Interstitial Cells of Cajal : Pathology, injury and repair

Interstitial cells of cajal (ICC) are specialised cells located within the musculature of the gastrointestinal tract (GIT). Although they form only 5% of the cells in the musculature of the GIT, they play a critical role in regulating smooth muscle function and GIT motility in coordination with the enteric nervous system. C-kit is a transmembrane glycoprotein that plays a critical role in ICC development and maturation. Physiological conditions such as ageing, as well as pathological conditions that have different disease processes, negatively affect ICC networks and function. Absent or disordered ICC networks can be associated with disorders in GIT motility. This review highlights the mechanism of ICC recovery from various types of injury which entails understanding the development of ICC and the factors affecting it. ICC transformation into malignant tumours (gastrointestinal stromal tumours) and their potential as contributors to therapeutic resistance is also discussed

Guillain-Barre syndrome:expanding the concept of molecular mimicry

Guillain-Barre syndrome (GBS) is a rapidly progressive, monophasic, and potentially devastating immune-mediated neuropathy in humans. Preceding infections trigger the production of cross-reactive antibodies against gangliosides concentrated in human peripheral nerves. GBS is elicited by at least five distinct common bacterial and viral pathogens, speaking to the notion of polymicrobial disease causation. This opinion emphasizes that GBS is the best-supported example of true molecular mimicry at the B cell level. Moreover, we argue that mechanistically, single and multiplexed microbial carbohydrate epitopes induce IgM, IgA, and IgG subclasses in ways that challenge the classic concept of GBS. Finally, we discuss how GBS can be exemplary for driving innovation in diagnostics and immunotherapy for other antibody-driven neurological diseases

Two Independent Networks of Interstitial Cells of Cajal Work Cooperatively with the Enteric Nervous System to Create Colonic Motor Patterns

Normal motility of the colon is critical for quality of life and efforts to normalize abnormal colon function have had limited success. A better understanding of control systems of colonic motility is therefore essential. We report here a hypothesis with supporting experimental data to explain the origin of rhythmic propulsive colonic motor activity induced by general distention. The theory holds that both networks of interstitial cells of Cajal (ICC), those associated with the submuscular plexus (ICC–SMP) and those associated with the myenteric plexus (ICC–MP), orchestrate propagating contractions as pacemaker cells in concert with the enteric nervous system (ENS). ICC–SMP generate an omnipresent slow wave activity that causes propagating but non-propulsive contractions (“rhythmic propagating ripples”) enhancing absorption. The ICC–MP generate stimulus-dependent cyclic depolarizations propagating anally and directing propulsive activity (“rhythmic propulsive motor complexes”). The ENS is not essential for both rhythmic motor patterns since distention and pharmacological means can produce the motor patterns after blocking neural activity, but it supplies the primary stimulus in vivo. Supporting data come from studies on segments of the rat colon, simultaneously measuring motility through spatiotemporal mapping of video recordings, intraluminal pressure, and outflow measurements

First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques

Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders. This Consensus Statement provides a conceptual and methodological framework to expand research on colonic motility in experimental animals and humans. The work is intended to facilitate the development of new drugs for common colonic motility disorders and of appropriate diagnostic and therapeutic algorithms for the management of paediatric and adult patients

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Tumor biomarkers:association with heart failure outcomes

Background: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. Objectives: To explore the association between tumor biomarkers and HF outcomes. Methods: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumor biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1, and AFP. Results: During a median follow-up of 21 months, 555 (27%) patients reached the primary endpoint of all-cause mortality. CA125, CYFRA 21-1, CEA, and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P<0.001, P for trend <0.001), and were respectively associated with a hazard ratio of 1.17 (95% CI 1.12 – 1.23; P<0.0001), 1.45 (95% CI 1.30 – 1.61; P<0.0001), 1.19 (95% CI 1.09 – 1.30; P =0.006), and 1.10 (95% CI 1.05 – 1.16; P<0.001)for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, hemoglobin, and beta-blocker). All tumor biomarkers (except AFP) had significant associations with secondary endpoints (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality, and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a non-inferior AUC compared to NT-proBNP (0.68) for all-cause mortality (P =0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC =0.71) improved the predictive value of the model for all-cause mortality (P =0.0002 compared to NT-proBNP). Conclusions: Several established tumor biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumor biomarkers are also dysregulated in HF

Characterization of Simultaneous Pressure Waves as Biomarkers for Colonic Motility Assessed by High-Resolution Colonic Manometry

Simultaneous pressure waves (SPWs) in manometry recordings of the human colon have been associated with gas expulsion. Our hypothesis was that the SPW might be a critical component of most colonic motor functions, and hence might act as a biomarker for healthy colon motility. To that end, we performed high-resolution colonic manometry (HRCM), for the first time using an 84-sensor (1 cm spaced) water-perfused catheter, in 17 healthy volunteers. Intraluminal pressure patterns were recorded during baseline, proximal and rectal balloon distention, after a meal and following proximal and rectal luminal bisacodyl administration. Quantification was performed using software, based on Image J, developed during this study. Gas expulsion was always associated with SPWs, furthermore, SPWs were associated with water or balloon expulsion. SPWs were prominently emerging at the termination of proximal high amplitude propagating pressure waves (HAPWs); we termed this motor pattern HAPW-SPWs; hence, SPWs were often not a pan-colonic event. SPWs and HAPW-SPWs were observed at baseline with SPW amplitudes of 12.0 ± 8.5 mmHg and 20.2 ± 7.2 mmHg respectively. The SPW occurrence and amplitude significantly increased in response to meal, balloon distention and luminal bisacodyl, associated with 50.3% anal sphincter relaxation at baseline, which significantly increased to 59.0% after a meal, and 69.1% after bisacodyl. Often, full relaxation was achieved. The SPWs associated with gas expulsion had a significantly higher amplitude compared to SPWs without gas expulsion. SPWs could be seen to consist of clusters of high frequency pressure waves, likely associated with a cluster of fast propagating, circular muscle contractions. SPWs were occasionally observed in a highly rhythmic pattern at 1.8 ± 1.2 cycles/min. Unlike HAPWs, the SPWs did not obliterate haustral boundaries thereby explaining how gas can be expelled while solid content can remain restrained by the haustral boundaries. In conclusion, the SPW may become a biomarker for normal gas transit, the gastrocolonic reflex and extrinsic neural reflexes. The SPW assessment reveals coordination of activities in the colon, rectum and anal sphincters. SPWs may become of diagnostic value in patients with colonic dysmotility

Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases