7,158 research outputs found

    Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia implicates an antigen-driven response.

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    Although much has been learned about the molecular basis of immunoglobulin M (IgM) rheumatoid factors (RFs) in healthy individuals and in patients with mixed cryoglobulinemia and rheumatoid arthritis, little is known about the genetic origins of the potentially pathogenic IgG RFs in the inflamed rheumatoid synovia of patients. Recently, we generated from unmanipulated synovium B cells several hybridomas that secreted self-associating IgG RFs. To delineate the genetic origins of such potentially pathogenic RFs, we adapted the anchored polymerase chain reaction to rapidly clone and characterize the expressed Ig V genes for the L1 and the D1 IgG RFs. Then, we identified the germline counterparts of the expressed L1 IgG RF V genes. The results showed that the L1 heavy chain was encoded by a Vh gene that is expressed preferentially during early ontogenic development, and that is probably located within 240 kb upstream of the Jh locus. The overlap between this RF Vh gene and the restricted fetal antibody repertoire is reminiscent of the natural antibody-associated Vh genes, and suggests that at least part of the "potential pathogenic" IgG RFs in rheumatoid synovium may derive from the "physiological" natural antibody repertoire in a normal immune system. Indeed, the corresponding germline Vh gene for L1 encodes the heavy chain of an IgM RF found in a 19-wk-old fetal spleen. Furthermore, the comparisons of the expressed RF V genes and their germline counterparts reveal that the L1 heavy and light chain variable regions had, respectively, 16 and 7 somatic mutations, which resulted in eight and four amino acid changes. Strikingly, all eight mutations in the complementarity determining regions of the V gene-encoded regions were replacement changes, while only 6 of 11 mutations in the framework regions caused amino acid changes. Combined with L1's high binding affinity toward the Fc fragment, these results suggest strongly that the L1 IgG RF must have been driven by the Fc antigen

    Preventing Advanced Persistent Threats in Complex Control Networks

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    An Advanced Persistent Threat (APT) is an emerging attack against Industrial Control and Automation Systems, that is executed over a long period of time and is difficult to detect. In this context, graph theory can be applied to model the interaction among nodes and the complex attacks affecting them, as well as to design recovery techniques that ensure the survivability of the network. Accordingly, we leverage a decision model to study how a set of hierarchically selected nodes can collaborate to detect an APT within the network, concerning the presence of changes in its topology. Moreover, we implement a response service based on redundant links that dynamically uses a secret sharing scheme and applies a flexible routing protocol depending on the severity of the attack. The ultimate goal is twofold: ensuring the reachability between nodes despite the changes and preventing the path followed by messages from being discovered.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

    Delay in Retreatment of Helicobacter pylori Infection Increases Risk of Upper Gastrointestinal Bleeding

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    Background & Aims: Little is known about risk of upper gastrointestinal bleeding (UGIB) in patients failed by Helicobacter pylori eradication therapy. We investigated the effects of different time until retreatment, after failure of initial H. pylori eradication therapy, on subsequent risk of UGIB. / Methods: We performed a territory-wide retrospective cohort study of 70,518 patients with H pylori infection who had received their first course of clarithromycin-based triple therapy from January 2003 through December 2012 in Hong Kong. Patients who required retreatment after failed initial therapy (n = 8330, 11.8%) were categorized based on time between initial and final H pylori eradication (3 months or less, 3–12 months, and more than 12 months). We collected clinical data from 30 days after prescription of the last course of H pylori therapy until hospitalization for non-variceal UGIB, death, or the end of the study (30 Jun 2016; median follow-up time, 7.65 years). The primary outcome was difference in development UGIB (determined from ICD-9 codes) between patients who required retreatment and those who did not (reference group). / Results: Compared with the reference group, patients who required retreatment had an overall higher risk of UGIB, even after last eradication therapy (adjusted hazard ratio (HR), 1.50, 95% CI, 1.34–1.69). There was a progressive increase in risk of UGIB with longer time from initial until final eradication therapy: hazard ratio for time less than 3 months, 1.16; 95% CI, 0.88–1.54, hazard ratio for time 3–12 months, 1.35; 95% CI, 1.07–1.69, and hazard ratio for time more than 12 months, 1.68; 95% CI, 1.46–1.94 (P for trend = .038). / Conclusion: In a retrospective study of patients in Hong Kong, we found that those failed by initial H pylori eradication have an increased risk of UGIB, compared to patients who responded to the initial therapy. Risk increased progressively with longer time until retreatment. Early retreatment within 3 months should be considered to minimize subsequent UGIB risk

    Metformin Use and Gastric Cancer Risk in Diabetic Patients After Helicobacter pylori Eradication

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    Background: Although prior studies showed metformin could reduce gastric cancer (GC) risk in patients with diabetes mellitus (DM), they failed to adjust for Helicobacter pylori infection and glycemic control. We aimed to investigate whether metformin reduced GC risk in H. pylori -eradicated diabetic patients and its association with glycemic control. Methods: This was a territory-wide cohort study using hospital registry database, recruiting all diabetic patients who were prescribed clarithromycin-based triple therapy for H. pylori infection from 2003 to 2012. Subjects were observed from H. pylori therapy prescription until GC diagnosis, death or end of study (December 2015). Exclusion criteria included GC diagnosed within first year of H. pylori therapy, prior history of GC or gastrectomy, and failure of H. pylori eradication. The hazard ratio (HR) of GC with metformin (defined as at least 180-day use) was estimated by Cox model with propensity score adjustment for covariates (age, sex, comorbidities, medications [including insulin], and time-weighted average hemoglobin A1c [HbA1c]). All statistical tests were two-sided. Results: During a median follow-up of 7.1 years (IQR:4.7–9.8), 37 (0.51%) of 7,266 diabetic patients developed GC at a median age of 76.4 years (IQR: 64.8–81.5 years). Metformin use was associated with a reduced GC risk (adjusted HR:0.49; 95% CI:0.24–0.98). There was a trend towards a lower GC risk with increasing duration (ptrend =0.01) and dose of metformin (ptrend=0.02) HbA1c level was not an independent risk factor for GC. Conclusions: Metformin use was associated with a lower GC risk among H. pylori -eradicated diabetic patients in a duration- and dose-response manner, which was independent of HbA1c level

    Statins Were Associated with a Reduced Gastric Cancer Risk in Patients with Eradicated Helicobacter Pylori Infection: A Territory-Wide Propensity Score Matched Study

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    BACKGROUND: Individuals may still develop gastric cancer even after Helicobacter pylori eradication. We aimed to investigate statin effect on gastric cancer development in H. pylori-eradicated subjects. METHODS: All adult subjects who were prescribed clarithromycin-based triple therapy between 2003 and 2012 were identified in this retrospective cohort study utilizing a territory-wide electronic healthcare database. Patients were observed from index date of H. pylori therapy, and censored at gastric cancer diagnosis, death, or December 2015 (study end date). Statin use was defined as ≥180-day use after index date. Exclusion criteria included gastric cancer diagnosed within the first year after index date, previous gastric cancer or gastrectomy, and H. pylori treatment failure. Subdistribution hazard ratio (SHR) of gastric cancer with statins was calculated by competing risk regression with propensity score (PS) analysis matching 19 variables (age, sex, comorbidities, and other drug usage, including proton pump inhibitors, nonsteroidal anti-inflammatory drugs, aspirin, cyclooxygenase-2 inhibitors, and metformin). RESULTS: During a median follow-up of 7.6 years (interquartile range = 5.1-10.3), 169 (0.27%) of 63,605 patients developed gastric cancer at an incidence rate of 3.5 per 10,000 person-years. Among 22,870 PS-matched subjects, statins were associated with a lower gastric cancer risk (SHR = 0.34; 95% confidence interval, 0.19-0.61), in a duration- and dose-response manner (Ptrend < 0.05). CONCLUSIONS: Statins were associated with a lower gastric cancer risk in a duration- and dose-response manner among H. pylori-eradicated patients. IMPACT: This study provides evidence on the additional benefits of statins as chemopreventive agents against gastric cancer among H. pylori-eradicated patients

    Your Proof Fails? Testing Helps to Find the Reason

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    Applying deductive verification to formally prove that a program respects its formal specification is a very complex and time-consuming task due in particular to the lack of feedback in case of proof failures. Along with a non-compliance between the code and its specification (due to an error in at least one of them), possible reasons of a proof failure include a missing or too weak specification for a called function or a loop, and lack of time or simply incapacity of the prover to finish a particular proof. This work proposes a new methodology where test generation helps to identify the reason of a proof failure and to exhibit a counter-example clearly illustrating the issue. We describe how to transform an annotated C program into C code suitable for testing and illustrate the benefits of the method on comprehensive examples. The method has been implemented in STADY, a plugin of the software analysis platform FRAMA-C. Initial experiments show that detecting non-compliances and contract weaknesses allows to precisely diagnose most proof failures.Comment: 11 pages, 10 figure
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