ObjectiveColonic mucosa-associated Escherichia coli are increased in Crohn's disease (CD) and colorectal cancer (CRC). They variously haemagglutinate, invade epithelial cell lines, replicate within macrophages, translocate across M (microfold) cells and damage DNA. We investigated genes responsible for these effects and their co-association in colonic mucosal isolates.DesignA fosmid library yielding 968 clones was prepared in E coli EPI300-T1 using DNA from a haemagglutinating CRC isolate, and resulting haemagglutinating clones were 454-pyrosequenced. PCR screening was performed on 281 colonic E coli isolates from inflammatory bowel disease (IBD) (35 patients), CRC (21) and controls (24; sporadic polyps or irritable bowel syndrome).Results454-Pyrosequencing of fosmids from the haemagglutinating clones (n=8) identified the afimbrial adhesin afa-1 operon. Transfection of afa-1 into E coli K-12 predictably conferred diffuse adherence plus invasion of HEp-2 and I-407 epithelial cells, and upregulation of vascular endothelial growth factor. E coli expressing afaC were common in CRC (14/21, p=0.0009) and CD (9/14, p=0.005) but not ulcerative colitis (UC; 8/21) compared with controls (4/24). E coli expressing both afaC and lpfA (relevant to M-cell translocation) were common in CD (8/14, p=0.0019) and CRC (14/21, p=0.0001), but not UC (6/21) compared with controls (2/24). E coli expressing both afaC and pks (genotoxic) were common in CRC (11/21, p=0.0015) and UC (8/21, p=0.022), but not CD (4/14) compared with controls (2/24). All isolates expressed dsbA and htrA relevant to intra-macrophage replication, and 242/281 expressed fimH encoding type-1 fimbrial adhesin.ConclusionsIBD and CRC commonly have colonic mucosal E coli that express genes that confer properties relevant to pathogenesis including M-cell translocation, angiogenesis and genotoxicity.

Ca2+- and voltage-activated K+ channels are found in many electrically excitable cells and have an important role in regulating electrical activity. Recently, the large K+ channel has been found in the baso-lateral plasma membranes of salivary gland acinar cells, where it may be important in the regulation of salt transport. Using patch-clamp methods to record single-channel currents from excised fragments of baso-lateral acinar cell membranes in combination with current recordings from isolated single acinar cells and two- and three-cell clusters, we have now for the first time characterized the K+ channels quantitatively. In pig pancreatic acini there are 25-60 K+ channels per cell with a maximal single channel conductance of about 200 pS. We have quantified the relationship between internal ionized Ca2+ concentration [( Ca2+]i) membrane potential and open-state probability (p) of the K+ channel. By comparing curves obtained from excised patches relating membrane potential to p, at different levels of [Ca2+]i, with similar curves obtained from intact cells, [Ca2+]i in resting acinar cells was found to be between 10(-8) and 10(-7) M. In microelectrode experiments acetylcholine (ACh), gastrin-cholecystokinin (CCK) as well as bombesin peptides evoked Ca2+-dependent opening of the K+ conductance pathway, resulting in membrane hyperpolarization. The large K+ channel, which is under strict dual control by internal Ca2+ and voltage, may provide a crucial link between hormone-evoked increase in internal Ca2+ concentration and the resulting NaCl-rich fluid secretion.

Summary Background Anti‐tumour necrosis factor (TNF) agents are effective in Crohn's disease but some patients lose response and require alternative biologic therapy. There are few data on comparative effectiveness of vedolizumab and ustekinumab in this setting. Aim To compare the effectiveness of ustekinumab and vedolizumab in anti‐TNF‐refractory Crohn's disease over 12 months. Methods Patients commencing ustekinumab or vedolizumab for anti‐TNF‐refractory Crohn's disease with minimum follow‐up of 12 months were included. The primary outcome measure was the difference in steroid‐free remission rates at end of induction (2 months) and at 12 months. We also assessed rates of clinical response and remission, treatment persistence, surgery and adverse events in both groups. We performed logistic regression analysis to assess factors associated with steroid‐free remission and clinical response and remission. Results We included 85 patients commencing vedolizumab and 45 commencing ustekinumab. In an unadjusted model, rates of steroid‐free and clinical remission were significantly higher among ustekinumab‐treated patients. After adjusting for confounders, steroid‐free remission was higher among ustekinumab‐treated patients at 2 months (odds ratio, OR 2.79, 95% confidence interval, CI 1.06‐7.39, P = 0.038) and 12 months (OR 2.01, 95% CI 0.89‐4.56, P = 0.095). More patients treated with ustekinumab remained on therapy at the end of 12 months (84.4% vs 61.5%, P = 0.007). Conclusions Ustekinumab appeared more effective in treating anti‐TNF‐refractory Crohn's disease and more patients persisted with therapy.

For many years it has been recognized that seemingly benign neck cysts may contain carcinoma. The true incidence is unknown. This paper investigated nine out of 270 patients presenting with a neck mass — which proved to contain a squamous carcinoma. Records (from a 30-year period) of over 3400 patients with squamous carcinoma of the head and neck, were examined. The histology slides were reviewed, the number of cystic lesions was noted and also the clinical outcome. Out of the 270 patients nine presented with a cystic lesion and these were studied. Six cystic lesions were originally diagnosed as branchial cysts although the youngest age was 39 years. All patients underwent a simple excision.In six cases the tonsil was the primary site, in one the primary was in the base of tongue and in two the primary remained occult. One-third of the patients had died of their disease by the time this report was written and the maximum follow-up time for the remaining patients was 18 months. Therefore 16 per cent of branchial cysts in this series represented metastases from squamous cell carcinoma.At the Royal Liverpool University Hospital only 25 patients had branchial cysts excised between 1988 and 1993: out of these only four contained squamous carcinoma.In patients over 40 years of age panendoscopy and ipsilateral tonsillectomy is mandatory prior to cyst excision.

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Background Intravenous (IV) infliximab is a well-established therapy for inflammatory bowel diseases (IBD) patients. A subcutaneous (SC) formulation of infliximab (CT-P13) has recently been shown to be as effective as IV infliximab after 2 doses of IV induction in a randomised trial but there are no data to support elective switching of patients on maintenance IV infliximab therapy. We aimed to assess the effectiveness of an elective switching program to SC CT-P13 in patients treated with IV infliximab. Methods Patients on established maintenance IV infliximab who switched to SC CT-P13 were included in this retrospective multi-centre cohort study. Disease activity was monitored serially with Harvey-Bradshaw Index (HBI) for Crohn’s disease (CD) and simple clinical colitis activity index (SCCAI) for up to 12 months at months 3, 6 and 12. Faecal calprotectin (FC) and C-reactive protein (CRP) was recorded at baseline and follow-up, if available. Infliximab trough levels were measured prior to switch and at months 3, 6 and 12 following switch. The primary outcome measure was treatment persistence at last follow-up. Secondary outcome measures included infliximab pharmacokinetics (PK), safety, need for corticosteroid rescue therapy and need for surgery. Results We included 181 patients of who 115 (63.5%) had CD. The majority (72.4%) were on 8-weekly dosing of intravenous infliximab prior to switching and more than half (59.1%) were on concomitant immunomodulatory therapy. The majority of patients (CD: N=106, 92.2%, UC: N=46, 76.7% and IBD-U: N=5, 83.3%) were in clinical remission. Treatment persistence rate was high (N=167, 92.3%) and only 14 patients (7.7%) stopped treatment during the follow-up period. There was no significant difference between baseline and repeat measurements at 3, 6 or 12 months for HBI, SCCAI, CRP or FC. Of the total cohort, 25 patients (21.7%) had perianal CD. Of these, only two patients (8%) had worsening of perianal CD and required antibiotic therapy and further examination under anaesthesia (EUA). Both these patients also switched back to intravenous infliximab. Median infliximab level increased from a baseline of 8.9 µg/dl (range 0.4-16) to 16.0 µg/dl (range 2.3-16, P<0.001) at 3 months. Serum levels stayed stable at 6 months (median 16 µg/dl, range 0.3-17.2) and 12 months (median 16 µg/dl, range 0.3-19.1, both P<0.001 compared to baseline). Among the variables examined, only antibodies to infliximab (ATI) was associated with infliximab levels (OR -13.369, 95% CI -15.405, -11.333, P<0.001). A total of 14 patients (7.7%) developed ATI of which 9 (64.3%) were on concomitant immunomodulatory therapy. Immunomodulatory therapy was not significantly associated with development of ATI (P=0.15). In a subset of patients receiving escalated IV infliximab dosing frequency prior to switch, no difference in treatment persistence was observed in patients receiving weekly versus alternate weekly SC CT-P13. Patient acceptance and satisfaction rates with SC CT-P13 were very high. Conclusions Among patients on IV infliximab maintenance therapy switched to SC CT-P13, we observed high treatment persistence rates and low rates of immunogenicity with no change in clinical disease activity indices or biomarkers. Infliximab levels increased after switch to SC CT-P13 and only ATI was associated with serum infliximab levels. Patient acceptance and satisfaction rates were high with SC CT-P13.

Twin studies have demonstrated the importance of environmental factors in the pathogenesis of inflammatory bowel disease, but progress has been relatively slow in identifying these, with the exception of smoking, which is positively associated with Crohn's disease and negatively associated with ulcerative colitis. Genetic studies have identified risk alleles which are involved in host-bacterial interactions and the mucosal barrier, and evidence is building for a likely pathogenic role for changes in the gut microbiome, with respect to both faecal and mucosa-associated microbiota. Some of these changes may be secondary to inflammation, nevertheless promising new therapeutic targets are beginning to emerge.

Article first published online 1 April 2015. Supplemental Digital Content is Available in the Text.