Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis.

Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.

Modular assembly using sequential palladium coupling gives easy access to the SMoC class of cellular transporters.

The transducing ability of the third helix of transcription factor homeodomains is effectively mimicked by a biphenyl system displaying guanidine groups. The biphenyl class of small molecule carriers (SMoCs) can carry biomolecules into a wide variety of cell types. A "combinatorial" approach to the synthesis of SMoCs is described using sequential Pd(0) coupling chemistry to assemble the molecules from highly functionalized building blocks. SMoCs coupled to the DNA licensing repressor protein geminin can inhibit DNA replication in vitro. We conducted a structure-activity investigation utilizing a range of SMoC-geminin conjugates and demonstrate that both electrostatic and structural features are important for efficient uptake and functional activity. The best analogue was more efficient than either (Arg)(4) or (Arg)(8) linked to geminin. Effective inhibition of DNA synthesis was achieved in fibroblasts and osteosarcoma cell lines.

Some problems in use of the moral judgment test.

The Moral Judgment Test has been widely used in evaluation of moral development; however, it presents some problems related to the trait measured, reliability, and validity of its summary score (C-index). This index reflects consistency in moral judgment, but this construct is different from moral development as stated by Kohlberg. Therefore, users interested in the latter evaluation should refer to other indexes derived from the test. Some of the analyzed problems could be partially corrected with more theory and research on moral consistency as a component of moral competence.

Imidazol-1-ylethylindazole voltage-gated sodium channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis.

A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Nav channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.

Moral Disengagement Mechanisms and Armed Violence. A Comparative Study of Paramilitaries and Guerrillas in Colombia / Los Mecanismos de Desconexión Moral y la Violencia Armada. Un Estudio Comparativo de Paramilitares y Guerrilleros en Colombia / Mecanismos de Desengajamento Moral e a Violência Armada. Um Estudo Comparativo dos Paramilitares e da Guerrilha na Colômbia

Abstract Moral disengagement mechanisms are strategies to make immoral actions appear moral. This study explores their usage by two Colombian illegal armed groups (guerrillas and paramilitaries), as well as differences between the groups. The analysis covered 367 communiqués issued in 55 months. A deductive content analysis revealed that the most used mechanisms were: attribution of blame, euphemistic labeling, moral justification and labeling with undesirable names. Results showed differences between groups only in the number of press releases, but not in frequency or type of the mechanisms used. The findings are analyzed in the discussion section in relation to the theory of dissonance, extreme violence and motives for joining illegal armed groups.

Resumen Los mecanismos de desconexión moral son estrategias mediante las cuales las acciones inmorales parecen morales. El estudio examina la utilización de dichas estrategias por parte de dos grupos armados ilegales en Colombia (guerrillas y paramilitares), así como las diferencias entre los dos grupos, para lo cual se analizaron 367 comunicados emitidos a lo largo de 55 meses. El análisis deductivo del contenido reveló que los mecanismos más utilizados eran la atribución de culpabilidad, los eufemismos, la justificación moral y la calificación con nombres indeseables. Según los resultados, solo hubo diferencias entre los grupos en cuanto al número de comunicados de prensa, mas no en cuanto a la frecuencia o al tipo de mecanismos utilizados. Los hallazgos del estudio se analizan en la sección de discusión según la teoría de la disonancia, la violencia extrema y las razones para enrolarse en grupos armados ilegales.

Resumo Os mecanismos de desengajamento moral são estratégias para fazer ações imorais aparentarem ser morais. Este estudo explora seu uso por dois grupos armados ilegais da Colômbia (guerrilhas e paramilitares), assim como as diferenças entre eles. Analisaram-se 367 comunicados emitidos em 55 meses. Uma análise dedutiva do conteúdo revelou que os mecanismos mais usados eram: atribuição de culpa, linguagem eufemística, justificativa moral e rotulação com nomes indesejáveis. Os resultados mostraram diferenças entre os grupos só no número de comunicados à imprensa, mas não na frequência ou tipo de mecanismos usados. Os resultados são analisados na seção de discussão no que se refere à teoria da dissonância, à violência extrema e aos motivos para se unir a grupos armados ilegais.

Oxadiazolylindazole sodium channel modulators are neuroprotective toward hippocampal neurones.

We report the discovery of a new class of neuroprotective voltage-dependent sodium channel modulators exemplified by (5-(1-benzyl-1H-indazol-3-yl)-1,2,4-oxadiazol-3-yl)methanamine 11 (CFM1178). The compounds were inhibitors of [(14)C]guanidinium ion flux in rat forebrain synaptosomes and displaced binding of the sodium channel ligand [(3)H]BW202W92. 11 and the corresponding N(2)-benzyl isomer, 38 (CFM6058), demonstrated neuroprotective activity in hippocampal slices comparable to sipatrigine. CYP450 enzyme inhibition observed with 11 was reduced with 38. In electrophysiological experiments on dissociated hippocampal neurons, these two compounds caused use- and voltage-dependent block of sodium currents. Sodium channel isoform profiling against Na(v)1.1-1.8 demonstrated that the standard sodium channel blocker lamotrigine had modest activity against Na(v)1.1, while sipatrigine was generally more potent and less selective. 11 and 38 showed potent activity against Na(v)1.6, pointing to pharmacological block of this isoform being consistent with the neuroprotective effect. 38 also showed use dependent block of Na(v)1.6 in HEK cells.

Factores predictores de bienestar subjetivo en una muestra colombiana / Predective factors of subjective well-being in a Colombian sample

The study assessed subjective well-being (SWB) and its prediction from self-efficacy and satisfaction in some specific life domains (e.g., health, affective relationships, work), in a Colombian period of social and economical crisis. 795 members (students, faculty, employees) of a private university in Colombia participated in the study. Questionnaires were used to gather relevant information. Results showed high SWB, self-efficacy, and satisfaction with most life domains. Out of these domains, affective relationships, future and work, as well as self-efficacy, explained a high percentage of variance in SWB. These domains are the closest to the individual's emotional lives. In spite of the explained variance, other variables, not considered in this work, must be explored in future researches.

Esta investigación evaluó el bienestar subjetivo (BS) y su predicción a partir de la auto-eficacia y la satisfacción con algunos dominios de la vida (p.ej., salud, relaciones afectivas, trabajo) en un momento de crisis económica y social en Colombia. 795 estudiantes, profesores y empleados de una universidad respondieron cuestionarios que evaluaban las variables estudiadas. Los resultados mostraron alto BS, elevada auto-eficacia, y satisfacción con la mayor parte de los dominios vitales. Los dominios referidos a relaciones afectivas, futuro y trabajo, y la percepción de auto-eficacia explicaron un porcentaje alto de la varianza del BS. Estos dominios son los más cercanos a la vida emocional. Estas variables explican una alta proporción de la varianza del BS.

Influencia de Piaget en el estudio del desarrollo moral / Piaget's influence on the study of moral development

Se analiza la concepción de Piaget acerca de la moral y su forma de abordar la investigación acerca del desarrollo moral. Se ponen de presente algunas inconsistencias en la posición de Piaget. Se señala su influencia particularmente en Kohlberg y Habermas.

Accion moral. De una moralidad estrategica a una moralidad de principios o solidaridad / Moral action. From a strategic morality to a morality of principles or solidarity

Se presenta la necesidad de un nuevo modelo que explique tanto la conducta moral como la inmoral. Se describen casos particulares como el narcotráfico y la violencia. El nuevo modelo debe incluir relaciones costo/beneficio y también sentimientos auto-evaluativos. Un replanteamiento de las etapas de desarrollo moral de Kohlberg en términos del modelo propuesto permite ver su utilidad y extraer conclusiones para el sistema legal.