Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Background: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders\u2014namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)\u2014and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD\u2013immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD

Glass conservation, an intricate matter: three situations, different answers but the same thread

Three case studies were analysed, the purpose of the conservation treatments was the same: they all need to improve their appearance to be displayed in exhibitions. The objects were: the Ennion cup from Civic Museums, Pavia, Italy for the traveling exhibition Ennion, the Metropolitan Museum of Art, New York in 2015 and The Corning Museum of Glass, Corning, New York in 2016. The square two-handled bottle with gladiators on the base from Acqui Terme (AL), Italy traveling to be exposed at the industrial glass fair Vitrum in Milan, followed by Antiquarium Alda Levi, Milan in 2015. Lastly, renaissance decorated vessels from the excavation of Padoa Santa Chiara Monastery for display at Restituzioni 2016 in the Gallerie d\u2019Italia, Milan

Una coppia di corni potori longobardi in vetro dallo scavo di lodi vecchio; l\u2019intervento conservativo dal prelievo al microscavo, alla ricostruzione

L\u2019intervento descritto riguarda due reperti longobardi rinvenuti durante lo scavo di Cascina Corte Bassa nel 2008 a Lodi Vecchio, si tratta di una coppia di corni potori gemelli in vetro azzurro con decorazioni applicate dello stesso colore e con filamenti spiraliformi in vetro bianco, i manufatti rappresentano una testimonianza molto importante e di particolare pregio per la relativa esiguit\ue0 di confronti. La tomba femminile dalla quale provengono \ue8 caratterizzata da un corredo molto ricco e anche questi oggetti, confermato l\u2019alto rango della sepoltura che fu probabilmente violata in antico. Dall\u2019analisi dello stato di conservazione dei recipienti vitrei al momento dello scavo si \ue8 ipotizzato che i corni potessero essere stati danneggiati anche dal calpestio durante le fasi di depredazione della sepoltura. I recipienti molto frammentati erano conservati in parte in situ, mentre varie porzioni e frammenti erano sparsi in pi\uf9 punti all\u2019interno dell\u2019area della tomba. Per preservare il pi\uf9 possibile gli oggetti in condizioni critiche, i tecnici della Soprintendenza sono intervenuti sullo scavo con un preconsolidamento e velinatura delle porzioni pi\uf9 danneggiate e fragili e con un prelievo in zolla dei nuclei principali. Questo intervento ha permesso nel 2013, quando si decise di sottoporli ad intervento di restauro di evitare la perdita di connessioni. L\u2019intervento conservativo \ue8 partito dalle porzioni rinvenute distaccate e non pi\uf9 in connessione con i recipienti, questo ha permesso di analizzare approfonditamente lo stato di conservazione dei reperti vitrei e di individuare la procedura pi\uf9 adatta per la ricostruzione dei manufatti. Si \ue8 evidenziato in generale un forte degrado del corpo vetroso. Il microscavo \ue8 iniziato dal corno conservato meglio, che manteneva ancora la sezione circolare, per poi separarli fisicamente appena possibile, per evitare che i frammenti si mescolassero. Il secondo manufatto in peggiori condizioni, era invece completamente schiacciato e maggiormente lacunoso. Il grado di estrema frammentazione ha portato a individuare strategie ben definite durante il microscavo che \ue8 proceduto distaccando gradualmente dalla terra piccole porzioni mappandole, e a mettere in atto le fasi conservative in parallelo. La particolare forma conica dei manufatti, la posizione ed estensione delle lacune hanno reso necessario progettare nel dettaglio la ricostruzione, lasciando delle sezioni di distacco per riuscire a procedere con le integrazioni. Nonostante il pessimo stato iniziale, grazie ai preconsolidamenti effettuati sullo scavo e al prelievo in zolla, \ue8 stato possibile ricostruire il profilo completo di entrambi i reperti e a restituirne la leggibilit\ue0. Le integrazioni effettuate con metodo diretto sono state realizzate con la stessa resina di tipo epossidico utilizzata per l\u2019incollaggio, per aumentare la stabilit\ue0 per uno dei due manufatti \ue8 stato costruito un supporto interno sagomato. Durante la fase operativa dell\u2019intervento \ue8 stato spesso necessario trovare un difficile compromesso tra minimo intervento e la sopravvivenza dei manufatti stessi rendendo applicabile solo parzialmente il criterio della reversibilit\ue0. L\u2019influenza della ricerca in questo campo a livello internazionale sposta l\u2019attenzione sull\u2019utilizzo di adesivi e integranti di natura acrilica in sostituzione alle epossidiche pi\uf9 comunemente usate in questo campo in Italia e sull\u2019applicazione di metodi integrativi indiretti in alternativa a quelli diretti ci porta a nuovi spunti di riflessione e alla possibilit\ue0 di individuare strategie conservative diverse

Personal non-commercial use only

ABSTRACT. Objective. To determine whether anti-peptidylarginine deiminase type 4 (PAD4) antibodies were present in first-degree relatives (FDR) of patients with rheumatoid arthritis (RA) in 2 indigenous North American populations with high prevalence of RA. Methods. Participants were recruited from 2 indigenous populations in Canada and the United States, including patients with RA (probands), their unaffected FDR, and healthy unrelated controls. Sera were tested for the presence of anti-PAD4 antibodies, anticyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF). HLA-DRB1 subtyping was performed and participants were classified according to number of shared-epitope alleles present. Results. Antibodies to PAD4 were detected in 24 of 82 (29.3%) probands; 2 of 147 (1.4%) relatives; and no controls (p &lt; 0.0001). Anti-CCP was present in 39/144 (27.1%) of the relatives, and there was no overlap between positivity for anti-CCP and PAD4 in the relatives. In RA patients, anti-PAD4 antibodies were associated with disease duration (p = 0.0082) and anti-CCP antibodies (p = 0.008), but not smoking or shared-epitope alleles. Conclusion. Despite a significant prevalence of anti-CCP in FDR, anti-PAD4 antibodies were almost exclusively found in established RA. The prevalence of anti-PAD4 antibodies in RA is similar to the prevalence described in other populations and these autoantibodies are associated with disease duration an

Anti-PAD4 in RA relatives Personal non-commercial use only. The Journal of Rheumatology-CCP in RA

ABSTRACT. Objective. To determine whether anti-peptidylarginine deiminase type 4 (PAD4) antibodies were present in first-degree relatives (FDR) of patients with rheumatoid arthritis (RA) in 2 indigenous North American populations with high prevalence of RA. Methods. Participants were recruited from 2 indigenous populations in Canada and the United States, including patients with RA (probands), their unaffected FDR, and healthy unrelated controls. Sera were tested for the presence of anti-PAD4 antibodies, anticyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF). HLA-DRB1 subtyping was performed and participants were classified according to number of shared-epitope alleles present. Results. Antibodies to PAD4 were detected in 24 of 82 (29.3%) probands; 2 of 147 (1.4%) relatives; and no controls (p &lt; 0.0001). Anti-CCP was present in 39/144 (27.1%) of the relatives, and there was no overlap between positivity for anti-CCP and PAD4 in the relatives. In RA patients, anti-PAD4 antibodies were associated with disease duration (p = 0.0082) and anti-CCP antibodies (p = 0.008), but not smoking or shared-epitope alleles. Conclusion. Despite a significant prevalence of anti-CCP in FDR, anti-PAD4 antibodies were almost exclusively found in established RA. The prevalence of anti-PAD4 antibodies in RA is similar to the prevalence described in other populations and these autoantibodies are associated with disease duration an