Reply: Biological Plausibility Behind the Benefits of Intravenous Metoprolol in Severe COVID-19.

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Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption

The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the {alpha}5, {alpha}3, and {beta}4 nicotinic acetylcholine receptor (nAChR) subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN) tract is particularly enriched in {alpha}3{beta}4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb) in mice altered nicotine consumption. Given that {beta}4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs) in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of {beta}4 to nicotine receptor activity in the MHb. We screened for missense SNPs that had allele frequencies >0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with {alpha}3. We found that {beta}4A90I and {beta}4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant {beta}4D447Y, significantly increased nicotine-evoked current amplitudes, while {beta}4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS), showed reduced nicotine currents. We employed lentiviruses to express {beta}4 or {beta}4 variants in the MHb. Immunoprecipitation studies confirmed that {beta}4 lentiviral-mediated expression leads to specific upregulation of {alpha}3{beta}4 but not {beta}2 nAChRs in the Mhb. Mice injected with the {beta}4-containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the {beta}4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the {beta}4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular {beta}4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine consumption in mice

An in vivo tethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents in nociceptors

Understanding information flow in sensory pathways requires cell-selective approaches to manipulate the activity of defined neurones. Primary afferent nociceptors, which detect painful stimuli, are enriched in specific voltage-gated sodium channel (VGSC) subtypes. Toxins derived from venomous animals can be used to dissect the contributions of particular ion currents to cell physiology. Here we have used a transgenic approach to target a membrane-tethered isoform of the conotoxin MrVIa (t-MrVIa) only to nociceptive neurones in mice. T-MrVIa transgenic mice show a 44 ± 7% reduction of tetrodotoxin-resistant (TTX-R) VGSC current densities. This inhibition is permanent, reversible and does not result in functional upregulation of TTX-sensitive (TTX-S) VGSCs, voltage-gated calcium channels (VGCCs) or transient receptor potential (TRP) channels present in nociceptive neurones. As a consequence of the reduction of TTX-R VGSC currents, t-MrVIa transgenic mice display decreased inflammatory mechanical hypersensitivity, cold pain insensitivity and reduced firing of cutaneous C-fibres sensitive to noxious cold temperatures. These data validate the use of genetically encoded t-toxins as a powerful tool to manipulate VGSCs in specific cell types within the mammalian nervous system. This novel genetic methodology can be used for circuit mapping and has the key advantage that it enables the dissection of the contribution of specific ionic currents to neuronal function and to behaviour.This work was supported by grants from the DFG to I.I.-T. and G.R.L. within the collaborative research centre (SFB 665) and from the Alexander von Humboldt Foundation to E.St.J.S

Evaluating Educators’ Attitudes, Skills Readiness, and Teaching Performance on the Online Distance Learning

The purpose of this study was to evaluate teachers’ attitude, skill readiness. and teaching performance towards online distance learning under the new normal setting. Using a descriptive research design, it performed multiple linear regression analysis to determine whether attitude and skill readiness could influence teaching performance. 43 teachers from pre-school to senior high school of Philippine International English School (PIES) of Kuwait were selected. On the teacher’s attitude, respondents described all the four indicators: course design, course communication, time management and technical competence, as strongly important. They also perceived that they were highly competent when it comes to skill readiness in the implementation of online distance learning in all the four indicators. Teaching performance of the respondents was excellent, being knowledge worker and learning catalyst, specifically in terms of environmental and classroom management, and professional attitudes and qualities. They also performed excellent as a character shaper. Respondents’ attitude and skill readiness, specifically in terms of course communication and technical competence respectively, influence teaching performance in the implementation of online distance learning

Solution conformation of the major adduct between the carcinogen (+)-anti-benzo[ɑ]pyrene diol epoxide and DNA

We have synthesized, separated, and purified ≈10 mg of a deoxyundecanucleotide duplex containing a single centrally positioned covalent adduct between (+)-anti-benzo[a]pyrene (BP) diol epoxide and the exocyclic amino group of guanosine. Excellent proton NMR spectra are observed for the (+)-trans-anti-BP diol epoxide-N^2-dG adduct positioned opposite dC and flanked by G.C pairs in the d[C1-C2-A3-T4-C5-(BP)G6-C7-T8-A9-C10-C11].d[12- G13-T14-A15-G16-C17-G18-A19-T20-G 21-G22] duplex +ADdesignated (BP)G.C 11-mer+BD. We have determined the solution structure centered about the BP covalent adduct site in the (BP)G.C 11-mer duplex by incorporating intramolecular and intermolecular proton-proton distance bounds deduced from the NMR data sets as constraints in energy minimization computations. The BP ring is positioned in the minor groove and directed toward the 5' end of the modified strand. One face of the BP ring of (BP)G6 is stacked over the G18 and A19 sugar-phosphate backbone on the partner strand and the other face is exposed to solvent. A minimally perturbed B-DNA helix is observed for the d[T4-C5-(BP)G6-C7-T8].d[A15-G16-C17-G18-A19] segment centered about the adduct site with Watson-Crick alignment for both the (BP)G6.C17 pair and flanking G.C pairs. A widening of the minor groove at the adduct site is detected that accommodates the BP ring whose long axis makes an angle of ≈45° with the average direction of the DNA helix axis. Our study holds future promise for the characterization of other steroisomerically pure adducts of BP diol epoxides with DNA to elucidate the molecular basis of structure-activity relationships associated with the stereoisomer-dependent spectrum of mutational and carcinogenic activities

Relação entre transtorno de ansiedade e os estudantes de medicina: revisão sistemática de literatura: The relationship between anxiety disorder and medical students: a systematic literature review

Através de um apanhado teórico, este trabalho tem por objetivo demonstrar e analisar referências bibliográficas e estudos que demonstrem, explicam e exemplificam os transtornos de ansiedade. Esse transtorno tem se tornado uma doença agravante no meio acadêmico, principalmente entre os alunos de medicina. Vivemos em um século muito imediatista, assim o estado de ansiedade vem se tornando comum, com isso e junto de tanto anseio a sensação de incapacidade, angústia estão ligadas agravando ainda mais a situação do indivíduo. A maioria dos alunos não percebem que estão em um estado crítico e quando a percepção e os sintomas são repentinos, a doença já não está em um estágio fácil. Este quer proporcionar reflexões ao tema demonstrando o quanto o autoconhecimento e o diálogo podem auxiliar a sair de um estágio ansioso e que cada indivíduo tem o seu momento em seu próprio tempo

Tratamento de maxila atrófica com implante personalizado: relato de caso

Atualmente, um dos maiores desafios para a implantodontia é reestabelecer e reconstruir as funções fisiológicas, estéticas e fonéticas em maxilas atróficas. Quando o nível ósseo do paciente não permite a instalação dos implantes convencionais, o tratamento de reabilitação pode ser realizado através dos procedimentos cirúrgicos reabilitadores, utilizando a tecnologia customizada, fabricada a base de titânio, a partir de análise computadorizada de toda a anatomia bucomaxilofacial do paciente. Neste trabalho é relatar um caso de uma paciente com perda óssea severa em região maxilar, sendo feita a reconstrução utilizando a precisão da Prótese Customizada da Maxila para Reabilitação Protética implantossuportada

Reabilitação em região anterior da maxila com instalação de implantes customizados: relato de caso

A maxila por se tratar de uma região estética influencia totalmente na autoestima e bem-estar do paciente, a ausência dentária, principalmente, em região estética desenvolve problemas emocionais, além de afetar as funções fisiológicas e habituais do dia a dia do indivíduo, influenciando na mastigação, fonação e estado nutricional do paciente. Com o avanço da tecnologia, nasceu a possibilidade de reabilitar as maxilas atróficas por meio de implantes customizados produzidos exclusivamente para cada paciente, sem a necessidade de realizar enxerto ósseo. Neste trabalho é relatado o caso de uma paciente com perda óssea severa na região da maxila, indicada para tratamento de reconstrução maxilar para posterior reabilitação protética após insucesso no tratamento convencional. Realizados exames e consultas pré-operatórias, a paciente foi internada para realização da cirurgia. Após aprovação do planejamento cirúrgico, procedeu-se a realização do procedimento, o implante personalizado foi instalado com 08 parafusos de suporte. Ao finalizar a cirurgia, a paciente permaneceu internada por 16 horas no hospital, sem complicações pós-operatórias, recebeu as recomendações imprescindíveis para um bom pós-operatório e em seguida, alta hospitalar. No dia seguinte deu-se início ao processo de reabilitação protética da paciente, com 3 dias foi instalada a prótese provisória implantossuportada, realizou-se a radiografia panorâmica para avaliação e inspeção final. Os implantes customizados representam uma solução inovadora e eficiente nos casos de reabilitações complexas e possui altos índices de sucesso quando está associado a uma indicação correta, precisão na execução e cuidados operatórios

Magnetic resonance imaging reference values for cardiac morphology, function and tissue composition in adolescents.

BACKGROUND Cardiovascular magnetic resonance (CMR) is a precise tool for the assessment of cardiac anatomy, function, and tissue composition. However, studies providing CMR reference values in adolescence are scarce. We aim to provide sex-specific CMR reference values for biventricular and atrial dimensions and function and myocardial relaxation times in this population. METHODS Adolescents aged 15-18 years with no known cardiovascular disease underwent a non-contrast 3-T CMR scan between March 2021 and October 2021. The imaging protocol included a cine steady-state free-precession sequence for the analysis of chamber size and function, as well as T2-GraSE and native MOLLI T1-mapping for the characterization of myocardial tissue. FINDINGS CMR scans were performed in 123 adolescents (mean age 16 ± 0.5 years, 52% girls). Mean left and right ventricular end-diastolic indexed volumes were higher in boys than in girls (91.7 ± 11.6 vs 78.1 ± 8.3 ml/m2, p < 0.001; and 101.3 ± 14.1 vs 84.1 ± 10.5 ml/m2, p < 0.001), as was the indexed left ventricular mass (48.5 ± 9.6 vs 36.6 ± 6.0 g/m2, p < 0.001). Left ventricular ejection fraction showed no significant difference by sex (62.2 ± 4.1 vs 62.8 ± 4.2%, p = 0.412), whereas right ventricular ejection fraction trended slightly lower in boys (55.4 ± 4.7 vs. 56.8 ± 4.4%, p = 0.085). Indexed atrial size and function parameters did not differ significantly between sexes. Global myocardial native T1 relaxation time was lower in boys than in girls (1215 ± 23 vs 1252 ± 28 ms, p < 0.001), whereas global myocardial T2 relaxation time did not differ by sex (44.4 ± 2.0 vs 44.1 ± 2.4 ms, p = 0.384). Sex-stratified comprehensive percentile tables are provided for most relevant cardiac parameters. INTERPRETATION This cross-sectional study provides overall and sex-stratified CMR reference values for cardiac dimensions and function, and myocardial tissue properties, in adolescents. This information is useful for clinical practice and may help in the differential diagnosis of cardiac diseases, such as cardiomyopathies and myocarditis, in this population. FUNDING Instituto de Salud Carlos III (PI19/01704).Instituto de Salud Carlos III (PI19/01704). The authors are indebted to the adolescents who participated in this study. Rodrigo Fernández-Jiménez is recipient of grant PI19/01704 by the Instituto de Salud Carlos III (ISCIII) - Fondo de Investigación Sanitaria and the European Regional Development Fund/European Social Fund (A way to make Europe/Investing in your future), which funded the EnIGMA (Early ImaGing Markers of unhealthy lifestyles in Adolescents) study. Jesús Martínez-Gómez was a postgraduate fellow of the Ministerio de Ciencia e Innovación at the Residencia de Estudiantes (2020–2022) and is a recipient of grant FPU21/04891 (Ayudas para la formación de profesorado universitario, FPU-2021) from the Ministerio de Educación, Cultura y Deporte Gloria Santos-Beneit is recipient of grant LCF/PR/MS19/12220001 funded by ““la Caixa” Foundation (ID 100010434). The SHE Foundation is supported by “la Caixa” Foundation (LCF/PR/CE16/10700001). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). Simon Bartlett (CNIC) provided English editing.S

Association of size at birth with adolescent hormone levels, body size and age at menarche: relevance for breast cancer risk

Birth size has been positively associated with age at menarche and height in adolescence and adulthood, but the relevant biological mechanisms remain unclear. Among 262 Norwegian term-born singleton girls, birth size measures (weight, length, ponderal index, head circumference and subscapular skin-fold thickness) were analysed in relation to adolescent hormone levels (oestradiol, prolactin, dehydroepiandrosterone sulphate, androstenedione and free testosterone index), age at menarche and adolescent (ages 12.7–15.5 years) and body size (height, weight, body mass index and waist-to-hip ratio) using survival analysis and general linear modelling. The results were adjusted for gestational age at birth, age and menarcheal status at measurement in adolescence and maternal age at menarche. Birth weight, birth length and head circumference were positively associated with adolescent weight and height, and small birth size was associated with earlier age at menarche. Subscapular skin-fold thickness at birth was not associated with adolescent body size, but low fold-thickness was associated with earlier age at menarche. Measures of birth size were inversely related to circulating levels of dehydroepiandrosterone sulphate in adolescence, but there was no clear association with other hormones. These results suggest that physical and sexual development in puberty and adolescence is influenced by prenatal factors, and in combination, these factors may influence health and disease later in life