Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats.

Infection and inflammation impose a suppression in the expression and activity of several drug transporters and drug-metabolizing enzymes in liver. In the intestine, cytochrome P450 3A (CYP3A), P-glycoprotein (PGP/mdr1), and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs; thus, the expression and activity of these proteins were examined in inflammation. Transport and metabolism were determined in jejunum segments isolated at 24 h from endotoxin-treated or control rats (n = 8) mounted in Ussing chambers. Transport and metabolism of (3)H-digoxin, 5-carboxyfluorescein (5-CF), amiodarone (AM), and 7-benzyloxyquinoline (7-BQ) were measured for 90 min in the presence and absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. As compared with controls, levels of mdr1a and mrp2 mRNA were significantly decreased by approximately 50% in the jejunum of LPS-treated rats. Corresponding reductions in the basolateral-->apical efflux of digoxin, AM, and 5-CF were observed, resulting in significant increases in the apical-->basolateral absorption of these compounds. Intestinal CYP3A mRNA levels and CYP3A-mediated metabolism of 7-BQ and AM were also decreased by approximately 50 to 70% (p < 0.05) in the LPS group. Mannitol permeability and lactate dehydrogenase release were not altered. These studies indicate that endotoxin-induced inflammation imposes a reduction in the intestinal expression and activity of PGP, mrp2, and CYP3A in rats, which elicits corresponding changes in the intestinal transport and metabolism of their substrates. Hence, infection and inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters and metabolic enzymes.

Parkinson's syndrome: cranial computed-tomography findings. Their dependence on sex and age.

Cranial Computed Tomography (CCT) findings in 123 patients suffering from Parkinson's syndrome were compared with a sex- and age-matched normal control group. Signs of supratentorial atrophy--cortical and subcortical--were more significantly marked in the Parkinson group. In both groups, signs of atrophy were more prevalent in men than in women. Parkinsonian women also more frequently showed limited features, such as lacunar lesions, around the lateral ventricles. Moreover, in these patients atrophy was marked in the frontal cortex.

Saccade-related brain potentials during reading correct and incorrect versions of proverbs.

Using a reading task, the present study investigated saccade-related brain potentials (SRPs) accompanying the perception of the final words of proverbs, i.e. of sentences where the context allows a strong anticipation of the final word. The sentences were presented one at a time on a TV monitor. The proverbs appeared either in their original form or with their final word changed to be incongruous with the sentence context. SRPs to the two types of final words were recorded from 4 scalp areas. The onset of the saccade leading to the final word was used to trigger the averaging of SRPs. Incongruent and congruent brain responses were also compared by means of difference waveforms. The results showed that a difference between SRPs to congruous vs incongruous final words of proverbs already appeared simultaneously with the SRP component indicating the analysis of the visual pattern of the word. This finding supports an interactive model of word perception.

Brain potentials associated with pattern displacement and saccadic eye movements in humans and rhesus monkeys.

Visual evoked potentials (VEPs) to the onset of motion of visual patterns and brain responses associated with saccadic eye movements (SRPs) were compared in human subjects and in rhesus monkeys. Three different velocities of pattern motion were employed. In humans, brain responses were recorded from six scalp areas. In monkeys, transcortical recordings were obtained from chronically implanted electrodes in the occipital, temporo-parietal, and frontal areas. In humans there was a clear difference in VEPs to the pattern motion between the anterior (Fz, Cz) and posterior (Pz, Oz) scalp regions. The earliest component was a positive peak at 85 ms at Oz followed by a negativity around 110 ms. In the fronto-central leads the VEP was characterized by a negativity at 145 ms and a subsequent broad positive component around 250 ms. SRP responses differed in the early components from the VEPs to pattern motion but a good correspondence was found in the morphology of the late components of the two types of brain potentials. Furthermore, flashed-on VEPs and SRPs elicited a late positivity of more pronounced amplitude than VEPs to pattern displacement. In monkeys similar findings were found: an early negative component of the pattern-displacement VEP could not be observed in the SRP responses over the visual cortex while the late portion of the SRP waveform was greater than the late positivity of the VEP to motion-onset.

Context effects on saccade-related brain potentials to words during reading.

In two experiments saccade-related brain potentials (SRPs) to sentences were investigated under conditions approximating natural reading. Our aim was to look for electrophysiological (SRP) signs of sentence context on the processing of final words that were either congruent or incongruent with the meaning of the sentence. In Experiment 1 subjects indicated by a button-press whether or not the final word was congruent with the context, while in Experiment 2 they read silently without an overt decision. In Experiment 1, SRPs to incongruent words were more negative than SRPs to congruent words between 80-310 msec (from saccade offset). In Experiment 2, however, the inconcruent SRPs became more negative than the congruent SRPs only between 280-460 msec. These results suggest that in Experiment 1, during the processing of incongruent words the early sign of registering mismatch appears simultaneously with the analysis of the visual features of the word.

Visual information processing with brain potentials that accompany saccadic eye movements.

The relation between stimulus probability and the late components of the saccade-related brain (lambda) potentials (SRPs) was studied in three kinds of cognitive tasks: guessing, counting and word categorization. These tasks, traditionally used to study event-related potentials, were modified in such a way that subjects had to perform a saccadic eye movement in order to perceive the target stimulus. In guessing and counting tasks three kinds of target stimulus appeared with the probabilities of 17, 33 and 50 percent, respectively. In the semantic word categorization task the stimuli belonged to one of two categories: frequent (80 percent, female names) and infrequent (20 percent, male names). In all three tasks the late positive components (P300 and P4) had greater amplitudes of SRPs elicited by the infrequent stimuli than by the frequent ones. A Principal Component-Varimax Analysis of the SRP data revealed factors corresponding to (1) a positive Slow Wave, (2) the positive P300 and (3) the P4 components, respectively. In addition, the semantic categorization task was correlated with a late (negative) SRP component.

Electrocortical signs of word categorization in saccade-related brain potentials and visual evoked potentials.

Visual evoked potentials (VEPs) elicited by foveal presentation of words were compared to brain potentials evoked by the same words in a condition where subjects had to make a saccadic eye movement in order to perceive the words (saccade-related brain potentials, SRPs). Subjects had to categorize the words responding with a button press to stimuli belonging to the target (infrequent, P = 0.2) category. The VEP and SRP waveforms showed divergences in the early (up to 250 ms) components, but a marked similarity between the late components. Principal Component Analysis also revealed the same relationship between the two types of brain responses. Peak latency of the late SRP components measured from saccade offset showed an apparent processing advantage over the corresponding late components of VEPs. The N3 component, indexing semantic processing of visual patterns, peaked between 310 and 375 ms in the SRPs, while in the VEPs it appeared between 410 and 470 ms. The P4 component, associated with final stimulus evaluation, showed a similar latency benefit in favour of SRPs (420-500 ms vs 530-590 ms in VEPs). The mean reaction time was 74 ms shorter in the eye movement condition (measured from saccade offset) than in the VEP condition (703 vs 777 ms). The question of what kind of processes may contribute to the differences in mean RTs and to the latencies of the late components between the two conditions are discussed. We suggest that the late components (P3, N3 and P4) of the VEP and the SRP, respectively, index identical brain processes.

Saccade-related brain potentials in semantic categorization tasks.

Saccade-related brain potentials (SRPs) were recorded in word categorization tasks in which subjects had to perform a saccade in order to perceive the stimulus. For all three conditions representing different degrees of complexity of semantic categorization, the stimuli belonged to one of two categories which appeared with the respective probabilities of either 0.20 or 0.80. The late positivity (P4) of the SRPs to infrequent stimuli appeared systematically later as the complexity of stimulus evaluation increased: The easiest categorization was accompanied by a P4 at 400 msec, in the more complex condition it peaked at 600 msec, and in the most difficult semantic categorization the P4 peaked even later, at 680 msec. This shift in peak latency with increasing complexity of categorization is in agreement with the results for traditional ERPs (e.g. Kutas and Donchin, 1978). The possible overlap of the late components was investigated by applying Principal Component-Varimax Analysis to the SRPs.

Late components of lambda responses in cognitive tasks.

The effects of stimulus probability were investigated on the late components of saccade-related brain potentials (lambda responses) in two paradigms, 'counting' and 'guessing.' Subjects performed saccadic eye movements from a middle light to the target area where one of three kinds of target light stimuli appeared in a randomized sequence, each with a different probability (0.17, 0.33, and 0.50). Brain activity was recorded from six scalp areas. In the counting task subjects were instructed to count the prespecified low-probability stimuli. In the guessing experiment they had to make a guess before each trial as to which kind of target stimulus would appear. In both experiments the late positive components showed significantly greater amplitude in the lambda responses associated with infrequent stimuli than in those elicited by frequent stimuli. Principal component-Varimax analysis of the lambda responses revealed factors corresponding to the P300 and the slow wave components of traditional evoked potential studies.

Late components of saccade-related brain potentials in guessing tasks.

The late positive components of lambda responses were studied in a guessing task modified in such a way that subjects had to perform a saccadic eye movement in order to perceive task-relevant information. Responses from 6 scalp areas were investigated in 9 subjects and in 2 conditions: control and guessing. In both conditions subjects performed two consecutive saccades in a given trial: the first to the middle light, the second to the target area. In the control condition the subjects knew beforehand what the 'target' would be. In the guessing condition they had to make a guess before each trial as to which of the three target stimuli would appear. The target stimuli occurred with unequal probability and were presented in a randomized sequence. Unlike the control condition, the guessing task led to the appearance of a late positive component in the lambda response. Similar to traditional ERP findings, this late positivity showed an amplitude maximum at the parietal area and a peak latency at 375 msec from saccade onset. Furthermore, Principal Component-Varimax Analysis (PCVA) of the lambda responses revealed a first factor giving the strongest loading in the latency range of the P300, and a second factor which was identified as the slow wave. These factors are quite similar to the factors found in the PCVA of ERPs. Our results suggest that the late components of lambda responses reflect the effects of information processing in cognitive tasks similarly to the way the late positive components of ERPs do.

Auditory evoked potentials to verbal stimuli in health, aphasic, and right hemisphere damaged subjects. Pathway effects and parallels to language processing and attention.

Acoustic evoked potentials to meaningful words were recorded in healthy, aphasic, and right hemisphere-damaged subjects under four conditions: monaural left and right, binaural, and dichotic stimulation. Four major findings emerged. First, healthy and brain-damaged subjects differed in amplitude and latency values of the N1 and P2 components. In healthy subjects N1 was greater and P2 smaller than in aphasics. Both components peaked earlier inpatients than in normals. Second, evoked potentials of healthy subjects showed a late sustained component which was decreased in aphasics. Third, the latencies of P1 and N1 as well as the amplitude of N1 showed a "pathway effect", i.e. shorter latency and greater amplitude to contralateral stimulation. Fourth, under the dichotic condition, P1 and N1 peaked earlier over the left hemisphere. The N1 amplitude behaved differently in the three groups depending upon stimulating conditions. It is suggested that these differences reflect linguistic coding and related attentional processes in patients and normals.

Cortical potentials associated with vocalization in the rhesus monkey.

Cortical potentials associated with vocalization have been investigated in two rhesus monkeys. In both animals a slow negative potential shift beginning approximately 1 sec prior to the onset of vocalization has been observed in transcortical recordings from precentral areas. It is suggested that this slow potential change might be the phylogenetic antecedent of the voluntary control of speech in humans.