[Show abstract][Hide abstract] ABSTRACT: Coeliac disease is a common enteropathy characterized by an increased mortality mainly due to its complications. The natural history of complicated coeliac disease is characterised by two different types of course: patients with a new diagnosis of coeliac disease that do not improve despite a strict gluten-free diet (type A cases) and previously diagnosed coeliac patients that initially improved on a gluten-free diet but then relapsed despite a strict diet (type B cases). Our aim was to study the prognosis and survival of A and B cases.
[Show abstract][Hide abstract] ABSTRACT: Background
The clinical presentation of organic and functional intestinal disorders can overlap and clinicians often rely on invasive and time-consuming procedures to make a final diagnosis. Regenerating islet-derived 3-alpha (Reg3α) is detectable in the circulation of patients with intestinal graft-versus host disease and patients with inflammatory bowel disease (IBD).AimTo determine whether serum Reg3α testing is useful for discriminating mucosal enteropathies from functional intestinal disorders.Methods
We prospectively included 47 patients with active coeliac disease (ACD), 13 patients with refractory coeliac disease (RCD), seven patients with common variable immunodeficiency (CVID), 72 patients with active Crohn's disease, 22 patients with active ulcerative colitis (UC) and 28 patients with irritable bowel syndrome (IBS)-related diarrhoea. Sera were also taken from 10 CD patients before and after 6–12 months of a gluten-free diet (GFD) and from 14 patients with IBD before and after induction therapy with Infliximab (IFX). Sera of 119 healthy volunteers were used to determine the cut-off value. Reg3α levels were measured by a commercial ELISA kit.ResultsLevels of Reg3α exceeded the cut-off value of the assay in 43/47(91%) ACD patients, 13/13(100%) RCD patients, 7/7(100%) CVID patients, 65/72(90%) Crohn's disease patients, 17/22(77%) UC patients and one patient with IBS(4%). Reg3α levels distinguished mucosal enteropathies from IBS with a sensitivity of 90% and a specificity of 96%. Reg3α levels significantly decreased in CD patients following a GFD and in IBD patients after treatment with IFX.Conclusion
Reg3α is a serum biomarker of intestinal damage that, combined with clinical data, identifies patients who should undergo invasive tests for diagnosing enteropathies.
[Show abstract][Hide abstract] ABSTRACT: Non-valvular atrial fibrillation (NVAF) represents a major health-care problem, needing an extensive and strict thrombosis prevention for stroke and cardiovascular (CV) disease risks. NVAF management guidelines recommend adequate antithrombotic and anti-atherosclerotic therapies. Medication adherence has been recognized as a pivotal element in health quality promotion and in the achievement of better clinical outcomes. We conducted a post-hoc analysis of the "Atrial fibrillation Registry for Ankle-brachial index Prevalence Assessment-Collaborative Italian Study (ARAPACIS)" with the aim of discerning differences in pharmacological management and medication adherence among NVAF Italian patients. Furthermore, data were analysed according to Italian geographical macro-regions (North, Center, South) to evaluate whether socioeconomic conditions might also influence medication adherence. Thus, we selected 1,366 NVAF patients that fulfilled the Morisky Medication Adherence Scale-4 items. Regional disparities in drug prescriptions were observed. In particular, in high-risk patients (CHA2DS2-VASc ≥2) oral anticoagulants were more prescribed in Northern and Center patients (61 and 60 %, respectively) compared to 53 % of high-risk Southern patients. Also, medication adherence showed a progressive decrease from North to South (78 vs. 60 %, p < 0.001). This disparity was independent of the number of drugs consumed for any reason, since prevalence of poly-therapy among the three macro-regions was similar. Our results show regional differences in NVAF patients' antithrombotic management and medication adherence, potentially reflecting well-known disparities in socioeconomic status among Italian regions. Future interventions promoting campaigns to global health-care education may be desirable to improve clinical outcomes in NVAF patients.
Internal and Emergency Medicine 07/2014; · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
Patients affected by primary immunodeficiency usually undergo a wide range of infections, including reactivation of latent ones. Here we report two cases suffering from late-onset combined immunodeficiency in which ulcerative enteritis due to human Cytomegalovirus caused a life-threatening malabsorption syndrome.
The assessment of the viral load was carried out on both blood and mucosal samples by quantitative real-time polymerase chain reaction assay. The generation of autologous virus-specific cytotoxic T cell lines was performed according to Good Manufacturing Practice protocol after peripheral blood mononuclear cells were collected through a single leukapheresis.
In both patients, the viral load resulted negligible in peripheral blood, but very high in mucosal specimens (range 1.064 - 1.031.692 copies/105 cells). After two rounds of antiviral therapy proved unsuccessful, the generation of virus-specific cytotoxic T cell lines was carried out despite severe lymphopenia, and their infusion resulted safe and durably effective in healing intestinal ulcerations and resetting the viral load.
Virus-specific cellular therapy was useful in reconstituting specific immunity and treating severe human Cytomegalovirus-related enteritis in patients with primary immunodeficiency.
Journal of Clinical Immunology 06/2014; · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-celiac gluten sensitivity (NCGS) is still an undefined syndrome with several unsettled issues despite the increasing awareness of its existence. We carried out a prospective survey on NCGS in Italian centers for the diagnosis of gluten-related disorders, with the aim of defining the clinical picture of this new syndrome and to establish roughly its prevalence compared with celiac disease.
[Show abstract][Hide abstract] ABSTRACT: Introduction. Coeliac disease is a chronic enteropathy requiring a close follow-up. However, the best way to follow up coeliac patients has not yet been established. In the last 14 years, we have been offering patients a thorough series of periodical examinations including a histological re-evaluation at 12-18 months. Patients and methods. The notes of all coeliac patients attending our clinic between September 1999 and March 2013 were examined. Results. Data from 317 adult patients were collected. Duodenal biopsy showed a lack of satisfactory histological response in 25/317 patients; endomysial antibodies were still positive in 76, and diet adherence and clinical response were unsatisfactory in 58 and 97, respectively. Correlations of serological data, clinical response, and diet adherence with histological findings were evaluated. Although the P values showed statistically significant differences, sensitivity and specificity were disappointing: 64% and 80% for serological response, 48% and 71% for clinical response, 56% and 85% for diet adherence. Conclusions. After 12-18 months on a gluten-free diet, 8% of the patients do not present a satisfactory histological response; only some of them could have been identified with a serological and/or clinical re-evaluation. Therefore, a duodenal biopsy seems to be the only tool that could identify patients with unsatisfactory histological response.
[Show abstract][Hide abstract] ABSTRACT: Celiac disease is caused by a dysregulated immune response toward dietary gluten, whose only treatment is a lifelong gluten-free diet. We investigated the effects of mesenchymal stromal cells (MSCs) on gliadin-specific T cells, which are known to induce intestinal lesions, in view of a possible use as new therapy.
Bone marrow-derived MSCs and gliadin-specific T-cell lines were obtained from allogeneic donors and mucosal specimens of celiac patients, respectively. The immunosuppressant effect of MSCs was evaluated in terms of proliferative response and interferon (IFN)-γ production upon gliadin stimulation of long-term T-cell lines; the immunomodulant effect was assessed in terms of apoptotic rate, immunophenotype and cytokine profile of short-term T-cell lines generated in the presence of MSCs. Different MSC:T-cell ratios were applied, and statistics were performed as appropriate.
MSCs inhibited both proliferative response and IFN-γ production of long-term T-cell lines in a dose-dependent manner while limiting the expansion of short-term T-cell lines by increasing the apoptotic rate. Moreover, a reduction of the CD4(+) population and expansion of the regulatory FoxP3(+) subset were found in T-cell lines cultured with MSCs, in which a significant decrease of interleukin (IL)-21, IFN-γ and IL-10 paralleled by an upregulation of transforming growth factor-β1, IL-6 and IL-8 were observed. Finally, an increase of the indoleamine 2,3-dioxygenase activity was found, possibly playing a key role in mediating these effects.
MSCs exert potent immunomodulant effects on gliadin-specific T cells, which may be exploited for future therapeutic application in celiac disease.
[Show abstract][Hide abstract] ABSTRACT: Intestinal fibrosis with stricture formation is a complication of Crohn's disease (CD) that may mandate surgical resection. Accurate biomarkers that reflect the relative contribution of fibrosis to an individual stricture are an unmet need in managing patients with CD. The microRNA (miR)-29 family has been implicated in cardiac, hepatic and pulmonary fibrosis. We investigated the expression of miR-29a, miR-29b and miR-29c in mucosa overlying a stricture in CD patients (SCD) paired with mucosa from non-strictured areas (NSCD). There was significant down-regulation of the miR-29 family in mucosa overlying SCD compared to mucosa overlying NSCD. MiR-29b showed the largest fold-decrease and was selected for functional analysis. Over-expression of miR-29b in CD fibroblasts led to a down-regulation of collagen I and III transcripts and collagen III protein, but did not alter matrix metalloproteinase (MMP)-3, MMP-12 and tissue inhibitor of metalloproteinase (TIMP)-1 production. TGF-β1 up-regulated collagen I and III transcripts and collagen III protein as a consequence of the down-regulation of miR-29b and TGF-β1-induced collagen expression was reversed by exogenous overexpression of miR-29b. Furthermore, serum levels of miR-29 were lower in patients with stricturing disease compared to those without. These data implicate the miR-29 family in the pathogenesis of intestinal fibrosis in CD and provides impetus for the further evaluation of the miR-29 family as biomarkers.
[Show abstract][Hide abstract] ABSTRACT: Autoimmune enteropathy (AIE) is a rare cause of small bowel villous atrophy, characterized by malabsorption, unresponsiveness to dietary restriction, circulating autoantibodies to enterocytes, and an overall predisposition to autoimmunity. Albeit mainly regarded as a disease of early childhood, several adult-onset AIE cases have been identified. This report describes for the first time the life-threatening clinical presentation and the management of overlapping AIE in a compliant-to-diet young celiac girl. A 13-year-old celiac girl was admitted because of vomiting, weight loss, diarrhea, hypoproteinemia, and neurological disturbances such as head tremors, vertical nystagmus, and lower limb hyperesthesia. Before this, she had always been compliant on a strict gluten-free diet and her medical history was unremarkable. The diagnosis of AIE was established on histologic findings and on the presence of antienterocyte antibodies. She was initially treated with high-dose Methylprednisolone and Azathioprine. However, only Infliximab proved itself as a highly effective tool for achieving clinical remission and restoring small bowel villous architecture.
Journal of clinical gastroenterology 03/2014; 48(3):264-6. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several biomarkers have been proposed for the diagnosis of autoimmune atrophic gastritis (AAG), but at the present there is no appropriate testing strategy for the disease.
The aim of this study was to develop and validate a laboratory score able to address the diagnosis of AAG in a general practice setting.
We prospectively evaluated a number of serum biomarkers (vitamin B12, mean corpuscular volume, hemoglobin, gastrin, and chromogranin A levels) in a case-control population and built 2 biochemical scores, the first with all the parameters [Global Score (GS)], and the second as the best statistical combination of them [Simple Score (SS)]. In the second phase we validated the score that proved to be more efficient on a random population referred to our center (Gastroenterology Outpatient Clinic).
Both models turned out to be reliable in detecting patients with suspected AAG, showing excellent accuracy [area under the receiver operating curve (AUC-ROC) 0.94; 95% confidence interval (CI), 0.91-0.97 for GS and AUC-ROC 0.93; 95% CI, 0.89-0.86 for SS]. The SS proved to be more convenient because of its accessibility and availability in a general setting and its low cost. The validation of the SS showed a sensitivity of 85.7% (95% CI, 57.2-98.2) and a specificity of 83.7% (95% CI, 74.2-90.89).
Herein, we describe 2 nonexpensive and reliable score models, particularly the SS, that can be applied in daily medical practice for identifying patients potentially affected by AAG.
Journal of clinical gastroenterology 02/2014; · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The celiac disease is an ancient pathology, present since the introduction of the wheat in the diet, of which the first description of the compatible clinical symptoms and signs goes back to 250 A.D. Today it is known that the expression of this pathology is multifaceted, ranging from clinical features indicative of bowel disease and malabsorption, until symptoms once unexpected, because of their extra-digestive clinical features. With our work, we wanted to retrace the history of this disease, correlating it with the intake of gluten present in wheat after cooking , ever since mankind has increased the cultivation of cereals. Re-evaluating the clinical and instrumental methods for the diagnosis of Celiac Disease, and benefitting from the most modern techniques for the morphological, biochemical and genetic study of the patients, we sought to understand whether the incidence of the disease is actually increased or if has been considered less frequent for the lower valuation of the signs once deemed more atypical, but currently considered preliminary indicative of the pathology, for its association with other autoimmune diseases, and for the study of some genetic and familiar characteristics. Each of these factors has led the modern medicine to increase epidemiological studies and expand the research potential carriers of celiac disease with safer diagnostic tests.
Internal and Emergency Medicine 01/2014; · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES:Several immune-mediated gastrointestinal disorders, including celiac disease (CD), are associated with neuroendocrine cell hyperplasia. However, neuroendocrine cells have never been explored in refractory CD (RCD).METHODS:Serial duodenal sections from 17 patients with RCD (6 type 1 and 11 type 2), 16 uncomplicated CD patients before and after gluten-free diet, 14 patients with potential CD, 27 patients with non-CD villous atrophy, i.e., common variable immunodeficiency (n=12), Whipple's disease (n=10) and giardiasis (n=5), and 16 healthy subjects were processed for the immunohistochemical detection of chromogranin A (CgA), serotonin, and somatostatin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative reverse transcription-PCR. Serum CgA and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) were assessed. Biopsies from treated CD patients were cultured with serotonin or peptic tryptic digest of gliadin (PT-gliadin), and interferon (IFN)-γ was detected by ELISA in culture supernatants.RESULTS:Epithelial cells positive for CgA and serotonin, but not somatostatin, were significantly increased in RCD. Raised mucosal transcripts of TpH-1, but not SERT, were found in RCD. On biopsies from treated CD patients, serotonin upregulated IFN-γ production at levels comparable to those induced by PT-gliadin. Serum CgA, but not urine 5-HIAA, was increased in RCD. No significant difference was found between RCD type 1 and type 2 in terms of neuroendocrine cells, mucosal TpH-1 transcripts, and serum CgA.CONCLUSIONS:Serotonin-producing neuroendocrine cells are increased in RCD mucosa. IFN-γ upregulation induced by serotonin suggests that this monoamine may have a role in sustaining the local inflammatory response in CD.Am J Gastroenterol advance online publication, 7 January 2014; doi:10.1038/ajg.2013.426.
The American Journal of Gastroenterology 01/2014; · 7.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been shown that mortality rates of coeliac patients correlate with age at diagnosis of coeliac disease, diagnostic delay for coeliac disease, pattern of clinical presentation and HLA typing. Our aim was to create a tool that identifies coeliac patients at higher risk of developing complications.
To identify predictors of complications in patients with coeliac disease, we organised an observational multicenter case-control study based on a retrospective collection of clinical data. Clinical data from 116 cases (patients with complicated coeliac disease) and 181 controls (coeliac patients without any complications) were collected from seven European centres. For each case, one or two controls, matched to cases according to the year of assessment, gender and age, were selected. Diagnostic delay, pattern of clinical presentation, HLA typing and age at diagnosis were used as predictors.
Differences between cases and controls were detected for diagnostic delay and classical presentation. Conditional logistic models based on these statistically different predictors allowed the development of a score system. Tertiles analysis showed a relationship between score and risk of developing complications.
A score that shows the risk of a newly diagnosed coeliac patient developing complications was devised for the first time. This will make it possible to set up the follow-up of coeliac patients with great benefits not only for their health but also for management of economic resources.
We think that our results are very encouraging and represent the first attempt to build a prognostic score for coeliac patients.
PLoS ONE 01/2014; 9(1):e84163. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background aims
Celiac disease is caused by a dysregulated immune response toward dietary gluten, whose only treatment is a lifelong gluten-free diet. We investigated the effects of mesenchymal stromal cells (MSCs) on gliadin-specific T cells, which are known to induce intestinal lesions, in view of a possible use as new therapy.
Bone marrow–derived MSCs and gliadin-specific T-cell lines were obtained from allogeneic donors and mucosal specimens of celiac patients, respectively. The immunosuppressant effect of MSCs was evaluated in terms of proliferative response and interferon (IFN)-γ production upon gliadin stimulation of long-term T-cell lines; the immunomodulant effect was assessed in terms of apoptotic rate, immunophenotype and cytokine profile of short-term T-cell lines generated in the presence of MSCs. Different MSC:T-cell ratios were applied, and statistics were performed as appropriate.
MSCs inhibited both proliferative response and IFN-γ production of long-term T-cell lines in a dose-dependent manner while limiting the expansion of short-term T-cell lines by increasing the apoptotic rate. Moreover, a reduction of the CD4+ population and expansion of the regulatory FoxP3+ subset were found in T-cell lines cultured with MSCs, in which a significant decrease of interleukin (IL)-21, IFN-γ and IL-10 paralleled by an upregulation of transforming growth factor-β1, IL-6 and IL-8 were observed. Finally, an increase of the indoleamine 2,3-dioxygenase activity was found, possibly playing a key role in mediating these effects.
MSCs exert potent immunomodulant effects on gliadin-specific T cells, which may be exploited for future therapeutic application in celiac disease.
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-13 has been implicated in the pathogenesis of ulcerative colitis (UC), and may have a role in animal models of gut fibrosis. We studied the involvement of IL-13 in inflammation and fibrosis in UC and Crohn's disease (CD). Intestinal biopsies and anti-CD3/CD28- or anti-CD2/CD28-stimulated lamina propria mononuclear cells (LPMCs) from UC and CD patients and control subjects were cultured, and IL-13, IL-4, IL-5, IL-17A and interferon (IFN)-γ production was measured. Mucosal IL-13-producing cells were characterised by flow cytometry. Gut explants from strictured CD, non-strictured CD and healthy donors were cultured ex vivo, and secreted IL-13, IL-1β and collagen were measured. IL-13 production by mucosal explants and activated LPMCs did not differ between CD, UC and control subjects, and was at least a log lower than IFN-γ and IL-17A. IL-13-producing cells, and in particular natural killer T cells, were uniformly low in all groups. IL-4 and IL-5 were undetectable in culture supernatants. Explants of CD strictures produced low amounts of IL-13, whereas IL-1β and collagen were elevated. We could not confirm that UC or strictured CD are associated with elevated IL-13 production. These data suggest that an anti-IL-13 antibody would not be an appropriate therapeutic strategy in inflammatory bowel disease. This article is protected by copyright. All rights reserved.
European Journal of Immunology 12/2013; · 4.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the level of mucosal expression and the involvement of the receptor for the advanced glycation end products (RAGE) in delayed apoptosis and tumor necrosis factor (TNF)-α production in Crohn's disease (CD).
Surgical and endoscopic specimens from both inflamed and non-inflamed areas of the ileum and/or colon were collected from 20 and 14 adult CD patients, respectively, and used for the assessment of RAGE expression by means of immunohistochemistry and western blotting analysis. Normal tissues from 21 control subjects were used for comparison. The same polyclonal anti-human RAGE antibody (R and D System) was used in all experimental conditions. RAGE staining was quantized by a score including both the amount of positive cells and intensity of immunoreactivity; cellular pattern was also described. The effects of RAGE blocking on apoptotic rate and TNF-α production were investigated on immune cells freshly isolated from CD mucosa and incubated both with and without the muramyl dipeptide used as antigenic stimulus. Statistical analysis was performed via the test for trend, with regression models to account for intra-patient correlations. A 2-sided P < 0.05 was considered significant.
In inflamed areas, RAGE expression in both the epithelial and lamina propria compartments was higher than control tissues (P = 0.001 and 0.021, respectively), and a cluster of positive cells were usually found in proximity of ulcerative lesions. Similar results were obtained in the lamina propria compartment of non-inflamed areas (P = 0.025). The pattern of staining was membranous and granular cytosolic at the epithelial level, while in the lamina propria it was diffuse cytosolic. When evaluating the amount of protein expression by immunoblotting, a significant increase of both surface area and band intensity (P < 0.0001 for both) was observed in CD inflamed areas compared to control tissue, while in non-inflamed areas a significant increase was found only for band intensity (P < 0.005). Moreover, a significantly lower expression in non-inflamed areas in comparison with inflamed areas was found for both surface area and band intensity (P < 0.0006 for both). Finally, RAGE blocking largely affects both the apoptotic rate of mucosal cells (towards an increase in both non-inflamed and inflamed areas of P < 0.001 and < 0.0001, respectively) and TNF-α secretion (towards a decrease in both non-inflamed and inflamed areas of P < 0.05 and < 0.01, respectively), mainly in the presence of antigenic stimulation.
RAGE is up-regulated in CD, especially in inflamed areas, and it appears to play a role in the mechanisms involved in chronic inflammation.
World Journal of Gastroenterology 12/2013; 19(45):8269-81. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite extensive use in clinical practice, difficulties regarding interpretation of hydrogen breath test are still very frequent, even on research grounds. After the administration of a non-absorbable sugar, such as lactulose, an increase of breath hydrogen and methane is evident; this phenomenon is considered an index of colonic fermentation. It is not clear, however, if the levels of these compounds correlate with the presence and severity of functional symptoms, nor if they accurately reflect gas production at colonic level. So far, apart from flatulence, we have no indications regarding the ability of hydrogen or methane to act as biomarkers of intraluminal events. On the other hand, it has been shown that in functional bowel disease a colonic dysbiosis exists, and that the modification of bacterial flora might result in a reduction of symptom severity. Consequently, it is not clear if hydrogen and methane colonic production could have a role in the pathophysiology of functional complaints, but it is possible that other fermentation products should be taken into consideration, such as acetate, propionate, and alcohol.
European review for medical and pharmacological sciences 12/2013; 17(2 Suppl):36-38. · 1.09 Impact Factor