Methods of Generation of Induced Pluripotent Stem Cells and Their Application for the Therapy of Central Nervous System Diseases.

The use of induced pluripotent stem cells (IPSC) is a promising approach to the therapy of CNS diseases. The undeniable advantage of IPSC technology is the possibility of obtaining practically all types of somatic cells for autologous transplantation bypassing bioethical problems. The review presents integrative and non-integrative methods for obtaining IPSC and the ways of their in vitro and in vivo application for the study and treatment of neurological diseases.

Distribution and Migration of Human Placental Mesenchymal Stromal Cells in the Brain of Healthy Rats after Stereotaxic or Intra-Arterial Transplantation.

Human placenta mesenchymal stromal cells were injected to healthy rats either stereotaxically into the striatum or intra-arterially through the internal carotid artery. Some cells injected into the brain migrated along the corpus callosum both medially and laterally or concentrated around small blood vessels. A small fraction of MSC injected intra-arterially adhered to the endothelium and stayed inside blood vessels for up to 48 hours mostly in the basin of the middle cerebral artery. Neither stereotaxic, nor intra-arterial transplantation of mesenchymal stromal cells modulated the proliferation of neural stem cells in the subventricular zone of the brain, but stereotaxic transplantation suppressed activation of their proliferation in response to traumatization with the needle.

Comparative Analysis of the Effects of Intravenous Administration of Placental Mesenchymal Stromal Cells and Neural Progenitor Cells Derived from Induced Pluripotent Cells on the Course of Acute Ischemic Stroke in Rats.

We compared the effects of placental mesenchymal stromal cells and neural progenitor cells derived from induced human pluripotent cells after their intravenous administration to rats in 24 h after transitory occlusion of the middle cerebral artery. The therapeutic effects were evaluated by the dynamics of animal survival, body weight, neurological deficit, and the volume of infarction focus in 7, 14, 30, and 60 days after surgery. Intravenous injection of neural progenitor cells produced a therapeutic effect on the course of experimental ischemic stroke by increasing animal survival in the most acute period and accelerating compensation of neurological deficit and body weight recovery. Neural progenitor cells were more effective than mesenchymal stromal cells from human placenta. The effectiveness of intravenous transplantation of neural progenitor cells in the model of occlusion of the middle cerebral artery is shown by us for the first time, although the therapeutic effect of their direct transplantation into the brain has already been described.

[Gestagens and the brain].

Modern data on molecular mechanisms underlying intracerebral pleutropic action ofgestagens (progesterone, its metabolites, and synthetic gestagens) are reviewed. Properties of classical and membrane-bound progesterone receptors involved in regulation of gene expression, modulation of neurotransmitter systems, and activation of signal cascades in neurons are described along with data of regional distribution of progesterone receptor subtypes in brain, metabolism, functional activity, and mechanisms of action of progesterone metabolites. Special attention is given to analysis of progesterone and metabolite neuroprotective activity in CNS, such as anti-inflammatory and antiapoptotic effects, and participation in neurogenesis regulation. Clinical application of progesterone-based drugs is discussed with reference to the treatment of brain injuries and prospects for extension of indications for their use in neurologic practice.

Connection between p53 gene Bam HI RFLP polymorphism with the volume of brain infarction in patients with carotid atherothrombotic ischemic stroke.

PURPOSE: The aim of our investigation was to study the connection between p53 gene Bam HI RFLP polymorphism and the brain infarction volume in patients with atherothrombotic ischemic stroke that could highlight certain genetic aspects of the individual sensibility of brain tissue to acute ischemia. MATERIALS AND METHODS: Diallelic Bam HI RFLP polymorphism in 5' flanking region p53 gene was studied in 96 patients with carotid atherothrombotic stroke from Moscow population. Magnetic resonance imaging was conducted on day 7 after the stroke onset. The manual morphometry and "Osiris" morphometric hardware (by the Hospital of the University of Geneva) were used for assessment of the infarction volume. RESULTS: The predominance of small-size infarctions (< 40 cm3) was revealed in patients with (-/-) Bam HI RFLP p53 genotype versus patients with (-/+) (X2 = 19.7; P < 0.001) and (+/+) (X2 = 12.288; P < 0.001) genotypes. According to the Bayesian's statistics, in patients with (-/-) p53 Bam HI genotype the development of a small-size infarction in atherothrombotic ischemic stroke can be prognosticated with probability more than 65%. CONCLUSIONS: A significant association between p53 gene Bam HI RFLP polymorphism and the infarction volume was found in patients with carotid atherothrombotic stroke from Moscow population. These results additionally confirm that apoptosis plays an important role in the formation of ischemic brain lesion and that drugs with anti-apoptotic properties may prove beneficial in stroke patients.

[Locked-in syndrome in vascular pathology of the brain]. / Sindrom zamykaniia pri sosudistoi patologii golovnogo mozga.

Seven patients with vascular abnormalities of the brain (infarct of the ventral portions of the pons varolii and/or the midbrain--5, hemorrhage into the base of the pons varolii--1 and transient impairment of the cerebral circulation in the vertebro-basilar system--presented the locked-in syndrome with such underlying disorders as tetraplegia with the maintenance of tendon and the appearance of abnormal plantar muscle reflexes, pseudobulbar syndrome with intact consciousness and the absence of any significant changes in the EEG. Other findings included disorders of eye movement, mainly in the horizontal plane and involuntary muscular activity such as forced crying, decerebrational and decorticational muscular spasms, as well as masticatory automatisms. The authors emphasize the identity of the given syndrome and Filimonov's syndrome which was repeatedly described in Soviet literature before 1966 when the term "locked-in syndrome" was proposed. They also discuss the pathogenetic mechanisms of the development of the locked-in syndrome in occlusion of the basilar artery.

[Features of the clinical picture and pathogenesis of strokes complicating rheumatism among patients in the older age groups]. / Osobennosti kliniki i patogeneza tserebral'nykh insul'tov pri revmatizme u lits starshikh vozrastnykh grupp.

Clinical and pathogenetic peculiarities of cerebral strokes in patients suffering from rheumatism were studied. Comparative data (little described in literature) on certain peculiarities of the manifestations of acute cerebral circulation disorders in patients of different age, as well as in patients with rheumatism-accompanying cerebral atherosclerosis and arterial hypertension are presented. A considerable incidence of hemorrhagic strokes and their clinical heterogeneity are noted. Problems of the pathogenesis of the cerebrovascular disorders are discussed.

[The clinical and computed tomographic criteria of the diagnosis of multiple systemic cerebral atrophy with progressive autonomic insufficiency (the Shy-Drager syndrome)]. / Klinicheskie i komp'iuterno-tomograficheskie kriterii diagnostiki mnozhestvennoi sistemnoi atrofii mozga s progrssiruiushchei vegetativnoi nedostatochnost'iu (sindroma Shaia--Dreidzhera).

Based on clinical and CT examination of 3 patients with Shy-Drager syndrome and the reported data, differential diagnosis of the given diseases is under discussion. Shy-Drager syndrome is characterized by CT signs of progressive atrophy of the pons and cerebellum with no essential changes in the supratentorial brain structures. The authors support a proposal to use the term "multiple systemic atrophy" for designation of the disease entity that includes both Shy-Drager syndrome and sporadic patterns of olivopontocerebellar and strionigral degenerations in which the disease debuts by motor disorders of the extrapyramidal and cerebellar nature rather than by vegetative disturbances.

[Diagnostic significance of electrocortical responses to rhythmic and solitary photic stimuli in patients with hepato-portal encephalopathy]. / Diagnosticheskoe znachenie reaktsii na ritmicheskie i odinochnye svetovye stimuly u bol'nykh s gepato-portal'noi éntsefalopatiei

In order to clarify some diagnostical criteria of latent hepato-portal encephalopathy in 57 patients with intrahepatic forms of portal hypertension the authors studied the character of driving response in photorhythmical stimulation. In 9 patients the development of evoked potentials depending upon the significance of the stimula was studied as well. The studies confirmed the prognostical significance of a slowing down the mean frequency of rhythms in the EEG in relation to the development of acute encephalopathy and a certain tendency to the shift in the spectrum of driving responses to low frequency and a worsening of driving responses in slowing down the medium rhythm frequency of EEG. In patients with changed resting activity in the Background EEG there was a drop in the amplitude of late components of evoked potentials.

[Natural modulators of the function of the amine oxidase system in the body]. / O prirodnykh moduliatorakh funktsii sistemy aminoksidaz v organizme.

In cerebrospinal fluid (CSF) obtained from patients with chronic alcoholism natural modulators of monoamine oxidase (MAO) activity, containing in human mitochondrial and microsomal fractions or in rat brain mitochondria, have been found. These modulators, which were previously unknown, did not affect the activity of partially purified diamine oxidase from human placenta with 14C-putrescine as a substrate. The MAO modulators from CSF were thermostable (during 3 min at 100 degrees), penetrated through dialysing membrane thus differing from high molecular modulators of MAO previously described. In the system containing membrane bound MAO from human placenta, where the MAO-A is predominating, the modulators studied mostly inhibited deamination of 14C-serotonin. However, in the system containing membrane bound MAO from rat brain with prevalence of the MAO-B, the modulators from human CSF caused either inhibition or stimulation of oxidative deamination of 14C-serotonin or 14C-beta-phenylethylamine used as substrates. The modulators studied were not similar to tribulin (isatin) or quinolinic acid in their effects on catalytic properties of the amine oxidases investigated.

[Mathematical modeling of group of neurons and astrocytes in ischemic stroke].

The mathematical model of group of neurons and astrocytes in the ischemic stroke is discussed. The model includes the description of synaptic signal transmission between the neurons, calcium signaling in astrocytes, ionic currents between the cells and extracellular space and the diffusion through extracellular space. The new modeling approach, based on the creation of appropriate graph, is developed to describe the structure of the system. Using the model, we have analyze the influence of inhibitory synapses on system functioning. We also have shown how the use of medications supporting the activity of inhibitory synapses affects the system behavior in ischemic stroke.

[Dynamics of perfusion CT parameters in the early acute phase of ischemic stroke].

Perfusion computed tomography (CT) allows to evaluate brain perfusion and provides additional information about local cerebral hemodynamics in stroke patients. Twenty-seven patients underwent CT-perfusion in the early acute phase of ischemic stroke. Significant differences between ischemic lesion and contralateral hemisphere on CBF and MTT scans during the first 3 hours after stroke were revealed. In the following 24 h, the differences were seen in all perfusion parameters. CT-perfusion allows to reveal perfusion parameters associated with stroke severity and outcome that is relevant for prescription of reperfusion treatment beyond the boundaries of 3-4.5h "therapeutic window".

[Computer tomographic and laboratory predictors of clinical outcomes of acute ischemic stroke patients after the systemic thrombolytic therapy].

Today the systemic thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is the most effective treatment of ischemic stroke. We included 116 patients with stroke, 82 received rt-PA, 34 were enrolled to the control group. Median NIHSS score was 16,2 +/- 5,4 in the main group and 16,2 +/- 5,4 in the control group. The trial revealed the prognostic significance of some early CT sings of ischemic brain damage for the hemorrhagic transformation and functional outcomes to the 90th day. It was shown that hyperfibrinogenemia (over 450 mg/dl) might be a risk factor of the hemorrhagic transformation. The excess of segmental leukocytes over 78% might be a predictor of the lethal outcome. The initial activity of tissue plasminogen inhibitor (first type) over 11,65 IU/L might be a risk factor of the vascular reocclusion after successful thrombolysis. The analysis of characteristic curves of leukocyte elastase revealed the informativeness of its initial values in the prognosis of reocclusion and hemorrhagic transformation.