Représentations et fonctions de l'objet-livre dans les enluminures du Paradis du ms Yates Thompson 36

Caractéristique propre au Paradis enluminé par Giovanni di Paolo, absente des enluminures de l'Enfer et du Purgatoire, la représentation de l'objet livre revient dans pas moins de dix enluminures distribuées entre les chants 5 et 28 du Paradis. L'enquête porte sur ce processus de mise en abyme et en démontre le potentiel hexégétique. Le volume, souvent les volumes (une seule enluminure peut contenir jusqu'à sept livres représentés), correspondent aux textes (théologiques, juridiques) mentionnés par Dante dans les vers du grand poème. Toujours chargés de connotations positives, les manuscrits véhiculent le savoir et la sagesse morale promus par Dante. Ils sont en outre un objet de transition, culturelle et esthétique : narrativement reliés aux figures médiévales (Justinien, Denys, Isidore, …), ils exaltent l'appréciation du manuscrit typique de l'humanisme et de la Bibliothèque Alphonsine. En somme, concentrer le regard et l'analyse sur la présence de l'objet livre au sein des enluminures, elles-mêmes insérées dans le manuscrit Yates Thompson 36, permet tout à la fois de saisir l'« intelligence picturale » du peintre et la bibliophilie du commanditaire.Una característica exclusiva del Paradís il·luminat per Giovanni di Paolo, absent en les miniatures de l'Infern i el Purgatori, és la representació recurrent de l'objecte del llibre, en deu miniatures distribuïdes entre els cants 5 i 28 del Pd. La investigació se centra en aquest procés de posada en comú i demostra el seu potencial exegètic. El llibre, sovint els llibres (una sola miniatura també pot contenir-ne set), són els textos (teològics, jurídics) que Dante esmenta en els versos del poema. No només això, els manuscrits, carregats sempre de connotacions positives, són vehicles de saviesa i saber moral promoguts per Dante. A més, són objecte de transició cultural i estètica: narrativament connectatss a figures medievals (Justinià, Dionís, Isidor...), potencien l'apreciació del manuscrit propi de l'humanisme i de la Biblioteca Alfonsiana. En definitiva, centrar la mirada i l'anàlisi en la presència de l'objecte del llibre dins de les miniatures al seu torn dins del manuscrit Yates Thompson 36 permet capturar conjuntament la intel·ligència visual del pintor i el gust del llibre del client.An exclusive characteristic of the Paradise illuminated by Giovanni di Paolo, absent in the miniatures of the Inferno and the Purgatorio, is the recurring representation of the object book, in ten miniatures distributed between Pd V and Pd XXVIII. The investigation focuses on this process of mise en abyme and demonstrates its exegetical potential. The volume, often the volumes (a single miniature can contain up to seven), are the texts (theological, juridical) mentioned by Dante in the lines of the poem. Not only, always loaded with positive connotations, the manuscripts are vehicles of wisdom and moral wisdom promoted by Dante. Moreover, they are an object of cultural and aesthetic transition: narratively connected to medieval figures (Justinian, Dionysius, Isidore...), they enhance the appreciation of manuscripts typical of humanism and of the Biblioteca Alfonsina. In short, focusing our attention and analysis on the presence of the book object inside the miniatures, which are in turn inside the Yates Thompson 36 manuscript, allows us to understand both the visual intelligence of the painter and the bookish taste of the patron.Característica específica del Paraíso Iluminado de Giovanni di Paolo, ausente de las iluminaciones del Infierno y el Purgatorio, la representación del objeto del libro regresa en no menos de diez iluminaciones distribuidas entre las canciones 5 y 28 del Paraíso. La investigación se centra en este proceso de mise en abyme y demuestra su potencial hexegético. El volumen, a menudo los volúmenes (una sola iluminación puede contener hasta siete libros representados), corresponden a los textos (teológicos, legales) mencionados por Dante en los versos del gran poema. Siempre cargados de connotaciones positivas, los manuscritos transmiten el conocimiento y la sabiduría moral promovida por Dante. También son objeto de transición, cultural y estética: ligados narrativamente a figuras medievales (Justiniano, Dionisio, Isidoro,...), exaltan la apreciación del manuscrito típico del humanismo y de la Biblioteca Alfonsina. En definitiva, centrar la mirada y el análisis en la presencia del objeto libro dentro de las iluminaciones, insertadas en el manuscrito Yates Thompson 36, permite captar tanto la "inteligencia pictórica" del pintor como la bibliofilia del patrocinador.Caratteristica esclusiva del Paradiso miniato da Giovanni di Paolo, assente nelle miniature dell'Inferno e del Purgatorio, è la rappresentazione ricorrente dell'oggetto libro, in ben dieci miniature distribuite fra Pd 5 e Pd 28. L'indagine verte su questo processo di mise en abyme e ne dimostra le potenzialità esegetiche. Il volume, spesso i volumi (un'unica miniatura può contenerne anche sette), sono i testi (teologici, giuridici) menzionati da Dante nei versi del poema. Non solo, sempre carichi di connotati positivi, i manoscritti sono veicoli della sapienza e saggezza morale promosse da Dante. Inoltre ancora, sono un oggetto di transizione culturale ed estetica : narrativamente connessi a figure medioevali (Giustiniano, Dionigi, Isidoro…), esaltano l'apprezzamento del manoscritto tipico dell'umanesimo e della Biblioteca Alfonsina. Insomma, concentrare lo sguardo e l'analisi sulla presenza dell'oggetto libro all'interno delle miniature a loro volta all'interno del manoscritto Yates Thompson 36 consente insieme di carpire l'intelligenza visiva del pittore e il gusto librario del committente

[Budget impact analysis for peginterferon beta-1a in relapsing remitting multiple sclerosis in Italy]

 BACKGROUND: Peginterferon beta-1a, injected every two weeks, is the first approved pegylated interferon beta-1a for the treatment of relapsing remitting multiple sclerosis (RRMS). The objective of this analysis was to estimate the economic impact due to the introduction of peginterferon beta-1a in Italy.METHODS: This analysis was conducted with a three-year time horizon with the support of a simple decision-analytic model adopting the perspective of the Italian National Healthcare Service (NHS). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, monitoring, relapse management, adverse events management) were calculated over 3 years and compared in two scenarios: the base scenario where interferons-beta and glatiramer acetate (GA) are used to treat RRMS patients, and an alternative scenario where peginterferon beta-1a can also be used to treat RRMS patients. The target population was approximately 35,500, 37,500 and 39,500 patients at year 1, 2 and 3 respectively, based on the published literature and market data. The efficacy of treatments was simulated as a reduction of relapse rates and was derived from a Network Meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A one-way sensitivity analysis was developed.RESULTS: According to current price and described assumptions, it was estimated that the introduction of peginterferon beta-1a would result in a decrease of total costs when compared with the base scenario. The cost in the base scenario was estimated to be  € 321.5, € 339.7 and € 357.8 million in years 1, 2, and 3, respectively. In the alternative scenario, the same costs resulted in about € 321.1, € 338.6 and € 356.2 million, respectively. The cumulative budget impact over three years period was approximately a cost saving of € 3.1 million (about 0.3% saving).CONCLUSION: The adoption of peginterferon beta-1a for the treatment of RRMS would be viewed as economically sustainable by the Italian NHS.[Article in Italian

[Cost-effectiveness analysis of peginterferon beta-1a in Italian relapsing remitting multiple sclerosis management]

BACKGROUND: Peginterferon beta-1a is indicated in adult patients for the treatment of relapsing remitting multiple sclerosis (RRMS). The efficacy and safety of peginterferon beta-1a was demonstrated in the placebo-controlled ADVANCE trial.OBJECTIVE: The objective of this study was to assess the cost-effectiveness of peginterferon beta-1a as compared with injectable first-line treatments for RRMS in Italy.METHODS: The cost-effectiveness analysis was developed through a Markov model with lifetime simulation in the perspective of the Italian National Healthcare Service (NHS). It was added an alternative scenario to take into account the Italian societal perspective. Outcomes were measured in terms of life years (LYs), quality adjusted life years (QALYs), lifetime costs and incremental cost-effectiveness ratio (ICER). The natural progression of the disease was informed by the published literature and previously published modelling exercises. The efficacy of treatments was simulated as reduction of disability progression (EDSS) and relapse rate. Efficacy data were derived from a published network meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A 3.5% discount rate was applied to costs and outcomes. One-way and probabilistic sensitivity analyses were developed and cost-effectiveness acceptability curves generated.RESULTS: Peginterferon beta-1a was more effective than the comparators in terms of survival (19.94 vs.19.68-19.81 discounted LYs, respectively), and QALYs (9.07 vs. 8.06 and 8.55 discounted QALY, respectively). In the perspective of the Italian NHS, the ICER was € 11,111/QALY vs. interferon beta-1a 30 µg, € 12,604/QALY vs. interferon beta-1a 22 µg, € 10,580/QALY and € 16,702/QALY vs. interferon beta-1b 250 µg and € 22,023/QALY vs. glatiramer acetate 20 mg. Peginterferon beta-1a dominated interferon beta-1a 44 µg. In the societal perspective, peginterferon beta-1a was dominant due to being more effective and with a lower social cost compared to first-line injectable treatments (interferon beta -1a, interferon beta-1b, glatiramer acetate) for RRMS. The outcomes of the sensitivity analyses confirmed the trend of the base case results.CONCLUSIONS: Peginterferon beta-1a shows a favourable pharmaco-economic profile for the treatment of RRMS. Even if an official threshold for the cost-effectiveness does not exist in Italy, the ICER values obtained were far below the commonly accepted thresholds (30,000-50,000 €/per QALY gained).[Article in Italian

[Pegylation and interferons in multiple sclerosis]

Pegylation is a procedure used for drug development since the 1970s and consists of the conjugation of a polyethylene glycol molecule (PEG) to a drug. PEG has shown to be safe and effective in improving the pharmacokinetic and pharmacodynamic profile of drugs. Recently, a 20 kDa linear chain of PEG was conjugated to interferon beta-1a with the aim to offer a new treatment option to relapsing-remitting multiple sclerosis (RRMS) patients. Due to a prolonged bioavailability, this new drug can be administered less frequently (every two weeks) than the other interferons beta available, thus allowing to hypothesize a better adherence to the treatment, which, in turn, should result in better clinical and economic outcomes. A phase III clinical trial has proven its effectiveness compared to placebo in RRMS patients, as well as a safety profile comparable to that found in other interferon beta preparations. The immunogenicity of this new molecule is < 1%, thus minimizing the suppression or reduction of interferon beta biological activity that could come from the development of Neutralizing Antibodies (NAbs).[Article in Italian

Intracellular accumulation of tau oligomers in astrocytes and their synaptotoxic action rely on Amyloid Precursor Protein Intracellular Domain-dependent expression of Glypican-4

: Several studies including ours reported the detrimental effects of extracellular tau oligomers (ex-oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex-oTau whose intracellular accumulation alters neuro/gliotransmitter handling thereby negatively affecting synaptic function. Both amyloid precursor protein (APP) and heparan sulfate proteoglycans (HSPGs) are required for oTau internalization in astrocytes but the molecular mechanisms underlying this phenomenon have not been clearly identified yet. Here we found that a specific antibody anti-glypican 4 (GPC4), a receptor belonging to the HSPG family, significantly reduced oTau uploading from astrocytes and prevented oTau-induced alterations of Ca2+-dependent gliotransmitter release. As such, anti-GPC4 spared neurons co-cultured with astrocytes from the astrocyte-mediated synaptotoxic action of ex-oTau, thus preserving synaptic vesicular release, synaptic protein expression and hippocampal LTP at CA3-CA1 synapses. Of note, the expression of GPC4 depended on APP and, in particular, on its C-terminal domain, AICD, that we found to bind Gpc4 promoter. Accordingly, GPC4 expression was significantly reduced in mice in which either APP was knocked-out or it contained the non-phosphorylatable amino acid alanine replacing threonine 688, thus becoming unable to produce AICD. Collectively, our data indicate that GPC4 expression is APP/AICD-dependent, it mediates oTau accumulation in astrocytes and the resulting synaptotoxic effects

Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine. A post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial

Background: The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication. Methods: Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation. Results: A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037). Conclusions: This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. Trial registration: ClinicalTrials.gov identifier: NCT02686034

Interleukin 1β triggers synaptic and memory deficits in Herpes simplex virus type-1-infected mice by downregulating the expression of synaptic plasticity-related genes via the epigenetic MeCP2/HDAC4 complex

Extensive research provides evidence that neuroinflammation underlies numerous brain disorders. However, the molecular mechanisms by which inflammatory mediators determine synaptic and cognitive dysfunction occurring in neurodegenerative diseases (e.g., Alzheimer's disease) are far from being fully understood. Here we investigated the role of interleukin 1 beta (IL-1 beta), and the molecular cascade downstream the activation of its receptor, to the synaptic dysfunction occurring in the mouse model of multiple Herpes simplex virus type-1 (HSV-1) reactivations within the brain. These mice are characterized by neuroinflammation and memory deficits associated with a progressive accumulation of neurodegenerative hallmarks (e.g., amyloid-beta protein and tau hyperphosphorylation). Here we show that mice undergone two HSV-1 reactivations in the brain exhibited increased levels of IL-1 beta along with significant alterations of: (1) cognitive performances; (2) hippocampal long-term potentiation; (3) expression synaptic-related genes and pre- and post-synaptic proteins; (4) dendritic spine density and morphology. These effects correlated with activation of the epigenetic repressor MeCP2 that, in association with HDAC4, affected the expression of synaptic plasticity-related genes. Specifically, in response to HSV-1 infection, HDAC4 accumulated in the nucleus and promoted MeCP2 SUMOylation that is a post-translational modification critically affecting the repressive activity of MeCP2. The blockade of IL-1 receptors by the specific antagonist Anakinra prevented the MeCP2 increase and the consequent downregulation of gene expression along with rescuing structural and functional indices of neurodegeneration. Collectively, our findings provide novel mechanistic evidence on the role played by HSV-1-activated IL-1 beta signaling pathways in synaptic deficits leading to cognitive impairment

1383, Niccolò di Pietro Gerini, Londres, National Gallery (NH 2076)

Niccolò di Pietro Gerini, Adoration des bergers, 1383, détrempe sur bois, 23 x 39 cm, Londres, National Gallery (Collection particulière, prêt)