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.

Juan Luis Vives and Richard Mulcaster: a humanist view of language

Humanist writers were multifaceted and thcir writings eclectic, delving into a wide range of fields of enquiry Many issues wcre raised and addressed, pursued ur abandoned, uftcn unsystematically. ‘[his hetcrogeneity has frequently lcd tu the neglect of specific facets of authurs who have gained renuwn in uthcr fzelds. ‘[his 1 believe tu be the case fur Richard Mulcaster and Juan Luis Vives, whuse contribution tu language Éhcory has been eclipsed by their rclatively mudem views un educatiun. ‘[heir views un language merit mure attention, if not fur their originality as such, at least fur te testimony they pruvide uf a periud in transition. ‘[he work uf these authors show 1mw views un language evolved thruughout te periud mié convey a sense uf its dynamic character. Profoundly cunservative attitudes coexist with progressive unes and, tliough ruoted in the past, thcy strain tuwards a new vision uf the nature and functioning uf language in human sucicty.

Aa, Pieter van der

- Kolumbus 1492. Kuva s. 42-43. (Luku 1. Kristoffer Kolumbuksen ensimmäinen matka Länsi-Intiaan vuonna 1492. Kuvassa saapuminen Kuubaan.)

Postmortem measurement of human chorionic gonadotropin in vitreous humor and bile.

Postmortem human chorionic gonadotrophin (HCG) blood assay can confirm postmortem diagnosis of pregnancy or document situations in which HCG levels are elevated. In some cases, however, blood sampling is not possible at autopsy. In this study, HCG was quantified by enzyme-linked fluorescent assay (ELFA) in the bile (n = 5), vitreous humor (n = 4), and postmortem blood (n = 4) of five pregnant women. There were no false negatives in the pregnant subjects (n = 5) or false positives in controls (n = 34), enabling this test to be recommended for routine use in forensic contexts in which the detection of elevated HCG levels could be of interest.

La noció d'Espanya a la Catalunya medieval

A partir de la necessitat de conèixer les bases del propi present i d'assolir puntals on arrelar els discursos de futur, ara i adés les diferents col·lectivitats es remeten als orígens, "l'obsessió pels orígens" deia Marc Bloch. I aquests, en una Europa que parla de l'Edat Mitjana com la infantesa de la pròpia identitat, s'aboquen a una època medieval on conflueixen -en el que des de la llunyania de la nostra quotidianitat pot semblar una amalgama poc destriada- tant les realitats gresoladores dels actuals signes d'identitat culrurals, socials i lingüístics, com les projeccions que delerosament hi cerquen les justificacions del present i els condicionants del furur. Així doncs, convé apamar bé l'espai físic i conceptual per definir adientment la realitat existent en aquells moments que han alimentat les arrels d'identitats que, travessant diferents estímuls al llarg de la història, han menat fins als nostres dies.

Fer mapes per conèixer la Història: aportacions de la cartografia a l'estudi de l'Alta Edat Mitjana

To make maps to know history: contributions from the cartography to the study of the early middle ages. The accomplishment of maps can allow us to know many aspects that documents written do not allow us to have knowledge. This paper focuses on the boundaries of the townships or the parishes, on the routes and ways, and on the place names or on the invocations of the churches, in order to get to know like it was the territory in the early medieval centuries. One reaches the conclusion that often the limits, the ways and the settlements were created at early middle ages. This study allows to raise the ruptures and the continuities that took place throughout these centuries in the settlement.

Entorn al testament de Brunissèn d'Alentorn i alguns costums funeraris de la Lleida medieval

In this research from the late medieval period, we want to analyze diferent aspects related to funerary world through Brunissèn d’Alentorn’s will. The document is compared with other wills from Lleida’s area that acquire knowledge to these customs, for instance, the draps d’or’s uses. These were provided of deceased’ heraldry, and were comissioned to cover the tomb. Also, in Lleida’s case, they were used to decorate the ancient cathedral’s presbitery during the main festivities, and the patrons’ wedding bed. Artistic patronage, social prestige, family arms ostentation, pomp and devotion are other aspects that would be emphasized in this tour, just as the private devotions in the chapels and altars that were founded regarding this topic.

The international multidisciplinary consensus conference on multimodality monitoring in neurocritical care: evidentiary tables : a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine.

A variety of technologies have been developed to assist decision-making during the management of patients with acute brain injury who require intensive care. A large body of research has been generated describing these various technologies. The Neurocritical Care Society (NCS) in collaboration with the European Society of Intensive Care Medicine (ESICM), the Society for Critical Care Medicine (SCCM), and the Latin America Brain Injury Consortium (LABIC) organized an international, multidisciplinary consensus conference to perform a systematic review of the published literature to help develop evidence-based practice recommendations on bedside physiologic monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews on physiologic processes important in the care of acute brain injury. In this article we provide the evidentiary tables for select topics including systemic hemodynamics, intracranial pressure, brain and systemic oxygenation, EEG, brain metabolism, biomarkers, processes of care and monitoring in emerging economies to provide the clinician ready access to evidence that supports recommendations about neuromonitoring.

The international multidisciplinary consensus conference on multimodality monitoring in neurocritical care: a list of recommendations and additional conclusions : a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine.

Careful patient monitoring using a variety of techniques including clinical and laboratory evaluation, bedside physiological monitoring with continuous or non-continuous techniques and imaging is fundamental to the care of patients who require neurocritical care. How best to perform and use bedside monitoring is still being elucidated. To create a basic platform for care and a foundation for further research the Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to develop recommendations about physiologic bedside monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews as a background to the recommendations. In this article, we highlight the recommendations and provide additional conclusions as an aid to the reader and to facilitate bedside care.

Monitoring of brain and systemic oxygenation in neurocritical care patients.

Maintenance of adequate oxygenation is a mainstay of intensive care, however, recommendations on the safety, accuracy, and the potential clinical utility of invasive and non-invasive tools to monitor brain and systemic oxygenation in neurocritical care are lacking. A literature search was conducted for English language articles describing bedside brain and systemic oxygen monitoring in neurocritical care patients from 1980 to August 2013. Imaging techniques e.g., PET are not considered. A total of 281 studies were included, the majority described patients with traumatic brain injury (TBI). All tools for oxygen monitoring are safe. Parenchymal brain oxygen (PbtO2) monitoring is accurate to detect brain hypoxia, and it is recommended to titrate individual targets of cerebral perfusion pressure (CPP), ventilator parameters (PaCO2, PaO2), and transfusion, and to manage intracranial hypertension, in combination with ICP monitoring. SjvO2 is less accurate than PbtO2. Given limited data, NIRS is not recommended at present for adult patients who require neurocritical care. Systemic monitoring of oxygen (PaO2, SaO2, SpO2) and CO2 (PaCO2, end-tidal CO2) is recommended in patients who require neurocritical care.