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Introduction In this study we characterized disease progression over 48 weeks among boys receiving deflazacort vs prednisone/prednisolone placebo arm treatment in two recent Duchenne muscular dystrophy (DMD) clinical trials. Methods Ambulatory boys with DMD receiving placebo in the phase 3 ataluren (N = 115) and tadalafil (N = 116) trials were included. The trials required at least 6 months of prior corticosteroid use and stable baseline dosing. Associations between corticosteroid use and 48‐week changes in ambulatory function were estimated using mixed models. Adjusted differences between corticosteroid groups were pooled in a meta‐analysis. Results In the meta‐analysis, deflazacort‐treated patients vs prednisone/prednisolone‐treated patients experienced, on average, lower declines of 28.3 meters on 6‐minute walk distance (95% confidence interval [CI], 5.7, 50.9; 2.9 seconds on rise from supine [95% CI, 0.9, 4.9 seconds]; 2.3 seconds on 4‐stair climb [95% CI, 0.5, 4.1 seconds]; and 2.9 [95% CI, 0.1, 5.8] points on the North Star Ambulatory Assessment linearized score). Discussion Deflazacort‐treated patients experienced significantly lower functional decline over 48 weeks.

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

In questa relazione sono descritte le attività svolte nell'ambito del WP6-LA6.1 del progetto PANACEA riguardante le "Prove sperimentali sul comportamento del motore in modalità dual-fuel in diversi regimi di carico, analisi dei gas di scarico", con i principali risultati ottenuti sia nell'attività di caratterizzazione sperimentale che in quella di simulazione numerica di un motore ad accensione per compressione in alimentazione dual-fuel con OVE e syngas. Anche ai fini comparativi, le attività sia sperimentali che numeriche, hanno avuto come fase iniziale una caratterizzazione e combustibile liquido, ovvero con gasolio e con OVE.

Aims: The main aim of this multicentric longitudinal project is to investigate the specificity and sensitivity of three memory tests (FCSRT, STMBT, DMS48) proposed as cognitive marker for Alzheimer's disease (AD). Here, we report preliminary baseline data on healthy controls, people with MCI and patients with AD. Subjects and methods: Data collected on 13 AD, 16 MCI, 16 healthy older (HO) and 16 healthy younger (HY) adults were analysed. All participants underwent the three experimental tests along with a standard neuropsychological evaluation in one single session. Results: For the FCSRT, a three-way ANOVA with GROUP as the between-subjects factor and TASK (free, cued) and TIME (immediate, delayed) as within-subjects measures revealed a significant effect of GROUP (HY = HO > MCI > AD; p< .001), TASK (cued > free, ; p< .001), TIME (immediate > delayed; p< .001), and a significant interaction between GROUP and TASK (p< .001). For the DMS48, a three-way ANOVA with GROUP as the between-subjects factor and STIMULUS (paired, abstract, unpaired) and TIME (immediate, delayed) as within-subjects measures revealed a significant effect of GROUP (HY = HO > MCI > AD; p< .001), STIMULUS (unpaired > paired = abstract; p< .001) and a significant interaction between GROUP and STIMULUS (p< . 001). For the STMBT a three-way ANOVA with GROUP as the between-subjects factor and STIMULUS (2 or 3 items) and TASK (shape only, binding) as within-subjects measures revealed a significant effect of GROUP (HY > HO > MCI > AD; p < .001), STIMULUS (2 > 3; p< .001) and TASK (shape > binding; p< .001) and a significant interaction between STIMULUS and GROUP (p= .003). Discussion: The present report study shows reports for the first time a comparison across Controls, MCI and AD on three memory tests proposed as cognitive markers for AD. For the FCSRT both the timing of recall and the presence of a cue are relevant factors to influence patient performances. For the DMS48 the most sensitive indexes to differentiate between controls and patients are the unpaired and abstract items, while for the STMBT the binding condition is more affected in patients are regardless of the number of items presented are. These preliminary data are encouraging in confirming that these tests may offer an aid to diagnosis of early AD, but a larger sample and longitudinal data are needed to address the main research question of this planned study. *** References: Barbeau, E, Didic, M, Tramoni, E, Felician, O, Joubert, S, Sontheimer, A, Ceccaldi, M, Poncet, M. (2004). Evaluation of visual recognition memory in MCI patients. Neurology 62, 1317-1322. Frasson P, Ghiretti R, Catricala E, Pomati S, Marcone A, Parisi L, Rossini PM, Cappa SF, Mariani C, Vanacore N, Clerici F (2011) Free and cued selective reminding test: an Italian normative study. Neurological Sciences 32:1057-1062 Parra MA, Abrahams S, Fabi K, Logie R, Luzzi S, Della Sala S (2009) Short-term memory binding deficits in Alzheimer's disease. Brain 132:1057-1066

Background: Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). Methods: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. Results: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by –1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P Conclusions: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537. opens in new tab.)

Introduction: Primary antiphospholipid syndrome (APS) is a thrombophilic disease that should be suspected in the presence of thrombotic events associated with hematologic abnormalities such as thrombocytopenia and prolongation of the activated partial thromboplastin time. The diagnosis must be confirmed by the demonstration of autoantibodies directed against anionic phospholipids and/or phospholipid-binding proteins. The disease can cause arterial thrombosis in any vascular district, including those of the kidney and central nervous system. Case report: In 2006 a 29-year-old male presented with kidney and brain involvement that was attributed to primary APS. The clinical diagnosis was confirmed by the results of a renal biopsy, which excluded the presence of systemic lupus erythematosus (SLE). The patient remained stable through 32 months of follow-up and then developed a malar rash with deteriorating renal function, decreasing platelet count, and reduced complement levels. Serological studies revealed positivity for ANA (homogeneous pattern), dsDNA, ACA, and beta-2-glycoprotein-1 antibodies. The diagnosis was revised to APS secondary to SLE. Conclusions: A diagnosis of primary APS should not be considered permanent: progression to SLE can occur, in some cases years after the original diagnosis. This case highlights the importance of ongoing follow-up of patients diagnosed with primary APS to detect changes that herald the emergence of SLE.

Assessment of dynamic inspiratory function may provide valuable information about the degree and progression of pulmonary involvement in patients with Duchenne muscular dystrophy (DMD). The aims of this study were to characterize inspiratory function and to assess the efficacy of idebenone on this pulmonary function outcome in a large and well-characterized cohort of 10-18 year-old DMD patients not taking glucocorticoid steroids (GCs) enrolled in the phase 3 randomized controlled DELOS trial. We evaluated the effect of idebenone on the highest flow generated during an inspiratory FVC maneuver (maximum inspiratory flow; V'I,max(FVC)) and the ratio between the largest inspiratory flow during tidal breathing (tidal inspiratory flow; V'I,max(t)) and the V'I,max(FVC). The fraction of the maximum flow that is not used during tidal breathing has been termed inspiratory flow reserve (IFR). DMD patients in both treatment groups of DELOS (idebenone, n = 31; placebo: n = 33) had comparable and abnormally low V'I,max(FVC) at baseline. During the study period, V'I,max(FVC) further declined by -0.29 L/sec in patients on placebo (95%CI: -0.51, -0.08; P = 0.008 at week 52), whereas it remained stable in patients on idebenone (change from baseline to week 52: 0.01 L/sec; 95%CI: -0.22, 0.24; P = 0.950). The between-group difference favoring idebenone was 0.27 L/sec (P = 0.043) at week 26 and 0.30 L/sec (P = 0.061) at week 52. In addition, during the study period, IFR improved by 2.8% in patients receiving idebenone and worsened by -3.0% among patients on placebo (between-group difference 5.8% at week 52; P = 0.040). Although the clinical interpretation of these data is currently limited due to the scarcity of routine clinical practice experience with dynamic inspiratory function outcomes in DMD, these findings from a randomized controlled study nevertheless suggest that idebenone preserved inspiratory muscle function as assessed by V'I,max(FVC) and IFR in patients with DMD. Pediatr Pulmonol. © 2016 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc. ispartof: Pediatric Pulmonology vol:52 issue:4 pages:508-515 ispartof: location:United States status: published

Summary Introduction Primary antiphospholipid syndrome (APS) is a thrombophilic disease that should be suspected in the presence of thrombotic events associated with hematologic abnormalities such as thrombocytopenia and prolongation of the activated partial thromboplastin time. The diagnosis must be confirmed by the demonstration of autoantibodies directed against anionic phospholipids and/or phospholipid-binding proteins. The disease can cause arterial thrombosis in any vascular district, including those of the kidney and central nervous system. Case report In 2006 a 29-year-old male presented with kidney and brain involvement that was attributed to primary APS. The clinical diagnosis was confirmed by the results of a renal biopsy, which excluded the presence of systemic lupus erythematosus (SLE). The patient remained stable through 32 months of follow-up and then developed a malar rash with deteriorating renal function, decreasing platelet count, and reduced complement levels. Serological studies revealed positivity for ANA (homogeneous pattern), dsDNA, ACA, and beta-2-glycoprotein-1 antibodies. The diagnosis was revised to APS secondary to SLE. Conclusions A diagnosis of primary APS should not be considered permanent: progression to SLE can occur, in some cases years after the original diagnosis. This case highlights the importance of ongoing follow-up of patients diagnosed with primary APS to detect changes that herald the emergence of SLE.

Using diffusion tensor (DT) magnetic resonance imaging (MRI), damage to brain intrahemispheric and interhemispheric connections was assessed in 26 sporadic primary lateral sclerosis (PLS) patients compared with 28 sporadic amyotrophic lateral sclerosis (ALS) patients with similar disability and 35 healthy controls. DT MRI diagnostic accuracy in distinguishing the two motor neuron disease (MND) variants was tested. PLS and ALS patients showed a distributed pattern of abnormalities of the motor system, including the corticospinal tracts and corpus callosum (CC). PLS versus ALS patients showed a more severe damage to the motor CC fibers and subcortical white matter (WM) underlying the primary motor cortices. Both patient groups showed an extra‐motor damage, which was more severe in PLS. This did not appear to be driven by longer disease duration in PLS. In PLS patients, damage to the CC mid‐body correlated with the severity of upper motor neuron clinical burden. CC fractional anisotropy values had the highest accuracy in distinguishing PLS from controls and ALS. PLS and ALS share an overlapped pattern of WM abnormalities. This underscores that PLS, despite its distinct clinical phenotype and long survival, still lies within the wider MND spectrum. Whether CC diffusivity may be a novel marker to increase confidence in an early diagnostic separation of PLS from ALS still needs to be investigated. Hum Brain Mapp 35:1710–1722, 2014. © 2013 Wiley‐Periodicals, Inc.

The anthiphospholipid syndrome (APS) is characterized by a high risk of venous and arterial thrombosis and by complications during pregnancy, especially recurrent miscarriages. The thrombotic event is caused by a complex interaction between antiphospholipid antibodies (aPLs) and endothelium and platelets. Inflammation may play a role in the pathology of APS even though the consensus of Sydney (Miyakis et al., 2006) requires the absence of vascular inflammation signs for the diagnosis of APS. However, the complement system has recently been involved in the pathogenesis of fetal losses in animal models and, interestingly, the protective role of heparin in such cases could be due to the complement inhibition rather than to anticoagulation. The treatment of APS is based on antiplatelet drugs (aspirin) and anticoagulants (both heparins and vitamin K antagonists). In the acute phase the treatment is in general very similar to that of non-APS thrombosis, that is with unfractionated heparin (UFH) therapy followed by oral anticoagulation. However, APS treatment remains problematic due to lack of standardized laboratory tests and of randomized controlled trials (RCTs).

The Istituto Superiore di Sanità (ISS, the National Institute of Health of Italy) and the Istituto dei Motori (IM) of the Consiglio Nazionale delle Ricerche (CNR, National Research Council) have carried out this study, jointly funded by the two institutes together with the Ministry of Environment. The chemical and toxicological characteristics of emissions from two urban bus engines were studied: a diesel engine fueled with both diesel oil and biodiesel blend and an equivalent spark-ignition one fuelled with compressed natural gas, operating in steady-state conditions. Regulated and unregulated pollutants, such as carcinogenic polycyclic aromatic hydrocarbons and nitrated derivatives, carbonyl compounds and light aromatic hydrocarbons were quantified. Mutagenicity of the emissions was evaluated by the Salmonella typhimurium/mammalian microsome assay. The effect of the fuels under study on the size distribution of particulate matter was also evaluated. The impact of diesel-powered transport on urban air quality, and the potential benefits for human health deriving from the use of natural gas for public transport, are discussed.

The Istituto Superiore di Sanità (ISS, the National Institute of Health of Italy) and the Istituto dei Motori (IM) of the Consiglio Nazionale delle Ricerche (CNR, National Research Council) have carried out this study, jointly funded by the two institutes together with the Ministry of Environment. The chemical and toxicological characteristics of emissions from two urban bus engines were studied: a diesel engine fueled with both diesel oil and biodiesel blend and an equivalent spark-ignition one fuelled with compressed natural gas, operating in steady-state conditions. Regulated and unregulated pollutants, such as carcinogenic polycyclic aromatic hydrocarbons and nitrated derivatives, carbonyl compounds and light aromatic hydrocarbons were quantified. Mutagenicity of the emissions was evaluated by the Salmonella typhimurium/mammalian microsome assay. The effect of the fuels under study on the size distribution of particulate matter was also evaluated. The impact of diesel-powered transport on urban air quality, and the potential benefits for human health deriving from the use of natural gas for public transport, are discussed.

L’impiego nei trasporti del gas naturale liquido, costituito per il 95-98% di metano (CH4), potrebbe ampliare il raggio di azione dei veicoli a gas naturale (GN), oggi limitato dallo stato gassoso di stoccaggio nei serbatoi (gas naturale compresso a 200 bar). La disponibilità di GNL nei trasporti potrebbe essere favorita dal prevedibile aumento delle sue importazioni dovuto a vantaggi economici e geo-politici. Esso, infatti, riveste un ruolo di importanza strategica nell’integrazione del fabbisogno energetico e nella diversificazione dei siti di approvvigionamento grazie all’assenza del legame fisico (metanodotto) tra produttore e consumatore. Il GNL viene prodotto attraverso processi di liquefazione, basati sull’applicazione dell’effetto Joule-Thompson (con un consumo pari a circa il 10% del contenuto energetico del GN), e successivamente trasportato via nave per essere poi rigassificato ed immesso nell’esistente rete nazionale di metanodotti.

Generally, nowadays, natural gas heavy duty engines are derived from the equivalent in production diesel ones. As a consequence, they have elevated swirl index, essential for diesel combustion, but not for homogeneous charge spark ignition engines. To improve the benefits obtaining from natural gas spark ignited engines it is primary the development of dedicated engines, according to fuel and its combustion characteristics. Therefore an analysis has been carried out on the swirl ratio (SR) effect on engine behaviour and combustion development. Experimental data have been obtained on a heavy duty engine with two different heads at SR 1.8 and 0.8, and instrumented to acquire the pressure cycle in the combustion chamber. Tests at wide open throttle (WOT) and 50% of maximum load have been carried out. Small benefits on BSFC and volumetric efficiency have been found with the 0.8 SR head.

Le emissioni autoveicolari contribuiscono in maniera significativa all’inquinamento urbano e rappresentano un serio rischio per la salute umana, tanto che la IARC (IARC, 1989) ha classificato le emissioni diesel nel gruppo 2A (probabile cancerogeno umano) e le emissioni da autoveicoli a benzina nel gruppo 2B (possibile cancerogeno umano). In particolare, i motori diesel sono tra le sorgenti principali di particelle fini nelle aree urbane. Queste particelle si depositano facilmente nel tratto respiratorio e possono fungere da iniziatori di tumori polmonari o provocare altre malattie dell’apparato respiratorio (USEPA, 2002; Health Effects Institute, 2002). Il articolato proveniente da emissioni autoveicolari è costituito da una matrice solida carboniosa sulla quale sono adsorbiti centinaia di composti tossici, molti dei quali presentano attività mutagena e/o cancerogena. Fra questi, particolare rilevanza tossicologica hanno gli idrocarburi policiclici aromatici (IPA) e i loro derivati nitrati (Nitro-IPA), la cui presenza nelle emissioni è stata correlata con il combustibile usato e con la tecnologia motoristica impiegata (Concawe, 1998; Westerholm, 1994). Poiché la maggior parte degli autobus destinati al trasporto pubblico urbano è dotata di motori diesel, l’emissione di particolato avviene in aree densamente popolate, contribuendo significativamente all’esposizione della popolazione generale. Specificamente esposte alle emissioni risultano anche le categorie dei lavoratori impiegati sulle strade a tutela della disciplina del traffico, come ad esempio gli agenti di polizia municipale e di polizia stradale.

A 29- year-old male was admitted because of exertion dyspnea and intense headache. These symptoms were associated with severe hypertension, small multiple areas of cerebral ischemia, thrombocytopenia, prolonged aPTT and renal failure. The diagnostic tests performed during hospitalization resulted in a diagnosis of Primary Antiphospholipids Syndrome. The renal biopsy sample suggested histopathological features of uncommon simultaneous occurrence of antiphospholipids nephropathy and a "collapsing variant" of segmental focal glomerulosclerosis. It is fundamental to be aware that this syndrome is very likely to occur, and therefore to perform antiphospholipids antibodies assessment, since only an anticoagulant therapy proves effective; nevertheless, in view of the pathological renal findings, other therapies such as steroids might be added.