Interleukin 17 (IL17) is now known to be involved in a number of chronic inflammatory disorders. However, the mechanisms regulating its production in inflammatory bowel disease (IBD) are still ...unclear.
Endoscopic biopsies or surgical specimens were taken from inflamed and uninflamed colonic mucosa of 72 patients with IBD (38 with Crohn's disease and 34 with ulcerative colitis), and normal colon of 38 control subjects. IL17 and interferon gamma (IFNgamma) were detected by ELISA in the supernatants of biopsies cultured ex vivo, and anti-CD3/CD28-stimulated lamina propria mononuclear cells (LPMCs) incubated with IL12, IL23, IL1beta plus IL6, transforming growth factor beta1 (TGFbeta1), or anti-IL21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells.
IL17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFNgamma. Anti-CD3/CD28-stimulated IBD LPMCs produced higher IL17 amounts compared to controls. The percentages of Th17 and Th1/Th17 cells were increased in patients with IBD. IL23 and IL1beta plus IL6 had no effect on IBD LPMC production of IL17; however, IL12 markedly increased IFNgamma production and decreased IL17 production. TGFbeta1 dose-dependently decreased IFNgamma, but had no significant inhibitory effect on IL17 production. Blocking IL21 significantly downregulated IL17 production.
Our findings support a role for IL12, TGFbeta and IL21 in modulating IL17/IFNgamma production in IBD. The abundant IL17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFNgamma antibodies in clinical trials of Crohn's disease.
Complications of intestinal stomas Nastro, P.; Knowles, C. H.; McGrath, A. ...
British journal of surgery,
December 2010, Letnik:
97, Številka:
12
Journal Article
Guidelines on histopathological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology have been produced recently by an international working group (IWG). These ...addressed the important but relatively neglected areas of histopathological practice of the general pathologist, including suction rectal biopsy and full-thickness intestinal tissue. Recommendations were presented for the indications, safe acquisition of tissue, histological techniques, reporting and referral of such histological material.
Consensual processes undertaken by the IWG and following established guideline decision group methodologies.
This report presents a contemporary and structured classification of gastrointestinal neuromuscular pathology based on defined histopathological criteria derived from the existing guidelines. In recognition of its origins and first presentation in London at the World Congress of Gastroenterology 2009, this has been named 'The London Classification'. The implementation of this classification should allow some diagnostic standardisation, but should necessarily be viewed as a starting point for future modification as new data become available.
Self-assembling peptide-based hydrogels are a class of tunable soft materials that have been shown to be highly useful for a number of biomedical applications. The dynamic formation of the ...supramolecular fibrils that compose these materials has heretofore remained poorly characterized. A better understanding of this process would provide important insights into the behavior of these systems and could aid in the rational design of new peptide hydrogels. Here, we report the determination of the microscopic steps that underpin the self-assembly of a hydrogel-forming peptide, SgI37‑49. Using theoretical models of linear polymerization to analyze the kinetic self-assembly data, we show that SgI37‑49 fibril formation is driven by fibril-catalyzed secondary nucleation and that all the microscopic processes involved in SgI37‑49 self-assembly display an enzyme-like saturation behavior. Moreover, this analysis allows us to quantify the rates of the underlying processes at different peptide concentrations and to calculate the time evolution of these reaction rates over the time course of self-assembly. We demonstrate here a new mechanistic approach for the study of self-assembling hydrogel-forming peptides, which is complementary to commonly used materials science characterization techniques.
Background
Evacuatory dysfunction (ED) is a common cause of constipation and may be sub‐classified on the basis of specialist tests. Such tests may guide treatment e.g., biofeedback therapy for ...‘functional’ defecatory disorders (FDD). However, there is no gold standard, and prior studies have not prospectively and systematically compared all tests that are used to diagnose forms of ED.
Methods
One hundred consecutive patients fulfilling Rome III criteria for functional constipation underwent four tests: expulsion of a rectal balloon distended to 50 mL (BE50) or until patients experienced the desire to defecate (BEDDV), evacuation proctography (EP) and anorectal manometry. Yields and agreements between tests for the diagnosis of ED and FDD were assessed.
Key Results
Positive diagnostic yields for ED were: BEDDV 18%, BE50 31%, EP 38% and anorectal manometry (ARM) 68%. Agreement was substantial between the two balloon tests (k = 0.66), only fair between proctography and BE50 (k = 0.27), poor between manometry and proctography (k = 0.01), and there was no agreement between the balloon tests and manometry (k = −0.07 for both BE50 and BEDDV). For the diagnosis of FDD, there was only fair agreement between ARM and EP (k = 0.23), ARM ± BE50 and EP (k = 0.18), ARM and EP ± BE50 (k = 0.30) and ARM ± BE50 and EP ± BE50 (k = 0.23).
Conclusions & Inferences
There is considerable disagreement between the results of various tests used to diagnose ED and FDD. This highlights the need for a reappraisal of both diagnostic criteria, and what represents the ‘gold standard’ investigation.
100 constipated patients were prospectively investigated using manometry, evacuation proctography and balloon expulsion test, strictly following the ROME III criteria. Our results showed significant discordance between outcome of investigations.
Background
Fecal incontinence (FI) is a common and socially disabling condition with obstetric trauma considered the principal etiological factor. This study aimed to systematically evaluate symptom ...presentation and anorectal function in both females and males with FI.
Methods
One hundred males (M) and 100 age‐matched females (F) with FI presenting between 2012 and 2014 were identified from a prospectively collected database. Comparison of clinical (history, symptom profile, and severity using validated questionnaires) and anorectal physiological (manometry, rectal sensory testing, endoanal ultrasonography, and evacuation proctography) data between M and F was performed.
Key Results
Incidence of prior anal surgery (M: 28% vs F: 18%, p = 0.13) and abdominal surgery (M: 25% vs F: 26%, p = 0.90) was similar between sexes, but females had a higher incidence of previous pelvic surgery (M: 4% vs F: 47%, p < 0.001). Eighty‐five females were parous and 75% reported history of traumatic vaginal delivery. There was a trend toward higher St Mark's incontinence scores in females (mean ± SD; M: 13 ± 4 vs F: 14 ± 5, p = 0.06). In men, structural sphincter abnormalities were uncommon (M: 37% vs F: 77%, p < 0.001), while impaired rectal sensation (M: 24% vs F: 7%, p = 0.001) and functional disturbances of evacuation (M: 36% vs F: 13%, p = 0.001) were more common than in women. No abnormality on all tests performed was observed in twice as many males (M: 18% vs F: 9%, p = 0.10).
Conclusions & Inferences
Pathophysiological mechanisms of FI differ between sexes. Anal sphincter dysfunction was an uncommon finding in males, with impaired rectal sensation and functional disturbances of evacuation much more prominent than in the female cohort. These findings are likely to impact options for symptom management.
This study analyzed the clinical histories and results of anorectal physiological investigations of 100 consecutive males and 100 case‐matched females presenting to our unit with a primary complaint of fecal incontinence.
Background
Sacral nerve stimulation (SNS) is now well established as a treatment for fecal incontinence (FI) resistant to conservative measures and may also have utility in the management of chronic ...constipation; however, mechanism of action is not fully understood. End organ effects of SNS have been studied in both clinical and experimental settings, but interpretation is difficult due to the multitude of techniques used and heterogeneity of reported findings. The aim of this study was to systematically review available evidence on the mechanisms of SNS in the treatment of FI and constipation.
Methods
Two systematic reviews of the literature (performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta‐Analyses framework) were performed to identify manuscripts pertaining to (a) clinical and (b) physiological effects of SNS during the management of hindgut dysfunction.
Key Results
The clinical literature search revealed 161 articles, of which 53 were deemed suitable for analysis. The experimental literature search revealed 43 articles, of which nine were deemed suitable for analysis. These studies reported results of investigative techniques examining changes in cortical, gastrointestinal, colonic, rectal, and anal function.
Conclusions & Inferences
The initial hypothesis that the mechanism of SNS was primarily peripheral motor neurostimulation is not supported by the majority of recent studies. Due to the large body of evidence demonstrating effects outside of the anorectum, it appears likely that the influence of SNS on anorectal function occurs at a pelvic afferent or central level.
A modified figure from Griffin et al. 2011 showing effect of sacral nerve stimulation (SNS) on anal evoked cortical potentials in the anaesthesised rat.
Background
Over the past 18 years neuromodulation therapies have gained support as treatments for faecal incontinence (FI); sacral nerve stimulation (SNS) is the most established of these. A ...systematic review was performed of current evidence regarding the clinical effectiveness of neuromodulation treatments for FI.
Methods
The review adhered to the PRISMA framework. A comprehensive search of the literature included PubMed, MEDLINE, Embase and Evidence‐Based Medicine Reviews. Methodological quality assessment and data extraction were completed in a systematic fashion.
Results
For SNS, 321 citations were identified initially, of which 61 studies were eligible for inclusion. Of studies on other neuromodulation techniques, 11 were eligible for review: seven on percutaneous tibial nerve stimulation (PTNS) and four on transcutaneous tibial nerve stimulation (TTNS). On intention‐to‐treat, the median (range) success rates for SNS were 63 (33–66), 58 (52–81) and 54 (50–58) per cent in the short, medium and long terms respectively. The success rate for PTNS was 59 per cent at the longest reported follow‐up of 12 months. SNS, PTNS and TTNS techniques also resulted in improvements in Cleveland Clinic Incontinence Score and quality‐of‐life measures. Despite significant use of neuromodulation in treatment of FI, there is still no consensus on outcome reporting in terms of measures used, aetiologies assessed, length of follow‐up or assessment standards.
Conclusion
Emerging data for SNS suggest maintenance of its initial therapeutic effect into the long term. The clinical effectiveness of PTNS is comparable to that of SNS at 12 months, although there is no evidence to support its continued effectiveness after this period. PTNS may be a useful treatment before SNS. The clinical effectiveness of TTNS is still uncertain owing to the paucity of available evidence. A consensus to standardize the use of outcome measures is recommended in order that further reports can be compared meaningfully.
Sacral nerve stimulation of benefit long term
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