[Efficacy of fesoterodine for prevention of autonomic dysreflexia in patients with neurogenic dysfunction of the bladder after spinal cord injury].

AIM: to evaluate the effectiveness of fesoterodine for the prevention of autonomic dysreflexia (AD) in patients with neurogenic bladder dysfunction (NBD) after spinal cord injury (SCI). MATERIALS AND METHODS: a total of 53 patients with AD were included in the study. In the main group (n=33) patients received fesoterodine 4 mg per day for 12 weeks as a treatment for neurogenic bladder dysfunction and prevention of AD. In the control group (n=20), patients were monitored for 12 weeks without specific treatment. The assessment was based on the results of ADFSCI and NBSS questionnaires, daily blood pressure monitoring with the completion of a self-observation diary, cystometry with simultaneous monitoring of blood pressure and heart rate. RESULTS: In the main group there was a significant decrease in episodes and severity of AD according to ADFSCI questionnaire and an improvement in the quality of life according to NBSS questionnaire compared to the control group (p<0.001). Also, in the main group, the number of episodes of AD and systolic blood pressure decreased. The maximum bladder capacity and bladder compliance increased (p<0.001), and the maximum detrusor pressure and systolic blood pressure when the cystometric capacity was reached, decreased significantly (p<0.001) in the main group compared in comparison with the control group. CONCLUSION: Fesoterodine at a dosage of 4 mg for 12 weeks reduced the severity of symptoms of AD in patients with SCI and NBD, which was manifested by the stabilization of blood pressure and a decrease in the number of episodes of AD, which significantly improved the quality of life. Also, the drug led to a significant improvement in urodynamic parameters during cystometry, in the form of a decrease in detrusor pressure and an increase in cystometric capacity. We can conclude that fesoterodine is effective in the prevention of AD in patients with NBD after SCI.

[Premature ejaculation: the main physiological mechanisms and new approaches to the treatment].

Premature ejaculation (PE) is characterized by an early ejaculation, which occurs within 1 minute after or before vaginal penetration. PE is the most common sexual problem and leads to a number of negative psychological consequences. To understand the etiopathogenesis of PE, it is necessary to understand the physiological mechanisms of the ejaculatory reflex. A group of galanine-ergic lumbar spinothalamic cells (LSt cells) with their numerous projections to various structures of the central nervous system plays a crucial role. The main approaches to the treatment of PE are based on the inhibition of glans sensitivity. In recent years, most of the studies on PE are dedicated to various technologies of reflexotherapy and a possibility of biofeedback. We have analyzed the available literature data and explained the main links of ejaculatory reflex, as well as possible approaches to treatment.

Disruption of flavin homeostasis in isolated rat liver mitochondria.

It has been shown that spontaneous release of non-covalent flavins (from flavoenzymes) begins after isolation of mitochondria from rat liver, which is hydrolyzed to riboflavin. This process is stopped by 1 mM EDTA in the incubation medium. In the presence of NADH, deflavinization of flavoproteins leads to formation of superoxide by at least of three processes. The first of these occurs in complex I as a result of the spontaneous release of FMN from the active center. This process is inhibited by adenosine and guanosine phosphates, as well as NAD, but amplified by nicotinamide. The second process is associated with enzymatic hydrolysis of FAD and FMN to riboflavin; it is blocked by EDTA, AMP, NA, NAD. The third process is associated with non-enzymatic hydrolysis of FAD by iron ions in matrix; it is blocked by EDTA and AMP.

Atherosclerosis of brachiocephalic arteries and arterial stiffness in patients with breast cancer.

Cardiovascular toxicity is one of the important problems of clinical oncology. Atherosclerosis progression was demonstrated in patients with cancer and chemotherapy.Te aim - to evaluate the vascular wall characteristics and to determine the predictors of AS of brachiocephalic arteries progression during anticancer therapy in patients with breast cancer. METHODS: Te study involved 43 patients with newly diagnosed breast cancer (BC) (II-III stage) with overexpression of HER2; median age 50 (40;57) years. All patients underwent neoadjuvant drug therapy with antracyclines, taxanes and trastuzumab followed by surgery, radiation and hormone therapy according to the indications. Before anticancer therapy the general clinical examination was conducted and lipid profle, plasma lipoprotein (a) [Lp(a)] level, titres of autoantibodies IgM and IgG to lipoproteins and their oxidized derivatives were estimated. Te vascular wall stiffness (pulse wave velocity on the carotid-femoral (PWVcf) and shoulder-ankle (PWVsa) segments, the central pressure, carotid intima-media thickness (CIMT) and the degree of stenosis of the brachiocephalic arteries) were determined at baseline and at each stage of anticancer therapy. Te atherosclerosis progression was determined if the new stenosis (≥15%) or increase of preexisting stenosis (≥5%) were revealed; CIMT increase ≥ 0.1 mm. Te parameters of cellular immunity (peripheral blood lymphocyte phenotyping via direct immunofluorescence and flow cytometry), lipid spectrum parameters, serum concentration of Lp (a), autoantibodies IgM and IgG against lipoproteins and their oxidized derivatives, as well as PWVсf and PWVsa were assessed in 17 BC patients before the onset of neoadjuvant therapy and in 20 healthy women. RESULTS: BC patients and healthy women were comparable in traditional cardiovascular risk factors but differed in PWVsa and PWVcf levels (p<0.05). In BC patients the activation of T-cell immunity with the stimulation of both subpopulations with pro-inflammatory and regulatory properties was observed (p<0.05). Te direct correlations between the content of activated T-lymphocytes (T-act), T-helpers (T) 1 and PWVsa (p<0.05), as well as T-act, T1 and T2 and PWVcf (p<0.05) were revealed in the general group. Te decrease of systolic blood pressure (SBP), central SBP (SBPc), central diastolic blood pressure (DBPc), PWVcf and PWVsa levels accompanied with a temporary heart rate increase were observed during anticancer therapy; SBP, SBPc, PWVcf levels restored by the end of the follow-up period. Te CIMT increase was detected in 22 (51%), and the atherosclerosis progression in 26 (60%) BC patients during anticancer therapy. Lp (a) level above 12.8 mg/dl was associated with CIMT increase (p<0.05). Age > 48 years and radiation therapy were risk factors for CIMT increase and atherosclerosis progression (p<0.05), respectively. CONCLUSIONS: Te vascular stiffness is increased in BC patients, which is associated with the activation of effector subpopulations of T-lymphocytes and the elevation of circulating level of both pro-atherogenic and anti-atherogenic T-cells. Te level of Lp (a) above 12.8 mg/dl is associated with atherosclerosis progression, which requires further research. Age and radiation therapy are the risk factors for atherosclerosis progression during anticancer therapy.

[The clinical/laboratory support for using melatonin in chronic cerebrovascular diseases and metabolic syndrome]. / Kliniko-laboratornoe obosnovanie primeneniia melatonina pri khronicheskikh tserebrovaskuliarnykh zabolevaniiakh i metabolicheskom sindrome.

AIM: To evaluate a role of melatonin deficiency in the metabolic syndrome and chronic cerebral ischemia (CCI). MATERIAL AND METHODS: One hundred and seventy-nine men, aged 45-75 years, with CCI and components of metabolic syndrome (MS) were examined. Intima-media thickness (IMT) in the carotid arteries and cerebrovascular reactivity was assessed by the results of duplex scanning and hypercapnic test. Cholesterol spectrum parameters, glucose metabolism, inflammatory mediators, markers of lipid metabolism were measured in the blood serum. Daily changes in melatonin production were determined by measuring 6-SMT, a melatonin metabolite, in morning, evening and night urine. RESULTS AND CONCLUSION: The levels of total 6-SMT excretion were 17.2 [10.01; 36.8] mcg/day. Patients with the values <10.01 and >36.8 mcg/day significantly differed by the PAI-1, leptin/adiponectin ratio, IMT and cerebrovascular activity. The combination of 4 or 5 MS components was identified in 19 (42%) patients with low 6-SMT excretion and only in 7 (15%) with high excretion (OR=3.9; 95% CI 1.3-12.2; p=0.01). Thus, the low level of endogenic melatonin and disturbances of circadian dynamics of its synthesis with the decrease in the night and increase in the evening portions are the risk factors for MS and CCI. Addition of melatonin in the complex treatment of CCI associated with MS and the low level of endogenic melatonin is pathogenetically explained.

[COMPARATIVE ANALYSIS OF SEROTONIN LEVELS IN RAT PLATELETS, SERUM AND BRAIN ON THE AGING].

Serotonin functions as neurotransmitter in central nervous system and is involved in the regulation of vascular tone, gastro-intestinal motility and blood coagulation in the periphery. The appearance of new data on the significant correlation between serotonin levels in platelets and cerebrospinal fluid (Audhya et al., 2012) renewed interest in the hypothesis in which the platelet is seen as a model of cerotoninergic neuron. In our study, the levels of serotonin in platelets, serum and various brain regions of rats aged 6 and 24 months have been determined and comparatively analyzed. The method of high performance liquid chromatography was used. The decrease of serotonin level in platelets from 0.768 to 0.359 µg per 10(9) cells and its increase in the middle brain from 0.260 to 0.439 µg per 1 of wet weight have been clearly demonstrated in aging of animals. The differences in the content of serotonin in other parts of the brain and in the blood serum of young and old animals were statistically insignificant. Therefore, despite the attractiveness of the concept of platelet as a model of a neuron, the extrapolation of the data on platelet serotonin transport into neuronal ones requires caution, especially in the study of aging.

[The effect of high-molecular weight chitosans on the antioxidant and immune systems of the honeybee].

High-molecular weight chitosan (200 kDa, 75% deacetylated) and N-succinoyl chitosan (300 kDa, 75% deacetylated) were shown to have a preadaptive effect and increase the lifespan of honeybees due to the induction of protective antioxidant and immune mechanisms. Chitosan with a molecular weight of 200 kDa had a fungistatic effect on a pathogenic fungus that causes ascospherosis, a disease of bee larvae and pupae.

[Tyndall's hypochromism in suspensions].

Since the passage of light through each individual particle in a suspension includes the competition of processes of absorption and scattering, it leads to hypochromism--a decrease in the extinction coefficient. Such "scattering" hypochromism increases with the particle size and its refractive index. Since the Tyndall's light scattering in suspensions, where the size of each particle is substantially larger with respect to wavelengths of light, is not strongly dependent on the wavelength, the absorption spectrum (and excitation spectrum) attenuated almost uniformly at different wavelengths. A simple method to find true extinction coefficients from the absorption (or excitation) spectra of diluted suspensions (not having multiple light scattering) is suggested. The experimental data on spectra of hemoglobin in erythrocytes, actinomycin in DNA and flavins in mitochondria are given.

[Degradation of Mitochondria to Lipofuscin upon Heating and Illumination].

In the present work, it has been shown that the isolated mitochondria can undergo transformation to lipofuscin granules without any additional factors (oxygen saturation, prooxidants). The process occurs spontaneously and slowly at low temperature, and rapidly--by heating (thermo-lipofuscin) or under UV irradiation (photo-lipofuscin). The main contribution to the formation of mitochondrial lipofuscin comes from denatured proteins. Thermo-formation of lipofuscin depends on lipid peroxidation, while the presence of lipids is not required for photo-lipofuscin formation. It is shown that the use of detergent able to degrade mitochondria is necessary to measure lipofuscin content properly.

Analysis of circulating tumor cells in patients with triple negative breast cancer during preoperative chemotherapy.

The presence of circulating tumor cells in the blood of patients with triple negative breast cancer (early and locally advanced cancer) before and after preoperative chemotherapy was assessed using expression markers. Before therapy, circulating tumor cells were detected in 5 of 13 (38%) patients with early cancer and in 7 of 17 (41.2%) patients with locally advanced cancer. After therapy, the circulating immune cells were detected in one patient with locally advanced cancer, who had no circulating cells before therapy. The tumor was resistant to chemotherapy and the disease progressed. The detected circulating tumor cells were HER-2-positive, while the primary tumor was HER-2-negative. It was concluded that the circulating immune cells can be a potential marker of the efficiency of therapy and predictors of the disease course, while their phenotype can differ from the phenotype of the primary tumor.

Stabilization of NADH-dehydrogenase in mitochondria by guanosine phosphates and adenosine phosphates.

It is known that one of the reasons, leading to the development of neuromuscular diseases, including Parkinson's disease, is damage of the mitochondrial NADH-dehydrogenase. Perhaps, it happens when NADH-dehydrogenase loses connection with its coenzyme--flavine mononucleotide (FMN) that occurs at various influences on the enzyme. Previously, we have developed a method, based on fluorescence spectroscopy, to monitor the rate of exit of FMN from isolated mitochondria to solution. Also, we obtained the data that this process is blocked by the enzyme substrate - NADH or by the product - NAD. Recently, we found that this process is strongly blocked by adenine analogs of NAD, contained phosphates: ATP, ADP, and AMP. Adenosine phosphates are able to stabilize the FMN molecule in NADH-dehydrogenase. Using fluorescence spectroscopy and photocolorimetry, we have tested also other natural purine compounds - cAMP, cGMP, GMP, GDP, GTP, IMP, inosine, guanine, and caffeine. It is found that such derivatives of guanine as GMP, GDP, and GTP can prevent the release of FMN into solution. Guanine, cGMP, cAMP and caffeine did not prevent this process. The obtained data allow understand the mechanism of mitochondrial diseases, involving damage of mitochondrial NADH-dehydrogenase, and may help in development of medicines for treatment of these diseases.

Nitrogen concentrations in mosses indicate the spatial distribution of atmospheric nitrogen deposition in Europe.

In 2005/6, nearly 3000 moss samples from (semi-)natural location across 16 European countries were collected for nitrogen analysis. The lowest total nitrogen concentrations in mosses (<0.8%) were observed in northern Finland and northern UK. The highest concentrations (≥ 1.6%) were found in parts of Belgium, France, Germany, Slovakia, Slovenia and Bulgaria. The asymptotic relationship between the nitrogen concentrations in mosses and EMEP modelled nitrogen deposition (averaged per 50 km × 50 km grid) across Europe showed less scatter when there were at least five moss sampling sites per grid. Factors potentially contributing to the scatter are discussed. In Switzerland, a strong (r(2) = 0.91) linear relationship was found between the total nitrogen concentration in mosses and measured site-specific bulk nitrogen deposition rates. The total nitrogen concentrations in mosses complement deposition measurements, helping to identify areas in Europe at risk from high nitrogen deposition at a high spatial resolution.

Mosses as biomonitors of atmospheric heavy metal deposition: spatial patterns and temporal trends in Europe.

In recent decades, mosses have been used successfully as biomonitors of atmospheric deposition of heavy metals. Since 1990, the European moss survey has been repeated at five-yearly intervals. Although spatial patterns were metal-specific, in 2005 the lowest concentrations of metals in mosses were generally found in Scandinavia, the Baltic States and northern parts of the UK; the highest concentrations were generally found in Belgium and south-eastern Europe. The recent decline in emission and subsequent deposition of heavy metals across Europe has resulted in a decrease in the heavy metal concentration in mosses for the majority of metals. Since 1990, the concentration in mosses has declined the most for arsenic, cadmium, iron, lead and vanadium (52-72%), followed by copper, nickel and zinc (20-30%), with no significant reduction being observed for mercury (12% since 1995) and chromium (2%). However, temporal trends were country-specific with sometimes increases being found.

[Comparative analysis of virulence of the Siberian and Far-East subtypes of the tick-born encephalitis virus]. / Sravnitel'nyi analiz virulentnosti sibirskogo i dal'nevostochnogo podtipov virusa kleshchevogo entsefalita.

The Siberian subtype of the tick-borne encephalitis virus (TEV) is different from the Far-East subtype by a moderate virulence observed in Siberian hamsters and by a low infection development rate (100 strains were compared). No differences were found in neuro-invasiveness. Clinical findings and experiments with monkeys denote the ability of the Siberian subtype to provoke severe forms of tick-borne encephalitis (TBE). The inflammation-and-degenerative changes were localized in the brain cortex, subcortical ganglions, nuclei of medulla oblongata, in the cortex and nuclei of the cerebellum as well as in the anterior horns of the spinal cord. 18 disease cases triggered by the Siberian TEV subtypes in residents of the Western and Eastern Siberia and of Central Russia (Yaroslavl Region), including 7 acute TBE cases (5 lethal outcomes), as well as 11 chronic TBE cases are analyzed. The viral RNA was found in the cortex, medulla oblongata, horn and in the cervical part of the spinal cord of those diseased of acute TBE. Sequences of genotyped strains were presented to Gen Bank, NCBI (AY363846-AY363865).

Characterization of a siberian virus isolated from a patient with progressive chronic tick-borne encephalitis.

A strain of Tick-borne encephalitis virus designated Zausaev (Za) was isolated in Siberia from a patient who died of a progressive (2-year) form of tick-borne encephalitis 10 years after being bitten by a tick. The complete genomic sequence of this virus was determined, and an attempt was made to correlate the sequence with the biological characteristics of the virus. Phylogenetic analysis demonstrated that this virus belongs to the Siberian subtype of Tick-borne encephalitis virus. Comparison of Za virus with two related viruses, a Far Eastern isolate, Sofjin, and a Siberian isolate, Vasilchenko, revealed differences among the three viruses in pathogenicity for Syrian hamsters, cytopathogenicity for PS cells, plaque morphology, and the electrophoretic profiles of virus-specific nonstructural proteins. Comparative amino acid alignments revealed 10 individual amino acid substitutions in the Za virus polyprotein sequence that were different from those of other tick-borne flaviviruses. Notably, the dimeric form of the Za virus NS1 protein migrated in polyacrylamide gels as a heterogeneous group of molecules with a significantly higher electrophoretic mobility than those of the Sofjin and Vasilchenko viruses. Two amino acid substitutions, T(277)-->V and E(279)-->G, within the NS1 dimerization domain are probably responsible for the altered oligomerization of Za virus NS1. These studies suggest that the patient from whom Za virus was isolated died due to increased pathogenicity of the latent virus following spontaneous mutagenesis.

[Netilmicin in the complex therapy of pneumonia in newborns]. / Netilmitsin v kompleksnom lechenii pnevmonii u novorozhdennykh detei.

Clinical efficacy of netilmicin was evaluated at 22 newborns (body weight from 1000 to 3600 g, delivery on pregnancy period from 28 to 41 weeks) with pneumonia caused by artificial pulmonary ventilation. Pneumonia was moderate at 13 patients and severe at 9 patients. Microorganisms isolated from tracheobronchial aspirates were mainly (in 19 cases of 22) susceptible to netilmicin. The usage of netilmicin in combination with cephalosporins was effective at the main part of the newborns and resulted with the full recovery of 11 newborns (all the patients with moderate pneumonia), in 9 cases improvement was registered (including 7 newborns with severe pneumonia). Newborns with severe pneumonia had a slow pathogens elimination.

[Efficiency of detection and preventive treatment of retinopathy in premature neonates]. / Effektivnost' vyiavleniia i profilakticheskogo lecheniia retinopatii nedonoshennykh.

A total of 580 preterm babies born weighing 540-2500 g at terms less than 35 weeks were examined. The mean incidence of neonatal retinopathy under standard conditions of care in Moscow is 26%. The incidence of disease depends on body weight at birth and term of gestation. Risk factors conducive to the development of neonatal retinopathy are maternal diseases (gestosis, chronic somatic and gynecological diseases, hemorrhages in labor, detachment of placenta), and diseases of babies other than low body weight at birth and those due to preterm delivery (bronchopulmonary dysplasia, periventricular leukomalacia, intragastric hemorrhages, severe infection, early anemia, periods of hypercapnia and long oxygen therapy). The disease spontaneously regressed in 78% babies with stages I-II. In 32 (22%) babies the condition progressed to stage III. Preventive cryocoagulation was performed in 24 babies (48 eyes). The efficiency of preventive treatment is 70.4% and depends on the disease pattern. Cooperation of neonatologists and ophthalmologists essentially improves the diagnosis and prevention of severe forms of retinopathy neonatorum.

[Effect of gentamycin on persistence of tick-borne encephalitis]. / Effekt gentamitsina pri persistentsii virusa kleshchevogo éntsefalita.

Effect of gentamicin, an aminoglycoside antibiotic, on the persistence of tick-borne encephalitis (TBE) virus in Syrian hamsters and Macaca iris in remote periods (70-434 days) after inoculation is studied. Attempts at virus isolation from animals treated with gentamicin failed. Unlike other aminoglycosides, e.g. streptomycin, gentamicin exerted no immunodepressive effect; moreover, immunocorrection was observed in some experiments on monkeys and hamsters. None of the 10 previously tested antibiotics elicited such an effect or inhibited the persisting TBE virus. Morphological study of the central nervous system in hamsters and monkeys showed that injection of gentamicin did not cause an exacerbation of chronic encephalitis. The mechanism of immunocorrecting effect of gentamicin is to be further investigated.

[Some mechanisms of the action of oligonucleotides: stimulation of the immune system and decreased infection of the brain in tickborne encephalitis]. / Nekotorye mekhanizmy deistviia oligonukleotidov: stimuliatsiia immunnoi sistemy i umen'shenie porazhenii golovnogo mozga pri kleshchevom éntsefalite.

Morphological changes in the thymus, spleen, and brain are analyzed in white mice injected 16-component oligonucleotide (ON) pE16 complementary to the NS3 protein gene sequences of tickborne encephalitis (TBE) virus in doses of 1 to 0.001 nM. ON stimulated thymic and splenic cells. Besides the stimulating effect, injection of ON to mice infected with TBE enhanced the destruction of lymphocytes and boosted the macrophagal activity, which was paralleled by a decrease in the intensity of virus-specific injuries in the brain. Thus, the antiviral activity of ON may be due to not only the fact that it is complementary to the TBE virus genome, but to stimulation of the immune system, specifically, the thymus and T-related elements, as well.