Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ.

Background&aimsHepatic stellate cells (HSCs) play a key role in liver fibrosis in various chronic liver disorders including nonalcoholic fatty liver disease (NAFLD). The development of liver fibrosis requires a phenotypic switch from quiescent to activated HSCs. The triggers for HSCs activation in NAFLD remain poorly understood. We investigated the role and molecular mechanism of extracellular vesicles (EVs) released by hepatocytes during lipotoxicity in modulation of HSC phenotype.MethodsEVs were isolated from fat-laden hepatocytes by differential centrifugation and incubated with HSCs. EV internalization and HSCs activation, migration and proliferation were assessed. Loss- and gain-of-functions studies were performed to explore the potential role of PPAR-γ-targeting miRNAs carried by EVs into HSC.ResultsHepatocyte-derived EVs released during lipotoxicity are efficiently internalized by HSCs resulting in their activation, as shown by marked up-regulation of pro-fibrogenic genes (Collagen-I, α-SMA and TIMP-2), proliferation, chemotaxis and wound healing responses. These changes were associated with miRNAs shuttled by EVs and suppression of PPAR-γ expression in HSC. Hepatocyte-derived EVs miRNA content included various miRNAs that are known inhibitors of PPAR-γ expression with miR-128-3p being the most effectively transferred. Furthermore loss- and gain-of-function studies identified miR-128-3p as a central modulator of the effects of EVs on PPAR-γ inhibition and HSC activation.ConclusionOur findings demonstrate a link between fat-laden hepatocyte-derived EVs and liver fibrosis and have potential implications for the development of novel anti-fibrotic targets for NAFLD and other fibrotic diseases

KNH2 - KH: a metal amide - hydride solid solution

We report for the first time the formation of a metal amide-hydride solid solution. The dissolution of KH into KNH2 leads to an anionic substitution, which decreases the interaction among NH2 - ions. The rotational properties of the high temperature polymorphs of KNH2 are thereby retained down to room temperature.Fil: Santoru, Antonio. Helmholtz-zentrum Geesthacht; Alemania. Università di Torino; ItaliaFil: Pistidda, Claudio. Helmholtz-zentrum Geesthacht; AlemaniaFil: Sørby, Magnus H.. Institute for Energy Technology. Physics Department; NoruegaFil: Chierotti, Michele R.. Università di Torino; ItaliaFil: Garroni, Sebastian. University of Sassari; ItaliaFil: Pinatel, Eugenio. Università di Torino; ItaliaFil: Karimi, Fahim. Helmholtz-zentrum Geesthacht; AlemaniaFil: Cao, Hujun. Helmholtz-zentrum Geesthacht; AlemaniaFil: Bergemann, Nils. Helmholtz-zentrum Geesthacht; AlemaniaFil: Le, Thi T.. Helmholtz-zentrum Geesthacht; AlemaniaFil: Puszkiel, Julián Atilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Gobetto, Roberto. Università di Torino; ItaliaFil: Baricco, Marcello. Università di Torino; ItaliaFil: Hauback, Bjorn C.. Institute for Energy Technology. Physics Department; NoruegaFil: Klassen, Thomas. Helmholtz-zentrum Geesthacht; AlemaniaFil: Dornheim, Martín. Helmholtz-zentrum Geesthacht; Alemani

Significância prognóstica das micrometástases ocultas em linfonodos no câncer gástrico: estudo histoquímico e imunoistoquímico baseado nas classificações UICC TNM de 1997 e JCGCA de 1998

BACKGROUND: Micrometastasis is a single or a cluster of malignant cells inside the lymph node that are not detected by routine histopathological sections. Micrometastasis is related to poorer prognosis in many gastric cancer studies the real significance of these cells is still controversial. AIM: To evaluate if lymph node micrometastasis is a significant independent prognostic factor and important risk factor for recurrence in gastric cancer. METHODS: A total of 1290 lymph nodes from 28 patients with gastric cancer, since 1998 until 2003, treated by radical resection (D2 and modified D3 lymphadenectomies) were studied. Three sections per lymph node were stained by Hematoxilin-Eosin, histochemical (AB-PAS) and immunohistochemical (AE1-AE3) techniques. Kaplan-Meier's survival curves and Log-rank/Cox tests were used in order to compares lymph node micrometastasis positivity, depth (pT) and location of tumor in gastric wall, histologic type, lymphatic, vascular and perineural invasion, lymph node status (pN) and stage. RESULTS: There were worse prognosis and recurrence in patients with positive lymph node micrometastasis related to vascular and perineural invasions, advanced lymph node status and advanced stages. CONCLUSION: Lymph node micrometastasis seems to be a significant independent prognostic factor and important risk factor for recurrence in gastric cancer, in a context of radical D2 lymphadenectomyRACIONAL: Micrometástases são um conjunto de células malignas dentro de linfonodo que não são detectadas pelos exames histopatológicos de rotina. Elas são relacionadas a prognóstico mais pobre em muitos estudos sobre câncer gástrico, mas a real significância dessas células permanece controversa. OBJETIVO: Avaliar se micrometástase linfonodal é um fator independente de prognóstico e importante para detectar a recurrência do câncer gástrico. MÉTODOS: Um total de 1290 lifonodos de 28 pacientes com câncer gástrico, de 1998 a 2003, tratados com operações radicais (D2 e D3 modificadas) foram revistos. Três secções por linfonodo foram corados por Hematoxilina-Eosina, histoquímica (AB-PAS) e imunoistoquímica (AE1-AE3). Curvas de sobrevida de Kaplan-Meyer e teste de Log-rank/Cox foram usados para comparar positividade das imcrometástases, profundidade (pT) e localização tumoral na parede gástrica, tipo histológico, invasão linfática, vascular e perineural, estado linfonodal (pN) e estádio onde se encontra a doença. RESULTADOS: Houve pior prognóstico e recurrência nos pacientes com linfonodos com micrometástases relacionadas às invasões vascular e perineural , avançado estado de invasão linfática e estadiamento mais elevado. CONCLUSÃO: Micrometástase parece ser importante e independente fator de risco para recurrência no câncer gástrico no contexto das linfadenectomias radicais D2

Inhibitory axons are targeted in hippocampal cell culture by anti-Caspr2 autoantibodies associated with limbic encephalitis

International audienceContactin-associated protein-like 2 (Caspr2), also known as CNTNAP2, is a cell adhesion molecule that clusters voltage-gated potassium channels (Kv1.1/1.2) at the juxtaparanodes of myelinated axons and may regulate axonal excitability. As a component of the Kv1 complex, Caspr2 has been identified as a target in neuromyotonia and Morvan syndrome, but also in some cases of autoimmune limbic encephalitis (LE). How anti-Caspr2 autoimmunity is linked with the central neurological symptoms is still elusive. In the present study, using anti-Caspr2 antibodies from seven patients affected by pure LE, we determined that IgGs in the cerebrospinal fluid of four out seven patients were selectively directed against the N-terminal Discoïdin and LamininG1 modules of Caspr2. Using live immunolabeling of cultured hippocampal neurons, we determined that serum IgGs in all patients strongly targeted inhibitory interneurons. Caspr2 was highly detected on GAD65-positive axons that are surrounding the cell bodies and at the VGAT-positive inhibitory presynaptic contacts. Functional assays indicated that LE autoantibodies may induce alteration of Gephyrin clusters at inhibitory synaptic contacts. Next, we generated a Caspr2-Fc chimera to reveal Caspr2 receptors on hippocampal neurons localized at the somato-dendritic compartment and post-synapse. Caspr2-Fc binding was strongly increased on TAG-1-transfected neurons and conversely, Caspr2-Fc did not bind hippocampal neurons from TAG-1-deficient mice. Our data indicate that Caspr2 may participate as a cell recognition molecule in the dynamics of inhibitory networks. This study provides new insight into the potential pathogenic effect of anti-Caspr2 autoantibodies in central hyperexcitability that may be related with perturbation of inhibitory interneuron activity

Melhoria da Atenção ao Pré- Natal e Puerpério na UBS/ESF Pedro Bairro Monteiro, Macapá/AP

PINATEL, Enma Rodrigues. Melhoria da Atenção ao Pré- natal e Puerpério na UBS/ESF Pedro Bairro Monteiro, Macapá/AP. 2015. 105 folhas. Trabalho de Conclusão de Curso – Programa de Pós-Graduação em Saúde da Família – Modalidade a Distância, Faculdade de Medicina, Universidade Federal de Pelotas. 2015. Ao realizar um projeto de intervenção através de estudos e levantamento de dados desenvolveu- se uma ação programática prioritária na atenção básica, intervindo na assistência, promoção e prevenção à saúde das gestantes e puérperas da área de abrangência da UBS/ESF Pedro Bairro Monteiro, situado no município de Macapá – Amapá, durante 16 semanas, compreendido entre setembro a dezembro 2014. Nosso objetivo foi melhorar a atenção pré-natal e puerpério, incluindo atenção odontológica, assim como diminuir a morbimortalidade materno – infantil em nossa área. Para realização da intervenção, utilizou- se o banco de dados do SIAB, prontuários e registros específicos, relatos dos ACS, planilha de coletas de dados e ficha-espelho, fornecidos pela Universidade Federal de Pelotas. Alcançou-se o cadastramento adequado no Programa de Pré-natal de 71 gestantes e 74 puérperas, com o 100% de cobertura ao final da intervenção, assim como a solicitação de todos os exames laboratoriais de acordo com o protocolo do Ministério da Saúde, havendo a prescrição de Sulfato Ferroso e Ácido Fólico. Realizou- se a busca ativa às gestantes faltosas as consulta de pré-natal, realizou- se a orientação sobre anticoncepção após o parto, orientação nutricional, aleitamento materno, tabaquismo e higiene bucal. Em relação ao puerpério alcançou- se metas propostas, destacando-se a busca de faltosas, consulta até 30 dias após o parto, orientação sobre cuidados do recém- nascidos, aleitamento materno e planejamento familiar. Em correspondência ao início na intervenção se resultou a melhora qualitativamente e quantitativamente da realização do exame ginecológico, mama e abdominal, a vacinação com dupla adulta (Difteria e Tétano) e Hepatite B, assim como atendimento odontológico em gestantes e puérperas. Palavras-chave: Atenção primária à saúde; saúde da família; saúde da mulher; Pré-natal; puerpério

Ionic conductivity and the formation of cubic CaH₂ in the LiBH₄-Ca(BH₄)₂ composite

Abstract LiBH4–Ca(BH4)2 composites were prepared by ball milling. Their crystal structures and phase composition were investigated using synchrotron X-ray diffraction and Rietveld refinement, and their ionic conductivity was measured using impedance spectroscopy. The materials were found to form a physical mixture. The composites were composed of α-Ca(BH4)2, γ-Ca(BH4)2 and orthorhombic LiBH4, and the relative phase quantities of the Ca(BH4)2 polymorphs varied significantly with LiBH4 content. The formation of small amounts of orthorhombic CaH2 and cubic CaH2 in a CaF2-like structure was observed upon heat treatment. Concurrent formation of elemental boron may also occur. The ionic conductivity of the composites was measured using impedance spectroscopy, and was found to be lower than that of ball milled LiBH4. Electronic band structure calculations indicate that cubic CaH2 with hydrogen defects is electronically conducting. Its formation along with the possible precipitation of boron therefore has an effect on the measured conductivity of the LiBH4–Ca(BH4)2 composites and may increase the risk of an internal short-circuit in the cells.</p

Ionic conductivity and the formation of cubic CaH₂ in the LiBH₄-Ca(BH₄)₂ composite

Transient absorption spectroscopy is used to follow the reactive intermediates involved in the first steps in the photochemistry initiated by ultraviolet (266-nm wavelength) excitation of solutions of 1,5-hexadiene, isoprene, and 2,3-dimethylbut-2-ene in carbon tetrachloride or chloroform. Ultraviolet and visible bands centered close to 330 and 500 nm in both solvents are assigned respectively to a charge transfer band of Cl-solvent complexes and the strong absorption band of a higher energy isomeric form of the solvent molecules (iso-CCl3–Cl or iso-CHCl2–Cl). These assignments are supported by calculations of electronic excitation energies. The isomeric forms have significant contributions to their structures from charge-separated resonance forms and offer a reinterpretation of previous assignments of the carriers of the visible bands that were based on pulsed radiolysis experiments. Kinetic analysis demonstrates that the isomeric forms are produced via the Cl–solvent complexes. Addition of the unsaturated hydrocarbons provides a reactive loss channel for the Cl–solvent complexes, and reaction radii and bimolecular rate coefficients are derived from analysis using a Smoluchowski theory model. For reactions of Cl with 1,5-hexadiene, isoprene, and 2,3-dimethylbut-2-ene in CCl4, rate coefficients at 294 K are, respectively, (8.6 ± 0.8) × 109, (9.5 ± 1.6) × 109, and (1.7 ± 0.1) × 1010 M–1 s–1. The larger reaction radius and rate coefficient for 2,3-dimethylbut-2-ene are interpreted as evidence for an H-atom abstraction channel that competes effectively with the channel involving addition of a Cl-atom to a C═C bond. However, the addition mechanism appears to dominate the reactions of 1,5-hexadiene and isoprene. Two-photon excited CCl4 or CHCl3 can also ionize the diene or alkene solute