[Peripheral nerve tumors]. / Tumeurs des nerfs périphériques.

Peripheral nerve tumors are most often benign tumors of the nerve sheath; uncommonly they come from the nerve cells or are metastatic tumors. A precise diagnosis is required for well-adapted and effective treatment, as is good knowledge of fibromatosis diseases. In some cases, the diagnosis of the nerve tumor will lead to a diagnosis of phakomatosis. Surgical treatment must be clearly discussed, which, in case of schwannomas gives very good functional results. Primitive malignant tumors remain an unsolved therapeutic problem.

[Molecular architecture of the sarcoplasmic reticulum and its role in the ECC]. / Architecture moléculaire du réticulum sarcoplasmique et son rôle dans le couplage excitation-contraction.

The sarcoplasmic reticulum (SR) plays a fundamental role in excitation-contraction coupling, which propagates the electric signal conversion along the muscle fiber's plasmic membrane to a mechanical event manifested as a muscle contraction. It plays a crucial role in calcium homeostasis and intracellular calcium storage control (storage, liberation and uptake) necessary for fiber muscle contraction and then relaxation. These functions take place at the triad, made up of individualized SR subdomains where the protein-specific organization provides efficient and fast coupling. Ryanodine receptors (RyR) and dihydropyridine receptors (DHPR) mainly act in calcium exchanges in the SR. This particular structural and molecular architecture must be correlated to its functional specificity.

[Mechanisms controlling axonal sprouting at the neuromuscular junction]. / Mécanismes contrôlant le bourgeonnement axonal à la jonction neuromusculaire.

This paper explores the specific roles of sprouting stimuli, perisynaptic Schwann cells and neuromuscular activity in axonal sprouting at the neuromuscular junction in partially denervated muscles. As for sprouting stimuli, insulin-like growth factor II which is generated from inactive muscle fibers in partially denervated and paralysed skeletal muscle is described. Likewise, perisynaptic Schwann cells can induce and guide axonal sprouting in partially denervated muscles. Finally, excessive neuromuscular activity significantly reduces bridging of the perisynaptic Schwann cell processes between denervated and innervated endplates and thereby inhibits axonal sprouting in partially denervated muscle. The lack of neuromuscular activity is also harmful in axonal sprouting, probably by impeding calcium influx into the nerve.

[Structural and molecular organization, development and maturation of the neuromuscular junction]. / Organisation structurale, moléculaire, formation et maturation de la jonction neuromusculaire.

The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are surrounded by a basal lamina, dedicated to molecular signal exchanges controlling neuromuscular formation, maturation and maintenance. This functional and structural differentiated complex conducts synaptic neurotransmission to the skeletal muscle fiber. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and the motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK. Neuregulin is essentially involved in Schwann cell survival and guidance for axonal growth.

[Anatomy and physiology of the peripheral nerve]. / Organisation anatomique et physiologique du nerf périphérique.

The peripheral nerve provides the pathway for motor, sensory and vegetative axons belonging to the peripheral nervous system. It transmits information between these neurons and their peripheral effectors in both directions (sensory receptors, skeletal muscles and viscera). The afferences to the periphery correspond to the nerve motor content, whereas efferences from the periphery, in charge of delivering information to the central integrators, correspond to nerve-sensitive content. This information support depends on intrinsic properties of the nerve itself. Recent advances in cellular and molecular biology have provided a better understanding of nerve physiology, which are reviewed here as an indispensable basis to the study of its pathology.

[Synapse formation and regeneration]. / Formation et régénération synaptique.

Synapse formation is probably the key process in neural development allowing signal transmission between nerve cells. As an interesting model of synapse maturation, we considered first the neuromuscular junction (NMJ), whose development is particularly dependent on intercellular interactions between the motor nerve and the skeletal muscle. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK and rapsyn. The agrin or motoneuron dependence of this process continues to be debated while the following steps of axonal growth and postsynaptic apparatus maintenance essentially depend on neuronal agrin and a neuron-specific signal dispersing ectopic AChR aggregate remainders, possibly mediated by acetylcholine itself. Neuregulin is essentially involved in Schwann's cell survival and guidance for axonal growth. In this paper, we will discuss the similarities between Central Nervous System (CNS) synaptic formation and Motor innervation. The limited ability of the CNS to create new synapses after nervous system injury will be then discussed with a final consideration of some new strategies elaborated to circumvent the limitations of lesion extension processes.

[Major mechanisms involved in the synaptic transmission of the neuromuscular apparatus]. / Principaux mécanismes impliqués dans la transmission synaptique au sein de l'appareil neuromusculaire.

Neuromuscular transmission results from a double signal transduction from electric impulses to chemical messengers, taking place at a highly differentiated region, the neuromuscular junction (NMJ). A nerve cell responds to a specific stimulus by modifications of its plasmic membrane properties, generating an action potential (AP). This electric signal is transmitted along the axon to the NMJ, where it induces the voltage-gated calcium channels to open. Intracellular calcium entry leads to acetylcholine release in the synaptic space at the active zones but all scientists do not consider it the major release factor. Acetylcholine binding with its receptor at the muscle membrane generates an endplate potential when the induced depolarization is greater than the sodium voltage channel opening threshold. Muscle AP causes a muscle contraction involving the three phases. This paper will successively review the electrophysiological and molecular mechanisms involved at the pre-, inter- and postsynaptic levels. The last part of the article will discuss electromechanical considerations directly affecting the mechanical properties of the muscle fiber, most particularly the factors influencing the predetermined involvement of motor units, motor neuron electrical properties determining responses to synaptic inputs and finally the impact of recruited motor neurons and their electrical impulse rates on muscle contraction strength and velocity.

[Physiology of the injured peripheral nerve]. / Physiologie du nerf traumatisé.

Peripheral nerve injuries are frequent and generate significant deficits. Their treatment sometimes leads to functional recovery but is mostly incomplete or unpredictable, despite the regular use of sophisticated repair techniques. The clinician must clearly understand the peripheral nervous system's responses to injury, which reveal surprising degenerating and spontaneous regenerating abilities. This potential recovery is a peripheral nervous system specificity and follows a relatively complex process. Peripheral neurons depend on glial cell structure and metabolism, inducing a global and dynamic response of the whole axon environment, even in cases of focal lesion, modulated by the initial type and mechanism of injury. Today's progress remains insufficient to improve functional prognosis significantly, but a better understanding of peripheral nerve regenerating processes has opened the door to new medical and surgical advances.

[The anatomical substrate of muscle contractility]. / Le support anatomique de la contraction musculaire.

Muscle fiber action participates in a true contractile machinery associated with noncontractile components providing mechanical stability. The myofibril, the muscle fiber subentity, has an extremely consistent architecture, composed of longitudinal cylindrical units called sarcomeres, the skeletal muscle length functional unit, a highly important place in the transduction of chemical signal into mechanical contractile energy, for the most part mediated by calcium. The sarcoplasmic reticulum is the other major component of muscle fiber and is dedicated to calcium storage, liberation and distribution to the fiber, under the influence of action potential propagation. This phenomenon is called excitation-contraction coupling. This paper explores muscle anatomy from its main embryologic stages of development to its histochemical specificity, including its molecular constitution, and details the main morphofunctional relations supporting muscle contraction.

Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker?

Gliomas are characterised by local infiltration, migration of tumour cells across long distances and sustained angiogenesis; therefore, proteins involved in these processes are most likely important. Such candidates are semaphorins involved in axon guidance and cell migration. In addition, semaphorins regulate tumour progression and angiogenesis. For cell signalling, class-4 semaphorins bind directly to plexins, whereas class-3 semaphorins require additional neuropilin (NRP) receptors that also bind VEGF(165). The anti-angiogenic activity of class-3 semaphorins can be explained by competition with VEGF(165) for NRP binding. In this study, we analysed the expressions of seven semaphorins of class-3, SEMA4D, VEGF and the NRP1 and NRP2 receptors in 38 adult glial tumours. In these tumours, SEMA3B, SEMA3G and NRP2 expressions were related to prolonged survival. In addition, SEMA3D expression was reduced in high-grade as compared with low-grade gliomas. In contrast, VEGF correlated with higher grade and poor survival. Thus, our data suggest a function for a subset of class-3 semaphorins as inhibitors of tumour progression, and the prognostic value of the VEGF/SEMA3 balance in adult gliomas. Moreover, in multivariate analysis, SEMA3G was found to be the only significant prognostic marker.

Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study.

This study assessed the prognostic value of several markers involved in gliomagenesis, and compared it with that of other clinical and imaging markers already used. Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes, oncogenes, MGMT and hTERT expressions, losses of heterozygosity, as well as relevant clinical and imaging information were recorded. This prospective study was based on all adult gliomas. Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort. The endpoint was overall survival, estimated by the Kaplan-Meier method. Univariate analysis was followed by multivariate analysis according to a Cox model. p14(ARF), p16(INK4A) and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only. This study confirms the prognostic value of several markers. However, the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making.

[Molecular biology of adult gliomas: some landmarks for neurosurgeons]. / Biologie moléculaire des gliomes de l'adulte : quelques repères pour le neurochirurgien.

BACKGROUND AND PURPOSE: Recent developments in molecular biology have provided the clinician with opportunities to investigate a number of new biomarkers. This has led to an abundant literature reporting the biological role, the relation to survival, and the predictive value of treatment responses in adult glioma patients. Consequently, the clinician must assimilate a large amount of information, raising the question of the genuine role of these biomarkers in the daily care of these patients. METHODS: The authors report the data on biomarkers from the literature relevant to this context. DISCUSSION: Molecular biology today sheds new and valuable light on the natural history of adult glioma, bringing to the forefront a number of therapeutic principles for glioma patients as a group. However, each of these biomarkers does not have sufficient power to amount to a criterion for individual patient therapeutics. CONCLUSIONS: Biomarkers are not pertinent today for decision making, but the authors believe that the principle of including this approach in adult glioma workups must be encouraged as a promising means of study in the years to come.

Added Value of Spectroscopy to Perfusion MRI in the Differential Diagnostic Performance of Common Malignant Brain Tumors.

BACKGROUND AND PURPOSE: Perfusion and spectroscopic MR imaging provide noninvasive physiologic and metabolic characterization of tissues, which can help in differentiating brain tumors. We investigated the diagnostic role of perfusion and spectroscopic MR imaging using individual and combined classifiers of these modalities and assessed the added performance value that spectroscopy can provide to perfusion using optimal combined classifiers that have the highest differential diagnostic performance to discriminate lymphomas, glioblastomas, and metastases. MATERIALS AND METHODS: From January 2013 to January 2016, fifty-five consecutive patients with histopathologically proved lymphomas, glioblastomas, and metastases were included after undergoing MR imaging. The perfusion parameters (maximum relative CBV, maximum percentage of signal intensity recovery) and spectroscopic concentration ratios (lactate/Cr, Cho/NAA, Cho/Cr, and lipids/Cr) were analyzed individually and in optimal combinations. Differences among tumor groups, differential diagnostic performance, and differences in discriminatory performance of models with quantification of the added performance value of spectroscopy to perfusion were tested using 1-way ANOVA models, receiver operating characteristic analysis, and comparisons between receiver operating characteristic analysis curves using a bivariate χ2, respectively. RESULTS: The highest differential diagnostic performance was obtained with the following combined classifiers: maximum percentage of signal intensity recovery-Cho/NAA to discriminate lymphomas from glioblastomas and metastases, significantly increasing the sensitivity from 82.1% to 95.7%; relative CBV-Cho/NAA to discriminate glioblastomas from lymphomas and metastases, significantly increasing the specificity from 92.7% to 100%; and maximum percentage of signal intensity recovery-lactate/Cr and maximum percentage of signal intensity recovery-Cho/Cr to discriminate metastases from lymphomas and glioblastomas, significantly increasing the specificity from 83.3% to 97.0% and 100%, respectively. CONCLUSIONS: Spectroscopy yielded an added performance value to perfusion using optimal combined classifiers of these modalities, significantly increasing the differential diagnostic performances for these common brain tumors.

The Na, K-ATPase alpha3-isoform specifically localizes in the Schmidt-Lanterman incisures of human nerve.

INTRODUCTION: To our knowledge, there is little reference in literature with regards to alpha3-isoform of Na+,K+-ATPase in human peripheral nerves. The aim of this study was to determine the expression of the neuronal alpha3-isoform of Na+,K+-ATPase in human sural nerves from patients with a permanent medullary central nervous system injury. MATERIALS AND METHODS: We studied the immunolocalization of alpha3-isoform of Na+,K+-ATPase using a polyclonal antibody against the amino sequence near the phosphorylation site of the alpha3-isoforms of Na+,K+-ATPase using immunohistochemistry and confocal laser scanning microscopy. An antibody specific for alpha2-isoform of Na+,K+-ATPase was used to label the Schwann cells. RESULTS: Morphometric analysis of longitudinal section of human sural nerves showed that the alpha3-isoform of Na+,K+-ATPase was distributed along the length of axolemma. The myelin sheath of the Schwann cells showed clearly a distribution of alpha3- but not alpha2-isoforms of Na+,K+-ATPase at the level of Schmidt-Lanterman incisures. CONCLUSION: The human sural nerve shows a specific localization of the Na+,K+-ATPase alpha3-isoform in the Schmidt-Lanterman incisures of Schwann cells in addition to its localization in axonal membranes.

Operating environment for awake brain surgery - Choice of tests.

INTRODUCTION: The indication for awake brain surgery depends on a prerequisite, i.e. recognition that the brain area concerned is truly eloquent, and identification of one or more functions that must be preserved. These functions are determined preoperatively in collaboration with the patient, and neuropsychological tests considered to be the most relevant are performed in the operating room according to each team's technical preferences. OPERATING ENVIRONMENT: The neurosurgeon must choose transfer equipment considered to be relevant. Although a minimal technological environment is an option, a surgical team with great human wealth is essential, composed of specialized personnel with complementary skills. CHOICE AND IMPLEMENTATION OF INTRAOPERATIVE TESTS: The choice of intraoperative tests, which can be relatively simple for certain primary functions, can be much more difficult for high-level cognitive functions. No consensus has been reached concerning these tests, which must therefore be selected on an individual basis. Intraoperative testing must be based on preoperative multidisciplinary decisions made jointly by the neurosurgeon, neurologist, speech therapist and neuropsychologist. CONCLUSIONS: Numerous operating tools and technology transfers are available for neurosurgical teams performing awake brain surgery but none - or very few - of them constitutes a mandatory prerequisite. In contrast, the transition from the concept of eloquent brain area to that of brain functions that must be preserved requires highly skilled multidisciplinary human resources. This goal will be more likely achieved in centers highly specialized in functional oncological neurosurgery.

Resection of cavernous angioma located in eloquent areas using functional cortical and subcortical mapping under awake conditions. Outcomes in a 50-case multicentre series.

INTRODUCTION: Surgical resection of supratentorial cavernous angiomas located in eloquent areas poses a significant risk to the patient of postoperative neurological impairment and justifies intraoperative functional monitoring. METHODS: Multicentre retrospective series of adult patients with cavernous angiomas located within eloquent areas and treated with functional-based surgical resection according to functional boundaries under intraoperative functional cortico-subcortical monitoring under awake conditions. RESULTS: Fifty patients (18 males, mean 36.3±10.8 year-old) underwent surgical resection with intraoperative cortico-subcortical functional mapping using direct electrostimulation under awake conditions for a cavernous angioma located in eloquent areas with a mean postoperative follow-up of 21.0±21.2 months. At presentation, the cavernous angioma had previously resulted in severe impairment (neurological deficit in 34%, seizures in 70%, uncontrolled seizures in 34%, reduced Karnofsky Performance Status score of 70 or less in 24%, inability to work in 52%). Functional-based surgical resection allowed complete removal of the cavernous angioma in 98% and of the haemosiderin rim in 82%. Postoperative seizures and other complications were rare, and similarly so across all centres included in this series. Postoperatively, we found functional improvement in 84% of patients (reduced Karnofsky Performance Status score of 70 or less in 6%, uncontrolled seizures in 16%, and inability to work in 11%). CONCLUSION: Functional-based surgical resection aids the safe and complete resection of cavernous angiomas located in eloquent areas while minimizing the surgical risks. Functional mapping has to be considered in such challenging cases.

[Gene MGMT and oligodendrogliomas. Fundamental data and short review of the literature]. / Gène MGMT et oligodendrogliomes. Données fondamentales et brève revue de la littérature.

MGMT (O6 methyl guanine methyl transferase) is a gene involved in DNA repair. Its mechanism of action is to remove alkyl groups created by alkylating chemotherapy and therefore induces chemoresistances. Recent studies show that this gene expression seems to be related to the promoter's methylation, which could predict a possible chemosensitivity. The study of MGMT could be of some therapeutic and prognostic interest. Few series of oligodendrogliomas have been published and their results appear to be controversial. This is probably due to both tumour heterogeneity and multiple parameters associated with chemosensitivity. To date, it thus appears difficult to choose the adjuvant treatment according to the sole status of MGMT.

Primary intracerebral malignant lymphoma: report of 248 cases.

OBJECT: The authors present a retrospective analysis of 248 immunocompetent patients with primary intracerebral lymphoma treated at 19 French and Belgian medical centers between January 1980 and December 1995. METHODS: This study involved 127 female and 121 male patients with a median age of 61 years (range 2-88 years). All tumors available for review were classic diffuse non-Hodgkin's lymphoma, for which the phenotype was determined in 220 patients: 212 (96.4%) were B-cell and eight (3.6%) were T-cell type tumors. According to the Revised European-American classification of lymphoid neoplasms, most lesions were diffuse large cell tumors (62%). A total of 196 tumors were reviewed in 127 patients for whom preoperative computerized tomography and magnetic resonance studies were available. There was a single lesion in 66% of the cases, with a supratentorial location in 87%. Tumor location in the basal ganglia, corpus callosum, or fornix, infiltration of the periventricular ependyma, or a mirror pattern, were strongly suggestive of a lesion of lymphomatous origin. The histological diagnosis was obtained after surgical resection in 116 patients, with the remainder undergoing biopsy sampling only. Of the 248 patients studied, 129 (52%) received chemotherapy plus radiation therapy, 60 (24%) received radiation therapy alone, 35 (14%) received chemotherapy alone, and 24 (10%) received no postsurgical treatment. CONCLUSIONS: Using univariate analysis, the authors determined prognostic factors that were significantly associated with a favorable impact on survival including age younger than 60 years, radiation therapy (without evidence of a dose-response relationship), radiation therapy combined with chemotherapy, and chemotherapy consisting of anthracycline. Partial surgical resection was an unfavorable prognostic factor. Multivariate analysis was used to confirm the independent prognostic value of radiation therapy, age, chemotherapy consisting of anthracyclines or methotrexate, and partial surgical resection. This European survey provides a reasonable basis for the treatment of primary intracerebral lymphoma with the following sequence: stereotactic biopsy sampling, chemotherapy with a methotrexate- and anthracycline-based regimen, followed by cranial irradiation.

Teaching interns and residents about death and dying.

Residents and interns should receive intensive, interactive training regarding death and dying. This program should be presented early in training. Other physicians and allied health professionals (or both) may be brought in to manage this program. A reference list for the teaching program is provided.

[Glutamate in traumatic brain injuries]. / Glutamate et traumatismes encéphaliques.

During the past years, studies dealing with the pathophysiology of brain injuries have focused on certain agents that seem to be particularly involved in secondary brain lesions. Of them, some amino acids, and particularly glutamate, appears to deserve special attention. We discuss the role of glutamate neurotransmitters, review glutamate metabolism and actions, and then review in the pertinent literature devoted to the role of glutamate in the onset of brain injuries secondary to head trauma.