[Cost-effectiveness of pneumococcal vaccination among patients with chronic heart failure].

Aim      To analyze the cost-effectiveness of pneumococcal vaccination in 40- and 65-year-old patients with chronic heart failure (CHF).Material and methods  Analysis was performed by Markov modeling from the perspective of the healthcare system. The evaluation was based on Russian epidemiological data taking into account results of international studies. The analyzed schedule of vaccination included one dose of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent polysaccharide vaccine (PPSV23) after one year and vaccination with only one dose of PCV13. The time horizon of the study was 5 years. Costs and life expectancy were discounted at 3.5% per year.Results The cost-effectiveness of vaccination for both 65-year-old and 40-year-old CHF patients is very high: the incremental cost of one additional QALY (Quality-Adjusted Life Year) for PCV13+PPSV23 vaccination is 113.24 thousand rubles, while vaccination with PCV13 entails a reduction in costs by 556.50 rubles per one vaccinated patient. For vaccination of 40-year-old CHF patients with PCV13+PPSV23, the incremental costs per 1 QALY will be 519.72 thousand rubles, while for vaccination with PCV13 it will be 99.33 thousand rubles.Conclusion      Pneumococcal vaccination of CHF patients reduces the associated morbidity and mortality and is highly cost effective.

Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection.

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

[Latencies of Repeated Responses to Single Pulse Stimulation of the Schaffer Collaterals Registered in Hippocampal Field CA1 in Rats During Sleep].

It is assumed that hippocampal neurons which were activated via the neocortex by new stimulus during the wakefulness and after that maintain its transient memory trace must be reactivated during the sleep to consolidate corresponding permanent memory trace in the neocortex. So we investigated the possibility of reverberation of excitation in the neuronal circuits connecting the hippocampus and entorhinal cortex. In sleeping rats within proximal part of the field CA1 of dorsal hippocampus we recorded double and triple responses to single pulse stimulation of Schaffer collaterals with previously potentiated synapses. Analysis of latent periods of repeated responses permitted to assume that the wave of excitation that was initiated in the field CA1 and returned from the entorhinal cortex to the locus of registration in the CA1 directly via perforant path fibers or throw the field CA2, can evoke repeated discharge of neurons in the CA1 but not the same that were activated initially by stimulation of Schaffer collaterals. So the neuronal circuits connecting the hippocampus and entorhinal cortex don't maintain reactivation of "learned" neurons in following periods of sleep.

[Method for correction of perspective distortions during videotracking of the animal in Morris watermaze].

Analysis of correlations between the neuronal activity and animal behavior requires recordings of neuronal activity combined with video tracking. Recordings of neuronal activity in animals performing spatial task in Morris water maze requires angular position of recording camera to avoid "dead zones". If optical axe forms the angle with the water surface, perspective distortions occur. This leads to false results in analysis of trajectories. The paper suggests the method for correction of perspective distortions.

Pharmacological inhibition of Axl affects smooth muscle cell functions under oxidative stress.

We previously demonstrated that reactive oxygen species (ROS) activate Axl, a receptor tyrosine kinase, resulting in increased survival of rat aortic smooth muscle cells (RASMs). Our experiments in Axl knockout mice showed significant reduction in vascular pathologies. We hypothesize that selective pharmacological inhibitors of Axl could prove beneficial in treating vascular diseases associated with oxidative stress. We investigated a role for two novel compounds specific for Axl (R428 and R572) on ligand independent activation of Axl mediated cell survival and migration. Stimulation of RASMs with H(2)O(2) for 5 min significantly increased Akt phosphorylation (p-Akt). Inhibition at 50% (IC(50)) of p-Akt was calculated at lower concentrations in R428 (100 nM) and R572 (10 nM) compared to Fc-Axl (2 microg/mL). Flow cytometry staining with Annexin V showed a 2-fold increase in apoptosis with R428 and R572 compared to Fc-Axl after H(2)O(2), which was validated by concomitant increases in cleaved caspase-3. Pretreatment with R428 and R572 decreased cell migration by approximately 50% in response to 20% serum (similar to that after Fc-Axl). R428 and R572 decreased intracellular production of ROS in comparison to Fc-Axl. In conclusion, R428 and R572 are more potent inhibitors of ligand independent mediated Axl signaling compared to Fc-Axl in RASMs under oxidative stress.

[Study of extracellular concentration of dopamine and its metabolites in mice striatum by a microdialysis technique at intraperitoneal administration of MPTP].

In this paper a structure of a microdialytic cannula inserted into brain areas just before a microdialysis is described. The cannula used allowed to find out a correspondence of behavioral and biochemical changes in C57BL/6 mice at various time intervals after a single dose administration (20 mg/kg) of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, without any additional pharmacological actions enhancing an extracellular striatal dopamine concentration. Immediately after 1-methyl-4-phenyl-1.2,3.6-tetrahydropyridine administration an essential disturbance of mice behavior and a significant reduction of the extracellular concentration of dopamine and homovanillic acid were observed in striatum. A week after the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration neither behavior nor the extracellular dopamine and homovanillic acid striatal concentration substantially differed from those of controls. 30 days after the neurotoxin administration there was again an essential disturbance of behavior and the large reduction of dopamine and its metabolite concentration in striatum. There was suggested that a reduction of the dopamine concentration immediately after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection connected with abnormalities of dopamine synthesis and metabolism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine whereas a reduction of the extracellular striatal dopamine concentration 30 days after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration related to damage of the nigrastriatal dopaminergic system.

Return of excitatory waves from field CA1 to the hippocampal formation is facilitated after tetanization of Schäffer collaterals during sleep.

Current concepts hold that during learning in waking animals, new information is transmitted from the neocortex to the hippocampus, where it leaves a temporary trace in the form of a mosaic of modified synapses. During sleep, reactivation of the neuron population initially activated by the new stimulus has the result that this information is returned to the neocortex, ensuring consolidation of a permanent memory trace. Exchange of information between the neocortex and hippocampal formation is mediated mainly by the entorhinal cortex, whose internal connections, in principle, allow "messages" from the output of the hippocampal formation to return to its inputs. Our experiments in awake and sleeping rabbits demonstrated that waves of excitation can return to hippocampal field CA1 and the dentate gyrus via fibers of the perforant path, these waves having initially entered field CA1 via potentiated synapses of Schäffer collaterals; during sleep, re-entrant waves of excitation reach a maximum and have a high probability of evoking discharges of dentate gyrus neurons. Thus, the new stimulus, potentiating synaptic connections in the hippocampus and, probably, the entorhinal cortex during waking, create conditions for reactivation of the corresponding hippocampal neuron populations during sleep by waves of excitation returning via the entorhinal cortex.

[The excitation wave returning to the hippocampus through the entorhinal cortex can reactivate the populations of "trained" CA1 neurons during deep sleep].

It is suggested that the information about a new stimulus from the neocortex is transferred to the hippocampus and forms there a transient trace in the form of a distributed pattern of modified synapses. During sleep, the neuronal populations which store this trace are reactivated and return to the neocortex the information necessary for consolidation of the permanent memory trace. A possible mechanism of the reactivation of the "learned" hippocampal neurons during memory consolidation is the reverberation of excitation in the neuronal circuits connecting the hippocampus and the entorhinal cortex. In rats, we recorded responses in hippocampal field CA1 to stimulation of the Schaffer collaterals with potentiated synapses during wakefulness and sleep. We showed that in the periods of deep sleep, after the discharge of CA1 neurons, the wave of excitation passes through the entorhinal cortex and via the perforant path fibers enters the hippocampus and the dentate gyrus, causing in the latter the discharge of neurons. The repeated discharge of the CA1 neurons develops as the result of interaction of the early wave which is returned directly via the perforant path fibers and the late wave which is returned via the Schaffer collaterals, but not through the dentate gyrus and hippocampal field CA3 (trisynaptic pathway), but, probably, through the field CA2.

[Return of excitatory waves from the field CA1 to the hippocampal formation is facilitated after Schaffer collateral tetanization and during sleep].

In agreement with existing notion, in a waking animal, novel information during learning transfers from the neocortex to the hippocampus where creates a transient trace in the form of a distributed pattern of modified synapses. During sleep, due to reactivation of neuronal populations initially activated by novel stimulus, this information flows back to the neocortex thus facilitating permanent memory trace consolidation. Information transfer between the neocortex and hippocampal formation is realized, in general, via the entorhinal cortex whose intrinsic connections basically permit "messages" from the exit of the hippocampal formation to return to its entrances. In waking and sleeping rats, we demonstrated a possibility of the return of the excitatory waves to hippocampal field CA1 and dentate gyrus via perforant path fibers that initially enter the CA1 via potentiated Schaffer collateral synapses. During sleep the returned excitatory waves were of maximal amplitude and with a high probability elicited a discharge of dentate neurons. Thus, a novel stimulus that potentiates synaptic connections during waking in the hippocampus and probably in the entorhinal cortex creates conditions for reactivation of corresponding neuronal populations in the hippocampus during sleep by excitatory waves returning via the entorhinal cortex.

A miniature multichannel preamplifier for recording electrophysiological activity in freely moving animals.

A design for a miniature preamplifier for recording electrophysiological activity in freely moving small animals is proposed. The preamplifier is relatively simple to make and use and allows differential recording of neuron activity, EEG, and evoked potentials in multiple channels. When necessary the preamplifier can easily be disassembled for repair. A thin, flexible cable and a "gentle" suspension system prevent interference with the animal's free movement. The design is light in weight and allows electrophysiological activity to be recorded in mice even while they are swimming in a Morris tank.

[A miniature multichannel preamplifier for recording electrophysiological activity in freely moving animals].

A design of a miniature lightweight multichannel preamplifier for recording electrophysiological activity in freely moving small animals is presented. The advantages of this construction include the possibility to obtain differential multichannel recording of neuronal activity, EEG and evoked potentials, relatively simple fabrication and exploitation. If necessary, the preamplifier may be easily disassembled for repair. Fine and flexible cable and "soft" hanger do not disturb free movement of an animal. The lightweight construction may be used for recording neuronal activity even in mice performing spatial task in Morris water maze.

Conditions required for the appearance of double responses in hippocampal field CA1 to application of single stimuli to Shäffer collaterals in freely moving rats.

Stimulation of Shäffer collaterals with single current impulses could evoke double responses in hippocampal field CA1 in freely moving rats. The late response - the population excitatory postsynaptic potential with a preceding transient potential, often biphasic - occurred only after an early population spike and was time-locked to it. The shape characteristics of the late response, its polarity, and its latent period relative to the early population spike suggest that stimulation of Shäffer collaterals gives rise, in CA1, to a wave of excitation which passes through the entorhinal cortex and returns to CA1 directly via fibers of the perforant path. In conscious rats, medium-strength stimulation of Shäffer collaterals, sufficient to evoke a quite early population spike in CA1, did not usually lead to the appearance of a late response; the same stimulation became effective after tetanization of Shäffer collaterals in conditions of long-term potentiation of the early population spike. Furthermore, the appearance of the late response was facilitated in rats falling asleep on the background of high-amplitude, low-frequency EEG oscillations in CA1 characteristic of slow-wave sleep, as well as in sleeping rats, regardless of the EEG pattern.

[Conditions required for appearance of a double response to a single-shock stimulation of Schaffer collaterals in hippocampal field CA1 in freely moving rats].

Schaffer collateral stimulation with a single current impulse can evoke a double response in hippocampal field CA1 of freely moving rats. The late response appears as a population excitatory postsynaptic potential with a preceding short-term potential (frequently biphasic) only after the early population spike and is time-locked to it. The wave shape and polarity of the late response, its latency with respect to the peak of the early population spike suggest that the excitation wave produced in the CA1 field by the stimulation of Schaffer collaterals passes across the entorhinal cortex and returns to the CA1 directly via the perforant path fibers. In waking rat, the medium-intensity stimulation of Schaffer collaterals (able to evoke in the CA1 an early population spike of sufficiently high amplitude) usually does not result in the appearance of the late response. However, similar stimulation becomes efficient after the tetanization of Schaffer collaterals, under conditions of the long-term potentiation of the early population spike. Moreover, the late response occurrence is facilitated in a rat falling asleep after the development in the CA1 of high-amplitude low-frequency EEG oscillations typical for the slow-wave sleep and in a sleeping rat independently of the EEG pattern.

[Plasminogen activators and matrix metalloproteinases during arterial remodeling].

To evaluate the role and interaction of plasminogen activators and matrix metalloproteinases (MMPs) in arterial remodeling in vivo we compared effects of recombinant urokinase- (uPA) and tissue-type (tPA) plasminogen activators on vessel morphology, cell proliferation, inflammatory reaction and MMPs expression in arterial wall after experimental balloon angioplasty. We observed that the periadventitial application of uPA to the injured artery in pluronic gel stimulated neointima formation and inward arterial remodeling as well as cell proliferation and inflammatory leukocytes recruitment. In contrast, tPA attenuated neointima growth, contributed to outward arterial remodeling and did not affect significantly leukocytes recruitment in injured arterial wall. Perivascular uPA increased the content and activity of MMPs, while tPA did not induce such changes. In mouse model of vascular remodeling based on partial ligation of the carotid the content of uPA correlated with neointima growth, tPA content correlated with outward arterial remodeling. Our experiments suggest that plasminogen activators represent specific functional target for attenuating unfavorable inward arterial remodeling.

Effect of cholinergic and adrenergic receptor blockade on arrhythmogenic activity of endothelin-1 during inhibition of nitric oxide synthesis in awake mice.

We studied the effects of blockade of nicotinic receptors in sympathetic and parasympathetic ganglia (hexamethonium), muscarinic receptors (atropine), and beta1-adrenoceptors (atenolol) on arrhythmogenic activity of endothelin-1 during inhibition of nitric oxide synthesis with Nomega-nitro-L-arginine in NMRI mice. Atropine reduced, while hexamethonium completely abolished the arrhythmogenic effect of endothelin-1 during nitric oxide synthase inhibition. Atenolol potentiated arrhythmogenic activity of Nomega-nitro-L-arginine, but endothelin-1 had no effect on the incidence of arrhythmias under these conditions.

[Double evoked responses to the electrical stimulation of Shaffer's collaterals in CA1 hippocampal field]. / Dvoinye vyzvannye otvety v pole CA1 gippokampa pri stimuliatsii kollateralei Shaffera.

Double evoked responses to single current pulses applied to Shaffer's collaterals were observed in CAI hippocampal field in freely moving rats. The second response was an irregular population EPSP with constant latency sometimes accompanied by a population spike. The effect was observed in 22 of 54 tested rats (40.74%). In 10 of these 22 animals (45.45%) the second response was evoked by a weak testing stimulus of at least of a single collateral, in the remaining 12 rats the second response appeared to stimulation with increased current or after potentiation of the stimulated pathways. The second responses were very sensitive to the functional state of an animal and were recorded at the state of rest or during sleep. The latencies of the second response measured from the beginning of the first response were very close in different animals and with low intraindividual variability indicating that the same circuits are involved in its generation. It is suggested that hippocampus can support dynamic processes such as reverberation of signals.

Stimulation of the lateral hypothalamus provokes the initiation of robust long-term potentiation of the thalamo-cortical input to the barrel field of the adult, freely moving rat.

Long-term potentiation in the thalamo-cortical input to the somatosensory cortex barrel field has been reported to be inducible in vitro only during a narrow critical period of the first postnatal week. Here we explored whether this is due to inability of adult synapses to express LTP or lack of appropriate conditions for LTP induction in slice preparations. We recorded thalamo-cortical field potentials (FPs) from the barrel field of chronically prepared adult rats. In the first series, several parameters of conditioning tetanization of thalamus (T) have been tried. Statistically significant LTP of 135-150% relative to the baseline was observed only in rare cases (3/18) so that the mean changes were not statistically significant. In the second series, five trains of 100 Hz stimulation of T were paired with a "reinforcing" stimulation of the lateral hypothalamus (LH). In most cases (9/13), thalamo-cortical FPs were potentiated. The mean post-tetanic amplitude was 238 +/- 42% (+/- SEM) relative to the baseline (n = 13). The potentiation persisted for >1 h and typically even further increased when tested 24-48 h later. LTP magnitude strongly correlated with the initial paired-pulse ratio (PPR, coefficient of correlation r = 0.98) so that the LTP magnitude was larger (333 +/- 107, n = 6) in cases with PPR > 1.3. The mean PPR tended to decrease after LTP (from 2.05 to 1.65). Altogether the results suggest that LTP is inducible in the thalamo-cortical input to the barrel field of normal adult rats. The dependence of the LTP magnitude upon the initial PPR suggests that inputs with low initial release probability undergo larger LTP. Together with the tendency to a decrease in the PPR this suggests an involvement of presynaptic mechanisms in the maintenance of neocortical LTP.

Stimulation of the lateral hypothalamus provokes the initiation of robust long-term potentiation of the thalamo-cortical input to the barrel field of the adult, freely moving rat.

Long-term potentiation in the thalamo-cortical input to the somatosensory cortex barrel field has been reported to be inducible in vitro only during a narrow critical period of the first postnatal week. Here we explored whether this is due to inability of adult synapses to express LTP or lack of appropriate conditions for LTP induction in slice preparations. We recorded thalamo-cortical field potentials (FPs) from the barrel field of chronically prepared adult rats. In the first series, several parameters of conditioning tetanization of thalamus (T) have been tried. Statistically significant LTP of 135-150% relative to the baseline was observed only in rare cases (3/18) so that the mean changes were not statistically significant. In the second series, five trains of 100 Hz stimulation of T were paired with a "reinforcing" stimulation of the lateral hypothalamus (LH). In most cases (9/13) thalamo-cortical FPs were potentiated. The mean post-tetanic amplitude was 238 +/- 42% (+/- SEM) relative to the baseline (n = 13). The potentiation persisted for > > 1 hr and typically even further increased when tested 24-48 hr later. LTP magnitude strongly correlated with the initial paired-pulse ratio (PPR, coefficient of correlation r = 0.98) so that LTP magnitude was larger (333 +/- 107, n = 6) in cases with PPR > 1.3. The mean PPR tended to decrease after LTP (from 2.05 to 1.65). Altogether the results suggest that LTP is inducible in the thalamo-cortical input to the barrel field of normal adult rats. The dependence of LTP magnitude upon the initial PPR suggests that inputs with low initial release probability undergo larger LTP. Together with the tendency to a decrease in the PPR this suggests an involvement of presynaptic mechanisms in the maintenance of neocortical LTP.