Cytokine profile of the blood in mice with normal and abnormal heart rhythm.

Differences in the pools of 10 cytokine were found in blood samples from the caudal vein of mice with normal and abnormal heart rhythm. Both groups were albino mice bred by us and differing from mdx albino mice by the absence of mutation in muscular dystrophin gene. Mice with normal heart rhythm had low IL-17 content and elevated concentrations of proinflammatory cytokines IL-6 and IL-1α in comparison with the normal (according to published data). In mice with bradyarrhythmias, increased blood levels of IL-10, IL-6, IL-5, IL-2, IL-1α, IL-17, IL-4, TNF-α, and granulocyte-macrophage colony-stimulating factor were detected. The relative content of IL-4 and IL-17 in the total cytokine pool increased. The lifespan of mice with bradyarrhythmias and cytokine hyperexpression was shorter by 2-3 months in comparison with mice without heart rhythm disturbances and moderate changes in the cytokine pool.

[Pathological changes in heart activity of mdx mice and future prospects of mdx model in cardioimmunulogy].

Dystrophin is a protein linking the cytoskeleton to a complex of transmembrane proteins that interact with the extracellular matrix. The fragility of the cardiomyocyte cell membrane resulting from the lack of dystrophin is thought to cause an excessive susceptibility to mechanical stress. Based on surface ECC we demonstrate the differences of cardiac phenotype in young (2- to 3-mo-old) and aged (over 1,5 years) dystrophin-deficient mdx mouse and normal mouse with the same genetic background. It was shown that main alterations in the mdx electrocardiogram concern primarily ventricular conduction velocity (QRS complex duration) and time of ventricular repolarization (QT interval) duration).The issue under discussion is whether dystrophin deficient mdx model can be used in research studies in cardioimmunology.

A new genetic variant of mdx mice: study of the phenotype.

Genetic selection in a colony of mdx mice (suffering from X-chromosome-linked muscular dystrophy) resulted in generation of their new genetic variant. In this new variant, the genetic, biochemical, and histological markers of muscular dystrophy are combined with signs of oculocutaneous albinism (skin and fur depigmentation), transillumination of the iris, sharply reduced pigmentation of the retinal epithelium, and increase of the eyeball refraction). Two sensorimotor tests (negative geotaxis and wire back down hanging) detected other phenotypical characteristics of albino mdx mice carrying, in addition to the mutation in the dystrophin gene exon 23 (intrinsic of the "classical" black mdx mice), an extra mutation responsible for pigmentation disorders. Slow geotaxis, despite longer wire back down hanging capacity, was regarded as aggravation of the neurological dysfunction in albino mdx mice in comparison with black mdx mice.

[Regenerative activity of muscle tissue and thymus status in young and old mdx mice with muscle injury and wound xenoplasty].

Responses of the skeletal muscle tissue and thymus to muscle injury (complete transection) and wound xenoplasty with the minced muscle tissue of newborn rats (tissue therapy) were studied in mdx mice aged 12-16 and 40-48 weeks. The muscle tissue of mdx mice has genetic defects causing chronic dystrophic processes in it. The muscle tissue of young mdx mice proved to retain a relatively high capacity for regeneration. Under conditions of tissue therapy of the wound, the formation of muscle fibers from muscle cells of the graft and active regeneration of muscle fibers in the recipient mice were observed, and no structural defects were detected in the thymus. The capacity of posttraumatic regeneration in old mdx mice was lower. The xenogenic graft was undergoing resorption, thereby suppressing regeneration of muscle fibers and causing further tissue destruction in the injured muscle. The thymus parenchyma was subject to degenerative changes such as the formation of gaps, hemorrhagic foci, and increased numbers of macrophages and mast cells.

Restoration of gastrocnemius muscle in MDX mice of different age after injury and implantation of xenogenic muscle tissue.

The intensity of regeneration of crossed gastrocnemius muscle was evaluated in two groups of mdx mice of different age 2 weeks after implantation of crushed muscle tissue from newborn rats into the wound defect area. The effect of xenoplasty manifested in increased weight of the damaged muscle. The effect was observed in mice aging 12-16 weeks but not in those aged 40-48-weeks. Structural changes in the skeletal muscle tissue intrinsic of mdx mice and augmenting with age were detected in intact mice before the experiment. Activity of muscle fiber regeneration in intact and injured muscle of 40-48-week-old mice was significantly lower than in 12-16-week-old ones. Myoblasts of the xenogenic transplant retained viability in recipient muscles for at least 2 weeks. posttraumatic regeneration was stimulated in only 12-16-week animals. Xenoplasty was ineffective in older animals and even somewhat enhanced the destructive processes in the muscle. It seems that age-specific regeneration activity of the recipient skeletal muscle tissue should be taken into consideration in the development of effective strategy of cell therapy for progressive muscular dystrophy.

Cardiotropic effect of extracardiac transplantation of embryonic human myoblasts to mice with bradycardia: various effects of cell material.

Animals with bradycardia were detected in reproductive colony of mdx mice. Low pulse rate was associated with poor survival and predisposition to sudden death, but did not directly depend on the presence of dystrophin mutant gene or animal age. Heart rate increased in old mice with bradycardia after extracardial, intramuscular, and intravenous injection of human embryonic myoblasts. Stable normalization of the pulse was observed 2 weeks after transplantation, but early peak of heart rate was observed as early as 24 h after cell transplantation. Cell suspensions, which could contain stem cells (blood mononuclears and CD34+ lymphocytes), also corrected heart rhythm. Unlike the effect of myoblasts, cardiotropic effect of mononuclears was preceded by a period of tachycardia, while the effect of CD34+ lymphocytes was very unstable. The cardiotropic effect of myoblasts was combined with life span prolongation and certain rejuvenation in some animals. Erythrocytes and supernatant obtained during blood cell fractionation did not modify the heart rhythm in mice with bradycardia. After injection of myoblasts to mice with rare and normal pulses serum creatine kinase activity decreased with different rates. These data attest to a variety of biological effects of stem cells and/or their derivatives and to ambiguous mechanisms of these effects.

Experimental gastric ulcer: gastro- and duodenoprotective effects of sibusol.

We studied the influence of pretreatment with chemical mildronate analogue sibusol on the course of experimental gastric ulcer in rats. Sibusol produced a protective effects on the stomach and duodenum.

Hereditary muscular dystrophy in MDX mice as a homologous model for introduction of cell technologies in the treatment of progressive muscular dystrophies in humans.

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.

[Comparative morpho-functional assessment of the impact produced by prolonged infusions of prostaglandins E and F on the course of genetically preconditioned arterial hypertension]. / Sravnitel'naia morfofunktsional'naia otsenka vliianiia prolongirovannykh infuzii prostaglandinov E i F na techenie geneticheski obuslovlennoi arterial'noi gipertonii.

The administration of prolonged intravenous infusions of prostaglandins is defined; the method provided for specifying a long-term impact produced by prostaglandins on a nature of the course of genetically preconditioned arterial hypertension (AHT) in rats. Infusions of PGE-2 bring about a prolonged and stable reduction of mean arterial presser (AP) by 10% versus its original value; they intensify 2-fold the depressor baroreflectory regulation and stimulate the urinary excretion of endogenous renal PGF-2 alpha; besides, they contribute to a better blood supply to organs, i.e. an increased perfusion of the cortical and medullary layers of the kidneys and of the brain substances; and dilatation of the intramural branches of the coronary arteries, due to which the AP becomes milder. Infusions of PGF-2 alpha contribute to a prolonged and stable elevation of mean AP by 12% versus the original value; they inhibit the depressor baroreflectory regulation and intensify the pressor baroreflectory regulation; they, additionally, induce the urinary excretion of endogenous renal PGF-2 alpha and correct the lesions in the blood supply to organs, i.e. pathological microcirculation, anemia and spasm of the renal parenchyma, ischemic foci in the myocardium, spastic contraction of small cerebral arteries, edema and destructive changes (of the local necrosis variation) in the cerebral substance microvessels concomitant with a commencing diapedetic hemorrhages. Finally, all above listed lesions are signs of the malignant AP course.

Xenotransplantation of embryonic precursors of human myogenesis for the correction of dystrophinopathy in mice with hereditary muscular dystrophy.

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.

[Probable mechanisms of the regulation in the jejunum motility]. / Vozmozhnye mekhanizmy reguliatsii pishchevoi motoriki toshchei kishki.

It is a well-known fact that serotonin has a stimulative action on the motor-secretory activity of the gastrointestinal tract. Activation of 5HT3,4-receptors regulates neuronal responses of this action; it is possible to regulate efferent reactions by activating 5HT1,2-receptors (1, 2, 3). Carcinoid cells containing 5HT have 5HT3 and 5HT4 receptors on their superficial membranes. The object of this research was to determine the possible participation of serotonergic structures in the regulation of the jejunum motility.

[Experimental and clinical studies of coronary circulation after administration of mildronate]. / Eksperimental'noe i klinicheskoe issledovanie koronarnogo krovoobrashcheniia pri primenenii mildronata.

In experiments on dogs, application of the cross-over circulation method revealed that mildronate increased coronary blood flow due to active coronary dilation. In experiments on cats, a cardioprotective effect of mildronate was found, which prevented the development of acute ischemic heart failure by stabilizing the major hemodynamic parameters. Clinical studies of patients with Functional Classes I-III angina provided evidence for positive effects of mildronate on coronary blood flow.

[Clinico-experimental substantiation of the use of physical exercise in patients with ischemic heart disease for the prevention of arrhythmia]. / Kliniko-éksperimental'nye dannye k obosnovaniiu primeneniia fizicheskikh trenirovok u bol'nykh ishemicheskoi bolezn'iu serdtsa s tsel'iu profilaktiki narushenii ritma.

In experimental conditions, exercise increased electrical stability of the heart in trained rats, promoted an improvement of heart electrical stability in hypoxic hypoxia and under the effect of dextran, which is known to worsen blood rheologic properties, and had no effect on heart electrical stability in curantyl-treated rats. In 50 postmyocardial-infarction coronary patients, exercise was conductive to a drop in erythrocyte cholesterol/phospholipid ratio and total plasma cholesterol, and a rise in alpha-cholesterol level. In 10 untrained control coronary patients, erythrocyte cholesterol/phospholipid ratio remained unchanged.

[Method of applying colchicine to the rat vagus nerve for the purpose of selective action on axonal transport]. / Metod applikatsii kholkhitsina na bluzhdaiushchii nerv krysy s tsel'iu izbiratel'nogo vozdeistviia na aksonal'nyi transport.

A method of local application of colchicine deposited in a wax and paraffin alloy to the nerve is suggested. The doses of 25, 50, 75 and 100 micrograms were tested. Four days after application of 75 and 100 micrograms of colchicine, light microscopy demonstrated a non-uniform thickening of neurofibrils and the increase in their argyrophilic properties. Electron microscopy discovered the reduced number of microtubules, disordered arrangement of neurofilaments and accumulation of the latter ones beneath the neurolemma. The overall electric activity of the nerve was not disturbed. The method of colchicine application in vivo ensures the prolonged action of the drug without nerve compression or injury, thereby enabling one to assess consistently the sequels of the blockade of neurotrophic factors for metabolism of the innervated structures.

[Functional characteristics of the different types of heart receptors]. / K funktsional'noi kharakteristike razlichnykh vidov retseptorov serdtsa.

A methodical procedure for the study of receptors was elaborated by means of which three types of nerve endings were detected and differentiated in the heart: mechano-, chemo-, and polymodal receptors. A difference was determined between them by the form of the reaction to mechanical (hemodynamic) and chemical stimulation of the heart. The polymodal receptors are characterized by a mixed form of reaction providing for the integration of sensory polyvalence.

[Activity of total serum creatine phosphokinase and its MB fraction in reversible coronary blood flow disorders in dogs in a chronic experiment]. / Aktivnost' obshchei syvorotochnoi kreatinfosfokinazy i ee fraktsii pri obratimykh narusheniiakh venechnogo krovotoka u sobak v khronicheskom opyte.

On a model of reversible coronary blood flow disturbances in dogs short-term myocardial ischemia (2 to 15 min) in 16 chronic experiments caused an increase in the activity of total blood CPK by 57.3 +/- +/- 11.7 mE/ml (p less than 0.001) and of MB fraction by 6.9 +/- 1.23 mE/ml (p less than 0.001). Experiments in which the disturbances in coronary blood flow were repeated at intervals of 2-3 days showed that the changes in the activity of the enzymes occurred in definite stages. The results obtained on this model present new possibilities for elaborating diagnostic criteria of microfocal myocardial lesions.