Variable Clinical Phenotypes and Relation of Interferon Signature with Disease Activity in ADA2 Deficiency

Objective.An upregulation of type I interferon (IFN) stimulated genes [IFN score (IS)] was described in patients with adenosine deaminase 2 deficiency (DADA2). We describe the clinical course of 5 such patients and the role of IS as a marker of disease activity and severity.Methods.Expression levels of IS were determined by quantitative real-time PCR.Results.Five white patients were identified as carrying CECR1 mutations. The IS before treatment was elevated in 4 out of 5 patients and decreased after treatment.Conclusion.Our data confirm the high variability of DADA2 and suggest type I IS as a biomarker of disease activity

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Functional and Morphological Improvement of Dystrophic Muscle by Interleukin 6 Receptor Blockade

The anti-inflammatory agents glucocorticoids (GC) are the only available treatment for Duchenne muscular dystrophy (DMD). However, long-term GC treatment causes muscle atrophy and wasting. Thus, targeting specific mediator of inflammatory response may be more specific, more efficacious, and with fewer side effects. The pro-inflammatory cytokine interleukin (IL) 6 is overproduced in patients with DMD and in the muscle of mdx, the animal model for human DMD. We tested the ability of inhibition of IL6 activity, using an interleukin-6 receptor (Il6r) neutralizing antibody, to ameliorate the dystrophic phenotype. Blockade of endogenous Il6r conferred on dystrophic muscle resistance to degeneration and alleviated both morphological and functional consequences of the primary genetic defect. Pharmacological inhibition of IL6 activity leaded to changes in the dystrophic muscle environment, favoring anti-inflammatory responses and improvement in muscle repair. This resulted in a functional homeostatic maintenance of dystrophic muscle. These data provide an alternative pharmacological strategy for treatment of DMD and circumvent the major problems associated with conventional therapy

Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features

Objective: To evaluate the expression of type I interferon (IFN\u3b1/\u3b2)\u2013 and type II IFN (IFN\u3b3)\u2013inducible genes in muscle biopsy specimens from patients with juvenile dermatomyositis (DM) and to correlate their expression levels with histologic and clinical features. Methods: Expression levels of IFN-inducible genes and proinflammatory cytokines were assessed by quantitative polymerase chain reaction in muscle biopsy specimens from patients with juvenile DM (n = 39), patients with Duchenne's muscular dystrophy (DMD), and healthy controls. Muscle biopsy sections were stained and scored for severity of histopathologic features. The charts of patients with juvenile DM were reviewed for clinical features at the time of sampling and long-term outcomes. Results: Muscle expression levels of IFN\u3b1/\u3b2-inducible genes (type I IFN score), IFN\u3b3, IFN\u3b3-inducible genes (type II IFN score), and tumor necrosis factor (TNF) were significantly higher in juvenile DM patients not receiving glucocorticoid therapy before muscle biopsy (n = 27) compared to DMD patients (n = 24) (type I IFN score, P < 0.0001; type II IFN score, P < 0.001; TNF, P < 0.05) and healthy controls (n = 4) (type I IFN score, P < 0.01; type II IFN score, P < 0.01; TNF, P < 0.05). Immunofluorescence staining of muscle biopsy sections from untreated juvenile DM patients showed increased immunoreactivity for IFN\u3b3 and HLA class II molecules compared to controls. Type I and type II IFN scores were correlated with typical histopathologic features of juvenile DM muscle biopsy samples, such as infiltration of endomysial CD3+ cells (type I IFN score, r = 0.68; type II IFN score, r = 0.63), perimysial CD3+ cells (type I IFN score, r = 0.59; type II IFN score, r = 0.66), CD68+ cells (type II IFN score, r = 0.46), and perifascicular atrophy (type I IFN score, r = 0.61; type II IFN score, r = 0.77). Juvenile DM patients with a high type I IFN score, a high type II IFN score, and high TNF expression levels showed more severe disease activity at biopsy (P < 0.05). In addition, juvenile DM patients with a high type II IFN score at biopsy reached clinically inactive disease significantly later than patients with low type II IFN score (log rank chi-square value 13.53, P < 0.001). Conclusion: The increased expression of IFN-inducible genes in the muscle in juvenile DM patients and their association with histologic and clinical features further support a pathogenic role for both type I and type II IFNs in juvenile DM

The Uprise of Human Leishmaniasis in Tuscany, Central Italy: Clinical and Epidemiological Data from a Multicenter Study

Human leishmaniasis is facing important epidemiological changes in Southern Europe, driven by increased urbanization, climate changes, emerging of new animal reservoirs, shifts in human behavior and a growing population of immunocompromised and elderly individuals. In this evolving epidemiological landscape, we analyzed the clinical and epidemiological characteristics of human leishmaniasis in the Tuscany region of Central Italy. Through a multicentric retrospective analysis, we collected clinical and demographic data about all cases of leishmaniasis recorded between 2018 and 2023. We observed 176 cases of human leishmaniasis, with 128 (72.7%) visceral leishmaniasis (VL) and 47 (26.7%) cutaneous leishmaniasis (CL). Among these, 92.2% of VL and 85.1% of CL cases were autochthonous. The cumulative incidence of autochthonous human leishmaniasis was 0.22 cases per 100,000 inhabitants in 2018, but reached 1.81/100,000 in 2023. We identified three main areas of transmission: around the city of Florence (North-East Tuscany), around Grosseto city (South-West Tuscany) and Elba Island. Our findings confirm that the epidemiology of leishmaniasis is undergoing significant changes in Central Italy. Awareness towards this emerging health threat and surveillance strategies need to be improved in order to reliably assess the disease's burden. Further research is needed in a "One-Health" perspective, to clarify the epidemiological dynamics at the environmental, reservoir, vector and human levels. The role of climate change and specific climatic factors affecting the epidemiological patterns of human leishmaniasis should be assessed. Further knowledge in these fields would promote targeted control and prevention strategies at regional and national levels

Electroweak parameters of the z0 resonance and the standard model

Contains fulltext : 124399.pdf (publisher's version ) (Open Access

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade