Effects of the peripherally acting µ-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity: study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial.

BACKGROUND: Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting µ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. METHODS: PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer's lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. DISCUSSION: This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18.

Altered Structural Expression and Enzymatic Activity Parameters in Quiescent Ulcerative Colitis: Are These Potential Normalization Criteria?

Mucosal healing determined by endoscopy is currently the remission standard for ulcerative colitis (UC). However, new criteria for remission are emerging, such as histologic normalization, which appears to correlate better to the risk of relapse. Here, we study mucosal healing on a molecular and functional level in quiescent UC. We obtained endoscopic biopsies from 33 quiescent UC patients and from 17 controls. Histology was assessed using Geboes score. Protein and mRNA levels were evaluated for the tight junction proteins claudin-2, claudin-4, occludin, and tricellulin, as well as Cl-/HCO3- exchanger DRA, and cyclo-oxygenase enzymes (COX-1, COX-2). The mucosal activity of COX-1 and COX-2 enzymes was assessed in modified Ussing chambers, measuring electrogenic ion transport (short-circuit current, SCC). Chronic inflammation was present in most UC patients. The protein level of claudin-4 was reduced, while mRNA-levels of claudin-2 and claudin-4 were upregulated in UC patients. Surprisingly, the mRNA level of COX-1 was downregulated, but was unaltered for COX-2. Basal ion transport was not affected, while COX-2 inhibition induced a two-fold larger decrease in SCC in UC patients. Despite being in clinical and endoscopic remission, quiescent UC patients demonstrated abnormal mucosal barrier properties at the molecular and functional level. Further exploration of mucosal molecular signature for revision of current remission standards should be considered.

Characterisation of the fibroinflammatory process involved in progression from acute to chronic pancreatitis: study protocol for a multicentre, prospective cohort study.

INTRODUCTION: Chronic pancreatitis (CP) is thought to present the end stage of a continuous disease process evolving from acute pancreatitis (AP), over recurrent AP, to early and end-stage CP. Due to the irreversible nature of CP, early detection and prevention is key. Prospective assessment based on advanced imaging modalities as well as biochemical markers of inflammation, fibrosis and oxidative stress may provide a better understanding of the underlying pathological processes and help identify novel biomarkers of disease with the ultimate goal of early diagnosis, intervention and prevention of disease progression. This paper describes the protocol of a prospective multicentre cohort study investigating the fibroinflammatory process involved in progression from acute to CP using state-of-the-art diagnostic imaging modalities and circulating biomarkers of inflammation, fibrosis and oxidative stress. METHODS AND ANALYSIS: Adult control subjects and patients at different stages of CP according to the M-ANNHEIM system will be recruited from outpatient clinics at the participating sites and form three cohorts: controls (n=40), suspected CP (n=60) and definitive CP (n=60). Included patients will be followed prospectively for 15 years with advanced MRI and contrast-enhanced endoscopic ultrasound with elastography, assessment of endocrine and exocrine pancreatic function, biochemical and nutritional assessment, and evaluation of pain processing using quantitative sensory testing. Blood samples for a biobank will be obtained. The purpose of the biobank is to allow analyses of potential circulating biomarkers of disease progression, including markers of inflammation, fibrosis and oxidative stress. ETHICS AND DISSEMINATION: Permissions from the Regional Science Ethics committee and the Regional Data Protection Agency have been obtained. We will submit the results of the study for publication in peer-reviewed journals regardless of whether the results are positive, negative or inconclusive.

Possible predisposition for colorectal carcinogenesis due to altered gene expressions in normal appearing mucosa from patients with colorectal neoplasia.

BACKGROUND: Investigations of colorectal carcinogenesis have mainly focused on examining neoplastic tissue. With our aim of identifying potentially cancer-predisposing molecular compositions, we chose a different approach by examining endoscopically normal appearing colonic mucosa of patients with and without colorectal neoplasia (CRN). Directed by this focus, we selected 18 genes that were previously found with altered expression in colorectal cancer affected mucosa. METHODS: Biopsies of colonic mucosa were sampled from 27 patients referred for colonoscopy on suspicion of colorectal disease. Of these, 14 patients had present or previous CRN and the remaining 13 patients served as controls. Using qPCR and Western blot technique, we investigated mRNA and protein expressions. Expressions were investigated for selected kinases in the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK), the phosphoinositide 3-kinase/Akt, and the Wnt/ß-catenin pathways as well as for selected phosphatases and several entities associated with prostaglandin E2 (PGE2) signaling. Colonic mucosal contents of PGE2 and PGE2 metabolites were determined by use of ELISA. RESULTS: We found up-regulation of ERK1, ERK2, Akt1, Akt2, PLA2G4A, prostanoid receptor EP3 and phosphatase scaffold subunit PPP2R1B mRNA expression in normal appearing colonic mucosa of CRN patients compared to controls. CONCLUSION: Present study supports that even normal appearing mucosa of CRN patients differs from that of non-CRN patients at a molecular level. Especially expression of ERK1 mRNA was increased (p = 0.007) in CRN group. ERK1 may therefore be considered a potential candidate gene as predictive biomarker for developing CRN. Further validation in larger cohorts are required to determine such predictive use in translational medicine and clinics.

Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate-to-Severe Ulcerative Colitis.

BACKGROUND & AIMS: The α4ß7 integrin is a validated target in inflammatory bowel disease. This randomized, phase 2b, placebo-controlled, double-blind study evaluated the efficacy and safety of the anti-α4ß7 antibody abrilumab in patients with moderate-to-severe ulcerative colitis despite treatment with conventional therapies. METHODS: Patients (total Mayo Score 6-12, recto-sigmoidoscopy score ≥2) with inadequate response or intolerance to conventional therapies were randomized to receive subcutaneous abrilumab (7, 21, or 70 mg) on day 1, weeks 2 and 4, and every 4 weeks; abrilumab 210 mg on day 1; or placebo. The primary end point was remission (total Mayo Score ≤2 points, no individual sub-score >1 point) for the 2 highest dosages at week 8. Key secondary end points were response and mucosal healing (centrally read) at week 8. RESULTS: For 354 patients who received ≥1 dose of investigational product (placebo, n = 116; 7 mg, n = 21; 21 mg, n = 40; 70 mg, n = 98; 210 mg, n = 79), non-adjusted remission rates at week 8 were 4.3%, 13.3%, and 12.7% for the placebo and abrilumab 70-mg and 210-mg groups, respectively (P < .05 for 70 and 210 mg vs placebo); odds of achieving remission were significantly greater with abrilumab 70 mg (odds ratio 3.35; 90% CI 1.41-7.95; P = .021) and 210 mg (odds ratio 3.33; 90% confidence interval 1.34-8.26; P = .030) than with placebo. Response and mucosal healing rates with these dosages also were significantly greater than with placebo. Higher baseline α4ß7 levels on naïve CD4+ T cells were a prognostic indicator for overall outcome, but not a predictive biomarker of abrilumab response. There were no cases of progressive multifocal leukoencephalopathy or deaths. CONCLUSIONS: Abrilumab treatment for 8 weeks induced remission, clinical response, and mucosal healing in patients with moderate-to-severe ulcerative colitis. ClinicalTrials.gov, number NCT01694485.

Targeted Analysis of Serum Proteins Encoded at Known Inflammatory Bowel Disease Risk Loci.

Background: Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential. Methods: Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn's disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping. Results: By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity. Conclusions: Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD.

MicroRNA-31 Targets Thymic Stromal Lymphopoietin in Mucosal Infiltrated CD4+ T Cells: A Role in Achieving Mucosal Healing in Ulcerative Colitis?

Background: Ulcerative colitis (UC) is characterized by disruption of the mucosal intestinal barrier. MicroRNAs, single-stranded noncoding RNAs of approximately 22nt, are dysregulated in UC. MicroRNAs targeting thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation and polarization, may be involved in regulating UC inflammation and mucosal healing. Methods: Biopsy samples from non-UC (n = 38), inactive UC (n = 18), and active UC (n = 23) patients were analyzed for mRNA (real-time quantitative polymerase chain reaction) or TSLP protein expression (enzyme-linked immunosorbent assay). Flow cytometry was used to isolate CD4+ T cells from biopsies. The functional mechanism was shown using luciferase assays and antago-miR transfections. The TSLP/miR-31 association was analyzed on 196 subjects from a previous clinical trial that tested the anti-IL-13 drug tralokinumab, whereas mucosal healing effects were studied on a subset of patients (n = 13) from this trial. Results: We found that TSLP is reduced at both mRNA and protein levels in inflamed UC patients when compared with healthy subjects, in both whole biopsies and biopsy-isolated CD4+ CD25+ T cells. The expression of miR-31, predicted to target TSLP, inversely co-related to the levels of TSLP mRNA in T cells. Blocking miR-31 in vitro in T cells increased both TSLP mRNA expression and protein secretion. Luciferase assays showed that miR-31 directly targeted TSLP mRNA, suggesting a direct mechanistic link. We also found that TSLP is increased in patients who achieve mucosal healing, comparing biopsies before and after treatment from the tralokinumab trial. Conclusions: Our data suggest a role for TSLP in promoting mucosal healing and regulating inflammation in UC, whereas miR-31 can directly block this effect.

Combined activity of COX-1 and COX-2 is increased in non-neoplastic colonic mucosa from colorectal neoplasia patients.

BACKGROUND: Cyclooxygenase (COX) activity is increased in endoscopic normal colonic mucosa from patients with colorectal neoplasia (CRN). COX-2 is thought to be the predominant COX isozyme involved in neoplasia. Meanwhile, relative contributions of COX-1 and COX-2 isoforms are unknown. Knowledge about their mutual activity in colonic mucosa is important for diagnostics and targeted therapy for CRN. The aim of this study was to assess the relative function, expression and localization of COX-1 and COX-2 enzymes in colonic non-neoplastic human mucosa and thereby to potentially reveal a mucosal disease predisposition for better treatment. METHODS: Biopsies were pinched from normal appearing colonic mucosa in patients undergoing endoscopy. Ussing chamber technique was applied for an indirect assessment of epithelial activity, RT-qPCR for expression and immunohistochemistry for localization of COX-1 and COX-2 enzymes in patients without (ctrls) and with a history of CRN (CRN-pts). RESULTS: Combined COX-1 and COX-2 activity was higher in CRN-pts, p = 0.036. COX-2 was primarily localized in absorptive cells, while COX-1 appeared to be restricted to nonenteroendocrine tuft cells of the colonic epithelium. CONCLUSIONS: In biopsies from endoscopic normal appearing colonic mucosa, combined activity of COX-1 and COX-2 enzymes is increased in CRN-pts compared with ctrls. This indicates that COX-1 and COX-2 together contribute to an increased proliferation process. Of note, in colonic epithelial cell lining, the COX-1 enzyme seems localized in tuft cells.

Selective matrix metalloproteinase inhibition increases breaking strength and reduces anastomotic leakage in experimentally obstructed colon.

PURPOSE: Colonic obstruction causes loss of collagen and impairment of anastomotic integrity by matrix metalloproteinases (MMPs). Unexpectedly, pharmacological MMP inhibition increased anastomotic leakage (AL) in obstructed colon possibly due to the non-selective nature of these compounds and the experimental model applied. We therefore studied the effects of selective MMP inhibition on the healing of anastomoses in colon obstructed by a novel laparoscopic technique. METHODS: Left colon was obstructed in 38 male Sprague-Dawley rats (226-284 g). After 12 h, stenoses were resected and end-to-end anastomoses constructed. Baseline breaking strength was determined in 6 animals on day 0. The remaining 32 rats were randomized to daily treatment with the selective MMP-8, MMP-9, and MMP-12 inhibitor AZD3342 (n = 16) or vehicle (n = 16). On day 3, anastomoses were evaluated for AL and breaking strength. Isolated anastomotic wound tissue was analyzed on total collagen and pepsin-insoluble and pepsin-soluble collagen by hydroxyproline. The soluble collagens were further differentiated into native, measured by Sircol, and fragmented forms. RESULTS: Baseline breaking strength was maintained with AZD3342 but decreased by 25% (P = 0.023) in the vehicle group. The anastomotic breaking strength of AZD3342-treated rats was 44% higher (P = 0.008) than the vehicle-treated rats. Furthermore, the AL rate was reduced (P = 0.037) with AZD3342 compared with vehicle treatment. AZD3342 treatment influenced neither the total or insoluble collagen concentrations nor the degree of fragmentation of the soluble collagen triple helices. CONCLUSION: Selective MMP inhibition increased anastomotic breaking strength and reduced AL after resection of colonic obstruction.

Acetylcholine-related proteins in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia.

The pathogenesis of colorectal neoplasia (CRN) has been associated with altered non-neuronal acetylcholine (ACh) metabolism. The aim of this study was to characterize expression, function, and cellular location of ACh-related proteins in biopsies obtained from endoscopic normal-appearing sigmoid colon in patients with and without CRN. Messenger-RNA (mRNA) levels of 17 ACh-related proteins were quantified by rt-qPCR. Functional responses to ACh, measured as electrogenic transepithelial short circuit current (SCC), were recorded using the Ussing chamber technique. Finally, cellular localization of choline transporter-like proteins (CTLs) and butyryl-cholinesterase enzyme (BChE) was determined by immunohistochemistry. mRNA expression of CTL1 and CTL4 was increased in patients with CRN (P = 0.002 and P = 0.04, respectively). In functional experiments, baseline SCC was increased in CRN patients. ACh induced rapid biphasic changes in SCC. An initial decreasing phase was observed in the minority of CRN patients versus the majority of controls (25% vs 69%, respectively, P = 0.031). For the second increasing phase of SCC, data indicated ACh-activation of two receptors. For both parts of the biphasic response, the half maximal effective concentration and maximal responses showed no difference between patient groups. Immunohistochemistry demonstrated CTL1, 3 and 4 and BChE to be localized to colonic crypt cells. We conclude that CRN is associated with increased expression of CTL1 and CTL4, augmented basal prostaglandin-dependent secretion, and altered functional channel response to ACh in human endoscopic normal-appearing colonic mucosa. The immunohistochemical findings support CTL1, CTL3, CTL4, and BChE to be involved in non-neuronal mucosal ACh metabolism.

Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia.

BACKGROUND: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. METHODS: Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. RESULTS: In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients. CONCLUSION: In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer.

Effect of oral administration of AZD8309, a CXCR2 antagonist, on the severity of experimental pancreatitis.

INTRODUCTION: Acute pancreatitis is a common gastrointestinal disorder burdened with a high mortality. Two pathophysiological events during experimental pancreatitis are thought to determine the clinical course: premature digestive protease activation and tissue infiltration by inflammatory cells. We have investigated the effect of AZD8309, a potent and orally bioavailable antagonist of the chemokine receptor CXCR2, which has been proposed to regulate the transmigration of neutrophils. METHODS: Male C57BL6 mice (25-30 g) received gavage feeding of AZD8309 (50 mg/kg/BW) or mannitol (controls) twice daily starting 3 h prior to pancreatitis induction. Mild pancreatitis was induced by i.p. caerulein administration (50 µg/kg BW), severe pancreatitis by intraductal taurocholate (2%). Pancreas, lung, and serum was harvested up to 48 h after pancreatitis induction and used for histopathology, amylase, lipase, cathepsin B, trypsin, and elastase activity measurements, myeloperoxidase (MPO) content and cytokine concentrations. RESULTS: Oral administration of AZD8309 significantly reduced MPO in the pancreas and lungs (8 h & 24 h) and reduced intrapancreatic trypsin and elastase activity (8 h) in caerulein-pancreatitis. In taurocholate-pancreatitis AZD8309 reduced cathepsin B activity and MPO. Serum cytokine levels were reduced by AZD8309 as well as histopathological damage. CONCLUSION: The CXCR2 antagonist AZD8309 reduced the transmigration of neutrophils as well as intrapancreatic protease activation in experimental pancreatitis. This effect was sufficient to reduce the overall severity of the disease. CXCR2 may therefore be a viable therapeutic target and AZD8309 a suitable agent for the treatment of acute pancreatitis.

Effect of body weight on fixed dose of diclofenac for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis.

OBJECTIVE: The aim of this study was to assess the influence of patient body weight on the clinical effect of 100 mg diclofenac administered as a single dose for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). MATERIALS AND METHODS: All patients subjected to endoscopic retrograde cholangiopancreatography (ERCP) from 2009 to 2014 were evaluated for inclusion. In total, 772 patients were included of whom 378 (49%) received diclofenac prophylaxis. RESULTS: In the diclofenac prophylaxis group, body weight was higher in patients with PEP (mean ± SD: 82 ± 18 kg) than in patients without PEP (74 ± 18 kg) (p = 0.029). In patients not receiving prophylaxis, body weight was not associated with the occurrence of PEP (mean ± SD: 77 ± 18 vs 75 ± 18 kg, respectively, p = 0.450). In an adjusted analysis, higher patient body weight was inversely associated with the clinical effect of 100 mg diclofenac for the prophylaxis of PEP. CONCLUSIONS: High patient body weight was associated with a reduced effect of 100 mg diclofenac for prophylaxis of PEP.

Short-term oxycodone treatment does not affect electrogenic ion transport in isolated mucosa from the human rectosigmoid colon.

OBJECTIVE: Opioid therapy is associated with altered secretion and motility of the gut. The relative contribution of decreased secretion to the development of opioid-induced constipation remains unknown. MATERIALS AND METHODS: Twenty-five healthy males were treated with oxycodone for 5 d in a placebo-controlled, randomised cross-over design. Gastrointestinal adverse effects were assessed with validated questionnaires (bowel function index and gastrointestinal symptom rating scale). Rectosigmoid mucosal biopsies were taken at baseline and on day 5 during both treatments and mounted in Ussing chambers. Electrogenic ion transport parameters (short circuit current (SCC) and slope conductance) were measured after addition of secretagogues (prostaglandin E2 (PGE2) (6 µm), theophylline (400 µm)), and an inhibitor (ouabain (200 µm)). Additionally, morphine (50 µm) was added to investigate the direct opioid effect on colonic mucosa. RESULTS: Questionnaires showed pronounced bowel symptoms, including constipation during oxycodone treatment (eight-fold increase in bowel function index score from day 1 to day 5 (p < 0.001) while no significant change occurred during placebo treatment (p = 0.47). Basal SCC and slope conductance did not differ between treatments (all p > 0.05) and application with PGE2, theophylline, and ouabain yielded comparable results on all examinations (all p > 0.05). Morphine application consistently did not evoke a change in ion transport. CONCLUSION: Compared to placebo, epithelial electrogenic ion transport is not altered in mucosal biopsies from the rectosigmoid colon following 5-d oxycodone treatment. The secretory mechanisms in isolated mucosa appear to play a negligible role in the development of opioid-induced constipation.

[Acute pancreatitis after ingestion of ibuprofen in a 16-year-old boy]. / Akut pankreatitis hos en 16-årig dreng efter indtag af ibuprofen.

This is a case report of a 16-year-old boy with possible drug-induced pancreatitis (DIP) caused by ibuprofen. The patient had a history of psychiatric, but no somatic, disease, and he was admitted with a clinical presentation consistent with acute pancreatitis after a bolus ingestion of 10 g of ibuprofen in a suicidal attempt. No evidence of other causality for acute pancreatitis was identified. The patient was treated with a standard pancreatitis treatment regime and was discharged against medical advice after four days. The case represents a possible causality between ibuprofen and DIP.

Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study.

OBJECTIVE: Interleukin-13 (IL-13) has been implicated as a key driver of UC. This trial evaluates the efficacy and safety of tralokinumab, an IL-13-neutralising antibody, as add-on therapy in adults with moderate-to-severe UC despite standard treatments. DESIGN: Non-hospitalised adults with UC (total Mayo score ≥6) were randomised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks. The primary end point was the rate of clinical response at week 8. Secondary efficacy end points included clinical remission and mucosal healing rates at week 8 and changes in total Mayo score, total modified Riley score, partial Mayo score and disease activity markers. RESULTS: Clinical response rate was 38% (21/56) for tralokinumab vs. 33% (18/55) for placebo (p=0.406). Clinical remission rate was 18% (10/56) vs. 6% (3/55) (p=0.033) and mucosal healing rate was 32% (18/56) vs. 20% (11/55) (p=0.104) for tralokinumab vs placebo. Changes to week 8 in total Mayo score and total modified Riley score were similar for tralokinumab and placebo (least-squares mean difference between groups: -0.49 (p=0.394) and 0.25 (p=0.449), respectively). Partial Mayo score at week 4 was lower with tralokinumab than placebo (least-squares mean difference between groups: -0.90 (p=0.041)). No consistent patterns were observed for disease activity markers. Tralokinumab had an acceptable safety profile. CONCLUSIONS: Add-on therapy with tralokinumab did not significantly improve clinical response. However, the higher clinical remission rate with tralokinumab than placebo suggests that tralokinumab may benefit some patients with UC. Tralokinumab was well tolerated. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01482884.

Diclofenac is associated with a reduced incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis: results from a Danish cohort study.

OBJECTIVE: The aim of this study was to assess the clinical effect of diclofenac administered as a single dose for the prevention of postprocedure pancreatitis in a consecutive series of patients who had undergone endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Patients with a native papilla Vateri subjected to ERCP during 2010 (control group, n = 218) and 2012 (diclofenac group, n = 182) were included. Patients with a history of chronic pancreatitis or recent acute pancreatitis were excluded. From January 2012, a rectal suppository containing 100 mg of diclofenac was administered immediately after endoscopy in all patients. The primary outcome of post-ERCP pancreatitis was assessed retrospectively by reviewing the patients' charts. RESULTS: The overall incidence of post-ERCP pancreatitis was 32 (14.7%) of the 218 patients in the control group and 9 (4.9%) of the 182 patients in the diclofenac group (P = 0.002). Moderate to severe pancreatitis occurred in 22 (10.1%) of the 218 patients in the control group versus 8 (4.4%) of the 182 patients in the diclofenac group (P = 0.036). CONCLUSIONS: This controlled cohort study suggests that the implementation of a single dose of 100 mg of diclofenac rectally administered significantly reduces the incidence of post-ERCP pancreatitis in an unselected material of patients with native papilla.

Duodenal epithelial transport in functional dyspepsia: Role of serotonin.

AIM: To investigate functional duodenal abnormalities in functional dyspepsia (FD) and the role of serotonin (5-hydroxytryptamine, 5-HT) in mucosal ion transport and signalling. METHODS: Duodenal mucosal biopsies were obtained from 15 patients with FD and 18 healthy controls. Immunohistochemistry was used to study the number of 5-HT-containing cells and real-time polymerase chain reaction for expression of 5-HT receptors 1A, 1B, 2A, 2B, 3A, 3B, 3C, 3D, 3E, 4 and 7, as well as expression of the serotonin re-uptake transporter (SERT) gene SLC6A4 and tryptophan hydroxylase 1 (TPH1). Biopsies were mounted in Ussing chambers for evaluation of basal and 5-HT-stimulated short-circuit current (SCC). RESULTS: Conductance was lower in FD [42.4 ± 4.7 mS/cm(2) (n = 15) vs 62.5 ± 4.5 mS/cm(2) (n = 18), P = 0.005]. 5-HT induced a dose dependent rise in SCC in both FD (n = 8) and controls (n = 9), the rise was lower in FD (P < 0.001). Mean number of 5-HT stained cells per high power field was the same [34.4 ± 8.4 in FD (n = 15) and 30.4 ± 3.7 in controls (n = 18), P = 0.647]. The following genes were highly expressed: 5-HT receptor HTR3E, HTR4, HTR7, SERT gene (SLC6A4) and TPH1. Differences in expression levels were observed for HTR3E (higher expression in FD, P = 0.008), HTR7 (lower expression in FD, P = 0.027), SLC6A4 (higher expression in FD, P = 0.033) and TPH1 (lower expression in FD, P = 0.031). CONCLUSION: Duodenal ion transport in response to exogenous 5-HT is abnormal in FD patients and associated with high expression of the HTR3E receptor and the serotonin transporter.

[Monitorering and complications by conservative treatment of severe acute pancreatitis]. / Monitorering og komplikationer ved konservativ behandling af svær, akut pankreatitis.

Severe acute pancreatitis (SAP) is associated with a high morbidity and a mortality risk of up to 20%. Although much progress has occurred during the latest couple of years, there are still some major controversies on important issues such as monitoring, fluid therapy, antibiotic treatment, and nutrition. In this article we describe the underlying, pathophysiologic mechanisms responsible for organ failure in SAP, and the rationale for monitoring and conservative treatment of SAP.