Facies characteristics and diversity in carbonate eolianites

Carbonate eolian dunes can form huge sand bodies along the coasts but are seldom described in the pre-Quaternary record. The study of more than 600 thin-sections collected in present-day, Holocene and Pleistocene dunes from Sardinia, Crete, Cyprus, Tunisia, Morocco, Australia and Baja California confirms that these deposits can be easily misinterpreted as shallow marine at core or thin-section scale. The classical eolian criteria (fine-grained and well-sorted sands) are exceptional in carbonate dunes because the diversity of shapes and densities of carbonate particles lowers the critical shear velocity of the sediment thus blurring the sedimentary structures. Wind carbonate deposits are mainly heterogeneous in size and often coarse-grained. The paucity of eolianites in the pre-Quaternary record could be due to misinterpretation of these deposits. The recognition should be based on converging sedimentological and stratigraphic elements at core scale, and diagenetic (vadose diagenesis, pedogenetic imprints) and petrographical (grain verticalization, scarcity of micritic envelopes, broken and/or reworked foraminifera) clues in thin-section. Bioclastic or oolitic grainstones showing evidence of vadose diagenesis or pedogenetic imprints, should always be suspected of having an eolian origi

A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS)

Objectives Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. Methods An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. Results The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions: 1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by . (reference to symptoms, signs, routine labs). 2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment. 3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics. The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. Conclusions The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.Identification of new causative genes in spinocerebellar degenerations by combination of whole genome scan, next-generation sequencing and biological validation in vitro and in vivoInfrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesEuropean Union’s Horizon 2020 research and innovation programm

Geology, geochemistry and earthquake history of Lō`ihi Seamount, Hawai`i

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Chemie der Erde - Geochemistry 66 (2006): 81-108, doi:10.1016/j.chemer.2005.09.002.A half century of investigations are summarized here on the youngest Hawaiian volcano, Lō`ihi Seamount. It was discovered in 1952 following an earthquake swarm. Surveying in 1954 determined it has an elongate shape, which is the meaning of its Hawaiian name. Lō`ihi was mostly forgotten until two earthquake swarms in the 1970’s led to a dredging expedition in 1978, which recovered young lavas. This led to numerous expeditions to investigate the geology, geophysics, and geochemistry of this active volcano. Geophysical monitoring, including a realtime submarine observatory that continuously monitored Lō`ihi’s seismic activity for three months, captured some of the volcano’s earthquake swarms. The 1996 swarm, the largest recorded in Hawai`i, was preceded by at least one eruption and accompanied by the formation of a ~300-m deep pit crater, renewing interest in this submarine volcano. Seismic and petrologic data indicate that magma was stored in a ~8-9 km deep reservoir prior to the 1996 eruption. Studies on Lō`ihi have altered conceptual models for the growth of Hawaiian and other oceanic island volcanoes and led to a refined understanding of mantle plumes. Petrologic and geochemical studies of Lō`ihi lavas showed that the volcano taps a relatively primitive part of the Hawaiian plume, producing a wide range of magma compositions. These compositions have become progressively more silica-saturated with time reflecting higher degrees of partial melting as the volcano drifts towards the center of the hotspot. Seismic and bathymetric data have highlighted the importance of landsliding in the early formation of an ocean island volcano. Lō`ihi’s internal structure and eruptive behavior, however, cannot be fully understood without installing monitoring equipment directly on the volcano. The presence of hydrothermal activity at Lō`ihi was initially proposed based on nontronite deposits on dredged samples that indicated elevated temperatures (31oC), and on the detection of water temperature, methane and 3He anomalies, and clumps of benthic micro-organisms in the water column over the volcano in 1982. Submersible observations in 1987 confirmed a low temperature system (15-30oC) prior to the 1996 formation of Pele’s Pit. The sulfide mineral assemblage (wurtzite, pyrrhotite, and chalcopyrite) deposited after the pit crater collapsed are consistent with hydrothermal fluids >250oC. Vent temperatures have decreased to ~60oC during the 2004 dive season indicating the current phase of hydrothermal activity may be waning.This work was supported by a NSF grant to M. Garcia (OCE 97-29894)

Genome-Wide Scan Identifies TNIP1, PSORS1C1, and RHOB as Novel Risk Loci for Systemic Sclerosis

Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10−5 were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10−8, OR = 0.69, 95% CI [0.60–0.79]; rs6457617, P = 1.14×10−7 and rs9275245, P = 1.39×10−7. Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10−5, OR = 1.36 [1.18–1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10−5) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10−10, OR:1.25), TNIP1 (P = 4.68×10−9, OR:1.31), and RHOB loci (P = 3.17×10−6, OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325

Génétique moléculaire et corrélations phénotype génotype des formes autosomiques récessives de maladie de Charcot Marie Tooth démyélinisante

La maladie de Charcot-Marie-Tooth (CMT) est une neuropathie sensitivomotrice héréditaire très hétérogène. Dans ce travail, nous nous sommes intéressés aux formes autosomiques récessives démyélinisantes de CMT (CMTAR). Dans un premier temps, nous avons montré l importance du phénotypage. Par la suite, avec une étude portant sur 34 familles avec un CMTAR démyélinisant et une consanguinité, nous avons recherché la fréquence des loci/gènes connus. Ceci nous a permis d élargir le spectre mutationnel des gènes testés et de montrer que plus de 50% des familles ne sont pas associées à ces gènes. Nous avons aussi étudié la répartition géographique des mutations identifiées. Ce travail nous a permis d établir ensuite des corrélations phénotypes génotypes. Nous avons participé à l'identification d'un nouveau gène, la Periaxine pour le CMT4F. Enfin, nous avons réalisé une cartographie primaire impliquant 26 familles et avons identifié plusieurs régions candidates qui sont en cours d'exploration.Charcot Marie Tooth (CMT) disease is a very heterogeneous inherited peripheral neuropathy. In this work, we were interested in autosomal recessive and demyelinating CMT. A linkage and sequencing study with known loci/genes was carried out in 34 families with demyelinating ARCMT and consanguineous marriages. In this study we enlarged the mutation spectrum in the know genes and observed geographic repartition of each locus/mutation. Loci frequencies were estimated and phenotype genotype correlations were established. We also showed that more than 50% of these families were not associated to one of the known loci/genes. Another part of this work was devoted to the gene identification strategies and allowed us to incriminate Periaxin (PRX) as the responsible gene for the CMT4F. Finally, we performed a genome scan in 26 families without linkage to the known loci and identified several regions of interest. The study of these loci is in progress.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF