[Sensitivity and specificity of urinary and serum neurotrophins in the diagnosis of neurogenic detrusor overactivity in multiple sclerosis].

Lower urinary tract dysfunction is common among neurological patients. Traditionally, the basic method of diagnosis is a complex urodynamic study. In recent years, many studies have focused on the search for new non-invasive diagnostic modalities. In particular, neurotrophins are considered as potential biological markers of a neurogenic bladder. AIM: To estimate the sensitivity and specificity of the serum and urinary nerve growth factor (NGF) and brain neurotrophic factor (BDNF) in MS patients as markers of detrusor overactivity. MATERIALS AND METHODS: The study comprised 20 patients with multiple sclerosis, who complained of voiding problems. The control group consisted of 20 people without neurological diseases, lower urinary tract symptoms and detrusor overactivity estimated by filling cystometry. Apart from standard laboratory tests, diagnostic evaluation included a complex urodynamic study, ultrasound of the urinary tract, cystoscopy, testing serum and urinary NGF and BDNF using the enzyme immunoassay. The diagnostic significance of neurotrophins was evaluated using ROC analysis. RESULTS: According to the ROC analysis, the diagnostic sensitivity and specificity of serum NGF as a marker of detrusor hyperactivity was 57% and 93%, respectively (for serum NGF more or equal 26 pg/ml). The quality of the test according to the expert scale of AUC values was "very good" (AUC=0.806). Detecting NGF in patients urine was less effective. The sensitivity and specificity were 52% and 40%, respectively (for NGF more or equal 6 pg/ml). The quality of the test according to the expert scale of AUC values was "average" (AUC=0.64). The serum BDNF demonstrated high sensitivity (90%) and low specificity (23%), AUC=0.56. The urinary BDNF was more informative, (AUC=0.65). The combination of all four markers provides a sensitivity of 85.7% and a specificity of 66.7% (AUC=0.824). CONCLUSIONS: Testing serum and urinary neurotrophins in patients with multiple sclerosis can be used to diagnose detrusor overactivity. The NGF is a highly specific biomarker, while the BDNF is highly sensitive. Combined testing for serum NGF and BDNF is most informative.

Local and Systemic Functional Responses of Mouse Macrophages to Intravaginal Infection with Type 2 Herpes Simplex Virus and Vaccination.

Activity of cathepsin D and phagocytosis of macrophages from vaginal lavage fluid, peritoneal exudation, and spleen were studied in mice of sensitive (DBA/2) and resistant (BALB/c) lines after intravaginal infection with type 2 herpes simplex virus and vaccination. Activity of cathepsin D and intensity of phagocytosis (irrespective of the macrophage source) and their ratio in BALB/c mice in early terms after infection were close to the control levels taken as a unit. In DBA/2 mice, these parameters and their balance were shifted and changes in cathepsin D activity depended on the time after challenge. Activities of cellular and extracellular cathepsin D increased sharply on day 1 postinfection under conditions of local virus interaction with the vaginal mucosa and activation of the pathological process. Later, after generalization of the infection, activity of cathepsin D decreased, while phagocytosis increased in all the studied macrophage populations. Vaccination corrected the cathepsin D/phagocytosis imbalance and created conditions for rapid elimination of the virus.

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment.

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM.

Cyanobacteria(?) in iron banded formations of the Kursk magnetic anomaly.

Fossilized cyanobacteria(?) represented by trichomes enclosed in common sheaths were detected in early Proterozoic iron banded formations of the Kursk magnetic anomaly (limonite-martite ores of the Lebedinsky mine and iron banded formations of the Korobkovskoye deposit). These fossils morphologically similar to current representatives of the genus Microcoleus were buried in situ.

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival.

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5' untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics.

[Dual role of photosensibilizator merocyanine 540 as a bactericidal agent and immune reaction regulator].

AIM: Develop conditions for inactivation of staphylococcus by using photosensibilizator merocyanine 540 (MC540) for the production of antigenic preparation (AP). Study some of immune reactions to AP and the possibility of regulation of DTH reaction to AP under the effect of MC540. MATERIALS AND METHODS: Merocyanine 540 (MC540, Sigma-Aldrich, Switzerland) is used in the study. MC540 and Staphylococcus aureus, strain 78 (Sa78) were irradiated by light of a mercury-quartz lamp DRSH-250 (Zelenograd). C56BL/6 line mice were immunized once by subcutaneous administration of AP. DTH reaction was tested 7 days after the immunization. Functional activity of peritoneal exudate macrophages was determined 1 and 9 days after the immunization. Immune modulating effect of MC540 in DTH was determined after its per os administration to mice 1 hour after AP sensibilization. RESULTS: In order to obtain AP, S. aureus suspension at the concentration of 2.5 x 10(7) CFU/ml in 25 microM MC540 solution and 0.25 M NaCl solution were exposed to irradiation for 5 minutes. During DTH reaction induction its intensity dependence on AP dose was revealed. A persistent increase of a lysosomatic enzyme cathepsin D in macrophages of peritoneal exudate after a single administration of AP was noted. During MC540 irradiation an accumulation of photoproducts that have a pronounced immune suppression effect in DTH reaction had a dose-dependent character. CONCLUSION: Use of saline allows to increase bactericidal potential of a photosensibilizator (PS). However during therapy of localized forms of infection a possible immune modulating effect of PS on macro organism should be considered. By varying PS dose and irradiation time not only maximum bactericidal effect can be achieved but also regulation of inflammatory reactions in the area of PS effect can be ensured.

[Accumulation and precipitation of Mn2+ by the cells of Oscillatoria terebriformis].

The cyanobacterium Oscillatoria terebriformis was shown to exhibit resistance to high manganese concentrations, remaining viable at 2.5 mM MnCl2 in the medium. Cyanobacterial cells were capable of considerable manganese consumption from the medium. Dynamics of Mn sorption by the cells was the same in all experimental variants, independent on the manganese concentration. Manganese concentration in the biomass peaked after 2-3 days and depended on Mn2+ concentration in the medium and on the amount of biomass introduced. In the case of O. terebriformis, manganese removed from the medium may be subdivided into Mn absorbed by the cell, Mn bound to the cell wall, Mn absorbed by the glycocalix, and chemically precipitated Mn. Of the total 21.25 ± 1.0 mg of consumed manganese, biological absorption and chemical precipitation were responsible for 11.78 ± 0.98 and 9.2 ± 0.8 mg, respectively. In the presence of cyanobacteria, Mn removal from the medium was 2.28 times higher than in the control. This process depended considerably on Mn sorption by exopolysaccharides. At 1.3 mM Mn2+, a lamellar mat was formed with interlayers of manganese carbonate.

[Oxidative and hydrolytic deterioration of palm oil and fat products based on it under various conditions of storage and transportation].

Studies have been conducted on the effect of storage conditions for refined deodorized palm oil on the quality and safety: in containers made of ferrous metals (mild steel) at unregulated temperature, in sealed plastic bags at the temperature -20 degrees C in stainless steel under stratification of nitrogen at the temperature of 40+/-1 degrees C. The choice of the objects of study determined by the normative documents of the Russian Federation governing the transportation and storage of vegetable oils and fat products based on them. All samples of palm oil with peroxide value of 1,0 to 1,5 meq O2/kg indicated the presence of a weak foreign taste, is not peculiar impersonalfat, the samples with peroxide value above 1,5 meq O2/kg were observed pronounced off-flavors and odors characteristic of stale oil. Rancidity was observed in samples having peroxide value of 2,0 meq O2/kg or more. Free acid value and anizidin value for the studied period changed to a lesser extent, from 0,06 to 0,1 mg KOH/g and from 1,2 to 1,4 respectively. It is proved that, transportation/storage of palm oil at the temperature above 50 degrees C without stratification of nitrogen greatly accelerates the process of oxidative damage. Based on these data we can recommend transportation/storage and management process with the least possible time of contact of melted palm oil with oxygen to produce high-quality final product (within 2-3 hours from the time of melting).

[The features of system organization of the brain activity during different sleep stages and transition states].

Electropoligraphical study of the natural night sleep in 16 adults with the use of correlation, coherent, cluster and factor analysis were used to obtain new data describing the active nature of sleep, which is expressed especially in periods of falling asleep and the transition from one stage to another. It is shown that the process of falling asleep and deeper sleep is accompanied by intense reorganization of cortico-subcortical relations, which is reflected in the dynamics ofcrosscorrelation and coherent estimates of interrelations of biopotentials of the brain. The results of factor analysis of multichannel EEG heterogeneity of the transition process from wakefulness to sleep is manifested in significant changes of I, II and III factors weight during I(B) stage of sleep, which may reflect changes in the degree of contribution of the main integrative brain systems in the reorganization of its integral activity. A considerable increase in the I factor weight (reflecting the generalized modulatory brainstem effect on the cortex), along with a decrease in the balance of factors II and III (associated with organization of fronto-occipital and interhemispheric interactions) clearly indicates a special role of sleep synchronizing influences from the brain stem in the development of this initial stage. Reduction of EEG interhemispheric interrelations in the anterior and inferior frontal areas with the deepening of sleep may be indication of the reorganization of the frontal areas activity associated with the coordinated increasing of inactivation process in the cortex of both hemispheres. Degree of stability of the spatial structure of interregional interactions of different brain cortex areas (according to the analysis of average dispersion of crosscorrelation EEG relations) increases on falling asleep with the onset of stage I(A), but with the transition to the stage I(B) there is a significant increase of instability of values EEG crosscorrelation. With the deepening of sleep the subsequent decrease of the dispersion of EEG crosscorrelations in frontal cortex is revealed. During REM sleep the dispersion levels of inter-regional interactions increases as much as possible, especially for EEG crosscorrelations of posterotemporal and inferiofrontal parts of both hemispheres.

[Organisation of the hemisphere interaction in preschool children and in adults during mental speech production and speech perception].

The main goal of this study was to investigate reorganisation of the EEG systemic interactions spatial structure during mental speech production in preschool children: generating sentences from the set of words and generating words from the set of phonemes. In both cases, interhemisphere biopotential relations significantly increased as compared with the baseline (resting with closed eyes). Results of the EEG cross-correlation and coherent analyses showed that during verbal tasks marked intensification of hemisphere interaction was observed. High coefficients of statistic similarity between intercortical interactions patterns in adults and children during sentence and words generating were observed (SC = 0.71 & 0.62 respectively). Opposite to that, lesser coefficients of statistic similarity were observed between these two groups during grammar and semantic mistakes identification (SC < or = 0.50). According to this data we could expect a relatively high maturation level of central mechanisms which underlie the processes of speech production rather than mechanisms which underlie grammar and semantic mistakes identification in preschool children.

[Features of cortex areas system interactions in the left and right brain hemospheres during different human sleep stages].

The article is devoted to analysis of research brain biopotential field structure during different stages of natural night sleep in adults. The special attention is given to distinctions of the spatial organization of EEG interregional relations in the left and right hemispheres which are shown most strongly in the II and III sleep stages. The special role of frontal cortical areas in reorganization of brain system activity during falling asleep is highlighted. Essential strengthening of hemispherical interaction of cortex biopotentials fluctuations during falling asleep--a stage of I(B)--along with its reduction in central and occipital cortical areas is shown during a slow wave sleep (II--IV stage) versus wakefulness.

[Peculiarities of disorders of brain bioelectrical activity spatial-time organization in patients with different consciousness depression after severe head injury].

Specific changes of bioelectrical brain activity was found in 27 patients with different level of posttraumatic consciousness depression by the methods of crosscorrelation, coherence and factor analysis of EEG. The changes of activity of morphofunctional systems of intracerebral integrations were revealed partially by decreasing of unspecific activity from brainstem structures reflected with increasing of slow wave activity and decreasing of EEG coherence in alpha- and beta-range. Depression of system organization of interconnections of bioelectrical brain activity in frontal and occipital regions of both hemispheres was also detected, and testified about decreasing of intercortical and thalamocortical brain system action under brain dislocation. The changes of integrative brain system activity, provides interhemispheric interaction, had the specific characted. Our results propose a "facilitation" of activity of system, providing "direct" interhemispheric connections through corpus callosum and other commissural tracts of telencephalon as a sequel of mesodiencephalon structures depression with steady reciprocal, antiphase relations of slow weve activity in symmetrical areas of hemispheres in coma II patients. The data of our research had shown no complete disintegration of system brain activity in coma II patients in spite of consciousness and brainstem reflexes depression.

[Antihypertensive therapy optimization and endothelial function in patients with gout and chronic urate tubulointerstitial nephritis].

AIM: to characterize the markers of endothelial dysfunction and the effect of antihypertensive drugs on them in patients with chronic urate tubulointestinal nephritis (UTIN) and articular gout. SUBJECTS AND METHODS: The study enrolled 81 patients aged 39 to 59 years with gout and urate nephropathy. All the patients were diagnosed as having grade 1-2 arterial hypertension. A lower glomerular filtration rate (GFR) was noted in 49.9%; microalbuminuria (MAU) and elevated serum endothelin-1 (ET-1) levels were recorded in all the patients. Combination antihypertensive therapy based on the use of angiotensin-converting enzyme (ACE) inhibitors and/or an angiotensin II receptor blocker (ARB) in combination with calcium channel blockers was performed during 12 months. The time course of changes in blood pressure, the parameters of target organ lesion, and the markers of endothelial dysfunction were monitored. RESULTS: Before the study, all the examinees were found to have MAU and increased serum ET-1, which are regarded simultaneously as signs of renal lesion and as markers of endothelial function. A combination of an ACE inhibitor or an ARB could diminish albuminuria and reduce ET-1 concentrations, lower systolic and diastolic blood pressure significantly, and increase GFR. CONCLUSION: The patients with articular gout and chronic UTIN are observed to have signs of endothelial dysfunction eliminated by combination antihypertensive therapy.

[Ontogenetic formation of stereognosis brain mechanism (EEG study)].

In this study the age specificity of inter- and intrahemispheric relations during stereognostic task (tactile identification of predetermined chess-like pieces with right or left hand) in adults and children of 5-6, 7-8 an 9-10 years old is considered. The combined pattern of cortical interactions was revealed in adults. Its appeared in significant increasing (compared to baseline) of interhemispheric EEG relations along with increasing of system interactions of anterior and posterior cortex areas bioelectrical activity. This combined pattern is observed both in case of using EEG coherence and correlation analysis. In children interhemispheric EEG relations increasing is appeared already in 5-6 years (maximum in 7-8 yo.), whereas increasing of EEG relations in fronto-occipital direction expanses gradually with age, and only in age 9-10 approaches to definitive level, typical for adults. The data obtained evidence the gradually formation in postnatal ontogenesis of central mechanisms of such important function--stereognosis. Our results suppose that brain mechanisms of right (leading) hand stereognostic activity maturate earlier than left (nonleading) hand activity. Heterochronic involving in stereognostic activity of inter- and intrahemispheric relations can be closely related with gradual and heterochronic processes of commissural and associative hemispheric tracts mielinization.

[Endothelial function in patients with arterial hypertension and impaired uric acid metabolism].

The aim of the study was to investigate endothelial function in patients with arterial hypertension and impaired uric acid metabolism in comparison with patients having arterial hypertension and normal uric acid metabolism. 46 patients aged 32-56 yr with grade I-II AH were included in the study. A group of 36 patients (27 male, 9 female) presented with AH and impaired uric acid metabolism (hyperuricemia), the control group included 10 patients with AH and unaffected uric acid metabolism. Inclusion criteria in the two groups were identical. Endothelial dysfunction was documented in all patients and confirmed by increased levels of serum endothelin-1 and microalbuminuria, qualitative and quantitative changes in the intima-media complex and its thickening. These changes were much more pronounced in patients with hyperuricemia It is concluded that impaired uric acid metabolism in patients with AH leads to rapid onset and progression of endothelial dysfunction. This fact should be taken into consideration by doctors practicing antihypertensive treatment and for the evaluation of cardiovascular risks.

Functional activity of peritoneal macrophages from sensitive and resistant mouse strains during intravaginal infection with herpes simplex virus type 2 and mucosal vaccination.

In the early period after intravaginal infection with herpes simplex virus type 2 (2 h), macrophages from sensitive DBA/2 mice were characterized by higher capacity to engulf the antigen, decreased function of the lysosomal apparatus, lower activity of cathepsin D, and reduced oxygen metabolism compared to cells from resistant BALB/c mice. Mucosal vaccination with herpes vaccine and hyaluronic acid promoted the increase in functional activity of macrophages and improved survival of sensitive mice (by 60%).

[Use of laws of interelement interactions for understanding of mechanisms of various human diseases].

The review considers the basic laws of interaction of elements in real physiological conditions of metabolism. The law of replacement and two it consequences have been formulated taking into account a major principle of cybernetics, the feedback principle. A rule of a fractional threshold and the law of toxicity based on the Mertz's rules have been formulated. These laws have been used here for consideration of mechanisms of occurrence and development of apoptosis and also side-effects of statins. Study of bioinorganic mechanisms of different diseases is a erspective way for search of complex connections of metals and ligands, capable to interaction with initiators of chain reactions, and for a finding of substances--inhibitors these reactions.

[Transformation of carbonate minerals in a cyano-bacterial mat in the course of laboratory modeling].

A laboratory model of a cyano-bacterial mat with mineral layers of carbonates was used to examine the dynamics of the transformation of calcium-magnesium carbonate under the conditions of a soda lake. The activity of various organisms of the cyanobacterial community results in conditions under which the Ca-Mg carbonate precipitate undergoes changes. The crystal lattice of the initial carbonate is restructured; its mineralogical composition changes depending on the conditions of the mat. In magnesium calcites, which are formed under such low-temperature conditions, a rudimentary cation adjustment can occur with the formation of dolomite domains. These experiments confirm the hypothesis that the dolomite found in stromatolites is of a secondary origin and can be formed in the course of transformation of Ca-Mg carbonates under alkaline conditions in an alkaliphilic cyanobacterial community.