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1.
J Infect Chemother ; 27(1): 76-82, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33051144

RESUMEN

INTRODUCTION: The severity of coronavirus disease (COVID-19) in Japanese patients is unreported. We retrospectively examined significant factors associated with disease severity in symptomatic COVID-19 patients (COVID-Pts) admitted to our institution between February 20 and April 30, 2020. METHODS: All patients were diagnosed based on the genetic detection of severe acute respiratory syndrome coronavirus 2. Information on the initial symptoms, laboratory data, and computed tomography (CT) images at hospitalization were collected from the patients' records. COVID-Pts were categorized as those with critical or severe illness (Pts-CSI) or those with moderate or mild illness (Pt-MMI). All statistical analyses were performed using R software. RESULTS: Data from 61 patients (16 Pt-CSI, 45 Pt-MMI), including 58 Japanese and three East Asians, were analyzed. Pt-CSI were significantly older and had hypertension or diabetes than Pt-MMI (P < 0.001, 0.014 and < 0.001, respectively). Serum albumin levels were significantly lower in Pt-CSI than in Pt-MMI (P < 0.001), whereas the neutrophil-to-lymphocyte ratio and C-reactive protein level were significantly higher in Pt-CSI than in Pt-MMI (P < 0.001 and P < 0.001, respectively). In the CT images of 60 patients, bilateral lung lesions were more frequently observed in Pt-CSI than in Pt-MMI (P = 0.013). Among the 16 Pt-CSI, 15 received antiviral therapy, 12 received tocilizumab, five underwent methylprednisolone treatment, six received mechanical ventilation, and one died. CONCLUSIONS: The illness severity of Japanese COVID-Pts was associated with older age, hypertension and/or diabetes, low serum albumin, high neutrophil-to-lymphocyte ratio, and C-reactive protein.


Asunto(s)
Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus , Proteína C-Reactiva/análisis , Infecciones por Coronavirus/terapia , Femenino , Humanos , Japón/epidemiología , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Neutrófilos , Pandemias , Neumonía Viral/terapia , Respiración Artificial , Estudios Retrospectivos , Factores de Riesgo , Albúmina Sérica/análisis , Tomografía Computarizada por Rayos X , Adulto Joven
2.
Gene ; 766: 145022, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32758579

RESUMEN

BACKGROUND: A better understanding of the mechanism(s) underlying cardioembolic stroke can promote recovery and reduce the risk of recurrent embolisms. METHODS: Peripheral blood mononuclear cell (PBMC) gene expression datasets from cardioembolic patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database (GSE58294). The Limma software package was utilized to identify differentially-expressed genes (DEGs). Protein-protein interaction (PPI) analysis of the DEGs was performed using STRING. A weighted gene co-expression network analysis (WGCNA) was used to build a gene co-expression network. In vitro experiments assessed the effects on neutrophils exposed to oxygen and glucose-deprived (OGD) cortical neurons. An in vivo murine model of thromboembolic stroke was constructed through thrombin injection to examine effects on circulating neutrophils. Mechanistic in vitro studies were conducted using the proteasome inhibitor MG132, the p53-Mdm2 binding inhibitor Nutlin-3a, Mdm2 small-interfering RNA (siRNA), and Ctnnb1 siRNA. RESULTS: DEG analysis identified 44 upregulated and 66 downregulated genes in cardioembolic stroke PBMCs. PPI analysis of these DEGs yielded one eight-node protein module with ß-catenin (CTNNB1) as the central hub protein. Integration of the DEGs with WGCNA-derived hub genes revealed the key hub DEGs CTNNB1 and mouse double minute 2 (MDM2). Follow-up experiments revealed Mdm2, p53, and phospho-ß-catenin upregulation in neutrophils exposed to OGD neurons in vitro and following thromboembolic stroke in vivo. Mechanistic studies revealed that neutrophils transcriptionally upregulate Ctnnb1 expression to compensate for Mdm2/p53-mediated ß-catenin degradation induced by exposure to OGD neurons, thereby promoting neutrophil survival. CONCLUSION: Compensatory Ctnnb1 transcriptional upregulation in neutrophils induced by ischemic neuron exposure may be involved in promoting neutrophil survival following cardioembolic stroke.


Asunto(s)
Neutrófilos/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismo , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba/genética , beta Catenina/genética , Animales , Células Cultivadas , Regulación hacia Abajo/genética , Expresión Génica/genética , Redes Reguladoras de Genes/genética , Corazón/fisiopatología , Humanos , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Transcripción Genética/genética , Activación Transcripcional/genética
3.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-33198751

RESUMEN

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.


Asunto(s)
Líquido del Lavado Bronquioalveolar/inmunología , Infecciones por Coronavirus/inmunología , Inflamación/inmunología , Interleucina-6/inmunología , Interleucina-8/inmunología , Leucocitos/inmunología , Pulmón/inmunología , Macrófagos Alveolares/inmunología , Neumonía Viral/inmunología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Corticoesteroides/uso terapéutico , Anciano , Alanina/análogos & derivados , Alanina/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus , Lavado Broncoalveolar , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/virología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/terapia , Combinación de Medicamentos , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Unidades de Cuidados Intensivos , Interleucina-10/inmunología , Italia , Leucocitos Mononucleares/virología , Lopinavir/uso terapéutico , Pulmón/citología , Pulmón/virología , Linfocitos/inmunología , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Neutrófilos/inmunología , Pandemias , Neumonía Viral/terapia , Pronóstico , Estudios Prospectivos , Respiración Artificial/métodos , Ritonavir/uso terapéutico , Glicoproteína de la Espiga del Coronavirus/metabolismo , Tasa de Supervivencia , Virión/metabolismo , Virión/ultraestructura
4.
PLoS One ; 15(11): e0240347, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33175876

RESUMEN

BACKGROUND: As a pandemic, a most-common pattern resembled organizing pneumonia (OP) has been identified by CT findings in novel coronavirus disease (COVID-19). We aimed to delineate the evolution of CT findings and outcome in OP of COVID-19. MATERIALS AND METHODS: 106 COVID-19 patients with OP based on CT findings were retrospectively included and categorized into non-severe (mild/common) and severe (severe/critical) groups. CT features including lobar distribution, presence of ground glass opacities (GGO), consolidation, linear opacities and total severity CT score were evaluated at three time intervals from symptom-onset to CT scan (day 0-7, day 8-14, day > 14). Discharge or adverse outcome (admission to ICU or death), and pulmonary sequelae (complete absorption or lesion residuals) on CT after discharge were analyzed based on the CT features at different time interval. RESULTS: 79 (74.5%) patients were non-severe and 103 (97.2%) were discharged at median day 25 (range, day 8-50) after symptom-onset. Of 67 patients with revisit CT at 2-4 weeks after discharge, 20 (29.9%) had complete absorption of lesions at median day 38 (range, day 30-53) after symptom-onset. Significant differences between complete absorption and residuals groups were found in percentages of consolidation (1.5% vs. 13.8%, P = 0.010), number of involved lobe > 3 (40.0% vs. 72.5%, P = 0.030), CT score > 4 (20.0% vs. 65.0%, P = 0.010) at day 8-14. CONCLUSION: Most OP cases had good prognosis. Approximately one-third of cases had complete absorption of lesions during 1-2 months after symptom-onset while those with increased frequency of consolidation, number of involved lobe > 3, and CT score > 4 at week 2 after symptom-onset may indicate lesion residuals on CT.


Asunto(s)
Infecciones por Coronavirus/diagnóstico por imagen , Neumonía Viral/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Betacoronavirus/aislamiento & purificación , Proteína C-Reactiva/análisis , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Femenino , Humanos , Tiempo de Internación , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Pandemias , Alta del Paciente , Neumonía Viral/diagnóstico , Neumonía Viral/patología , Neumonía Viral/virología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad
5.
PLoS One ; 15(11): e0241262, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33137167

RESUMEN

The coronavirus disease 2019 (COVID-19) has become a pandemic. Rapidly distinguishing COVID-19 from other respiratory infections is a challenge for first-line health care providers. This retrospective study was conducted at the Taipei Medical University Hospital, Taiwan. Patients who visited the outdoor epidemic prevention screening station for respiratory infection from February 19 to April 30, 2020, were evaluated for blood biomarkers to distinguish COVID-19 from other respiratory infections. Monocyte distribution width (MDW) ≥ 20 (odds ratio [OR]: 8.39, p = 0.0110, area under curve [AUC]: 0.703) and neutrophil-to-lymphocyte ratio (NLR) < 3.2 (OR: 4.23, p = 0.0494, AUC: 0.673) could independently distinguish COVID-19 from common upper respiratory tract infections (URIs). Combining MDW ≥ 20 and NLR < 3.2 was more efficient in identifying COVID-19 (AUC: 0.840). Moreover, MDW ≥ 20 and NLR > 5 effectively identified influenza infection (AUC: 0.7055). Thus, MDW and NLR can distinguish COVID-19 from influenza and URIs.


Asunto(s)
Infecciones por Coronavirus/patología , Gripe Humana/patología , Linfocitos/citología , Monocitos/citología , Neutrófilos/citología , Neumonía Viral/patología , Área Bajo la Curva , Biomarcadores/metabolismo , Infecciones por Coronavirus/inmunología , Femenino , Humanos , Gripe Humana/inmunología , Linfocitos/metabolismo , Masculino , Monocitos/metabolismo , Neutrófilos/metabolismo , Oportunidad Relativa , Pandemias , Proyectos Piloto , Neumonía Viral/inmunología , Curva ROC , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/patología
6.
Clin Nutr ESPEN ; 40: 101-102, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33183520

RESUMEN

Systemic inflammation has been reported as a new predictor for COVID-19 outcomes. Thus, we highlight in this viewpoint the importance of the neutrophil to lymphocyte ratio in COVID-19 pandemic-infected patients.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/mortalidad , Linfocitos/citología , Neutrófilos/citología , Neumonía Viral/mortalidad , Biomarcadores , Infecciones por Coronavirus/sangre , Enfermedad Crítica , Humanos , Pandemias , Neumonía Viral/sangre , Pronóstico
7.
Medicine (Baltimore) ; 99(45): e22980, 2020 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-33157941

RESUMEN

Coronavirus disease 2019 (COVID-19) has spread worldwide, causing significant stress on the medical system. We explored the risk factors for condition changes in COVID-19 pneumonia patients after admission.The patients diagnosed with COVID-19 pneumonia at 2 medical centers in Hunan Province were studied, and those whose conditions changed after admission were compared. Their clinical characteristics and experimental indicators were compared using SPSS software and R language to build a disease risk prediction model.Patients with condition changes after admission were older and had more blood cell abnormalities and impaired organ function (decreased albumin, elevated D-dimer) than normal patients. We found that age, neutrophil ratio, D-dimer, chest Computed tomograpgy (CT) changes, and glucocorticoid use were risk factors for COVID-19 pneumonia after admission.Elderly patients are more susceptible to disease changes after COVID-19 pneumonia; COVID-19 pneumonia patients who develop disease changes after admission have higher neutrophil ratios, increased D-dimer levels, chest imaging changes, and glucocorticoid usage. Additional research is needed.


Asunto(s)
Infecciones por Coronavirus/diagnóstico , Hospitalización , Neumonía Viral/diagnóstico , Adulto , Factores de Edad , Anciano , Betacoronavirus , China , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Pandemias , Radiografía Torácica , Estudios Retrospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos X
8.
PLoS One ; 15(10): e0237520, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33002030

RESUMEN

OBJECTIVES: Gout is the most prevalent inflammatory arthritis. To study the effects of regular physical activity and exercise intensity on inflammation and clinical outcome, we examined inflammatory pathogenesis in an acute model of murine gout and analyzed human gout patient clinical data as a function of physical activity. METHODS: NF-κB-luciferase reporter mice were organized into four groups and exercised at 0 m/min (non-exercise), 8 m/min (low-intensity), 11 m/min (moderate-intensity), and 15 m/min (high-intensity) for two weeks. Mice subsequently received intra-articular monosodium urate (MSU) crystal injections (0.5mg) and the inflammatory response was analyzed 15 hours later. Ankle swelling, NF-κB activity, histopathology, and tissue infiltration by macrophages and neutrophils were measured. Toll-like receptor (TLR)2 was quantified on peripheral monocytes/neutrophils by flow cytometry and both cytokines and chemokines were measured in serum or synovial aspirates. Clinical data and questionnaires accessing overall physical activity levels were collected from gout patients. RESULTS: Injection of MSU crystals produced a robust inflammatory response with increased ankle swelling, NF-κB activity, and synovial infiltration by macrophages and neutrophils. These effects were partially mitigated by low and moderate-intensity exercise. Furthermore, IL-1ß was decreased at the site of MSU crystal injection, TLR2 expression on peripheral neutrophils was downregulated, and expression of CXCL1 in serum was suppressed with low and moderate-intensity exercise. Conversely, the high-intensity exercise group closely resembled the non-exercised control group by nearly all metrics of inflammation measured in this study. Physically active gout patients had significantly less flares/yr, decreased C-reactive protein (CRP) levels, and lower pain scores relative to physically inactive patients. CONCLUSIONS: Regular, moderate physical activity can produce a quantifiable anti-inflammatory effect capable of partially mitigating the pathologic response induced by intra-articular MSU crystals by downregulating TLR2 expression on circulating neutrophils and suppressing systemic CXCL1. Low and moderate-intensity exercise produces this anti-inflammatory effect to varying degrees, while high-intensity exercise provides no significant difference in inflammation compared to non-exercising controls. Consistent with the animal model, gout patients with higher levels of physical activity have more favorable prognostic data. Collectively, these data suggest the need for further research and may be the foundation to a future paradigm-shift in conventional exercise recommendations provided by Rheumatologists to gout patients.


Asunto(s)
Quimiocina CXCL1/sangre , Gota/terapia , Inflamación/prevención & control , Condicionamiento Físico Animal , Receptor Toll-Like 2/sangre , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo , Ejercicio Físico/fisiología , Femenino , Gota/sangre , Gota/patología , Humanos , Inflamación/sangre , Inflamación/patología , Interleucina-1beta/sangre , Interleucina-1beta/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Neutrófilos/metabolismo , Neutrófilos/patología , Dolor/prevención & control , Pronóstico , Membrana Sinovial/metabolismo , Membrana Sinovial/patología
9.
Cells ; 9(10)2020 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-33003471

RESUMEN

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host-pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.


Asunto(s)
Infecciones por Coronavirus/sangre , Células Dendríticas/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Neumonía Viral/sangre , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Células Cultivadas , Infecciones por Coronavirus/inmunología , Citocinas/genética , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Innata , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología
10.
Nat Commun ; 11(1): 5243, 2020 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-33067472

RESUMEN

SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients reveals a dramatic increase in the number of immature neutrophils. This increase strongly correlates with disease severity and is associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts is observed for CD8 T-cells and VD2 γδ T-cells, which both exhibit increased differentiation and activation. ROC analysis reveals that the count ratio of immature neutrophils to VD2 (or CD8) T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.


Asunto(s)
Betacoronavirus/inmunología , Linfocitos T CD8-positivos/inmunología , Neutrófilos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Biomarcadores/sangre , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Citometría de Flujo , Humanos , Inmunofenotipificación/métodos , Interleucina-10/sangre , Interleucina-6/sangre , Recuento de Linfocitos , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/patología , Índice de Severidad de la Enfermedad
11.
PLoS One ; 15(10): e0240012, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33079950

RESUMEN

COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared throughout the World and currently affected more than 9 million people and caused the death of around 470,000 patients. The novel strain of the coronavirus disease is transmittable at a devastating rate with a high rate of severe hospitalization even more so for the elderly population. Naso-oro-pharyngeal swab samples as the first step towards detecting suspected infection of SARS-CoV-2 provides a non-invasive method for PCR testing at a high confidence rate. Furthermore, proteomics analysis of PCR positive and negative naso-oropharyngeal samples provides information on the molecular level which highlights disease pathology. Samples from 15 PCR positive cases and 15 PCR negative cases were analyzed with nanoLC-MS/MS to identify the differentially expressed proteins. Proteomic analyses identified 207 proteins across the sample set and 17 of them were statistically significant. Protein-protein interaction analyses emphasized pathways like Neutrophil degranulation, Innate Immune System, Antimicrobial Peptides. Neutrophil Elastase (ELANE), Azurocidin (AZU1), Myeloperoxidase (MPO), Myeloblastin (PRTN3), Cathepsin G (CTSG) and Transcobalamine-1 (TCN1) were found to be significantly altered in naso-oropharyngeal samples of SARS-CoV-2 patients. The identified proteins are linked to alteration in the innate immune system specifically via neutrophil degranulation and NETosis.


Asunto(s)
Betacoronavirus/genética , Degranulación de la Célula/inmunología , Infecciones por Coronavirus/inmunología , Nasofaringe/virología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Neumonía Viral/inmunología , Proteoma , Regulación hacia Arriba , Adulto , Cromatografía Liquida/métodos , Infecciones por Coronavirus/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/virología , Mapas de Interacción de Proteínas , Proteómica/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa , Espectrometría de Masas en Tándem/métodos , Adulto Joven
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(10): 1465-1471, 2020 Oct 30.
Artículo en Chino | MEDLINE | ID: mdl-33118515

RESUMEN

OBJECTIVE: To elucidate the pathogenic role of leukotriene B4 (LTB4) in pulmonary hyper-permeability and inflammation induced by lung-protective mechanical ventilation (LPMV) in rabbits. METHODS: Thirty-two healthy Japanese white rabbits were randomized into 4 groups for treatment with vehicle or bestatin (a leukotriene A4 hydrolase inhibitor that inhibits LTB4 production) administered intragastrically at the daily dose of 8 mg/kg for 5 days, followed by sham operation (group S and group BS, respectively, in which the rabbits were anesthetized only) or LPMV (group PM and group BPM, respectively, in which the rabbits received ventilation with 50% oxygen at a tidal volume of 8 mL/kg for 5 h). The concentrations of LTB4 and cyclic adenosine monophosphate (cAMP) in the lung tissues were analyzed by ELISA. cAMP content, protein kinase A (PKA) protein expression and the Rap1-GTP protein to total Rap1 protein ratio were determined to assess the activities of cAMP/PKA and Rap1 signaling pathways. The lung injury was evaluated by assessing lung permeability index, lung wet/dry weight ratio, polymorphonuclear leukocyte (PMN) count in bronchoalveolar lavage fluid (BALF), pulmonary myeloperoxidase (MPO) activity and lung histological scores. RESULTS: None of the examined parameters differed significantly between group S and group BS. All the parameters with the exception of lung histological score increased significantly in group PM and group BPM as compared to those in group S (P < 0.05). Compared with those in PM group, the rabbits in group BPM showed significantly reduced LTB4 production in the lungs (P < 0.05), up-regulated cAMP/ PKA and Rap1 signaling pathway activities (P < 0.05), and alleviated lung hyper-permeability and inflammation (P < 0.05). CONCLUSIONS: LPMV can induce LTB4 overproduction to down-regulate cAMP/PKA and Rap1 signaling pathways in the lungs of rabbits, which results in lung hyper-permeability and inflammation. Bestatin can inhibit LTB4 production in the lungs to protect against LPMV-induced lung hyper-permeability and inflammation.


Asunto(s)
Lesión Pulmonar , Animales , Líquido del Lavado Bronquioalveolar , Leucotrieno B4 , Pulmón , Lesión Pulmonar/etiología , Lesión Pulmonar/prevención & control , Neutrófilos , Conejos , Respiración Artificial/efectos adversos
13.
Medicine (Baltimore) ; 99(42): e22774, 2020 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-33080747

RESUMEN

Elevated serum lactate dehydrogenase (LDH) was commonly reported in COVID-19 patients. However, the relationship between LDH and the incidence of severe cases has not been characterized in those patients.We retrospectively analyzed the characteristics of patients from a designated isolation medical center for COVID-19 patients diagnosed from February 6 to March 1. Variables accessed within 48 hours on admission were compared between patients with and without the severe disease. Logistic model analyses were performed to examine the prognostic value of LDH for predicting severe disease.52 (28.6%) patients later developed severe disease. Comparing to non-severe cases, severe cases had a higher level of serum LDH (321.85 ±â€Š186.24 vs 647.35 ±â€Š424.26, P < .001), neutrophils (5.42 ±â€Š3.26 vs 9.19 ±â€Š6.33, P < .001), and C-reactive protein (38.63 ±â€Š43.14 vs 83.20 ±â€Š51.01, P < .001). The patients with severe disease tended to be male (44.6% vs 80.8%, P < .001), lower level of serum albumin (31.41 ±â€Š6.20 vs 27.18 ±â€Š5.74, P < .001), and SpO2 (96.30 ±â€Š2.75 vs 92.37 ±â€Š8.29, P < .001). In the multivariate analysis model, LDH and sex remained independent risk factors for severe disease. The serum LDH predicted severe cases with an area under the curve (AUC) of 0.7999. A combination of serum LDH and sex predicted severe cases with an AUC of 0.849. A combination of serum LDH accessed on admission and sex had a better predictive performance than the serum LDH (P = .0238).Serum LDH on admission combined with sex is independently associated with severe disease in COVID-19.


Asunto(s)
Infecciones por Coronavirus/fisiopatología , L-Lactato Deshidrogenasa/sangre , Neumonía Viral/fisiopatología , Adulto , Anciano , Betacoronavirus , Proteína C-Reactiva/análisis , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Oxígeno/sangre , Pandemias , Neumonía Viral/sangre , Neumonía Viral/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Albúmina Sérica/análisis , Índice de Severidad de la Enfermedad , Factores Sexuales , Fumar/epidemiología
14.
Front Cell Infect Microbiol ; 10: 560899, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33117727

RESUMEN

Background: Coronavirus disease (COVID-19) is a current global public health emergency. However, current research on the blood test results of pregnant women with COVID-19 is insufficient. Methods: A case-control study was carried out based on clinical blood test results. Pregnant COVID-19 patients, pregnant COVID-19 patients with diabetes, and pregnant COVID-19 patients with hypertension, were assessed in this study. Also, 120 controls were matched by age, parity, fetus number, and presence of chronic disease. T-tests, Chi-square tests, Wilcoxon signed-rank tests, and Kruskal-Wallis tests were used to compare data from the blood tests and liver function indices among the selected groups. Results: Between January 24 and March 14, 2020, 60 pregnant COVID-19 patients delivered at the Maternal and Child Health Hospital of Hubei Province. The average maternal age of pregnant COVID-19 patients was 30.97 years and the mean gestational period was 37.87 weeks. 71.67% (43/60) of pregnant COVID-19 patients gave birth by cesarean delivery. In total, 21.67% (13/60) were diagnosed with diabetes and 18.33% (11/60) were diagnosed with hypertension during pregnancy. Compared to controls, pregnant COVID-19 patients showed significantly lower numbers of blood lymphocytes and higher numbers of neutrophils, as well as higher levels of C-reactive protein and total bilirubin. Among the three groups, pregnant COVID-19 patients with diabetes had significantly higher levels of neutrophils and lower levels of total protein. Aspartate transaminase levels were higher in pregnant COVID-19 patients with hypertension than in pregnant COVID-19 patients with no comorbidities and controls with hypertension. Interpretations: Blood and liver function indices indicate that chronic complications, including hypertension and diabetes, could increase the risk of inflammation and liver injury in pregnant COVID-19 patients.


Asunto(s)
Infecciones por Coronavirus/fisiopatología , Diabetes Mellitus/diagnóstico , Hipertensión/diagnóstico , Neumonía Viral/fisiopatología , Complicaciones Infecciosas del Embarazo/virología , Adulto , Aspartato Aminotransferasas/sangre , Betacoronavirus , Bilirrubina/sangre , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Cesárea/estadística & datos numéricos , Diabetes Mellitus/sangre , Femenino , Humanos , Hipertensión/sangre , Hígado/fisiología , Pruebas de Función Hepática , Recuento de Linfocitos , Linfocitos/citología , Neutrófilos/citología , Pandemias , Embarazo
15.
Front Immunol ; 11: 573662, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33123152

RESUMEN

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.


Asunto(s)
Senescencia Celular/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Neumonía Viral/inmunología , Neumonía Viral/patología , Envejecimiento/inmunología , Betacoronavirus/inmunología , Diabetes Mellitus Tipo 2/inmunología , Femenino , Humanos , Masculino , Monocitos/inmunología , Neutrófilos/inmunología , Obesidad/inmunología , Pandemias , Factores de Riesgo , Linfocitos T/inmunología
16.
Science ; 370(6513)2020 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-33033192

RESUMEN

The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17- and tumor necrosis factor-related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8+ T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure.


Asunto(s)
Mucosa Nasal/inmunología , Mucosa Nasal/virología , Activación Neutrófila , Neutrófilos/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios , Adolescente , Adulto , Animales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocina CXCL1/farmacología , Humanos , Inflamación/inmunología , Inflamación/virología , Interleucina-17/inmunología , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mucosa Nasal/patología , Neutrófilos/efectos de los fármacos , Infecciones por Virus Sincitial Respiratorio/patología , Factor de Necrosis Tumoral alfa/inmunología , Adulto Joven
17.
Zool Res ; 41(6): 621-631, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-33045777

RESUMEN

Understanding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clarifying antiviral immunity in hosts are critical aspects for the development of vaccines and antivirals. Mice are frequently used to generate animal models of infectious diseases due to their convenience and ability to undergo genetic manipulation. However, normal adult mice are not susceptible to SARS-CoV-2. Here, we developed a viral receptor (human angiotensin-converting enzyme 2, hACE2) pulmonary transfection mouse model to establish SARS-CoV-2 infection rapidly in the mouse lung. Based on the model, the virus successfully infected the mouse lung 2 days after transfection. Viral RNA/protein, innate immune cell infiltration, inflammatory cytokine expression, and pathological changes in the infected lungs were observed after infection. Further studies indicated that neutrophils were the first and most abundant leukocytes to infiltrate the infected lungs after viral infection. In addition, using infected CXCL5-knockout mice, chemokine CXCL5 was responsible for neutrophil recruitment. CXCL5 knockout decreased lung inflammation without diminishing viral clearance, suggesting a potential target for controlling pneumonia.


Asunto(s)
Betacoronavirus/inmunología , Quimiocina CXCL5/inmunología , Infecciones por Coronavirus/inmunología , Inmunidad Innata/inmunología , Neutrófilos/inmunología , Peptidil-Dipeptidasa A/inmunología , Neumonía Viral/inmunología , Animales , Betacoronavirus/genética , Betacoronavirus/fisiología , Línea Celular , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neutrófilos/metabolismo , Neutrófilos/virología , Pandemias , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/genética , Neumonía Viral/virología
18.
J Stroke Cerebrovasc Dis ; 29(11): 105203, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33066933

RESUMEN

OBJECTIVES: We investigate the relationship between the severity of vascular disease and epicardial adipose tissue thickness(EAT-t) and the neutrophil/lymphocyte (NEU/LY) ratio in acute stroke patients. METHODS: Seventy-six patients and 38 healthy controls were included in the study. Strokes were divided into three groups: lacunar infarction, middle cerebral artery infarction (MCA), and other arterial infarcts. Patients were assessed using the GCS (Glasgow coma scale) and NIHSS (National Institutes of Health Stroke Scale) scales. In addition to laboratory measurements, EAT-t was evaluated in all patients by using echocardiography. RESULTS: The EAT-t value and NEU/LY ratio were higher in the patient group than in the control group. The MCA group was found to have a significantly higher NEU/LY ratio than the lacuna group (p = 0.017) as well as the other patient (p = 0.025) group. There was a positive correlation of NIHSS score with EAT-t (r = 0.291; p = 0.013), and NEU/LY ratio (r = 0.289; p = 0.014). CONCLUSION: The EAT-t and NEU/LY ratio were high in patients with acute ischemic stroke patients. The higher ratio of NEU/LY compared to other infarcts in the MCA group. These findings support the relationship between acute ischemic stroke severity and inflammation .


Asunto(s)
Tejido Adiposo/diagnóstico por imagen , Isquemia Encefálica/sangre , Isquemia Encefálica/diagnóstico por imagen , Ecocardiografía , Linfocitos , Neutrófilos , Pericardio/diagnóstico por imagen , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico por imagen , Tejido Adiposo/fisiopatología , Adiposidad , Anciano , Isquemia Encefálica/fisiopatología , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pericardio/fisiopatología , Valor Predictivo de las Pruebas , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/fisiopatología
19.
Sci Rep ; 10(1): 16826, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033405

RESUMEN

Excessive interleukin-6 signaling is a key factor contributing to the cytokine release syndrome implicated in clinical manifestations of COVID-19. Preliminary results suggest that tocilizumab, a humanized monoclonal anti-interleukin-6 receptor antibody, may be beneficial in severely ill patients, but no data are available on earlier stages of disease. An anticipated blockade of interleukin-6 might hypothetically prevent the catastrophic consequences of the overt cytokine storm. We evaluated early-given tocilizumab in patients hospitalized with COVID-19, and identified outcome predictors. Consecutive patients with initial Sequential-Organ-Failure-Assessment (SOFA) score < 3 fulfilling pre-defined criteria were treated with tocilizumab. Serial plasma biomarkers and nasopharyngeal swabs were collected. Of 193 patients admitted with COVID-19, 64 met the inclusion criteria. After tocilizumab, 49 (76.6%) had an early favorable response. Adjusted predictors of response were gender, SOFA score, neutrophil/lymphocyte ratio, Charlson comorbidity index and systolic blood pressure. At week-4, 56.1% of responders and 30% of non-responders had cleared the SARS-CoV-2 from nasopharynx. Temporal profiles of interleukin-6, C-reactive protein, neutrophil/lymphocyte ratio, NT-ProBNP, D-dimer, and cardiac-troponin-I differed according to tocilizumab response and discriminated final in-hospital outcome. No deaths or disease recurrences were observed. Preemptive therapy with tocilizumab was safe and associated with favorable outcomes in most patients. Biological and clinical markers predicted outcomes.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Puntuaciones en la Disfunción de Órganos , Neumonía Viral/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Femenino , Estudios de Seguimiento , Humanos , Interleucina-6/sangre , Recuento de Linfocitos , Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/virología , España/epidemiología , Resultado del Tratamiento
20.
Breast Cancer Res ; 22(1): 117, 2020 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-33126915

RESUMEN

Severe coronavirus disease 2019 (COVID-19) causes a hyperactivation of immune cells, resulting in lung inflammation. Recent studies showed that COVID-19 induces the production of factors previously implicated in the reawakening of dormant breast cancer cells such as neutrophil extracellular traps (NETs). The presence of NETs and of a pro-inflammatory microenvironment may therefore promote breast cancer reactivation, increasing the risk of pulmonary metastasis. Further studies will be required to confirm the link between COVID-19 and cancer recurrence. However, an increased awareness on the potential risks for breast cancer patients with COVID-19 may lead to improved treatment strategies to prevent metastatic relapse.


Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/virología , Infecciones por Coronavirus/inmunología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/virología , Neumonía Viral/inmunología , Betacoronavirus/inmunología , Neoplasias de la Mama/patología , Infecciones por Coronavirus/virología , Trampas Extracelulares/inmunología , Femenino , Humanos , Pulmón/inmunología , Pulmón/patología , Recurrencia Local de Neoplasia/patología , Neutrófilos/inmunología , Pandemias , Neumonía/inmunología , Neumonía/virología , Neumonía Viral/virología , Microambiente Tumoral/inmunología
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