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Previous investigations have increased the knowledge about the pathological processes of inflammatory bowel diseases. Besides the complex organization of immune reactions, the mucosal epithelial lining has been recognized as a crucial regulator in the commencement and persistence of intestinal inflammation. As the intestinal epithelium is exposed to various environmental factors, the intestinal epithelial cells are confronted with diverse cellular stress conditions. In eukaryotic cells, an imbalance in the endoplasmic reticulum (ER) might cause aggregation of unfolded or misfolded proteins in the lumen of ER, a condition known as endoplasmic reticulum stress. This cellular mechanism stimulates the unfolded protein response (UPR), which elevates the potential of the endoplasmic reticulum protein folding, improves protein production and its maturation, and also stimulates ER-associated protein degradation. Current analyses reported that in the epithelium, the ER stress might cause the pathogenesis of inflammatory bowel disease that affects the synthesis of protein, inducing the apoptosis of the epithelial cell and stimulating the proinflammatory reactions in the gut. There have been significant efforts to develop small molecules or molecular chaperones that will be potent in ameliorating ER stress. The restoration of UPR balance in the endoplasmic reticulum via pharmacological intervention might be a novel therapeutic approach for the treatment of inflammatory bowel diseases (IBDs). This review provides novel insights into the role of chemical chaperone UPR modulators to modify ER stress levels. We further discuss the future directions/challenges in the development of therapeutic strategies for IBDs by targeting the ER stress. Figure depicting the role of endoplasmic reticulum stress-mediated inflammatory bowel disease and the therapeutic role of endoplasmic reticulum stress inhibitors in alleviating the diseased condition.

The expression of leptin and leptin receptor (Ob-R) has been partially elucidated in colon of patients with inflammatory bowel diseases (IBDs), even though leptin is involved in angiogenesis and inflammation. We previously reported overexpression of GLUT5 fructose transporter, in aberrant clusters of lymphatic vessels in lamina propria of IBD and controls. Here, we examine leptin and Ob-R expression in the same biopsies. Specimens were obtained from patients with ulcerative colitis (UC), Crohn’s disease (CD) and controls who underwent screening for colorectal cancer, follow-up after polypectomy or with a history of lower gastrointestinal symptoms. Immunohistochemistry revealed leptin in apical and basolateral membranes of short epithelial portions, Ob-R on the apical pole of epithelial cells. Leptin and Ob-R were also identified in structures and cells scattered in the lamina propria. In UC, a significant correlation between leptin and Ob-R in the lamina propria was found in all inflamed samples, beyond non-inflamed samples of the proximal tract, while in CD, it was found in inflamed distal samples. Most of the leptin and Ob-R positive areas in the lamina propria were also GLUT5 immunoreactive in inflamed and non-inflamed mucosa. A significant correlation of leptin or Ob-R expression with GLUT5 was observed in the inflamed distal samples from UC. Our findings suggest that there are different sites of leptin and Ob-R expression in large intestine and those in lamina propria do not reflect the status of mucosal inflammation. The co-localization of leptin and/or Ob-R with GLUT5 may indicate concomitance effects in colorectal lamina propria areas.

Background: Faecal microbiota transplantation (FMT) is a reasonable therapeutic option for the treatment of Clostridioides difficile infection (CDI) recurrent and refractory (RCDI) to therapy, but little evidence on the long-term impact of this therapy is currently available in the literature. The aim of this study was to evaluate the efficacy and safety of FMT in recurrent and refractory CDI and the modifications of the recipient’s gut microbiota in the medium–long term. Methods: This prospective study collects the clinical and laboratory data of RCDI patients treated with FMT by colonoscopy from February 2016 to October 2019. Stool samples for metagenomic analysis were collected pre-FMT at 1 week and at 6 and 12–24 months post-FMT. Results: In the study period, 20 FMT procedures were performed on 19 patients. Overall, FMT was effective in 85% of treated patients. No serious adverse event was recorded. In the medium- to long-term follow up, a newly diagnosed case of collagenous colitis was observed. Post-FMT, significant changes in microbiota were observed, characterised by the transition from a low- to a greater-diversity profile. Therefore, FMT restores eubiosis and maintains it over time. Conclusion: FMT is a safe and effective treatment option in RCDI patients. This procedure induces profound microbiota changes that explain its high clinical efficacy.

Background Butyrate has shown anti‐inflammatory and regenerative properties, providing symptomatic relief when orally supplemented in patients suffering from various colonic diseases. We investigated the effect of a colonic‐delivery formulation of butyrate on the fecal microbiota of patients with inflammatory bowel diseases (IBDs). Methods In this double‐blind, placebo‐controlled, pilot study, 49 IBD patients (n = 19 Crohn's disease, CD and n = 30 ulcerative colitis, UC) were randomized to oral administration of microencapsulated‐sodium‐butyrate (BLM) or placebo for 2 months, in addition to conventional therapy. Eighteen healthy volunteers (HVs) were recruited to provide a healthy microbiota model of the local people. Fecal microbiota from stool samples was assessed by 16S sequencing. Clinical disease activity and quality of life (QoL) were evaluated before and after treatment. Key Results At baseline, HVs showed a different microbiota composition compared with IBD patients. Sodium‐butyrate altered the gut microbiota of IBD patients by increasing bacteria able to produce SCFA in UC patients (Lachnospiraceae spp.) and the butyrogenic colonic bacteria in CD patients (Butyricicoccus). In UC patients, QoL was positively affected by treatment. Conclusions and Inferences Sodium‐butyrate supplementation increases the growth of bacteria able to produce SCFA with potentially anti‐inflammatory action. The clinical impact of this finding requires further investigation., We evaluated the effect of a sodium butyrate microencapsulated oral formulation on the gut microbiota of IBD patients. The butyrate can modulate the gut bacteria, stimulating the growth of butyrogenic and SCFA genera.

Background: The frequency of overweight (OW) and obese (OB) children has increased worldwide, particularly in economically developed countries. No studies have been conducted to verify whether the ...

[Background and Aims] Steroid-dependency occurs in up to 30% of patients with ulcerative colitis [UC]. In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim of this study was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis [GMA] to oral prednisone in patients with steroid-dependent UC., [Methods] This was a randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone [40 mg/day and tapering] with prednisone alone, in patients with active, steroid-dependent UC [Mayo score 4–10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation]. Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary endpoint was steroid-free remission [defined as a total Mayo score ≤2, with no subscore >1] at Week 24, with no re-introduction of corticosteroids. [Results] In all 123 patients were included [63 GMA group, 62 prednisone alone]. In the intention-to-treat analysis, steroid-free remission at Week 24 was achieved in 13% (95% confidence interval [CI] 6–24) in the GMA group and 7% [95% CI 2–16] in the control group [p = 0.11]. In the GMA group, time to relapse was significantly longer (hazard ratio [HR] 1.7 [1.16–2.48], P = 0.005) and steroid-related adverse events were significantly lower [6% vs 20%, P < 0.05]. [Conclusions] In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse., This work was supported by an unrestricted research grant from Otsuka Pharmaceuticals.

Ectopy is the most common embryogenetic defect of the thyroid gland, representing between 48 and 61% of all thyroid dysgeneses. Persistence of thyroid tissue in the context of a thyroglossal duct remnant and lingual thyroid tissue are the most common defects. Although most cases of ectopic thyroid are asymptomatic, any disease affecting the thyroid may potentially involve the ectopic tissue, including malignancies. The prevalence of differentiated thyroid carcinoma in lingual thyroid and thyroglossal duct cyst is around 1% of patients affected with the above thyroid ectopies. We here review the current literature concerning primary thyroid carcinomas originating from thyroid tissue on thyroglossal duct cysts and lingual thyroid.

IBD98-M is a delayed-release formulation of mesalamine (mesalazine) and SH with a potential therapeutic role in ulcerative colitis (UC). A total of 51 patients with a modified Ulcerative Colitis Disease Activity Index (UCDAI) score of &ge, 4 and &le, 10, and a modified UCDAI endoscopy subscore &ge, 1 were randomized for 6 weeks of double-blind treatment with IBD98 0.8 g/day or IBD 1.2 g/day or placebo. The efficacy and safety of IBD98-M in mild to moderate active UC were primarily evaluated. At week 6, 1 (5.9%), 2 (12.5%), and 2 (11.1%) patients receiving IBD98-M 0.8 g, IBD98-M 1.2 g, and placebo, respectively, (p &gt, 0.999) achieved clinical remission. Higher clinical response was seen in IBD98-M 1.2 g (31.3%) versus placebo (16.7%) and endoscopic improvement in IBD98-M 0.8 g (29.4%) versus placebo (22.2%) was seen. Fecal calprotectin levels were reduced in IBD98-M groups versus placebo (p &gt, 0.05). IBD98-M patients achieved significant improvement in physical health summary score component of the SF-36 (p = 0.01 and p = 0.03 respectively) compared to placebo. IBD98-M did not meet the primary end point but had higher clinical response (1.2 g/day) and endoscopic improvement (0.8 g/day) compared to placebo. The safety result shown that IBD98-M treatment was safe and well tolerated in this patient population. No new safety signals or unexpected safety findings were observed during the study. Further trials with different stratification and longer follow-up may be needed to evaluate the efficacy.

Hyperthyroidism during pregnancy is uncommon. Nonetheless, prompt identification and adequate management of hyperthyroidism in a pregnant woman is essential, because uncontrolled thyrotoxicosis significantly increases the risk of maternal and fetal complications. Also, fetal prognosis may be affected by the transplacental passage of maternal thyroid stimulating antibodies or thyrostatic agents, both of which may disrupt fetal thyroid function. Birth defects have been reported in association with the use of antithyroid drugs during early pregnancy. Although rarely, offspring of mothers with Graves’ disease may develop fetal/neonatal hyperthyroidism, the management of which requires a close collaboration between endocrinologists, obstetricians, and neonatologists.Because of the above considerations, the management of pregnant and lactating women with hyperthyroidism requires special care, bearing in mind that both maternal thyroid excess per se and related treatments may adversely affect the newborn’s health.In this review we discuss the diagnosis and management of hyperthyroidism in pregnancy, along with the impact of thyrotoxicosis and medications on fetal outcome. Keywords: Pregnancy, Hyperthyroidism, Thyrotoxicosis, Gestational transient thyrotoxicosis, Graves’ disease

Intestinal fibrosis is a key feature of Crohn's Disease lesions, and mucosal biopsies do not exactly represent transmural damage. Magnetic resonance enterography (MRE) allows for a panoramic study of the bowel loops. Diffusion-weighted imaging (DWI) through the restriction of the apparent diffusion coefficient (ADC) allows for an accurate evaluation of disease activity in Crohn's Disease patients avoiding contrast agents. The aim of this study was to investigate whether DWI sequences were able to identify intestinal fibrosis in candidates for surgery, using histopathology as the gold standard.Thirty Crohn's Disease patients undergoing surgery for stricturing ileo-colonic disease were consecutively enrolled from October 2010 to November 2015. All patients underwent MRE with DWI before surgery. Radiological parameters were calculated in the stenotic segment and in the ileum proximal to the stenosis. The histopathological examination was performed using a histological score for fibrosis and inflammation.ADC value correlated with the fibrosis score (r = -0.648; p 0.0001), inflammation score (r = -0.763; p 0.0001) and percentage of gain (r = -0.687; p 0.0001). A correlation emerged between wall thickness and fibrosis score (r = 0.671; p 0.0001). The threshold of wall thickness for fibrosis was 6.3 mm (AUC 0.89, specificity 100% and sensitivity 69.23%). The cut-off of ADC value for fibrosis was 1.1 × 10The DWI sequence with ADC value could be useful to identify fibrosis in the intestinal wall of Crohn's Disease patients.

Background and Aims: Sexual functions are sometimes adversely affected by the therapeutic drugs delivered for treating IBD. Much attention has been focused on pregnancy/sexual issues in women. Relatively less attention has been poured in to address this issue in men. This systematic review assesses the drugs having potential detrimental effects on fertility in men. Methods: Three databases were searched by two researchers independently for potentially relevant publications between 1964 to 2015 and 249 papers were retrieved. Studies that dealt with sexual problems after IBD drugs administration were included in the purview of this review. Results: Fourteen studies with 327 human patients and 110 animals were analysed. Sulphasalazine treated patients had lower spermatozoa count, lower sperm motility and higher risk of oligospermia compared to mesalazine treated ones. Biologics seem to be safe to use while attempting to conceive however, proper clinical studies reporting male fertility problems in IBD patients are lacking. Azathioprine caused oligospermia but a meta-analytical approach was not possible due to heterogeneity in studies. Some animal studies showed methotrexate affects abnormal testis structure and spermatogenesis. Conclusion: This study summarises the current literature and safety issues affecting fertility parameters in men and animals treated with IBD therapeutic drugs, which can further assist clinicians in better management of adult male IBD patients.

Background: Papillary thyroid cancer (PTC) prevalence is nearly 3 times higher in females than in males. This gender difference suggests that growth and progression of PTC might be influenced by female sex hormones. Objectives: To analyze the expression of both estrogen receptor (ER)-α and progesterone receptor (PR) by immunohistochemistry in 203 PTC patients. Methods: ER-α and PR expression was evaluated in paraffin-embedded tumor tissue samples of 45 males and 158 females followed up for 7.2 ± 3.7 years. Results: ER-α was expressed in 52 (25.6%) patients (41 females and 11 males) and PR in 94 (46.3%) patients (75 females and 19 males). ER-α and PR were coexpressed in 31 (15.3%) patients (27 females and 4 males). ER-α expression correlated significantly with tumor size in the whole sample (ER-α positive 22.8 ± 11.8 mm vs. ER-α negative 15.1 ± 12.4 mm; p = 0.02) and in the subgroup of women (ER-α positive 18.8 ± 12.8 mm vs. ER-α negative 14.9 ± 12.3 mm; p = 0.048). In addition, ER-α expression significantly correlated with remission of the disease. In fact, of the 192 patients followed up, 50/153 (32.7%) disease-free patients were ER-α positive, in contrast to only 3/39 (7.7%) with evidence of disease persistence/recurrence (χ2 = 8.5, p = 0.0036). PR expression was not associated with any of the parameters analyzed. Conclusions: The present study confirmed recent data indicating that ER-α and PR expression is a common finding in thyroid tumor tissue. However, in contrast to previous reports, we observed an association between ER-α expression and a more favorable outcome in PTC patients.

Aim To investigate by immunostaining glucose transporter expression in human colorectal mucosa in controls and patients with inflammatory bowel disease (IBD). Methods Colorectal samples were obtained from patients undergoing lower endoscopic colonoscopy or recto-sigmoidoscopy. Patients diagnosed with ulcerative colitis (n = 18) or Crohn's disease (n = 10) and scheduled for diagnostic colonoscopy were enrolled. Patients who underwent colonoscopy for prevention screening of colorectal cancer or were followed-up after polypectomy or had a history of lower gastrointestinal symptoms were designated as the control group (CTRL, n = 16). Inflammatory status of the mucosa at the sampling site was evaluated histologically and/or endoscopically. A total of 147 biopsies of colorectal mucosa were collected and processed for immunohistochemistry analysis. The expression of GLUT2, SGLT1, and GLUT5 glucose transporters was investigated using immunoperoxidase labeling. To compare immunoreactivity of GLUT5 and LYVE-1, which is a marker for lymphatic vessel endothelium, double-labeled confocal microscopy was used. Results Immunohistochemical analysis revealed that GLUT2, SGLT1, and GLUT5 were expressed only in short epithelial portions of the large intestinal mucosa. No important differences were observed in glucose transporter expression between the samples obtained from the different portions of the colorectal tract and between the different patient groups. Unexpectedly, GLUT5 expression was also identified in vessels, mainly concentrated in specific areas where the vessels were clustered. Immunostaining with LYVE-1 and GLUT5 antibodies revealed that GLUT5-immunoreactive (-IR) clusters of vessels were concentrated in areas internal to those that were LYVE-1 positive. GLUT5 and LYVE-1 did not appear to be colocalized but rather showed a close topographical relationship on the endothelium. Based on their LYVE-1 expression, GLUT5-IR vessels were identified as lymphatic. Both inflamed and non-inflamed mucosal colorectal tissue biopsies from the IBD and CTRL patients showed GLUT5-IR clusters of lymphatic vessels. Conclusion Glucose transporter immunoreactivity is present in colorectal mucosa in controls and IBD patients. GLUT5 expression is also associated with lymphatic vessels. This novel finding aids in the characterization of lymphatic vasculature in IBD patients.

Thyroid autoimmunity affects 5–20% of the female population of childbearing age. Even in the absence of overt maternal thyroid dysfunction, thyroid autoimmunity has been reported to be associated with an increased risk of adverse pregnancy outcomes and impaired fetal neurodevelopment. Present evidence indicates that thyroid autoimmunity poses a risk for miscarriage and preterm delivery. By contrast, with regard to infertility most studies failed to find significantly different likelihood of pregnancy in euthyroid women with and without thyroid antibodies undergoing assisted reproduction procedures. Finally, uncertainty surrounds the role of thyroid autoantibodies on fetal and neonatal outcomes, since an increased risk for perinatal death, intrauterine growth restriction (IUGR), and respiratory distress syndrome has been inconsistently reported, and only few studies addressed the impact of maternal thyroperoxidase antibodies (TPOAbs) during pregnancy on cognitive functioning of the child, once again providing mixed results. Whether thyroid antibodies have a direct effect on neonatal outcomes, including neurodevelopment in the progeny, or whether the observed associations are related to maternal autoimmune-related thyroid insufficiency needs to be still clarified.

PURPOSE: The study aimed to evaluate the QoL in patients who underwent elective surgery for uncomplicated diverticulitis using a recently developed diverticulitis quality of life questionnaire (DV-QoL). METHODS: All consecutive patients who underwent surgery for uncomplicated diverticulitis or who were hospitalized and treated conservatively for acute uncomplicated diverticulitis episodes in three referral centers, in a 5-year period, were included in the study. The 36-Item Short Form Survey and the DV-QoL were administered to the patients to assess their QoL before and after treatment of diverticular disease. RESULTS: Ninety-seven patients who underwent surgery, 44 patients who were treated conservatively, and 44 healthy volunteers were included in the study. DV-QoL scores correlated with SF-36 scores (p

Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) signaling can mediate inflammatory responses as well as tissue remodeling. Intestinal mucosal myofibroblast (IMF) activation drives gut fibrosis in Crohn's disease (CD); however, the molecular pathways involved are largely unknown. Thus we investigated the yet-unknown expression and function of TAK1 in human CD-associated fibrosis. Ileal surgical specimens, ileal biopsies, and IMF isolated from controls and CD patients were analyzed for TAK1 and its active phosphorylated form (pTAK1) by Western blotting, immunohistochemistry, and real-time quantitative PCR. TAK1 pharmacological inhibition and silencing were used to assess its role in collagen and inflammatory cytokine synthesis in IMF. TAK1 and pTAK1 levels increased in ileum specimens from CD patients compared with controls and correlated to tissue fibrosis. Similarly, TAK1 mRNA in ileal biopsies of CD patients correlated with fibrogenic marker expression but not inflammatory cytokines. CD-derived IMF showed higher TAK1 and pTAK1 expression associated with increased collagen1(α)1 mRNA levels compared with control IMF. TGF-β1 promoted pTAK1 nuclear translocation and collagen synthesis. TAK1 inhibition or silencing significantly reduced TGF-β1-stimulated collagen production and normalized the profibrogenic phenotype of CD-derived IMF. Taken together, these data suggest that TAK1 activation and nuclear translocation induce and maintain a fibrogenic phenotype in the IMF. Thus the TAK1 signaling pathway may represent a suitable target to design new, antifibrotic therapies.

The lingual thyroid is the most common form of thyroid ectopy. The ectopic tissue may display any disease affecting the thyroid, including malignancies, which have an estimated incidence of less than 1%. To date only 51 cases of lingual thyroid cancer were reported. Analogously to what observed in orthotopic thyroid, papillary carcinoma is the predominant histotype in lingual thyroid carcinoma. The higher frequency of lingual follicular thyroid carcinoma previously reported is possibly related to histological misclassification in some early reports, prior to the standardization of histological typing of differentiated thyroid carcinomas. Nonetheless, the frequency of the follicular histotype is not negligible, accounting for about one-third of the reported cases. Both natural history and prognosis of lingual thyroid carcinoma are poorly known, likely because of the rarity of the disease and the heterogeneity in the therapeutic approach. However, among the cases more recently reported, surgical excision of the mass, either alone or followed by radioiodine ablation, is the first-line approach, with only two cases treated by radioiodine alone. The nonsignificant rate of neoplastic transformation in lingual thyroid should encourage efforts to obtain a widely accepted consensus for the management of this rare condition, along with standardization of either diagnostic or therapeutic handling of malignancies arising in ectopic thyroid.

PURPOSE: Wilson disease (WD) is a disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs, as the brain and cornea. The aim of this study was to investigate central corneal changes and in particular to assess the parameters of corneal subbasal nerve plexus (SBNP) in patients affected by WD, using corneal confocal microscopy (CCM). METHODS: A total of 24 patients affected by WD and 24 healthy control subjects were included in this cross-sectional comparative study. One eye of each subject was examined to quantify different corneal parameters. Mean cell diameter and mean cell density of the epithelium; number of fibers (NF), nerve fiber length density (NFLD), number of branchings (NBr), number of beadings (NBe), and fiber tortuosity (FT) of the SBNP; mean cell density of keratocytes of the anterior, medium, and posterior stroma; and mean cell density, polimegatism, and pleomorphism of the endothelium, and central corneal sensitivity were analyzed. RESULTS: Wilson disease induced significant alterations in SBNP, and corneal epithelium. The NFLD (P < 0.0001), NF (P = 0.001), NBe (P = 0.025), and NBr (P < 0.0001) were significantly lower, whereas FT (P < 0.0001) was significantly higher in WD subjects compared to controls. Moreover mean epithelial cell diameter (P < 0.0001) and mean epithelial cell density (P < 0.0001) were significantly higher and lower compared to controls, respectively. CONCLUSIONS: The CCM showed significant corneal changes in SBNP, with concomitant corneal epithelium changes in WD, demonstrating the presence of small fiber peripheral neuropathy in these patients. The CCM may contribute to diagnosis and monitoring of the peripheral nervous system involvement in WD.

Background and Aims Assessment of prognostic factors in patients with Crohn's disease (CD) is of pivotal importance for early intervention and "treat-to-target" strategies. Confocal laser endomicroscopy (CLE) enables on-demand in vivo characterization of mucosal inflammatory and architectural changes during endoscopy. We prospectively assessed the value of CLE for prediction of clinical outcome parameters in CD. Methods Consecutive patients with CD undergoing colonoscopy were included in a multicenter study. Confocal imaging focused on 2 highly reproducible histologic hallmarks of active colonic inflammation: focal cryptitis and crypt architectural abnormality. We evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP), and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural adverse events, and CD-related hospitalization or surgery during a 4-year follow-up. Results Among 49 patients (53% men, median age, 39 years), baseline CRP was ≥5 mg/L in 47%, CDEIS ≥3 in 75%, and CDAI >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% (CLE + group). CLE + patients showed an increased incidence of medical treatment escalation ( P P = .025; RR = 1.70), whereas patients with CRP ≥5 mg/L had increased CD-related hospitalization and surgery ( P = .020, RR = 2.71) at 1-year follow-up. No further association with prognostic clinical outcomes was found over the 1-year follow-up as well as for CDEIS and CDAI at any time. Conclusions CLE reveals CD-related features of mucosal inflammation and allows for early prediction of relevant clinical outcomes. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients with CD.

Differentiated thyroid cancer (DTC) is markedly more common in women than men, the highest female-to-male ratio being recorded during the reproductive period. This evidence has led to the suggestion that female hormonal and reproductive factors may account for the observed DTC gender disparity. This review focuses on current evidence on the risk of DTC in conjunction with major female reproductive factors, including the impact of pregnancy on DTC occurrence and progression/recurrence. Overall, studies exploring the link between the risk of DTC and menstrual and menopausal factors, oral contraceptives and/or hormone replacement therapy, showed these associations, if any, to be generally weak. Nonetheless, there is some evidence that higher levels of exposure to estrogens during reproductive years may confer an increased risk of DTC. As far as pregnancy is concerned, it is unclear whether a potential association between parity and risk of DTC actually exists, and whether it is enhanced in the short-term following delivery. A possible role for pregnancy-related factors in DTC progression has been recently suggested by some reports, the results of which are consistent with a worse outcome in the short-term of women diagnosed with DTC during gestation compared to non-pregnant control patients. Also, some progression of disease has been described in women with structural evidence of disease prior to pregnancy. However, there seems to be no impact from pregnancy in DTC-related death or overall survival. Several in vitro and animal studies have evaluated the influence of estrogens (E) and estrogen receptors (ERs) on thyroid cell proliferation. Presently available data are indicative of a role of E and ERs in thyroid cancer growth, although considerable discrepancies in respect to ER expression patterns in thyroid cancer tissues actually exist. Further studies providing more direct evidence on the possible role of E and of placental hormones and growth factors on thyroid growth may expand our knowledge on the mechanisms beyond the gender disparity of proliferative thyroid diseases.

Discrimination between Crohn disease (CD) and ulcerative colitis (UC) is an unsolved clinical issue in up to 10–15% of inflammatory bowel disease (IBD) patients. We developed a method capable to discriminate between the two clinical conditions by combining random peptide phage display screenings and nanoparticle (NP) based assays. We identified two peptides able to recognize selectively biopsies of inflamed mucosa of either CD or UC patients. The peptides were integrated into synthetic virus-mimicking nanoassemblies using a poly-avidin NP platform. Peptide functionalized nanoassemblies carrying about 400 peptides/NP were used to optimize a highly selective and specific microplate colorimetric test which allowed us to distinguish CD from UC in inflamed IBD epithelia tissues. The method could complement and expand the diagnostic armamentarium in IBDs, especially when discrimination between these CD and UC is not straightforward.

Recent evidence suggests thyroidectomy (Tx) followed by radioiodine remnant ablation to be beneficial to Graves' orbitopathy (GO) patients.The aim of the study was to evaluate the effect of (131)I thyroid ablation after recombinant human TSH stimulation in patients with moderate-to-severe GO.The study was prospective, randomized, and single-blind, and it included 40 consecutive patients with moderate-to-severe GO randomized into: 1) a Tx-radioactive iodine (RAI) group (20 subjects who underwent total-Tx and (131)I ablation after recombinant human TSH stimulation); and 2) a Tx group (20 subjects who underwent total-Tx alone).The overall GO outcome 12 months after Tx/radioiodine ablation was the main measure.GO evaluation at the end of iv glucocorticoids showed eye disease to be improved in 65% of the Tx-RAI group and 60% of the Tx group patients. At 6 and 12 months, no further changes in the GO outcome could be observed in the Tx-RAI group. Conversely, five patients from the Tx group exhibited a deterioration in GO. At 12 months, GO was found to be improved in 70% of the Tx-RAI and 20% of the Tx group patients, the latter being found to be stable (55%) or worse (25%) than at baseline evaluation. At 12 months, GO was found to be inactive in a significantly higher percentage of patients in the Tx-RAI than in the Tx group (75 vs 30%; P.01).Postoperative radioiodine ablation proved more effective than Tx alone in inducing earlier and steadier GO improvement in patients with moderate-to-severe GO treated with iv glucocorticoids over a 24-month follow-up period.

Human epidermal growth factor receptor 2 (HER2) is involved in the malignant progression of several human cancers, including esophageal adenocarcinoma (EAC). The purpose of this study was to evaluate HER2 overexpression and to explore the feasibility of confocal laser endomicroscopy for in vivo molecular imaging of HER2 status in an animal model of Barrett's-related EAC. Rats underwent esophagojejunostomy with gastric preservation. At 30 weeks post-surgery, the esophagus of 46 rats was studied; endoscopic and histological findings were correlated with HER2 immunofluorescence on excised biopsies and gross specimens. At this age, 23/46 rats developed Barrett's esophagus (BE), and 6/46 had cancer (four EAC and two squamous cell carcinomas). A significant overexpression of HER2 was observed in esophageal adenocarcinoma compared with normal squamous esophagus (9.4-fold) and BE (6.0-fold). AKT and its phosphorylated form were also overexpressed in cancer areas. Molecular imaging was performed at 80 weeks post-surgery in four rats after tail injection of fluorescent-labeled anti-HER2 antibody. At this age, 3/4 rats developed advance adenocarcinoma and showed in vivo overexpression of HER2 by molecular confocal laser endomicroscopy with heterogeneous distribution within cancer; no HER2 signal was observed in normal or Barrett's tissues. Therefore, HER2 overexpression is a typical feature of the surgical induced model of EAC that can be easily quantified in vivo using an innovative mini-invasive approach including confocal endomicroscopy; this approach may avoid limits of histological evaluation of HER2 status on 'blinded' biopsies.

a b s t r a c t Background: Gastrointestinal bleeding is the most frequent emergency for gastroenterologists. Despite advances in management, an improvement in mortality is still not evident. Aim: Determining time trends of gastrointestinal bleeding hospitalization and outcomes from 2001 to 2010 in the Veneto Region (Italy). Patients and methods: Data of patients admitted with gastrointestinal bleeding from Veneto regional discharge records were retrospectively evaluated. Chi-squared and multivariate logistic regression model were used. Results: Overall, 44,343 patients (mean age 64.2 ± 8.6 years) with gastrointestinal bleeding were analysed: 23,450 (52.9%) had upper, 13,800 (31.1%) lower, and 7093 (16%) undefined gastrointestinal bleeding. Admission rate decreased from 108.0 per 100,000 in 2001 to 80.7 in 2010, mainly owing to a decrease in upper gastrointestinal bleeding (64.4 to 35.9 per 100,000, p < 0.05). Reductions in hospital fatality rate (from 5.3% to 3%, p < 0.05), length of hospital stay (from 9.3 to 8.7 days, p < 0.05), and need for surgery (from 5.6% to 5%, p < 0.05) were observed. Surgery (OR: 2.97, 95% CI: 2.59-3.41) and undefined gastrointestinal bleeding (OR: 2.89, 95% CI: 2.62-3.19) were found to be risk factors for mortality. Conclusions: Patient admissions for gastrointestinal bleeding decreased significantly over the years, owing to a decrease in upper gastrointestinal bleeding. Improved outcomes could be related to regional dedi- cated clinical gastroenterological management.

Background & Aims In the intestines, Toll-like receptor 2 (TLR2) mediates immune responses to pathogens and regulates epithelial barrier function; polymorphisms in TLR2 have been associated with inflammatory bowel disease phenotype. We assessed the effects of TLR2 signaling on the enteric nervous system (ENS) in mice. Methods TLR2 distribution and function in the ileal neuromuscular layer of mice were determined by immunofluorescence, cytofluorimetric analysis, immunoprecipitation, and immunoblot analyses. We assessed morphology and function of the ENS in Tlr2 −/− mice and in mice with wild-type Tlr2 (wild-type mice) depleted of intestinal microbiota, using immunofluorescence, immunoblot, and gastrointestinal motility assays. Levels and signaling of glial cell line−derived neurotrophic factor (GDNF) were determined using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and immunoprecipitation analyses. Colitis was induced by administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid to Tlr2 −/− mice after termination of GDNF administration. Results TLR2 was expressed in enteric neurons, glia, and smooth muscle cells of the intestinal wall. Tlr2 −/− mice had alterations in ENS architecture and neurochemical profile, intestinal dysmotility, abnormal mucosal secretion, reduced levels of GDNF in smooth muscle cells, and impaired signaling via Ret−GFRα1. ENS structural and functional anomalies were completely corrected by administration of GDNF to Tlr2 −/− mice. Wild-type mice depleted of intestinal microbiota had ENS defects and GDNF deficiency, similar to Tlr2 −/− mice; these defects were partially restored by administration of a TLR2 agonist. Tlr2 −/− mice developed more severe colitis than wild-type mice after administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid; colitis was not more severe if Tlr2 −/− mice were given GDNF before dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid. Conclusions In mice, TLR2 signaling regulates intestinal inflammation by controlling ENS structure and neurochemical coding, along with intestinal neuromuscular function. These findings provide information as to how defective TLR2 signaling in the ENS affects inflammatory bowel disease phenotype in humans.

Background CD80 has been thought to play an active role in immunosurveillance as it has been found to be up-regulated in ulcerative colitis (UC) patients with dysplasia. The aim of the present study was to analyse early events in UC-related and non-inflammatory carcinogenesis with reference to CD80 expression to clarify what stimuli are involved in its up-regulation in these patients. Patients and methods Sixty-two patients affected with UC, UC with dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enroled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of Toll-like receptor-4 (TLR4) and nuclear factor-kappaB (NF-κB) was quantified with Real Time RT-PCR. TLR4, β-catenin and p53 expressions were analysed by immunohistochemistry. Mucosal levels of activated NF-κB were measured with immunometric assays while 8-Hydroxydeoxyguanosine (8-OHdG) levels were quantified by high-performance liquid chromatography with electrochemical detection (HPLC-ED). Non-parametric tests were used for statistical analysis. Results 8-OHdG mucosal levels were higher in the patients with UC + dysplasia with respect to those in the patients with UC only ( p = 0.03). CD80 mRNA mucosal levels were directly correlated with 8-OHdG mucosal levels ( τ = 0.26, p = 0.04), TLR4 protein expression ( τ = 0.45, p τ = 0.24, p = 0.02; τ = 0.34, p = 0.02, respectively). CD80 protein expression, instead, was directly correlated with 8-OHdG mucosal levels ( τ = 0.19, p = 0.05) and inversely correlated with TLR4 mRNA expression ( τ = −0.25, p = 0.03). Conclusion Oxidative DNA damage peaked in UC-related dysplasia and was found to be directly correlated to CD80 expression. The direct correlation between TLR4 protein expression and CD80 mRNA and the indirect correlation between CD80 protein and TLR4 mRNA expressions give substance to the hypothesis that they play a role in immunosurveillance. No significant correlations between CD80 expression and p53 and β-catenin accumulation during oncogenesis were, instead, observed.

Metastatic cancersmake up fewer than 2% of pancreaticmalignancies, and themajority of them mimic a primary adenocarcinoma [1]. Limited data are available concerning the assessment of pancreatic secondary cancers using endoscopic ultrasound-guided fine needle biopsy (EUSFNB) [2]. In this study we report the first case of metastatic pancreatic melanoma to be diagnosed by combining EUS with biopsy sampling using the SharkCore needle (SharkCore Fine Needle Biopsy System, Covidien IIc, NewtonMassachusetts, USA). A 57-year-old woman presented with evidence of a pancreatic mass. Her past medical history included a choroidal melanoma in 2009, which had been treated by iodine-125 brachytherapy. At the time of treatment no metastatic lesions had been documented. In May 2015, a magnetic resonance imaging (MRI) scan performed for clinical surveillance demonstrated a nodular liver consistent with metastasis. The patient underwent transarterial chemoembolization with irinotecan. A subsequent MRI scan showed a nodular lesion of the pancreatic tail (20×17mm), which was a mixture of isointense and hyperintense on T1-weighted images (●" Fig.1), and was hypointense on T2-weighted images, compatible with either primary cancer or metastatic disease. The patient was asymptomatic, with no suspicious skin lesions and no palpable lymphadenopathy. Laboratory test results were within normal limits. The patient was referred to our institution for EUS evaluation. The EUS (Olympus UCT 140 linear arrayechoendoscope) showed a 2-cm hypoechoic mass in the pancreatic tail (●" Fig.2). Five transduodenal FNB passes (22-gauge SharkCore needle) into the mass resulted in multiple tissue samples (maximum diameter 0.08–0.1cm) (●" Video1). Histological examination showed malignant pigmented epithelioid lesions, which were immunohistochemically confirmed as metastatic melanoma (●" Fig.3). The patient underwent chemotherapy and has currently completed her induction cycleswith fotemustine.

Over the last years, there have been several reports on the occurrence of acute liver damage (ALD) in patients affected with Graves’ ophthalmopathy (GO) receiving intravenous glucocorticoids (ivGCs). This article is aimed at reviewing the literature on this specific topic and reporting two new cases of ALD occurring in GO patients while on ivGCs. The terms “glucocorticoid therapy” and “Graves’ Ophthalmopathy”/“Graves’ Orbitopathy”/”Thyroid eye disease” were used both separately and in conjunction with the terms “liver disease,” “liver damage,” “hepatotoxicity,” “liver failure,” to search MEDLINE for articles published since the first report of ALD in 2000 and up to 2015. ALD [defined as an increase in alanine aminotransferase (ALT) >300 U/L] during or after completion of ivGCs has been so far reported in 17 fully documented cases. Overall, one-half of those patients were diagnosed as having autoimmune hepatitis (AIH) and in the vast majority of the remaining cases a diagnosis of methylprednisolone(MP)-induced hepatotoxicity was suspected. The clinical course of liver injury varied from asymptomatic hypertransaminasemia in the vast majority of patients to fatal hepatic failure in four patients receiving higher (>8 g) cumulative doses of MP. The overall risk of ALD is relatively low (~1 %), and seems higher using a single dose >0.5 g and a cumulative dose >8.5 g MP. Whenever ivGC treatment is required, serum liver enzymes, viral hepatitis markers, and autoantibodies related to AIH should be obtained prior to ivGC administration. Liver function should be monitored during ivGC and up to 6 months after the end of treatment. Prolonging observation after 6 months is likely unnecessary, since all cases of ALD so far reported always occurred well within this term.

Background Crohn’s disease (CD) is a life-long, chronic, relapsing condition requiring often morphological assessment. MR enterography (MRE) offers advantages of not using ionizing radiation and yielding intraluminal and intra-abdominal informations. The aim of our study was to identify how MRE can be useful in planning surgical procedures. Patients and Methods In this retrospective study, 35 patients who underwent MRE and then surgery for CD were enrolled from 2006 to 2010. MRE findings were compared to intraoperative findings. Histology of operative specimens, systemic inflammatory parameters, and fecal lactoferrin were also evaluated. Cohen’s κ agreement test, sensitivity and sensibility, uni-/multivariate logistic regression, and non-parametric statistics were performed. Results MRE identified bowel stenosis with a sensitivity of 0.95 (95% CI 0.76–0.99) and a specificity of 0.72 (95% CI 0.39–0.92). The concordance of MRE findings with intraoperative findings was high [Cohen’s κ=0.72 (0.16)]. Abscesses were detected at MRE with a sensitivity of 0.92 (95% CI 0.62–0.99) and a specificity of 0.90 (95% CI 0.69–0.98) with a Cohen’s κ=0.82 (0.16). The grade of proximal bowel dilatation resulted to be a significant predictor of the possibility of using strictureplasty instead of/associated to bowel resection either at univariate or at multivariate analysis. Conclusion Our study confirmed that MRE findings correlate significantly with disease activity. Detailed information about abscess could suggest percutaneous drainage that could ease the following surgery or avoid emergency laparotomy. Proximal bowel dilatation can suggest the possibility to perform bowel sparing surgery such as strictureplasty.

An imbalance in gut microbiota seems to contribute to the development of chronic inflammatory disorders of the gastrointestinal tract, such as ulcerative colitis (UC). Although it has been suggested that probiotic supplementation is an effective approach to colitis, its effects on intestinal flora and on mucosal cytokine balance have never been explored. To evaluate the effect of Lactobacillus casei (L. casei) DG, a probiotic strain, on colonic-associated microbiota, mucosal cytokine balance, and toll-like receptor (TLR) expression. Twenty-six patients with mild left-sided UC were randomly allocated to one of three groups for an 8-week treatment period: the first group of 7 patients received oral 5-aminosalicylic acid (5-ASA) alone, the second group of 8 patients received oral 5-ASA plus oral L. casei DG, and the third group of 11 patients received oral 5-ASA and rectal L. casei DG. Biopsies were collected from the sigmoid region to culture mucosal-associated microbes and to assess cytokine and TLR messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (RT-PCR). 5-ASA alone or together with oral L. casei DG failed to affect colonic flora and TLR expression in a significant manner, but when coupled with rectally administered L. casei DG, it modified colonic microbiota by increasing Lactobacillus spp. and reducing Enterobacteriaceae. It also significantly reduced TLR-4 and interleukin (IL)-1β mRNA levels and significantly increased mucosal IL-10. Manipulation of mucosal microbiota by L. casei DG and its effects on the mucosal immune system seem to be required to mediate the beneficial activities of probiotics in UC patients.

The aim of this prospective study was to analyze the impact of different surgical techniques on patients undergoing intestinal surgery for Crohn's disease (CD) in terms of recovery, quality of life, and direct and indirect costs.Forty-seven consecutive patients admitted for intestinal surgery for CD were enrolled in this prospective study. Surgical procedures were evaluated as possible predictors of outcome in terms of disability status (Barthel's Index), quality of life (Cleveland Global Quality of Life score), body image, disease activity (Harvey-Bradshaw Activity Index), and costs (calculated in 2008 Euros). Univariate and multivariate analyses were performed.Significant predictors of a long postoperative hospital stay were the creation of a stoma, postoperative complications, disability status on the third post-operative day, and surgical access (R (2) = 0.59, p0.01). Barthel's index at discharge was independently predicted by laparoscopic-assisted approach, ileal CD, and colonic CD (R (2) = 0.53, p0.01). The disability status at admission showed to be an independent predictor of quality of life score at follow-up. The overall cost for intestinal surgery for CD was 12,037 (10,117-15,795) euro per patient and stoma creation revealed to be its only predictor (p = 0.006).Laparoscopy was associated with a shorter postoperative length of stay; stoma creation was associated with a long and expensive postoperative hospital stay, and stricturoplasty was associated with a slower recovery of bowel function.

Accumulating evidence indicates that the peroxisome proliferator activated receptor (PPAR)-gamma is a major player in maintaining intestinal mucosa homeostasis, but whether PPAR-gamma is directly involved in probiotic-mediated effects and the molecular events involved in its activation are not known.We investigated the role of PPAR-gamma in the immunomodulatory effects of Lactobacillus crispatus M247 on intestinal epithelial cells (IEC) and the role of probiotic-derived H(2)O(2) on PPAR-gamma activity.L crispatus M247 supplementation in mice significantly increased PPAR-gamma levels and transcriptional activity in the colonic mucosa. L crispatus M247 induced PPAR-gamma nuclear translocation and enhanced transcriptional activity in epithelial (CMT-93) cells, as demonstrated by the increased luciferase activity of a PPAR-gamma-responsive element, PPAR-gamma-responsive gene up-regulation, and reduced activity of an nuclear factor-kappaB-responsive element. Pharmacologic PPAR-gamma inhibition or silencing by small interfering RNA cancelled the L crispatus M247-mediated effects in CMT-93 cells. Because Lactobacillus strains producing little H(2)O(2) failed to activate PPAR-gamma, we investigated the role of L crispatus M247-derived H(2)O(2) in PPAR-gamma activation. L crispatus M247 induced a transient rise in intracellular H(2)O(2) and PPAR-gamma transcriptional activity was cancelled by antioxidant or H(2)O(2) scavenger. Toll-like receptor (TLR)-2 was not required for PPAR-gamma up-regulation mediated by L crispatus M247 in mice, although the protective effects of L crispatus M247 on dextran sodium sulfate-induced colitis were less pronounced in TLR-2(-/-) mice.L crispatus M247 uses H(2)O(2) as a signal transducing molecule to induce PPAR-gamma activation in IEC, directly modulating epithelial cell responsiveness to inflammatory stimuli.

The aim of this prospective study was to evaluate the changes of the metabolism of circulating and storage lipids in patients with ulcerative colitis after restorative proctocolectomy. Fifteen consecutive patients and 15 sex- and age-matched healthy controls were enrolled. Disease activity, diet, inflammatory parameters, plasma lipoprotein concentrations, and fatty acids (FA) of serum phospholipids and of the subcutaneous adipose tissue were assessed at colectomy and at ileostomy closure. In ulcerative colitis patients, total cholesterol and docosahexaenoic acid were lower than in healthy subjects (p < 0.01 and p < 0.05). The median interval between colectomy and ileostomy closure was 6 (range 2-9) months. During that interval, the inflammatory parameters improved, high-density lipoproteins (HDL) cholesterol increased (p < 0.01), and low-density (LDL) cholesterol decreased (p = 0.01). At ileostomy closure, serum arachidonic acid levels were increased (p = 0.04), whereas serum oleic acid level was decreased (p = 0.02). In this interval, no significant alteration, either in serum n-3 FA precursors or in the FA of subcutaneous adipose tissue, was observed. The increase of serum arachidonic acid after colectomy might suggest a lower utilization for inflammatory process. The reduction of LDL cholesterol is an index of malabsorption probably due to the accelerated transit and to the exclusion of the terminal ileum caused by the covering ileostomy.

Background Alternative and complementary therapies are increasingly used by patients with inflammatory bowel disease, but no data are available on their use in Italy. Aim To ascertain the prevalence and pattern of the use of alternative and complementary therapies, and demographic and clinical factors associated with their use in a large sample of Italian inflammatory bowel disease patients. Methods A structured questionnaire was administered to a cohort of outpatients at a tertiary referral centre. Results Five hundred and fifty-two patients completed the questionnaire; 156 (28%) reported using alternative and complementary therapies, which mainly involved homeopathy (43.6%), followed by controlled diets or dietary supplements (35.5%), herbs (28.2%), exercise (25.6%) and prayer (14.7%). Alternative and complementary therapies were used to ameliorate intestinal symptoms (52.5%), in the hope of being cured (41%) and to reduce the intake of drugs (39.7%). An improvement in well-being (45.5%) and inflammatory bowel disease symptoms (40.3%) were the most commonly reported benefits. A higher education (p = 0.027), a more frequently relapsing disease (p = 0.001) and dissatisfaction with the doctor's communication (p = 0.001) correlated with alternative and complementary therapy use. Non-compliance with conventional drugs, disease severity and curiosity regarding novel therapies were predictors of alternative and complementary therapy use. Conclusions Alternative and complementary therapies are frequently used by Italian inflammatory bowel disease patients. Doctors should improve their empathy and their understanding about possible benefits of alternative and complementary therapies.

Rheumatic manifestations, in particular joint complaints, are frequent features in inflammatory bowel disease (IBD), with a prevalence varying from 10 to 35%. Their spectrum is almost wide, involving bone, tendons, entheses and joints. Joint manifestations may be seen as arthralgia and/or inflammatory arthropathies. These latter may in turn be found in three principal forms: the peripheral, the axial or spondylitis and that overlapping between these two varieties. Peripheral arthritis may be classified in oligoarticular (type I) and polyarticular (type II) forms. Oligoarthritis is the most frequent. Usually asymmetric, involving large joints of lower limbs, it is transient, commonly associated with IBD flares, and may disappear after few weeks, although in 10% of cases it may evolves to chronic arthritis. Type II arthritis is polyarticular and symmetric, involving hands and feet but also large joints. The prevalence is about 2-4% of IBD patients, its course is independent from IBD flares and usually evolves in chronic disease. Peripheral arthritis is classically nondeforming, non erosive, and seronegative for the rheumatoid factor. Axial involvement is equally frequent in both CD and UC and varies in different studies from 10 to 30% for sacroiliitis and from 3 to 10% for ankylosing spondylitis. Its course is independent from IBD state, the extension of IBD involvement and the occurrence of flares. The treatment of rheumatic manifestations in IBD is frequently problematic, due to the possibility of frequent side effects. Among drugs used for IBD, corticosteroids, also effective in joint complaints, may have osteopenic effects; sulfasalazine, sometimes able to control peripheral arthritis, is ineffective for the axial involvement. A potential gut toxicity is associated with the use of NSAIDs, which in some patients may induce asymptomatic lesions causing small gut bleeding and loss of proteins. Local injections with steroid may be used for tendonitis, monoarthritis or isolated sacroiliac inflammation. In patients with peripheral arthritis, especially when involving several joints and/or refractory to other therapies, disease modifying drugs for rheumatoid arthritis (DMARDs) should be used. Among these, methotrexate is also useful for CD while it seems inefficacious in UC. Cyclosporin, administrated alone or in association, may contain flares of steroid refractory UC. Azathioprine is commonly used to induce and maintain remission in refractory CD while its role on arthritis is marginal. Aminobisphosphonates seem effective for both axial and peripheral involvements and probably, it may represent a good option for the future in the management of enteropathic arthritis, because of their anti-osteopenic effect. Finally, the most promising opportunities derive from the recently introduced biologic agents, in particular anti-tumour necrosis factor (TNF) . Infliximab, a chimeric anti-TNFα monoclonal IgGI antibody, has largely demonstrated its efficacy in refractory CD and in all rheumatic manifestations. Other biologic agents are proposed, including the human anti-TNF monoclonal antibody adalimumab, antibodies to integrins (anti-α 4 β7), anti-ICAM-1 (intracellular adhesion molecule 1) and IL-10. Concerning the surgical options, the colectomy may be protective on type I peripheral arthritis but is not influent on the course of axial disease, while the surgery on small intestine usually do not prevent the appearance of peripheral arthritis. In the case of destructive arthritis, like coxitis, joint prosthesis may be necessary.

Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, relapsing conditions resulting from uncontrolled inflammation of the intestinal mucosa. Both conditions are associated with significant disability and patients with CD face higher mortality rates compared to the general population. The increasing understanding of the immunological basis of the disease led to the introduction of biologic therapies targeting key pathways of the natural and adaptive immune response such as Tumor Necrosis Factor alpha (TNF-alpha) inhibitors and, more recently, integrin-receptor antagonists. Treatment with TNF-alpha inhibitors improved clinical and patient-reported outcomes for many patients who did not benefit from conventional therapy. However, a sizeable share of patients still face suboptimal outcomes due to primary or secondary therapy failure. With the introduction of VDZ, a biologic treatment targeting novel IBD-relevant biologic pathways, it is crucial to understand how to integrate such innovations into current clinical practice. To this end, a panel of 14 Italian experts in the management of IBD met for a roundtable discussion. Recommendations concerning the management of moderate-to-severe IBD based on experts' opinions and literature review are discussed in the present report. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Andrea Buda,1,* Sonia Facchin,1,* Elisa Dassie,2 Elisabetta Casarin,3 Mark A Jepson,4 Helmut Neumann,5 Giorgia Hatem,1 Stefano Realdon,6 Renata D’Incà,1 Giacomo Carlo Sturniolo,1 Margherita Morpurgo3 1Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padova, 2Department of Molecular Medicine, University of Padova, Padova, Italy; 3Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; 4School of Biochemistry and Wolfson Bioimaging Facility, University of Bristol, Bristol, UK; 5Ludwig Demlig Endoscopic Center of Excellence, ESGE Endoscopy Training Center, University of Erlangen-Nuremberg, Erlangen, Germany; 6Veneto Institute of Oncology IOV-IRCCS, Padova, Italy *These authors contributed equally to this work Abstract: Inflammatory bowel diseases are chronic gastrointestinal pathologies causing great discomfort in both children and adults. The pathogenesis of inflammatory bowel diseases is not yet fully understood and their diagnosis and treatment are often challenging. Nanoparticle-based strategies have been tested in local drug delivery to the inflamed colon. Here, we have investigated the use of the novel avidin-nucleic acid nanoassembly (ANANAS) platform as a potential diagnostic carrier in an experimental model of inflammatory bowel diseases. Fluorescent-labeled ANANAS nanoparticles were administered to mice with chemically induced chronic inflammation of the large intestine. Localization of mucosal nanoparticles was assessed in vivo by dual-band confocal laser endomicroscopy. This technique enables characterization of the mucosal microvasculature and crypt architecture at subcellular resolution. Intravascular nanoparticle distribution was observed in the inflamed mucosa but not in healthy controls, demonstrating the utility of the combination of ANANAS and confocal laser endomicroscopy for highlighting intestinal inflammatory conditions. The specific localization of ANANAS in inflamed tissues supports the potential of this platform as a targeted carrier for bioactive moieties in the treatment of inflammatory bowel disease. Keywords: confocal laser endomicroscopy, inflammatory bowel disease, diagnostics, dextran sodium sulfate, avidin-nucleic acid nanoassembly, fluorescent nanoparticles, ulcerative colitis

Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7.In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28.The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P0.001, and P0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease.We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).

Purposes: Patients affected by Crohn's disease (CD) require lifelong medical therapy, but they can also often require abdominal surgery. The effect of CD therapy on postoperative course is still unclear. The aim of this study was to evaluate the effect of preoperative medical therapy on the outcome of intestinal surgery in these patients. Methods: Data from a consecutive series of 167 patients with CD operated on at the University of Padova Hospital from 2000 to 2013 were retrieved. Data of preoperative therapy during the 6 months before surgery were available for 146 patients who were enrolled in this retrospective study. Clinical data and surgical details were retrieved and postoperative complications and reoperation were considered outcome measures. Univariate and multivariate analysis were performed. Results: No significant difference was observed between patients without data about their preoperative therapy and those with them. Eight patients underwent reoperation in the first 30 postoperative days: two of them for anastomotic leak, three for bleeding, one for obstruction and two for abdominal wound dehiscence. At multivariate analysis, preoperative adalimumab and budesonide resulted to be an independent predictor of reoperation (OR = 7.67 (95% CI = 1.49-39.20), p = 0.01 and OR = 6.7749 (95% CI = 0.98-46.48), p = 0.05, respectively). At multivariate analysis neither pharmacological nor clinical variables resulted to predict anastomotic leak. Conclusions: In our series, adalimumab seemed to be associated to early reoperation after intestinal surgery. This may be due to a worst disease severity in patients who needed surgery in spite of biological therapy. Preoperative tapering of budesonide dose seems a safe option before elective abdominal surgery for CD.

Background High-resolution manometry (HRM) provides information on esophagogastric junction (EGJ) morphology, distinguishing three different subtypes. Data on the correlation between EGJ subtypes and impedance-pH detected reflux patterns are lacking. We aimed to correlate the EGJ subtypes with impedance-pH findings in patients with reflux symptoms. Methods Consecutive patients with suspected gastroesophageal reflux disease (GERD) were enrolled. All patients underwent HRM and impedance-pH testing off-therapy. EGJ was classified as: Type I, no separation between the lower esophageal sphincter (LES) and crural diaphragm (CD); Type II, minimal separation (>1 and

Introduction Inflammatory bowel diseases (IBD) are complex multi-factorial diseases with increasing incidence worldwide but their treatment is far from satisfactory. Unconventional strategies have consequently been investigated, proposing the use of cells as an effective alternative approach to IBD. In the present study we examined the protective potential of exogenously administered human umbilical cord derived mesenchymal stem cells (UCMSCs) against Dextran Sulfate Sodium (DSS) induced acute colitis in immunodeficient NOD.CB17-Prkdcscid/J mice with particular attention to endoplasmic reticulum (ER) stress. Methods UCMSCs were injected in NOD.CB17-Prkdcscid/J via the tail vein at day 1 and 4 after DSS administration. To verify attenuation of DSS induced damage by UCMSCs, Disease Activity Index (DAI) and body weight changes was monitored daily. Moreover, colon length, histological changes, myeloperoxidase and catalase activities, metalloproteinase (MMP) 2 and 9 expression and endoplasmic reticulum (ER) stress related proteins were evaluated on day 7. Results UCMSCs administration to immunodeficient NOD.CB17-Prkdcscid/J mice after DSS damage significantly reduced DAI (1.45 ± 0.16 vs 2.08 ± 0.18, p 3-fold), which were significantly reduced in mice receiving UCMSCs. Moreover, positive modulation in ER stress related proteins was observed after UCMSCs administration. Conclusions Our results demonstrated that UCMSCs are able to prevent DSS-induced colitis in immunodeficient mice. Using these mice we demonstrated that our UCMSCs have a direct preventive effect other than the T-cell immunomodulatory properties which are already known. Moreover we demonstrated a key function of MMPs and ER stress in the establishment of colitis suggesting them to be potential therapeutic targets in IBD treatment.

Shorter infusions of infliximab for inflammatory bowel disease seem to be as tolerated as standard procedures and nurses may be able to manage them safely.To test tolerability and effectiveness of a fast nurse-led infusion procedure and the related patients' satisfaction.We retrospectively compared three different regimens adopted in our outpatient infusion unit from 2010 to 2013: Group 1, a standard procedure with two-hour infusions, preceded by hydrocortisone medication (87 patients, 311 infusions); Group 2, a similar regimen without physician supervision (130 patients, 464 infusions); Group 3, a one-hour nurse-led procedure without routine premedication (176 patients, 1356 infusions). Disease characteristics, infusion reactions, infusions per month and patients' satisfaction were recorded.There were significantly fewer infusion reactions in Group 3 than Group 1 (2.2% versus 5.8% respectively; p=0.001). The only significant risk factor for side effects was premedication (odds ratio 4.71, 95% confidence interval 2.21-10.02, p0.001) which was related to the presence of previous side effects. Number of infusions per month increased by 27% (83 versus 61, p0.001) without increasing nurses' workload and patients were satisfied.Our fast nurse-led procedure was well tolerated, effective and satisfactory for patients.

Summary Background Two variants in the organic cation transporter gene cluster have been recently reported to confer susceptibility to Crohn's disease (CD). Aim To investigate these variants in CD and ulcerative colitis (UC), and their interaction with CARD15 gene and correlation to clinical subphenotypes. Methods Case–control association analysis was performed in 899 patients (444 CD and 455 UC) and 611 controls. The organic cation transporter gene cluster single nucleotide polymorphisms G207GC and 1672CT, the IGR2198a_1 single nucleotide polymorphism in the IBD5 locus, and the R702W, G908R and L1007finsC variants of CARD15 gene were genotyped by ABI-7700, restriction fragment length polymorphic analysis and multiplex pyrosequencing, respectively. Results The 1672TT and −207CC genotype frequencies were increased in both CD (OR = 1.5, P = 0.011; OR = 1.6, P = 0.002), and UC (OR = 1.5, P = 0.017; OR = 1.4, P = 0.033), respectively. Compared with controls, the TC haplotype frequency was increased in both CD (36% vs. 44%, P ≤ 0.01) and UC (36% vs. 45%, P ≤ 0.01). The frequency of the TC haplotype was 43% in CARD15-positive and 44% in CARD15-negative CD, respectively. Similar results were found in UC. In CD a significant association of the TC haplotype was found with presence of perianal fistulae (P = 0.007) and steno-fistulizing behaviour (P = 0.037). In UC, the TC haplotype was more frequent in patients with more extensive disease (P = 0.015), and those on immunosuppressives (P = 0.004). Conclusions Organic cation transporter gene cluster variants may confer susceptibility to both CD and UC, and the TC haplotype may influence some clinical features of IBD, but does not interact with CARD15 variants.