Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France)

New records and detailed distribution and abundance of selected arthropod species collected between 1999 and 2011 in Azorean native forests.

Of the total 286 species identified, 81% were captured between 1999 and 2000, a period during which only 39% of all the samples were collected. On average, arthropod richness for each island increased by 10% during the time frame of these projects. The classes Arachnida, Chilopoda and Diplopoda represent the most remarkable cases of new island records, with more than 30% of the records being novelties. This study stresses the need to expand the approaches applied in these projects to other habitats in the Azores, and more importantly to other less surveyed taxonomic groups (e.g. Diptera and Hymenoptera). These steps are fundamental for getting a more accurate assessment of biodiversity in the archipelago

Updated cardiovascular prevention guideline of the Brazilian Society of Cardiology: 2019

Sem informação113478788

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Measuring the health-related Sustainable Development Goals in 188 countries : a baseline analysis from the Global Burden of Disease Study 2015

Background In September, 2015, the UN General Assembly established the Sustainable Development Goals (SDGs). The SDGs specify 17 universal goals, 169 targets, and 230 indicators leading up to 2030. We provide an analysis of 33 health-related SDG indicators based on the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015). Methods We applied statistical methods to systematically compiled data to estimate the performance of 33 health-related SDG indicators for 188 countries from 1990 to 2015. We rescaled each indicator on a scale from 0 (worst observed value between 1990 and 2015) to 100 (best observed). Indices representing all 33 health-related SDG indicators (health-related SDG index), health-related SDG indicators included in the Millennium Development Goals (MDG index), and health-related indicators not included in the MDGs (non-MDG index) were computed as the geometric mean of the rescaled indicators by SDG target. We used spline regressions to examine the relations between the Socio-demographic Index (SDI, a summary measure based on average income per person, educational attainment, and total fertility rate) and each of the health-related SDG indicators and indices. Findings In 2015, the median health-related SDG index was 59.3 (95% uncertainty interval 56.8-61.8) and varied widely by country, ranging from 85.5 (84.2-86.5) in Iceland to 20.4 (15.4-24.9) in Central African Republic. SDI was a good predictor of the health-related SDG index (r(2) = 0.88) and the MDG index (r(2) = 0.2), whereas the non-MDG index had a weaker relation with SDI (r(2) = 0.79). Between 2000 and 2015, the health-related SDG index improved by a median of 7.9 (IQR 5.0-10.4), and gains on the MDG index (a median change of 10.0 [6.7-13.1]) exceeded that of the non-MDG index (a median change of 5.5 [2.1-8.9]). Since 2000, pronounced progress occurred for indicators such as met need with modern contraception, under-5 mortality, and neonatal mortality, as well as the indicator for universal health coverage tracer interventions. Moderate improvements were found for indicators such as HIV and tuberculosis incidence, minimal changes for hepatitis B incidence took place, and childhood overweight considerably worsened. Interpretation GBD provides an independent, comparable avenue for monitoring progress towards the health-related SDGs. Our analysis not only highlights the importance of income, education, and fertility as drivers of health improvement but also emphasises that investments in these areas alone will not be sufficient. Although considerable progress on the health-related MDG indicators has been made, these gains will need to be sustained and, in many cases, accelerated to achieve the ambitious SDG targets. The minimal improvement in or worsening of health-related indicators beyond the MDGs highlight the need for additional resources to effectively address the expanded scope of the health-related SDGs.Peer reviewe

A experiência estética: a revista Vogue e os blogs de moda e fitness

This paper debates the aesthetic experience as an important point of adherence to fashion discourse. It is understood that the images construct the feminine are seen primarily as tyrannical. However, tyranny alone would not be able to explain the power that they have in everyday life. In order to demonstrate this paradoxical relationship, we present a brief overview of the fashion editorials of Vogue magazine since 1950 and some notes on fashion and fitness blogs as a development of fashion images.Este artigo pretende colocar em debate a experiência estética como um ponto importante de aderência ao discurso da moda. Entende-se que as imagens que constroem o feminino são tidas, prioritariamente, como tirânicas. No entanto, somente a tirania não seria capaz de explicar a forca que elas possuem no cotidiano feminino. Para demonstrar essa relação paradoxal, apresentamos um breve apanhado dos editoriais de moda da revista Vogue, a partir de 1950, e alguns apontamentos sobre blogs de moda e de fitness como desdobramentos das imagens de moda

Bonequinhas de luxo: um olhar sobre a tirania e o prazer nas revistas de moda

Exportado OPUSMade available in DSpace on 2019-08-13T12:18:49Z (GMT). No. of bitstreams: 2 tesecarlacomp.pdf: 6163942 bytes, checksum: 7cb5d17e3308e58082883a25991303ff (MD5) tese_carla_maria_camargos_mendon_a___bonequinhas__de_luxo_um_olhar_sobre_a___tiran_20150116114205589.pdf: 6146365 bytes, checksum: 0ec948ff462a4c14b2162e8a6ee5ed55 (MD5) Previous issue date: 27O objetivo desta tese é analisar de que forma a moda, por meio da mídia revista, enforma os corpos e subjetividades femininos. No entanto, discute-se também um paradoxo instaurado na relação entre os periódicos impressos e fenômeno da moda: o prazer estético gerado por textos verbo-visuais com pretensões de incitar o consumo. Dessa forma, entende-se que há um movimento que tenta formatar as possíveis leitoras enquanto mulheres, naquilo que são e aparentam, mas ao mesmo tempo é entregue a elas objetos que primam por levá-las a mundos de sonho e deixá-las mergulhar em inúmeras possibilidades que em nada se assemelham à dureza do cotidiano. Para aprofundar nesse paradoxo, foi realizada uma pesquisa que buscou compreender a moda enquanto comunicação, suas relações com a estetização do corpo e do cotidiano e os usos que os sujeitos fazem de sua indumentária. Buscou-se também compreender as dinâmicas de instauração do jornalismo feminino, do qual o de moda torna-se sinônimo, para que fosse elucidada a emergência e importância das imagens na tarefa de tornar a moda pública e consolidá-la tal qual a conhecemos. Os estudos contemporâneos sobre corpo e subjetividade foram cruciais para a análise dos textos verbo-visuais das revistas Vogue America e Brasil, objeto de estudo desta pesquisa. As publicações foram escolhidas por serem as mais importantes em escala mundial e nacional, respectivamente que tratam do tema.The general mission of this investigation is to examine how fashion, through the media magazine, forms the female body and subjectivity. However, the discussion also brought a paradox in framed by the relationship between magazines and fashion phenomenon: the aesthetic pleasure generated by word-visual texts with pretensions to encourage consumption. Thus, it is understood that there is a movement that attempts to format the possible readers as women, what they are and appear, but at the same time is given to them objects that bring dream worlds and let them soak in many possibilities that have no resemblance to the hard life. To examine this paradox, we researched fashion as communication and its relations with the aesthetics of the body and daily life and how people wear their clothes. Also sought to understand the dynamics of the beginning of the female journalism, of which fashion journalism becomes synonym, to elucidate the emergence and importance of the images in making fashion public and consolidate it as we know it. Contemporary studies on the body and subjectivity were crucial for the analysis of verb-visual texts of Vogue America and Brazil, the object of this research. The publications were chosen because they are the most important - national and worldwide, respectively on fashion

Direct laser writing by two-photon polymerization as a tool for developing microenvironments for evaluation of bacterial growth

Monitoring bacteria growth and motion in environments is fundamental to understand, for instance, how they proliferate and contaminate organism. Therefore, techniques to fabricate microenvironments for in situ and in vivo studies are interesting for that purpose. In this work we used two-photon polymerization to fabricate microenvironments and, as a proof of principle, we demonstrated the development of the bacteria ATCC 25922 Escherichia coil (E. coil) into the microstructure surroundings. Two varieties of polymeric microenvironments are presented: (i) a microenvironment doped at specific site with ciprofloxacin, an antibiotic typically used in the treatment of diseases caused by E. coil and (ii) micro-fences, which serve as traps for bacteria. These microenvironments, fabricated by two-photon polymerization, may be a potential platform for drug delivery system, by promoting or inhibiting the growth of bacteria in specific biological or synthetic sites. (C) 2013 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

A double-blind, randomized, comparative study of two type a botulinum toxins in the treatment of primary axillary hyperhidrosis

BACKGROUND Botulinum toxin (BTX) is an effective treatment for primary axillary hyperhidrosis. in this study we used two toxins not bioequivalent: BOTOX (Allergan, Inc.) and Dysport (Beaufour Ipsen Biotech).OBJECTIVE the objective was to compare the efficacy, safety, and tolerability of BOTOX and Dysport in the treatment of primary axillary hyperhidrosis using a conversion factor of 1: 3, respectively.METHODS in a double-blind, randomized prospective study, 10 patients with primary axillary hyperhidrosis and sweat production exceeding 50mg/minute received 50U of BOTOX in one axilla and 150U of Dysport in the other. We performed Minor's test and gravimetry at 0 days, at 15 days, and monthly for 1 year.RESULTS No significant difference was observed in the sweating quantity at baseline. After 1 month all patients had achieved success for both axillae. the sweat rate was reduced by a mean of 97.7% for BOTOX and 99.4% for Dysport, without statistical difference. the duration of benefits was similar between both toxins, with a mean of 260 days for BOTOX and 290 days for Dysport, without statistical difference. the longest symptom-free interval was 12 months (5 patients, 55.6%).CONCLUSIONS BOTOX and Dysport presented similar levels of safety and efficacy in the treatment of primary axillary hyperhidrosis when a conversion factor of 1: 3 was used.Universidade Federal de São Paulo, Dept Dermatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Dermatol, São Paulo, BrazilWeb of Scienc