A polymeric nanomedicine diminishes inflammatory events in renal tubular cells

The polyglutamic acid/peptoid 1 (QM56) nanoconjugate inhibits apoptosis by interfering with Apaf-1 binding to procaspase-9. We now describe anti-inflammatory properties of QM56 in mouse kidney and renal cell models. In cultured murine tubular cells, QM56 inhibited the inflammatory response to Tweak, a non-apoptotic stimulus. Tweak induced MCP-1 and Rantes synthesis through JAK2 kinase and NF-kB activation. Similar to JAK2 kinase inhibitors, QM56 inhibited Tweak-induced NF-kB transcriptional activity and chemokine expression, despite failing to inhibit NF-kB-p65 nuclear translocation and NF-kB DNA binding. QM56 prevented JAK2 activation and NF-kB-p65(Ser536) phosphorylation. The anti-inflammatory effect and JAK2 inhibition by QM56 were observed in Apaf-12/2 cells. In murine acute kidney injury, QM56 decreased tubular cell apoptosis and kidney inflammation as measured by downmodulations of MCP-1 and Rantes mRNA expression, immune cell infiltration and activation of the JAK2-dependent inflammatory pathway. In conclusion, QM56 has an anti-inflammatory activity which is independent from its role as inhibitor of Apaf-1 and apoptosis and may have potential therapeutic relevance.This work was supported by grants from the Instituto de Salud Carlos III (www.isciii.es), FIS: PI07/0020, CP08/1083, PS09/00447 and ISCIII-RETICS REDINREN RD 06/0016; Sociedad Española de Nefrología (www.senefro.org). Álvaro Ucero, Sergio Berzal and Carlos Ocaña supported by Fundacion Conchita Rabago (www.fundacionconchitarabago.net), Alberto Ortiz by the Programa de Intensificación de la Actividad Investigadora in the Sistema Nacional de Salud of the Instituto de Salud Carlos III and the Agencia ‘‘Pedro Lain Entralgo’’ of the Comunidad de Madrid and CIFRA S-BIO 0283/2006 www.madrid.org/lainentralgo) and Adrián Ramos, by FIS (Programa Miguel Servet)

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

OBJECTIVE: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. DESIGN AND METHODS: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. RESULTS: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. CONCLUSIONS: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias

Predicción de la gravedad de neumonías por SARS-CoV-2 a partir de información clínica y contaminación, mediante inteligencia artificial

Introducción La contaminación del aire exterior se ha relacionado con mayor gravedad de las infecciones respiratorias. Por tanto, su inclusión en algoritmos predictivos podrían añadir información para pronosticar la gravedad de neumonías SARS-CoV-2. Material y métodos Estudio observacional longitudinal retrospectivo de cohortes, multicéntrico en 4 hospitales. Se incluyeron ingresos por neumonía SARS-CoV-2 en el primer pico epidémico de COVID-19 (febrero-mayo 2020). Se recogieron hasta 93 variables clínicas, analíticas y radiológicas por cada paciente (sexo, edad, peso, comorbilidades, síntomas, variables fisiológicas en urgencias, sangre, gasometría, etc.). Además, se calcularon los niveles exposición a contaminación por PM$_{10}$, PM$_{2.5}$, O$_{3}$, NO$_{2}$, NO, NO$_{X}$, SO$_{2}$ y CO en su código postal. En función de la evolución clínica de la neumonía, se definieron 3 niveles de gravedad [Tabla 1]. Para predecir dicha gravedad, se desarrolló un algoritmo de inteligencia artificial (IA), tipo ‘Random Forest’ con balanceo y ajuste automático de sus parámetros internos. El algoritmo se entrenó y evaluó mediante 20 repeticiones de validación cruzada 10-fold (90% entrenamiento, 10% validación), estratificando aleatoriamente por hospital y gravedad. Resultados En los conjuntos de validación, el algoritmo alcanzó una capacidad predictiva (área bajo la curva ROC) promedio AUC=0.834 para gravedad nivel 0, AUC=0.724 para 1 y AUC=0.850 para 2 [Figura 1]. Sin la información de contaminantes, su capacidad predictiva se degradó ligeramente (AUCs = 0.829, 0.722, 0.844; respectivamente). Conclusiones Nuestro algoritmo IA es capaz de predecir de manera satisfactoria la evolución de la gravedad en la neumonía; en particular para los casos más leves y más severos. El algoritmo IA extrae las reglas más relevantes a partir principalmente de la información clínica, analítica y radiológica de cada individuo; no obstante, la incorporación de la exposición a contaminantes mejora ligeramente la capacidad predictiva. El impacto de la contaminación podría estar ya reflejado en las analíticas de sangre, a través de su efecto en los niveles de inflamación del paciente (PCT, PCR, LDH, etc.)

Impacto cuantitativo de la contaminación en la probabilidad de muerte por neumonía por SARS-CoV-2

Introducción La evidencia científica disponible señala que la contaminación del aire exterior podría agravar la severidad de la COVID-19 y por ende, incrementar las probabilidades de fallecimiento. Material y métodos Estudio observacional longitudinal retrospectivo de cohortes, multicéntrico en 4 hospitales: 2 en Bizkaia (1 urbano, 1 urbano-rural), Valencia y Barcelona (urbanos). Se incluyeron ingresos por neumonía SARS-CoV-2 en el primer pico epidémico de COVID-19 (febrero-mayo 2020). Para determinar la exposición a contaminación por PM$_{10}$ y NO$_{2}$, se obtuvieron los datos publicados por los organismos autonómicos de calidad del aire, para 2019 y 1er semestre 2020. Se utilizó un Modelo Aditivo Generalizado (GAM) para estimar el nivel diario de contaminante en cada código postal, en función de las coordenadas geográficas y la altitud de las estaciones de medición [Figura 1]. Para determinar la exposición crónica, se calcularon media y máximo en 2019; la aguda se caracterizó por media y máximo en los 7 días anteriores al ingreso. Se estudió la razón de probabilidades (‘odds ratio’, OR) de muerte frente a supervivencia entre nuestra cohorte. Se modeló mediante un GAM con regresión logística, incorporando como efectos fijos sexo, edad y contaminante; hospital como efecto aleatorio e índice de comorbilidad de Charlson como función suave mediantes splines penalizados. Resultados De los 1548 pacientes reclutados, 243 (15.7%) fallecieron durante su hospitalización y/o 30 días postingreso. Según los modelos [Tabla 1], existe evidencia estadística significativa de que la exposición crónica a PM$_{10}$ y NO$_{2}$ incrementan la probabilidad de muerte por neumonía SARS-CoV-2. Compensando por sexo, edad y Charlson -todos factores relacionados positivamente con el OR de muerte- así como por hospital; por cada incremento de 10 μg/m$^{3}$ en el nivel de PM$_{10}$ (máximo anual) el OR aumenta en 10.5%, linealmente proporcional al incremento en la contaminación. Mientras, cada 10 μg/m$^{3}$ más de NO2 (media anual) aumentan OR en 35.7%; cada 10 μg/m$^{3}$ más en exposición aguda a NO2 (media semana pre-ingreso): 62.9%; y NO$_{2}$ (máximo semana): 34.4%. Conclusiones Se cuantificaron y compensaron los efectos de los factores sexo, edad, Charlson y hospital. A igualdad de estos, incrementos en la exposición crónica y aguda a PM$_{10}$ y NO$_{2}$ aumentan de manera lineal y estadísticamente significativa la probabilidad de muerte por neumonía SARS-CoV-2

European Red List of Habitats Part 1. Marine habitats

The European Red List of Habitats provides an overview of the risk of collapse (degree of endangerment) of marine, terrestrial and freshwater habitats in the European Union (EU28) and adjacent regions (EU28+), based on a consistent set of categories and criteria, and detailed data and expert knowledge from involved countries1. A total of 257 benthic marine habitat types were assessed. In total, 19% (EU28) and 18% (EU28+) of the evaluated habitats were assessed as threatened in categories Critically Endangered, Endangered and Vulnerable. An additional 12% were Near Threatened in the EU28 and 11% in the EU28+. These figures are approximately doubled if Data Deficient habitats are excluded. The percentage of threatened habitat types differs across the regional seas. The highest proportion of threatened habitats in the EU28 was found in the Mediterranean Sea (32%), followed by the North-East Atlantic (23%), the Black Sea (13%) and then the Baltic Sea (8%). There was a similar pattern in the EU28+. The most frequently cited pressures and threats were similar across the four regional seas: pollution (eutrophication), biological resource use other than agriculture or forestry (mainly fishing but also aquaculture), natural system modifications (e.g. dredging and sea defence works), urbanisation and climate change. Even for habitats where the assessment outcome was Data Deficient, the Red List assessment process has resulted in the compilation of a substantial body of useful information to support the conservation of marine habitats

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Decreased Retinal Thickness in Type 1 Diabetic Children with Signs of Nonproliferative Diabetic Retinopathy

The retina functions as a neurovascular unit. How early vascular alterations affect neuronal layers remains controversial; early vascular failure could lead to edema increasing retinal thicknesses, but alternatively neuronal loss could lead to reduced retinal thickness. Objective. To evaluate retinal thickness in a cohort of pediatric patients with type 1 diabetes mellitus (PwT1DM) and to analyze differences according to the presence or absence of nonproliferative diabetic retinopathy (NPDR), poor metabolic control, and diabetes duration. Patients and Methods. We performed retinographies and optical coherence tomography (OCT) (TOPCON 3D1000®) to PwT1DM followed at our center and healthy controls. Measurements of the control group served to calculate reference values. Results. 59 PwT1DM (age 12.51 ± 2.59) and 22 healthy controls (age 10.66 ± 2.51) volunteered. Only two PwT1DM, both adolescents with poor metabolic control, presented NPRD. Both showed decreased thicknesses and retinal volumes. The odds ratio of having decreased retinal thickness when signs of NPDR were present was 11.72 (95% IC 1.16–118.28; p=0.036). Conclusions. PwT1DM with NPDR have increased odds of decreased retinal thicknesses and volumes. Whether these changes are reversible by improving metabolic control or not remains to be elucidated

Functional approach to the random mean of a compound Cox process

Marked Poisson processes, Cox processes, Functional data analysis, Narrow-band process,