Emerging patterns of genetic overlap across autoimmune disorders.

Most of the recently identified autoimmunity loci are shared among multiple autoimmune diseases. The pattern of genetic association with autoimmune phenotypes varies, suggesting that certain subgroups of autoimmune diseases are likely to share etiological similarities and underlying mechanisms of disease. In this review, we summarize the major findings from recent studies that have sought to refine genotype-phenotype associations in autoimmune disease by identifying both shared and distinct autoimmunity loci. More specifically, we focus on information from recent genome-wide association studies of rheumatoid arthritis, ankylosing spondylitis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and inflammatory bowel disease. Additional work in this area is warranted given both the opportunity it provides to elucidate pathogenic mechanisms in autoimmunity and its potential to inform the development of improved diagnostic and therapeutic tools for this group on complex human disorders

An Economic Model of Fair Use

The doctrine of fair use allows limited copying of creative works based on the rationale that copyright holders would consent to such uses if bargaining were possible. This paper develops a formal model of fair use in an effort to derive the efficient legal standard for applying the doctrine. The model interprets copies and originals as differentiated products and defines fair use as a threshold separating permissible copying from infringement. The analysis highlights the role of technology in shaping the efficient standard. Discussion of several key cases illustrates the applicability of the model.Fair use, Copyright law, Technological improvement

The Relevance of Tag along Rights and Identity of Controlling Shareholders for the Price Spreads between Dual-Class Shares: the Brazilian Case

This paper analyzes the determinants of the differential pricing of equity classes (the so-called dual-class premium [DCP]) in Brazil from 1995 to 2006 with a focus on two specific corporate governance aspects: i) the granting of tag along rights, a mandatory bid rule that extends to minority shareholders the right to sell their shares in case of a control transfer; and ii) the identity of the controlling shareholders, with an emphasis on family control. We examined 87 Brazilian listed firms throughout the period, resulting in a sample of 3,287 observations. We found empirical evidence that changes in Corporate Law decreased (increased) the advantage of voting shares in terms of tag along rights reduced (incremented) DCP. However, we did not find empirical evidence that the voluntary granting of tag along rights altered DCP. We also found evidence suggesting that family control is positively associated with DCP level. Overall, our results indicate that regulations regarding shareholders’ rights and the identity of controlling shareholders are the two relevant corporate governance variables for DCP level in environments characterized by concentrated ownership structures

Targeting RyR Activity Boosts Antisense Exon 44 and 45 Skipping in Human DMD Skeletal or Cardiac Muscle Culture Models.

Systemic delivery of antisense oligonucleotides (AO) for DMD exon skipping has proven effective for reframing DMD mRNA, rescuing dystrophin expression, and slowing disease progression in animal models. In humans with Duchenne muscular dystrophy treated with AOs, low levels of dystrophin have been induced, and modest slowing of disease progression has been observed, highlighting the need for improved efficiency of human skipping drugs. Here, we demonstrate that dantrolene and Rycals S107 and ARM210 potentiate AO-mediated exon skipping of exon 44 or exon 45 in patient-derived myotube cultures with appropriate mutations. Further, dantrolene is shown to boost AO-mediated exon skipping in patient-derived, induced cardiomyocyte cultures. Our findings further validate the ryanodine receptors (RyR) as the likely target responsible for exon skip boosting and demonstrate potential applicability beyond exon 51 skipping. These data provide preclinical support of dantrolene trial as an adjuvant to AO-mediated exon-skipping therapy in humans and identify a novel Rycal, ARM210, for development as a potential exon-skipping booster. Further, they highlight the value of mutation-specific DMD culture models for basic discovery, preclinical drug screening and translation of personalized genetic medicines

Markers of B-lymphocyte activation are elevated in patients with early rheumatoid arthritis and correlated with disease activity in the ESPOIR cohort

International audienceINTRODUCTION: Little is known about systemic B-cell activation in early rheumatoid arthritis (RA). We therefore evaluated the serum levels of markers of B-cell activation in patients included in the ESPOIR early arthritis cohort. METHODS: In the ESPOIR early arthritis cohort (at least 2 swollen joints for more than 6 weeks but less than 6 months), 710 patients were assessed at 1 year and either met the 1987 American College of Rheumatology criteria for RA (n = 578) or had undifferentiated arthritis (n = 132). Baseline serum samples of patients naïve to corticosteroid and disease-modifying antirheumatic drug treatment were assessed for beta2-microglobulin, IgG, IgA, IgM, immunoglobulin free light chains of immunoglobulins, and B-cell activating factor of the tumor necrosis factor family (BAFF). The BAFF gene 871T>C polymorphism was genotyped in all patients. RESULTS: All markers of B-cell activation except BAFF and IgM were significantly higher in patients with early RA than those with undifferentiated arthritis. Anti-cyclic citrullinated peptide (anti-CCP) and beta2-microglobulin were associated with a diagnosis of early RA in the multivariate analysis. Markers of B-cell activation, except BAFF, were associated with disease activity, rheumatoid factor and anti-CCP secretion. The BAFF gene polymorphism was not associated with early RA. CONCLUSIONS: Markers of B-cell activation are elevated in patients with early RA, compared with undifferentiated arthritis, independently of any systemic increase in BAFF secretion, and correlate with disease activity. This study sheds new light on the early pathogenic role of B-lymphocytes in RA and suggests that targeting them might be a useful therapeutic strategy in early RA

B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren's syndrome

B cell-activating factor (BAFF) has a key role in promoting B-lymphocyte activation and survival in primary Sjögren's syndrome (pSS). The cellular origin of BAFF overexpression in salivary glands of patients with pSS is not fully known. We investigated whether salivary gland epithelial cells (SGECs), the main targets of autoimmunity in pSS, could produce and express BAFF. We used quantitative RT-PCR, ELISA and immunocytochemistry in cultured SGECs from eight patients with pSS and eight controls on treatment with IL-10, tumor necrosis factor α (TNF-α), IFN-α and IFN-γ. At baseline, BAFF expression in SGECs was low in pSS patients and in controls. Treatment with IFN-α, IFN-γ and TNF-α + IFN-γ increased the level of BAFF mRNA in pSS patients (the mean increases were 27-fold, 25-fold and 62-fold, respectively) and in controls (mean increases 19.1-fold, 26.7-fold and 17.7-fold, respectively), with no significant difference between patients and controls. However, in comparison with that at baseline, stimulation with IFN-α significantly increased the level of BAFF mRNA in SGECs of pSS patients (p = 0.03) but not in controls (p = 0.2), which suggests that SGECs of patients with pSS are particularly susceptible to expressing BAFF under IFN-α stimulation. Secretion of BAFF protein, undetectable at baseline, was significantly increased after IFN-α and IFN-γ stimulation both in pSS patients (40.8 ± 12.5 (± SEM) and 47.4 ± 18.7 pg/ml, respectively) and controls (24.9 ± 8.0 and 9.0 ± 3.9 pg/ml, respectively), with no significant difference between pSS and controls. Immunocytochemistry confirmed the induction of cytoplasmic BAFF expression after stimulation with IFN-α and IFN-γ. This study confirms the importance of resident cells of target organs in inducing or perpetuating autoimmunity. Demonstrating the capacity of SGECs to express and secrete BAFF after IFN stimulation adds further information to the pivotal role of these epithelial cells in the pathogenesis of pSS, possibly after stimulation by innate immunity. Our results suggest that an anti-BAFF therapeutic approach could be particularly interesting in pSS

The response to whistleblowing by regulators: a practical perspective

The Public Interest Disclosure Act 1998 provides protection for whistleblowers; it does not place statutory obligations on regulators to act in response to whistleblowing concerns. Using Freedom of Information requests as a research methodology, this paper seeks to examine how whistleblowing is approached by regulators and what happens when a whistleblowing disclosure is made. Forty-eight national regulators in a variety of fields and 408 county, district and unitary local authorities with responsibility for the regulation of food were contacted. The paper begins by considering the importance of whistleblowing disclosures and how they are protected in PIDA. The examination of the law reveals that several organisations with important regulatory functions are not prescribed, and this has the potential to create inconsistencies in the protection of whistleblowers. The bulk of the paper examines the results of the Freedom of Information requests. By examining the results of these requests, it was possible to show that there are a number of inconsistencies in the way in which regulatory agencies handle concerns. Several changes to practice are suggested in order to ensure that the whistleblowers receive appropriate treatment and that the concerns that they express can be properly addressed