Publications by authors named "Francesca Zorzi"

39 Publications

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Clin Gastroenterol Hepatol 2021 May 6. Epub 2021 May 6.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.1016/j.cgh.2021.05.007DOI Listing
May 2021

Ultrasonography Tight Control and Monitoring in Crohn's Disease During Different Biological Therapies: A Multicenter Study.

Clin Gastroenterol Hepatol 2021 Mar 26. Epub 2021 Mar 26.

Gastroenterology, Department of Clinical Medicine and Surgery, Federico II, School of Medicine, Naples.

Background & Aims: Bowel ultrasonography (BUS) is a noninvasive tool for evaluating bowel activity in Crohn's disease (CD) patients. Aim of our multicenter study was to assess whether BUS helps to monitor intestinal activity improvement/resolution following different biological therapies.

Methods: Adult CD patients were prospectively enrolled at 16 sites in Italy. Changes in BUS parameters [i.e. bowel wall thickening (BWT), lesion length, echo pattern, blood flow changes and transmural healing (TH: normalization of all BUS parameters)] were analyzed at baseline and after 3, 6 and 12 months of different biological therapies.

Results: One hundred eighty-eight out of 201 CD patients were enrolled and analyzed (116 males [62%]; median age 36 years). Fifty-five percent of patients were treated with adalimumab, 16% with infliximab, 13% with vedolizumab and 16% with ustekinumab. TH rates at 12 months were 27.5% with an NNT of 3.6. TH at 12 months after adalimumab was 26.8%, 37% after infliximab, 27.2% after vedolizumab and 20% after ustekinumab. Mean BWT improvement from baseline was statistically significant at 3 and 12 months (P < .0001). Median Harvey-Bradshaw index, C-reactive protein and fecal calprotectin decreased after 12 months from baseline (P < .0001). Logistic regression analysis showed colonic lesion was associated with a higher risk of TH at 3 months and a greater BWT at baseline was associated with a lower risk of TH at 3 months [P = .03 (OR 0.70, 95% CI 0.50-0.97)] and 12 months [P = .01 (OR 0.58, 95% CI 0.38-0.89)]. At 3 months therapy optimization during the study was the only independent factor associated with a higher risk of no ultrasonographic response [P = .02 (OR 3.34, 95% CI 1.18-9.47)] and at 12 months disease duration [P = .02 (OR 3.03, 95% CI 1.15-7.94)].

Conclusions: Data indicate that BUS is useful to monitor biologics-induced bowel activity improvement/resolution in CD.
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http://dx.doi.org/10.1016/j.cgh.2021.03.030DOI Listing
March 2021

High Smad7 in the early post-operative recurrence of Crohn's disease.

J Transl Med 2020 10 19;18(1):395. Epub 2020 Oct 19.

Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Roma, Italy.

Background: In Crohn's disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this study was to assess whether Smad7 over-expression occurs in the early and/or late phases of CD.

Methods: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with or without (early CD) post-operative endoscopic recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (late CD). Smad7 was examined by immunohistochemistry and cytokine expression was analysed by flow-cytometry.

Results: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of Smad7-expressing cells in both the epithelial and lamina propria compartments. Transition from this stage to endoscopic recurrence was marked by persistence of high number of Smad7-positive cells, which reduced significantly in the late stages of the disease, where Smad7 expression remained, however, greater than that seen in normal controls. In samples with early lesions, Smad7 expression positively correlated with the number of interferon-γ-secreting cells.

Conclusions: Smad7 induction is an early event in the inflammatory sequence occurring in CD, thus suggesting that knockdown of Smad7 can help prevent post-operative recurrence.
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http://dx.doi.org/10.1186/s12967-020-02558-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574182PMC
October 2020

Onset of ulcerative colitis during SARS-CoV-2 infection.

Dig Liver Dis 2020 11 11;52(11):1228-1229. Epub 2020 Jun 11.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Italy.

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http://dx.doi.org/10.1016/j.dld.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287422PMC
November 2020

Response Assessed by Ultrasonography as Target of Biological Treatment for Crohn's Disease.

Clin Gastroenterol Hepatol 2020 08 20;18(9):2030-2037. Epub 2019 Dec 20.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Background & Aims: Mucosal healing, determined by ileocolonoscopy, is a goal for treatment of Crohn's disease (CD), but this is an invasive assessment procedure. We investigated whether response to tumor necrosis factor (TNF) antagonists, determined by small-intestine contrast ultrasonography, associates with long-term outcomes.

Methods: We performed observational study of 80 patients with CD treated with anti-TNF agents for at least 1 year who underwent serial small intestine contrast ultrasonography (SICUS) at the University of Rome, in Italy. SICUS was used to evaluate disease site (based on bowel wall thickness), extent of lesions, and presence of complications. Inclusion criteria required pre-therapy SICUS with follow-up SICUS after 18 months. At second SICUS, patients were assigned to categories of complete or partial responder or non-responder. CD-related outcomes (corticosteroid need, hospitalization, and surgery) were assessed at 1 year from the second SICUS, using multivariate models, and were analyzed after long term follow up (5 years) using Kaplan-Meier survival analysis.

Results: Based on SICUS, after a median of 18 months, 36 patients (51%) were complete responders, 30 were partial responders (34%), and 13 were non-responders (15%). At 1 year from the second SICUS, no patients with a complete response, based on ultrasonography, underwent surgery, in comparison to partial responders (P = .0003) or non-responders (P = .001). Complete responders used smaller amounts of corticosteroids than partial responders (P = .0001) or non-responders (P < .0001). Complete responders required fewer hospitalizations than non-responders (P = .001). Kaplan-Meier survival analysis of long-term follow up data demonstrated a lower cumulative probability of need for surgery, hospitalization, and need for steroids among SICUS-categorized complete responders (P < .0001, P = .003 and P = .0001 respectively) than SICUS-categorized non-responders.

Conclusions: In patients with CD, response to anti-TNF agents, determined by SICUS, is associated with better long-term outcomes than partial or no response. Ultrasonographic assessment therefore provides a relatively non-invasive method for monitoring response to treatment in patients with CD.
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http://dx.doi.org/10.1016/j.cgh.2019.10.042DOI Listing
August 2020

Exploring the genetic diversity of the 16S rRNA gene of in IBD and IBS.

Future Microbiol 2019 11 18;14:1497-1509. Epub 2019 Dec 18.

Unit of Medical Statistics & Molecular Epidemiology, University Campus Bio-Medico, Rome, Italy.

The human gastrointestinal tract harbors diverse, abundant microbiota and is involved in this community. The aim of this study is to characterize 16 new 16S ribosomal RNA sequences selected from a metagenomic database from stools of patients with irritable bowel syndrome (IBS), inflammatory bowel diseases and control (CTRLs) subjects by a phylogenetic approach. A phylogenetic approach was used to study the genetic diversity and SNPs in 16 16S ribosomal RNA sequences from stools of 107 individuals, 36 of which were patients affected by IBS, 30 by inflammatory bowel disease and 41 were CTRLs. Phylogenetic analysis confirmed the subdivision into different supported clusters. An increase of variability in IBS has been identified. The genetic variation combined to the relative abundance, contribute to the protective role of . Phylogenesis represent an additional approach to investigate genetic variability.
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http://dx.doi.org/10.2217/fmb-2019-0175DOI Listing
November 2019

Fecal and Mucosal Microbiota Profiling in Irritable Bowel Syndrome and Inflammatory Bowel Disease.

Front Microbiol 2019 17;10:1655. Epub 2019 Jul 17.

Unit of Digestive Disease, Campus Bio-Medico University, Rome, Italy.

An imbalance in the bacterial species resulting in the loss of intestinal homeostasis has been described in inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). In this prospective study, we investigated whether IBD and IBS patients exhibit specific changes in richness and distribution of fecal and mucosal-associated microbiota. Additionally, we assessed potential 16S rRNA gene amplicons biomarkers for IBD, IBS, and controls (CTRLs) by comparison of taxonomic composition. The relative abundance of bacteria, at phylum and genus/species levels, and the bacterial diversity were determined through 16S rRNA sequence-based fecal and mucosal microbiota analysis. Linear discriminant analysis effect size (LEfSe) was used for biomarker discovery associated to IBD and IBS as compared to CTRLs. In fecal and mucosal samples, the microbiota richness was characterized by a microbial diversity reduction, going from CTRLs to IBS to IBD. β-diversity analysis showed a clear separation between IBD and CTRLs and between IBD and IBS with no significant separation between IBS and CTRLs. β-diversity showed a clear separation between mucosa and stool samples in all the groups. In IBD, there was no difference between inflamed and not inflamed mucosa. Based upon the LEfSe data, the and Ruminococcaceae were identified as the most differentially abundant bacterial taxa in CTRLs. Erysipelotrichi was identified as potential biomarker for IBS, while Gammaproteobacteria, , and Enterococcaceae for IBD. This study provides an overview of the alterations of microbiota and may aid in identifying potential 16S rRNA gene amplicons mucosal biomarkers for IBD and IBS.
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http://dx.doi.org/10.3389/fmicb.2019.01655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650632PMC
July 2019

Real-time Interobserver Agreement in Bowel Ultrasonography for Diagnostic Assessment in Patients With Crohn's Disease: An International Multicenter Study.

Inflamm Bowel Dis 2018 08;24(9):2001-2006

Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata," Italy.

Background: The unavailability of standardized parameters in bowel ultrasonography (US) commonly used in Crohn's disease (CD) and the shortage of skilled ultrasonographers are 2 limiting factors in the use of this imaging modality around the world. The aim of this study is to evaluate interobserver agreement among experienced sonographers in the evaluation of bowel US parameters in order to improve standardization in imaging reporting and interpretation.

Methods: Fifteen patients with an established diagnosis of CD underwent blinded bowel US performed by 6 experienced sonographers. Prior to the evaluation, the sonographers and clinical and radiological IBD experts met to formally define the US parameters. Interobserver agreement was tested with the Quatto method (s).

Results: All operators agreed on the presence/absence of CD lesions and distinguished absence of/mild activity or moderate/severe lesions in all patients. S values were moderate for bowel wall thickness (s = 0.48, P = n.s.), bowel wall pattern (s = 0.41, P = n.s.), vascularization (s = 0.52, P = n.s.), and presence of lymphnodes (s = 0.61, P = n.s.). Agreement was substantial for lesion location (s = 0.68, P = n.s.), fistula (s = 0.74, P = n.s.), phlegmon (s = 0.78, P = 0.04), and was almost perfect for abscess (s = 0.95, P = 0.02). Poor agreement was observed for mesenteric adipose tissue alteration, lesion extent, stenosis, and prestenotic dilation.

Conclusions: In this study, the majority of the US parameters used in CD showed moderate/substantial agreement. The development of shared US imaging interpretation patterns among sonographers will lead to improved comparability of US results among centers and facilitate the development of multicenter studies and the spread of bowel US training, thereby allowing a wider adoption of this useful technique.
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http://dx.doi.org/10.1093/ibd/izy091DOI Listing
August 2018

Small bowel Epstein-Barr virus-positive lympho-epithelioma-like carcinoma in Crohn's disease.

Histopathology 2017 04 18;70(5):837-839. Epub 2017 Jan 18.

Department of Internal Medicine, San Matteo Hospital, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1111/his.13133DOI Listing
April 2017

Sodium chloride-enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice.

J Crohns Colitis 2017 Feb 29;11(2):237-245. Epub 2016 Jul 29.

Cattedra di Gastroenterologia, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.

Background And Aim: Environmental factors are supposed to play a decisive role in the pathogenesis of inflammatory bowel diseases [IBDs]. Increased dietary salt intake has been linked with the development of autoimmune diseases, but the impact of a salt-enriched diet on the course of IBD remains unknown. In this study, we examined whether high salt intake alters mucosal cytokine production and exacerbates colitis.

Methods: Normal intestinal lamina propria mononuclear cells [LPMCs] were activated with anti-CD3/CD28 in the presence or absence of increasing concentrations of sodium chloride [NaCl] and/or SB202190, a specific inhibitor of p38/MAP Kinase. For in vivo experiments, a high dose of NaCl was administered to mice 15 days before induction of trinitrobenzene-sulfonic acid [TNBS]-colitis or dextran sulfate sodium [DSS]-colitis. In parallel, mice were given SB202190 before induction of TNBS-colitis. Transcription factors and effector cytokines were evaluated by flow-cytometry and real-time PCR.

Results: IL-17A, IL-23R, TNF-α, and Ror-γT were significantly increased in human LPMCs following NaCl exposure, while there was no significant change in IFN-γ, T-bet or Foxp3. Pharmacologic inhibition of p38/MAPK abrogated the NaCl-inducing effect on LPMC-derived cytokines. Mice receiving the high-salt diet developed a more severe colitis than control mice, and this effect was preventable by SB202190.

Conclusions: Our data indicated that exposure of intestinal mononuclear cells to a high-NaCl diet enhanced effector cytokine production and contributed to the exacerbation of experimental colitis in mice.
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http://dx.doi.org/10.1093/ecco-jcc/jjw139DOI Listing
February 2017

Positioning Ultrasonography Into Clinical Practice for the Management of Crohn's Disease.

Gastroenterol Hepatol (N Y) 2015 Jun;11(6):384-90

Dr Calabrese is a researcher, Dr Zorzi and Dr Lolli are trainees in gastroenterology, and Dr Pallone is a professor of gastroenterology in the Gastrointestinal Unit of the Department of Systems Medicine at the University of Rome Tor Vergata in Rome, Italy.

Over the past few years, the technical evolution of ultrasound equipment, the use of oral and intravenous contrast agents, and an increase in the expertise of operators have enhanced the role that ultrasonography plays in the assessment of the gastrointestinal tract. For patients with chronic inflammatory conditions, particularly Crohn's disease, it has been suggested that ultrasonography can be used not only for diagnostic purposes but also in disease management. These developments are reviewed in this article.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843032PMC
June 2015

Bowel Ultrasonography in the Management of Crohn's Disease. A Review with Recommendations of an International Panel of Experts.

Inflamm Bowel Dis 2016 May;22(5):1168-83

*Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; †Ambulanzzentrum Gastroenterologie am Klinikum Lüneburg, Lüneburg, Germany; ‡Klinik für Allgemeine Innere Medizin und Gastroenterologie, Lüneburg, Germany; §Digestive Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois; ‖Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota; ¶Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Canada; **Department of Clinical Sciences, L. Sacco University Hospital, Milan, Italy; ††University Hospital Erlangen, Erlangen, Germany; and ‡‡Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University Hospital, Tokyo, Japan.

Background: Bowel ultrasonography (US) is considered a useful technique for assessing mural inflammation and complications in Crohn's disease (CD). The aim of this review is to appraise the evidence on the accuracy of bowel US for CD. In addition, we aim to provide recommendations for its optimal use.

Methods: Publications were identified by literature search from 1992 to 2014 and selected based on predefined criteria: 15 or more patients; bowel US for diagnosing CD, complications, postoperative recurrence, activity; adequate reference standards; prospective study design; data reported to allow calculation of sensitivity, specificity, agreement, or correlation values; articles published in English.

Results: The search yielded 655 articles, of which 63 were found to be eligible and retrieved as full-text articles for analysis. Bowel US showed 79.7% sensitivity and 96.7% specificity for the diagnosis of suspected CD, and 89% sensitivity and 94.3% specificity for initial assessment in established patients with CD. Bowel US identified ileal CD with 92.7% sensitivity, 88.2% specificity, and colon CD with 81.8% sensitivity, 95.3% specificity, with lower accuracy for detecting proximal lesions. The oral contrast agent improves the sensitivity and specificity in determining CD lesions and in assessing sites and extent.

Conclusions: Bowel US is a tool for evaluation of CD lesions in terms of complications, postoperative recurrence, and monitoring response to medical therapy; it reliably detects postoperative recurrence and complications, as well as offers the possibility of monitoring disease progression.
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http://dx.doi.org/10.1097/MIB.0000000000000706DOI Listing
May 2016

Smad7 Knockdown Restores Aryl Hydrocarbon Receptor-mediated Protective Signals in the Gut.

J Crohns Colitis 2016 Jun 27;10(6):670-7. Epub 2016 Jan 27.

Dipartimento di Medicina dei Sistemi.

Background And Aim: In Crohn's disease [CD], the pathological process is driven by an excessive immune response that is poorly counterbalanced by regulatory mechanisms. One such a mechanism involves aryl hydrocarbon receptor [AhR], a transcription factor that delivers protective signals in the gut. Expression of AhR is reduced in CD lamina propria mononuclear cells [LPMC] even though factors accounting for such a defect remain unknown. Since CD LPMC express elevated levels of Smad7, an inhibitor of transforming growth factor beta 1 [TGF-β1] activity, and TGF-β1 regulates AhR in other systems, we examined the link between AhR and Smad7 in the gut.

Methods: AhR and interleukin [IL]-22 were evaluated in normal LPMC stimulated with TGF-β1 and 6-formylindolo[3,2-b]carbazole [Ficz], an activator of AhR, and in CD LPMC incubated with a Smad7 antisense oligonucleotide and then stimulated with Ficz and TGF-β1. AhR and IL-22 expression was evaluated in LPMC of Smad7-transgenic mice. Finally, we evaluated the protective effect of Ficz on colitis in RAG1 mice injected with naïve or Smad7-overexpressing T cells.

Results: In normal LPMC, TGF-β1 induced AhR and this event was associated with increased production of IL-22 following stimulation with Ficz. Treatment of CD LPMC with Smad7 antisense oligonucleotide enabled TGF-β1 to enhance AhR expression. Consistently, AhR expression and Ficz-induced IL-22 production were markedly reduced in T cells of Smad7-transgenic mice. In RAG1 mice, Ficz ameliorated colitis induced by wild type T cells but did not affect colitis induced by transfer of Smad7-overexpressing T cells.

Conclusions: The inverse correlation between Smad7 and AhR expression helps to propagate inflammatory signals in the gut.
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http://dx.doi.org/10.1093/ecco-jcc/jjw030DOI Listing
June 2016

Aryl hydrocarbon receptor-driven signals inhibit collagen synthesis in the gut.

Eur J Immunol 2016 Apr 5;46(4):1047-57. Epub 2016 Feb 5.

Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.

Fibrostrictures (FS) are a major complication of Crohn's disease (CD). Pathogenesis of FS is not fully understood, but activation of fibroblasts and excessive collagen deposition are crucial in the development of FS. Here, we investigated the role of aryl hydrocarbon receptor (AhR) in intestinal fibrosis. AhR RNA and protein expression were evaluated in intestinal fibroblasts of CD patients and controls. CD fibroblasts were stimulated with TGF-β1 or TNF-α in the presence or absence of the AhR activator Ficz, an AhR antagonist CH223191, or a specific AhR-silencing RNA. In CD fibroblasts, TGF-β1 and TNF-α increased Col1A1, Col3A1 and α-SMA transcripts and collagen secretion and this effect was reduced by Ficz and upregulated by CH22319. TGF-β1 or TNF-α induced activation of p38 and ERK1/2 MAP kinases was decreased by Ficz and increased by CH223191. The inhibitory effect of Ficz on Map kinase activation and collagen induction was abolished by AhR silencing. To assess the role of AhR in vivo, mice with trinitrobenzene-sulfonic-acid induced colonic fibrosis were given Ficz or CH223191. Mice given either Ficz or CH223191 produced less or more collagen respectively as compared with control mice. Our results indicate that AhR is a negative regulator of profibrotic signals in the gut.
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http://dx.doi.org/10.1002/eji.201445228DOI Listing
April 2016

Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease.

Clin Sci (Lond) 2015 Dec;129(12):1107-13

Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy

In Crohn's disease, one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation promotes fibrotic processes thereby facilitating formation of strictures, the most common indication for surgical intervention in this disorder. The pathogenesis of Crohn's disease-associated fibrosis is not fully understood, but variants of genes involved in the recognition of microbial components/products [e.g. CARD15 (caspase-activating recruitment domain 15) and ATG16L1 (autophagy-related 16-like 1)] are associated with this phenotype, and experimental evidence suggests that intestinal fibrosis results from an altered balance between deposition of ECM (extracellular matrix) and degradation of ECM by proteases. Studies have also contributed to identify the main phenotypic and functional alterations of cells involved in the fibrogenic process, as well as molecules that stimulate such cells to produce elevated amounts of collagen and other ECM-related proteins. In the present review, we assess the current knowledge about cellular and molecular mediators of intestinal fibrosis and describe results of recent studies aimed at testing the preventive/therapeutic effect of compounds in experimental models of intestinal fibrosis.
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http://dx.doi.org/10.1042/CS20150472DOI Listing
December 2015

Frequency and Cause of Persistent Symptoms in Celiac Disease Patients on a Long-term Gluten-free Diet.

J Clin Gastroenterol 2016 Mar;50(3):239-43

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Goals: To estimate the frequency and cause of nonresponsive celiac disease (CD).

Background: Treatment of CD is based on life-long adherence to a gluten-free diet (GFD). Some celiac patients experience persistence of symptoms despite a GFD. This condition is defined as nonresponsive CD.

Study: Celiac patients on a GFD for at least 12 months underwent diet compliance assessment, laboratory tests, breath tests, endoscopic, and histologic evaluations according to the symptoms/signs reported.

Results: Seventy of 321 (21.8%) patients had persistent or recurrent symptoms/signs. The cause of symptom persistence was evaluated in 56 of 70 patients. Thirteen of 56 (23%) patients were antiendomysial antibody positive. Among the patients with negative serology, 1 had fibromyalgia, and 3 had evidence that disproved the diagnosis of CD. The remaining 39 patients with negative serology underwent duodenal biopsy sampling, which evidenced histologic alterations in 24 patients. Among the 15 patients with normal histology 3 were lactose intolerant, 9 had irritable bowel syndrome, 2 had gastroesophageal reflux disease, and in 1 patient a cause for the persistent symptom was not identified. In patients with confirmed diagnosis of CD, exposure to dietary gluten was the main cause of persistence of symptoms/signs, and consistently after dietary modification, symptoms resolved in 63% of the patients at later time points during follow-up.

Conclusion: Nonresponsive CD occurs in nearly one fifth of celiac patients on GFD and its occurrence suggests further investigations to optimize the management of celiac patients.
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http://dx.doi.org/10.1097/MCG.0000000000000392DOI Listing
March 2016

Reply: To PMID 24813174.

Clin Gastroenterol Hepatol 2015 Aug 9;13(8):1551. Epub 2015 May 9.

Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.

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http://dx.doi.org/10.1016/j.cgh.2015.05.007DOI Listing
August 2015

A sonographic lesion index for Crohn's disease helps monitor changes in transmural bowel damage during therapy.

Clin Gastroenterol Hepatol 2014 Dec 6;12(12):2071-7. Epub 2014 May 6.

Gastrointestinal Unit, Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy. Electronic address:

Background & Aims: Therapeutic antibodies against tumor necrosis factor α (anti-TNF) are effective in patients with Crohn's disease (CD). Mucosal healing is a surrogate marker of efficacy, but little is known about the effects of anti-TNF agents on structural damage in the intestine. Small-intestine contrast ultrasonography (SICUS) is a valuable tool for assessing CD lesions. A new sonographic quantitative index (the sonographic lesion index for CD [SLIC]) was developed to quantify changes in CD lesions detected by SICUS. We explored whether the SLIC can be used to monitor transmural bowel damage in CD patients during anti-TNF therapy.

Methods: We performed a prospective study of 29 patients with ileal or ileocolonic CD treated with anti-TNF agents; patients underwent SICUS before and after scheduled induction and maintenance therapy. To determine whether changes that can be detected by SICUS occur independently of anti-TNF therapy, 7 patients with ileal CD treated with mesalamine were enrolled as controls. A clinical response was defined as steroid-free remission, with CD activity index scores less than 150.

Results: We observed significant improvements in SLIC scores and subscores after induction and maintenance therapy with anti-TNFs, compared with before therapy. SLIC scores and subscores and index classes were improved significantly in patients with vs without clinical responses. Controls had no improvements in terms of CD activity index or SLIC scores, or index classes.

Conclusions: Sonographic assessment using the quantitative index SLIC can be used to monitor changes in transmural bowel damage during anti-TNF therapy for CD.
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http://dx.doi.org/10.1016/j.cgh.2014.04.036DOI Listing
December 2014

A family study of asymptomatic small bowel Crohn's disease.

Dig Liver Dis 2014 Mar 17;46(3):276-8. Epub 2013 Dec 17.

GI Unit, Department of Systems Medicine, University of Tor Vergata, Rome, Italy.

Background: Discrepancies between severity of lesions and symptoms may be observed in Crohn's disease. We prospectively assessed whether Crohn's disease may be diagnosed among asymptomatic relatives of patients, using Small Bowel Contrast Ultrasonography.

Methods: Diagnosis of asymptomatic Crohn's disease relatives was defined ultrasonographically as: bowel wall thickness >3mm, bowel dilation/stricture, lumen diameter >2.5 cm. Diagnosis was confirmed by ileocolonoscopy. Subjects were also screened for the Leu3020insC mutation.

Results: Consent was given by 35 asymptomatic first-degree relatives of 18 Crohn's disease patients. Ultrasonography indicated increased bowel wall thickness (5mm) compatible with ileal Crohn's disease in 1 relative (2.8%), a 42 year-old male. Ileocolonoscopy, histology, and radiology confirmed the diagnosis of stricturing ileal Crohn's disease. Gallbladder stones were detected in 7/35 (20%) relatives and Leu3020insC mutation in 3/35 (8.5%).

Conclusions: Small Bowel Contrast Ultrasonography may be a useful tool to diagnose asymptomatic small bowel Crohn's disease among first-degree relatives of patients.
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http://dx.doi.org/10.1016/j.dld.2013.11.003DOI Listing
March 2014

Local immune activity in acute coronary syndrome: oxLDL abrogates LPS-tolerance in mononuclear cells isolated from culprit lesion.

Int J Cardiol 2013 Oct 7;169(1):44-51. Epub 2013 Sep 7.

Dipartimento di Medicina dei Sistemi, Università di Roma Tor Vergata, Rome, Italy. Electronic address:

Background: OxLDL plays a major role in the initiation and progression of atherosclerotic lesions even though further factors are needed to promote fibrous cap rupture and thrombotic occlusion of the arterial lumen. Pathogens have been implicated in this process but it remains unclear how they can cooperate with oxLDL in amplifying the destructive inflammatory response.

Objective: To phenotypically analyze culprit coronary inflammatory cells, evaluate their responsiveness to endotoxins and ascertain whether oxLDL alters the sensitivity of coronary mononuclear cells to bacterial components.

Methods: Mononuclear cells isolated from culprit and non-culprit coronary blood samples of patients with ST-segment elevation myocardial infarction (STEMI) and controls were analyzed for cell-specific surface markers and cytokines by flow-cytometry.

Results And Conclusions: CD14+ cells contained elevated levels of TLR4, expressed high CD80, and produced huge amounts of inflammatory cytokines in response to LPS. Using a well-established model of endotoxin tolerance, we next showed that mononuclear cells isolated from control coronary artery, but not from culprit coronary artery, were tolerant to LPS, but pre-treatment of such cells with oxLDL abrogated LPS tolerance. Flow-cytometry analysis also showed that IL-17A, IL-21 and IFN-γ were over-produced by CD4+ and CD56+ cells isolated from the culprit coronary artery. All this data indicate that monocytes circulating in the culprit coronary artery of patients with STEMI are primed to synthesize high levels of inflammatory cytokines and suggest that oxLDL can amplify the inflammatory response of such cells to endotoxins.
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http://dx.doi.org/10.1016/j.ijcard.2013.08.082DOI Listing
October 2013

Lesional accumulation of CD163-expressing cells in the gut of patients with inflammatory bowel disease.

PLoS One 2013 26;8(7):e69839. Epub 2013 Jul 26.

Department of Systems Medicine, University TOR VERGATA of Rome, Rome, Italy.

Monocytes/macrophages displaying different markers of activation/differentiation infiltrate the inflamed gut of patients with inflammatory bowel diseases (IBD), but the role that each monocyte/macrophage subpopulation plays in the pathogenesis of IBD is not fully understood. The hemoglobin scavenger receptor CD163, a specific marker of monocytes/macrophages, has been associated with either anti-inflammatory or inflammatory functions of macrophages in several pathologies. In this study we examined the tissue distribution and function of CD163-expressing monocytes/macrophages in IBD. CD163 RNA and protein expression was more pronounced in IBD in comparison to normal controls, with no significant difference between Crohn's disease and Ulcerative colitis. In IBD, over-expression of CD163 was restricted to areas with active inflammation and not influenced by current therapy. Immunohistochemical analysis confirmed the accumulation of CD163-expressing cells in IBD, mostly around and inside blood vessels, thus suggesting that these cells are partly recruited from the systemic circulation. Indeed, FACS analysis of circulating mononuclear cells showed that the fractions of CD163-positive monocytes were increased in IBD patients as compared to controls. Functionally, interleukin-6 up-regulated CD163 expression in lamina propria mononuclear cells and mucosal explants of normal subjects. In IBD blood and mucosal cell cultures, cross-linking of CD163 with a specific monoclonal anti-CD163 antibody enhanced tumor necrosis factor-α synthesis. These findings indicate that IBD mucosa is abundantly infiltrated with CD163-positive cells, which could contribute to amplify the inflammatory cytokine response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069839PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724902PMC
April 2014

Bowel ultrasonography as an aid for diagnosis of intestinal acute graft-versus-host-disease after allogeneic haematopoietic stem cell transplantation.

Dig Liver Dis 2013 Nov 13;45(11):899-904. Epub 2013 May 13.

Gastroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Italy. Electronic address:

Objective: Aim of our prospective study was to investigate accuracy of bowel ultrasonography in detecting gastrointestinal acute graft versus host disease (GVHD), when using clinical assessment as gold standard. In a subgroup of patients, bowel ultrasonography was compared with colonoscopy and histology in diagnosing of gastrointestinal acute GVHD.

Methods: Fifty-two patients underwent allogeneic hematopoietic stem cell transplantation and developed gastrointestinal symptoms.

Results: Clinical assessment lead to a diagnosis of gastrointestinal acute GVHD in 17/52 patients, no gastrointestinal acute GVHD was detected in 20/52 patients, while 15 patients were not able to complete the study. Bowel ultrasonography detected either bowel wall thickness of the ileum and the colon or dilation in 16/17 patients and showed 94% sensitivity (95% CI 0.69-0.99), 95% specificity (95% CI 0.73-0.99), and 94.5% accuracy. Colonoscopy was performed in 13/52 patients, showing gastrointestinal acute GVHD in 11/13. In these 11 patients, histology confirmed the diagnosis of gastrointestinal acute GVHD, and bowel ultrasonography detected findings compatible with gastrointestinal acute GVHD in all 11 patients, and was negative in the 2 patients with no gastrointestinal acute GVHD.

Conclusion: Bowel ultrasonography can be considered a valuable tool to add to clinical assessment for patients with suspected gastrointestinal acute GVHD for addressing a prompt and appropriate treatment.
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http://dx.doi.org/10.1016/j.dld.2013.04.004DOI Listing
November 2013

TGF-Beta signaling manipulation as potential therapy for IBD.

Curr Drug Targets 2013 Nov;14(12):1400-4

Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy.

Crohn's disease (CD) and ulcerative colitis (UC), two chronic and relapsing inflammatory bowel diseases (IBD), are supposed to develop in genetically-predisposed individuals as a result of an excessive immune mucosal response directed against normal components of the gut microbiota. There is also evidence that defects in counter-regulatory mechanisms play a major role in the pathogenesis of IBD. One such a defect involves TGF-β1, a cytokine produced by multiple cells types and able to inhibit pathogenic responses in the gut. In both CD and UC, TGF-β1 is highly produced but unable to signal through the TGF-β receptor-associated Smad pathway and suppress production of inflammatory molecules. Abrogation of TGF-β1 activity has been related to Smad7, an intracellular protein that binds to TGF-β receptor and inhibits TGF-β1-driven Smad-dependent signalling. Indeed, silencing of Smad7 with a specific antisense oligonucleotide restores TGF-β1/Smad signalling, thereby down-regulating inflammatory cytokine production and ameliorating experimental colitis in mice. Altogether these observations led to the development of an oral pharmaceutical compound containing the specific Smad7 antisense oligonucleotide (herein termed GED0301), which seems to be safe and well tolerated in CD patients. In this article we summarize the data supporting the pathogenic role of Smad7 in IBD and discuss the recent results of the use of GED0301 in CD.
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http://dx.doi.org/10.2174/13894501113149990157DOI Listing
November 2013

Accuracy of small-intestine contrast ultrasonography, compared with computed tomography enteroclysis, in characterizing lesions in patients with Crohn's disease.

Clin Gastroenterol Hepatol 2013 Aug 29;11(8):950-5. Epub 2013 Jan 29.

Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background & Aims: Small-intestine contrast ultrasonography (SICUS) is a radiation-free technique that can detect intestinal damage in patients with Crohn's disease (CD). We evaluated the diagnostic accuracy of SICUS in determining the site, extent, and complications of CD, compared with computed tomography (CT) enteroclysis as the standard.

Methods: We performed a retrospective analysis of data from 59 patients with CD evaluated by SICUS and CT enteroclysis 3 months apart, between January 2007 and April 2012. We evaluated disease site (based on bowel wall thickness), extent of lesions, and presence of complications (stenosis, prestenotic dilation, abscess, or fistulas) using CT enteroclysis as the standard. Sensitivity, specificity, and diagnostic accuracy were calculated. We determined the correlations in maximum wall thickness and disease extent in the small bowel between results from SICUS and CT enteroclysis.

Results: SICUS identified the site of small bowel CD with 98% sensitivity, 67% specificity, and 95% diagnostic accuracy; it identified the site of colon CD with 83% sensitivity, 97.5% specificity, and 93% diagnostic accuracy. Results from SICUS and CT enteroclysis correlated in determination of bowel wall thickness (rho, 0.79) and disease extent (rho, 0.89; P < .0001 for both). SICUS detected ileal stenosis with 95.5% sensitivity, 80% specificity, and 91.5% diagnostic accuracy, and prestenotic dilation with 87% sensitivity, 67% specificity, and 75% diagnostic accuracy. SICUS detected abscesses with 78% sensitivity, 100% specificity, and 97% diagnostic accuracy, and fistulas with 78.5% sensitivity, 95.5% specificity, and 91.5% diagnostic accuracy.

Conclusions: SICUS identified lesions and complications in patients with CD with high levels of sensitivity, specificity, and accuracy compared with CT enteroclysis. SICUS might be used as an imaging tool as part of a focused diagnostic examination of patients with CD.
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http://dx.doi.org/10.1016/j.cgh.2013.01.015DOI Listing
August 2013

Distinct profiles of effector cytokines mark the different phases of Crohn's disease.

PLoS One 2013 17;8(1):e54562. Epub 2013 Jan 17.

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Objective: Crohn's Disease (CD)-associated inflammation is supposed to be driven by T helper (Th)1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD.

Design: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions) or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions). Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA.

Results: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-α and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-α induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-γ or IL-17A.

Conclusions: Distinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054562PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547873PMC
July 2013

Smad7 antisense oligonucleotide-based therapy for inflammatory bowel diseases.

Dig Liver Dis 2013 Jul 1;45(7):552-5. Epub 2013 Jan 1.

Department of Systems Medicine, University of Rome Tor Vergata, Italy.

The aetiology of both Crohn's disease and ulcerative colitis, the major forms of inflammatory bowel diseases in human beings, remains unknown. However, compelling evidence suggests that the associated pathological process in inflammatory bowel disease is driven by an excessive immune response directed against normal components of the bacterial microflora and marked by defects in counter-regulatory mechanisms, such as those involving transforming growth factor-β1. Indeed, a diminished activity of transforming growth factor-β1, as indicated by a reduced phosphorylation of Smad3, a signalling molecule associated with the activated transforming growth factor-β receptor, is evident in the inflamed gut of inflammatory bowel disease patients and this alteration is due to high Smad7, an intracellular inhibitor of Smad3 phosphorylation. Consistently, silencing of Smad7 with a specific antisense oligonucleotide restores transforming growth factor-β1/Smad3 signalling, thereby leading to inhibition of inflammatory cytokine production and attenuation of experimental colitis in mice. These findings together with the demonstration that Smad7 antisense oligonucleotide is safe and well-tolerated in patients with Crohn's disease indicate that Smad7 antisense oligonucleotide-based pharmaceutical compounds could enter the therapeutic armamentarium of these disorders. In this article we review the available data supporting the pathogenic role of Smad7 in the gut and discuss why Smad7 antisense therapy could help dampen the mucosal inflammation in inflammatory bowel disease.
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http://dx.doi.org/10.1016/j.dld.2012.11.011DOI Listing
July 2013

Anti-TNF-alpha treatments and obstructive symptoms in Crohn's disease: a prospective study.

Dig Liver Dis 2013 Mar 26;45(3):258-62. Epub 2012 Nov 26.

GI Unit, Department of Systems Medicine, University Tor Vergata, Rome, Italy.

Background: The development of symptomatic strictures in Crohn's Disease after anti-Tumour Necrosis Factor-α antibodies is undefined.

Aim: To assess, in a prospective longitudinal study, the frequency of sub/obstructions in Crohn's Disease patients after treatment with Infliximab or Adalimumab. Changes of small bowel lesions after these biological therapies were searched by ultrasonography.

Materials And Methods: From January 2007 to October 2008, 36 Crohn's Disease patients with no previous sub/obstructions were treated with either Infliximab (n=13) or Adalimumab (n=23) for ≥12months (mean follow-up duration after the first treatment 23.2±6.8months). Small Intestine Contrast Ultrasonography was performed before and after treatment in 19/36 patients. Sonographic parameters included: bowel wall thickness, lumen diameter, bowel dilation and lesion extent.

Results: Sub/obstructions developed in 3/36 patients treated with Infliximab (n=1) or Adalimumab (n=2), all with fibrostricturing Crohn's Disease. Sonographic parameters did not significantly change after treatment.

Conclusions: Sub/obstructive symptoms may develop in one tenth of Crohn's Disease patients treated with anti-Tumour Necrosis Factor-α antibodies, with no significant sonographic changes of the small bowel lesions.
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http://dx.doi.org/10.1016/j.dld.2012.10.009DOI Listing
March 2013

Small intestine contrast ultrasonography vs computed tomography enteroclysis for assessing ileal Crohn's disease.

World J Gastroenterol 2012 Nov;18(42):6088-95

Department of Systems Medicine, University "Tor Vergata", 00133 Rome, Italy.

Aim: To compare computed tomography enteroclysis (CTE) vs small intestine contrast ultrasonography (SICUS) for assessing small bowel lesions in Crohn's disease (CD), when using surgical pathology as gold standard.

Methods: From January 2007 to July 2008, 15 eligible patients undergoing elective resection of the distal ileum and coecum (or right colon) were prospectively enrolled. All patients were under follow-up. The study population included 6 males and 9 females, with a median age of 44 years (range: 18-80 years).

Inclusion Criteria: (1) certain diagnosis of small bowel requiring elective ileo-colonic resection; (2) age between 18-80 years; (3) elective surgery in our Surgical Unit; and (4) written informed consent. SICUS and CTE were performed ≤ 3 mo before surgery, followed by surgical pathology. The following small bowel lesions were blindly reported by one sonologist, radiologist, surgeon and histolopathologist: disease site, extent, strictures, abscesses, fistulae, small bowel dilation. Comparison between findings at SICUS, CTE, surgical specimens and histological examination was made by assessing the specificity, sensitivity and accuracy of each technique, when using surgical findings as gold standard.

Results: Among the 15 patients enrolled, CTE was not feasible in 2 patients, due to urgent surgery in one patients and to low compliance in the second patient, refusing to perform CTE due to the discomfort related to the naso-jejunal tube. The analysis for comparing CTE vs SICUS findings was therefore performed in 13 out of the 15 CD patients enrolled. Differently from CTE, SICUS was feasible in all the 15 patients enrolled. No complications were observed when using SICUS or CTE. Surgical pathology findings in the tested population included: small bowel stricture in 13 patients, small bowel dilation above ileal stricture in 10 patients, abdominal abscesses in 2 patients, enteric fistulae in 5 patients, lymphnodes enlargement (> 1 cm) in 7 patients and mesenteric enlargement in 9 patients. In order to compare findings by using SICUS, CTE, histology and surgery, characteristics of the small bowel lesions observed in CD each patient were blindly reported in the same form by one gastroenterologist-sonologist, radiologist, surgeon and anatomopathologist. At surgery, lesions related to CD were detected in the distal ileum in all 13 patients, also visualized by both SICUS and CTE in all 13 patients. Ileal lesions > 10 cm length were detected at surgery in all the 13 CD patients, confirmed by SICUS and CTE in the same 12 out of the 13 patients. When using surgical findings as a gold standard, SICUS and CTE showed the exactly same sensitivity, specificity and accuracy for detecting the presence of small bowel fistulae (accuracy 77% for both) and abscesses (accuracy 85% for both). In the tested CD population, SICUS and CTE were also quite comparable in terms of accuracy for detecting the presence of small bowel strictures (92% vs 100%), small bowel fistulae (77% for both) and small bowel dilation (85% vs 82%).

Conclusion: In our study population, CTE and the non-invasive and radiation-free SICUS showed a comparable high accuracy for assessing small bowel lesions in CD.
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http://dx.doi.org/10.3748/wjg.v18.i42.6088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496885PMC
November 2012

Tissue inhibitor of metalloproteinase-3 regulates inflammation in human and mouse intestine.

Gastroenterology 2012 Nov 20;143(5):1277-1287.e4. Epub 2012 Jul 20.

Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy. Electronic address:

Background & Aims: Tissue inhibitor of metalloproteinases (TIMP)-3 is an inhibitor of matrix metalloproteinases, which regulates tissue inflammation, damage, and repair. We investigated the role of TIMP-3 in intestinal inflammation in human beings and mice.

Methods: We used real-time polymerase chain reaction and flow cytometry to measure levels of TIMP-3 in intestine samples from patients with Crohn's disease (CD) and those without (controls). We also analyzed TIMP-3 levels in lamina propria mononuclear cells (LPMCs) collected from biopsy samples of individuals with or without CD (controls) and then stimulated with transforming growth factor (TGF)-β1, as well as in biopsy samples collected from patients with CD and then incubated with a Smad7 anti-sense oligonucleotide (knock down). LPMCs and biopsy samples from patients with CD were cultured with exogenous TIMP-3 and levels of inflammatory cytokines were measured. We evaluated the susceptibility of wild-type, TIMP-3-knockout (TIMP-3-KO), and transgenic (TIMP-3-Tg) mice to induction of colitis with 2, 4, 6-trinitrobenzene-sulfonic-acid (TNBS), and the course of colitis in recombinase-activating gene-1-null mice after transfer of wild-type or TIMP-3-KO T cells.

Results: Levels of TIMP-3 were reduced in intestine samples from patients with CD compared with controls. Incubation of control LPMCs with TGF-β1 up-regulated TIMP-3; knockdown of Smad7, an inhibitor of TGF-β1, in biopsy samples from patients with CD increased levels of TIMP-3. Exogenous TIMP-3 reduced levels of inflammatory cytokines in CD LPMCs and biopsy samples. TIMP-3-KO mice developed severe colitis after administration of TNBS, whereas TIMP-3-Tg mice were resistant to TNBS-induced colitis. Reconstitution of recombinase-activating gene-1-null mice with T cells from TIMP-3-KO mice increased the severity of colitis, compared with reconstitution with wild-type T cells.

Conclusions: TIMP-3 is down-regulated in inflamed intestine of patients with CD. Its expression is regulated by TGF-β1, and knock-down of Smad7 in intestinal tissues from patient with CD up-regulates TIMP-3. Loss or reduction of TIMP-3 in mice promotes development of colitis.
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http://dx.doi.org/10.1053/j.gastro.2012.07.016DOI Listing
November 2012

Ultrasound in Crohn's disease.

Curr Drug Targets 2012 Sep;13(10):1224-33

Gastrointestinal Unit, Department of Internal Medicine, University of Rome Tor Vergata, Viale Oxford 81, Rome, Italy.

Over the past few years, the technical evolution of ultrasound equipment, the use of oral and intravenous contrast agents, and an increase in the expertise of sonographers has enhanced the role of ultrasonography that plays in the assessment of the gastrointestinal tract. In chronic inflammatory conditions, primarily CD, this technology can be used not only for diagnostic purposes, but it has also been suggested that it could play a role in the management of the disease.
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http://dx.doi.org/10.2174/138945012802429697DOI Listing
September 2012
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