Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. The axonal form of the disease is designated as "CMT type 2" (CMT2). Although four loci known to be implicated in autosomal dominant CMT2 have been mapped thus far (on 1p35-p36, 3q13. 1, 3q13-q22, and 7p14), no one causative gene is yet known. A large Russian family with CMT2 was found in the Mordovian Republic (Russia). Affected members had the typical CMT2 phenotype. Additionally, several patients suffered from hyperkeratosis, although the association, if any, between the two disorders is not clear. Linkage with the CMT loci already known (CMT1A, CMT1B, CMT2A, CMT2B, CMT2D, and a number of other CMT-related loci) was excluded. Genomewide screening pinpointed the disease locus in this family to chromosome 8p21, within a 16-cM interval between markers D8S136 and D8S1769. A maximum two-point LOD score of 5.93 was yielded by a microsatellite from the 5' region of the neurofilament-light gene (NF-L). Neurofilament proteins play an important role in axonal structure and are implicated in several neuronal disorders. Screening of affected family members for mutations in the NF-L gene and in the tightly linked neurofilament-medium gene (NF-M) revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a conserved Gln333 amino acid to proline. This alteration was not found in 180 normal chromosomes. Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT, also were screened for mutations in NF-L, but no additional mutations were found. It is suggested that Gln333Pro represents a rare disease-causing mutation, which results in the CMT2 phenotype.

Diabetic neuropathy (DN) represents the main cause of morbidity and mortality among diabetic patients. Clinical data support the conclusion that the severity of DN is related to the frequency and duration of hyperglycemic periods. The presented experimental and clinical evidences propose that changes in cellular function resulting in oxidative stress act as a leading factor in the development and progression of DN. Hyperglycemia- and dyslipidemia-driven oxidative stress is a major contributor, enhanced by advanced glycation end product (AGE) formation and polyol pathway activation. There are several polymorphous pathways that lead to oxidative stress in the peripheral nervous system in chronic hyperglycemia. This article demonstrates the origin of oxidative stress derived from glycation reactions and genetic variations within the antioxidant genes which could be implicated in the pathogenesis of DN. In the diabetic state, unchecked superoxide accumulation and resultant increases in polyol pathway activity, AGEs accumulation, protein kinase C activity, and hexosamine flux trigger a feed-forward system of progressive cellular dysfunction. In nerve, this confluence of metabolic and vascular disturbances leads to impaired neural function and loss of neurotrophic support, and over the long term, can mediate apoptosis of neurons and Schwann cells, the glial cells of the peripheral nervous system. In this article, we consider AGE-mediated reactive oxygen species (ROS) generation as a pathogenesis factor in the development of DN. It is likely that oxidative modification of proteins and other biomolecules might be the consequence of local generation of superoxide on the interaction of the residues of L-lysine (and probably other amino acids) with α-ketoaldehydes. This phenomenon of non-enzymatic superoxide generation might be an element of autocatalytic intensification of pathophysiological action of carbonyl stress. Glyoxal and methylglyoxal formed during metabolic pathway are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. Genetic variations within the antioxidant genes therefore could be implicated in the pathogenesis of DN. In this work, the supporting data about the association between the -262T > C polymorphism of the catalase (CAT) gene and DN were shown. The -262TT genotype of the CAT gene was significantly associated with higher erythrocyte catalase activity in blood of DN patients compared to the -262CC genotype (17.8 ± 2.7 × 10(4) IU/g Hb vs. 13.5 ± 3.2 × 10(4) IU/g Hb, P = 0.0022). The role of these factors in the development of diabetic complications and the prospective prevention of DN by supplementation in formulations of transglycating imidazole-containing peptide-based antioxidants (non-hydrolyzed carnosine, carcinine, n-acetylcarcinine) scavenging ROS in the glycation reaction, modifying the activity of enzymic and non-enzym...

Human embryonic myogenic precursors were transplanted into muscles of mdx mice with hereditary dystrophin-deficient muscular dystrophy. Transplantation induced the synthesis of human dystrophin. The number of dystrophin-positive fibers progressively decreased, however, some of them were preserved even 5 months after transplantation. Our results indicate that xenogeneic transplantation of embryonic myogenic precursors compensates the genetic defect in dystrophin-deficient mice.

Life-time monitoring of the main clinical and laboratory manifestations of hereditary muscular dystrophy in mdx mice confirmed the presence of mutation in exon 23 of dystrophin gene and the absence of this protein in skeletal muscles of mutant animals. Muscular dystrophy in mice was similar to human progressive muscle disorder, which allows the use of this model for the development of cell technologies for the treatment of hereditary muscular diseases in humans.

The sympathetic system can induce cholinergic vasodilatation in the vessels of skeletal muscles [1][2][3]. This vasodilatation is one of the autonomic components of the state of rage or anxiety [4][5][6]. Cholinergic vasodilatation arises in man during emotional stress (intensive mental arithmetic, fright, and so on). Experiments on cats have shown that this form of increase in the velocity of blood flow is connected with the activation of glyeolysis in the muscle, with an increase in phosphorylase activity and in the production of lactic acid [7, 8]. The sympathetic system is considered to act primarily on the muscle fiber, in which it activates t:he enzyme phosphorylase. The activation of glycolysis thereby produced induces vasodilatation secondarily, through the action of metabolites on the smooth muscle of the vessel [7][8][9][10][11][12].To establish a relationship of cause and effect between the activation of glycolysis and dilatation of the muscle, vessels in emotional stress in man, the vasodilatation in nonworking muscles was investigated in patients with muscular glycogen disease. Muscular glycogen disease is a rare hereditary disease caused by deficient activity of myophosphorylase or of some other enzymes (amylo-l,6-glucosidase, phosphofructokinase, phosphoglucomutase, acid maltase), leading to the development of a partial or total block of glycogenolysis and to the accumulation of large masses of unsplit glycogen in the skeletal muscles [13]. If the above hypothesis is correct, cholinergic dilatation of the muscle vessels in this disease ought to be reduced or absent altogether because of disturbance of the processes of glycogenolysis.Cholinergic vasodilatation in animals is stronger in white than in red muscles [14][15][16]. In the writers' opinio n, tl~[s difference may be connected with the fact that ~4aite muscle fibers are distinguished by a very intensive course of glycolysis, whereas red muscle fibers satisfy their energy requirements mainly by aerobic metabolism. In this investigation emotional vascular responses were studied in the red soleus and mixed tibialis anterior muscles of healthy persons. EXPERIMENTAL METHODThe ,volume velocity of the blood flow in the forearm of 23 healthy subjects (aged 17-30 years) and in nine patients (20-50 years) was determined by venous occlusion plethysmography [12]. Changes in the limb volume in :response to temporary cessation of the venous drainage were measured with a flexible plethysmographic sensor and, after conversion into electrical'signals by means of the ]~M'PD-2 electromedical pressure transducer of the model 064 Krasnogvardeets sphygmograph, there were recorded as arterial inflow curve,s on the KSP-4 automatic writer. The pulse rate was calculated from the ECG, recorded on the 060 electrocardiograph.The blood supply to the soleus muscle (SM) and to the tibialis-anterior muscle (rAM) in ten healthy subjects was determined from the rate of elimination of radioactive isotope 133Xe from the intramuscular depot. A sterile solution of 133Xe was inject...