1,720,974 research outputs found
PROFILO FUNZIONALE DI PAZIENTI CON LUPUS ERITEMATOSO SISTEMICO E CORRELAZIONE CON I MECCANISMI COINVOLTI IN DIVERSE FORME MONOGENICHE DELLA MALATTIA
Full text linkIl lupus eritematoso sistemico (LES) rappresenta una complessa patologia multisistemica, all’interno del cui universo si possono spesso individuare eventi patogenetici diversi ma riconducibili a quadri clinici sovrapponibili. Una possibile caratteristica comune può considerarsi l’utilizzo improprio della risposta immunitaria agli acidi nucleici. Per comprendere il ruolo di questo tipo di risposta, ci siamo concentrati sullo studio delle Interferonopatie di tipo I, un gruppo di malattie monogeniche di recente definizione, causate da alterazioni nel meccanismo di riconoscimento e metabolismo degli acidi nucleici e caratterizzate da un’aberrante stimolazione della via degli interferoni di tipo I. Queste malattie sono clinicamente eterogenee ma mostrano alcune sovrapposizioni con il lupus, la sindrome di Aicardi-Goutières ed alcune infezioni virali congenite. Lo studio di questi modelli monogenici risulta di grande interesse soprattutto per indirizzare il trattamento terapeutico verso l’utilizzo di farmaci attivi a livello della via dell’interferone.
Nel nostro laboratorio è stato descritto il caso di Simone, nato con una grave epatopatia risoltasi poi spontaneamente, che ha successivamente sviluppato alcuni sintomi lupus-like quali artrite, glomerulonefrite, lipodistrofia, anticorpi anti-DNA e geloni. Le analisi genetiche condotte per le più comuni malattie auto-infiammatorie sono risultate negative, e solo in seguito ad analisi di esoma è stata identificata una nuova mutazione nel gene DNASI2. Questo gene codifica per un’endonucleasi lisosomiale, il cui deficit porta alla mancata digestione degli acidi nucleici, che persistono all’interno della cellula e causano la continua attivazione della via interferonica. Esistono infatti numerose evidenze a dimostrazione del ruolo causale della DNAsi2 nella patologia di Simone, e, insieme alle prove funzionali eseguite grazie alla collaborazione con Yanick Crow, che ha descritto la stessa malattia in una seconda famiglia, abbiamo dimostrato che il difetto di DNAsi2 rappresenta una nuova interferonopatia monogenica. In seguito a questa conoscenza, è stata rimodulata la terapia con farmaci indirizzati verso il meccanismo patogenetico: l’inibitore di JAK1/2, Ruxolitinib, è stato utilizzato in combinazione con due antimalarici, Mepacrina ed Idrossiclorochina, portando ad un generale miglioramento della qualità di vita di Simone.
Durante questo studio, inoltre, sono stati messi a punto due strumenti che risultano interessanti per la valutazione e l’ottimizzazione di trattamenti attivi nella via interferonica: l’analisi della signature interferonica (SI), che misura nel sangue periferico l’espressione dei geni indotti dall’interferone, permettendo di capire se ci troviamo in presenza di un’alterazione interferonica e quindi di un’interferonopatia, ed il test di infezione di fibroblasti con E. coli, attraverso cui si può valutare l’attivazione della via in seguito ad un sovraccarico di DNA batterico.
Considerando le conoscenze acquisite durante questo studio, e la crescente disponibilità di farmaci attivi a livello della via interferonica, abbiamo condotto uno screening con SI per identificare altri soggetti con patologie dipendenti dall’eccesso di risposta interferonica. La nostra proposta si riassume in una traccia di “protocollo diagnostico terapeutico assistenziale” (PDTA) per lo studio delle interferonopatie all’interno dell’IRCCS Burlo Garofolo
Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain
Full text linkMore and more findings suggest that neurological disorders could have an immunopathological cause. Thus, immune-targeted therapies are increasingly proposed in neurology (even if often controversial), as anakinra, inhibiting IL-1 for febrile inflammatory illnesses, and JAK inhibitors for anti-interferons treatment. Precision medicine in neurology could be fostered by a better understanding of the disease machinery, to develop a rational use of immuno-modulators in clinical trials. In this review, we focus on monogenic disorders with neurological hyper-inflammation/autoimmunity as simplified “models” to correlate immune pathology and targeted treatments. The study of monogenic models yields great advantages for the elucidation of the pathogenic mechanisms that can be reproduced in cellular/animal models, overcoming the limitations of biological samples to study. Moreover, monogenic disorders provide a unique tool to study the mechanisms of neuroinflammatory and autoimmune brain damage, in all their manifestations. The insight of clinical, pathological, and therapeutic aspects of the considered monogenic models can impact knowledge about brain inflammation and can provide useful hints to better understand and cure some neurologic multifactorial disorders
Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs
Full text linkThe story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also known as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway leading from the sensing of cytoplasmic nucleic acids to the production of type I interferons. This pathway is a fundamental mechanism of host defence, since it is able to detect microbial DNA and induce the type I interferon-mediated immune response. Of note, genetic defects in the degradation of nucleic acids lead to inappropriate cGAS-STING activation and inflammation. These disorders, called type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials. We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and likely multifactorial disorders characterised by interferon inflammation, such as Systemic Lupus Erythematosus
Study on mupirocin treatment in cutaneous lupus erythematosus: comment on the article by Abernathy-Close et al
No full textAbernathy-Close et al1 provide a valuable contribution to theunderstanding of therapy for cutaneous lupus erythematosus(CLE) through their proof-of-concept study examining the effectsof mupirocin, a topical antibiotic, on inflammatory pathways withinCLE lesions. Their data indicate a correlation between reducedStaphylococcus aureus bacterial load and a subsequent declinein local inflammation, as well as decreased expression of inflam-matory genes, .particularly those related to type I interferon (IFN)signaling. These findings highlight the pivotal role of the skinmicrobiome in influencing immune responses and advancingtreatment options for lupus-associated skin lesion
A toddler with an unusually severe polyarticular arthritis and a lung involvement: a case report
Full text linkBACKGROUND: COPA syndrome is a rare hereditary inflammatory disease caused by mutations in the gene encoding the coatomer protein subunit alpha, causing excessive production of type I interferon. This case is a reminder for the general paediatrician, highlighting the relevance of the association between arthritis and lung involvement in toddlers. CASE PRESENTATION: We report the case of a 2-year-old girl with intermittent limping and joint pain. Her family history was relevant for a Still disease with lung involvement in the mother. Physical examination showed moderate wrist swelling. Laboratory findings on admission showed an increase in inflammatory markers, positive rheumatoid factor, antibodies antinuclear antibody (ANA) and cyclic citrullinated peptide (anti-CCP). Wrists’ ultrasound documented synovial thickening, and chest X-rays showed an unexpected severe interstitial pneumopathy. Genetic testing confirmed the diagnosis of a heterozygous mutation of the COPA gene in c.841C > T (p.R281W). Janus kinase treatment was started (baricitinib, 4 mg daily per os) with a remarkable improvement in limping and joint pain after two weeks. CONCLUSIONS: In cases of recurrent arthritis with family history and multiple involvement organs, a genetic disorder should be suspected and genetic testing should be performed. Furthermore, this case suggests that therapy with jak inhibitors may be effective and safe in interferonopathies
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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