Research needs in allergy: an EAACI position paper, in collaboration with EFA

Abstract In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21 st century. The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients' Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients' organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels. Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein

Implication des toxines environnementales, L-BMAA et roténone dans la neurodégénérescence rétinienne

L étiologie des principales pathologies neurodégénératives est source de débats. Leurs fortes incidences au sein de certaines populations ont suggéré l implication de facteurs étiologiques environnementaux. La roténone est une molécule extraite des racines de plantes tropicales. Largement utilisée en laboratoire en tant qu inhibiteur de la chaîne respiratoire mitochondriale, elle est depuis quelques années une des toxines permettant d obtenir des modèles animaux de la maladie de Parkinson. Les parkinsoniens présentant des atteintes visuelles, nous avons étudié la toxicité de la roténone sur la rétine in vivo. Quelle que soit la voie d administration, les enregistrements d électrorétinographie suggèrent que la roténone altère l activité rétinienne chez la souris, en diminuant l amplitude de l onde-b et des potentiels oscillatoires. De façon surprenante, seulement 50% des souris traitées avec la neurotoxine présentent des lésions rétiniennes. Sur des neurones en culture, la neurotoxicité est indépendante de l état d oxydation de la molécule. Le L-BMAA (ß-N-méthylamino-L-alanine) est un acide aminé cyanobactérien produit dans les racines et les graines de Cycas Circinalis. A fortes doses, il provoquerait le complexe pathologique de l île de Guam appelé "Sclérose Latérale Amyotrophique/ Complexe Parkinson-Démence " (SLA/CPD). Les patients atteints par cette maladie présentent pour la grande majorité une rétinopathie spécifique. Nous avons ainsi étudié la toxicité du L-BMAA in vivo sur le modèle rétinien. L analyse des électrorétinogrammes de souris montre que son injection par voie intra-oculaire réduit l amplitude de l onde-b, sans avoir d effet apparent sur celles de l onde-a ou sur les latences de ces deux ondes. Les potentiels oscillatoires présentent également une forte diminution. La mort des cellules rétiniennes est mise en évidence par des analyses histologiques, l activation de la caspase-3, l incorporation d'iodure de propidium et la production de composés oxygénés réactifs. La co-injection d antagonistes spécifiques du récepteur NMDA (MK-801 et Ifenprodil) protège significativement les neurones rétiniens de l apoptose induite par le L-BMAA seul ou additionné de NMDA. Ainsi, d une part nous apportons la preuve que le L-BMAA induit une mort neuronale in vivo, soutenant l hypothèse d un lien de causalité direct entre cette neurotoxine et les dommages neuronaux ; d autre part, nous montrons que la neurotoxicité implique le récepteur NMDA. Le rôle de la Roténone et du L-BMAA dans l étiologie des pathologies neurodégénératives est discuté. Nos travaux montrent que ces deux toxines environnementales sont bel et bien toxiques in vivo sur les neurones rétiniens. Bien que ciblant des populations différentes (respectivement les neurones dopaminergiques et glutamatergiques), leurs effets délétères sont estimés par électrorétinographie, prouvant ainsi l intérêt du modèle rétinien comme méthode d étude in vivo de la toxicité des neurotoxines.NICE-BU Sciences (060882101) / SudocSudocFranceF

Alkaptonuria: From Molecular Insights to a Dedicated Digital Platform

Alkaptonuria (AKU) is a genetic disorder that affects connective tissues of several body compartments causing cartilage degeneration, tendon calcification, heart problems, and an invalidating, early-onset form of osteoarthritis. The molecular mechanisms underlying AKU involve homogentisic acid (HGA) accumulation in cells and tissues. HGA is highly reactive, able to modify several macromolecules, and activates different pathways, mostly involved in the onset and propagation of oxidative stress and inflammation, with consequences spreading from the microscopic to the macroscopic level leading to irreversible damage. Gaining a deeper understanding of AKU molecular mechanisms may provide novel possible therapeutical approaches to counteract disease progression. In this review, we first describe inflammation and oxidative stress in AKU and discuss similarities with other more common disorders. Then, we focus on HGA reactivity and AKU molecular mechanisms. We finally describe a multi-purpose digital platform, named ApreciseKUre, created to facilitate data collection, integration, and analysis of AKU-related data

Dural and pial pain-sensitive structures in humans: new inputs from awake craniotomies

International audienc

ROPMate: Visually Assisting the Creation of ROP-based Exploits

Exploits based on ROP (Return-Oriented Programming) are increasingly present in advanced attack scenarios. Testing systems for ROP-based attacks can be valuable for improving the security and reliability of software. In this paper, we propose ROPMATE, the first Visual Analytics system specifically designed to assist human red team ROP exploit builders. In contrast, previous ROP tools typically require users to inspect a puzzle of hundreds or thousands of lines of textual information, making it a daunting task. ROPMATE presents builders with a clear interface of well-defined and semantically meaningful gadgets, i.e., fragments of code already present in the binary application that can be chained to form fully-functional exploits. The system supports incrementally building exploits by suggesting gadget candidates filtered according to constraints on preserved registers and accessed memory. Several visual aids are offered to identify suitable gadgets and assemble them into semantically correct chains. We report on a preliminary user study that shows how ROPMATE can assist users in building ROP chains

Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria

Alkaptonuria (AKU) is an ultra-rare genetic disease caused by a deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD) leading to the accumulation of homogentisic acid (HGA) on connective tissues. Even though AKU is a multi-systemic disease, osteoarticular cartilage is the most affected system and the most damaged tissue by the disease. In chondrocytes, HGA causes oxidative stress dysfunctions, which induce a series of not fully characterized cellular responses. In this study, we used a human chondrocytic cell line as an AKU model to evaluate, for the first time, the effect of HGA on autophagy, the main homeostasis system in articular cartilage. Cells responded timely to HGA treatment with an increase in autophagy as a mechanism of protection. In a chronic state, HGA-induced oxidative stress decreased autophagy, and chondrocytes, unable to restore balance, activated the chondroptosis pathway. This decrease in autophagy also correlated with the accumulation of ochronotic pigment, a hallmark of AKU. Our data suggest new perspectives for understanding AKU and a mechanistic model that rationalizes the damaging role of HGA

Corpus callosum abnormalities: neuroimaging, cytogenetics and clinical characterization of a very large multicenter Italian series

Corpus callosum abnormalities (CCA) have an estimated prevalence ranging from 0.3% up to 0.7% in patients undergoing brain imaging. CCA can be identified incidentally, or can be part of a developmental disease. We performed a retrospective study of 551 patients, identified non-syndromic (NS) CCA and syndromic (S) CCA, reviewing clinical features, neuroradiological aspects, genetic etiology, and chromosomal microarray (CMA) results. Syndromic CCA subjects were prevalent (60%) and they showed the most severe clinical features. Cortical malformations and cerebellar anomalies were 23% of cerebral malformation associated to CCA (plus), 23 and 14% respectively in syndromic forms. A clinical and/or genetic diagnosis was obtained in 37% of syndromic CCA including chromosomal rearrangements on high-resolution karyotype (18%), microdeletion/microduplication syndromes (31%) and monogenic diseases (51%). Non-syndromic CCA anomalies had mildest clinical features, although intellectual disability was present in 49% of cases and epilepsy in 13%. CMA diagnostic rate in our cohort of patients ranged from 11 to 23% (NS to S). A high percentage of patients (76% 422/551) remain without a diagnosis. Combined high resolution CMA studies and next-generation sequencing (NGS) strategies will increase the probability to identify new causative genes of CCA and to redefine genotype–phenotype correlation

Research needs in allergy: an EAACI position paper, in collaboration with EFA

In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients' Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients' organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herei