, a protein of the tricellular TJ essential for the barrier against macromolecules, and hypothesized a role in paracellular antigen uptake. We report that tricellulin is downregulated in UC, but not in CD, and that its reduction increases the passage of macromolecules. Using a novel visualization method, passage sites were identified at TJ regions usually sealed by tricellulin. We show that interleukin-13 (IL-13), beyond its known effect on claudin-2, downregulates tricellulin expression. These two effects of IL-13 are regulated by different signaling pathways: The IL-13 receptor α1 upregulates claudin-2, while IL-13 receptor α2 downregulates tricellulin. We suggest to target the α2 receptor in future developments of therapeutical IL-13-based biologicals.

Purpose This overview sums up the Classification of Diverticular Disease (CDD) with regard to its application in computed tomographic diagnosis and briefly recapitulates its targeted advantages over preliminary systems. Primarily, application of the CDD in computed tomography diagnostics is described. Differences with respect to the categories of the older systems are pointed out on the level of each CDD type using imaging examples. Materials and Methods The presented images are derived from our institute according to the S2k criteria. Literature was researched on PubMed. Results The CDD constitutes an improvement compared to older systems for categorizing the stages of diverticular disease. It provides more discriminatory power on the descriptive-morphological level and defines as well as differentiates more courses of the disease. Furthermore, the categories translate more directly into state-of-the-art decision-making concerning hospitalization and therapy. Conclusion The CDD should be applied routinely in the computed tomographic diagnosis of diverticular disease. Typical imaging patterns are presented. Key points Citation Format

Graft-versus-host disease (GvHD) is a major complication of allogeneic stem cell transplantation. High-resolution in vivo histology of the intestine by confocal endomicroscopy (CEM) detects acute GvHD (aGvHD) with high sensitivity. This pilot study aims to evaluate the diagnostic value of CEM for intestinal chronic GvHD (cGvHD). The study included 20 patients with gastrointestinal symptoms and confirmed cGvHD in other organs as well as 20 patients with clinically suspected acute GvHD for control. Confocal endomicroscopy was performed as gastroscopy followed by sigmoidoscopy after intravenous injection of fluorescein (10%) and topical application of acriflavine (0.05%). Histopathology from H&E-stained biopsy samples throughout the intestinal tract complemented the survey. All histological features of intestinal cGvHD were predominantly mild to moderate. Stroma fibrosis detected by standard histology (16/20 patients) was not seen by CEM. Apoptosis assessed by histology in 12/20 patients was concordant with CEM (8/12 patients). Confocal endomicroscopy revealed esophageal manifestation of cGvHD in 3 patients. For each biopsy site, CEM correlated with intestinal histology (r = 0.64). Classical histology from intestinal biopsy samples taken under CEM monitoring confirmed the final diagnosis of cGvHD. The sensitivity of CEM with 40% in cGvHD was significantly lower compared to 70% in patients with aGvHD. Confocal endomicroscopy detected acute features of cGvHD and contributed to the diagnosis of esophageal cGvHD but failed to display stroma fibrosis in vivo. Although CEM represents a useful noninvasive tool in routine diagnostic of intestinal aGvHD, the method is not sufficient to fully establish the diagnosis of cGvHD within the intestinal tract. Confocal endomicroscopy allowed acquisition of targeted biopsies in patients suspected of having cGvHD.

Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn’s disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn’s disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn’s disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn’s disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner., The adipokine leptin modulates intestinal inflammation in mice. Here the authors describe a patient with inflammatory bowel disease and lipodystrophy, providing evidence that leptin aggravates intestinal inflammation with proinflammatory effects on leukocytes that are reversible by TNFα blockade.

In recent years, mucosal healing has emerged as a key therapeutic goal in the clinical management of patients with Crohn’s disease, as it has been associated with improved long-term clinical outcomes. With the vast improvements in endoscopic imaging techniques and the increase in available treatment options, which reportedly are able to induce mucosal healing, the practising physician is left to wonder: how is endoscopic mucosal healing exactly defined in Crohn’s disease, and how can it effectively be achieved and monitored in daily clinical practice? Within this review, we will give an overview of the ongoing debate about the definition of mucosal healing and the modalities to monitor inflammation, and finally present available therapies with the capacity to induce mucosal healing.

Background and study aims Hemostatic powders have been introduced to improve the management of gastrointestinal (GI) bleeding and to extend the variety of tools available for emergency endoscopy. The aim of the present pilot study was to evaluate the indication profiles and the short-term outcome of EndoClot. Patients, materials and methods In a prospective observational pilot study patients with acute nonvariceal GI bleeding were included. Primary or secondary application of EndoClot was assessed. Hemoglobin, prothrombine time and platelets were documented before and after hemostasis. The efficacy of EndoClot was assessed 72 hours and 1 week after application. Results Seventy patients with acute GI bleeding were recruited into the study. Eighty-three percent (58/70) of the patients had upper and 17% (12/70) had lower GI bleeding. In the upper GI tract treatment success was achieved in 64% (30/47, 95% confidence interval, 50%-76%) after primary use and in all patients, when used after established techniques had failed (95% confidence interval, 70%-100%). In lower GI bleeding hemostasis was achieved in 83% of cases (10/12, 95% confidence interval 54%-97%). Rebleeding occurred in 11% (8/70), in 10% EndoClot served as a bridge to surgery (7/70). Conclusions EndoClot expanded the therapeutic options in the management of GI bleeding. It was applicable as a monotherapy or in combination with other techniques from oozing bleeding type or lower. It was most effective in diffuse or extensive bleeding activity or when access to the bleeding vessel was difficult. EndoClot can be applied as a bridge to surgery when classical methods of hemostasis have failed.

Endoscopic stent implantation is a common short-treatment option in palliative settings in patients with esophageal cancer. Advanced disease is associated with low survival rates; therefore, data on the long-term outcome are limited. So far, cases of long-term remission or even cure of metastasized adenocarcinoma of the gastroesophageal junction or stomach (AGS) have only been reported from Asia. A 51-year-old male patient primarily diagnosed with metastasized adenocarcinoma of the gastroesophageal junction (GEJ) [type I, cT3cN+cM1 (hep), CEA positive, UICC stage IV] received palliative esophageal stenting with a self-expandable metal stent. As disease progressed after four cycles with epirubicin, oxaliplatin, and capecitabin, treatment was changed to 5-FU and Irinotecan. The patient did not return after 5 cycles of FOLFIRI, but presented 4 years later with mild dysphagia. Endoscopy surprisingly revealed no relevant stenosis or stent migration. Repeated histological analyses of a residual mass at the GEJ did not detect malignancy. Since the initially diagnosed hepatic metastases were no longer detectable by computed tomography, cure from esophageal cancer was assumed. Dysphagia was ascribed to esophageal motility disorder by a narrowed esophageal lumen after long-term stenting. Thus, endoscopic stent implantation is an important method in palliative treatment of dysphagia related to AGS. New systemic treatment strategies like trastuzumab in Her2neu positive cases or new VEGF-inhibitors like ramucirumab will lead to more long-time survivors with AGS. In conclusion, future endoscopic treatment strategies in AGS represent a challenge for the development of new stent techniques in either extraction or programmed complete dissolution.

Since refractory celiac disease (RCD) may cause severe complications and is associated with a poor prognosis in a portion of patients, early diagnosis and treatment is of importance. Current diagnostics include complex PCR-based molecular pathology and FACS techniques in order to differentiate type I and type II RCD, the latter being associated with the development of an enteropathy-associated T cell lymphoma (EATL). Recently established treatment options also include high-dose chemotherapeutic regimens for RCD type II which have significantly improved survival. However, treatment strategies are highly individual targeting also complications of malabsorption and should be started in the RCD phase of the disease. Therefore, adequate diagnostics are pivotal for patient outcome.

Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.

The aim of the study was to evaluate the usefulness and diagnostic and therapeutic outcome of the single-operator cholangiopancreatoscopy (SOC) with SpyGlassDS™. In a retrospective multicenter study between November 2015 and January 2017, SpyGlassDS™ procedures were analyzed in participating centers. Indications, accuracy of SOC-guided biopsies, management of large bile duct stones, and complications were analyzed. Follow-up was 4 months. Two hundred and six patients out of 250 examinations were evaluated. Indications were biliary stones (n = 132), bile duct stenosis (n = 93), stones and stenosis combined (n = 24), and bile duct leakage (n = 1). Of the 117 cases which were suspicious of malignancy, in 99 cases the lesion could be stratified into benign (n = 55) or malignant (n = 44) indicating a sensitivity of 95.5% and a specificity of 94.5% for the indication tumor. SOC-guided biopsies revealed a sensitivity of 57.7% with a specificity of 100%. In 107 examinations, biliary stones were visualized and could be completely removed in 91.1% with a need of three procedures (range 1–6) to achieve final stone clearance. In 75 cases, lithotripsy was performed and was successful in 71 cases (95%). Four out of 45 patients (8.9%) underwent cholecystectomy with surgical bile duct revision as a final therapy. Adverse Event (AE) occurred in 33/250 patients (13.2%) and Serious Adverse Event (SAE) occurred in 1/250 patients (0.4%). Cholangitis was 1% (n = 102) after peri-interventional administration of antibiotics and 12.8% (n = 148) without antibiotic prophylaxis (p

Campylobacter jejuni is the most prevalent cause of foodborne bacterial enteritis worldwide. Patients present with diarrhea and immune responses lead to complications like arthritis and irritable bowel syndrome. Although studies exist in animal and cell models, we aimed at a functional and structural characterization of intestinal dysfunction and the involved regulatory mechanisms in human colon. First, in patients' colonic biopsies, sodium malabsorption was identified as an important diarrheal mechanism resulting from hampered epithelial ion transport via impaired epithelial sodium channel (ENaC) β- and γ-subunit. In addition, barrier dysfunction from disrupted epithelial tight junction proteins (claudin-1, -3, -4, -5, and -8), epithelial apoptosis, and appearance of lesions was detected, which cause leak-flux diarrhea and can perpetuate immune responses. Importantly, these effects in human biopsies either represent direct action of Campylobacter jejuni (ENaC impairment) or are caused by proinflammatory signaling (barrier dysfunction). This was revealed by regulator analysis from RNA-sequencing (cytometric bead array-checked) and confirmed in cell models, which identified interferon-γ, TNFα, IL-13, and IL-1β. Finally, bioinformatics' predictions yielded additional information on protective influences like vitamin D, which was confirmed in cell models. Thus, these are candidates for intervention strategies against C. jejuni infection and post-infectious sequelae, which result from the permissive barrier defect along the leaky gut.

Watery diarrhea is the cardinal symptom of lymphocytic colitis (LC). We have previously shown that colonic Na malabsorption is one of the major pathologic alterations of LC and found evidence for an epithelial barrier defect. On these grounds, this study aimed to identify the inherent mechanisms of this epithelial barrier dysfunction and its regulatory features.Epithelial resistance (RREpithelial barrier dysfunction in LC occurs through downregulation of claudin-4, -5, and -8, and redistribution of claudin-5 and -8 off the tight junction, which contributes to diarrhea by a leak-flux mechanism. The key effector cytokines TNFα and IFNγ turned out to be the trigger for redistribution of claudin-5 and -8. Thus, alongside sodium malabsorption, leak-flux is yet another important diarrheal mechanism in LC.

In this paper, we identify mechanisms of watery diarrhea in microscopic colitis (MC). Biopsies from the sigmoid colon of patients with collagenous colitis and treated lymphocytic colitis were analyzed in miniaturized Ussing chambers for electrogenic sodium transport and barrier function with one-path impedance spectroscopy. Cytometric bead arrays (CBA) served to analyze cytokine profiles. In active MC, electrogenic sodium transport was diminished and epithelial resistance decreased. CBA revealed a Th1 cytokine profile featuring increased IFN-γ, TNF-α, and IL-1β levels. After four weeks of steroid treatment with budesonide, electrogenic sodium transport recovered while epithelial barrier defects remained. Diarrhea in MC results at least in part from a combination of impaired electrogenic sodium transport and barrier defects. From a therapeutic perspective it can be postulated that the functional importance of loss of ions may be higher than that caused by barrier impairment.

In some cases the diagnosis of gastric cancer is difficult and the endoscopic presentation may be misleading. Diffuse type gastric carcinoma with peritoneal metastasis may present primarily with abdominal pain, colonic infiltration and/or diarrhea, thus other differential diagnoses like Crohn's disease (CD) may be considered at first. Therefore intensive diagnostic work-up is important. We report two cases of gastric cancer with ascites due to peritoneal carcinomatosis who were first diagnosed as CD. The patients were hospitalized in different institutions for weight loss, abdominal pain and nausea. The first colonoscopy, upper endoscopy with multiple biopsies and ascites puncture were negative for malignant disease, but macroscopic lesions resembling CD were described. Both patients were released on a prednisolone-based treatment for suspected CD. They presented to our hospital for further evaluation due to persistent symptoms. Neither lower nor upper endoscopy were suggestive of CD and endoscopic ultrasound was suspicious of malignancy in one case. Histology was diagnostic and showed gastric infiltration by a poorly differentiated adenocarcinoma. Diffuse type gastric cancer (gastric linitis plastica) with peritoneal metastasis may mimic certain clinical, endoscopic and CT imaging features of CD. Repeated biopsies and endoscopic investigations are often necessary to confirm a malignant process, especially in case of an inconclusive clinical and endoscopic picture. Endoscopic ultrasound may be useful to evaluate the risk of malignancy in patients with macroscopic suspicion of malignancy and negative biopsies. © 2012 S. Karger AG, Basel.

Endoscopic surveillance in patients with long-standing inflammatory bowel disease (IBD) improves early detection of intraepithelial neoplasia (IEN). We aimed to compare three different endoscopic surveillance strategies in the detection of IEN.One hundred fifty surveillance colonoscopies (ulcerative colitis, UC n = 141; Crohn's disease, CD n = 9) were carried out. Random quadrant biopsies were taken (group I, n = 50). Chromoendoscopy with indigo carmine was performed and subsequently quadrant biopsies were collected (group II, n = 50). Patients in group III (n = 50) underwent confocal endomicroscopy (CEM), and CEM-guided as well as random quadrant biopsies were taken (group III, n = 50). The findings of CEM were correlated to conventional histology. Patients with high-grade IEN underwent surgery or strict follow-up by patients' request.In group I (1531 biopsies), no IEN was detected by histology. In group II (1,811 biopsies), chromoendoscopy-guided biopsies revealed high-grade IEN in two patients (4% detection rate). In four patients of group III (1477 biopsies), areas with high-grade IEN were clearly visible by CEM and confirmed by histology (8% detection rate, p 0.05). Of six patients with high-grade IEN, five patients underwent proctocolectomy. Colorectal cancer was detected in one out of five patients.Targeted biopsy protocols guided by either chromoendoscopy or CEM led to higher detection rates of IEN and are thus mandatory for surveillance colonoscopies in patients with long-standing UC. Random biopsy protocols should be replaced by chromoendoscopy-guided protocols.

The epithelium in inflamed intestinal segments of patients with Crohn's disease is characterized by a reduction of tight junction strands, strand breaks, and alterations of tight junction protein content and composition. In ulcerative colitis, epithelial leaks appear early due to micro-erosions resulting from upregulated epithelial apoptosis and in addition to a prominent increase of claudin-2. Th1-cytokine effects by interferon-gamma in combination with TNFalpha are important for epithelial damage in Crohn's disease, while interleukin-13 (IL-13) is the key effector cytokine in ulcerative colitis stimulating apoptosis and upregulation of claudin-2 expression. Focal lesions caused by apoptotic epithelial cells contribute to barrier disturbance in IBD by their own conductivity and by confluence toward apoptotic foci or erosions. Another type of intestinal barrier defect can arise from alpha-hemolysin harboring E. coli strains among the physiological flora, which can gain pathologic relevance in combination with proinflammatory cytokines under inflammatory conditions. On the other hand, intestinal barrier impairment can also result from transcellular antigen translocation via an initial endocytotic uptake into early endosomes, and this is intensified by proinflammatory cytokines as interferon-gamma and may thus play a relevant role in the onset of IBD. Taken together, barrier defects contribute to diarrhea by a leak flux mechanism (e.g., in IBD) and can cause mucosal inflammation by luminal antigen uptake. Immune regulation of epithelial functions by cytokines may cause barrier dysfunction not only by tight junction impairments but also by apoptotic leaks, transcytotic mechanisms, and mucosal gross lesions.

Patients with a long-standing history of ulcerative colitis (UC) or Crohn’s disease (CD) with a history of inflammation in the colon have a risk for the development of colon cancer. To these patients at least one colonoscopy per year should be offered according to national surveillance guidelines in patients with inflammatory bowel disease (IBD). Following general recommendations, surveillance colonoscopy should be performed without disease activity and four tissue samples each 10 cm should be taken. Beside high-resolution videoendoscopy and magnification endoscopy, the application of dyes applied via a spraying catheter are of additional diagnostic value with a factor 3–4 higher detection rate of intraepithelial neoplasia (IEN). It is under current evaluation if the use of computerized virtual chromoendoscopy techniques (NBI, FICE, High Line/HD+) has the same diagnostic output compared to classical spraying techniques. The detection rate of IEN can be further improved by using newly developed in-vivo histology techniques. A combination of chromoendoscopy with confocal endomicroscopy (CEM) can detect 5-fold higher rates of IEN compared with random biopsy protocols. An alternative technique to CEM is the miniprobe-based CEM. Autofluorescence imaging is an interesting approach for the surveillance of IBD patients with first clinical data published.

Background Antineuronal antibodies can be associated with both gastrointestinal (GI) and brain disorders. For example, antibodies against the potassium channel subunit dipeptidyl-peptidase-like protein-6 (DPPX) bind to neurons in the central nervous system (CNS) and myenteric plexus and cause encephalitis, commonly preceded by severe unspecific GI symptoms. We therefore investigated the prevalence of antineuronal antibodies indicative of treatable autoimmune CNS etiologies in GI patients. Methods Serum samples of 107 patients (Crohn's disease n = 42, ulcerative colitis n = 16, irritable bowel syndrome n = 13, others n = 36) and 44 healthy controls were screened for anti-DPPX and further antineuronal antibodies using immunofluorescence on rat brain and intestine and cell-based assays. Functional effects of high-titer reactive sera were assessed in organ bath and Ussing chamber experiments and compared to non-reactive patient sera. Key results Twenty-one of 107 patients (19.6%) had antibodies against the enteric nervous system, and 22 (20.6%) had anti-CNS antibodies, thus significantly exceeding frequencies in healthy controls (4.5% each). Screening on cell-based assays excluded established antienteric antibodies. Antibody-positive sera were not associated with motility effects in organ bath experiments. However, they induced significant, tetrodotoxin (TTX)-insensitive secretion in Ussing chambers compared to antibody-negative sera. Conclusions & inferences Antineuronal antibodies were significantly more frequent in GI patients and associated with functional effects on bowel secretion. Future studies will determine whether such antibodies indicate patients who might benefit from additional antibody-directed therapies. However, well-characterized encephalitis-related autoantibodies such as against DPPX were not detected, underlining their rarity in routine cohorts.

Background & Aims: Collagenous colitis is an inflammatory disease of unknown etiology with diarrhea as the leading symptom. The aim of this study was to examine the pathogenic mechanisms of this disease. Methods: Biopsy specimens of the sigmoid colon were obtained endoscopically. Short-circuit current and 22Na and 36Cl fluxes were measured in miniaturized Ussing chambers. Alternating current impedance analysis discriminated epithelial from subepithelial resistance. Tight junction proteins occludin and claudin 1–5 were characterized in membrane fractions by Western blotting. Apoptotic ratio was determined by DAPI and TUNEL staining. Results: In collagenous colitis, net Na+ flux decreased from 8.8 ± 1.8 to 0.2 ± 1.5 and net Cl− flux from 11.2 ± 3.0 to −3.0 ± 2.7 μmol · h−1 · cm−2, indicating a pronounced decrease in NaCl absorption. The fact that short-circuit current increased from 1.5 ± 0.4 to 3.9 ± 0.8 μmol · h−1 · cm−2, together with the negative net Cl− flux, points to activation of active electrogenic chloride secretion. Subepithelial resistance increased from 7 ± 1 to 18 ± 2 Ω · cm2 due to subepithelial collagenous bands of 48 ± 8–μm thickness. Epithelial resistance was diminished from 44 ± 3 to 29 ± 2 Ω · cm2, and this was accompanied by a decrease in occludin and claudin-4 expression. Neither mucosal surface area nor apoptotic ratio was altered in collagenous colitis. Conclusions: Reduced net Na+ and Cl− absorption is the predominant diarrheal mechanism in collagenous colitis, accompanied by a secretory component of active electrogenic chloride secretion. The subepithelial collagenous band as a significant diffusion barrier is a cofactor. Down-regulation of tight junction molecules but not epithelial apoptoses is a structural correlate of barrier dysfunction contributing to diarrhea by a leak flux mechanism. GASTROENTEROLOGY 2002;123:433-443

Objective α-Haemolysin (HlyA) influences host cell ionic homeostasis and causes concentration-dependent cell lysis. As a consequence, HlyA-producing Escherichia coli is capable of inducing ‘focal leaks’ in colon epithelia, through which bacteria and antigens translocate. This study addressed the role of HlyA as a virulence factor in the pathogenesis of colitis according to the ‘leaky gut’ concept. Design To study the action of HlyA in the colon, we performed oral administration of HlyA-expressing E coli -536 and its isogenic α-haemolysin-deficient mutant (HDM) in three mouse models: wild type, interleukin-10 knockout mice ( IL-10 −/− ) and monoassociated mice. Electrophysiological properties of the colonised colon were characterised in Ussing experiments. Inflammation scores were evaluated and focal leaks in the colon were assessed by confocal laser-scanning microscopy. HlyA quantity in human colon biopsies was measured by quantitative PCR. Results All three experimental mouse models infected with HlyA-producing E coli -536 showed an increase in focal leak area compared with HDM. This was associated with a decrease in transepithelial electrical resistance and an increase in macromolecule uptake. As a consequence, inflammatory activity index was increased to a higher degree in inflammation-prone mice. Mucosal samples from human colon were E coli HlyA-positive in 19 of 22 patients with ulcerative colitis, 9 of 9 patients with Crohn9s disease and 9 of 12 healthy controls. Moreover, focal leaks were found together with 10-fold increased levels of HlyA in active ulcerative colitis. Conclusions E coli HlyA impairs intestinal barrier function via focal leak induction in the epithelium, thereby intensifying antigen uptake and triggering intestinal inflammation in vulnerable mouse models. Therefore, HlyA-expressing E coli strains should be considered as potential cofactors in the pathogenesis of intestinal inflammation.

It is assumed that esophageal adenocarcinoma is the end result of a stepwise disease process that transitions through gastroesophageal reflux disease (GERD) and Barrett's esophagus. The aim of this study was to examine at what stage known risk factors exert their influence toward the progression to cancer.We enrolled 113 consecutive outpatients without GERD, 188 with GERD, 162 with Barrett's esophagus, and 100 with esophageal adenocarcinoma or high-grade dysplasia (HGD). All patients underwent a standard upper endoscopy and completed a standardized questionnaire about their social history, symptoms, dietary habits, and prescribed medications. We used adjusted logistic regression analysis to assess risk factors between each two consecutive disease stages from the absence of reflux disease to esophageal adenocarcinoma.Overall, male gender, smoking, increased body mass index (BMI), low fruit and vegetable intake, duration of reflux symptoms, and presence of a hiatal hernia were risk factors for cancer/HGD. However, different combinations of risk factors were associated with different disease stages. Hiatal hernia was the only risk factor to be strongly associated with the development of GERD. For GERD patients, male gender, age, an increased BMI, duration of reflux symptoms, and presence of a hiatal hernia were all associated with the development of Barrett's esophagus. Finally, the development of cancer/HGD among patients with Barrett's esophagus was associated with male gender, smoking, decreased fruit and vegetable intake, and a long segment of Barrett's esophagus, but not with age, BMI, or a hiatal hernia.While some risk factors act predominantly on the initial development of reflux disease, others appear to be primarily responsible for the development of more advanced disease stages.

Confocal neurolasermicroscopy (NLM)(Schlosser et al., 2009 (Epub)) is the current front end of the innovative process in neurosurgery for optimizing the operative results. Hence NLM is the continuance of a protracted development. Microscopic imaging technologies in neurosurgery invented 50 years ago revealed new strategies and possibilities for surgeons. These techniques were first used with magnifying lenses in research for introducing blood into the subarachnoid space in the region of circle of Willis in dog (Lougheed and Tom, 1961). It was further used in cerebrovascular diseases (Jacobson et al., 1962) (Chou, 1963), graft interposition (Woringer and Kunlin, 1963) (Lougheed et al., 1971) and aneurysm surgery (Pool and Colton, 1966) (Rand and Jannetta, 1967). From studies assessing radical surgery in the excision of fluorescence labelled tumours (Stummer et al., 2006) (Stummer et al., 1998) the necessity for a high-resolution imaging technique was clearly evident. Intravital fluorescence microscopy was used in animal studies to investigate tumorangiogenesis and microcirculation (Read et al., 2001) (Vajkoczy et al., 2000). In the following section our pilot study using NLM in the neurosurgical operating condition is introduced (Schlosser et al., 2009 (Epub)). We aimed to demonstrate a technique with the potential to be adapted intraoperatively to define cellular and subcellular structures during ongoing neurosurgery. Here we show our results of miniaturized confocal lasermicroscopy in normal brain and brain tumor tissue which we termed NLM. Our pilot study was initiated to test the feasibility of this new technique and to open the door for high resolution imaging during ongoing neurosurgery.

Familial adenomatous polyposis (FAP) and Peutz–Jeghers syndrome (PJS) are hereditary polyposis syndromes with a high risk for benign small-bowel polyps and cancer. The aim of this study was to assess the prevalence of small-bowel polyps beyond the duodenum in patients with FAP and PJS and to examine the clinical value and the optimal interval of capsule endoscopy (CE) for the surveillance of small-bowel polyps in patients with FAP. Between 2002 and 2009, standard gastroscopy, duodenoscopy, and CE were performed on 19 consecutive patients with hereditary polyposis syndromes (FAP n = 15; PJS n = 4). The number, size, and location of polyps detected by CE were assessed. Five FAP patients had repeated CEs in intervals of 2–7 years. In 13 of the 15 (87%) FAP patients, small-bowel polyps were detected by CE ranging from estimated 10 mm in size. Thereof, in four patients, medium-sized (5–10 mm) or large-sized (>10 mm) polyps were seen—all of them located in the proximal jejunum. In three FAP patients with repeated CEs, the latest CE displayed medium- and large-sized polyps in the proximal jejunum, whereas previous CEs had detected only small-sized (

BACKGROUND AND STUDY AIMS: Conventional histology with hematoxylin and eosin (H&E) staining is the accepted standard for diagnosing acute intestinal graft-versus-host disease (GvHD). Confocal endomicroscopy (CEM) is a noninvasive method that allows in vivo histology to be performed during endoscopy. The aim of this study was to evaluate CEM for the diagnosis of acute intestinal GvHD. PATIENTS AND METHODS: This observational pilot study conducted between September 2006 and August 2008 included patients with acute diarrhea after stem cell transplantation, infectious diarrhea, or active ulcerative colitis. CEM (EC-3870CIFK, Pentax, Tokyo, Japan) was performed after intravenous injection of fluorescein 10 % and topical application of acriflavine 0.05 %. RESULTS: A total of 35 patients with acute diarrhea after stem cell transplantation were examined. In 16 patients, CEM and histology showed no evidence of GvHD. In 14/19 patients with histologically confirmed GvHD, the diagnosis could already be established by CEM during ongoing endoscopy. In GvHD grade IV, near complete destruction of the colonic crypts (”flat mucosa”) was visible. Control patients with infectious colitis ( N = 15) or ulcerative colitis ( N = 15) displayed inflammatory changes but no evidence of GvHD. Altogether, sensitivity of CEM was 74 % and specificity was 100 %. CONCLUSIONS: CEM improves rapid diagnosis of acute intestinal GvHD with high accuracy while performing endoscopy. Platelet transfusions and unnecessary biopsy acquisition can be avoided once acute intestinal GvHD has been diagnosed in vivo.

About half of all Crohn's disease (CD) patients undergo surgery at some point, many because of strictures. An alternative possibility is to dilate strictures endoscopically. However, little is known about prognostic factors.Thirty-two patients with primary CD (n=2), radiogenic strictures (n=1), or postoperative strictures (27 because of CD; 2 after resection because of cancer), were planned to undergo colonoscopic dilatation of which 25 patients were dilated (10 men; 15 women; median age 48). Length of stenosis, diameter of stricture, balloon size, smoking status, ulcer in the stricture, passage postdilatation, hemoglobin level, complications, redilatation, and subsequent surgery were recorded. Only patients with at least 6 months follow up were included.Five out of 32 patients had no stenosis, marked inflammation, or fistulas adjacent to the stricture. One patient each had a long stricture (8 cm) or a filiform stenosis ruling out dilatation [technical success, 25/27 (92.6%)]. Among these 25 patients, 39 colonoscopies with 51 dilatations were performed. After a single dilatation, 52% were asymptomatic while 48% needed another intervention, half of them surgery. Bleeding without need for transfusion occurred in 3 out of 39 colonoscopies and one perforation required surgery. Significant prognostic factors were smoking and ulcers in the stricture (P0.05 each). Some ulcers led to intussusception requiring surgery in spite of good dilatation results.Through the endoscope balloon stricture dilatation is a relatively safe and often effective treatment modality in ileocolonic strictures. The presence of ulcers in the stricture have a worse outcome as do smokers.

Proctocolectomy with ileoanal pouch construction is the standard therapy for patients with familial adenomatous polyposis coli (FAP) to prevent the genesis of colorectal carcinomas. In our patient population, we observed the postoperative development of adenomas not only in the pouch but also in the remaining small intestine. The exact incidence of these ileal polyps is still unknown, since the diagnostic possibilities of examining the small intestine are limited. We performed wireless capsule endoscopy (CE) in patients who developed postoperative pouch adenomas (PA) to record the simultaneous occurrence of small bowel adenomas and PA. We operated on 46 patients with FAP (m:f 17:10, age 33 ± 9 years). Thirty-five patients underwent proctocolectomy with ileoanal pouch creation. Pouch endoscopy was performed in regular intervals at 3 months and then annually after proctocolectomy. Capsule endoscopy was additionally carried out in all patients with PA. Ileal PA occurred in 22.8% (n = 8) of the patients with proctocolectomy (n = 35) after a mean of 5 years after surgery. Eight PA patients (all with PA) also had adenomas in the small intestine diagnosed by CE. Since jejunal and ileal adenomas occur in all patients with PA, we recommend regular follow-up examinations, which include pouch endoscopy at 3 months and annually after surgery in the presence of PA after proctocolectomy and pouch creation. On the basis of our observations, we recommend adding CE or double-balloon enteroscopy to the follow-up examination.

Epithelial barrier function is determined by trans- and paracellular permeabilities, the latter of which is mainly influenced by tight junctions (TJs) and apoptotic leaks within the epithelium. The present article aims to present experimental evidence for a functional role of epithelial apoptoses by means of cell culture models as well as in tissues from patients with inflammatory bowel disease. It is shown that epithelial apoptoses are sites of elevated conductance within the intestinal epithelium and that proinflammatory cytokines like TNF-alpha upregulate both the apoptotic rate and single apoptotic conductivity, making cytokine-induced apoptosis functionally far more relevant than is spontaneous apoptosis. In ulcerative colitis and Crohn's disease (CD), but not in collagenous colitis, apoptotic rates are increased to about 5%, in mild-to-moderately inflamed colon specimens, where as the control apoptotic rate is about 2%. Thus, epithelial apoptoses lead to a loss of ions and water into the intestinal lumen, causing leak flux diarrhea and enabling small antigens of

Background: East Asian countries have historically reported low incidences of microscopic colitis and inflammatory bowel disease. (Ahuja & Tandon, J Dig Dis, 2010). However, it is unclear whether these data reflect genetic or environmental factors or are the result of different diagnostic criteria among physicians and pathologists. To address this question, we have designed a study to estimate the prevalence of these conditions among adult patients of East Asian ancestry who live in the U.S., have had colonoscopies in the U.S., and had their biopsies evaluated by a single group of U.S. gastrointestinal pathologists. Methods: From a large national pathology database of subjects who had colonoscopy with ileocolonic biopsies between 1.2008 and 8.2013 in endoscopy centers through the U.S., we extracted all adult patients identified as Korean, Chinese, Japanese, or Vietnamese (collectively referred to as East Asians). Controls were all other adults. We then recorded the histopathologic diagnoses of Crohn's Disease, Ulcerative Colitis, Lymphocytic Colitis, and Collagenous Colitis, and compared their prevalence in East Asian patients to that of controls using unadjusted odds ratios. If a patient had multiple procedures during the study period, only the first chronological procedure was selected. Results: There were 14,209 unique East Asian patients (median age 59 years; 53.2% men) and 1,254,986 unique controls (median age 60 years; 48.9% men). Figure 1 shows the relative prevalence of the four types of colitis in each group. Conclusions: In our series, patients of East Asian descent living in the U.S. were affected by microscopic colitis and inflammatory bowel disease to a much lesser extent that those of other ancestries. The two groups of patients were similar in age and sex distribution, had their endoscopic procedures in similar U.S. settings, and their histopathologic diagnoses were made by a single pathology group whose members adhere to common criteria. Therefore, the remarkably low prevalence of non-infectious colitides detected in this analysis is likely to reflect, at least in part, genetic factors. Determining the relative risk in several generations of Asians in the U.S. might help determine whether environmental factors play a significant role in the development of these conditions.

The standard treatment of IBD involves the application of anti-inflammatory drugs. These drugs become systemically bioavailable and bear a potential of strong adverse effects. Thus, targeting the inflamed areas of the intestine can reduce adverse effects. Polymeric particles have turned out to be a promising tool for the targeted delivery of drugs. We aimed to investigate the distribution of fluoresceine-labelled nanoparticles (NP) and microparticles (MP) in the rectal mucosa of patients with IBD by use of CLE. Fluoresceinaminewas covalently bound to poly(L-lactide-co-glycolide) (PLGA). From this modified polymer, nanoparticles of approximately 300 nm size and microparticles of 3.5 μm size were prepared. After bowel preparation a 30 ml enema containing 10E9 MP or 10E13 NP, resp., has been applied to patients with rectal Crohns disease (CD) or ulcerative colitis (UC). After two hours endoscope based CLE has been performed to visualize nanoparticles in areas of different stages of inflammation. Biopsies have been obtained from IBD patients to evaluate mucosal transport processes in miniaturized Ussing chambers by confocal laser endoscopy. We examined 16 patients with IBD (8 patients with CD, 10 patients with (UC), 7 of whom received NP while 9 received MP. No particles have been visualized on intact mucosal surfaces. In areas of mild to moderate inflammation only minor amounts of particles were visible. In contrast, we observed a marked accumulation of MP rather than NP in ulcerous lesions. Preliminary results from Ussing chamber experiments suggest an influx of particles into the gut mucosa through epithelial lesions. Representative images are shown in fig. 1. This is the first study demonstrating mucosal accumulation of microparticles and nanoparticles in intestinal lesions of patients with IBD. Drug containing particles may have a great potential to target these lesions more specifically in order to maximize therapeutic efficacy and minimize potential side effects. CLE is a useful tool to investigate drug delivery to mucosal surfaces.