In this study, recombinant human interleukin-6 (rIL-6) was tested for its ability to alter the resistance of mice to experimental Listeria monocytogenes infection. Single bolus or repeated injections of rIL-6 by itself did not increase antilisteria resistance. When rIL-6 was injected in combination with suboptimal concentrations of rIL-1 alpha and tumor necrosis factor alpha (rTNF-alpha), it did not augment their abilities to mediate protection in the spleen and had a marginal effect on the level of protection in the liver. Injection of rIL-6 together with protective doses of rIL-1 alpha did not diminish the protection stimulated by the latter. Unlike rIL-1 alpha and recombinant tumor necrosis factor alpha, rIL-6 appears to have little ability to elevate antibacterial resistance.
Mice that received an anti-interleukin-10 (anti-IL-10) neutralizing monoclonal antibody (MAb) (SXC-1) prior to infection with Listeria monocytogenes initially demonstrated resistance to the infection, as indicated by reduced recovery of L. monocytogenes from their spleens and livers during the first 5 days after challenge. Anti-IL-10 MAb-treated mice then demonstrated reduced resistance during the later stage of infection, as indicated by persistent infection with L. monocytogenes in their livers 11 days after challenge. Aspartate aminotransferase (AST) levels (a measure of liver damage) in the sera of control mice increased between 1 and 5 days after challenge, while anti-IL-10 MAb-treated mice maintained lower AST levels. At 7 days after challenge, AST levels in the sera of control mice decreased as the numbers of organisms declined. In contrast, AST levels increased as the infections persisted in anti-IL-10 MAb-treated mice. The AST levels in serum reflected liver histopathology as anti-IL-10 MAb-treated mice exhibited fewer granulomatous lesions and less necrosis of liver tissue than the control mice during the first 5 days after challenge. Anti-IL-10 MAb treatment altered the expression of inflammatory cytokine mRNAs during L. monocytogenes infection. Control MAb-treated mice exhibited increased expression of tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor mRNA in their lives during L. monocytogenes infection, but this increase did not occur in anti-IL-10 MAb-treated mice. Gamma interferon mRNA expression in the livers of the control MAb-treated mice was increased between 1 and 5 days after L. monocytogenes challenge and then decreased at 7 days after challenge. In contrast, gamma interferon mRNA expression in the livers of anti-IL-10 MAb-treated mice was not decreased until 7 days after challenge. These results indicate that endogenous IL-10 has both beneficial and detrimental effects on the host response to L. monocytogenes infection in mice.
ABSTRACT The influx and death of polymorphonuclear leukocytes within the infected lung are hallmarks of bovine pasteurellosis. Recent reports have shown that the Pasteurella haemolytica leukotoxin (LKT) and other RTX toxins bind β 2 -integrins on target cells. In this study we demonstrate that exposure of bovine neutrophils to recombinant bovine interleukin-1β upregulates β 2 -integrins (CD11a/CD18), which in turn enhance the binding and amplify the biological effects of partially purified LKT on these cells. LKT binding and cytotoxicity were inhibited by addition of an anti-integrin antibody (CD11a/CD18). These findings help to clarify the early events that occur in bovine pasteurellosis and support the hypothesis that inflammatory mediators might increase the severity of pasteurellosis by causing upregulation of β 2 -integrins that serve as an LKT receptor on bovine neutrophils.
The mechanisms involved in mediating bacterial endotoxin lipopolysaccharide (LPS)‐induced injury in the colon of neonatal rat pups aged 10–12 days was examined. Administration of LPS (3 mg kg −1 , i.p.) caused a time‐related increase in the plasma concentration of rat mast cell protease‐II (RMCP‐II) which was attenuated dose‐dependently, by the non‐selective mast cell stabilizer doxantrazole (0.05–5 mg kg −1 , i.p.). The selective connective tissue mast cell stabilizer ketotifen (5–25 mg kg −1 , i.p.) was without effect at the lower dose and had only a limited inhibitory effect at the higher dose. In addition, doxantrazole (5 mg kg −1 , i.p.) inhibited mast cell degranulation in response to LPS in sections of neonatal rat colon, but ketotifen (5 mg kg −1 , i.p.) was without effect. The increase in plasma RMCP‐II concentration in response to LPS treatment preceded increases in tissue myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) activity and tissue lipid peroxidation. These events were all attenuated by pretreatment with doxantrazole (5 mg kg −1 , i.p.), antineutrophil serum (100 μl kg −1 , i.p.), dexamethasone (2 mg kg −1 , i.p.) and the selective iNOS inhibitor, aminoguanidine (25 mg kg −1 , i.p.). In addition, lipid peroxidation was inhibited by pre‐administration of the antioxidant enzymes superoxide dismutase (2000 u kg −1 , i.p.) and catalase (2000 u kg −1 , i.p.), the xanthine oxidase inhibitor allopurinol (100 mg kg −1 , i.p.) and the peroxyl scavenger deferoxamine (10 mg kg −1 , i.p.), suggesting the involvement of reactive oxygen metabolites in the colonic injury. These findings suggest that the sequence of events resulting in colonic damage in the neonatal rat following administration of LPS include mast cell degranulation, neutrophil infiltration, elevation in iNOS activity and subsequent lipid peroxidation. British Journal of Pharmacology (1998) 123 , 31–38; doi: 10.1038/sj.bjp.0701576
Abstract Background Studies examining the impact of training modules on characterization of diminutive colonic polyps (DCP) show varying results. Aim We aimed to assess the impact of a novel web-based training module on the accuracy of in vivo characterization of DCPs using different imaging modalities. Differences between groups with varying degrees of endoscopic experience were also assessed. Methods In total, 90 images of 30 DCPs viewed with high definition white light (HDWL), i-Scan, and indigo carmine chromoendoscopy were included in an online test module. Testing was undertaken before and after completing a novel web-based in vivo characterization training module. In total, 21 subjects (medical students (MS), gastroenterology trainees (GT), and gastroenterology consultants (GC)) undertook the tests and training module. Results No statistically significant difference in overall accuracy was found between the three groups either pre- (MS 59.1 %, GR 65.7 %, GC 62.4 %, P = ns for all three comparisons) or post-training (MS 69.2 %, GR 71.1 %, GC 71.3 %, P = ns for all three comparisons). Accuracy improved significantly for all three groups post-training (P < 0.001) as did interobserver agreement. No significant differences in accuracy between modalities were found pre-training (HDWL 64.8 %, i-Scan 60.0 %, chromoendoscopy 62.2 %, P = ns). Post-training accuracy with HDWL and chromoendoscopy was better than with i-Scan (HDWL 72.9 % vs i-Scan 65.1 %, P = 0.002; i-Scan 65.1 % vs chromoendoscopy 73.7 %, P < 0.001). The proportion of high confidence predictions increased from 25.7 % to 41.5 %, with a high confidence prediction accuracy of 81.7 %. Conclusions Skills for in vivo characterization of DCPs are not acquired through endoscopic experience alone. A novel web-based training intervention results in modest improvements in accuracy with further improvements likely to require more prolonged training.
Background and study aims: Mucosal views can be impaired by residual bubbles and mucus during gastroscopy. This study aimed to determine whether a pre-gastroscopy drink containing simethicone and N-acetylcysteine improves mucosal visualisation. Patients and methods: We conducted a randomized controlled trial recruiting 126 subjects undergoing routine gastroscopy. Subjects were randomized 1:1:1 to receive: A—pre-procedure drink of water, simethicone and N-acetylcysteine (NAC); B—water alone; or C—no preparation. Study endoscopists were blinded to group allocation. Digital images were taken at 4 locations (lower esophagus/upper gastric body/antrum/fundus), and rated for mucosal visibility (MV) using a 4-point scale (1 = best, 4 = worst) by 4 separate experienced endoscopists. The primary outcome measure was mean mucosal visibility score (MVS). Secondary outcome measures were procedure duration and volume of fluid flush required to achieve adequate mucosal views. Results: Mean MVS for Group A was significantly better than for Group B (1.35 vs 2.11, P < 0.001) and Group C (1.35 vs 2.21, P < 0.001). Mean flush volume required to achieve adequate mucosal views was significantly lower in Group A than Group B (2.0 mL vs 31.5 mL, P = 0.001) and Group C (2.0 mL vs 39.2 mL P < 0.001). Procedure duration did not differ significantly between any of the 3 groups. MV scores at each of the 4 locations demonstrated significantly better mucosal visibility in Group A compared to Group B and Group C (P < 0.0025 for all comparisons). Conclusions: A pre-procedure drink containing simethicone and NAC significantly improves mucosal visibility during gastroscopy and reduces the need for flushes during the procedure. Effectiveness in the lower esophagus demonstrates potential benefit in Barrett's oesophagus surveillance gastroscopy.
Ulcerative colitis (UC) is a colonic inflammatory disorder of unconfirmed aetiology. Clinical assessment involves invasive endoscopic examination with a small yet significant procedural risk, on which therapeutic decisions are made. Non-invasive biomarkers may be better tolerated and reduce procedural costs and risks. Matrix metalloproteinases (MMP) are enzymes involved in tissue remodelling; MMP are elevated in mucosa and urine of children with active UC. We measured urinary MMP activity in adult patients with UC, matched controls investigated for functional symptoms and normal healthy volunteers to evaluate as a potential biomarker of disease activity.
Methods
Ethical approval and informed consent were obtained. Patients with UC and age-sex matched controls, identified during outpatient assessment, were prospectively recruited and flexible sigmoidoscopy (FS) performed. Endoscopic (Sutherland) and histological (Gomes) appearance in patients with UC was graded. A group of healthy volunteers were recruited at a local University. Urine samples, snap frozen at collection in liquid nitrogen, were thawed, centrifuged, and assayed using commercially obtained fluorescein-labelled gelatinase activity kits. MMP activity was corrected for creatinine concentration. Results were expressed as median ± IQR. Statistical tests included Kruskal–Wallis analysis and Spearman9s correlation.
Results
80 active and 16 quiescent UC patients, 77 age-sex matched controls and 22 normal healthy volunteers were compared. Urinary MMP activity in active compared with quiescent UC (p=0.185) and in each compared with age-sex matched controls (p=0.237, p=0.525 respectively) was not significantly different. Exclusion of patients taking 5-aminosalicylates and corticosteroids did not alter significance. There was no correlation between urinary MMP activity and UC disease activity measured endoscopically (r=0.09, p=0.425) or histologically (r=0.178, p=0.127). Urinary MMP activity in healthy volunteers was significantly lower than patients with active UC (p<0.0001), quiescent UC (p<0.002), and controls (p<0.0001).
Conclusion
Contrary to previously published work, our findings suggest that urinary MMP activity, measured using fluorescein-labelled gelatinase assay, does not discriminate between quiescent and active UC and does not correlate with UC disease activity. Significant differences noted between healthy volunteers and patients with UC were unexpected, but may reflect difference in group demographics. MMP gelatinase assays are therefore a poor non-invasive biomarker of disease activity in UC.
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