Therapy of steroid-resistant inflammatory bowel disease.

Background and Aims: Although systemic corticosteroids are successfully administered for the induction of clinical response and remission in the majority of patients with inflammatory bowel disease (IBD) presenting with a flare, a proportion of these patients demonstrate a primary nonresponse to steroids or in the case of an initial response, they develop a resistance or a steroid dependence. Long-term therapy with corticosteroids for treatment of IBD should be avoided, given the high frequency of adverse treatment effects. Knowledge about treatment strategies in case of steroid nonresponse is therefore highly relevant. Methods: A systematic literature research was performed using Medline and Embase to summarize the currently recommended treatment strategies for steroid-resistant IBD. Results: Treatment of steroid-resistant Crohn's disease is based on the introduction of immunomodulators such as azathioprine, 6-mercaptopurine or methotrexate, the anti-TNF drugs infliximab, adalimumab and certolizumab pegol. In the case of steroid resistance in ulcerative colitis, aminosalicylates, the above-mentioned immunomodulators, infliximab, adalimumab or calcineurin inhibitors such as ciclosporin or tacrolimus may be administered. Conclusion: This review summarizes the current evidence for treating steroid-resistant IBD.

Application of Multi-SNP Approaches Bayesian LASSO and AUC-RF to Detect Main Effects of Inflammatory-Gene Variants Associated with Bladder Cancer Risk

The relationship between inflammation and cancer is well established in several tumor types, including bladder cancer. We performed an association study between 886 inflammatory-gene variants and bladder cancer risk in 1,047 cases and 988 controls from the Spanish Bladder Cancer (SBC)/EPICURO Study. A preliminary exploration with the widely used univariate logistic regression approach did not identify any significant SNP after correcting for multiple testing. We further applied two more comprehensive methods to capture the complexity of bladder cancer genetic susceptibility: Bayesian Threshold LASSO (BTL), a regularized regression method, and AUC-Random Forest, a machine-learning algorithm. Both approaches explore the joint effect of markers. BTL analysis identified a signature of 37 SNPs in 34 genes showing an association with bladder cancer. AUC-RF detected an optimal predictive subset of 56 SNPs. 13 SNPs were identified by both methods in the total population. Using resources from the Texas Bladder Cancer study we were able to replicate 30% of the SNPs assessed. The associations between inflammatory SNPs and bladder cancer were reexamined among non-smokers to eliminate the effect of tobacco, one of the strongest and most prevalent environmental risk factor for this tumor. A 9 SNP-signature was detected by BTL. Here we report, for the first time, a set of SNP in inflammatory genes jointly associated with bladder cancer risk. These results highlight the importance of the complex structure of genetic susceptibility associated with cancer risk.

Correlations between negative-induced cerebral dynamics and idiopathic intellectual disability: an EEG study

Intellectual disability has long been associated with deficits in socio-emotional processing. However, studies investigating brain dynamics of maladaptive socio-emotional skills associated with intellectual disability are scarce. Here, we compared differences in brain activity between low intelligence quotient (I.Q.<75, N=13) and normal controls (N=15) while evaluating their subjective emotions. Positive (P) and negative (N) valenced pictures were presented one at a time to participants of both groups, at a rate of ¾. The task required that each participant evaluate their subjective emotion and press a predefined push-button when done, alternatively P and N. Electroencephalographic (EEG) signals were continuously recorded, and the 1000ms time window following each picture was analyzed offline for power in frequency domain. Alpha low (8-10Hz) and upper (10-13Hz) frequency bands were then compared for both groups and for both P and N emotions in 12 distributed scalp electrodes. The qualitative evaluation of emotions was similar between both groups, with constant longer reaction times for the low IQ participants. The EEG signal comparison shows marked power decrease in upper alpha frequency range for N emotions in low intelligence group. Otherwise no significant difference was noticed between low and normal IQ. Main findings of the present study are (1) results do not support the hypothesis that impairment in developmental intelligence roots in maladaptive emotional processing; (2) the strong alpha power suppression during negative-induced emotions suggests the involvement of an extended neural network and more effortful inhibition processes than positive ones. We call for further studies with a larger sample.

Association between Inflammatory and Obesity Markers in a Swiss Population-Based Sample (CoLaus Study).

Objective: To assess the associations between obesity markers (BMI, waist circumference and %body fat) and inflammatory markers (interleukin-1β (IL-1β); interleukin-6 (IL-6); tumor necrosis factor-α (TNF-α) and high-sensitivity C-reactive protein (hs-CRP)). Methods: Population sample of 2,884 men and 3,201 women aged 35-75 years. Associations were assessed using ridge regression adjusting for age, leisure-time physical activity, and smoking. Results: No differences were found in IL-1β levels between participants with increased obesity markers and healthy counterparts; multivariate regression showed %body fat to be negatively associated with IL-1β. Participants with high %body fat or abdominal obesity had higher IL-6 levels, but no independent association between IL-6 levels and obesity markers was found on multivariate regression. Participants with abdominal obesity had higher TNF-α levels, and positive associations were found between TNF-α levels and waist circumference in men and between TNF-α levels and BMI in women. Obese participants had higher hs-CRP levels, and these differences persisted after multivariate adjustment; similarly, positive associations were found between hs-CRP levels and all obesity markers studied. Conclusion: Obesity markers are differentially associated with cytokine levels. %Body fat is negatively associated with IL-1β; BMI (in women) and waist circumference (in men) are associated with TNF-α; all obesity markers are positively associated with hs-CRP. Copyright © 2012 S. Karger GmbH, Freiburg.

Frequency and chronology of extraintestinal manifestations in the Swiss Inflammatory Bowel Disease Cohort

Background: Data on the frequency of extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) is scarce, especially the one evaluating the time of occurrence of the EIM relative to IBD diagnosis. Aim: To assess the type and frequency of EIM in IBD patients and to evaluate when EIMs occur relative to IBD diagnosis. Methods: Analysis of data from the Swiss Inflammatory Bowel Disease Cohort (SIBDCS) which collects data on a large sample of IBD patients from hospitals and private practices across Switzerland starting in 2005. While parametric data are shown as mean ± SD, non-parametric data are presented as median and interquartile range (IQR). Results: A total of 1143 patients were analyzed (572 (50%) female, mean age 42.1 ± 14.4 years): 629 (55%) with Crohn's disease (CD), 501 (44%) with ulcerative colitis (UC), and 13 (1%) with indeterminate colitis (IC). Of 1143 patients, 374 (32.7%) presented with EIM (65% with CD, 33% with UC, 2% with IC). Of those patients suffering from EIMs, 37.4% presented with one, 41.7% with two, 12.4% with three, 5.3% with four, and 3.2% with five EIM during their lifetime. The IBD patients initially presented with the following EIMs: peripheral arthritis (PA) 63.4%, ankylosing spondylitis (AS) 8.1%, primary sclerosing cholangitis (PSC) 6.0%, uveitis 5.7%, oral aphthosis 5.7%, erythema nodosum (EN) 5.0%, pyoderma gangrenosum 1.8%, psoriasis 0.7%. While 92.9% of EIM occurred once IBD diagnosis was established (median 72 months, IQR 9-147 months, p < 0.001), 7.1% of EIMs preceded IBD diagnosis (median time 28 months before IBD diagnosis, IQR 7-60 months). Over a course of a lifetime, IBD patients presented with the following EIM (total exceeds 100 due to potential presence of multiple EIM): peripheral arthritis 69.3%, oral aphthosis 23%, ankylosing spondylitis 19.4%, uveitis 15.5%, erythema nodosum 14.5%, PSC 7.8%, pyoderma gangrenosum 6%, psoriasis 2.8%. Conclusion: EIMs frequently occur in a lifetime of IBD patients. The vast majority of patients present with EIMs once IBD diagnosis has been established. IBD patients most often present with peripheral arthritis, ankylosing spondylitis and PSC as their first EIM. However, peripheral arthritis, oral aphthosis, and ankylosing spondylitis are the most common EIMs in a lifetime of IBD patients.

Pathogenesis of adult-onset Still's disease: new insights from the juvenile counterpart.

Adult-onset Still's disease (AOSD) is a rare inflammatory disease characterized by the classical triad of daily fever, arthritis, and typical salmon-colored rash. Recent accumulation of knowledge, mostly arising from hereditary autoinflammatory diseases and from the systemic-onset juvenile idiopathic arthritis (sJIA), has given raise to new hypotheses on the pathophysiology of AOSD. In this review, we first discuss on the continuum between AOSD and sJIA. Then, we summarize current hypotheses on the underlying pathogenesis: (1) an infectious hypothesis; (2) an autoinflammatory hypothesis; (3) a lymphohistiocytic hypothesis; and (4) a hyperferritinemic hypothesis. Finally, we present the recent data suggesting that patients with AOSD fall into two distinct subgroups with different courses, one with prominent systemic features and one with chronic arthritis.

Ultrastructural changes of the internal limiting membrane removed during indocyanine green assisted peeling versus conventional surgery for an idiopathic epimacular membrane

Purpose:To evaluate the histological features of cellular retinal fragments on the internal limiting membrane (ILM) removed during epiretinal membrane peeling surgery with and without the aid of ICG diluted in 5% glucose Methods:ILM specimens removed from 88 eyes undergoing vitrectomy and membrane peeling surgery for idiopathic epiretinal membrane between 1995 and 2003 were reviewed retrospectively. Surgery was performed in all cases by the same surgeon using the same technique. ICG was diluted with 5% glucose. Histological analysis focused on the presence and characteristics of retinal structures on the retinal surface of the ILM. Statistical analysis compared the results between group I (conventional surgery without ICG) and group II (ICG-assisted peeling) Results:Seventy-one eyes underwent EMM surgery without the aid of ICG (group I) and seventeen underwent EMM ICG-assisted surgery assisted using ICG (group II). The amount of Muller cell debris on the retinal surface of the ILM was more significant in the group I (no ICG) than in the group II (ICG) (40.8 versus 11.8; p = 0.024). Large fragments of Muller cells were more frequently observed in the group I (no ICG) than in the group II (ICG) (63.4% versus 23.5%; p= 0.003).The presence of larger retinal elements such as neural axons and vessels were observed attached to retinal face of the ILM in 5 (7%) cases of the no-ICG group. No such retinal elements were detected in any of the histological ILM specimens of the ICG-assisted group Conclusions:The use of ICG diluted with 5% glucose in the aid of ILM removal during epiretinal membrane surgery was associated with less retinal debris attached to retinal face of the ILM compared to surgery in which ICG was not used. Our findings contradict previous reports in the literature, in which use of ICG diluted with balanced salt solution (BSS) was associated with more retinal fragments attached to the retinal face of the ILM. According to our results, we hypothesize that diluting ICG with 5% glucose may decrease the adhesion of the ILM to the underlying retinal layers such that less retinal debris is removed with peeling of the ILM.

How do Swiss Gastroenterologists assess Activity of Inflammatory Bowel Disease in Daily Practice: by Clinical Indices, Endoscopic Activity, or Biomarkers?

Background a nd A ims: There is a n ongoing d ebate which i sthe most appropriate w ay t o measure inflammatory boweldisease (IBD) activity (be it b y clinical i ndices, e ndoscopy, orbiomarkers). Accumulating evidence associates m ucosalhealing with a reduction in I BD-related s urgery andhospitalizations. We a imed to i nvestigate which outcomeparameters are used in daily practice for IBD monitoring.Methods: A q uestionnaire was sent in J uly 2010 t o all boardcertified gastroenterologists in S witzerland to evaluate t heassessment strategy of IBD activity, t he items on whichtherapeutic decisions w ere based upon, and the kind ofbiomarkers used for monitoring IBD activity.Results: Response rate was 57% (153/270). Mean physician'sage was 5 0±9years, mean duration o f gastroenterologicpractice 1 4±8years, 52% of them were working in p rivatepractice a nd 48% in h ospitals. S eventy-eight percent usedclinical activity i ndices as g old standard for IBD activityassessment, followed by 15% choosing endoscopic activity, and7% favouring biomarkers. Gastroenterologists based theirtherapeutic decisions in 70% on clinical activity indices, 24% onendoscopic activity, a nd 6% o n biomarkers. Most frequentlyused biomarkers were C-reactive protein (94%), complete bloodcount (78%) and fecal calprotectin (74%).Conclusions: I n daily p ractice, most IBD patients a remonitored based u pon t heir clinical a ctivity. B iomarkers a reperceived as l ess important compared to clinical andendoscopic activity. S imilar to activity a ssessment, alsotherapeutic decisions a re mostly made on the basis of clinicalactivity indices. The upcoming scientific evidence on the impactof mucosal h ealing does n ot yet seem to influence the dailypractice of gastroenterologists.

Differential effects of pro- and anti-inflammatory cytokines alone or in combinations on the metabolic profile of astrocytes.

We have previously reported that the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) induce profound modifications of the metabolic profile of astrocytes. The present study was undertaken to further characterize the effects of cytokines in astrocytes and to determine whether similar effects could also be observed in neurons. To do so, selected pro-inflammatory (IL-6 and interferon-γ, in addition to the above-mentioned TNFα and IL-1β) and anti-inflammatory cytokines (IL-4, IL-10, transforming growth factor-β1 and interferon-β) were applied to primary neuronal and astrocytic cultures, and key metabolic parameters were assessed. As a general pattern, we observed that pro-inflammatory cytokines increased glucose utilization in astrocytes while the anti-inflammatory cytokines IL-4 and IL-10 decreased astrocytic glucose utilization. In contrast, no significant change could be observed in neurons. When pairs of pro-inflammatory cytokines were co-applied in astrocytes, several additive or synergistic modifications could be observed. In contrast, IL-10 partially attenuated the effects of pro-inflammatory cytokines. Finally, the modifications of the astrocytic metabolism induced by TNFα + IL-1β and interferon-γ modulated neuronal susceptibility to an excitotoxic insult in neuron-astrocyte co-cultures. Together, these results suggest that pro- and anti-inflammatory cytokines differentially affect the metabolic profile of astrocytes, and that these changes have functional consequences for surrounding neurons.

High cardiovascular morbidity and mortality in myofibrillar myopathies due to DES gene mutations: a 10-year longitudinal study.

To determine incidence and type of major cardiac adverse events in patients with mutated desmin (DES) gene, we retrospectively reviewed baseline medical information, and examined the long-term outcomes of 28 DES patients (17 men, baseline mean age=37.7±14.4 years [min=9, max=71]) from 19 families. Baseline studies revealed skeletal muscle involvement in 21 patients and cardiac abnormalities in all but one patient. Over a mean follow-up of 10.4±9.4 years [min=1, max=35], cardiac death occurred in three patients, death due to cardiac comorbidities in two, one or more major cardiac adverse events in 13 patients. Among the 19 patients with mild conduction defects at baseline, eight developed high-degree conduction blocks requiring permanent pacing. Cardiac involvement was neither correlated with the type of DES mutation nor with the severity of skeletal muscle involvement. Our study underscores that in DES patients in-depth cardiac investigations are needed to prevent cardiac conduction system disease.

Comparison of interferon-gamma release assay versus tuberculin skin test for tuberculosis screening in inflammatory bowel disease.

OBJECTIVES: Reactivation of latent tuberculosis (TB) in inflammatory bowel disease (IBD) patients treated with antitumor necrosis factor-alpha medication is a serious problem. Currently, TB screening includes chest x-rays and a tuberculin skin test (TST). The interferon-gamma release assay (IGRA) QuantiFERON-TB Gold In-Tube (QFT-G-IT) shows better specificity for diagnosing TB than the skin test. This study evaluates the two test methods among IBD patients. METHODS: Both TST and IGRA were performed on 212 subjects (114 Crohn's disease, 44 ulcerative colitis, 10 indeterminate colitis, 44 controls). RESULTS: Eighty-one percent of IBD patients were under immunosuppressive therapy; 71% of all subjects were vaccinated with Bacille Calmette Guérin; 18% of IBD patients and 43% of controls tested positive with the skin test (P < 0.0001). Vaccinated controls tested positive more often with the skin test (52%) than did vaccinated IBD patients (23%) (P = 0.011). Significantly fewer immunosuppressed patients tested positive with the skin test than did patients not receiving therapy (P = 0.007); 8% of patients tested positive with the QFT-G-IT test (14/168) compared to 9% (4/44) of controls. Test agreement was significantly higher in the controls (P = 0.044) compared to the IBD group. CONCLUSIONS: Agreement between the two test methods is poor in IBD patients. In contrast to the QFT-G-IT test, the TST is negatively influenced by immunosuppressive medication and vaccination status, and should thus be replaced by the IGRA for TB screening in immunosuppressed patients having IBD.

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells.

Induction of the C/EBP homologous protein (CHOP) is considered a key event for endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is characterized by an autoimmune destruction of the pancreatic β-cells. Pro-inflammatory cytokines are early mediators of β-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in β-cells, but the role for CHOP overexpression in cytokine-induced β-cell apoptosis remains controversial. We presently observed that CHOP knockdown (KD) prevents cytokine-mediated degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner caspases 9 and 3, and apoptosis. Nuclear factor-κB (NF-κB) is a crucial transcription factor regulating β-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-κB activity and expression of key NF-κB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased IκB degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting β-cell death: (1) CHOP directly contributes to cytokine-induced β-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-κB activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis.