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International audience; Aims: We aimed at describing outcomes and predictors of cardiac avulsion or tear (CA/T) with tamponade and vascular avulsion or tear (VA/T) after transvenous lead extraction (TLE) in the ESC-EHRA European Lead Extraction ConTRolled (ELECTRa) registry.Methods and results: A total of 3555 consecutive patients of whom 3510 underwent TLE at 73 centres in 19 European countries were enrolled. Among 58 patients (1.7%) with procedure-related major complications, 49 (84.5%) patients (30 CA/T and 19 VA/T) presented cardiovascular complications requiring pericardiocentesis, chest tube positioning and/or surgical repair. The mortality was 20% in patients with tamponade due to CA/T and 31.6% in patients with VA/T. Pericardiocentesis as first manoeuvre followed by rescue surgical repair was highly effective in case of CA/T (93.8%). At multivariate analysis, CA/T with tamponade was more common in RIATA lead extraction, female patients, leads with a mean dwelling time more than 10 years, and when ≥3 leads were extracted or multiple sheaths required. Occlusion or critical stenosis of superior venous access and the leads mean dwelling time more than 10 years were independent predictors for VA/T, while mechanical dilatation was an independent predictor of a lower incidence of this complication as compared to the use of powered sheaths.Conclusions: In the ELECTRa registry, RIATA lead extraction and superior venous access occlusion/thrombosis are two new independent predictors for cardiac tamponade and major vascular complications, respectively. The use of mechanical sheaths seems to be associated with a lower incidence of VA/T. A strategy of pericardiocentesis followed by a rescue surgical approach seems to be reasonable in order to treat a CA/T with tamponade.

International audience; Today, ethno-pharmacology is a very important resource in order to discover new therapies for the current diseases. Moreover, another good justification for the ethno-pharmacological approach is to obtain new, effective, less expensive and simple therapies, limiting at the same time the cost of pharmaceutical research. Two major anti-malarial drugs widely used today, i.e. quinine and artemisinin, came respectively from Peruvian and Chinese ancestral treatments reported in the traditional medicines. In this contest, there is an urgent need for the discovery of new drugs, due to the critical epidemiological situation of this disease and to the growth of resistances. In Mali, malaria and liver diseases remain one of the leading public health problems. Many medicinal plants are often used, in local traditional medicine, for the treatment at the same time of malaria and liver diseases, including hepatic syndromes, jaundice, hepatitis and other hepatic disorders. Moreover, in the local language Bamanan, the word "Sumaya" is used both for malaria and some liver diseases. In addition, we noted that some of the improved traditional phytomedicines produced by the Department of Traditional Medicine are prescribed by modem doctors both for malaria and liver diseases. In this review, pharmacological, toxicological and phytochemical data on Argemone mexicana L. (Papaveraceae), Cochlospermum tinctorium Pen. ex A. Rich (Cochlospermaceae), Combretum micranthum G.Don (Combretaceae), Entada africana Guillet Pen. (Mimosaceae), Erythrina senegalensis A. DC (Fabaceae), Mitragyna inermis (Willd) Kuntze (Rubiaceae), Nauclea latifolia Smith syn. Sarcocephalus latifolius (Smith) Bruce (Rubiaceae), Securidaca longepedunculata Fresen (Polygalaceae), Trichilia emetica Vahl. (Meliaceae), and Vernonia colorata (Willd) Drake (Asteraceae) are reported. Some of the collected data could be used to improve the actual herbal drugs and to propose new phytomedicines for the management of malaria and liver diseases.

Contains fulltext : 96445.pdf (Publisher’s version ) (Closed access) BACKGROUND: Increased expression of type I IFN genes, also referred to as an IFN signature, has been detected in various autoimmune diseases including rheumatoid arthritis (RA). Interferon regulatory factors, such as IRF5, coordinate type I IFN expression. Multiple IRF5 variants were suggested as autoimmunity susceptibility factors. OBJECTIVE: As the linkage proof remains important to establish fully any genetic RA susceptibility factor, the authors took advantage of the largest reported European trio family resource dedicated to RA to test for linkage IRF5 and performed a genotype-phenotype analysis. METHODS: 1140 European Caucasian individuals from 380 RA trio families were genotyped for IRF5 rs3757385, rs2004640 and rs10954213 single nucleotide polymorphisms (SNP). RESULTS: Single marker analysis provided linkage evidence for each IRF5 SNP investigated. IRF5 linked to RA with two haplotypes: the CTA risk haplotype 'R' (transmission (T)=60.6%, p=23.1x10(-5)) and the AGG protective haplotype 'P' (T=39.6%, p=0.0015). Linkage was significantly stronger in non-erosive disease for both IRF5 R and P haplotypes (T=73.9%, p=4.20x10(-5) and T=19.6%, p=3.66x10(-5), respectively). Multivariate logistic regression analysis found IRF5 linked to RA independently of the rheumatoid factor status. IRF5 RR and PP haplotypic genotypes were associated with RA, restricted to the non-erosive phenotype: p=1.68x10(-4), OR 4.80, 95% CI 2.06 to 11.19; p=0.003, OR 0.17, 95% CI 0.05 to 0.57, respectively. CONCLUSION: This study provides the 'association and linkage proof' establishing IRF5 as a RA susceptibility gene and the identification of a genetic factor that seems to contribute to the modulation of the erosive phenotype. Further studies are warranted to clarify the role of IRF5 in RA and its subphenotypes.

Contains fulltext : 71178.pdf (Publisher’s version ) (Closed access) OBJECTIVE: We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. METHODS: A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. RESULTS: We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50). CONCLUSION: Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.

International audience; Objectives: The study of polymorphisms of genes differentially expressed may lead to the identification of putative causal genetic variants in multifactorial diseases such as rheumatoid arthritis (RA). Based on preceding transcriptomic results, we genotyped 10 single nucleotide polymorphisms (SNPs) belonging to six genes (S100A8, RNASE2, PGLYRP1, RUNX3, IL2RB, and LY96) showing the highest fold change (\backslashtextgreater 1.9) when level of expression was compared between RA patients and controls. These SNPs were then analysed to evaluate their role in RA. Method: The relationship between gene expression and genotypes of SNPs was first investigated by Kruskal-Wallis and Mann-Whitney tests in RA patients and controls. The genetic association of these SNPs with RA were then analysed using family-based association tests in trio families. Results: We found that RNASE2 gene expression was related to rs2013109 genotypes in 14 RA patients (p = 0.030). The association study in a discovery sample of 200 French trio families revealed a significant association with RA for one SNP, PGLYRP1-rs2041992 (p = 0.019); this association was stronger in trios where RA patients carried the HLA-DRB1 shared epitope (SE) (p = 0.003). However, this association was not found in a replication sample of 240 European trio families (p = 0.6). Conclusions: Family-based association tests did not reveal an association between RA and any SNP of the candidate genes tested. However, RNASE2 gene expression was differentially expressed in RA patients considering a sequence polymorphism. This result led us to highlight the potential disease-specific regulation for this candidate gene in RA. © 2015 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation.

In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p

International audience; Autoantibody production is genetically controlled and anti-citrullinated protein/peptide antibodies (ACPA) are not an exception to the rule. ACPA are highly specific markers of rheumatoid arthritis (RA) and are also associated with a more severe disease course. The production of ACPA is almost invariably observed in HLA-shared epitope (SE) positive patients. The DRB1 alleles sharing SE are those conferring susceptibility to RA. SE alleles behave like immune response genes, controlling both the specificity and the amount of ACPA produced. These data suggest a role of SE in the presentation of citrullinated antigens. The ability of SE alleles to bind selectively to citrullinated sequences as compared to the native counterparts has been demonstrated in the case of peptides derived from several joint associated proteins (vimentin, fibrinogen and cartilage intermediate-layer protein). On the contrary, EBV-derived citrullinated peptides do not display a biologically relevant binding to SE alleles even if the immune response to VCPs is under the genetic control of these alleles (namely *0401 and *0404). Thus, the presentation of citrullinated epitopes does not represent the only molecular mechanisms underlying the HLA-DRB1 effect on ACPA production.

The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF + ). No interaction was shown with HLA-DRB1 , the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of ≈5% on average and large variations of population allele frequencies (2.1–15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22–1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 “trio” families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF + families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF + RA for the French Caucasian population and the susceptibility genotype ( 1858T / T or T / C ) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2–2.8)]. In conclusion, we provided the linkage proof for the PTPN22–1858T allele and RF + RA. With diabetes and RA, PTPN22 is therefore a “linkage-proven” autoimmunity gene. PTPN22 accounting for ≈1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.

Contains fulltext : 81416.pdf (Publisher’s version ) (Open Access) INTRODUCTION: A candidate gene approach, in a large case-control association study in the Dutch population, has shown that a 480 kb block on chromosome 4q27 encompassing KIAA1109/Tenr/IL2/IL21 genes is associated with rheumatoid arthritis. Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure. Therefore, our aim was to test this association in populations of European origin by using a family-based approach. METHODS: A total of 1,302 West European white individuals from 434 trio families were genotyped for the rs4505848, rs11732095, rs6822844, rs4492018 and rs1398553 polymorphisms using the TaqMan Allelic discrimination assay (Applied Biosystems). The genetic association analyses for each SNP and haplotype were performed using the Transmission Disequilibrium Test and the genotype relative risk. RESULTS: We observed evidence for association of the heterozygous rs4505848-AG genotype with rheumatoid arthritis (P = 0.04); however, no significance was found after Bonferroni correction. In concordance with previous findings in the Dutch population, we observed a trend of undertransmission for the rs6822844-T allele and rs6822844-GT genotype to rheumatoid arthritis patients. We further investigated the five SNP haplotypes of the KIAA1109/Tenr/IL2/IL21 gene region. We observed, as described in the Dutch population, a nonsignificant undertransmission of the AATGG haplotype to rheumatoid arthritis patients. CONCLUSIONS: Using a family-based study, we have provided a trend for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in populations of European descent. Nevertheless, we failed to replicate a significant association of this region in our rheumatoid arthritis family sample. Further investigation of this region, including detection and testing of all variants, is required to confirm rheumatoid arthritis association.