NADPH oxidase 1 is a novel pharmacological target for the development of an antiplatelet drug without bleeding side effects

This is the final version. Available from FASEB via the DOI in this record. Growing evidence supports a central role of NADPH oxidases (NOXs) in the regulation of platelets, which are circulating cells involved in both hemostasis and thrombosis. Here, the use of Nox1−/− and Nox1+/+ mice as experimental models of human responses demonstrated a critical role of NOX1 in collagen-dependent platelet activation and pathological arterial thrombosis, as tested in vivo by carotid occlusion assays. In contrast, NOX1 does not affect platelet responses to thrombin and normal hemostasis, as assayed in tail bleeding experiments. Therefore, as NOX1 inhibitors are likely to have antiplatelet effects without associated bleeding risks, the NOX1-selective inhibitor 2-acetylphenothiazine (2APT) and a series of its derivatives generated to increase inhibitory potency and drug bioavailability were tested. Among the 2APT derivatives, 1-(10H-phenothiazin-2-yl)vinyl tert-butyl carbonate (2APT-D6) was selected for its high potency. Both 2APT and 2APT-D6 inhibited collagen-dependent platelet aggregation, adhesion, thrombus formation, superoxide anion generation, and surface activation marker expression, while responses to thrombin or adhesion to fibrinogen were not affected. In vivo administration of 2APT or 2APT-D6 led to the inhibition of mouse platelet aggregation, oxygen radical output, and thrombus formation, and carotid occlusion, while tail hemostasis was unaffected. Differently to in vitro experiments, 2APT-D6 and 2APT displayed similar potency in vivo. In summary, NOX1 inhibition with 2APT or its derivative 2APT-D6 is a viable strategy to control collagen-induced platelet activation and reduce thrombosis without deleterious effects on hemostasis. These compounds should, therefore, be considered for the development of novel antiplatelet drugs to fight cardiovascular diseases in humans.British Heart FoundationAlzheimer's Research U

fMRI Supports the Sensorimotor Theory of Motor Resonance

The neural mechanisms mediating the activation of the motor system during action observation, also known as motor resonance, are of major interest to the field of motor control. It has been proposed that motor resonance develops in infants through Hebbian plasticity of pathways connecting sensory and motor regions that fire simultaneously during imitation or self movement observation. A fundamental problem when testing this theory in adults is that most experimental paradigms involve actions that have been overpracticed throughout life. Here, we directly tested the sensorimotor theory of motor resonance by creating new visuomotor representations using abstract stimuli (motor symbols) and identifying the neural networks recruited through fMRI. We predicted that the network recruited during action observation and execution would overlap with that recruited during observation of new motor symbols. Our results indicate that a network consisting of premotor and posterior parietal cortex, the supplementary motor area, the inferior frontal gyrus and cerebellum was activated both by new motor symbols and by direct observation of the corresponding action. This tight spatial overlap underscores the importance of sensorimotor learning for motor resonance and further indicates that the physical characteristics of the perceived stimulus are irrelevant to the evoked response in the observer

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Toxoplasmic retinochoroiditis in an Italian referral center

PURPOSE. To evaluate the clinical features of ocular toxoplasmosis (OT).METHODS. Retrospective review of 3080 new patients with uveitis was performed to identify patients with active OT. The main outcome measures were ocular features and ocular complications.RESULTS. Active OT was diagnosed in 88 patients (2.85% of all uveitis), 39 male (44.3%) and 49 female (55.7%), at an average age of 20.4+/-14.6 years, lower than in other types of uveitis (p<0.0001). Acquired OT diagnosis was possible in 4 cases (4.5%), while in the others a differentiation between acquired or congenital OT was impossible. Unilateral OT occurred in 76 patients (86.36%), with lesions located inside the vascular arcade in 64 of them (84.2%). Among bilateral cases (12 patients, 13.63%), at least one lesion was central in 9 (75%). Isolated peripheral lesions were observed in 12 out of 88 patients (13.6%). During an average follow-up of 70+/-73.5 months, OT recurrences appeared in 70 patients (79.54%). Mean interval between diagnosis and first relapse was 43.57+/-48.46 months, while it shortened between subsequent relapses (24.44+/-26.5 months; p=0.001).CONCLUSIONS. Ocular toxoplasmosis is a highly recurrent disease, mainly unilateral, with an average age at onset lower than those observed in other types of uveitis. Time between relapses shortens significantly over time. (Eur J Ophthalmol 2009; 19: 824-30

Oral Lesions in Pediatric Subjects: SARS-CoV-2 Infection and COVID-19 Vaccination

Featured Application A deeper insight into oral lesions potentially detectable in pediatric SARS-CoV-2 positive subjects and following COVID-19 vaccination may enhance clinicians' preparedness to improve inter-disciplinary pediatric oral and general healthcare. A plethora of systemic manifestations of COVID-19 and adverse reactions to COVID-19 vaccines have been described in pediatric subjects. Therefore, the present systematic review primarily aimed to assess the prevalence and macro-microscopic features of oral lesions following SARS-CoV-2 infection, grading primary oral lesions based on COVID-19 forms, in pediatric subjects. The secondary aim was to evaluate the epidemiology, clinical appearance, and histopathology of oral lesions following the WHO Emergency Use Listing approved and EMA authorized vaccines, in relation to cases and vaccine characteristics. The study protocol was compliant with the PRISMA statement and registered on PROSPERO (CRD42022351821). Case reports, case series, and observational studies were electronically searched till 27 July 2022, on MEDLINE/PubMed, Scopus, and Cochrane library databases, and the PROSPERO register. Data from nine studies describing oral lesions following viral infection and two records reporting oral lesions following vaccine administration, evaluated through the ROBINS-I tool for quality, were independently extracted and qualitatively synthesized, resulting in scarce, jeopardized, and incomplete findings. Since most of the rare lesions recorded were a part of broad-spectrum systemic disorders and syndromes and, thus. undetailed or nonspecific, further studies should assess oral lesions following SARS-CoV-2 infection and vaccination in pediatric subjects, considering novel viral variants and newly developing vaccines

Development and implementation of the AIDA International Registry for patients with non-infectious scleritis

Introduction: This article points out the design, methods, development and deployment of the international registry promoted by the AutoInflammatory Disease Alliance (AIDA) Network with the aim to define and assess paediatric and adult patients with immune-mediated scleritis. Methods: This registry collects both retrospec-tive and prospective real-world data from patients with non-infectious scleritis through the Research Electronic Data Capture (REDCap) tool and aims to promote knowledge and real-life evidence from patients enrolled worldwide; the registry also allows the collection of standardised data, ensuring the highest levels of security and anonymity of patients’ data and flexibility to change according to scientific acquisitions over time. The communication with other similar registries has been also ensured in order to pursue the sustainability of the project with respect to the adaptation of collected data to the most diverse research projects. Results: Since the launch of the registry, 99 centres have been involved from 20 countries and four continents. Forty-eight of the centres have already obtained a formal approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers); the platform collects baseline and follow-up data using 3683 fields organised into 13 instruments, including patient’s demographics, history, symptoms, trigger or risk factors, therapies and health care utilization. Conclusions: The development of the AIDA International Registry for patients with non-infectious scleritis will allow solid research on this rare condition. Real-world evidence result-ing from standardised real-life data will lead to the optimisation of routine clinical and therapeutic management, which are currently limited by the rarity of this ocular inflammatory condition