Sellar fracture followed by sudden death: an autopsy case

The authors describe a case of sellar fracture followed by sudden death. The victim was involved in a wrangle. The autopsy revealed facial damage and sellar fracture and no evidence of cerebral damage, except for a mild subarachnoid hemorrhage in the left parietotemporal regions and undersurface of both frontal lobes. Sellar fracture is a rare and severe entity, associated with serious complications, which is frequently diagnosed postmortem. In any case, death is rarely a direct consequence of the sellar fracture itself and is usually considered to be the result of associated cerebral trauma. This case prompted us to screen the literature on sellar fracture to gain a better understanding of the mechanism of death.

Platelet-activating factor is crucial in psoralen and ultraviolet A-induced immune suppression, inflammation, and apoptosis.

Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA's mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects.

Impact of biatrial defragmentation in patients with paroxysmal atrial fibrillation: Results from a randomized prospective study

Background Single procedure success rates of pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (PAF) are still unsatisfactory. In patients with persistent atrial fibrillation (AF), ablation of complex fractionated atrial electrograms (CFAEs) after PVI results in improved outcomes. Objective We aimed to investigate if PAF-patients with intraprocedurally sustained AF after PVI might benefit from additional CFAE ablation. Methods A total of 1134 consecutive patients underwent a first catheter ablation procedure of PAF between June 2008 and December 2012. In most patients, AF was either not inducible or terminated during PVI. In 68 patients (6%), AF sustained after successful PVI. These patients were randomized to either cardioversion (PVI-alone group; n = 33) or additional CFAE ablation (PVI+CFAE group; n = 35) and followed up every 1–3 months and serial Holter recordings were also obtained. The primary end point was the recurrence of AF/atrial tachycardia (AT) after a blanking period of 3 months. Results Procedure duration (127 ± 6 minutes vs 174 ± 10 minutes), radiofrequency application time (44 ± 3 minutes vs 74 ± 5 minutes), and fluoroscopy time (26 ± 2 minutes vs 41 ± 3 minutes) were longer in the PVI+CFAE group (all P < .001). In 30 of 35 patients (86%) in the PVI+CFAE group, ablation terminated AF. There was no significant group difference with respect to freedom from AF/AT (22 of 33 [67%] vs 22 of 35 [63%]; P = .66). Subsequently, 10 of 11 patients in the PVI-alone group (91%) and 11 of 13 patients in PVI+CFAE group (85%) underwent repeat ablation (P = 1.00). Overall, 29 of 33 [88%] vs 30 of 35 [86%] patients (P = 1.00) were free from AF/AT after 1.4 ± 0.1 vs 1.4 ± 0.2 (P = .87) procedures. Conclusion Patients with sustained AF after PVI in a PAF cohort are rare. Regarding AF/AT recurrence, these patients did not benefit from further CFAE ablation compared to PVI alone, but are exposed to longer procedure duration, fluoroscopy time, and radiofrequency application time.

Deep Into the Fibers! Postmortem Diffusion Tensor Imaging in Forensic Radiology.

PURPOSE In traumatic brain injury, diffusion-weighted and diffusion tensor imaging of the brain are essential techniques for determining the pathology sustained and the outcome. Postmortem cross-sectional imaging is an established adjunct to forensic autopsy in death investigation. The purpose of this prospective study was to evaluate postmortem diffusion tensor imaging in forensics for its feasibility, influencing factors and correlation to the cause of death compared with autopsy. METHODS Postmortem computed tomography, magnetic resonance imaging, and diffusion tensor imaging with fiber tracking were performed in 10 deceased subjects. The Likert scale grading of colored fractional anisotropy maps was correlated to the body temperature and intracranial pathology to assess the diagnostic feasibility of postmortem diffusion tensor imaging and fiber tracking. RESULTS Optimal fiber tracking (>15,000 fiber tracts) was achieved with a body temperature at 10°C. Likert scale grading showed no linear correlation (P > 0.7) to fiber tract counts. No statistically significant correlation between total fiber count and postmortem interval could be observed (P = 0.122). Postmortem diffusion tensor imaging and fiber tracking allowed for radiological diagnosis in cases with shearing injuries but was impaired in cases with pneumencephalon and intracerebral mass hemorrhage. CONCLUSIONS Postmortem diffusion tensor imaging with fiber tracking provides an exceptional in situ insight "deep into the fibers" of the brain with diagnostic benefit in traumatic brain injury and axonal injuries in the assessment of the underlying cause of death, considering influencing factors for optimal imaging technique.

Interventional management of recurrent paroxysmal atrial fibrillation despite isolated pulmonary veins: impact of an ablation strategy targeting inducible atrial tachyarrhythmias

AIMS Pulmonary vein isolation (PVI) is an effective treatment option for paroxysmal atrial fibrillation (PAF). Reconnection of pulmonary veins (PVs) is the predominant cause for recurrence of PAF. However, treatment of patients with recurrence of PAF despite isolated PV in the absence of extra-PV foci remains challenging. METHODS AND RESULTS Of 265 patients undergoing repeat catheter ablation (CA) for recurrence of PAF 21 (8%) patients (14 men, age 58 ± 14 years) showed no reconnection of PV. Therefore, inducibility of sustained atrial arrhythmias was tested. If sustained atrial fibrillation (AF) or sustained atrial tachycardia (AT) was induced, patients underwent CA. During follow-up (FU), Holter- and Tele-electrocardiogram were performed. In 19 (91%) of 21 patients, sustained atrial arrhythmias [16 (84%) AF; 3 (15%) patients AT] were induced. One patient showed PAF. Eighteen patients underwent CA aiming for termination of induced arrhythmia. In 14 (77%) patients, termination into sinus rhythm was achieved. Despite extensive CA, three (16%) patients were externally cardioverted. No periprocedural complications occurred. During 21.2 ± 6.8-month FU, 10 (53%) patients were free of any arrhythmia. Paroxysmal atrial fibrillation recurred in 4 (21%) and AT in 5 (26%) patients. One patient showed persistent AF. Repeat CA was scheduled and successfully performed for these patients. CONCLUSION In patients with recurrence of PAF despite isolated PV, termination of induced atrial arrhythmias can be achieved in most patients by defragmentation and AT ablation. Moreover, this ablation strategy results in favourable mid-term outcome results.

Ultraviolet radiation modulates the immune system through the platelet -activating factor receptor

Ultraviolet radiation plays a critical role in the induction of non-melanoma skin cancer. UV radiation is also immune suppressive. Moreover, UV-induced systemic immune suppression is a major risk factor for skin cancer induction. Previous work had shown that UV exposure in vivo activates a cytokine cascade involving PGE2, IL-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV-exposure, especially those upstream of PGE2, were not well defined. To determine the initial events and mediators that lead to immune suppression after a pathological dose of UV, mouse keratinocytes were analyzed after sunlamp irradiation. It is known that UV-irradiated keratinocytes secrete the phospholipid mediator of inflammation, platelet-activating factor (PAF). Since PAF stimulates the production of immunomodulatory compounds, including PGE2, the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression was tested. Both UV and PAF activated the transcription of cyclooxygenase (COX)-2 and IL-10 reporter gene constructs. A PAF receptor antagonist blocked UV-induced IL, 10 and COX-2 transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH), and immune suppression was blocked when UV-irradiated mice were injected with a PAF receptor antagonist. This work shows that UV generates PAF-like oxidized lipids, that signal through the PAF receptor, activate cytokine transcription, and induce systemic immune suppression. ^

Simulación de maniobras de buques con sistemas de propulsión no convencional en aguas poco profundas

Los requisitos cada vez más exigentes en cuanto a misiones, limitaciones operacionales y ambientales así como nuevas tecnologías, imponen permanentemente retos a los arquitectos navales para generar alternativas de buques y valorar su bondad en las primeras etapas del proyecto. Este es el caso de los Buques Patrulleros de Apoyo Fluvial Pesados PAF-P, que por requerimiento de la Armada Nacional de Colombia ha diseñado y construido COTECMAR. Los PAF-P, son buques fluviales cuya relación Manga-Calado excede la mayoría de los buques existentes (B/T=9,5), debido principalmente a las restricciones en el calado a consecuencia de la escasa profundidad de los ríos. Estos buques están equipados con sistemas de propulsión acimutales tipo “Pum-Jet”. Las particularidades del buque y del ambiente operacional, caracterizado por ríos tropicales con una variabilidad de profundidad dependiente del régimen de lluvias y sequía, así como la falta de canalización y la corriente, hacen que la maniobrabilidad y controlabilidad sean fundamentales para el cumplimiento de su misión; adicionalmente, no existen modelos matemáticos validados que permitan predecir en las primeras etapas del diseño la maniobrabilidad de este tipo de buques con los efectos asociados por profundidad. La presente tesis doctoral aborda el desarrollo de un modelo matemático para simulación de maniobrabilidad en aguas poco profundas de buques con relación manga-calado alta y con propulsores acimutales tipo “Pump-Jet”, cuyo chorro además de entregar el empuje necesario para el avance del buque, genera la fuerza de gobierno en función del ángulo de orientación del mismo, eliminando la necesidad de timones. El modelo matemático ha sido validado mediante los resultados obtenidos en las pruebas de maniobrabilidad a escala real del PAF-P, a través de la comparación de trayectorias, series temporales de las variables de estado más significativas y parámetros del círculo evolutivo como son diámetro de giro, diámetro táctico, avance y transferencia. El plan de pruebas se basó en técnicas de Diseño de Experimentos “DOE” para racionalizar el número de corridas en diferentes condiciones de profundidad, velocidad y orientación del chorro (ángulo de timón). En el marco de la presente investigación y para minimizar los errores por efectos ambientales y por inexactitud en los instrumentos de medición, se desarrolló un sistema de adquisición y procesamiento de datos de acuerdo con los lineamientos de ITTC. La literatura existente describe los efectos negativos de la profundidad en los parámetros de maniobrabilidad de buques convencionales (Efecto tipo S), principalmente las trayectorias descritas en los círculos evolutivos aumentan en la medida que disminuye la profundidad; no obstante, en buques de alta relación manga-calado, B/T=7,51 (Yoshimura, y otros, 1.988) y B/T=6,38 (Yasukawa, y otros, 1.995) ha sido reportado el efecto contrario (Efecto tipo NS Non Standart). Este último efecto sin embargo, ha sido observado mediante experimentación con modelos a escala pero no ha sido validado en pruebas de buques a escala real. El efecto tipo NS en buques dotados con hélice y timones, se atribuye al mayor incremento de la fuerza del timón comparativamente con las fuerzas del casco en la medida que disminuye la profundidad; en el caso de estudio, el fenómeno está asociado a la mejor eficiencia de la bomba de agua “Pump-Jet”, debido a la resistencia añadida en el casco por efecto de la disminución de la profundidad. Los resultados de las pruebas con buque a escala real validan el excelente desempeño de esta clase de buques, cumpliendo en exceso los criterios de maniobrabilidad existentes y muestran que el diámetro de giro y otras características de maniobrabilidad mejoran con la disminución de la profundidad en buques con alta relación manga-calado. ABSTRACT The increasingly demanding requirements in terms of missions, operational and environmental constraints as well as new technologies, constantly impose challenges to naval architects to generate alternatives and asses their performance in the early stages of design. That is the case of Riverine Support Patrol Vessel (RSPV), designed and built by COTECMAR for the Colombian Navy. RSPV are riverine ships with a Beam-Draft ratio exceeding most of existing ships (B/T=9,5), mainly due to the restrictions in draft as a result of shallow water environment. The ships are equipped with azimuthal propulsion system of the “Pump-Jet” type. The peculiarities of the ship and the operational environment, characterized by tropical rivers of variable depth depending on the rain and dry seasons, as well as the lack channels and the effect of water current, make manoeuvrability and controllability fundamental to fulfill its mission; on the other hand, there are not validated mathematical models available to predict the manoeuvrability of such ships with the associated water depth effects in the early stages of design. This dissertation addresses the development of a mathematical model for shallow waters’ manoeuvrability simulation of ships with high Beam-Draft ratio and azimuthal propulsion systems type “Pump-Jet”, whose stream generates the thrust required by the ship to advance and also the steering force depending on the orientation angle, eliminating the need of rudders. The mathematical model has been validated with the results of RSPV’s full scale manoeuvring tests, through a comparison of paths, time series of state variables and other parameters taken from turning tests, such as turning diameter, tactical diameter, advance and transfer. The test plan was developed applying techniques of Design of Experiments “DOE”, in order to rationalize the number of runs in different conditions of water depth, ship speed and jet stream orientation (rudder angle). A data acquisition and processing system was developed, following the guidelines of ITTC, as part of this research effort, in order to minimize errors by environmental effects and inaccuracy in measurement instruments, The negative effects of depth on manoeuvrability parameters for conventional ships (Effect Type S: the path described by the ship during turning test increase with decrease of water depth), has been documented in the open literature; however for wide-beam ships, B/T=7,51 (Yoshimura, y otros, 1.988) and B/T=6,38 (Yasukawa, y otros, 1.995) has been reported the opposite effect (Type NS). The latter effect has been observed thru model testing but until now had not been validated with full-scale results. In ships with propellers and rudders, type NS effect is due to the fact that increment of rudder force becomes larger than hull force with decrease of water depth; in the study case, the phenomenon is associated with better efficiency of the Pump-Jet once the vessel speed becomes lower, due to hull added resistance by the effect of the decrease of water depth. The results of full scale tests validates the excellent performance of this class of ships, fulfilling the manoeuvrability criteria in excess and showing that turning diameter and other parameters in high beam-draft ratio vessels do improve with the decrease of depth.

Nuevas arquitecturas de transpondedores de microondas = New transponder architectures at microwave frequencies = Nouvelles architectures des transpondeurs d’hyperfréquences

En la última década, los sistemas de telecomunicación de alta frecuencia han evolucionado tremendamente. Las bandas de frecuencias, los anchos de banda del usuario, las técnicas de modulación y otras características eléctricas están en constante cambio de acuerdo a la evolución de la tecnología y la aparición de nuevas aplicaciones. Las arquitecturas de los transceptores modernos son diferentes de las tradicionales. Muchas de las funciones convencionalmente realizadas por circuitos analógicos han sido asignadas gradualmente a procesadores digitales de señal, de esta manera, las fronteras entre la banda base y las funcionalidades de RF se difuminan. Además, los transceptores inalámbricos digitales modernos son capaces de soportar protocolos de datos de alta velocidad, por lo que emplean una elevada escala de integración para muchos de los subsistemas que componen las diferentes etapas. Uno de los objetivos de este trabajo de investigación es realizar un estudio de las nuevas configuraciones en el desarrollo de demostradores de radiofrecuencia (un receptor y un transmisor) y transpondedores para fines de comunicaciones y militares, respectivamente. Algunos trabajos se han llevado a cabo en el marco del proyecto TECRAIL, donde se ha implementado un demostrador de la capa física LTE para evaluar la viabilidad del estándar LTE en el entorno ferroviario. En el ámbito militar y asociado al proyecto de calibración de radares (CALRADAR), se ha efectuado una actividad importante en el campo de la calibración de radares balísticos Doppler donde se ha analizado cuidadosamente su precisión y se ha desarrollado la unidad generadora de Doppler de un patrón electrónico para la calibración de estos radares. Dicha unidad Doppler es la responsable de la elevada resolución en frecuencia del generador de “blancos” radar construido. Por otro lado, se ha elaborado un análisis completo de las incertidumbres del sistema para optimizar el proceso de calibración. En una segunda fase se han propuesto soluciones en el desarrollo de dispositivos electro-ópticos para aplicaciones de comunicaciones. Estos dispositivos son considerados, debido a sus ventajas, tecnologías de soporte para futuros dispositivos y subsistemas de RF/microondas. Algunas demandas de radio definida por software podrían cubrirse aplicando nuevos conceptos de circuitos sintonizables mediante parámetros programables de un modo dinámico. También se ha realizado una contribución relacionada con el diseño de filtros paso banda con topología “Hairpin”, los cuales son compactos y se pueden integrar fácilmente en circuitos de microondas en una amplia gama de aplicaciones destinadas a las comunicaciones y a los sistemas militares. Como importante aportación final, se ha presentado una propuesta para ecualizar y mejorar las transmisiones de señales discretas de temporización entre los TRMs y otras unidades de procesamiento, en el satélite de última generación SEOSAR/PAZ. Tras un análisis exhaustivo, se ha obtenido la configuración óptima de los buses de transmisión de datos de alta velocidad basadas en una red de transceptores. ABSTRACT In the last decade, high-frequency telecommunications systems have extremely evolved. Frequency bands, user bandwidths, modulation techniques and other electrical characteristics of these systems are constantly changing following to the evolution of technology and the emergence of new applications. The architectures of modern transceivers are different from the traditional ones. Many of the functions conventionally performed by analog circuitry have gradually been assigned to digital signal processors. In this way, boundaries between baseband and RF functionalities are diffused. The design of modern digital wireless transceivers are capable of supporting high-speed data protocols. Therefore, a high integration scale is required for many of the components in the block chain. One of the goals of this research work is to investigate new configurations in the development of RF demonstrators (a receiver and a transmitter) and transponders for communications and military purposes, respectively. A LTE physical layer demonstrator has been implemented to assess the viability of LTE in railway scenario under the framework of the TECRAIL project. An important activity, related to the CALRADAR project, for the calibration of Doppler radars with extremely high precision has been performed. The contribution is the Doppler unit of the radar target generator developed that reveals a high frequency resolution. In order to assure the accuracy of radar calibration process, a complete analysis of the uncertainty in the above mentioned procedure has been carried out. Another important research topic has been the development of photonic devices that are considered enabling technologies for future RF and microwave devices and subsystems. Some Software Defined Radio demands are addressed by the proposed novel circuit concepts based on photonically tunable elements with dynamically programmable parameters. A small contribution has been made in the field of Hairpin-line bandpass filters. These filters are compact and can also be easily integrated into microwave circuits finding a wide range of applications in communication and military systems. In this research field, the contributions made have been the improvements in the design and the simulations of wideband filters. Finally, an important proposal to balance and enhance transmissions of discrete timing signals between TRMs and other processing units into the state of the art SEOSAR/PAZ Satellite has been carried out obtaining the optimal configuration of the high-speed data transmission buses based on a transceiver network. RÉSUMÉ Les systèmes d'hyperfréquence dédiés aux télécommunications ont beaucoup évolué dans la dernière décennie. Les bandes de fréquences, les bandes passantes par utilisateur, les techniques de modulation et d'autres caractéristiques électriques sont en constant changement en fonction de l'évolution des technologies et l'émergence de nouvelles applications. Les architectures modernes des transcepteurs sont différentes des traditionnelles. Un grand nombre d’opérations normalement effectuées par les circuits analogiques a été progressivement alloué à des processeurs de signaux numériques. Ainsi, les frontières entre la bande de base et la fonctionnalité RF sont floues. Les transcepteurs sans fils numériques modernes sont capables de transférer des données à haute vitesse selon les différents protocoles de communication utilisés. C'est pour cette raison qu’un niveau élevé d'intégration est nécessaire pour un grand nombre de composants qui constitue les différentes étapes des systèmes. L'un des objectifs de cette recherche est d'étudier les nouvelles configurations dans le développement des démonstrateurs RF (récepteur et émetteur) et des transpondeurs à des fins militaire et de communication. Certains travaux ont été réalisés dans le cadre du projet TECRAIL, où un démonstrateur de la couche physique LTE a été mis en place pour évaluer la faisabilité de la norme LTE dans l'environnement ferroviaire. Une contribution importante, liée au projet CALRADAR, est proposée dans le domaine des systèmes d’étalonnage de radar Doppler de haute précision. Cette contribution est le module Doppler de génération d’hyperfréquence intégré dans le système électronique de génération de cibles radar virtuelles que présente une résolution de fréquence très élevée. Une analyse complète de l'incertitude dans l'étalonnage des radars Doppler a été effectuée, afin d'assurer la précision du calibrage. La conception et la mise en oeuvre de quelques dispositifs photoniques sont un autre sujet important du travail de recherche présenté dans cette thèse. De tels dispositifs sont considérés comme étant des technologies habilitantes clés pour les futurs dispositifs et sous-systèmes RF et micro-ondes grâce à leurs avantages. Certaines demandes de radio définies par logiciel pourraient être supportées par nouveaux concepts de circuits basés sur des éléments dynamiquement programmables en utilisant des paramètres ajustables. Une petite contribution a été apportée pour améliorer la conception et les simulations des filtres passe-bande Hairpin à large bande. Ces filtres sont compacts et peuvent également être intégrés dans des circuits à micro-ondes compatibles avec un large éventail d'applications dans les systèmes militaires et de communication. Finalement, une proposition a été effectuée visant à équilibrer et améliorer la transmission des signaux discrets de synchronisation entre les TRMs et d'autres unités de traitement dans le satellite SEOSAR/PAZ de dernière génération et permettant l’obtention de la configuration optimale des bus de transmission de données à grande vitesse basés sur un réseau de transcepteurs.

Use of ovary culture techniques in reproductive toxicology

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgements The author's studies in this field are supported by MRC grants G1002118 (NS and RAA) and G110357 (RAA), MR/L010011/1 (PAF), the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 212885 (PAF) and the Wellcome Trust (080388 to PAF). AS was funded by a BBSRC CASE Studentship co-funded by AstraZeneca.

In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements: We thank Ms Margaret Fraser, Ms Samantha Flannigan, and Dr Wing Yee Kwong for their expert assistance. The staff at Grampian NHS Pregnancy Counselling Service were essential for collecting fetuses. We thank Professor Geoffrey Hammond and Dr Marc Simard, University of British Colombia for helpful comments on the manuscript. Supported by grants as follows: Scottish Senior Clinical Fellowship (AJD); Chief Scientist Office (Scottish Executive, CZG/1/109 to PAF, & CZG/4/742 (PAF & PJOS); NHS Grampian Endowments 08/02 (PAF, SB & PJOS); the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 212885 (PAF & SMR); the Medical Research Council grants MR/L010011/1 (PAF & PJOS) and MR/K018310/1 (AJD). None of the funding bodies played any role in the design, collection, analysis, and interpretation of data, in the writing of the manuscript, nor in the decision to submit the manuscript for publication

Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization

Lissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimics a mutation described in one lissencephaly patient with a milder phenotype. Homozygotes are early lethal, although heterozygotes are viable and fertile. Most strikingly, the morphology of cortical neurons and radial glia is aberrant in the developing cortex, and the neurons migrate more slowly. This is the first demonstration, to our knowledge, of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalomocortical innervation are also abnormal. Biochemically, the mutant protein is not capable of dimerization, and enzymatic activity is elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of PAF-AH. This mutation allows us to determine a hierarchy of functions that are sensitive to LIS1 dosage, thus promoting our understanding of the role of LIS1 in the developing cortex.

Tissue-specific response of the human platelet-activating factor receptor gene to retinoic acid and thyroid hormone by alternative promoter usage.

We have studied the effects of retinoic acid (RA) and thyroid hormone (3,3',5-triiodothyronine; T3) on platelet-activating factor receptor (PAFR) gene expression in intact rats and the ability of two human PAFR gene promoters (PAFR promoters 1 and 2) to generate two transcripts (PAFR transcripts 1 and 2). Northern blotting showed that RA and T3 regulated PAFR gene expression only in rat tissues that express PAFR transcript 2. Functional analysis of the human PAFR promoter 2 revealed that responsiveness to RA and T3 was conferred through a 24-bp element [PAFR-hormone response element (HRE) located from -67 to -44 bp of the transcription start site, whereas PAFR promoter 1 did not respond to these hormones. The PAFR-HRE is composed of three direct repeated TGACCT-like hexamer motifs with 2-and 4-bp spaces, and the two upstream and two downstream motifs were identified as response elements for RA and T3. Thus, the PAF-PAFR pathway is regulated by the PAFR level altered by a tissue-specific response to RA and T3 through the PAFR-HRE of the PAFR promoter 2.

Memory enhancement by intrahippocampal, intraamygdala, or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance task.

Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), which is thought to be a retrograde messenger in long-term potentiation (LTP), enhances glutamate release and LTP through an action on presynaptic nerve endings. The PAF antagonist BN 52021 blocks CA1 LTP in hippocampal slices, and, when infused into rat dorsal hippocampus pre- or posttraining, blocks retention of inhibitory avoidance. Here we report that memory is affected by pre- or posttraining infusion of the PAF analog 1-O-hexadecyl-2-N-methylcarbamoyl-sn-glycerol-3-phosphocholine (mc-PAF) into either rat dorsal hippocampus, amygdala, or entorhinal cortex. Male Wistar rats were implanted bilaterally with cannulae in these brain regions. After recovery from surgery, the animals were trained in step-down inhibitory avoidance or in a spatial habituation task and tested for retention 24 h later. mc-PAF (1.0 microgram per side) enhanced retention test performance of the two tasks when infused into the hippocampus before training without altering training session performance. In addition, mc-PAF enhanced retention test performance of the avoidance task when infused into (i) the hippocampus 0 but not 60 min after training; (ii) the amygdala immediately after training; and (iii) the entorhinal cortex 100 but not 0 or 300 min after training. In confirmation of previous findings, BN 52021 (0.5 microgram per side) was found to be amnestic for the avoidance task when infused into the hippocampus or the amygdala immediately but not 30 or more minutes after training or into the entorhinal cortex 100 but not 0 or 300 min after training. These findings support the hypothesis that memory involves PAF-regulated events, possibly LTP, generated at the time of training in hippocampus and amygdala and 100 min later in the entorhinal cortex.

Avaliação do efeito de polimorfismos genéticos com a dependência à nicotina

Introdução: A identificação de variantes genéticas que predispõem a maior susceptibilidade à dependência à nicotina pode ser importante para a prevenção e o tratamento do tabagismo. No contexto de medicina personalizada, os principais objetivos do presente estudo foram avaliar se polimorfismos nos genes CHRNA2, CHRNA3, CHRNA5 e CHRNB3 estão associados com o nível de dependência em indivíduos fumantes e com o resultado do tratamento antitabágico. Métodos: Estudo de coorte com 1049 pacientes fumantes que receberam tratamento farmacológico (vareniclina, vareniclina e bupropiona, bupropiona e/ou terapia de reposição nicotínica). O sucesso na cessação tabágica foi considerado para os pacientes que completaram 6 meses de abstinência contínua. O teste de Fagerström para a dependência à nicotina (FTND) e o escore de consumo situacional Issa foram utilizados para avaliar a dependência à nicotina. A escala de conforto PAF foi utilizada para avaliar o conforto do paciente durante o tratamento. Os polimorfismos CHRNA2 rs2472553, CHRNA3 rs1051730, CHRNA5 rs16969968, CHRNA5 rs2036527 e CHRNB3 rs6474413 foram genotipados pela análise da curva de melting. Resultados: As mulheres portadoras dos genótipos GA e AA para os polimorfismos CHRNA5 rs16969968 e rs2036527 obtiveram maior taxa de sucesso no tratamento antitabagismo: 44,0% e 56,3% (rs16969968), 41,5% e 56,5% (rs2036527), respectivamente; em comparação com as mulheres portadoras do genótipo GG: 35,7% (rs16969968) e 34,8% (rs2036527), (P=0,03; n=389; P=0,01; n=391). Os genótipos GA ou AA para os rs16969968 e rs2036527 foram associados com maior OR para o sucesso em mulheres (OR=1,63; IC 95%=1,04-2,54; P=0,03 e OR=1,59; IC 95%=1,02-2,48; P=0,04; respectivamente), em um modelo multivariado. Não foi encontrada associação dos polimorfismos no gene CHRNA5 com o escore de FTND. Para os polimorfismos CHRNA2 rs2472553, CHRNA3 rs1051730 e CHRNB3 rs6474413 não foram encontradas associações significativas com os fenótipos estudados. Conclusão: Os polimorfismos rs16969968 e rs2036527 no gene CHRNA5 foram associados com maior taxa de sucesso no tratamento antitabagismo em mulheres. Estes resultados podem contribuir com avanços na terapêutica baseada em medicina personalizada

Platelet-activating factor downregulates the expression of liver X receptor-α and its target genes in human neutrophils

Liver X receptors (LXRs) are ligand-activated members of the nuclear receptor superfamily that regulate the expression of genes involved in lipid metabolism and inflammation, although their role in inflammation and immunity is less well known. It has been reported that oxysterols/LXRs may act as anti-inflammatory molecules, although opposite actions have also been reported. In this study, we investigated the effect of platelet-activating factor (PAF), a proinflammatory molecule, on LXRα signalling in human neutrophils. We found that PAF exerted an inhibitory effect on mRNA expression of TO901317-induced LXRα, ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and sterol response element binding protein 1c. This negative action was mediated by the PAF receptor, and was dependent on the release of reactive oxygen species elicited by PAF, as it was enhanced by pro-oxidant treatment and reversed by antioxidants. Current data also support the idea that PAF induces phosphorylation of the LXRα molecule in an extracellular signal-regulated kinase 1/2-mediated fashion. These results suggest that a possible mechanism by which PAF exerts its proinflammatory effect is through the downregulation of LXRα and its related genes, which supports the notion that LXRα ligands exert a modulatory role in the neutrophil-mediated inflammatory response.