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Biomedical subjects

M Filion

Publications and source records attributed to M Filion.

At least 37 records · Page 2Linked to original sources

Action of 5-hydroxytryptamine, substance P, thyrotropin-releasing hormone and clonidine on motoneurone excitability.

We have investigated the influence on the excitability of lumbar motoneurons of 5-hydroxytryptamine (5-HT), substance P and thyrotropin releasing hormone (TRH), three substances which coexist in the same bulbospinal descending pathway and end in large part around motoneurons. We have also studied the effect of clonidine, an alpha 2 noradrenergic agonist. This was done in spinalized rats (T5) treated three weeks before with 5-7-dihydroxytryptamine. Under those circumstances 5-HTP (I.P.), 5-HT (intrathecally) TRH (I.P. or I.T.) and substance P (I.T.) all elicited a strong excitation of motoneurons as measured by integrated EMG of the hindlimb muscles. Substance P reduced by almost half the subsequent response to 5-HTP, 1 hour and 24 hours later. TRH given acutely did not modify the response to 5-HTP but given chronically for twenty one days by means of Alzet minipump, markedly increased the response to 5-HTP. Clonidine by itself decreased the excitability of motoneurons and antagonized the excitatory effect of 5-HTP and TRH. In a pilot trial, cyproheptadine, a 5-HT antagonist was shown to decrease the manifestations of spasticity in patients with a partial spinal lesion. Clonidine also appears to be of potential use in the treatment of spasticity.

5-Hydroxytryptophan

Activities of both ribonucleotide reductase subunits, M1 and M2, decrease upon serum starvation of baby hamster kidney 21/C13 cells.

Ribonucleotide reductase from mammalian cells is composed of two nonidentical subunits M1 and M2 which are both required to form the catalytic site. The level of ribonucleotide reductase activity is cell cycle controlled and several reports suggest that this control is achieved mainly by the regulation of M2 subunit synthesis. In the present study, we have found that the activities of both subunits decreased markedly upon serum starvation in the Syrian baby hamster kidney 21/C13 cell line. These decreases did not seem to be correlated with the appearance of an inhibitory factor in serum-starved cells. Quantification of the amount of the M1 subunit protein (89,000 molecular weight) by [32P]dTTP photoaffinity labelling revealed that the decrease in M1 activity was not due to variation in M1 protein level. Therefore, a posttranslational mechanism probably exists which inactivates M1 subunit when cells stay in the quiescent (G0) state and this mechanism could play an important role in the control of ribonucleotide reductase activity.

Animals

Identification of distinct messenger RNAs for nuclear lamin C and a putative precursor of nuclear lamin A.

The lamins are the major components of the nuclear matrix and are known as lamins A, B, and C with Mr 72,000, 68,000, and 62,000 when analysed by SDS PAGE. These three polypeptides are very similar, as determined by polypeptide mapping and immunological reactivity. Lamins A and C are so homologous that a precursor-product relationship has been proposed. Using an antiserum against nuclear matrix proteins that specifically immunoprecipitates the three lamins, we examined their synthesis in the rabbit reticulocytes lysate. Four bands of Mr 62,000, 68,000, 70,000, and 74,000 were specifically immunoprecipitated when polysomes or polyadenylated RNA were translated in vitro. By two-dimensional gel electrophoresis, the 68,000- and the 62,000-mol-wt proteins were identified as lamins B and C, respectively, and the 74,000-mol-wt polypeptide had properties of a precursor of lamin A. The mRNAs of lamin C and of the putative precursor of lamin A were completely separated by gel electrophoresis under denaturing conditions, and their respective sizes were determined. These results suggest that lamin A is not a precursor of lamin C.

Animals

Direction of synthesis of the message for a 35 000 polypeptide of herpes simplex virus type 2.

A restriction endonuclease map of the coding sequences for the transformation-related 35 000 polypeptide of herpes simplex virus type 2 is reported, using 11 enzymes that cut DNA infrequently. Hybrid-arrested translation with small DNA fragments was used to locate the 5' terminus of these coding sequences. A novel procedure involving translation of the 35 000 mRNA selected with cloned viral DNA that had been digested with exonuclease was employed to confirm that this message is transcribed from left to right. The 35 000 polypeptide can thus be assigned to a 1.2-kilobase mRNA recently reported with the same starting point and direction.

Cell Transformation, Viral

Secretagogues cause a preferential discharge of large size granules in rat pancreas.

We have compared the diameters of zymogen granules in the exocrine pancreas of fasted or stimulated rats. The average granule diameter was 0.73 microns +/- 0.18 SD (sample size, 1460) in fasted animals and significantly reduced to 0.68 microns +/- 0.17 SD (sample size, 860) after 120 min and two intraperitoneal injections of urecholine. Reduction of granule size was attributable to the preferential discharge of large size granules. The range between first and third quartiles of the distribution curve was identical in the two groups at 0.24 microns. There was no significant increase in the proportion of granules smaller than 0.40 microns after urecholine stimulation. A third group of animals was "hyperstimulated" by an infusion of a mixture of caerulein, secretin, and urecholine. After 210 min, the average granule diameter was reduced to 0.43 microns +/- 0.14 SD (sample size, 786). The range between first and third quartiles of the distribution curve was 0.16 microns. In this group, 43.5% of the granules was smaller than 0.40 microns. Granule size reduction was accompanied by the appearance of numerous pleiomorphic condensing vacuoles. The present results strongly support the views that secretagogues cause the preferential release of large size granules and favor the formation of small size granules.

Animals

Redundancy in ascending and descending pathways mediating head turning elicited by entopenducular stimulation in the cat.

Contraversive turning movements of the head were elicited in alert cats by unilateral electrical stimulation of the entopeduncular nucleus. To determine the relative functional importance of ascending and descending pathways activated by the stimulation, the animals were submitted to thalamocortical or midbrain lesions and to combinations of the two lesions interrupting the pathways. Head turning was hindered considerably only after combinations of the two lesions and not after either lesion alone. Taking into account the results of previous studies, showing that most efferent fibers of the entopeduncular nucleus branch to the thalamus and to the midbrain, it is concluded that not only one but two main efferent pathways, corresponding to each branch, are used by the entopeduncular nucleus to control motoneurons, each pathway carrying enough redundant information to mediate head turning.

Afferent Pathways

Localization of the coding region for a 35000 Dalton polypeptide on the genome of herpes simplex virus type 2.

The cloned BglII N fragment of herpes simplex virus type 2 (HSV-2) DNA has been shown to code for a 35K polypeptide. Subfragments made by cleavage with XhoI, BamHI, SstII and XorII were then cloned and used with RNA extracted from HSV-2-infected cells for mRNA selection and in vitro protein synthesis. We found that the major translation product of such hybrid-selected mRNA has a molecular weight of 35 000. By further mapping, DNA coding sequences for this mRNA were located within the region of BglII N, at approximately 0.585 to 0.596 genome map units. DNA sequences complementary to mRNA encoding a 56K polypeptide were located between 0.607 and 0.612 map units.

Chromosome Mapping

Effect of age and glucocorticoid administration on the proteolytic activity of gastric mucosa: a comparative study in the young rat, calf and piglet.

The proteolytic activity of gastric mucosa markedly increased from 2 to 4 wk of age in rats and from birth to 8 wk in pigs. In calves it was at adult level at birth, then decreased until d 14 and remained at a relatively low level up to d 56 of age. Early postnatal glucocorticoid injections increased (P less than .05) the proteolytic activity of gastric mucosa in rats, decreased (P less than .05) the abomasal proteolytic activity in calves and had no significant effect in pigs. The high levels of proteolytic activity observed in the rat at earlier ages after glucocorticoid treatment suggested a precocious maturation of the gastric mucosa. Injections of different doses of hydrocortisone acetate and dexamethasone to calves and rats indicated that proteolytic activity of gastric mucosa is only sensitive to high doses (i.e., nonphysiological) of glucocorticoids. The response of gastric mucosa to glucocorticoid injections depended on the animal's age; maximum response was obtained in the early postnatal period while minimal response was observed after weaning.

Abomasum

Pallidofugal projections to thalamus and midbrain: a quantitative antidromic activation study in monkeys and cats.

The projections of monkey medial globus pallidus (and of cat entopeduncular nucleus) to thalamus and midbrain were studied with antidromic activation in order to determine the number of pallidal neurons sending axonal branches to the two sites. The animals were anesthetized with pentobarbital and several movable electrodes were used to stimulate the thalamic nuclear complex ventralis anterior - ventralis lateralis (VA-VL), the nucleus "centre médian" (CM), and the midbrain nucleus tegmenti pedunculopontinus (TPP). The responses of pallidal neurons were recorded with extracellular microelectrodes. In 3 monkeys 99% and 87% of 145 medial pallidal neurons responded antidromically to stimulation of VA-VL and TPP respectively. Reciprocal collision tests demonstrated that 86% of the 145 neurons sent axonal branches to the two sites. By comparison in 2 cats the tests demonstrated that 72% of 46 entopeduncular neurons branched to VA-VL and TPP. In 2 monkeys 68% of 53 medial pallidal neurons were shown to branch to VA-VL and CM thalamic nuclei. In the monkeys, the latencies of responses indicate that all pallidofugal fibers have the same mean conduction rate: 6 m/s. The fibers appear to branch profusely in VA-VL where less current was required to activate neurons antidromically than in TPP. The location of neurons in the medial pallidum is weakly correlated with the location of stimulation points in VA-VL activating the neurons antidromically at low threshold, suggesting some topography in the pallidothalamic projection. However there is no particular localization of medial pallidal neurons with and without branching projections. Apart from one exception, the 162 neurons recorded in the lateral pallidum failed to respond antidromically to the stimulation sites. We conclude that the great majority of medial pallidal neurons can send signals to both the thalamus and the midbrain in the cat and in the monkey.

Animals

Effects of interruption of the nigrostriatal pathway and of dopaminergic agents on the spontaneous activity of globus pallidus neurons in the awake monkey.

Interruption of the nigrostriatal pathway has been shown to change parameters of striatal activity. These changes are often difficult to explain because the functional structure of the striatum is not understood sufficiently. The function of the globus pallidus appears to be simpler. It transmits the output of the striatum to the thalamus and to the midbrain. Yet the effects of interruption of the nigrostriatal pathway on the activity of pallidal neurons are unknown. To study these effects the spontaneous activity of globus pallidus neurons was recorded in intact monkeys and in monkeys with lesions of the ventromedial midbrain tegmentum. The two groups of animals were studied with and without administration of dopaminergic agents. In intact monkeys medial pallidal neurons discharge uninterruptedly at high firing rates, while the discharge of most lateral pallidal neurons is interrupted by relatively long periods of silence. Lesions involving the nigrostriatal pathway change the firing patterns but not the mean firing rates of pallidal neurons. In lesioned monkeys pallidal neurons fire in bursts continuously: during movement, rest and sleepiness. Two lines of evidence strongly suggest that the bursting pallidal activities are a consequence of the interruption of the nigrostriatal dopaminergic pathway: (1) the percentage of bursting pallidal neurons is proportional to the amount of degeneration in the pars compacta of the ipsilateral substantia nigra; (2) chronic administration of dopamine antagonists, haloperidol and reserpine, reproduces in intact monkeys the bursting activities observed in lesioned animals. On the other hand, single injections of dopamine agonists, apomorphine and piribedil, silence the medial pallidum and concomittantly abolish the signs of parkinsonism displayed by lesioned monkeys.

Animals

A comparison of projections of entopeduncular neurons to the thalamus, the midbrain and the habenula in the cat.

Anatomical studies have demonstrated that the output of the striopallidal system is distributed to two areas of the thalamus: the ventrolateral-ventroanterior and the centromedian nuclei. The two areas are involved in different ways in the control of somatic motor activity. Pallidal efferents are also distributed to a still obscure tegmental area in the midbrain, the pedunculopontine nucleus, and to the lateral habenular nucleus, a structure of the limbic system. The present study compares the projections of entopeduncular neurons to the four sites in cats. The comparison is based on an estimation of the number of entopeduncular neurons sending fibers to each site and branching to more than one site. The four projection sites were stimulated electrically in anesthetized cats and the number of entopeduncular neurons excited antidromically were counted. At least 68% of entopeduncular neurons were excited antidromically by stimulation of the ventrolateral nucleus, an equal number were excited antidromically by stimulation of the nucleus centromedian and slightly fewer but still more than 50% by stimulation of the pedunculopontine nucleus. The three sites gave rise to antidromic responses of the same entopeduncular neuron in at least 33% of the cases. Only 25% of entopeduncular neurons responded antidromically to stimulation of the lateral habenular nucleus exclusively (one-third) or not (two-thirds). Some neurons recorded incidentally in the globus pallidus responded antidromically to the stimulation sites. Neurons were also recorded in the preoptico-hypothalamic area and 67% responded antidromically exclusively to the stimulation of the lateral habenular nucleus.

Action Potentials

Physiopathology of experimental Parkinsonism in the monkey.

Postural or Parkinson-like tremor, which results from the impairment of mechanisms which are predominantly lateralized in the brain, is most likely related to the combined impairment of the dopaminergic nigrostriatal pathway and the corresponding rubro-olivo-cerebello-rubral loop (without excluding the possiblity that other nervous mechanisms interconnected with these structures may represent an alternative disturbance). The integrity of the internal division of the pallidum and the ventrolateral area of the thalamus and their efferent fibers as well as the motor cortex and certain of its cortico-subcortico-spinal pathways (Figures 1 and 2) is apparently an essential feature for the elaboration of the rhythmic bursts associated with the appearance of postural tremor. The integrity of the spinal sensory roots and the rubro-tegmentospinal tract is not a prerequisite for the expression of postural tremor, a condition which seems essential for the production of rigidity. The latter facts suggest that the disturbances which subserve these two types of motor impairment, often concomitantly present in Parkinsonism, partially involve the impairment of different mechanisms although the loss of the DA fibers originating in the substantia nigra and ending in the neostriatum (Figure 1) appears to represent a disturbance common to both types of disorders. Bradykinesia which may be associated with an impairment of catecholamine metabolism (and more especially the neostriatal DA mechanisms) on both sides of the brain may also result from bilateral lesions of the pallidum or of its outflow corresponding, in the main, to the pallidothalamic fibers ending in the ventrolateral thalamus. The latter types of lesion most likely exclude the influence of the monoaminergic, cholinergic and gabaminergic activities normally originating in the striopallidal system and influencing the activity transmitted to other CNS mechanisms. Severe akinesia, however, apparently depends on more profound and generalized disturbances of brain monoamine metabolism with or without the involvement of other ill-defined mechanisms. At any rate the impairment of the brain DA mechanisms (and especially those of the neostriatum) seems to represent a major feature in the production of the Parkinsonian type of akinesia. Further work is needed to establish the relative importance of the loss of catecholaminergic mechanisms other than those of the neostriatum in the production of akinesia.

Animals