Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions

Aplicación de estrategias en la gestión de proyectos en el sector de la ingeniería contra incendios

En la actualidad, la aplicación de estrategias en la gestión de proyectos en el sector de la ingeniería contra incendios será un mecanismo que permitirá el desarrollo estructural y comercial de las organizaciones pertenecientes al sector. Se encuentran diversos estudios centrados en la toma de decisiones estratégicas, herramientas como las metodologías ágiles y cuadro de mando integral, gestión de riesgos y sostenibilidad empresarial que permiten disminuir la incertidumbre y aumentar el éxito en los proyectos en el sector de la ingeniería contra incendios. Lo anterior permite crear un sistema que mejora los procesos estructurales de la gestión de proyectos en el sector de la ingeniería contra incendios en procura del aumento de la competitividad y de la aplicación de estrategias focalizadas, garantizando así la rentabilidad del sector económico y el impacto positivo para una sociedad más sostenible. El objetivo de este estudio permitió identificar las estrategias claves para la planeación, ejecución y cierre de los proyectos cuando se intervienen desde una perspectiva holística enfocada a la mejora continua

Educação e participação

Español: 173 páginas. Portugués: 200 páginas. Publicación Miscelánea (IICA) no. 646.Recopila una serie de trabajos que ponen de relieve los márgenes de acción que realmente existen para desarrollar prácticas educativas participativas en el contexto de los países latinoamericanos. Tres de los trabajos que integran el documento son reflexiones y sistematizaciones generadas en las acciones de cooperación del IICA en Brasil. Los otros dos constituyen valiosas contribuciones de educadores latinoamericanos. No se intenta presentar una teoría de la educación participante, sino dar testimonio de los espacios que podría originar una práctica educativa cada vez más participativa. Los trabajos que se recopilan en el documento son presentados bajo los siguientes títulos: 1) La participación popular en América Latina; 2) Elaboración curricular y aprendizaje colectivo en la educación participativa; 3) Evaluación educacional: tendencias hacia el desarrollo de enfoques participativos; 4) La planificación del desarrollo local como proceso de aprendizaje social; 5) Participación, educación y cultura popular.Compila uma série de trabalhos que destacam as margens de ação realmente existentes para desenvolver práticas educativas participativas no contexto dos países latino-americanos. Três dos trabalhos que compõem o documento são reflexões e sistematizações geradas nas ações de cooperação do IICA no Brasil. Os outros dois são contribuições valiosas de educadores latino-americanos. Não se pretende apresentar uma teoria da educação participativa, mas dar testemunho dos espaços que uma prática educativa cada vez mais participativa pode dar lugar. Os trabalhos compilados no documento são apresentados sob os seguintes títulos: 1) Participação popular na América Latina; 2) Desenvolvimento curricular e aprendizagem coletiva em educação participativa; 3) Avaliação educacional: tendências para o desenvolvimento de abordagens participativas; 4) O planejamento do desenvolvimento local como processo de aprendizagem social; 5) Participação, educação e cultura popular

Diversity of 16S rRNA Genes within Individual Prokaryotic Genomes▿ †

Analysis of intragenomic variation of 16S rRNA genes is a unique approach to examining the concept of ribosomal constraints on rRNA genes; the degree of variation is an important parameter to consider for estimation of the diversity of a complex microbiome in the recently initiated Human Microbiome Project (http://nihroadmap.nih.gov/hmp). The current GenBank database has a collection of 883 prokaryotic genomes representing 568 unique species, of which 425 species contained 2 to 15 copies of 16S rRNA genes per genome (2.22 ± 0.81). Sequence diversity among the 16S rRNA genes in a genome was found in 235 species (from 0.06% to 20.38%; 0.55% ± 1.46%). Compared with the 16S rRNA-based threshold for operational definition of species (1 to 1.3% diversity), the diversity was borderline (between 1% and 1.3%) in 10 species and >1.3% in 14 species. The diversified 16S rRNA genes in Haloarcula marismortui (diversity, 5.63%) and Thermoanaerobacter tengcongensis (6.70%) were highly conserved at the 2° structure level, while the diversified gene in B. afzelii (20.38%) appears to be a pseudogene. The diversified genes in the remaining 21 species were also conserved, except for a truncated 16S rRNA gene in “Candidatus Protochlamydia amoebophila.” Thus, this survey of intragenomic diversity of 16S rRNA genes provides strong evidence supporting the theory of ribosomal constraint. Taxonomic classification using the 16S rRNA-based operational threshold could misclassify a number of species into more than one species, leading to an overestimation of the diversity of a complex microbiome. This phenomenon is especially seen in 7 bacterial species associated with the human microbiome or diseases

Cyanobacterial population and harmful metabolites dynamics during a bloom in Yanghe Reservoir, North China

A significant outbreak of odorous and toxic cyanobacteria occurred in Yanghe Reservoir, North China, in the summer of 2007. The dominant species was Anabaena spiroides and it was accompanied with the occurrence of very high concentrations of the odor metabolite geosmin. The event included two cycles of growth of A. spiroides: the first one of approximately 16 days between 21 June and 8 July, with the peak density 70,000 cells mL−1 on 2 July, and the second smaller bloom of over 50 days between 9 July and the end of August. The bloom also included a range of species of Microcystis, predominantly M. aeruginosa, as the second largest population, which varied from 5800 cells mL−1 to 28,000 cells mL−1 in the first cycle and from 2000 cells mL−1 to 11,000 cells mL−1 in the second. Geosmin reached the peak value of 7100 ng L−1 on 3 July, which was the highest value ever reported. The average geosmin production potential for A. spiroides cells was approximately 0.1 pg cell−1, which was also very high and 85–97% of geosmin was found within the cells and in addition the dissolved geosmin did not increase even during the cyanobacterial decay period. In addition to odor metabolites, three microcystin variants MC-LR, MC-RR, MC-YR and anatoxin-a, most of which were intracellular, were detected, with MC-RR being the dominant cyanotoxin. The highest cyanotoxin concentrations were: dissolved: MC-RR 1.56 μg L−1, MC-YR 0.066 μg L−1, MC-LR 0.544 μg L−1, anatoxin-a 0.106 μg L−1; intracellular: MC-RR 70.1 μg L−1, MC-YR 3.76 μg L−1, MC-LR 24.6 μg L−1, anatoxin-a 0.184 μg L−1, and these occurred on 2 July. The correlation between geosmin and A. spiroides was excellent (R2 = 0.912), however the correlation between anatoxin-a concentrations and Anabaena densities and between MCs concentrations and Microcystis densities was not as strong. This study demonstrated the relatively complex requirement for monitoring cyanobacterial blooms in this lake in China, where both the range of odors and cyanotoxins can be produced in concentrations which can change rapidly over a short time along with the bloom composition. It also demonstrated that both odor compounds and cyanotoxins should be considered in terms of the potential hazard to public water supply when a bloom was dominated by Anabaena and Microcystis occurs.Zonglai Li, Jianwei Yu, Min Yang, Jing Zhang, Michael D. Burch and Wei Ha

Early role of vascular dysregulation on late-onset Alzheimer\u27s disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer\u27s disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system\u27s integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.status: publishe