Biomedical subjects
Publications and source records attributed to R Tissot.
After measuring the difficulty to relate biochemical data with an essential concept as the concept of inhibition in psychiatry, physiopathological models trying to integrate biochemical, neurophysiological and clinical data are proposed for the inhibition of depressive syndromes and the schizophrenic inhibition.
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Peptic peptides containing a tyrosyl residue from the binding site of a rabbit anti-p-azobenzoate antibody were isolated by means of the paired-iodination procedure. The peptides were from the light chain, and the tyrosyl residue is 29, 30, 31, 32, 32A, 32B, 33 at position 30 in the sequence -Val-Tyr-Asn-Asx-Lys-Gly-Leu- and thus is in the first hypervariable region. The sequence of the N-terminal 40 residues was determined. The major antibody-site peptide isolated was a diiodotyrosyl (DIT) tetrapeptide representing residues 30-32A; the monoiodotyrosyl (MIT) tetrapeptide was also isolated, but in a smaller yield. By isoelectric focusing, the light chain appeared to be homogeneous. No heterogeneity was apparent in the light chain sequencing until position 32B when, in addition to the phenylthiohydantoin derivative of tyrosine present as the major residue, a significant amount of the phenylthiohydantoin derivative of glycine was obtained. The glycine presumably represents a light chain variant population and explains the source of the other antibody-site peptides isolated, i.e. two pentapeptides, apparently of the sequence Tyr-Asn-Asx-Lys-Gly, isolated as the DIT and MIT derivatives. The tetrapeptides must have been derived from the peptic cleavage between Lys 32A and Tyr 32B in the major light chain variant and the pentapeptides from the peptic cleavage between Gly 32B and Leu 33 in the other variant. It is interesting that position 30 is occupied by a tyrosyl residue in five out of twelve other rabbit antibody light chains of known sequence (Margolies, M.N. et al., Proc. Nat. Acad. Sci. US 1975.72: 2180). One light chain is from another rabbit anti-p-azobenzoate antibody in which Tyr 30 is apparently not important in hapten binding although a tyrosyl at position 96 is clearly involved in hapten binding (Roholt, O.A. et al., J. Immunol. 1973.111:1367). The other four of the five light chains are from anti-pneumococcal polysaccharide antibodies in which the role of this tyrosyl residue is not known.
Our laboratory sleep polygraphic recordings are all automatically scored by a scoring system previously described. The automatic scoring reliability has already been estimated by a comparison with visual scoring. Nevertheless, it was interesting to investigate whether the picture of sleep given by this system, of a precisely defined group of subjects, was very different from that obtained by visual scoring for similar subjects in other laboratories. Therefore, we compared the results given by automatic analysis in a group of normal subjects aged 20--29 years with the results of Williams et al. (1974) for subjects of the same age. We thus mixed on purpose three sources of difference: the studied population, the laboratory and its habits, and the technique of scoring the records. This comparison showed a clear difference in the total time of sleep for men and women. This time, longer in our conditions, depended certainly on subjects and on recording conditions more than on automatic scoring. Sleep and stage latencies were not significantly different by the two scoring techniques. A difference appeared for waking latency, longer in our findings, but probably resulting from the definition of this parameter. The number of sleep cycles and their average duration were not different in the two techniques. Concerning sleep stages, stage 3 was slightly overestimated and stage 4 underestimated by automatic scoring compared with visual scoring, while there was no marked difference for the other stages. Finally, a larger number of stages are detected by the machine than by the human eye, which is probably due to the fact that the latter neglects some transitions from one stage to another when they are not important with regard to the context. Thus, apart from some differences resulting from the definition of parameters, there is a very large analogy between visual and automatic results of sleep scoring. The only effects of the latter are a slightly different assessment of the ratio of stages 3 and 4, in favour of stage 3, a larger estimate of the number of sleep stages, and a slight underestimation of REM sleep.
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Modern linguistics, like genetic psychology, postulate a non-linguistic basis for the structurisation of the semantic fields. If such is the case, it should be possible to observe in aphasia, where semantic deficiency predominates, a related disturbance in the semantic fields and logic. Paraxodically, such disturbances have been observed both in Broca's aphasia and in the predominantly semantic aphasia of Wernicke. A qualitative analysis shows that quantitatively identical results in the semantic aphasias of Broca and Wernicke are the result of phenomenological convergence. The related disturbance in the semantic fields and logic appears characteristic of the semantic deficiency which, in aphasic semiology, is marked by the substitution of one word for another. These finding support the theory of the relative autonomy of phonemic and semantic disorders in Wernicke's aphasia. They confirm the linguistic and genetic theory that the structure of vocabulatory is based on extralinguistic factors. They do not however provide an explantation for semantic disorders in aphasia. Further research is required to discover on what functional system articulation of the symbolic function and general operative capacity is based.
One of the major difficulties in the treatment of Parkinson's disease with L-Dopa alone or associated with a decarboxylase inhibitor lies in the frequent occurrence of involuntary movements. In some cases these movements can be prevented (eliminated) by increasing the plasma DCI concentration or by associating 3-oxy-methyl-dopa. In resistant cases the authors have conducted a trial with EP 19-088, which belongs to a new class of tricyclic derivatives of indenopyridine. The trial population comprised 42 patients. In 12 of these there was complete cessation of symptoms. In 9 patients a marked improvement was noted, while in 10 others the improvement was slight but definite. The treatment was discontinued in 2 cases due to episodes of increased confusion. In the other 9 patients the experimental treatment had no effect. No side effects were observed in 24 of the 42 patients tested. In addition to symptoms such as nausea or transient heartburn, the remaining patients reported either a slight worsening of their parkinsonian symptoms or an increase in diurnal fatigability.
Fluorescence microscopy of rat brains after administration of (+)-erythro-DOPS has been studied. (+)-erythro-DOPS induced an increase of brain NE part of which was formed in the capillary walls. The slight diminution of this increase when (+)-erythro-DOPS was administered after inhibition of peripheral decarboxylase, might result from the algebraic sum of two inversely acting processes: suppression of NE synthesis in the capillary walls and enhancement of parenchymatous NE in some brain areas. (+)-erythro-DOPS enters different brain structures non specifically and NE is formed in DA and 5-HT systems, displacing the amines especially at the terminals; the NE formed by (+)-erythro-DOPS in NE systems should be rapidly catabolised. Possible pharmacological effects of (+)-erythro-DOPS administration involve consideration of the lack of topical specificity of NE formation; the displacement of 5-HT and DA; and the fact (+)-erythro-DOPS produces (+)-NE, and not naturally occurring NE.
Rabbits were haplotyped for the major rabbit leukocyte-locus A (RL-A locus), which is analogous to the human leukocyte-locus A (HL-A locus). The rabbits were divided into five groups, and the groups were arranged to provide a controlled experimental setting. Standardized alkali burns were induced in selected groups to produce heavy vascularization of the corneal bed. Groups with completely histocompatible corneal donors for the RL-A locus had a 9 out of 10 success rate when keratoplasty was performed on a vascularized bed. Another group of rabbits mismatched at the RL-A locus with histoincompatible corneal donors were prepared in the same manner and had a success rate of 1 out 9. A probable significant difference (P less than 0.005) using Fischer's exact test was found between the two groups.
The effects of benserazide on the level of homovanillic acid and 5-hydroxyindoleacetic acid in CSF have been investigated in 1 manic and 11 depressed patients. Benserazide induced no change on both metabolites. This negative result supports the view that monoamine metabolites in CSF, in the absence of loading with an exogenous precursor, originate mostly from brain parenchyma, without significant contribution of the metabolism in capillary walls.
Several recent data indicate the blood-brain transport of amino acids as a critical factor in the synthesis of monoamines. The complex, peripheral and central regulation of TP transport plays an essential role sine TP-hydroxylase is not a saturated enzyme. The hydroxylated derivatives 5-HTP and dopa are probably transported into the brain by similar mechanisms as their precursors TP and tyrosine, respectively. The maic-depressive patients show an increased uptake of administered L-5-HTP in the depressive phase, whereas L-dopa uptake is enhanced in the manic phase. Heuristically, we propose a biochemical model of manic-depressive psychosis in which an increased TP uptake causes alternation in the balance of monoaminergic system activity. Depression is possibly characterized by a hyperserotonergic and a relative hypocatecholaminergic activity. In contrast, mania is possibly determined by a hypercatecholaminergic (NA and DA) and a relative hyposerotonergic activity. The data offered by the physiology of monoamines, the semeiology and the biological alterations of the manic-depressive psychosis, as well as the monoaminergic and the electrolyte theory of manic-depressive psychosis. A diminution of the transport of TP with consequent increase of that of tyrosine represents a possible biochemical model of schizophrenia which may be well explained by a hyposerotonergic-hyperdopaminergic activity, with or without noradrenergic insufficiency. This model is compatible with our knowledge on the monoamine physiology, the biological alterations of schizophrenia, the therapeutical results as well as with the classical clinical notions (typology, intermediate syndromes and crossed heritance).
This study investigates the effect of flunitrazepam, a new benzodiazepine, on the sleep of insomniac patients under chronic treatment. Polygraphic recordings have shown that this drug decreases not only the activity of the wakefulness system, but also the activity of the synchronizing system of slow-wave sleep. The subjective feeling of improved and sounder sleep seems to be related to a decrease of wakefulness pressure as well as to a decrease of body motoricity, but not with the modification of sleep stages themselves. Flunitrazepam appears to possess some regulatory properties on REM sleep, since this stage is enhanced in patients with an initial low amount of REM sleep and decreased in those having a higher initial REM sleep. Flunitrazepam possesses potent and useful hypnogenic properties in man but does not induce physiological sleep.
The importance of amino acid transport across the blood-brain barrier as the limiting factor in the metabolism of monoamines has been emphasized by many recent publications. Particularly critical is the transport of tryptophan, since tryptophan hydroxylase is not saturated. This transport is regulated by complex mechanisms, both at the periphery (total and free plasmatic levels and levels of the other essential amino acids) and centraly (by feedback mechanism initiated at the pre- and post-synaptic levels). The hydroxylated derivatives of tryptophan and tyrosine, i.e. 5-HTP and L-DOPA, most probably share the same transport mechanism as these amino acids themselves. In manic-depressive patients, the uptake of L-5-HTP is increased during the depressive phase, while the uptake of L-DOPA, is increased during the manic phase. We suggest that an increase in the uptake of tryptophan may set off oscillations in all the monoaminergic systems, thus providing a biochemical model of manic-depressive psychosis. In terms of this model, melancholy would be due to a hyperserotoninergic syndrome together with a relative hypocatecholaminergic syndrome. Mania would be due to a homogeneous hypercatecholaminergic syndrome together with a relative hyposerotoninergic syndrome. Such a model is compatible with present knowledge of the physiology of monoamines, of the semeiology and biological disturbances of manic-depressive psychosis, and of the treatment of this disease. It reconciles the monoaminergic and ionic theories of the disease better than other existing hypotheses. A reduced transport of tryptophan with a secondary increase in the transport ot tyrosine provides a conceivable model for schizophrenia. Indeed, a serotoninergic hypoactivity coupled with a dopaminergic hyperactivity, with or without a noradrenergic deficiency, would account for the semeiology quite adequately. This model too would be compatible with present knowledge of monoamine physiology, of the biochemical disturbances underlying schizophrenia and of the mode of action of anti-psychotic drugs. This unitarian heuristic concept of the monoaminergic psychoses would be in better agreement with the classic clinical data concerning this disease (typology intermediate syndromes and crossed heredity).
The action of the four stereoisomers of 3,4-dihydroxyphenylserine (DOPS) on the monoamine content of brain and heart was investigated with biochemical and histochemical methods. The (+)-erythro-DOPS (50-250 mg/kg i.p.), due to its alphaS configuration, was readily decarboxylated in vivo leading to an accumulation of norepinephrine (NE) in brain and heart. The amino probably corresponded to the unnatural (+) form since the amino acid shows betaS configuration. The NE was located in brain regions rich in noradrenergic (hypothalamus, locus ceruleus), dopaminergic (neostriatum, substantia nigra) and 5-hydroxytryptaminergic (raph'e nuclei) neurons. In addition, (+)-erythro-DOPS decreased the level of endogenous 5-hydroxytryptamine and dopamine and increased that of 5-hydroxyindoleacetic and homovanillic acid in the brain indicating a displacement of 5-hydroxytryptamine and dopamine, respectively, from their storage sites. Inhibitors of extracerebral decarboxylase (benserazid and carbidopa) diminished the (+)-erythro-DOPS-induced increase in cerebral NE by inhibiting the decarboxylation of the amino acid in the walls of the brain capillaries. The (-)-threo-DOPS, which also show alphaS configuration, was decarboxylated too, leading to a rise in cardiac NE. The amine was likely to correspond to the natural(-)-isomer since (-)-threo-DOPS has betaR configuration. This increase in NE lasted much longer than that caused by (+)-erythro-DOPS. In the brain, the accumulation of NE was negligible after i.p. administration of (-)-threo-DOPS but marked after injection of the isomer into a cerebral ventricle indicating a poor penetration of (-)-threo-DOPS through the blood-brain barrier. High doses (500 and 1000 mg/kg i.p.) of (-)-erythro- and (+)-threo-DOPS caused only a slight increase in cerebral and cardiac NE since, due to their alphaR configuration, they were probably not decarboxylated to a major extent. In conclusion, (+)-NE formed from (+)-erythro-DOPS probably accumulates in the storage sites of the endogenous monoamines where it might function as a false neurotransmitter.
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