Intestinal Conventional Ultrasonography, Contrast-Enhanced Ultrasonography and Magnetic Resonance Enterography in Assessment of Crohn's Disease Activity: A Comparison with Surgical Histopathology Analysis.

BACKGROUND AND AIMS: Contrast-enhanced ultrasonography (CEUS) is a potential interesting method for assessing accurately Crohn's disease (CD) activity. We compared the value of intestinal ultrasonography (US) coupled with contrast agent injection with that of magnetic resonance enterography (MRE) in the assessment of small bowel CD activity using surgical histopathology analysis as reference. METHODS: Seventeen clinically active CD patients (14 women, mean age 33 years) requiring an ileal or ileocolonic resection were prospectively enrolled. All performed a MRE and a US coupled with contrast agent injection (CEUS) less than 8 weeks prior to surgery. Various imaging qualitative and quantitative parameters were recorded and their respective performance to detect disease activity, disease extension and presence of complications was compared to surgical histopathological analysis. RESULTS: The median wall thickness measured by US differed significantly between patients with non-severely active CD (n = 5) and those with severely active CD (n = 12) [7.0 mm, IQR (6.5-9.5) vs 10.0 mm, IQR (8.0-12.0), respectively; p = 0.03]. A non-significant trend was found with MRE with a median wall thickness in severe active CD of 10.0 mm, IQR (8.0-13.7) compared with 8.0 mm, IQR (7.5-10.5) in non-severely active CD (p = 0.07). The area under the ROC curve (AUROC) of the wall thickness assessed by US and MRE to identify patients with or without severely active CD on surgical specimens were 0.85, 95% CI (0.64-1.04), p = 0.03 and 0.80, 95% CI (0.56-1.01), p = 0.07, respectively. Among the parameters derived from the time-intensity curve during CEUS, time to peak and rise time were the two most accurate markers [AUROC = 0.88, 95% CI (0.70-1.04), p = 0.02 and 0.86, 95% CI (0.68-1.04), p = 0.03] to detect patients with severely active CD assessed on surgical specimens. CONCLUSION: The accuracy of intestinal CEUS is close to that of conventional US to detect disease activity. A thickened bowel and shortened time to peak and rise time were the most accurate to identify CD patients with severe histological disease activity.

[Infantile spinal muscular atrophy : therapeutic (R)evolution]. / Amyotrophie spinale infantile. (R)évolution thérapeutique.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. The infantile form is the most common genetic cause of infantile death due to respiratory insufficiency. The disorder is caused by the premature death of motor neurons of anterior horn, leading to progressive weakness and muscular atrophy. Longtime considered as untreatable, the pathology knew a real revolution during the last two years. Views on this terrible disease have completely changed, changing, therefore, the management of the patients and constituting new challenges.

L'amyotrophie spinale est une maladie neuromusculaire autosomique récessive qui, dans sa forme la plus précoce et la plus sévère, constitue la cause génétique la plus fréquente de décès chez l'enfant, en raison de ses complications respiratoires. Elle est caractérisée par la mort prématurée des neurones moteurs de la moelle épinière, responsable d'une faiblesse et d'une atrophie musculaire progressive. Longtemps considérée comme incurable, cette pathologie a connu, au cours de ces deux dernières années, une véritable révolution thérapeutique, changeant ainsi radicalement la vision que l'on pouvait avoir de la maladie, mais également de sa prise en charge, et ouvrant la voie à de nouveaux défis.

[(S)un (M)ay (A)rise on SMA : the hope of a region without spinal muscular atrophy]. / (S)un (M)ay (A)rise on SMA : l'espoir d'une région sans amyotrophie spinale.

The treatment of spinal muscular atrophy (SMA) has considerably changed over the last 3 years. Several approaches that aim to increase the deficient SMN protein have demonstrated an efficacy that is inversely correlated with disease duration. In this context, newborn screening (NBS) is increasingly considered as the next step in several countries or regions. In 2018, we initiated a pilot study for NBS of SMA in French- and German-speaking Belgium. We aim to evaluate the feasibility, the efficacy, and the cost-effectiveness of such a program. Initially covering the region of Liege, the program was recently extended to the whole Southern Belgium and currently covers about 55.000 newborns per year. On June 1st 2019, 35.000 newborns had been screened and 5 affected babies were identified and referred to neuromuscular centers for early treatment. A full evaluation of the program will take place after three years to consider the inclusion of SMA screening in the publically-funded NBS program in Southern Belgium.

La prise en charge de l'amyotrophie spinale antérieure (SMA) a considérablement évolué au cours des trois dernières années. Les différents essais visant à augmenter la production de la protéine SMN déficitaire dans la SMA ont systématiquement montré une efficacité inversement proportionnelle à la durée de la maladie. Dès lors, l'implémentation d'un programme de dépistage néonatal s'est rapidement imposée comme une évidence médico-économique dans de nombreux pays. Dans ce contexte, nous avons initié un programme de dépistage néonatal pour la SMA en Belgique francophone et germanophone. En 2018, une étude pilote de trois ans visant à évaluer la faisabilité, l'efficacité et la rentabilité du screening a été initiée au sein du centre de dépistage de Liège. L'étude a récemment été étendue à l'ensemble de la Fédération Wallonie-Bruxelles (FWB) pour couvrir environ 55.000 naissances annuelles. Au 1er juin 2019, 35.000 bébés ont été dépistés et cinq nouveau-nés atteints de SMA ont été identifiés. Tous ont été immédiatement référés pour assurer leur prise en charge dans un centre de référence pour les maladies neuromusculaires. Une évaluation complète du programme aura lieu à l'issue de la phase pilote, afin d'envisager que la SMA soit reconnue comme maladie officielle du programme de dépistage néonatal en FWB.

[Congenital myasthenic syndromes: difficulties in the diagnosis, course and prognosis, and therapy--The French National Congenital Myasthenic Syndrome Network experience]. / Syndromes myasthéniques congénitaux: difficultés diagnostiques, évolution et pronostic, thérapeutique--l'expérience du réseau national "Syndromes Myasthéniques Congénitaux".

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by members of the national French CMS Network: the difficulties in making a proper diagnosis; the course and long-term prognosis; and the response to therapy, especially for CMS that do not respond to cholinesterase inhibitors. CMS diagnosis is late in most cases because of confusion with other entities such as: congenital myopathies, due to the frequent presentation in patients of myopathies such as permanent muscle weakness, atrophy and scoliosis, and the abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy) seen on biopsy; seronegative autoimmune myasthenia gravis, when CMS is of late onset; and metabolic myopathy, with the presence of lipidosis in muscle. The long-term prognosis of CMS was studied in a series of 79 patients recruited with the following gene mutations: CHRNA; CHRNE; DOK7; COLQ; RAPSN; AGRN; and MUSK. Disease-course patterns (progressive worsening, exacerbation, stability, improvement) could be variable throughout life in a given patient. DOK7 patients had the most severe disease course with progressive worsening: of the eight wheelchair-bound and ventilated patients, six had mutations of this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first-line therapy for CMS patients, except for cases of slow-channel CMS, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss or RAPSN gene mutations. Ephedrine was given to 18 patients (eight DOK7, five COLQ, four AGRN and one RAPSN). Tolerability was good. Therapeutic responses were encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient who was allergic to ephedrine.

Safety, tolerability and pharmacokinetics of eteplirsen in young boys aged 6-48 months with Duchenne muscular dystrophy amenable to exon 51 skipping.

Eteplirsen is FDA-approved for the treatment of Duchenne muscular dystrophy (DMD) in exon 51 skip-amenable patients. Previous studies in boys > 4 years of age indicate eteplirsen is well tolerated and attenuates pulmonary and ambulatory decline compared with matched natural history cohorts. Here the safety, tolerability and pharmacokinetics of eteplirsen in boys aged 6-48 months is evaluated. In this open-label, multicenter, dose-escalation study (NCT03218995), boys with a confirmed mutation of the DMD gene amenable to exon 51 skipping (Cohort 1: aged 24-48 months, n = 9; Cohort 2: aged 6 to < 24 months, n = 6) received ascending doses (2, 4, 10, 20, 30 mg/kg) of once-weekly eteplirsen intravenously over 10 weeks, continuing at 30 mg/kg up to 96 weeks. Endpoints included safety (primary) and pharmacokinetics (secondary). All 15 participants completed the study. Eteplirsen was well tolerated with no treatment-related discontinuations, deaths or evidence of kidney toxicity. Most treatment-emergent adverse events were mild; most common were pyrexia, cough, nasopharyngitis, vomiting, and diarrhea. Eteplirsen pharmacokinetics were consistent between both cohorts and with previous clinical experience in boys with DMD > 4 years of age. These data support the safety and tolerability of eteplirsen at the approved 30-mg/kg dose in boys as young as 6 months old.

miR-379 links glucocorticoid treatment with mitochondrial response in Duchenne muscular dystrophy.

Duchenne Muscular Dystrophy (DMD) is a lethal muscle disorder, caused by mutations in the DMD gene and affects approximately 1:5000-6000 male births. In this report, we identified dysregulation of members of the Dlk1-Dio3 miRNA cluster in muscle biopsies of the GRMD dog model. Of these, we selected miR-379 for a detailed investigation because its expression is high in the muscle, and is known to be responsive to glucocorticoid, a class of anti-inflammatory drugs commonly used in DMD patients. Bioinformatics analysis predicts that miR-379 targets EIF4G2, a translational factor, which is involved in the control of mitochondrial metabolic maturation. We confirmed in myoblasts that EIF4G2 is a direct target of miR-379, and identified the DAPIT mitochondrial protein as a translational target of EIF4G2. Knocking down DAPIT in skeletal myotubes resulted in reduced ATP synthesis and myogenic differentiation. We also demonstrated that this pathway is GC-responsive since treating mice with dexamethasone resulted in reduced muscle expression of miR-379 and increased expression of EIF4G2 and DAPIT. Furthermore, miR-379 seric level, which is also elevated in the plasma of DMD patients in comparison with age-matched controls, is reduced by GC treatment. Thus, this newly identified pathway may link GC treatment to a mitochondrial response in DMD.

Respiratory and upper limb function as outcome measures in ambulant and non-ambulant subjects with Duchenne muscular dystrophy: A prospective multicentre study.

The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5-18 years) and functional abilities, from ambulant (n = 60) to non-ambulant (n = 29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI [-7.44,-0.72], p = 0.02 in ambulant; 4.81, 95% CI [-6.79,-2.82], p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI [-6.48,-4.45], p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI [-4.79,3.47], p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force -5.51%, 95% CI [-6.54,-4.48], p < 0.001 in ambulant and a slower decline -2.86%; 95% CI -3.29,-2.43, p < 0.001, in non-ambulant; pinch force: -2.66%, 95% CI [-3.82,-1.51], p < 0.001 in ambulant and -2.23%, 95% CI [-2.92,-1.53], p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.

Cerebellar network plasticity: from genes to fast oscillation.

The role of the cerebellum has been increasingly recognized not only in motor control but in sensory, cognitive and emotional learning and regulation. Purkinje cells, being the sole output from the cerebellar cortex, occupy an integrative position in this network. Plasticity at this level is known to critically involve calcium signaling. In the last few years, electrophysiological study of genetically engineered mice has demonstrated the topical role of several genes encoding calcium-binding proteins (calretinin, calbindin, parvalbumin). Specific inactivation of these genes results in the emergence of a fast network oscillation (ca. 160 Hz) throughout the cerebellar cortex in alert animals, associated with ataxia. This oscillation is produced by synchronization of Purkinje cells along the parallel fiber beam. It behaves as an electrophysiological arrest rhythm, being blocked by sensorimotor stimulation. Pharmacological manipulations showed that the oscillation is blocked by GABA(A) and NMDA antagonists as well as gap junction blockers. This cerebellar network oscillation has also been documented in mouse models of human conditions with complex developmental cerebellar dysfunction, such as Angelman syndrome and fetal alcohol syndrome. Recent evidence suggests a relationship between fast oscillation and cerebellar long term depression (LTD). This may have major implications for future therapeutic targeting.

Neuromuscular diseases: Diagnosis and management.

Neuromuscular diseases (NMDs) affect the peripheral nervous system, which includes the motor neurons and sensory neurons; the muscle itself; or the neuromuscular junction. Thus, the term NMDs encompasses a vast array of different syndromes. Some of these syndromes are of direct relevance to paediatric orthopaedic surgeons, either because the presenting manifestation is a functional sign (e.g., toe-walking) or deformity (e.g., pes cavus or scoliosis) suggesting a need for orthopaedic attention or because orthopaedic abnormalities requiring treatment develop during the course of a known NMD. The main NMDs relevant to the orthopaedic surgeon are infantile spinal muscular atrophy (a motor neuron disease), peripheral neuropathies (chiefly, Charcot-Marie-Tooth disease), congenital muscular dystrophies, progressive muscular dystrophies, and Steinert myotonic dystrophy (or myotonic dystrophy type 1). Muscle weakness is a symptom shared by all these conditions. The paediatric orthopaedic surgeon must be familiar, not only with the musculoskeletal system, but also with many other domains (particularly respiratory and cardiac function and nutrition) that may interfere with the treatment and require preoperative management. Good knowledge of the natural history of each NMD is essential to ensure optimal timing of the therapeutic interventions, which must be performed under the best possible conditions in these usually frail patients. Timing is particularly crucial for the treatment of spinal deformities due to paraspinal muscle hypotonia during growth: depending on the disease and natural history, the treatment may involve non-operative methods or growing rods, followed by spinal fusion. A multidisciplinary approach is always required. Finally, the survival gains achieved in recent years increasingly require attention to preparing for adult life, to orthopaedic problems requiring treatment before the patient leaves the paediatric environment, and to the transition towards the adult healthcare system.

An integrated modelling methodology for estimating the prevalence of centronuclear myopathy.

Centronuclear myopathies (CNM) are a group of rare inherited muscular disorders leading to a significantly reduced quality of life and lifespan. To date, CNM epidemiologic reports provide limited incidence and prevalence data. Here, an integrated model utilizing available literature is proposed to obtain a better estimate of overall CNM patient numbers by age, causative gene, severity and geographic region. This model combines published epidemiology data and extrapolates limited data over CNM subtypes, resulting in patient numbers related to age and disease subtype. Further, the model calculates a CNM incidence twofold the current estimates. The estimated incidence of 17 per million births for severe X-linked myotubular myopathy (XLMTM), the main subtype of CNM, corresponds to an estimated prevalence of 2715 in the US, 1204 in the EU, 688 in Japan and 72 in Australia. In conclusion, the model provides an estimate of the CNM incidence, prevalence and survival, and indicates that the current estimates do not fully capture the true incidence and prevalence. With rapid advances in genetic therapies, robust epidemiologic data are needed to further quantify the reliability of incidence, prevalence and survival rates for the different CNM subtypes.

Childhood-onset form of myotonic dystrophy type 1 and autism spectrum disorder: Is there comorbidity?

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder with neuromuscular symptoms and brain dysfunctions. Depending on the phenotypic expression, the degree of cognitive impairment remains heterogeneous, ranging from moderate to severe intellectual disability in the congenital form, to executive, visuospatial and personality dysfunction in the adult-onset form. Studies exploring the cognitive or psychiatric impairments in the childhood form of DM1, characterized by an age of onset between one and ten years, uneventful pre and post natal history and normal development the first year of life, are scarce and show conflicting results in regard to a comorbid diagnosis of Autism Spectrum Disorder (ASD). The aim of the current review is to summarize diagnostic criteria and update the state of the debate regarding comorbidity. Evidence from 9 studies collected in PubMed database (representing a total of 175 cases) focusing on clinical, neuropsychological and neuroimaging domains in childhood DM1 is considered and similarities or differences between childhood DM1 and ASD are identified. Highlighting what is known about the neurocognitive features specific to the childhood-onset form of DM1 could help (1) propose early screening regarding socio-emotional and attentional/executive functions or (2) implement therapeutic programs based on reinforcement of executive skills or social cognition.

Platelets contribute to the initiation of colitis-associated cancer by promoting immunosuppression.

Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity. SUMMARY: Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8+ T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.

Targeting of C-type lectin-like receptor 2 or P2Y12 for the prevention of platelet activation by immunotherapeutic CpG oligodeoxynucleotides.

Essentials CpG oligodeoxynucleotide (ODN) immuotherapeutics cause undesired platelet activating effects. It is crucial to understand the mechanisms of these effects to identify protective strategies. CpG ODN-induced platelet activation depends on C-type lectin-like receptor 2 (CLEC-2) and P2Y12. Targeting CLEC-2 or P2Y12 fully prevents CpG ODN-induced platelet activation and thrombosis. SUMMARY: Background Synthetic phosphorothioate-modified CpG oligodeoxynucleotides (ODNs) show potent immunostimulatory properties that are widely exploited in clinical trials of anticancer treatment. Unexpectedly, a recent study indicated that CpG ODNs activate human platelets via the immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor glycoprotein VI. Objective To further analyze the mechanisms of CpG ODN-induced platelet activation and identify potential inhibitory strategies. Methods In vitro analyses were performed on human and mouse platelets, and on cell lines expressing platelet ITAM receptors. CpG ODN platelet-activating effects were evaluated in a mouse model of thrombosis. Results We demonstrated platelet uptake of CpG ODNs, resulting in platelet activation and aggregation. C-type lectin-like receptor 2 (CLEC-2) expressed in DT40 cells bound CpG ODNs. CpG ODN uptake did not occur in CLEC-2-deficient mouse platelets. Inhibition of human CLEC-2 with a blocking antibody inhibited CpG ODN-induced platelet aggregation. CpG ODNs caused CLEC-2 dimerization, and provoked its internalization. They induced dense granule release before the onset of aggregation. Accordingly, pretreating platelets with apyrase, or inhibiting P2Y12 with cangrelor or clopidogrel, prevented CpG ODN platelet-activating effect. In vivo, intravenously injected CpG ODN interacted with platelets adhered to mouse injured endothelium, and promoted thrombus growth, which was inhibited by CLEC-2 deficiency or by clopidogrel. Conclusions CLEC-2 and P2Y12 are required for CpG ODN-induced platelet activation and thrombosis, and might be targeted to prevent adverse events in patients at risk.

Effect of gravity on human spontaneous 10-Hz electroencephalographic oscillations during the arrest reaction.

Electroencephalographic oscillations at 10 Hz (alpha and mu rhythms) are the most prominent rhythms observed in awake, relaxed (eye-closed) subjects. These oscillations may be considered as a marker of cortical inactivity or an index of the active inhibition of the sensory information. Different cortical sources may participate in the 10-Hz oscillation and appear to be modulated by the sensory context and functional demands. In microgravity, the marked reduction in multimodal graviceptive inputs to cortical networks participating in the representation of space could be expected to affect the 10-Hz activity. The effect of microgravity on this basic oscillation has heretofore not been studied quantitatively. Because the alpha rhythm has a functional role in the regulation of network properties of the visual areas, we hypothesised that the absence of gravity would affect its strength. Here, we report the results of an experiment conducted over the course of 3 space flights, in which we quantified the power of the 10-Hz activity in relation to the arrest reaction (i.e., in 2 distinct physiological states: eyes open and eyes closed). We observed that the power of the spontaneous 10-Hz oscillation recorded in the eyes-closed state in the parieto-occipital (alpha rhythm) and sensorimotor areas (mu rhythm) increased in the absence of gravity. The suppression coefficient during the arrest reaction and the related spectral perturbations produced by eye-opening/closure state transition also increased in on orbit. These results are discussed in terms of current theories on the source and the importance of the alpha rhythm for cognitive function.

Purkinje cell rhythmicity and synchronicity during modulation of fast cerebellar oscillation.

Fast (approximately 160 Hz) cerebellar oscillation has been recently described in different models of ataxic mice, such as mice lacking calcium-binding proteins and in a mouse model of Angelman syndrome. Among them, calretinin-calbindin double knockout mice constitute the best model for evaluating fast oscillations in vivo. The cerebellum of these mice may present long-lasting episodes of very strong and stable local field potential oscillation alternating with the normal non-oscillating state. Spontaneous firing of the Purkinje cells in wild type and double knockout mice largely differs. Indeed, the Purkinje cell firing of the oscillating mutant is characterized by an increased rate and rhythmicity and by the emergence of synchronicity along the parallel fiber axis. To better understand the driving role played by these different parameters on fast cerebellar oscillation, we simultaneously recorded Purkinje cells and local field potential during the induction of general anesthesia by ketamine or pentobarbitone. Both drugs significantly increased Purkinje cell rhythmicity in the absence of oscillation, but they did not lead to Purkinje cell synchronization or to the emergence of fast oscillation. During fast oscillation episodes, ketamine abolished Purkinje cell synchronicity and inhibited fast oscillation. In contrast, pentobarbitone facilitated fast oscillation, induced and increased Purkinje cell synchronicity. We propose that fast cerebellar oscillation is due to the synchronous rhythmic firing of Purkinje cell populations and is facilitated by positive feedback whereby the oscillating field further phase-locks recruited Purkinje cells onto the same rhythmic firing pattern.

Fast cerebellar oscillation associated with ataxia in a mouse model of Angelman syndrome.

Ataxia may result from various cerebellar cortex dysfunctions. It is included in the diagnostic criteria of Angelman syndrome, a human neurogenetic condition. In order to better understand the cerebellar dysfunction in this condition, we recorded in vivo cerebellar activity in a mouse model of Angelman syndrome produced by null mutation of the maternal Ube3a gene. We found fast oscillation (approximately 160 Hz) in the cerebellar cortex sustained by abnormally increased Purkinje cell firing rate and rhythmicity. This oscillation is inhibited by sensory stimulation and gap junction or GABA(A) receptor blockers. A physiologically similar oscillation was previously found in mice lacking calcium-binding proteins that also present ataxia, but never in wild-type mice. We propose that fast oscillation in the cerebellar cortex is implicated in the cerebellar symptomatology of Angelman syndrome.

Role of calcium binding proteins in the control of cerebellar granule cell neuronal excitability: experimental and modeling studies.

Calcium binding proteins, such as calretinin, are abundantly expressed in distinctive patterns in the central nervous system but their physiological function remains poorly understood. Calretinin is expressed in cerebellar granule cells which provide the major excitatory input to Purkinje cells through parallel fibers. Calretinin deficient mice exhibit dramatic alterations in motor coordination and in Purkinje cell firing recorded in vivo through unknown mechanisms. In the present paper, we review the results obtained with the patch clamp recording techniques in acute slice preparation. This data allow us to investigate the effect of a null mutation of the calretinin gene on the intrinsic electroresponsiveness of cerebellar granule cells at a mature developmental stage. Calretinin deficient granule cells exhibit faster action potentials and generate repetitive spike discharge showing an enhanced frequency increase with injected currents. These alterations disappear when 0.15 mM of the exogenous fast calcium buffer BAPTA is infused in the cytosol to restore the calcium buffering capacity. Furthermore, we propose a mathematical model demonstrating that the observed alterations of granule cell excitability can be explained by a decreased cytosolic calcium buffering capacity due to the absence of calretinin. We suggest that calcium binding proteins modulate intrinsic neuronal excitability and may therefore play a role in the information processing in the central nervous system.

Event-related potentials (ERPs) in ecstasy (MDMA) users during a visual oddball task.

Ecstasy is the common name for a drug mainly containing a substance identified as 3,4-methylenedioxymethamphetamine (MDMA). It has become popular with participants in "raves", because it enhances energy, endurance and sexual arousal, together with the widespread belief that MDMA is a safe drug [Byard, R.W., Gilbert, J., James, R., Lokan, R.J., 1998. Amphetamine derivative fatalities in South Australia. Is "ecstasy" the culprit? Am. J. Forensic Med. Pathol. 19, 261-265]. However, it is suggested that this drug causes a neurotoxicity to the serotonergic system that could lead to permanent physical and cognitive problems. In order to investigate this issue, and during an ERP recording with 32 channels, we used a visual oddball design, in which subjects (14 MDMA abusers and 14 paired normal controls) saw frequent stimuli (neutral faces) while they had to detect as quickly as possible rare stimuli with happy or fearful expression. At a behavioral level, MDMA users imply longer latencies than normal controls to detect rare stimuli. At the neurophysiological level, ERP data suggest as main result that the N200 component, which is involved in attention orienting associated to the detection of stimulus novelty (e.g. [Campanella, S., Gaspard, C., Debatisse, D., Bruyer, R., Crommelinck, M., Guerit, J.M., 2002. Discrimination of emotional facial expression in a visual oddball task: an ERP study. Biol. Psychol. 59, 171-186]), shows shorter latencies for fearful rare stimuli (as compared to happy ones), but only for normal controls. This absence of delay was interpreted as an attentional deficit due to MDMA consumption.