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Biomedical subjects

J M Launay

Publications and source records attributed to J M Launay.

At least 55 records · Page 3Linked to original sources
PubMed1999

Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives.

BACKGROUND: Whole blood serotonin (5-HT) and C-terminally directed beta-endorphin protein immunoreactivity (C-ter-beta-EP-ir) are known to be elevated in autistic subjects and might be possible markers of genetic liability to autism. This study thus investigates the familial aggregation of 5-HT and of C-ter-beta-EP-ir levels in first degree relatives of autistic probands. METHODS: In a sample of 62 autistic subjects and 122 of their first-degree relatives, compared to age and sex-matched controls, we measured 5-HT by radioenzymology and C-ter-beta-EP-ir by radioimmunoassay. RESULTS: We confirm the previously reported familiality of hyperserotoninemia in autism as mothers (51%), fathers (45%) and siblings (87%) have elevated levels of 5-HT, and we reveal presence of elevated levels of C-ter-beta-EP-ir in mothers (53%) of autistic subjects. CONCLUSIONS: Familial aggregation of quantitative variables, such as concentration of neurotransmitters, within unaffected relative could serve as an intermediate phenotype and might thus help the search of genetic susceptibility factors in autism.

Adolescent↗
PubMed1999

Apolipoprotein(a) size polymorphism in young adults with ischemic stroke.

High serum lipoprotein(a) (Lp(a)) concentration which is largely determined by genetic factors, mainly the apolipoprotein(a) (apo(a)) polymorphism, is associated with ischemic cerebrovascular disease. The aim of this study was to investigate whether apo(a) size was associated with acute ischemic stroke in young adults for which causal factors often remain undetermined. Lipid parameters, Lp(a) concentration and apo(a) isoform size distribution were determined in 90 young patients (37.4+/-8.7 years) with acute cerebral ischemia, and compared to those of control subjects with similar age and sex ratio. Apo(a) size was expressed as its apparent number of kringle 4 (Kr 4) repeats. Serum Lp(a) concentrations were significantly higher in patients than in controls (median values: 0.18 vs. 0.07 g/l, P=0.009) and were as expected inversely related to the number of kringle 4 repeats in both controls (r2=-0.61, P < 0.001) and patients (r2=-0.56, P < 0.001). However there was no difference in the apo(a) isoform size distributions between the two groups (median isoform size: 27 vs. 27 Kr 4, P=0.25). Lp(a) levels were increased as well in patients with size apo(a) isoform < or = 22 Kr 4 as in those with isoforms > 25 Kr 4. Multivariate analysis showed that apo(a) phenotype did not appear as a risk factor for cerebrovascular infarction. Thus, our results indicate that serum Lp(a) was significantly increased in young people with ischemic stroke but fail to reveal a role of small-sized apo(a) isoforms in the occurrence of this event. They suggest that other factors, genetic or environmental in nature, than the apo(a) size contribute to increase the serum Lp(a) concentrations in these young patients.

Acute Disease↗
PubMed1999

Maternal and zygotic control of serotonin biosynthesis are both necessary for Drosophila germband extension.

In the accompanying paper, we report that Drosophila gastrulae genetically depleted for the 5-HT(2Dro) serotonin receptor or for serotonin show abnormal germband extension. In wild-type gastrulae, peaks of both the 5-HT(2Dro) receptor and serotonin coincide precisely with the onset of germband extension. Here, we assessed the genetic requirement for this peak of serotonin. We report the characterisation of the serotonin content of individual Drosophila embryos, progeny from flies heterozygous for mutations in genes that are involved in the serotonin synthesis pathway and include the GTP-cyclohydrolase, tryptophan hydroxylase and DOPA decarboxylase loci. The peak of serotonin synthesis at the beginning of germband extension appears strictly dependent upon the maternal deposition of biopterins, products of GTP-cyclohydrolase and cofactors of tryptophan hydroxylase and upon the zygotic synthesis of both tryptophan hydroxylase and DOPA decarboxylase enzymes. Mutant embryos with an impairment in this peak of serotonin synthesis die with a cuticular organisation which is also observed in embryos deficient for the 5-HT(2Dro) receptor. This characteristic cuticular phenotype is thus the hallmark of desynchronisation of the morphogenetic movements during gastrulation. Together, these findings provide additional support for the notion that serotonin, acting through the 5-HT(2Dro) receptor, is necessary for proper gastrulation.

Alleles↗
PubMed1999

Serotonin synchronises convergent extension of ectoderm with morphogenetic gastrulation movements in Drosophila.

During Drosophila gastrulation, convergent extension of the ectoderm is required for germband extension. Adhesive heterogeneity within ectodermal cells has been proposed to trigger the intercalation of cells responsible for this movement. Segmentation genes would impose this heterogeneity by establishing a pair-rule pattern of cell adhesion properties. We previously reported that the serotonin receptor (5-ht(2Dro)) is expressed in the presumptive ectoderm with a pair-rule pattern. Here, we show that the peaks of 5-ht(2Dro) expression and serotonin synthesis coincide precisely with the onset of convergent extension of the ectoderm. Gastrulae genetically depleted of serotonin or the 5-ht(2Dro) receptor do not extend their germband properly, and the ectodermal movements becomes asynchronous with the morphogenetic movements in the endoderm and mesoderm. Associated with the beginning of this desynchronisation, is an altered subcellular localisation of adherens junctions within the ectoderm. Combined, these data highlight the role of the ectoderm in Drosophila gastrulation and support the notion that serotonin signalling through the 5-HT(2Dro) receptor triggers changes in cell adhesiveness that are necessary for cell intercalation.

Animals↗
PubMed1999

Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: effects of clomipramine and fluoxetine.

BACKGROUND: The central serotonergic system has been implicated in the pathophysiology of depression and in the mechanism of the action of antidepressant drugs. The human platelet has been proposed as a peripheral model of central serotonergic neurons. METHODS: Six peripheral serotonergic parameters were determined simultaneously in 27 patients with unipolar depression before and after 2, 4, and 12 weeks of clomipramine or fluoxetine treatment according to the psychiatrist. RESULTS: In patients with depression versus matched control subjects, platelet [3H]paroxetine binding sites were found to be significantly decreased (2.10 +/- 0.70 versus 3.88 +/- 0.77 fmol/10(9) platelets; P = .0001), platelet serotonin (5-HT) content was found to be significantly decreased (1.90 +/- 1.52 versus 2.74 +/- 1.12 nmol/10(9) platelets; P = .001), and platelet inositol triphosphate levels were found to be significantly increased (2.85 +/- 0.70 versus 1.85 +/- 0.77 fmol/10(9) platelets; P = .0001). No significant difference between patients and control subjects was found for platelet [3H]-lysergic acid diethylamide ([3H]LSD) binding sites, aggregation tests with 5-HT or adenosine diphosphate and plasma 5-HT levels. Treatment with both clomipramine and fluoxetine gradually further reduced the density of platelet [3H]paroxetine binding sites and induced a dramatic decrease in platelet and plasma 5-HT levels. With clomipramine, the decreased blood 5-HT levels are associated with increased platelet [3H]LSD binding sites and aggregation responses. After 12 weeks, nonresponders to both treatments had platelet inositol triphosphate levels that were still increased (2.81 +/- 0.75 fmol/10(9) platelets) when responders levels were not different from those of control subjects (1.41 +/- 0.45 versus 1.70 +/- 0.25 fmol/10(9) platelets). CONCLUSIONS: Drug-free patients with depression had simultaneously decreased 5-HT transporter (5-HTT) sites and overstimulated phosphoinositide signaling systems. Clomipramine and fluoxetine treatments, which further decreased the density of 5-HTT sites, allowed platelet inositol triphosphate levels to return to normal values only in responders.

Adult↗
PubMed1998

Mouse 5-HT2B receptor-mediated serotonin trophic functions.

5-HT2B receptors, in addition to phospholipase C stimulation, are able to trigger activation of the proto-oncogene product p21ras. During mouse embryogenesis, a peak of 5-HT2B receptor expression is detected at the neurulation stage; we localized the 5-HT2B expression in neural crest cells, heart myocardium, and somites. The requirement for functional 5-HT2B receptors shortly after gastrulation, is supported by culture of embryos exposed to 5-HT2B-high affinity antagonist such as ritanserin, which induces morphological defects in the cephalic region, heart and neural tube. Functional 5-HT2B receptors are also expressed during the serotonergic differentiation of the mouse F9 teratocarcinoma-derived clonal cell line 1C11. Upon 2 days of induction by cAMP, 5-HT2B receptors become functional, and on day 4, the appearance of 5-HT2A receptors coincides with the onset of active serotonin transporter by these cells. Active serotonin uptake is modulated by serotonin suggesting autoreceptor functions for 5-HT2B receptors.

Animals↗
PubMed1998

Relationships between low red blood cell count and clinical response to fluoxetine in depressed elderly patients.

Biological variables specifically linked with serotonin deficiency were assessed in geriatric depression. Sixteen depressed patients, all > or = 60 years of age and with scores on the Montgomery-Asberg Depression Rating Scale (MADRS) > or = 20, were treated with fluoxetine (20 mg/day) for 42 days. Biological variables measured on days 1 and 42 included whole blood and plasma serotonin, plasma total and free tryptophan, and platelet paroxetine and ketanserin binding. Seven of the 16 patients showed a positive clinical response (i.e. MADRS score < or = 12 at day 42). The pre-treatment red blood cell count was the variable most related to clinical response; low levels were found in almost all responders. To a lesser extent, plasma free tryptophan before treatment was also correlated to therapeutic response, with lower values being found in responders. During treatment, plasma free tryptophan was increased in responders and decreased in non-responders. The finding that elderly depressed patients with low pre-treatment red blood cell counts subsequently responded to fluoxetine treatment is consistent with the view that tryptophan, the precursor of serotonin in brain, is taken up by red blood cells.

Aged↗
PubMed1998

Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression.

To explore the involvement of serotonin transporter (5HTT) in mood disorder, we studied two polymorphisms of the 5HTT gene (a variable number of tandem repeats in the second intron (VNTR) and a 44 bp insertion/deletion in the 5HTT linked polymorphic region (5-HTTLPR)) in a sample of unipolar and bipolar patients and controls. Homozygosity for the short variant of the 5-HTTLPR was significantly more frequent in bipolar patients than in controls (chi2 = 4.68, d.f. = 1, P = 0.03) whereas there was no difference between bipolar patients and controls for allele distribution, suggesting a recessive effect. The interaction between the two markers suggests that the two polymorphisms probably have independent effects to determine the susceptibility to affective disorder. Further studies are required to identify the precise phenotype associated with 5HTT polymorphisms in depressed patients.

Adult↗
PubMed1998

Cross-talk between 5-hydroxytryptamine receptors in a serotonergic cell line. Involvement of arachidonic acid metabolism.

The study of signaling cascades and of functional interactions between 5-hydroxytryptamine (5-HT) receptor pathways with heterogenous brain cell populations remains an arduous task. We took advantage of a serotonergic cell line to elucidate cross-talks between 5-HT receptors and to demonstrate the involvement of two 5-HT2 receptor subtypes in the regulation of 5-HT1B/1D function. The inducible 1C11 cell line has the unique property of acquiring within 4 days a complete serotonergic phenotype (1C11* cells), including three 5-HT receptors. 5-HT1B/1D and 5-HT2B receptors are expressed since day 2 of the serotonergic differentiation while 5-HT2A receptors are induced at day 4. We first established that 5-HT2B receptors are coupled with the phospholipase A2 (PLA2)-mediated release of arachidonic acid (AA) and that the activation of 5-HT2B receptors in 1C11*d2 cells inhibits the 5-HT1B/1D receptor function via a cyclooxygenase-dependent AA metabolite. At day 4, this 5-HT2B-mediated inhibition of the 5-HT1B/1D function can be blocked upon concomitant 5-HT2A activation although a 5-HT2A/PLA2 positive coupling was evidenced. This suggests the existence in 1C11*d4 cells of pathway(s) for 5-HT2A receptors, distinct from PLC and PLA2. Finally, this study reveals the antagonistic roles of 5-HT2A and 5-HT2B receptors in regulating the function of 5-HT1B/1D, a receptor involved in neuropsychiatric disorders and migraine pathogenesis.

Arachidonic Acid↗
PubMed1998

Determination of melatonin in rat pineal, plasma and retina by high-performance liquid chromatography with electrochemical detection.

A sensitive method for the routine measurement of endogenous melatonin (MEL) in pineal, retina and plasma rat tissues has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Quantification limit for MEL was 0.2 ng/mg protein in pineal, 15 pg/ml in plasma and 2.0 pg/mg protein in retina. To improve both MEL quantification and the reproducibility of the assay, an internal standard was used when an extraction in organic solvent was required, in contrast with other available chromatographic methods. MEL values and the circadian profile obtained in this study from both rat pineal and plasma agree with those reported previously. This method allows MEL detection in mammal retina, particularly in rat, where MEL levels are very low.

Animals↗
PubMed1998

Effects of monoamine oxidase A inhibition on barrel formation in the mouse somatosensory cortex: determination of a sensitive developmental period.

Genetic inactivation of monoamine oxidase A (MAOA) in C3H/HeJ mice causes a complete absence of barrels in the somatosensory cortex, and similar alterations are caused by pharmacological inhibition of MAOA in wild type mice. To determine when and how MAOA inhibition affects the development of the barrel field, the MAOA inhibitor clorgyline was administered to mice of the outbred strain OF1 for various time periods between embryonic day 15 (E15) and postnatal day 7 (P7), and the barrel fields were analyzed with cytochrome oxidase and Nissl stains in P10 and adult mice. High-pressure liquid chromatography measures of brain serotonin (5-HT) showed three- to eightfold increases during the periods of clorgyline administration. Perinatal mortality was increased and weight gain was slowed between P3 and P6. Clorgyline treatments from E15 to P7 or from P0 to P7 disrupted the formation of barrels in the anterior snout representation and in parts of the posteromedial barrel subfield (PMBSF). Treatments from P0 to P4 caused similar although less severe barrel field alterations. Clorgyline treatments only during embryonic life or starting on P4 caused no detectable abnormalities. In cases with barrel field alterations, a rostral-to-caudal gradient of changes was noted: Rostral barrels of the PMBSF were most frequently fused and displayed an increased size tangentially. Thus, MAOA inhibition resulting in increased brain levels of 5-HT affects barrel development during the entire first postnatal week, with a sensitive period between P0 and P4. The rostral-to-caudal gradient of changes in the barrel field parallels known developmental gradients in the sensory periphery and in the maturation thalamocortical afferents. The observed barrel fusions could correspond to a default in the initial segregation of thalamic fibers or to a continued, exuberant growth of these fibers that overrides the tangential domain that is normally devoted to individual whiskers.

Animals↗
PubMed1998

Renal tolerance of digoxin-specific Fab fragments in the rat.

Renal markers were investigated over 96 h in male Sprague-Dawley rats after i.v. administration of 10.7 mg kg(-1) of digoxin-specific Fab fragments (DSFab). The dose was calculated by an allometric equation as equivalent to a high clinical dose. DSFab both alone and pre-incubated with digoxin were tested. None of the markers (creatinine clearance, fractional excretion of sodium, urinary activities of gamma-glutamyl transferase and alkaline phosphatase) were significantly altered in treated rats compared to control rats. Thus no renal toxicity due to DSFab alone or bound to digoxin was observed when administered at 10.7 mg kg(-1) in rats.

Alkaline Phosphatase↗
PubMed1998

Genetic selection of mouse lines differing in sensitivity to a benzodiazepine receptor inverse agonist.

Mice were selectively bred according to their sensitivity or their resistance to the convulsive effects of a 4-mg/kg dose of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine (BZ) receptor inverse agonist. The selection proved to be easy, with a clear separation of the two lines, convulsing with short latencies or resistant, already at the first generation of selection. Selection of a third line of animals convulsing with long latencies did not succeed. 3H-Ro 15-1788 binding analysis provided evidence for a strong decrease in Bmax in the resistant line.

Animals↗
PubMed1998

Human bone marrow platelet progenitors express and release endothelin-1.

Because it has been shown that human platelet precursors from normal bone marrow express preproendothelin-1 (ET-1) mRNA, this investigation was designed to find out whether these cells could synthesize and release mature ET-1 and express ET receptors. Therefore, we examined the expression of endothelin-converting enzyme (ECE) mRNA and of mRNAs for ET receptors in cells purified from normal bone marrow and measured immunoreactive (ir)ET in their culture medium. RT-PCR applied to RNAs from platelet precursors yielded amplified fragments of the expected sizes of 567, 428, and 299 bp for ECE, ETB and ETA receptors, respectively. These cells released ir-ET into the culture medium in a time-dependent fashion. These results raise the possibility of autocrine actions of the intrinsic ET system in bone marrow platelet precursor cells.

Aspartic Acid Endopeptidases↗
PubMed1998

Phosphoramidon-sensitive and -insensitive endothelin-converting enzyme in human megakaryoblastic cell lines.

The human megakaryoblastic cell lines HEL, MEG-01, and DAMI express preproendothelin-1 mRNA. This investigation was designed to find out whether they could also express endothelin-converting enzyme (ECE) and release mature endothelin (ET). RT-PCR applied to RNA isolated from the cell lines amplified fragments of the expected size. The amplified cDNA of MEG-01 was submitted to restriction enzymes, which generated the expected subfragments. Membrane ECE activity was phosphoramidon-sensitive, in contrast to the cytosolic activity capable of producing ET-1 from big ET-1. The three cell lines produced ir-ET in a time-dependent manner. These results show that human megakaryoblastic cell lines express functional, phosphoramidon-sensitive and insensitive ECE activity and produce mature ET.

Aspartic Acid Endopeptidases↗
PubMed1998

Effect of dexfenfluramine treatment in rats exposed to acute and chronic hypoxia.

The anorexiant dexfenfluramine, which inhibits 5-hydroxytryptamine (5-HT) uptake, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. The aim of this study was to investigate in rats whether dexfenfluramine (1) alters the pulmonary vasomotor effects of 5-HT and (2) aggravates the development of pulmonary hypertension during exposure to various levels of chronic hypoxia. In isolated lungs from normoxic rats, dexfenfluramine up to 10(-4) M did not elicit any vasoactive effects, and neither did pretreatment with dexfenfluramine (10[-5] M in the perfusate) modify the vasoactive effects of 5-HT. In normoxic conscious rats, dexfenfluramine given intravenously potentiated the pulmonary pressor response to acute hypoxia (10% O2). In rats chronically treated with dexfenfluramine during a 2-wk exposure to 15% or 10% O2, plasma 5-HT concentrations were significantly increased compared with hypoxic controls, whereas no differences were found for pulmonary artery pressure, right ventricular hypertrophy, or pulmonary vessel muscularization. In contrast, a continuous 5-HT infusion providing a sustained increase in plasma 5-HT levels was associated with increased muscularization of distal pulmonary arteries in response to 10% O2. Simultaneous administration of dexfenfluramine prevented the effect of exogenous 5-HT on vascular remodeling. Our findings show that dexfenfluramine does not potentiate the development of pulmonary hypertension in rats exposed to chronic hypoxia, despite its effect on plasma 5-HT concentrations.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗