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  • 2000-2004  (41)
  • 1995-1999  (3,565)
  • Cell & Developmental Biology  (2,833)
  • Human  (776)
  • 101
    ISSN: 1432-1106
    Keywords: Key words Grip force ; Force control ; Parabolic flight ; Microgravity ; Hypergravity ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In the present study, grip forces exerted against a stationary held object were recorded during parabolic flights. Such flight maneuvers induce changes of gravity with two periods of hypergravity, associated with a doubling of normal terrestrial gravity, and a 20 s period of microgravity. Accordingly, the object’s weight changed from being twice as heavy as normally experienced and weightless. Grip-force recordings demonstrated that force control was seriously disturbed only during the first experience of hyper- and microgravity, with the grip forces being exceedingly high and yielding irregular fluctuations. Thereafter, however, grip force traces were smooth, the force level was scaled to the object’s weight under normal and high-G conditions, and the grip force changed in parallel with the weight during the transitions between hyper- and microgravity. In addition, during weightlessness, when virtually no force was necessary to stabilize the object, a low force was established, which obviously represented a reasonable safety margin for preventing possible perturbations. Thus, all relevant aspects of grip-force control observed under normal gravity conditions were preserved during gravity changes induced by parabolic flights. Hence, grip-force control mechanisms were able to cope with hyper- and microgravity, either by incorporating relevant receptor signals, such as those originating from cutaneous mechanoreceptors, or by adequately including perceived gravity signals into control programs. However, the adaptation to the uncommon gravity conditions was not complete following the first experience; finer tuning of the control system to both hyper- and microgravity continued over the measurement interval, presumably with a longer observation period being necessary before a stable performance can be reached.
    Type of Medium: Electronic Resource
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  • 102
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 126 (1999), S. 235-251 
    ISSN: 1432-1106
    Keywords: Key words Motor learning and memory ; Perseveration ; Prefrontal cortex ; Reversal learning ; Basal ganglia ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The ability to inhibit previously learned visuomotor associations is essential for efficient learning of novel behaviors. While the neural basis of the system that might control interactions between competing motor memories is not known, it has been demonstrated that animals with ventral and orbital prefrontal cortex (PFC) deficits have particular difficulties in learning to withhold responses to previously conditioned sensory stimuli. Here we measured regional cerebral blood flow (rCBF), using positron emission tomography, during learning of a novel motor task that required inhibition of a previously learned motor memory. Subjects (n=24) learned reaching movements in a force field (field A). After a variable time interval, some subjects (n=15) learned to reach in a field with a reversed pattern of forces (field B). When the time interval was short (10 min), learning in field B was coincident with a reactivation of regions that had become initially activated during learning in field A: the left putamen and bilaterally in the dorsolateral PFC. Behaviorally, this was accompanied with perseveration that lasted for hundreds of movements, suggesting an instantiation of the internal model for field A during learning in field B. Neither the reactivation nor the perseveration were observed in a different group of subjects that learned field B at 5.5 h. We found that the regions which significantly differentiated the two groups during learning of B were in the ventrolateral PFC (bilaterally): there were sharp decreases in rCBF here in the 5.5 group but not in the 10-min group. At 5.5 h motor learning again involved the striatum, but this time in the left caudate. Neither the caudate nor the ventral PFC had exhibited learning-related activity in field A. Instead, they showed changes in rCBF during the reversal of the learning problem when the previously acquired motor memory was successfully gated. The results demonstrate that: (1) perseveration of a competing motor memory may be linked to reactivation of the neural circuit that participated in acquiring that memory, and (2) the ventral PFC may play an important role in the inhibitory control of the competing motor memory.
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  • 103
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 129 (1999), S. 156-160 
    ISSN: 1432-1106
    Keywords: Key words Optokinetic nystagmus ; Depth-from-motion ; Transparent motion ; Ambiguous ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  When two visual patterns moving in opposite directions are superimposed, they appear to be at different depths and to slide over each other. Because the stimulus does not specify the depth-order between the surfaces, this transparent motion perception is essentially ambiguous. With prolonged observation, the perceived depth-order of the two moving surfaces reverses spontaneously. In the present study, the correlation between the perceived direction of transparent motion and optokinetic nystagmus (OKN) was examined. While viewing superimposed random-dot patterns moving in opposite horizontal or vertical directions, subjects attempted to fixate the center of the stimulus, while paying attention to either the near or far depth plane, and reported any changes of the direction of surface-motion at the attended depth. Even with attention focused on a particular depth, the spontaneous reversal of transparent motion perception still occurred. This indicates that the perceptual reversal may reflect a preattentive mechanism for depth-from-motion. Furthermore, the OKN slow-phase tended to be in the same direction as the perceived motion of the surface at the attended depth. These results support the idea that the mechanisms for OKN maintenance are sensitive to perception of depth-from-motion and, therefore, cortically mediated.
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  • 104
    ISSN: 1432-1106
    Keywords: Key words Paired-pulse transcranial magnetic stimulation ; Threshold hunting ; Intracortical inhibition ; Intracortical I-wave facilitation ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Short-interval, paired-pulse transcranial magnetic stimulation (TMS) is usually used to demonstrate intracortical inhibition. It was shown recently that with short-interval, paired-pulse TMS a facilitation – called intracortical I-wave facilitation – can also be demonstrated. It was the aim of this study to investigate which stimulus conditions lead to intracortical inhibition and what conditions yield an intracortical I-wave facilitation in a hand muscle of normal subjects. Paired-pulse TMS responses with an interstimulus interval of 1.2 ms were obtained from the abductor digiti minimi muscle of four normal subjects. A threshold-hunting paradigm with hunting through first or second stimulus variation was used to obtain a curve of threshold-pair strengths. All subjects showed two branches of stimulus interaction on this diagram. If the first stimulus of a threshold pair was below approximately 65% of resting motor threshold it modified the response primarily due to the second stimulus through intracortical inhibition. However, if the first stimulus of a threshold pair exceeded approximately 65% of resting motor threshold it became responsible for the spinal action-potential initiation. The subsequent second stimulus served as a ”booster” for the ongoing intracortical I-wave activity, making it impossible to observe the intracortical inhibition evoked by the first stimulus.
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  • 105
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 128 (1999), S. 200-204 
    ISSN: 1432-1106
    Keywords: Key words Eye-hand coordination ; Human ; Saccade ; Vision ; Bimanual coordination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Two different drawer tasks were investigated with the aim of assessing the role of eye movements in well-coordinated hand movements. In an unimanual step-tracking task, which had a predictive and an unpredictive movement, a two-way repeated-measures ANOVA showed a significant effect of prediction on the onset of grip-force (GF) rate (300±39 ms for the predictive condition versus 394±53 ms for the non-predictive condition, P〈0.0001). Correlation coefficients, computed from the eye and the hand movements were low for the right and the left hand. The saccade was more coupled with the visual step change than with the action of the hand per se. In a second bimanual pull-and-pick task, the instruction was to pull a drawer with the left hand from a closed position to a LED-cued open position and then to grasp and reinsert a small peg in the drawer with the right hand. Correlation coefficients, computed from the latencies of saccades and of the leading left hand or of the right hand, were significant in four of five subjects. Intermanual correlations were significant in all five subjects. In conclusion, we found that the initial saccade in the unimanual task was best related with the visual step change, but was poorly correlated with the pulling/pushing hand. In the bimanual task, a moderate, but significant temporal coupling between the eyes and hand events was observed. This coupling was, however, less tight than that between both hands.
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  • 106
    ISSN: 1432-1106
    Keywords: Key words Elbow movement ; Motor learning ; Reaction time ; Kinematics ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Learning of a motor task, such as making accurate goal-directed movements, is associated with a number of changes in limb kinematics and in the EMG activity that produces the movement. Some of these changes include increases in movement velocity, improvements in end-point accuracy, and the development of a biphasic/triphasic EMG pattern for fast movements. One question that has remained unanswered is whether the time course of the learning-related changes in movement parameters is similar for all parameters. The present paper focuses on this question and presents evidence that different parameters evolve with a specific temporal order. Neurologically normal subjects were trained to make horizontal, planar movements of the elbow that were both fast and accurate. The performance of the subjects was monitored over the course of 400 movements made during experiments lasting approximately 1.5 h. We measured time-related parameters (duration of acceleration, duration of deceleration, and movement duration) and amplitude-related parameters (peak acceleration, peak deceleration, peak velocity), as well as movement distance. In addition, each subject’s reaction time and EMG activity was monitored. We found that reaction time was the parameter that changed the fastest and that reached a steady baseline earliest. Time-related parameters decreased at a somewhat slower rate and plateaued next. Amplitude-related parameters were slowest in reaching steady-state values. In subjects making the fastest movements, a triphasic EMG patterns was observed to develop. Our findings reveal that movement parameters change with different time courses during the process of motor learning. The results are discussed in terms of the neural substrates that may be responsible for the differences in this aspect of motor learning and skill acquisition.
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  • 107
    ISSN: 1432-1106
    Keywords: Key words Three-dimensional pointing ; Human ; Remembered targets
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The accuracy of visually guided pointing movements decreases with speed. We have shown that for movements to a visually defined remembered target, the variability of the final arm endpoint position does not depend on movement speed. We put forward a hypothesis that this observation can be explained by suggesting that movements directed at remembered targets are produced without ongoing corrections. In the present study, this hypothesis was tested for pointing movements in 3D space to kinesthetically defined remembered targets. Passive versus active acquisition of kinesthetic information was contrasted. Pointing errors, movement kinematics, and joint-angle coordination were analyzed. The movements were performed at a slow speed (average peak tangential velocity of about 1.2 m/s) and at a fast speed (2.7 m/s). No visual feedback was allowed during the target presentation or the movement. Variability in the final position of the arm endpoint did not increase with speed in either the active or the passive condition. Variability in the final values of the arm-orientation angles determining the position of the forearm and of the upper arm in space was also speed invariant. This invariance occurred despite the fact that angular velocities increased by a factor of two for all the angles involved. The speed-invariant variability supports the hypothesis that there is an absence of ongoing corrections for movements to remembered targets: in the case of a slower movement, where there is more time for movement correction, the final arm endpoint variability did not decrease. In contrast to variability in the final endpoint position, the variability in the peak tangential acceleration increased significantly with movement speed. This may imply that the nervous system adopts one of two strategies: either the final endpoint position is not encoded in terms of muscle torques or there is a special on-line mechanism that adjusts movement deceleration according to the muscle-torque variability at the initial stage of the movement. The final endpoint position was on average farther from the shoulder than the target. Constant radial-distance errors were speed dependent in both the active and the passive conditions. In the fast speed conditions, the radial distance overshoots of the targets increased. This increase in radial-distance overshoot with movement speed can be explained by the hypothesis that the final arm position is not predetermined in these experimental conditions, but is defined during the movement by a feedforward or feedback mechanism with an internal delay.
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  • 108
    Electronic Resource
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    Springer
    Experimental brain research 125 (1999), S. 265-270 
    ISSN: 1432-1106
    Keywords: Key words Tendon reflexes ; Biceps femoris ; Gait ; Ia afferents ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  During gait it is generally accepted that there is a reduction in amplitude of H-reflexes as compared to standing. For short-latency stretch reflexes, however, it is less clear whether a similar reduction in reflex gain is present during locomotion. Stretches of constant amplitude are hard to produce under these circumstances and for this reason some previous studies on the biceps femoris (BF) have used ”reduced gait” in which the stimulated leg is stepping on the spot while the contralateral leg is walking on a treadmill. With this method it was possible to show that BF tendon jerk reflexes are larger at end swing and therefore are likely to contribute to the EMG burst normally occurring in that part of the step cycle when the BF is rapidly stretched. In the present study two questions were addressed: first, whether the reflex is different in size during gait compared to standing and, second, whether it is modulated in size during the gait cycle not only during reduced but also during normal gait. It was found that during both types of gait there was a general reflex depression with regard to the respective control values obtained during standing at similar EMG activity levels. In previous studies on soleus and quadriceps, discrepancies between EMG activity and reflex amplitude have been ascribed to changes in presynaptic inhibition of Ia terminals mediating the afferent volley of the reflex. Based on the data presented, this may also be true for the BF. In both normal and reduced gait the reflex was similarly modulated in size, showing a maximum at the end of swing. This similarity implies that reduced gait may be useful as an acceptable alternative for normal gait in studies on phase-dependent reflex modulation during locomotion.
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  • 109
    Electronic Resource
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    Springer
    Experimental brain research 125 (1999), S. 521-524 
    ISSN: 1432-1106
    Keywords: Key words Light touch ; Sway ; Centre of pressure ; Hand force ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  It has previously been shown that light contact with the finger tip on a fixed surface reduces centre of pressure (CoP) fluctuations in the frontal plane when standing in an unstable posture with the feet in line (tandem Romberg stance). Positive cross-correlations between horizontal finger forces and CoP fluctuations with finger forces exhibiting a phase lead suggest the hand provides sensory input for postural stability. The present study investigates whether this is the case for normal posture. We report reduced CoP fluctuations in the sagittal plane when light touch is permitted during normal bipedal stance. Moreover, we find positive crosscorrelations between finger tip forces and CoP fluctuations which are of similar magnitude and phase lag to those observed in tandem Romberg stance. This shows the utility of hand touch input for regulation of normal upright posture as well as inherently unstable postures such as tandem Romberg.
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  • 110
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    Springer
    Surgical and radiologic anatomy 21 (1999), S. 139-141 
    ISSN: 1279-8517
    Keywords: Anatomy ; Human ; Cross-section ; Computer-assisted instruction ; Education ; Medical
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The NPAC visible human viewer (NPAC VHV), graphical interface written in JAVA, freely accessible by the Web, allows the display of anatomic cross-sections of the Visible Human Project developed by the National Library of Medicine. In April 1997, the Medical Media Library of Lyons undertook the construction of a French-language mirror site of the NPAC VHV. The aim of this work is to evaluate first year utilisation of this site. From May 1st, 1997 to April 30th, 1998, the mirror site was consulted 34,752 times. In 45.14% of cases, the request came from France, in 4.42% of cases from Belgium, in 3.98% from Canada and in 2.12% from Switzerland. Other connections came either from a country responsible for fewer than 1% of connections or from unidentified computers. Data analysis showed a peak of connections between 15:00 and 17:00, and an increased number of connections from September to March 1998. The NPAC VHV is housed in 5 sites in the world. It is a software very simple to use. As the figures have no legends, it is more appropriate for group teaching than for self-teaching.
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  • 111
    ISSN: 1432-2072
    Keywords: Key words Marijuana ; Human ; THC ; Withdrawal ; Dependence ; Tolerance ; Subjective effect ; Performance ; Food intake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral Δ9-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in private or social recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20 mg qid) and on days 12–15 (30 mg qid). Both active doses of THC increased ratings of “High,”“Good Drug Effect,” and “Willingness to Take Dose Again” compared to baseline (days 1–3). THC also increased food intake by 35–45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of “Anxious,”“Depressed,” and “Irritable,” decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use.
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  • 112
    Electronic Resource
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    Springer
    Psychopharmacology 141 (1999), S. 395-404 
    ISSN: 1432-2072
    Keywords: Key words Marijuana ; Dependence ; Withdrawal ; Human ; Tolerance ; Subjective effect ; Performance ; Residential laboratory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Symptoms of withdrawal after oral Δ9-tetrahydrocannabinol (THC) administration have been reported, yet little is known about the development of dependence on smoked marijuana in humans. In a 21-day residential study, marijuana smokers (n = 12) worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day. Food and beverages were available ad libitum from 0830 to 2330 hours. Marijuana cigarettes (0.0, 1.8, 3.1% THC) were smoked at 1000, 1400, 1800, and 2200 hours. Placebo marijuana was administered on days 1–4 . One of the active marijuana doses was administered on days 5–8, followed by 4 days of placebo marijuana (days 9–12). The other concentration of active marijuana cigarettes was administered on days 13–16, followed by 4 days of placebo marijuana (days 17–20); the order in which the high and low THC-concentration marijuana cigarettes were administered was counter-balanced between groups. Both active doses of marijuana increased ratings of “High,” and “Good Drug Effect,” and increased food intake, while decreasing verbal interaction compared to the placebo baseline (days 1–4). Abstinence from active marijuana increased ratings such as “Anxious,”“Irritable,” and “Stomach pain,” and significantly decreased food intake compared to baseline. This empirical demonstration of withdrawal from smoked marijuana may suggest that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms.
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  • 113
    ISSN: 1432-2072
    Keywords: Key words Aggression ; Tryptophan ; Serotonin ; Human ; Diet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Some studies have shown that sharp reduction of L-tryptophan (Trp) concentration in plasma results in increases in laboratory-measured aggression. Conversely, raising plasma Trp has blunted aggression. These effects are presumably due to impaired or enhanced serotonin synthesis and neurotransmission in the brain. In this study, the laboratory-measured aggressive behavior of eight men under both Trp depletion (T-) and Trp loading (T+) conditions was compared to their aggressive behavior under food-restricted control conditions (overnight fast without an amino acid beverage). Subjects were provoked by periodic subtraction of money which was attributed to a fictitious other participant, and aggression was defined as the number of retaliatory responses the subject made ostensibly to reduce the earnings of the (fictitious) other participant. Following ingestion of the T- beverage, aggressive responding was significantly elevated relative to the food-restricted control condition, and this increased aggressive behavior became more pronounced across behavioral testing sessions on a time-course which paralleled previously documented decreases in plasma Trp concentrations. In contrast, no changes were observed in aggressive responding under T+ conditions relative to food-restricted conditions. These within-subject behavioral changes under depleted plasma Trp conditions support earlier indications of a role of serotonin in regulating aggression.
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  • 114
    ISSN: 1432-2072
    Keywords: Key words Cocaine ; Craving ; Cytidine ; CDP-choline ; Human ; Medication ; Drug dependent ; Citicoline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The administration of cytidine-5′-diphosphate choline (CDP-choline, citicoline) to animals increases the rate of membrane phospholipid synthesis and elevates brain dopamine levels. Because cocaine dependence has been associated with increases in brain phospholipid precursors, as well as depletion of dopamine within the central nervous system, the present outpatient study was conducted to assess the safety of citicoline (500 mg bid) and to determine if short-term treatment alters mood states and cocaine craving in subjects with a history of cocaine dependence. In addition, measures of drug craving and mood states after presentation of cocaine-related cues were collected on two occasions: before and after 14 days of double-blind treatment with either citicoline or placebo. Subjects did not experience any side effects and citicoline treatment was associated with decreases in self-reported mood states associated with cocaine craving. These preliminary data are encouraging and suggest that citicoline warrants further study as a promising potential treatment for cocaine abuse and dependence that is devoid of side effects.
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  • 115
    Electronic Resource
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    Springer
    Psychopharmacology 142 (1999), S. 149-157 
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Craving ; Smoking ; Rapid smoking ; Cigarette ; Self-report ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Craving is thought to play an important role in maintaining regular smoking patterns in current smokers, and in leading to relapse in smokers attempting to quit. Within the scientific community however, the concept is surrounded by controversy. In an effort to 1) identify interventions that can reliably influence cigarette cravings, and 2) assess the relationship between cigarette craving and smoking behavior, effects of aversive rapid smoking (up to nine cigarettes with puffs taken every 6 s) on self-reported craving and subsequent smoking behavior were compared to effects of self-paced smoking or no smoking. Subjects (n = 14) engaged in a rapid, self-paced or no smoking procedure at the start of three separate sessions. Craving levels, measured repeatedly during the next 3 h of no smoking, were significantly lower after rapid smoking than after either self-paced or no smoking. Measures of subsequent smoking behavior (latency to first cigarette, number of cigarettes, number of puffs) did not differ systematically across conditions. Thus, craving was reliably suppressed by aversive rapid smoking, but craving scores did not predict actual smoking behavior.
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  • 116
    ISSN: 1432-2072
    Keywords: Key words Cannabinoids ; THC ; Dronabinol ; Binocular depth inversion ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Binocular depth inversion represents an illusion of visual perception that is sensitive to various behavioural and psychiatric conditions. It is affected by cannabinoids, reflecting associated changes in perception. The present study investigated the differences in binocular depth inversion of different classes of natural and artificial objects and the effect of synthetic Δ9-tetrahydrocannabinol (Dronabinol) on these illusionary perceptions. Using this model, the effects of orally administered Dronabinol on binocular depth inversion were investigated in 17 healthy male volunteers. Pictures from natural and artificial objects were presented stereoscopically and the depth perception of the volunteers was scored in an operationalized way. The time-course of the effects of Dronabinol on binocular depth inversion was analyzed with regard to the stimulus classes (natural and synthetic objects). Significant differences in binocular depth inversion of the different groups of stimuli were revealed. Objects with a higher degree of everyday familiarity were generally seen as more illusionary than those with a lower degree of everyday familiarity. A strong impairment of binocular depth inversion due to Dronabinol was found in most classes of objects. Analysis of different stimulus classes provides further information on the underlying perceptual processing of binocular depth inversion. An impairment of top-down processing of visual sensory data by Dronabinol is suggested. The anandamidergic system seems to be involved in areas of visual information processing.
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  • 117
    ISSN: 1432-2072
    Keywords: Key words Cocaine ; Human ; Self-administration ; D1 agonist ; Subjective effect ; Craving ; Cardiovascular effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: Data in laboratory animals suggest that D1 receptor agonists may have potential utility for the treatment of cocaine abuse. Objective: The effects of ABT-431, a selective agonist at the dopamine D1 receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. Method: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4 mg IV) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus $5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. Results: ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of “High,”“Stimulated,” dose liking, estimates of dose value, “Quality,” and “Potency.” Furthermore, there was a trend for ABT-431 (4 mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. Conclusions: These data suggest that D1 agonists may have potential utility for the treatment of cocaine abuse.
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  • 118
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Alprazolam ; Placebo ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present study, we assessed the effects of the potent benzodiazepine alprazolam on the human acoustic startle response in healthy volunteers. Eight undergraduate students received single oral doses of placebo and alprazolam 2 mg on 2 separate days, according to a double-blind balanced crossover design. Electromyographic activity of the orbicularis oculi muscle was recorded 5, 7 and 11 h after drug administration. At each recording time, subjects received 21 acoustic stimuli (1 KHz, 116 dB, 50 ms duration) separated by variable intervals (8–30 s, mean 16.5 s). Consistent with previous results obtained for diazepam in humans, alprazolam significantly reduced the amplitude of the startle reflex. A patent increase in onset latency was also observed, this being a novel effect not previously described for benzodiazepines in human studies. Both effects were maximum at 5 h after dosing, the startle response experiencing a recovery as the drug disappeared from systemic circulation. These results indicate a potent inhibitory effect of alprazolam on baseline startle at the dose used, with a robust time-dependent recovery of initial values effectively counteracting between-session habituation.
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  • 119
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    Psychopharmacology 143 (1999), S. 339-346 
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Smoking ; Naltrexone ; Opiates ; Mechanism ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior. Objective: This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior. Methods: In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory. Results: Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood. Conclusions: The blockade of nicotine’s effects by naltrexone supports a role for opioid mechanisms in cigarette smoking.
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  • 120
    ISSN: 1432-2072
    Keywords: Key words Alternative reinforcers ; Heroin ; Human ; Intranasal ; Intravenous ; Opioids ; Performance ; Progressive ratio ; Reinforcing effect ; Self-administration ; Subjective effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Eight heroin-dependent individuals, maintained on divided daily doses of oral morphine, participated in a 2.5-week inpatient study comparing the effects of intranasal (IN) (placebo, 12.5, 25, 50, 100 mg) and intravenous (IV) (placebo, 6.25, 12.5, 25, 50 mg) heroin. Each morning, participants received $20 and a sample dose of heroin, and each afternoon they had the opportunity to self-administer all or part of the morning heroin dose or money amount. Participants responded under a modified progressive-ratio schedule (PR 50, 100, 200, 400, 800, 1200, 1600, 2000, 2400, 2800) during a ten-trial self-administration task. During each trial, participants could respond for 1/10th of the heroin dose or 1/10th of the money amount. The total amount of heroin and/or money chosen during the self-administration task was given at the end of the task. Thus, participants received drug and/or money twice each day: once during the morning sample session and once during the afternoon self-administration session. Participants received IV solution and IN powder simultaneously during each dosing; only one route contained active drug. Heroin produced dose-related increases in break point values by both routes of administration. Although IV heroin was approximately four-fold more potent than IN heroin, the maximal break point values for both routes were not significantly different. A similar difference in potency between the IV and IN routes was found for several ratings of subjective effects (e.g., “I feel a good drug effect,”“I feel high”), but maximal subjective ratings were lower for IN compared to IV heroin. These results suggest that the reinforcing efficacy of heroin is similar by the two routes of administration, but that IN heroin is less potent than IV heroin. The results also underscore the importance of evaluating drug self-administration in the evaluation of the abuse liability of drugs.
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  • 121
    ISSN: 1432-2072
    Keywords: Key words MDMA (3 ; 4-methylenedioxymethamphetamine) ; Serotonin ; Psychopathology ; Human ; Rat ; Prepulse inhibition ; Habituation ; Schizophrenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: Prepulse inhibition of acoustic startle refers to the reduction in the startle response when the startling stimulus is preceded by a weak prepulse stimulus. This phenomenon provides an operational measure of sensorimotor gating that has been found to be reduced in patients with schizophrenia and rats treated with serotonin agonists or serotonin releasers. Objective: In this study, we compared the effects of a serotonin releaser, MDMA, on prepulse inhibition in laboratory rats and healthy human volunteers. In particular, we investigated whether MDMA disrupts PPI in humans as observed in animal studies. Methods: Rats were tested after placebo and MDMA in a counterbalanced order at an interval of 1 week, with separate groups of rats being used for each dose of MDMA (1.7, 5.4 and 17.0 mg/kg). On each test day, rats were first tested after no injections and retested 2 h later, 10 min after a subcutaneous injection of placebo or MDMA. For the human study, a placebo-controlled within-subject design and double-blind procedures were used. Subjects were examined twice at a 2 to 4 week interval after either placebo or drug administration (order being counterbalanced). On each test day, subjects underwent baseline testing including psychological and PPI measures. Ninety minutes later, subjects received placebo or MDMA (1.7 mg/kg PO) and were retested after 75 min during the peak of behavioral effects of MDMA. Results: As expected, MDMA decreased prepulse inhibition in a dose-related fashion in rats. In contrast, a typical recreational dose of MDMA (1.7 mg/kg, orally) increased prepulse inhibition in subjects experiencing robust psychological effects. Conclusions: This surprising disparity between the effects of the drug in rats and humans may reflect a species-specific difference in the mechanism of action of MDMA or in the behavioral expression of a similar pharmacological effect, or both.
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  • 122
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    Psychopharmacology 147 (1999), S. 200-209 
    ISSN: 1432-2072
    Keywords: Key words Benzodiazepine ; Flumazenil ; Precipitated withdrawal ; Antagonist ; Physical dependence ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon®) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. Objectives: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. Methods: The acute physiological, participant-rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. Results: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. Conclusions: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.
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  • 123
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    Psychopharmacology 147 (1999), S. 266-273 
    ISSN: 1432-2072
    Keywords: Key words Benzodiazepine ; Lorazepam ; Human ; Memory ; Auditory priming ; Visual priming ; Explicit memory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Lorazepam has been repeatedly shown to impair both explicit memory and perceptual priming, a form of implicit memory, in the visual domain. However, the effects of this benzodiazepine on priming in other perceptual domains, such as auditory priming, have never been explored. Objective:The present study investigated whether the deleterious effects of lorazepam on perceptual priming are restricted to the visual domain, or if they could be extended to the auditory domain. Methods: Thirty-two healthy volunteers were randomly assigned to two parallel groups, placebo and lorazepam 0.038 mg/kg. The drug was administered orally, following a double-blind procedure. In the same subjects, perceptual priming was assessed in the auditory and visual domains using similar word-stem completion tasks, and explicit memory was explored using a free- recall task. Results: Lorazepam markedly reduced free-recall performance for visually and auditorily presented words. Lorazepam equally impaired visual and auditory priming. In the auditory word-stem completion task, prior presentation of a word facilitated perception of its stem in the placebo group. This facilitation effect was not observed in the lorazepam group. The lorazepam-induced impairment of priming was not due to sedation or explicit contamination. Conclusion: These results indicate that the deleterious effects of lorazepam on priming are not restricted to the visual modality, but extend to the auditory modality.
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  • 124
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    Psychopharmacology 145 (1999), S. 162-174 
    ISSN: 1432-2072
    Keywords: Key words Opioid blockade ; Buprenorphine ; Naltrexone ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: One therapeutic benefit of mu opioid agonist or antagonist maintenance is the resultant attenuation of the effects of illicit opioids. It is important to characterize the development and duration of opioid blockade produced by buprenorphine, a novel opioid dependence pharmacotherapy. Objective: This study characterized the ability of buprenorphine to attenuate opioid effects during treatment initiation and discontinuation compared to naltrexone and placebo. Methods: Opioid-experienced volunteers (n = 8) participated in this 10-week, inpatient, double-blind, within-subject, crossover study. Five randomized conditions [buprenorphine (2 and 8 mg, sublingually), naltrexone (25 and 100 mg, PO) and placebo] were each examined during a 2-week period; the test drug was given for 7 days followed by a 7-day placebo wash-out. Cumulative doses of hydromorphone (0, 2 and 4 mg, IM, 45 min apart) were administered thrice-weekly corresponding with treatment and wash-out days 1, 3, and 5; behavioral, physiological and pharmacokinetic measures were collected. Results: Buprenorphine alone produced dose-related prototypic agonist effects during induction (i.e., positive mood, respiratory depression, miosis); tolerance developed only to the subjective effects. Buprenorphine 2 mg partially attenuated the effects of hydromorphone, while nearly complete attenuation was observed with 8 mg that lasted up to 72 h after discontinuation. Both naltrexone doses produced complete hydromorphone blockade after a single dose; blockade of the behavioral, but not physiological, effects persisted for 5 days after discontinuation of 100 mg. Conclusions: These data suggest that 2 mg buprenorphine is a sub-therapeutic maintenance dose, both buprenorphine 8 mg and naltrexone produce immediate and efficacious opioid blockade, and adequate protection against illicit opioids may be achieved with less-than-daily dosing.
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  • 125
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Drug discrimination ; Training conditions ; Testing conditions ; Three-choice procedure ; Subjective effect ; Human ; Smoking status
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Discrimination of a drug’s interoceptive stimulus effects often depends substantially on training and testing conditions. Objectives: We examined changes in nicotine discrimination behavior in humans as a function of lowering the training dose and of varying the discrimination testing procedure. Methods: Smokers and never-smokers (n=10 each) were initially trained to discriminate 20 µg/kg nicotine by nasal spray from placebo (0) and tested on generalization of discrimination responding across a range of doses from 0 to 20 µg/kg. Each subsequently learned to reliably discriminate progressively smaller doses of nicotine from placebo until his or her threshold dose for discrimination was identified (mean=2.7 µg/kg). A repeat testing of generalization responding across 0–20 µg/kg was then conducted, using placebo and the subject’s threshold dose as training doses. Generalization testing involved both two-choice and three-choice (novel response option) quantitative procedures. Results: A significant shift to the left was seen in nicotine-appropriate responding in the two-choice procedure when the nicotine training dose was lowered (i.e. from the first to the second test of generalization). In the three-choice procedure, however, there was no such leftward shift. Instead, in never-smokers, a flattening of nicotine-appropriate responding occurred with a lowering of the training dose, while novel-appropriate responding significantly increased. The subjective effects of ”head rush” and, in never-smokers only, ”jittery” also showed a shift to the left in their relationship with nicotine generalization dose when the training dose was lowered. Conclusions: These results confirm the importance of training and testing conditions on discrimination behavior and subjective drug responses within subjects and demonstrate the utility of the novel-response, three-choice procedure for assessing qualitatively different stimulus effects of novel drug doses.
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  • 126
    ISSN: 1432-2072
    Keywords: Key words Alcohol effect ; Impulsivity ; Working memory ; Executive function ; High-risk ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Impulsivity is associated with increased risk for alcoholism. Alcohol also may increase impulsive behavior, although little is known about the processes underlying this effect. Objectives: This study tested a model proposing that the executive processes of working memory (WM) and conditional associative learning (CAL) modulate behavioral inhibition. Subjects had either a positive (FHP) or a negative (FHN) family history of alcoholism. Hypotheses were that alcohol would increase Go/No-Go impulsive responding but only in subjects with low working memory capacity (low-WM), low-CAL ability, or FHP for alcoholism. The model also predicted that WM and CAL modulate inhibitory responses to contingency reversal on a Go/No-Go task. Methods: A Go/No-Go learning task with a midway contingency reversal was administered to 71 FHP and 78 FHN subjects when sober and after drinking one of two moderate doses of alcohol. WM (digits backward) and CAL (conditional spatial association task) were also assessed when sober. Results: Alcohol resulted in more false alarms but only in low-WM subjects. Both WM and CAL modulated learning to inhibit behavior after contingency reversal, suggesting separate modulation mechanisms for WM and CAL. Subjects with low- capacity WM and subjects with low-capacity CAL ability had more difficulty learning response inhibition after contingency reversal. FHPs and FHNs did not differ in their response to alcohol. Conclusions: The results support our model of the modulatory role of WM and CAL in the ongoing regulation of behavioral inhibitory systems. The results also suggest that individuals with low capacity WM are more susceptible to alcohol’s effect of increasing impulsive behavior, suggesting that alcohol reduces the capacity of working memory to modulate response inhibition.
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  • 127
    ISSN: 1432-2072
    Keywords: Key words Buprenorphine ; Naloxone ; Dose ratio ; Opiate dependence ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist effects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The effects of three intravenous (IV) buprenorphine and naloxone combinations on agonist effects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist effects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist effects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2:1 and 4:1 produced moderate to high increases in global opiate withdrawal, bad drug effect, and sickness. These dose ratios also decreased the pleasurable effects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8:1 produced only mild withdrawal symptoms. Dose combinations at 2:1 and 4:1 ratios may be useful in treating opiate dependence.
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  • 128
    ISSN: 1432-2072
    Keywords: Key words Methadone maintenance treatment ; Chiral analysis ; Methadone ; Plasma ; Urine ; Abused drug ; Daily variation ; Rating scales ; Dose-adjustment ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: One of the major problems in methadone maintenance treatment is to find optimal individual doses for the patients. Objective: The present study investigated whether the use of rating scales together with enantioselective analysis of l-methadone might facilitate dose adjustments in a clinical situation. Methods: Rating scales were used to evaluate subjective and objective signs of well-being in relation to plasma methadone concentrations in two groups of patients receiving methadone maintenance treatment. The first group (n = 25) was well-adjusted according to clinical observations and were satisfied with their methadone doses (86.2 ± 4.3 mg). The second group (n = 25) was in need of the methadone dose adjustment; they complained of low dosing, despite a dose level of 69.2 ± 4.0 mg/day. Results: Results indicated a significant correlation between dose and methadone concentration among dissatisfied patients only. The trough levels of d,l-methadone and l-methadone, as well as their elimination rates, were similar in the two groups of patients. There was a variable predominance of l- over d-methadone in plasma (ratio ≈1.2; range 0.7–3.6). Illicit use of drugs by the patients was related to the methadone dose and to satisfaction with the dose received. Increased illicit drug use among dissatisfied patients was successfully eliminated by raising the methadone dose. Subjective and objective ratings of the satisfied patients were quite stable throughout the evaluation period, whereas the ratings of the dissatisfied patients were unstable. These patients seemed to be more sensitive to low trough levels of methadone than the satisfied patients. Associations between the subjective and objective ratings and plasma methadone, along with background characteristics, were characterized by multiple regression analyses. The plasma concentrations of l-methadone were one of the most important explanatory variables in these analyses. Associations between well-being and methadone concentrations in plasma were stronger for l-methadone than for d,l-methadone. Conclusions: Selective measurements of the active isomer and the use of rating scales should be of clinical value when monitoring methadone maintenance treatment patients.
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    Psychopharmacology 145 (1999), S. 39-51 
    ISSN: 1432-2072
    Keywords: Key words Zaleplon ; Triazolam ; Benzodiazepine ; Hypnotics ; Learning ; Memory ; Abuse potential ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Zaleplon, a pyrazolopyrimidine that is under development as a hypnotic, produces its pharmacological effects at the benzodiazepine-recognition site on the GABAA benzodiazepine-receptor complex. Unlike most benzodiazepines, zaleplon binds selectively to the BZ1 (ω1) subtype of the benzodiazepine receptor. The present study compared the acute subject-rated effects, performance-impairing effects, and abuse potential of zaleplon and triazolam, a triazolobenzodiazepine hypnotic, in 14 healthy volunteers with histories of drug abuse. Zaleplon (25, 50, and 75 mg), triazolam (0.25, 0.5, and 0.75 mg) and placebo were administered orally in this double-blind, crossover study. Zaleplon and triazolam produced comparable dose-related effects on several subject-rated drug-effect questionnaires. Zaleplon and triazolam also produced comparable dose-dependent decrements on several performance tasks including balance, circular lights, digit-enter and recall, DSST, picture recall/recognition and repeated acquisition. Same-day and next-day subject-rated measures reflecting abuse potential (e.g., drug liking, good effects, and monetary street value) also suggest that zaleplon and triazolam were comparable. The only notable between-drug difference observed in the present study was that the time-action function of zaleplon differed from that of triazolam. The onset time, time to maximum drug effect, and duration of action were shorter with zaleplon than triazolam. Thus, despite its non-benzodiazepine structure and unique benzodiazepine-receptor binding profile, the behavioral pharmacological profile of zaleplon is similar to that of triazolam.
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  • 130
    ISSN: 1432-2072
    Keywords: Key words MDMA ; Ecstasy ; Human ; EEG ; Power ; Coherence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rationale: Despite animal studies implicating 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) in serotonergic neurotoxicity, there is little direct evidence of changes in neural function in humans who use MDMA as a recreational drug. Objective: The present study investigated whether there is a correlation between quantitative EEG variables (spectral power and coherence) and cognitive/mood variables, and level of prior use of MDMA. Methods: Twenty-three recreational MDMA users were studied. Resting EEG was recorded with eyes closed, using a 128-electrode geodesic net system, from which spectral power, peak frequency and coherence levels were calculated. Tests of intelligence (NART), immediate and delayed memory, frontal function (card sort task), and mood (BDI and PANAS scales) were also administered. Pearson correlation analyses were used to examine the relationship between these measures and the subject’s consumption of MDMA during the previous 12-month period. Partial correlation was used to control for the use of other recreational drugs. Results: MDMA use was positively correlated with absolute power in the alpha (8–12 Hz) and beta (12–20 Hz) frequency bands, but not with the delta (1–3 Hz) or theta (4–7 Hz) bands. MDMA use was negatively correlated with EEG coherence, a measure of synchrony between paired cortical locations, in posterior brain sites thought to overly the main visual association pathways of the occipito-parietal region. MDMA use did not correlate significantly with any of the mood/cognitive measures except the card sort task, with which it was weakly negatively correlated. Conclusions: Alpha power has been shown to be inversely related to mental function and has been used as an indirect measure of brain activation in both normal and abnormal states. Reduced coherence levels have been associated with dysfunctional connectivity in the brain in disorders such as dementia, white-matter disease and normal aging. Our results may indicate altered brain function correlated with prior MDMA use, and show that electroencephalography may be a cheap and effective tool for examining neurotoxic effects of MDMA and other drugs.
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  • 131
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    Psychopharmacology 146 (1999), S. 111-118 
    ISSN: 1432-2072
    Keywords: Key words Buprenorphine ; Heroin dependence ; Opioid dependence ; Human ; Opioid withdrawal ; Treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Administration of double the maintenance dose of buprenorphine has been shown to permit every-other-day dosing. Whether longer periods between dosing can be achieved is unknown. Objectives: To examine whether triple the maintenance dose can be administered every 72 h without opioid withdrawal or intoxication. Methods: Sixteen opioid-dependent outpatients each received three conditions (1) the maintenance dose of buprenorphine every 24 h, (2) double the maintenance dose every 48 h, and (3) triple the maintenance dose every 72 h under double-blind placebo-controlled conditions. Each conditions was imposed in a random sequence for 21–22 days. Self report and observer measures were taken at 24-h intervals. Results: No significant differences were observed on measures of opioid agonist and withdrawal effects between the dosing conditions. However, averaging effects across conditions may obscure important within-condition effects. When conditions were analyzed by individual days within a condition, several significant effects were observed. For example, 24 h after administration of triple the maintenance dose, significant effects were observed in eight opioid agonist measures. Also, 72 h after administration of triple the maintenance dose, significant effects were observed on four measures of withdrawal. Neither adverse medical reactions nor excessive opioid intoxication were observed. Conclusions: These results suggest that buprenorphine may be administered safely every 72 h by tripling the maintenance dose, with only minimal withdrawal complaints. Importantly, this 72-h dosing may permit patients to attend clinic thrice weekly without the use of take-home doses.
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  • 132
    ISSN: 1432-1211
    Keywords: Key words NK cells ; Human ; Surface molecule ; Lectin superfamily ; NK gene complex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Natural killer (NK) cells constitute the third major population of lymphocytes. They possess the inherent capacity to kill various tumor and virally infected cells and mediate the rejection of bone-marrow grafts in lethally irradiated animals. A large family of NK cell receptors belong to the C-type lectin superfamily and are localized to the NK gene complex on Chromosome (Chr) 6 in the mouse and Chr 12 in the human. Genes in the NK gene complex encode type II receptors and examples include the families of NKR-P1, Ly-49, and NKG2 receptors. Examples of other C-type lectin-like NK cell receptors that occur as individual genes are CD94, CD69, and AICL. Here we report the molecular characterization and chromosomal mapping of a human lectin-like transcript (LLT1) expressed on NK, T, and B cells and localized to the NK gene complex within 100 kilobases of CD69. The cDNA encodes a predicted protein of 191 amino acid residues with a transmembrane domain near the N-terminus and an extracellular domain of 132 amino acid residues with similarity to the carbohydrate recognition domain of C-type lectins. The predicted protein of LLT1 shows 59 and 56% similarity to AICL and CD69, respectively. The predicted protein does not contain any intracellular ITIM motifs, suggesting that LLT1 may be involved in mediating activation signals.
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  • 133
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    Immunogenetics 49 (1999), S. 438-445 
    ISSN: 1432-1211
    Keywords: Key words PA28 ; Proteasome ; Gene structure ; Evolution ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Two proteasome activators PA28α and β, which have been implicated in antigen processing for loading class I MHC molecules, are synthesized in response to Ifn-γ. The human genes encoding these activators (PSME1 and PSME2, respectively) were analyzed by sequencing. Each gene comprised 11 exons, consistent with gene duplication during vertebrate evolution. The intron/exon organization of both genes was highly conserved, the major difference being the absence of the exon encoding the lysine and glutamic acid-rich 'KEKE' motif in PA28β. Two other genes of relevance to the immune system were located close to those for PA28 at 14q11.2 including ISGF3G, a protein involved in transcription after IFNα signalling. These sequences were also characterized.
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  • 134
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    Plant foods for human nutrition 53 (1999), S. 359-365 
    ISSN: 1573-9104
    Keywords: Consumed ; Different levels ; Fenugreek seeds (Trigonella foenum graecum) ; Germinated ; HDL ; Human ; Hypocholesterolemia ; LDL ; Triglycerides ; VLDL
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The effect of consumption of germinated fenugreek seed powder at two different levels, i.e., 12.5 g and 18.0 g on the blood lipid profiles of twenty hypocholesterolemic adults of both sexes in the age range of 50–65 years was studied. The subjects were divided into two groups, i.e., Group I and Group II who were asked to incorporate the powder into any dish of their choice at the rates of one packet per day containing 12.5 g and 18.0 g of the germinated powder, respectively, for a period of one month. Fasting blood was drawn intravenously one day before and at the end of 30 days feeding trials. The findings revealed that germination had brought distinct changes in soluble fiber content of the seeds. Consumption of the seed at both the levels resulted in a hypocholesterolemic effect. Between the two levels, higher levels of consumption, i.e., 18.0 g of the germinated seed resulted in a significant reduction in total cholesterol and LDL levels. No significant changes were found in HDL, VLDL and triglyceride levels in all the subjects.
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  • 135
    ISSN: 1573-4943
    Keywords: Human ; aldehyde dehydrogenase ; 4-trans-(N,N-dimethylamino)cinnamaldehyde ; binding ; incorporation ; stoichiometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract 4-trans-(N,N-Dimethylamino)cinnamaldehyde (DACA) is a chromophoric substrate of aldehyde dehydrogenase (EC 1.2.1.3) whose fate can be followed during catalysis. During this investigation we found that DACA also fluoresces and that this fluorescence is enhanced and blue-shifted upon binding to aldehyde dehydrogenase. Binding of DACA to aldehyde dehydrogenase also occurs in the absence of coenzyme. Benzaldehyde (a substrate), acetophenone (a substrate-competitive inhibitor), and the substrate-competitive affinity reagent bromoaceto-phenone interfere with DACA binding. Thus, DACA binds to the active site and can be employed for titration of active aldehyde dehydrogenase. Both E1 and E2 isozymes, which are homotetramers, bind DACA with dissociation constants of 1–4 μM with a stoichiometry of 2 mol DACA/mol enzyme. The stoichiometry of enzyme–acyl intermediate was also found to be 2 mol DACA/mol enzyme for both E1 and E2 isozymes. Thus, both enzymes appear to have only two substrate-binding sites which participate in catalysis. The level of enzyme–acyl intermediate remained constant at different pH values, showing that enhancement of velocity with pH was not due to altered DACA–enzyme levels. When the reaction velocity was increased even further by using 150 μM Mg2+ the intermediate level was decreased, suggesting that both increased pH and Mg2+ promote decomposition of the DACA–enzyme intermediate. Titration with DACA permits study of aldehyde substrate catalysis before central complex interconversion.
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  • 136
    ISSN: 1434-0879
    Keywords: Key words Alpha-1-microglobulin ; Calcium oxalate ; Crystallization ; ELISA ; Human ; Urine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the past few years, alpha-1-microglobulin (α1m) has been copurified from human urine with bikunin, a potent inhibitor of calcium oxalate (CaOx) crystallization in vitro. In this study, we have purified α1m without bikunin contamination and investigated its possible role in CaOx crystallization by in vitro and in vivo studies. Alpha-1m was purified with an anti-α1m antibodies CNBr-activated sepharose column. Two molecular species of α1m of respectively 30 and 60 kDa were purified. For each protein, two blots of 30 and 60 kDa cross-reacted with anti-α1m antibodies, suggesting that these two forms were derived one from the other. Both protein species inhibited CaOx crystallization in a dose-dependent manner in two in vitro tests. In the first test, the presence of α1m of 30 kDa (8 μg/ml) in a medium containing 0.76 mM CaCl2 (with 45Ca) and 0.76 mM Ox(NH4)2 inhibited CaOx crystallization by 38% as estimated by supernatant radioactivity after 1 h of agitation. In the second test, CaOx kinetics were examined for 3 to 10 min in a turbidimetric model at 620 nm. The presence of α1m of 30 kDa in a medium containing 4 mM CaCl2 and 0.5 mM Na2Ox inhibited CaOx crystallization by 41.5%, as estimated by the slope modification of turbidimetric curve. Alpha-1m can be considered as another inhibitor of urinary CaOx crystal formation, as shown by the present in vitro studies. Using an ELISA assay, we found that urinary α1m concentration was significantly lower in 31 CaOx stone formers than in 18 healthy subjects (2.95 ± 0.29 vs 5.34 ± 1.08 mg/l respectively, P = 0.01). The decreased concentration of α1m in CaOx stone formers could be responsible in these patients, at least in part, for an increased risk of CaOx crystalluria.
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    Knee surgery, sports traumatology, arthroscopy 7 (1999), S. 177-183 
    ISSN: 1433-7347
    Keywords: Key words Knee joint ; Human ; Anterior knee pain ; Innervation ; Substance-P fibers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Sports Science
    Notes: Abstract The etiology of pain in anterior knee pain syndrome is a matter of controversy. The normal, articular cartilage is aneural, so defects in the surface are not thought to produce pain. Some authors have sought the origin of the pain in soft tissue structures around the knee. Knowledge of the distribution of nociceptive nerve fibers around the knee would provide insight for treating anterior knee pain syndrome. Twenty consecutive patients (28 knees), all women, with anterior knee pain syndrome (group I) participated in the study. For comparison we used two groups of patients: 20 patients with an osteoarthritic knee (group II) and 20 patients with anterior cruciate ligament rupture or meniscal lesion with no history of pain in the anterior compartment (group III). Immunohistochemical techniques using a monoclonal antibody to substance-P (SP) were employed to identify nociceptive fibers. For statistical analyses we used the one-way ANOVA test, which was corrected with the LSD test, at the level of significance P 〈 0.05. Results of the study demonstrate that SP-immunoreactive nerve fibers are widespread within the soft tissues around the knee. These tissues include the retinaculum, synovium, fat pad and, in some circumstances, bone. In cases of anterior knee pain, the presence of neuropeptide-containing fibers was statistically significant in the medial retinaculum (P 〈 0.005) and in the fat pad (P 〈 0.001) compared to group III, and compared to group II (P 〈 0.05 and P 〈 0.007, respectively). For lateral retinaculum this relationship was not so statistically strong (P 〈 0.02) and was equal in comparison between anterior knee pain patients (group I) and group II or group III. There were no statistically significant differences in the distribution of substance-P nerve fibers in the fat pad, lateral and medial retinaculum or synovium between groups II and III. The results of this study provide immunohistochemical evidence suggesting that pain may originate in the fat pad and medial retinaculum of many patients with anterior knee pain syndrome.
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  • 138
    ISSN: 1432-2307
    Keywords: Key words p21 ; p53 ; Colon ; Immunohistochemistry ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The WAF1/CIP1 gene product, p21, an inhibitor of cyclin-dependent kinases, is a critical downstream effector in the p53 pathway. The expression of p21 in human neoplasms is heterogeneous, and may be related to p53 functional status. We evaluated p21 immunoreactivity in 103 colorectal carcinomas (CC) in relation to the p53 gene and protein alterations and clinico-pathologic parameters. High p21 expression (more than 10% reactive cells) was seen in 39% of cases. p21 staining was heterogeneous and often detected in clusters of tumour cells; in some tumours p21 staining was more pronounced in superficial areas. No relation was seen between p21 immunoreactivity and site of the tumours (right vs left), TNM stage and grade. p21 expression was related to p53 status as evaluated with IHC or with SSCP analyses, low p21 expression usually being associated with p53 protein overexpression (P=0.048) and p53 gene alteration (P=0.005). The strongest associations were seen when the combined p53/p21 immunophenotype was compared with p53 gene alterations (P=0.0002). These data support the hypothesis that p21 expression in CC is mainly related to p53 functional status, suggesting that p21 expression could be an interesting adjunct in the evaluation of the functional status of the p53 pathway in CC.
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  • 139
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    European archives of oto-rhino-laryngology and head & neck 256 (1999), S. 370-372 
    ISSN: 1434-4726
    Keywords: Key words Gastroesophageal reflux disease ; Human ; papilloma virus ; Laryngeal papillomatosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The hallmark of gastroesophageal reflux disease (GERD) is an increased exposure of esophageal and laryngeal mucosa to gastric juice. This exposure can cause complications such as chronic laryngitis or chronic respiratory diseases. We report our experience in managing three pediatric patients with severe recurrent juvenile laryngeal papillomatosis (JLP) associated with GERD. All patients showed a high rate of recurrence requiring multiple laser surgeries. Systemic αinterferon therapy over a period of more than 1 year and photodynamic therapy with dihematoporphyrin produced no improvement. However, after therapy for GERD, the rate of recurrence of JLP decreased significantly. Although the course of respiratory papillomatosis is known to fluctuate, our findings suggest that gastroesophageal reflux may have a role in aggravating papillomatosis.
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  • 140
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    European journal of applied physiology 79 (1999), S. 347-352 
    ISSN: 1439-6327
    Keywords: Key words Citrate synthase activity ; Human ; Myoglobin concentration ; Protocols ; Resistance training ; Vastus lateralis muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of this study was to determine the effects of 8 weeks of resistance training (RT) on the myoglobin concentration ([Mb]) in human skeletal muscle, and to compare the change in the [Mb] in two different RT protocols. The two types of protocol used were interval RT (IRT) of moderate to low intensity with a high number of repetitions and a short recovery time, and repetition RT (RRT) of high intensity with a low number of repetitions and a long recovery time. A group of 11 healthy male adults voluntarily participated in this study and were divided into IRT (n = 6) and RRT (n = 5) groups. Both training protocols were carried out twice a week for 8 weeks. At the completion of the training period, the one-repetition maximal force values and isometric force were increased significantly in all the subjects, by about 38.8% and 26.0%, respectively (P 〈 0.01). The muscle fibre composition was unchanged by the 8 weeks of training. The muscle fibre cross-sectional areas were increased significantly by both types of training in all fibre types (I, IIa and IIb, mean +16.1%, P 〈 0.05). The [Mb] showed no significant changes at the completion of the training [IRT from 4.63 (SD 0.63) to 4.48 (SD 0.72), RRT from 4.47 (SD 0.75) to 4.24 (SD 0.80) mg · g−1 wet tissue] despite a significant decrease in citrate synthase activity [IRT from 5.27 (SD 1.45) to 4.49 (SD 1.48), RRT from 5.33 (SD 2.09) to 4.85 (SD 1.87) μmol · min−1 · g−1 wet tissue; P 〈 0.05] observed after both protocols. These results suggested that myoglobin and mitochondria enzymes were regulated by different mechanisms in response to either type of RT. Moreover, the maintained [Mb] in hypertrophied muscle should preserve oxygen transport from capillaries to mitochondria even when diffusion distance is increased.
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  • 141
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    European journal of applied physiology 80 (1999), S. 386-393 
    ISSN: 1439-6327
    Keywords: Key words Skeletal Muscle ; Human ; Force/velocity ; Fatigue ; Isokinetic testing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of the study was to obtain force/velocity relationships for electrically stimulated (80 Hz) human adductor pollicis muscle (n = 6) and to quantify the effects of fatigue. There are two major problems of studying human muscle in situ; the first is the contribution of the series elastic component, and the second is a loss of force consequent upon the extent of loaded shortening. These problems were tackled in two ways. Records obtained from isokinetic releases from maximal isometric tetani showed a late linear phase of force decline, and this was extrapolated back to the time of release to obtain measures of instantaneous force. This method gave usable data up to velocities of shortening equivalent to approximately one-third of maximal velocity. An alternative procedure (short activation, SA) allowed the muscle to begin shortening when isometric force reached a value that could be sustained during shortening (essentially an isotonic protocol). At low velocities both protocols gave very similar data (r 2 = 0.96), but for high velocities only the SA procedure could be used. Results obtained using the SA protocol in fresh muscle were compared to those for muscle that had been fatigued by 25 s of ischaemic isometric contractions, induced by electrical stimulation at the ulnar nerve. Fatigue resulted in a decrease of isometric force [to 69 (3)%], an increase in half-relaxation time [to 431 (10)%], and decreases in maximal shortening velocity [to 77 (8)%] and power [to 42 (5)%]. These are the first data for human skeletal muscle to show convincingly that during acute fatigue, power is reduced as a consequence of both the loss of force and slowing of the contractile speed.
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  • 142
    ISSN: 1439-6327
    Keywords: Key words Fatigue ; Movement ; Position ; Muscle ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have tested the hypothesis that agonist and antagonist muscle fatigue could affect the final position of rapid, discrete movements. Six subjects performed consecutive elbow flexion and extension movements between two targets, with their eyes closed prior to, and after fatiguing the elbow extensor muscles. The results demonstrate that elbow extension movements performed in the post-test period systematically undershot the final position as compared to pre-test movements. However, attainment of the aimed final position in elbow flexion movements was unaffected by fatiguing of the extensor muscles. Undershoot of the final position obtained in extension movements was associated with agonist muscle fatigue, a result that was expected from the point of view of current motor control theories, and that could be explained by a reduced ability of the shortening muscle to exert force. On the other hand, the absence of the expected overshoot of the final position when the antagonist is fatigued, indicates the involvement of various reflex and/or central mechanisms operating around the stretched muscle that could contribute to returning the limb to the standard final position after a brief prominent overshoot.
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  • 143
    ISSN: 1615-6102
    Keywords: Cumulus oophorus ; Ovarian follicle ; Fertilization ; Ultrastructure ; Immunocytochemistry ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The fine structure of the human cumulus oophorus has been reviewed on the basis of scanning and transmission electron microscopic observations as well as of immunofluorescence data. Tissues sampled from preovulatory ovarian follicles and cumulus-enclosed oocytes and fertilized eggs (collected from the oviduct or obtained during in vitro fertilization procedures) have been evaluated from a microtopographic and morphodynamic point of view in order to better clarify the possible role of this population of cells. In particular, the following aspects have been studied and discussed: the presence of multiple close contacts (modulated by the interposition of the zona pellucida) between the oocyte surface and the long microvillous evaginations projecting from the inner aspect of corona cells surface (through these structures the intraovarian cumulus oophorus may control oocyte growth and metabolism up until the time of ovulation); the occurrence of different subpopulations of cells (steroid-synthetic cells, cells producing adhesive proteins, leukocytes, macrophages) in the postovulatory, extraovarian cumulus oophorus surrounding oocytes, zygotes and early developing embryos. All these elements found in the cumulus mass may positively act, through their paracrine activities, on the chemical composition of the microenvironment in which fertilization occurs.
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  • 144
    ISSN: 1432-0878
    Keywords: Key words Cytokine ; ELISA ; FACScan ; Lipids ; Macrophage ; Monocyte ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Diabetes (type I and type II) affects approximately 13 million people in the United States. Delayed and incomplete healing of wounds can be a major problem for diabetic patients. Macrophages are an important cell in the complex process of wound repair representing the major source of cytokines throughout the wound-healing process. Cytokines mediate many of the cellular responses critical to timely wound repair. It has been suggested that diabetes impairs wound healing through disruption of local cytokine production. Our previous in vivo studies in rats demonstrated that diabetes-induced and diet-induced hyperlipidemia cause changes in macrophage phenotype and function (Iacopino 1995; Doxey et al. 1998), suggesting that alterations in macrophage cytokine profiles represent the cellular/molecular mechanism responsible for delayed wound healing. The purpose of this study was to investigate how monocyte maturation/differentiation and cytokine production were altered by serum lipids in an in vitro system using human cells. Commercially prepared purified human monocytes were cultured and exposed to serum lipids. Phenotypic analysis of differentiated macrophages was then performed by flow cytometry and fluorescent microscopy using surface antigens specific for various macrophage subsets. Selected cytokines in conditioned medium were assayed using commercial human enzyme-linked immunosorbent assay (ELISA) kits. We demonstrate that serum lipids cause an increase in monocytic differentiation leading to an inflammatory macrophage phenotype rather than a reparative/proliferative phenotype. We also show that serum lipids cause a generalized decrease in macrophage cytokine production using interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), platelet-derived growth factor (PDGF), and transforming growth factor beta 1 (TGF-β1) as marker cytokines. Our present in vitro results using human cells confirm our previous in vivo studies in the rat and support the hypothesis that diabetes-induced hyperlipidemia alters the monocyte differentiation process resulting in changes of macrophage subsets and cytokine release at the wound site, ultimately impairing the wound-healing process.
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  • 145
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    Cell & tissue research 295 (1999), S. 297-305 
    ISSN: 1432-0878
    Keywords: Key words Trophoblast ; Macrophages ; Placenta ; Cell culture ; Paracrine regulation ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract In view of the accumulating evidence for paracrine mechanisms regulating trophoblast function, we tested the hypothesis that placental macrophages affect trophoblast activity in a paracrine fashion. Trophoblast was isolated from 17 term placentas (–IP). One aliquot of cells was further immunopurified (+IP) using an HLA class I antibody. This increased the proportion of trophoblast (+IP 〉97%; –IP ∼70%) as identified by rigorous immunocytochemistry. Most (∼70%) non-trophoblast cells in –IP were macrophages. The cells were cultured for 5 days with a daily medium change. In addition, +IP cells from seven placentas were cultured with lipopolysaccharide (LPS)-stimulated or -unstimulated macrophage-conditioned media. The concentrations of lactate, trophoblast-specific hormones, human chorionic gonadotropin-β (hCG-β) and human placental lactogen (hPL), of several prostanoids and of endothelin-1 and angiotensin II were determined in the culture media. The accumulated amounts of substances released into the culture media, corrected for the greater proportion of trophoblast in +IP cultures, were on average two- to threefold higher (hCG-β: 18-fold) in +IP than in –IP, with the exception of endothelin-1,2 (no change), angiotensin II (–70%) and 6-keto-prostaglandin-F1α (–40%). [3H]leucine incorporation into the trichloroacetic acid (TCA)-precipitable pool measured on day 5 was twofold higher in +IP than in –IP. Addition of conditioned media reverted these changes. The data demonstrate that placental macrophages in culture affect trophoblast biosynthetic activity in a paracrine fashion. We conclude that macrophages are important regulators of trophoblast activity.
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  • 146
    ISSN: 1432-0878
    Keywords: Key words Interleukin-18 ; Hyperosmotic conditions ; Epithelial cells ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Interleukin-18 is a novel multifunctional cytokine, which enhances natural killer cell activity and promotes the induction of cytokine production, including that of interferon-γ by T cells and antitumor effects. Interleukin-18 is produced by cells of several different tissues (e.g., macrophages, keratinocytes, osteoblasts, and intestinal epithelium); however, it is unclear what physiological conditions or stimuli induce interleukin-18 production. To determine physiological conditions for the production of interleukin-18, we have examined the effect of mannitol-induced hyperosmotic conditions on normal human umbilical vein endothelial cells (HUVEC) and eight established human epithelial-like cell lines (Intestine 407, Caco-2, A253, HeLa, SCC25, HT1197, ACHN, A549). Hyperosmotic conditions induced interleukin-18 immunoreactivity in all the human cell lines tested, as detected by immunocytochemistry. The enhanced interleukin-18 production was also observed when mannitol was replaced with NaCl as the inducer of hyperosmotic stress. Enzyme-linked immunosorbent assays revealed that interleukin-18 concentrations in cell extracts were significantly increased by hyperosmotic conditions. Reporter gene assays also revealed that hyperosmotic conditions stimulated transcriptional activity of the interleukin-18 promoter. These results show for the first time that hyperosmotic stress is a stimulator of interleukin-18 production in epithelial-like cells.
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  • 147
    ISSN: 1573-6792
    Keywords: Magnetoencephalography ; Human ; Words ; Tones ; Cerebral dominance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The magnetic flux normal to the scalp surface was measured with a whole-head neuromagnetometer while right-handed subjects (N = 15) were engaged in either an auditory word- or a tone-recognition task. Sources of the recorded magnetic fields were modeled as equivalent current dipoles at 4 ms intervals and the number of sources in the later portion of the magnetic response was used as an index of the degree of brain activation. Significantly more sources were found in the left as compared to the right hemisphere in the word but not the tone task on a group basis. On an individual basis, 13/15 subjects had more sources in the left as compared to the right hemisphere during the word task, while in the tone task 3/10 subjects showed this pattern. Sources of activity were found in the left superior and middle temporal gyri in all subjects with available MRI scans. Sources were also found in the supramarginal gyrus and in medial temporal areas, including the hippocampus, in the majority of cases. MEG appears to be a promising tool for detecting activity in cerebral areas specialized for language and memory function.
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  • 148
    ISSN: 1573-6792
    Keywords: EEG ; Alpha activity ; Spatial segmentation techniques ; Wakefulness ; Sleep onset ; REM sleep ; Dream imagery ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Spontaneous alpha activity clearly present in relaxed wakefulness with closed eyes, drowsiness period at sleep onset, and REM sleep was studied with spatial segmentation methods in order to determine if the brain activation state would be modulating the alpha spatial microstates composition and duration. These methods of spatial segmentation show some advantages: i) they extract topographic descriptors independent of the chosen reference (reference-free methods), and ii) they achieve spatial data reduction that are more data-driven than dipole source analysis. The results obtained with this study revealed that alpha activity presented a different spatio-temporal pattern of brain electric fields in each arousal state used in this study. These differences were reflected in a) the mean duration of alpha microstates (longer in relaxed wakefulness than in drowsy period and REM sleep), b) the number of brain microstates contained in one second (drowsiness showed more different microstates than did relaxed wakefulness and REM state), and c) the number of different classes (more abundant in drowsiness than in the rest of brain states). If we assume that longer segments of stable brain activity imply a lesser amount of different information to process (as reflected by a higher stability of the brain generator), whereas shorter segments imply a higher number of brain microstates caused by more different steps of information processing, it is possible that the alpha activity appearing in the sleep onset period could be indexing the hypnagogic imagery self-generated by the sleeping brain, and a phasic event in the case of REM sleep. Probably, REM-alpha bursts are associated with a brain microstate change (such as sleep spindles), as demonstrated by its phasic intrusion in a desynchronized background of brain activity. On the other hand, alpha rhythm could be the “baseline” of brain activity when the sensory inputs are minimum and the state is relaxed wakefulness.
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  • 149
    ISSN: 1432-0878
    Keywords: Key words Vesicle protein ; Physin ; Secretory carrier-associated membrane protein ; Vesicle-associated membrane protein ; Synaptobrevin ; Expression ; Liver ; Bovine ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  The cell-type restricted expression of cytoplasmic microvesicle membrane protein isoforms may be a consequence of the functional adaptation of these vesicles to the execution of specialized processes in cells of different specialization. To characterize the expression of the vesicle protein pantophysin, an isoform of the synaptic vesicle proteins synaptophysin and synaptoporin, we have prepared and characterized antibodies useful for the immunological detection of pantophysin in vitro and in situ. Using these reagents, we show by immunoblot analyses that pantophysin expression is not homogeneous but differs significantly between various bovine tissues. Furthermore, these differences are not exactly paralleled by the expression of other vesicle proteins of the SCAMP (secretory carrier-associated membrane protein) and VAMP (vesicle-associated membrane protein) types that have previously been localized to pantophysin vesicles in cultured cells. By immunofluorescence microscopy, pantophysin expression is seen predominantly in non-neuroendocrine cells with pronounced membrane traffic. Pantophysin staining codistributes with SCAMP and VAMP immunoreactivities in most instances but differs in some. Remarkably, pantophysin staining in liver is restricted to cells surrounding sinusoids and is not detectable in hepatocytes, similar to that of the SCAMP and VAMP isoforms as detected by our reagents in tissue sections.
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  • 150
    ISSN: 1432-0878
    Keywords: Key words Apoptosis ; p53 ; Ischemia ; Enterocytes ; Proliferation ; Differentiation ; ISEL ; Glomeruli ; Mouse (Balb/c) ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Morphological changes associated with apoptosis are closely correlated with the expression of specific proteins. However, the cause-effect relationships between the expression of these proteins and DNA degradation are barely known. For studying expression of apoptosis-related proteins in relation to different degrees of DNA fragmentation, the small intestine with its spatially organized continuum of proliferation, differentiation and death is a very useful preparation. Enterocytes towards the apex of the villi become increasingly susceptible to apoptosis. Here, this ”apoptotic gradient” is used to demonstrate the presence of BAX and BCL-2 proteins in the cytoplasm of cells at the onset of apoptosis. In semithin serial sections of the small intestine, BAX, BCL-2 and DNA fragmentation were demonstrated. BAX and BCL-2 are always colocalized and only in cells with fragmented DNA. The gradient of BAX or BCL-2 staining is similar to the gradient of DNA fragmentation. Immunoreactivity for BCL-2 or BAX is most intense in cells that are prone to become apoptotic next in the course of cellular turnover but not in cells in an advanced apoptotic state, showing strongly condensed chromatin. When using the same technique on semithin sections of kidney biopsies, containing epithelia with low cellular turnover, we found DNA fragmentation mainly in the epithelial cells of the distal tubules. Similar to the situation in the enterocytes, BAX staining was confined to the cytoplasm of epithelial cells with a moderate degree of DNA fragmentation and reduced in epithelial cells with a high degree of DNA fragmentation. In contrast to the situation in the small intestine, very low levels of BCL-2 were found. The results suggest that expression of BCL-2 and BAX is related to cell damage as indicated by DNA fragmentation but not to advanced stages of cellular death, as indicated by chromatin condensation and cellular shrinkage.
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  • 151
    ISSN: 1432-0878
    Keywords: Key words Mammary gland ; Differentiation ; Neoplasia ; Homeodomain ; Cancer ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  In the mouse mammary gland, homeobox gene expression patterns suggest roles in development and neoplasia. In the human breast, we now identify a family of Iroquois-class (IRX) homeobox genes. One gene, IRX-2, is expressed in discrete epithelial cell lineages being found in ductal and lobular epithelium, but not in myoepithelium. Expression is absent from associated mesenchymal adipose stroma. During gland development, expression is concentrated in terminal end buds and terminal lobules and is reduced in a subset of epithelial cells during lactation. In contrast to observations for many homeobox genes in the mouse mammary gland in which homeobox gene expression is lost on neoplastic progression, IRX-2 expression is maintained in human mammary neoplasias. Data suggest IRX-2 functions in epithelial cell differentiation and demonstrate regulated expression during ductal and lobular proliferation as well as lactation.
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  • 152
    ISSN: 1432-0878
    Keywords: Key words Cultured epidermis ; Keratinocyte ; Epithelialization ; Wound healing ; Human ; Mouse (NMRI)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Sheets of cultured allogeneic human keratinocytes have been used for the treatment of burns and chronic leg ulcers but there has been no animal assay for the therapeutic action of these cultures. In order to analyze the effects of frozen cultures of human keratinocytes on wound healing, we have developed such an assay based on the rate of repair of full-thickness skin wounds in immunocompetent NMR1 mice. Reepithelialization of the control wounds, originating from the murine epithelium at the edge of the wound, occurred at a constant rate of advance of 150 µm/day. When frozen cultured human epidermal sheets were thawed at room temperature for 5–10 min and applied to the surface of the wound, the murine epithelium advanced at 267 µm/day. Most wounds treated with frozen cultures completely healed after 10 days, whereas most control wounds required 16 days. The accelerated reepithelialization did not depend on the presence of proliferative human keratinocytes in the frozen cultures. The cultures also promoted early formation of granulation tissue and laminin deposition over the surface of the wound bed. This simple assay should permit quantitative analysis of the effects on healing exerted not only by cultured cells, but also by proteins and small molecules.
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  • 153
    ISSN: 1615-2573
    Keywords: Smooth muscle cell ; Heterogeneity ; Coronary artery ; Human ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The arterial media is composed of a heterogeneous population of smooth muscle cells (SMCs). Recently, the properties of SMCs were observed to be heterogeneous not only among individual cells but also among arteries of the same vascular bed. To test the hypothesis that a site-specific heterogeneity exists in the SMCs of human coronary arteries, we examined the expression of desmin, vimentin, calponin, and high-molecular-weight (h-) caldesmon in arteries of various sizes. Specimens of arteries were obtained at autopsy from 12 patients: 6 adults (67 ± 4 years old); 3 younger adults (26 ± 2 years old); and 3 neonates. The size of the arteries was estimated by the number of SMC layers of the media. The expression was compared in SMCs of large arteries (〉10 layers in adults, 〉5 layers in neonates), medium-sized arteries (5–10 layers in adults, 3–5 SMC layers in neonates), and small arteries (〈3 layers). In adults, the percentage of arteries positive for desmin was lower in the small (17% ± 3%) and medium-sized arteries (44% ± 12%) than in the large arteries (94% ± 6%) (P 〈 0.01). The percentage of arteries positive for calponin was also lower in the small (18% ± 2%) and medium-sized arteries (66% ± 5%) than in the large arteries (100%) (P 〈 0.01). The percentage for vimentin and h-caldesmon did not differ among large, medium-sized, and small arteries. These observations in adults were similar to those in younger adults or neonates. The phenotypes of medial SMCs are vessel sizedependent in human coronary arteries. This finding should be important for understanding the site-specific characteristics of vascular function in the regulation of myocardial perfusion or those of vascular responses to environmental changes.
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  • 154
    ISSN: 1437-1596
    Keywords: Key words Poisoning ; Benfuracarb ; Carbofuran ; Human ; Blood ; Urine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Law
    Notes: Abstract We describe here three cases involving acute fatalities due to benfuracarb ingestion and the forensic toxicological implications. Benfuracarb, a carbamate insecticide and its main metabolite carbofuran, were detected using thin layer chromatography (TLC) and gas chromatography/mass spectrophotometry (GC/MS) after extraction with ethyl acetate and then quantified using gas chromatography (GC) equipped with NPD. The blood levels of benfuracarb and carbofuran were in the range of 0.30∼2.32 μg/ml and 1.45∼1.47 μg/ml, respectively. Benfuracarb was not detected in urine, but carbofuran was detected in the range of 0.53∼2.66 μg/ml.
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  • 155
    ISSN: 1432-0878
    Keywords: Key words Cerebrovascular development and injury ; Hemangioma ; Angiogenesis ; Immunocytochemistry ; Adhesion molecules ; Conventional transmission and high-voltage electron microscopy ; Mouse (C57BL ; SJL/J) ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Blood vessels from the vasculature of mouse brains during postnatal development and from human brain tumors (hemangiomas) removed at biopsy were examined immunocytochemically by transmission electron microscopy (TEM) or high-voltage transmission electron microscopy (HVEM) to determine the expression of intercellular adhesion molecule-1 (ICAM-1). In the mouse brains, ICAM-1 was shown to be initially expressed on the luminal and abluminal endothelial cell (EC) surfaces on day 3 after birth. ICAM-1 intensity increased on the luminal EC surfaces and labeled vesiculotubular profiles (VTS, defined in the present report) between days 5 and 7. After 2 weeks and at 6 months after birth, ICAM-1 labeling was weak or absent on the luminal EC surfaces. The hemangiomas presented a strong ICAM-1 reaction product on the luminal EC surfaces of small and large blood vessels associated with the VTS, with a weaker labeling of the abluminal or adventitial aspects of larger blood vessels. TEM of vesiculovacuolar structures (VVOs) within ECs from arteries and veins also demonstrated reaction product for ICAM-1 labeling. Three-dimensional stereo-pair images in the HVEM enhanced the visualization of gold particles that were attached to the inner-delimiting membrane surfaces of EC VTS, and VVOs, respectively. These observations raise the possibility that the neonatal leukocytes and tumor cells may utilize these endothelial structures as a route across the developing and injured blood-brain barrier (BBB).
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  • 156
    ISSN: 1432-0878
    Keywords: Key words Atherosclerosis ; Culture model ; Endothelial cell ; Endothelin-1 ; Oxidized LDL ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We investigated the structural and functional properties of human umbilical vein endothelial cells (HUVECs) cultured on a two-chamber culture model system using an amnion membrane. Compared to HUVECs cultured on a plastic dish, HUVECs cultured on the model system exhibited several features similar to those of in vivo vessels, including formation of the intercellular junctional devices and expression of tight junction-associated protein ZO-1 and adherence junction-associated protein α-catenin. Furthermore, we found that HUVECs had a property of polar secretion of endothelin-1 (ET-1). About 90% of the total amount of synthesized ET-1 was found in the lower well, designated as the basal side. When HUVECs were incubated with either native low-density lipoproteins (nLDLs) or oxidized LDLs (oxLDLs) at a concentration of 100 μg/ml, ET-1 secretion was significantly increased, dependent on the cell side (apical vs basal) on which the nLDLs or oxLDLs were loaded. When the LDLs were loaded on the apical side, the secretion of ET-1 from HUVECs on the apical side was increased by 48% (nLDL) and 61% (oxLDL), whereas it was accompanied by a concomitant decrease of ET-1 on the basal side (45% by nLDLs and 38% by oxLDLs). When loaded on the basal side, however, ET-1 was increased by 23% (nLDLs) and 53% (oxLDLs) on the basal side, with a 26% simultaneous decrease of ET-1 on the opposite side for both nLDLs and oxLDLs. On the contrary, high-density lipoproteins (HDLs) inhibited ET-1 secretion from HUVECs on the opposite side of the well on which HDLs were loaded; there was a 57% decrease on the basal side when HDLs were loaded on the apical side, and a 46% decrease on the apical side when loaded on the basal side. These results indicate that modulation of ET-1 secretion from ECs by lipoproteins is virtually dependent on the place (apical vs basal) where these proteins are present. The finding that nLDLs and oxLDLs enhance ET-1 secretion by ECs in a polarized pattern suggests that ET-1 may be involved in pathophysiological processes such as atherogenesis.
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  • 157
    ISSN: 1432-0878
    Keywords: Key words Endothelin ; Endothelin receptors ; Endothelin-converting enzyme ; Ovary ; In situ hybridization ; Human ; Cynomolgus monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The endothelin system is composed of three endothelin isoforms (ET-1, ET-2, and ET-3), the endothelin receptors ETA and ETB, and the endothelin-converting enzyme (ECE). Besides having a major vasoactive role, endothelins have roles in different cell types at a local level. We investigated the presence of the different components of the endothelin system in primate ovaries. Human ovaries and gonadotropin-stimulated monkey ovaries were studied using immunohistochemistry for endothelin, and in situ hybridization with probes for ET-1, ET-2, ET-3, ETA and ETB receptors, and ECE. ET-1 and ETA receptors were detected in endothelial cells and vascular smooth muscle cells, respectively, in stromal vessels adjacent to follicles and corpora lutea. ETB receptors and ET-1 were found in the endothelial cells of capillaries of corpora lutea. ECE was present in internal theca cells of secondary, de Graaf, atretic follicles, and in luteinized granulosa cells of the corpora lutea. The endothelin system components are present in or around the follicles of human and monkey ovaries. Although the components are not expressed in the same cell types, they are synthesized, mainly in follicles, by cells that are in close proximity. Thus, the endothelin system could act in a paracrine manner. ECE expression in steroid-producing cells changes its compartmentalization during follicle maturation.
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  • 158
    ISSN: 1432-0878
    Keywords: Key words α1-Microglobulin ; Bikunin ; Inter-α-trypsin inhibitor ; Mast cells ; Trypstatin ; Urinary trypsin inhibitor ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  We recently reported that the rat mast cell proteinase inhibitor trypstatin is genetically identical with the second half of inter-α-trypsin inhibitor light chain (ITI-LC), also known as bikunin or urinary trypsin inhibitor (UTI). In this study, therefore, immunoreactivities of mast cells of various human tissues were examined with three antibodies, anti-human ITI-LC, anti-ITI, which recognizes mainly heavy chains or the sugar moiety of ITI, and anti-α 1-microglobulin (α1mG). ITI-LC immunoreactivity was strongly found in mast cells in the connective tissues of various organs except for those of the propria mucosae of small intestine. Neither anti-ITI antibody nor anti-α1mG antibody reacted with mast cells in various tissues. By reverse transcription-polymerase chain reaction (RT-PCR) analysis, α1mG/ITI-LC mRNA was not detected in the skin and tongue, and only weakly in small intestine, although ITI-LC immunoreactivity was strongly detected in these tissues. Furthermore, the mRNA was not expressed in cultured human mast cells. These results suggest that ITI-LC protein is stored in the granules of human connective tissue mast cells, though is not produced by them.
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  • 159
    ISSN: 1432-0878
    Keywords: Key words Osteoblasts ; Extracellular matrix ; Transforming growth factor-β1 ; Basic fibroblast growth factor ; Apert’s syndrome ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  The phenotype of Apert osteoblasts differs from that of normal osteoblasts in the accumulation of macromolecules in the extracellular matrix. Apert osteoblasts increase type I collagen, fibronectin and glycosaminoglycans secretion compared with normal osteoblasts. Because the extracellular matrix macromolecule accumulation is greatly modulated by transforming growth factor-β1, we examined the ability of normal and Apert osteoblasts to secrete transforming growth factor-β1 by CCL-64 assay and to produce transforming growth factor-β1 by analysis of the mRNA expression of transforming growth factor-β1. Northern blot analysis revealed an increased amount of transforming growth factor-β1 mRNA expression in Apert osteoblasts compared with normal ones. Moreover, the level of the active transforming growth factor-β1 isoform was higher in Apert than in normal media. In pathologic cells, the increase in transforming growth factor-β1 gene expression was associated with a parallel increase in the factor secreted into the medium. The level of transforming growth factor-β1 was decreased by the addition of basic fibroblast growth factor. Transforming growth factor-β1 is controlled temporally and spatially during skeletal tissue development and produces complex stimulatory and inhibitory changes in osteoblast functions. We hypothesise that in vitro differences between normal and Apert osteoblasts may be correlated to different transforming growth factor-β1 cascade patterns, probably due to an altered balance between transforming growth factor-β1 and basic fibroblast growth factor.
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  • 160
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    Cell & tissue research 295 (1999), S. 151-158 
    ISSN: 1432-0878
    Keywords: Key words Class II MHC-positive cells ; Human leukocyte antigen-DR ; Dental pulp ; Dendritic cells ; Macrophages ; Ultrastructure ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The distribution and ultrastructure of class II major histocompatibility complex (MHC)-positive cells were investigated in human dental pulp, employing immunohistochemistry using an anti-human leukocyte antigen (HLA)-DR-monoclonal antibody. HLA-DR-immunopositive cells, appearing spindle-like or dendritic in profile, were densely distributed throughout the dental pulp. Under the electron microscope, these cells exhibited various sizes of vesicles containing clear or opaque contents, multivesicular bodies and characteristic fine tubulovesicular structures in their cytoplasm. Some reactive cells possessed coated pits and vesicles including electron-dense materials, indicating an active endocytosis. At the periphery of the pulp tissue, the HLA-DR-immunopositive cells were predominantly situated in the subodontoblastic layer, with some located in the odontoblast layer and/or predentin and extending their cytoplasmic processes into the dentinal tubules. Cell processes of these cells occasionally made contact with several odontoblast processes in the same way as the nerve fibers in the predentin. These cells never contained the typical phagosomes frequently observed in the HLA-DR-immunoreactive macrophages in the subodontoblastic layer and the pulp core. The results suggest that the HLA-DR-immunopositive cells in the odontoblast layer and/or predentin have some regulatory function on the odontoblasts under physiological conditions, in addition to their involvement in the initial defense reaction after tooth injury.
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  • 161
    ISSN: 1432-2307
    Keywords: Key words Monoclonal antibody ; Multidrug resistance ; P-Glycoprotein peptide ; Mouse ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A novel immunization protocol together with stringent selection criteria have been employed to generate a new murine monoclonal antibody (’’D8’’, isotype IgG1, kappa) which specifically recognizes the human p170 drug resistance glycoprotein. This antibody is directed towards a defined peptide sequence located in the −COOH terminal region of the first external loop of the molecule. It is reactive with its epitope within the intact native glycoprotein in formalin-fixed and conventionally processed histological tissues, in flow-cytometric preparations and by Western blotting. The antibody precipitates its target peptide sequence from solution, and thus may be a useful reagent with which to establish an ELISA, RIMA or other similar assay. The peptide epitope recognized by this monoclonal antibody is restricted to the human MDR1 gene product and is not contained within the rodent homologue of the P-170 molecule. Immunohistochemistry has consistently failed to detect this epitope in rodent tissues, thus confirming that it does not exhibit the cross-reactivity of other currently available anti-P-glycoprotein monoclonal antibodies. The experience of this study emphasizes the value of the tuberculin-PPD (purified protein derivative) immunization protocol as a powerful strategy when generating monoclonal antibodies to small synthetic peptides. The resulting monoclonal antibody (D8) will be an invaluable reagent with which to analyse P-170 glycoprotein expression when assessing the role of multidrug resistance in human cancers.
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  • 162
    ISSN: 1432-2277
    Keywords: Key words Liver transplantation ; Tacrolimus ; Human ; Child
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tacrolimus (FK506) is an effective and relatively safe novel immunosuppressant able to revert refractory rejection after pediatric liver transplantation (LTx). Between April 1993 and October 1996, 20 pediatric patients were converted to tacrolimus for biopsy-proven, steroid-resistant liver rejection. The mean follow-up was 18 months. The median time from LTx to switch was 20 days. Tacrolimus was administered per os at a mean dosage of 0.23 mg/kg per day to maintain median blood levels of 10.8 ng/ml at 1 week and 9.2 ng/ml at 1 year from the switch. Of the 20 patients, 15 are alive and they all recovered from rejection without the need of OKT3 after conversion. The major causes of death were: one multiorgan failure, two infections (cytomegalovirus Aspergillus), one bowel perforation, and one posttransplant lymphoproliferative disease. One patient experienced late side effects and was reconverted to cyclosporine when she was already rescued from hepatic allograft rejection. The results confirm that an earlier conversion to tacrolimus should be recommended after pediatric liver transplantation in order to revert hepatic allograft rejection with the best safety profile.
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  • 163
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    Immunogenetics 48 (1998), S. 312-323 
    ISSN: 1432-1211
    Keywords: Key words Recombination ; Gene conversion ; Allele ; MHC ; HLA ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Some alleles of the major histocompatibility complex (MHC) genes have a reticulate pattern of evolution, probably resulting from the exchange of segments by gene conversion or recombination. Here we compare the extent and patterns of reticulate evolution among the classical class I and class II loci of the human MHC using the recently developed compatibility and partition matrix methods. A complex pattern is revealed with substantial differences among loci in the extent and pattern of reticulation. Extremely high levels of reticulation are observed at HLA-B and HLA-DPB1, high levels at HLA-A and HLA-DRB1, moderate levels at HLA-C and HLA-DQB1, and low levels at HLA-DQA1. The reticulate events are concentrated in the exons encoding the highly variable, peptide-binding domains, suggesting that the sequence combinations produced by these events are maintained by natural selection.
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  • 164
    ISSN: 1432-0843
    Keywords: Key words Topoisomerase II ; Human ; Yeast ; Antitumour drugs ; Bisdioxopiperazine compounds ; ICRF-193
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To identify and characterize the specificity and potency of topoisomerase II-interacting antitumour drugs in an in vivo model utilizing the yeast Saccharomyces cerevisiae. Methods: Four yeast transformants were selected for the expression of either human or yeast DNA topoisomerase II at different, biologically relevant, levels under the tight control of promoters of various strengths. Results: Analyses of 24 drugs permitted their classification into three distinct groups, depending on whether they induced topoisomerase II-related cytotoxicity (etoposide), showed nonspecific cytotoxicity (camptothecin), or exerted no cytotoxicity at all (vinorelbine). Within the first group different patterns of action were distinguishable: (1) classical topoisomerase II expression-dependent cytotoxicity for both species of enzyme (e.g. etoposide, amsacrine, doxorubicin, actinomycin D), although amsacrine and TOP 53 were more active, respectively, on human and yeast topoisomerase II; and (2) compounds that appeared to poison only one species of topoisomerase II with, for example, genistein and the bisdioxopiperazine ICRF-193 lethally targeting only the human type, and mitoxantrone only the yeast isozyme. Three of the 16 known topoisomerase II inhibitors tested were not correctly identified with this assay, possibly owing to restricted cell wall permeability or to the absence of correct processing pathways such as, for example, in the case of the prodrug etopophos. Conclusion: This methodology, in vivo in yeast, selected for a large range of potent topoisomerase II-targeting anticancer agents. Of particular interest in this yeast model, and in contrast to yeast topoisomerase II, human topoisomerase II was shown to confer dominant sensitivity in the presence of the series of bisdioxopiperazine derivatives tested. This assay therefore has the potential easily to identify and characterize the potency and specificity of synthesized anticancer drugs with modified original chemical structures or those present, for example, in natural plant extracts or marine organisms.
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  • 165
    ISSN: 1432-0533
    Keywords: Key words Autoantibody ; Ganglioside ; Guillain-Barré ; Human ; Neuropathy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A series of monoclonal IgM anti-GM1 ganglioside antibodies has been cloned from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain-Barré syndrome. In solid-phase immunoassay, the antibodies react with GM1, and also in differing degrees to the structurally related glycolipids asialo-GM1 (GA1) and GD1b. Here we describe the binding patterns of six human anti-GM1 antibodies to epitopes within the human nervous system. Antibodies were observed to bind to motor neurons and spinal grey matter, dorsal and ventral spinal roots, dorsal root ganglion neurons, nodes of Ranvier, neuromuscular junctions and skeletal muscle. The distribution of immunoreactive epitopes, which included sensory structures, extended beyond those sites conventionally regarded as pathologically affected in anti-GM1 antibody-associated motor nerve syndromes. This undermines a model of disease pathogenesis based solely on antigen distribution. Factors other than the presence or absence of antigen, such as the local ganglioside topography, antibody penetration into, and pathophysiological vulnerability of a particular site may also influence the clinicopathological outcome of anti-GM1 antibody-mediated autoimmune attack.
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  • 166
    ISSN: 1432-0533
    Keywords: Key words B-50(GAP-43) ; Spinal cord ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract B-50(GAP-43) is a phosphoprotein mainly found in the nervous system which plays a major role in neurite growth during development and regeneration as well as in synaptic remodelling. In the mature intact central nervous system, intense B-50 immunoreactivity (B-50-IR) can still be detected in regions which maintain residual capacity for structural re-organization. B-50 expression has been studied extensively in laboratory animals; however, its distribution and regulation in the human spinal cord is largely unknown. As a first step to analyze lesion-induced structural alterations, we investigated the distribution of B-50 protein and mRNA in the normal adult human spinal cord and dorsal root ganglia. Intense B-50-IR was localized to the superficial laminae of the dorsal horn at all segmental levels, the intermediolateral nucleus at thoracic levels and Onuf’s nucleus at sacral levels. Scattered neurons, particularly in the ventral horn of lumbar and sacral segmental levels (and occasionally also in Clarke’s nucleus) displayed intense B-50-IR in close apposition to the perikaryal and proximal dendritic surfaces. Nonradioactive in situ hybridization indicated that B-50 mRNA could also be detected in neurons of the ventral horn and also in the intermediolateral nucleus. The distribution of B-50 mRNA and protein in the normal human spinal cord shows a marked similarity to that reported in experimental animals, including the selective labelling of Onuf’s nucleus. However, the strong B-50-IR on the surface of some large anterior horn motor neurons has not been observed in other mammals. This finding might reflect a particular state of readiness for synaptic plasticity.
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  • 167
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    Acta neuropathologica 96 (1998), S. 22-28 
    ISSN: 1432-0533
    Keywords: Key words Cerebral arteries ; Human ; Immunohistochemistry ; Vasa vasorum ; Atherosclerosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Vasa vasorum are adventitial vessels that play a role in pathogenesis of atherosclerosis, aneurysm, vasculitides, and graft vascular disease. The existence of vasa vasorum in human intracranial arteries is not yet well defined. The specific aims of this study are to determine whether the human intracranial arteries have vasa vasorum, whether their existence is related to the thickness of tunica media as is in systemic vessels, and whether they are acquired in reaction to pathological conditions, such as atherosclerosis and arterial occlusion. Human intracranial internal carotid (i-ICA), vertebral (i-VA), basilar (BA) and middle cerebral arteries (MCA) from adults, children and newborns were examined. Systemic vessels of comparable medial thickness were used as controls. Immunohistochemical staining for Factor VIII and CD 31 was used to identify the endothelial cells. Human intracranial arteries in neonates, children and adults do not have vasa vasorum, although their medial thickness is comparable to their systemic counterparts with vasa vasorum. Only in adults did the proximal intracranial segments of i-ICA and i-VA reveal a few vasa vasorum-like vessels with unusually large diameter. They were more frequently seen in atherosclerosis and thrombotic but again limited to the proximal segments of i-ICA and i-VA. Completely obstructed bilateral carotid arteries in a child with sickle cell disorder revealed a rich adventitial neovascularization in the proximal intracranial part of the vessel. It is not yet known whether obstruction of the distal segments may create similar neovascularizations. Adventitial neovascularizations seen in the proximal i-ICA and i-VA may represent a focal intracranial extension of the vascular pathologies involving the extracranial segments of major cerebral arteries.
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  • 168
    ISSN: 1432-0533
    Keywords: Key words Non-astrocytic brain tumors ; p53 mutation ; Yeast functional assay ; Malignant lymphoma ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract While it is established that p53 mutation plays a critical role in the carcinogenesis of astrocytic brain tumors, its role remains to be clarified for other types of tumors in the central nervous system (CNS). Using a yeast-based assay which tests the ability of human p53 to activate transcription, we analyzed p53 mutations in 85 non-astrocytic CNS tumors, including 4 benign neuronal tumors (3 central neurocytomas and 1 pineocytoma), 12 primitive neuroectodermal tumors, 14 germ cell tumors (7 germinomas, 7 non-germinomatous tumors), 4 craniopharyngiomas, 14 ependymomas, 22 schwannomas, 10 primary brain lymphomas in immunocompetent patients, and 5 bone tumors of the skull. The only tumors found to contain p53 mutations were 3 malignant lymphomas. The presence of mutations in these cases was confirmed by DNA sequencing. Given the high accuracy and sensitivity of the yeast assay and previous negative results using conventional techniques, this indicates that p53 mutation is a rare event in non-astrocytic CNS tumor types examined here.
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  • 169
    ISSN: 1432-0533
    Keywords: Key words Cytochrome c oxidase ; Fibre type ; Human ; Immunohistochemistry ; Myalgia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Muscular changes in male forest machine operators with work-related neck and shoulder myalgia were studied. Enzyme cyto- and immunohistochemical analysis was carried on muscle biopsies obtained from ten myalgic subjects (M), nine non-myalgic selected in the same work place (NM) and six healthy young men (C). The M group displayed a significant increase in type IIA fibres in comparison to the C group. This hypertrophy was accompanied by a parallel increase in the capillary bed. Both the M and NM groups exhibited an increase in fibres with a disorganised mitochondrial pattern. Interestingly, fibres lacking cytochrome c oxidase occurred in the M group (0.9%) but also in the NM group (0.5%), suggesting a mitochondrial defect. Central nuclei (5.2%) and developmental myosin (3%) were also more frequent in the M group. These changes are probably related to injury-regeneration cycles. These data support the association between the work conditions and muscle changes in work-related trapezius myalgia.
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  • 170
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    European spine journal 7 (1998), S. 66-68 
    ISSN: 1432-0932
    Keywords: Key words Autopsy ; Cadaver ; Cervical vertebrae ; Human ; Laboratory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cadaveric osseoligamentous lower cervical spines (C2-C7) are often used in the investigation of spinal biomechanics in vitro. Surprisingly, however, the techniques of harvesting at postmortem and preparation of cadaveric osseoligamentous lower cervical spine for biomechanical testing have not been described in detail. We describe a simple and effective method that can be readily integrated into the routine autopsy procedure. Points on the avoidance of disfiguring the cadaver and damaging the spinal osseoligamentous structures are highlighted.
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  • 171
    ISSN: 1432-1041
    Keywords: Key words CYP2D6 ; Genetic polymorphism ; Metoprolol ; Pharmacokinetics ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Aim: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians. Methods: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared. Each formulation contained 200 mg metoprolol tartrate/(tablet). In each of the three periods of the trial, one of the formulations was administered under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the last dose and in selected time intervals thereafter. A sensitive and specific high-performance liquid chromatography (HPLC) method with fluorescence detection was applied for the quantification of metoprolol. Pharmacokinetic parameters were determined for each subject and statistically compared in two groups of 16 homozygous (CYP2D6*1/CYP2D6*1) and six heterozygous (CYP2D6*1/CYP2D6*4) volunteers. Results: Significant differences between homozygous and heterozygous individuals were observed for all pharmacokinetic parameters. The AUC in the course of one those interval of 24 h (AUCτ), minium steady-state concentration (Cmin ss) and average steady-state concentration (Cav ss) values for heterozygous individuals were more than twice those of individuals. Significantly higher values for Css max , t1/2, half-value duration (HVD) and mean residence time (MRT) were also observed in heterozygous volunteers. The higher concentrations of metoprolol in heterozygous individuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction.
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  • 172
    ISSN: 1432-1106
    Keywords: Key words Cerebellar patients ; Double-step paradigm ; Pointing movement ; Kinematic analysis ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Three patients with cerebellar limb ataxia and three age-matched controls performed arm-pointing movements towards a visual stimulus during an experimental procedure using a double-step paradigm in a three-dimensional space. Four types of trajectories were defined: P1, single-step pointing movement towards the visual stimulus in the initial position S1; P2, double-step pointing movement towards S1; P3, double-step straight pointing movement towards the second position S2; and P4, double-step pointing movement towards S2 with an initial direction towards S1. We found that the cerebellar patients, as well as the controls, were able to modify their motor programs, but with impaired timing, severe anomalies in the direction and amplitude of the changed movement trajectories and alteration of the precision of the pointing movements.
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  • 173
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    Experimental brain research 119 (1998), S. 467-474 
    ISSN: 1432-1106
    Keywords: Key words Aging ; Feedback ; Vision ; Program control ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Young and elderly subjects performed aiming movements to a visual target with a manipulandum to determine whether the elderly reduce their reliance on visual feedback after extended practice. Reliance on visual feedback was assessed by performance on trials in which the cursor displaying arm movement was unpredictably extinguished. Movements were divided into two subcomponents: a primary, ballistic submovement and a secondary, corrective submovement. For both age groups, removal of visual feedback prior to practice resulted in a decrease in the distance covered in the primary submovement, an increase in the distance of the secondary submovement, and a decrease in endpoint accuracy. After extensive practice with the cursor present, the proportion of distance traveled with the primary submovement was again assessed under trial conditions in which the cursor randomly disappeared. Following practice, the young demonstrated that they were capable of extending the primary submovement distance closer to the target. In addition, primary submovement distance was unaffected by the removal of vision following practice. After practice the elderly did not show evidence of lengthening the primary submovement, and submovement distance and endpoint accuracy continued to be altered by the removal of vision. This suggests that, unlike the young, the elderly do not benefit from practice so that they can place a greater proportion of the movement under program control. Thus, on a relative basis, a greater proportion of their overall movement requires corrective adjustments.
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  • 174
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    Experimental brain research 119 (1998), S. 475-482 
    ISSN: 1432-1106
    Keywords: Key words Proprioception ; Eye position ; Botulinum toxin ; Strabismus ; Palisade ending ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Botulinum toxin is sometimes injected into human eye muscles as an alternative to surgery in the correction of strabismus. Within minutes of botulinum injections into ungulate eye muscles, proprioceptive discharge from muscle spindles decreases dramatically. It is only over 7–48 h, however, that surgically treated strabismus patients usually show an altered proprioceptive signal about eye position, presumably from the palisade endings attached to the global multiply innervated fibers. How quickly will botulinum toxin alter proprioceptive registration of eye position in humans? First, to examine the short-term effects, we measured open-loop pointing responses (which requires knowledge of eye position) in six strabismus patients preinjection and then over a 45 min postinjection period, and in six normal controls over the same time period. Second, to examine the long-term effects, 13 strabismus patients were tested preinjection and then daily over the next 3 weeks, and three normal controls over the same time period. We compared their open-loop pointing responses with the injected eye fixating the target to the photographically determined position of the occluded other eye (a measure of where the patient would point if eye position were determined by efference, not proprioception). There were three groups of patients: esotropes with no previous injection, exotropes with no previous injection, and exotropes with previous injection. First, all patients showed significant correction of their tropias. Second, over the short-term, there was no difference in pointing responses found between the patients and the controls (t(18) = –1.427, P = 0.1706). Third, over the long-term, however, the difference between the pointing responses and eye position information was compared among the four groups across four posttests and a significant difference found (F 3,12 = 58.988, P 〈 0.00001). Only in patients with no previous injections was there altered proprioceptive feedback about eye position. Also, injections into the medial rectus induced a significantly greater proprioceptive response than those injected into the lateral rectus. In humans, botulinum toxin alters proprioception from eye muscles only over the long-term. We suggest that the toxin temporarily affects proprioceptive feedback from palisade endings.
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  • 175
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    Experimental brain research 119 (1998), S. 483-492 
    ISSN: 1432-1106
    Keywords: Key words Cerebellar ataxia ; Limb movement ; Multijoint movement ; Kinematics ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Kinematic abnormalities of fast multijoint movements in cerebellar ataxia include abnormally increased curvature of hand trajectories and an increased hand path and are thought to originate from an impairment in generating appropriate levels of muscle torques to support normal coordination between shoulder and elbow joints. Such a mechanism predicts that kinematic abnormalities are pronounced when fast movements are performed and large muscular torques are required. Experimental evidence that systematically explores the effects of increasing movement velocities on movement kinematics in cerebellar multijoint movements is limited and to some extent contradictory. We, therefore, investigated angular and hand kinematics of natural multijoint pointing movements in patients with cerebellar degenerative disorders and healthy controls. Subjects performed self-paced vertical pointing movements with their right arms at three different target velocities. Limb movements were recorded in three-dimensional space using a two-camera infrared tracking system. Differences between patients and healthy subjects were most prominent when the subjects performed fast movements. Peak hand acceleration and deceleration were similar to normals during slow and moderate velocity movements but were smaller for fast movements. While altering movement velocities had little or no effect on the length of the hand path and angular motion of elbow and shoulder joints in normal subjects, the patients exhibited overshooting motions (hypermetria) of the hand and at both joints as movement velocity increased. Hypermetria at one joint always accompanied hypermetria at the neighboring joint. Peak elbow angular deceleration was markedly delayed in patients compared with normals. Other temporal movement variables such as the relative timing of shoulder and elbow joint motion onsets were normal in patients. Kinematic abnormalities of multijoint arm movements in cerebellar ataxia include hypermetria at both the elbow and the shoulder joint and, as a consequence, irregular and enlarged paths of the hand, and they are marked with fast but not with slow movements. Our findings suggest that kinematic movement abnormalities that characterize cerebellar limb ataxia are related to an impairment in scaling movement variables such as joint acceleration and deceleration normally with movement speed. Most likely, increased hand paths and decomposition of movement during slow movements, as described earlier, result from compensatory mechanisms the patients may employ if maximum movement accuracy is required.
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  • 176
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    Experimental brain research 118 (1998), S. 533-540 
    ISSN: 1432-1106
    Keywords: Key words Otolith ; Utricle ; Linear acceleration ; Vestibulo-ocular reflex ; Vestibular compensation ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We studied horizontal eye movements evoked by lateral whole body translation in nine patients who underwent vestibular nerve section. Preoperatively, all had preserved caloric function on both sides. Testing was performed before, 1 week and 6–10 weeks after surgery. Patients were seated upright in an electrically powered car running on a linear track. The car executed acceleration steps of 0.24 g, randomly to the left and right in the dark. The normal response consisted of a bidirectionally symmetrical nystagmus with compensatory slow phases. Response asymmetry of the slow-phase velocity of the desaccaded and averaged eye position signal was less than 13% in normals (n = 21). Before surgery, patients’ responses were mostly symmetrical. Postoperatively, responses were diminished or absent with head acceleration towards the operated ear in all patients, causing a marked asymmetry which averaged 56% after correction for spontaneous nystagmus. On follow-up, responses regained symmetry. Thus, early after vestibular nerve section, a single utricle produces a normal LVOR only with ipsilateral head translation. Therefore, afferents for the LVOR seem to originate from the mid-lateral area of the macula, where hair cells are stimulated in their on-direction during ipsilateral head translation. Compensation may depend on recovery of the off-directional responses from lateral hair cells of the remaining utricle.
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  • 177
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    Experimental brain research 118 (1998), S. 541-550 
    ISSN: 1432-1106
    Keywords: Key words Balance ; Auditory information ; Vision ; Blindness ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  This study assessed whether stationary auditory information could affect body and head sway (as does visual and haptic information) in sighted and congenitally blind people. Two speakers, one placed adjacent to each ear, significantly stabilized center-of-foot-pressure sway in a tandem Romberg stance, while neither a single speaker in front of subjects nor a head-mounted sonar device reduced center-of-pressure sway. Center-of-pressure sway was reduced to the same level in the two-speaker condition for sighted and blind subjects. Both groups also evidenced reduced head sway in the two-speaker condition, although blind subjects’ head sway was significantly larger than that of sighted subjects. The advantage of the two-speaker condition was probably attributable to the nature of distance compared with directional auditory information. The results rule out a deficit model of spatial hearing in blind people and are consistent with one version of a compensation model. Analysis of maximum cross-correlations between center-of-pressure and head sway, and associated time lags suggest that blind and sighted people may use different sensorimotor strategies to achieve stability.
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  • 178
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    Experimental brain research 118 (1998), S. 564-568 
    ISSN: 1432-1106
    Keywords: Key words Laser stimulation ; Nociceptive afferents ; Jaw-opening reflex ; Trigeminal nuclei ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  CO2 laser pulses selectively excite A-δ and C mechano-thermal nociceptors in the superficial layers of the skin. To study the jaw-opening reflex elicited by a purely nociceptive input, we delivered laser pulses to the perioral region in 15 subjects. Sensory threshold was very low (9 mJ/mm2). High-intensity noxious laser pulses (more than 4 × sensory threshold) evoked a single phase of electromyogram suppression (laser silent period, LSP) at an onset latency of 70 ms in the contracted masseter and temporal muscles, bilaterally. Even maximum-intensity laser pulses failed to activate the suprahyoid muscles. The recovery curves to paired laser stimuli showed that at short interstimulus intervals the test LSP was strongly suppressed. At about 380 ms it recovered to 50%, i.e. its recovery curve resembled that of the masseter late silent period after electrical mental nerve stimulation (SP2). In experiments studying the interaction with heterotopic stimuli and non-nociceptive responses, chin-taps or electrical shocks delivered to the supraorbital, infraorbital or mental nerves before laser stimulation strongly suppressed the LSP. A preceding perioral laser pulse strongly suppressed the masseter SP evoked by supraorbital stimulation and the SP2 evoked by mental stimulation, but left SP1 unaffected. We conclude that the perioral A-δ fibre input elicits a jaw-opening reflex simply by inhibiting the jaw-closers. The LSP response is mediated by a multisynaptic chain of brainstem interneurons and shares with the masseter SP2 part of the central circuit in the ponto-medullary region. We also propose that a common centre processes the various inputs for jaw opening.
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  • 179
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    Experimental brain research 119 (1998), S. 9-16 
    ISSN: 1432-1106
    Keywords: Key words Hand posture ; Prehension ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  This paper describes the transport and grasp kinematic parameters associated with four initial hand postures (palm flat and thumb against the hand, palm flat and thumb extended laterally, index and thumb in opposition, and index and thumb in opposition and elbow flexed 90°). A group of healthy adult subjects reached for and picked up a wooden dowel placed midsagittally, at one of three distances (20 cm, 25 cm and 30 cm). The initial posture of the hand and arm altered transport (peak velocity and peak negative acceleration) as well as grasp (peak angle and time to peak angle) parameters, particularly when the elbow was flexed 90°. The pattern of results was reproduced in a pointing paradigm. The findings are discussed in the context of joint space models of reaching.
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  • 180
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    Experimental brain research 119 (1998), S. 27-38 
    ISSN: 1432-1106
    Keywords: Key words Short-term synchronization ; First dorsal interosseous ; Motor cortex ; Muscle usage patterns ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We examined motor unit (MU) discharge properties (mean interspike interval, ISI, discharge variability, short-term synchronization, common drive) and force tremor in the first dorsal interosseous (FDI) muscle of five musicians (skill-trained), five weight-lifters (strength-trained) and six untrained subjects during low-force isometric abduction of the index finger. Mean MU ISI was slightly shorter in skill-trained subjects than in untrained subjects. Discharge variability of FDI MUs did not differ significantly between groups. The mean strength of MU synchronization (expressed as the frequency of extra synchronous discharges above chance) was different in skill-trained (0.22±0.02 s–1, 162 MU pairs), untrained (0.32±0.02 s–1, 199 MU pairs) and strength-trained subjects (0.44±0.03 s–1, 183 MU pairs). FDI MU synchrony was weak and of equivalent strength in both hands of skill-trained subjects and the dominant (skilled) hand of untrained subjects. The stronger FDI MU synchrony in the non-dominant hand of untrained subjects was equivalent to that found in both hands of strength-trained subjects. The extent of common modulation of firing rates (common drive) was assessed for a subset of MU pairs and was weaker in skill-trained subjects (0.30±0.04, n=14) than untrained (0.43±0.3, n=14) and strength-trained (0.48±0.03, n=21) subjects. Force tremor was quantified for each hand in the same subjects during isometric index finger abduction at target forces of 0.5 N and 3.5 N. Tremor rms amplitude and peak power in the force frequency spectrum were significantly lower in skill-trained subjects than strength-trained subjects with the 3.5-N target force. The peak tremor frequency was similar in the three groups. The relatively more independent discharge of pairs of FDI MUs in skill-trained subjects was not responsible for the reduced tremor amplitudes in these subjects. Correlations between the overall extent of MU synchrony and common drive in FDI muscles and tremor measures obtained during the same experimental session were all non-significant. Differences in the central descending command signals are the most likely explanation for the more independent discharge of FDI MUs in skill-trained hands, while neural or peripheral muscular factors may be responsible for the weaker tremor.
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  • 181
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    Experimental brain research 120 (1998), S. 129-133 
    ISSN: 1432-1106
    Keywords: Key words Eye movements ; Smooth pursuit ; Prediction ; Motor memory ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Anticipatory smooth pursuit before the expected appearance of a moving target can reduce the initial retinal blur caused by the 100-ms delay of visual feedback. Humans, though, can only voluntarily generate smooth velocities up to about 5°/s without a moving target. However, previous experiments have shown that repetitive brief presentations of a moving target every few seconds appear to charge an internal store, the contents of which can later be released to generate higher velocity anticipatory movements. This store’s longevity was assessed here by repetitively presenting a moving target for 500 ms at different known intervals up to 7.2 s. Target motion at 25°/s or 50°/s was tested, with presentations in alternate directions or the same direction. Anticipatory velocity, measured 100 ms after target onset, decreased with increasing interval for all target motion conditions. A decrease was still seen when accurate timing cues were given before each presentation, suggesting that the drive for anticipatory pursuit is held in a short-term store lasting a few seconds which can enhance the low velocities produced by volition alone. The results also demonstrate that high-velocity anticipatory pursuit helps to overcome the temporal delays in the system and allows target velocity to be matched at an earlier time.
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  • 182
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    Keywords: Key words Orthotic gait ; Paraplegia ; Electromyography ; Locomotion ; Spinal stepping generator ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We examined the lower-limb electromyographic (EMG) activity from a patient with clinically complete spinal cord injury during orthotic gait. A newly developed gait orthosis was used to obtain bipedal locomotion. The surface EMG data during the gait together with the biomechanical variables were collected by way of a radio EMG system. A cyclic EMG activation pattern corresponding to the gait cycles were observed in each of the paralyzed lower-limb muscles during the orthotic gait. Although the EMG activation did not seem to contribute toward generating the gait, it showed some similarities to that of the infant stepping or immature gait. These results might be regarded as one of the indirect pieces of evidence that suggest the existence of a spinally originating motor mechanism underlying human locomotion.
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  • 183
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    Keywords: Key words Locomotion ; Slip ; Dynamic equilibrium ; Interlimb coordination ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Studies on the proactive control of gait have shown that proximal (hip/trunk) muscles are the primary contributors to balance control, while studies on reactive balance control during perturbed gait, examining only activity in distal (leg/thigh) muscles, have shown that these muscles are important in compensating for a gait disturbance. This study tested the hypothesis that proximal muscles are also primary contributors to reactive balance control during perturbed gait. Thirty-three young adults participated in a study in which an anterior slip was simulated at heel strike by the forward displacement of a force plate on which they walked. Surface electromyographic data were recorded from bilateral leg, thigh, hip and trunk muscles. Kinematic data were collected on joint angle changes in response to the perturbation. The results did not support the hypothesis that the proximal muscles contribute significantly to balance control during perturbed gait. The proximal muscles did not demonstrate more consistent activation, earlier onset latency, longer burst duration or larger burst magnitude than distal muscles. Moreover, although proximal postural activity was often present in the first slip trial, it tended to adapt away in later trials. By contrast, the typical postural responses exhibited by young adults consisted of an early (90–140 ms), high-magnitude (4–9 times muscle activity during normal walking) and relatively long duration (70–200 ms) activation of bilateral anterior leg muscles as well as the anterior and posterior thigh muscles. Thus, postural activity from bilateral leg and thigh muscles and the coordination between the two lower extremities were the key to reactive balance control and were sufficient for regaining balance within one gait cycle. The adaptive attenuation of proximal postural activity over repeated trials suggests that the nervous system overcompensates for a novel balance threat in the first slip trial and fine-tunes its responses with experience.
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  • 184
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    Keywords: Key words G proteins ; Intractable epilepsy ; Immunoelectrophoresis ; Cytoarchitecture ; Gliosis ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The relative levels of guanine nucleotide-binding protein α-subunits Gi1α, Gi2α, Gi3α, Goα, Gsα, and Gx/zα were measured in neocortex removed at surgery from patients with intractable temporal lobe epilepsy. Immunoreactivity was quantified using specific polyclonal antisera against the Gα-subunits according to the Laurell “rocket” immunoelectrophoresis technique. We compared the G protein contents of spiking (active) and nonspiking (nonactive) cortical regions, based on intraoperative electrocorticography, within the same and different patients. There were no clear trends for lower or higher levels of G-protein subtypes to be found in the samples of protein extracts from nonspiking regions as compared to spiking regions. However, comparison of paired samples of spiking and nonspiking cortex within the same patient demonstrated that levels of certain G-protein subtypes were either increased or decreased in all patients. This indicates that cortical regions with enhanced neuronal activity may produce microzonal alterations in the levels of G proteins. Moreover, our results suggest that high levels of Gi1α and low levels of the other G-protein subtypes appear to be associated with a greater susceptibility to maintaining spiking activity.
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    Experimental brain research 119 (1998), S. 171-178 
    ISSN: 1432-1106
    Keywords: Key words Rapid body sway ; Leg muscle activity ; EMG pattern ; Ischemic nerve block ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Electromyographic (EMG) patterns of leg muscles associated with rapid body sway were studied in relation to displacement of the center of foot pressure (CFP). Standing subjects were instructed to shift the CFP by swaying their bodies, pivoting at the ankle as rapidly and accurately as possible after an auditory signal. CFP position was designated as N when the subject maintained a relaxed bending posture and as F when a maximally forward-leaning posture was maintained. A serial, stereotyped triphasic EMG pattern was observed in the rapid shift of CFP from N to F: cessation of EMG activity in the gastrocnemius (GC) muscle was followed by a burst in the tibialis anterior (TA) muscle (acceleration phase), and then resumed discharge occurred in the GC muscle with cessation of activity in the TA muscle (deceleration and stop). When the subject shifted the CFP from N to F to different degrees, the duration and amount of EMG activity in the TA muscle during acceleration and the GC muscle in deceleration were proportionate to the amount of CFP displacement associated with forward body sway. To determine the functional roles of sensory inputs from the foot on the triphasic EMG pattern, body sway was studied under the condition of sensory block in the feet induced by ischemia from tourniquets placed bilaterally just above the ankle joints. The triphasic EMG pattern persisted during ischemia. The time of GC cessation and the onset of TA burst at acceleration remained unchanged, but the times of TA cessation and resumption of GC discharge at deceleration were altered during ischemia. Moreover, subjects were unable to stop at F and eventually fell. These results indicate that both amount and duration of EMG activity associated with rapid body sway are functions of the amount of CFP displacement. Somatic sensation from the feet is important for control of burst and cessation timing and duration in leg muscle activity.
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  • 186
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    Experimental brain research 122 (1998), S. 367-377 
    ISSN: 1432-1106
    Keywords: Key words Proprioception ; Hand position sense ; Joint angle ; Visual localization ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The purpose of this study was to determine the precision of proprioceptive localization of the hand in humans. We derived spatial probability distributions which describe the precision of localization on the basis of three different sources of information: proprioceptive information about the left hand, proprioceptive information about the right hand, and visual information. In the experiment subjects were seated at a table and had to perform three different position-matching tasks. In each task, the position of a target and the position of an indicator were available in a different combination of two of these three sources of information. From the spatial distributions of indicated positions in these three conditions, we derived spatial probability distributions for proprioceptive localization of the two hands and for visual localization. For proprioception we found that localization in the radial direction with respect to the shoulder is more precise than localization in the azimuthal direction. The distributions for proprioceptive localization also suggest that hand positions closer to the shoulder are localized more precisely than positions further away. These patterns can be understood from the geometry of the arm. In addition, the variability in the indicated positions suggests that the shoulder and elbow angles are known to the central nervous system with a precision of 0.6–1.1°. This is a considerably better precision than the values reported in studies on perception of these angles. This implies that joint angles, or quantities equivalent to them, are represented in the central nervous system more precisely than they are consciously perceived. For visual localization we found that localization in the azimuthal direction with respect to the cyclopean eye is more precise than localization in the radial direction. The precision of the perception of visual direction is of the order of 0.2–0.6°.
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  • 187
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    Keywords: Key words Intracortical inhibitory circuits ; Brain stimulation ; Motor cortex ; descending volleys ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A magnetic transcranial conditioning stimulus given over the motor cortex at intensities below threshold for obtaining electromyographical (EMG) responses in active hand muscles can suppress responses evoked in the same muscles at rest by a suprathreshold magnetic test stimulus given 1–5 ms later. In order to define the mechanism of this inhibitory effect, we recorded descending volleys produced by single and paired magnetic transcranial stimulation of motor cortex through high cervical, epidural electrodes implanted for pain relief in two conscious subjects with no abnormality of the central nervous system. The conditioning stimulus evoked no recognisable descending activity in the spinal cord, whilst the test stimulus evoked 3–4 waves of activity (I-waves). Conditioning stimulation suppressed the size of both the descending spinal cord volleys and the EMG responses evoked by the test stimulus. Inhibition of the descending spinal volleys was most pronounced at ISI 1 ms and had disappeared by ISI 5 ms. It was evident for all components following the I1-wave, while the I1-wave itself was not inhibited at all. We conclude that a small conditioning magnetic stimulus can suppress the excitability of human motor cortex, probably by activating local cortico-cortical inhibitory circuits.
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  • 188
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    Experimental brain research 119 (1998), S. 276-286 
    ISSN: 1432-1106
    Keywords: Key words Hand ; Finger forces ; Force sharing ; Motor redundancy ; Voluntary movement ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this study was to test Bernstein’s idea that motor synergies provide solutions to the motor redundancy problem. Forces produced by individual fingers of one hand were recorded in one-, two-, three-, and four-finger tasks. The subjects (n=10) were asked to produce maximal total force (maximal voluntary contraction, MVC) and to match a ramp total force profile using different combinations of fingers. We found that individual finger forces were smaller in multifinger MVC tasks than in single-finger tasks. The deficit increased with the number of fingers involved. A saturation effect was observed: when several effectors were involved, adding a new effector did not significantly change the total force output. The data confirmed the idea that the central neural drive arriving at the level of synergies has a certain limit, a ceiling, that cannot be exceeded. The central nervous system cannot maximally activate the muscles serving all the fingers at the same time. Secondly, during the course of ramp trials, forces produced by individual fingers were linearly related to each other. Hence, a force sharing pattern was established at the beginning of the trial and did not change during the ramp period. A hypothesis is suggested that force distribution among fingers may be organized so as to minimize unnecessary rotational moment with respect to the functional longitudinal axis of the hand. Finally, in the four-finger trials, variance of the total maximal force output in ten consecutive attempts was smaller than the sum of variances of the maximal individual finger forces. The finding suggests that the control system of the motor tasks studied involves at least two levels, a central neural drive level and a synergy level. At the synergy level, an intercompensation in individual finger force production is observed.
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  • 189
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    Experimental brain research 119 (1998), S. 307-314 
    ISSN: 1432-1106
    Keywords: Key words Tilt ; Otolith organs ; Vestibular system ; Perception ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Head tilt is a rotation of the head relative to gravity, as exemplified by head roll or pitch from the natural upright orientation. Tilt stimulates both the otolith organs, owing to shifts in gravitational orientation, and the semicircular canals in response to head rotation, which in turn drive a variety of behavioral and perceptual responses. Studies of tilt perception typically have not adequately isolated otolith and canal inputs or their dynamic contributions. True tilt cannot readily dissociate otolith from canal influences. Alternatively, centrifugation generates centripetal accelerations that simulate tilt, but still entails a rotatory (canal) stimulus during important periods of the stimulus profiles. We reevaluated the perception of head tilt in humans, but limited the stimulus to linear forces alone, thus isolating the influence of otolith inputs. This was accomplished by employing a centrifugation technique with a variable-radius spinning sled. This allowed us to accelerate the sled to a constant angular velocity (128°/s), with the subject centered, and then apply dynamic centripetal accelerations after all rotatory perceptions were extinguished. These stimuli were presented in the subjects’ naso-occipital axis by translating the subjects 50 cm eccentrically either forward or backward. Centripetal accelerations were thus induced (0.25 g), which combined with gravity to yield a dynamically shifting gravitoinertial force simulating pitch-tilt, but without actually rotating the head. A magnitude-estimation task was employed to characterize the dynamic perception of pitch-tilt. Tilt perception responded sluggishly to linear acceleration, typically reaching a peak after 10–30 s. Tilt perception also displayed an adaptation phenomenon. Adaptation was manifested as a per-stimulus decline in perceived tilt during prolonged stimulation and a reversal aftereffect upon return to zero acceleration (i.e., recentering the subject). We conclude that otolith inputs can produce tilt perception in the absence of canal stimulation, and that this perception is subject to an adaptation phenomenon and low-pass filtering of its otolith input.
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    Experimental brain research 123 (1998), S. 346-350 
    ISSN: 1432-1106
    Keywords: Key words Prehension ; Trunk ; Spatial coordination ; Human ; Motor control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To understand the internal representations used by the nervous system to coordinate multijoint movements, we examined the coordination among the body segments during reach-to-grasp movements which involve grasping by the hand and reaching by the arm and trunk. Subjects were asked to reach and grasp an object using the arm only, the trunk only, and some combinations of both arm and trunk. Results showed that kinematic parameters related to the transport component of the arm and the trunk, such as peak velocity and time to peak velocity, varied across conditions and that the coordination pattern between the arm and trunk was different across conditions. However, parameters related to the grasp component, such as peak aperture, time to peak aperture, and closing distance, were invariant, regardless of whether the hand was delivered to the target by the arm only, the trunk only, or both. We hypothesize that a hierarchy of motor control processes exists, in which the reach and grasp components are governed by independent neuromotor synergies, which in turn are coordinated temporally and spatially by a higher-level synergy.
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    Experimental brain research 121 (1998), S. 223-229 
    ISSN: 1432-1106
    Keywords: Key words Interlimb coordination ; Inertial load ; Human ; Motor control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Two-limb coordination of homologous and non-homologous effectors was examined during isofrequency (1:1) and multifrequency (2:1) conditions. The coordination patterns involved flexion and extension movements in the sagittal plane and were performed under unloaded and single-limb (right arm) loaded conditions. Previous studies suggested that the lower degree of 1:1 synchronization observed during nonhomologous as compared to homologous coordination results from natural differences in biophysical (inertial) properties. Elaborating on this idea, adding weight to the right arm was hypothesized to modulate its inertial characteristics, rendering homologous limbs more dissimilar and nonhomologous limbs more similar by enhancing and decreasing their inertial differences, respectively. Therefore, the observations made during unloaded conditions were predicted to be completely reversed during loaded conditions. Findings revealed that during 1:1 coordination (experiment 1) single-limb loading resulted in a decreased relative phase stability, whereas relative phase accuracy depended upon the limb combination. In particular, phase-locking was more accurately maintained for loaded homologous than for nonhomologous limbs, whereas loading the nonhomologous limbs resulted in a deterioration of the quality of synchronization. These findings suggest that there is an additional explanation of differential coordination capabilities among limb combinations. It is hypothesized that the neural networks subserving the control centers of the homologous limbs are more tightly connected than those of the nonhomologous effectors, allowing 1:1 synchronization to be more successfully preserved in the face of (load) perturbations. During 2:1 coordination (experiment 2), the loading procedure disturbed the coordination dynamics across all limb combinations. That no differential effect of loading on effector combination was observed is possibly a result of the fact that only an initial level of practice was studied in which optimal relative phase dynamics are still being explored for both homologous and nonhomologous limbs.
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  • 192
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    Keywords: Key words Experimental muscle pain ; H-reflex ; M-response ; Jaw muscles ; Trigeminal reflexes ; Motoneuron excitability ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Muscle pain generally has an inhibitory effect on voluntary orofacial motor function. However, it is not known whether muscle pain causes direct or indirect changes in motoneuron excitability. In this study a monopolar needle stimulation technique was used to evoke the direct motor response (M-response) in the left masseter muscle and the heteronymous H-reflex in the left temporalis muscle as an indirect measure of motoneuron excitability. Series of 20 repeated electrical stimuli were delivered at 50% of maximal voluntary contraction (MVC) before, during, and after periods with experimental jaw-muscle pain in 11 healthy subjects. Pain was induced by standardized infusion of hypertonic (5%) saline into the mid-portion of the right masseter muscle. The mean pain intensity rating on a 100-mm visual analog scale was 42±5 mm. The short-latency responses (less than 6 ms) could be evoked in all subjects. Analysis of the latency and amplitude of the temporal H-reflex indicated no significant effect of jaw-muscle pain. The amplitude of the masseteric M-response was significantly smaller in the postpain condition than in the pain conditions (ANOVA, P=0.018), but no differences were found between the prepain and postpain conditions. In nine subjects, poststimulus periods (mean offset latency, 69.6±8.6 ms) with significantly (more than 50%) suppressed EMG activity were detected in the ipsilateral masseter muscle following the M-response (mean offset latency, 5.5±0.2 ms). These reflex responses did not show a systematic change during the pain conditions. In conclusion, acute contralateral jaw-muscle pain does not seem to modulate the motoneuron excitability as measured by the heteronymous H-reflex.
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  • 193
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    Keywords: Key words Adaptive plasticity ; Behavioral sparing ; Extrastriate cortex ; Transsynaptic labeling ; Monkey ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We used anterograde and retrograde transsynaptic pathway tracing techniques to reveal the retinal origin and the cortical termination of the expanded retino-geniculo-middle suprasylvian (MS) cortex pathway in adult cats which sustained lesions of areas 17 and 18 on the day of birth (P1) or at 1 month of age (P28). Following anterograde transsynaptic transport of tritiated amino acids from the eye, four major results were obtained: (1) a strong and specific pathway from retina through dorsal lateral geniculate nucleus (dLGN) to the posterior half of MS cortex was identified; this pathway is a substantial expansion of an insignificant pathway present in intact cats; (2) the terminus of the pathway was lower layer III and layer IV; (3) contralateral projections were stronger than ipsilateral projections; (4) projections in P28 cats were stronger than those in P1 cats. Following retrograde transsynaptic transport of WGA-HRP from posterior MS cortex, four additional results were obtained: (1) the pathway was enlarged and visuotopically organized; (2) the pathway arose primarily from α- and γ-retinal ganglion cells; (3) a small number of β-cells in P1 cats and a modest number in P28 cats also contribute to the pathway; (4) the combined numbers of γ- and β-cells relative to α-cells was greater in temporal retina than in nasal retina. The combined demonstration of both origin and terminus of the pathway with transsynaptic tracers argued strongly for high levels of coupling between primary and secondary pathway limbs in both P1 and P28 cats. This level of coupling, as well as other features of the pathway, have much in common with the retino-geniculo-17/18 pathway of intact cats. However, the retino-geniculo-MS system in P1 cats transmits primarily Y and W signals, in P28 cats X, Y, and W signals; whereas the retino-geniculo-17/18 pathway transmits primarily X and Y signals. These results have implications for understanding the repercussions of early visual cortex lesions in monkeys and humans.
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  • 194
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    Experimental brain research 118 (1998), S. 19-26 
    ISSN: 1432-1106
    Keywords: Key words Visual system ; Transcranial magnetic brain stimulation ; Visual field defect ; Phosphenes ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Transient visual field defects (VFDs) and phosphenes were induced in normal volunteers by means of transcranial magnetic stimulation (TMS) using a circular magnetic coil of 12.5 cm diameter placed with its lower rim 2–4 cm above the inion in the midline. Subjects had to detect small, bright dots presented randomly for 14 ms in one of 60 locations on a computer screen resulting in a plot of the central 9° of the visual field. In 8 of 17 subjects, transient VFDs were inducible at peak magnetic field strenghts of 1.1–1.4 T. In the central 1–3°, detection of targets was impaired in both the upper and lower visual field, whereas at 4–9° large parts of only the lower visual field were affected with a sharp cut-off along the horizontal meridian. Targets at 1° in the lower field were affected with lower TMS intensities than corresponding locations in the upper or peripheral locations in the lower field. Detection of central targets was affected at more caudal stimulation sites than detection of peripheral targets. Phosphenes were elicitable in 14 of 17 subjects at clearly lower field strengths of 0.6–1.0 T. Many subjects perceived chromatophosphenes. From a discussion of the literature on patients with VFDs and the known topography of the human visual system, it is concluded that the transient VFDs at 1–3° are probably due to stimulation of both striate cortex (V1) and extrastriate areas (V2/V3), while VFDs in the lower visual field at eccentricities 4–9° are due to stimulation of V2/V3 but not V1.
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  • 195
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    Keywords: Key words Electromyogram ; Movement ; Elbow ; Wrist ; Ankle ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Studies of rapid, single degree-of-freedom movements have shown different changes in electromyographic patterns for movement tasks that appear very similar (e.g., movements over different ranges of distance). However, it is not clear whether these differences are a result of joint-specific control schemes or whether they are instead due to the limited range of task parameters studied relative to the mechanical constraints of each joint (e.g., short compared with long movements relative to the range of motion of a particular joint). In this study, we measured and compared the kinematic trajectories and electromyograms recorded during various movement tasks at the wrist, elbow, and ankle. Subjects performed movements over a wide range of distances “as fast as possible,”“at a comfortable speed,” and against two inertial loads (at the elbow only), and they performed movements over a fixed distance at three different speeds at the wrist and ankle. For fast movements we show that, in spite of some joint-specific differences, the basic pattern of electromyographic (EMG) modulation is similar at all three joints; for example, the agonist EMG burst transitions from a fixed duration to an increasing duration with increasing movement distance at all three joints. Moreover, the distance at which this transition occurs in one joint relative to the distance at which this transition occurs in the other two joints is consistent across subjects. The transition occurs at the shortest distance at the ankle and the longest distance at the wrist. In general we suggest that the data are consistent with a single set of control rules applied at all three joints, with the biomechanical constraints at each joint accounting for the differences in the EMG and kinematic patterns observed across joints.
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  • 196
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    Experimental brain research 118 (1998), S. 52-60 
    ISSN: 1432-1106
    Keywords: Key words Affect ; Limbic system ; Cognition ; Functional imaging ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Investigations of pain using functional imaging techniques have revealed an extensive central network associated with nociception. This network includes the thalamus, insula, prefrontal cortex and anterior cingulate cortex (ACC) as well as the somatosensory cortices. Positron emission tomography (PET) of regional cerebral blood flow (rCBF) has demonstrated activation of the ACC during cognitively challenging tasks such as the Stroop interference task and divided attention. One interpretation of this research is that ACC is involved in the general features of attention and that it does not play a specific role in pain processing per se. Three-dimensional PET imaging provides a method for assessments of rCBF in a single individual during multiple tasks. In addition, coregistration of PET and magnetic resonance (MR) images allows for better localisation of the PET signals so that differences in cortical activation sites can be more accurately determined. This approach was used to assess rCBF during the experience of pain by subtracting images collected during heat from those during noxious heat stimulation. Two regions of the ACC had elevated rCBF, one in the perigenual region and one in the mid-rostrocaudal region (i.e. midcingulate cortex). During the execution of the Stroop task, the group result showed the midcingulate region overlapping with the site seen during the experience of pain. This group result, however, was not confirmed in the individual subject analysis, which revealed widespread and independent areas of ACC response to pain and Stroop. It is concluded that the ACC contributes to multiple cognitive procedures. It is inadequate to describe the primary contribution of ACC to pain processing as “attention” because it is unlikely that the multiple small and independent activation sites produced by pain and Stroop subserve attentive processing throughout the brain.
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  • 197
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    Experimental brain research 118 (1998), S. 105-110 
    ISSN: 1432-1106
    Keywords: Key words Motor control ; Hand muscles ; Stretch reflex ; Gating ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The reflex responses to brisk, ramp stretch perturbations of the human flexor pollicis longus muscle (FPL) were recorded during isometric and slow concentric or eccentric contractions at similar levels of muscle excitation. The subjects flexed their thumb to push down against a thumb-rest, whose position was controlled by a servo-controlled motor. In different runs, the stretch perturbations were imposed when the thumb-rest was stationary (isometric) or was flexing or extending the interphalangeal joint of the thumb at a constant velocity, i.e. during concentric or eccentric contractions of FPL. The latency of the most prominent component of the electromyographic reflex in the isometrically contracting muscle was about 60 ms, measured from the command signal. The amplitude of this response was sharply reduced during the non-isometric contractions. While not dependent on the direction, this modulation of the reflex response increased with the speed of active movement of the interphalangeal joint (flexion or extension). The response was greatly reduced during concentric or eccentric movements as slow as 1.6 mm·s–1 (approximately 5°·s–1 at the joint). When the force rather than the position of the thumb-rest was servo-controlled, the stretch response to perturbation again diminished with speed in a self-paced flexion task, compared with an isometric “hold” condition.
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  • 198
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    Experimental brain research 118 (1998), S. 131-134 
    ISSN: 1432-1106
    Keywords: Key words Touch ; Finger ; Spatial perception ; Texture ; Hyperacuity ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We investigated intermanual transfer and long-term retention of practice-related perceptual learning in the domain of tactile hyperacuity. Subjects discriminated a row of three dots in which the central dot was offset laterally from a row without such offset. Performance at the right index fingerpad improved with practice. Practice effects transferred essentially completely to the left index fingerpad. When tested some months later at the right index fingerpad, long-term retention of learning was limited and further practice was required to stabilize discrimination thresholds. Intermanual transfer of tactile learning appears to be a general phenomenon, while long-term retention appears to be limited in hyperacuity tasks.
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  • 199
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    Experimental brain research 118 (1998), S. 221-229 
    ISSN: 1432-1106
    Keywords: Key words Express saccades ; Gap effect ; Auditory saccades ; Fixation disengagement ; Attentional disengagement ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Latencies of eye movements to peripheral targets are reduced when there is a short delay (typically 200 ms) between the offset of a central visual fixation point and the target onset. This has been termed the gap effect. In addition, some subjects, usually with practice, exhibit a separate population of very short latency saccades, called express saccades. Both these phenomena have been attributed to disengagement of visual attention when the fixation point is extinguished. A competing theory of the gap effect attributes it to disengagement of oculomotor fixation during the temporal gap. It is known that auditory targets are effective in eliciting saccadic eye movements, and also that covert attention operates in the auditory modality. If the gap effect and express saccades are due to disengagement of spatial attention, both should persist in the auditory modality. However, fixation of gaze is largely under visual control. If the gap effect results from disengagement of fixation, then at least a reduced effect should be seen in the auditory modality. Human subjects performed the gap task and a control task in the dark, using auditory fixation points and saccadic targets, on five successive days. Despite this practice, express saccades were not observed. There was a reliable gap effect, but the reduction in saccadic latency was only 17 ms, compared with 32 ms for the same subjects in the visual modality. This suggests that about half the gap effect is due to disengagement of visual fixation. The remainder was not due to non-specific warning effects and could be attributed to offset of the auditory fixation stimulus.
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  • 200
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    Experimental brain research 118 (1998), S. 352-360 
    ISSN: 1432-1106
    Keywords: Key words Attention ; Inhibition of return ; Crossmodal ; Orienting ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  It is currently controversial whether auditory events produce inhibition of return (IOR). Although some authors argue that this can arise, others propose that peripheral auditory cues do not produce the characteristic IOR pattern of delayed detection latencies for ipsilaterally presented auditory or visual targets, unless a saccade is made to the cued location. We suggest that these previous discrepancies may depend on whether attention is reoriented centrally following the peripheral sound. We presented spatially uninformative peripheral auditory cues prior to visual targets requiring speeded detection responses. IOR was found in the absence of eye movements, provided an auditory reorienting event was presented at central fixation between onset of the peripheral cue and the subsequent target, but not when the central reorienting event was visual. A subsequent experiment demonstrated that auditory IOR between successive targets is similarly significantly reduced in the absence of an appropriate central reorienting event. These results imply that auditory stimuli can induce IOR directly. Previous failures to demonstrate IOR following auditory cues may have been due to an opposing influence of long-lasting attentional facilitation at the cued location, rather than to the putative inability of auditory stimuli to engage oculomotor processes generating IOR.
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