series of analogues of potent antiviral perylene nucleoside dUY11 with methylthiomethyl (MTM), azidomethyl (AZM) and HO-C1e4-alkyl-1,2,3-triazol-1,4-diyl groups at 30-O-position as well as the two products of copper-free alkyne-azide cycloaddition of the AZM derivative were prepared and evaluated against tick-borne encephalitis virus (TBEV). Four compounds (4, 6, 8a, 8b) showed EC50 10 nM, thus appearing the most potent TBEV inhibitors to date. Moreover, these nucleosides have higher lipophilicity (clogP) and increased solubility in aq. DMSO vs. parent compound dUY11.
This paper considers the problem of abortion in modern Russia. Using official statistics, we analyze the dynamics of abortion indicators since the early 1990s. On the basis of representative national sample surveys, we conclude that official statistics are complete and reliable. This in turn confirms the steady decline of abortions during the post-Soviet years.
A particularly rapid decline in abortions is seen among the youngest women. Modern teenagers have fewer abortions than their predecessors at this age. The current level of induced abortions in women under age 20 in Russia today is less than in France, Great Britain, Sweden, and a number of other developed countries of European culture.
The major differentiating factor for frequency of abortion is age. There are no clear correlations between the risks of abortion in Russia and such standard social characteristics as income, type of settlement and education. Despite the positive trend, Russia remains one of the countries with the highest abortion rates in the world.
The country’s turn to traditional values and the allegedly growing role of religion are inadequate mechanisms to reduce abortions. Government support is given not to proven, evidence-based measures like the promotion of family planning, sex education, etc., but to repression and restrictions. During the past 10-15 years, a number of restrictive amendments have been introduced into legislation. The authors indicate the counterproductive effects of these restrictions on abortion as an instrument of a pronatalist population policy.
In practical medicine, a diagnostic procedure is used only when it can be interpreted at the individual level. The aim of this work was to systematically investigate the relative and absolute reliability of different TMS motor maps parameters. 18 young healthy male right-handed volunteers were enrolled. Two TMS motor mapping sessions of three right-hand muscles were separated by 6-10 days. The analysis was performed using TMSmap software (http://tmsmap.ru). For reliability assessment, intra-class correlation coefficient (ICC) and smallest detectable changes (SDC) were calculated, while for quantitative comparison of the excitability profiles we used a novel earth mover's distance metrics (EMD), the convergence of the parameters depending on the number of stimuli was estimated.
Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR−/−; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differentially expressed between DKO and WT hearts implicating 72 pathways. Hallmarks of metabolic cardiomyopathy were increased activity in integrin-linked kinase signalling, Rho signalling, dendritic cell maturation, production of nitric oxide and reactive oxygen species in macrophages, atherosclerosis, LXR-RXR signalling, cardiac hypertrophy, and acute phase response pathways. ACE-inhibition had a limited effect on gene expression in WT (55 genes, 23 pathways), and a prominent effect in DKO hearts (1143 genes, 104 pathways). In DKO hearts, ACE-I appears to counteract some of the MetS-specific pathways, while also activating cardioprotective mechanisms. We conclude that MetS and control murine hearts have unique transcriptional profiles and exhibit a partially specific transcriptional response to ACE-inhibition.
Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.
A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)–thalamocortical (TC) network, more specifically on CT 5–9-Hz and TC spindle (10–16-Hz) oscillations. Two to three successive 5–9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5–9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5–9-Hz depolarizing wave–hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately −70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5–9-Hz waves can trigger TC spindles.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue-cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR-122 falls, while the secretion of miRNA-containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver-supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease-associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR-122 and, possibly, some other miRNAs may be efficient for preventing NAFLD-associated hepatocellular carcinoma. The best candidates for exosome-wrapped miRNA producer are adipose tissue-derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC-derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co-manufactured along with their cargo. Exosome-delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue‐cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR‐122 falls, while the secretion of miRNA‐containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver‐supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease‐associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR‐122 and, possibly, some other miRNAs may be efficient for preventing NAFLD‐associated hepatocellular carcinoma. The best candidates for exosome‐wrapped miRNA producer are adipose tissue‐derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC‐derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co‐manufactured along with their cargo. Exosome‐delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.
The adoption of new medical technologies often generates losses in efficiency associated with the excess or insufficient acquisition of new equipment, an inappropriate choice (in terms of economic and clinical parameters) of medical equipment, and its poor use. Russia is a good example for exploring the problem of the ineffective adoption of new medical technologies due to the massive public investment in new equipment for medical institutions in 2006–2013. This study examines the procurement of new technologies in Russian hospitals to find the main causes of inefficiency. The research strategy was based on in-depth semistructured interviews with representatives of prominent actors (regional health care authorities, hospital executives, senior physicians). The main result is that inefficiencies arise from the contradiction between hospitals’ and authorities’ motivation for acquiring new technologies: hospitals tend to adopt technologies which bring benefits to their department heads and physicians and minimize maintenance and servicing costs, while the authorities’ main concern is the initial cost of the technology.
The paper analyzes the impact of nighttime alcohol trade restrictions in regions of Russia on the consumption of alcoholic beverages. Evaluation has been carried out based on the regional Rosstat data and individual data of the Russia Longitudinal Monitoring Survey by the HSE for 2009–2010. Econometric analysis has revealed a positive correlation between the amount of consumed alcohol and the duration of the allowed time for alcohol sales in the region. In addition, it has been found that night restrictions are more efficient than morning restrictions in the context of a decrease in alcohol consumption. The obtained results indicate the expediency of further tightening of the restrictive policy.
The present study reports alterations of task-based functional brain connectivity in a group of 11 cosmonauts after a long-duration spaceflight, compared to a healthy control group not involved in the space program. To elicit the postural and locomotor sensorimotor mechanisms that are usually most significantly impaired when space travelers return to Earth, a plantar stimulation paradigm was used in a block design fMRI study. The motor control system activated by the plantar stimulation involved the pre-central and post-central gyri, SMA, SII/operculum, and, to a lesser degree, the insular cortex and cerebellum. While no post-flight alterations were observed in terms of activation, the network-based statistics approach revealed task-specific functional connectivity modifications within a broader set of regions involving the activation sites along with other parts of the sensorimotor neural network and the visual, proprioceptive, and vestibular systems. The most notable findings included a post-flight increase in the stimulation-specific connectivity of the right posterior supramarginal gyrus with the rest of the brain; a strengthening of connections between the left and right insulae; decreased connectivity of the vestibular nuclei, right inferior parietal cortex (BA40) and cerebellum with areas associated with motor, visual, vestibular, and proprioception functions; and decreased coupling of the cerebellum with the visual cortex and the right inferior parietal cortex. The severity of space motion sickness symptoms was found to correlate with a post- to pre-flight difference in connectivity between the right supramarginal gyrus and the left anterior insula. Due to the complex nature and rapid dynamics of adaptation to gravity alterations, the post-flight findings might be attributed to both the long-term microgravity exposure and to the readaptation to Earth’s gravity that took place between the landing and post-flight MRI session. Nevertheless, the results have implications for the multisensory reweighting and gravitational motor system theories, generating hypotheses to be tested in future research.
Background: We present a method for reclassifying external causes of death categorized as “event of undetermined intent” (EUIs) into non-transport accidents, suicides, or homicides. In nations like Russia and the UK the absolute number of EUIs is large, the EUI death rate is high, or EUIs comprise a non-trivial proportion of all deaths due to external causes. Overuse of this category may result in (1) substantially underestimating the mortality rate of deaths due to specific external causes and (2) threats to the validity of studies of the patterns and causes of external deaths and of evaluations of the impact of interventions meant to reduce them.
Methods: We employ available characteristics about the deceased and the event to estimate the most likely cause of death using multinomial logistic regression. We use the set of known non-transport accidents, suicides, and homicides to calculate an mlogit-based linear score and an estimated classification probability (ECP). This ECP is applied to EUIs, with varying levels of minimal classification probability. We also present an optional second step that employs a population-level adjustment to reclassify deaths that remain undetermined (the proportion of which varies based on the minimal classification probability). We illustrate our method by applying it to Russia. Between 2000 and 2011, 521,000 Russian deaths (15 % percent of all deaths from external causes) were categorized as EUIs. We used data from anonymized micro-data on the ~3 million deaths from external causes. Our reclassification model used 10 decedent and event characteristics from the computerized death records.
Results: Results show that during this period about 14 % of non-transport accidents, 13 % of suicides, and 33 % of homicides were officially categorized as EUIs. Our findings also suggest that 2011 levels of non-transport accidents and suicides would have been about 24 % higher and of homicide about 82 % higher than that reported by official vital statistics data.
Conclusions: Overuse of the external cause of death classification “event of undetermined intent” may indicate questionable quality of mortality data on external causes of death. This can have wide-ranging implications for families, medical professionals, the justice system, researchers, and policymakers. With our classification probability set as equal to or higher than 0.75, we were able to reclassify about two-thirds of EUI deaths in our sample. Our optional additional step allowed us to redistribute the remaining unclassified EUIs. Our method can be applied to data from any nation or sub-national population in which the EUI category is employed.
Brazil, Russia, India, China, and South Africa (BRICS) represent almost half the world's population, and all five national governments recently committed to work nationally, regionally, and globally to ensure that universal health coverage (UHC) is achieved. This analysis reviews national efforts to achieve UHC. With a broad range of health indicators, life expectancy (ranging from 53 years to 73 years), and mortality rate in children younger than 5 years (ranging from 10·3 to 44·6 deaths per 1000 livebirths), a review of progress in each of the BRICS countries shows that each has some way to go before achieving UHC. The BRICS countries show substantial, and often similar, challenges in moving towards UHC. On the basis of a review of each country, the most pressing problems are: raising insufficient public spending; stewarding mixed private and public health systems; ensuring equity; meeting the demands for more human resources; managing changing demographics and disease burdens; and addressing the social determinants of health. Increases in public funding can be used to show how BRICS health ministries could accelerate progress to achieve UHC. Although all the BRICS countries have devoted increased resources to health, the biggest increase has been in China, which was probably facilitated by China's rapid economic growth. However, the BRICS country with the second highest economic growth, India, has had the least improvement in public funding for health. Future research to understand such different levels of prioritisation of the health sector in these countries could be useful. Similarly, the role of strategic purchasing in working with powerful private sectors, the effect of federal structures, and the implications of investment in primary health care as a foundation for UHC could be explored. These issues could serve as the basis on which BRICS countries focus their efforts to share ideas and strategies.
The volume fraction of water related to myelin (fmy) is a promising MRI index for in vivo assessment of brain myelination, that can be derived from multi-component analysis of T1 and T2 relaxometry signals. However, existing quantification methods require rather long acquisition and/or post-processing times, making implementation difficult both in research studies on healthy unsedated children and in clinical examinations. The goal of this work was to propose a novel strategy for fmy quantification within acceptable acquisition andpost-processing times. Our approach is based on a 3-compartment model (myelin-related water, intra/extra-cellular water and unrestricted water), and uses calibrated values of inherent relaxation times (T1c and T2c) for each compartment c. Calibration was first performed on adult relaxometry datasets (N = 3) acquired with large numbers of inversion times (TI) and echo times (TE), using an original combination of a region contraction approach and a non-negative least-square (NNLS) algorithm. This strategy was compared with voxel-wise fitting, and showed robust estimation of T1c and T2c. The accuracy of fmy calculations depending on multiple factors was investigated using simulated data. In the testing stage, our strategy enabled fast fmy mapping, based on relaxometry datasets acquired with reduced TI and TE numbers (acquisition <6 min), and analyzed with NNLS algorithm (post-processing <5min). In adults (N = 13, mean age 22.4±1.6 years), fmy maps showed variability across white matter regions, in agreement with previous studies. In healthy infants (N = 18, aged 3 to 34 weeks), asynchronous changes in fmy values were demonstrated across bundles, confirming the well-known progression of myelination.
-We study an epidemic propagation between M popuilation centra. The novelty of the model lies in the explicit analysis of the dynamics of host (remaining nin the same cemtre) and guest (migrated from another centre) population separately.
Research on existing drugs often discovers novel mechanisms of their action and leads to the expansion of their therapeutic scope and subsequent remarketing. The Wnt signaling pathway is of the immediate therapeutic relevance, as it plays critical roles in cancer development and progression. However, drugs which disrupt this pathway are unavailable despite the high demand. Here we report an attempt to identify antagonists of the Wnt-FZD interaction among the library of the FDA-approved drugs. We performed an in silico screening which brought up several potential antagonists of the ligand-receptor interaction. 14 of these substances were tested using the TopFlash luciferase reporter assay and four of them identified as active and specific inhibitors of the Wnt3a-induced signaling. However, further analysis through GTP-binding and beta-catenin stabilization assays showed that the compounds do not target the Wnt-FZD pair, but inhibit the signaling at downstream levels. We further describe the previously unknown inhibitory activity of an anti-leprosy drug clofazimine in the Wnt pathway and provide data demonstrating its efficiency in suppressing growth of Wnt-dependent triple-negative breast cancer cells. These data provide a basis for further investigations of the efficiency of clofazimine in treatment of Wnt-dependent cancers. (C) 2013 Elsevier Inc. All rights reserved.
The phenoxazine scaffold is widely used to stabilize nucleic acid duplexes, as a part of fluorescent probes for the study of nucleic acid structure, recognition, and metabolism, etc. Here we present the synthesis of phenoxazine-based nucleoside derivatives and their antiviral activity against a panel of structurally diverse viruses: enveloped DNA herpesviruses varicella zoster virus (VZV) and human cytomegalovirus, enveloped RNA tick-borne encephalitis virus (TBEV), and non-enveloped RNA enteroviruses. Studied compounds were effective against DNA and RNA viruses reproduction in cell culture. 3-(2′-Deoxy-β-D-ribofuranosyl)-1,3-diaza-2-oxophenoxazine proved to be a potent inhibitor of VZV replication with superior activity against wild type than thymidine kinase deficient strains (EC50 0.06 and 10 μM, respectively). This compound did not show cytotoxicity on all the studied cell lines. Several compounds showed promising activity against TBEV (EC50 0.35–0.91 μM), but the activity was accompanied by pronounced cytotoxicity. These compounds may be considered as a good starting point for further structure optimization as antiherpesviral or antiflaviviral compounds.
Most antivirals target viral proteins and are specific for only one virus, or viral type. Whereas viral proteins are encoded in the plastic viral genome, virion lipids are not and their rearrangements during fusion are conserved among otherwise unrelated enveloped viruses. Antivirals that inhibit these lipid rearrangements could thus pose a high barrier to resistance and have broad-spectrum activity. Fusion occurs through a hemifusion stalk in which only the outer leaflets are fused and thus curved with a smaller radius for the polar heads than for the hydrophobic tails (negative curvature). Outer leaflets enriched in phospholipids with head groups of larger cross sections than their lipid tails (“inverted cone”) disfavor negative curvature, inhibiting fusion. The rigid amphipathic fusion inhibitors (RAFIs) are synthetic compounds of inverted cone molecular geometry. They inhibit infectivity of otherwise unrelated enveloped viruses. The leading RAFI, aUY11, has an ethynyl-perylene hydrophobic and an uracil-arabinose polar moiety. aUY11 intercalates in viral envelopes and inhibits virion-to-cell fusion of a broad spectrum of otherwise unrelated enveloped viruses. Previous studies showed that amphipathicity, rigidity, and inverted cone molecular geometry were required. We propose that the inverted cone molecular geometry of the RAFIs increases the energy barrier for the hemifusion stalk, inhibiting fusion. Then, chemically distinct compounds with similar amphipathicity, rigidity, and inverted cone shape would have similar antiviral potencies, regardless of specific chemical groups. Alternatively, the perylene group exposed to visible light may induce viral lipid peroxidation. Then, the perylene group and absorbance at visible spectrum would be required. We now evaluated twenty-five chemically distinct RAFIs. The perylene moiety and absorption at visible spectrum were not required, but a minimum length of the hydrophobic moiety was, 10.3 Å. The arabino moiety could be modified or replaced by other groups. Cytidine was not tolerated. Bilayer intercalation was required but not sufficient. The vast majority of RAFIs had no overt cytotoxicity (CC50 > 20 μM; TI > 250–1200). Carbonyl or butylamide substitutions for arabino, or cytidine replacement for uracil, increased cytotoxicity. Cytotoxicity was mainly determined by the polar moiety and there was no correlation between antiviral and cytostatic activities. The definition of the effects of shape and chemical groups of the RAFIs opens the possibility to the rational design of lipid-acting antivirals active against a broad spectrum of enveloped viruses.
Recovery after stroke relates tightly to the white matter integrity. Currently, the main methodology for non-invasive white matter integrity assessment is diffusion-weighted magnetic resonance imaging (DW-MRI), a state-of-the-art approach which is, however, prone to multiple limitations. Using DW-MRI, it was demonstrated that many pathways including corticospinal tract (CST) and corpus callosum contribute to structural brain reserve after stroke, but only a few of these tracts were found to be useful in the clinical practice. The most widely known measure is an asymmetry of the fractional anisotropy (FA) in CST at the level of the internal capsule, which could be used for predicting motor recovery in acute stroke. Recently, a new complementary motor component of the structural reserve, the so-called alternate motor fibers (AMFs), was proposed for motor recovery prognosis in stroke patients, and it was even reported to correlate with the effect of the transcranial direct current stimulation in chronic stroke. Here, we would like to point out a possible additional sensory interpretation of the AMF that appears plausible after taking into account technical limitations of DW-MRI approach, which may potentially give rise to different interpretations of the same results.
The article discusses the comparative evaluation of combined treatment results in patients with DTC (differentiated thyroid cancer) at different levels of TSH-stimulated prior to RAI (radioactive iodine) treatment. The study included 197 patients (36 female, 161 male) of the age group 18-75 years with a mean age of 47 years. The data was analyzed using several statistical methods: analysis of variance (ANOVA), linear and logistic regression models. The resulting data from the analysis showed that there was no statistically significant association between serum TSH levels prior to RAI and DTC remission.