Investigation of the effects of the novel anticonvulsant compound carisbamate(RWJ-333369) on rat piriform cortical neurones in vitro

Background and purpose: Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence-type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II-III neurones in piriform cortical brain slices. Experimental approach: Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings. Key results: Carisbamate (50–400 mmol·L-1) reversibly decreased amplitude, duration and rise-time of evoked action potentials and inhibited repetitive firing, consistent with use-dependent Na+ channel block; 150–400 mmol·L-1 carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl- loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100–400 mmol·L-1) also selectively depressed lateral olfactory tract-afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl conductance. Lidocaine (40–320 mmol·L-1) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 mmol·L-1) had no effect on spontaneous GABAA miniature inhibitory postsynaptic currents and at lower concentrations (50–200 mmol·L-1) inhibited Mg2+-free or 4-aminopyridine-induced seizure-like discharges. Conclusions and implications: Carisbamate blocked evoked action potentials use-dependently, consistent with a primary action on Na+ channels and increased Cl- conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia-afferent terminals.

An ichnofabric approach to the depositional interpretation of the intensely burrowed Bateig Limestone, Miocene, SE Spain

The foraminiferal-rich pelagic Bateig Limestone forms several varieties of the important building stones quarried at Bateig Hill in southeastern Spain. Three principal ichnofabrics (Bichordites, mottled-Palaeophycus and mottled-Ophiomorpha) are recognized, which are present in at least two (possibly up to four) repeated successions (cycles). Each succession begins with an erosional event. The Bichordites ichnofabric represents a new type of facies, formed as thin turbidity/grain flow, stratiform units derived from sediment slips off a fault into deep water. Each slipped unit became almost completely bioturbated by infaunal echinoids, colonizing by lateral migration. Because of the thinness of the units, successive colonizations tended to truncate the underlying burrows giving rise to a pseudo-stratification. As the Bichordites ichnofabric accumulated on the fault apron, thus reducing the effective height of the fault scarp, the substrate gradually came under the influence of currents traversing the shelf. This led to a change in hydraulic regime, and to the mottled-Palaeophycus and mottled-Ophiomorpha ichnofabrics in sediment deposited under bed load transport, and associated with laminar and cross-stratified beds and local muddy intervals. Reactivation of the fault triggered erosion and channeling and a return to grain flow sedimentation, and to the Bichordites ichnofabric of the succeeding cycle. The highest unit of the Bateig Limestone is formed entirely of cross-stratified calcarenites with occasional Ophiomorpha (Ophiomorpha-primary lamination ichnofabric) and is similar to many shallow marine facies but they still bear a significant content of pelagic foraminifera. The sedimentary setting bears resemblance with that described for the Pleistocene Monte Torre Paleostrait and the modem Strait of Messina (Italy), where the narrow morphology of the depositional area enhanced tidal currents and allowed for high-energy sandy deposition in relatively deep areas. More data on the Miocene paleogeography of the Bateig area should provide further testing for this hypothesis. The ichnofacies and stacking of the Bateig Limestone differ from the classic Seilacherian model in that they reflect changes in hydraulic process and are associated with faulting and subsidence and changes in sediment supply. Recognition of the unusual ichnofabrics and their relationships provides a clear indication of the overall dynamic setting. (c) 2006 Elsevier B.V. All rights reserved.

The sediment trapping efficiency of the macro-tidal Daly Estuary, tropical Australia

Field studies were carried out on the water and sediment dynamics in the tropical, macro-tidal, Daly Estuary. The estuary is shallow, very-turbid, about 100 km long, and the entrance is funnel-shape. In the wet, high flow season, normal tidal ranges can be suppressed in the estuary, depending on inflow rates, and freshwater becomes dominant up to the mouth. At that time a fraction of the fine sediment load is exported offshore as a bottom-tagging nepheloid layer after the sediment falls out of suspension of the thin, near-surface, river plume. The remaining fraction and the riverine coarse sediment form a large sediment bar 10 km long, up to 6 m in height and extending across the whole width of the channel near the mouth. This bar, as well as shoals in the estuary, partially pond the mid- to upper-estuary. This bar builds up from the deposition of riverine sediment during a wet season with high runoff and can raise mean water level by up to 2 m in the upper estuary in the low flow season. This ponding effect takes about three successive dry years to disappear by the sediment forming the bar being redistributed all over the estuary by tidal pumping of fine and coarse sediment in the dry season, which is the low flow season. The swift reversal of the tidal currents from ebb to flood results in macro-turbulence that lasts about 20 min. Bed load transport is preferentially landward and occurs only for water currents greater than 0.6 m s(-1). This high value of the threshold velocity suggests that the sand may be cemented by the mud. The Daly Estuary thus is a leaky sediment trap with an efficiency varying both seasonally and inter-annually. (c) 2006 Elsevier Ltd. All rights reserved.

Surface determination of the air-earth electrical current density using co-located sensors of different geometry

A vertical conduction current flows in the atmosphere as a result of the global atmospheric electric circuit. The current at the surface consists of the conduction current and a locally generated displacement current, which are often approximately equal in magnitude. A method of separating the two currents using two collectors of different geometry is investigated. The picoammeters connected to the collectors have a RC time constant of approximately 3 s, permitting the investigation of higher frequency air-earth current changes than previously achieved. The displacement current component of the air-earth current derived from the instrument agrees with calculations using simultaneous data from a co-located fast response electric field mill. The mean value of the nondisplacement current measured over 9 h was 1.76 +/- 0.002 pA m(-2). (c) 2006 American Institute of Physics.

Observational evidence of a coronal mass ejection distortion directly attributable to a structured solar wind

We present the first observational evidence of the near-Sun distortion of the leading edge of a coronal mass ejection (CME) by the ambient solar wind into a concave structure. On 2007 November 14, a CME was observed by coronagraphs onboard the STEREO-B spacecraft, possessing a circular cross section. Subsequently the CME passed through the field of view of the STEREO-B Heliospheric Imagers where the leading edge was observed to distort into an increasingly concave structure. The CME observations are compared to an analytical flux rope model constrained by a magnetohydrodynamic solar wind solution. The resultant bimodal speed profile is used to kinematically distort a circular structure that replicates the initial shape of the CME. The CME morphology is found to change rapidly over a relatively short distance. This indicates an approximate radial distance in the heliosphere where the solar wind forces begin to dominate over the magnetic forces of the CME influencing the shape of the CME.

Observations of the inter-ocean exchange around South Africa

There is growing evidence that the interocean exchange south of Africa is an important link in the global overturning circulation of the ocean, the so‐called ocean conveyer belt. At this location, warm and salty Indian Ocean waters enter the South Atlantic and are pulled by currents that eventually reach the North Atlantic, where water cools and sinks. A major contributor to the exchange is the frequent shedding of ring eddies from the termination of the Agulhas Current south of the tip of Africa. This shedding is controlled by developments far upstream in the Indian Ocean, and variations in this ‘Agulhas Leakage’ can lead to changes in the rate and stability of the Atlantic overturning, with possible associated global climate variations [Weijer et al., 1999]. Regional climate variations in the tropical and subtropical Indian Ocean are known to affect the whole system of the Agulhas Current, including the interocean exchanges. This article reports on some of the seminal results of ongoing multinational, multidisciplinary projects that explore these issues.

ASYM20: a program for force constant and normal coordinate calculations, with a critical review of the theory involved

The theory of harmonic force constant refinement calculations is reviewed, and a general-purpose program for force constant and normal coordinate calculations is described. The program, called ASYM20. is available through Quantum Chemistry Program Exchange. It will work on molecules of any symmetry containing up to 20 atoms and will produce results on a series of isotopomers as desired. The vibrational secular equations are solved in either nonredundant valence internal coordinates or symmetry coordinates. As well as calculating the (harmonic) vibrational wavenumbers and normal coordinates, the program will calculate centrifugal distortion constants, Coriolis zeta constants, harmonic contributions to the α′s. root-mean-square amplitudes of vibration, and other quantities related to gas electron-diffraction studies and thermodynamic properties. The program will work in either a predict mode, in which it calculates results from an input force field, or in a refine mode, in which it refines an input force field by least squares to fit observed data on the quantities mentioned above. Predicate values of the force constants may be included in the data set for a least-squares refinement. The program is written in FORTRAN for use on a PC or a mainframe computer. Operation is mainly controlled by steering indices in the input data file, but some interactive control is also implemented.

Microwave activation of the electro-oxidation of glucose in alkaline media

The oxidation of glucose is a complex process usually requiring catalytically active electrode surfaces or enzyme modified electrodes. In this study the effect of high intensity microwave radiation on the oxidation of glucose in alkaline solution at Au, Cu, and Ni electrodes is reported. Calibration experiments with the Fe(CN)(6)(3-/4-) redox system in aqueous 0.1 M NaOH indicate that strong thermal effects occur at both 50 and 500 mu m diameter electrodes with temperatures reaching 380 K. Extreme mass transport effects with mass transport coefficients of k(mt) > 0.01 m s(-1) (or k(mt) > 1.0 cm s(-1)) are observed at 50 mu m diameter electrodes in the presence of microwaves. The electrocatalytic oxidation of glucose at 500 mu m diameter Au, Cu, or Ni electrodes immersed in 0.1 M NaOH and in the presence of microwave radiation is shown to be dominated by kinetic control. The magnitude of glucose oxidation currents at Cu electrodes is shown to depend on the thickness of a pre-formed oxide layer. At 50 mu m diameter Au, Cu, or Ni electrodes microwave enhanced current densities are generally higher, but only at Au electrodes is a significantly increased rate for the electrocatalytic oxidation of glucose to gluconolactone observed. This rate enhancement appears to be independent of temperature but microwave intensity dependent, and therefore non-thermal in nature. Voltammetric currents observed at Ni electrodes in the presence of microwaves show the best correlation with glucose concentration and are therefore analytically most useful.

Microwave activation of the electro-oxidation of glucose in alkaline media

The oxidation of glucose is a complex process usually requiring catalytically active electrode surfaces or enzyme-modified electrodes. In this study the effect of high intensity microwave radiation on the oxidation of glucose in alkaline solution at Au, Cu, and Ni electrodes is reported. Calibration experiments with the Fe(CN)63–/4– redox system in aqueous 0.1 M NaOH indicate that strong thermal effects occur at both 50 and 500 µm diameter electrodes with temperatures reaching 380 K. Extreme mass transport effects with mass transport coefficients of kmt > 0.01 m s–1(or kmt > 1.0 cm s–1) are observed at 50 µm diameter electrodes in the presence of microwaves. The electrocatalytic oxidation of glucose at 500 µm diameter Au, Cu, or Ni electrodes immersed in 0.1 M NaOH and in the presence of microwave radiation is shown to be dominated by kinetic control. The magnitude of glucose oxidation currents at Cu electrodes is shown to depend on the thickness of a pre-formed oxide layer. At 50 µm diameter Au, Cu, or Ni electrodes microwave enhanced current densities are generally higher, but only at Au electrodes is a significantly increased rate for the electrocatalytic oxidation of glucose to gluconolactone observed. This rate enhancement appears to be independent of temperature but microwave intensity dependent, and therefore non-thermal in nature. Voltammetric currents observed at Ni electrodes in the presence of microwaves show the best correlation with glucose concentration and are therefore analytically most useful.

The threading of [(CuCN)(2)(mu-4,4 '-bpy)] sheets by CuCN chains

Yellow (CuCN)(2)[(CuCN)(2)(mu-4,4'-bpy)], formed in the hydrothermal reaction of CuCN with 4,4'-bipyridine at 453 K, contains two types of infinite CuCN chains. One set of CuCN chains is linked by 4,4'-bpy ligands to form almost flat sheets of composition [(CuCN)(2)(mu-4,4'-bpy)]. Holes in these sheets are aligned to allow pairs of approximately linear, infinite -(CuCN)- chains to thread through them. The closest interatomic approach between copper atoms in the threading chains and host sheets (similar to2.74 Angstrom) does not appear to represent a significant covalent bond as it leads to only a small distortion of the -(CuCN)- chains from linearity The relationship of this material to the previously determined structures of the host [(CuCN)(2)(mu-4,4'-bpy)] sheets and (CuCN)(3)[(CuCN)(2)(mu-4,4'-bPY)](2), in which these sheets are threaded by single -(CuCN)- chains, is discussed.

The consequences of diffractively spreading beams in ultrafast THz spectroscopy

There are established methods for calculating optical constants from measurements using a broadband terahertz (THz) source. Applications to ultrafast THz spectroscopy have adopted the key assumption that the THz beam is treated as a normal incidence plane-wave. We show that this assumption results in a frequency-dependent systematic error, which is compounded by distortion of the beam on introduction of the sample.

Kinetic energy analysis of the response of the Atlantic meridional overturning circulation to CO2-forced climate change

Atmosphere–ocean general circulation models (AOGCMs) predict a weakening of the Atlantic meridional overturning circulation (AMOC) in response to anthropogenic forcing of climate, but there is a large model uncertainty in the magnitude of the predicted change. The weakening of the AMOC is generally understood to be the result of increased buoyancy input to the north Atlantic in a warmer climate, leading to reduced convection and deep water formation. Consistent with this idea, model analyses have shown empirical relationships between the AMOC and the meridional density gradient, but this link is not direct because the large-scale ocean circulation is essentially geostrophic, making currents and pressure gradients orthogonal. Analysis of the budget of kinetic energy (KE) instead of momentum has the advantage of excluding the dominant geostrophic balance. Diagnosis of the KE balance of the HadCM3 AOGCM and its low-resolution version FAMOUS shows that KE is supplied to the ocean by the wind and dissipated by viscous forces in the global mean of the steady-state control climate, and the circulation does work against the pressure-gradient force, mainly in the Southern Ocean. In the Atlantic Ocean, however, the pressure-gradient force does work on the circulation, especially in the high-latitude regions of deep water formation. During CO2-forced climate change, we demonstrate a very good temporal correlation between the AMOC strength and the rate of KE generation by the pressure-gradient force in 50–70°N of the Atlantic Ocean in each of nine contemporary AOGCMs, supporting a buoyancy-driven interpretation of AMOC changes. To account for this, we describe a conceptual model, which offers an explanation of why AOGCMs with stronger overturning in the control climate tend to have a larger weakening under CO2 increase.

The climate response to CO2 of the Hadley Centre coupled AOGCM with and without flux adjustment

Coupled atmosphere‐ocean general circulation models have a tendency to drift away from a realistic climatology. The modelled climate response to an increase of CO2 concentration may be incorrect if the simulation of the current climate has significant errors, so in many models, including ours, the drift is counteracted by applying prescribed fluxes of heat and fresh water at the ocean‐atmosphere interface in addition to the calculated surface exchanges. Since the additional fluxes do not have a physical basis, the use of this technique of “flux adjustment” itself introduces some uncertainty in the simulated response to increased CO2. We find that the global‐average temperature response of our model to CO2 increasing at 1% per year is about 30% less without flux adjustment than with flux adjustment. The geographical patterns of the response are similar, indicating that flux adjustment is not causing any gross distortion. The reduced size of the response is due to more effective vertical transport of heat into the ocean, and a somewhat smaller climate sensitivity. Although the response in both cases lies within the generally accepted range for the climate sensitivity, systematic uncertainties of this size are clearly undesirable, and the best strategy for future development is to improve the climate model in order to reduce the need for flux adjustment.

On the response of the Antarctic Circumpolar Current transport to climate change in coupled climate models

The CMIP3 (IPCC AR4) models show a consistent intensification and poleward shift of the westerly winds over the Southern Ocean during the 21st century. However, the responses of the Antarctic Circumpolar Currents (ACC) show great diversity in these models, with many even showing reductions in transport. To obtain some understanding of diverse responses in the ACC transport, we investigate both external atmospheric and internal oceanic processes that control the ACC transport responses in these models. While the strengthened westerlies act to increase the tilt of isopycnal surfaces and hence the ACC transport through Ekman pumping effects, the associated changes in buoyancy forcing generally tend to reduce the surface meridional density gradient. The steepening of isopycnal surfaces induced by increased wind forcing leads to enhanced (parameterized) eddy-induced transports that act to reduce the isopycnal slopes. There is also considerable narrowing of the ACC that tends to reduce the ACC transport, caused mainly by the poleward shifts of the subtropical gyres and to a lesser extent by the equatorward expansions of the subpolar gyres in some models. If the combined effect of these retarding processes is larger than that of enhanced Ekman pumping, the ACC transport will be reduced. In addition, the effect of Ekman pumping on the ACC is reduced in weakly stratified models. These findings give insight into the reliability of IPCC-class model predictions of the Southern Ocean circulation, and into the observed decadal-scale steady ACC transport.

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB1 Receptor Modulation in the Cerebellum

PSNCBAM-1 has recently been described as a cannabinoid CB1 receptor allosteric antagonist associated with hypophagic effects in vivo; however, PSNCBAM-1 effects on CB1 ligand-mediated modulation of neuronal excitability remain unknown. Here, we investigate PSNCBAM-1 actions on CB1 receptor-stimulated [35S]GTPγS binding in cerebellar membranes and on CB1 ligand modulation of presynaptic CB1 receptors at inhibitory interneurone-Purkinje cell (IN-PC) synapses in the cerebellum using whole-cell electrophysiology. PSNCBAM-1 caused non-competitive antagonism in [35S]GTPγS binding studies, with higher potency against the CB receptor agonist CP55940 than for WIN55,212-2 (WIN55). In electrophysiological studies, WIN55 and CP55940 reduced miniature inhibitory postsynaptic currents (mIPSCs) frequency, but not amplitude. PSNCBAM-1 application alone had no effect on mIPSCs; however, PSNCBAM-1 pre-treatment revealed agonist-dependent functional antagonism, abolishing CP55940-induced reductions in mIPSC frequency, but having no clear effect on WIN55 actions. The CB1 antagonist/inverse agonist AM251 increased mIPSC frequency beyond control, this effect was reversed by PSNCBAM-1. PSNCBAM-1 pre-treatment also attenuated AM251 effects. Thus, PSNCBAM-1 reduced CB1 receptor ligand functional efficacy in the cerebellum. The differential effect of PSNCBAM-1 on CP55940 versus WIN55 actions in [35S]GTPγS binding and electrophysiological studies and the attenuation of AM251 effects are consistent with the ligand-dependency associated with allosteric modulation. These data provide the first description of functional PSNCBAM-1 allosteric antagonist effects on neuronal excitability in the mammalian CNS. PSNCBAM-1 allosteric antagonism may provide viable therapeutic alternatives to orthosteric CB1 antagonists/inverse agonists in the treatment of CNS disease.