Inflammatory Bowel Disease: Autoimmune or Immune-mediated Pathogenesis?

The pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), is still unclear, but both autoimmune and immune-mediated phenomena are involved. Autoimmune phenomena include the presence of serum and mucosal autoantibodies against intestinal epithelial cells in either form of IBD, and against human tropomyosin fraction five selectively in UC. In addition, perinuclear antineutrophil cytoplasmic antibodies (pANCA) are common in UC, whereas antibodies against Saccharomyces cerevisiae (ASCA) are frequently found in CD. Immune-mediate phenomena include a variety of abnormalities of humoral and cell-mediated immunity, and a generalized enhanced reactivity against intestinal bacterial antigens in both CD and UC. It is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function, excessive stimulation of mucosal dendritic cells, infections or variants of proteins critically involved in bacterial antigen recognition, such as the products of CD-associated NOD2/CARD15 mutations

Le parole e la visioneComunicare l'esperienza visionaria: il caso di Ildegarda di Bingen

L'articolo intende evidenziare la strategia adottata da Ildegarda di Bingen per divulgare le visioni ricevute.Si mette allora in luce la strada dell'annullamento della personalità che riduce Ildegarda a uno specchio che deve riflettere le parole e le immagini di cui è stata testimone.L'esperienza di Ildegarda si dimostra essenzialmente visiva e parzialmente auditiva, con rarissimi accenni alla percezione di altri sensi.L'analisi del testo mette in evidenza una profonda sfiducia nella parola umana ritenuta strutturalmente incapace di inadatta a comunicare l'esperienza visionaria.Per questo motivo assume importanza l'adozione di immagini miniate, disegnate dalla stessa Ildegarda, al fine di supplire ai limiti del linguaggio degli uomini

L’ordine cristiano dei laici

Quando si usa il termine laico, occorre sempre rispondere ad alcune domande implicite: laico rispetto a chi? Quando? Un percorso tra le varie classificazioni che si possono trovare nei testi medievali. Nella convinzione che la struttura stessa della classificazione sia importante, l'articolo procede sulla base di un criterio quantitativo, facendo riferimento al numero di classi o generi identificati, a partire dalla divisione più semplice. Una passaggio dal semplice al complesso alla luce della centralità del binomio concettuale di unità-differenza. When we use the term laico, we must ever answer to some implicit questions: laico compared to whom? When? A path among the various classifications that we can find in medieval texts. Persuaded that the very structure of the classification is important, the paper goes on, according to a quantitative criterion, by reference to the number of identified classes or genres, starting from the simplest partition. A transition from the simple to the complex in the light of the centrality of two-faced concept of unit-difference

Theratyping of the Rare CFTR Variants E193K and R334W in Rectal Organoid-Derived Epithelial Monolayers

Background: The effect of presently available CFTR modulator combinations, such as elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA), on rare CFTR alleles is often unknown. Several assays have been developed, such as forskolin-induced swelling (FIS), to evaluate the rescue of such uncommon CFTR alleles both by established and novel modulators in patient-derived primary cell cultures (organoids). Presently, we assessed the CFTR-mediated electrical current across rectal organoid-derived epithelial monolayers. This technique, which allows separate measurement of CFTR-dependent chloride or bicarbonate transport, was used to assess the effect of ELX/TEZ/IVA on two rare CFTR variants. Methods: Intestinal organoid cultures were established from rectal biopsies of CF patients carrying the rare missense mutations E193K or R334W paired with F508del. The effect of the CFTR modulator combination ELX/TEZ/IVA on CFTR-mediated Cl- and HCO3- secretion was assessed in organoid-derived intestinal epithelial monolayers. Non-CF organoids were used for comparison. Clinical biomarkers (sweat chloride, FEV1) were monitored in patients receiving modulator therapy. Results: ELX/TEZ/IVA markedly enhanced CFTR-mediated bicarbonate and chloride transport across intestinal epithelium of both patients. Consistent with the rescue of CFTR function in cultured intestinal cells, ELX/TEZ/IVA therapy improved biomarkers of CFTR function in the R334W/F508del patient. Conclusions: Current measurements in organoid-derived intestinal monolayers can readily be used to monitor CFTR-dependent epithelial Cl- and HCO3- transport. This technique can be explored to assess the functional consequences of rare CFTR mutations and the efficacy of CFTR modulators. We propose that this functional CFTR assay may guide personalized medicine in patients with CF-like clinical manifestations as well as in those carrying rare CFTR mutations

Interleukin 1␤-Induced Production of H 2 O 2 Contributes to Reduced Sigmoid Colonic Circular Smooth Muscle Contractility in Ulcerative Colitis

ABSTRACT We have shown that neurokinin A-induced contraction of human sigmoid circular muscle (HSCM) is reduced in patients with ulcerative colitis and that interleukin (IL)-1␤ may play a role in this change. We now examine changes in the signal transduction pathway mediating neurokinin A-induced contraction of HSCM and explore the role of IL-1␤ and of H 2 O 2 in these changes. In Fura 2-AM-loaded ulcerative colitis HSCM cells, neurokinin A-and caffeine-induced peak Ca 2ϩ increase and cell shortening were significantly reduced. In normal cells, neurokinin A-induced contraction was decreased by protein kinas

Probiotic Sonicates Selectively Induce Mucosal Immune Cells Apoptosis Through Ceramide Generation Via Neutral Sphingolyelinase

Background: Probiotics appear to be beneficial in inflammatory bowel disease, but their mechanism of action is incompletely understood. We investigated whether probiotic-derived sphingomyelinase mediates this beneficial effect. Methodology/Principal Findings: Neutral sphingomyelinase (NSMase) activity was measured in sonicates of the probiotic L.brevis (LB)and S. thermophilus (ST) and the non-probiotic E. coli EC) and E. faecalis (EF). Lamina propria mononuclear cells (LPMC) were obtained from patients with Crohn"s disease (CD) and Ulcerative Colitis (UC), and peripheral blood mononuclear cells (PBMC) from healthy volunteers, analysing LPMC and PBMC apoptosis susceptibility, reactive oxygen species (ROS) generation and JNK activation. In some experiments, sonicates were preincubated with GSH or GW4869, a specific NSMase inhibitor. NSMase activity of LB and ST was 10-fold that of EC and EF sonicates. LB and ST sonicates induced significantly more apoptosis of CD and UC than control LPMC, whereas EC and EF sonicates failed to induce apoptosis. Pre-stimulation with anti-CD3/CD28 induced a significant and time-dependent increase in LB-induced apoptosis of LPMC and PBMC. Exposure to LB sonicates resulted in JNK activation and ROS production by LPMC. NSMase activity of LB sonicates was completely abrogated by GW4869, causing a dose-dependent reduction of LB -induced poptosis. LB and ST selectively induced immune cell apoptosis, an effect dependent on the degree of cell activation and mediated by bacterial NSMase. Conclusions: These results suggest that induction of immune cell apoptosis is a mechanism of action of some probiotics and that NSMase-mediated ceramide generation contributes to the therapeutic effects of probiotics

Amino Acid Position 11 of HLA-DRβ1 is a Major Determinant of Chromosome 6p Association with Ulcerative Colitis

The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn’s disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single nucleotide polymorphism (SNP) genotyping and from imputation of classical HLA types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD, and 1,428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67×$10^{-13}$). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRβ1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68×$10^{-13}$). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC versus control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRβ1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with ulcerative colitis

Procedura di montaggio del sistema di movimentazione e controllo del ramo N/S per il sistema BIRALES

Lo scopo di questo documento è quello di descrivere la procedura dell’installazione del nuovo sistema di movimentazione delle antenne cilindrico paraboliche del ramo Nord/Sud del radiotelescopio “Croce del Nord”, studiato per venire incontro alle esigenze del programma “Space Surveillance and Tracking”, oltre a programmi scientifici quale la ricerca degli FRB. Oltre alla procedura di installazione, è indicata la lista del materiale necessario alla replicazione e i disegni costruttivi, e viene inoltre descritta la procedura di manutenzione