SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.

Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2/KIAA1985, was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2(DeltaEx1/DeltaEx1) animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2(DeltaEx1/DeltaEx1) animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.

Continuous electroencephalographic monitoring in critically ill patients with central nervous system infections.

OBJECTIVES: To determine the prevalence, predictors, and clinical significance of electrographic seizures (ESz) and other continuous electroencephalographic monitoring findings in critically ill patients with central nervous system infections. DESIGN: Retrospective cohort study. SETTING: Eighteen-bed neurocritical care unit. PATIENTS: We identified 42 consecutive patients with primary central nervous system infection (viral, 27 patients [64%]; bacterial, 8 patients [18%]; and fungal or parasitic, 7 patients [17%]) who underwent continuous electroencephalographic monitoring between January 1, 1996, and February 28, 2007. MAIN OUTCOME MEASURES: Presence of ESz or periodic epileptiform discharges (PEDs). RESULTS: Electrographic seizures were recorded in 14 patients (33%), and PEDs were recorded in 17 patients (40%). Twenty patients (48%) had either PEDs or ESz. Of the 14 patients with ESz, only 5 (36%) had a clinical correlate. Periodic epileptiform discharges (odds ratio=13.4; P=.001) and viral cause (odds ratio=13.0; P=.02) were independently associated with ESz. Both ESz (odds ratio=5.9; P=.02) and PEDs (odds ratio=6.1; P=.01) were independently associated with poor outcome at discharge (severe disability, vegetative state, or death). CONCLUSIONS: In patients with central nervous system infections undergoing continuous electroencephalographic monitoring, ESz and/or PEDs were frequent, occurring in 48% of our cohort. More than half of the ESz had no clinical correlate. Both ESz and PEDs were independently associated with poor outcome. Additional studies are needed to determine whether prevention or treatment of these electrographic findings improves outcome.

Mobilization of hemopoietic stem cells with high-dose methotrexate plus granulocyte-colony-stimulating factor in patients with primary central nervous system lymphoma.

BACKGROUND: High-dose therapy with autologous stem cell support after standard dose induction is a promising approach for therapy of primary central nervous system lymphoma (PCNSL). High-dose methotrexate (HD-MTX) is a standard drug for induction of PCNSL; however, data about the capacity of HD-MTX plus granulocyte-colony-stimulating factor (G-CSF) to mobilize hemopoietic progenitors are lacking. STUDY DESIGN AND METHODS: This investigation describes the data from stem cell mobilization and apheresis procedures after one or two cycles of HD-MTX for induction of PCNSL within the East German Study Group for Haematology and Oncology 053 trial. Eligible patients proceeded to high-dose busulfan/thiotepa after induction therapy and mobilization. RESULTS: Data were available from nine patients with a median age of 58 years. The maximal CD34+ cell count per microL of blood after the first course of HD-MTX was 13.89 (median). Determination was repeated in six patients after the second course with a significantly higher median CD34+ cell count of 33.69 per microL. Five patients required two apheresis procedures and in four patients a single procedure was sufficient. The total yield of CD34+ cells per kg of body weight harvested by one or two leukapheresis procedures was 6.60 x 10(6) (median; range, 2.68 x 10(6)-15.80 x 10(6)). The yield of CD34+ cells exceeded the commonly accepted lower threshold of 3 x 10(6) cells per kg of body weight in eight of nine cases. Even in the ninth, hemopoietic recovery after stem cell reinfusion was rapid and safe. CONCLUSION: HD-MTX plus G-CSF is a powerful combination for stem cell mobilization in patients with PCNSL and permits safe conduction of time-condensed and dose-intense protocols with high-dose therapy followed by stem cell reinfusion after HD-MTX induction.

Neuronal death in the development of the vertebrate central nervous system

Neuronal death occurs naturally in the development of the vertebrate central nervous system, deleting large numbers of neurons at the time when afferent and efferent connections are being formed. It is these that regulate it, by means of anterograde and retrograde survival signals that depend on trophic molecules and electrical activity. Possible roles include the regulation of neuronal numbers (numerical matching) and the elimination of axonal targeting errors.

Relevance of death receptors in nervous system: role in the pathogenesis of neurodegenerative diseases and targets for therapy

L’apoptosi és un procés fisiològic que controla el nombre de cèl·lules en organismes superiors. L’apoptosi està estrictament regulada i s’ha vist que està implicada en la patogènesi d’algunes malalties del sistema nerviós. En aquest sentit, un excés de mort cel·lular contribueix a les malalties neurodegenerati- ves, mentre que, el seu dèficit és una de les raons del desenvolupament de tumors. El punt principal de regulació del procés apoptòtic és l’activació de les caspases, cisteïna-proteases que tenen especificitat pels residus aspàrtic. Les caspases es poden activar per dos mecanismes principals: (1) alliberament de citocrom C dels mitocondris alterats al citoplasma i (2) l’activació dels receptors de la membrana anomenats receptors de mort (DR, de l’anglès death receptor). Aquests receptors s’han caracteritzat extensament en el sistema immunitari, mentre que en el sistema nerviós les seves funcions són encara desconegudes. El present article se centra en el paper dels DR en la patogènesi de malalties neurodegeneratives i suggereix el seu potencial des del punt de vista terapèutic. També es descriuen diverses molècules intracel·lulars caracteritzades per la seva habilitat en la modulació dels DR. Entre elles, presentem dues noves proteïnes – lifeguard i FAIM – que s’expressen específicament al sistema nerviós.

The planarian flatworm: an in vivo model for stem cell biology and nervous system regeneration

Planarian flatworms are an exception among bilaterians in that they possess a large pool of adult stem cells that enables them to promptly regenerate any part of their body, including the brain. Although known for two centuries for their remarkable regenerative capabilities, planarians have only recently emerged as an attractive model for studying regeneration and stem cell biology. This revival is due in part to the availability of a sequenced genome and the development of new technologies, such as RNA interference and next-generation sequencing, which facilitate studies of planarian regeneration at the molecular level. Here, we highlight why planarians are an exciting tool in the study of regeneration and its underlying stem cell biology in vivo, and discuss the potential promises and current limitations of this model organism for stem cell research and regenerative medicine.

On the existence and function of galanin receptor heteromers in the central nervous system

Galanin receptor (GalR) subtypes 1-3 linked to central galanin neurons may form heteromers with each other and other types of G protein-coupled receptors in the central nervous system (CNS). These heteromers may be one molecular mechanism for galanin peptides and their N-terminal fragments (gal 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional and the cardiovascular networks. GalR-5-HT1A heteromers likely exist with antagonistic GalR-5-HT1A receptor-receptor interactions in the ascending midbrain raphe 5-HT neuron systems and their target regions. They represent a novel target for antidepressant drugs. Evidence is given for the existence of GalR1-5-HT1A heteromers in cellular models with trans-inhibition of the protomer signaling. A GalR1-GalR2 heteromer is proposed to be a galanin N-terminal fragment preferring receptor (1-15) in the CNS. Furthermore, a GalR1-GalR2-5-HT1A heterotrimer is postulated to explain why only galanin (1-15) but not galanin (1-29) can antagonistically modulate the 5-HT1A receptors in the dorsal hippocampus rich in gal fragment binding sites. The results underline a putative role of different types of GalR-5-HT1A heteroreceptor complexes in depression. GalR antagonists may also have therapeutic actions in depression by blocking the antagonistic GalR-NPYY1 receptor interactions in putative GalR-NPYY1 receptor heteromers in the CNS resulting in increases in NPYY1 transmission and antidepressant effects. In contrast the galanin fragment receptor (a postulated GalR1-GalR2 heteromer) appears to be linked to the NPYY2 receptor enhancing the affinity of the NPYY2 binding sites in a putative GalR1-GalR2-NPYY2 heterotrimer. Finally, putative GalR-α2-adrenoreceptor heteromers with antagonistic receptor-receptor interactions may be a widespread mechanism in the CNS for integration of galanin and noradrenaline signals also of likely relevance for depression

Diagnosis by imaging : the case of textbooks of diseases of the nervous system (1850-1920)

Les traités scientifiques ne font que depuis peu d'années l'objet d'études en histoire des sciences. Pourtant, ces traités ont énormément à apporter car ils renseignent sur la manière de raisonner des auteurs, ainsi que sur le développement d'une discipline. Dans ce travail de doctorat, différents traités des maladies du système nerveux ont été dépouillés, notamment le traité de Sémiologie des affections du système nerveux (1914) de Jules Dejerine (1849-1917). Ce traité a été analysé de trois manières différentes. Il a tout d'abord été comparé à une édition précédente publiée sous forme de chapitre (1901), révélant un large remodelage du contenu du traité, suggérant une évolution rapide de la discipline neurologique en l'espace de quelques années. Deuxièmement, l'analyse de la Sémiologie a permis de recréer un réseau de professionnels avec qui Jules Dejerine était en contact et, en parcourant les livres publiés par ces auteurs, il a été possible de décrire de quelle manière ces auteurs se citent mutuellement. Finalement, ces livres contiennent de nombreuses illustrations, qui sont associées à la notion de « preuve » : les auteurs utilisent des images sous forme de dessins, de photographies ou de schémas qui illustrent des patients ou des pièces anatomiques pour « montrer » la maladie ou la lésion. Chaque illustration a un rôle à jouer pour décrire la lésion, montrer la progression de la maladie et elle aide le médecin à poser le diagnostic. Grâce à ces trois axes de recherche, un traité devient un outil de travail dynamique, qui évolue au fil des rééditions, influencé par les critiques et commentaires retrouvés dans d'autres traités et articles, et par les progrès accomplis dans la discipline traitée. Des, passages et certaines images de l'ouvrage circulent également de traité en traité et véhiculent l'autorité de l'auteur de ces passages et images qui en viennent à représenter la maladie. Ce transfert d'images joue également un rôle dans la standardisation du diagnostic et dans l'unification de la neurologie à travers le monde occidental au début du XXe siècle, une période charnière pour l'histoire de la médecine. -- Au début du XXe siècle, la neurologie est une jeune spécialité médicale qui se développe rapidement. Les différents médecins publient des traités, communiquent entre eux et échangent leurs données. Un traité scientifique est un outil de travail dynamique qui évolue avec les rééditions et le développement d'une discipline. Ces ouvrages recèlent toutes sortes d'informations et leur analyse ne fait que depuis peu de temps l'objet d'études en histoire des sciences. Ces traités regorgent notamment d'illustrations qui sont associées à la notion de « preuve » : les auteurs utilisent des images sous forme de dessins, de photographies ou de schémas qui représentent des patients ou des pièces anatomiques afin de « montrer » la maladie ou la lésion. Chaque illustration a un rôle à jouer pour décrire la pathologie, montrer la progression de la maladie et elle aide le médecin à poser le diagnostic. Les auteurs des traités, qui viennent d'Europe et d'Amérique du Nord, se citent mutuellement, permettant au lecteur de recréer leur réseau de professionnels au niveau international. De plus, comme ces auteurs réutilisent les observations et les illustrations des autres, celles-ci circulent de traité en traité et en viennent à représenter la maladie. Ce transfert d'images joue également un rôle dans la standardisation du diagnostic et dans l'unification de la neurologie à travers le monde occidental au début du XXe siècle, une période charnière pour l'histoire de la médecine. -- Until recently, the study of textbooks has been neglected in the history of the sciences. However, textbooks can provide fruitful sources of information regarding the way authors work and the development of a particular discipline. This dissertation reviews editions of a single textbook, the Sémiologie des affections du système nerveux (1914) by Jules Dejerine (1849-1917). This textbook enabled the description of three axes of research. Firstly, by comparing the book to a first edition published as a chapter, one can acknowledge an extensive remodeling of the content of the book, suggesting a vast increase in knowledge over time. Secondly, by looking at the authors that Dejerine quotes repeatedly, it becomes possible to recreate his professional network, to review the works of these authors and to determine how they cross-reference each other. Thirdly, these textbooks contain numerous medical illustrations, which are linked with the concept of "proof;" the authors demonstrate a willingness to "show" the lesion or the pathology by publishing an image. Drawings, schematic representations, radiographies, or photographs of patients or of anatomical preparations all have their own purpose in describing the lesion and the progression of the disease. They assist in the diagnosis of the pathology. By looking at all of these aspects, it is therefore possible to conclude that a neurological textbook is a dynamic object that evolves through re-editions, comments and references found in other textbooks and by the circulations of parts of these books, such as the images. The illustrations also carry the author's authority, since their ongoing use claims that the work by the owner of the image has been endorsed by others. At the same time, it validates the borrowers' arguments. By using medical illustrations from different authors worldwide, the authors are also making a claim to a common language, to a similar way of examining patients, and about how much they depend on medical imagery to prove their points. In that sense, by focusing upon these textbooks, one can affirm that neurology already existed as a worldwide specialty at the turn of the twentieth century. Much more than mere accompaniments to the text, images were of paramount importance to the unification of neurology.

Impact of round-the-clock CSF Gram stain on empirical therapy for suspected central nervous system infections.

The impact of round-the-clock cerebrospinal fluid (CSF) Gram stain on overnight empirical therapy for suspected central nervous system (CNS) infections was investigated. All consecutive overnight CSF Gram stains between 2006 and 2011 were included. The impact of a positive or a negative test on empirical therapy was evaluated and compared to other clinical and biological indications based on institutional guidelines. Bacterial CNS infection was documented in 51/241 suspected cases. Overnight CSF Gram stain was positive in 24/51. Upon validation, there were two false-positive and one false-negative results. The sensitivity and specificity were 41 and 99 %, respectively. All patients but one had other indications for empirical therapy than Gram stain alone. Upon obtaining the Gram result, empirical therapy was modified in 7/24, including the addition of an appropriate agent (1), addition of unnecessary agents (3) and simplification of unnecessary combination therapy (3/11). Among 74 cases with a negative CSF Gram stain and without formal indication for empirical therapy, antibiotics were withheld in only 29. Round-the-clock CSF Gram stain had a low impact on overnight empirical therapy for suspected CNS infections and was associated with several misinterpretation errors. Clinicians showed little confidence in CSF direct examination for simplifying or withholding therapy before definite microbiological results.

Distribution of monocarboxylate transporters in the peripheral nervous system suggests putative roles in lactate shuttling and myelination.

Lactate, a product of glycolysis, has been shown to play a key role in the metabolic support of neurons/axons in the CNS by both astrocytes and oligodendrocytes through monocarboxylate transporters (MCTs). Despite such importance in the CNS, little is known about MCT expression and lactate function in the PNS. Here we show that mouse MCT1, MCT2, and MCT4 are expressed in the PNS. While DRG neurons express MCT1, myelinating Schwann cells (SCs) coexpress MCT1 and MCT4 in a domain-specific fashion, mainly in regions of noncompact myelin. Interestingly, SC-specific downregulation of MCT1 expression in rat neuron/SC cocultures led to increased myelination, while its downregulation in neurons resulted in a decreased amount of neurofilament. Finally, pure rat SCs grown in the presence of lactate exhibited an increase in the level of expression of the main myelin regulator gene Krox20/Egr2 and the myelin gene P0. These data indicate that lactate homeostasis participates in the regulation of the SC myelination program and reveal that similar to CNS, PNS axon-glial metabolic interactions are most likely mediated by MCTs.