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Competing Interests: C.B. served as a consultant for AbbVie, Celtrion, Ferring, Galapagos, Janssen, MSD, and Takeda. E.V.S. has served as speaker for AbbVie, Agave, AG Pharma, Alfasigma, Aurora Pharma, Cadigroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; has served as a consultant for AbbVie, Agave, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Diadema Farmaceutici, Dr Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlé, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas, Takeda, and Unifarco; and has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, and Zeta Farmaceutici. M.M. has received lecture fees and has been an Advisory Board member for Takeda, Galapagos, Biogen, Aurora Pharma, and AbbVie. F.A.C. served as consultant and advisory board member for Mundipharma, AbbVie, MS&D, Takeda, Janssen, Roche, and Celgene; has received lecture fees from AbbVie, Amgen, Ferring, Takeda, and Allergy Therapeutics; and has received unrestricted research grants from Giuliani, Sofar, MSD, Takeda, and AbbVie. G.B. served as speaker for AbbVie, Takeda, Galapagos, Lilly, and Janssen. A.V. has received lecture fees from and has been an advisory board member for Janssen-Cilag, Takeda, Pfizer, Ferring, MSD, Zambon, AbbVie, and Celltrion. F.S. has served as a lecturer for Sanofi. F.F. received consulting fees from Amgen, AbbVie, and Galapagos and lecture fees from Janssen and Pfizer; has served as an advisory board member; and/or received lecture grants from AbbVie, Biogen, Galapagos, Janssen, MSD, Pfizer, Takeda Pharmaceuticals. E.C. served as advisory board member for Takeda and AbbVie; and received lecture fees from AbbVie, Janssen, Galapagos, Ferring, Takeda. M.B.P. served as advisory board member and received lecture fee from MSD, AbbVie, Janssen, Pfizer, and Takeda. A.A. has been an advisory board member for Galapagos and consultant for AbbVie, Galapagos, Pfizer, Takeda, and Janssen. M.C. served as a speaker or advisory board member for Takeda, MSD, AbbVie, Shire, Fresenius, and Janssen. B.B. has served as a speaker for AbbVie, Agave, Alfasigma, AG Pharma, Janssen, MSD, Procise, Sofar, Takeda, and Unifarco. S.S. has received consultancy and lecture fees and has been an advisory board member for AbbVie, Arena, Ferring, Galapagos, Gilead, Janssen, MSD, Pfizer, and Takeda. P.B. has participated on advisory boards for Janssen and Takeda. A.A. has received consulting and/or advisory board fees from AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, and Takeda; has received lecture and speaker bureau fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mitsubishi Tanabe, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, and TiGenix; and has received research grants from Biogen, MSD, Pfizer, and Takeda. L.B. has received lecture fees, consultancy fees, or advisory board honoraria from Abbvie, Aliveda, Janssen, Noos, Pfizer, Pharmanutra, Takeda, and Zambon. S.D. received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor. G.F., M.M., G.B., A.M., C.C., M.C., L.C., V.C., A.S., and F.S.C. declare no conflict of interest.

Achalasia is a rare and complex esophageal disease of unknown etiology characterized by difficulty in swallowing due to the lack of opening of the lower esophageal sphincter and the absence of esophageal peristalsis. Recent advancements in technology for analyzing DNA, RNA and biomolecules in high-throughput techniques are offering new opportunities to better understand the etiology and the pathogenetic mechanisms underlying achalasia. Through this narrative review of the scientific literature, we aim to provide a comprehensive assessment of the state-of-the-art knowledge on omics of achalasia, with particular attention to those considered relevant to the pathogenesis of the disease. The notion and importance of the multi-omics approach, its limitations and future directions are also introduced, and it is highlighted how the integration of single omics data will lead to new insights into the development of achalasia and offer clinical tools which will allow early diagnosis and better patient management.

Inflammatory bowel diseases (IBD) are classified into two entities, namely Crohn's disease (CD) and ulcerative colitis (UC), which differ in disease trajectories, genetics, epidemiological, clinical, endoscopic, and histopathological aspects. As no single golden standard modality for diagnosing IBD exists, the differential diagnosis among UC, CD, and non-IBD involves a multidisciplinary approach, considering professional groups that include gastroenterologists, endoscopists, radiologists, and pathologists. In this context, histological examination of endoscopic or surgical specimens plays a fundamental role. Nevertheless, in differentiating IBD from non-IBD colitis, the histopathological evaluation of the morphological lesions is limited by sampling and subjective human judgment, leading to potential diagnostic discrepancies. To overcome these limitations, artificial intelligence (AI) techniques are emerging to enable automated analysis of medical images with advantages in accuracy, precision, and speed of investigation, increasing interest in the histological analysis of gastrointestinal inflammation. This review aims to provide an overview of the most recent knowledge and advances in AI methods, summarizing its applications in the histopathological analysis of endoscopic biopsies from IBD patients, and discussing its strengths and limitations in daily clinical practice., Competing Interests: S Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, millennium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor. The other authors have no relevant disclosures., (© 2024 The Authors.)

Various extrinsic and intrinsic factors such as drug exposures, antibiotic treatments, smoking, lifestyle, genetics, immune responses, and the gut microbiome characterize ulcerative colitis and Crohn's disease, collectively called inflammatory bowel disease (IBD). All these factors contribute to the complexity and heterogeneity of the disease etiology and pathogenesis leading to major challenges for the scientific community in improving management, medical treatments, genetic risk, and exposome impact. Understanding the interaction(s) among these factors and their effects on the immune system in IBD patients has prompted advances in multi-omics research, the development of new tools as part of system biology, and more recently, artificial intelligence (AI) approaches. These innovative approaches, supported by the availability of big data and large volumes of digital medical datasets, hold promise in better understanding the natural histories, predictors of disease development, severity, complications and treatment outcomes in complex diseases, providing decision support to doctors, and promising to bring us closer to the realization of the "precision medicine" paradigm. This review aims to provide an overview of current IBD omics based on both individual (genomics, transcriptomics, proteomics, metagenomics) and multi-omics levels, highlighting how AI can facilitate the integration of heterogeneous data to summarize our current understanding of the disease and to identify current gaps in knowledge to inform upcoming research in this field., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Growing evidence suggests that alterations in the gut microbiome impact the development of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Although IBD often requires the use of immunosuppressant drugs and biologic therapies to facilitate clinical remission and mucosal healing, some patients do not benefit from these drugs, and the reasons for this remain poorly understood. Despite advancements, there is still a need to develop biomarkers to help predict prognosis and guide treatment decisions. The aim of this study was to investigate the gut microbiome of IBD patients using biologics to identify microbial signatures associated with responses, following standard accepted criteria. Microbiomes in 66 stool samples from 39 IBD patients, comprising 20 CD and 19 UC patients starting biologic therapies, and 29 samples from healthy controls (HCs) were prospectively analyzed via NGS and an ensemble of metagenomics analysis tools. At baseline, differences were observed in alpha and beta metrics among patients with CD, UC and HC, as well as between the CD and UC groups. The degree of dysbiosis was more pronounced in CD patients, and those with dysbiosis exhibited a limited response to biological drugs. Pairwise differential abundance analyses revealed an increasing trend in the abundance of an unannotated genus from the Clostridiales order, Gemmiger genus and an unannotated genus from the Rikenellaceae family, which were consistently identified in greater abundance in HC. The Clostridium genus was more abundant in CD patients. At baseline, a greater abundance of the Odoribacter and Ruminococcus genera was found in IBD patients who responded to biologics at 14 weeks, whereas a genus identified as SMB53 was more enriched at 52 weeks. The Collinsella genus showed a higher prevalence among non-responder IBD patients. Additionally, a greater abundance of an unclassified genus from the Barnesiellaceae family and one from Lachnospiraceae was observed in IBD patients responding to Vedolizumab at 14 weeks. Our analyses showed global microbial diversity, mainly in CD. This indicated the absence or depletion of key taxa responsible for producing short-chain fatty acids (SCFAs). We also identified an abundance of pathobiont microbes in IBD patients at baseline, particularly in non-responders to biologic therapies. Furthermore, specific bacteria-producing SCFAs were abundant in patients responding to biologics and in those responding to Vedolizumab.

An increasing amount of evidence suggests the emerging role of the gut microbiota in the development of colorectal cancer (CRC). This study aimed to elucidate the architecture of microbial communities within normal and neoplastic colonic mucosa., Methods: Microbiota were analyzed by NGS and by an ensemble of metagenomics analysis tools in a total of 69 tissues from 9 patients with synchronous colorectal neoplasia and adenomas (27 specimens: 9 from normal tissues, 9 adenomas, and 9 tumours), 16 patients with only colonic adenomas (32 specimens: 16 from normal tissues and 16 adenomas), and from healthy subjects (10 specimens of normal mucosa)., Results: Weak differences were observed in alpha and beta metrics among the synchronous tissues from CRC and controls. Through pairwise differential abundance analyses of sample groups, an increasing trend of Rikenellaceae, Pseudomonas and Fusobacterium, and decreasing trends of Staphylococcus , Actinobacillus and Gemmiger were observed in CRC, while Staphylococcus and Bifidobacterium were decreased in patients with only adenomas. At RT-qPCR analysis, Fusobacterium nucleatum was significantly enriched in all the tissues of subjects with synchronous colorectal neoplasia., Conclusion: Our findings provide a comprehensive view of the human mucosa-associated gut microbiota, emphasizing global microbial diversity mostly in synchronous lesions and proving the constant presence of Fusobacterium nucleatum, with its ability to drive carcinogenesis.

Achalasia is an esophageal smooth muscle motility disorder with unknown pathogenesis. Taking into account our previous results on the downexpression of miR-200c-3p in tissues of patients with achalasia correlated with an increased expression of PRKG1 , SULF1 , and SYDE1 genes, our aim was to explore the unknown biological interaction between these genes and human miR-200c-3p and if this relation could unravel their functional role in the etiology of achalasia. To search for putative miR-200c-3p binding sites in the 3'-UTR of PRKG1 , SULF1 and SYDE1 , a bioinformatics tool was used. To test whether PRKG1 , SULF1 , and SYDE1 are targeted by miR-200c-3p, a dual-luciferase reporter assay and quantitative PCR on HEK293 and fibroblast cell lines were performed. To explore the biological correlation between PRKG1 and miR-200c-3p, an immunoblot analysis was carried out. The overexpression of miR-200c-3p reduced the luciferase activity in cells transfected with a luciferase reporter containing a fragment of the 3'-UTR regions of PRKG1 , SULF1 , and SYDE1 which included the miR-200c-3p seed sequence. The deletion of the miR-200c-3p seed sequence from the 3'-UTR fragments abrogated this reduction. A negative correlation between miR-200c-3p and PRKG1 , SULF1 , and SYDE1 expression levels was observed. Finally, a reduction of the endogenous level of PRKG1 in cells overexpressing miR-200c-3p was detected. Our study provides, for the first time, functional evidence about the PRKG1 gene as a direct target and SULF1 and SYDE1 as potential indirect substrates of miR-200c-3p and suggests the involvement of NO/cGMP/PKG signaling in the pathogenesis of achalasia.

Celiac disease (CD) is an autoimmune disease with the destruction of small intestinal villi, which occurs in genetically predisposed individuals. At the present moment, a gluten-free diet (GFD) is the only way to restore the functionality of gut mucosa. However, there is an open debate on the effects of long-term supplementation through a GFD, because some authors report an unbalance in microbial taxa composition., Methods: For microbiome analysis, fecal specimens were collected from 46 CD individuals in GFD for at least 2 years and 30 specimens from the healthy controls (HC). Data were analyzed using an ensemble of software packages: QIIME2, Coda-lasso, Clr-lasso, Selbal, PICRUSt2, ALDEx2, dissimilarity-overlap analysis, and dysbiosis detection tests., Results: The adherence to GFD restored the alpha biodiversity of the gut microbiota in celiac people but microbial composition at beta diversity resulted as different to HC. The microbial composition of the CD subjects was decreased in a number of taxa, namely Bifidobacterium longum and several belonging to Lachnospiraceae family, whereas Bacteroides genus was found to be more abundant. Predicted metabolic pathways among the CD bacterial communities revealed an important role in tetrapyrrole biosynthesis., Conclusions: CD patients in GFD had a non-dysbiotic microbial composition for the crude alpha diversity metrics. We found significant differences in beta diversity, in certain taxon, and pathways between subjects with inactive CD in GFD and controls. Collectively, our data may suggest the development of new GFD products by modulating the gut microbiota through diet, supplements of vitamins, and the addition of specific prebiotics.

Background and study aims  Adenoma detection rate (ADR) is a well-accepted quality indicator of screening colonoscopy. In recent years, the added value of artificial intelligence (AI) has been demonstrated in terms of ADR and adenoma miss rate (AMR). To date, there are no studies evaluating the impact of AI on the performance of trainee endoscopists (TEs). This study aimed to assess whether AI might eliminate any difference in ADR or AMR between TEs and experienced endoscopists (EEs). Patients and methods  We performed a prospective observational study in 45 subjects referred for screening colonoscopy. A same-day tandem examination was carried out for each patient by a TE with the AI assistance and subsequently by an EE unaware of the lesions detected by the TE. Besides ADR and AMR, we also calculated for each subgroup of endoscopists the adenoma per colonoscopy (APC), polyp detection rate (PDR), polyp per colonoscopy (PPC) and polyp miss rate (PMR). Subgroup analyses according to size, morphology, and site were also performed. Results  ADR, APC, PDR, and PPC of AI-supported TEs were 38 %, 0.93, 62 %, 1.93, respectively. The corresponding parameters for EEs were 40 %, 1.07, 58 %, 2.22. No significant difference was found for each analysis between the two groups ( P  > 0.05). AMR and PMR for AI-assisted TEs were 12.5 % and 13 %, respectively. Sub-analyses did not show any significant difference ( P  > 0.05) between the two categories of operators. Conclusions  In this single-center prospective study, the possible impact of AI on endoscopist quality training was demonstrated. In the future, this could result in better efficacy of screening colonoscopy by reducing the incidence of interval or missed cancers., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Patients with inflammatory bowel diseases (IBD), both ulcerative colitis (UC) and Crohn's disease (CD), are at risk of developing a colorectal cancer (CRC). No information is available on the contribution of patients' genetic background to CRC occurrence. This study investigates germline alterations in patients with IBD-associated CRC., Methods: We profiled a panel of 39 genes potentially involved in cancer predisposition and searched for germline variants in IBD patients with CRC or high-grade dysplasia., Results: After clinical exclusion of genetic cancer syndromes, 25 IBD patients (4 CD and 21 UC) with CRC or high-grade dysplasia were studied. After excluding variants with low likelihood of pathogenicity (classes 1 or 2 according the International Agency for Research on Cancer [IARC]), the panel identified pathogenic variants, likely pathogenic, or variants with unknown significance in 18 patients (72%). Six patients (24%) carried pathogenic or likely variants (IARC class 5 or 4). Of the identified variants, 4 encompassed the APC region, 3 the MLH1 gene, and the remaining ones the MSH2, MSH3, monoallelic MUTYH, EPCAM, BRCA1, CHEK2, POLD1, POLE, CDKN2A, and PDGFRA genes. Four patients carried at least 2 variants in different genes. Duration of IBD was significantly shorter in carriers of 4 or 5 IARC variants (7 years; range 0-21; P = .002) and in those with variants with unknown significance (12 years; range 0-22; P = .005) compared with patients without or with only benign variations (23.5 years; range 15-34)., Conclusions: In silico analysis and sequence-based testing of germline DNA from IBD patients with CRC or high-grade dysplasia detected 24% of variants positioned in pathogenic classes. In patients with type 3, 4, and 5 variants, the onset of high-grade dysplasia or CRC was significantly earlier than in patients with benign or unidentified variants. The screening for these genes could identify IBD patients requiring a more intensive endoscopic surveillance for earlier detection of dysplastic changes., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The pathogenesis of ulcerative colitis (UC) is unknown, although genetic loci and altered gut microbiota have been implicated. Up to a third of patients with moderate to severe UC require proctocolectomy with ileal pouch ano-anastomosis (IPAA). We aimed to explore the mucosal microbiota of UC patients who underwent IPAA., Methods: For microbiome analysis, mucosal specimens were collected from 34 IPAA individuals. Endoscopic and histological examinations of IPAA were normal in 21 cases, while pouchitis was in 13 patients. 19 specimens from the healthy control (10 from colonic and 9 from ileum) were also analyzed. Data were analyzed using an ensemble of software packages: QIIME2, coda-lasso, clr-lasso, PICRUSt2, and ALDEx2., Results: IPAA specimens had significantly lower bacterial diversity as compared to normal. The microbial composition of the normal pouch was also decreased also when compared to pouchitis. Faecalibacterium prausnitzii , Gemmiger formicilis , Blautia obeum , Ruminococcus torques , Dorea formicigenerans , and an unknown species from Roseburia were the most uncommon in pouch/pouchitis, while an unknown species from Enterobacteriaceae was over-represented. Propionibacterium acnes and Enterobacteriaceae were the species most abundant in the pouchitis and in the normal pouch, respectively. Predicted metabolic pathways among the IPAA bacterial communities revealed an important role of immunometabolites such as SCFA, butyrate, and amino acids., Conclusions: Our findings showed specific bacterial signature hallmarks of dysbiosis and could represent bacterial biomarkers in IPAA patients useful to develop novel treatments in the future by modulating the gut microbiota through the administration of probiotic immunometabolites-producing bacterial strains and the addition of specific prebiotics and the faecal microbiota transplantation.

Background: Efficacy and safety of ustekinumab for the treatment of ulcerative colitis (UC) has been demonstrated in clinical trials, but few real-world data are available so far. The aim of this study was to assess effectiveness and safety of ustekinumab in a cohort of refractory UC patients., Methods: Data of patients with moderate to severe UC treated with ustekinumab were retrospectively collected. Primary endpoint was steroid-free clinical remission at weeks 24 and 52 of therapy. Secondary endpoints were treatment response, endoscopic remission, treatment persistence at 12 months and safety., Results: A total of 68 patients [males 63%; median (range) age 42 (16-72) years] were included. Almost all patients (97%) were biologics experienced. At weeks 24 and 52, 31% and 50% of patients achieved steroid-free clinical remission, 84% and 82% had clinical response, respectively. At the end of follow-up, there was a significant reduction of pMS from baseline (p < 0.001) and of steroid use (p < 0.001). At week 52, 22% of the available endoscopies (18/38) showed mucosal healing. The probability to persist in therapy at week 52 was 87%. Only one adverse event occurred., Conclusions: Data from our real-life cohort of refractory UC patients suggest satisfactory effectiveness and a good safety of ustekinumab.

Idiopathic achalasia is a disease that is characterized by the absence of peristalsis and incomplete relaxation of the lower esophageal sphincter, which is accompanied by dysphagia, regurgitation, chest pain and weight loss. The role of inflammatory infiltrates in the pathogenesis of achalasia remains controversial, although the infiltrating cell profile in the tissue has been previously characterized histologically and immunohistochemically. The present study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with achalasia and the clinical disease characteristics. The cytokine, chemokine and growth factor serum profiles of 68 patients with achalasia and 39 healthy individuals were explored using the 27-Bio-Plex Pro Human Cytokine assay. Reductions in the levels of inflammatory mediators IL-1β, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, monocyte chemoattractant protein-1, macrophage inflammatory protein-1 (MIP-1)α and MIP-1β, regulated upon activation normal T cell expressed and presumably secreted, TNF-α and VEGF were detected in the serum samples of patients with achalasia compared with those in the control group (P<0.05). However, significant associations between the expression in the levels of inflammatory factors and clinical characteristics of the patients were not found (P>0.05). These results suggest that achalasia is a disease that has a local but not a systemic inflammatory pattern. Further studies are required to improve the current understanding of the mechanism underlying this disease., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Panza et al.)

Inverted colonic diverticulum (ICD) is a rare intraluminal lesion occurring in about 0.7-1.7% of people, often endoscopically indistinguishable from polyps. Some unspecific endoscopic features may assist to distinguish polypoid ICD from true polyps. This differentiation bears relevance for the therapeutic approach, as colonic polyps require snare polypectomy, a practice which may be associated with colonic perforation in case of true ICD. The endoscopist, therefore, should be aware of the likelihood of detecting these lesions during colonoscopy. A close inspection and a gentle probing could assist in a correct diagnosis and avoid risky procedures such as biopsy or polypectomy. Rarely, a neoplasm arising over an ICD and its treatment has been described. We reported two cases, one of which with dysplasia, and their treatment, and reviewed all the ICD endoscopic cases so far reported in the literature, remarking the possibility of finding pedunculated ICDs or neoplasm arising over an ICD., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objectives: Aside from the outbreak of the coronavirus disease 2019 (COVID-19), serological tests are not well known for their diagnostic value. We assessed the performance of serological tests using stored sera from patients with a variety of pathologic conditions, collected before the 2020 pandemic in Italy., Methods: Rapid lateral flow tests and Enzyme-Linked Immunosorbent Assays (ELISA) that detect Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were carried out using 1150 stored human serum samples that had been collected in 2018 and 2019. The tests were also run using samples from 15 control patients who had positive or negative oral swab test results, as assessed using real-time reverse transcription-polymerase chain reaction (rRT-PCR). The urea dissociation test was employed to rule out false-positive reactivity in the two antibody detection methods., Results: The lateral flow tests revealed 21 positive samples from the stored sera: 12 for IgM, four for IgG, and five for IgM/IgG. Among the nine rRT-PCR- positive controls, six individuals presented IgG and three IgM/IgG positivity. Using the urea (6 mol/L) dissociation test, two of the twelve stored samples that had shown IgM positivity were confirmed to be positive. The ELISA test detected four IgM-positive and three IgG-positive specimens. After treatment with 4 mol/L urea, the IgM-positive samples became negative, whereas the IgG positivity persisted. All of the rRT-PCR-positive controls were found to retain IgM or IgG positivity following the urea treatment., Conclusions: Our findings highlight the limited utility of serological testing for the SARS-CoV-2 virus based on the results of specimens collected before the outbreak of the infection., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: For patients with inflammatory bowel diseases, switching from infliximab originator to biosimilars is effective and safe. Few data on single switch have been published, and data on multiple switches of different infliximab are unavailable., Methods: A retrospective analysis of patients who switched from CT-P13 to SB2, and of those with multiple switches among different infliximab compounds was conducted. Clinical activity, C reactive protein (CRP), adverse events (AE) and loss of response (LOR) were recorded., Results: Thirty-six patients (26 males, 14 Crohn's disease and 22 ulcerative colitis) were enrolled and followed up for >6 months. All patients switched from CT-P13 to SB2; 12 of them (33.3%) had already switched from reference Infliximab to CT-P13, and for the remaining patients CT-P13 was the first infliximab. The clinical remission rate six months before and three months after SB2-switch was the same (58.3%) and the rate of mild activity varied from 27.8 to 33.3% (P = 0.68); the percentage of patients with normal CRP values passed from 94.4 to 91.7% (P = 1). Two patients (5.5%) had AE and 11 (30.5%) a LOR. At univariate analysis, patients with a single switch had a non-significant risk of LOR during SB2 [odds ratio (OR) = 7.86; 95% confidence interval (CI) 0.87-71, P = 0.06]. SB2-LOR was associated with previous AE under CT-P13 (OR = 9.1, 95% CI 0.82-100, P = 0.07). None of such factors was significant at multivariate analysis., Conclusion: Switching from CT-P13 to SB2 seems to be safe and effective either in patients with a single than in those with multiple switches., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Inflammatory bowel disease (IBD) is a chronic and disabling disorder. Severity of IBD is prominent among refractory with patients with concomitant immune-mediated disorders. Among those patients, dual biological therapy (DBT) has been suggested as an alternative approach to spare steroids and avoid surgery. However, pieces of evidence on clinical outcomes among patients receiving DBT are still limited. We present two cases of IBD patients, with dermatological comorbidity, treated with a combination of vedolizumab and ustekinumab, identifying possible landmarks to address therapeutic choice. No patient experienced adverse events in the follow-up period and both obtained complete clinical remission. DBT may be an effective approach to consider in selected patients with refractory IBD with concomitant severe immune-mediated diseases taking into account medical history of the patient, presence, and type of concomitant extraintestinal manifestations, safety profile of selected DBT, licensed therapeutic indications, and costs.

Fusion genes and epigenetic regulators (i.e., miRNAs and long non-coding RNAs) constitute essential pieces of the puzzle of the tumor genomic landscape, in particular in mechanisms behind the adenoma-to-carcinoma progression of colorectal cancer (CRC). In this work, we aimed to identify molecular signatures of the different steps of sporadic CRC development in eleven patients, of which synchronous samples of adenomas, tumors, and normal tissues were analyzed by RNA-Seq. At a functional level, tumors and adenomas were all characterized by increased activity of the cell cycle, cell development, cell growth, and biological proliferation functions. In contrast, organic survival and apoptosis-related functions were inhibited both in tumors and adenomas at different levels. At a molecular level, we found that three individuals shared a tumor-specific fusion named MRPS31-SUGT1, generated through an intra-chromosomal translocation on chromosome 13, whose sequence resulted in being 100% identical to the long non-coding RNA (lncRNA) MRPS31P5. Our analyses suggest that MRPS31P5 could take part to a competitive endogenous (ce)RNA network by acting as a miRNA sponge or/and as an interactor of other mRNAs, and thus it may be an important gene expression regulatory factor and could be used as a potential biomarker for the detection of early CRC events.

Background: Golimumab is a new anti-TNF-alpha monoclonal antibody for patients with ulcerative colitis., Aims: To assess the short- and long-term effectiveness and safety of golimumab in daily clinical practice and to identify predictors of response., Methods: Consecutive patients treated with golimumab in 22 Italian centers were enrolled. Clinical, laboratory, and endoscopic data were prospectively collected before and during treatment. A subgroup of patients completed a questionnaire to assess personal satisfaction with a golimumab autoinjector system., Results: A total of 196 patients were included. After 3 months, 130 patients were responders (66.3%) and showed significant reductions in mean partial, total, and endoscopic Mayo scores and in mean ESR, C-reactive protein, and fecal calprotectin levels (p < 0.001). Multivariate analysis revealed that a higher total Mayo score (p < 0.001, OR 1.5, 95% CI 1.2-1.8) and naïve status to anti-TNF-alpha (p = 0.015, OR 3.0, 95% CI 1.2-7.5) were predictive of a favorable response. Seventy-seven (39.3%) of the 130 responders maintained a response at month 12 of therapy. There were 17 adverse events, 28 patients needed hospitalization, and 15 patients underwent surgery. Self-administration of the drug was appreciated by most patients., Conclusions: The efficacy and safety of golimumab in daily clinical practice were confirmed for the short- and long-term treatment of patients with active ulcerative colitis. Patients naïve to the anti-TNF-alpha monoclonal antibody and those with a higher total Mayo score were more likely to respond to golimumab.

Crohn's disease (CD) is a debilitating inflammatory bowel disease (IBD) that emerges due to the influence of genetic and environmental factors. microRNAs (miRNAs) have been identified in the tissue and sera of IBD patients and may play an important role in the induction of IBD. Our study aimed to identify differentially expressed miRNAs and miRNAs with the ability to alter transcriptome activity by comparing inflamed tissue samples with their non-inflamed counterparts. We studied changes in miRNA-mRNA interactions associated with CD by examining their differential co-expression relative to normal mucosa from the same patients. Correlation changes between the two conditions were incorporated into scores of predefined gene sets to identify biological processes with altered miRNA-mediated control. Our study identified 28 miRNAs differentially expressed ( p -values < 0.01), of which 14 are up-regulated. Notably, our differential co-expression analysis highlights microRNAs (i.e., miR-4284, miR-3194 and miR-21) that have known functional interactions with key mechanisms implicated in IBD. Most of these miRNAs cannot be detected by differential expression analysis that do not take into account miRNA-mRNA interactions. The identification of differential miRNA-mRNA co-expression patterns will facilitate the investigation of the miRNA-mediated molecular mechanisms underlying CD pathogenesis and could suggest novel drug targets for validation., Competing Interests: The authors declare no conflict of interest.

Background: Crohn's disease (CD) is a pathologic condition with different clinical expressions that may reflect an interplay between genetics and environmental factors. Recently, it has been highlighted that three genetic markers, NOD2, MHC and MST1, were associated to distinct CD sites, supporting the concept that genetic variations may contribute to localize CD. Genetic markers, previously shown to be associated with inflammatory bowel disease (IBD), were tested in CD patients with the aim to better dissect the genetic relationship between ileal, ileocolonic and colonic CD and ascertain whether a different genetic background would support the three disease sites as independent entities., Methods: A panel of 29 SNPs of 19 IBD loci were analyzed by TaqMan SNP allelic discrimination method both evaluating their distinct contribute and analyzing all markers jointly., Results: Seven hundred and eight CD patients and 537 healthy controls were included in the study. Of the overall population of patients, 237 patients had an ileal involvement (L1), 171 a colonic localization (L2), and the 300 remaining an ileocolon location (L3). We confirmed the association for 23 of 29 variations (P < 0.05). Compared to healthy controls, 16 variations emerged as associated to an ileum disease, 7 with a colonic disease and 14 with an ileocolonic site (P < 0.05). Comparing ileum to colonic CD, 5 SNPs (17%) were differentially associated (P < 0.05). A genetic model score that aggregated the risks of 23 SNPs and their odds ratios (ORs), yielded an Area Under the Curve (AUC) of 0.70 for the overall CD patients. By analyzing each CD location, the AUC remained at the same level for the ileal and ileocolonic sites (0.73 and 0.72, respectively), but dropped to a 0,66 value in patients with colon localization., Conclusions: Our findings reaffirm the existence of at least three different subgroups of CD patients, with a genetic signature distinctive for the three main CD sites., Competing Interests: The authors have declared that no competing interests exist.

Background: A pelvic magnetic resonance imaging (MRI) represents the front-line method for evaluating perianal disease in patients with inflammatory bowel disease (IBD). Recently, transperineal ultrasonography (TPUS) has been proposed as a simple, safe, time-sparing and useful diagnostic technique to assess different pathological conditions of the pelvic floor., Aim: The aim of this prospective single centre study was to evaluate the accuracy of TPUS versus MRI for the detection and classification of perineal disease in IBD patients., Methods: From November 2013 to November 2014, 28 IBD patients underwent either TPUS or MRI. Fistulae and abscesses were classified according to Parks' and AGA's classification methods. A concordance was assessed by k statistics., Results: Overall, 33 fistulae and 8 abscesses were recognized by TPUS (30 and 7 by MRI, respectively). The agreement between TPUS and MRI was 75% according to Parks' classification (k=0.67) and 86% according to AGA classification (k=0.83), while it was 36% (k=0.34) for classifying abscesses., Conclusions: TPUS proved to be as accurate as MRI for detecting superficial and small abscesses and for classifying perianal disease. Both examinations may be performed at the initial presentation of the patient, but TPUS is a cheaper, time-sparing procedure. The optimal use of TPUS might be in follow-up patients., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Ulcerative colitis (UC) and Crohn's disease (CD) share some pathogenetic features. To provide new steps on the role of altered gene expression, and the involvement of gene networks, in the pathogenesis of these diseases, we performed a genome-wide analysis in 15 patients with CD and 14 patients with UC by comparing the RNA from inflamed and noninflamed colonic mucosa., Methods: Two hundred ninety-eight differentially expressed genes in CD and 520 genes in UC were identified. By bioinformatic analyses, 34 pathways for CD, 6 of them enriched in noninflamed and 28 in inflamed tissues, and 19 pathways for UC, 17 in noninflamed and 2 in inflamed tissues, were also highlighted., Results: In CD, the pathways included genes associated with cytokines and cytokine receptors connection, response to external stimuli, activation of cell proliferation or differentiation, cell migration, apoptosis, and immune regulation. In UC, the pathways were associated with genes related to metabolic and catabolic processes, biosynthesis and interconversion processes, leukocyte migration, regulation of cell proliferation, and epithelial-to-mesenchymal transition., Conclusions: In UC, the pattern of inflammation of colonic mucosa is due to a complex interaction network between host, gut microbiome, and diet, suggesting that bacterial products or endogenous synthetic/catabolic molecules contribute to impairment of the immune response, to breakdown of epithelial barrier, and to enhance the inflammatory process. In patients with CD, genes encoding a large variety of proteins, growth factors, cytokines, chemokines, and adhesion molecules may lead to uncontrolled inflammation with ensuing destruction of epithelial cells, inappropriate stimulation of antimicrobial and T cells differentiation, and inflammasome events.

Simultaneous analysis of the transcripts of thousands of genes by cDNA microarrays allows the identification of genetic regulatory mechanisms involved in disease pathophysiology. The circadian clock circuitry controls essential cell processes and the functioning of organ systems, which are characterized by rhythmic variations with 24-hour periodicity. The derangement of these processes is involved in the basic mechanisms of inflammatory, metabolic, degenerative and neoplastic diseases. We evaluated by genome-wide cDNA microarray analysis the transcriptome of endoscopic mucosal biopsies of patients with inflammatory bowel diseases (IBD) focusing on the expression of circadian genes in Crohn's disease (CD) and ulcerative colitis (UC). Twenty-nine IBD patients (15 with CD and 14 with UC) were enrolled and mucosal biopsies were sampled at either inflamed or adjacent non-inflamed areas of the colon. A total of 150 circadian genes involved in pathways controlling crucial cell processes and tissue functions were investigated. In CD specimens 50 genes were differentially expressed, and 21 genes resulted up-regulated when compared to healthy colonic mucosa. In UC specimens 50 genes were differentially expressed, and 27 genes resulted up-regulated when compared to healthy colonic mucosa. Among the core clock genes ARNTL2 and RORA were up-regulated, while CSNK2B, NPAS2, PER1 and PER3 were down-regulated in CD specimens. Conversely, ARNTL2, CRY1, CSNK1E, RORA and TIPIN were up-regulated, while NR1D2 and PER3 were down-regulated in UC. In conclusion, in CD and UC patients there are differences in the expression of circadian genes between normal and diseased intestinal mucosa. The deregulated genes evidenced by transcriptome analysis in the major IBDs may play a crucial role in the pathophysiological mechanisms and may suggest novel therapeutic approaches.

Introduction: Endometriosis is a common chronic gynaecological disease affecting 10 % of women of reproductive age. Of these 5-12 % may present bowel endometriosis that may be asymptomatic or associated with aspecific symptoms even bowel obstruction., Case Presentation: The case of a 41-year-old woman with history of ulcerative colitis, previous diagnosis of ovarian endometriosis, recurrent abdominal pain not related to the menstrual cycle, with abdominal pain and obstinate constipation for 2 weeks was referred. The patient underwent colonoscopy, transabdominal ultrasound and ultrasound-guided fine-needle biopsy to have a diagnosis., Discussion: Endometriosis should be considered in the differential diagnosis of every woman of childbearing age who presents with gastrointestinal or abdominal symptoms. As demonstrated in our case and by the burgeoning literature in this field, we believe that the role of transabdominal ultrasound should be reconsidered in the management of abdominal diseases because this examination associated with ultrasound-guided fine-needle biopsy allows, in expert hands, to obtain adequate histological samples avoiding patients to undergo more invasive tests to get a diagnosis.

Background: Juvenile polyposis syndrome with gastric involvement may mimic Ménétrier's disease, which is correlated to transforming growth factor (TGF)α overproduction and PDX1 upregulation in the gastric fundus., Aim: We report a family with juvenile polyposis syndrome where one member showed typical features of Ménétrier's disease and concomitant Helicobacter pylori infection., Methods: We studied a 31-year-old woman belonging to a family with juvenile polyposis syndrome, who exhibited a particular form of hyperplastic gastropathy diagnosed as Ménétrier's disease with Helicobacter pylori infection., Results: TGFα overexpression and undetectable PDX1 expression were demonstrated in the fundic gastric biopsy specimens. In all affected members of the family we identified a 4-bp deletion in exon 9 of SMAD4 gene, a mutation usually associated with a more virulent form of juvenile polyposis syndrome with a higher incidence of gastric and colonic polyposis., Conclusion: To explain the association of juvenile polyposis syndrome with Ménétrier's disease we hypothesized a new mechanism that involves TGFβ-SMAD4 pathway inactivation and TGFα overexpression related to Helicobacter pylori infection., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Low-volume bowel preparations with polyethylene glycol (PEG) have been shown to provide an equivalent cleansing with improved tolerability as compared with standard PEG bowel preparation for colonoscopy. A new iso-osmotic sulphate-free formulation of PEG-Citrate-Simethicone (PEG-CS) in combination with bisacodyl has been recently developed., Aim: To compare the quality of bowel cleansing with PEG-CS with bisacodyl vs. PEG-Ascorbate (PEG-ASC) in adult out-patients undergoing colonoscopy., Methods: Randomised, observer-blind, parallel group study in adult out-patients undergoing colonoscopy in five Italian centres. Both preparations were taken the evening before the procedure. Subjects were instructed to take 2-4 tablets of 5 mg bisacodyl at 16:00 hours and 2 L of PEG-CS at 20:00 hours or 2 L of PEG-ASC plus 1 L of additional water the day before colonoscopy. Bowel cleansing was evaluated according to the Boston Bowel Preparation Scale (≥6 scores were considered as 'clinical success'), and mucosal visibility according to a 3-point scale. Tolerability, acceptability and compliance were also evaluated., Results: Four hundred and eight patients were randomly allocated to PEG-CS and bisacodyl (n = 204, male patient 48%, mean age 59.1 years) or PEG-ASC (n = 204, male patient 51%, age 59.4 years). In the planned per-protocol analysis, the rate of successful preparation was 79.1% following PEG-CS with bisacodyl, and 70% following PEG-ASC (P < 0.05). Mucosal visibility was evaluated as optimal in 56.1% in the PEG-CS and bisacodyl and 46.3% in the PEG-ASC group (P < 0.05). There were no serious adverse events (AE) in each of the two experimental groups. Two subjects in the PEG-ASC group discontinued the study because of AE., Conclusions: Polyethylene glycol-Citrate-Simethicone in combination with bisacodyl was more effective for bowel cleansing than PEG-ASC for out-patient colonoscopy. Tolerability, safety, acceptability and compliance of the two low-volume bowel preparations were similar., (© 2012 Blackwell Publishing Ltd.)

Altered body rhythmicity and deregulated clock gene expression may cause circadian disruption, which can lead to immune dysregulation and chronic inflammatory diseases. PERIOD3 (PER3) polymorphisms have been associated with circadian disruption and changed secretion of cytokines involved in chronic inflammation. Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases resulting from complex interaction among environmental/microbial factors and the intestinal immune system, triggering an abnormal immune response in genetically susceptible individuals. We evaluated the influence of a polymorphism of the clock gene PER3 on susceptibility and behavior of these inflammatory bowel diseases. The rs2797685 variant of the PER3 gene was assessed in 1082 CD and 972 UC patients, 754 of whom had been diagnosed <18 yrs of age, and 1311 unrelated healthy controls. Allele and genotype frequencies of rs2797685 were significantly increased in both CD (p = 1.6 × 10(-4), odds ratio [OR] = 1.38, 95% confidence interval [CI]: 1.17-1.63) and UC (p = .012, OR = 1.25, 95% CI: 1.05-1.48) patients. Difference between frequency distributions remained statistically significant after stratifying the cohort according to age at diagnosis for CD, but not for UC. Statistically significant association was found between PER3 polymorphism and use of immunosuppressive drugs in pediatric CD patients (p < .001) and with stricturing and fistulizing disease behavior in adult CD patients (p = .031). In conclusion, results of this association study suggest a possible role of PER3 polymorphism in determining susceptibility to CD and UC and phenotypic characteristics of CD. In particular, the rs2797685 variant of the PER3 gene is associated with a more aggressive form of CD, highlighted by higher use of immunosuppressants and more frequent stricturing and fistulizing disease behaviors, as well as early onset of CD. This is a descriptive study, and functional data are needed to prove a causal relationship; nonetheless, involvement of the clock gene machinery in the susceptibility and the behavior of inflammatory bowel diseases may suggest new pathophysiological mechanisms and new therapeutic approaches.

Background and Aim: Altered expression of microRNAs (miRNAs) hallmarks many cancer types. The study of the associations of miRNA expression profile and cancer phenotype could help identify the links between deregulation of miRNA expression and oncogenic pathways., Methods: Expression profiling of 866 human miRNAs in 19 colorectal and 17 pancreatic cancers and in matched adjacent normal tissues was investigated. Classical paired t-test and random forest analyses were applied to identify miRNAs associated with tissue-specific tumors. Network analysis based on a computational approach to mine associations between cancer types and miRNAs was performed., Results: The merge between the two statistical methods used to intersect the miRNAs differentially expressed in colon and pancreatic cancers allowed the identification of cancer-specific miRNA alterations. By miRNA-network analysis, tissue-specific patterns of miRNA deregulation were traced: the driving miRNAs were miR-195, miR-1280, miR-140-3p and miR-1246 in colorectal tumors, and miR-103, miR-23a and miR-15b in pancreatic cancers., Conclusion: MiRNA expression profiles may identify cancer-specific signatures and potentially useful biomarkers for the diagnosis of tissue specific cancers. miRNA-network analysis help identify altered miRNA regulatory networks that could play a role in tumor pathogenesis.

The clock gene machinery controls cellular metabolism, proliferation, and key functions, such as DNA damage recognition and repair. Dysfunction of the circadian clock is involved in tumorigenesis, and altered expression of some clock genes has been found in cancer patients. The aim of this study was to evaluate the expression levels of core clock genes in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qPCR) was used to examine ARNTL1, CLOCK, PER1, PER2, PER3, CRY1, CRY2, Timeless (TIM), TIPIN, and CSNK1? expression levels in the tumor tissue and matched apparently healthy mucosa of CRC patients. In the tumor tissue of CRC patients, compared to their matched healthy mucosa, expression levels of ARNTL1 (p=.002), PER1 (p=.002), PER2 (p=.011), PER3 (p=.003), and CRY2 (p=.012) were lower, whereas the expression level of TIM (p=.044) was higher. No significant difference was observed in the expression levels of CLOCK (p=.778), CRY1 (p=.600), CSNK1 (p=.903), and TIPIN (p=.136). As to the clinical and pathological features, a significant association was found between low CRY1 expression levels in tumor mucosa and age (p=.026), and female sex (p=.005), whereas high CRY1 expression levels in tumor mucosa were associated with cancer location in the distal colon (p?=?.015). Moreover, high TIM mRNA levels in the tumor mucosa were prevalent whenever proximal lymph nodes were involved (p= .013) and associated with TNM stages III-IV (p=.005) and microsatellite instability (p=.015). Significantly poorer survival rates were evidenced for CRC patients with lower expression in the tumor tissue of PER1 (p=.010), PER3 (p= .010), and CSNKIE (p=.024). In conclusion, abnormal expression levels of core clock genes in CRC tissue may be related to the process of tumorigenesis and exert an influence on host/tumor interactions.

Background: Recent GWAs and meta-analyses have outlined about 100 susceptibility genes/loci for inflammatory bowel diseases (IBD). In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort., Methods: Eight SNPs were assessed in 1,070 Crohn's disease (CD), 1,213 ulcerative colitis (UC), 557 of whom being diagnosed at the age of ≤16 years, and 789 healthy controls. Correlations with sub-phenotypes and major variants of NOD2 gene were investigated., Results: The SNPs tagging the TNFSF15, NKX2-3, ZNF365, and PTPN2 genes were associated with CD (P values ranging from 0.037 to 7×10(-6)). The SNPs tagging the PTGER4, NKX2-3, ZNF365, IFNG, PSMG1, and HLA area were associated with UC (P values 0.047 to 4×10(-5)). In the pediatric cohort the associations of TNFSF15, NKX2-3 with CD, and PTGER4, NKX2-3, ZNF365, IFNG, PSMG1 with UC, were confirmed. Association with TNFSF15 and pediatric UC was also reported. A correlation with NKX2-3 and need for surgery (P  =  0.038), and with HLA and steroid-responsiveness (P  =  0.024) in UC patients was observed. Moreover, significant association in our CD cohort with TNFSF15 SNP and colonic involvement (P  =  0.021), and with ZNF365 and ileal location (P  =  0.024) was demonstrated., Conclusions: We confirmed in a large Italian cohort the associations with CD and UC of newly identified genes, both in adult and pediatric cohort of patients, with some influence on sub-phenotypes.

Current guidelines for managing ulcer bleeding state that patients with major stigmata should be managed by dual endoscopic therapy (injection with epinephrine plus a thermal or mechanical modality) followed by a high dose intravenous infusion of proton pump inhibitors (PPIs). This paper aims to review and critically evaluate evidence supporting the purported superiority of a continuous infusion over less intensive regimens of PPIs administration and the need for adding a second hemostatic endoscopic procedure to epinephrine injection. Systematic searches of PubMed, EMBASE and the Cochrane library were performed. There is strong evidence for an incremental benefit of PPIs over H2-receptor antagonists or placebo for the outcome of patients with peptic ulcer bleeding following endoscopic hemostasis. However, the benefit of PPIs is unrelated to either the dosage (intensive vs standard regimen) or the route of administration (intravenous vs oral). There is significant heterogeneity among the 15 studies that compared epinephrine with epinephrine plus a second modality, which might preclude the validity of reported summary estimates. Studies without second look endoscopy plus re-treatment of re-bleeding lesions showed a significant benefit of adding a second endoscopic modality for hemostasis, while studies with second-look and re-treatment showed equal efficacy between endoscopic mono and dual therapy. Inconclusive experimental evidence supports the current recommendation of the use of dual endoscopic hemostatic means and infusion of high-dose PPIs as standard therapy for patients with bleeding peptic ulcers. Presently, the combination of epinephrine monotherapy with standard doses of PPIs constitutes an appropriate treatment for the majority of patients.

The adenylate cyclase-cyclic AMP-phosphodiesterase system of human thyroid tissues adjacent to cold nodules (control), two follicular adenomas, one hyperplastic thyroid and one hyperfunctioning follicular carcinoma have been compared. In the hyperfunctional follicular carcinoma the basal adenylate cyclase is much higher than in control tissue, carcinoma adenylate cyclase does not respond to TSH and prostaglandin E1, whereas it responds normally to fluoride. In the hyperplastic, but hypofunctional thyroid the basal adenylate cyclase is higher than in normal tissue whereas the response to TSH, PGE1, and fluoride is normal. No difference between the follicular adenomas and normal thyroid stimulated and unstimulated adenylate cyclase was observed. Furthermore in various thyroid tissues no changes in the level of cyclic AMP phosphodiesterase was found. Our data indicate a greater change in the synthesis rather than in degradation of cyclic AMP in the human pathological thyroids studied.

Aim of this report was to define the correlation between hepatic acute damage and thyroxine metabolism. We have studied plasma levels of T4, T3, rT3 and TSH in 18 adult male subjects with acute viral hepatitis. No significant variation of T4, T3 and TSH plasma levels was found in different phases of disease. However, plasma rT3 levels were clearly elevated in 72% of patients in the first 7 days (mean 440 pg/ml vs 198 pg/ml of normal controls) and in 17% of cases in the second 10 days of disease (mean 269 pg/ml). Plasma rT3 concentration was always normal in the subsequent phases of disease. Our results indicate a diversion of peripheral thyroxine metabolism in the early stages of acute hepatitis.