Possible mechanisms to improve sleep spindles via closed loop stimulation during slow wave sleep: A computational study.

Sleep spindles are one of the prominent EEG oscillatory rhythms of non-rapid eye movement sleep. In the memory consolidation, these oscillations have an important role in the processes of long-term potentiation and synaptic plasticity. Moreover, the activity (spindle density and/or sigma power) of spindles has a linear association with learning performance in different paradigms. According to the experimental observations, the sleep spindle activity can be improved by closed loop acoustic stimulations (CLAS) which eventually improve memory performance. To examine the effects of CLAS on spindles, we propose a biophysical thalamocortical model for slow oscillations (SOs) and sleep spindles. In addition, closed loop stimulation protocols are applied on a thalamic network. Our model results show that the power of spindles is increased when stimulation cues are applied at the commencing of an SO Down-to-Up-state transition, but that activity gradually decreases when cues are applied with an increased time delay from this SO phase. Conversely, stimulation is not effective when cues are applied during the transition of an Up-to-Down-state. Furthermore, our model suggests that a strong inhibitory input from the reticular (RE) layer to the thalamocortical (TC) layer in the thalamic network shifts leads to an emergence of spindle activity at the Up-to-Down-state transition (rather than at Down-to-Up-state transition), and the spindle frequency is also reduced (8-11 Hz) by thalamic inhibition.

Existence of dual solution for MHD boundary layer flow over a stretching/shrinking surface in the presence of thermal radiation and porous media: KKL nanofluid model.

Present study is dedicated to analyze the closed form solution of nanofluid flow over a stretching/shrinking sheet with dual availability. Flow is developed through two-dimensional boundary layer theory. Appropriate tensor is used to generate the continuity, energy, and momentum equations. Converted governing partial differential equations (PDEs) into dimensionless non-linear ordinary differential equations (ODEs) by adoption of favorable similarity variables. The dimensionless ODEs of energy and momentum produced a dual nature solution in closed form under certain conditions. To deal with the nanofluid, the Koo-Kleinstreuer and Li (KKL) model is used, and the equations are solved using well-known software Maple. The effect of porosity Φ, suction/injection fw, stretching/shrinking λ, and magnetic effect M on skin friction, velocity, temperature, and streamlines are well explored and showcased. The results for the stable solutions have been showed that the upper branch's fluid velocity is increasing as the magnetic parameter M rises whereas the lower branch's fluid velocity is decreasing as M rises. Additionally, the CuO-nanofluid's velocity is impacted by the volume fraction of nanoparticles, with an increase in volume fraction causing a decrease in velocity. On both the lower and upper branches, the temperature profile is seen to improve as the Biot number increases. On the other hand, as the magnetic parameter varies and the magnetic field increases, the local Nusselt number against suction/injection decreases, as well as the rate of heat transfer in the upper branch decreases.

Probiotics (Bacillus clausii and Lactobacillus fermentum NMCC-14) Ameliorate Stress Behavior in Mice by Increasing Monoamine Levels and mRNA Expression of Dopamine Receptors (D1 and D2) and Synaptophysin.

Stress is a physiological consequence of the body to adversity. The gut-brain axis and probiotics are gaining interest to provide better treatment for stress and other neurological disorders. Probiotic (Lactobacillus fermentum NMCC-14 and Bacillus clausii, 1010 colony-forming unit/day/animal, per oral) effects were investigated in acute (up to day 7) and subacute (days 8-14) restraint-stressed and normal mice through behavioral paradigms (elevated plus maze: EPM, light dark box/dark light box: LDB, and open field test: OFT). Time spent in the open arms of the EPM, time spent in the light compartment of the LDB, and movable time and time spent in the center of the OFT were significantly (p ≤ 0.05, n = 5) increased in probiotic-treated restraint-stressed mice. Enzyme-linked immunoassay determined blood cortisol and adrenocorticotropic hormone (ACTH) levels, which were reduced significantly (p < 0.05, n = 5) in probiotic-treated restraint-stressed mice. Hematoxylin and eosin-stained hippocampal slides also showed less or no neurodegeneration in the probiotic-treated animals. High-performance liquid chromatography and quantitative polymerase chain reaction were performed to determine the monoamine levels and mRNA expression of dopamine receptor subtypes (D1 and D2) and synaptophysin in the mice hippocampus (HC) and prefrontal cortex (PFC). The dopamine, serotonin, and norepinephrine levels were also significantly (p < 0.05, n = 5) increased in the HC and PFC of probiotic-treated animal brains. Fold expression of mRNA of D1 and D2 (except HC, LF-S, day 14) receptors and synaptophysin was also significantly (p < 0.05, n = 5) increased in the same brain parts of probiotic-treated restraint-stressed mice. Comparing mice in the Lactobacillus fermentum NMCC-14 and Bacillus clausii groups to mice in the normal group, only a significant (p < 0.05, n = 5) decrease was observed in the serum ACTH and cortisol levels on day 14 in Bacillus clausii-treated mice, where all other parameters also showed improvement. In comparison, Bacillus clausii showed greater stress suppressant activity than Lactobacillus fermentum NMCC-14. However, both probiotic bacteria can be a better and safer therapeutic alternative for ailments than currently available drugs.

Anticonvulsant activity of methanolic extract of Withania cogulans in mice.

Mental and neurological diseases including depression, Parkinson's disease, dementia, epilepsy, anxiety disorders and bipolar disorders account for a considerable amount of the world's disease burden. Unfortunately, drugs used in the treatment of neurological diseases are expensive, symptomatic and they produce undesirable side effects. People from different cultures prefer to use medicinal plants for the treatment of various ailments ranging from plain to perplex disorders because they are most affordable, cost effective and easily accessible source of treatment in the primary healthcare system throughout the world. Withania coagulans, an erect grayish under-shrub belongs to family Solanaceae. It is common in Pakistan, East India, Iran and Afghanistan. The objective of this study was to analyze the anti-seizure activity of crude methanolic extract of Withania coagulans fruits (MeWc). For screening of this activity, maximal electroshock seizures model (MES) and chemically-induced seizures models were used. In maximal electroshock seizures test MeWc showed significant dose dependent percent protection against hind-limb tonic extension; significant and dose-dependent increase in latency to myoclonic jerks and tonic clonic convulsions and decrease in seizures duration were observed in PTZ-induced seizures. In strychnine-induced convulsions MeWc significantly increased latency to hind-limb tonic extension and percent protection from death in a dose-dependent manner. Thus, it was inferred from the experiments that extract of Withania coagulans showed anticonvulsant activity.

Comparison of acute and chronic effects of Bacopa monnieri, Ginkgo biloba, and Lavandula angustifolia and their mixture on learning and memory in mice.

Forty-seven million people are living with memory-related disorders worldwide. Phytomedicines are gaining extensive interest in the treatment of these ailments. Memory-enhancing (acute and chronic) potentials of commercial grade extracts of Bacopa monnieri (200 mg/kg, po), Ginkgo biloba (150 mg/kg, po), and Lavandula angustifolia (200 mg/kg, po) and their mixture (B. monnieri 100 mg/kg, G. biloba 75 mg/kg, and L. angustifolia 100 mg/kg, po) were compared for their synergistic/additive effects on the Morris water maze (MWM) test and elevated plus maze (EPM) test in scopolamine-induced amnesia in mice. Escape latency and accumulative path length were significantly reduced both in acute (up to day 6) and chronic trials (days 8-14) in B. monnieri-, G. biloba-, and L. angustifolia-treated animals and their mixtures (n = 8, p < .05) in MWM. Furthermore, in probe trials (acute on day 7 and chronic on day 15), the number of crossing-overs at platform position and time spent in platform quadrant were significantly increased, while transfer latency in EPM was decreased in treated animals as compared to the saline group (n = 8, p < .05). The mixture showed synergistic effects on memory enhancement as compared to each extract individually in mice. Further studies may be carried out on the active compounds of B. monnieri at the cellular and molecular levels.

Contribution of Intrinsic Lactate to Maintenance of Seizure Activity in Neocortical Slices from Patients with Temporal Lobe Epilepsy and in Rat Entorhinal Cortex.

Neuronal lactate uptake supports energy metabolism associated with synaptic signaling and recovery of extracellular ion gradients following neuronal activation. Altered expression of the monocarboxylate transporters (MCT) in temporal lobe epilepsy (TLE) hampers lactate removal into the bloodstream. The resulting increase in parenchymal lactate levels might exert both, anti- and pro-ictogen effects, by causing acidosis and by supplementing energy metabolism, respectively. Hence, we assessed the contribution of lactate to the maintenance of transmembrane potassium gradients, synaptic signaling and pathological network activity in chronic epileptic human tissue. Stimulus induced and spontaneous field potentials and extracellular potassium concentration changes (∆[K⁺]O) were recorded in parallel with tissue pO2 and pH in slices from TLE patients while blocking MCTs by α-cyano-4-hydroxycinnamic acid (4-CIN) or d-lactate. Intrinsic lactate contributed to the oxidative energy metabolism in chronic epileptic tissue as revealed by the changes in pO2 following blockade of lactate uptake. However, unlike the results in rat hippocampus, ∆[K⁺]O recovery kinetics and field potential amplitude did not depend on the presence of lactate. Remarkably, inhibition of lactate uptake exerted pH-independent anti-seizure effects both in healthy rat and chronic epileptic tissue and this effect was partly mediated via adenosine 1 receptor activation following decreased oxidative metabolism.

Pretreatment with ß-adrenergic receptor agonists facilitates induction of LTP and sharp wave ripple complexes in rodent hippocampus.

Norepinephrine, is involved in the enhancement of learning and memory formation by regulating synaptic mechanisms through its ability to activate pre- and post-synaptic adrenergic receptors. Here we show that ß-agonists of norepinephrine facilitate the induction of both associational LTP and sharp wave ripples (SPW-Rs) in acute slices of rat hippocampus in area CA3. Surprisingly, this facilitating effect persists when slices are only pretreated with ß-receptor agonists followed by wash out and application of the unspecific ß-adrenoreceptor (ßAR) antagonist propranolol. During application of ßAR agonists repeated stimulation resulted in facilitated induction of SPW-Rs. Since SPW-Rs are thought to be involved in memory replay we studied the effects of ßAR-agonists on spontaneous SPW-Rs in murine hippocampus and found that amplitude and incidence of SPW-Rs increased. These effects involve cyclic-AMP and the activation of protein kinase A and suggest a supportive role in memory consolidation. © 2016 Wiley Periodicals, Inc.

Thermophysical effects of water driven copper nanoparticles on MHD axisymmetric permeable shrinking sheet: Dual-nature study.

The present study is dedicated to analyze the dual-nature solutions of the axisymmetric flow of a magneto-hydrodynamics (MHD) nanofluid over a permeable shrinking sheet. In those phenomena where the fluid flow is due to the shrinking surface, some reverse behaviors of the flow arise because of vorticity effects. Despite of heat transfer analysis, the main purpose of the present study is to attain the solutions of the complex nature problem that appear in reverse flow phenomena. Thermophysical properties of both base fluid (water) and nanoparticles (copper) are also taken into account. By means of similarity transformation, partial differential equations are converted into a system of coupled nonlinear ordinary differential equations and then solved via the Runge-Kutta method. These results are divided separately into two cases: the first one is the unidirectional shrinking along the surface (m = 1) and the other one is for axisymmetric shrinking phenomena (m = 2) . To enhance the thermal conductivity of base fluid, nanoparticle volume fractions (0≤φ ≤ 0.2)) are incorporated within the base fluid. The numerical investigation explores the condition of existence, non-existence and the duality of similarity solution depends upon the range of suction parameter (S) and Hartmann number (M). The reduced skin friction coefficient and local Nusselt number are plotted to analyze the fluid flow and heat transfer at the surface of the shrinking sheet. Streamlines and isotherms are also plotted against the engineering control parameters to analyze the flow behavior and heat transfer within the whole domain. Throughout this analysis it is found that both nanoparticle volume fraction and Hartmann number are increasing functions of both skin friction coefficient and Nusselt number.

Serotonin dependent masking of hippocampal sharp wave ripples.

Sharp wave ripples (SPW-Rs) are thought to play an important role in memory consolidation. By rapid replay of previously stored information during slow wave sleep and consummatory behavior, they result from the formation of neural ensembles during a learning period. Serotonin (5-HT), suggested to be able to modify SPW-Rs, can affect many neurons simultaneously by volume transmission and alter network functions in an orchestrated fashion. In acute slices from dorsal hippocampus, SPW-Rs can be induced by repeated high frequency stimulation that induces long-lasting LTP. We used this model to study SPW-R appearance and modulation by 5-HT. Although stimulation in presence of 5-HT permitted LTP induction, SPW-Rs were "masked"--but appeared after 5-HT wash-out. This SPW-R masking was dose dependent with 100 nM 5-HT being sufficient--if the 5-HT re-uptake inhibitor citalopram was present. Fenfluramine, a serotonin releaser, could also mask SPW-Rs. Masking was due to 5-HT1A and 5-HT2A/C receptor activation. Neither membrane potential nor membrane conductance changes in pyramidal cells caused SPW-R blockade since both remained unaffected by combining 5-HT and citalopram. Moreover, 10 and 30 µM 5-HT mediated SPW-R masking preceded neuronal hyperpolarization and involved reduced presynaptic transmitter release. 5-HT, as well as a 5-HT1A agonist, augmented paired pulse facilitation and affected the coefficient of variance. Spontaneous SPW-Rs in mice hippocampal slices were also masked by 5-HT and fenfluramine. While neuronal ensembles can acquire long lasting LTP during higher 5-HT levels, lower 5-HT levels enable neural ensembles to replay previously stored information and thereby permit memory consolidation memory.

Early adenosine release contributes to hypoxia-induced disruption of stimulus-induced sharp wave-ripple complexes in rat hippocampal area CA3.

We investigated the effects of hypoxia on sharp wave-ripple complex (SPW-R) activity and recurrent epileptiform discharges in rat hippocampal slices, and the mechanisms underlying block of this activity. Oxygen levels were measured using Clark-style oxygen sensor microelectrodes. In contrast to recurrent epileptiform discharges, oxygen consumption was negligible during SPW-R activity. These network activities were reversibly blocked when oxygen levels were reduced to 20% or less for 3 min. The prolongation of hypoxic periods to 6 min caused reversible block of SPW-Rs during 20% oxygen and irreversible block when 0% oxygen (anoxia) was applied. In contrast, recurrent epileptiform discharges were more resistant to prolonged anoxia and almost fully recovered after 6 min of anoxia. SPW-Rs were unaffected by the application of 1-butyl-3-(4-methylphenylsulfonyl) urea, a blocker of KATP channels, but they were blocked by activation of adenosine A1 receptors. In support of a modulatory function of adenosine, the amplitude and incidence of SPW-Rs were increased during application of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Interestingly, hypoxia decreased the frequency of miniature excitatory post-synaptic currents in CA3 pyramidal cells, an effect that was converted into increased frequency by the adenosine A1 agonist DPCPX. In addition, DPCPX also delayed the onset of hypoxia-mediated block of SPW-Rs. Our data suggest that early adenosine release during hypoxia induces a decrease in pre-synaptic glutamate release and that both might contribute to transient block of SPW-Rs during hypoxia/anoxia in area CA3.

Determinants of differentials in pneumonia mortality in the UK and France.

Pneumonia is one of the major causes of death in the world. Age-adjusted mortality from pneumonia in the United Kingdom was three times higher than it was in France in 2004. The purpose of this article is to find the underlying determinants of pneumonia mortality differences between these two countries. The main research question is "what are the determinants of pneumonia mortality in the UK and France?" Reviewing the underlying determinants of health inequalities, we expected that behavioral factors, environmental factors, and the health care system would account for the differences, but they do not actually account for much of the differences in Pneumonia mortality between the UK and France. The main difference is due to data quality problems particularly relating to diagnosis and certification in both countries.

Antitussive Efficacy and Safety Profile of Ethyl Acetate Fraction of Terminalia chebula.

Antitussive effects of ethyl acetate fraction of Terminalia chebula on sulphur dioxide (SO2) gas induced cough have been examined in mice. Safety profile of Terminalia chebula was established by determining LD50 and acute neurotoxicity. The result showed that extract of Terminalia chebula dose dependently suppressed SO2 gas induced cough in mice. Terminalia chebula, after i.p. administration at dose level 500 mg/kg, offered maximum cough suppressive effects; that is, number of coughs at 60 min was 12 ± 1.52 (mean ± SEM) as compared to codeine 10 mg/kg; i.p., dextromethorphan 10 mg/kg; i.p., and saline, having frequency of cough 10.375 ± 0.866, 12.428 ± 0.81, and 46 ± 2.61, respectively. LD50 value of Terminalia chebula was approximately 1265 mg/kg, respectively. No sign of neural impairment was observed at antitussive doses of extract. Antitussive effect of Terminalia chebula was partly reversed with treatment by naloxone (3 mg/kg; s.c.) while rimcazole (3 mg/kg; s.c.) did not antagonize its cough suppression activity. This may suggest that opioid receptors partially contribute in antitussive action of Terminalia chebula. Along with this, the possibility of presence of single or multiple mechanisms activated by several different pharmacological actions (mainly anti-inflammatory, antioxidant, spasmolytic, antibacterial, and antiphlegmatic) could not be eliminated.

Numerical study of boundary layer flow and heat transfer of oldroyd-B nanofluid towards a stretching sheet.

In the present article, we considered two-dimensional steady incompressible Oldroyd-B nanofluid flow past a stretching sheet. Using appropriate similarity variables, the partial differential equations are transformed to ordinary (similarity) equations, which are then solved numerically. The effects of various parameters, namely, Deborah numbers [Formula: see text] and [Formula: see text], Prandtl parameter [Formula: see text], Brownian motion [Formula: see text], thermophoresis parameter [Formula: see text] and Lewis number [Formula: see text], on flow and heat transfer are investigated. To see the validity of the present results, we have made the comparison of present results with the existing literature.

Partial disinhibition is required for transition of stimulus-induced sharp wave-ripple complexes into recurrent epileptiform discharges in rat hippocampal slices.

Sharp wave-ripple complexes (SPW-Rs) in the intact rodent hippocampus are characterized by slow field potential transients superimposed by close to 200-Hz ripple oscillations. Similar events have been recorded in hippocampal slices where SPW-Rs occur spontaneously or can be induced by repeated application of high-frequency stimulation, a standard protocol for induction of long-lasting long-term potentiation. Such stimulation is reminiscent of protocols used to induce kindling epilepsy and ripple oscillations may be predictive of the epileptogenic zone in temporal lobe epilepsy. In the present study, we investigated the relation between recurrent epileptiform discharges (REDs) and SPW-Rs by studying effects of partial removal of inhibition. In particular, we compared the effects of nicotine, low-dose bicuculline methiodide (BMI), and elevated extracellular potassium concentration ([K(+)](o)) on induced SPW-Rs. We show that nicotine dose-dependently transformed SPW-Rs into REDs. This transition was associated with reduced inhibitory conductance in CA3 pyramidal cells. Similar results were obtained from slices where the GABAergic conductance was reduced by application of low concentrations of BMI (1-2 µM). In contrast, sharp waves were diminished by phenobarbital. Elevating [K(+)](o) from 3 to 8.5 mM did not transform SPW-Rs into REDs but significantly increased their incidence and amplitude. Under these conditions, the equilibrium potential for inhibition was shifted in depolarizing direction, whereas inhibitory conductance was significantly increased. Interestingly, the propensity of elevated [K(+)](o) to induce seizure-like events was reduced in slices where SPW-Rs had been induced. In conclusion, recruitment of inhibitory cells during SPW-Rs may serve as a mechanism by which hyperexcitation and eventually seizure generation might be prevented.

Anticonvulsant activities of nutmeg oil of Myristica fragrans.

The purpose of this study was to investigate the anticonvulsant activity of the volatile oil of nutmeg, the dried seed kernel of Myristica fragrans Houtt, using well-established animal seizure models and to evaluate its potential for acute toxicity and acute neurotoxicity. The volatile oil of nutmeg (nutmeg oil) was tested for its effects in maximal electroshock, subcutaneous pentylenetetrazole, strychnine and bicuculline seizure tests. All the experiments were performed at the time of peak effect of nutmeg oil. Nutmeg oil showed a rapid onset of action and short duration of anticonvulsant effect. It was found to possess significant anticonvulsant activity against electroshock-induced hind limb tonic extension. It exhibited dose dependent anticonvulsant activity against pentylenetetrazole-induced tonic seizures. It delayed the onset of hind limb tonic extensor jerks induced by strychnine. It was anticonvulsant at lower doses, whereas weak proconvulsant at a higher dose against pentylenetetrazole and bicuculline induced clonic seizures. Nutmeg oil was found to possess wide therapeutic margin, as it did not induce motor impairment when tested up to 600 microL/kg in the inverted screen acute neurotoxicity test. Furthermore, the LD(50) (2150 microL/kg) value was much higher than its anticonvulsant doses (50-300 microL/kg). The results indicate that nutmeg oil may be effective against grand mal and partial seizures, as it prevents seizure spread in a set of established animal models. Slight potentiation of clonic seizure activity limits its use for the treatment of myoclonic and absence seizures.

A pharmacological and toxicological evaluation of Haloxylon recurvum.

Haloxylon recurvum Bunge ex Boiss (Chenopodiaceae) is distributed chiefly from the Mediterranean region to Central and South Asia and traditionally applied externally for a variety of disorders. We investigated the in vivo toxic potential of crude methanolic extract of the whole plant and its n-hexane, chloroform, butanol, ethylacetate and aqueous soluble fractions by determining their acute toxicity and acute neurotoxicity in mice using Lorke's method and inverted screen test. In vitro studies were also conducted in order to investigate its antilipoxygenase, antibacterial and antifungal activities. All the fractions showed a narrow margin of safety in mice, except the aqueous fraction, which did not produce any mortality even at the highest tested dose (5000 mg kg(-1)). At non-lethal doses, only the aqueous fraction (TD(50) 1264 mg kg(-1)) was found to produce neurotoxicity in mice. In in vitro lipoxygenase inhibition assay, the ethylacetate fraction showed the most significant inhibitory activity. Crude methanolic extract and its butanol soluble fraction showed the most potent antifungal and antibacterial activity for all the materials tested. Thus, this report verifies the traditionally reported toxicity of this plant, as the majority of its components have exhibited a narrow margin of safety, however, they have been found active in in vitro studies, therefore, further studies are required in order to isolate the most active toxic compounds and differentiate them from these fractions.