1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): A review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals.

Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis. © 2012 Wiley Periodicals, Inc.

Les épithetes : livre non seulement utile à ceux qui font profession de la poësie, mais fort propre aussi pour illustrer toute autre composition françoise... ([Reprod.]) / de M. de La Porte,...

Collection : Archives de la linguistique française ; 217

Luoteis-Venäjän metsävaratja niiden hyödyntämismahdollisuudet

Suomen metsäteollisuuden käyttämästä puusta neljännes on tuontipuuta, josta Venäjän tuonnin osuus on hyvin merkittävä. Suomen metsäteollisuus on riippuvainen etenkin Luoteis-Venäjän metsien puusta. Venäjä pyrkii nostamaan metsäteollisuuden jalostusastetta ja hyödyntämään voimallisemmin omia metsävaroja, mikä merkitsee suuria haasteita suomalaiselle metsäteollisuudelle ja sen raaka-ainehuollolle. Tässä raportissa tarkastellaan Luoteis-Venäjän metsävaroja, metsänkäyttöä ja sen ongelmia sekä metsien hallinnointia. Lisäksi käsitellään Luoteis-Venäjän metsäsektoria ja siihen tehtyjä suoria ulkomaisia investointeja. Lopuksi kuvataan Luoteis-Venäjän kuljetusinfrastruktuuria sekä arvioidaan Luoteis-Venäjän metsävarojen käytön potentiaalia.

Psychometric properties of the French version of the Zuckerman-Kuhlman Personality Questionnaire

Este estudio instrumental fue diseñado para investigar las propiedades psicométricas de la versión francesa y replicabilidad transcultural del Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) en sus factores y facetas. El ZKPQ es un instrumento destinado a evaluar los cinco factores básicos del Alternative Five-Factor Model (AFFM). Los participantes fueron 843 suizos francófonos, principalmente estudiantes universitarios. Obtenidos los factores estos mostraron una fiabilidad entre 0,73 y 0,87, y sus facetas entre 0,57 y 0,77. Las diferencias entre géneros son similares a las informadas en la muestra americana. Las mujeres alcanzaron puntuaciones superiores en N-Anx, y puntuaciones más bajas en ImpSS y Act. El resultado de los análisis factoriales exploratorios respaldó la estructura de cinco factores y sus correspondientes facetas. Las correlaciones entre las escalas sostienen que los cinco factores básicos del AFFM son ortogonales. Los coeficientes de congruencia muestran la elevada eplicabilidad transcultural de los factores y sus facetas. Se puso a prueba el ajuste del modelo en sus factores y facetas mediante análisis factorial confirmatorio. Los resultados indican que la versión en lengua francesa del ZKPQ es un instrumento fiable y válido y posee buena replicabilidad transcultural.

Colonic perianastomotic carcinogenesis in an experimental model

Background To examine the effect of anastomosis on experimental carcinogenesis in the colon of rats. Methods Forty-three 10-week-old male and female Sprague-Dawley rats were operated on by performing an end-to-side ileorectostomy. Group A:16 rats received no treatment. Group B: 27 rats received 18 subcutaneous injections weekly at a dose of 21 mg/kg wt of 1–2 dimethylhydrazine (DMH), from the eighth day after the intervention. Animals were sacrificed between 25–27 weeks. The number of tumours, their localization, size and microscopic characteristics were recorded. A paired chi-squared analysis was performed comparing tumoral induction in the perianastomotic zone with the rest of colon with faeces. Results No tumours appeared in the dimethylhydrazine-free group. The percentage tumoral area was greater in the perianastomotic zone compared to tumours which had developed in the rest of colon with faeces (p = 0.014). Conclusion We found a cocarcinogenic effect due to the creation of an anastomosis, when using an experimental model of colonic carcinogenesis induced by DMH in rats.

Avaluació de la competència en castellà de l'alumnat immigrat de secundària a la província d'Osca

Ante la creciente incorporación de alumnado de origen inmigrante a nuestros centros educativos, y dada la práctica inexistencia de estudios empíricos que aborden esta nueva situación, entre el profesorado suelen primar ciertas creencias o ideas previas que condicionan las respuestas educativas en torno al proceso de enseñar la lengua o lenguas de la sociedad de acogida a estos alumnos. Nuestra investigación, a partir de la evaluación del conocimiento lingüístico adquirido en castellano por parte de un grupo de alumnos y alumnas de 1º de ESO, ha analizado algunos de los factores que determinan sus niveles de competencia lingüística. Ello, además de contrastar determinadas creencias sobre el aprendizaje de la lengua de estos colectivos, nos ha permitido formular ciertas indicaciones o sugerencias para abordar la cuestión.

Metcalfa pruinosa (Say) (Homoptera: Flatidae), ¿una plaga potencial de plantas ornamentales en espacios verdes urbanos de Cataluña?

Se ha determinado la presencia y abundancia de Metcalfa pruinosa (Say) en espacios verdes urbanos de Cataluña. M. pruinosa es una especie ampliamente establecida en Cataluña, especialmente en la zona costera. Se ha registrado el insecto sobre más de 100 plantas distintas. La abundancia del insecto ha sido grande en parques y jardines de localidades como Figueres, Girona, Barcelona, Vilanova i la Geltrú, Tarragona o Salou, ocasionando daños estéticos de consideración. Por tanto, M. pruinosa puede considerarse ya una plaga real de los espacios verdes urbanos de Cataluña, aunque su abundancia y capacidad de daño pueden aumentar en el futuro.

Notas críticas al texto de la Alejandra de Licofrón

Con el fin de poder justificar algunas lecturas adoptadas frente a las ediciones de la Alejandra de Licofrón a cargo de L. Mascialino 1 y de M. Fusillo - A. Hurst - G. Paduano 2, publicada en fecha muy reciente, he tenido que plantearme algunas cuestiones textuales al abordar la tarea de edición y traducción (al catalán) de dicho poema helenístico 3. Ofrezco, pues, un breve elenco de notas críticas al texto mencionado.

Las revistas españolas de Ciencias de la Actividad Física y el Deporte: cómo elegir la revista donde publicar

La calidad, el prestigio y la influencia de una revista de Ciencias de la Actividad Física y el Deporte no son fáciles de determinar. El criterio de evaluación más extendido y conocido es el impact factor (IF) del Institute for Scientific Information (ISI de Thomson-Reuters). Sin embargo, pese a sus indudables cualidades, el IF tiene muchas limitaciones y utilizar solo el IF para evaluar las revistas españolas de Educación Física es delicado. A partir de estas consideraciones, el objetivo de nuestro trabajo es repasar los criterios para evaluar las revistas españolas de Educación Física. A la hora de considerar la revista donde publicar un autor debe considerar su difusión, visibilidad y prestigio, con el fin de orientar en la elección de la revista adecuada al área de interés de los autores se realiza una revisión de las revistas existentes, sus características y relevancia dentro de la comunidad científica

Prospective pathways between heroin use and nonmedical use of prescription opioids: Trajectories among young Swiss men

BACKGROUND. So far few studies have focused on the last steps of drug-use trajectories. Heroin has been described as a final stage, but the non-medical use of prescription opioids (NMUPOs) is often associated with heroin use. There is, however, no consensus yet about which one precedes the other. AIMS. The objective of this study was to test which of these two substances was likely to be induced by the other using a prospective design. MATERIAL AND METHODS. We used data from the Swiss Longitudinal Cohort Study on Substance Use Risk Factors (C-SURF) to assess exposure to heroin and NMUPO at two times points (N = 5,041). Cross-lagged panel models provided evidence regarding prospective pathways between heroin and NMUPOs. Power analyses provided evidence about significance and clinical relevance. RESULTS. Results showed that heroin use predicted later NMUPO use (? = 1.217, p < 0.001) and that the reverse pathway was non-significant (? = 0.240, p = .233). Heroin use seems to be an important determinant, causing a 150% risk increase for NMUPO use at follow-up, whereas NMUPO use at baseline increases the risk of heroin use at follow-up by a mere non-significant 20%. CONCLUSIONS. Thus, heroin users were more likely to move to NMUPOs than non-heroin users, whereas NMUPO users were not likely to move to heroin use. The pathway of substance use seemed to include first heroin use, then NMUPO use.