[11C]PBR28 MR-PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder.

Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a simultaneous magnetic resonance-positron emission tomography (MR-PET) scanner with the second-generation TSPO radiotracer [11C]PBR28. By comparing TSPO in 15 young adult males with ASD with 18 age- and sex-matched controls, we showed that individuals with ASD exhibited lower regional TSPO expression in several brain regions, including the bilateral insular cortex, bilateral precuneus/posterior cingulate cortex, and bilateral temporal, angular, and supramarginal gyri, which have previously been implicated in autism in functional MR imaging studies. No brain region exhibited higher regional TSPO expression in the ASD group compared with the control group. A subset of participants underwent a second MR-PET scan after a median interscan interval of 3.6 months, and we determined that TSPO expression over this period of time was stable and replicable. Furthermore, voxelwise analysis confirmed lower regional TSPO expression in ASD at this later time point. Lower TSPO expression in ASD could reflect abnormalities in neuroimmune processes or mitochondrial dysfunction.

Structural investigation of the (010) surface of the Al13 Fe4 catalyst.

We have investigated the structure of the Al(13)Fe(4)(010) surface using both experimental and ab initio computational methods. The results indicate that the topmost surface layers correspond to incomplete puckered (P) planes present in the bulk crystal structure. The main building block of the corrugated termination consists of two adjacent pentagons of Al atoms, each centered by a protruding Fe atom. These motifs are interconnected via additional Al atoms referred to as "glue" atoms which partially desorb above 873 K. The surface structure of lower atomic density compared to the bulk P plane is explained by a strong Fe-Al-Fe covalent polar interaction that preserves intact clusters at the surface. The proposed surface model with identified Fe-containing atomic ensembles could explain the Al(13)Fe(4) catalytic properties recently reported in line with the site-isolation concept [M. Armbrüster et al., Nat. Mater. 11, 690 (2012)].

Nanodomains due to phason defects at a quasicrystal surface.

Among the three coexisting types of terraces found on the twofold surface of the d-Al-Cu-Co quasicrystal, nanodomains are essentially observed on the transition-metal rich ones, with a coherent interface boundary. Both clean surface and Ag growth analyses, demonstrate that nanodomain surfaces are structurally identical to one of the two other terraces, which contains 85 at. % Al. We provide evidence that the nanodomains are a manifestation of phason defects that extend downward toward the bulk, and state that nanodomains develop because the energetic cost of creating the phason is outweighed by the change in surface energy. Consequently, the formation of nanodomains involves more than just the surface layer, but is driven by surface energetics.

Abnormalities of cortical thickness in postictal psychosis.

Postictal psychosis (PIP), the occurrence of psychotic episodes following a seizure, is a common and serious comorbidity in patients with epilepsy. Yet, the anatomical correlates remain poorly defined. Here, we used quantitative MRI morphometry to identify structural abnormalities in the cortex of patients with PIP relative to patients with epilepsy without PIP and age- and gender-matched normal healthy controls. Comparison of patients with epilepsy and PIP with patients with epilepsy without PIP revealed increased cortical thickness in the right lateral prefrontal cortex, right anterior cingulate cortex, and right middle temporal gyrus. The PIP group was distinguished from the EC and NC groups by thicker cortex in the right rostral anterior cingulate cortex and thinner cortex in the right angular gyrus and the left middle temporal region. Findings indicate that PIP is associated with thickening of the right anterior cingulate cortex, which may serve as a marker for patients at risk for developing PIP.

Seizure prediction and recall.

Using separate generalized mixed-effects models, we assessed seizure recall and prediction, as well as contributing diagnostic variables, in 83 adult patients with epilepsy undergoing video/EEG monitoring. The model revealed that when participants predicted a seizure, probability equaled 0.320 (95% CI: 0.149-0.558), a significant (P<0.05) increase over negative predictions (0.151, 95% CI: 0.71-0.228]). With no seizure, the rate of remembering was approximately 0.130 (95% CI: 0.73-0.219), increasing significantly to 0.628 (95% CI: 0.439 to 0.784) when a seizure occurred (P<0.001). Of the variables analyzed, only inpatient seizure rate influenced predictability (P<0.001) or recollection (P<0.001). These models reveal that patients were highly aware of their seizures, and in many cases, were able to make accurate predictions, for which seizure rate may be an important factor.

Is rapid organ recovery a good idea? An exploratory study of the public's knowledge and attitudes.

In 2006, the Institute of Medicine (IOM) recommended demonstration projects on uncontrolled donation after cardiac death or rapid organ recovery (ROR). To investigate what the public thinks about key ethical and policy questions associated with ROR, 70 African-American, Caucasian and Latino community members in St. Louis, MO, participated in focus groups and completed surveys, before and after being educated about ROR. Before the focus group, most participants believed mistakenly that they could donate organs following an unexpected cardiac arrest (76%). After the focus group, 84% would want to donate organs after unexpected cardiac arrest; 81% would support organ cooling to enable this. The public generally supported organ cooling without family consent if the individual had joined the donor registry, but were mixed in their opinions about what should be done if they were not on the registry. African-American and Latino participants expressed greater fears than Caucasians that if they consented to organ donation, physicians might do less to save their life; however, support for ROR was not significantly lower in these subgroups. Although this study is exploratory, public support for ROR was present. We recommend that adequate consent processes and safeguards be established to foster trust and support for ROR.

Model for the transformation of an icosahedral phase into a B2 crystalline phase.

A model for the transformation of an Al-Cu-Fe icosahedral quasicrystal into a crystal with a B2-type phase is proposed. The model is based on two assumptions: (1) the main building block for the quasicrystal structure is a hierarchical dodecahedron composed of two icosahedral clusters, coinciding with two different sections of the {3, 3, 5} polytope; (2) the transformation of the quasicrystal into a B2-type crystal phase can be described as the transition between 3D sections of two polytopes, namely {3, 3, 5} and {3, 4, 3}. In the framework of the proposed model, two experimental facts gain plausible explanations: the transformation of the Al-Cu-Fe quasicrystal into the BCC phase specifically and the orientational relationships observed between this BCC phase and the initial icosahedral quasicrystal.

Oxaliplatin, an anticancer agent that affects both Na+ and K+ channels in frog peripheral myelinated axons.

The use of oxaliplatin, a relatively new chemotherapeutic agent, is somewhat limited since it produces a specific peripheral neuropathy regarding other neurotoxic anticancer platinum analogues. In order to investigate the mechanism of such a peripheral neuropathy, the effects of 1-100 micromol/l oxaliplatin were assessed on the nodal ionic currents of single frog myelinated axons as a model of peripheral excitable membranes. Oxaliplatin decreased both Na(+) and K(+) currents in a dose-dependent manner and within 5-10 min, without producing any marked changes in the current kinetics. It was about three to eight times more effective in reducing the Na(+) than the K(+) current. In addition, it shifted the voltage-dependence of both Na(+) and K(+) conductances towards negative membrane potentials. A negative shift in the steady-state inactivation-voltage curve of the peak Na(+) current was also observed in the presence of oxaliplatin. These effects were not reversed by washing the myelinated axons with an oxaliplatin-free solution for at least 30 min. It is concluded that oxaliplatin modifies the voltage-dependent ionic channels mainly by altering the external surface membrane potential. The knowledge of such a mechanism may help to counteract the neurotoxic action of this anticancer agent.

Effects of dimethylsulfoxide on membrane currents of neuroblastoma x glioma hybrid cell.

Giga-ohm seal whole cell recording technique was used to examine ionic currents changes induced by dimethylsulfoxide (DMSO) in neuroblastoma X glioma hybrid NG 108-15 cells. DMSO (0.5-1%) reversible blocks sodium, potassium and calcium currents and shifts by about 6 mV the sodium inactivation curve towards more negative voltages.

Decreased rate of sodium conductance inactivation in the node of Ranvier induced by a polypeptide toxin from sea anemone.

The effects of two toxins extracted from the tentacles of Anemonia sulcata on ionic currents have been tested on the nodal membrane of myelinated nerve fibres from Rana esculenta. While external application of Toxin I at 100 muM leaves both specific ionic currents unmodified, Toxin II at 10 muM reacts with a receptor site associated with the sodium conductance inactivation gating. Since internal application by diffusion of Toxin II at a concentration of 700 muM leaves the ionic currents unchanged, the receptor site is most likely located on the external side of the nodal membrane. An equilibrium dissociation constant for the effects of Toxin II was estimated as 20 muM. The on-reaction is fast (rate constant for the on-reaction roughly equal to 3.103 M-1) suggesting a readily accesible receptor site for the toxin. The kinetics characteristics of the sodium currents recorded in the presence of Toxin II suggest that there are at least two steps in the reaction leading to Na+ -channels with the inactivation gate completely immobilized. The relatively fast reversibility of the intermediate stage of the reaction and the rather slow but, in the end, complete reversal of the toxin effects suggest that the toxin acts by modifying the energy profile for the transition "inactivation gate in the open configuration to inactivation gate in the closed configuration." Toxin II at higher concentrations (greater than 100 muM) also inhibits the potassium currents but these effects were not studied in any detail.

Kinetics of intramembrane charge movement and conductance activation of batrachotoxin-modified sodium channels in frog node of Ranvier.

Sodium current and intramembrane gating charge movement (Q) were monitored in voltage-clamped frog node of Ranvier after modification of all sodium channels by batrachotoxin (BTX). Sodium current activation followed a single-exponential time course, provided a delay was interposed between the onset of the step ON depolarization and that of the current change. The delay decreased with increased ON depolarization and, for a constant ON depolarization, increased with prehyperpolarization. ON charge movement followed a single-exponential time course with time constants tau Q,ON slightly larger than tau Na, ON. For pulses between -70 and -50 mV, tau Q,ON/tau Na,ON = 1.14 +/- 0.08. The OFF charge movement and OFF sodium current tails after a depolarizing pulse followed single-exponential time courses, with tau Q, OFF larger than tau Na, OFF. tau Q,OFF/tau Na,OFF increased with OFF voltage from 1 near -100 mV to 2 near -160 mV. At a set OFF potential (-120 mV), both tau Q,OFF and tau Na,OFF increased with ON pulse duration. The delay in INa activation and the effect of ON pulse duration on tau Q,OFF and tau Na,OFF are inconsistent with a simple two-state, single-transition model for the gating of batrachotoxin-modified sodium channels.

Kinetics of intramembrane charge movement and sodium current in frog node of Ranvier.

Intramembrane charge movement (Q) and sodium current (INa) were monitored in isolated voltage-clamped frog nodes of Ranvier, ON charge movements (QON) for pulses from the holding potential (-100 mV) to potentials V less than or equal to 0 mV followed single exponential time courses, whereas two exponentials were found for pulses to V greater than or equal to 20 mV. The voltage dependence of both QON and its time constant tauON indicated that the two ON components resolved at V greater than or equal to 20 mV were also present, though not resolvable, for pulses to V less than or equal to 0 mV. OFF charge movements (QOFF) monitored at various potentials were well described by single exponentials. When QOFF was monitored at -30 or -40 mV after a 200-microsecond pulse to +20 mV and QON was monitored at the same potential using pulses directly from -100 mV, tauON/tauOFF = 2.5 +/- 0.3. At a set OFF potential (-90 to -70 mV), tauOFF first increased with increasing duration tON of the preceding pulse to a given potential (0 to +30 mV) and then decreased with further increases in tON. The declining phase of tauOFF followed a time course similar to that of the decline in QOFF with tON. For the same pulse protocol, the OFF time constant tauNa for INA also first increased with tON but then remained constant over the tON interval during which tauOFF and QOFF were declining. After 200- or 300-microsecond pulses to +20, +20, or +50 mV, tauOFF/tauNa at -70 to -90 mV was 1.2 +/- 0.1. Similar tauOFF/tauNa ratios were predicted by channel models having three identical charged gating particles that can rapidly and reversibly form an immobile dimer or trimer after independently crossing the membrane from their OFF to their ON locations.

Current-dependent inactivation induced by sodium depletion in normal and batrachotoxin-treated frog node of Ranvier.

In batrachotoxin (BTX)-treated frog node of Ranvier, in spite of a marked reduction in Na inactivation, the Na current still presents a time- and voltage-dependent inactivation that could induce a 50-60% decrease in the current. The inactivation was found to be modified by changing the amplitude of a conditioning pulse, adding tetrodotoxin in the external solution, or replacing NaCl with KCl in the external solution. Conditioning pulses were able to alter the reversal potential of the BTX-modified Na current (Vrev). Vrev was shifted toward negative values for inward conditioning currents and was shifted toward positive values for outward conditioning currents. The change in Vrev was proportional to the conditioning current amplitude. Large inward currents induced 15-25 mV shifts of Vrev. During a 10-20-ms depolarizing pulse, the inactivation and change in Vrev were proportional to the time integral of the current. For longer depolarizations, Vrev reached a steady state level proportional to the current amplitude. The conductance, as calculated from the current and the actual Vrev, showed an inactivation proportional to exp(Vrev F/RT). These observations suggest that the BTX-modified Na current induces a decrease in local Na concentrations, which results in an alteration of the driving force and the conductance. During a pulse that induced a large inward current, the Na space concentration [( Na]s) changed from 114 to 50-60 mM. In normal fibers, the reversal potential of Na current was also shifted toward negative values by a prepulse that induced a large inward current. The change in Vrev reached 5-15 mV, which corresponded to a decrease in [Na]s of 20-50 mM. This change in Vrev slightly altered the time course of Na current. On the basis of a three-compartment model (axoplasm-perinodal space-bulk solution), a Na permeability of the barrier between the space and the bulk solution (PNa,s) and a mean thickness of the space (theta) were calculated. The mean value of PNa,s was 0.0051 cm X s-1 in both normal and BTX-treated fibers, whereas the value of theta was 0.29 micron in BTX-treated fibers and 0.05 micron in normal fibers. When compared with the values calculated during K accumulation, PNa,s was 10 times smaller than PK,s and theta Na-BTX was equal to theta K.(ABSTRACT TRUNCATED AT 400 WORDS)

Voltage dependence of intramembrane charge movement and conductance activation of batrachotoxin-modified sodium channels in frog node of Ranvier.

Sodium current and sodium channel intramembrane gating charge movement (Q) were monitored in voltage-clamped frog node of Ranvier after modification of all sodium channels by batrachotoxin (BTX). BTX caused an approximately threefold increase in steepness of the Q vs. voltage relationship and a 50-mV negative shift in its midpoint. The maximum amount of intramembrane charge was virtually identical before and after BTX treatment. BTX treatment eliminated the charge immobilization observed in untreated nodes after relatively long depolarizing pulses and slowed the rate of OFF charge movement after a pulse. After BTX treatment, the voltage dependence of charge movement was the same as the steady-state voltage dependence of sodium conductance activation. The observations are consistent with the hypothesis that BTX induces an aggregation of the charged gating particles associated with each channel and causes them to move as a unit having approximately three times the average valence of the individual particles. Movement of this single aggregated unit would open the BTX-modified sodium channel.

Tamoxifen blocks both proliferation and voltage-dependent K+ channels of neuroblastoma cells.

The effects of tamoxifen (TAM) on cell proliferation and voltage-dependent K+ channels were studied on the mouse neuroblastoma cells NG 108-15. TAM inhibited cell proliferation with an effective dose inducing a half maximum effect (ED50) of 2 microM and was cytotoxic from and beyond 2.5 microM. TAM accelerated the apparent inactivation of the whole cell K+ current with an apparent dissociation constant of 0.46 microM, and shifted the peak K+ conductance-voltage curve towards negative voltages with an apparent dissociation constant of 1.07 microM. The K+ flux at the resting potential, calculated from the time integral of the K+ current recorded during depolarizations, was decreased by TAM. The effect of TAM on the cell proliferation was perfectly correlated with the effect of TAM on the resting K+ flux. The results suggest that cell mitosis is, in some way, controlled by the functioning of K+ channels and that the antitumour action of tamoxifen could be due to its interaction with K+ channels.

A quantitative analysis of the role of K+ channels in mitogenesis of neuroblastoma cells.

The role of K+ channels in mitogenesis was studied on mouse neuroblastoma cells by analysing the effects of various chemical agents on the whole-cell K+ current and the cell proliferation. The outward current recorded during depolarizations on undifferentiated cells was made up of a small and slow inactivating K+ current. Foetal calf serum, which is mitogen for neuroblastoma cells, shifted in opposite directions by 7-10 mV peak activation and steady-state inactivation-voltage curves of the K+ current. The resulting effect was an increase in K+ conductance. The effect on the resting K+ flux of the classical K+ channel blockers tetraethylammonium, 4-aminopyridine and capsaicin, the anticancer agent tamoxifen, the heat inactivated serum and the increase in external K+ concentration were estimated from their effects on the K+ current. The cell proliferation was determined under the same conditions. The results indicate that cell proliferation is correlated to the resulting K+ flux. It is supposed that mitogenesis is controlled by the intracellular Na+ concentration which, via a cell volume regulation, is a function of the K+ flux. A quantitative model is developed on the basis of these hypotheses.

Block of sodium current in myelinated nerve fibre with enkephalins.

The effects of leu- and met-enkephalin were investigated on the node of Ranvier of isolated nerve fibers of frog under current and voltage clamp conditions. When added to the external solutions, enkephalins (1--5 mM) caused a slight decrease in peak Na+ and steady state K+ currents. The action potential was not significantly affected. When added to the internal medium (by diffusion from the two cut ends of the fibre), enkephalins (less than 5 mM) drastically reduced the peak Na+ current without significantly affecting the steady state K+ current. The block of Na+ current was greatly accelerated and enhanced by repetitive depolarizations. The sodium current slowly recovered after the end of pulsing. The extent of the block and rate of accumulation increased with increasing magnitude and frequency of the depolarizing pulses. Internal applications of enkephalins induced a blockade of the action potential when the fibre was stimulated at frequencies above 0.1 Hz. The results suggest that during depolarizations, enkephalin molecules plug the inner end of Na+ channels or immobilize the channel gates leaving the channels in a closed configuration, and remain in or near the pores for a long time after the end of depolarizations. Possible physiological significance and molecular mode of action of enkephalins on myelinated nerve fibres are discussed.

Evidence for several mechanisms of volume regulation in neuroblastoma x glioma hybrid NG108-15 cells.

Volumes of neuroblastoma x glioma hybrid NG 108-15 cells were electronically measured in order to characterize the mechanisms involved in volume regulation in isosmotic and anisosmotic conditions. The cells behave as perfect osmometers when tonicity was changed at constant chloride concentration by adding sucrose or replacing NaCl with CaCl2 or MgCl2. In contrast, the cell volume was poorly dependent on tonicity when the Cl- concentration was changed by adding NaCl or H2O. Cell shrinkage was induced by cell stirring or after a hypotonicity-induced swelling. These volume decreases were abolished by caffeine but not by ryanodine or EGTA. Shrinkage was also induced by the Ca2+ ionophore ionomycin. The ionomycin-induced volume decrease was abolished by EGTA. Cell swelling induced an outwardly rectifying Cl- current which was blocked by 5-nitro-2-(3-phenylpropylamino)benzoic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid and dihydroindenyloxy-alkanoic acid. When the tonicity was reduced at constant Cl- concentration by replacing NaCl with CaCl2 or MgCl2, the volume increased and then slowly decreased towards its control value. This regulatory volume decrease was blocked by 5-nitro-2-(3-phenylpropylamino)benzoic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid and dihydroindenyl-oxy-alkanoic acid. Long-term (hours-days) cell shrinkage was induced by a reduction of the culture medium osmolarity. Long-term cell swelling was induced by an increase of the culture medium osmolarity. These volume changes were abolished by the protein translation inhibitor cycloheximide. The results suggest that NG 108-15 cell volume is regulated by at least four interacting mechanisms controlled, respectively, by intracellular Ca2+, extracellular NaCl, cell volume and intracellular ionic strength. The speculative nature of ionic systems responsible for these volume regulating mechanisms is discussed.

Mechanism of action of ketamine in the current and voltage clamped myelinated nerve fibre of the frog.

The effects of the general anaesthetic ketamine, on the frog isolated node of Ranvier, were studied under current and voltage clamp conditions. Ketamine (0.5 and 1 mM) reversibly decreased the amplitude of the action potential and increased both the duration of the action potential and the threshold potential. When the K current was blocked, spontaneous action potentials appeared after washout of the drug. Ketamine rapidly blocked the Na current and more slowly modified a fraction of Na channels (about 10%) to give rise to a non-inactivatable (late) Na current. After washout of the drug, the block reversed more rapidly than the ketamine-induced late Na current disappeared. Steady-state outward, peak Na and ketamine-induced late Na currents were rapidly and reversibly blocked by ketamine with an apparent dissociation constant of 0.7 mM. Both peak Na and ketamine-induced late Na currents were reversibly blocked by procaine.