The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy.

This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders.

An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn's disease.

BACKGROUND: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD. AIM: To standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Chron's disease. METHODS: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. RESULTS: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre-stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post-prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24-48 weeks is considered the appropriate endpoint in pharmacological trials. CONCLUSIONS: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.

Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation.

BACKGROUND: Fibrosis in ulcerative colitis has remained largely unexplored despite its clinical implications. AIMS: This cross-sectional study was aimed at characterising the presence, anatomical location and degree of ulcerative colitis-associated fibrosis and its possible link to clinical parameters. METHODS: Seven hundred and six individual tissue cross-sections derived every 10 cm along the length of 89 consecutive Ulcerative colitis colectomy specimens were examined and compared to Crohn's disease colitis, diverticular disease and uninvolved areas from colorectal cancer patients. Degree of inflammation, fibrosis and morphometric measurements of all layers of the intestinal wall were evaluated. Three gastrointestinal pathologists independently assessed colon sections stained with haematoxylin and eosin, Masson trichrome and Sirius red. Clinical data were collected prospectively. RESULTS: Submucosal fibrosis was detected in 100% of ulcerative colitis colectomy specimens, but only in areas affected by inflammation. Submucosal fibrosis was associated with the severity of intestinal inflammation (Spearman correlations rho (95% confidence interval): 0.58 (P < 0.001) and histopathological changes of chronic mucosal injury, but not active inflammation. Colectomy for refractory disease rather than presence of dysplasia was associated with increased fibrosis and a thicker muscularis mucosae, whereas a thinner muscularis mucosae was associated with anti-tumour necrosis factor therapy. No feature on endoscopic mucosal biopsies could predict the underlying amount of fibrosis or the thickness of the muscularis mucosae. CONCLUSIONS: A significant degree of fibrosis and muscularis mucosae thickening should be considered as common complications of chronic progressive ulcerative colitis. These features may have clinical consequences such as motility abnormalities and increased wall stiffness.

Immediate effects of whole body vibration on patellar tendon properties and knee extension torque.

PURPOSE: Reports about the immediate effects of whole body vibration (WBV) exposure upon torque production capacity are inconsistent. However, the changes in the torque-angle relationship observed by some authors after WBV may hinder the measurement of torque changes at a given angle. Acute changes in tendon mechanical properties do occur after certain types of exercise but this hypothesis has never been tested after a bout of WBV. The purpose of the present study was to investigate whether tendon compliance is altered immediately after WBV, effectively shifting the optimal angle of peak torque towards longer muscle length. METHODS: Twenty-eight subjects were randomly assigned to either a WBV (n = 14) or a squatting control group (n = 14). Patellar tendon CSA, stiffness and Young's modulus and knee extension torque-angle relationship were measured using ultrasonography and dynamometry 1 day before and directly after the intervention. Tendon CSA was additionally measured 24 h after the intervention to check for possible delayed onset of swelling. RESULTS: The vibration intervention had no effects on patellar tendon CSA, stiffness and Young's modulus or the torque-angle relationship. Peak torque was produced at ~70° knee angle in both groups at pre- and post-test. Additionally, the knee extension torque globally remained unaffected with the exception of a small (-6%) reduction in isometric torque at a joint angle of 60°. CONCLUSION: The present results indicate that a single bout of vibration exposure does not substantially alter patellar tendon properties or the torque-angle relationship of knee extensors.

Whole-body vibration training induces hypertrophy of the human patellar tendon.

Animal studies suggest that regular exposure to whole-body vibration (WBV) induces an anabolic response in bone and tendon. However, the effects of this type of intervention on human tendon properties and its influence on the muscle-tendon unit function have never been investigated. The aim of this study was to investigate the effect of WBV training on the patellar tendon mechanical, material and morphological properties, the quadriceps muscle architecture and the knee extension torque-angle relationship. Fifty-five subjects were randomized into either a vibration, an active control, or an inactive control group. The active control subjects performed isometric squats on a vibration platform without vibration. Muscle and tendon properties were measured using ultrasonography and dynamometry. Vibration training induced an increase in proximal (6.3%) and mean (3.8%) tendon cross-sectional area, without any appreciable change in tendon stiffness and modulus or in muscle architectural parameters. Isometric torque at a knee angle of 90° increased in active controls (6.7%) only and the torque-angle relation remained globally unchanged in all groups. The present protocol did not appreciably alter knee extension torque production or the musculo-tendinous parameters underpinning this function. Nonetheless, this study shows for the first time that WBV elicits tendon hypertrophy in humans.

Alpine Skiing With total knee ArthroPlasty (ASWAP): muscular adaptations.

This study investigated the effectiveness of recreational skiing as an intervention to improve quadriceps muscle architecture, strength, and antagonistic co-activation in patients with unilateral total knee arthroplasty (TKA). Hence, patients with TKA were assigned to either an intervention group (IG) or control group (CG). The IG completed a 12-week guided skiing program whereas the CG was instructed not to change their daily routines for the same period and was not allowed to ski. Before, after the intervention/after an 8-week retention period m. rectus femoris (RF) cross-sectional area (CSA), m. vastus lateralis muscle thickness, fascicle length, and pennation angle were measured with ultrasonography, while isometric (90° knee angle) knee extension, flexion torque and m. biceps femoris co-activation were assessed on an isokinetic dynamometer in 26 patients. There were significant and stable increases in RF CSA for the operated (10%; P < 0.05) and non-operated leg (12%; P < 0.01) after the training period in the IG whereas no changes were observed for the CG (all P > 0.05). There were no significant effects for other parameters (all P > 0.05). Overall, the skiing intervention was successful in increasing muscle mass in TKA older patients.

Alpine Skiing With total knee ArthroPlasty (ASWAP): impact on molecular and architectural features of musculo-skeletal ageing.

This study investigated features of skeletal muscle ageing in elderly individuals having previously undergone unilateral total knee arthroplasty (TKA) and whether markers of sarcopenia could be mitigated by a 12-week alpine skiing intervention. Novel biomarkers agrin, indicative of neuromuscular junction (NMJ) degeneration, tumor suppressor protein p53, associated with muscle atrophy, and a new ultrasound-based muscle architecture biomarker were used to characterize sarcopenia. Participant details and study design are presented by Kösters et al. (2015). The results of this study show that NMJ degeneration is widespread among active septuagenarians previously subjected to TKA: all participants showed elevated agrin levels upon recruitment. At least 50% of individuals were identified as sarcopenic based on their muscle architecture, supporting the hypothesis that NMJ alterations precede sarcopenia. Notably, sarcopenia was strongly associated with the expression of p53, which seems to confirm its validity as a biomarker of muscle atrophy. Training did not significantly modify any of these biomarkers. In view of the lack of accretion of muscle mass in response to the alpine skiing intervention, we hypothesize that local muscle inflammation and oxidative stress may have blunted the anabolic response to training and promoted muscle breakdown in this elderly post-TKA population.

Alpine Skiing With total knee ArthroPlasty (ASWAP): effect on tendon properties.

The aim of this study was to investigate the effect of alpine skiing on patellar tendon properties in patients with total knee arthroplasty (TKA). Thirty-one adults (70.4 ± 4.7 years) with unilateral TKA were recruited 2.7 ± 0.9 years after surgery and assigned to an intervention (IG) or a control group (CG). The IG underwent a 12-week guided skiing program. Tendon stiffness, Young's modulus, and cross-sectional area (CSA) were measured before and after the intervention. In both groups, mean tendon CSA was 28% (P < 0.001) larger in the operated (OP) than in the non-operated (NOP) leg at baseline, without any difference in other tendon properties. After training, stiffness increased in the IG by 5.8% and 15.8%, respectively, in the OP and NOP legs. Likewise, mean CSA increased in the IG by 2.9% in the OP and 3.8% in the NOP leg, whereas no significant changes were found for the Young's modulus. None of the tendon parameters changed in the CG. Results indicate that patellar tendon structure and/or loading pattern are altered following TKA, but this tissue seems to retain its adaptation capacity. Further, alpine skiing appears to offer a suitable rehabilitation strategy for TKA patients.

Review article: breath analysis in inflammatory bowel diseases.

BACKGROUND: There is an urgent need for cheap, reproducible, easy to perform and specific biomarkers for diagnosis, differentiation and stratification of inflammatory bowel disease (IBD) patients. Technical advances allow for the determination of volatile organic compounds in the human breath to differentiate between health and disease. AIM: Review and discuss medical literature on volatile organic compounds in exhaled human breath in GI disorders, focusing on diagnosis and differentiation of IBD. METHODS: A systematic search in PubMed, Ovid Medline and Scopus was completed using appropriate keywords. In addition, a bibliography search of each article was performed. RESULTS: Mean breath pentane, ethane, propane, 1-octene, 3-methylhexane, 1-decene and NO levels were elevated (P < 0.05 to P < 10(-7)) and mean breath 1-nonene, (E)-2-nonene, hydrogen sulphide and methane were decreased in IBD compared to healthy controls (P = 0.003 to P < 0.001). A combined panel of 3 volatile organic compounds (octene, (E)-2-nonene and decene) showed the best discrimination between paediatric IBD and controls (AUC 0.96). Breath condensate cytokines were higher in IBD compared to healthy individuals (P < 0.008). Breath pentane, ethane, propane, isoprene and NO levels correlated with disease activity in IBD patients. Breath condensate interleukin-1ß showed an inverse relation with clinical disease activity. CONCLUSIONS: Breath analysis in IBD is a promising approach that is not yet ready for routine clinical use, but data from other gastrointestinal diseases suggest the feasibility for use of this technology in clinical practice. Well-designed future trials, incorporating the latest breath detection techniques, need to determine the exact breath metabolome pattern linked to diagnosis and phenotype of IBD.

Cytomegalovirus vaccine: phase II clinical trial results.

Cytomegalovirus (CMV) is one of the most significant viral pathogens during pregnancy and in immunocompromised patients. Antiviral prophylactic strategies are limited by toxicities, drug-drug interactions and development of antiviral resistance. A safe and protective vaccine against CMV is highly desirable in view of the potential positive impact on CMV-associated morbidity and mortality as well as healthcare costs. Unfortunately, this demand could not be met in the past four decades although development of a CMV vaccine has been ranked at the highest priority by the US Institute of Medicine. Multiple different vaccine candidates have been developed and evaluated in phase I clinical trials and few succeeded to phase II trials. Nevertheless, two different vaccines showed recently promising results in trials that studied healthy adults and immunocompromised solid-organ and bone-marrow transplant recipients, respectively. The gB/MF59 vaccine exhibited a vaccine efficacy of 50% in healthy, postpartum females. In transplant patients, gB/MF59 and the DNA vaccine TransVax both limited the periods of viraemia and consequently the need for antiviral treatment. The success of these trials is encouraging and will probably give new impetus to the development of an effective CMV vaccine. Sterilizing immunity may not be attainable in the near future and may not be necessary for a CMV vaccine to have a significant impact on health care as discussed in the present review.

Platelet-activating factor and distinct chemokines are elevated in mucosal biopsies of erosive compared with non-erosive reflux disease patients and controls.

BACKGROUND: A distinction between symptomatic non-erosive reflux disease (NERD) and erosive esophagitis (EE) patients is supported by the presence of inflammatory response in the mucosa of EE patients, leading to a damage of mucosal integrity. To explore the underlying mechanism of this difference, we assessed inflammatory mediators in mucosal biopsies from EE and NERD patients and compared them with controls. METHODS: Nineteen NERD patients, 15 EE patients, and 16 healthy subjects underwent endoscopy after a 3-week washout from PPI or H(2) antagonists. Biopsies obtained from the distal esophagus were examined by quantitative real-time polymerase chain reaction (qPCR) and multiplex enzyme-linked immunosorbent assay for selected chemokines and lyso-PAF acetyltransferase (LysoPAF-AT), the enzyme responsible for production of platelet-activating factor (PAF). KEY RESULTS: Expression of LysoPAF-AT and multiple chemokines was significantly increased in mucosal biopsies derived from EE patients, when compared with NERD patients and healthy controls. Upregulated chemokines included interleukin 8, eotaxin-1, -2, and -3, macrophage inflammatory protein-1α (MIP-1α), and monocyte chemoattractant protein-1 (MCP-1). LysoPAF-AT and the chemokine profile in NERD patients were comparable with healthy controls. CONCLUSIONS & INFERENCES: Levels of selected cytokines and Lyso-PAF AT were significantly higher in the esophageal mucosa of EE patients compared with NERD and control patients. This difference may explain the distinct inflammatory response occurring in EE patients' mucosa. In contrast, as no significant differences existed between the levels of all mediators in NERD and control subjects, an inflammatory response does not appear to play a major role in the pathogenesis of the abnormalities found in NERD patients.

Crohn's disease of the esophagus: treatment of an esophagobronchial fistula with the novel liquid embolic polymer "onyx".

Esophageal involvement in Crohn's disease is very rare. In only a small subgroup of these patients -- up to date fourteen cases have been described in the literature -- the course of the illness may be complicated by esophageal fistula formation. The therapy for fistulizing esophageal Crohn's disease so far has been disappointing, recurrence and progression are likely, and surgery still is the primary treatment modality for refractory patients. We here present a case of severe Crohn's disease with an esophagobronchial fistula and the successful closure of the fistula tract with the novel liquid polymer sealant "Onyx". This approach offers a new option for the treatment of this rare complication of Crohn's disease and should be considered if surgery is not possible.

Use of anticoagulation during wireless capsule endoscopy for the investigation of recurrent obscure gastrointestinal bleeding.

Detecting the source of obscure gastrointestinal bleeding can be difficult. Capsule endoscopy is a promising diagnostic tool for investigating patients with this condition, although identifying the source of intermittent or low-grade bleeding remains a diagnostic challenge. We present case reports of two patients with obscure gastrointestinal bleeding, in whom the source of recurrent bleeding episodes was diagnosed by capsule endoscopy while they were on anticoagulation therapy. The first patient, an 81-year-old white woman, was on long-term oral anticoagulation because she had chronic atrial fibrillation. Capsule endoscopy demonstrated a bleeding tumor in the region of the terminal ileum. The second patient, a 59-year-old white man, underwent an initial capsule endoscopy, which was negative. After initiation of anticoagulation with heparin, a second capsule endoscopy procedure in this patient revealed several small bleeding lesions in the proximal small bowel. In both cases a gastrointestinal stromal tumor was identified as the bleeding source and was resected. These two cases demonstrate that provocation of bleeding during capsule endoscopy may increase its sensitivity.

Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production.

Interleukin (IL)-18, initially described as interferon (IFN)-gamma-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-gamma concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-alpha, IL-18, and IFN-gamma production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-gamma synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.

Adenosine kinase inhibitor GP515 improves experimental colitis in mice.

Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-gamma (IFNgamma) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNgamma concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNgamma synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNgamma synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.

[15 year's results with combined caries prophylaxis according to the recommendations of the seminar for juvenile dental health (1961)]. / 15-Jahr-Resultate mit kombinierter Kariesprophylaxe nach den Empfehlungen des Seminars für Jugendzahnpflege (1961).

Consistent combination of the prophylaxis measures as recommended by the Seminar for youth dental health has led to a 67% decrease in caries incidence for the Bettlach schoolchildren, during the last 15 years. A very important factor is the good collaboration between school dentists and teaching staff of the school; centralized examination makes thorough and universal prophylactic measures possible.