Background & Aims: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus ...(chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn’s disease (CD) or ulcerative colitis (UC). Methods: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C→T), and OCTN2 variant (SLC22A5 −207G→C) was performed using the TaqMan system. Results: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D′, >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. Conclusions: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required.
Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) ...signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis.
Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C-->G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model.
HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.
ObjectiveWe aimed to investigate the clinical utility of follow-up oesophagogastroduodenoscopy (OGD2) in patients with severe oesophagitis (Los Angeles grades C or D) through evaluating the yield of ...Barrett’s oesophagus (BO), cancer, dysplasia and strictures. Second, we aimed to determine if the Clinical Frailty Scale (CFS) may be used to identify patients to undergo OGD2s.Design/methodPatients in NHS Lothian with an index OGD (OGD1) diagnosis of severe oesophagitis between 1 January 2014 and 31 December 2015 were identified. Univariate analysis identified factors associated with grade. Patients were stratified by frailty and a diagnosis of stricture, cancer, dysplasia and BO.ResultsIn total 964 patients were diagnosed with severe oesophagitis, 61.7% grade C and 38.3% grade D. The diagnostic yield of new pathology at OGD2 was 13.2% (n=51), new strictures (2.3%), dysplasia (0.5%), cancer (0.3%) and BO (10.1%). A total of 140 patients had clinical frailty (CFS score ≥5), 88.6% of which were deceased at review (median of 76 months). In total 16.4% of frail patients underwent OGD2s and five new pathologies were diagnosed, none of which were significantly associated with grade. Among non-frail patients at OGD2, BO was the only pathology more common (p=0.010) in patients with grade D. Rates of cancer, dysplasia and strictures did not vary significantly between grades.ConclusionOur data demonstrate that OGD2s in patients with severe oesophagitis may be tailored according to clinical frailty and only be offered to non-frail patients. In non-frail patients OGD2s have similar pick-up rates of sinister pathology in both grades of severe oesophagitis.
Background & Aims The mechanisms by which specific mutations in NOD2 / CARD15 increase the risk for Crohn's disease (CD) are unclear. We identified proteins that interact with NOD2 and investigated ...them by expression, genetic, and functional analyses. Methods By using a yeast 2-hybrid screen of an intestinal epithelial library, we identified proteins that interact with NOD2 and confirmed the interactions in mammalian cells using co-immunoprecipitation. We used microarray analysis to analyze gene expression patterns in 302 intestinal biopsy samples (129 from patients with ulcerative colitis UC, 106 with CD, and 67 controls). Eighty single-nucleotide polymorphisms within the genes that encoded 6 interacting proteins were genotyped in a discovery cohort (869 cases of inflammatory bowel disease IBD, 885 controls) and a replication cohort (504 patients with IBD, 713 controls). We investigated interaction between transducin-like enhancer of split 1 (TLE1) and NOD2 in HEK293 cells. Results We identified 6 NOD2-interacting proteins (TLE1, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 GALNT2, HIV-1 Tat interactive protein HTATIP, Vimentin, fission 1 (mitochondrial outer membrane) homolog FIS1, and protein phosphatase 2, regulatory subunit B′, epsilon isoform PPP2R5E). Of these, expression of GALNT2 (CD, P = .004) and vimentin (CD, P = .006; UC, P = .0025) was altered in patients with IBD compared with controls. Single-nucleotide polymorphisms within TLE1 were associated with susceptibility to CD, specifically with ileal disease (rs6559629, P = 3.1 × 10−5 ; odds ratio, 1.45). The TLE1 risk allele is required for susceptibility to CD in carriers of NOD2 mutations. In cells, TLE1 and NOD2 co-localized around the nuclear membrane and TLE1 inhibited activation of nuclear factor-κB by NOD2. Conclusions Epistatic and biological interactions between TLE1 and NOD2 are involved in IBD pathogenesis. NOD2 might be involved in a series of pathways such as epigenetic regulation of expression (via TLE1 and HTATIP), biosynthesis of mucin (via GALNT2), apoptosis (via PPP2R5E and FIS1), and integrity of the intracellular cytoskeleton (vimentin).
Abstract Background Three-dimensional imaging in capsule endoscopy is not currently feasible due to hardware limitations. However, software algorithms that enable three-dimensional reconstruction in ...capsule endoscopy are available. Methods Feasibility study. A phantom was designed to test the accuracy of three-dimensional reconstruction. Thereafter, 192 small-bowel capsule endoscopy images (of vascular: 50; inflammatory: 73; protruding structures: 69) were reviewed with the aid of a purpose-built three-dimensional reconstruction software. Seven endoscopists rated visualisation improved or non-improved. Subgroup analyses performed for diagnostic category, diagnosis, image surface morphology and colour and SBCE equipment used (PillCam® vs. MiroCam® ). Results Overall, phantom experiments showed that the three-dimensional reconstruction software was accurate at 90% of red, 70% of yellow and 45% of white phantom models. Enhanced visualisation for 56% of vascular, 23% of inflammatory and <10% of protruding structures was noted ( P = 0.007, 0.172 and 0.008, respectively). Furthermore, three-dimensional software application enhanced 53.7% of red, 21.8% of white, 17.3% of red and white, and 9.2% of images of lesions with colour similar to that of the surrounding mucosa, P < 0.0001. Conclusions Application of a three-dimensional reconstruction software in capsule endoscopy leads to image enhancement for a significant proportion of vascular, but less so for inflammatory and protruding lesions. Until optics technology allows hardware-enabled three-dimensional reconstruction, it seems a plausible alternative.
ObjectiveDebate is ongoing regarding the need for universal endoscopic follow-up to ensure gastric ulcer healing. We aimed to assess the value of follow-up oesophago-gastro-duodenoscopies (OGDs) for ...gastric ulcer healing and stratify patients according to risk of malignancy by developing a risk score.Design/methodAll patients in National Health Service (NHS) Lothian with an index OGD and a diagnosis of gastric ulcer between 1 January 2014 and 31 December 2018 were identified. Data were analysed with logistic regression to identify factors significantly associated with a diagnosis of cancer; a risk score was derived and externally validated.Results778 patients were identified and 60.3% (469/778) of patients had a follow-up OGD. 8.6% (66/778) of patients were diagnosed with cancer. No cases of cancer were found on follow-up OGD of a benign appearing ulcer with negative biopsies. Macroscopic suspicion of malignancy was present at index OGD in 100% (3/3) of those diagnosed with cancer on subsequent OGDs. Older age (p=0.014), increased ulcer size (p<0.001) and non-antral location (p=0.030) were significantly associated with malignancy. A risk score (area under the curve (AUC) 0.868, p<0.001, minimum score=0, maximum score=6) was derived from these variables. 78.0% of patients with malignant ulcers scored ≥3, only 15.8% with benign ulcers scored ≥3 (negative predictive value (NPV) 97.4%). External validation yielded an AUC of 0.862 (p<0.001) and NPV of 98.6%; 84.0% of those with malignant ulcers scored ≥3.ConclusionUlcers with a combination of macroscopically benign appearances, at least six negative biopsies and a low risk score do not necessarily need endoscopic follow-up.
Background:
Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). ...The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF‐κB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD.
Methods:
Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2‐mediated activation of NF‐κB.
Results:
The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval CI 1.34–2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44–0.90). The PepT1 variant encoded by the C allele (PepT1‐Ser117) was associated with reduced signaling downstream of NOD2 (P < 0.0001 compared to Pept1‐Asn117).
Conclusions:
A functional polymorphism in the SLC15A1 gene might be of relevance to inflammation and antibacterial responses in IBD. Whether this polymorphism truly contributes to disease susceptibility needs to be further addressed, and should stimulate additional studies in other populations. Inflamm Bowel Dis 2009
To compare colonoscopy quality with nitrous oxide gas (Entonox
) against intravenous conscious sedation using midazolam plus opioid.
A retrospective analysis was performed on a prospectively held ...database of 18608 colonoscopies carried out in Lothian health board hospitals between July 2013 and January 2016. The quality of colonoscopies performed with Entonox was compared to intravenous conscious sedation (abbreviated in this article as IVM). Furthermore, the quality of colonoscopies performed with an unmedicated group was compared to IVM. The study used the following key markers of colonoscopy quality: (1) patient comfort scores; (2) caecal intubation rates (CIRs); and (3) polyp detection rates (PDRs). We used binary logistic regression to model the data.
There was no difference in the rate of moderate-to-extreme discomfort between the Entonox and IVM groups (17.9%
18.8%; OR = 1.06, 95%CI: 0.95-1.18,
= 0.27). Patients in the unmedicated group were less likely to experience moderate-to-extreme discomfort than those in the IVM group (11.4%
18.8%; OR = 0.71, 95%CI: 0.60-0.83,
< 0.001). There was no difference in caecal intubation between the Entonox and IVM groups (94.4%
93.7%; OR = 1.08, 95%CI: 0.92-1.28,
= 0.34). There was no difference in caecal intubation between the unmedicated and IVM groups (94.2%
93.7%; OR = 0.98, 95%CI: 0.79-1.22,
= 0.87). Polyp detection in the Entonox group was not different from IVM group (35.0%
33.1%; OR = 1.01, 95%CI: 0.93-1.10,
= 0.79). Polyp detection in the unmedicated group was not significantly different from the IVM group (37.4%
33.1%; OR = 0.97, 95%CI: 0.87-1.08,
= 0.60).
The use of Entonox was not associated with lower colonoscopy quality when compared to intravenous conscious sedation using midazolam plus opioid.
Boys' underachievement is grabbing headlines in the education debate, and it has never been more important to solve the problem. This book offers clear and practical strategies to headteachers, ...classroom teachers and other professionals for ways to address the issue. The book looks at: *reasons for boys' underachievement *ways of adapting teaching styles to maximise learning gains for boys ... and girls *guidance on how to plan successful pyramid, whole-school and classroom approaches *practical strategies for subject leaders and teachers *examples of successful case studies After introductory chapters examining whole-school issues and strategies there are further subject-specific chapters that advise on particular teaching approaches.
Colin Noble is a PSE Advisor and Raising Boys Achievement Manager in Kirklees Local Education Authority and has been responsible for publishing a range of packs, videos, leaflets and posters on the subject of raising boys achievement. Wendy Bradford is a Deputy Headteacher at a large and successful mixed secondary school with a wealth of classroom experience behind her.
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