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Introduction: Coeliac disease and dermatitis herpetiformis are immune-mediated diseases triggered by the consumption of gluten in genetically predisposed individuals. These guidelines were developed to provide general practitioners, paediatricians, gastroenterologists, and other clinicians with an overview on the diagnosis, management and follow-up of coeliac patients and those with dermatitis herpetiformis.Methods: Guidelines were developed by the Italian Societies of Gastroenterology. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodol-ogy was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists and a paediatrician with expertise in this field.Results: These guidelines provide a practical guidance for the diagnosis, management and follow-up of coeliac patients and dermatitis herpetiformis in children and adults, both in primary care and in specialist settings. We developed four sections on diagnosis, gluten-free diet, follow-up and risk of complications in adults, one section focused on diagnosis and follow-up in children and one on the diagnosis and man-agement of dermatitis herpetiformis.Conclusions: These guidelines may support clinicians to improve the diagnosis and management of pa-tients with coeliac disease.(c) 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Data on factors governing long-term adherence to a gluten-free diet (GFD) in celiac disease (CD) are scarce. We aimed to determine trends and clinical predictors of long-term GFD adherence in adult CD.Initial and long-term (3 years) GFD adherence, clinical characteristics at baseline and follow-up were collected retrospectively from celiac patients followed-up over 20 years (2000-2020). Predictors of long-term GFD adherence at diagnosis, and follow-up were evaluated by multivariate logistic regression.248 patients (37 ± 12 years, 186F, median time on a GFD 90 months) were included. Twenty-five (10.1%) had only short-term follow-up (3 years) while 223 (89.9%) had initial and long-term dietary assessment. 187/223 (83.9%) patients were initially adherent and 36/223 (16.1%) were not. 17/36 (47.2%) patients initially not adherent become adherent, while only 4/187 (2.1%) initially adherent patients became not adherent. In the long-term, 200/223 (89.7%) were adherent and 21/223 (9.4%) patients were not. Adherence improved more frequently than worsened (OR, 39.5; 95% CI, 11.4-178.5; P.01). Classical symptoms (diarrhea, weight loss) at diagnosis of CD predicted stricter long-term GFD adherence (OR, 3.27; 95% CI, 1.21-8.81; P = .02), while anemia (OR, 0.31; 95% CI, 0.12-0.82; P = .02) and dermatitis herpetiformis (OR, 0.23; 95% CI, 0.06-0.91; P = .04) predicted poorer long-term adherence. At follow-up, initial GFD adherence (OR, 42.70; 95% CI, 10.70-171.00; P = .04) was the major determinant of long-term GFD adherence.GFD adherence changes over time in10% of patients, generally improving when it does. Major determinants of long-term GFD adherence are classical symptoms at diagnosis and initial adherence to a GFD. Patients with anemia or dermatitis herpetiformis at diagnosis require stricter dietetic input.

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Summary Recent advances in medical microbiology, epidemiology, cellular biology, and the availability of an expanded set of diagnostic methods such as histopathology, immunohistochemistry, PCR, and bacterial culture have improved our understanding of the clinical range and natural course of Tropheryma whipplei infection and Whipple's disease. Interdisciplinary and transnational research activities have contributed to the clarification of the pathogenesis of the disorder and have enabled controlled trials of different treatment strategies. We summarise the current knowledge and new findings relating to T whipplei infection and Whipple's disease.

We consider alternative European public procurement mechanisms for acquiring RD (ii) degree of specificity of the innovation; (iii) role of SMEs in the market and level of market competition; (iv) risk of market foreclosure and supplier lock-in. This article contributes to the literature on incentives in demand-side innovation policy by tapping into the contractual design features and by offering relevant implications for academics and policy makers.

Background and aims Although prevalence of coeliac disease among first degree relatives of coeliac patients is well-known, only four studies are available about its incidence. We investigated whether first degree relatives found to be negative at a first serological screening can subsequently develop coeliac disease. Patients and methods In the last 6 years, endomysial antibodies were tested in 158 adult first degree relatives referred to our coeliac out-patient clinic. After at least a year, negative subjects were offered a second testing. Sixty-three accepted. Results 130/158 first degree relatives tested negative initially. Although one of them had developed coeliac disease after the first testing, at the second testing none of the 63 endomysial antibody negative first degree relatives proved positive. Incidence of coeliac disease among first degree relatives was 1/64 in 51 months, 0.437% year (95%CI 0.05–2.62). An analysis of the sample size showed that 10,000 first degree relatives must be followed up to significantly reduce the CI. Conclusions Although we confirmed the high prevalence of coeliac disease among first degree relatives (28/158, 17.7%), we found that the low incidence suggests that further studies are required to understand whether endomysial antibody negative first degree relatives need to be followed up.

Background Tissue transglutaminase, the coeliac autoantigen, was shown to localise in the enterocytes of coeliac patients and controls. It was speculated that surface tissue transglutaminase has a role in the pathogenesis of coeliac disease. Aims To study localisation of tissue transglutaminase in different stages of coeliac disease and other enteropathies with and without villous flattening. Methods Imunofluorescent and immunoblotting assays were used. Duodenal cryostat sections from 23 coeliac patients (10 untreated, 8 treated, 5 potential) and 18 controls (2 autoimmune enteropathy and 16 normal duodenal mucosa) were incubated with an anti-tissue transglutaminase monoclonal antibody. Slides were blindly examined. Results The immunofluorescent assay showed that monoclonal antibody localised in the subepithelial layer, in the lamina propria, and in the pericryptal connective tissue of all samples. It also bound to surface enterocytes in 8/10 untreated, 1/8 treated, and 3/5 potential coeliac patients. None of the controls showed an epithelial distribution of tissue transglutaminase. Immunoblotting experiments performed in enterocytes freshly isolated from duodenal biopsy confirmed these findings. Conclusion Epithelial distribution of tissue transglutaminase is specific for coeliac disease rather than due to a non-specific mucosal inflammation. Analysis of different stages of coeliac disease suggests that the epithelial distribution of tissue transglutaminase is gluten dependent.

Background & Aims: In view of the excellent quality of the images obtained and its magnification capability, videocapsule endoscopy was proposed as a promising tool to evaluate the degree of duodenal villous atrophy. We studied whether the capsule can discriminate different degrees of mucosal damage caused by different conditions; we also evaluated interobserver and intraobserver variability in the assessment of villous atrophy with the capsule. Methods: Thirty-two patients underwent both gastroscopy with multiple duodenal biopsies and videocapsule endoscopy. Twenty-six had different forms of celiac disease with different stages of villous atrophy; 5 patients had irritable bowel syndrome and 1 had Crohn’s disease. Videocapsule findings were evaluated blindly by 3 observers. Histologic Marsh criteria and a specifically developed classification of videocapsule mucosal patterns were used to compare videocapsule findings and histology. Results: The study of the correlation between videocapsule and histologic findings showed a Kappa statistic of .45, .49, and .51 for observers 1, 2, and 3, respectively. The sensitivity was 90.5% for observer 1 and 95.2% for observers 2 and 3; the specificity was 63.6% for all observers. Conclusions: Videocapsule findings regarding the degree of intestinal mucosal atrophy show only moderate agreement with the histologic pattern; they have a very high sensitivity but a disappointing specificity. This method therefore cannot be proposed as an alternative to traditional biopsy examinations, but it suggests that a duodenal biopsy examination should be performed when an atrophic mucosal pattern is observed in patients undergoing videocapsule examination for other reasons.

Background & Aims: We investigated the prevalence of functional hyposplenism in autoimmune disorder (AID)-associated and complicated celiac disease (CD). In addition, because the association between hyposplenism and overwhelming infections caused by Streptococcus pneumoniae in patients with CD is well known, we investigated whether immunoglobulin (Ig)M memory B cells, which are responsible for protection against infections by encapsulated bacteria and require the spleen for their generation and/or survival, mirror the reduced splenic function in CD. Methods: Peripheral blood samples were collected from 73 adult CD patients (27 with AID, 36 without AID, and 10 with CD-related complications including enteropathy-associated T-cell lymphoma, refractory sprue, and ulcerative jejunoileitis). Thirty-four non-CD patients with AID, 35 healthy volunteers, and 29 splenectomized patients also were studied. Counting of erythrocytes with membrane abnormalities (pitted red cells) was used as an indicator of splenic function, and flow cytometry was performed to analyze peripheral blood B cells. Results: A significantly higher risk for hyposplenism was found in AID-associated CD (59%) and complicated CD (80%) than in uncomplicated CD without AID (19%). In AID-associated CD, the degree of splenic function did not correlate to the duration of gluten-free diet. In AID-associated and complicated CD, the frequency of circulating IgM memory B cells was significantly lower than in CD patients without AID or healthy subjects. A significant inverse correlation between IgM memory B cells and pitted red cells was found in all 73 CD patients. Conclusions: The prevalence of splenic hypofunction is increased in CD with AID and in complicated CD, and is not related to the duration of gluten-free diet. IgM memory B cells are reduced in AID-associated and complicated CD. This defect, which is related to the impairment of splenic function, might predispose hyposplenic CD patients to infections by encapsulated bacteria.

Matrix metalloproteinases (MMPs) are a family of endopeptidases playing a key role in tissue remodelling in both physiological and pathological conditions. Since little information is available about their role in celiac disease (CD), our aims were to quantify their expression/activity and to investigate their relation to proinflammatory cytokines in this condition. Duodenal biopsies from untreated, treated celiac patients and controls were used to quantify the expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, MMP-14, their inhibitor TIMP-1, IFN-gamma and TNF-alpha by using real-time reverse transcription-polymerase chain reaction and the gelatin/casein/elastin activities by gel zymography, and to isolate lamina propria mononuclear cells (LPMCs). These cells and myofibroblasts isolated from jejunal specimens were incubated in the absence or presence of IFN-gamma and TNF-alpha. MMP-1 and MMP-12 mRNA levels were significantly increased in active CD compared to treated (P0.01 and P0.0005, respectively) and normal mucosa (P0.01 and P0.0005, respectively), and this was paralleled by an upregulation of caseinolytic and elastolytic activities. Furthermore, MMP-12 levels significantly (P0.05) correlated with those of IFN-gamma and the degree of villous flattening. MMP-2 turned out to be significantly (P0.05) reduced in untreated and treated celiacs compared to controls. In active CD, transcripts of TIMP-1 were higher than in treated and controls (P0.005 and P0.05, respectively), such as those of IFN-gamma (P0.05), whereas TNF-alpha levels were suppressed (P=0.0001). In physiological condition, myofibroblasts represent the main source of MMP-2, whereas LPMCs produce almost all MMPs only after cytokine stimulation. Conversely, cells isolated from active patients constitutively express MMPs without any increase after cytokine stimulation, while those from treated patients are in a resting condition. In conclusion, our results show the presence of a peculiar MMP pattern in active CD strongly dominated by MMP-12, correlating either with IFN-gamma or the degree of mucosal damage.

Background. Dermatitis herpetiformis may be regarded as the cutaneous counterpart of coeliac disease. These conditions are related to the ingestion of gluten and both are characterised by circulating antibodies against tissue transglutaminase. Aims. To study the distribution of tissue transglutaminase in the skin of dermatitis herpetiformis patients and controls, and to investigate whether the dermal IgA deposits, diagnostic for dermatitis herpetiformis, are related to tissue transglutaminase expression in the skin. Methods. A series of 11 patients with dermatitis herpetiformis had a 4 mm punch biopsy taken from the uninvolved perilesional skin. A group of 16 controls, undergoing surgical removal of benign nevi, gave perilesional skin. Biopsies were covered with OCT and frozen at −80 °C. After washing, skin biopsy sections were incubated with an IgG anti-tissue transglutaminase mouse monoclonal antibody. After washing, sections were incubated with anti-mouse IgG. Results. The anti-tissue transglutaminase monoclonal antibody specifically recognised the basal epidermal cells. This staining was no different between patients and controls. Conclusion. Our results suggest that tissue transglutaminase can be recognised in the basal epidermal layer both of patients with dermatitis herpetiformis and controls. Since this distribution does not correspond to the distribution of dermal IgA deposits, it is concluded that dermatitis herpetiformis dermal IgA deposits are not due to antibodies directed against cutaneous tissue transglutaminase.

Introduction Whipple's disease is a rare chronic infection caused by Tropheryma whipplei. Although most patients respond to antibiotics, in some of them the start of the treatment is followed by recurrence of inflammation. Since polymerase chain reaction is negative for Tropheryma whipplei, this reinflammation cannot be a relapse of Whipple's disease itself. Very recently, it has been recognised as a complication of Whipple's disease and defined immune reconstitution inflammatory syndrome (IRIS). Our aim is to study the prevalence and the clinical features of IRIS in Italian patients with Whipple's disease. Methods Evidence of IRIS was retrospectively revaluated in the clinical notes of 22 patients with Whipple's disease. Patients with no evidence of IRIS served as controls for the clinical findings. Results Recurrence of arthralgia and/or fever allowed a diagnosis of IRIS in 5/22 patients. One patient died. Previous immunosuppressive therapy was found in all patients with IRIS but only in 7/17 controls (Fisher test, p = 0.039). Age at diagnosis and diagnostic delay were higher in patients with IRIS compared to controls. However, statistical significance was not reached. Conclusions IRIS is a frequent complication of Whipple's disease and it can be fatal. The risk of IRIS is greatly increased in patients previously treated with immunosuppressive therapy.

Background . Family studies suggested that an altered intestinal permeability plays a role in the genesis of Crohn's disease. Aim . Aim of the present study was to investigate a possible genetic alteration of the mucosal barrier in Crohn's disease. Subjects . 16 Crohn's disease patients and 26 of their cohabiting first degree relatives were studied. Methods . To investigate intestinal permeability, Cellobiose/Mannitol test was administered to both groups. Results . In the two groups, we found that the median intestinal permeability values were higher and statistically different from those obtained in 32 healthy control subjects as well as in five healthy control families. Six (37.5%) Crohn's disease patients and three (11.5%) of their first degree relatives showed increased individual intestinal permeability values. Intestinal permeability alteration in Crohn's disease patients was unrelated to sex, age, disease activity, localisation, duration, treatment schedule, as well as to serum anti-Saccharomyces cervisiae antibody positivity in a pilot study conducted in 7 Crohn's disease patients; anti-Saccharomyces cervisiae antibody values were negative in all 10 first degree relatives investigated. Conclusions . These findings demonstrate the increase in IP in 37% of the patients and in 11 % of their relatives. More extensive investigation of the correlation between ASCA alterations and IP will be needed in both patients with Crohn's disease and their relatives.

Summary Background Autoimmune enteropathy is a condition described in children and characterised by villous atrophy, which is unresponsive to any dietary restrictions, and by the presence of enterocyte autoantibodies. We report two adult patients who fulfilled all the criteria for the diagnosis of this disorder. Methods Over the past 5 years we have seen four adult patients (all women, median age 51·5 [range 38–64] years) with subtotal villous atrophy, which was unresponsive to a gluten-free diet. The patients were HLA-DQ2 positive. IgA antigliadin and antiendomysial antibodies were not found in any of the patients. We did an indirect immunofluorescence search for enterocyte autoantibodies on monkey jejunum and for other autoantibodies for all four patients. Findings Of the four patients, two were positive for enterocyte autoantibodies and one of these two patients was positive for antiactin, antiparietal cell, and antithyroid microsomal autoantibodies. Interpretation To the best of our knowledge the two patients affected by severe enteropathy, who had never responded to any exclusion diet, and who were positive for enterocyte autoantibodies are the first cases of autoimmune enteropathy described in adults. We propose that adult patients whose disorders are unresponsive to a gluten-free diet should be tested for enterocyte autoantibodies.

In this paper we look at the evolution of the R&D intensity gap between the EU and its major competitors using data from the Industrial Scoreboard covering the period 2002-2010. We focus on R&D intensity as it is normally recognized as an important determinant of the competitiveness of economic regions and we assess whether the gaps relative to major competitors arise from differences in industrial composition (structural component) or differences within sectors (intrinsic component). This is important from a policy perspective since the task of modifying the industrial structure is a much harder one. The paper is divided in two parts. In the first part of the paper we first present the evolution of the R&D intensity gap between the EU and its major competitors (US, Japan, BRIC, Asian Tigers) and then we look more closely at the role and evolution of the structural and intrinsic component for each pair-wise comparison, by looking at four basic macro-sectors defined in term of their R&D intensity. In the second part of our work we concentrate on the EU-US R&D intensity gap and, by applying firm level analysis, we test whether the results obtained by the statistical decomposition of aggregate R&D intensity are confirmed. The evidence provided by this exercise is especially important because it allows us to perform a comparison where the ceteris paribus condition is more likely to be satisfied. In particular we test whether there is evidence of across-sector variability in R&D intensity and whether, within sectors, EU and US firms are performing differently. To do this we have to control for various factors such as size, cyclical effects, common macroeconomic shocks and company’s age. Age is important for at least two reasons. First, young companies might have more problems in finding access to funds necessary in order to invest in R&D. Second, young companies might have to be especially aggressive in terms of innovation if they want to enter and succeed in markets where incumbents already exist. More generally, company age is important because it takes time to build, test and eventually change a given business model and there is plenty of evidence that young firms are those exhibiting the highest dynamism. Therefore, our aim here is also to document the age profile for R&D intensity and to verify whether the R&D intensity gap between EU and non-EU companies is related to age of the firm. Finally we check if R&D intensity is affected by the abundance of internal funds (as captured by the profit/sales ratio), if this relationship changes with the age of the company and if the latter shows across-regional variation. Our results indicate that there is evidence of strong across-sector variation and some evidence of within-sectors-across-region variation, which –however- is not always in favour of the US. This allows us to conclude that firm level analysis confirms the results from the aggregate analysis. Moreover we find that R&D intensity tends to decrease as firm size increases (as measured by the number of employees), that the age profile for R&D intensity behaves very differently in the two regions and that young and middle age companies in the EU exhibit a much higher reactivity to lagged profits-to-sales ratio, when compared to their US counterpart. We believe that this is an indication that the conditions for accessibility and cost of funds differ significantly across the two regions.

We study determinants of the probability of introducing an organizational innovation using three large cross sections of Italian manufacturing firms in the period 1995-2003. We analyze the effect and complementarity of other types of investments, like ICT, R&D, human and physical capital and the adoption of product or process innovations. Furthermore, we estimate the effect of introducing organizational innovations and indirectly technical innovations on the growth rate of labor productivity for the unbalanced panel of firms. Disembodied technological change is well represented by OIs, while product