Previous research indicates that, under explicit instructions to listen to spoken stimuli or in speech-oriented behavioural tasks, the brain's responses to senseless pseudowords are larger than those to meaningful words; the reverse is true in non-attended conditions. These differential responses could be used as a tool to trace linguistic processes in the brain and their interaction with attention. However, as previous studies relied on explicit instructions to attend or ignore the stimuli, a technique for automatic attention modulation (i.e., not dependent on explicit instruction) would be more advantageous, especially when cooperation with instructions may not be guaranteed (e.g., neurological patients, children etc). Here we present a novel paradigm in which the stimulus context automatically draws attention to speech. In a non-attend passive auditory oddball sequence, rare words and pseudowords were presented among frequent non-speech tones of variable frequency and length. The low percentage of spoken stimuli guarantees an involuntary attention switch to them. The speech stimuli, in turn, could be disambiguated as words or pseudowords only in their end, at the last phoneme, after the attention switch would have already occurred. Our results confirmed that this paradigm can indeed be used to induce automatic shifts of attention to spoken input. At ~250ms after the stimulus onset, a P3a-like neuromagnetic deflection was registered to spoken (but not tone) stimuli indicating an involuntary attention shift. Later, after the word-pseudoword divergence point, we found a larger oddball response to pseudowords than words, best explained by neural processes of lexical search facilitated through increased attention. Furthermore, we demonstrate a breakdown of this orderly pattern of neurocognitive processes as a result of sleep deprivation. The new paradigm may thus be an efficient way to assess language comprehension processes and their dynamic interaction with those of attention allocation. It does it in an automatic and task-free fashion, indicating its potential benefit for assessing uncooperative clinical populations.
Although schizophrenia was previously associated with affected spatial neuronal synchronization, surprisingly little is known about the temporal dynamics of neuronal oscillations in this disease. However, given that the coordination of neuronal processes in time represents an essential aspect of practically all cognitive operations, it might be strongly affected in patients with schizophrenia. In the present study we aimed at quantifying long-range temporal correlations (LRTC) in patients (18 with schizophrenia; 3 with schizoaffective disorder) and 28 healthy control subjects matched for age and gender. Ongoing neuronal oscillations were recorded with multi-channel EEG at rest condition. LRTC in the range 5-50s were analyzed with Detrended Fluctuation Analysis. The amplitude of neuronal oscillations in alpha and beta frequency ranges did not differ between patients and control subjects. However, LRTC were strongly attenuated in patients with schizophrenia in both alpha and beta frequency ranges. Moreover, the cross-frequency correlation between LRTC belonging to alpha and beta oscillations was stronger for patients than healthy controls, indicating that similar neurophysiological processes affect neuronal dynamics in both frequency ranges. We believe that the attenuation of LRTC is most likely due to the increased variability in neuronal activity, which was previously hypothesized to underlie an excessive switching between the neuronal states in patients with schizophrenia. Attenuated LRTC might allow for more random associations between neuronal activations, which in turn might relate to the occurrence of thought disorders in schizophrenia.
To address the hotly debated question of motor system involvement in language comprehension, we recorded neuromagnetic responses elicited in the human brain by unattended action-related spoken verbs and nouns and scrutinized their timecourse and neuroanatomical substrates. We found that already very early on, from ∼80 ms after disambiguation point when the words could be identified from the available acoustic information, both verbs and nouns produced characteristic somatotopic activations in the motor strip, with words related to different body parts activating the corresponding body representations. Strikingly, along with this category-specific activation, we observed suppression of motor-cortex activation by competitor words with incompatible semantics, documenting operation of the neurophysiological principles of lateral/surround inhibition in neural word processing. The extremely early onset of these activations and deactivations, their emergence in the absence of attention, and their similar presence for words of different lexical classes strongly suggest automatic involvement of motor-specific circuits in the perception of action-related language.
Russia has consistently been among those countries with a high level of alcohol intake and, according to the WHO, the most dangerous model of consumption. Recently, the government turned to more radical instruments of anti-alcohol policy. In 2010, 72 of 83 Russian regions had adopted a ban on all alcoholic beverages, except beer, during various night hours, although 11 regions had not. Using this case as a natural experiment we aim to determine how these new temporal restrictions influence alcohol consumption. We use official statistical data on regional alcohol sales provided by Rosstat and micro-data from the RLMS-HSE survey. Two methods are combined: descriptive analysis of per capita alcohol sales at the regional level and regression analysis of pure spirit consumption at the individual level, controlling for various socioeconomic factors, including sales bans.
We revealed a significant positive correlation between the amount of alcohol consumed and the number of hours of allowed alcohol sales when other factors were controlled. The results gained from analyzing the micro-data were confirmed using the regional sales information. In terms of drinking reduction, sales restrictions in the evening hours seem more efficient than restrictions in the morning hours. Temporal sales bans do not increase beer or home-distilled alcohol consumption. Temporal bans on alcohol sales in Russian regions have the potential to reduce consumption levels. These findings indicate a need for a further reduction in sales hours in the regions where heavy drinking is especially widespread.
Russia has a large HIV epidemic, but medical care engagement is low. Eighty HIV-positive persons in St. Petersburg completed in-depth interviews to identify barriers and facilitators of medical HIV care engagement. The most commonly-reported barriers involved difficulties accessing care providers, dissatisfaction with the quality of services, and negative attitudes of provider staff. Other barriers included not having illness symptoms, life stresses, low value placed on health, internalized stigma and wanting to hide one's HIV status, fears of learning about one's true health status, and substance abuse. Care facilitators were feeling responsible for one's health and one's family, care-related support from other HIV-positive persons, and the onset of health decline and fear of death. Substance use remission facilitated care engagement, as did good communication from providers and trust in one's doctor. Interventions are needed in Russia to address HIV care infrastructural barriers and integrate HIV, substance abuse, care, and psychosocial services.
Our aim is to model the frequency of certain behavioral acts, especially those that are likely to transmit communicable diseases between persons. We develop a generalized linear model based on the beta prime distribution to model the responses to a survey question of the form, “When was the last time that you engaged in this behavior?” Intuitively, individuals reporting more recent events are more likely to have greater frequency of the risky behavior. The beta prime distribution is especially suited to this application because of its long tail. We adjust for length-biased sampling. We show how to use this distribution as the basis of a linear regression model that accounts for differences in demographic and psychological characteristics of the respondents. We discuss estimation of parameters, residuals, tests for heterogeneity of these parameters, and jackknife measures of influence. The methods are applied to a survey of alcohol abuse use among individuals who are at high risk for spreading HIV and other communicable diseases in a study conducted in St. Petersburg, Russia.
Purpose: To compare the prognostic significance of blood urea nitrogen (BUN) versus creatinine levels for estimating the risk of death in patients with acute coronary syndrome (ACS). Methods and results: A prospective study of all patients admitted with suspected (n=1613) and retrospectively confirmed (n=54) myocardial infarction or unstable angina was conducted. The ROC analysis established that the area under the curve for BUN was higher than that of creatinine: 0.76 (95% CI 0.70 to 0.82) and 0.69 (95% CI 0.63 to 0.76), respectively (p=0.005). The threshold level (that maximised the combined sensitivity and specificity) was 8.8 mmol/l for BUN and 110 mcmol/l for creatinine. Sensitivity (true positive cases) was 60% and 55% for threshold levels of BUN and creatinine, respectively, and specificity (true negative cases) was 82% and 77%, respectively. An increase of only BUN levels and a combination of increased BUN and creatinine levels, but not isolated hypercreatinaemia, proved to be the independent risk factors of death from ACS. Separate inclusion of BUN and creatinine as continuous variables in the regression model showed that both were associated with the risk of death: OR 1.22 (95% CI 1.17 to 1.28) and 1.016 (95% CI 1.011 to 1.021) per unit increase (R=14.5 and 8.4%, respectively). When both were simultaneously included, only an increased BUN level was pertinent to the prognosis of ACS: OR after multivariate adjustment 1.17 (95% CI 1.08 to 1.27). Conclusion: An increased level of BUN is a more significant risk factor for ACS outcomes than that of creatinine.
Reading utilises at least two neural pathways. The temporal lexical route visually maps whole words to their lexical entries, whilst the nonlexical route decodes words phonologically via parietal cortex. Readers typically employ the lexical route for familiar words, but poor comprehension plus precocity at mechanically 'sounding out' words suggests that differences might exist in autism. Combined MEG/EEG recordings of adults with autistic spectrum conditions (ASC) and controls while reading revealed preferential recruitment of temporal areas in controls and additional parietal recruitment in ASC. Furthermore, a lack of differences between semantic word categories was consistent with previous suggestion that people with ASC may lack a 'default' lexical-semantic processing mode. These results are discussed with reference to dual-route models of reading.
Long-duration spaceflight induces detrimental changes in human physiology. Its residual effects and mechanisms remain unclear. We prospectively investigated the changes in cerebrospinal fluid (CSF) volume of the brain ventricular regions in space crew by means of a region of interest analysis on structural brain scans. Cosmonaut MRI data were investigated preflight (n = 11), postflight (n = 11), and at long-term follow-up 7 mo after landing (n = 7). Post hoc analyses revealed a significant difference between preflight and postflight values for all supratentorial ventricular structures, i.e., lateral ventricle (mean % change ± SE = 13.3 ± 1.9), third ventricle (mean % change ± SE = 10.4 ± 1.1), and the total ventricular volume (mean % change ± SE = 11.6 ± 1.5) (all P < 0.0001), with higher volumes at postflight. At follow-up, these structures did not quite reach baseline levels, with still residual increases in volume for the lateral ventricle (mean % change ± SE = 7.7 ± 1.6; P = 0.0009), the third ventricle (mean % change ± SE = 4.7 ± 1.3; P = 0.0063), and the total ventricular volume (mean % change ± SE = 6.4 ± 1.3; P = 0.0008). This spatiotemporal pattern of CSF compartment enlargement and recovery points to a reduced CSF resorption in microgravity as the underlying cause. Our results warrant more detailed and longer longitudinal follow-up. The clinical impact of our findings on the long-term cosmonauts’ health and their relation to ocular changes reported in space travelers requires further prospective studies.
The paper presents results of a comprehensive analysis of the cardiovascular diseases (CVD) situation, both in the global and Russian contexts. It introduces original data illustrating the declining mortality rate from CVD, and the diminishing contribution of these diseases to overall mortality rate - globally and, to a larger extent, in developed countries. The paper also analyses the reasons for continuing CVD epidemic in Russia. Based on factual evidence, it argues that those include insufficient expenditures on treating CVD patients, and critically inadequate funding of prevention programmes. Unsatisfactory use of these funds to subsidise Russian regions (without taking into account their actual needs determined by the CVD mortality rate) only makes the problem worse. Through modelling, «average» efficiency of the Russian health care system in reducing CVD mortality was revealed. The paper describes various scenarios for future development of the Russian CVD situation. In the context of innovation-based scenario, the advantages of technological foresight are analysed; specifically, the authors summarise major S&T development trends in the health sector (using data of the Russian S&T Foresight 2030), which could significantly contribute to stopping the CVD epidemic in Russia.
Non-alcoholic fatty liver disease (NAFLD) is the worldwide most common cause of chronic liver pathology, which prevalence strongly correlates with the increasing incidence of diabetes, obesity and metabolic syndrome in the general population. Simple steatosis, the earliest NAFLD stage, usually remains asymptomatic, and appropriate changes in the lifestyle, as well as the diet, can reverse the affected liver into the healthy state. The potential of simple steatosis to progress into severe fibrotic stages and to facilitate carcinogenesis necessitates timely NAFLD detection and risk stratification in community-based healthcare settings. Since their initial discovery a decade ago, extracellular circulating miRNAs have been found in all human biological fluids including blood and shown to hold great promises as non-invasive biomarkers. Normally, intracellular miRNAs participate in the regulation of gene expression, but once released by dying/dead cells they remain highly stable in the extracellular environment for prolonged periods. Therefore, circulating miRNA profiles can reflect the ongoing pathogenic processes in body's tissues and organs, and enable highly sensitive non-invasive diagnosis of multiple disorders. A non-urgent character of the NAFLD-related decision-making justifies the use of chronic liver diseases as an excellent test case for examining the practical utility of circulating miRNAs as biomarkers for longitudinal monitoring of human health. In this review, we summarize the state-of-the-art in the field of early diagnosis of NAFLD using circulating blood miRNAs, and stress the necessity of additional experimental validation of their diagnostic potential. We further emphasize on the potential diagnostics promises of other cell-free RNA species found in human biological fluids.
Voltage-gated sodium (NaV) channels are essential for the normal functioning of cardiovascular, muscular, and nervous systems. These channels have modular organization; the central pore domain allows current flow and provides ion selectivity, whereas four peripherally located voltage-sensing domains (VSDs-I/IV) are needed for voltage-dependent gating. Mutations in the S4 voltage-sensing segments of VSDs in the skeletal muscle channel NaV1.4 trigger leak (gating pore) currents and cause hypokalemic and normokalemic periodic paralyses. Previously, we have shown that the gating modifier toxin Hm-3 from the crab spider Heriaeus melloteei binds to the S3-S4 extracellular loop in VSD-I of NaV1.4 channel and inhibits gating pore currents through the channel with mutations in VSD-I. Here, we report that Hm-3 also inhibits gating pore currents through the same channel with the R675G mutation in VSD-II. To investigate the molecular basis of Hm-3 interaction with VSD-II, we produced the corresponding 554-696 fragment of NaV1.4 in a continuous exchange cell-free expression system based on the Escherichia coli S30 extract. We then performed a combined nuclear magnetic resonance (NMR) and electron paramagnetic resonance spectroscopy study of isolated VSD-II in zwitterionic dodecylphosphocholine/lauryldimethylamine-N-oxide or dodecylphosphocholine micelles. To speed up the assignment of backbone resonances, five selectively 13C,15N-labeled VSD-II samples were produced in accordance with specially calculated combinatorial scheme. This labeling approach provides assignment for ∼50% of the backbone. Obtained NMR and electron paramagnetic resonance data revealed correct secondary structure, quasi-native VSD-II fold, and enhanced ps–ns timescale dynamics in the micelle-solubilized domain. We modeled the structure of the VSD-II/Hm-3 complex by protein–protein docking involving binding surfaces mapped by NMR. Hm-3 binds to VSDs I and II using different modes. In VSD-II, the protruding ß-hairpin of Hm-3 interacts with the S1-S2 extracellular loop, and the complex is stabilized by ionic interactions between the positively charged toxin residue K24 and the negatively charged channel residues E604 or D607. We suggest that Hm-3 binding to these charged groups inhibits voltage sensor transition to the activated state and blocks the depolarization-activated gating pore currents. Our results indicate that spider toxins represent a useful hit for periodic paralyses therapy development and may have multiple structurally different binding sites within one NaV molecule.
Background: Since May 2004, ten Central and East European (CEE) countries have joined the European Union. While HIV rates remain low among men who have sex with men (MSM) in CEE countries, there is no research on the sexual behaviour of CEE MSM in the UK.
Methods: CEE MSM living in the UK (n=691) were recruited for an online questionnaire via two popular MSM websites.
Results: The majority of men had arrived in the UK since May 2004. A previous STI diagnosis was reported by 30.7% and 4.8% reported being HIV-positive, the majority diagnosed in the UK. Unprotected anal intercourse with a casual partner of unknown or discordant HIV status was reported by 22.8%. Men who had been in the UK for longer (>5 years vs <1 year) reported more partners in the past five years (67.2% vs 50.4% had >10 partners, p<0.001) and were less likely to report their most recent partner was from their home country (14.9% vs 33.6%, p<0.001). Among migrant CEE MSM living in London, 15.4% had been paid for sex in the UK and 41.5% had taken recreational drugs in the past year.
Conclusion: CEE MSM in the UK are at risk for acquisition and transmission of STIs and HIV through UAI with non-concordant casual partners. Sexual mixing with men from other countries, commercial sex and increased partner numbers may introduce additional risk. This has important implications for cross-border transmission of infections between the UK and CEE countries. peer-00594792
Importance Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health.
Objective To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion.
Evidence Review Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss.
Findings Global child and adolescent mortality decreased from 14.18 million (95% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75%) in 2015 than was the case in 1990 (61%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3% (95% UI, 3.1%-5.6%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries.
Conclusions and Relevance Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.
Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.
Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1, 2, 3, and inverse associations with obesity and hypercholesterolemia are described3, 4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6, 7, 8, 9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
Prior to 2010, medical care for people living with HIV/AIDS was provided at an outpatient facility near the center of St. Petersburg. Since then, HIV specialty clinics have been established in more outlying regions of the city. The study examined the effect of this decentralization of HIV care on patients' satisfaction with care in clinics of St. Petersburg, Russia. We conducted a cross-sectional study with 418 HIV-positive patients receiving care at the St. Petersburg AIDS Center or at District Infectious Disease Departments (centralized and decentralized models, respectively). Face-to-face interviews included questions about psychosocial characteristics, patient's satisfaction with care, and clinic-related patient experience. Abstraction of medical records provided information on patients' viral load. To compare centralized and decentralized models of care delivery, we performed bivariate and multivariate analysis. Clients of District Infectious Disease Departments spent less time in lines and traveling to reach the clinic, and they had stronger relationships with their doctor. The overall satisfaction with care was high, with 86% of the sample reporting high level of satisfaction. Nevertheless, satisfaction with care was strongly and positively associated with the decentralized model of care and Patient-Doctor Relationship Score. Patient experience elements such as waiting time, travel time, and number of services used were not significant factors related to satisfaction. Given the positive association of satisfaction with decentralized service delivery, it is worth exploring decentralization as one way of improving healthcare services for people living with HIV/AIDS.
Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC50 values vary from 0.077 mM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8 showed even more pronounced activity. All the compounds showed no activity against several nonenveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC50 50e100 mM, with a non-specific mode of action. The results suggest that the carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity advocate their potential role in antiviral therapy.
Applying bootstrapped quantile regression to the Russian Longitudinal Monitoring Survey (RLMS) data, we examine the channels through which individuals experience and seek to cope with changes in consumption. We find that married individuals living in small households, with educated heads in urban areas are better equipped to smooth consumption. Investigating the impact of idiosyncratic shocks, we find that the labour market is an important transmission mechanism allowing households to smooth their consumption but also exposing them to risk, mainly through job loss. Outside of pension payments the formal social safety net does not facilitate consumption smoothing, thus heightening the importance of informal coping institutions. It transpires that both support from relatives/friends and home production act as important insurance mechanisms for the most vulnerable.