Different sensitivity of miniature endplate currents in rat external and internal intercostal muscles to the acetylcholinesterase inhibitor C-547 as compared with diaphragm and extensor digitorum longus

Derivative of 6-methyluracil, selective cholinesterase inhibitor C-547 potentiates miniature endplate currents (MEPCs) in rat external intercostal muscles (external ICM) more effectively than in internal intercostal muscles (internal ICM). Effect of the C-547 on intercostal muscles was compared with those on extensor digitorum longus (EDL) and diaphragm muscles. Half-effective concentrations for τ of MEPC decay arranged in increasing order were as follows: EDL, locomotor muscle, most sensitive = 1.3 nM, external ICM, inspiration muscle = 6.8 nM, diaphragm, main inspiration muscle = 28 nM, internal ICM, expiration muscle = 71 nM. External ICM might therefore be inhibited, similarly as the limb muscles, by nanomolar concentrations of the drug and do not participate in inspiration in the presence of the C-547. Moreover, internal ICM inhibition can hinder the expiration during exercise-induced fast breathing of C-547- treated experimental animals. © 2009 by the Institute of Physiology, Czech Academy of Sciences

Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via N-methyl-d-aspartate receptor activation

Acetylcholinesterase (AChE) is an enzyme that hydrolyses the neurotransmitter acetylcholine, thereby limiting spillover and duration of action. This study demonstrates the existence of an endogenous mechanism for the regulation of synaptic AChE activity. At the rat extensor digitorum longus neuromuscular junction, activation of N-methyl-d-aspartate (NMDA) receptors by combined application of glutamate and glycine led to enhancement of nitric oxide (NO) production, resulting in partial AChE inhibition. Partial AChE inhibition was measured using increases in miniature endplate current amplitude. AChE inhibition by paraoxon, inactivation of NO synthase by Nω-nitro-l-arginine methyl ester, and NMDA receptor blockade by dl-2-amino-5-phosphopentanoic acid prevented the increase in miniature endplate current amplitude caused by amino acids. High-frequency (10 Hz) motor nerve stimulation in a glycine-containing bathing solution also resulted in an increase in the amplitude of miniature endplate currents recorded during the interstimulus intervals. Pretreatment with an NO synthase inhibitor and NMDA receptor blockade fully eliminated this effect. This suggests that endogenous glutamate, released into the synaptic cleft as a co-mediator of acetylcholine, is capable of triggering the NMDA receptor/NO synthase-mediated pathway that modulates synaptic AChE activity. Therefore, in addition to well-established modes of synaptic plasticity (e.g. changes in the effectiveness of neurotransmitter release and/or the sensitivity of the postsynaptic membrane), another mechanism exists based on the prompt regulation of AChE activity. NO molecules depress AChE activity in the neuromuscular junction thereby enhancing endplate current amplitude. Endogenous glutamate, released into the synaptic cleft as a co-mediator of acetylcholine, is capable of triggering the NMDA receptor-/NO synthase-mediated pathway that modulates synaptic AChE activity. In addition to well-established modes of synaptic plasticity another mechanism exists based on the prompt regulation of AChE activity. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd

Изучение биофармацевтических свойств препарата поливалентного бактериофага в капсулированной лекарственной форме

Scientific relevance. Rational phage therapy is a highly effective way to combat bacterial infections, especially in conditions of steadily increasing antibiotic resistance. Most bacteriophage preparations are formulated as oral and topical solutions. However, oral administration of liquid phage preparations results in significant inactivation in the stomach. To shield active ingredients from the acidic environment, Sextaphag® Pyobacteriophage, polyvalent, has been formulated into capsules.Aim. This study evaluated the polyvalent bacteriophage preparation in capsules in terms of its potency and biopharmaceutical properties.Materials and methods. The study compared the polyvalent bacteriophage preparation formulated as capsules with the polyvalent bacteriophage preparation formulated as a solution. The potency was evaluated by the Appelmans method, and phage particles were quantified by the Gratia method. To evaluate the acid-neutralising capacity, the authors placed test samples of the bacteriophage preparation in 0.1 M hydrochloric acid and analysed their potency by the Appelmans method. Chinchilla rabbits were used to analyse anti-phage immune responses, and their antibody levels were measured using an enzyme immunoassay test system developed by the authors. The pharmacokinetic parameters were studied in outbred white mice after oral dosing.Results. The polyvalent bacteriophage preparation exhibited high lytic activity towards Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Pseudomonas aegidinosa, Staphylococcus aureus, and Streptococcus pneumoniae, which accounted for a dilution factor of 10-6. Following oral administration of the polyvalent bacteriophage preparation in capsules to mice, the level of absorption was 3.1–3.7 times higher than that observed with the solution. Repeated oral administration of therapeutic doses did not induce anti-phage antibodies in rabbits. The stability study showed that the polyvalent bacteriophage preparation retained high lytic activity for 18 months.Conclusions. According to the study results, the polyvalent bacteriophage preparation in capsules exerts significant antibacterial activity against the studied microorganisms, has a high level of absorption, retains its lytic activity for a long time, and does not induce anti-phage antibodies after oral dosing, which confirms its safety and efficacy.Актуальность. Рациональная фаготерапия — высокоэффективный способ борьбы с бактериальными инфекциями в условиях неуклонно растущей антибиотикорезистентности. Основной лекарственной формой препаратов бактериофагов является раствор для приема внутрь, местного и наружного применения. Однако при пероральном приеме жидких лекарственных форм фаговых препаратов происходит их значительная инактивация за счет кислой среды желудочного сока. С целью устранения негативного влияния кислой среды разработан лекарственный препарат поливалентного бактериофага в форме капсул — Секстафаг® Пиобактериофаг поливалентный.Цель. Изучение специфической активности и биофармацевтических свойств лекарственного препарата поливалентного бактериофага в капсулированной форме.Материалы и методы. Объект исследования  —  препарат  поливалентного  бактериофага в капсулированной форме; препарат сравнения — препарат поливалентного  бактериофага в форме раствора. Специфическую активность изучали с использованием метода Аппельмана, количество фаговых частиц — методом Грациа. Исследование кислотонейтрализующей способности проводили путем выдерживания препарата в 0,1 М растворе хлористоводородной кислоты с последующим  определением  специфической активности по методу Аппельмана.  Антифаговый  иммунный  ответ  на  антигены  бактериофага изучали  на  кроликах  породы  Шиншилла,  уровень  иммунного  ответа  детектировали с помощью разработанной иммуноферментной тест-системы. Исследование фармакокинетических параметров проводили на беспородных белых мышах при пероральном введении препарата.Результаты. Выявлен высокий уровень литической активности исследуемого препарата, который по величине отрицательной степени десятичного разведения составлял 10-6 в отношении исследуемых микроорганизмов: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Pseudomonas аeruginosa, Staphylococcus aureus и Streptococcus pneumoniae. Показатель степени всасывания после перорального введения мышам препарата поливалентного  бактериофага  в  капсулированной  форме  был  в  3,1–3,7  раза  выше  в  сравнении с препаратом поливалентного бактериофага в форме раствора. Многократное  пероральное введение исследуемого препарата кроликам в терапевтических дозах не стимулировало образования антифаговых антител. Исследование стабильности препарата показало сохранение высокого уровня литической активности в течение 18 мес.Выводы. Препарат поливалентного бактериофага в  капсулированной  лекарственной форме обладает высоким антибактериальным действием в отношении исследуемых микроорганизмов, характеризуется высокой степенью всасывания и длительным сохранением литической активности,  а  также  не  вызывает  выработку  антифаговых  антител при пероральном применении, что свидетельствует об эффективности и безопасности разработанного препарата

Trust in government regarding COVID-19 and its associations with preventive health behaviour and prosocial behaviour during the pandemic: A cross-sectional and longitudinal study

Background The effective implementation of government policies and measures for controlling the coronavirus disease 2019 (COVID-19) pandemic requires compliance from the public. This study aimed to examine cross-sectional and longitudinal associations of trust in government regarding COVID-19 control with the adoption of recommended health behaviours and prosocial behaviours, and potential determinants of trust in government during the pandemic. Methods This study analysed data from the PsyCorona Survey, an international project on COVID-19 that included 23 733 participants from 23 countries (representative in age and gender distributions by country) at baseline survey and 7785 participants who also completed follow-up surveys. Specification curve analysis was used to examine concurrent associations between trust in government and self-reported behaviours. We further used structural equation model to explore potential determinants of trust in government. Multilevel linear regressions were used to examine associations between baseline trust and longitudinal behavioural changes. Results Higher trust in government regarding COVID-19 control was significantly associated with higher adoption of health behaviours (handwashing, avoiding crowded space, self-quarantine) and prosocial behaviours in specification curve analyses (median standardised beta = 0.173 and 0.229, p < 0.001). Government perceived as well organised, disseminating clear messages and knowledge on COVID-19, and perceived fairness were positively associated with trust in government (standardised beta = 0.358, 0.230, 0.056, and 0.249, p < 0.01). Higher trust at baseline survey was significantly associated with lower rate of decline in health behaviours over time (p for interaction = 0.001). Conclusions These results highlighted the importance of trust in government in the control of COVID-19

Pandemic Boredom: Little Evidence That Lockdown-Related Boredom Affects Risky Public Health Behaviors Across 116 Countries

Some public officials have expressed concern that policies mandating collective public health behaviors (e.g., national/regional "lockdown ") may result in behavioral fatigue that ultimately renders such policies ineffective. Boredom, specifically, has been singled out as one potential risk factor for noncompliance. We examined whether there was empirical evidence to support this concern during the COVID-19 pandemic in a large cross-national sample of 63,336 community respondents from 116 countries. Although boredom was higher in countries with more COVID-19 cases and in countries that instituted more stringent lockdowns, such boredom did not predict longitudinal within-person decreases in social distancing behavior (or vice versa; n = 8,031) in early spring and summer of 2020. Overall, we found little evidence that changes in boredom predict individual public health behaviors (handwashing, staying home, self-quarantining, and avoiding crowds) over time, or that such behaviors had any reliable longitudinal effects on boredom itself. In summary, contrary to concerns, we found little evidence that boredom posed a public health risk during lockdown and quarantine

Conceptual replication and extension of health behavior theories' predictions in the context of COVID-19: Evidence across countries and over time

Virus mitigation behavior has been and still is a powerful means to fight the COVID-19 pandemic irrespective of the availability of pharmaceutical means (e.g., vaccines). We drew on health behavior theories to predict health-protective (coping-specific) responses and hope (coping non-specific response) from health-related cognitions (vulnerability, severity, self-assessed knowledge, efficacy). In an extension of this model, we proposed orientation to internal (problem-focused coping) and external (country capability) coping resources as antecedents of health protection and hope; health-related cognitions were assumed as mediators of this link. We tested these predictions in a large multi-national multi-wave study with a cross-sectional panel at T1 (Baseline, March-April 2020; N = 57,631 in 113 countries) and a panel subsample at two later time points, T2 (November 2020; N = 3097) and T3 (April 2021; N = 2628). Multilevel models showed that health-related cognitions predicted health-protective responses and hope. Problem-focused coping was mainly linked to health-protective behaviors (T1-T3), whereas country capability was mainly linked to hope (T1-T3). These relationships were partially mediated by health-related cognitions. We conceptually replicated predictions of health behavior theories within a real health threat, further suggesting how different coping resources are associated with qualitatively distinct outcomes. Both patterns were consistent across countries and time

Lives versus Livelihoods? Perceived economic risk has a stronger association with support for COVID-19 preventive measures than perceived health risk

This paper examines whether compliance with COVID-19 mitigation measures is motivated by wanting to save lives or save the economy (or both), and which implications this carries to fight the pandemic. National representative samples were collected from 24 countries (N = 25,435). The main predictors were (1) perceived risk to contract coronavirus, (2) perceived risk to suffer economic losses due to coronavirus, and (3) their interaction effect. Individual and country-level variables were added as covariates in multilevel regression models. We examined compliance with various preventive health behaviors and support for strict containment policies. Results show that perceived economic risk consistently predicted mitigation behavior and policy support—and its effects were positive. Perceived health risk had mixed effects. Only two significant interactions between health and economic risk were identified—both positive

Concern with COVID-19 pandemic threat and attitudes towards immigrants: The mediating effect of the desire for tightness

Tightening social norms is thought to be adaptive for dealing with collective threat yet it may have negative consequences for increasing prejudice. The present research investigated the role of desire for cultural tightness, triggered by the COVID-19 pandemic, in increasing negative attitudes towards immigrants. We used participant-level data from 41 countries (N = 55,015) collected as part of the PsyCorona project, a crossnational longitudinal study on responses to COVID-19. Our predictions were tested through multilevel and SEM models, treating participants as nested within countries. Results showed that people’s concern with COVID19 threat was related to greater desire for tightness which, in turn, was linked to more negative attitudes towards immigrants. These findings were followed up with a longitudinal model (N = 2,349) which also showed that people’s heightened concern with COVID-19 in an earlier stage of the pandemic was associated with an increase in their desire for tightness and negative attitudes towards immigrants later in time. Our findings offer insight into the trade-offs that tightening social norms under collective threat has for human groups

Хронические нарушения сознания: клинические рекомендации Общероссийской общественной организации «Федерация анестезиологов и реаниматологов»

Хронические нарушения сознания (ХНС) представляют собой синдромы тяжелого поражения центральной нервной системы, приводящие к длительной грубой инвалидизации и требующие значительных усилий по лечению и реабилитации, которые ложатся на медицинские учреждения и на плечи близких пациентов. ХНС развиваются у пациентов после комы и характеризуются наличием бодрствования при полном или практически полном отсутствии признаков осознанного поведения. К ХНС относятся вегетативное состояние (ВС) и состояние минимального сознания (СМС). Также для описания начальных стадий этих состояний используется термин «продленное нарушение сознания» (ПНС). Отдельно выделяют выход из СМС — состояние, которое формируется по мере восстановления когнитивных функций. Диагностика ХНС основывается на многократном структурированном клиническом осмотре с применением специализированных шкал при условии исключения обратимых причин нарушения сознания. Лечение пациентов с ХНС включает в себя поддержание жизненно важных функций, обеспечение оптимального питания и борьбу с типичными осложнениями и сопутствующими состояниями (пролежни, спастичность, боль, пароксизмальная симпатическая гиперактивность и др.). У пациентов с ХНС должна проводиться реабилитация с участием мультидисциплинарной реабилитационной команды в объеме, который определяется проблемами и возможностями конкретного пациента. Наиболее эффективной реабилитация является при условии ее раннего начала. На данный момент однозначных доказательств эффективности каких-либо специфических методов, направленных на восстановление сознания, не получено; изучается ряд соответствующих фармакологических и нефармакологических вмешательств, обязательным условием применения которых является максимально возможная коррекция соматических проблем пациента. Важную роль в ведении пациентов с ХНС играет вовлечение близких пациента, которые, в свою очередь, нуждаются в получении объективной практической информации о состоянии своего родственника и о направлениях реабилитации, а также в психологической помощи

Identifying important individual‐ and country‐level predictors of conspiracy theorizing: a machine learning analysis

Psychological research on the predictors of conspiracy theorizing—explaining important social and political events or circumstances as secret plots by malevolent groups—has flourished in recent years. However, research has typically examined only a small number of predictors in one, or a small number of, national contexts. Such approaches make it difficult to examine the relative importance of predictors, and risk overlooking some potentially relevant variables altogether. To overcome this limitation, the present study used machine learning to rank-order the importance of 115 individual- and country-level variables in predicting conspiracy theorizing. Data were collected from 56,072 respondents across 28 countries during the early weeks of the COVID-19 pandemic. Echoing previous findings, important predictors at the individual level included societal discontent, paranoia, and personal struggle. Contrary to prior research, important country-level predictors included indicators of political stability and effective government COVID response, which suggests that conspiracy theorizing may thrive in relatively well-functioning democracies