Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Background: Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. Methods: A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. Results: WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. Conclusion: This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice

Right Structural and Functional Reorganization in Four-Year-Old Children with Perinatal Arterial Ischemic Stroke Predict Language Production

Brain imaging methods have contributed to shed light on the mechanisms of recovery after early brain insult. The assumption that the unaffected right hemisphere can take over language functions after left perinatal stroke is still under debate. Here, we report how patterns of brain structural and functional reorganization were associated with language outcomes in a group of 4-year-old children with left perinatal arterial ischemic stroke. Specifically, we gathered specific fine-grained developmental measures of receptive and productive aspects of language as well as standardized measures of cognitive development. We also collected structural neuroimaging data as well as functional activations during a passive listening story-telling fMRI task and a resting state session (rs-fMRI). Children with a left perinatal stroke showed larger lateralization indices of both structural and functional connectivity of the dorsal language pathway towards the right hemisphere that, in turn, were associated with better language outcomes. Importantly, the pattern of structural asymmetry was significantly more right-lateralized in children with a left perinatal brain insult than in a group of matched healthy controls. These results strongly suggest that early lesions of the left dorsal pathway and the associated perisylvian regions can induce the inter-hemispheric transfer of language functions to right homolog regions. This study provides combined evidence of structural and functional brain reorganization of language networks after early stroke with strong implications for neurobiological models of language development

Espècie equina: manual lesional de suport per al dictamen de carns fresques

Escorxador; Equina; Carn; Control oficialMatadero; Equina; Carne; Control oficialSlaughterhoure; Equine; Meat; Official controlLa inspecció post mortem que efectua el col·lectiu de veterinaris oficials d’escorxador és una part important dels controls oficials relatius a la carn fresca i, com a tal, és un dels elements que condiciona que es dictamini com a apta o no per al consum humà i que s’hagin de notificar les malalties de declaració obligatòria. Els escorxadors són entorns òptims per observar i registrar les particularitats de la variada patologia animal que s’hi presenta. Aquesta informació, si és compartida, pot esdevenir una eina molt útil i interessant per al col·lectiu de professionals. En conseqüència, s’ha creat una comunitat de pràctica per tal de desenvolupar també el Manual lesional de suport per al dictamen de carns fresques de l’espècie equina. L’autoria d’aquest manual és de veterinaris oficials d’escorxador de la Generalitat de Catalunya i de l’Agència de Salut Pública de Barcelona, amb la col·laboració de veterinaris oficials d’altres comunitats autònomes. El contingut s’ha volgut transmetre per mitjà de fitxes que contenen informació científica, tècnica i legal per a cada una de les malalties i lesions que s’hi descriuen. Alhora, les fitxes s’il·lustren amb imatges obtingudes a diferents escorxadors de Catalunya i de Navarra. El propòsit és que les fitxes puguin ser un suport pràctic per a la inspecció post mortem i una ajuda per al dictamen. Per això, s’ha procurat establir un posicionament vers el dictamen de les carns amb els motius desenvolupats de la manera més concreta possible.La inspección post mortem que efectúa el colectivo de veterinarios oficiales de matadero es una parte importante de los controles oficiales relativos a la carne fresca y, como tal, es uno de los elementos que condiciona que se dictamine como apta o no para el consumo humano y que deban notificarse las enfermedades de declaración obligatoria. Los mataderos son entornos óptimos para observar y registrar las particularidades de la variada patología animal que se presenta. Esta información, si es compartida, puede convertirse en una herramienta muy útil e interesante para el colectivo de profesionales. En consecuencia, se ha creado una comunidad de práctica para desarrollar también el Manual lesional de soporte para el dictamen de carnes frescas de la especie equina. La autoría de este manual es de veterinarios oficiales de matadero de la Generalidad de Cataluña y de la Agencia de Salud Pública de Barcelona, con la colaboración de veterinarios oficiales de otras comunidades autónomas. El contenido se ha querido transmitir por medio de fichas que contienen información científica, técnica y legal para cada una de las enfermedades y lesiones que se describen. Asimismo, las fichas se ilustran con imágenes obtenidas en diferentes mataderos de Cataluña y Navarra. El propósito es que las fichas puedan ser un soporte práctico para la inspección post mortem y una ayuda para el dictamen. Por eso, se ha procurado establecer un posicionamiento hacia el dictamen de las carnes con los motivos desarrollados de la forma más concreta posible.The post-mortem inspection carried out by the group of official slaughterhouse veterinarians is an important part of the official controls related to fresh meat and, as such, is one of the elements that determines whether or not it is deemed fit for human consumption and Notifiable diseases must be notified. Slaughterhouses are optimal environments to observe and record the particularities of the varied animal pathology that occurs. This information, if shared, can become a very useful and interesting tool for the group of professionals. Consequently, a community of practice has been created to also develop the Support Injury Manual for the opinion of fresh meat of the equine species. The authorship of this manual is official slaughterhouse veterinarians of the Generalitat de Catalunya and the Barcelona Public Health Agency, with the collaboration of official veterinarians from other autonomous communities. The content has been conveyed through sheets containing scientific, technical and legal information for each of the diseases and injuries described. Likewise, the sheets are illustrated with images obtained in different slaughterhouses in Catalonia and Navarre. The purpose is that the cards can be a practical support for the post mortem inspection and an aid for the opinion. For this reason, an attempt has been made to establish a position towards the opinion of meats with the reasons developed in the most concrete way possible

ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

BackgroundWhole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts.MethodsWe developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA).ResultsClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes.ConclusionsClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses

Management of wild boar populations in EU countries before and during the ASF crisis

In recent decades, wild boar populations have been increasing worldwide due to several potential causes, including human-induced and natural environmental changes and biological and ecological factors. In Europe, this phenomenon has several economic, social and environmental implications such as the increase of agricultural and forest damage, road traffic accidents and potential ecological impact on animal and plant biodiversity. In addition, wild boar population growth and expansion can contribute to the maintenance and dissemination of infectious pathogens affecting animal and human health. In this context, the emergence of African swine fever (ASF) in Europe has become a serious challenge for animal disease control. The high susceptibility of wild boar to ASF infections and the capacity of the virus to remain infective in wild boar carcasses require a combination of wildlife management and veterinary strategies in order to eradicate this virus from EU forests. The goal of this chapter is to provide a thorough overview of those efforts. After illustrating the current situation of wild boar populations in Europe, the chapter describes the different methods applied by wildlife managers in the absence of ASF. Subsequently, the chapter reviews different approaches and tools applied in the context of ASF control, with a particular focus on the strategies implemented by countries that were successful in their eradication, such as Belgium and the Czech Republic. The last section of the chapter highlights areas that require future research to improve ASF management in natural wild boar populations, which remains a serious challenge for the large majority of countries in the EU.This publication is based upon work from COST Action CA15116, ASF-STOP, supported by COST (European Cooperation in Science and Technology).Peer reviewe

Los asentamientos fortificados del curso inferior del Ebro. Siglos V – III aC.

La documentación arqueológica disponible en el curso inferior del Ebro indica que el poblamiento ibérico entre los siglos v y iii a.C. se estructura en una distribución homogénea de pequeños núcleos de hábitat fortificados, que siguen unas pautas similares en cuanto al tamaño, localización, urbanismo y sistemas defensivos. Estas pautas son diferentes de las características del poblamiento contemporáneo en zonas limítrofes, lo que sugiere que se trata de un territorio con una cierta entidad sociopolítica, la Ilercavonia del Ebro. Este tipo de hábitat empieza a ser relativamente bien conocido gracias a los trabajos en curso en distintos yacimientos. En cambio, desconocemos la posible existencia de otras formas de ocupación, sobre todo en la llanura aluvial, especialmente todos aquellos yacimientos relacionados con funciones productivas específicas: explotaciones agrícolas, ganaderas, alfares, etc. Por otra parte, aún desconocemos el proceso de formación de esta estructura de poblamiento, ya que en general la documentación arqueológica sugiere una cierta discontinuidad entre el Ibérico Antiguo y el Pleno. Las novedades del siglo vi a.C. aparecidas en los yacimientos de L’Assut (Tivenys) y de Sebes (Flix) incrementan de forma significativa la información disponible y abren la puerta a nuevas hipótesis.The available archaeological documentation on the lower reaches of the Ebro indicates that the Iberian population between the 5th and the 3rd centuries BC was distributed homogenously in small fortified habitats that were all similar in terms of size, location, urban planning and defensive systems. These features were different to those that characterised the contemporary settlement patterns of the bordering areas, suggesting that it was a territory with a certain sociopolitical significance, the Ilercavonia of the Ebro. This type of habitat is beginning to become relatively well known thanks to the work currently being undertaken at various archaeological sites. On the other hand, we do not know if there were other types of occupation, especially on the alluvial plain, particularly all those archaeological sites related to specific productive functions: farming, stockbreeding, potteries, etc. Neither do we know how this population structure came about, as in the archaeological documentation there is normally a certain discontinuity between the Early and Middle Iberian periods. The new discoveries from the 6th century BC at the archaeological sites of L’Assut (Tivenys) and Sebes (Flix) significantly increase the available information and open the way to new hypotheses

Right structural and functional reorganization in four-year-old children with perinatal arterial ischemic stroke predict language production

Brain imaging methods have contributed to shed light on the mechanisms of recovery after early brain insult. The assumption that the unaffected right hemisphere can take over language functions after left perinatal stroke is still under debate. Here, we report how patterns of brain structural and functional reorganization were associated with language outcomes in a group of four-year-old children with left perinatal arterial ischemic stroke (PAIS). Specifically, we gathered specific fine-grained developmental measures of receptive and productive aspects of language as well as standardized measures of cognitive development. We also collected structural neuroimaging data as well as functional activations during a passive listening story-telling fMRI task and a resting state session (rs-fMRI). Children with a left perinatal stroke showed larger lateralization indices of both structural and functional connectivity of the dorsal language pathway towards the right hemisphere that, in turn, were associated with better language outcomes. Importantly, the pattern of structural asymmetry was significantly more right-lateralized in children with a left perinatal brain insult than in a group of matched healthy controls. These results strongly suggest that early lesions of the left dorsal pathway and the associated perisylvian regions can induce the interhemispheric transfer of language functions to right homolog regions. This study provides combined evidence of structural and functional brain reorganization of language networks after early stroke with strong implications for neurobiological models of language development