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The biogenesis of mammalian autophagosomes remains to be fully defined. Here, we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. A previously unrecognized apparatus defined here controls HyPAS biogenesis and mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes, which emerge via convergence of secretory and endosomal pathways, and show that this process is targeted by microbial factors such as coronaviral membrane-modulating proteins.
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Autofagossomos/virologia , COVID-19/virologia , Autofagia , COVID-19/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Endossomos/fisiologia , Endossomos/virologia , Complexo de Golgi/fisiologia , Células HEK293 , Células HeLa , Humanos , Fusão de Membrana , Microscopia Confocal , Fagossomos/metabolismo , Fagossomos/virologia , Proteínas Qa-SNARE/biossíntese , Receptores sigma/biossíntese , SARS-CoV-2 , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/biossíntese , Sinaptotagminas/biossíntese , Receptor Sigma-1RESUMO
Orthohantaviruses cause hantavirus cardiopulmonary syndrome; most cases occur in the southwest region of the United States. We discuss a clinical case of orthohantavirus infection in a 65-year-old woman in Michigan and the phylogeographic link of partial viral fragments from the patient and rodents captured near the presumed site of infection.
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Infecções por Hantavirus , Orthohantavírus , Feminino , Humanos , Idoso , Michigan/epidemiologia , Filogeografia , SíndromeRESUMO
Sin Nombre orthohantavirus (SNV), a negative-sense, single-stranded RNA virus that is carried and transmitted by the North American deer mouse Peromyscus maniculatus, can cause infection in humans through inhalation of aerosolized excreta from infected rodents. This infection can lead to hantavirus cardiopulmonary syndrome (HCPS), which has an â¼36% case-fatality rate. We used reverse transcriptase quantitative PCR (RT-qPCR) to confirm SNV infection in a patient and identified SNV in lung tissues in wild-caught rodents from potential sites of exposure. Using viral whole-genome sequencing (WGS), we identified the likely site of transmission and discovered SNV in multiple rodent species not previously known to carry the virus. Here, we report, for the first time, the use of SNV WGS to pinpoint a likely site of human infection and identify SNV simultaneously in multiple rodent species in an area of known host-to-human transmission. These results will impact epidemiology and infection control for hantaviruses by tracing zoonotic transmission and investigating possible novel host reservoirs. IMPORTANCE Orthohantaviruses cause severe disease in humans and can be lethal in up to 40% of cases. Sin Nombre orthohantavirus (SNV) is the main cause of hantavirus disease in North America. In this study, we sequenced SNV from an infected patient and wild-caught rodents to trace the location of infection. We also discovered SNV in rodent species not previously known to carry SNV. These studies demonstrate for the first time the use of virus sequencing to trace the transmission of SNV and describe infection in novel rodent species.
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Reservatórios de Doenças/virologia , Síndrome Pulmonar por Hantavirus/transmissão , Síndrome Pulmonar por Hantavirus/veterinária , Síndrome Pulmonar por Hantavirus/virologia , Doenças dos Roedores/transmissão , Doenças dos Roedores/virologia , Roedores/virologia , Vírus Sin Nombre , Animais , Anticorpos Antivirais , Sequência de Bases , Feminino , Orthohantavírus/genética , Infecções por Hantavirus/genética , Infecções por Hantavirus/transmissão , Infecções por Hantavirus/veterinária , Síndrome Pulmonar por Hantavirus/epidemiologia , Humanos , Pulmão , Masculino , Camundongos , América do Norte , Peromyscus/virologia , Prevalência , RNA Viral/genética , Doenças dos Roedores/epidemiologia , Vírus Sin Nombre/genética , População Branca , Sequenciamento Completo do GenomaRESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.
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1-Desoxinojirimicina/análogos & derivados , Tratamento Farmacológico da COVID-19 , Indolizinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , 1-Desoxinojirimicina/farmacologia , Animais , COVID-19/virologia , Chlorocebus aethiops , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Células VeroRESUMO
BACKGROUND: Convalescent plasma (CP) is a potentially important therapy for coronavirus disease 2019 (COVID-19). However, knowledge regarding neutralizing antibody (NAb) titers in donor plasma and their impact in patients with acute COVID-19 remains largely undetermined. We measured NAb titers in CP and in patients with acute COVID-19 before and after transfusion through the traditional Food and Drug Administration investigational new drug pathway. METHODS: We performed a single-arm interventional trial measuring NAb and total antibody titers before and after CP transfusion over a 14-day period in hospitalized patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection. RESULTS: NAb titers in the donor CP units were low (<1:40 to 1:160) and had no effect on recipient neutralizing activity 1 day after transfusion. NAb titers were detected in 6 of 12 patients on enrollment and in 11 of 12 at ≥2 time points. Average titers peaked on day 7 and declined toward day 14 (Pâ =â .004). Nab titers and immunoglobulin G levels were correlated in donor plasma units (ρâ =â 0.938; Pâ <â .001) and in the cumulative patient measures (ρâ =â 0.781; Pâ <â .001). CONCLUSIONS: CP infusion did not alter recipient NAb titers. Prescreening of CP may be necessary for selecting donors with high titers of neutralizing activity for infusion into patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04434131.
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Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Doadores de Sangue , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/genética , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunização Passiva , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , New Mexico/epidemiologia , Pandemias , Pneumonia Viral/virologia , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia , Resultado do Tratamento , Soroterapia para COVID-19RESUMO
OBJECTIVES: To analyze the risk factors for postoperative deep vein thrombosis (DVT) in neurosurgical patients to provide the basis for the prevention of postoperative DVT. METHODS: A total of 141 patients underwent neurosurgery were enrolled. Thrombelastography (TEG) test was performed before and at the end of surgery. According to whether there was DVT formation after operation, the patients were divided into a thrombosis group and a non-thrombosis group. T-test and rank sum test were used to compare the general clinical characteristics of the 2 groups, such as age, gender, intraoperative blood loss, D-dimer, intraoperative crystal input, colloid input, blood product transfusion, operation duration, length of postoperative hospitalization. The application of chi-square test and rank-sum test were used to compared TEG main test indicators such as R and K values between the 2 groups. Logistic regression was used to analyze the possible risk factors for postoperative DVT in neurosurgical patients. RESULTS: There were significant differences in postoperative TEG index R, clotting factor function, intraoperative blood loss, hypertension or not, length of postoperative hospital stay, and postoperative absolute bed time (all P<0.05). Logistic regression analysis showed hypercoagulability, more intraoperative blood loss and longer postoperative absolute bed time were risk factors for DVT formation after craniotomy. CONCLUSIONS: Hypercoagulability in postoperative TEG test of patients is an important risk factor for the formation of postoperative DVT after neurosurgery, which can predict the occurrence of postoperative DVT to some extent.
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Trombofilia , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia , Craniotomia/efeitos adversos , Humanos , Complicações Pós-Operatórias/epidemiologia , Período Pós-Operatório , Fatores de RiscoRESUMO
The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20%↓) at 2 days postinfection (dpi) and death at 7 dpi in mice, but the relevant mechanisms are not fully understood. Glomus cells in the carotid body and catecholaminergic neurons in locus coeruleus (LC), neurokinin 1 receptor (NK1R)-expressing neurons in the retrotrapezoid nucleus (RTN), and serotonergic neurons in the raphe are chemosensitive and responsible for HCVR. We asked whether the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intranasally inoculated with saline or the HK483 virus were exposed to hypercapnia for 5 min at 0, 2, 4, or 6 dpi, followed by immunohistochemistry to determine the expression of nucleoprotein of H5N1 influenza A (NP) alone and coupled with 1) tyrosine hydroxylase (TH) in the carotid body and LC, 2) NK1R in the RTN, and 3) tryptophan hydroxylase (TPH) in the raphe. HK483 viral infection blunted HCVR by â¼20, 50, and 65% at 2, 4, and 6 dpi. The NP was observed in the pontomedullary respiratory-related nuclei (but not in the carotid body) at 4 and 6 dpi, especially in 20% of RTN NK1R, 35% of LC TH, and â¼10% raphe TPH neurons. The infection significantly reduced the local NK1R or TPH immunoreactivity and population of neurons expressing NK1R or TPH. We conclude that the HK483 virus infects the pontomedullary respiratory nuclei, particularly chemosensitive neurons in the RTN, LC, and raphe, contributing to the severe depression of HCVR and respiratory failure at 6 dpi. NEW & NOTEWORTHY The H5N1 virus infection is lethal due to respiratory failure, but the relevant mechanisms remain unclear. In this study, we demonstrated a gradual diminution of hypercapnic ventilatory response to a degree, leading to respiratory failure over a 6-day infection. Death was associated with viral replication in the pontomedullary respiratory-related nuclei, especially the central chemosensitive neurons. These results not only provide insight into the mechanisms of the lethality of H5N1 viral infection but also offer clues in the development of corresponding treatments to minimize and prevent respiratory failure.
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Hipercapnia/virologia , Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Humana/virologia , Neurônios/virologia , Animais , Aves/virologia , Feminino , Humanos , Vírus da Influenza A/patogenicidade , Influenza Aviária/virologia , Camundongos Endogâmicos BALB C , Receptores da Neurocinina-1/metabolismoRESUMO
INTRODUCTION AND AIM: Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality, and predicting the prognosis is challenging. This study aimed to compare the performance of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CysC) in predicting the 90-day mortality in patients with hepatitis B virus (HBV)-associated ACLF (HBV-ACLF). MATERIALS AND METHODS: This prospective, observational study enrolled 54 patients with HBV-ACLF. The serum NGAL and CysC levels were determined. A multivariate logistic regression analysis was used to analyze the independent risk factors of mortality. RESULTS: Serum NGAL, but not CysC, was found to significantly correlate with the total bilirubin, international normalized ratio, and model for end-stage liver disease (MELD). Serum NGAL [odds ratio (OR), 1.008; 95% confidence interval (CI), 1.004-1.012; P < 0.01], but not CysC, was an independent risk factor for developing hepatorenal syndrome. Moreover, NGAL (OR, 1.005; 95% CI, 1.001-1.010; P < 0.01) along with the MELD score was independently associated with the overall survival in patients with HBV-ACLF. Patients with HBV-ACLF were stratified into two groups according to the serum NGAL level at baseline (low risk: <217.11 ng/mL and high risk: ≥ 217.11 ng/mL). The 90-day mortality rate was 22.73% (5/22) in the low-risk group and 71.88% (23/32) in the high-risk group. Moreover, NGAL, but not CysC, significantly improved the MELD score in predicting the prognosis of HBV-ACLF. CONCLUSION: The serum NGAL might be superior to CysC in predicting the prognosis of HBV-ACLF with the normal creatinine level.
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Insuficiência Hepática Crônica Agudizada/sangue , Cistatina C/sangue , Lipocalina-2/sangue , Insuficiência Hepática Crônica Agudizada/diagnóstico , Insuficiência Hepática Crônica Agudizada/mortalidade , Adulto , Biomarcadores/sangue , China/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
The objective of this study was to analyze the prevalence of drug-resistant HBV mutants in patients with treatment failure during the past seven years (2010-2016). 4055 HBV-infected patients who underwent HBV polymerase gene mutation test from 2010 to 2016 were enrolled. The nucleos(t)ide analogues (NAs) resistance mutation positions, including rtL180, rtA181, rtT184, rtS202, rtM204, rtI233, rtN236, rtI169, rtV173, and rtM250 were analyzed. Genotypic resistance mutations were detected in 30.8% (1248/4055) of the patients with treatment failure. Rates of drug-resistant mutations associated with LAM, ADV, ETV, and multidrug were 27.23% (1104/4055), 9.67% (392/4055), 3.69% (150/4055), and 0.79% (32/4055). Among the primary NA-resistant mutations, rtM204I (13.44%, 545/4055) occurred more frequently, followed by rtM204V, rtN236T, rtA181T, and rtA181V. For single-base mutations, rtL180M and rtA181V increased gradually during the past seven years, while rtM204I/V and rtN236T decreased after 2015. The development of drug-resistant mutations positively correlated with the consumption of ETV (r = 0.964, P = 0.002), and weakly correlated with that of LAM (r = 0.679, P = 0.109) and ADV (r = 0.429, P = 0.354). Moreover, single-base mutation rtA181V and multi-base mutations (rtL180M + M204I and rtL180M + M204V + M204I) were more common in HBV genotype C than those in genotype B (1.94% vs. 0.66%, 1.84% vs. 0.16%, 1.02% vs. 0.16%, respectively). NA-related mutations in HBV RT region increased in the past seven years, especially for LAM. Frequencies of rtL180M and rtA181T/V increased gradually in the past seven years, to which we should pay more attention.
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Antivirais/uso terapêutico , Farmacorresistência Viral , Evolução Molecular , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Frequência do Gene , Genoma Viral , Vírus da Hepatite B/isolamento & purificação , Humanos , Mutação , Falha de TratamentoRESUMO
The reduction of pulmonary surfactant (PS) is essential for decreased pulmonary compliance and edema in acute lung injury (ALI). Thyroid transcription factor-1 (TTF-1) plays a major role in the regulation of surfactant protein-A (SP-A), the most abundant protein component of PS. Simultaneously, the glucagon-like peptide-1 (GLP-1) analogue can enhance SP-A expression in the lung. However, the underlying mechanism is still unknown. The purpose of this study was to explore whether liraglutide, a GLP-1 analogue, upregulates SP-A expression through the TTF-1 signaling pathway in ALI. In vivo, a murine model of ALI was induced by lipopolysaccharide (LPS). Pulmonary inflammation, edema, insulin level, ultrastructural changes in type II alveolar epithelial (ATII) cells, and SP-A and TTF-1 expression were analyzed. In vitro, rat ATII cells were obtained. SP-A and TTF-1 expression in cells was measured. ShRNA-TTF-1 transfection was performed to knock down TTF-1 expression. Our data showed that LPS-induced lung injury and increase in insulin level, and LPS-induced reduction of SP-A and TTF-1 expression in both the lung and cells, were significantly compromised by liraglutide. Furthermore, we also found that these effects of liraglutide were markedly blunted by shRNA-TTF-1. Taken together, our findings suggest that liraglutide enhances SP-A expression in ATII cells and attenuates pulmonary inflammation in LPS-induced ALI, most likely through the TTF-1 signaling pathway.
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Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Lipopolissacarídeos/toxicidade , Liraglutida/uso terapêutico , Proteína A Associada a Surfactante Pulmonar/metabolismo , Fator Nuclear 1 de Tireoide/metabolismo , Lesão Pulmonar Aguda/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Lethal influenza A (H5N1) induces respiratory failure in humans. Although it also causes death at 7 days postinfection (dpi) in mice, the development of the respiratory failure and the viral impact on pre-Botzinger complex (PBC) neurons expressing neurokinin 1 receptor (NK1R), which is the respiratory rhythm generator, have not been explored. Body temperature, weight, ventilation, and arterial blood pH and gases were measured at 0, 2, 4, and 6 dpi in control, lethal HK483, and nonlethal HK486 viral-infected mice. Immunoreactivities (IR) of PBC NK1R, H5N1 viral nucleoprotein (NP), and active caspase-3 (CASP3; a marker for apoptosis) were detected at 6 dpi. HK483, but not HK486, mice showed the following abnormalities: 1) gradual body weight loss and hypothermia; 2) tachypnea at 2-4 dpi and ataxic breathing with long-lasting apneas and hypercapnic hypoxemia at 6 dpi; and 3) viral replication in PBC NK1R neurons with NK1R-IR reduced by 75% and CASP3-IR colabeled at 6 dpi. Lethal H5N1 viral infection causes tachypnea at the early stage and ataxic breathing and apneas (hypercapnic hypoxemia) leading to death at the late stage. Its replication in the PBC induces apoptosis of local NK1R neurons, contributing to ataxic breathing and respiratory failure.
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Apoptose/fisiologia , Virus da Influenza A Subtipo H5N1 , Neurônios/virologia , Infecções por Orthomyxoviridae/virologia , Receptores da Neurocinina-1/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Hipercapnia/virologia , Influenza Humana/virologia , Camundongos Endogâmicos BALB C , Respiração/imunologiaRESUMO
BACKGROUND: Delayed neurocognitive recovery (DNR) is a common complication in patients undergoing laparoscopic surgery, and there are currently no effective therapies. It is vital to provide a reliable basis for clinical prediction. This study tried to analyse the risk factors for DNR in patients undergoing laparoscopic colorectal surgery and to establish a risk prediction model. METHODS: A retrospective analysis of the clinical data and DNR status of patients undergoing laparoscopic colorectal surgery at Xiangya Hospital of Central South University from March 2018 to July 2020 was conducted. Logistic regression was performed to analyse the related risk factors for DNR post-operatively, and the predictive model of DNR post-operatively was constructed and validated internally. Patients who underwent laparoscopic colorectal surgery between January and July 2021 were also selected for external validation of the predictive model, to ultimately investigate the risk factors for DNR in patients undergoing laparoscopic colorectal surgery. RESULTS: The incidence of DNR in patients undergoing laparoscopic colorectal surgery was 15.2% (31/204). The maximum variability of cerebral oxygen, age, education, and pre-existing diabetes was related to the incidence of DNR (p < 0.05). The risk prediction model of DNR after laparoscopic colorectal surgery was established. The internal and external validation showed that the discrimination was good (the AUCs were 0.751 and 0.694, respectively). CONCLUSIONS: The risk prediction model of DNR related to cerebral oxygen saturation monitoring shows good predictive performance and clinical value, providing a basis for postoperative DNR prevention.
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STUDY OBJECTIVE: The use of hydroxyethyl starch 130/0.4 has been linked to renal injury in critically ill patients, but its impact on surgical patients remains uncertain. DESIGN: A retrospective cohort study. SETTING: This study was conducted at one tertiary care hospital in China. PATIENTS: We evaluated the records of 51,926 Chinese adults who underwent noncardiac surgery from 2013 to 2022. Patients given a combination of hydroxyethyl starch 130/0.4 and crystalloids were propensity-matched at a 1: 1 ratio of baseline characteristics to patients given only crystalloids (11,725 pairs). INTERVENTIONS: Eligible patients were divided into those given a combination of hydroxyethyl starch 130/0.4 and crystalloid during surgery and a reference crystalloid group consisting of patients who were not given any colloid. MEASUREMENTS: The primary outcome was the incidence of acute kidney injury. Secondarily, acute kidney injury stage, need for renal replacement therapy, intensive care unit transfer rate, and duration of postoperative hospitalization were considered. MAIN RESULTS: After matching, hydroxyethyl starch use [8.5 (IQR: 7.5-10.0) mL/kg] did not increase the incidence of acute kidney injury compared with that in the crystalloid group [2.0 vs. 2.2%, OR: 0.90 (0.74-1.08), P = 0.25]. Nor did hydroxyethyl starch use worsen acute kidney injury stage [OR 0.90 (0.75-1.08), P = 0.26]. No significant differences between the fluid groups were observed in renal replacement therapy [OR 0.60 (0.41-0.90), P = 0.02)] or intensive care unit transfers [OR 1.02 (0.95-1.09), P = 0.53] after Bonferroni correction. Even in a subset of patients at high risk of renal injury, hydroxyethyl starch use was not associated with worse outcomes. CONCLUSIONS: Hydroxyethyl starch 130/0.4 use was not significantly associated with a greater incidence of postoperative acute kidney injury compared to receiving crystalloid solutions only.
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Injúria Renal Aguda , Soluções Cristaloides , Derivados de Hidroxietil Amido , Complicações Pós-Operatórias , Pontuação de Propensão , Humanos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/induzido quimicamente , Derivados de Hidroxietil Amido/efeitos adversos , Derivados de Hidroxietil Amido/administração & dosagem , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , China/epidemiologia , Soluções Cristaloides/administração & dosagem , Soluções Cristaloides/efeitos adversos , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Incidência , Substitutos do Plasma/efeitos adversos , Substitutos do Plasma/administração & dosagem , Adulto , Terapia de Substituição Renal/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/efeitos adversosRESUMO
Epidemiological data is scarce regarding the association between exposure to mixtures of per- and polyfluoroalkyl substances (PFASs) and liver injury in the general populace. The current research used data from the National Health and Nutrition Examination Survey (2009-2018). The PFAS exposure levels were defined by the serum concentrations of PFASs with > 70% detection in samples, namely perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDeA), and perfluorooctane sulfonic acid (PFOS). Liver injury was assessed from two aspects: first, the degree of liver inflammation was determined based on serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyltransferase (GGT), and total bilirubin (TBIL) levels; second, the degree of liver fibrosis was determined based on fibrosis-4 (FIB-4) index. We assessed the associations between individual or total PFAS exposure and these outcomes using multivariable linear regression models and logistic regression models, restricted cubic splines, and weighted quantile sum regression. Among the samples of 7484 American adults, the median concentration of PFOS was the highest, followed by PFOA and PFHxS. Using multivariable linear regression, a positive correlation was observed between all PFASs and liver enzymes such as ALT, AST, and TBIL. Additionally, the weighted quantile sum model indicated an overall positive association between the five PFASs and liver injury indicators. For liver function biomarkers and liver fibrosis, PFNA and PFOS were the most heavily weighting chemicals, respectively. Our findings provide new epidemiological evidence indicating a potential association between PFAS exposure and adverse effects on liver injury biomarkers, highlighting the potentially harmful effects of PFAS exposure on liver health.
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Programmed cell death protein 1 (PD-1), a coinhibitory T cell checkpoint, is also expressed on macrophages in pathogen- or tumor-driven chronic inflammation. Increasing evidence underscores the importance of PD-1 on macrophages for dampening immune responses. However, the mechanism governing PD-1 expression in macrophages in chronic inflammation remains largely unknown. TGF-ß1 is abundant within chronic inflammatory microenvironments. Here, based on public databases, significantly positive correlations between PDCD1 and TGFB1 gene expression were observed in most human tumors. Of note, among immune infiltrates, macrophages as the predominant infiltrate expressed higher PDCD1 and TGFBR1/TGFBR2 genes. MC38 colon cancer and Schistosoma japonicum infection were used as experimental models for chronic inflammation. PD-1hi macrophages from chronic inflammatory tissues displayed an immunoregulatory pattern and expressed a higher level of TGF-ß receptors. Either TGF-ß1-neutralizing antibody administration or macrophage-specific Tgfbr1 knockdown largely reduced PD-1 expression on macrophages in animal models. We further demonstrated that TGF-ß1 directly induced PD-1 expression on macrophages. Mechanistically, TGF-ß1-induced PD-1 expression on macrophages was dependent on SMAD3 and STAT3, which formed a complex at the Pdcd1 promoter. Collectively, our study shows that macrophages adapt to chronic inflammation through TGF-ß1-triggered cooperative SMAD3/STAT3 signaling that induces PD-1 expression and modulates macrophage function.
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Receptor de Morte Celular Programada 1 , Fator de Crescimento Transformador beta1 , Animais , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo , Proteína Smad3/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
BACKGROUND AND AIMS: Diarrhea occurs in up to 50% of cases of COVID-19. Nonetheless, the pathophysiologic mechanism(s) have not been determined. METHODS: This was examined using normal human enteroid monolayers exposed apically to live SARS-CoV-2 or non-replicating virus like particles (VLPs) bearing the four SARS-CoV-2 structural proteins or irradiated virus, all of which bound and entered enterocytes. RESULTS: Live virus and VLPs increased secretion of multiple cytokines and reduced mRNAs of ACE2, NHE3 and DRA. IL-6 plus IL-8 alone reduced NHE3 mRNA and protein and DRA mRNA. Neither VLPs nor IL-6 plus IL-8 alone altered Cl- secretion, but together they caused Cl- secretion, which was Ca2+ dependent, CFTR independent, blocked partially by a specific TMEM16 A inhibitor, and entirely by a general TMEM16 family inhibitor. VLPs and irradiated virus, but not IL-6 plus IL-8, produced Ca2+ waves that began within minutes of VLP exposure, lasted for at least 60 min, and were prevented by pretreatment with apyrase; a P2Y1 receptor antagonist; and general TMEM16 family inhibitor but NOT by the specific TMEM16A inhibitor. CONCLUSIONS: The pathophysiology of COVID-19 diarrhea appears to be a unique example of a calcium dependent inflammatory diarrhea, that is caused by direct viral effects plus the virus-induced intestinal epithelial cytokine secretion.
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Deer mice are the principal reservoir hosts of Sin Nombre virus, the etiologic agent of most hantavirus cardiopulmonary syndrome cases in North America. Infection of deer mice results in persistence without conspicuous pathology, and most, if not all, infected mice remain infected for life, with periods of viral shedding. The kinetics of viral load, histopathology, virus distribution, and immune gene expression in deer mice were examined. Viral antigen was detected as early as 5 days postinfection and peaked on day 15 in the lungs, hearts, kidneys, and livers. Viral RNA levels varied substantially but peaked on day 15 in the lungs and heart, and antinucleocapsid IgG antibodies appeared in some animals on day 10, but a strong neutralizing antibody response failed to develop during the 20-day experiment. No clinical signs of disease were observed in any of the infected deer mice. Most genes were repressed on day 2, suggesting a typical early downregulation of gene expression often observed in viral infections. Several chemokine and cytokine genes were elevated, and markers of a T cell response occurred but then declined days later. Splenic transforming growth factor beta (TGF-ß) expression was elevated early in infection, declined, and then was elevated again late in infection. Together, these data suggest that a subtle immune response that fails to clear the virus occurs in deer mice.
Assuntos
Peromyscus/imunologia , Peromyscus/virologia , Vírus Sin Nombre/imunologia , Vírus Sin Nombre/patogenicidade , Animais , Anticorpos Antivirais/sangue , Sequência de Bases , Citocinas/genética , Primers do DNA/genética , Reservatórios de Doenças/virologia , Feminino , Expressão Gênica , Síndrome Pulmonar por Hantavirus/genética , Síndrome Pulmonar por Hantavirus/imunologia , Síndrome Pulmonar por Hantavirus/patologia , Síndrome Pulmonar por Hantavirus/virologia , Humanos , Imunoglobulina G/sangue , Cinética , Masculino , RNA Viral/genética , RNA Viral/metabolismo , Vírus Sin Nombre/genética , Carga Viral , Eliminação de Partículas ViraisRESUMO
In China, dezocine is commonly employed as a partial agonist of mu/kappa opioid receptors during anesthesia induction for surgical patients, yet evidence supporting its causal association with emergence delirium is limited. The objective of this investigation was to evaluate the impact of intravenous dezocine administered during anesthesia induction on emergence delirium. The retrospective studied existing data containing medical records of patients undergoing an elective laparoscopy procedure and the study was conducted with ethics-board approval. The primary outcome was the incidence of emergence delirium. Secondary outcomes included the VAS in the PACU and 24 h after surgery, the RASS score in the PACU, postoperative MMSE, hospital stay, and ICU stay. A total of 681 patients were analyzed, after being propensity score-matched, the dezocine and non-dezocine group each had 245 patients. Emergence delirium occurred in 26/245 (10.6%) of patients who received dezocine and 41/245 (16.7%) of patients did not receive dezocine. Patients on whom dezocine was used were associated with a significantly lower incidence of emergence delirium (absolute risk difference, -6.1%, 95% CI, -12% to -0.2%; relative risk [RR], 0.63; 95% CI, 0.18-0.74). All secondary outcome measures and adverse outcomes were not significantly different. The use of dezocine during anesthesia induction was associated with a decreased incidence of emergence delirium after elective laparoscopic surgeries.
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Background: Neuroinflammation and neuronal injury have been reported to be associated with the development of postoperative delirium in both preclinical and clinical settings. This study aimed to investigate the potential correlation between biomarkers of neurofilament light chain and glial fibrillary acidic protein and emergence and postoperative delirium in elderly patients undergoing surgery. Methods: Patients who developed emergence delirium (n = 30) and postoperative delirium (n = 32), along with their matched controls, were enrolled after obtaining ethics approval and written informed consent. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit or Confusion Assessment Method scale, and blood samples were collected before and after surgery for plasma neurofilament light chain and glial fibrillary acidic protein measurements using a single-molecule array. Results: The study found that in patients with emergence delirium, the increase in plasma neurofilament light chain protein levels during surgery was significantly higher than in non-delirium patients (P = 0.002). Additionally, in patients with postoperative delirium, both the increase in plasma neurofilament light chain protein levels (P < 0.001) and the increase in plasma glial fibrillary acidic protein levels during surgery (P = 0.008) were significantly higher than in non-delirium patients. Multivariate logistic regression analysis showed that the increase in plasma neurofilament light chain protein was associated with emergence delirium (adjusted OR = 1.872, P = 0.005), and the increase in plasma glial fibrillary acidic protein was associated with postoperative delirium (adjusted OR = 1.419, P = 0.016). Moreover, the American Society of Anesthesiologists Physical Status Classification and surgical duration were also found to be associated with delirium in elderly patients. Conclusion: Our findings suggest that emergence delirium is linked to elevated levels of neurofilament light chain, a biomarker of axonal injury, during surgery. Furthermore, in addition to axonal injury, postoperative delirium was also associated with an increase in glial fibrillary acidic protein, a marker of astrocyte activation.
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Objective: This study was determined to investigate the impact of intranasal dexmedetomidine (DEX) on postoperative sleep quality in older patients (age over 65) with chronic insomnia during their hospitalization after surgery. Design: A randomized double-blind controlled trial was conducted to compare the effects of intranasal dexmedetomidine spray with a placebo group. Setting and Participants: The study was carried out at Xiangya Hospital, Central South University. 110 participants with chronic insomnia were analyzed. Methods: This trial enrolled older patients who underwent total hip/knee arthroplasty and randomized them to receive intranasal dexmedetomidine (2.0 µg/kg) or saline daily at around 9 p.m. after surgery until discharge. The primary outcomes were subjective sleep quality assessed with the Leeds Sleep Evaluation Questionnaire (LSEQ). The secondary outcomes included the objective sleep quality measured with the Acti-graph, the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI). The other outcomes included the incidence of delirium, levels of inflammatory factors, visual analog scale (VAS) pain scores, postoperative opioid consumption, and treatment-related adverse events. Results: 174 patients were screened for eligibility, and 110 were recruited and analyzed. The DEX group had significantly higher scores on both the LSEQ-Getting to sleep and LSEQ-Quality of Sleep at each time point compared to the placebo (p < 0.0001), The least squares (LS) mean difference in LSEQ-GTS score at T0 between placebo group and DEX group was 2 (95% CI, -1-6), p = 0.4071 and at T5 was -14 (95% CI, -17 to -10), p < 0.0001; The LS mean difference in the LSEQ-QOS score at T0 was -1 (95% CI, -4 to 1), p = 0.4821 and at T5 was -16 (95% CI, -21 to -10), p < 0.0001. The DEX group exhibited significant improvement in Total Sleep Time (TST), Sleep Onset Latency (SOL), and Sleep Efficiency (SE), at each time point after treatment compared to the placebo group (p < 0.0001). The PSQI and ISI scores in the DEX group were reduced after treatment (p < 0.001). No significant adverse events were reported with the use of dexmedetomidine. Conclusion and Implications: This study demonstrates that intranasal administration of dexmedetomidine improves postoperative sleep quality in older patients with chronic insomnia who undergo surgery, without increasing the incidence of adverse effects. Clinical Trial Registration: http://www.chictr.org.cn/, identifier ChiCTR2200057133.