Chromatic adaptation from achromatic stimuli with implied color.

Previous research has shown that the typical or memory color of an object is perceived in images of that object, even when the image is achromatic. We performed an experiment to investigate whether the implied color in greyscale images could influence the perceived color of subsequent, simple stimuli. We used a standard top-up adaptation technique along with a roving-pedestal, two-alternative spatial forced-choice method for measuring perceptual bias without contamination from any response or decision biases. Adaptors were achromatic images of natural objects that are normally seen with diagnostic color. We found that, in some circumstances, greyscale adapting images had a biasing effect, shifting the achromatic point toward the implied color, in comparison with phase-scrambled images. We interpret this effect as evidence of adaptation in chromatic signaling mechanisms that receive top-down input from knowledge of object color. This implied color adaptation effect was particularly strong from images of bananas, which are popular stimuli in memory color experiments. We also consider the effect in a color constancy context, in which the implied color is used by the visual system to estimate an illuminant, but find our results inconsistent with this explanation.

Enhanced BaZrO3 mechanosynthesis by the use of metastable ZrO2 precursors.

The current work assesses the impact of structural differences between stable and metastable ZrO2 precursors on the mechanochemical preparation of BaZrO3. Monoclinic (m-ZrO2) and tetragonal (t-ZrO2) zirconia polymorphs were prepared without stabilizing additives by slow alkaline precipitation. High-energy milling of the individual ZrO2 precursors induced different partial transformations in each case. The as-synthesized m-ZrO2 powders showed partial conversion to the tetragonal polymorph on mechanical activation, reaching about 10% t-ZrO2 after 420 min accompanied by increases in strain. In contrast, the as synthesized t-ZrO2 powders underwent the inverse transformation to the monoclinic phase, producing about 50% m-ZrO2 after 120 min with the liberation of strain. The t-ZrO2 precursor was shown to exhibit the higher reactivity with barium peroxide, yielding significantly earlier formation of barium zirconate under room-temperature mechanosynthesis. The progress of the mechanochemical formation of BaZrO3 has been discussed with respect to the differing behaviour of the ZrO2 precursors upon mechanical activation and associated thermodynamic perspectives.

Visual perception in Parkinson disease dementia and dementia with Lewy bodies.

OBJECTIVE: To quantify visual discrimination, space-motion, and object-form perception in patients with Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD). METHODS: The authors used a cross-sectional study to compare three demented groups matched for overall dementia severity (PDD: n = 24; DLB: n = 20; AD: n = 23) and two age-, sex-, and education-matched control groups (PD: n = 24, normal controls [NC]: n = 25). RESULTS: Visual perception was globally more impaired in PDD than in nondemented controls (NC, PD), but was not different from DLB. Compared to AD, PDD patients tended to perform worse in all perceptual scores. Visual perception of patients with PDD/DLB and visual hallucinations was significantly worse than in patients without hallucinations. CONCLUSIONS: Parkinson disease dementia (PDD) is associated with profound visuoperceptual impairments similar to dementia with Lewy bodies (DLB) but different from Alzheimer disease. These findings are consistent with previous neuroimaging studies reporting hypoactivity in cortical areas involved in visual processing in PDD and DLB.

Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients.

PURPOSE: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment. METHODS: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations. RESULTS: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (+/-SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 +/- 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 microM (11% inhibition) and 900 microM (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy CONCLUSIONS: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT.

Object-oriented models of cognitive processing.

Information-processing models of vision and cognition are inspired by procedural programming languages. Models that emphasize object-based representations are closely related to object-oriented programming languages. The concepts underlying object-oriented languages provide a theoretical framework for cognitive processing that differs markedly from that offered by procedural languages. This framework is well-suited to a system designed to deal flexibly with discrete objects and unpredictable events in the world.

Depth cue integration: stereopsis and image blur.

Depth-of-focus limitations introduce spatial blur in images of three-dimensional scenes. It is not clear how the visual system combines depth information derived from image blur with information from other depth cues. Stereoscopic disparity is the pre-eminent depth cue, so experiments were conducted to investigate interactions between image blur and stereoscopic disparity. Observers viewed two random dot stereograms (RDSs) in a 2AFC task, and were required to identify the RDS depicting the greatest depth. In control observations, all dots in both RDSs were sharply defined. In experimental observations, one RDS contained only sharply defined dots, but the other contained differential spatial blur to introduce an additional depth cue. Results showed that the addition of differential blur made only a marginal difference to apparent depth separation, and only when the blur difference was consistent with the sign of disparity. Cue combination between blur and disparity cues is thus weighted very heavily in favour of the latter. It is shown that blur and disparity cues co-vary according to geometric optics. Since the two cues are effective over different distances, the visual system is not normally called upon to integrate them, and is most likely to make use of blur cues over distances beyond the range of disparity mechanisms.

Perceived speed of motion in depth is reduced in the periphery.

The perceived speed of motion in depth (MID) for a monocularly visible target was measured in central and peripheral vision using a 2AFC speed discrimination task. Only binocular cues to MID were available: changing disparity and interocular velocity difference (IOVD). Perceived speed for monocular lateral motion and perceived depth for static disparity were also assessed, again in both central and peripheral vision. The purpose of the experiment was to assess the relative contributions of changing disparity and IOVD cues to the perceived speed of stereomotion. Although peripheral stimuli appeared to lie at approximately the same depth as their central counterparts, their apparent speed was reduced. Monocular/lateral and binocular/MID speeds were reduced to a similar extent. It seems that reduced apparent monocular speed leads to reduced perceived MID speed, despite the fact that the disparity system appears to be unaffected. These results suggest that the IOVD cue makes a significant contribution to MID speed perception.

Integration biases in the Ouchi and other visual illusions.

A texture pattern devised by the Japanese artist H Ouchi has attracted wide attention because of the striking appearance of relative motion it evokes. The illusion has been the subject of several recent empirical studies. A new account is presented, along with a simple experimental test, that attributes the illusion to a bias in the way that local motion signals generated at different locations on each element are combined to code element motion. The account is generalised to two spatial illusions, the Judd illusion and the Zöllner illusion (previously considered unrelated to the Ouchi illusion). The notion of integration bias is consistent with recent Bayesian approaches to visual coding, according to which the weight attached to each signal reflects its reliability and likelihood.

Luminance processing in apparent motion, Vernier offset and stereoscopic depth.

We obtained (apparently) linear responses to luminance from three special displays of apparent motion, Vernier offset and stereoscopic depth. In our motion stimulus a dark and a light bar exchanged luminances repetitively on a grey surround. Motion was attributed to the bar that differed more from the surround, that is, on a dark surround the light bar appeared to jump, and on a light surround the dark bar appeared to jump. The apparent motion disappeared when the luminance of the surround lay halfway between that of the bars--on a linear, not a logarithmic scale. Similar results were obtained for special Vernier offset and stereo stimuli. These results cannot be explained if all luminances are processed within the same luminance pathway and that pathway transforms input luminance using non-linear compression. However, the apparent linearity of our results could arise from opposite and equal non-linearities cancelling out within separate ON- and OFF-spatial luminance pathways. A second set of experiments presented one bar separately into each eye on different surrounds (dichoptic presentation of competing apparent motion signals) or manipulated the display spatially so that different surrounds were associated with different bars (binocular presentation of competing Vernier targets). Results showed that apparent motion and Vernier signals of equal Weber contrast (normalisation of linear difference to surround luminance) evoked equal-motion and equal Vernier offset strengths. Given that motion and Vernier strength followed Weber's law, we infer that the ON- and OFF-pathways transform luminance non-linearly. Our third experiment presents an example of a brightness bisection task in which we were able to influence the bisection steps, to follow either a linear or non-linear series. The benefits of parsing the visual scene so that visual information is processed within two opposite luminance pathways is discussed.

Nefopam enantiomers: preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration.

Nefopam (NEF) is a potent analgesic compound administered as a racemic mixture. Previous in vitro and in vivo studies with nefopam enantiomers have shown that (+)nefopam [(+)NEF] is substantially more potent than (-)nefopam [(-)NEF]. Differences between enantiomers have also been suggested in metabolic studies in vitro. The impact of these differences in vivo is not known because there is little or no information on the relative plasma concentrations of the enantiomers or on their kinetics. In this study, individual enantiomers of nefopam were synthesized and examined for acute toxicity in male and female rats and mice. Pharmacologic properties of enantiomers were examined using in vitro binding assays and antinociceptive tests in rats and mice. Additionally, a pharmacokinetic study was conducted in human volunteers. Subjects were administered 20 mg nefopam as Acupan(R) either as a 5- or 20-min intravenous infusion. In a control phase, subjects were administered only vehicle. Blood samples were collected through the following 24 h. Plasma samples were analyzed for individual enantiomers using a chiral assay developed for this purpose. The pharmacologic differences of previous studies were confirmed in receptor binding assays and in the hot plate and the formalin tests in mice. Neither enantiomer demonstrated substantial activity in the tail flick test in rats. No significant differences were revealed between LD(50) values of nefopam enantiomers after oral or intravenous administration in male and female rats or mice. There were no significant differences in AUC(0-infinity), C(max), or half-life between enantiomers following intravenous administration. Based on these findings, there is currently no compelling rationale to justify administering or monitoring individual enantiomers.

Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450.

Nevirapine (NVP), a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is concomitantly administered to patients with a variety of medications. To assess the potential for its involvement in drug interactions, cytochrome P-450 (CYP) reaction phenotyping of NVP to its four oxidative metabolites, 2-, 3-, 8-, and 12-hydroxyNVP, was performed. The NVP metabolite formation rates by characterized human hepatic microsomes were best correlated with probe activities for either CYP3A4 (2- and 12-hydroxyNVP) or CYP2B6 (3-and 8-hydroxyNVP). In studies with cDNA-expressed human hepatic CYPs, 2- and 3-hydroxyNVP were exclusively formed by CYP3A and CYP2B6, respectively. Multiple cDNA-expressed CYPs produced 8- and 12-hydroxyNVP, although they were produced predominantly by CYP2D6 and CYP3A4, respectively. Antibody to CYP3A4 inhibited the rates of 2-, 8-, and 12-hydroxyNVP formation by human hepatic microsomes, whereas antibody to CYP2B6 inhibited the formation of 3- and 8-hydroxyNVP. Studies using the CYP3A4 inhibitors ketoconazole, troleandomycin, and erythromycin suggested a role for CYP3A4 in the formation of 2-, 8-, and 12-hydroxyNVP. These inhibitors were less effective or ineffective against the biotransformation of NVP to 3-hydroxyNVP. Quinidine very weakly inhibited only 8-hydroxyNVP formation. NVP itself was an inhibitor of only CYP3A4 at concentrations that were well above those of therapeutic relevance (K(i) = 270 microM). Collectively, these data indicate that NVP is principally metabolized by CYP3A4 and CYP2B6 and that it has little potential to be involved in inhibitory drug interactions.

Cytotoxicity induced by the combination of valproic acid and tumor necrosis factor-alpha: implication for valproic acid-associated hepatotoxicity syndrome.

A previous study showed that valproic acid (VPA) and tumor necrosis factor-alpha (TNF-alpha) exhibit synergistic toxicity (lethality) in Sprague-Dawley and Wistar rats. The present study investigated a possible mechanism for this synergy using an in vitro system. Incubation of human U937 cells with 1 mM VPA or with 0.001 ng/mL of TNF-alpha alone had a negligible effect on cytotoxicity (less than 7%). However, the combination of the two drugs significantly increased the cytotoxicity up to 34%. Chronic treatment of U937 cells with VPA or TNF-alpha for 48 hr reduced protein kinase C (PKC) activity. Further, the PKC selective inhibitor Gö6976 potentiated VPA-induced cytotoxicity and TNF-alpha-induced cytotoxicity, whereas the PKC activator phorbol-12-myristate-13-acetate provided a significant protection against the cytotoxicity associated with VPA or TNF-alpha. These results suggest that the synergism in cytotoxicity exhibited by the combination of VPA and TNF-alpha may be mediated through attenuation of PKC activity.

Second-order processing of four-stroke apparent motion.

In four-stroke apparent motion displays, pattern elements oscillate between two adjacent positions and synchronously reverse in contrast, but appear to move unidirectionally. For example, if rightward shifts preserve contrast but leftward shifts reverse contrast, consistent rightward motion is seen. In conventional first-order displays, elements reverse in luminance contrast (e.g. light elements become dark, and vice-versa). The resulting perception can be explained by responses in elementary motion detectors turned to spatio-temporal orientation. Second-order motion displays contain texture-defined elements, and there is some evidence that they excite second-order motion detectors that extract spatio-temporal orientation following the application of a non-linear 'texture-grabbing' transform by the visual system. We generated a variety of second-order four-stroke displays, containing texture-contrast reversals instead of luminance contrast reversals, and used their effectiveness as a diagnostic test for the presence of various forms of non-linear transform in the second-order motion system. Displays containing only forward or only reversed phi motion sequences were also tested. Displays defined by variation in luminance, contrast, orientation, and size were effective. Displays defined by variation in motion, dynamism, and stereo were partially or wholly ineffective. Results obtained with contrast-reversing and four-stroke displays indicate that only relatively simple non-linear transforms (involving spatial filtering and rectification) are available during second-order energy-based motion analysis.

Effect of stiripentol dose on phenytoin-induced teratogenesis in a mouse model.

PURPOSE: Previous studies have suggested that polytherapy by design may aid in the management of human pregnancies complicated by epilepsy. However, mechanistic parallels must be drawn between the models of teratogenesis and human pregnancies, and doses of the second agent given to minimize side-effects must be justified. This study sought to determine the lowest dosage of stiripentol (STP) protective against phenytoin-induced teratogenesis in a mouse model, and to determine mechanistically if inhibition of oxidative metabolism by STP in vitro decreased production of reactive phenytoin (PHT) metabolites. METHODS: Pregnant SWV mice were assigned to control or treatment groups of STP alone, PHT alone, or PHT with ascending doses of STP coadministration. Treatments continued from Day 6 to Day 18 of gestation when fetuses were examined for developmental anomalies. [14C]PHT was incubated in mouse liver microsomes with and without NADPH and in the presence or absence of STP or piperonyl butoxide. Covalent binding of [14C] was measured. RESULTS: There were no dose-related differences in the frequency of fetal malformations per litter among groups treated with STP alone. However, STP (all doses) reduced the frequency of PHT-induced malformations. Covalent binding of [14C]PHT was NADPH-dependent and was inhibited by either piperonyl butoxide or STP. CONCLUSIONS: The beneficial effects of STP occurred at concentrations below the therapeutic range for its anticonvulsant effects. These results support the concept of polytherapy by design to reduce the risk of teratogenesis associated with PHT.

In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent.

Levetiracetam and its carboxylic metabolite (AcL) were tested for their potential inhibitory effect on 11 different drug metabolizing enzyme activities using human liver microsomes. The following specific assays were investigated: testosterone 6beta-hydroxylation [cytochrome P-450 3A4 (CYP3A4)], coumarin hydroxylation (CYP2A6), (R)-warfarin hydroxylation (CYP1A2), (S)-mephenytoin hydroxylation (CYP2C19), p-nitrophenol hydroxylation (CYP2E1) tolbutamide hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), epoxide hydrolase and UDP-glucuronyltransferase (UGT) toward paracetamol (UGT1*6), ethinyloestradiol (UGT1*1), p-nitrophenol (UGT(pl 6.2)), and valproic acid. None of these activities were affected by levetiracetam or AcL added at concentrations up to 1 mM. Additionally, primary cultures of rat hepatocytes were used to assess a potential inducing effect of levetiracetam on CYPs. Phenobarbital (2 mM), beta-naphtoflavone (40 microM), dexamethasone (1 microM), and phenytoin (up to 300 microM) were tested as positive controls. When added to cells for 48 h, all the positive controls increased 7-ethoxycoumarin O-deethylase activity demonstrating the inducibility of CYPs in the present culture conditions. By contrast, levetiracetam did not affect the activity up to 1 mM. The highest levetiracetam concentrations examined in the above in vitro studies are well in excess of those measured in the plasma of patients receiving therapeutic doses. It is thus concluded that levetiracetam is unlikely to produce pharmacokinetic interactions through inhibition of CYPs, UGTs, and epoxide hydrolase. Furthermore, based on the in vitro assays with rat hepatocytes, it could be speculated that levetiracetam does not act as a CYP inducer.

Evidence for global motion interactions between first-order and second-order stimuli.

Recent research indicates that the early stages of visual-motion analysis involve two parallel neural pathways, one conveying information from luminance-defined (first-order) image features, the other conveying information from texture-defined (second-order) features. It is still not clear whether these two pathways converge during later stages of global motion integration. According to one account they remain segregated, and feed separate global analyses. In the alternative account, all responses feed a common stage of global analysis. Two perceptual phenomena are universally held to result from interactions between detector responses during global motion integration--direction repulsion and motion capture. We conducted two psychophysical experiments on these phenomena to test for segregation of first-order and second-order responses during integration. Stimuli contained two components, either two random-block patterns transparently drifting in different directions (repulsion measurements), or a drifting square-wave grating superimposed on an incoherent random-block pattern (capture measurements). Repulsion and capture effects were measured when both stimulus components were the same order, and when one component was first order and the other was second order. Both effects were obtained for all combinations of first-order and second-order patterns. Repulsion effects were stronger with first-order inducing patterns, and capture effects were stronger with second-order inducers. The presence of perceptual interactions regardless of stimulus order strongly suggests that responses in first-order and second-order pathways interact during global motion analysis.

The motion aftereffect.

The motion aftereffect is a powerful illusion of motion in the visual image caused by prior exposure to motion in the opposite direction. For example, when one looks at the rocks beside a waterfall they may appear to drift upwards after one has viewed the flowing water for a short period-perhaps 60 seconds. The illusion almost certainly originates in the visual cortex, and arises from selective adaptation in cells tuned to respond to movement direction. Cells responding to the movement of the water suffer a reduction in responsiveness, so that during competitive interactions between detector outputs, false motion signals arise. The result is the appearance of motion in the opposite direction when one later gazes at the rocks. The adaptation is not confined to just one population of cells, but probably occurs at several cortical sites, reflecting the multiple levels of processing involved in visual motion analysis. The effect is unlikely to be caused by neural fatigue; more likely, the MAE and similar adaptation effects provide a form of error-correction or coding optimization, or both.

Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: in vitro and in vivo comparison and calculation of in vivo inhibition constants.

OBJECTIVE: The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo. METHODS: Stiripentol was incubated in vitro with (R)-warfarin, coumarin, (S)-warfarin, (S)-mephenytoin, bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6 beta-hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorphan O- and N-demethylation were used to measure CYP2D6 and CYP3A4 activity, respectively. In vivo inhibition constants for CYP3A4 were calculated with use of data that previously documented the interaction between stripentol and carbamazepine. RESULTS: In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant values at or slightly higher than therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of caffeine demethylation and dextromethorphan N-demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6 beta-hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibition of CYP2D6-mediated O-demethylation was not observed in vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged between 12 and 35 mumol/L, whereas the corresponding in vitro value was 80 mumol/L. CONCLUSIONS: Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.

Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation.

This article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with epilepsy and healthy individuals, and in vitro studies which identified the cytochromes P450 (CYP) inhibited by felbamate and those involved in its metabolism. In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions. Felbamate has been shown in vitro to inhibit CYP2C19, which would account for its effect on phenytoin clearance, and it had been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by felbamate. Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. Interactions involving felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in valproic acid (valproate sodium) clearance by felbamate is through the inhibition of beta-oxidation. No clinically relevant pharmacokinetic interactions were noted between felbamate and lamotrigine, clonazepam, vigabatrin, nor the active monohydroxy metabolite of oxcarbazepine. Information on the mechanisms underlying felbamate's drug:drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.