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Biomedical subjects

J M Launay

Publications and source records attributed to J M Launay.

At least 109 records · Page 6Linked to original sources
PubMed1994

Blood and plasma 5-hydroxytryptamine levels in patients with cirrhosis.

Serotoninergic mechanisms are thought to play a role in portal hypertension. Because this biomine is metabolized by the liver, peripheral blood and plasma levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid (the main metabolite of 5-hydroxytryptamine) were measured in 30 patients with cirrhosis. Whole-blood 5-hydroxytryptamine levels were significantly lower in patients with cirrhosis (158 +/- 28 nM) than in age-matched controls (332 +/- 19 nM), and no correlation was found between these levels and the severity of cirrhosis. Unconjugated plasma 5-hydroxytryptamine levels, an indication of the active form of 5-hydroxytryptamine, were significantly higher in patients with cirrhosis than in controls (6.8 +/- 1.7 nM and 3.4 +/- 0.5 nM, respectively), and in patients with cirrhosis these levels were higher in Pugh grade A than in Pugh grade C patients. Conjugated-plasma 5-hydroxytryptamine levels were not significantly different between patients with cirrhosis (32.2 +/- 8.1 nmol/L) and controls (16.4 +/- 1.4 nmol/L). Plasma 5-hydroxyindole acetic acid was significantly lower in patients with cirrhosis than in controls (1.5 +/- 0.1 nmol/L and 2.3 +/- 0.1 nmol/L, respectively). In conclusion, this study shows that serotoninergic mechanisms are altered in patients with cirrhosis.

Hepatic Veins↗
PubMed1994

Immunocyte enumeration in duodenal biopsies of migraine without aura patients with or without food-induced migraine.

The possibility of an IgE-mediated allergic mechanism in food-induced migraine remains controversial. Twenty consecutive migraine patients, 11 with food-induced migraine, 9 without, were investigated for determination and counting of immunocyte populations (IgA, IgM, IgE, IgG containing cells) by biopsies at duodenum 2 level. Conventional histology and plasmocyte populations were not significantly different between the two groups of migraine patients. This study does not support the existence of an IgE-mediated allergic mechanism in food-induced migraine.

Adult↗
PubMed1994

Increase of human platelet serotonin uptake by atypical histamine receptors.

Histamine and the guanosine 3',5'-cyclic monophosphate (cGMP)-inducing agent sodium nitroprusside both increased serotonin (5-HT) uptake and cGMP levels in isolated human platelets in vitro. Histaminergic stimulation was observed at concentrations ranging from 10 nM to 0.25 microM [mean effective concentration (EC50) = 0.1 microM histamine]. The inhibition produced by the H2-receptor antagonists tiotidine, metiamide, and cimetidine was 10-10(5) times more potent on histamine receptors regulating 5-HT uptake and cGMP generation in human platelets than on the histaminergic receptors H1, HIC, H2, and H3 in other tissues. The in vitro histamine-induced 5-HT uptake was prevented by preincubation of isolated human platelets in the presence of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine or the cGMP-lowering agent LY-83583. Histamine was ineffective in stimulating cAMP generation in human platelets and did not interact with effector sites known to downregulate 5-HT uptake, including imipramine, gamma-aminobutyric acid A, peripheral type benzodiazepine-binding sites, and V1a vasopressin receptors inducing human platelet shape change and aggregation. These atypical human platelet histaminergic receptors differ from the previously classified histamine receptors by their apparent high affinity to histamine H2-receptor antagonists and their apparent link with the soluble, nitric oxide-dependent guanylate cyclase. These findings suggest that human platelets express a new subtype H2h of histamine receptors.

Adult↗
PubMed1994

Estimation of rate constants for serotonin uptake and compartmentation in normal human platelets.

Biochemical and pharmacological experiments led to a model describing a thrombin-releasable (vesicular) compartment and two non-thrombin-releasable compartments for 5-hydroxytryptamine (5-HT, serotonin) in normal human platelets (J. L. Costa, K. L. Kirk, D. L. Murphy, and H. Stark. Br. J. Pharmacol. 72: 449-459, 1981). With tritiated 5-HT as substrate, the amounts of total and nonreleasable intraplatelet tritiated material were measured. Moreover, in the last set of experiments, the amounts of extraplatelet tritiated material and extraplatelet tritiated 5-HT were also measured. With these data, identification of the kinetic constants for movement between the various compartments was possible. A recent extension of the similarity transformation approach to nonlinear compartmental models was used to carry out the a priori identifiability analysis. Then numerical identification was performed by implementing and achieving efficient methods from optimal control theory. Under our experimental conditions, the main results are as follows: 1) the vesicular compartment corresponds to the platelet storage 5-HT compartment, 2) instead of pools I and II proposed previously, only a single nonreleasable thrombin-resistant pool could be detected, and 3) the optimized model computed to suit the first set of experiments fits homologous intraplatelet results obtained under similar experimental conditions in the last set of experiments and also fits one of the two supplementary extraplatelet investigations.

Blood Platelets↗
PubMed1994

Histamine H2 receptors and histidine decarboxylase in normal and leukemic human monocytes and macrophages.

Spontaneous and all-trans-retinoic acid (RA)-induced differentiation of normal human monocytes and of leukemic THP-1 monocytes into macrophages resulted in a progressive loss of adenosine 3',5'-cyclic monophosphate production induced by histamine via typical H2 receptors (H2R). In THP-1 cells and in HL-60 human acute myelocytic leukemia cells, RA treatment increased the abundance of the 4.5-kb messenger RNA of the H2R gene fourfold, suggesting transcriptional control by a RA response element. Scatchard plots of [3H]tiotidine binding indicated the expression of H2R with similar affinity and binding capacity in THP-1 monocytes and macrophages, while the conversion of normal monocytes into macrophages decreased H2R density from 91.8 to 43.1 fmol/mg protein, with no change in affinity (Kd = 9.9 to 11.2 nM). In THP-1 macrophages, histamine inhibited 4 beta-phorbol 12-myristate 13-acetate (PMA)-induced H2O2 formation via the activation of H2 receptors. Expression of the H2R gene, histamine accumulation, and histidine decarboxylase activity were also demonstrated in normal human monocytes/macrophages and peripheral lymphocytes. Histamine and H2R may therefore affect, via intracrine, autocrine, and paracrine pathways, various immune and inflammatory responses of the lymphoid and myeloid progenitors and lineages in the bone marrow and peripheral tissues.

Adenylyl Cyclases↗
PubMed1994

Substance P, calcitonin gene-related peptide, and capsaicin release serotonin from cerebrovascular mast cells.

Rabbit leptomeningeal arteries contain granular cells resembling mast cells that frequently contact autonomic and sensory nerve profiles. In the present in vitro study, we determined whether these cells could be stimulated by substance P (SP) and calcitonin gene-related peptide (CGRP), which are stored and released by sensory C fibers. Immunohistochemistry of the middle cerebral artery showed that 5-HT was stored only in mast cell-like granules. This pool of 5-HT decreased in a dose-dependent manner when exogenous SP and CGRP were added to the incubation solution or when endogenous neuropeptides were released from nerve terminals by capsaicin. The simultaneous administration of CGRP and SP induced a dramatic exocytosis and a 5-HT release significantly greater than the sum of the individual effects of the two neuropeptides. We conclude that, as in classical connective tissue mast cells, the amine content of these granular cells can be released by a degranulation process induced by neuropeptides. The effects of capsaicin suggest that this phenomenon can be triggered by axon reflex of C fibers. The data also provide the first evidence of a synergistic action of SP and CGRP on mast cell degranulation.

Animals↗
PubMed1994

Difference between plasma N- and C-terminally directed beta-endorphin immunoreactivity in infantile autism.

OBJECTIVE: The authors investigated whether there is excessive opioid activity in infantile autism by measuring plasma beta-endorphin in patients with autism compared with patients who had Rett's syndrome and normal comparison subjects. METHODS: Radioimmunoassays for beta-endorphin using C-terminally and N-terminally directed antisera were applied to plasma samples from 67 children who met both DSM-III-R and ICD-10 diagnostic criteria for infantile autism, 22 girls with Rett's syndrome, and 67 normal children matched in age and sex with the children with autism. RESULTS: Median N-terminally directed beta-endorphin immunoreactivity appeared to be slightly lower in subjects with autism (7 pg/ml) and clearly higher in the girls with Rett's syndrome (40 pg/ml) than in the comparison subjects (9 pg/ml). Median C-terminally directed beta-endorphin immunoreactivity was higher in the girls with Rett's syndrome (35 pg/ml) and much higher in patients with autism (70 pg/ml) than in comparison subjects (8 pg/ml). CONCLUSIONS: These findings demonstrate the existence of a wide discrepancy between C- and N-terminally directed beta-endorphin immunoreactivity among children with autism. Despite the fact that the nature of the antigen recognized in the plasma of autistic children by the C-terminally directed anti-beta-endorphin serum remains to be characterized, the difference between C- and N-terminally directed beta-endorphin immunoreactivity might suggest an abnormal processing of the pro-opiomelanocortin gene in infantile autism.

Adolescent↗
PubMed1994

Molecular genetics of prion diseases in France. French Research Group on Epidemiology of Human Spongiform Encephalopathies.

Human prion diseases are characterized by the accumulation in the brain of an abnormal form of the prion protein. Prion protein polymorphisms seem to play a key role in the pathogenesis of these diseases, probably by enhancing the amyloidogenic properties of the protein. We performed prion protein gene (PRNP) coding sequence analysis in 57 French subjects with Creutzfeldt-Jakob disease (CJD) and found a mutation of the PRNP coding sequence in nine subjects (15.8%); the mutation corresponded with a known family history of CJD in only three of these subjects. In 41 definite and probable cases without known PRNP mutations, codon 129 genotyping revealed an excess of the homozygous 129Met/Met genotype corresponding to a 3.4-fold increased risk of developing CJD when compared with the two other genotypes. We also found that the 129Val/Val genotype, which mainly governs susceptibility to iatrogenic CJD, does not seem to predispose to sporadic CJD.

Adult↗
PubMed1994

Serotonin receptors and therapeutics.

Since its discovery, serotonin (5-hydroxytryptamine = 5-HT) has become a major player on the neurotransmitter "stage". Multiple receptor subtypes for 5-HT have been identified and classified, and a vast pharmacology of 5-HT has emerged. In particular, 5-HT has been shown to exert marked effects on the cardiovascular system, central nervous system (CNS) and gastrointestinal (GI) tract, and important ligands have been developed that mimic or block its action selectively. Furthermore, drugs that release 5-HT, and others that prevent its uptake, have been developed. This brief review focuses on the pharmacology of 5-HT agonists and antagonists that exhibit, at least partly, clinical relevance.

Animals↗
PubMed1994

The mouse 5-HT2B receptor: possible involvement in trophic functions of serotonin.

The novel serotonin receptor 5-HT2B shows the highest homology to the 5-HT2 family of receptors. The pharmacological profile of membranes from 5-HT2B cDNA stably transfected LMTK- cell line, corresponds to a new 5-HT2-like receptor named 5-HT2B, although some difference exists between the mouse and rat pharmacology. A similar pharmacological profile is detected on the immortalized teratocarcinoma-derived cell line 1C11 upon 2 days of serotoninergic differenciation by cAMP. In both cell lines, the analysis 125I-DOI binding reveals the presence of a single class of sites, the affinity of which is one order of magnitude lower than the one reported for the 5-HT2A receptor. This demonstrates that the 5-HT2B receptor is functionally expressed before the complete serotoninergic differentiation of 1C11 cells. These observations are in good agreement with the presence of 5-HT2B mRNA in early mouse embryonic development. Furthermore, the major sites of 5-HT2B mRNA embryonic expression are in the heart, and in the neural fold before the closure of the neural tube. Therefore, this receptor could account at least in part for the trophic functions attributed to the 5-HT2-like receptors.

Animals↗
PubMed1993

Metabolism of 6-fluoro-DL-tryptophan and its specific effects on the rat brain serotoninergic pathway.

We administered 6-fluoro-DL-tryptophan (6F-Trp) to rats (50-200 mg/kg i.p.) and evaluated its neurochemical effects on central catechole and indole compounds; we also determined the time course of its action, together with its metabolism and kinetics in four rat brain areas. Neither norepinephrine nor dopamine and its major metabolites were affected by 6F-Trp. With regard to serotonin (5-HT), 6F-Trp induced a transient depletion in all the brain areas studied, with a maximum of about 60-65% obtained between 1 and 3 hr depending on the dose administered. After 6 hr, 5-HT levels generally returned to control values. 5-Hydroxyindolacetic acid (5-HIAA) levels were also reduced 3 hr after administration (-40 to -60%). A large dose-dependent increase in tryptophan (Trp) was observed in the four brain areas, possibly because of an inhibition of Trp incorporation into protein, as suggested by experiments with mouse neuroblastoma cells. The brain elimination half-life of 6F-Trp was estimated at 0.5-1 hr. Regarding 6F-Trp metabolism, three new compounds were detected in all four brain areas after 6F-Trp administration. They were identified by means of liquid chromatography with electrochemical detection and/or radioenzymology, in comparison with fluorinated standards, or after NSD 1015 or pargyline coadministration with 6F-Trp. The first two 6F-Trp metabolites detected were probably 6-fluoro-5-hydroxytryptophan and 6-fluoro-5-HIAA. The third, identified and quantified by means of the two analytical methods, was 6-fluoro-5-HT (6F-5-HT). These findings suggest that 6F-Trp could be used as the in vivo precursor of 6F-5-HT with a view to tracing neuronal serotoninergic pools, as has already been done with platelets.

Animals↗
PubMed1993

PrP polymorphisms associated with natural scrapie discovered by denaturing gradient gel electrophoresis.

Scrapie is a transmissible degenerative disease of the central nervous system occurring naturally in sheep and goats. An abnormal protease-resistant form of the host-encoded prion protein (PrP) accumulates in the brains of affected animals. As Sip, a gene controlling the incubation period of experimental and natural scrapie, is linked to the single-copy sheep PrP gene, we sought PrP coding sequence polymorphisms in flocks from the Romanov and Ile-de-France breeds endemically affected with natural scrapie. DNA samples from 153 sheep, including 29 natural scrapie cases, were screened by using polymerase chain reactions and denaturing gradient gel electrophoresis. Four predicted amino acid substitutions were found in the center of the PrP coding region: 112 Met-->Thr, 136 Ala-->Val, 154 Arg-->His, and 171 Gln-->Arg. These substitutions appeared mutually exclusive, defining five coding alleles. The 136Val allele, substituting a highly conserved Ala residue, in a homozygous or heterozygous state correlated with susceptibility to natural scrapie (chi 2 = 64.33, P < 0.001). This correlation indicates that the 136 Val allele may modulate development of the disease, implying a pivotal role for PrP molecules in natural scrapie, as has been observed for experimental scrapie and human prion diseases.

Amino Acid Sequence↗
PubMed1993

Characterization of estrone sulfatase activity in human thrombocytes.

Estrone sulfatase is an important enzyme which catalyzes the production of estrone from estrone sulfate in a variety of human and animal tissues. We report, for the first time, on the presence of estrone sulfatase activity in thrombocytes from human blood. Incubation of [3H]estrone sulfate in the presence of human thrombocyte lysates resulted in the formation of [3H]estrone as assessed by two-dimensional TLC. Estrone sulfatase activity was localized in the mitochondrial-microsomal fraction in thrombocytes from human blood. The enzyme was thermostable and had an optimum pH of 5.60 in acetate buffer. The highest activity was obtained in the presence of 0.1% of either Nonidet P-40 or Triton X-100. Phosphate ions (1 mM) inhibited the enzyme activity by 64% and similar effects were observed in the presence of platelet-free plasma. Endogenous inhibitors had no effect on the observed enzyme activity under assay conditions as evidenced in this study. The apparent Km value was 3.16 +/- 0.08 microM for [3H]estrone sulfate and V was 188.5 +/- 2.6 (mean +/- SEM, n = 22) pmol.mg protein-1.h-1. Comparison between two thrombocyte preparative procedures provided evidence that thrombocyte estrone sulfatase activity should be measured in thrombocyte samples representing the whole thrombocyte population. This parameter appeared critical for accurate measurements of enzyme activity. The presence of estrone sulfatase activity in human thrombocytes provides a new non-invasive tool for the study of this activity both in physiological and pathological conditions which could be of potential clinical relevance.

Adult↗
PubMed1993

In vitro production of cytokines by bone surface-derived osteoblastic cells in normal and osteoporotic postmenopausal women: relationship with cell proliferation.

To evaluate the role of cytokines produced by osteoblasts in the pathophysiology of bone lesions in postmenopausal osteoporosis (PMOP), we have determined by RIA and immunoradiometric assays the levels of prostaglandin E2 (PGE2), interleukin-1 beta (IL-1), tumor necrosis factor-alpha (TNF alpha), and IL-6 released by cultured bone surface-derived osteoblastic (OB) cells isolated from 24 untreated PMOP women with high, low, or normal bone turnover on bone biopsy. OB cells isolated from patients with high bone formation had a 2-fold increased proliferation rate in vitro compared to OB cells from patients with normal or low bone formation or OB cells from age-matched controls. The spontaneous in vitro production per cell protein of PGE2, IL-1, and TNF alpha, but not of IL-6, was 2- to 3-fold lower in rapidly proliferating OB cells isolated from PMOP patients with high bone formation compared to OB cells from patients with normal or low proliferation or control cells. Treatment with 10 nmol/L 1,25-dihydroxyvitamin D (48 h) increased PGE2 levels to normal values in OB cells with a high proliferation rate, but decreased PGE2 production in cells with low proliferation and in control cells, suggesting that the release of PGE2 was dependent on the stage of maturation of OB cells. Significant correlations were found between IL-1 and TNF alpha (r = 0.87; P < 0.001), IL-1 and PGE2 (r = 0.46; P < 0.05), IL-6 and IL-1 (r = 0.39; P < 0.05), and IL-6 and TNF alpha (r = 0.49; P < 0.05), suggesting that the production of these cytokines was under reciprocal control. The results indicate that the in vitro production of PGE2, IL-1, and TNF alpha, but not IL-6, by OB cells isolated from patients with PMOP is related to the proliferation rate of these cells and the rate of bone formation. The variable production of cytokines by OB cells may contribute to the histological heterogeneity of bone formation in PMOP.

Aged↗
PubMed1993

A new point mutation in the prion protein gene at codon 210 in Creutzfeldt-Jakob disease.

We screened 16 cases of sporadic Creutzfeldt-Jakob disease (CJD) and 28 healthy control subjects to detect possible polymorphisms in their prion protein gene (PRNP). The molecular analysis of the PRNP coding sequence was performed using denaturing gradient gel electrophoresis of polymerase chain reaction products and direct sequencing. We identified (1) a silent mutation at codon 177 in a healthy individual, (2) a codon 200 glutamate-to-lysine substitution in a 48-year-old CJD-affected Libyan Jew, and (3) a G-to-A point substitution at codon 210, leading a valine-to-isoleucine change, in a 63-year-old French CJD patient. This new mutation occurs in a highly conserved part of the PRNP coding sequence, close to the known CJD-associated codon 200 mutation, and might be linked to a symptomatologic and neuropathologic pattern of typical sporadic CJD. This mutation was also present in a sister of the patient who died at the age of 67 without neurologic symptomatology.

Aged↗
PubMed1992

Effects of endothelins on the human megakaryoblastic cell line MEG-01.

Some effects of endothelin-1 (ET-1) were studied on the megakaryoblastic cell line MEG-01. ET-1 induced an elevation of the intracellular levels of Ca2+([Ca2+]i) as measured with the fluorescent indicator indo-1, which consists of an initial transient increase and an ensuing sustained plateau. The plateau phase was abolished by removal of extracellular Ca2+. In addition, ET-1 induced a rapid (within 5 s) increase in the accumulation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and more delayed increases in Ins(1,3,4)P3 and Ins(1,3,4,5)P4, but did not modify cAMP levels. ET-1 homologues (ET-2, ET-3, sarafotoxin 6b and vasointestinal constrictor) also induced biphasic effects on [Ca2+]i. The Ca2+ elevation was concentration dependent, the order of potency being sarafotoxin 6b > ET-1 > ET-2 = vasointestinal constrictor > ET-3. The actions of ET analogs in raising [Ca2+]i were mutually exclusive, suggesting that they act through the same mechanism. These results suggest that cells of the megakaryoblast/megakaryocyte lineage are targets for endothelins.

Calcium↗