Patients with ALS show highly correlated progression rates in left and right limb muscles.

ObjectiveAmyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.MethodsA large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.ResultsThis report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.ConclusionsFirst, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials

Analytical Model of Socio-Technical Sustainability of Dynamic Hypermedia Devices

Este artículo presenta un modelo analítico de sostenibilidad de redes socio-técnicas para la construcción colaborativa de conocimiento en contextos institucionales y organizacionales. El objetivo se centra en fundamentar una perspectiva teórica-metodológica a partir de la noción de “dispositivo hipermedial dinámico” (DHD). En lo metodológico, desde un posicionamiento sociotécnico, se realiza una revisión de los principales debates y perspectivas teóricas sobre la expansión de TIC en relación a la problemática a tratar. Luego se desarrollan propositivamente las componentes del modelo de sostenibilidad-DHD siguiendo sus cuatro dimensiones: social, institucional, tecnológica y textual. El diseño del modelo, no jerárquico y relacional, se estima a su vez beneficioso para orientar el proceso constructivo de este tipo de dispositivos. Además, puede colaborar de manera flexible para analizar transformaciones socio-tecnológicas en diversos contextos situados. Finalmente, la consistencia de los resultados analíticos a alcanzar podría ser efectiva, ya que es posible vincular: el carácter dinámico, relacional e interactivo de las características de una tecnología; las tensiones sociales y políticas existentes en el marco socio-institucional donde se desarrolla; las posibles formas de diseño participativo, en función de los requerimientos de una institución u organización; y la producción colaborativa en red, promoviendo responsabilidades de gestión organizacional.Este artigo apresenta um modelo analítico de sustentabilidade de redes sociotécnicas para a construção colaborativa de conhecimento em contextos institucionais/organizacionais. O objetivo é focado na fundamentação de uma perspectiva teórico-metodológica a partir da noção de “dispositivo hipermedial dinâmico” (DHD). No metodológico, a partir de um posicionamento sociotécnico, é feita uma revisão dos principais debates e perspectivas teóricas sobre a expansão de TIC em relação à problemática a ser tratada. Depois, são desenvolvidos propositivamente os componentes do modelo de sustentabilidade-DHD seguindo suas quatro dimensões: social, institucional, tecnológica e textual. O design do modelo, não hierárquico e relacional, é também considerado propício para orientar o processo construtivo deste tipo de dispositivos. Além disso, pode colaborar de forma flexível para analisar transformações sociais tecnológicas em diversos contextos. Finalmente, a consistência dos resultados analíticos a serem alcançados poderia ser efetiva, pois é possível vincular: o caráter dinâmico, relacional e interativo das características de uma tecnologia; as tensões sociais e políticas existentes no plano social institucional onde é desenvolvido; as possíveis formas de design participativo, em função dos requerimentos de uma instituição ou organização; e a produção colaborativa em rede, promovendo responsabilidades de gestão organizacional.This paper presents an analytical model of sustainable socio-technical networks for the collaborative knowledge building in organizational/institutional contexts. Its objective focuses on supporting a theoretic-methodological perspective based on the idea of a “dynamic hypermedia device” (DHD). With regard to the methodological aspect, from a socio-technical position, the main debates and theoretical perspectives about the expansion of information and communication technologies pertinent to the issue to be discussed are reviewed. Then the components of the sustainability-DHD model are developed proactively, following its four dimensions: social, institutional, technological and textual. The design of the model, nonhierarchical and relational, is considered beneficial to guide the building process of these kinds of devices. In addition, it can collaborate in a flexible way in order to analyze the sociotechnological transformations in diverse situational contexts. Finally, the consistency of the analytical results to be reached could be effective, since it is possible to connect: the dynamic, relational and interactive aspects of the technology’s characteristics; the social and political tensions within the socio-institutional framework in which it develops; the possible ways of participative design, as a function of the institution or organization’s requirements; and the networked collaborative production, promoting organizational management responsibilities.Fil: Andres, Gonzalo Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto Rosario de Investigaciones en Ciencias de la Educación. Universidad Nacional de Rosario. Instituto Rosario de Investigaciones en Ciencias de la Educación; ArgentinaFil: San Martin, Patricia Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto Rosario de Investigaciones en Ciencias de la Educación. Universidad Nacional de Rosario. Instituto Rosario de Investigaciones en Ciencias de la Educación; ArgentinaFil: Rodriguez, Guillermo L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto Rosario de Investigaciones en Ciencias de la Educación. Universidad Nacional de Rosario. Instituto Rosario de Investigaciones en Ciencias de la Educación; Argentin

Development of an Antioxidant Phytoextract of Lantana grisebachii with Lymphoprotective Activity against In Vitro Arsenic Toxicity

Phytochemicals have been presumed to possess prophylactic and curative properties in several pathologies, such as arsenic- (As-induced immunosuppression. Our aim was to discover a lymphoprotective extract from Lantana grisebachii Stuck. (Verbenaceae)(LG). We assessed its bioactivity and chemical composition using cell-based assays. Fractions produced from a hexane extract acutely induced nitrite formation in T- Activated cell cultures (P < 0.0001). Water extraction released a fraction lacking nitrite inducing activity in both lymphocyte types. Aqueous LG was found to be safe in proliferated and proliferating cells. The infusion-derived extract presented better antioxidant capacity in proportion to phenolic amount in lymphocytes (infusive LG- 1i at 100g/mL), which protected them against in vitro As-induced lymphotoxicity (P < 0.0001). This infusive LG phytoextract contained 10.23 ± 0.43mg/g of phenolics, with 58.46% being flavonoids. Among the phenolics, the only predominant compound was 0.723 mg of chlorogenic acid per gram of dry plant, in addition to 10 unknown minor compounds. A fatty acid profile was assessed. It contained one-third of saturated fatty acids, one-third of 9, followed by 6 (∼24%) and 3 (∼4%), and scarce 7. Summing up, L. grisebachiiwas a source of bioactive and lymphoprotective compounds, which could counteract As-toxicity. This supports its phytomedical use and research in order to reduce As-related dysfunctionsFil: Soria, Elio Andres. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Biologia Celular; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Quiroga, Patricia L.. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Biologia Celular; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Albrecht, Claudia. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Biologia Celular; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Ramos Elizagaray, Sabina I.. Consejo Interuniversitario Nacional; ArgentinaFil: Cantero, Juan J.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Río Cuarto. Facultad de Agronomía y Veterinaria; ArgentinaFil: Bongiovanni, Guillermina Azucena. Universidad Nacional del Comahue. Facultad de Ciencis Agrarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas; Argentin

β-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice

β-site APP cleaving enzyme 1 (BACE1) initiates APP cleavage, which has been reported to be an inducer of tau pathology by altering proteasome functions in Alzheimer's disease (AD). However, the exact relationship between BACE1 and PHF (Paired Helical Filaments) formation is not clear. In this study, we confirm that BACE1 and Hsc70 are upregulated in the brains of AD patients, and we demonstrate that both proteins show enhanced expression in lipid rafts from AD-affected triple transgenic mouse brains. BACE1 targeting increased Hsc70 levels in the membrane and cytoplasm fractions and downregulated Hsp90 and CHIP in the nucleus in the hippocampi of 3xTg-AD mice. However, these observations occurred in a proteasome-independent manner in vitro. The BACE1miR-induced reduction of soluble hyperphosphorylated tau was associated with a decrease in MAPK activity. However, the BACE1 RNAi-mediated reduction of hyperphosphorylated tau was only blocked by 3-MA (3-methyladenine) in vitro, and it resulted in the increase of Hsc70 and LAMP2 in lipid rafts from hippocampi of 3xTg-AD mice, and upregulation of survival and homeostasis signaling. In summary, our findings suggest that BACE1 silencing neuroprotects reducing soluble hyperphosphorylated tau, modulating certain autophagy-related proteins in aged 3xTg-AD mice

Egg intervention effect on linear growth no longer present after two years.

The Lulun Project, a randomized controlled trial conducted in 2015, found that one egg per day for 6 months during early complementary feeding reduced stunting by 47% and increased linear growth by 0.63 length-for-age Z (LAZ). This follow-up cohort study (Lulun Project II) aimed to test whether the growth effect remained in the egg intervention group compared with the control group after approximately 2 years. Mothers or caregivers from the Lulun Project were recontacted and recruited for this study. Enumerators collected data on socio-economic and demographic factors, 24-hr frequency of dietary intakes, morbidities, and anthropometric measures of height, weight, and head circumference using World Health Organization protocols. Statistical analyses followed the same analytical plan as Lulun Project, applying generalized linear models and regression modelling to test group differences in height-for-age z (HAZ) from LAZ at Lulun Project endline, and structural equation modelling for mediation. One hundred thirty-five mother-child dyads were included in Lulun II, with 11% losses to follow-up from endline Lulun Project. Growth faltering across all children was evident with HAZ -2.07 ± 0.91 and a stunting prevelance of 50%. Regression modelling showed no difference between egg and control groups for the HAZ outcome and other anthropometric outcomes, and significant declines in HAZ from endline Lulun Project in the egg intervention are compared with control groups. Current dietary egg intake, however, was associated with reduced growth faltering in HAZ from Lulun Project endline to Lulun Project II, independent of group assignment and through mediation, explaining 8.8% of the total effect. Findings suggest the need for a longer intervention period and ongoing nutrition support to young children during early childhood

Reconstructing the Population Genetic History of the Caribbean

The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, by making use of genome-wide SNP array data, we characterize ancestral components of Caribbean populations on a sub-continental level and unveil fine-scale patterns of population structure distinguishing insular from mainland Caribbean populations as well as from other Hispanic/Latino groups. We provide genetic evidence for an inland South American origin of the Native American component in island populations and for extensive pre-Columbian gene flow across the Caribbean basin. The Caribbean-derived European component shows significant differentiation from parental Iberian populations, presumably as a result of founder effects during the colonization of the New World. Based on demographic models, we reconstruct the complex population history of the Caribbean since the onset of continental admixture. We find that insular populations are best modeled as mixtures absorbing two pulses of African migrants, coinciding with early and maximum activity stages of the transatlantic slave trade. These two pulses appear to have originated in different regions within West Africa, imprinting two distinguishable signatures in present day Afro-Caribbean genomes and shedding light on the genetic impact of the dynamics occurring during the slave trade in the Caribbean.Comment: 26 pages, 6 figures, and supporting informatio

Risperidone Treatment of Autistic Disorder: Longer-Term Benefits and Blinded Discontinuation After 6 Months

Objective: Risperidone is effective for short-term treatment of aggression, temper outbursts, and self-injurious behavior in children with autism. Because these behaviors may be chronic, there is a need to establish the efficacy and safety of longer-term treatment with this agent. Method: The authors conducted a multisite, two-part study of risperidone in children ages 5 to 17 years with autism accompanied by severe tantrums, aggression, and/or self-injurious behavior who showed a positive response in an earlier 8-week trial. Part I consisted of 4-month open-label treatment with risperidone, starting at the established optimal dose; part II was an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal. Primary outcome measures were the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression improvement scale. Results: Part I included 63 children. The mean risperidone dose was 1.96 mg/day at entry and remained stable over 16 weeks of open treatment. The change on the Aberrant Behavior Checklist irritability subscale was small and clinically insignificant. Reasons for discontinuation of part I included loss of efficacy (N=5) and adverse effects (N=1). The subjects gained an average of 5.1 kg. Part II included 32 patients. The relapse rates were 62.5% for gradual placebo substitution and 12.5% for continued risperidone; this difference was statistically significant. Conclusions: Risperidone showed persistent efficacy and good tolerability for intermediate-length treatment of children with autism characterized by tantrums, aggression, and/or self-injurious behavior. Discontinuation after 6 months was associated with a rapid return of disruptive and aggressive behavior in most subjects

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.