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Inflammatory Bowel Disease (IBD) patients on biological therapy are receiving vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). However, it is unclear if IBD therapy could influence the response to this vaccine. In a case-control study, we assessed the antibody profiling after anti-SARS-CoV-2 BNT162b2 vaccine in IBD patients on biological therapy.We analyzed seroprevalence and antibody titer, after 14 weeks from the first BNT162b2 vaccine dose, in IBD patients on biological therapy and Health Care Workers (HCWs). In IBD patients, medical history and disease data were recorded.Eighty-two subjects were enrolled in this study. Among them, 40 were IBD patients on biological therapy and 42 were HCWs. All subjects developed an IgG anti-Spike antibody titer above the cut-off. IBD patients on biological therapy developed a lower antibody titer than HCWs (P0.00001). No differences were reported in patients who received at least one dose of the vaccine within a period of 7 days from the last biological drug administration, compared to all other IBD patients. A difference was found between patients who were on concomitant immunosuppressive therapy and patients on sole biological therapy (P = 0.0287). Patients with presence of any sign of disease activity (clinical, endoscopic or laboratory) showed a higher development of antibody titer compared to those in complete disease remission (P = 0,0468).Our data indicate that in IBD patients, treatment with biological therapies do not affect the seroprevalence but leads to a lower antibody titer development after anti-SARS-CoV-2 BNT162b2 vaccine.

Digital single-operator cholangioscopy (D-SOC) is an endoscopic procedure that is increasingly used for the management of bilio-pancreatic diseases. We aimed to investigate the efficacy and safety of D-SOC for diagnostic and therapeutic indications.This is a multicenter, prospective study(January 2016-June 2019) across eighteen tertiary centers. The primary outcome was procedural success of D-SOC. Secondary outcomes were: D-SOC visual assessment and diagnostic yield of SpyBite biopsy in cases of biliary strictures, stone clearance rate in cases of difficult biliary stones, rate of adverse events(AEs) for all indications.D-SOC was performed in 369 patients (201(54,5%) diagnostic and 168(45,5%)therapeutic). Overall, procedural success rate was achieved in 360(97,6%) patients. The sensitivity, specificity, PPV, NPV and accuracy in biliary strictures were: 88,5%, 77,3%, 83,3%, 84,1% and 83,6% for D-SOC visual impression; 80,2%, 92,6%, 95,1%, 72,5% and 84,7% for the SpyBite biopsy, respectively. For difficult biliary stones, complete duct clearance was obtained in 92,1% patients (82,1% in a single session). Overall, AEs occurred in 37(10%) cases.The grade of AEs was mild or moderate for all cases, except one which was fatal.D-SOC is effective for diagnostic and therapeutic indications.Most of the AEs were minor and managed conservatively, even though a fatal event has happened that is not negligible and should be considered before using D-SOC.

Objective Arthritis is the most frequent extra-intestinal manifestation in patients with inflammatory bowel diseases (IBD). The coexistence of intestinal and articular inflammation advocates the need for a multidisciplinary management of patients with IBD-associated spondyloarthritis. Methods Consecutive IBD patients were evaluated jointly by the gastroenterologist and the rheumatologist in a combined clinic. All the patients were assessed and screened for articular involvement, disease activity and health related quality of life. After the prescription of a shared treatment, patients with spondyloarthritis were followed up for 24 months. Results Two hundred sixty-two IBD patients, including 80 who were classified as affected by spondyloarthritis according to the ASAS criteria, were included in the study. At baseline, patients with both IBD and spondyloarthritis showed worse quality of life in both the physical and mental domains. The multidisciplinary management provided a significant improvement of gastrointestinal and articular manifestations, as well as the health-related quality of life. Moreover, global and gastrointestinal-specific quality of life significantly correlated with articular disease activity. Conclusion The multidisciplinary management significantly improves both articular and gastrointestinal disease activities and the quality of life of patients with IBD-associated spondyloarthritis. An appropriate screening strategy and the integrated management of these patients should be encouraged and employed in clinical practice.

As examples of crucial interface organs gut and skin show more similarities than differences, therefore it is unsurprising that several gut pathologies have skin comorbidities, and vice versa. The relationship between gut and skin, referred as the “gut-skin axis”, is one of the most intriguing area of emerging research. However the complex interactions between skin and gut are far from to be completely elucidated, since neither mainstream gastroenterology nor dermatology research have systematically investigated the ‘gut-skin axis’. In the last years several clinical researches conducted jointly by Dermatology and Gastroenterology Unit of Department of Clinical and Molecular Sciences of Polytechnic Marche University have progressively contributed to give useful data to delineate the molecular mechanisms underlying the relationship between skin and gut. In the meantime, the improvement in the knowledge of pathogenic links between different disease involving skin and gastro-intestinal tract has contributed to increase the scientific cooperation between gastroenterologists and dermatologists, by feeding the research strands. Herein the results of several studies focusing on pathogenic relationship between gastrointestinal disorders as inflammatory bowel disease, non alcoholic fatty liver disease, helicobacter pylori infection and dermatologic disease like psoriasis, pyoderma gangrenosum, chronic spontaneous urticaria, suppurative hidradenitis and alopecia areata have been reported. Moreover results emerging from several other research lines involving gastroenterological and dermatological Unit independently, and focusing on cutaneous melanoma, wound healing, mesenchymal stem cells, and antimicrobial molecules are described.

Gastrointestinal complications (GICs) represent the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Differential diagnosis of GICs is of paramount importance since early and reliable identification of graft-versus-host disease (GVHD) is essential for a correct management of the patients. The aim of the present retrospective study was to evaluate the occurrence of GICs after allo-HSCT and to assess the diagnostic performance of a quick endoscopic and histological assessment in the differential diagnosis between GVHD and other GI conditions. Between January 2015 and August 2019, 122 consecutive patients receiving an allo-HSCT were managed by an interdisciplinary team, supported by a dedicated endoscopic service. Clinical, therapeutic, endoscopic and histological data were analyzed for each patient. Collectively, 94 of the patients developed GICs (77%). A moderate-severe mucositis was the most frequent complication, occurring in 79 patients (84%). Acute GI-GVHD was diagnosed in 35 patients (37% of whom with GICs) and 19 of them with a moderate-severe grade. Infective acute colitis developed in eight patients, mainly due to Clostridium difficile (CD) and Cytomegalovirus infections (8.5%). Rectal biopsy showed the highest sensitivity and specificity (80% and 100%, respectively). However, when biopsy procedures were guided by symptoms and performed on apparently intact mucosa, upper histology also provided a high negative predictive value (80%). Our multidisciplinary approach with a quick endoscopic/histologic investigation in the patients receiving an allo-HSCT and who suffered GICs could improve diagnostic and therapeutic management in this challenging setting.

Ulcerative Colitis (UC) and Crohn's Disease (CD) are chronic, progressive and disabling disorders characterized by a heterogeneous clinical course. Some years ago the main goal of the therapy was to achieve and maintain clinical remission, whereas at present the main goal of therapy is represented by the deep remission, characterized by sustained clinical remission, complete mucosal healing and normalization of serological markers of inflammation. In the last years new therapeutic approaches have been introduced which have led to a reduction in the mortality rate and have modified the natural history of Inflammatory Bowel Diseases (IBD). In addition, several prognostic factors have been identified which have allowed to better stratify the disease and to choose the most appropriate therapy for the single patient. Moreover, early treatment with immunosuppressive drugs and/or biologics has changed, at least in the short term, the course of the disease by reducing hospitalization rate and the need for surgery. Therefore, the development of biologic therapies has represented an important step in the treatment of IBD, since these drugs induce remission and response rates that are not achieved by other therapies. Since their use can result in significant adverse events that increase morbidity, patients must be aware of the risks associated with treatment and must be strictly monitored. Although treatment with biologic drugs is not successful in all patients and many of them lose clinical response, new therapies are currently under evaluation.

Background Abstract: Up to 80% of Crohn's disease (CD) patients require at least one surgical intervention in their lifetime and up to 70% of these patients develop postoperative endoscopic recurrence within 1 year. Methods The most important predictors of early postoperative recurrence are represented by smoking, prior intestinal surgery, penetrating disease and perianal location. Genetic factors, gut microbiota structure and immunological alterations may be involved in the pathogenesis of postoperative recurrence of CD, although their specific roles have to be determined yet. Results Different drugs, such as metronidazole, thiopurines and anti-tumor necrosis factor α (anti- TNFα) have been shown to reduce the risk of recurrence in many clinical trials, although the choice of the drug should take into consideration the benefits, the potential side effects and also the costs. Patients who are at high risk for postoperative recurrence should be considered for early medical prophylaxis with thiopurines or anti-TNFα drugs; on the contrary, patients who do not have risk factors may receive no treatment or receive a course of antibiotic or mesalazine followed by tailored therapy based on endoscopy at 6 months. Conclusion Therefore, stratifying patients according to their risk of recurrence and tailoring therapy are at present the ideal and most cost-effective ways to treat operated CD patients, although many aspects require further evaluation.

The aim of this study is to assess the associations between chronic spontaneous urticaria (CSU), Helicobacter pylori infection and small intestinal bacterial overgrowth. Forty- eight patients with CSU were studied by scoring the urticaria activity and assesing the quality of life. Patients with H. pylori infection (n=11) or small intestinal bacterial overgrowth (n=13) were specifically treated for one week and clinically evaluated both before and 4 weeks after the eradication therapy. Eradication of H. pylori infection led to a significant improvement in CSU (p

Crohn's disease (CD) is an inflammatory bowel disease (IBD) that can affect the whole gastrointestinal tract. The ileocolonic variant of CD, an inflammation of both the ileum and the large intestine, accounts for up to 50% of the cases with CD, whereas Crohn's ileitis affecting the ileum is diagnosed in about 30%. Crohn's colitis, which is confined to the large intestine and accounts for the remaining 20%, is difficult to distinguish from the large bowel inflammation seen in patients with ulcerative colitis (UC). The pathogenesis of CD is not yet completely understood. Autoimmunity is one factor that can partake in the triggering or modulation of inflammatory processes in IBD. The major zymogen-granule membrane glycoprotein 2 (GP2) has been recently identified as a major autoantigenic target in CD. Interestingly, GP2 is mainly expressed in the pancreas and has also been demonstrated to be a membrane-anchored receptor of microfold cells in the follicle-associated epithelium. Remarkably, GP2 is overexpressed at the site of CD inflammation in contrast to the one in UC. By utilizing novel enzyme-linked immunosorbent assays for the detection of GP2-specific IgA and IgG, the loss of tolerance to GP2 has been associated with a specific clinical phenotype in CD, in particular with the ileocolonic location of the disease.

Ethyl caffeate (CfE, caffeic acid ethyl ester) was extracted from dealcoholized Verdicchio, a white wine from Marche (Italy) with ethyl acetate and then purified with semipreparative reversed-phase high-performance liquid chromatography (RP-HPLC) using an ODS2 column (25 cm x 20 mm id) at an isocratic flow of 5 mL/min (the mobile phase A was formic acid 4.5% in water and the mobile phase B was acetonitrile). The CfE extract administered intraperitoneally at 1 mumol/L in rats previously treated with 10 mg/kg dimethylnitrosamine was able to prevent the dimethylnitrosamine-induced loss in body and liver weight, as well as to reduce the degree of liver injury, as determined by alanine aminotransferase values and necroinflammatory score, after a 1-week treatment. This was associated with a reduced hepatic stellate cells activation (from 16.8 to 8.3% of smooth muscle actin positive parenchyma) and proliferation (from 11.3 to 5.5 cells/mm(2)). The collagen synthesis was also reduced: the percentage of Sirius Red positive parenchyma decreased from 21.7 to 7.2%. The CfE levels of Verdicchio wine determined with RP-HPLC-DAD were about 14 times the active levels tested in the in vivo test. CfE can be considered as a promising natural compound for future application in chronic liver disease.

Background Data from the literature concerning the role of Helicobacter pylori (H. pylori) infection in psoriasis are still conflicting. This study was carried out to evaluate prevalence of H. pylori in patients with mild to severe psoriasis, correlation between H. pylori infection and severity of psoriasis, and effect of H. pylori eradication on the clinical course of psoriasis. Methods Two hundred and ten patients with psoriasis and 150 healthy controls were screened for H. pylori through [13C] urea breath test at baseline (T0). All patients with psoriasis received standardized phototherapy treatment, and those infected by H. pylori were also treated with a 1-week triple therapy, then they were all re-evaluated four weeks later at the end of therapy (T5). Results The prevalence of H. pylori was not higher in psoriasis than in the control group (20.27 vs. 22%; P > 0.05). Patients infected by H. pylori showed more severe psoriasis than uninfected patients (psoriasis area and severity index score 17.9 ± 7.1 vs. 13.7 ± 6.9; P = 0.04), and patients who received successful eradication of H. pylori infection showed a greater improvement of psoriasis than the others (psoriasis area and severity index score at T5 in patients infected by H. pylori was 8.36 ± 3.76, in uninfected patients was 10.85 ± 3.49; P = 0.006). Conclusions Patients with mild to severe psoriasis do not show a greater prevalence of H. pylori infection; however, H. pylori seems able to affect the clinical severity of psoriasis.

Analysis of Verdicchio (a white wine produced in Italy) with high performance liquid chromatography–tandem mass spectrometry (HPLC–ESI-MS–MS) showed a concentration of ethyl caffeoate (CfE), a natural phenolic substance, of 67.3 μmol L −1 ; CfE was then purified from wine with preparative reversed phase HPLC and tested on rat hepatic stellate cell cultures (HSC). HSC proliferation induced by iron(III) nitrilotriacetate (FeNTA), a pro-oxidant agent (absorbance = 0.68 ± 0.03 versus 0.32 ± 0.02 in controls), was significantly inhibited by CfE starting at a concentration of 10 μmol L −1 (absorbance = 0.45 ± 0.01), with a maximal effect at 20 μmol L −1 (absorbance = 0.32 ± 0.02). The formation of intracellular hydroperoxides induced by FeNTA was significantly reduced by CfE starting at a concentration of 10 μmol L −1 and completely prevented by CfE at a concentration of 20 μmol L −1 . The increase in α1(I) procollagen mRNA synthesis induced by FeNTA was inhibited by CfE starting at a concentration of 10 μmol L −1 and almost completely at a concentration of 20 μmol L −1 . Thus, Verdicchio wine is a remarkable source (about seven-fold the bioactive concentration) of CfE, an interesting drug to be tested as an antifibrotic agent.

Background/Aims : Pirfenidone has been recently shown to reduce dimethynitrosamine-induced liver fibrosis in the rat, but no information are available on the effect of this drug on cultured hepatic stellate cells (HSC). Methods : HSC proliferation was evaluated by measuring bromodeoxyuridine incorporation; PDGF-receptor autophosphorylation, extracellular signal-regulated kinase (ERK1/2) and pp70 S6K activation were evaluated by western blot; protein kinase C activation was evaluated by western blot and by ELISA; type I collagen accumulation and α1(I) procollagen mRNA expression were evaluated by ELISA and northern blot, respectively. Results : Pirfenidone significantly inhibited PDGF-induced HSC proliferation, starting at a concentration of 1 μM, with a maximal effect at 1000 μM, without affecting HSC viability and without inducing apoptosis. The inhibition of PDGF-induced HSC proliferation was associated neither with variations in PDGF-receptor autophosphorylation, or with ERK1/2 and pp70 S6K activation. On the other hand, pirfenidone was able to inhibit PDGF-induced activation of the Na + /H + exchanger, which is involved in PDGF-induced HSC proliferation in HSC, with a maximal effect at 1000 μM and inhibited PDGF-induced protein kinase C activation. Pirfenidone 100 and 1000 μM inhibited type I collagen accumulation in the culture medium induced by transforming growth factor β1 by 54% and 92%, respectively, as well as TGF β1 -induced α1(I) procollagen mRNA expression. Results : Pirfenidone could be a new candidate for antifibrotic therapy in chronic liver diseases.

Background & Aims: The Na + /H + exchanger is the main intracellular pH regulator in hepatic stellate cells (HSCs), and its activity is increased by platelet-derived growth factor (PDGF). Amiloride, an Na + /H + exchange inhibitor, reduces PDGF-induced HSC proliferation, suggesting that the Na + /H + exchanger plays a role in regulating HSC proliferative response. The aim of this study was to characterize the intracellular pathways mediating activation of the Na + /H + exchanger by PDGF in HSCs. Methods: The activity of the Na + /H + exchanger and HSC proliferation rate were evaluated under control condition and after incubation with PDGF in the absence or presence of specific inhibitors of the main intracellular pathways of signal transduction. Na + /H + exchange protein expression was evaluated by means of Western blot. Results: PDGF induced a significant increase in the activity of the Na + /H + exchanger without modifying protein expression. Inhibition of the calcium/calmodulin– and protein kinase C–dependent pathways resulted in a significant inhibition of both Na + /H + exchange activity and of PDGF-induced HSC proliferation. The involvement of the two pathways was confirmed by showing that incubation of HSCs with both phorbol-12-myristate-13-acetate, a potent protein kinase C activator, and thapsigargin, which increases intracellular calcium levels, significantly increased both the Na + /H + exchanger activity and HSC proliferation rate. Inhibition of the protein kinase A pathway did not modify either PDGF-induced Na + /H + exchange activation or PDGF-induced HSC proliferation. On the contrary, inhibition of the mitogen-activated protein kinase– and of phosphatidylinositol 3-kinase–dependent pathways significantly reduced PDGF-induced HSC proliferation without affecting the activity of the Na + /H + exchanger. Conclusions: Activation of the Na + /H + exchanger by PDGF in HSCs is mediated by calcium/calmodulin- and protein kinase C–dependent pathways. PDGF-induced HSC proliferation is mediated by Na + /H + exchange–dependent and –independent pathways. GASTROENTEROLOGY 1999;116:1155-1166

Since mortality related to gastric cancer correlates with tumor stage at diagnosis, the recognition of early lesions can significantly modify short- and long-term prognoses of patients with these tumors. At present, several methods able to increase diagnostic accuracy are available, such as vital stains and/or high-resolution endoscopic devices. The morphological evaluation of gastric lesions can be improved by performing intragastric ultrasonography, which allows the distinction of non-invasive from invasive lesions and plays an important role in gastric cancer staging. In the absence of signs of deep infiltration and metastases, endoscopic resection of gastric lesions can be performed, especially in patients at high surgical risk.

Acute pancreatitis is a disease of increasing annual incidence which is associated with significant morbidity and mortality. While many patients need only a general supportive care, about one out of five patients will develop severe acute pancreatitis, and 20% of these patients may die [1, 2].

Background/Aims : Cytoskeletal reorganization plays an important role in the regulation of different cell functions, such as proliferation and migration. Since platelet-derived growth factor (PDGF) stimulates both proliferation and chemotaxis of hepatic stellate cells (HSC), we investigated the effects of this cytokine on cytoskeletal components of cultured rat HSC. Methods/Results : Exposure of HSC to PDGF induced the formation of stress fibres and of a ruffled configuration of the plasma membrane, evaluated by both fluorescence and electron microscopy. These modifications were also induced by exposure to the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (PMA) and abolished by pretreatment with the PKC inhibitor calphostin C, with the Rho inhibitor C3 exoenzyme and with the intracellular calcium chelator MAPTAM, but not with the PI-3 kinase inhibitor wortmannin or with the mitogen-activated protein kinase kinase inhibitor PD 98059. PDGF induced a translocation of Rho from the cytosol to the membrane which was inhibited by C3 exoenzyme and by calpostin C, and which was also induced by PMA. Moreover, PDGF induced a rearrangement of vinculin which was prevented by C3 exoenzyme and calphostin C. Conclusions : PDGF-induced cytoskeletal reorganization in HSC is dependent on PKC and Rho, thus suggesting that these two pathways may play an important role in the response of liver to injury.

Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic action of acetaldehyde on hepatic stellate cells (HSC). However the mechanisms responsible for this effect are not well understood. In this communication we investigated signal transduction pathways triggered by acetaldehyde leading to upregulation of alpha2(I) collagen and fibronectin gene expression in human HSC. Run-on assays showed that acetaldehyde-enhanced transcription of these 2 genes as early as 2 hours, via de novo protein synthesis-independent and -dependent mechanisms. It also stimulated a time-dependent induction in phosphorylation of pp70(S6K) and extracellular-regulated kinase (1/2) (ERK1/2). These effects were completely prevented by calphostin C, a protein kinase C inhibitor. As expected, acetaldehyde-elicited ERK1/2 phosphorylation was inhibited by PD98059, a MEK inhibitor, but not by wortmannin, a PI3K inhibitor. On the other hand, both of these inhibitors partially inhibited phosphorylation of pp70(S6K) induced by acetaldehyde suggesting that its activation is ERK1/2- and PI3K-dependent. Acetaldehyde-elicited fibronectin and alpha2(I) collagen upregulation was inhibited by calphostin C. However, while PD98059, wortmannin and rapamycin (a pp70(S6K) inhibitor) completely abrogated alpha2(I) collagen upregulation, they had no effect on fibronectin expression. Overall, these data suggest that protein kinase C is an upstream component from which acetaldehyde signals are transduced to other pathways such as PI3K and ERK1/2. In addition, differential activation of these pathways is needed for the increase in fibronectin and alpha2(I) collagen gene expression induced by acetaldehyde in human HSC.

Background/Aims : The Na + /H + exchanger is involved in rat hepatic stellate cell (HSC) proliferation induced by platelet-derived growth factor (PDGF). We therefore evaluated in human HSC: (1) the mechanisms of intracellular pH regulation; (2) the relationship between Na + /H + exchange activation and cell proliferation induced by PDGF, insulin-like growth factor 1 (IGF-1) and insulin. Methods/Results : pH i regulation was mainly dependent on the activity of the Na + /H + exchanger, which was evaluated by measuring pH i recovery from an acute acid load. PDGF (25 ng/ml) gradually increased the activity of the Na + /H + exchanger which peaked at 18 h and remained stable until the 24th h. IGF-1 (10 nmol/l), but not insulin (100 nmol/l), slightly but significantly increased the activity of the Na + /H + exchanger. Amiloride (100 μ mol/l) and 20 μ mol/l 5- N -ethyl- N -isopropyl-amiloride completely inhibited HSC proliferation (evaluated by measurement of bromodeoxyuridine incorporation) induced by PDGF and IGF-1, but did not affect proliferation of HSC induced by insulin. Finally, IGF-1 did not modify the activity of the Na + /Ca 2+ exchanger. Conclusions : The Na + /H + exchanger is involved in HSC proliferation induced by PDGF and IGF-1, whereas the proliferative effect of insulin is mediated by intracellular pathways which are Na + /H + exchange-independent.

Background & Aims: The Na + /H + exchanger is the main intracellular pH (pH i ) regulator in hepatic stellate cells (HSCs) and plays a key role in regulating proliferation and gene expression. We evaluated the effect of specific inhibition of this exchanger on HSC proliferation and collagen synthesis in vivo and in vitro. Methods: Rat HSCs were incubated in the presence of platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β1, iron ascorbate (FeAsc), and ferric nitrilotriacetate solution (FeNTA) with or without the Na + /H + exchanger inhibitor 5- N -ethyl- N -isopropyl-amiloride (EIPA). pH i and Na + /H + exchanger activity, cell proliferation, and type I collagen accumulation were measured by using the fluorescent dye 2',7'-bis-(carboxyethyl)-5(6)-carboxyfluorescein, by immunohistochemistry for bromodeoxyuridine, and by enzyme-linked immunosorbent assay, respectively. In vivo liver fibrosis was induced by dimethylnitrosamine administration and bile duct ligation (BDL) in rats treated or not treated with amiloride. Results: PDGF, FeAsc, and FeNTA increased Na + /H + exchange activity and induced HSC proliferation. TGF-β1 had no effect on the Na + /H + exchanger and was able, as for FeAsc and FeNTA, to induce type I collagen accumulation. EIPA inhibited all the effects determined by PDGF, FeAsc, and FeNTA and had no effect on TGF-β1–induced collagen accumulation. In vivo, amiloride reduced HSC proliferation, activation, collagen deposition, and collagen synthesis. Conclusions: The Na + /H + exchanger can play a key role in the development of liver fibrosis and in HSC activation in vivo. GASTROENTEROLOGY 2001;120:545-556

G A A b st ra ct s opiate analgesics, non-steroidal anti-inflammatory drugs(NSAIDS), corticosteroids, aspirin and calcium antagonists. Results: A total of 899 patients with an incident diagnosis of perforated diverticular disease were identified. Compared with the population that did not smoke the OR of ever smoking was 1.49 (95% confidence interval [95% CI] 1.27-1.76), compared to those with a body mass index (BMI) 30 was 1.31 (95% CI, 1.03-1.66), and compared to those with no comorbidity those with a Charlson index >2 had an OR 2.39 (95% CI, 2.01-2.84) all data were mutually for each other. Current opiate analgesics and steroid use was associated with an increase in perforation (Table1) although the total percentage of cases exposed was small. Current use of a calcium antagonists, NSAIDs and aspirin were not associated with an increased risk of perforation. Data were adjusted for smoking, comorbidity, abdominal pain and BMI. Conclusion: Perforated diverticular disease is a serious surgical emergency and opiate analgesics and oral steroids increase the risk of diverticular perforation however obesity and smoking represent the principal modifiable risk factors at a population level. Table 1. Odds ratio for current use of NSAIDS, Opiate analgesics and steroids adjusted for BMI, smoking and comorbidity.

Results: We demonstrate 1) That both core tumour and non-tumourderived sequences inhibit the global antiviral effects of IFNa on VSV and EMCV replication in Ratl and HuH7 cells and sensitize Ref cells to transformation, in cooperation with ras oncogene. 2) That tumour and nontumour derived cores show, however, a quite distinct pattern of biological effects on IFNa signaling: inhibition of global antiviral effect of IFNa in tumour-derived expressing cells is much less pronounced, compared with non tumour-derived and reference lb cores.Expression of tumour-derived, and not non-tumour-derived nor reference lb cores, induces transactivafion of 0interferon sensitive response element0 (ISRE); tumour-derived core also increases phosphorylation of Statl and Stat 2, compared with nontumour-derived and reference lb proteins.Tumour-derived core show a markedly increased transforming activity in REF cells, in cooperation with ras oncogene, compared with non-tumour-derived and reference lb cores. Conclusion: Our data 1) support a role for HCV core in the resistance to global antiviral effect of IFNa (despite ISRE activation) and cell transformation in REF cells. 2) demonstrate a distinct pattern of biological effects of tumour and non-tumour-derived cores on interferon signaling and cell transformation, correlated with the hypothesis of selection of core mutants in clonaly expanding liver cells. Data obtained with 3 additional tumour and non-tumour-derived core sequences will be discussed.