The Incidence and Disease Course of Perianal Crohn's Disease: A Danish Nationwide Cohort Study, 1997-2015.

BACKGROUND AND AIMS: Perianal Crohn's disease [CD] places a considerable burden on patients' quality of life and is complex to treat. Despite its impact and high frequency, few studies have investigated the incidence and disease course of perianal CD. The aim of this study was to assess the incidence and disease course of perianal CD in adult patients throughout a 19-year period. METHODS: The cohort comprised all individuals aged 18 years or older who were diagnosed with CD in Denmark between January 1, 1997, and December 31, 2015, according to the National Patient Registry [NPR]. RESULTS: A total of 1812 [19%] out of 9739 patients with CD were found to have perianal CD. Perianal fistulas were the most common manifestation, accounting for 943 [52%] cases. The incidence of perianal CD remained stable over time. Patients with perianal CD were found to have an increased risk of undergoing major abdominal surgery compared with patients without perianal CD (hazard ratio: 1.51, 95% confidence interval [CI]: 1.40 to 1.64, p <0.001) in a multivariate Cox regression analysis. The incidence rate ratios of anal and rectal cancer in perianal CD patients were 11.45 [95% CI: 4.70 to 27.91, p <0.001] and 2.29 [95% CI: 1.25 to 4.20, p = 0.006], respectively, as compared with non-IBD matched controls. CONCLUSIONS: In this nationwide study, 19% of CD patients developed perianal disease. Patients with perianal CD were at increased risk of undergoing major surgery compared with non-perianal CD patients. The risk of anal and rectal cancer was increased in patients with perianal CD compared with non-IBD matched controls. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Species-specific engagement of human nucleotide oligomerization domain 2 (NOD)2 and Toll-like receptor (TLR) signalling upon intracellular bacterial infection: role of Crohn's associated NOD2 gene variants.

Recognition of bacterial peptidoglycan-derived muramyl-dipeptide (MDP) by nucleotide oligomerization domain 2 (NOD2) induces crucial innate immune responses. Most bacteria carry the N-acetylated form of MDP (A-MDP) in their cell membranes, whereas N-glycolyl MDP (G-MDP) is typical for mycobacteria. Experimental murine studies have reported G-MDP to have a greater NOD2-stimulating capacity than A-MDP. As NOD2 polymorphisms are associated with Crohn's disease (CD), a link has been suggested between mycobacterial infections and CD. Thus, the aim was to investigate if NOD2 responses are dependent upon type of MDP and further to determine the role of NOD2 gene variants for the bacterial recognition in CD. The response pattern to A-MDP, G-MDP, Mycobacterium segmatis (expressing mainly G-MDP) and M. segmatisΔnamH (expressing A-MDP), Listeria monocytogenes (LM) (an A-MDP-containing bacteria) and M. avium paratuberculosis (MAP) (a G-MDP-containing bacteria associated with CD) was investigated in human peripheral blood mononuclear cells (PBMCs). A-MDP and M. segmatisΔnamH induced significantly higher tumour necrosis factor (TNF)-α protein levels in healthy wild-type NOD2 PBMCs compared with G-MDP and M. segmatis. NOD2 mutations resulted in a low tumour necrosis factor (TNF)-α protein secretion following stimulation with LM. Contrary to this, TNF-α levels were unchanged upon MAP stimulation regardless of NOD2 genotype and MAP solely activated NOD2- and Toll-like receptor (TLRs)-pathway with an enhanced production of interleukin (IL)-1ß and IL-10. In conclusion, the results indicate that CD-associated NOD2 deficiencies might affect the response towards a broader array of commensal and pathogenic bacteria expressing A-MDP, whereas they attenuate the role of mycobacteria in the pathogenesis of CD.

Tissue-regenerating functions of coagulation factor XIII.

The protransglutaminase factor XIII (FXIII) has recently attracted attention within the field of tissue regeneration, as it has been found that FXIII significantly influences wound healing by exerting a multitude of functions. It supports hemostasis by enhancing platelet adhesion to damaged endothelium, and by its cross-linking activity it stabilizes the formed fibrin clot. Furthermore, FXIII limits bacterial dissemination from the wound and incorporates macromolecules of importance for cellular infiltration, supporting cell migration and survival. FXIII-mediated complex formation of the vascular endothelial growth factor receptor 2 and αV ß3 integrin is important for angiogenesis, supporting the formation of granulation tissue. Chronic inflammatory conditions involving bleeding and activation of the coagulation cascade have been shown to lead to reduced FXIII levels in plasma. Of particular importance for this review is the fact that patients suffering from inflammatory bowel disease (IBD) have reduced FXIII antigen levels and activity. Furthermore, these patients show impaired mucosal healing, which supports the inflammatory state of the disease. This review summarizes the role of FXIII in the healing of wounds, and briefly summarizes the previous use of FXIII in clinical settings. Moreover, it addresses the potential role for FXIII as a therapeutic agent in the healing of persistent wounds during chronic conditions, with an emphasis on IBD.

A role for interleukin-33 in T(H)2-polarized intestinal inflammation?

Interleukin 33 (IL-33) is a recently discovered cytokine member of the IL-1 superfamily that is widely expressed in fixed tissue cells, including endothelial and epithelial cells. IL-33 induces helper T cells, mast cells, eosinophils, and basophils to produce type-2 cytokines through binding to the ST2/IL-1 receptor accessory protein complex. Recent studies have shown IL-33 to be upregulated in intestinal parasite infection and in epithelial cells and myofibroblasts in ulcerative colitis (UC). The findings point to a role for IL-33 in directing the T(H)2-type immune responses in these types of mucosal inflammation. As the IL-33/ST2 receptor axis can be manipulated by various blocking antibodies, this could be a potential therapeutic target in the future treatment of UC.

Use of biological molecules in the treatment of inflammatory bowel disease.

The introduction of biological agents (i.e. antitumour necrosis factor-α and anti-integrin treatments) for the treatment of inflammatory bowel disease (IBD) [i.e. Crohn's disease (CD) and ulcerative colitis] has led to a substantial change in the treatment algorithms and guidelines, especially in CD. However, many questions still remain about the true efficacy and the best treatment regimens. Thus, a need for further treatment options still exists as up to 40% of IBD patients treated with the presently available biologicals do not have positive clinical responses. Better patient selection might maximize the clinical benefit for those in most need of an effective therapy to avoid disabling disease whilst also minimizing the complications associated with therapy. Further, the 'trough-level strategy' may help clinicians to optimize therapy and to avoid loss of response and/or immunogenicity. The idea behind this dosage regimen is that correct dosing must ensure that the patient's lowest level of drug concentration (i.e. the trough level) occurring just before the next drug administration is high enough for the full effect to be seen. Controversy continues regarding the appropriate use of biologicals; therefore, in this review, we focus on considerations that might lead to a more rational strategy for antitumour necrosis factor-α agents in IBD, emphasizing the situations in which the risks may outweigh the benefits. Finally, the need for an appropriate strategy for stopping biological treatment is discussed.

Alcohol modulates circulating levels of interleukin-6 and monocyte chemoattractant protein-1 in chronic pancreatitis.

BACKGROUND: Cytokines are markers of acute pancreatic inflammation and essential for distant organ injury, but they also stimulate pancreatic fibrogenesis and are thus involved in the progression from acute pancreatitis to chronic pancreatic injury and fibrosis. The aim of this study was to evaluate the circulating levels of IL-6, MCP-1, TGF-beta1, IGF-1 and IGFBP-3 in patients with alcoholic chronic pancreatitis (CP). METHODS: Twelve male patients with severe CP and 11 matched controls ingested 40 g alcohol. Plasma cytokine concentrations were measured for 24 h and assessed by sandwich ELISA techniques. RESULTS: IL-6 was higher in CP at fasting and 1, 4 and 24 h after alcohol intake (P < 0.04), and a significantly greater rise was found at 1 h compared to pre-stimulatory conditions and controls (P < 0.01). MCP-1 plasma levels in CP were significantly decreased at I h (P < 0.01) and 4 h (P < 0.001) compared to pre-stimulatory levels and controls, and a variance analysis showed significantly (P < 0.001) lower post-stimulatory levels at 1 h and 4 h both in CP and in controls. Alcohol consumption (40 g), however, did not influence plasma levels of TGF-1beta, IGF-I or IGFBP-3 in either of the two groups at the time frame applied. CONCLUSIONS: Acute alcohol intake induces a rise in the plasma levels of IL-6 in CP as compared to controls. The low circulating concentrations of MCP-1 1 and 4 h following alcohol consumption might possibly reflect that this mediator acts locally via autocrine mechanisms.

[Risk management by reporting critical incidents. Vitamin K and ephedrine mix-up at a birthing unit]. / Risikostyring med rapportering af kritiske situationer. Forveksling af K-vitamin og ephedrin på en fødegang.

INTRODUCTION: Errors of medication are frequent causes of hazards to patients. It has been suggested that containers that look alike constitute a risk of such errors. In this article, we present an example of how reporting incidents of potential risks, can be applied in their clinical management. MATERIAL AND METHODS: As part of a medical technology assessment project on risk management in a delivery department, the staff were encouraged to report incidents that could create a potential risk to patients. The incidents were assessed by a project group as either a general problem to patient safety or a solitary incident. If considered a general problem, procedures should be changed and implemented in the department. RESULTS: Two incidents were reported, where ephedrine and adrenaline were found in a box supposed to contain vitamin K for new-born babies. These were considered a general problem by the project group, and the procedure for storing and managing ephedrine and adrenaline in the delivery department was changed to prevent new cases. DISCUSSION: Near misses occur more often than actual errors, and we argue that, as they are easier to discover, it is important to learn from them and thus prevent further incidents. A forum should be set up to exchange experiences of acknowledged risks, hazards, analytical results and preventive solutions.

Established and emerging biological activity markers of inflammatory bowel disease.

Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn's disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion molecules. It is concluded that none of the pertinent laboratory surrogate markers of disease activity in IBD are specific or sensitive enough to replace basic clinical observation such as the number of daily bowel movements, general well-being, and other parameters in parallel. Further studies are highly warranted to identify and assess the clinical importance and applicability of new laboratory markers for the diagnosis or the disease activity of IBD.

Circulating L-selectin levels and endothelial CD34 expression in inflammatory bowel disease.

OBJECTIVE: Soluble L-selectin (sL-selectin) concentrations are positively correlated with disease activity in ulcerative colitis (UC) but not in Crohn's disease (CD). This difference in sL-selectin regulation could be due to a disease specific regulation of L-selectin ligands. The aim of this study was to compare levels of circulating sL-selectin, expression of the L-selectin ligand CD34 in the affected colon, and inflammatory bowel disease activity. METHODS: Twenty-three patients with UC, 16 patients with CD, and 18 control subjects were included in the study. In blood samples concentrations of serum sL-selectin were determined by an ELISA technique. In colonoscopically obtained biopsies, CD34 expression was evaluated by immunohistochemical methods using monoclonal CD34 antibodies. Disease activity was determined by a clinical semiquantitative scale. RESULTS: sL-selectin levels were found to be significantly increased along with increasing disease activity in UC (p < 0.001) but not in CD (p > 0.05) patients. UC patients with quiescent and severe disease activity had significantly lower (p < 0.005) and higher (p < 0.002) sL-selectin concentrations than controls, respectively. CD34 expression was found to be increased in both disease groups as compared with controls (p < 0.05). CONCLUSION: A disease-specific regulation of CD34 was not found as an explanation for the distinction in sL-selectin regulation. In the light of recent reports on low sL-selectin in other diseases, it is suggested instead that ongoing neutrophil activation may be the reason for low sL-selectin concentrations during quiescent disease stages, whereas chemokine secretion could explain the increased levels of sL-selectin associated with severe disease activity.

Seizure threshold to lidocaine is decreased following repeated ECS (electroconvulsive shock).

Seizure susceptibility to lidocaine was investigated in rats which had received repeated ECS (electroconvulsive shock). In the first experiment three groups of rats received an ECS daily for 18 days, an ECS weekly for 18 weeks, and 18 sham treatments, respectively. Twelve weeks after the last ECS all rats received a lidocaine challenge (LC) in the form of an intraperitoneal (IP) injection of lidocaine (65 mg/kg). After the injection the animals were observed for occurrence of motor seizures. A total of 67% (10/15), 47% (7/15), and 0% (0/18) of the daily, weekly, and sham groups, respectively, had motor seizures in response to the LC. In the second experiment five groups of rats received an ECS daily for 0, 1, 6, 18, and 36 days, respectively. Eighteen weeks after the last ECS all rats received an LC and 0% (0/15), 13% (2/15), 20% (3/15), 53% (8/15), and 58% (7/12), respectively, developed seizures in response to the LC. In the third experiment two groups of rats received daily ECS and sham-ECS, respectively. Twenty-four hours after the last ECS all rats received an LC. A total of 60% (9/15) of the ECS group and 0% (0/10) of the sham-ECS group had seizures in response to the LC.(ABSTRACT TRUNCATED AT 250 WORDS)

[Alcohol consumption and organic damage. Views and attitudes of Danish patients and their relatives]. / Alkoholforbrug og organskader. Danske patienters og pårørendes viden og holdninger.

A total of 201 patients and their relatives in a hospital in Copenhagen participated in a structured interview investigation about their knowledge of the long-term effects of alcohol and their attitudes to restrictions. The majority approved of an upper limit for alcohol consumption within the recommended limits but a total of approximately 1/3 preferred a higher limit. Only 28% realised that there was a difference in how much alcohol women and men can tolerate. The majority, but far from all of the participants knew that alcohol could damage the liver and brain but few knew of damage to other organs. A total of 64% had a positive attitude to prohibition of alcohol consumption in places of employment in Denmark. It is suggested that information about alcohol should be concentrated in the form of simple clear messages.

Assessment of verapamil in the treatment of angina pectoris.

A brief review is given of the pharmacological data of verapamil, which chemically shows a certain similarity to papaverine. The effect of the drug (80 mg) 3 times daily, on angina pectoris, as compared with placebo, was evaluated in a double-blind cross-over therapeutic trial with 4-wk periods in 47 patients. The incidence of attacks and the nitroglycerine consumption decreased in the second fortnight of the verapamil period by approximately 25% compared with the placebo period. An ergometer test showed a prolongation of the exerice time of 20%. The mean blood pressure and the heart rate fell under verapamil treatment if the patients had values which were relatively high in the placebo period. The increase in heart rate during exercise from two different resting levels showed a tendency to become more pronounced under treatment with verapamil than under placebo. The length of the P-Q intervals were not affected by verapamil. The mechanism of action in angina pectoris is discussed, but it is concluded that it is still not possible to explain it. Twelve Danish medical departments took part in the trial.