Neuromyopathy with congenital cataracts and glaucoma: A distinct syndrome caused by POLG variants

We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy

Communication for Peaceful Social Change and Global Citizenry

The adoption of the 17 Sustainable Development Goals (SDGs) by the United Nations (UN) in 2015 represents a universal call to action involving multiple international actors for the purpose of eradicating poverty, improving living conditions and promoting peace. This entry provides a theoretical overview of the contributions of scholars and practitioners who highlight the importance of a transformative, educational and emancipatory communication by different social actors to establish the main lines of action for the 2030 Agenda for Sustainable Development. This communicative model involves the coordination of actors and strategies, both short- and long-term, cross-cutting actions and discourses to build social, cultural and political settings based on the criteria of peace, equality, social justice and human rights. Specifically, this entails a contribution to the objectives set out in SDG 16, “Peace, Justice and Strong Institutions”, given that the proposed theoretical framework is grounded in Communication for Peace and Communication for Social Change, and includes a systematization of different strategies and experiences from a variety of social issuers, mainly institutions, non-governmental organizations (NGOs) or social movements, aimed at promoting peaceful and inclusive societies. Specifically, communication for peaceful social change and global citizenry contributes to the achievement of specific SDG 16 objectives, particularly 16.1: Significantly reduce all forms of violence... [...

Using a Non-Image-Based Medium-Throughput Assay for Screening Compounds Targeting N-myristoylation in Intracellular Leishmania Amastigotes

We have refined a medium-throughput assay to screen hit compounds for activity against N-myristoylation in intracellular amastigotes of Leishmania donovani. Using clinically-relevant stages of wild type parasites and an Alamar blue-based detection method, parasite survival following drug treatment of infected macrophages is monitored after macrophage lysis and transformation of freed amastigotes into replicative extracellular promastigotes. The latter transformation step is essential to amplify the signal for determination of parasite burden, a factor dependent on equivalent proliferation rate between samples. Validation of the assay has been achieved using the anti-leishmanial gold standard drugs, amphotericin B and miltefosine, with EC50 values correlating well with published values. This assay has been used, in parallel with enzyme activity data and direct assay on isolated extracellular amastigotes, to test lead-like and hit-like inhibitors of Leishmania Nmyristoyl transferase (NMT). These were derived both from validated in vivo inhibitors of Trypanosoma brucei NMT and a recent high-throughput screen against L. donovani NMT. Despite being a potent inhibitor of L. donovani NMT, the activity of the lead T. brucei NMT inhibitor (DDD85646) against L. donovani amastigotes is relatively poor. Encouragingly, analogues of DDD85646 show improved translation of enzyme to cellular activity. In testing the high-throughput L. donovani hits, we observed macrophage cytotoxicity with compounds from two of the four NMT-selective series identified, while all four series displayed low enzyme to cellular translation, also seen here with the T. brucei NMT inhibitors. Improvements in potency and physicochemical properties will be required to deliver attractive lead-like Leishmania NMT inhibitors

Global Metabolomic Profiling of Acute Myocarditis Caused by Trypanosoma cruzi Infection

© 2014 Gironès et al. Chagas disease is caused by Trypanosoma cruzi infection, being cardiomyopathy the more frequent manifestation. New chemotherapeutic drugs are needed but there are no good biomarkers for monitoring treatment efficacy. There is growing evidence linking immune response and metabolism in inflammatory processes and specifically in Chagas disease. Thus, some metabolites are able to enhance and/or inhibit the immune response. Metabolite levels found in the host during an ongoing infection could provide valuable information on the pathogenesis and/or identify deregulated metabolic pathway that can be potential candidates for treatment and being potential specific biomarkers of the disease. To gain more insight into those aspects in Chagas disease, we performed an unprecedented metabolomic analysis in heart and plasma of mice infected with T. cruzi. Many metabolic pathways were profoundly affected by T. cruzi infection, such as glucose uptake, sorbitol pathway, fatty acid and phospholipid synthesis that were increased in heart tissue but decreased in plasma. Tricarboxylic acid cycle was decreased in heart tissue and plasma whereas reactive oxygen species production and uric acid formation were also deeply increased in infected hearts suggesting a stressful condition in the heart. While specific metabolites allantoin, kynurenine and p-cresol sulfate, resulting from nucleotide, tryptophan and phenylalanine/tyrosine metabolism, respectively, were increased in heart tissue and also in plasma. These results provide new valuable information on the pathogenesis of acute Chagas disease, unravel several new metabolic pathways susceptible of clinical management and identify metabolites useful as potential specific biomarkers for monitoring treatment and clinical severity in patients.This work was supported by ‘‘Ministerio de Ciencia e Innovación’’ (SAF2010-17833); ‘‘Fondo de Investigaciones Sanitarias’’ (PS09/00538 and PI12/00289); ‘‘Red de Investigación de Centros de Enfermedades Tropicales’’ (RICET RD12/0018/0004); European Union (HEALTH-FE-2008-22303, ChagasEpiNet);‘‘Universidad Autónoma de Madrid’’ and ‘‘Comunidad de Madrid’’ (CC08-UAM/SAL-4440/08); AECID Cooperation with Argentine (A/025417/09 and A/031735/10), Comunidad de Madrid (S-2010/BMD-2332) and ‘‘Fundación Ramón Areces’Peer Reviewe

2 nd Brazilian Consensus on Chagas Disease, 2015

Abstract Chagas disease is a neglected chronic condition with a high burden of morbidity and mortality. It has considerable psychological, social, and economic impacts. The disease represents a significant public health issue in Brazil, with different regional patterns. This document presents the evidence that resulted in the Brazilian Consensus on Chagas Disease. The objective was to review and standardize strategies for diagnosis, treatment, prevention, and control of Chagas disease in the country, based on the available scientific evidence. The consensus is based on the articulation and strategic contribution of renowned Brazilian experts with knowledge and experience on various aspects of the disease. It is the result of a close collaboration between the Brazilian Society of Tropical Medicine and the Ministry of Health. It is hoped that this document will strengthen the development of integrated actions against Chagas disease in the country, focusing on epidemiology, management, comprehensive care (including families and communities), communication, information, education, and research

Baixa percepção de risco entre adolescentes espanhóis em relação ao consumo de álcool

Según los estudios recientes, los adolescentes españoles muestran una baja percepción del riesgo asociado al consumo de alcohol. El objetivo de la presente investigación es analizar los factores que favorecen esta baja percepción a partir de la opinión de un grupo de 32 profesionales/expertos en adolescencia, familia, escuela, medios de comunicación y políticas locales. Se utilizó una metodología cualitativa, fundamentada en Grounded Theory, a partir de la información obtenida mediante 5 grupos de discusión guiados por entrevistas semiestructuradas. Se identificaron 12 factores o subcategorías agrupados en 4 categorías generales: riesgo a corto plazo, inmediatez y percepción de invulnerabilidad (categoría ¿pensamiento adolescente¿); concepción benévola del alcohol, normalización del consumo y binomio alcohol-diversión (categoría ¿normas sociales¿); consumo habitual en los padres, inconsistencia verbal-no verbal en el modelado parental, consumo sin riesgo en los medios, consumo con resultados positivos en los medios (categoría ¿modelos sociales¿); excesivo contenido sanitario, riesgo a largo plazo (categoría ¿discurso preventivo¿). Tras discutir los resultados en el contexto de la literatura científica actual, se realizan varias propuestas con el objetivo de aumentar la percepción del riesgo en los adolescentes: incidir con mayor fuerza en contenidos sobre los riesgos a corto plazo del alcohol; orientar las estrategias educativas dirigidas al adolescente, también hacia los agentes de socialización, especialmente los padres; incidir en políticas centradas en la sustancia y en reducir la oferta.According to recent studies, Spanish adolescents show low perception of risk in alcohol consumption. The current study aims to analyze the factors that favor this low perception based on the opinion of a group of 32 professional experts on adolescence, family, school, mass media, and local policies. A qualitative methodology was used, based on Grounded Theory, using information from 5 focus groups guided by semi-structured interviews. Twelve factors or subcategories were identified, grouped in 4 general categories: short-term risk, immediacy, and perception of invulnerability (¿adolescent thinking¿ category); benevolent view of alcohol, normalization of consumption, and alcohol-entertainment binomial (¿social norms¿ category); parents¿ habitual consumption, verbal/non-verbal inconsistency in parental model, risk-free consumption depicted in the mass media, consumption with positive results in the media (¿social models¿ category); and excessive health content, long-term risk (¿preventive discourse¿ category). After discussing the results in the context of the current scientific literature, the article offers various proposals for increasing risk perception in adolescents: stronger impact of contents on short-term risks of alcohol; educational strategies targeted to adolescents to include agents of socialization, especially parents; and policies centered on the substance and reduction of supply.De acordo com estudos recentes, os adolescentes espanhóis mostram baixa percepção de risco em relação ao consumo de álcool. O estudo tem como objetivo analisar os fatores associados com a baixa percepção de risco, com base nas opiniões de um grupo de 32 especialistas em adolescência, família, escola, mídia e políticas locais. Foi utilizada uma metodologia qualitativa, baseada na Teoria Fundamentada, usando informações de cinco grupos focais orientados por entrevistas semi-estruturadas. Foram identificados 12 fatores ou subcategorias, agrupados em quatro categorias gerais: risco no curto prazo, imediatismo e percepção de invulnerabilidade (categoria de ¿pensamento adolescente¿); visão benevolente em relação ao álcool, normalização do consumo e binômio álcool-entretenimento (categoria de ¿normas sociais¿); consumo habitual pelos pais, inconsistência na comunicação verbal versus não verbal no modelo representado pelos pais, consumo isento de risco retratado pela mídia, consumo com resultados positivos na mídia (categoria de ¿modelos sociais¿) e excesso de conteúdo relacionado à saúde, risco no longo prazo (categoria de ¿discurso preventivo¿). Depois de discutir os resultados no contexto da literatura científica atual, o artigo oferece várias propostas para aumentar a percepção de risco entre os adolescentes: impacto mais forte de conteúdos sobre os riscos do álcool no curto prazo; estratégias educativas orientadas aos adolescentes para incluir os agentes da socialização, especialmente os pais, além de políticas centradas na substância e na redução da oferta.Departamento de Educación y Psicología SocialVersión del edito