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Biomedical subjects

Bernard Dan

Publications and source records attributed to Bernard Dan.

At least 19 recordsLinked to original sources
PubMed2007

Pathophysiology of duchenne muscular dystrophy: current hypotheses.

Duchenne muscular dystrophy is a devastating inherited neuromuscular disorder that affects one in 3300 live male births. Although the responsible gene and its product, dystrophin, have been characterized for more than 15 years, and a mouse model (mdx) has been developed, comprehensive understanding of the mechanism leading from the absence of dystrophin to the muscular degeneration is still debated. First, dystrophin is considered a key structural element in the muscle fiber, and the primary function of the dystrophin-associated protein complex is to stabilize plasma membrane, although a role of signaling is still possible. Mechanically induced damage through eccentric contractions puts a high stress on fragile membranes and provokes micro-lesions that could eventually lead to loss of calcium homeostasis, and cell death. Altered regeneration, inflammation, impaired vascular adaptation, and fibrosis are probably downstream events that take part in the muscular dystrophy and that probably vary a lot along species (i.e., mdx mice), probands within families, stressing the importance of epigenic factors. Because no etiologic therapy is available for Duchenne muscular dystrophy, a better understanding of the primary and downstream mechanisms could prove useful for producing new adjuvant treatments. All pathophysiologic mechanisms are reviewed together with perspectives on management.

Animals↗
PubMed2006

Recognition of the physiological actions of the triphasic EMG pattern by a dynamic recurrent neural network.

Triphasic electromyographic (EMG) patterns with a sequence of activity in agonist (AG1), antagonist (ANT) and again in agonist (AG2) muscles are characteristic of ballistic movements. They have been studied in terms of rectangular pulse-width or pulse-height modulation. In order to take into account the complexity of the EMG signal within the bursts, we used a dynamic recurrent neural network (DRNN) for the identification of this pattern in subjects performing fast elbow flexion movements. Biceps and triceps EMGs were fed to all 35 fully-connected hidden units of the DRNN for mapping onto elbow angular acceleration signals. DRNN training was supervised, involving learning rule adaptations of synaptic weights and time constants of each unit. We demonstrated that the DRNN is able to perfectly reproduce the acceleration profile of the ballistic movements. Then we tested the physiological plausibility of all the networks that reached an error level below 0.001 by selectively increasing the amplitude of each burst of the triphasic pattern and evaluating the effects on the simulated accelerating profile. Nineteen percent of these simulations reproduced the physiological action classically attributed to the 3 EMG bursts: AG1 increase showed an increase of the first accelerating pulse, ANT an increase of the braking pulse and AG2 an increase of the clamping pulse. These networks also recognized the physiological function of the time interval between AG1 and ANT, reproducing the linear relationship between time interval and movement amplitude. This task-dynamics recognition has implications for the development of DRNN as diagnostic tools and prosthetic controllers.

Action Potentials↗
PubMed2006

Opsoclonus-myoclonus associated with celiac disease.

Celiac disease may be associated with various neurologic manifestations, most commonly cerebellar ataxia. This report describes a 2-year-old male who presented with opsoclonus-myoclonus syndrome including action myoclonus, palpebral flutter, opsoclonus, and ataxia. Given the severity of ataxia, the child was unable to sit or walk independently. Brain magnetic resonance imaging was normal on two occasions (4-week interval). Oligoclonal bands were found in the cerebrospinal fluid. Blood and serum examinations were unremarkable, with no evidence of infectious seroconversion. However autoantibody testing indicated the presence of antigliadin antibodies of immunoglobulin A subtype, anti-endomysial antibodies, and anti-CV2 antibodies that were not, however, detected in the cerebrospinal fluid. Duodenal biopsy documented villous atrophy confirming the diagnosis of celiac disease. This case confirms that initial presentation of celiac disease may be restricted to neurologic features. We suggest that a search for evidence for celiac disease should be included in the evaluation of opsoclonus-myoclonus.

Celiac Disease↗
PubMed2006

Recognition of emotional facial expressions in attention-deficit hyperactivity disorder.

In ADHD, impaired interpersonal relationships have been documented. They have been hypothesized to be secondary to impairment of receptive nonverbal language. Recognition of emotional facial expressions is an important aspect of receptive nonverbal language, and it has been demonstrated to be central to organization of emotional and social behavior. This study investigated the identification of facial expression of four emotions (joy, anger, disgust, and sadness) in a group of 30 children aged 7-12 years who met the DSM-IV criteria for ADHD disorder of the predominantly hyperactive-impulsive type and have no comorbid mental retardation, specific learning difficulties, developmental coordination disorder, pervasive developmental disorders, conduct disorder, bipolar disorder, or substance abuse, and in 30 matched unimpaired control children. The test used includes 16 validated photographs depicting these emotions in varying intensities constructed by morphing. Children with ADHD exhibited a general deficit in decoding emotional facial expressions, with specific deficit in identifying anger and sadness. Self-rating of the task difficulty revealed lack of awareness of decoding errors in the ADHD group as compared with control subjects. Within the ADHD group, there was a significant correlation between interpersonal problems and emotional facial expression decoding impairment, which was more marked for anger expressions. These results suggest suboptimal nonverbal decoding abilities in ADHD that may have important implications for therapy.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

A neurophysiological perspective on sleep and its maturation.

Neurophysiological studies of sleep have increasingly focused on underlying dynamic processes. This would appear particularly relevant to the developmental aspects of sleep. Involvement of sleep-dependent mechanisms in emotional processing, as well as perceptual-sensory, perceptual-motor, and cognitive learning, mostly studied in adults, may play major roles in development. Rapid eye movement (REM) sleep, which is generated by complex neuronal interactions within the pontine reticular formation, and non-REM sleep, which arises from activities in the thalamocortical network, are specifically implicated in different aspects of long-term memory systems. They evolve from previous physiological and behavioural states which can be traced back to the fetal period. Further studies are needed to clearly identify functions reflected by hallmarks of sleep stages, such as spindles and K complexes. A better understanding of the maturational aspects of sleep should provide important insights into physiological development. Assessment approaches taking dynamic characteristics of sleep into account may contribute to the design of better targeted management of sleep-related problems in neurodevelopmental conditions.

Cerebral Cortex↗
PubMed2006

Stimulus-sensitive burst-spiking in burst-suppression in children: implications for management of refractory status epilepticus.

Status epilepticus refractory to sequential trials of multiple medication is a rare but significant problem in children. We describe stimulus sensitivity arising during the treatment of convulsive status epilepticus in children (stimulus-sensitive burst-spiking in burst-suppression). We reviewed retrospectively clinical and EEG features in six children (three months to ten years), with status epilepticus requiring intensive care, in whom tactile, auditory and visual stimulation induced myoclonic jerks and bursts of EEG spikes. Sensitivity was not present at onset, but appeared after 24 hours as myoclonic jerks of the eyes, face and limbs, irrespective of the modality and site of stimulation. These were associated with burst-suppression in the EEG, the induced spiking forming the burst component. Various antiepileptic drugs, including GABAergic and NMDA blockers had no effect, but halogenated agents (used in two patients) abolished the sensitivity. Two children died, but the remainder returned to their previous clinical state. We conclude that stimulus sensitivity may appear in the context of refractory status epilepticus treated with high-dose barbiturates. Outcome may be more favorable than previously reported in adults, mostly in the context of post-anoxic or toxic coma. Evaluation of ventilated children in status epilepticus should include electroclinical assessment using sensory stimulation. If present, the drug regime should be reviewed and halogenated agents considered.

Anesthetics, Inhalation↗
PubMed2005

Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features.

BACKGROUND: Unusual acute symptomatic and reversible early-delayed leukoencephalopathy has been reported to be induced by methotrexate (MTX). OBJECTIVE: We aimed to identify the occurrence of such atypical MTX neurotoxicity in children and document its MR presentation. MATERIALS AND METHODS: We retrospectively reviewed the clinical findings and brain MRI obtained in 90 children treated with MTX for acute lymphoblastic leukaemia or non-B malignant non-Hodgkin lymphoma. All 90 patients had normal brain imaging before treatment. In these patients, brain imaging was performed after treatment completion and/or relapse and/or occurrence of neurological symptoms. RESULTS: Of the 90 patients, 15 (16.7%) showed signs of MTX neurotoxicity on brain MRI, 9 (10%) were asymptomatic, and 6 (6.7%) showed signs of acute leukoencephalopathy. On the routine brain MRI performed at the end of treatment, all asymptomatic patients had classical MR findings of reversible MTX neurotoxicity, such as abnormal high-intensity areas localized in the deep periventricular white matter on T2-weighted images. In contrast, the six symptomatic patients had atypical brain MRI characterized by T2 high-intensity areas in the supratentorial cortex and subcortical white matter (n=6), cerebellar cortex and white matter (n=4), deep periventricular white matter (n=2) and thalamus (n=1). MR normalization occurred later than clinical recovery in these six patients. CONCLUSIONS: In addition to mostly asymptomatic classical MTX neurotoxicity, MTX may induce severe but reversible unusual leukoencephalopathy. It is important to recognize this clinicoradiological presentation in the differential diagnosis of acute neurological deterioration in children treated with MTX.

Acute Disease↗
PubMed2005

Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy.

We have investigated the breakpoints in a male child with pharmacoresistant epileptic encephalopathy and a de novo balanced translocation t(Y;4)(q11.2;q21). By fluorescence in situ hybridisation, we have identified genomic clones from both chromosome 4 and chromosome Y that span the breakpoints. Precise mapping of the chromosome 4 breakpoint indicated that the c-Jun N-terminal kinase 3 (JNK3) gene is disrupted in the patient. This gene is predominantly expressed in the central nervous system, and it plays an established role in both neuronal differentiation and apoptosis. Expression studies in the patient lymphoblastoid cell line show that the truncated JNK3 protein is expressed, i.e. the disrupted transcript is not immediately subject to nonsense-mediated mRNA decay, as is often the case for truncated mRNAs or those harbouring premature termination codons. Over-expression studies with the mutant protein in various cell lines, including neural cells, indicate that both its solubility and cellular localisation differ from that of the wild-type JNK3. It is plausible, therefore, that the presence of the truncated JNK3 disrupts normal JNK3 signal transduction in neuronal cells. JNK3 is one of the downstream effectors of the GTPase-regulated MAP kinase cascade, several members of which have been implicated in cognitive function. In addition, two known JNK3-interacting proteins, beta-arrestin 2 and JIP3, play established roles in neurite outgrowth and neurological development. These interactions are likely affected by a truncated JNK3 protein, and thereby provide an explanation for the link between alterations in MAP kinase signal transduction and brain disorders.

Base Sequence↗
PubMed2005

A pharmacological modulation of opiate withdrawal using an up-/down-regulation of the noradrenergic system in opiate-dependent rats.

Chronic opioid exposure induces neuroadaptative changes in several brain systems. Amongst others the alpha adrenergic system appears to be extremely sensitive to opioid exposure and has, therefore, been proposed to play a key role in opiate withdrawal symptoms. In order to better understand the influence of the noradrenergic system in opioid withdrawal and be able to develop new therapeutic strategies, we studied the effect of pre-treatment with the alpha2 agonist (clonidine) and alpha2 antagonist (yohimbine) on naloxone-precipitated withdrawal in opiate-dependent rats. As is already known clonidine pre-treatment significantly enhances autonomic and behavioural signs of opioid withdrawal whereas yohimbine significantly attenuates them with dose-related effect. We also tested the effect of clonidine (0.1 mg/kg) during naloxone-precipitated opiate withdrawal in rats pre-treated with yohimbine (5 mg/kg) and we observed that yohimbine pre-treatment potentiates clonidine efficiency in decreasing opiate withdrawal signs. This study supports the possibility of using a noradrenergic antagonist in order to regulate adrenoreceptors chronically exposed to opioids, therefore interfering with the intensity of naloxone-precipitated opiate withdrawal and potentiating later effectiveness of noradrenergic agonists like clonidine. These results may have various applications in clinical opiate detoxification protocols and are discussed through an up-/down- regulation of adrenoreceptors.

Adrenergic alpha-Agonists↗
PubMed2005

Effects of anaesthetic agents in interference of naloxone-induced opiate-withdrawal are dose-dependent in opiate-dependent rats.

In opiate-dependent rats previous studies showed that anaesthetic agents, such as chloral hydrate, midazolam and ketamine interfere with naloxone-precipitated opiate withdrawal. Each anaesthetic induces a specific pattern of interference, indicating that the interference is agent-dependent. In order to further investigate these effects and highlight a potential pharmacological basis of opiate withdrawal interference through anaesthetic agents, we hypothesized that anaesthetic-mediated interference of opiate withdrawal is also dose-dependent. Three groups of rats were compared in an experimental procedure of rapid withdrawal induction by an antagonist under anaesthesia using sub-anaesthetic dosage of midazolam, ketamine or saline. We observed that sub-anaesthetic dosage of ketamine, or midazolam, interferes significantly with opiate withdrawal expression. This brings arguments in favour of a pharmacological basis underlying rapid antagonists induction in opiate dependent rats.

Anesthetics↗
PubMed2005

Postinfectious immune-mediated encephalitis after pediatric herpes simplex encephalitis.

We report a 3-year-old patient who presented a secondary acute neurological deterioration clinically characterized by a partial Kluver-Bucy syndrome, 1 month after the onset of herpes simplex encephalitis. This episode is unlikely due to continuation or resumption of cerebral viral replication but might be related to an immune-inflammatory process. In children, postinfectious immune-mediated encephalitis occurring after HSE are usually clinically characterized by choreoathetoid movements. This type of movement disorder was, however, not observed in this patient. On the basis of this case and a review of the literature, we hypothesize the existence of a spectrum of secondary immune-mediated process triggered by herpes simplex virus cerebral infection ranging from asymptomatic cases with diffuse white matter involvement to secondary acute neurological deteriorations with or without extrapyramidal features.

Brain↗
PubMed2005

Pediatric SUNCT Syndrome.

This report describes a 5-year-old male with sudden unilateral headache attacks (2-50 seconds) accompanied by conjunctival injection, lacrimation, and nasal congestion. The episodes occurred without a precipitating factor, never during sleep. Brain imaging was normal. The attacks resolved spontaneously within 5 months. This headache syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) was previously described in two other children aged 10 and 11.

Child, Preschool↗
PubMed2005

Fast oscillation in the cerebellar cortex of calcium binding protein-deficient mice: a new sensorimotor arrest rhythm.

Fast oscillations (>100 Hz) may serve physiological roles when regulated properly. They may also appear in pathological conditions. In cerebellum, 160 Hz oscillation emerge in mice lacking calbindin and/or calretinin, two proteins devoted to calcium buffering in Purkinje and granule cells, respectively. Here, we review the pharmacological and spatiotemporal properties of this fast cerebellar oscillation and the related Purkinje cell firing behaviour in alert mice. We show that this oscillation is highly synchronized along the parallel fiber beam and reversibly inhibited by gap junctions, GABA(A) and NMDA receptors blockers. Cutaneous stimulation of the whisker region transiently suppressed the oscillation which shows in some aspects similarities with cerebral "resting" rhythmic activities of wakefulness arresting to sensory or motor information such as alpha and mu rhythms. The Purkinje cells of these mutants present an increased simple spike firing rate, rhythmicity and synchronicity, and a decreased complex spike duration and subsequent pause. Both simple and complex spikes may be tightly phase-locked with the oscillation. Contrastingly, on slice recordings, the intrinsic membrane properties of Purkinje cell are similar in wild type mice and in mice lacking calbindin. The role played by this fast cerebellar oscillation in the emergence of ataxia is yet to be solved.

Animals↗
PubMed2005

Proposed definition and classification of cerebral palsy, April 2005.

Because of the availability of new knowledge about the neurobiology of developmental brain injury, information that epidemiology and modern brain imaging is providing, the availability of more precise measuring instruments of patient performance, and the increase in studies evaluating the efficacy of therapy for the consequences of injury, the need for reconsideration of the definition and classification of cerebral palsy (CP) has become evident. Pertinent material was reviewed at an international symposium participated in by selected leaders in the preclinical and clinical sciences. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, and health officials, and provide a common language for improved communication. With leadership and direction from an Executive Committee, panels utilized this information and have generated a revised Definition and Classification of Cerebral Palsy. The Executive Committee presents this revision and welcomes substantive comments about it.

Cerebral Palsy↗