Audiogenic kindling activates glutamatergic system in the hippocampus of rats with genetic predisposition to audiogenic seizures.

Temporal lobe epilepsy (TLE) development is associated with dysregulation of glutamatergic transmission in the hippocampus; however, detailed molecular mechanisms of pathological changes are still poorly understood. In the present study, we performed the complex analysis of glutamatergic system in the hippocampus of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizures (AGS). Daily AGS stimulations (audiogenic kindling) were used to reproduce the dynamics of TLE development. Naïve KM rats were used as a control. After 14 AGS, at the stage of developing TLE, KM rats demonstrated significant upregulation of extracellular signal-regulated kinases (ERK) 1 and 2, cAMP response element-binding protein (CREB), and c-Fos in the hippocampus indicating activation of the hippocampal cells. These changes were accompanied with an increase in glutaminase and vesicular glutamate transporter (VGLUT) 2 suggesting the activation of glutamate production and loading into the synaptic vesicles. After 21 AGS, when TLE was fully-established, alterations were similar but more pronounced, with higher activation of glutaminase, increase in glutamate production, upregulation of VGLUT1 and 2, and Fos-related antigen 1 (Fra-1) along with c-Fos. Analysis of glutamate receptors showed variable changes. Thus, after 14 AGS, simultaneous increase in metabotropic glutamate receptor mGluR1 and decrease in ionotropic N-methyl-D-aspartate (NMDA) receptors could reflect compensatory anti-epileptic mechanism, while further kindling progression induced upregulation of ionotropic receptors, probably, contributing to the hippocampal epileptization. However, we revealed practically no alterations in the expression of synaptic proteins. Altogether, obtained results suggested that overactivation of glutamate production in the hippocampus strongly contributed to TLE development in KM rats.

Total expenditure elasticity of spending on self-treatment and professional healthcare: a case of Russia.

The studies on the demand for healthcare in low- and middle-income countries rarely take into consideration the fact that many people spend their income on self-treatment and professional treatment. The estimation of the income elasticity of demand for self-treatment and professional treatment can show a more precise picture of the affordability of professional care. This paper contributes to the discussion around estimates of income elasticity of health spending and discussion whether professional care and self-treatment are close to a luxury good and inferior good respectively in a middle-income country. We apply the switching regression model to explain the choice between self-treatment and professional healthcare via estimates of the income elasticity. Estimates are made with the use of the Russian Longitudinal Monitoring Survey - Higher School of Economics (RLMS-HSE), a nationally representative survey. While individual expenditure on professional treatment is higher than that on self-treatment, our estimates show that expenses on professional treatment can be income inelastic except when spending on medicines prescribed by a physician that are elastic. The results also indicate that cost of self-treatment is income elastic. In all cases, the considered income elasticities are statistically insignificant between professional and self-treatment.

Factors associated with psychological distress during the COVID-19 pandemic: Data from two early waves in Russia.

There is limited information about how the mental health of people has changed over time during the COVID-19 pandemic in low- and middle-income countries. In a cross-sectional study, we identified factors associated with psychological distress at two periods immediately after two peaks of the COVID-19 pandemic in Russia. Data were collected via online surveys. In May-June 2020, we surveyed 373 respondents across Russia. In January-February 2021, we surveyed 743 people, using the same approach for survey distribution. With Kessler-10 as a measure of psychological distress, we used regression analysis to determine factors associated with higher psychological distress among Russians. Levels of psychological distress were high in both time periods and did not significantly change between the surveys. Having had COVID-19, losing one's job, experiencing problems accessing healthcare, and changing drinking behaviour during the pandemic were associated with higher psychological distress. Apart from getting sick or worrying about the virus, psychological distress is affected by restrictions and the consequences of the pandemic situation. As the COVID-19 pandemic continues, actions are needed to address the mental well-being of the population in Russia.

Regulatory Elements Outside Established Pou5f1 Gene Boundaries Are Required for Multilineage Differentiation of Embryonic Stem Cells.

The transcription factor Oct4 can rightfully be considered a pivotal element in maintaining pluripotency. In addition, its ability to function as a pioneer factor enables the reprogramming of somatic cells back into a pluripotent state. To better understand the regulation of the Oct4-encoding gene (Pou5f1), the main genetic elements that regulate its expression in different states of pluripotency ought to be identified. While some elements have been well characterized for their ability to drive Pou5f1 expression, others have yet to be determined. In this work, we show that translocation of the Pou5f1 gene fragment purported to span all essential cis-elements, including the well-known distal and proximal enhancers (DE and PE), into the Rosa26 locus impairs the self-renewal of mouse embryonic stem cells (ESCs) in the naïve pluripotency state, as well as their further advancement through the formative and primed pluripotency states, inducing overall differentiation failure. These results suggest that regulatory elements located outside the previously determined Pou5f1 boundaries are critical for the proper spatiotemporal regulation of this gene during development, indicating the need for their better characterization.

First population norms for the EQ-5D-3L in the Russian Federation.

PURPOSE: The EQ-5D survey instrument is routinely applied to general and patient specific populations in many countries, as a means of measuring Health Related Quality of Life (HRQOL) and/or informing Health Technology Assessment. The instrument is the subject of growing interest in the Russian Federation, as too is Health Technology Assessment. This research is the first to systematically present the EQ-5D-3L nationally representative population norms and to examine the socioeconomic and socio-demographic characteristics of the instrument among a representative sample of the Russian population. METHODS: Based on a nationally representative health and well-being survey of the Russian population, conducted in November 2017, we establish the descriptive results, including the EQ-VAS and the EQ-5D Index, by age and gender, examine the correspondence between the EQ-5D health classifications and the separate EQ-VAS scores, and draw on a set of augmented logistic regressions to evaluate the association between the presence of problems in each dimension and various socio-economic and health-related characteristics. RESULTS: We find strong evidence that the EQ-5D instrument is sensitive to underlying observed and latent health experiences, that it mirrors many of the characteristics familiar from other settings but that there are Russian specificities which merit further research, particularly with respect to the anxiety/depression dimension of the instrument. CONCLUSION: This research represents an important landmark for HRQOL studies in Russia as well as for the prospects of continuing to develop the scholarly and practical infrastructure necessary for Russian Health Technology Assessment to advance.

Membrane Permeability of Modified Butyltriphenylphosphonium Cations.

The alkyltriphenylphosphonium (TPP) group is the most widely used vector targeted to mitochondria. Previously, the length of the alkyl linker was varied as well as structural modifications in the TPP phenyl rings to obtain the optimal therapeutic effect of a pharmacophore conjugated with a lipophilic cation. In the present work, we synthesized butyltriphenylphosphonium cations halogenated and methylated in phenyl rings (C4TPP-X) and measured electrical current through a planar lipid bilayer in the presence of C4TPP-X. The permeability of C4TPP-X varied in the range of 6 orders of magnitude and correlates well with the previously measured translocation rate constant for dodecyltriphenylphosphonium analogues. The partition coefficient of the butyltriphenylphosphonium analogues obtained by calculating the difference in the free energy of cation solvation in water and octane using quantum chemical methods correlates well with the permeability values. Using an ion-selective electrode, a lower degree of accumulation of analogues with halogenated phenyl groups was found on isolated mitochondria of rat liver, which is in agreement with their permeability decrease. Our results indicate the translocation of the butyltriphenylphosphonium cations across the hydrophobic membrane core as rate-limiting stage in the permeability process rather than their binding/release to/from the membrane.

Health Behaviors During the COVID-19 Epidemic: Perspectives From Studying International Coping and Compliance.

Control of the COVID-19 pandemic requires significant changes in people's health behaviors. We offer this multidisciplinary perspective on the extent of compliance with social distancing recommendations and on coping with these measures around the globe in the first months of the pandemic. We present descriptive data from our survey of 17,650 respondents across 18 countries and territories in June 2020. The majority of respondents worried about contracting the virus. Nearly all engaged in at least some preventive behaviors, particularly handwashing, mask wearing, and avoiding social events. Most reported that it would be difficult to continue these behaviors for more than a few months, and about half reported feeling more anxious since the start of the pandemic. Commonly reported coping behaviors included news consumption, watching television, and sleeping. Our cross-national study highlights areas for developing and implementing health behavior interventions in the global fight to stop the spread of COVID-19.

Audiogenic kindling stimulates aberrant neurogenesis, synaptopodin expression, and mossy fiber sprouting in the hippocampus of rats genetically prone to audiogenic seizures.

Temporal lobe epilepsy is associated with considerable structural changes in the hippocampus. Pharmacological and electrical models of temporal lobe epilepsy in animals strongly suggest that hippocampal reorganization is based on seizure-stimulated aberrant neurogenesis but the data are often controversial and hard to interpret. The aim of the present study was to estimate neurogenesis and synaptic remodeling in the hippocampus of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizures (AGS). In our experiments we exposed KM rats to audiogenic kindling of different durations (4, 14, and 21 AGS) to model different stages of epilepsy development. Naïve KM rats were used as a control. Our results showed that even 4 AGS stimulated proliferation in the subgranular layer of the dentate gyrus (DG) accompanied with increase in number of doublecortin (DCX)-positive immature granular cells. Elevated number of proliferating cells was also observed in the hilus indicating the enhancement of abnormal migration of neural progenitors. In contrast to the DG, all DCX-positive cells in the hilus expressed VGLUT1/2 and their number was increased indicating that seizure activity accelerates glutamatergic differentiation of ectopic hilar cells. 14-day kindling further stimulated proliferation, abnormal migration, and glutamatergic differentiation of new neurons both in the DG granular and subgranular layers and in the hilus. However, after 21 AGS increased proliferation was observed only in the DG, while the numbers of immature neurons expressed VGLUT1/2 were still enhanced in both hippocampal areas. Audiogenic kindling also stimulated sprouting of mossy fibers and enhanced expression of synaptopodin in the hippocampus indicating generation of new synaptic contacts between granular cells, mossy cells, and CA3 pyramid neurons. Thus, our data suggest that epilepsy progression is associated with exacerbation of aberrant neurogenesis and reorganization of hippocampal neural circuits that contribute to the enhancement and spreading of epileptiform activity.

Voluntary private health insurance, health-related behaviours and health outcomes: evidence from Russia.

This paper contributes to the discussion around ex-post (increased utilisation of health care) and ex-ante (changes in health behaviours) moral hazard in supplemental private health insurance. Applying a range of methodologies to data from the Russian Longitudinal Monitoring Survey-Higher School of Economics we exploit a selection mechanism in the data to compare the impact of workplace provided and individually purchased supplemental health insurance on the utilisation of health care, on a range of health behaviours and on self-assessed health. We find compelling policy-relevant evidence of ex-post moral hazard that confirms a theoretical prediction and empirical regularity found in other settings. In contrast to other empirical findings though, our data reveals evidence of ex-ante moral hazard demonstrated by clear behavioural differences between those with self-funded supplemental health insurance and those for whom the workplace finances the additional insurance. We find no evidence that either form of insurance is related to improved self-assessed health.

Lipophilic ion aromaticity is not important for permeability across lipid membranes.

To clarify the contribution of charge delocalization in a lipophilic ion to the efficacy of its permeation through a lipid membrane, we compared the behavior of alkyl derivatives of triphenylphosphonium, tricyclohexylphosphonium and trihexylphosphonium both in natural and artificial membranes. Exploring accumulation of the lipophilic cations in response to inside-negative membrane potential generation in mitochondria by using an ion-selective electrode revealed similar mitochondrial uptake of butyltricyclohexylphosphonium (C4TCHP) and butyltriphenylphosphonium (C4TPP). Fluorescence correlation spectroscopy also demonstrated similar membrane potential-dependent accumulation of fluorescein derivatives of tricyclohexyldecylphosphonium and decyltriphenylphosphonium in mitochondria. The rate constant of lipophilic cation translocation across the bilayer lipid membrane (BLM), measured by the current relaxation method, moderately increased in the following sequence: trihexyltetradecylphosphonium ([P6,6,6,14]) < triphenyltetradecylphosphonium (C14TPP) < tricyclohexyldodecylphosphonium (C12TCHP). In line with these results, measurements of the BLM stationary conductance indicated that membrane permeability for C4TCHP is 2.5 times higher than that for C4TPP. Values of the difference in the free energy of ion solvation in water and octane calculated using the density functional theory and the polarizable continuum solvent model were similar for methyltriphenylphosphonium, tricyclohexylmethylphosphonium and trihexylmethylphosphonium. Our results prove that both cyclic and aromatic moieties are not necessary for lipophilic ions to effectively permeate through lipid membranes.

Investigation of Salmonella enteritidis outbreak in four kindergartens.

In June 2018, in the city of Sofia, Bulgaria, 40 children from four different kindergartens suffered from salmonellosis caused by S. enteritidis. They were reported to have consumed food prepared and delivered by a private catering service. The patients had fever, diarrhea, and some had vomiting and abdominal pain. Sixteen of them were treated in hospital, and the other 24 received home treatment. Some of the outpatients received antibiotic treatment despite WHO recommendations. All 40 isolates were positive for O: D, H: gm and H: m, and were confirmed to be Salmonella enteritidis, respectively. Using conventional and molecular methods, such as serotyping, Multiplex-PCR and PFGE, it was confirmed that the strains were epidemiologically related. Based on molecular genetic methods, we established that the epidemic outbreak had a common origin: contaminated food delivered by a private catering service, which was consumed at all four kindergartens.