Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.

Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.

A library of analog operators based on the hodgkin-huxley formalism for the design of tunable, real-time, silicon neurons.

In this paper, we present a library of analog operators used for the analog real-time computation of the Hodgkin-Huxley formalism. These operators make it possible to design a silicon (Si) neuron that is dynamically tunable, and that reproduces different kinds of neurons. We used an original method in neuromorphic engineering to characterize this Si neuron. In electrophysiology, this method is well known as the "voltage-clamp" technique. We also compare the features of an application-specific integrated circuit built with this library with results obtained from software simulations. We then present the complex behavior of neural membrane voltages and the potential applications of this Si neuron.

Causes of death amongst French patients with amyotrophic lateral sclerosis: a prospective study.

BACKGROUND AND PURPOSE: To prospectively investigate causes of death and the circumstances surrounding death in 302 patients with amyotrophic lateral sclerosis (ALS). The functional status of patients immediately before death was also determined. METHODS: Information was obtained from neurologists at ALS centres, patients' files, and, when deaths occurred outside a medical facility, attending physicians. RESULTS: Most patients (63%) died in a medical facility. The most frequently reported cause of death was respiratory failure (77%), including terminal respiratory insufficiency (58%), pneumonia (14%), asphyxia due to a foreign body (3%) and pulmonary embolism (2%). Ten per cent of patients died from other causes: post-surgical or traumatic conditions (5%), cardiac causes (3.4%), suicide (1.3%) and sudden death of unknown origin (0.7%). The cause of death could not be determined in 13% of cases (6% inside a medical facility and 25% outside). At the time of death, only 55% of patients were receiving riluzole, 33% were undergoing non-invasive ventilation, 3% had a tracheotomy and 37% a gastrostomy. CONCLUSION: The information provided by this study helps to improve our understanding of the natural history of the disease and may help optimize the quality of care we can offer patients at the end of life.

A real-time closed-loop setup for hybrid neural networks.

Hybrid living-artificial neural networks are an efficient and adaptable experimental support to explore the dynamics and the adaptation process of biological neural systems. We present in this paper an innovative platform performing a real-time closed-loop between a cultured neural network and an artificial processing unit like a robotic interface. The system gathers bioware, hardware, and software components and ensures the closed-loop data processing in less than 50 micros. We detail here the system components and compare its performances to a recent commercial platform.

Cutaneous manifestations of primary Sjögren's syndrome are underestimated.

The association of kerato-conjunctivitis sicca and xerostomia has been termed Sjogren's syndrome (SS). Although this disease is referred to as a non-organ-specific autoimmune condition, the vast majority of the deleterious effects of primary SS are restricted to the exocrine glands. Among them, the lacrymal and salivary glands are at the foreground, owing to the severity of the objective consequences and the importance of the subjective manifestations. As a result, cutaneous manifestations are minimized, albeit relatively common. We have carefully analyzed the literature to draw up an inventory of the possible skin complications of this syndrome. In addition to xerosis and epidermal IgG deposits, they include vasculitis and cutaneous B cell lymphoma. Alopecia, vitiligo and papular lesions have also been reported to be associated with primary SS.

Mild recurrent neuropathy in CMT1B with a novel nonsense mutation in the extracellular domain of the MPZ gene.

Clinical, electrophysiological, and neuropathological features are reported associated with a novel heterozygote point mutation in the extracellular domain of the MPZ gene, where a transversion at codon 71 in exon 3 leads to a codon stop: Glu71stop (ie GAA-->TAA). A 36 year old woman developed a mild recurrent neuropathy after intensive manual work. The motor nerve conduction velocities were slow without conduction blocks and the nerve biopsy showed signs of demyelination-remyelination, axonal loss, and regular uncompacted myelin lamellae. She inherited the mutation from her father who displayed the same mutation with a normal phenotype. This nonsense mutation may cause a dosage difference of normal P0, and is probably underrepresented in the current mutation data bases. This report further extends the phenotype of MPZ mutations and also emphasises that mild phenotype of CMT1B may be more frequent than has been appreciated.

[Neuronal and synaptic properties: fundamentals of network plasticity]. / Propriétés neuronales et synaptiques: les fondements de la plasticité des réseaux.

Neurons, within the nervous system, are organized in different neural networks through synaptic connections. Two fundamental components are dynamically interacting in these functional units. The first one are the neurons themselves, and far from being simple action potential generators, they are capable of complex electrical integrative properties due to various types, number, distribution and modulation of voltage-gated ionic channels. The second elements are the synapses where a similar complexity and plasticity is found. Identifying both cellular and synaptic intrinsic properties is necessary to understand the links between neural networks behavior and physiological function, and is a useful step towards a better control of neurological diseases.

Peripheral myelin modification in CMT1B correlates with MPZ gene mutations.

Morphological modifications were investigated in the peripheral nerve of three unrelated patients with CMT1B. In two patients, molecular genetic analysis showed an Arg98His mutation in the extracellular domain of MPZ, associated with irregularly uncompacted lamellae. This observation confirms previous studies of a well-defined correlation between mutations and morphological phenotypes. In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations associated with this morphological phenotype.

Analog circuits for modeling biological neural networks: design and applications.

Computational neuroscience is emerging as a new approach in biological neural networks studies. In an attempt to contribute to this field, we present here a modeling work based on the implementation of biological neurons using specific analog integrated circuits. We first describe the mathematical basis of such models, then present analog emulations of different neurons. Each model is compared to its biological real counterpart as well as its numerical computation. Finally, we demonstrate the possible use of these analog models to interact dynamically with real cells through artificial synapses within hybrid networks. This method is currently used to explore neural networks dynamics.

Study of central and peripheral conductions to the diaphragm in 22 patients with definite multiple sclerosis.

Involvement of the diaphragm was evaluated electrophysiologically in 22 patients with definite multiple sclerosis. Magnetic transcranial stimulation (MTS), magnetic cervical stimulation at C4 level (MCS) and electric stimulation of the phrenic nerve at the neck (EPS) were performed for measuring latencies, motor conduction times and amplitudes of the responses recorded with a pair of surface or subcutaneous electrodes located at the xiphoid and the 8th costal interspace on the anterior axillary line. Latency of the motor evoked potentials (MEPs) was abnormal: in 9 patients following MTS, in 6 following MCS, in 2 following EPS. The motor conduction time between the cortex and the cervical spine, we called CMCT1, was abnormal in 11 patients and the motor conduction time between the cortex and the neck, we called CMCT2, was abnormal in 8 patients. However CMCT1 was more often unmeasurable than CMCT2 because the MEPs following MCS were unreliable in 4 patients. The conduction time between the cervical spine and the neck was abnormally long in 2 patients but it was paradoxically abnormally short in 3, probably because of the difficulties in locating exactly the place of the stimulation at the cervical C4 level. The MEP amplitude was not considered a reliable parameter because of the large range of the values in our controls, although the mean amplitude was significantly lower in the patients than in the controls. The amplitude of the compound muscle action potential (CMAP) following EPS was below the lower limit of the normal in 9 patients. The percentage of abnormal MEP latencies and CMCTs when both sides were combined was higher for the hemidiaphragms than for the upper limbs and was roughly the same for the hemidiaphragms and the lower limbs. Moreover electrophysiological study of the diaphragm was abnormal in 5 patients without pulmonary symptoms and with normal pulmonary function tests, demonstrating that this study is useful for revealing infraclinical demyelinating lesions on the central motor pathways down to diaphragm. In addition, alterations of the CMAPs in some patients suggest a possible extension of the lesions towards the anterior horns and anterior roots.

Single fibre electromyography in multifocal motor neuropathy with persistent conduction blocks.

OBJECTIVE: To study the process of denervation-reinnervation in multifocal motor neuropathy with persistent conduction blocks in clinically affected and unaffected muscles. METHOD: Volitional single fibre electromyography (SFEMG) was performed in the extensor digitorum communis (EDC) of seven patients. The jitter, the fibre density, and the mean interpotential interval were determined. The results before and after treatment with intravenous immunoglobulin (IVIg) between the unaffected EDC and affected EDC examined during the same SFEMG session were also compared. In addition the values of jitter, fibre density, and mean interpotential interval were analysed for correlation with the strength score on the MRC scale, the duration of the neuropathy, the number of IVIg treatment periods, and the radial nerve conduction block values. RESULTS: Mean jitter, percentage of jitters >60 micros, and impulse blocking percentage, were higher than normal in both the affected EDCs and to a lesser degree in unaffected EDCs. Jitter decreased significantly after IVIg and correlated only with the MRC score. Fibre density and mean interpotential interval were higher than normal equally in the affected EDC and unaffected EDCs, but no correlation was found with strength, duration of the neuropathy, number of treatment periods, and conduction block values. CONCLUSION: The major finding is the presence of SFEMG abnormalities in clinically unaffected EDCs. This shows a process of denervation-reinnervation even in the absence of clinical symptoms, probably more frequent than commonly supposed in this neuropathy. The rapid clinical improvement after IVIg infusions could be due to remyelination after demyelination and to an interference of IVIg with the blocking effect of antibodies on the Na+ channels at the motor nerve endings.

Involvement of respiratory muscles in adult-onset dystonia: a clinical and electrophysiological study.

Involvement of respiratory muscles is unusual in dystonia, but its occurrence may be underestimated either because it is not conspicuous or because it is improperly imputed to another cause. Three patients who had adult-onset dystonia and who were exhibiting respiratory problems were examined clinically and electrophysiologically. In the three patients the onset was focal-cervical in two and blepharospasm in one. The respiratory problems appeared later. The first patient had involuntary deep and loud inspirations combined with spasms of axial dystonia, the second complained of breathing arrests, and the third had deep inspirations mainly on speaking or reading aloud, thus causing broken speech. Electromyographic findings, including of the diaphragm, were quite consistent with a respiratory involvement in these three cases of dystonia. Assuming that respiratory troubles could be in the first sign of a focal dystonia, electrophysiological studies of respiratory muscles could be used to confirm this.

CD5-expressing B lymphocytes in the blood and salivary glands of patients with primary Sjögren's syndrome.

CD5, the human counterpart of Ly-1 molecules in the mouse, are detectable but weakly expressed on a minute fraction of circulating B cells. The number of CD5 + B cells in the blood of patients with Sjögren's syndrome was slightly higher than in control blood, but it became statistically significant after treatment of the cells with phorbol myristic acetate. These numbers were even higher in patients with homogeneous serum bands than in the others. A few scattered cells were stained with anti-human IgM antibody on salivary gland sections, and among them 5-10% were found to be positive for anti-CD5.