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Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund’s adjuvant (CFA) and spinal-cord homogenate (SC-H), whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group). Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, N-acetylaspartate, were decreased, and the astrocyte marker, myo-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE) or extra-cerebral (AA) inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and/or due to the presence of systemic proinflammatory molecules. Regardless of the nature of these mechanisms, our findings may be of interest for future clinical studies, e.g. by in-vivo magnetic resonance spectroscopy. [ABSTRACT FROM AUTHOR]

ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.European Journal of Human Genetics (2006) 14, 917–922. doi:10.1038/sj.ejhg.5201627; published online 26 April 2006 [ABSTRACT FROM AUTHOR]

Electron microscopy has a strategic position in the diagnosis of neuromuscular disorders. In muscular fibers, the main abnormalities include vacuoles, inclusion bodies, and myofibrillar disorganization with or without abnormal inclusion material. Vacuolar changes include lipidic and glycogenic storage vacuoles, rimmed vacuoles, and lysosomal and autophagic vacuoles. Accumulation of abnormal inclusion material is found in nemaline myopathy, actinopathies, and hyaline body myopathy. Myofibrillar disorganization involves cores, multiminicores, and myosin chain depletion. Myofibrillar myopathies associate a pathologic pattern of myofibrillar dissolution and ectopic protein expression. They can be divided into two groups: myofibrillar myopathies with multiple expression proteins and myofibrillar myopathies with desmin and αB-crystallin expression only. In these two conditions, electron microscopy shows accumulation of a granulofilamentous material immunoreactive for desmin. At least three genes are implicated: desmin, αB-crystallin, and myotilin. Lastly, electron microscopy serves to identify changes, pathogenic or not, which are not shown up by light microscopy. Moreover, electron microscopy gives insight on pathophysiological mechanisms and can guide molecular genetics analysis. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting 1 in 2,500 people. The only treatment currently available is rehabilitation or corrective surgery. The most frequent form of the disease, CMT-1A, involves abnormal myelination of the peripheral nerves. Here we used a mouse model of CMT-1A to test the ability of ascorbic acid, a known promoter of myelination, to correct the CMT-1A phenotype. Ascorbic acid treatment resulted in substantial amelioration of the CMT-1A phenotype, and reduced the expression of PMP22 to a level below what is necessary to induce the disease phenotype. As ascorbic acid has already been approved by the FDA for other clinical indications, it offers an immediate therapeutic possibility for patients with the disease. [ABSTRACT FROM AUTHOR]

X-linked myopathy with excessive autophagy (XMEA, MIM 310440) is a rare inherited mild myopathy. We have used 32 polymorphic markers spanning the entire X chromosome to exclude most of the chromosome except the Xq28 region in a large XMEA family. Using three additional families for linkage analysis, we have obtained a significant two-point Iod score with marker DXS1183 (Z = 2.69 at θ = 0). Multipoint linkage analysis confirmed the assignment of the disease locus with a maximal Iod score of 2.74 obtained at recombination fraction zero. Linkage of XMEA to the Xq28 region is thus firmly established. In addition, we have ruled out the Emery-Dreifuss muscular dystrophy to be allelic with XMEA by direct sequencing of the emerin gene in three of our families. [ABSTRACT FROM AUTHOR]

The article presents a study which compares the pathological appearance of fetal organs after medical termination of pregnancy. The study used four fetuses in which two were injected with potassium chloride (KCl) and the others with lidocaine and sufentanil. Microscopic examination in KCl-injected fetuses showed whitish deposits in tissues and histological examination found crystals in internal organs while in lidocaine- and sufentanil- injected fetuses, no deposits and crystals were observed.

Presents a letter to the editor about the recurrent glomerulonephritis in relapsing polychondritis, published in the February 01, 2002, issue of the journal "Nephron."

Presents a letter to the editor about the association of idiopathic membranous glomerulonephritis with primary antiphospholipid syndrome, published in the November 01, 2000 issue of the journal "Nephron."

A correction to the article "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay" that was published in a previous issue of the periodical is presented.

Studies dedicated to the repair of peripheral nerve focused almost exclusively on motor or mechanosensitive fiber regeneration. Poor attention has been paid to the metabosensitive fibers from group III and IV (also called ergoreceptor). Previously, we demonstrated that the metabosensitive response from the tibialis anterior muscle was partially restored when the transected nerve was immediately sutured. In the present study, we assessed motor and metabosensitive responses of the regenerated axons in a rat model in which 1 cm segment of the peroneal nerve was removed and immediately replaced by an autologous nerve graft or an acellular muscle graft. Four groups of animals were included: control animals (C, no graft), transected animals grafted with either an autologous nerve graft (Gold Standard-GS) or an acellular muscle filled with Schwann Cells (MSC) or Culture Medium (MCM). We observed that (1) the tibialis anterior muscle was atrophied in GS, M(SC) and M(CM) groups, with no significant difference between grafted groups; (2) the contractile properties of the reinnervated muscles after nerve stimulation were similar in all groups; (3) the metabosensitive afferent responses to electrically induced fatigue was smaller in M(SC) and MCM groups; and (4) the metabosensitive afferent responses to two chemical agents (KCl and lactic acid) was decreased in GS, M(SC) and M(CM) groups. Altogether, these data indicate a motor axonal regeneration and an immature metabosensitive afferent fiber regrowth through acellular muscle grafts. Similarities between the two groups grafted with acellular muscles suggest that, in our conditions, implanted Schwann cells do not improve nerve regeneration. Future studies could include engineered conduits that mimic as closely as possible the internal organization of uninjured nerve.

Objective: We asked whether blockade of voltage-gated K+ channel Kv1.1, whose altered axonal localization during myelin insult and remyelination may disturb nerve conduction, treats experimental autoimmune encephalomyelitis (EAE)., Methods: Electrophysiological, cell proliferation, cytokine secretion, immunohistochemical, clinical, brain magnetic resonance imaging, and spectroscopy studies assessed the effects of a selective blocker of Kv1.1, BgK-F6A, on neurons and immune cells in vitro and on EAE-induced neurological deficits and brain lesions in Lewis rats., Results: BgK-F6A increased the frequency of miniature excitatory postsynaptic currents in neurons and did not affect T-cell activation. EAE was characterized by ventriculomegaly, decreased apparent diffusion coefficient, and decreased (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Reduced apparent diffusion coefficient and impaired energy metabolism indicate astrocytic edema. Intracerebroventricularly BgK-F6A-treated rats showed attenuated clinical EAE with unexpectedly reduced ventriculomegaly and preserved apparent diffusion coefficient values and (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Thus, under BgK-F6A treatment, brain damage was dramatically reduced and energy metabolism maintained., Interpretation: Kv1.1 blockade may target neurons and astrocytes, and modulate neuronal activity and neural cell volume, which may partly account for the attenuation of the neurological deficits. We propose that Kv1.1 blockade has a broad therapeutic potential in neuroinflammatory diseases (multiple sclerosis, stroke, and trauma).

Objective: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases characterized by chronic inflammation of muscles. We investigated the role of cellular adhesion molecules implicated in the cohesion of endothelial cells in IIM., Methods: In 22 patients with IIM we investigated plasma concentrations of soluble junctional adhesion molecules [platelet-endothelial cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules [sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial cell interactions. Results were compared to a control group. Muscle biopsy samples from 8 out of 22 IIM patients were studied by immunohistochemistry for tissue expression of these molecules and compared to normal muscle samples. PECAM-1 and CD146 expression was also studied using immunoblots from muscle biopsies from 5 patients and 2 controls., Results: We observed distinct patterns of soluble levels and in situ expression between dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin, sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small group of s-IBM samples, results were similar to PM, but the only significant increase was the level of sPECAM-1. Immunoblots confirmed increased expression of PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the highest expression in PM and IBM samples., Conclusion: We observed abnormal increases of soluble levels of adhesion molecules implicated in endothelial cell junctions in PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM (sPECAM-1). We conclude that the distinctly different profiles between PM/s-IBM and DM reflect differences in the pathophysiological background of these diseases.