Beyond Autonomy: Coersion and Morality in Clinical Relationships

International audienc

Appeal No. 0678: Perto Drilling Corp., Inc. v. Division of Mineral Resources Management

Chief\u27s Order 99-15

The Conservation Status of the Southern Cavefish Typhlichthys subterraneus in Arkansas,

National audienc

Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B

Background Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs. Methods We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in GRIN1 are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in GRIN1. Results Heterozygous variants in GRIN1 and GRIN2B were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous GRIN1 variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous GRIN1 variants in an individual with microcephaly with simplified gyral pattern. Conclusion These findings expand our understanding of the clinical and imaging features of the ‘NMDARopathy’ spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients. Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised data from this study will be shared by request from any qualified investigator

De novo variants in SP9 cause a novel form of interneuronopathy characterized by intellectual disability, autism spectrum disorder, and epilepsy with variable expressivity

Purpose: Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of gamma-aminobutyric acidergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellectual disability, and schizophrenic disorders. SP9 is a transcription factor belonging to the Krüppel-like factor and specificity protein family, the members of which harbor highly conserved DNA-binding domains. SP9 plays a central role in interneuron development and tangential migration, but it has not yet been implicated in a human neurodevelopmental disorder. Methods: Cases with SP9 variants were collected through international data-sharing networks. To address the specific impact of SP9 variants, in silico and in vitro assays were carried out. Results: De novo heterozygous variants in SP9 cause a novel form of interneuronopathy. SP9 missense variants affecting the glutamate 378 amino acid result in severe epileptic encephalopathy because of hypomorphic and neomorphic DNA-binding effects, whereas SP9 loss-of-function variants result in a milder phenotype with epilepsy, developmental delay, and autism spectrum disorder. Conclusion: De novo heterozygous SP9 variants are responsible for a neurodevelopmental disease. Interestingly, variants located in conserved DNA-binding domains of KLF/SP family transcription factors may lead to neomorphic DNA-binding functions resulting in a combination of loss- and gain-of-function effects

Effects of prenatal alcohol exposure on the development of GABAergic system and myelination in humans

L’exposition prénatale à l’alcool est une cause non génétique majeure d’anomalies structurales et fonctionnelles du système nerveux central dont la forme la plus sévère est le syndrome d’alcoolisation fœtale, et dont les effets perdurent tout au long de la vie, associant retard mental, troubles neurocognitifs et comportementaux. L’exposition prénatale à l’alcool est un enjeu de Santé Publique, car actuellement, la plupart des enfants ne sont pas précocement dépistés en l’absence des signes majeurs que sont la dysmorphie crânio-faciale caractéristique et le retard de croissance. Si de nombreuses études sur les anomalies neurodéveloppementales ont été réalisées chez l’animal et dont les résultats sont souvent contradictoires, très peu de données sont disponibles chez l’humain et concernent essentiellement l’enfant. Afin d’expliquer la symptomatologie de ces enfants, nous avons réalisé une étude de la mise en place des interneurones et de la glie de myélinisation, éléments essentiels intervenant dans la synchronisation des réseaux neuronaux. A partir d’une cohorte de 15 fœtus humains à tous les stades du développement et de deux cas post-nataux âgés de trois mois et deux ans exposés à l’alcool, nous avons étudié l’ontogenèse des interneurones GABAergiques et calrétininergiques ainsi que les caractéristiques de leur migration vasculaire dans le cortex. Nous avons identifié une interneuronopathie consistant en un retard majeur de génération dans les zones de production (éminences ganglionnaires) aux stades précoces de développement et une malposition des interneurones calrétininergiques au sein du cortex des fœtus alcoolisés aux stades plus tardifs comparativement à des contrôles appariés. Ce retard de génération touche également les précurseurs des oligodendrocytes exprimant le PDGFRα qui restent ensuite anormalement nombreux aux dépends des précurseurs et préoligodendrocytes exprimant Olig2. Ces derniers restent pratiquement absents dans le cortex des fœtus alcoolisés jusqu’en fin de la grossesse. L’interneuronopathie et le défaut de différentiation oligodendrogliale pourraient expliquer en partie les troubles neurologiques observés chez les enfants et adultes exposés in utero à l’alcool, la modulation de l’activité neuronale et la myélinisation étant indispensables à l’établissement des réseaux neuronaux et à la conduction des influx nerveux.Prenatal alcohol exposure is a major non-genetic cause of structural and functional abnormalities of the central nervous system, the most severe form of which is fetal alcohol syndrome, and the effects of which persist throughout life, associating mental retardation, neurocognitive and behavioural disorders. Prenatal alcohol exposure is a public health issue, since currently most children are not early detected in the absence of the major signs consisting of characteristic cranio-facial dysmorphism and growth retardation. While numerous studies on neurodevelopmental abnormalities have been carried out in animals and the results of which are often contradictory, very little data is available in humans and mainly concerns children. In order to explain the symptoms of these children, we have conducted an ontogenetic study of interneurons and oligodendrocyte lineage, two essential events involved in the synchronization of neural networks. Using a cohort of 15 human fetuses at all stages of development and two postnatal cases aged three months and two years exposed to alcohol in utero, we studied the development of GABAergic and calretinergic interneurons as well as the characteristics of their vascular migration within the cortex. We identified an interneuronopathy consisting of a major generation delay in the production areas (ganglionic eminences) at the early stages of development and a mispositioning of calretinergic interneurons within the cortex of fetuses exposed to alcohol at later stages compared with age matched controls. This delay in generation also affects precursors of oligodendrocytes expressing PDGFRα, which then remain abnormally numerous at the expense of precursors and pre-oligodendrocytes expressing Olig2. The latter are virtually absent in the cortex of fetuses exposed to alcohol until the end of pregnancy. Interneuronopathy and the lack of oligodendroglial differentiation could partly explain the neurological disabilities observed in children and adults exposed in utero to alcohol, modulation of neuronal activity and myelination being essential for the establishment of neural networks and conduction of nerve outputs

Effets de l'alcoolisation prénatale sur le développement du système GABAergique et de la myélinisation chez l'humain

Prenatal alcohol exposure is a major non-genetic cause of structural and functional abnormalities of the central nervous system, the most severe form of which is fetal alcohol syndrome, and the effects of which persist throughout life, associating mental retardation, neurocognitive and behavioural disorders. Prenatal alcohol exposure is a public health issue, since currently most children are not early detected in the absence of the major signs consisting of characteristic cranio-facial dysmorphism and growth retardation. While numerous studies on neurodevelopmental abnormalities have been carried out in animals and the results of which are often contradictory, very little data is available in humans and mainly concerns children. In order to explain the symptoms of these children, we have conducted an ontogenetic study of interneurons and oligodendrocyte lineage, two essential events involved in the synchronization of neural networks. Using a cohort of 15 human fetuses at all stages of development and two postnatal cases aged three months and two years exposed to alcohol in utero, we studied the development of GABAergic and calretinergic interneurons as well as the characteristics of their vascular migration within the cortex. We identified an interneuronopathy consisting of a major generation delay in the production areas (ganglionic eminences) at the early stages of development and a mispositioning of calretinergic interneurons within the cortex of fetuses exposed to alcohol at later stages compared with age matched controls. This delay in generation also affects precursors of oligodendrocytes expressing PDGFRα, which then remain abnormally numerous at the expense of precursors and pre-oligodendrocytes expressing Olig2. The latter are virtually absent in the cortex of fetuses exposed to alcohol until the end of pregnancy. Interneuronopathy and the lack of oligodendroglial differentiation could partly explain the neurological disabilities observed in children and adults exposed in utero to alcohol, modulation of neuronal activity and myelination being essential for the establishment of neural networks and conduction of nerve outputs.L’exposition prénatale à l’alcool est une cause non génétique majeure d’anomalies structurales et fonctionnelles du système nerveux central dont la forme la plus sévère est le syndrome d’alcoolisation fœtale, et dont les effets perdurent tout au long de la vie, associant retard mental, troubles neurocognitifs et comportementaux. L’exposition prénatale à l’alcool est un enjeu de Santé Publique, car actuellement, la plupart des enfants ne sont pas précocement dépistés en l’absence des signes majeurs que sont la dysmorphie crânio-faciale caractéristique et le retard de croissance. Si de nombreuses études sur les anomalies neurodéveloppementales ont été réalisées chez l’animal et dont les résultats sont souvent contradictoires, très peu de données sont disponibles chez l’humain et concernent essentiellement l’enfant. Afin d’expliquer la symptomatologie de ces enfants, nous avons réalisé une étude de la mise en place des interneurones et de la glie de myélinisation, éléments essentiels intervenant dans la synchronisation des réseaux neuronaux. A partir d’une cohorte de 15 fœtus humains à tous les stades du développement et de deux cas post-nataux âgés de trois mois et deux ans exposés à l’alcool, nous avons étudié l’ontogenèse des interneurones GABAergiques et calrétininergiques ainsi que les caractéristiques de leur migration vasculaire dans le cortex. Nous avons identifié une interneuronopathie consistant en un retard majeur de génération dans les zones de production (éminences ganglionnaires) aux stades précoces de développement et une malposition des interneurones calrétininergiques au sein du cortex des fœtus alcoolisés aux stades plus tardifs comparativement à des contrôles appariés. Ce retard de génération touche également les précurseurs des oligodendrocytes exprimant le PDGFRα qui restent ensuite anormalement nombreux aux dépends des précurseurs et préoligodendrocytes exprimant Olig2. Ces derniers restent pratiquement absents dans le cortex des fœtus alcoolisés jusqu’en fin de la grossesse. L’interneuronopathie et le défaut de différentiation oligodendrogliale pourraient expliquer en partie les troubles neurologiques observés chez les enfants et adultes exposés in utero à l’alcool, la modulation de l’activité neuronale et la myélinisation étant indispensables à l’établissement des réseaux neuronaux et à la conduction des influx nerveux

Stereotactic brain biopsy: evaluation of robot-assisted procedure in 60 patients

International audienceBackground Frameless stereotactic biopsies, particularly robot-assisted procedures are increasing in neurosurgery centers.Results of these procedures should be at least equal to or greater than frame-based reference procedure. Evaluate robotassisted technology is necessary in particular, when a team has chosen to switch from one to another method.Objective The objective of our prospective work was (i) to evaluate the success rate of contributive robotic-assisted biopsy in 60patients, to report the morbidity and mortality associated with the procedure and (ii) to compare it with literature data.Methods We performed a prospective and descriptive study including 60 consecutive patients having had robotic-assistedstereotactic biopsy at the Rouen University Hospital, France. All patients had presurgical imaging before the procedure includedMagnetic Resonance Imaging merged with Computed Tomography scan acquisition. Registration was mostly performed with atouch-free laser (57/60). A control Computed Tomography scan was always realized at day 0 or day 1 after surgery. Datacollected were success rate, bleeding, clinical worsening, infection, and mortality.Results All the biopsies were considered as contributive and lead to the final diagnosis. In 41/60 patients (68%), the lesion wasglial. Six in 60 patients (10%) had visible bleeding without clinical worsening related, 5/60 patients (8.5%) showed clinicalimpairment following surgery, which was permanent in 2 patients, and 1/60 patient presented generalized seizures. We did notreport any infection and mortality.Conclusion Robot-assisted frameless surgery is efficient and provides a reasonable alternative to frame-based procedure. Theoperating time can be reduced, without increasing morbidity and mortality rates