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Biomedical subjects

N Mai

Publications and source records attributed to N Mai.

At least 19 recordsLinked to original sources
PubMed2005

Evidence for a multivalent interaction of symmetrical, N-linked, lidocaine dimers with voltage-gated Na+ channels.

The interaction of symmetrical lidocaine dimers with voltage-gated Na+ channels (VGSCs) was examined using a FLIPR membrane potential assay and voltage-clamp. The dimers, in which the tertiary amines of the lidocaine moieties are linked by an alkylene chain (two to six methylene units), inhibited VGSC activator-evoked depolarization of cells heterologously-expressing rat (r) Na(v)1.2a, human (h) Na(v)1.5, and rNa(v)1.8, with potencies 10- to 100-fold higher than lidocaine (compound 1). The rank order of potency (C4 (compound 4) > C3 (compound 3) > or = C2 (compound 2) = C5 (compound 5) = C6 (compound 6) >> compound 1) was similar at each VGSC. Compound 4 exhibited strong use-dependent inhibition of hNa(v)1.5 with pIC50 values < 4.5 and 6.0 for tonic and phasic block, respectively. Coincubation with local anesthetics but not tetrodotoxin attenuated compound 4-mediated inhibition of hNa(v)1.5. These data suggest that the compound 4 binding site(s) is identical, or allosterically coupled, to the local anesthetic receptor. The dissociation rate of the dimers from hNa(v)1.5 was dependent upon the linker length, with a rank order of compound 1 > compound 5 = compound 6 > compound 2 >> compound 3. The observation that both the potency and dissociation rate of the dimers was dependent upon linker length is consistent with a multivalent interaction at VGSCs. hNa(v)1.5 VGSCs did not recover from inhibition by compound 4. However, "chase" with free local anesthetic site inhibitors increased the rate of dissociation of compound 4. Together, these data support the hypothesis that compound 4 simultaneously occupies two binding sites on VGSCs, both of which can be bound by known local anesthetic site inhibitors.

Anesthetics, Local↗
PubMed2005

Quantitative evaluation of mirror movements in adults with focal brain lesions.

Mirror movements (MM), involuntary movements of homologous muscles opposite to unilateral limb activity, decrease in the course of motor development, but may reappear in adults after brain damage. To better characterize this type of acquired MM, grip forces of 36 healthy subjects and 35 patients suffering from focal brain lesions were compared. Holding force transducers in a pinch grip between thumb and index fingers of each hand, subjects had to repeatedly change the grip force in one hand, whilst the other (mirror) hand just had to prevent the manipulandum from dropping. In a second task, force changes had to be produced either in a symmetric or in an antiparallel manner. No significant group differences between patients and controls in the extent of coupling were found. During unimanual squeezing, only six patients had a co-activation in the pathologic range. Whilst performing bimanual asymmetric grip force changes, pathologic coupling was seen only in five patients. No association was found between the presence of pathologic MM and clinical or neuroanatomical features. Brain lesions in adults seem only rarely to be associated with pathologic MM. They might be non-specific and not related to the characteristics of the lesion.

Adolescent↗
PubMed2004

The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo.

1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity. 2 Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. 3 Tegaserod (0.1-3 microm) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the guinea-pig isolated colon (mean pEC50=8.3). 4 Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(-1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of alpha-methyl 5-HT (0.03 mg kg(-1)) and BW 723C86 (0.3 mg kg(-1)), selective 5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(-1) subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs. 5 The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concentrations similar to those that activate 5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clinical profile.

Animals↗
PubMed2004

Comparison of the pharmacological properties of rat Na(V)1.8 with rat Na(V)1.2a and human Na(V)1.5 voltage-gated sodium channel subtypes using a membrane potential sensitive dye and FLIPR.

A novel, membrane potential sensitive dye and a fluorescence imaging plate reader (FLIPR) have been used to characterize the pharmacological properties of rat Na(v)1.8 voltage-gated sodium channels (VGSC) in parallel with rat Na(v)1.2a and human Na(v)1.5 VGSC subtypes, respectively. The sensitivity of recombinant Na(v)1.2a-CHO, Na(v)1.5-293-EBNA, and Na(v)1.8-F-11 cells to VGSC activators was subtype dependent. Veratridine evoked depolarization of Na(v)1.2a-CHO and Na(v)1.5-293-EBNA cells with pEC(50) values of 4.78 +/- 0.13 and 4.84 +/- 0.12, respectively (n = 3), but had negligible effect on Na(v)1.8-F-11 cells (pEC(50) < 4.5). Type I pyrethroids were without significant effect at all subtypes. In contrast, the type II pyrethroids deltamethrin and fenvalerate evoked direct depolarization of Na(v)1.8-F-11 and Na(v)1.5-293-EBNA cells. Deltamethrin potentiated the veratridine-evoked response in Na(v)1.8-F-11 cells by > or =20-fold, in contrast to a <or =3-fold potentiation of the response in Na(v)1.2a, and Na(v)1.5 cells. Tetrodotoxin (TTX) inhibited VGSC activator-evoked depolarization of Na(v)1.8-F-11 cells with a biphasic concentration-response curve. The calculated pIC(50) values were 8.05 +/- 0.25 (n = 4) and 4.32 +/- 0.21 (n = 4), corresponding to TTX inhibition of endogenous TTX-sensitive (TTX-S), and recombinant Na(v)1.8 TTX-resistant (TTX-R) VGSCs, respectively. With the exception of TTX, the potencies of a number of ion channel blockers for the Na(v)1.8, Na(v)1.2a, and Na(v)1.5 VGSC subtypes were similar. In summary, these high-throughput FLIPR assays represent a valuable tool for the determination of the relative potencies of compounds at different VGSC subtypes and may prove useful for the identification of novel subtype-selective inhibitors.

Animals↗
PubMed2001

Is writer's cramp caused by a deficit of sensorimotor integration?

Writer's cramp is a highly specific movement disorder in which handwriting is impaired while most other manual skills are often unaffected. On the basis of abnormal findings in experiments measuring the control of grip forces, it has been suggested that writer's cramp is caused by a deficit of sensorimotor integration. The aim of our study was to determine whether there is a functional link between sensory deficits, abnormalities in the control of grip force, and handwriting disorders. We compared the grip force and handwriting performance of writer's cramp patients with that of control subjects and with that of a stroke patient suffering a purely somatosensory deficit of his dominant hand (patient S1). We found that: (1) writer's cramp patients and patient S1 had elevated grip-force levels; (2) training reduced the grip force to near-normal levels in all writer's cramp patients but not in S1; (3) effortful writing performance also induced increased grip-force levels in healthy subjects; and (4) patient S1 had normal handwriting movements. These findings suggest that the elevated pretraining gripforce levels of writer's cramp patients might be a consequence of their effortful writing style and do not reflect a deficit of sensorimotor integration. Moreover, the good handwriting performance of patient S1 shows that a severe somatosensory deficit is not a sufficient condition for a handwriting disorder. These findings disagree with the sensorimotor explanation of writer's cramp.

Adult↗
PubMed2001

The effects of digital anaesthesia on predictive grip force adjustments during vertical movements of a grasped object.

Grip force adjustments to fluctuations of inertial loads induced by vertical arm movements with a grasped object were analysed during normal and impaired finger sensibility. Normally grip force is modulated in a highly economical way in parallel with fluctuations of load force. Two subjects performed vertical up and down movements of a grasped object, both with normal finger sensibility and then cutaneously anaesthetized finger sensibility. Short breaks were taken in between single movements, during which the object was held stationary. After digital anaesthesia was applied to the grasping fingers, both subjects substantially increased the grip force. The grip force amplitude and timing still anticipated changes in load force, although the established grip force had already overcome movement-induced load force peaks. This implies that the increase of grip force and consequently the elevated force ratio between maximum grip and maximum load force are not processed to alter the feedforward system of grip force control. Cutaneous afferent information from the grasping digits appears to be necessary for economic scaling of the grip force level, but it plays a subordinate role in the precise anticipatory temporal coupling of grip and load forces during voluntary object manipulation.

Adult↗
PubMed2001

Effects of changing gravity on anticipatory grip force control during point-to-point movements of a hand-held object.

We investigated the quality of predictive grip force control during gravity changes induced by parabolic flight maneuvers. During these maneuvers gravity varied: There were 2 periods of hypergravity, in which terrestrial gravity nearly doubled, and a 20-s period of microgravity, during which a manipulated object was virtually weightless. We determined grip and load forces during vertical point-to-point movements of an instrumented object. Point-to-point movements were a combination of static (stationary holding) and dynamic (continuous movements) task conditions, which were separately analyzed in our previous studies. Analysis of the produced grip forces revealed that grip adjustments were closely linked to load force fluctuations under each gravity condition. In particular, grip force maxima coincided closely in time with load force peaks, although these occurred at different phases of the movement depending on the gravity level. However, quantitative analysis of the ratio of maximum grip force to the corresponding load force peak revealed an increased force ratio during microgravity when compared to that during normal and hypergravity. We hypothesize that the impaired precision of force coupling with respect to force magnitude during microgravity results from reduced feedback information about the object's mass during the stationary holding of the object in between each movement. The results indicate that the temporal grip force regulation is highly automatized and stable, whereas economical planning of force magnitude is more flexible and might reflect changes of the external loading condition.

Adaptation, Physiological↗
PubMed2000

A system for the study of visuomotor coordination during reaching for moving targets.

Prehensile behavior is a popular task in current research on human motor control. Most studies on reaching used stationary target objects and, therefore, most models do not address the challenges the motor system must respond to when reaching for moving objects. The machines used in earlier studies to produce object motion offered a limited range of trajectories and restricted control over various movement parameters. We have developed a device that allows a great variety of object trajectories along a flat-table surface and gives the experimenter full control over all movement parameters. A linear positioning system is used to move a sled beneath the table surface. Magnetic coupling transfers the sled's movement to the target object on the tabletop. This arrangement allows fast movements of the object (up to 5 m/s) and at the same time protects subjects from any harm due to the moving parts. The system is connected to LC shutter glasses, a 3-D movement registration device, and a switch that detects the onset of hand motion. This allows the selective withdrawal of vision during the reaching task or the introduction of changes in the object motion depending on the subject's reactions.

Electronic Data Processing↗
PubMed2000

Learning to write letters: transfer in automated movements indicates modularity of motor programs in human subjects.

Many automatic movements are open-loop, feed-forward motor programs (MP) that are kinematically well characterized by smooth speed and acceleration curves. However, it is unclear whether their internal representation consists of monolithic blocks or subroutines. This question was investigated using a learning paradigm of a writing task. Fifty-nine normal subjects were presented with two similar, but different new letters. Every subject practiced each letter in a series of 60 trials, with the order of letter series randomized. Every session was continuously recorded by a digitizing tablet. Using kinematic analysis, we measured the number of vertical acceleration peaks as an indication of the number of corrective movements (COM). Since COM declined as automatization was approached, we could quantitatively infer progress in motor learning under natural learning conditions. In the case of modular storage of MP, transfer in-between letters was expected due to the re-use of pre-learned motor subroutines. Statistical analysis showed that the exponential model described the data much better than the linear model (residual error: P<0.88 and P<0.00001, respectively), as expected for a learning paradigm. There was no difference between letters per se (P<0.77). Motor improvement differed significantly (P<0.02) between the first and the second series; there was a much greater reduction of COM in the second series (50.1 vs. 41.1%). This difference can be logically ascribed to transfer, indicating that automated movements are stored in motor subroutines.

Biomechanical Phenomena↗
PubMed2000

The DYT1 GAG deletion is infrequent in sporadic and familial writer' s cramp.

A 3-base pair (GAG) deletion in the DYT1 gene has recently been found to be responsible for most cases of early-onset primary generalized dystonia. In some cases, this mutation has been associated with writer's cramp. To determine the frequency of this mutation in a larger series of patients, we examined 44 index patients with sporadic or familial (seven patients) writer's cramp for the presence of the DYT1 GAG deletion, including eight patients with segmental dystonia involving at least one upper limb. We found the mutation in none of these index patients, which confirms that isolated writer's cramp is only in rare cases a phenotypic manifestation of this mutation, even if a positive family history of writer's cramp is present.

Adult↗
PubMed2000

Moving weightless objects. Grip force control during microgravity.

When we move grasped objects, our grip force precisely anticipates gravitational and inertial loads. We analysed the control of grip forces during very substantial load changes induced by parabolic flights. During these flight manoeuvres, the gravity varies between hypergravity associated with a doubling of normal terrestrial gravity and a 20-s period of microgravity. Accordingly, the contribution of the object's weight to the load changed from being twice the normal value to being absent. Two subjects continuously performed vertical and horizontal movements of an object equipped with grip force and acceleration sensors. Whereas, during vertical movements performed under normal and hypergravity, a load force maximum occurred at the lower turning point and a minimum at the upper turning point, the load force pattern was completely changed under microgravity. In particular, the upper turning point was also associated with a load force maximum. Analysis of the grip forces produced by the two subjects revealed that the grip forces underwent the same characteristic changes as the load forces. Thus, subjects were able to adjust grip forces in anticipation of arm movement-induced fluctuations in load force under different and novel load conditions. Adaptation to changing levels of gravity was also obvious when the vertical and horizontal movements were compared: grip forces depended heavily on movement direction during normal and hypergravity but not during microgravity. The predictive coupling of grip force and load force was observed even during transitions between gravity levels, indicating rapid adaptation to changing load conditions. To account for the striking preservation of the normal characteristics of grip force control, we suggest that a highly automatized, extremely flexible sensorimotor mechanism firmly implemented within the central nervous system can cope with even massive changes in the environmental conditions.

Adaptation, Physiological↗
PubMed2000

Can a motion-blind patient reach for moving objects?

It has been claimed that the visual brain is organized in two separate processing streams for spatial vision: one for perception and one for action. To determine whether motion vision is also divided into vision for action and for perception we examined the interceptive behaviour of the motion-blind patient LM. The task for LM and three age-matched control subjects was to reach-and-grasp for an object that moved away. Three experiments were conducted to examine the effects on perfomance of target speed (Expt 1), observation time (Expt 2) and visual feedback (Expt 3). As LM is only able to reach for objects which move at 0.5 m/s or less, her performance is inferior to that of controls who can reach for objects moving at 1.0 m/s, but it is better than would be expected from her performance in psychophysical experiments on her motion vision. Kinematic analysis of LM's reaching movements showed that she adapted the speed of her moving hand to the speed of the target but only when full vision was available. In contrast to normal subjects, LM required long observation times and vision of her moving hand to produce successful reaching responses. Thus, the impairment of both perception and action in LM suggests that the motion area MT/V5 is located at an early stage of the extrastriate hierarchy and provides input to both the perception and the action processing streams.

Aged↗
PubMed2000

Closed- and open-loop handwriting performance in patients with multiple sclerosis.

Normal subjects use an open-loop motor control strategy in handwriting, but they are able to switch to closed-loop motor control when the demands on accuracy increase. These closed-loop handwriting movements of normal subjects resemble the inefficient movements found in writing-impaired patients. The hypothesis that such movement deficits may in fact reflect the use of a closed-loop strategy was tested in a group of writing-impaired patients with multiple sclerosis (MS). The handwriting movements of 10 MS patients and 20 control subjects were examined with a digitizing tablet. Three conditions were used: a standard writing task (expt 1), a closed-loop condition (expt 2), and an open-loop condition (expt 3). Individual stroke movements were analysed. Stroke duration and segmentation were increased for MS patients in the standard writing task. The same was found for control subjects when they wrote under closed-loop conditions. However, under open-loop conditions, the handwriting movements of the MS patients were as fast and fluent as that of control subjects. The results support the hypothesis that the movement characteristics of the writing-impaired MS patients reflect an inadequate use of a closed-loop motor control strategy.

Adult↗
PubMed1999

Some of the amino acid chemistry going on in the Laboratory of Amino Acids, Peptides and Proteins.

Some of the chemistry of amino acids going on in our laboratory (Laboratoire des Amino acides Peptides et Protéines) is described as well as some mass spectrometry methodology for their characterization particularly on solid supports. Several aspects are presented including: (i) the stereoselective synthesis of natural and unnatural amino acids using 2-hydroxypinan-3-one as chiral auxiliary; (ii) the stereoselective synthesis of natural and unnatural amino acids by deracemization of alpha-amino acids via their ketene derivatives; (iii) the synthesis of alpha-aryl-alpha-amino acids via reaction of organometallics with a glycine cation; (iv) the diastereoselective synthesis of glycosyl-alpha-amino acids; (v) the synthesis of beta-amino acids using alpha-aminopyrrolidinopiperazinediones as chiral templates; (vi) the reactivity of urethane-N-protected N-carboxyanhydrides. To characterize natural and non natural amino acids through their immonium ions by mass spectrometry, some methodology is also described.

Amino Acids↗
PubMed1999

Grip forces exerted against stationary held objects during gravity changes.

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.

Adult↗
PubMed1999

Effects of unilateral brain damage on grip selection, coordination, and kinematics of ipsilesional prehension.

To determine whether the left and right hemispheres play specific roles in goal-directed movements, prehension with the ipsilesional hand was tested in patients with unilateral brain damage. The task required that subjects rotate the hand while reaching for a bar that was presented in different orientations in the frontal plane, thus making high demands on visuospatial processing. The grasped bar had to be put into a hole: under one task condition the placement of the bar was specified, while under another it was not. The constrained task required that the subject anticipate the placing action when planning the initial prehensile movement. Grip selection, reaction times, kinematics of the transport movement, and coordination of hand rotation during transport were assessed in ipsilesional movements of 22 patients with either left or right brain damage (LBD and RBD) and in control subjects. Patients in both groups exhibited performance deficits; however, impairment characteristics differed profoundly between the groups. RBD patients showed prolonged reaction time and degraded kinematics in the unconstrained task, whereas LBD patients performed relatively well when only the orientation of the bar varied, but slowly and frequently incoordinated when the subsequent action was specified. Our findings emphasize the dominant role of the right hemisphere in processing visuospatial aspects of goal-directed movements, whereas the left hemisphere subserves non-spatial aspects of preplanning under increased task demands. Correlations of the patient's performance with results from clinical tests showed that neither deficits in visuospatial perception of RBD patients nor apraxia of LBD patients could account for the observed abnormalities in the use of the ipsilesional hand.

Adult↗
PubMed1999

Time constraints improve reaching movements in an ataxic patient.

We report on a patient (AM) with a post-traumatic ataxia who has uncoordinated reaching movements to resting targets, but is able to catch moving objects. AM participated in three experiments to identify factors responsible for the favorable effect of object motion on her performance. In the first experiment, the task was to catch an object that moved away from AM. The speed of the object to be grasped (target object) varied. In experiment 2, the effect of time constraints on reaching performance was examined. AM had to reach for and grasp a stationary object and was allowed either 600 ms or 2000 ms to perform the task. In the third experiment, liquid crystal shutter glasses were used to manipulate the time that the subject was able to view the stationary target object and her reaching movements (vision-on time). While increased speed of the object, tighter time constraints, and short vision-on time hardly affected the performance of AM's unaffected left hand, they greatly improved her right-hand performance. These results are discussed in light of the hypothesis that the brain mechanisms controlling externally triggered movements differ from those controlling internally regulated movements.

Adult↗