Ulcerative colitis: Recent advances in the understanding of disease pathogenesis

Inflammatory bowel diseases are common, complex, immune-mediated conditions with a sharply rising global prevalence. While major advances since 2000 have provided strong mechanistic clues implicating a de-regulation in the normal interaction among host genetics, immunity, microbiome, and the environment, more recent progress has generated entirely new hypotheses and also further refined older disease concepts. In this review, we focus specifically on these novel developments in the pathogenesis of ulcerative colitis

Enhanced Reputation Scoring for Online Auctions

To handle the uncertainty inherent in eCommerce transactions, reputation systems have emerged as a way to represent reliability and develop trust between transaction participants. Despite the value added by reputation systems, limitations of existent systems remain (Malaga 2001). We empirically test Porter et al.’s (2004) reputation scoring procedure, which was designed to address the shortcomings of current systems. This study uses computer simulation to replicate the auction process between buyers and sellers with reputation scores calculated using both the Porter et al. model and the eBay auction model. Results from the two models are then analyzed to show that the Porter et al. model more accurately estimates reputation scores

Amino acid changes in the spike protein of feline coronavirus correlate with systemic spread of virus from the intestine and not with feline infectious peritonitis

Recent evidence suggests that a mutation in the spike protein gene of feline coronavirus (FCoV), which results in an amino acid change from methionine to leucine at position 1058, may be associated with feline infectious peritonitis (FIP). Tissue and faecal samples collected post mortem from cats diagnosed with or without FIP were subjected to RNA extraction and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) to detect FCoV RNA. In cats with FIP, 95% of tissue, and 81% of faecal samples were PCR-positive, as opposed to 22% of tissue, and 60% of faecal samples in cats without FIP. Relative FCoV copy numbers were significantly higher in the cats with FIP, both in tissues (P < 0.001) and faeces (P = 0.02). PCR-positive samples underwent pyrosequencing encompassing position 1058 of the FCoV spike protein. This identified a methionine codon at position 1058, consistent with the shedding of an enteric form of FCoV, in 77% of the faecal samples from cats with FIP, and in 100% of the samples from cats without FIP. In contrast, 91% of the tissue samples from cats with FIP and 89% from cats without FIP had a leucine codon at position 1058, consistent with a systemic form of FCoV. These results suggest that the methionine to leucine substitution at position 1058 in the FCoV spike protein is indicative of systemic spread of FCoV from the intestine, rather than a virus with the potential to cause FIP

Inflammatory bowel disease-associated colorectal cancer: translational risks from mechanisms to medicines

The cumulative impact of chronic inflammation in patients with inflammatory bowel diseases predisposes to the development of inflammatory bowel disease-associated colorectal cancer [IBD-CRC]. Inflammation can induce mutagenesis, and the relapsing–remitting nature of this inflammation, together with epithelial regeneration, may exert selective pressure accelerating carcinogenesis. The molecular pathogenesis of IBD-CRC, termed the ‘inflammation–dysplasia–carcinoma’ sequence, is well described. However, the immunopathogenesis of IBD-CRC is less well understood. The impact of novel immunosuppressive therapies, which aim to achieve deep remission, is mostly unknown. Therefore, this timely review summarizes the clinical context of IBD-CRC, outlines the molecular and immunological basis of disease pathogenesis, and considers the impact of novel biological therapies

QuPath algorithm accurately identifies MLH1 deficient inflammatory bowel disease-associated colorectal cancers in a tissue microarray

Current methods for analysing immunohistochemistry are labour-intensive and often confounded by inter-observer variability. Analysis is time consuming when identifying small clinically important cohorts within larger samples. This study trained QuPath, an open-source image analysis program, to accurately identify MLH1-deficient inflammatory bowel disease-associated colorectal cancers (IBD-CRC) from a tissue microarray containing normal colon and IBD-CRC. The tissue microarray (n = 162 cores) was immunostained for MLH1, digitalised, and imported into QuPath. A small sample (n = 14) was used to train QuPath to detect positive versus no MLH1 and tissue histology (normal epithelium, tumour, immune infiltrates, stroma). This algorithm was applied to the tissue microarray and correctly identified tissue histology and MLH1 expression in the majority of valid cases (73/99, 73.74%), incorrectly identified MLH1 status in one case (1.01%), and flagged 25/99 (25.25%) cases for manual review. Qualitative review found five reasons for flagged cores: small quantity of tissue, diverse/atypical morphology, excessive inflammatory/immune infiltrations, normal mucosa, or weak/patchy immunostaining. Of classified cores (n = 74), QuPath was 100% (95% CI 80.49, 100) sensitive and 98.25% (95% CI 90.61, 99.96) specific for identifying MLH1-deficient IBD-CRC; κ = 0.963 (95% CI 0.890, 1.036) (p &lt; 0.001). This process could be efficiently automated in diagnostic laboratories to examine all colonic tissue and tumours for MLH1 expression

Immediate-release granule formulation of hydrocortisone, Alkindi®, for treatment of paediatric adrenal insufficiency (Infacort development programme)

INTRODUCTION: Treatment of paediatric patients with adrenal insufficiency is challenging due to the lack of appropriate glucocorticoid preparations for children, and the use of either pharmacy- or parent-compounded hydrocortisone tablets. Alkindi (hydrocortisone granules in capsules for opening) is a new therapeutic option for paediatric adrenal insufficiency. Areas Covered: Drawbacks of current therapy and formulation and clinical trial programme for Alkindi. Expert Commentary: Compounding hydrocortisone has multiple issues including inconsistent dosing with under and over treatment and practical problems for parents who compound the drug themselves or travel long distances to a compounding pharmacy and the cost of compounding by the pharmacy. Alkindi® is a novel paediatric formulation of immediate release hydrocortisone licensed for use in paediatric adrenal insufficiency. Alkindi® is formulated to address the needs of neonates, infants and young children, being available at appropriate paediatric doses of 0.5, 1.0, 2.0 and 5.0 mg, is multiparticulate, allowing either direct oral dosing or dosing mixed with food, is taste masked to obscure the bitter taste of hydrocortisone and is bioequivalent to current hydrocortisone preparations. Clinical trials in young children with adrenal insufficiency demonstrated cortisol levels after dosing similar to those seen in healthy children and the drug was well tolerated and favoured over current therapy by parents. Alkindi® will provide a licenced treatment option for accurate dosing in children with adrenal insufficiency where compounded adult tablets of hydrocortisone are unsuitable

Fossilisation processes and our reading of animal antiquity

Estimates for animal antiquity exhibit a significant disconnect between those from molecular clocks, which indicate crown animals evolved ∼800 million years ago (Ma), and those from the fossil record, which extends only ∼574 Ma. Taphonomy is often held culpable: early animals were too small/soft/fragile to fossilise, or the circumstances that preserve them were uncommon in the early Neoproterozoic. We assess this idea by comparing Neoproterozoic fossilisation processes with those of the Cambrian and its abundant animal fossils. Cambrian Burgess Shale-type (BST) preservation captures animals in mudstones showing a narrow range of mineralogies; yet, fossiliferous Neoproterozoic mudstones rarely share the same mineralogy. Animal fossils are absent where BST preservation occurs in deposits ≥789 Ma, suggesting a soft maximum constraint on animal antiquity

Novel biomarkers for risk stratification of Barrett's oesophagus associated neoplastic progression-epithelial HMGB1 expression and stromal lymphocytic phenotype

The preparation of this paper was funded in part by the Pathological Society of Great Britain and Ireland (intercalated degree educational studentship to R.J.P.). All data is published within this paper and within accompanying supporting files (indicated in text) and accessed via weblink on the journal site.Peer reviewedPublisher PD

Interleukin-27 regulates the function of the gastrointestinal epithelial barrier in a human tissue derived organoid model

Funding: This research was funded by CICRA (CICRA: better lives for children with crohns and colitis. Available online: https://www.cicra.org (last accessed on 23 January 2022); Ph.D. studentship to DBP) and an NHS Grampian Endowment project grant. Acknowledgments: We wish to acknowledge the Grampian Tissue Biorepository for assistance in tissue preparation. Organoids were stored at −80 ◦C at the University of Aberdeen. Graphical abstract was created using Biorender with a licence for use in publication (agreement number AD22YOD1N6). DBP now at Lydia Becker Institute of Immunology and Inflammation and Wellcome Centre for Cell-Matrix Research, University of Manchester, UKPeer reviewedPublisher PD