Metabolomics improves the histopathological diagnosis of asphyxial deaths: an animal proof-of-concept model

The diagnosis of mechanical asphyxia remains one of the most difficult issues in forensic pathology. Asphyxia ultimately results in cardiac arrest (CA) and, as there are no specific markers, the differential diagnosis of primitive CA and CA secondary to asphyxiation relies on circumstantial details and on the pathologist experience, lacking objective evidence. Histological examination is currently considered the gold standard for CA post-mortem diagnosis. Here we present the comparative results of histopathology versus those previously obtained by 1H nuclear magnetic resonance (NMR) metabolomics in a swine model, originally designed for clinical purposes, exposed to two different CA causes, namely ventricular fibrillation and asphyxia. While heart and brain microscopical analysis could identify the damage induced by CA without providing any additional information on the CA cause, metabolomics allowed the identification of clearly different profiles between the two groups and showed major differences between asphyxiated animals with good and poor outcomes. Minute-by-minute plasma sampling allowed to associate these modifications to the pre-arrest asphyxial phase showing a clear correlation to the cellular effect of mechanical asphyxia reproduced in the experiment. The results suggest that metabolomics provides additional evidence beyond that obtained by histology and immunohistochemistry in the differential diagnosis of CA

Sintomas Cardiopulmonares Pós-COVID-19: Preditores e Características de Imagem de Pacientes após a Alta Hospitalar

Resumo Fundamento A maioria da evidência sobre o impacto da síndrome COVID pós-aguda (PACS, do inglês, post-acute COVID-19 syndrome) descreve sintomas individuais sem correlacioná-los com exames de imagens. Objetivos Avaliar sintomas cardiopulmonares, seus preditores e imagens relacionadas em pacientes com COVID-19 após alta hospitalar. Métodos Pacientes consecutivos, que sobreviveram à COVID-19, foram contatados 90 dias após a alta hospitalar. A equipe de desfechos clínicos (cega quanto aos dados durante a internação) elaborou um questionário estruturado avaliando sintomas e estado clínico. Uma análise multivariada foi realizada abordando a evolução da COVID-19, comorbidades, ansiedade, depressão, e estresse pós-traumático durante a internação, e reabilitação cardíaca após a alta. O nível de significância usado nas análises foi de 5%. Resultados Foram incluídos 480 pacientes (idade 59±14 anos, 67,5% do sexo masculino) que receberam alta hospitalar por COVID-19; 22,3% necessitaram de ventilação mecânica. A prevalência de pacientes com sintomas cardiopulmonares relacionados à PACS (dispneia, cansaço/fadiga, tosse e desconforto no peito) foi de 16,3%. Vários parâmetros de tomografia computadorizada do tórax e de ecocardiograma foram similares entre os pacientes com e sem sintomas cardiopulmonares. A análise multivariada mostrou que sintomas cardiopulmonares foram relacionados de maneira independente com sexo feminino (OR 3,023; IC95% 1,319-6,929), trombose venosa profunda durante a internação (OR 13,689; IC95% 1,069-175,304), nível elevado de troponina (OR 1,355; IC95% 1,048-1,751) e de proteína C reativa durante a internação (OR 1,060; IC95% 1,023-1,097) e depressão (OR 6,110; IC95% 2,254-16,558). Conclusão Os sintomas cardiopulmonares relacionados à PACS 90 dias após a alta hospitalar são comuns e multifatoriais. Além dos marcadores trombóticos, inflamatórios e de lesão miocárdica durante a internação, sexo feminino e depressão foram associados independentemente com sintomas cardiopulmonares relacionados à PACS. Esses resultados destacaram a necessidade de uma abordagem multifacetada direcionada a pacientes susceptíveis

Short Conduction Delays Cause Inhibition Rather than Excitation to Favor Synchrony in Hybrid Neuronal Networks of the Entorhinal Cortex

How stable synchrony in neuronal networks is sustained in the presence of conduction delays is an open question. The Dynamic Clamp was used to measure phase resetting curves (PRCs) for entorhinal cortical cells, and then to construct networks of two such neurons. PRCs were in general Type I (all advances or all delays) or weakly type II with a small region at early phases with the opposite type of resetting. We used previously developed theoretical methods based on PRCs under the assumption of pulsatile coupling to predict the delays that synchronize these hybrid circuits. For excitatory coupling, synchrony was predicted and observed only with no delay and for delays greater than half a network period that cause each neuron to receive an input late in its firing cycle and almost immediately fire an action potential. Synchronization for these long delays was surprisingly tight and robust to the noise and heterogeneity inherent in a biological system. In contrast to excitatory coupling, inhibitory coupling led to antiphase for no delay, very short delays and delays close to a network period, but to near-synchrony for a wide range of relatively short delays. PRC-based methods show that conduction delays can stabilize synchrony in several ways, including neutralizing a discontinuity introduced by strong inhibition, favoring synchrony in the case of noisy bistability, and avoiding an initial destabilizing region of a weakly type II PRC. PRCs can identify optimal conduction delays favoring synchronization at a given frequency, and also predict robustness to noise and heterogeneity

8‐Substituted 3‐Arylcoumarins as Potent and Selective MAO‐B Inhibitors: Synthesis, Pharmacological Evaluation, and Docking Studies

Neurodegenerative disorders are becoming more prevalent given the increase in the aging population. This has inspired active research in the development of new drugs that could mark an important advance in the treatment of complex diseases such as Alzheimer′s and Parkinson′s. With the aim of finding new MAO-B-selective inhibitors, we report the synthesis, in vitro evaluation, and docking simulation of a new series of 3-arylcoumarins variously substituted at the 8-position. Most of the studied compounds show high affinity and selectivity for the hMAO-B isoform, with IC50 values in the low micro- to nanomolar range. Some of them have greater hMAO-B inhibitory activity and selectivity than the reference compound, selegiline. Compounds 7 and 8 are the most active of this series, with compound 8 being fivefold more potent against MAO-B and severalfold more selective than selegiline. Docking experiments were carried out with hMAO-B crystal structures, providing new information about the enzyme–inhibitor interaction and the potential therapeutic application of the new 8-substituted 3-arylcoumarins