Lower Risk of Recurrence with a Higher Induction Dose of Mesalazine and Longer Duration of Treatment in Ulcerative Colitis: Results from the Dutch, Non-Interventional, IMPACT Study

Background & Aims: The dose and duration of mesalazine treatment for ulcerative colitis (UC) is a potentially important determinant of effectiveness, with evidence suggesting that continuing the induction dose for 6-12 months may improve outcomes; however, real-world data are lacking. We assessed mesalazine use in Dutch clinical practice, including how differences in dose and duration affected UC outcomes.Methods: Adults with mild-to-moderate UC who received oral prolonged-release mesalazine de novo or had a dose escalation for an active episode were followed for 12 months in this non-interventional study (ClinicalTrials.gov identifier: NCT02261636). The primary endpoint was time from start of treatment to dose reduction (TDR). Secondary endpoints included recurrence rate, adherence, and work productivity.Results: In total, 151 patients were enrolled, of whom 108 (71.5%) were newly diagnosed with UC. The majority (120; 79.5%) received a dose of >= 4 g/day. Nearly one-third (48; 31.8%) underwent dose reduction, with mean TDR being 8.3 months. Disease extent and endoscopic appearance did not influence duration of induction therapy, while TDR increased with higher baseline UCDAI scores. TDR was longer in patients without (mean 8.8 months) than with (4.1 months) recurrence, although not significantly (p=0.09). Patients on >= 4 g/day had a significantly lower chance of recurrence versus those on 2-6 months vs 3-6 months: 0.19 (95%CI: 0.08-0.46); p= 4 g/day [0.15 (0.06-0.40) vs 0.26 (0.01-11.9) for 2-= 4 g/day) and longer duration of treatment (>6 months) was associated with a lower recurrence risk.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Diagnostic value of triggering receptor expressed on myeloid cells-1 and C-reactive protein for patients with lung infiltrates: an observational study

<p>Abstract</p> <p>Background</p> <p>Differential diagnosis of patients with lung infiltrates remains a challenge. Triggering receptor expressed on myeloid cells (TREM)-1 is a neutrophil and monocyte receptor up-regulated during infection. The aim of this study was to evaluate the diagnostic accuracy of TREM-1 and of C-reactive protein (CRP) from patients with lung infiltrates to discern community acquired lung infections.</p> <p>Methods</p> <p>68 patients admitted to a medical ward with acute respiratory illness were enrolled in the study. Neutrophil and monocyte TREM-1 expression were measured by flow cytometry, sTREM-1 by an enzyme immunoassay and C-reactive protein by nephelometry. Clinical pulmonary infection score was recorded.</p> <p>Results</p> <p>34 patients were diagnosed with bacterial community acquired pneumonia (group A) and 34 with non-bacterial pulmonary disease (group B). Median serum TREM-1 concentration was 102.09 pg/ml in group A and lower than 15.10 pg/ml (p < 0.0001) in group B. Mean±SE neutrophil TREM-1 expression was 4.67 ± 0.53 MFI in group A and 2.64 ± 0.25 MFI (p = 0.001) in group B. Monocyte TREM-1 expression was 4.2 ± 0.42 MFI in group A and 2.64 ± 0.35 MFI (p = 0.007) in group B and mean±SE CRP was 18.03 ± 2 mg/ml in group A and 7.1 ± 1.54 mg/ml (p < 0.001) in group B. A cut-off of 19.53 pg/ml of sTREM-1 with sensitivity 82.6% and specificity 63% to discriminate between infectious and non-infectious pulmonary infiltrates was found. sTREM-1 at admission greater than 180 pg/ml was accompanied with unfavourable outcome.</p> <p>Conclusion</p> <p>TREM-1 myeloid expression and sTREM-1 are reliable markers of bacterial infection among patients with pulmonary infiltrates; sTREM-1 is a predictor of final outcome.</p

Serum sTREM-1 as a surrogate marker of treatment outcome in patients with peptic ulcer disease

Objective Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is elevated in the gastric juice and in cultures of gastric mucosa of patients with peptic ulcer disease (PUD). Its application as a surrogate marker for the treatment of PUD was assessed. Methods From 138 eligible patients, 96 were enrolled; 50 with duodenal ulcer, 29 with gastric ulcer and 17 with chronic gastritis. Patients were endoscoped twice; once before treatment and once after treatment. Biopsy specimens were collected for histopathologic estimation of gastritis. Blood was sampled prior to each endoscopy. Serum was collected and sTREM-1 was measured by an enzyme immunoabsorbent assay (http://www. clinicaltrials.gov identifier NCT00534443). Results At the end of treatment sTREM-1 was either: (a) below the limit of detection (this occurred in 62 patients and it was accompanied by lacks signs of residual disease in 58 patients, 93.5%); or (b) above the limit of detection (this occurred in 17 patients and it was accompanied by residual disease in 14 patients, 82.3%) (p&lt;0.0001). Odds ratio for complete healing of peptic ulcer with sTREM-1 below detection limit was 5.30 (95% CI: 1.89-14.83, p&lt;0.001) compared to serum sTREM-1 above the limit of detection. Conclusions Serum sTREM-1 below detection limit may effectively distinguish patients who successfully completed therapy for PUD from those with residual disease and apply as a surrogate marker. © Springer Science+Business Media, LLC 2011

Monocytes in systematic inflammatory response syndrome: Differences between sepsis and acute pancreatis

Aim: To unravel the differences between systematic inflammatory response syndrome (SIRS) of acute pancreatitis compared to the same syndrome in sepsis. Methods: Twenty-five patients were enrolled, 12 with sepsis and 13 acute pancreatitis. After diagnosis 20 mL blood was sampled. Half were assayed for isolation of monocytes and 10 mL was centrifuged for serum test of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6). Half of monocytes were incubated in the presence of patients&apos; serum and supernatants were collected. The other half was treated for estimation of optical photometry under caspase-3 inhibition. TNFα and IL-6 were estimated by an enzyme immunoassay. Results: Median ± SE of serum IL-6 in septic patients and acute pancreatitis patients was 192.30 ± 35.40 ng/L and 21.00 ± 16.05 ng/L, respectively (P &amp;lt; 0.01). Respective values of caspase-3 were 0.94 ± 0.17 pmol/min 104 cells and 0.34 ± 0.09 pmol/min 104 cells (P &amp;lt; 0.05). IL-6 of monocyte supernatants of patients with sepsis was significantly increased after addition of patients&apos; serum, while that of patients with acute pancreatitis did not show significant difference. Conclusion: The data have shown that monocyte activity is different between acute pancreatitis and sepsis. This phenomenon might be explained as a different pathway to the pro-inflammatory cytokines release or could be a novel anti-inflammatory response in acute pancreatitis. © 2006 The WJG Press. All rights reserved

The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: Relationship with irritable bowel syndrome

Objectives Many studies have linked irritable bowel syndrome (IBS) with small intestinal bacterial overgrowth (SIBO), although they have done so on a qualitative basis using breath tests even though quantitative cultures are the hallmark of diagnosis. The purpose of this study was to underscore the frequency of SIBO in a large number of Greeks necessitating upper gastrointestinal (GI) tract endoscopy by using quantitative microbiological assessment of the duodenal aspirate. Methods Consecutive subjects presenting for upper GI endoscopy were eligible to participate. Quantitative culture of aspirates sampled from the third part of the duodenum during upper GI tract endoscopy was conducted under aerobic conditions. IBS was defined by Rome II criteria. Results Among 320 subjects enrolled, SIBO was diagnosed in 62 (19.4%); 42 of 62 had IBS (67.7%). SIBO was found in 37.5% of IBS sufferers. SIBO was found in 60% of IBS patients with predominant diarrhea compared with 27.3% without diarrhea (P = 0.004). Escherichia coli, Enterococcus spp and Klebsiella pneumoniae were the most common isolates within patients with SIBO. A stepwise logistic regression analysis revealed that IBS, history of type 2 diabetes mellitus and intake of proton pump inhibitors were independently and positively linked with SIBO; gastritis was protective against SIBO. Conclusions Using culture of the small bowel, SIBO by aerobe bacteria is independently linked with IBS. These results reinforce results of clinical trials evidencing a therapeutic role of non-absorbable antibiotics for the management of IBS symptoms. © 2012 Springer Science+Business Media, LLC

Association between genotypes of rs34436714 of NLRP12 and serum tumor necrosis factor-alpha in inflammatory bowel disease: A case-control study

We aimed to investigate the impact of the single nucleotide polymorphisms of rs34436714 of the NOD-like receptor protein 12 gene on the production of tumor necrosis factor-alpha (TNFalpha) in patients with inflammatory bowel disease (IBD)In a matched case-control study 90 patients with IBD, 56 with Crohn disease (CD) and 34 with ulcerative colitis, were genotyped and compared to 98 healthy comparators matched for age and gender. Expression level of TNFalpha, interleukin (IL)-6, IL-12, and soluble triggering receptor expressed on myeloid cells were measured in patients' sera. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated for TNFalpha production.Serum TNFalpha was greater among carriers of GT/TT genotypes than GG genotypes of rs34436714. Stimulated TNFalpha production was also higher in carriers of GT/TT genotypes. The frequency of CD with fistulizing behavior and with CD involving the small intestine was greater among carriers of GT/TT genotypes than of the GG genotype. Distribution of the GG, GT, and TT genotypes of rs34436714 were in Hardy-Weinberg equilibrium in both groups. The genotype distribution was the same in both groups.Carriage of minor frequency alleles of rs34436714 was accompanied by greater circulating levels of TNFalpha and by greater capacity for stimulated TNFalpha production by PBMCs. These alleles had an impact on the phenotype of patients with CD

Changes in adaptive and innate immunity in patients with acute pancreatitis and systemic inflammatory response syndrome

Background: Acute pancreatitis is a form of inflammation with clinical features ranging from pancreatic inflammation to fatal systemic manifestations. The aim of this study was to clarify changes in lymphocyte subsets and alterations in the functioning of natural killer (NK) cells. Patients and Methods: Forty-five patients were enrolled into the study; 35 with acute pancreatitis and systemic inflammatory response syndrome (SIRS) and 10 healthy subjects. Blood was sampled early from all patients. Blood immune cells were studied on days 1 and 4 by flow cytometry. Tumor necrosis factor-α (TNFα) and interleukin (IL)-6 were estimated from supernatants of NK cells before/after stimulation with lipopolysaccharide (LPS). Results: Apoptosis in patients was significantly different on days 1 and 4 compared with controls. Apoptosis of CD4(+) lymphocytes was significantly correlated with the days to resolution of SIRS (r = +0.586, p = 0.022). Significant differences were observed in TNFα and IL-6 on day 1 with/without LPS stimulation between patients and healthy individuals. Significantly increased levels of TNFα and IL-6 were found after LPS stimulation compared with unstimulated supernatants in day 1. Conclusion: NK cells altered their secretory status when stimulated with LPS. This finding could be explained by the cellular reprogramming of NK cells in the field of acute pancreatitis and SIRS. Copyright © 2011 S. Karger AG, Basel and IAP

Immunomodulatory intervention in sepsis by multidrug-resistant Pseudomonas aeruginosa with thalidomide: an experimental study

Background: Thalidomide is an inhibitor of tumour necrosis factor-alpha (TNF alpha) that has been proven effective for the treatment of experimental sepsis by Escherichia coli. It was tested whether it might behave as an effective immunomodulator in experimental sepsis by multidrug-resistant (MDR) Pseudomonas aeruginosa. Methods: Sepsis was induced by the intraperitoneal injection of 1 x 10(8) cfu/kg inoculum of the test isolate in a total of 109 Wistar rats divided in three groups as follows: group A controls; group B administered seed oil 30 minutes before bacterial challenge; and group C administered 50 mg/ kg of thalidomide diluted in seed oil 30 minutes before bacterial challenge. Blood was sampled for estimation of endotoxins (LPS), TNF alpha, interferon-gamma (IFN gamma), nitric oxide ( NO) and malondialdehyde (MDA). LPS was measured by the QCL-1000 LAL assay, TNF alpha and IFN gamma by ELISA, NO by a colorimetric assay and MDA by the thiobarbiturate assay. Results: Mean ( +/- SE) survival of groups A, B and C were 18.60 +/- 1.84, 12.60 +/- 0.60 and 30.50 +/- 6.62 hours ( p of comparisons A to C equal to 0.043 and B to C equal to 0.002). Decreased TNF alpha and NO levels were found in sera of animals of group C compared to group A. Plasma levels of LPS, MDA and IFN gamma did not differ between groups. Conclusion: Intake of thalidomide considerably prolonged survival in experimental sepsis by MDR P. aeruginosa an effect probably attributed to decrease of serum TNF alpha

Evidence for the role of gastric mucosa at the secretion of soluble triggering receptor expressed on myeloid cells (strem-1) in peptic ulcer disease

Aim: To investigate the role of gastric mucosa at the secretion of sTREM-1 in peptic ulcer. Methods: Seventy two patients were enrolled; 35 with duodenal, 21 with gastric ulcer and 16 with chronic gastritis. Patients were endoscoped and gastric juice was aspirated. Patients with duodenal and gastric ulcer underwent a second endoscopy post-treatment. Biopsies were incubated in the absence/presence of endotoxins or gastric juice. Supernatants were collected and sTREM-1 and TNFα were measured by enzyme immunoabsorbent assays. Scoring of gastritis was performed before and after treatment according to updated Sydney score. Results: Patients with duodenal and gastric ulcer and those with chronic gastritis had similar scores of gastritis. sTREM-1 was higher in supernatants of tissue samples of H pylori-positive than of H pylori-negative patients with gastric ulcer. Median (± SE) sTREM-1 was found increased in supernatants of patients with gastric ulcer before treatment (203.21 ± 88.91 pg/1000 cells) compared to supernatants either from the same patients post-treatment (8.23 ± 5.79 pg/1000 cells) or from patients with chronic gastritis (6.21 ± 0.71 pg/1000 cells) (P &lt; 0.001 and &lt; 0.001, respectively). Similar differences for sTREM-1 were recorded among LPS-stimulated tissue samples of patients (P = 0.001). Similar differences were not found for TNFα. Positive correlations were found between sTREM-1 of supernatants from patients with both duodenal and gastric ulcer before treatment and the degree of infiltration of neutrophils and monocytes. Conclusion: sTREM-1 secreted by the gastric mucosa is an independent mechanism connected to the pathogenesis of peptic ulcer. sTREM-1 was released at the presence of H pylori from the inflamed gastric mucosa in the field of gastric ulcer. © 2007 WJG. All rights reserved

n-6 polyunsaturated fatty acids enhance the activities of ceftazidime and amikacin in experimental sepsis caused by multidrug-resistant Pseudomonas aeruginosa

Recent in vitro and ex vivo studies disclosed an enhancement of the activity of antimicrobials on multidrug-resistant Pseudomonas aeruginosa by n-6 polyumsaturated fatty acids (PUFAS); therefore their effect was evaluated in experimental sepsis in 60 rabbits. Solutions of gamma-linolenic acid (GLA) and arachidonic acid (AA) were administered intravenously with ceftazidime and amikacin in rabbits with sepsis caused by one multidrug-resistant isolate. Therapy was started after bacterial challenge in five groups comprising 12 animals in each group: A, normal saline; B, antimicrobials; C, 99% ethanol and antimicrobials; D, GLA and antimicrobials; and E, AA and antimicrobials. Blood was sampled for the estimation of levels of endotoxins in serum (lipopolysaccharide), leukocytes, tumor necrosis factor alpha (TNF-α) and antimicrobials. Animals were sacrificed 210 min after bacterial challenge for tissue cultures. All animals had considerable endotoxemia and evolved leukopenia. The number of viable cells in blood, lung, and mesenteric lymph nodes was significantly reduced in groups D and E compared to that in other groups. Levels of antimicrobials in serum were inadequate to achieve bacterial killing due to the level of resistance, n-6 PUFAs did not influence TNF-α. It is concluded that intravenous coadministration of n-6 PUFAs and antimicrobials enhanced antimicrobial bacterial killing in experimental sepsis caused by multidrug-resistant P. aeruginosa