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BackgroundImpact of commissural alignment (CA) strategies with self-expandable supra-annular transcatheter aortic valves (TAVR) has not been investigated yet.MethodsMulticentric ambispective study including patients who underwent self-expandable TAVR in 7 centers with the Evolut Pro/Pro+ (EP)(Medtronic, USA) and Acurate neo2 (AN2)(Boston Scientific, USA). Comparison of those with CA attempt vs. those with no CA attempt was performed. The degree of commissural misalignment (CMA) was assessed by computed tomography/angiography and 1-year transvalvular gradients/regurgitation evaluated by echocardiography. A matched comparison according to annular dimensions/eccentricity, prosthesis size/type, and baseline left ventricular function and gradients was performed.ResultsA total of 557 patients, mean age 80.7±6.6 years, 61.4% men, and STS score of 4.3±3.1% were analyzed. A CA technique was attempted in 215 patients (38.6%), including 113 patients with AN2 and 102 patients with EP. None/mild CMA was found in 158 (73.5% vs. 43.6% if no CA attempted, pConclusionsThe use of CA strategies significantly reduced the rate of CMA for the self-expandable TAVR devices ACN2 and EP which was associated to lower transvalvular gradients and intra-prosthetic regurgitation progression at 1-year although no criteria of structural deterioration were met at this follow up.Clinicaltrials.org:NCT05097183CONDENSED ABSTRACTCommissural alignment (CA) strategies with Evolut Pro and Acurate neo2 TAVR devices were similarly successful in ¾ of the patients, representing a significant increase compared to traditional implantation. Patients with moderate/severe commissural misalignment (CMA) had a significantly greater progression of both peak and mean gradients and higher rate of new central aortic regurgitation at 1-year, but not a greater proportion of patients with mean gradient above 10mmHg. Hence, even at only 1-year of follow up and despite the lack of formal structural deterioration criteria, some hints suggest a more rapid deterioration if moderate/severe CMA is present after supra-annular TAVR.

The objective of this paper is to develop a model that measures competitiveness among tourism businesses in Mexico. To that end, this research consists of three parts: the first refers to the theoretical framework to define the competitiveness of a tourism company and proposes a theoretical business competitiveness model; the second deals with the development of a questionnaire upon the theoretical model; in the third part, the questionnaire and the theoretic model are validated using factor analysis and a competitiveness index, is presented.

The study aims to model the evolution of stock prices and consumer/enterprise confidence index using the PLS-SEM path method to approach their behavior through different types of constructs. Furthermore, different construct sectors are analyzed using the most important enterprises of the Mexican Stock Index, modeling as explanatory variables confidence and macroeconomic single and non-single constructs. The PLS-SEM path model has arrived as a modeling option to be used in financial and economic sciences due to its numerous virtues in statistical assumptions. This research concludes that the Mexican Stock Market can be studied with constructs, improving flexibility and exploratory using different validity measures.

SummaryThe central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm that is driven by intrinsic activity of molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery but whether these molecular programs generate oscillations of membrane properties is unexplored. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-hour oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium conductances to reduce excitability during the light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the light phase, increasing engram recruitment and spatial discrimination memory. These results reveal that circadian transcriptional machinery regulates intrinsic excitability, highlighting the role of cell-autonomous oscillations in hippocampal function and behavior.HighlightsDentate neurons exhibit a 24-hour oscillation of excitability with low excitability during the Light phaseReduced excitability results from G-protein regulation of passive and active propertiesBmal1 deletion disrupts G-protein regulation to enhance excitability during the LightBmal1 deletion enhances the size of memory engrams and spatial discrimination

Purpose: Descriptive psychopathology (DP, sometimes called psychopathology or phenomenology) is the language of psychiatry and is dedicated to the description of mental symptoms. Due to its importance, there is an ongoing case to put it back at the heart of psychiatry and its training. This study seeks to examine the literature on how to train psychiatry residents in DP, including reported educational interventions and educational methods. Method: The authors conducted a systematic review following the PRISMA and BEME guidelines to identify literature on how to train psychiatry residents in DP. In May 2019, they searched in Embase, ERIC, PsycINFO, PubMed, Scopus, and Web of Science; of 7,199 initial results, 26 sources were finally included for analysis. The assessment tools were the CRAAP test, Kirkpatrick’s 4 levels, and (when applicable) the Medical Education Research Study Quality Instrument (MERSQI). Results: The mean CRAAP score was 38.885 of a possible 50 (SD 0.983; range: 36.859–40.910). Fourteen sources (53.8%) had some kind of training evaluation: Kirkpatrick’s level 1 was present in nearly all (13) and was the highest in half of them (7). Regarding the educational interventions, the mean MERSQI score was 10.592 of a possible 18 (SD 2.371; range 9.085–12.098). Lectures were the most widely reported educational method (5); among those in clinical settings, the live supervised interview with feedback was the most usual (4). Conclusions: Despite its core importance as the language of psychiatry, the literature about training psychiatry residents in DP is scarce and heterogeneous. General lack of training evaluation and ongoing overemphasis on Kirkpatrick’s levels 1–2 at the expense of levels 3–4 are causes for concern. During the review process, the authors identified a selection of educational interventions that could serve as the basis for the design of new training efforts in both clinical and nonclinical settings. Topics for future research are also suggested, such as the role of DP in competency-based training frameworks now in vogue and a series of neglected contents. Finally, the combined use of the CRAAP test and the MERSQI may be useful for future systematic reviews in medical education.

Currently, according to INEI in Peru, the courier sector has suffered a 26% contraction in demand. This means that SMEs belonging to the commerce and courier sector are facing great competition in the market due to the reduction in demand and that the same supply is maintained, i.e., the market has become more competitive. For this reason, SMEs that do not take into consideration this context present problems within their deliveries, these incidences harm the profitability of the company, which leads to a reduction in the level of service. This problem is mainly caused by an inadequate digitization method, an inadequate route assignment and over-deliveries produced by an inadequate plant distribution. To solve this problem, this research proposes an operations model based on Route Planning, SLP and Work Study tools. The research was able to reduce the delivery time by 18.6%, the percentage of classified documents was increased by 29.15% and the percentage of incidents by less than 3%, thus increasing the service level by 22%.

Background: The vast majority of transcatheter valve-in-valve (ViV) mitral procedures have been reported with the SAPIEN family. We aimed to report the preliminary experience with the Myval balloon-expandable device in this setting. Methods: Multicenter retrospective study of high-risk surgical patients with mitral bioprosthesis degeneration undergoing transcatheter ViV implantation with Myval device. Results: A total of 11 patients from five institutions were gathered between 2019 and 2022 (age 68 ± 7.8, 63% women). The peak and mean transvalvular gradients were 27 ± 5 mmHg and 14.7 ± 2.3 mmHg, respectively, and the predicted neo-left ventricular outflow tract (neo-LVOT) area was 183.4 ± 56 mm2 (range: 171 to 221 mm2). The procedures were performed via transfemoral access in all cases (through echocardiography-guided transeptal puncture (81.8% transesophageal, 11.2% intracardiac)). Technical success was achieved in all cases, with no significant residual mitral stenosis in any of them (peak 7.2 ± 2.7 and mean gradient 3.4 ± 1.7 mmHg) and no complications during the procedure. There were no data of LVOT obstruction, migration, or paravalvular leak in any case. Mean hospital stay was 3 days, with one major vascular complication and no stroke. At 6-month follow-up, there was one case with suboptimal anticoagulation presenting an increase in the transmitral gradients (mean 15 mmHg) that normalized after optimization of the anticoagulation, but no other relevant events. Conclusions: Transseptal ViV mitral implantation with the balloon-expandable Myval device was feasible and safe avoiding redo surgery in high-risk patients with bioprosthesis degeneration.

Summary: Voluntary running enhances adult hippocampal neurogenesis, with consequences for hippocampal-dependent learning ability and mood regulation. However, the underlying mechanism remains unclear. Here, we show that voluntary running induces unique and dynamic gene expression changes specifically within the adult-born hippocampal neurons, with significant impact on genes involved in neuronal maturation and human diseases. We identify the regulator of G protein signaling 6 (RGS6) as a key factor that mediates running impact on adult-born neurons. RGS6 overexpression mimics the positive effects of voluntary running on morphological and physiological maturation of adult new neurons and reduced sensitivity of adult-born neurons to the inhibitory effect of GABAB (γ-Aminobutyric acid B) receptor activation. Knocking down RGS6 abolishes running-enhanced neuronal maturation and hippocampal neurogenesis-dependent learning and anxiolytic effect. Our study provides a data resource showing genome-wide intrinsic molecular changes in adult-born hippocampal neurons that contribute to voluntary running-induced neurogenesis.

Parvalbumin-expressing interneurons (PVs) in the dentate gyrus provide activity-dependent regulation of adult neurogenesis as well as maintain inhibitory control of mature neurons. In mature neurons, PVs evoke GABAA postsynaptic currents (GPSCs) with fast rise and decay phases that allow precise control of spike timing, yet synaptic currents with fast kinetics do not appear in adult-born neurons until several weeks after cell birth. Here we used mouse hippocampal slices to address how PVs signal to newborn neurons prior to the appearance of fast GPSCs. Whereas PV-evoked currents in mature neurons exhibit hallmark fast rise and decay phases, newborn neurons display slow GPSCs with characteristics of spillover signaling. We also unmasked slow spillover currents in mature neurons in the absence of fast GPSCs. Our results suggest that PVs mediate slow spillover signaling in addition to conventional fast synaptic signaling, and that spillover transmission mediates activity-dependent regulation of early events in adult neurogenesis.

La pérdida de granos almacenados es un problema para los agricultores. Sitophilus zeamais Motschulsky, es la principal plaga en maíz almacenado. El objetivo del estudio fue determinar las propiedades bioinsecticidas de vegetales pulverizados reconocidos por productores de la Nueva y el Rosario, Copainalá, Chiapas, México, de septiembre 2015 a abril 2016. Se utilizó un diseño completamente al azar, con 25 tratamientos, un testigo absoluto y uno químico (fosfuro de aluminio) con tres repeticiones. En laboratorio se evaluaron cinco especies vegetales como pulverizados. R. communis L. al 4% genero la mortalidad mayor (53.3%). C. ambrosioides L. al 1% y R. communis L. al 3 y 5% con índice de repelencia (0.95) fueron los mejores. En maíz almacenado se evaluó el mejor tratamiento de la prueba en laboratorio; para mortalidad no se presentó diferencias significativas entre tratamientos. El porcentaje de maíz germinado no se ve afectado por la aplicación de pulverizados. R. comunis L. presentó resultados estadísticamente similares en grano dañado que el fosfuro de aluminio. La pérdida de peso del grano fue de 0.97 kg. Se puede concluir que el pulverizado de higuerilla tiene efectos de mortalidad al 4% y repelencia al 3 y 5% en condiciones de laboratorio. Mientras que en condiciones de almacenamiento no existieron diferencias lo cual pudo deberse a la perdida de efectividad de los metabolitos activos de higuerilla, el poder germinativo de las semillas de maíz no se ve afectado por la aplicación del pulverizado de R. communis L.

Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the principal neurons, the dentate granule cells (GCs). Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Here we demonstrate that intact G protein-mediated signaling contributes to the characteristic low resting membrane potential that differentiates mature dentate GCs from CA1 pyramidal cells and developing adult-born GCs. In mature GCs from male and female mice, intact G protein signaling robustly reduces intrinsic excitability, whereas deletion of G protein-activated inwardly rectifying potassium channel 2 (GIRK2) increases excitability and blocks the effects of G protein signaling on intrinsic properties. Similarly, pharmacological manipulation of GABAB receptors (GABABRs) or GIRK channels alters intrinsic excitability and GC spiking behavior. However, adult-born new GCs lack functional GIRK activity, with phasic and constitutive GABABR-mediated GIRK signaling appearing after several weeks of maturation. Phasic activation is interneuron specific, arising primarily from nNOS-expressing interneurons rather than parvalbumin- or somatostatin-expressing interneurons. Together, these results demonstrate that G protein signaling contributes to the intrinsic excitability that differentiates mature and developing dentate GCs and further suggest that late maturation of GIRK channel activity is poised to convert early developmental functions of GABAB receptor signaling into GABABR-mediated inhibition.SIGNIFICANCE STATEMENT The dentate gyrus exhibits sparse neural activity that is essential for the computational function of pattern separation. Sparse activity is ascribed to strong local inhibitory circuits in combination with low intrinsic excitability of the principal neurons, the granule cells. Here we show that constitutive activity of G protein-coupled inwardly rectifying potassium channels (GIRKs) underlies to the hallmark low resting membrane potential and input resistance of mature dentate neurons. Adult-born neurons initially lack functional GIRK channels, with constitutive and phasic GABAB receptor-mediated GIRK inhibition developing in tandem after several weeks of maturation. Our results reveal that GABAB/GIRK activity is an important determinant of low excitability of mature dentate granule cells that may contribute to sparse DG activity in vivo.

Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death. Electronic supplementary material The online version of this article (10.1186/s40478-018-0537-x) contains supplementary material, which is available to authorized users.

Deep learning algorithms have improved the speed and quality of segmentation for certain tasks in medical imaging. The aim of this work is to design and evaluate an algorithm capable of segmenting bones in dual-energy CT data sets. A convolutional neural network based on the 3D U-Net architecture was implemented and evaluated using high tube voltage images, mixed images and dual-energy images from 30 patients. The network performed well on all the data sets; the mean Dice coefficient for the test data was larger than 0.963. Of special interest is that it performed better on dual-energy CT volumes compared to mixed images that mimicked images taken at 120 kV. The corresponding increase in the Dice coefficient from 0.965 to 0.966 was small since the enhancements were mainly at the edges of the bones. The method can easily be extended to the segmentation of multi-energy CT data. Funding Agencies| [SNIC 2018/7-22]; [LiO-724181]; [CAN 2017/1029]; [VRNT 2016-05033]

The application of high concentrations of taurine induces long-lasting potentiation of synaptic responses and axon excitability. This phenomenon seems to require the contribution of a transport system with a low affinity for taurine. The prototypic taurine transporter TauT (SLC6A6) was discarded by experimental evidence obtained in TauT-KO mice. The purpose of the present study was to determine whether the proton-coupled amino acid transporter 1 (PAT1; SLC36A1) which is a transport system with low affinity and high capacity for a great variety of amino acids including taurine, contributes to the taurine-induced synaptic potentiation. In rat hippocampal slices, the application of several amino acids (L- and D-alanine, L-glutamine, β-guanidinopropionic acid, glycine, L-histidine, L- and D-serine, sarcosine, L- and D-threonine) imitated the synaptic potentiation induced by taurine. The magnitude of the potentiation caused by some of these amino acids was even greater than that induced by taurine. By contrast, the application of other amino acids (L-arginine, betaine, L-leucine, L-methionine, L- and D-proline, and L-valine) did not induce potentiation. The behaviour of these different amino acids on synaptic potentiation is not compatible with a role of PAT1 in synaptic potentiation. There was a positive correlation between the accumulation of the different amino acids in the slice and the magnitude of synaptic potentiation induced by them. Some of the amino acids inducing synaptic potentiation, like taurine and L-threonine, also increased electrical resistance of the slice, whereas L-leucine did not modify this parameter. Modifications induced by either taurine or L-threonine in synaptic potentiation, slice resistance and amino acid accumulation were dependent on extracellular chloride concentration. These findings support the idea that the accumulation of amino acids throughout the action of transporters causes cell swelling enhancing the electrical resistance of the slice, which by itself could be sufficient to increase field synaptic potentials.

Hippocampal gamma oscillation, involved in cognitive processes, can be induced by muscarinic acetylcholine receptors activation and depends in large part on the activation of γ-aminobutyric acidergic (GABAergic) interneurons. The precise role of the modulatory action of muscarinic receptors on GABAergic transmission still remains unclear due to the great heterogeneity of observed effects. We have examined the presynaptic and postsynaptic mechanisms involved. Methacholine induces a down-regulation of evoked inhibitory postsynaptic currents (eIPSCs) not associated with the change of postsynaptic receptors. The significant decrease in the paired-pulse depression strongly suggested a presynaptic mechanism of action. We have used cumulative amplitude profile analysis to show that the impairment of eIPSCs is not related to a decreased size of the readily releasable pool, but rather depends on the reduced release probability by a down-modulation of voltage-gated calcium channels. The decreased neurotransmitter release probability only partially accounts for the dramatic reduction in the rate of synaptic depression evoked by short- and long-lasting tetanic stimuli. This effect is accompanied by a significant enhancement in the rate of recovery from synaptic depression that demonstrates the reinforcement of the synaptic recycling processes. These results show that muscarinic modulation of hippocampal GABAergic synapses confers a greater resistance to sustain periods of intense synaptic activity in the gamma frequency range.

We investigated the effects of muscarinic acetylcholine receptor (mAChR) activation on GABAergic synaptic transmission in rat hippocampal neurons. Current-clamp recordings revealed that methacholine produced membrane depolarization and action potential firing. Methacholine augmented the bicuculline-sensitive and GABA(A) -mediated frequency of spontaneous inhibitory postsynaptic currents (sIPSCs); the action of methacholine had a slow onset and longer duration. The increase in methacholine-evoked sIPSCs was completely inhibited by atropine and was insensitive to glutamatergic receptor blockers. Interestingly, methacholine action was not inhibited by intracellular perfusion with GDP-β-S, suggesting that muscarinic effects on membrane excitability and sIPSC frequency are mainly presynaptic. McN-A-343 and pirenzepine, selective agonist and antagonist of the m1 mAChR subtype, respectively, neither enhanced sIPSCs nor inhibited the methacholine effect. However, the m3-m5 mAChR antagonist 4-DAMP, and the m2-m4 mAChR antagonist himbacine inhibited the methacholine effect. U73122, an IP(3) production inhibitor, and 2APB, an IP(3) receptor blocker, drastically decreased the methacholine effect. Recording of miniature events revealed that besides the effect exerted by methacholine on membrane firing properties and sIPSC frequency, muscarinic receptors also enhanced the frequency of mIPSCs with no effect on their amplitude, possibly modulating the molecular machinery subserving vesicle docking and fusion and suggesting a tight colocalization at the active zone of the presynaptic terminals. These data strongly suggest that by activating presynaptic m2, m3, m4 and m5 mAChRs, methacholine can increase membrane excitability and enhance efficiency in the GABA release machinery, perhaps through a mechanism involving the release of calcium from the endoplasmic reticulum.

The cardiovascular protecting effects of resveratrol, an antioxidant polyphenol present in grapes and wine, have been attributed to its vasorelaxing effects and to its anti-inflammatory, antioxidant, and antiplatelet actions. Inhibition of adrenal catecholamine release has also been recently implicated in its cardioprotecting effects. Here, we have studied the effects of nanomolar concentrations of resveratrol on quantal single-vesicle catecholamine release in isolated bovine adrenal chromaffin cells. We have found that 30 to 300 nM concentrations of resveratrol blocked the acetylcholine (ACh) and high K(+)-evoked quantal catecholamine release, amperometrically measured with a carbon fiber microelectrode. At these concentrations, resveratrol did not affect the whole-cell inward currents through nicotinic receptors or voltage-dependent sodium and calcium channels, neither the ACh- or K(+)-elicited transients of cytosolic Ca(2+). Blockade by nanomolar resveratrol of secretion in ionomycin- or digitonin-treated cells suggests an intracellular site of action beyond Ca(2+)-dependent exocytotic steps. The fact that nanomolar resveratrol augmented cGMP is consistent with the view that resveratrol could be blocking the quantal secretion of catecholamine through a nitric oxide-linked mechanism. Because this effect occurs at nanomolar concentrations, our data are relevant in the context of the low circulating levels of resveratrol found in moderate consumers of red wines, which could afford cardioprotection by mitigating the catecholamine surge occurring during stress.

Aim: This study examines the effect of reducing the corticosterone levels of gestating rat dams on the postnatal development and maturation of monoaminergic systems in their offspring’s brains. Methods: Metyrapone, an inhibitor of CORT synthesis, was administered to pregnant rats from E0 to E17 of gestation. Monoamine concentrations were determined in male and female offspring at postnatal days (PN) 23 and 90 in the hippocampus, hypothalamus and striatum. Results: Reducing maternal corticosterone (mCORT) during gestation led to alterations in dopamine and serotonin levels in all three brain areas studied at PN 23. Alterations persisted until at least PN 90 in the serotonergic systems; the dopamine content of the hippocampus also remained modified. Reduced mCORT during gestation also led to alterations in the development and maturation of the hypothalamic noradrenergic systems. Sexually dimorphic responses were observed in all these monoaminergic systems at different times. Conclusion: These results suggest that while they are still developing, brain monoaminergic systems are particularly sensitive to epigenetic influences. An adequate foetal level of CORT is required for the normal ontogeny of brain monoaminergic systems. The present data also provide that during the critical period of brain development, maternal CORT plays an important role in the sexual differentiation of monoaminergic systems, with particular influence on brain serotonergic neurones.

The recent analyses of monthly and seasonal Spanish mainland temperatures (1951-2010) at high spatial resolution using the MOTEDAS dataset shown that the monthly mean temperature values of maximum (Tmax) have risen mostly in late winter/early spring and the summer months, while the monthly mean temperature of minimum (Tmin) values have increased in summer, spring and autumn in southern areas. Consequently, a north-south gradient in diurnal temperature range (DTR) has been detected in summer months, with positive trends in the north and negative trends in the south, and negative pattern was found in the southeast in spring and autumn. During the same period, the Spanish mainland has suffered dramatic changes in the landscape related to urban and industrial sprawl, transportation infrastructures development, or the extension of irrigated areas for intensive agriculture. Those changes would be consistent with factors that affect Tmin, which are conditioned by the nature of the surfaces. In this research, we present the first approach to the relationship of temperature trend and landscapes changes at high spatial resolution in the Spanish mainland. Thus, we have compared the spatial distribution of temperature trend with changes in accessibility index and population potential simultaneously, and its spatial redistribution as indicator of landscape changes. The significance of temperature trends was evaluated by Mann-Kendal test, and its intensity by Sen0s estimator. A mix model of population potential and accessibility index weighted by route factor has been used to assess landscape changes. Crosstab analysis was applied to identify the association between temperature trends and accessibility changes.

The mechanism of the neuroprotective action of the tetracycline antibiotic minocycline against various neuron insults is controversial. In an attempt to clarify this mechanism, we have studied here its effects on various electrophysiological parameters, Ca 2+ signalling, and glutamate release, in primary cultures of rat hippocampal neurons, and in synaptosomes. Spontaneous excitatory postsynaptic currents and action potential firing were drastically decreased by minocycline at concentrations known to afford neuroprotection. The drug also blocked whole-cell inward Na + currents (INa) by 20%, and the whole-cell Ca 2+ current (ICa) by about 30%. Minocycline inhibited glutamate-evoked elevation of the cytosolic Ca 2+ concentration ([Ca 2+ ]c) by nearly 40%, and K + -evoked glutamate release from synaptosomes by 63%. Minocycline also depressed the frequency and amplitude of spontaneous excitatory postsynaptic currents, but did not affect the whole-cell inward current elicited by c-aminobutyric acid or glutamate. This pharmacological profile suggests that the neuroprotective effects of minocycline might be associated with the mitigation of neuronal excitability, glutamate release, and Ca 2+ overloading.

Intrastriatal injection (16microg) of the neurotoxic dopaminergic agent 6-hydroxydopamine (6-OHDA) in ovariectomized rats caused important reductions in striatal dopamine (DA) and serotonin (5-HT) levels and an increase in GABA content. Treatment of ovariectomized rats with estradiol (5 mg 17-beta-estradiol administered by a subcutaneous cannula) before 6-OHDA injection maintained the control levels of these neurotransmitters. The administration of estradiol after 6-OHDA injection did not lead to their recovery. These findings suggest that estradiol acts as a neuroprotectant--but not as a neuroreparatory agent--and that it might be able to attenuate striatal dopaminergic neuron degeneration caused by neurotoxic agents.

Total knee arthroplasty is a common operation for all types of arthritis, including chronic gouty arthritis. Tophi deposits are a well-known cause of joint destruction, but simultaneous subcutaneous and articular tophaceous gout is exceptional. We report a patient who required bilateral total knee replacement for this rare condition.

Chondroitin sulfate (CS) proteoglycans (CSPGs) are the most abundant PGs of the brain extracellular matrix (ECM). Free CS could be released during ECM degradation and exert physiological functions; thus, we aimed to investigate the effects of CS on voltage- and current-clamped rat embryo hippocampal neurons in primary cultures. We found that CS elicited a whole-cell Na(+)-dependent inward current (ICS) that produced drastic cell depolarization, and a cytosolic calcium transient ([Ca(2+)]c). Those effects were similar to those elicited by α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate, were completely blocked by NBQX and CNQX, were partially blocked by GYKI, and were unaffected by MK801 and D-APV. Furthermore, ICS and AMPA currents were similarly potentiated by cyclothiazide, a positive allosteric modulator of AMPA receptors. Because CSPGs have been attributed Ca(2) (+) -dependent roles, such as neural network development, axon pathfinding, plasticity and regeneration after CNS injury, CS action after ECM degradation could be contributing to the mediation of these effects through its interaction with AMPA and kainate receptors.

Cyclic nucleotide-gated channels (CNGCs) are important transducers of external signals in sensory processes. These channels are ubiquitously expressed in a variety of neurons, and are necessary to transduce signals for growth cone guidance and plasticity. Here, we demonstrate that the CNGC subunits (CNGA1 and CNGB1, presumably the 1b isoform) are expressed in rat cerebellar granule cells and that they combine to form functional channels. The expression of the mRNAs that encode these proteins is maximal after 7 days in cell culture, when the channels are expressed at synapses and co-localize with the synaptic marker synapsin I. These ligand-gated channels are functional and can be blocked by Mg2+ or L-cis-diltiazem. Moreover, channel opening in response to increases in intracellular cGMP results in Ca2+ entry into the cell. Chronic blockade (96 h) of these channels with L-cis-diltiazem significantly decreases the number of functional boutons, as determined by their capacity to load and unload the styryl dye FM1-43 when stimulated. Moreover, the unloading kinetics is modified from a biphasic to a monophasic profile in a subset of synaptic boutons. These channels are also expressed in early developmental stages, both in the soma and in emerging processes, and CNGA1 can be detected in growth cones. Pharmacological blockade of these channels with L-cis-diltiazem causes an overall change in growth cone morphology, impairing the formation of lamellipodia between filopodia and increasing the number of filopodia. J. Cell. Physiol. 227: 2252–2263, 2012. © 2011 Wiley Periodicals, Inc.

The effects of maternal exposure to 10 mg Cd/l (as cadmium acetate) in drinking water during gestation and lactation on the development of monoaminergic and aminoacidergic systems were studied in discrete brain areas of the pups: striatum, cerebral cortex, dorsal hippocampus and basal-medial hypothalamus. Hippocampal levels of serotonin and 5-hydroxyindolacetic acid were significantly reduced in rats exposed to Cd whereas the dopamine content was not significantly affected by Cd. Glutamate concentration decreased in hypothalamus and increased in hippocampus, while gamma-aminobutiric acid content decreased only in cerebral cortex. The present results demonstrate that maternal exposure to 10 mg/l of Cd leads to neurochemical disturbances on serotoninergic and aminoacidergic systems during development.

The role of postsynaptic nicotinic receptors for acetylcholine (nAChRs) in mediating fast neurotransmission processes in the CNS is controversial. Here we have studied the modulation of synaptic transmission by an agonist (choline) and an allosteric modulator (5-OH-indole) of alpha7 nAChRs in rat hippocampal neuronal cultures. Choline evoked a fast inactivating inward current, causing neuron depolarization and action potential discharge, thereby enhancing the spontaneous postsynaptic current activity (sPSCs). This effect was markedly enhanced when both choline and 5-OH-indole were applied together and was blocked by the selective alpha7 nAChR antagonist methyllycaconitine. This choline action was suppressed by the GABA(A) receptor antagonist bicuculline, while the glutamatergic receptor antagonist kynurenic acid had no effect. Frequency, but not amplitude or area, of both excitatory and inhibitory miniature postsynaptic currents (mEPSCs and mIPSCs) were drastically reduced when Ca(2+) influx was blocked by Cd(2+). Additionally, nAChR activation did not modify the mIPSCs. These data suggest that Ca(2+) influx through the highly Ca(2+)-permeablealpha7 nAChRs was insufficient to directly activate neurotransmitter release, suggesting that a tight colocalization of this receptor with secretory hot spots is unlikely. In a few cases, the activation of alpha7 AChRs led to a suppression of spontaneous synaptic transmission. This effect may be related to the potentiation of GABAergic interneurons that inhibit the spontaneous activity of neurons making synapses with the cell under study. We suggest that GABA release is modulated by alpha7 nAChRs. Thus, selective allosteric modulators of alpha7 nAChRs could have potential therapeutic applications in brain disorders such as epilepsy and schizophrenia and in alterations of cognition and sensory processing.