Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 +/- 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with 'slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's disease

Altered processing of sensory stimuli in patients with migraine

Migraine is a cyclic disorder, in which functional and morphological brain changes fluctuate over time, culminating periodically in an attack. In the migrainous brain, temporal processing of external stimuli and sequential recruitment of neuronal networks are often dysfunctional. These changes reflect complex CNS dysfunction patterns. Assessment of multimodal evoked potentials and nociceptive reflex responses can reveal altered patterns of the brain's electrophysiological activity, thereby aiding our understanding of the pathophysiology of migraine. In this Review, we summarize the most important findings on temporal processing of evoked and reflex responses in migraine. Considering these data, we propose that thalamocortical dysrhythmia may be responsible for the altered synchronicity in migraine. To test this hypothesis in future research, electrophysiological recordings should be combined with neuroimaging studies so that the temporal patterns of sensory processing in patients with migraine can be correlated with the accompanying anatomical and functional changes

LES MALFORMATIONS DU DEVELOPPEMENT CORTICAL (A PROPOS DE 23 OBSERVATIONS D'EPILEPSIE PHARMACO-RESISTANTE)

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Characterization and histological localization of multipotent mesenchymal stromal cells in the human postnatal thymus

The aim of this work was to characterize multipotent mesenchymal stromal cells (MSCs) in the postnatal human thymus and to localize these MSCs in the organ. Adherent cells isolated from thymus samples were characterized by cell-surface antigen expression. This showed that adherent cells have a MSC profile as assessed by the expression of CD73 and CD105 markers and the lack of CD45 expression. These cells are able to differentiate in vitro into adipocytes, osteoblasts, and chondrocytes and to inhibit mixed lymphocyte reaction. This indicates that isolated cells have all of the characteristics of MSC. The fibroblast colony-forming unit (CFU-F) assay was used to determine their frequency in the postnatal thymus. This frequency was 60.9 ± 14.8 CFU-F per 1 × 105 freshly isolated mononuclear cells. Moreover, taking advantage of CD34 and CD105 expression, immunohistological staining allowed us to localize MSC within interlobular trabeculae in close contact with the outer cortex. Polymerase chain reaction experiments indicated that thymic MSC expressed interleukin-7 and stromal cell-derived factor-1 messenger RNA. Overall, these results confirm previous findings of the presence in the adult human thymus of multipotent MSCs with a phenotype similar to adipose-derived adult stem cells. These results also show for the first time a histological localization of MSC in an organ. This suggests a possible role of thymic MSC in intrathymic differentiation. © Mary Ann Liebert, Inc. 2008

Use of Flt3 ligand to evaluate residual hematopoiesis after heterogeneous irradiation in mice

We evaluated the possibility of using plasma Flt3 ligand (FL) concentration as a biological indicator of bone marrow function after heterogeneous irradiation. Mice were irradiated with 4, 7.5 or 11 Gy with 25, 50, 75 or 100% of the bone marrow in the field of irradiation. This model of irradiation resulted in graded and controlled damage to the bone marrow. Mice exhibited a pancytopenia correlated with both the radiation dose and the percentage of bone marrow irradiated. The FL concentration in the blood increased with the severity of bone marrow aplasia. Nonlinear regression analysis showed that the FL concentration was strongly correlated with the total number of residual colony-forming cells 3 days after irradiation, allowing a precise estimate of residual hematopoiesis. Moreover, the FL concentration on day 3 postirradiation was correlated with the duration and severity of subsequent pancytopenia, suggesting that variations in FL concentrations might be used as a predictive indicator of bone marrow aplasia, especially by the use of linear regression equations describing these correlations. Our results provide a rationale for the use of FL concentration as a biological indicator of residual hematopoiesis after heterogeneous irradiation. © 2006 by Radiation Research Society

Correlation between plasma Flt3-ligand concentration and hematopoiesis during G-CSF-induced CD34+ cell mobilization

This study aimed to correlate blood Flt3-ligand (FL) concentration with CD34+ cell number in blood and bone marrow (BM) during granulocyte colony-stimulating factor (G-CSF) mobilization. Nonhuman primates were injected with 10 μg/kg of G-CSF (Lenograstim) daily over a period of 5 days. Daily blood sampling and repeated BM sampling showed that FL concentration before mobilization was negatively correlated to the absolute number of BM CD34 + cells, but also to the number of G-CSF-mobilized CD34+ cells on days 3-5 of treatment. This showed that FL concentration in the blood reflected BM status before mobilization, and suggested that this parameter could be used as a predictive indicator of G-CSF-induced CD34+ cell mobilization. © Mary Ann Liebert, Inc. 2008

Douze années de pose d’endoprothèses rectocoliques : résultats et suivi chez 204 patients

Objectifs : Les buts de cette étude étaient d’évaluer la faisabilité et l’efficacité à long terme de la mise en place d’endoprothèses métalliques ou plastiques pour des sténoses recto-coliques malignes ou bénignes dans la « vraie vie ». Patients et méthodes : De septembre 1994 à septembre 2006, 204 patients consécutifs (118 femmes, 86 hommes, âge moyen : 73,2 ans, extrêmes : 49-97 ans) présentant une obstruction rectocolique partielle ou complète, étaient traités par une ou plusieurs endoprothèses métalliques ou plastiques. Une pose d’endoprothèse était tentée pour 168 patients porteurs d’une sténose colique maligne en situation palliative, pour 17 malades porteurs également d’un cancer avant un geste chirurgical curatif, pour 19 patients présentant une sténose bénigne, mais contreindiqués pour la chirurgie en raison d’un état général trop altéré. La pose des prothèses était réalisée par voie endoscopique et radioscopique. Différents modèles de prothèses étaient utilisés, incluant les Enteral Wallstent, Wallflex, Colonic Z stent, Ultraflex precision, Choo Stent, Hanarostent et Polyflex. Les données sur l’efficacité de la procédure, les complications et le devenir des patients étaient collectées rétrospectivement à partir des médecins traitants qui ont suivi leurs patients jusqu’à leur décès. Résultats : La pose d’une endoprothèse était effectuée avec succès chez 154 patients en situation palliative (91,6 %), chez les 17 patients avant la chirurgie curative (100 %) et chez 15 malades porteurs d’une sténose bénigne (78 %). Une complication survenait pour 28 patients : perforation colique (n = 8) ; inefficacité (n = 8) ; ré-obstruction par matières fécales ou progression tumorale (n = 6) ; migration (n = 4) ; douleur abdominale sévère (n = 1). Une patiente décédait. Une deuxième endoprothèse était rendue nécessaire ultérieurement chez 6 malades. Conclusions : La pose d’une prothèse rectocolique par voie endoscopique est un traitement palliatif efficace en cas d’obstruction maligne. Ce traitement est également efficace avant un geste chirurgical curatif et pour certaines sténoses bénignes en l’absence d’alternatives thérapeutiques moins agressives

Radiation-induced increase in plasma Flt3 ligand concentration in mice: Evidence for the implication of several cell types

Circulating T lymphocytes were proposed as the main producer of Flt3 ligand. However, during aplasia, there is a drastic reduction in the number of T lymphocytes, while plasma Flt3 ligand concentration is increased. This contradiction prompted us to compare variations in plasma Flt3 ligand during radiation-induced aplasia in BALB/c mice and in T-lymphocyte-deficient NOD-SCID mice to delineate the role of T lymphocytes in the increase in Flt3 ligand concentration. The results showed that plasma Flt3 ligand concentration was increased similarly in the two strains of mice, and that Flt3 ligand concentration was negatively correlated to the number of residual hematopoietic progenitors. Moreover, the Flt3 ligand mRNA expression and Flt3 ligand protein concentration were similar in the two strains of mice in all organs tested, i.e. thymus, spleen, bone marrow, liver, brain and blood cells. These results confirm that Flt3 ligand concentration in the blood is a reflection of bone marrow function and that T lymphocytes are not the main regulator of Flt3 ligand variations during aplasia. © 2005 by Radiation Research Society