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Biomedical subjects

P Evrard

Publications and source records attributed to P Evrard.

At least 19 recordsLinked to original sources
PubMed2001

Striatal and pontocerebellar hypoperfusion in Hallervorden-Spatz syndrome.

Hallervorden-Spatz syndrome is a group of rare and severe disorders marked by extrapyramidal symptoms and iron accumulation in the globi pallidi, usually visible by magnetic resonance imaging. To assist in determining the functional correlates of these structural abnormalities, positron emission tomography was used to measure regional cerebral blood flows and dopaminergic function in a patient with Hallervorden-Spatz syndrome that manifested as progressive generalized dystonia, optic atrophy, and bilateral pallidal "eye of the tiger" sign. Voxel-by-voxel analysis of positron emission tomography images revealed no pallidal abnormalities but demonstrated significant hypoperfusion of the head of the right caudate nucleus, pons, and cerebellar vermis. Dopaminergic function of the basal ganglia, which was assessed based on visual- analysis of fixation of 18F-labeled fluoro-levodopa, was normal. These data suggest that Hallervorden-Spatz syndrome pathogenesis is not confined to the globi pallidi, and these data also may help to generate new pathogenic hypothesis.

Brain↗
PubMed2001

Caffeine does not affect excitotoxic brain lesions in newborn mice.

Caffeine is frequently administered to human pre-term newborns although its neurological impact has not been fully evaluated. In the present study performed in mice, we examined the effects of caffeine administration on neonatal excitotoxic lesions of the periventricular white matter, which mimics several aspects of human periventricular leukomalacia. In this model, caffeine exposure did not worsen white matter lesions. These data suggest that neonatal caffeine administration might not affect clastic lesions in pre-term infants.

Animals↗
PubMed2001

Caffeine-induced telencephalic vesicle evagination in early post-implantation mouse embryos involves cAMP-dependent protein kinase (PKA) inhibition.

Other studies have shown that caffeine accelerates telencephalic vesicle evagination in early post-implantation mouse embryos. The present study examines the effect of caffeine on gene modulation in post-implantation mouse embryos. Using mRNA differential display, we observed that caffeine increased gene expression of the regulatory subunit (RI alpha) of cAMP-dependent protein kinase (PKA). RT--PCR analysis confirmed an increase in expression of this gene in caffeine-exposed embryos when compared with saline-treated controls. Using a fluorescent substrate of PKA, we found that PKA activity in the presence of cAMP was lower in caffeine-treated embryos than in controls. Treatment with H89 and PKI(12-24)amide, two inhibitors of PKA activity, mimicked the effects of caffeine on telencephalic vesicle formation. Together these data suggest that in early post-implantation mouse embryos caffeine modulates gene expression of the RI alpha subunit of PKA and that caffeine-induced inhibition of PKA activity plays a role in early telencephalic evagination.

Animals↗
PubMed2001

Central role of microglia in neonatal excitotoxic lesions of the murine periventricular white matter.

Periventricular leukomalacia (PVL) is the main cause of neurologic handicap in pre-term infants. The understanding of cellular and molecular mechanisms leading to white matter damage is critical for development of innovative therapeutic strategies for PVL. The pathogenesis of PVL remains unclear but possibly involves glutamate excitotoxicity as an important molecular pathway. We previously described a neonatal mouse model of excitotoxic white matter lesion mimicking human PVL. In the present study, we used this experimental tool to investigate the cellular populations and the glutamate receptor subtypes involved in excitotoxic white matter lesions. Combined immunohistochemical, electron microscopic, and cell death detection data revealed that microglial activation and astrocytic death were the primary responses of white matter to excitotoxic insult. In vitro experiments suggested that microglia activated by ibotenate released soluble factors that kill astrocytes. The use of selective agonists and antagonists of glutamate receptors revealed that N-methyl-D-aspartate (NMDA) receptor activation was essential and sufficient to produce cystic white matter lesions. NMDA receptor immunohistochemistry labeled microglial cells in the neonatal periventricular white matter. The developing white matter displayed a window of sensitivity to excitotoxic damage that was paralleled by the transient presence of NMDA receptor-expressing white matter cells. Assuming that similar pathophysiologic mechanisms are present in human pre- term infants, microglia and NMDA receptors could represent key targets for treatment of PVL.

Animals↗
PubMed2001

Pathophysiology of perinatal brain damage.

Brain damage in the premature or full-term fetus or newborn infant encompasses multiple patterns of injury, many considered to be anomalous in origin. However, there is increasing evidence that such congenital lesions arise as a consequence of hypoxia or ischemia (reperfusion failure). Animal models have been helpful in elucidating the underlying cellular and molecular mechanisms responsible for perinatal brain damage. Ultimately, neuroprotective strategies will prevent or minimize the occurrence of these lesions and their consequent functional deficiencies.

Brain↗
PubMed2001

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain.

Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white-matter lesions, mimicking brain lesions that occur in human preterm infants. Nociceptin (NC), also called orphanin FQ, is the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor and does not bind classical high-affinity opioid receptors. In the present study, administration of NC exacerbated ibotenate-induced white-matter lesions while coadministration of ibotenate with either of two NC antagonists reduced excitotoxic white-matter lesions by up to 64%. Neither ibotenate plus endomorphin I (a selective mu receptor agonist), nor ibotenate plus naloxone (a classical opioid receptor antagonist) modulated the excitotoxic lesion. Pretreatment with antisense oligonucleotides targeting the NC precursor peptide mRNA significantly reduced ibotenate-induced white-matter damage. Finally, high doses of fentanyl, which stimulates both classical mu-opioid receptors and ORL1, exacerbated excitotoxic white-matter lesion. This toxic effect was blocked by inhibiting ORL1 but not classical opioid receptors. Together, these findings show that endogenous or exogenous stimulation of the ORL1 receptor can be neurotoxic and that blocking NC signaling protects the white matter against excitotoxic challenge. These data point to potential new avenues for neuroprotection in human preterm infants at high risk of brain lesions.

Animals↗
PubMed2001

Deleterious effects of IL-9-activated mast cells and neuroprotection by antihistamine drugs in the developing mouse brain.

Elevated mean IL-9 serum levels have been observed in human neonates who will later develop cerebral palsy. In earlier studies, using a newborn mouse model of excitotoxic lesions mimicking those described in human cerebral palsy, we found that IL-9 pretreatment exacerbated brain damage produced by intracerebral injections of the glutamatergic analog ibotenate. Among its different cell targets, the Th2 cytokine IL-9 is a mast cell growth and differentiation factor that can cause mast cells to release various substances including histamine. In the present study, we sought to determine whether the deleterious effects of IL-9 in our mouse model were mediated by mast cells through histamine release. All mouse pups were pretreated with intraperitoneal injections of IL-9 or saline between postnatal days (P) P1 and P5. Immunohistochemistry for murine mast cell protease-1 performed on P5 showed an increased density of labeled cells in the neopallium of IL-9-treated Swiss pups as compared with controls. Western blot analysis confirmed the increased murine mast cell protease-1 brain content of IL-9-treated Swiss mice. IL-9 pretreatment had no significant effect on ibotenate-induced excitotoxic brain lesions in mast cell-deficient P5 pups (WBB6F1/J kit(W/W-v)), whereas IL-9 exacerbated these lesions in the control littermates with normal mast cell populations. Finally, cromoglycate or antihistamine drugs significantly reduced ibotenate-induced brain lesions in IL-9-treated Swiss pups. Taken together, these data suggest that recruitment of cerebral mast cells with histamine release may contribute to the exacerbation of neonatal excitotoxic brain lesions produced by IL-9. Neuroprotective strategies targeting mast cells may be useful in some neonates at risk for cerebral palsy.

Animals↗
PubMed2000

Caffeine induces in vivo premature appearance of telencephalic vesicles.

Caffeine administered to pregnant mice during germinative neuroepithelium preparation (embryonic days 8-10) dramatically accelerated primitive neuroepithelium evagination into telencephalic vesicles, versus age-matched controls. This histologically-documented, dose-dependent effect seemed reversible during subsequent neuronal migration if caffeine exposure was discontinued. Our in vivo model provides a new tool for studying telencephalic symmetry acquisition and for identifying genes potentially involved in holoprosencephaly, a developmental disorder characterized by defective telencephalic vesicle formation.

Animals↗
PubMed2000

Expression of insulin-like growth factor-I in rat glioma cells is associated with change in both immunogenicity and apoptosis.

Insulin-like growth factor I (IGF-I), has a role in cellular differentiation and is also expressed in neoplastic transformation of glioma cells. We recently demonstrated inhibition in expression of cellular IGF-I after transfection with vectors that incodes a segment of the human IGF-I RNA in antisense orientation. The transfected cells expressed increased levels of both MHC-I and B7 molecules. In this paper we show that IGF-I antisense transfected cells also become apoptotic. Moreover, the phenomenon of programmed cell death is related to the phenomenon that results in increased expression of MHC-I and B7 molecules. Co-transfection of rat glioma cells with the vector expressing IGF-I antisense RNA and with vectors encoding the expression of MHC-I and B7 antisense cDNA suppressed the expression of both of these molecules and was associated with a decrease in apoptosis.

Animals↗
PubMed2000

Genotype determination at the survival motor neuron locus in a normal population and SMA carriers using competitive PCR and primer extension.

Precise quantitation of SMN1 copy number is of great interest in many clinical applications such as direct detection of SMA carriers or detection of an SMA-affected patient with a hemizygous deletion of the SMN1 gene. We describe a method that combines two independent nonradioactive PCR assays: determination of the relative ratio of the SMN1 and SMN2 genes using a primer extension assay and of the total SMN copy number using competitive PCR. Consistency of the results of two independent approaches ensures the reliability of the deduced genotype and thus avoids false interpretation of borderline results that can occur in quantitative assays. In all, 135 subjects were tested, including 91 normal controls and 44 SMA-affected children or SMA carriers. Two main genotypes were observed in controls: 2T/2C (45%) and 2T/1C (32%). A wide variability at the SMN locus is observed with nine different genotypes and up to six SMN genes. SMA carriers showed three frequent genotypes, 1T/2C (50%), 1T/3C (29%), and 1T/1C (18%). Normal chromosomes with two SMN1 genes per chromosome are not infrequent and thus, about 3% of SMA carriers are not detected using SMN1 copy number quantitation. Finally, as this method does not detect point mutations (4% of SMN1 gene mutations), reliability ranges from 93% to 100% depending on data available from the propositus.

Child, Preschool↗
PubMed2000

[Cortical dysgenesis. Current views on pathogenesis and pathophysiology].

Cortical dysgenesia are a heterogenous group of genetic or acquired disturbances of cortical development which, due to the enormous progress in modern neuroimaging techniques, are increasingly recognized in association with a variety of clinical disorders. The spectrum of clinical manifestations, depending on type and extent of the alterations, includes severe mental retardation and epilepsy as well as neuropsychological deficits and some psychiatric disorders. Although pathogenesis and pathophysiology of cortical dysgenesis are still not fully understood, the recent discovery of responsible genes, growth factors, neurotransmitters, and exogenous factors sheds light on elementary mechanisms. The development of animal models mimicking different types of human cortical malformations helped to increase further the understanding of functional consequences of focal cortical dysgenesis. Several studies on these models reveal widespread alterations of cortical connectivity and excitability which are probably of crucial importance in different clinical disorders.

Animals↗
PubMed2000

Prophylaxis of supraventricular and ventricular arrhythmias after coronary artery bypass grafting with low-dose sotalol.

BACKGROUND: Supraventricular tachyarrhythmia (SVT) commonly occurs shortly after coronary artery bypass grafting (CABG), but ventricular arrhythmias are less documented. METHODS: On the 1st postoperative day, 206 consecutive eligible patients were prospectively randomized to a sotalol group (80 mg b.i.d.; n = 103) or a control group without beta-blockade or antiarrhythmic drugs (n = 103). RESULTS: The SVT incidence (predominantly atrial fibrillation) accounted for 16% in the sotalol group versus 48% (p < 0.00001). Multivariate analysis showed that sotalol reduced the SVT incidence (p < 0.00001, odds ratio, 0.20; 95% confidence interval, 0.09 to 0.42), whereas a lower preoperative left ventricular ejection fraction (p = 0.019) and older age (p = 0.031) were independent risk factors of SVT occurrence. The Holter electrocardiographic analysis (24 hours) demonstrated that sotalol (32 versus 92; p = 0.031) decreased the median number of ventricular events, mostly isolated premature ventricular beats. Neither ventricular proarrhythmia effect nor "torsades de pointes" were detected. Despite strict hemodynamic-based selection, sotalol had to be discontinued in 8 patients (7.8%), for reasons related to asthma in 3 or cardiac reasons in 5. CONCLUSIONS: Oral low-dose sotalol provided considerable and reliable protection in selected nondepressed cardiac function patients, reducing the occurrence of both supraventricular and ventricular arrhythmias after CABG.

Administration, Oral↗
PubMed2000

Effective prevention of atrial fibrillation by continuous atrial overdrive pacing after coronary artery bypass surgery.

OBJECTIVES: The present study was aimed to evaluate the efficacy of a specific algorithm with continuous atrial dynamic overdrive pacing to prevent atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. BACKGROUND: Atrial fibrillation occurs in 30% to 40% of patients after cardiac surgery with a peak incidence on the second day. It still represents a challenge for postoperative prevention and treatment and may have medical and cost implications. METHODS: Ninety-six consecutive patients undergoing CABG for severe coronary artery disease and in sinus rhythm without antiarrhythmic therapy on the second postoperative day were randomized to have or not 24 h of atrial pacing through temporary epicardial wires using a permanent dynamic overdrive algorithm. Holter ECGs recorded the same day in both groups were analyzed to detect AF occurrence. RESULTS: No difference was observed in baseline data between the two study groups, particularly for age, male gender, history of AF, ventricular function, severity of coronary artery disease, preoperative beta-adrenergic blocking agent therapy or P-wave duration. The incidence of AF was significantly lower (p = 0.036) in the paced group (10%) compared with control subjects (27%). Multivariate analysis showed AF incidence to increase with age (p = 0.051) but not in patients with pacing (p = 0.078). It decreased with a better left ventricular ejection fraction only in conjunction with atrial pacing (p = 0.018). CONCLUSIONS: We conclude that continuous atrial pacing with an algorithm for dynamic overdrive reduces significantly incidence of AF the second day after CABG surgery, particularly in patients with preserved left ventricular function.

Adult↗
PubMed2000

In vivo study of percutaneous absorption of 4-chloroaniline using microdialysis in the rat.

The present work was undertaken to study the percutaneous absorption of 4-chloroaniline (parachloroaniline, PCPA, CAS 106-47-8), a chemical intermediate in pesticide manufacture, using in vivo microdialysis in the rat. The results of the microdialysis study showed that PCPA was able to cross the skin (Tmax = 3 h and area under the curve (AUC) = 332.1 ng.h/ml) and rapidly enter the systemic circulation (Tmax = 3.3 +/- 0.6 h). It could be also shown that PCPA was partly metabolised during its percutaneous absorption. The analysis of cutaneous dialysate samples using gas chromatography/mass spectrometry (GC-MS) showed that the metabolite was 4-chloracetanilide. Taken together, the data obtained showed that contact with the skin is a danger for exposed persons.

Acetylation↗
PubMed2000

VIP and PACAP 38 modulate ibotenate-induced neuronal heterotopias in the newborn hamster neocortex.

Intracerebral administration of ibotenate produces, through activation of N-methyl-D-aspartate (NMDA) receptors, neuronal heterotopias in the newborn hamster neocortex: high doses of ibotenate induce periventricular and subcortical neuronal heterotopias, while low doses of ibotenate produce intracortical heterotopias and molecular layer ectopias. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are closely related peptides with neurotrophic properties. They share common VPAC1 and VPAC2 receptors, which use cAMP as a second messenger. Previous studies have shown that VIP prevents excitotoxic neuronal death and exacerbates glutamate-induced c-fos neuronal expression. In order to gain new insight into the molecular control of neuronal migration, the present study examined the effects of VIP and PACAP on ibotenate-induced heterotopias in the newborn hamster. Co-treatment with VIP and a high dose of ibotenate produced a pattern of neuronal heterotopias similar to the one observed in animals treated with low doses of ibotenate alone. Pups co-injected with a low dose of ibotenate and a VIP antagonist displayed cortical dysgeneses similar to those observed in animals treated with high doses of ibotenate alone. The modulating effects of VIP on excitotoxin-induced heterotopias were mimicked by forskolin, PACAP, and by a specific VPAC2 receptor agonist but not by a VPAC1 agonist, and were blocked by a protein kinase A (PKA) inhibitor. Taken together, these data suggest that VIP and PACAP can attenuate ibotenate-induced heterotopias in newborn hamster and that this effect is mediated by the VPAC2 receptor utilizing the cAMP-PKA pathway.

Animals↗
PubMed2000

Prenatal blockade of vasoactive intestinal peptide alters cell death and synaptic equipment in the murine neocortex.

Vasoactive intestinal peptide (VIP) is a potent growth factor that stimulates murine neocortical astrocyte genesis during the period of ontogenesis corresponding to premature delivery in humans. In rodents, part of the VIP supplied to the fetal brain is maternal VIP that crosses the placenta. If these data also apply to human brain development, premature newborns may be partly VIP-deficient because of loss of the maternal supply, and this may adversely affect their brain development. The goal of the present study was to determine the effects of VIP blockade during mouse neocortical astrocyte genesis on neuritic survival and maturation. VIP blockade by a specific VIP antagonist on embryonic d 17 and 18 induced transient, postnatal depletion of astrocytes in the upper neocortical layers. Combined use of in situ DNA fragmentation analysis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, a marker of cell death); immunohistochemical detection of synaptophysin, microtubule-associated proteins, and neurofilaments; and quantification of mRNA for synaptophysin and N-methyl-D-aspartate R1 receptor subunit revealed that early VIP blockade significantly altered programmed neuritic death and impaired neuritic differentiation. VIP inhibition induced 1) exaggerated postnatal terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling of cortical neurons, 2) long-term overexpression of synaptophysin and N-methyl-D-aspartate R1 receptor subunit, and 3) long-term overexpression of microtubule-associated protein-5 and neurofilament 160 kD. Although the functional consequences of this deviant pattern of murine neocortical development remain to be determined, these data open up new avenues for investigating some of the cognitive deficits observed in human premature infants.

Animals↗
PubMed2000

Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium.

Many prenatal and perinatal factors are hypothesized to play a role in the cause of cerebral palsy (CP). Epidemiological data implicate maternal-fetal infection and associated increase in circulating cytokines. Murine model data suggest that excitotoxic damage can produce pathological change in brain tissue consistent with lesions observed in CP. Specifically, on day 5 after birth, mouse pups injected with ibotenate, a glutamatergic analogue, develop transcortical necrosis and white matter cysts mimicking some human perinatal lesions associated with CP. The present study builds on this murine model to assess the modulating role of several cytokines on the development of excitotoxic lesions. Pups pretreated with interleukin (IL)-1beta, IL-6, IL-9, or tumor necrosis factor-alpha developed significantly larger ibotenate-induced cortical and white matter damage than controls; IL-4 did not produce such an effect. In a similar manner, IL-9-overexpressing transgenic pups developed ibotenate-induced brain lesions, which were significantly larger than those induced in nontransgenic control pups. Pretreatment with proinflammatory cytokines significantly increased neopallial microglial density without affecting astrocytic density; IL-9 or IL-4 did not produce a similar effect. To our knowledge, this is the first in vivo study to demonstrate that systemically administered proinflammatory cytokines and IL-9 exacerbate brain lesions that are similar to those found in human infants with CP.

Animals↗