Etapa subaguda de pos-COVID-19 grave o crítico. Rehabilitación musculoesquelética, respiratoria y uso de corticoides. Experiencia de la Unidad de Rehabilitación del Hospital del Banco de Seguros del Estado (URHBSE) / Subacute stage of severe or critical post-COVID-19. Musculoskeletal and respiratory rehabilitation, and use of corticosteroids. Experience of the rehabilitation Unit of the Banco de Seguros del Estado Hospital (URHBSE) / Estadio subagudo de pós-COVID-19 grave ou crítico. Reabilitação musculoesquelética e respiratória e uso de corticosteroides. Experiência da Unidade de Reabilitação do Hospital do Banco de Seguros do Estado (URHBSE)

Introducción: en los pacientes que cursaron COVID-19 grave o crítico se ha descripto el uso de prednisona y rehabilitación musculoesquelética y respiratoria. No está claramente establecido el rol de estas intervenciones, ni el momento óptimo para su inicio. En este trabajo se muestran los resultados de la Unidad de Rehabilitación del Hospital del Banco de Seguros del Estado (URHBSE) que implementó un programa de rehabilitación integral y uso de corticoides en la etapa subaguda de pacientes pos-COVID-19 grave o crítico, con un enfoque sistematizado, trabajando desde la interdisciplina y centrado en la persona atendida. Se reportan hallazgos al ingreso, requerimiento de oxígeno, escala de Barthel, patrones tomográficos, uso de corticoides, su respuesta y complicaciones. Se describen los resultados de este enfoque sobre variables clínicas, respiratorias y funcionales. Material y método: estudio descriptivo, retrospectivo, de pacientes pos-COVID-19 que completaron la rehabilitación en la URHBSE, en el período comprendido entre abril y agosto de 2021. Datos obtenidos de revisión de historias clínicas. Análisis estadístico con PRISM (v8.2.1). Resultados: completaron el programa de rehabilitación 84 pacientes. Al ingreso a la URHBSE, 55% tenía dependencia total o grave en la escala de Barthel. No lograba marcha el 48%. Requería oxígeno el 89,2% de los pacientes con una media de saturación de 90,3 ± 4,8. El 25% ingresó requiriendo máscara con reservorio. Todos los pacientes que comenzaron el programa se encontraban en fase subaguda de la enfermedad (4 a 12 semanas), y recibieron un plan de rehabilitación integral e individualizado. El objetivo era alcanzar una situación funcional similar a la que presentaban previo al COVID-19. La duración de la internación en la URHBSE fue de 23,5 ± 13,8 días. A 76 pacientes (90,5%) se les realizó tomografía de alta resolución de tórax (TACAR), resultando patológica en 96,1%. Predominaba el vidrio deslustrado (49,3%), la consolidación en 8,23% y un patrón de tipo fibrosis like en 30,13%. Se detectaron alteraciones tomográficas "no típicas" de daño pos-COVID (derrame pleural, nódulos cavitados, cavidades apicales, etc.) en 11,8% de las tomografías. En dos pacientes (2,6%) se halló una aspergilosis pulmonar y en 6,6% tromboembolismo pulmonar. Recibieron prednisona 44 pacientes (52,3%). En 63,4% se suspendió el aporte de oxígeno en los primeros 15 días desde el inicio de prednisona. Encontramos asociación entre el patrón tomográfico con vidrio deslustrado y la suspensión precoz del aporte de oxígeno desde el inicio de prednisona (p = 0,047). A pesar del alto grado de colonización, incluso en aquellos casos en que utilizamos prednisona, no observamos infecciones por microorganismos colonizantes. Comparando ingreso y egreso se hallaron diferencias estadísticamente significativas en los siguientes parámetros: el grado de disnea, el requerimiento de oxígeno (un solo paciente fue dado de alta con oxígeno), la saturación, el grado de instrumentación (traqueostomía, sonda nasogástrica, etc.), y la escala de dependencia de Barthel. En cuanto a las variables respiratorias solo contamos con el dato de la presencia de disnea de los primeros 35 pacientes, de éstos, 83% presentaba disnea al ingreso, mientras que solo 17% la presentaba al egreso (p < 0,0001). Hubo, asimismo, diferencias significativas en el requerimiento de oxígeno entre el ingreso y el egreso (p < 0,0001) y en el grado de dependencia medido en la escala de Barthel, teniendo dependencia total o grave al ingreso 55% de los pacientes y solo 3,4% al alta. Conclusiones: las intervenciones realizadas en la etapa subaguda de la enfermedad se asociaron con mejoras significativas en variables de interés clínico. Faltan más estudios para definir el rol y el momento exacto del inicio de los corticoides y la rehabilitación en este grupo de pacientes. (AU)

Introduction: In patients with severe or critical COVID-19, the use of prednisone and musculoskeletal and respiratory rehabilitation has been described. The role of these interventions and the optimal time for their initiation are not clearly established. This study presents the results of the Rehabilitation Unit of the Banco de Seguro del Estado Hospital, which implemented a comprehensive rehabilitation program and the use of corticosteroids in the subacute stage of patients with severe or critical post-COVID-19, with a systematic approach, working interdisciplinary and centered on the person being treated. Findings at admission, oxygen requirement, Barthel scale, tomographic patterns, use of corticosteroids, their response, and complications are reported. The results of this approach on clinical, respiratory, and functional variables are described. Method: Descriptive, retrospective study of post-COVID-19 patients who completed rehabilitation at the Rehabilitation Unit of the Banco de Seguros del Estado Hospital (URHBSE) in the period April-August 2021. Data obtained from review of medical records, statistical analysis with PRISM (v8.2.1). Results: Eighty-four patients completed the rehabilitation program. Upon admission to the URHBSE, 55% had total or severe dependence on the Barthel scale. Forty-eight percent were unable to walk. Eighty-nine-point two percent required oxygen, with a mean saturation of 90.3 ± 4.8. Twenty-five percent of patients were admitted requiring a reservoir mask. All patients who entered the program were in the subacute phase of the disease (4 to 12 weeks) and received a comprehensive and individualized rehabilitation plan. The objective was to achieve a functional situation similar to what they had before COVID-19. The length of stay at the URHBSE was 23.5 ± 13.8 days. A total of 76 patients (90.5%) underwent high-resolution chest tomography (HRCT), which was pathological in 96.1% of cases. The predominant findings were ground-glass opacity in 49.3% of cases, consolidation in 8.23%, and a fibrosis-like pattern in 30.13%. "Non-typical" post-COVID damage tomographic alterations were detected (pleural effusion, cavitary nodules, apical cavities, etc.) in 11.8% of the tomographies. In 2 patients (2.6%), pulmonary aspergillosis was found, and in 6.6%, pulmonary thromboembolism. Forty-four patients (52.3%) received prednisone. In 63.4% of cases, oxygen supplementation was discontinued within the first 15 days from the start of prednisone. We found an association between the ground-glass opacity tomographic pattern and early discontinuation of oxygen supplementation from the start of prednisone (p = 0.047). Despite the high degree of colonization, we did not observe infections by colonizing microorganisms, even in those who used prednisone. Comparing admission and discharge, statistically significant differences were found in the following parameters: degree of dyspnea, oxygen requirement (only one patient was discharged with oxygen), saturation, degree of instrumentation (tracheostomy, nasogastric tube, etc.), and the Barthel dependency scale. Regarding respiratory variables, we only have data on the presence of dyspnea in the first 35 patients. Of these, 83% had dyspnea at admission, while only 17% had it at discharge (p < 0.0001). There were also significant differences in the oxygen requirement between admission and discharge (p < 0.0001) and in the degree of dependency measured on the Barthel scale. Fifty-five percent of patients had total or severe dependence at admission, compared to only 3.4% at discharge. Conclusions: The interventions carried out in the subacute stage of the disease were associated with significant improvements in clinical variables of interest. More studies are needed to define the role and the exact timing of the initiation of corticosteroids and rehabilitation in this group of patients.

Introdução: O uso de prednisona e reabilitação musculoesquelética e respiratória foi descrito no tratamento de pacientes com COVID-19 grave ou crítico. O papel destas intervenções e o momento ideal para o seu início não estão claramente estabelecidos. Este trabalho mostra os resultados da Unidade de Reabilitação Hospitalar do Banco de Seguro del Estado que implementou um programa abrangente de reabilitação e uso de corticosteroides na fase subaguda de pacientes graves ou críticos pós-COVID-19, com uma abordagem sistematizada, trabalhando de forma interdisciplinar e centrada no paciente. São relatados os achados na admissão, a necessidade de oxigênio, a escala de Barthel, os padrões tomográficos, o uso de corticosteroides, a resposta ao tratamento e as complicações. Os resultados desta abordagem sobre variáveis clínicas, respiratórias e funcionais são descritos. Material e métodos: Estudo descritivo e retrospectivo de pacientes pós-COVID-19 que completaram reabilitação na Unidade de Reabilitação do Hospital Banco de Seguros del Estado (URHBSE) no período de abril a agosto de 2021. Os dados foram obtidos dos prontuários de pacientes com posterior análise estatísticas usando PRISM (v8.2.1). Resultados: 84 pacientes completaram o programa de reabilitação. No momento da admissão na URHBSE, 55% apresentavam dependência total ou grave da escala de Barthel. 48% não conseguiam se mover. 89,2% necessitaram oxigênio com saturação média de 90,3 ± 4,8. 25% dos pacientes foram internados necessitando máscara com reservatório. Todos os pacientes que ingressaram no programa estavam na fase subaguda da doença (4 a 12 semanas) e receberam um plano de reabilitação abrangente e individualizado. O objetivo era alcançar uma situação funcional semelhante à que apresentavam antes da COVID-19. O tempo de permanência na URHBSE foi de 23,5±13,8 dias. A tomografia de tórax de alta resolução (TCAR) foi realizada em 76 pacientes (90,5%); os resultados foram patológicos em 96,1%. O vidro fosco predominou em 49,3% deles, a consolidação em 8,23% e o padrão fibroso em 30,13%. Alterações tomográficas "atípicas" de danos pós-COVID (derrame pleural, nódulos cavitados, cavidades apicais, etc.) foram detectadas em 11,8% dos exames tomográficos. Aspergilose pulmonar foi encontrada em 2,6% dos pacientes e tromboembolismo pulmonar em 6,6%. 44 pacientes (52,3%) receberam prednisona. Em 63,4% a oferta de oxigênio foi suspensa nos primeiros 15 dias após o início da mesma. Encontramos associação entre o padrão tomográfico em vidro fosco e a suspensão precoce da oferta de oxigênio desde o início da administração da prednisona (p = 0,047). Apesar do alto grau de colonização, mesmo naqueles que usaram prednisona, não observamos infecções. Em relação às variáveis respiratórias, só temos dados sobre a presença de dispneia nos primeiros 35 pacientes; destes, 83% apresentavam dispneia na admissão, enquanto apenas 17% a apresentavam na alta (p< 0,0001). Observou-se também diferenças significativas na necessidade de O2 entre a admissão e a alta (p< 0,0001) e no grau de dependência medido pela escala de Barthel, com 55% dos pacientes apresentando dependência total ou grave na admissão e apenas 3,4% na alta. Conclusões: As intervenções realizadas na fase subaguda da doença foram associadas a melhorias significativas nas variáveis de interesse clínico. São necessários mais estudos para definir o papel e o momento exato do início dos corticosteroides e da reabilitação neste grupo de pacientes.

Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening.

The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC50 ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure-activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP-IV available at the PDB.

Resveratrol Potently Counteracts Quercetin Starvation-Induced Autophagy and Sensitizes HepG2 Cancer Cells to Apoptosis.

SCOPE: Resveratrol (RSV) has been described as a potent antioxidant, antisteatotic, and antitumor compound, and it has also been identified as a potent autophagy inducer. On the other hand, quercetin (QCT) is a dietary flavonoid with known antitumor, anti-inflammatory, and antidiabetic effects. Additionally, QCT increases autophagy. To study the hypothetical synergistic effect of both compounds, we test the combined effect of QCT and RSV on the autophagy process in HepG2 cells. METHODS AND RESULTS: Autophagy is studied by western blotting, real-time RT-PCR, and cellular staining. Our results clearly indicate a bifunctional molecular effect of RSV. Both polyphenols are individually able to promote autophagy. Strikingly, when RSV is combined with QCT, it promotes a potent reduction of QCT-induced autophagy and influences proapoptotic signaling. CONCLUSION: RSV acts differentially on the autophagic process depending on the cellular energetic state. We further characterize the molecular mechanisms related to this effect, and we observe that AMP-activated protein kinase (AMPK) phosphorylation, heme oxygenase 1 (HO-1) downregulation, lysosomal membrane permeabilization (LMP), and Zinc (Zn2+ ) dynamics could be important modulators of such RSV-related effects and could globally represent a promising strategy to sensitize cancer cells to QCT treatment.

Ephedrine as a lead compound for the development of new DPP-IV inhibitors.

AIM: Extracts from Ephedra species have been reported to be effective as antidiabetics. A previous in silico study predicted that ephedrine and five ephedrine derivatives could contribute to the described antidiabetic effect of Ephedra extracts by inhibiting dipeptidyl peptidase IV (DPP-IV). Finding selective DPP-IV inhibitors is a current therapeutic strategy for Type 2 diabetes mellitus management. Therefore, the main aim of this work is to experimentally determine whether these alkaloids are DPP-IV inhibitors. Materials & methods: The DPP-IV inhibition of Ephedra's alkaloids was determined via a competitive-binding assay. Then, computational analyses were used in order to find out the protein-ligand interactions and to perform a lead optimization. RESULTS: Our results show that all six molecules are DPP-IV inhibitors, with IC50 ranging from 124 µM for ephedrine to 28 mM for N-methylpseudoephedrine. CONCLUSION: Further computational analysis shows how Ephedra's alkaloids could be used as promising lead molecules for designing more potent and selective DPP-IV inhibitors.

Decidual lymphocytes of human spontaneous abortions induce apoptosis but not necrosis in JEG-3 extravillous trophoblast cells.

The human decidua contains an unusually high proportion of lymphocytes, mainly NK and T cells, which are potentially cytotoxic to the trophoblast when they are stimulated with certain cytokines. Given the high incidence of spontaneous abortion in humans and other species, our working hypothesis is that decidual lymphocytes are involved in immunological mechanisms that attack the trophoblast and induce abortion when any gestational problem arises. To test this hypothesis, flow cytometry was used to compare decidual lymphocyte populations in first-trimester spontaneous abortions and elective terminations of first-trimester pregnancy. We found significantly higher proportions of decidual lymphocytes that expressed activation markers, and of T cells (mainly T helper cells) in spontaneous abortions than in elective terminations of pregnancy. Decidual lymphocytes from spontaneous abortion, like decidual lymphocytes from elective termination of pregnancy and peripheral blood lymphocytes, were however, unable to lyse the JEG-3 extravillous cytotrophoblast cell line in a (51)Cr-release assay. Nevertheless, decidual lymphocytes from spontaneous abortion, unlike decidual lymphocytes from elective termination of pregnancy and peripheral blood lymphocytes, induced apoptosis in JEG-3 cells as determined by DNA fragment-release assay. Hematoxylin and eosin staining showed a significantly higher proportion of apoptotic JEG-3 cells when these cells were treated with decidual lymphocytes from spontaneous abortion than when JEG-3 cells were cultured with decidual lymphocytes from elective termination of pregnancy. The ultrastructural signs of apoptosis were confirmed by electron microscopy. These data support the hypothesis that activated decidual lymphocytes participate in human spontaneous abortion by inducing apoptosis but not necrosis of the trophoblast.