RESUMO
We report a novel small-molecule screening approach that combines data augmentation and machine learning to identify Food and Drug Administration (FDA)-approved drugs interacting with the calcium pump (Sarcoplasmic reticulum Ca2+-ATPase, SERCA) from skeletal (SERCA1a) and cardiac (SERCA2a) muscle. This approach uses information about small-molecule effectors to map and probe the chemical space of pharmacological targets, thus allowing to screen with high precision large databases of small molecules, including approved and investigational drugs. We chose SERCA because it plays a major role in the excitation-contraction-relaxation cycle in muscle and it represents a major target in both skeletal and cardiac muscle. The machine learning model predicted that SERCA1a and SERCA2a are pharmacological targets for seven statins, a group of FDA-approved 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors used in the clinic as lipid-lowering medications. We validated the machine learning predictions by using in vitro ATPase assays to show that several FDA-approved statins are partial inhibitors of SERCA1a and SERCA2a. Complementary atomistic simulations predict that these drugs bind to two different allosteric sites of the pump. Our findings suggest that SERCA-mediated Ca2+ transport may be targeted by some statins (e.g., atorvastatin), thus providing a molecular pathway to explain statin-associated toxicity reported in the literature. These studies show the applicability of data augmentation and machine learning-based screening as a general platform for the identification of off-target interactions and the applicability of this approach extends to drug discovery.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Miocárdio/enzimologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Aprendizado de MáquinaRESUMO
Drug development is a complex, costly, and time-consuming endeavor. While high-throughput screening (HTS) plays a critical role in the discovery stage, it is one of many factors contributing to these challenges. In certain contexts, virtual screening can complement the HTS, potentially offering a more streamlined approach in the initial stages of drug discovery. Molecular docking is an example of a popular virtual screening technique that is often used for this purpose; however, its effectiveness can vary greatly. This has led to the use of consensus docking approaches that combine results from different docking methods to improve the identification of active compounds and reduce the occurrence of false positives. However, many of these methods do not fully leverage the latest advancements in molecular docking. In response, we present ESSENCE-Dock (Effective Structural Screening ENrichment ConsEnsus Dock), a new consensus docking workflow aimed at decreasing false positives and increasing the discovery of active compounds. By utilizing a combination of novel docking algorithms, we improve the selection process for potential active compounds. ESSENCE-Dock has been made to be user-friendly, requiring only a few simple commands to perform a complete screening while also being designed for use in high-performance computing (HPC) environments.
Assuntos
Algoritmos , Descoberta de Drogas , Simulação de Acoplamento Molecular , Consenso , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala , LigantesRESUMO
Since 2011 Direct Acting antivirals (DAAs) drugs targeting different non-structural (NS) viral proteins (NS3, NS5A or NS5B inhibitors) have been approved for clinical use in HCV therapies. However, currently there are not licensed therapeutics to treat Flavivirus infections and the only licensed DENV vaccine, Dengvaxia, is restricted to patients with preexisting DENV immunity. Similarly to NS5 polymerase, the NS3 catalytic region is evolutionarily conserved among the Flaviviridae family sharing strong structural similarity with other proteases belonging to this family and therefore is an attractive target for the development of pan-flavivirus therapeutics. In this work we present a library of 34 piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. The library was developed through a privileged structures-based design and then biologically screened using a live virus phenotypic assay to determine the half-maximal inhibitor concentration (IC50) of each compound against ZIKV and DENV. Two lead compounds, 42 and 44, with promising broad-spectrum activity against ZIKV (IC50 6.6 µM and 1.9 µM respectively) and DENV (IC50 6.7 µM and 1.4 µM respectively) and a good security profile were identified. Besides, molecular docking calculations were performed to provide insights about key interactions with residues in NS3 proteases' active sites.
Assuntos
Vírus da Dengue , Flaviviridae , Hepatite C Crônica , Infecção por Zika virus , Zika virus , Humanos , Zika virus/metabolismo , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Flaviviridae/metabolismo , Antivirais/farmacologia , Antivirais/química , Simulação de Acoplamento Molecular , Proteínas não Estruturais Virais , Peptídeo Hidrolases , Piperazinas/farmacologiaRESUMO
The endogenous protease furin is a key protein in many different diseases, such as cancer and infections. For this reason, a wide range of studies has focused on targeting furin from a therapeutic point of view. Our main objective consisted of identifying new compounds that could enlarge the furin inhibitor arsenal; secondarily, we assayed their adjuvant effect in combination with a known furin inhibitor, CMK, which avoids the SARS-CoV-2 S protein cleavage by means of that inhibition. Virtual screening was carried out to identify potential furin inhibitors. The inhibition of physiological and purified recombinant furin by screening selected compounds, Clexane, and these drugs in combination with CMK was assayed in fluorogenic tests by using a specific furin substrate. The effects of the selected inhibitors from virtual screening on cell viability (293T HEK cell line) were assayed by means of flow cytometry. Through virtual screening, Zeaxanthin and Kukoamine A were selected as the main potential furin inhibitors. In fluorogenic assays, these two compounds and Clexane inhibited both physiological and recombinant furin in a dose-dependent way. In addition, these compounds increased physiological furin inhibition by CMK, showing an adjuvant effect. In conclusion, we identified Kukoamine A, Zeaxanthin, and Clexane as new furin inhibitors. In addition, these drugs were able to increase furin inhibition by CMK, so they could also increase its efficiency when avoiding S protein proteolysis, which is essential for SARS-CoV-2 cell infection.
Assuntos
Clorometilcetonas de Aminoácidos/farmacologia , Enoxaparina/farmacologia , Furina/antagonistas & inibidores , Espermina/análogos & derivados , Zeaxantinas/farmacologia , Clorometilcetonas de Aminoácidos/química , Clorometilcetonas de Aminoácidos/metabolismo , COVID-19/transmissão , COVID-19/virologia , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Enoxaparina/química , Enoxaparina/metabolismo , Furina/química , Furina/metabolismo , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Proteólise , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Espermina/química , Espermina/metabolismo , Espermina/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus , Replicação Viral , Zeaxantinas/química , Zeaxantinas/metabolismoRESUMO
INTRODUCTION: Despite of the wide evidence of use fractional flow reserve (FFR), isolated angiography evaluation is still the main tool to indicate percutaneous coronary intervention. Quantitative flow ratio (QFR) is a new functional index to assess functional significance. Recently, few studies have showed the capacity of QFR to predict significance stenosis. The aim of this research has been to describe the evidence of QFR in this clinical setting, to analyze the global diagnosis accuracy of QFR versus FFR and to compare the difference in feasibility between retrospective and prospective analysis. METHODS AND RESULTS: Systematic review of literature was performed. Eligible studies for the meta-analysis were considered those directly evaluating de QFR versus FFR. Pooled values of diagnosis test and summary receiver operator curve were calculated. Main causes of not-perform QFR analysis according to study design were also evaluated. Sixteen studies were included. Good correlation and agreement were showed. Global sensibility, specificity, PPV, and NPV were 0.84, 0.89, 0.80, and 0.92, respectively. Then, 18% of evaluated vessels could not be analyzed. Significant differences were found in the percentage of discarded vessels and the cause of nonperformed analysis between retrospective or prospective analysis. CONCLUSIONS: Excellent correlation and agreement between QFR and FFR was demonstrated. QFR assessment could be improved by its prospective analysis with a dedicated protocol.
Assuntos
Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Humanos , Imageamento Tridimensional , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The primary objective of this paper is to provide a guide on implementing Bayesian generalized kernel regression methods for genomic prediction in the statistical software R. Such methods are quite efficient for capturing complex non-linear patterns that conventional linear regression models cannot. Furthermore, these methods are also powerful for leveraging environmental covariates, such as genotype × environment (G×E) prediction, among others. In this study we provide the building process of seven kernel methods: linear, polynomial, sigmoid, Gaussian, Exponential, Arc-cosine 1 and Arc-cosine L. Additionally, we highlight illustrative examples for implementing exact kernel methods for genomic prediction under a single-environment, a multi-environment and multi-trait framework, as well as for the implementation of sparse kernel methods under a multi-environment framework. These examples are followed by a discussion on the strengths and limitations of kernel methods and, subsequently by conclusions about the main contributions of this paper.
Assuntos
Interação Gene-Ambiente , Modelos Genéticos , Teorema de Bayes , Genômica , TriticumRESUMO
Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P(Bonferroni) = .009), depressive symptoms (r = .37, P(Bonferroni) = .015), trait anxiety (r = .41, P(Bonferroni) = .006), and perceived stress (r = .45, P(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.
Assuntos
Alcoolismo/fisiopatologia , Tonsila do Cerebelo/fisiopatologia , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Adulto , Idoso , Transtornos de Ansiedade/fisiopatologia , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Resposta Galvânica da Pele , Humanos , Imageamento por Ressonância Magnética , Masculino , Rememoração Mental , Pessoa de Meia-Idade , Córtex Pré-Frontal/fisiopatologiaRESUMO
The selectivity of encapsulation of leflunomide and teriflunomide by native α-, ß- and γ-cyclodextrins was investigated through 1H NMR and molecular modeling. Thermodynamic analysis revealed the main driving forces involved in the binding. For α-cyclodextrin, the partial encapsulation was obtained while deep penetration was characterized for the other two cyclodextrins, where the remaining polar fragment of the molecule is located outside the macrocyclic cavity. The interactions via hydrogen bonding are responsible for high negative enthalpy and entropy changes accompanying the complexation of cyclodextrins with teriflunomide. These results were in agreement with the molecular modeling calculations, which provide a clearer picture of the involved interactions at the atomic level.
Assuntos
Crotonatos/química , Ciclodextrinas/química , Leflunomida/química , Toluidinas/química , Entropia , Hidroxibutiratos , Modelos Moleculares , Nitrilas , Espectroscopia de Prótons por Ressonância Magnética , TermodinâmicaRESUMO
BACKGROUND: Malaria can be transmitted by blood transfusion from human to human and it is responsible for the majority of transfusion-transmitted infectious diseases worldwide. In sub-Saharan Africa, it had been estimated that almost a quarter of blood donations contain malaria parasites. Since rapid diagnostic tests and thick blood smear microscopy lack sensitivity for low density parasitaemia, particularly in asymptomatic adults, the most reliable method to assess the problem of transfusion-transmitted malaria are nucleic acid-based molecular approaches such as quantitative polymerase chain reaction. The study was undertaken to determine the prevalence of sub-microscopic malaria parasite infection among blood donors in Malabo, Equatorial Guinea. METHODS: Between July and August 2017, a total of 200 individual blood samples from blood donors at the Malabo Blood Bank were collected and screened by rapid diagnostic tests and thick blood smear microscopy. Retrospectively, the same samples were analysed for the presence of undetected, low-density malaria parasites using quantitative polymerase chain reaction. RESULTS: In comparison to 6.5% (13/200) by rapid diagnostic test and 2.0% (4/200) by microscopy, the proportion of Plasmodium falciparum positive blood donations analysed by quantitative polymerase chain reaction was significantly higher (26%, 52/200). Densities of P. falciparum positive blood donations were ranging from 0.06 to 3707.0 parasites/µL with 79.6% below 100 parasites/µL and therefore not detectable by non-molecular malaria diagnostic tests. qPCR based species identification revealed that P. falciparum was the dominating species responsible for 88.1% (52/59) of positive blood donations, followed by Plasmodium malariae (15.3%, 9/59) and Plasmodium ovale (3.4%, 2/59). CONCLUSIONS: This study confirms that in malaria endemic settings, sub-patent malaria infections among blood donors are prevalent. In blood collected from healthy donors living in Malabo, P. falciparum, P. malariae and P. ovale parasites were identified. Currently widely used malaria diagnostic tools have missed more than 75% of P. falciparum containing blood donations, demonstrating the value of quantitative polymerase chain reaction to reliably detect low density P. falciparum infections. Since the availability of molecular diagnostic methods in malaria endemic countries is still limited, the blood recipients living in malaria endemic countries should be treated following WHO recommendations.
Assuntos
Infecções Assintomáticas/epidemiologia , Doadores de Sangue , Plasmodium falciparum/genética , Plasmodium malariae/genética , Plasmodium ovale/genética , Reação Transfusional/prevenção & controle , Adolescente , Adulto , Monitoramento Epidemiológico , Guiné Equatorial/epidemiologia , Feminino , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Parasitemia/diagnóstico , Parasitemia/epidemiologia , Reação em Cadeia da Polimerase em Tempo Real , Reação Transfusional/epidemiologia , Adulto JovemRESUMO
Background and objectives: To identify the relationship between neck circumference (NC) and cardiometabolic risk factors in children. Materials and Methods: Children and adolescents 6-18 years old (n = 548) from five counties of San Luis Potosí, México were included. Data was collected for biological markers (glucose and lipid profile) and anthropometric and clinical measurements-weight, height, NC, waist circumference (WC), and blood pressure (BP). Body mass index (BMI) was calculated using Quetelet formula (kg/m2). Descriptive analysis, correlation tests, and receiver operating characteristic (ROC) analysis were performed. Results: NC was highly correlated with BMI and WC in both genders (p <0.0001). The most frequent risk factor was high BMI (38.7%). Sensitivity and specificity analysis of NC and high BMI showed an area under the ROC curve of 0.887. Conclusions: According to our findings, NC is a simple, low-cost, and non-invasive measurement, which has a high association with high BMI and increased WC.
Assuntos
Antropometria/métodos , Doenças Metabólicas/classificação , Pescoço , Pesos e Medidas/normas , Adolescente , Antropometria/instrumentação , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Doenças Metabólicas/fisiopatologia , México , Pediatria/instrumentação , Pediatria/métodos , Medição de Risco/métodos , Medição de Risco/normas , Fatores de Risco , Pesos e Medidas/instrumentaçãoRESUMO
BACKGROUND: Alcohol's reinforcement is mediated by dopamine signaling in the ventral striatum, which is modulated by the dopamine transporter (DAT). We hypothesized that methylomic variation in the DAT gene (DAT1/SLC6A3) affects DAT expression, thus contributing to differences in brain reward circuitry in individuals with alcohol dependence (ALC). METHODS: Blood from 45 recently detoxified ALC and 45 healthy control (HC) individuals was used to assess DNA methylation across 5 functional regions of SLC6A3. Participants completed the monetary incentive delay task in a 3-Tesla magnetic resonance imaging (MRI) scanner. Employing regression models, we examined effects of SLC6A3 methylation on nucleus accumbens (NAc) blood-oxygen-level dependent (BOLD) responses during anticipation of high/low reward/loss. RESULTS: Results showed that decreased methylation of the promoter region of SLC6A3 predicted NAc activation during high loss anticipation (p = 0.028) and low loss anticipation (at trend-level; p = 0.057) in HC but not in individuals with ALC. Specifically, percentage of methylation at 2 CpG sites, located -1,001 and -993 base pairs from the transcription start site, accounted for significant variability in NAc activation in the HC group during high (ps ≤ 0.010) and low (ps ≤ 0.006) loss anticipation. There was no effect on reward anticipation. Furthermore, promoter methylation was positively associated with age, which replicates previous findings. CONCLUSIONS: Our data suggest that methylation in the promoter region of SLC6A3 predicts NAc activation during the anticipation of monetary loss in HCs. However, this effect was not present in the ALC group, suggesting that epigenetic regulation of striatal DAT expression might be disrupted in ALC, which may contribute to previously reported differences in sensitivity to reward and punishment in this population. Alternatively, it is possible that a similar relationship in the ALC group remained undetected possibly due to methodological limitations inherent in functional MRI (e.g., poor spatial resolution, low signal-to-noise ratio) that generally restrict interpretations regarding mechanisms of epigenetic factors involved in group differences in BOLD responses. Future neuroimaging studies are needed to further elucidate the relationship between SLC6A3 methylation and NAc activation in ALC.
Assuntos
Alcoolismo/metabolismo , Metilação de DNA/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Recompensa , Adulto , Alcoolismo/diagnóstico por imagem , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Núcleo Accumbens/diagnóstico por imagem , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologiaRESUMO
AIMS: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. METHODS: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. RESULTS: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. CONCLUSION: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. SHORT SUMMARY: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task.
Assuntos
Alcoolismo/diagnóstico por imagem , Alcoolismo/psicologia , Córtex Cerebral/diagnóstico por imagem , Tomada de Decisões/fisiologia , Emoções/fisiologia , Imageamento por Ressonância Magnética/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Distribuição Aleatória , Tempo de Reação/fisiologia , Comportamento SocialRESUMO
AIM: We aimed to illustrate the physiopathology of anterior mitral leaflet perforation after TAVI in patients suffering from infective endocarditis (IE). METHODS AND RESULTS: The first known case of balloon-expandable transapical case from our series suffering from this complication was reported. In addition, a systematic electronic search of all published cases reporting both entities was performed. Five transfemoral cases have been published to the date, all males with mean age of 79.2 year (range: 66-88). Four were treated with self-expandable prostheses (deeply implanted in the outflow tract). There was moderate residual aortic regurgitation in four. Fever and positive blood cultures for typical micoorganisms were present at certain time point in all cases between the first week and up to 11 months (early IE). Three cases underwent cardiac surgery with adequate outcomes and two others died during hospitalization. Medical management in the case from our series allowed patient's survival at 1-year follow up. CONCLUSIONS: Early suspicion of IE whenever anterior mitral perforation is found after TAVI can be life-saving. The hypothetical higher risk of this complication due to higher rate of aortic regurgitation has to be prevented through adequate prosthesis depth and careful sterile surgical technique. © 2016 Wiley Periodicals, Inc.
Assuntos
Estenose da Valva Aórtica/cirurgia , Endocardite Bacteriana/complicações , Ruptura Cardíaca/etiologia , Valva Mitral , Infecções Relacionadas à Prótese/diagnóstico , Substituição da Valva Aórtica Transcateter/efeitos adversos , Idoso , Ecocardiografia Doppler em Cores , Ecocardiografia Transesofagiana , Endocardite Bacteriana/diagnóstico , Evolução Fatal , Ruptura Cardíaca/diagnóstico , Humanos , Masculino , Ruptura EspontâneaRESUMO
Alcohol dependence is characterized by impulsiveness toward consumption despite negative consequences. Although neuro-imaging studies have implicated some regions underlying this disorder, there is little information regarding its large-scale connectivity pattern. This study investigated the within- and between-network functional connectivity (FC) in alcohol dependence and examined its relationship with clinical impulsivity measures. Using probabilistic independent component analysis on resting-state functional magnetic resonance imaging (rs-fMRI) data from 25 alcohol-dependent (AD) and 26 healthy control (HC) participants, we compared the within- and between-network FC between AD and HC. Then, the relationship between FC and impulsiveness as measured by the Barratt Impulsiveness Scale (BIS-11), the UPPS-P Impulsive Scale and the delay discounting task (DDT), was explored. Compared with HC, AD exhibited increased within-network FC in salience (SN), default mode (DMN), orbitofrontal cortex (OFCN), left executive control (LECN) and amygdala-striatum (ASN) networks. Increased between-network FC was found among LECN, ASN and SN. Between-network FC correlations were significantly negative between Negative-Urgency and OFCN pairs with right executive control network (RECN), anterior DMN (a-DMN) and posterior DMN (p-DMN) in AD. DDT was significantly correlated with the between-network FC among the LECN, a-DMN and SN in AD. These findings add evidence to the concept of altered within-network FC and also highlight the role of between-network FC in the pathophysiology of AD. Additionally, this study suggests differential neurobiological bases for different clinical measures of impulsivity that may be used as a systems-level biomarker for alcohol dependence severity and treatment efficacy.
Assuntos
Alcoolismo/fisiopatologia , Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Comportamento Impulsivo/fisiologia , Imageamento por Ressonância Magnética/métodos , Adulto , Feminino , Humanos , Masculino , Descanso , Adulto JovemRESUMO
BACKGROUND: This study sought to evaluate the prevalence of previously undiagnosed arrhythmias in candidates for transcatheter aortic valve replacement (TAVR) and to determine the impact on therapy changes and arrhythmic events after the procedure. METHODS AND RESULTS: A total of 435 candidates for TAVR underwent 24-hour continuous ECG monitoring the day before the procedure. Newly diagnosed arrhythmias were observed in 70 patients (16.1%) before TAVR: paroxysmal atrial fibrillation (AF)/atrial tachycardia (AT) in 28, advanced atrioventricular block or severe bradycardia in 24, nonsustained ventricular tachycardia in 26, and intermittent left bundle-branch block in 3 patients. All arrhythmic events but one were asymptomatic and led to a therapy change in 43% of patients. In patients without known AF/AT, the occurrence of AF/AT during 24-hour ECG recording was associated with a higher rate of 30-day cerebrovascular events (7.1% versus 0.4%; P=0.030). Among the 53 patients with new-onset AF/AT after TAVR, 30.2% had newly diagnosed paroxysmal AF/AT before the procedure. In patients who needed permanent pacemaker implantation after the procedure (n=35), 31.4% had newly diagnosed advanced atrioventricular block or severe bradycardia before TAVR. New-onset persistent left bundle-branch block after TAVR occurred in 37 patients, 8.1% of whom had intermittent left bundle-branch block before the procedure. CONCLUSIONS: Newly diagnosed arrhythmias were observed in approximately a fifth of TAVR candidates, led to a higher rate of cerebrovascular events, and accounted for a third of arrhythmic events after the procedure. This high arrhythmia burden highlights the importance of an early diagnosis of arrhythmic events in such patients to implement the appropriate therapeutic measures earlier.
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Estenose da Valva Aórtica/diagnóstico , Arritmias Cardíacas/diagnóstico , Efeitos Psicossociais da Doença , Eletrocardiografia Ambulatorial/tendências , Índice de Gravidade de Doença , Substituição da Valva Aórtica Transcateter/tendências , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/cirurgia , Arritmias Cardíacas/fisiopatologia , Compreensão , Feminino , Humanos , Masculino , Cuidados Pré-Operatórios/tendências , Resultado do TratamentoRESUMO
Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting-state fMRI functional connectivity (FC) analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting-state FC in 4 networks in alcoholics compared to controls (P < 0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (P < 0.05, corrected), but not in controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles.
Assuntos
Alcoolismo/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Descanso , Adulto , Alcoolismo/genética , Alcoolismo/metabolismo , Feminino , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Mutação/genética , Vias Neurais/irrigação sanguínea , Vias Neurais/patologia , Oxigênio/sangue , Análise de Componente Principal , Escalas de Graduação Psiquiátrica , Proteínas Vesiculares de Transporte de Monoamina/genéticaRESUMO
INTRODUCTION: Gliosarcoma is a rare neoplasm of the central nervous system, similar to glioblastoma multiforme. In contrast to glioblastoma, it is characterised by its propensity for extracranial metastasis (11% of the cases) due to its sarcomatous component. Intramedullary metastasis from primary gliosarcoma is extremely rare. CASE REPORT: A patient who had surgery for primary cerebral gliosarcoma developed paraparesis during the course of the disease. A magnetic resonance image showed an intramedullary spinal cord metastasis requiring surgical treatment. This article reviews the literature on intramedullary spinal cord metastasis from gliosarcoma, and highlights the characteristics, treatment and overall survival. CONCLUSIONS: Only 4 cases of intramedullary gliosarcoma metastasis are described in the literature. This extremely rare entity should be suspected with the onset of spinal cord symptoms during the course of primary cerebral gliosarcoma.
Assuntos
Neoplasias Encefálicas/patologia , Gliossarcoma/secundário , Neoplasias da Medula Espinal/secundário , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
The current study illuminates the multifaceted role of Serum Amyloid A (SAA), an essential acute-phase protein implicated in diverse biological realms, encompassing inflammation, oncogenesis, and stress modulation. With a focus on delineating the intricate protein-protein interactions orchestrated by SAA, this investigation unravels its diverse functions within the human physiological landscape. Utilizing the HepG2 cell line, renowned for its proficiency in facilitating SAA overexpression, we meticulously generated protein extracts after inducing SAA hyperexpression. Integrating Co-Immunoprecipitation techniques with Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS) enabled discernment and characterization of the protein complexes intricately associated with SAA. Our data elucidates a pronounced upregulation in SAA expression levels within induced samples compared to controls, substantiating its pivotal role among inflammatory cascades. Specifically, LC/MS/MS profiling delineated interactions with nine distinct proteins, encompassing pivotal players in actin dynamics, neuronal morphogenesis, lipid homeostasis, and immunomodulation. Furthermore, this investigation underscores the plausible ramifications of these molecular interactions in pathologies, including Alzheimer's disease, oncological manifestations, and rheumatoid arthritis. Through comprehensive analyses, this investigation sheds light on the intricate roles of SAA and provides a foundation for future therapeutic modalities targeting SAA pathologies.
RESUMO
Sensory processing sensitivity (SPS) is a personality trait that makes certain individuals excessively sensitive to stimuli. People carrying this trait are defined as Highly Sensitive People (HSP). The SPS trait is notably prevalent among nursing students and nurse staff. Although there are HSP diagnostic tools, there is little information about early detection. Therefore, the aim of this work was to develop a prediction model to identify HSP and provide an individualized nursing assessment. A total of 672 nursing students completed all the evaluations. In addition to the HSP diagnosis, emotional intelligence, communication skills, and conflict styles were evaluated. An interpretable machine learning model was trained to predict the SPS trait. We observed a 33% prevalence of HSP, which was higher in women and people with previous health training. HSP were characterized by greater emotional repair (p = 0.033), empathy (p = 0.030), respect (p = 0.038), and global communication skills (p = 0.036). Overall, sex and emotional intelligence dimensions are important to detect this trait, although personal characteristics should be considered. The present individualized prediction model could help to predict the presence of the SPS trait in nursing students, which may be useful in conducting intervention strategies to avoid the negative consequences and reinforce the positive ones of this trait.
RESUMO
This study aimed to develop and implement a nanotechnology-based alternative to traditional tracers used in the oil and gas industry for assessing interwell connectivity. A simple and rapid hydrothermal protocol for synthesizing carbon quantum dots (CQDs) using agroindustry waste was implemented. Three commercial CQDs were employed (CQDblue, CQDgreen, and CQDred); the fourth was synthesized from orange peel (CQDop). The CQDs from waste and other commercials with spherical morphology, nanometric sizes less than 11 nm in diameter, and surface roughness less than 3.1 nm were used. These tracers demonstrated high colloidal stability with a negative zeta potential, containing carbonyl-type chemical groups and unsaturations in aromatic structures that influenced their optical behavior. All materials presented high colloidal stability with negative values of charge z potential between -17.8 and -49.1. Additionally, individual quantification of these tracers is feasible even in scenarios where multiple CQDs are present in the effluent with a maximum percentage of interference of 15.5% for CQDop in the presence of the other three nanotracers. The CQDs were injected into the field once the technology was insured under laboratory conditions. Monitoring the effluents allowed the determination of connectivity for five first-line producer wells. This study enables the application of CQDs in the industry, particularly in fields where the arrangement of injector and producer wells is intricate, requiring the use of multiple tracers for a comprehensive description of the system.