Showing papers by "French Institute of Health and Medical Research published in 1991"

Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome

Abstract: The fragile X syndrome, a common cause of inherited mental retardation, is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of...

Body Mass Index variations: centiles from birth to 87 years.

Abstract: This report provides Body Mass Index (weight/height2) values for the French population from birth to the age of 87 years. BMI curves increase during the first year, decrease until the age of 6, increase again up to 65 years and decrease thereafter. These variations reflect the total changes of fat body mass during life. The 50th centile values of Wt/Ht2 at the ages of 20, 40, 60, 80 years are 21.5, 24.6, 25.4, 24.4 kg/m2 for men and 20.6, 22.6, 24.1, 23.4 kg/m2 for women. The values for the 3rd, 50th and 97th centiles in the middle years are approximately 18, 24 and 32 kg/m2. Graphs for these and four other percentiles are plotted against age, and two other graphs summarising the variation and skewness of the Wt/Ht2 distribution are provided to calculate exact percentiles and Z-scores for individuals.

Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia.

Abstract: Levels of iron, copper, zinc and manganese were measured by inductively coupled plasma spectroscopy in frozen postmortem brain tissue from patients with Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy with strionigral degeneration (MSA), and Huntington's disease (HD) compared with control subjects. Total iron levels were found to be elevated in the areas of basal ganglia showing pathological change in these disorders. In particular, total iron content was increased in substantia nigra in PD, PSP and MSA, but not in HD. Total iron levels in the striatum (putamen and/or caudate nucleus) were increased in PSP, MSA and HD but not in PD. Total iron levels were decreased in the globus pallidus in PD. There were no consistent alterations of manganese levels in basal ganglia structures in any of the diseases studied. Copper levels were decreased in the substantia nigra in PD, and in the cerebellum in PSP, and were elevated in the putamen and possibly substantia nigra in HD. Zinc levels were only increased in PD, in substantia nigra and in caudate nucleus and lateral putamen. Levels of the iron binding protein ferritin were measured in the same patient groups using a radio-immunoassay technique. Increased iron levels in basal ganglia were generally associated with normal or elevated levels of ferritin immunoreactivity, for example, the substantia nigra in PSP and possibly MSA, and in putamen in MSA. The exception was PD where there was a generalized reduction in brain ferritin immunoreactivity, even in the substantia nigra. An increase in total iron content appears to be a response to neurodegeneration in affected basal ganglia regions in a number of movement disorders. However, only in PD was there an increased total iron level, decreased ferritin content, decreased copper content, and an increased zinc concentration in substantia nigra. These findings suggest an alteration of iron handling in the substantia nigra in PD. Depending on the form in which the excess iron load exists in nigra in PD, it may contribute to the neurodegenerative process.

Histaminergic transmission in the mammalian brain

Abstract: Article de synthese sur le metabolisme de l'histamine, sur la localisation des voies neuronales et des recepteurs histaminergiques. Role de l'histamine dans le controle neuroendocrine, dans la regulation cardiovasculaire, dans la circulation cerebrale, dans la thermoregulation, dans le controle de certains comportements, dans la nociception, dans la vigilance, le sommeil et l'eveil chez les mammiferes

Incidence and main causes of infertility in a resident population (1 850 000) of three French regions (1988–1989)*

Abstract: To estimate the prevalence and main causes of infertility, a multicentre survey was conducted over 1 year (July 1988-June 1989) in three regions of France. All the 1686 couples in these regions, who consulted a practitioner for primary or secondary infertility during this period, were included in the investigation. The prevalence rate of infertility was found to be 14.1%, indicating that one woman out of seven in France will consult a doctor for an infertility problem during her reproductive life. The main causes of female infertility were ovulation disorders (32%) and tubal damage (26%), and of male infertility oligo-terato-asthenozoospermia (21%), asthenozoospermia (17%), teratozoospermia (10%) and azoospermia (9%). Infertility was also found to be caused by disorders in both the male and female partners together; thus in 39% of cases both the man and woman presented with disorders. The woman alone was responsible for infertility in one-third of cases and the man alone in one-fifth. Unexplained infertility was found in 8% of the couples surveyed.

A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.

Abstract: Background. In primary biliary cirrhosis the hepatic lesions may result, at least in part, from the intracellular accumulation of potentially toxic endogenous bile acids. Preliminary work suggests that the administration of ursodiol (also called ursodeoxycholic acid), a hydrophilic bile acid without hepatotoxicity, leads to improvement in the condition of patients with primary biliary cirrhosis. Methods. We conducted a two-year, multicenter, double-blind trial to compare the efficacy of ursodiol with that of placebo. Patients with biopsy-proved primary biliary cirrhosis were randomly assigned to receive either ursodiol (13 to 15 mg per kilogram of body weight per day) (n = 73) or placebo (n = 73). Treatment failure was defined as a doubling of bilirubin levels to more than 70 μmol per liter or the occurrence of a severe complication (ascites or variceal bleeding) or an adverse reaction. Results. Treatment failed in 6 patients in the ursodiol group, as compared with 13 in the placebo group (P<0.01...

Cortical control of reflexive visually-guided saccades.

Abstract: Reflexive visually-guided saccade triggering may be facilitated or inhibited by the cerebral cortex. To study this control, saccades made towards suddenly appearing visual targets (saccade task) or away from them (antisaccade task) were recorded electro-oculographically in 45 patients with limited unilateral cerebral infarction. Lesions affected (1) the superior part of the angular gyrus (area 39 of Brodmann) in the posterior parietal cortex (PPC), (2) the dorsolateral prefrontal cortex (PFC) (area 46 of Brodmann), (3) the frontal eye field (FEF), or (4) the supplementary motor area (SMA). As these 4 types of lesions were located either in the right or the left cerebral hemisphere, patients were divided into 8 groups. Saccade latency, in the saccade task, and the percentage of errors (misdirected saccades made towards the visual target), in the antisaccade task, were compared in each group of patients with the values of 20 control subjects. In the saccade task, saccade latency was significantly increased bilaterally in the right PPC group. In the left PPC group, the increase in latency was less marked, and significant only for saccades made contralaterally to the lesion. In the different frontal groups, latency was unchanged or only slightly increased. These results confirm that the main area facilitating the triggering of reflexive visually-guided saccades is located in the PPC, in or near the superior part of the angular gyrus. The difference between right and left parietal lesions could be due to the predominance of the right hemisphere in the control of these saccades. In the antisaccade task, the percentage of errors was significantly increased bilaterally in both PFC groups compared with the control group and also to the FEF and SMA groups. These results suggest that the PFC is the main area in the cerebral hemisphere inhibiting reflexive visually-guided saccades.

Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation.

Abstract: Background. The fragile X syndrome, the most common form of inherited mental retardation, is caused by mutations that increase the size of a specific DNA fragment of the X chromosome (in Xq27.3). Affected persons have both a full mutation and abnormal DNA methylation. Persons with a smaller increase in the size of this DNA fragment (a premutation) have little or no risk of retardation but are at high risk of having affected children or grandchildren. The passage from premutation to full-mutation status occurs only with transmission from the mother. We have devised a method of identifying carriers of these mutations by direct DNA analysis. Method. We studied 511 persons from 63 families with the fragile X syndrome. Mutations and abnormal methylation were detected by Southern blotting with a probe adjacent to the mutation target. Analysis of EcoRI and EagI digests of DNA distinguished clearly in a single test between the normal genotype, the premutation, and the full mutation. Results. DNA analysis...

Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation.

Abstract: Mouse gut intraepithelial lymphocytes (IEL) consist mainly (90%) of two populations of CD8+ T cells. One bears heterodimeric alpha/beta CD8 chains (Lyt-2+, Lyt-3+), a T cell receptor (TCR) made of alpha/beta chains, and is Thy-1+; it represents the progeny of T blasts elicited in Peyer's patches by antigenic stimulation. The other bears homodimeric alpha/alpha CD8+ chains, contains no beta chain mRNA, and is mostly Thy-1- and TCR-gamma/delta + or -alpha/beta +; it is thymo-independent and does not require antigenic stimulation, as shown by its presence: (a) in nude and scid mice; (b) in irradiated and thymectomized mice repopulated by T-depleted bone marrow cells bearing an identifiable marker; (c) in thymectomized mice treated by injections of monoclonal anti-CD8 antibody, which lead to total depletion of peripheral CD8+ T lymphocytes; and (d) in germ-free mice and in suckling mice. In young nude mice, alpha/alpha CD8 chains, CD3-TCR complexes, and TCR mRNAs (first gamma/delta) are found on IEL, while they are not detectable on or in peripheral or circulating lymphocytes or bone marrow cells. IEL, in contrast to mature T cells, contain mRNA for the RAG protein, which is required for the rearrangement of TCR and Ig genes. We propose that the gut epithelium (an endoderm derivative, as the thymic epithelium) has an inductive property, attracting progenitors of bone marrow origin, and triggering their TCR rearrangement and alpha/alpha CD8 chains expression, thus giving rise to a T cell population that appears to belong to the same lineage as gamma/delta thymocytes and to recognize an antigenic repertoire different from that of alpha/beta CD8+ IEL.

Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein.

Abstract: OOCYTES arrested in the G2 phase of the cell cycle contain a p34cdc2/cyclin B complex which is kept in an inactive form by phosphorylation of its p34cdc2 subunit on tyrosine, threonine and perhaps serine residues (see refs 1 and 2 for review). The phos-phatase(s) involved in p34cdc2 dephosphorylation is unknown, but the product of the fission yeast cdc25+ gene3,4, and its homologues in budding yeast5 and Drosophila6 are probably positive regulators of the transition from G2 to M phase. We have purified the inactive p34cdc2/cyclin B complex from G2-arrested starfish oocytes. Addi-tion of the purified bacterially expressed product of the human homologue of the fission yeast cdc25+ gene7 (p54CDC25H) triggers p34cdc2 dephosphorylation and activates HI histone kinase activity in this preparation. We propose that the cdc25+ gene product directly activates the p34cdc2–cyclin B complex.

Corticosterone levels determine individual vulnerability to amphetamine self-administration.

Abstract: Individual vulnerability to the reinforcing properties of drugs appears to be an essential characteristic predisposing humans to addiction. In animals, a greater behavioral reactivity to a mild stress, such as exposure to a novel environment, is an index of the vulnerability to acquire amphetamine self-administration. Biological responses to stress as well as behavioral reactivity may predict such a vulnerability. In the present study, rats with a longer duration of corticosterone secretion after exposure to novelty showed facilitation of acquisition of amphetamine self-administration. Furthermore, corticosterone administration in nonpredisposed individuals increased the reinforcing value of the drug and facilitated the acquisition of amphetamine self-administration. These results indicate that the stress-related activity of the hypothalamic-pituitary-adrenal axis may play a role in the pathogenesis of psychostimulant addiction.

Retinoic acid receptors and cellular retinoid binding proteins. II, Their differential pattern of transcription during early morphogenesis in mouse embryos

Abstract: In situ hybridization with 35S-labelled RNA probes was used to study the distribution of transcripts of genes coding for the retinoic acid receptors, RAR-alpha, -beta and -gamma, and the cellular binding proteins for retinoic acid (CRABP I) and retinol (CRBP I), in mouse embryos during the period of early morphogenesis. Primary mesenchyme formation was associated with CRBP I labelling of both epiblast and mesenchyme of the primitive streak, while the CRABP probe labelled the migrating primary mesenchyme cells. Neural crest cell emigration and migration were associated with CRABP labelling of both neural epithelium (excluding the floor plate) and neural crest cells, while CRBP I expression was restricted to basal and apical regions of the epithelium (excluding the floor plate). The strongest neuroepithelial signal for CRABP was in the preoptic hindbrain. RAR-beta was present in presomitic stage embryos, being expressed at highest levels in the lateral regions. RAR-alpha was associated with crest cell emigration and migration, while RAR-gamma was present in the primitive streak region throughout the period of neurulation. There was a change from RAR-beta to RAR-gamma expression at the junction between closed and open neural epithelium at the caudal neuropore. RAR-alpha and RAR-beta were expressed at specific levels of the hindbrain and in the spinal cord. These distribution patterns are discussed in relation to segmental expression patterns of other genes, and to maturational changes in the caudal neuropore region. The CRABP transcript distribution patterns correlated well with known target tissues of excess retinoid-induced teratogenesis (migrating primary mesenchyme and neural crest cells, preoptic hindbrain), providing further support for our hypothesis that cells expressing CRABP are those that cannot tolerate high levels of RA for their normal developmental function.

Selective perturbation of visual input during prehension movements. 2. The effects of changing object size.

Abstract: 1. Subjects were instructed to reach and grasp cylindrical objects, using a precision grip. The objects were two concentric dowels made of translucent material placed at 35 cm from the subject. The inner ("small") dowel was 10 cm high and 1.5 cm in diameter. The outer ("large") dowel was 6 cm high and 6 cm in diameter. Prehension movements were monitored using a Selspot system. The displacement of a marker placed at the wrist level was used as an index for the transport of the hand at the location of the object. Markers placed at the tips of the thumb and the index finger were used for measuring the size of aperture of the finger grip. 2. Kinematics of transport and grasp components were computed from the filtered displacement signals. Movement time (MT), time to peak velocity (TPV) and time to peak deceleration (TPD) of the wrist, time to peak velocity of grip aperture (TGV), time to maximum grip aperture (TGA) were the main parameters used for comparing the movements in different conditions. Spatial paths of the wrist, thumb and index markers were reconstructed in two dimensions. Variability of the spatial paths over repeated trials was computed as the surface of the ellipses defined by X and Y standard deviations from the mean path. 3. Computer controlled illumination of one of the dowels was the signal for reaching toward that dowel. Blocks of trials were made to the small dowel and to the large dowel. Mean MT during blocked trials was 550 ms. The acceleration phase of the movements (measured by parameter TPV) represented 33% of MT. About half of MT (52%) was spent after TPD in a low velocity phase while the hand was approaching the object. This kinematic pattern was not influenced by whether movements were directed at small or large dowels. 4. Grip aperture progressively increased during transport of the hand. TGA corresponded to about 60% of MT, that is, maximum grip aperture was reached during the low velocity phase of transport. Following TGA, fingers closed around the object until contact was made. This pattern of grip formation differed whether the movement was directed at the large or the small dowel: TGA occurred often earlier for the small dowel, and the size of the maximum grip aperture was larger for the large dowel. Variability of both the wrist and finger spatial paths was larger during the first half of MT, and tended to become very low as the hand approached the dowels.(ABSTRACT TRUNCATED AT 400 WORDS)

Iron and Aluminum Increase in the Substantia Nigra of Patients with Parkinson's Disease: An X-Ray Microanalysis

Abstract: The levels of different elements were studied by x-ray microanalysis in the substantia nigra and the central gray substance of patients with Parkinson's disease, progressive supranuclear palsy, and matched controls In control brains, only iron, potassium, silicium, sodium, sulfur, and zinc were within the limit of detection of the technique The abundance of each element was different, but their respective concentrations in the two brain regions were similar, except for sulfur levels which were higher on neuromelanin aggregates in the substantia nigra than in nigral regions lacking neuromelanin, and in the central gray substance In Parkinson's disease, but not in progressive supranuclear palsy, nigral iron levels increased in regions devoid of neuromelanin and decreased on neuromelanin aggregates, but were unchanged in the central gray substance, when compared to control values Concentrations of the other elements in the central gray substance and substantia nigra were not different from controls in brains from patients with Parkinson's disease and progressive supranuclear palsy Analysis of Lewy bodies in the parkinsonian substantia nigra revealed high levels of iron and the presence of aluminum Metal abundance was not affected in progressive supranuclear palsy, in spite of the nigral cell death This suggests that the increased iron levels and the detection of aluminum observed in Parkinson's disease are not solely the consequence of the neuronal degeneration

Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes.

Abstract: Regulation of cardiac contraction by neurotransmitters and hormones is often correlated with regulation of the L-type Ca2(+)-channel current (ICa) through the opposite actions of two second messengers, cyclic AMP and cyclic GMP. While cyclic AMP stimulation of ICa is mediated by the activation of cyclic AMP-dependent protein kinase, inhibition of ICa by cyclic GMP in frog heart is largely mediated by activation of cyclic AMP phosphodiesterase. The present patch-clamp study reveals that, in rat ventricular cells, cyclic GMP can also regulate ICa via activation of endogenous cyclic GMP-dependent protein kinase (cGMP-PK). Indeed, the effect of cyclic GMP on ICa was mimicked by intracellular perfusion with the proteolytic active fragment of purified cGMP-PK. Moreover, cGMP-PK immunoreactivity was detected in pure rat ventricular myocytes by using a specific polyclonal antibody. These results demonstrate a dual mechanism for the inhibitory action of cyclic GMP in heart, as well as a physiological role for cGMP-PK in the control of mammalian heart function.

CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location.

Abstract: CD28, initially detected on human T lymphocytes with the help of antibodies, and CTLA-4, obtained by reverse genetics through its preferential expression in mouse activated T cells, are both single-V domain members of the Ig superfamily. Early work showed a relationship between these two molecules, which we wished to further document, in particular because of the growing realization of the functional importance of CD28 in some T cell activation pathways. Isolation and analysis of the mouse CTLA-4 gene and further analysis of the human CTLA-4 gene showed that both of these and the human CD28 gene share the same overall intron/exon organization. The nucleic acid sequence homology of the exons was found to extend across both molecules and species, whereas the 5' and 3' flanking regions exhibited homology across species but not between molecules. Message expression of human CTLA-4 was only detected in activated T cells and, thus, shares with that of mouse CTLA-4 and of mouse and human CD28 a lymphoid tissue distribution, although apparently broader for the latter. Two main human CTLA-4 transcripts of about 1.8 and 0.8 kb were detected, the smaller of which may derive, as reported for human CD28, from the use of an alternate degenerated polyadenylation signal sequence. The nucleic acid sequence data allowed a direct comparison of the four putative complete protein sequences of CD28 and CTLA-4 in the mouse and the human, showing striking homologies, especially in some stretches (such as a MYPPPY hexamer in the hinge region) conserved across molecules and across species. The mouse CD28 gene was localized to chromosome 1 band C by in situ hybridization with three different radioactive probes, indicating, together with previous data, that the CD28 and CTLA-4 genes map to the same chromosomal region in both the mouse and the human. Thus, CD28 and CTLA-4 were found to be strikingly similar in most respects, in terms of structure, sequence, expression, and gene location, furthermore in two species, strongly suggesting that their genes are the direct products of a duplication event and raising the possibility of functional homologies between the corresponding proteins.