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1.
Medicine (Baltimore) ; 99(46): e23181, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181696

RESUMO

Renal cell carcinoma (RCC) is the leading cancer affecting humans; however, the relationship between tumour-infiltrating lymphocytes (TILs) and patient prognosis in RCC is relatively unreported. This study aimed to investigate the relationships among factors (TIL, clinicopathological characteristics, and patient prognosis in RCC).This retrospective study evaluated 533 patients with clear cell renal cell carcinoma (ccRCC) deposited in the the Cancer Genome Atlas between 2004 and 2015. We downloaded immune cell type absolute fraction data for ccRCC patients from the Cancer Immunome Atlas database. The CIBERSORT method was used to transform RNA-sequencing data into microarray data for the cancer genome atlas -ccRCC samples for which microarray and RNA-sequencing data were available on the the Cancer Immunome Atlas website.The overall survival (OS) and disease free survival (DFS) analyses of ccRCC patients showed that M1 macrophages (OS, P = .00000134; DFS, P = .00958) and neutrophils (OS, P = .00000723; DFS, P = .0255) were significant. Age at diagnosis (P < .0001, c-index = 0.59), tumour stage (P < .0001, c-index = 0.667), stage (P < .0001, c-index = 0.729), neoplasm histological grade (P < .0001, c-index = 0.624), and haemoglobin level (P < .0001, c-index = 0.583) were independent predictors of OS. Similarly, the stage, haemoglobin level, and serum calcium level were independent predictors of DFS. There were significant correlations between the M1 macrophage fraction and tumour stage, stage, and neoplasm histological grade. Stage and neoplasm histological grade showed associations with the neutrophil fraction.The correlations between TILs and prognosis and clinicopathological characteristics in ccRCC were demonstrated. The prognosis of ccRCC patients may differ according to the TIL fractions.


Assuntos
Carcinoma de Células Renais/sangue , Linfócitos do Interstício Tumoral/patologia , Valor Preditivo dos Testes , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Prognóstico , Estudos Retrospectivos
2.
PLoS One ; 15(10): e0237520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33002030

RESUMO

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.


Assuntos
Quimiocina CXCL1/sangue , Gota/terapia , Inflamação/prevenção & controle , Condicionamento Físico Animal , Receptor 2 Toll-Like/sangue , Animais , Modelos Animais de Doenças , Regulação para Baixo , Exercício Físico/fisiologia , Feminino , Gota/sangue , Gota/patologia , Humanos , Inflamação/sangue , Inflamação/patologia , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neutrófilos/metabolismo , Neutrófilos/patologia , Dor/prevenção & controle , Prognóstico , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
3.
Rinsho Shinkeigaku ; 60(10): 699-705, 2020 Oct 24.
Artigo em Japonês | MEDLINE | ID: mdl-32893247

RESUMO

A 75-year-old woman developed low back pain, weakness of the lower extremities, and urinary retention. On day 7 after the onset of symptoms, she was brought to the emergency department of our hospital by an ambulance because of progressive weakness of both lower extremities. Spine MRI showed longitudinally extensive spinal cord lesion (LESCL) at the Th8-Th11 spinal cord level and flow voids around the lesions. Lumbar puncture revealed a normal opening pressure, yellowish appearance, pleocytosis with polymorphonuclear predominance, and decreased cerebrospinal fluid (CSF) glucose levels. Based on the rapidly progressing myelopathy, LESCL, and CSF findings, we initially diagnosed the patient with myelitis and administered acyclovir and high-dose intravenous immunoglobulin on day 7. Spine MRI with gadolinium-enhancement showed longitudinally extending flow voids of the thoracic cord, and digital subtraction arteriogram (DSA) revealed arteriovenous shunt on the dura with dilated and tortuous intradural veins. We finally diagnosed her with spinal dural arteriovenous fistula (SDAVF). Cases of SDAVF might be initially misdiagnosed as myelitis because of showing rapid progressive myelopathy, pleocytosis with polymorphonuclear predominance, and decreased CSF glucose levels. Lumbar puncture and steroid administration for the cases of SDAVF could aggravate the patient's neurological symptoms. Therefore, lumbar puncture and initiation of immunotherapy should be avoided until SDAVF is completely excluded in patients with suspected myelitis on spine MRI without gadolinium-enhancement, even if their neurological symptoms progress rapidly.


Assuntos
Malformações Vasculares do Sistema Nervoso Central/complicações , Malformações Vasculares do Sistema Nervoso Central/diagnóstico , Glucose/líquido cefalorraquidiano , Leucocitose/diagnóstico por imagem , Leucocitose/etiologia , Neutrófilos/patologia , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/etiologia , Medula Espinal/diagnóstico por imagem , Angiografia Digital , Biomarcadores/líquido cefalorraquidiano , Malformações Vasculares do Sistema Nervoso Central/patologia , Malformações Vasculares do Sistema Nervoso Central/terapia , Progressão da Doença , Embolização Terapêutica/métodos , Feminino , Humanos , Imagem por Ressonância Magnética , Vértebras Torácicas , Resultado do Tratamento
5.
PLoS Pathog ; 16(9): e1008854, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956405

RESUMO

Aspergillus fumigatus is an opportunistic fungal pathogen of immunocompromised patient populations. Mortality is thought to be context-specific and occurs via both enhanced fungal growth and immunopathogenesis. NLRX1 is a negative regulator of immune signaling and metabolic pathways implicated in host responses to microbes, cancers, and autoimmune diseases. Our study indicates loss of Nlrx1 results in enhanced fungal burden, pulmonary inflammation, immune cell recruitment, and mortality across immuno-suppressed and immuno-competent models of IPA using two clinically derived isolates (AF293, CEA10). We observed that the heightened mortality is due to enhanced recruitment of CD103+ dendritic cells (DCs) that produce elevated amounts of IL-4 resulting in a detrimental Th2-mediated immune response. Adoptive transfer of Nlrx1-/- CD103+ DCs in neutropenic NRG mice results in enhanced mortality that can be ablated using IL-4 neutralizing antibodies. In vitro analysis of CD103+ DCs indicates loss of Nlrx1 results in enhanced IL-4 production via elevated activation of the JNK/JunB pathways. Interestingly, loss of Nlrx1 also results in enhanced recruitment of monocytes and neutrophils. Chimeras of irradiated Nlrx1-/- mice reconstituted with wild type bone marrow have enhanced neutrophil recruitment and survival during models of IPA. This enhanced immune cell recruitment in the absence of Nlrx1 is mediated by excessive production of CXCL8/IL-8 family of chemokines and IL-6 via early and enhanced activation of P38 in response to A. fumigatus conidia as shown in BEAS-2B airway epithelial cells. In summary, our results point strongly towards the cell-specific and contextual function of Nlrx1 during invasive pulmonary aspergillosis and may lead to novel therapeutics to reduce Th2 responses by CD103+ DCs or heightened recruitment of neutrophils.


Assuntos
Aspergillus fumigatus/imunologia , Células Dendríticas/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Proteínas Mitocondriais/imunologia , Aspergilose Pulmonar/imunologia , Células Th2/imunologia , Animais , Linhagem Celular , Citocinas/genética , Citocinas/imunologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Neutrófilos/imunologia , Neutrófilos/patologia , Aspergilose Pulmonar/genética , Aspergilose Pulmonar/patologia , Células Th2/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
6.
J Clin Invest ; 130(11): 5674-5676, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32925166

RESUMO

In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have been up to the task of deciphering the mechanisms by which SARS-CoV-2 induces the multisystem and multiorgan inflammatory responses that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros and Mitsios et al. is one such team who report that the complement system plays a substantial role in creating the hyperinflammation and thrombotic microangiopathy that appear to contribute to the severity of COVID-19. In support of the hypothesis that the complement system along with neutrophils and platelets contributes to COVID-19, the authors present empirical evidence showing that treatment with the complement inhibitor compstatin Cp40 inhibited the expression of tissue factor in neutrophils. These results confirm that the complement axis plays a critical role and suggest that targeted therapy using complement inhibitors is a potential therapeutic option to treat COVID-19-induced inflammation.


Assuntos
Betacoronavirus/metabolismo , Ativação do Complemento/efeitos dos fármacos , Infecções por Coronavirus , Pandemias , Peptídeos Cíclicos/farmacologia , Pneumonia Viral , Tromboplastina/biossíntese , Microangiopatias Trombóticas , Plaquetas/metabolismo , Plaquetas/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/virologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Índice de Gravidade de Doença , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/metabolismo , Microangiopatias Trombóticas/patologia , Microangiopatias Trombóticas/virologia
7.
J Cancer Res Ther ; 16(4): 909-916, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930139

RESUMO

Background: The predictive value of different prognostic biomarkers has been studied in various cancer types. Aims and Objectives: The purpose of this study was to examine the degree of risk and prognostic significance of pretreatment neutrophil-to-lymphocyte ratio (NLR) and carbohydrate antigen (CA) 19-9 levels in patients with metastatic pancreatic cancer (PC) and reveal its relevance with survival. Materials and Methods: Clinical and laboratory data of 118 patients with metastatic PC at the time of diagnosis were retrospectively analyzed. The overall survival (OS) was estimated according to the Kaplan-Meier method. To determine the prognostic factors affecting PC, the Cox regression analysis was performed. Results: The average age of the patients was 67 ± 9.57 years. The patients were analyzed during the follow-up period, and their average OS was 12 months (95% confidence interval [CI] = 9.73-14.26). The cutoff value was 3.54 (area under the curve [AUC] = 0.653, 95% CI = 0.56-0.73, P = 0.006) for NLR and 437 (AUC = 0.670, 95% CI = 0.57-0.75, P = 0.002) for CA19-9. Statistically significant difference was found between CA19-9 (P < 000.1) and NLR (P < 000.1) and OS. Analysis of multivariate Cox regression showed that NLR (hazard ratio [HR] = 2.17, 95% CI = 1.17-4.03, P = 0.013) and CA19-9 (HR = 1.81, 95% CI = 1.08-3.03, P = 0.022) were important prognostic factors in OS analysis. Conclusion: Pretreatment NLR and CA19-9 levels were found to be reliable estimative markers for poor prognosis in patients with metastatic PC. Our findings revealed that NLR and CA19-9 levels can be used to estimate the survival of patients with PC. We believe that our findings will shed light on the management of treatment protocols for patients diagnosed with metastatic PC.


Assuntos
Antígeno CA-19-9/sangue , Linfócitos/patologia , Neutrófilos/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores Tumorais/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
8.
J Cancer Res Ther ; 16(4): 731-736, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930111

RESUMO

Background: Chronic state of inflammation is an important factor in advanced cancer which is used by tumor cells for maintaining survival and growth. Hematological parameters such as neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), and lymphocyte/monocyte ratio (LMR) are reliable indicators of systemic inflammation. We aimed to elucidate the effect of hematological parameters and clinical features of patients on the prognosis of advanced-stage non-small cell lung cancer (NSCLC). Methods: We included 102 Stage IV NSCLC patients who presented to the oncology clinic between 2010 and 2016. Pretreatment clinical parameters and NLR, TLR, and LMR were retrieved from the medical records. The cutoff values, calculated with receiver operating curve analysis, for NLR, LMR, and TLR were 2.5, 3, and 183, respectively. All patients were divided into two groups according to cutoff values and analyzed accordingly. Results: Median overall survival and progression-free survival were 10 and 6 months, respectively. In univariate analysis, high NLR, high TLR, and low LMR were found to be significantly associated with survival. Among clinical parameters having eastern cooperative oncology group performance score 0-1, older age (≥70 years) single metastatic disease was prognostic. In multivariate Cox regression analysis, only the number of metastatic lesions and LMR were found to be independent predictors for survival. Conclusion: Among hematological parameters, only LMR was found to be an independent predictor of survival in patients with advanced-stage NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Inflamação/sangue , Neoplasias Pulmonares/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Inflamação/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos
10.
Life Sci ; 260: 118307, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841665

RESUMO

AIM: Liver plays a crucial role in innate immunity reactions. This role predisposes the liver to innate-mediated liver injury when uncontrolled inflammation occurs. In this study, the effect of febuxostat administration on acute liver injury induced by concanavalin A (Con A) injection into mouse eye orbital sinus was studied. MATERIALS AND METHODS: Two doses of febuxostat (10 and 20 mg/kg, orally) were administered either 1 h before or 30 min after the administration of Con A. Febuxostat at a low dose (10 mg/kg) before and after Con A modulated the elevation of serum ALT, liver uric acid, liver myeloperoxidase (MPO), and interleukin-1ß (IL-1ß) induced by Con A. The same dose of febuxostat before Con A also decreased serum total bilirubin and neutrophil infiltration, as evidenced by flow cytometry and histopathological analysis. KEY FINDINGS: Febuxostat at a high dose (20 mg/kg) significantly improved serum ALT, AST, albumin, total bilirubin, liver uric acid, MPO, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), IL-1ß, and neutrophil infiltration induced by Con A administration. The results of histopathological examination of liver cells paralleled the observed biochemical improvements. Hepatocyte apoptosis as evidenced by immunohistochemical examination of cleaved caspase-3 was markedly decreased in the febuxostat protection and treatment groups, in a dose-dependent manner SIGNIFICANCE: These results indicate that febuxostat, especially at the higher dose, may be an effective inhibitor of immune reactions evoked by Con A administration.


Assuntos
Quimiocina CCL2/análise , Concanavalina A/farmacocinética , Febuxostat/administração & dosagem , Hepatite/prevenção & controle , Interleucina-1beta/análise , Fator de Necrose Tumoral alfa/análise , Animais , Apoptose/efeitos dos fármacos , Caspase 3/análise , Febuxostat/farmacologia , Hepatite/imunologia , Hepatite/fisiopatologia , Fígado/química , Fígado/patologia , Fígado/fisiopatologia , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Peroxidase/análise , Ácido Úrico/análise
11.
Eur J Haematol ; 105(6): 773-778, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32794205

RESUMO

BACKGROUND: A lot remains unknown about the features and laboratory findings that may predict worse outcomes in patients with coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the difference in complete blood count parameters and differential counts in patients hospitalized with COVID-19 who survived compared to those who died. DESIGN: We performed a single-center retrospective study including 242 patients with confirmed COVID-19. We described the characteristics of the complete blood count parameters in these patients. Mann-Whitney U test was used to compare hematologic parameters of patients who died and those who survived; multivariate logistic regression was used to look for associations with mortality. RESULTS: Patients with COVID-19 who died had significantly lower median absolute monocyte count (AMC) (0.4 vs 0.5, P = .039) and median platelet count (169 vs 213, P = .009) compared to those who survived. Patients who died had a significantly higher neutrophil-to-lymphocyte ratio (6.4 vs 4.5, P = .001). The NLR was positively associated with death (OR = 1.038; 95% CI, 1.003-1.074, P = .031), while AMC was inversely associated with death (OR = 0.200; 95% CI, 0.052-0.761, P = .018). CONCLUSION: Among patients with COVID-19, a lower AMC and higher NLR are associated with higher mortality.


Assuntos
Betacoronavirus/patogenicidade , Plaquetas/patologia , Infecções por Coronavirus/diagnóstico , Linfócitos/patologia , Neutrófilos/patologia , Pneumonia Viral/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Plaquetas/virologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/virologia , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida
13.
PLoS One ; 15(8): e0236596, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750099

RESUMO

Leukocyte viability (determined by e.g. propidium iodide [PI] staining) is automatically measured by hematology analyzers to check for delayed bench time. Incidental findings in fresh blood samples revealed the existence of leukocytes with decreased viability in critically ill surgical patients. Not much is known about these cells and their functional and/or clinical implications. Therefore, we investigated the incidence of decreased leukocyte viability, the implications for leukocyte functioning and its relation with clinical outcomes. An automated alarm was set in a routine hematology analyzer (Cell-Dyn Sapphire) for the presence of non-viable leukocytes characterized by increased fluorescence in the PI-channel (FL3:630±30nm). Patients with non-viable leukocytes were prospectively included and blood samples were drawn to investigate leukocyte viability in detail and to investigate leukocyte functioning (phagocytosis and responsiveness to a bacterial stimulus). Then, a retrospective analysis was conducted to investigate the incidence of fragile neutrophils in the circulation and clinical outcomes of surgical patients with fragile neutrophils hospitalized between 2013-2017. A high FL3 signal was either caused by 1) neutrophil autofluorescence which was considered false positive, or by 2) actual non-viable PI-positive neutrophils in the blood sample. These two causes could be distinguished using automatically generated data from the hematology analyzer. The non-viable (PI-positive) neutrophils proved to be viable (PI-negative) in non-lysed blood samples, and were therefore referred to as 'fragile neutrophils'. Overall leukocyte functioning was not impaired in patients with fragile neutrophils. Of the 11 872 retrospectively included surgical patients, 75 (0.63%) were identified to have fragile neutrophils during hospitalization. Of all patients with fragile neutrophils, 75.7% developed an infection, 70.3% were admitted to the ICU and 31.3% died during hospitalization. In conclusion, fragile neutrophils occur in the circulation of critically ill surgical patients. These cells can be automatically detected during routine blood analyses and are an indicator of critical illness.


Assuntos
Estado Terminal , Neutrófilos/patologia , Procedimentos Cirúrgicos Operatórios , Idoso , Sobrevivência Celular , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade
14.
PLoS Pathog ; 16(8): e1008781, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810179

RESUMO

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that has a heterogeneous population composed of a pool of strains with distinct characteristics, including variable levels of virulence. In previous work, transcriptome analyses of parasite genes after infection of human foreskin fibroblasts (HFF) with virulent (CL Brener) and non-virulent (CL-14) clones derived from the CL strain, revealed a reduced expression of genes encoding parasite surface proteins in CL-14 compared to CL Brener during the final steps of the intracellular differentiation from amastigotes to trypomastigotes. Here we analyzed changes in the expression of host genes during in vitro infection of HFF cells with the CL Brener and CL-14 strains by analyzing total RNA extracted from cells at 60 and 96 hours post-infection (hpi) with each strain, as well as from uninfected cells. Similar transcriptome profiles were observed at 60 hpi with both strains compared to uninfected samples. However, at 96 hpi, significant differences in the number and expression levels of several genes, particularly those involved with immune response and cytoskeleton organization, were observed. Further analyses confirmed the difference in the chemokine/cytokine signaling involved with the recruitment and activation of immune cells such as neutrophils upon T. cruzi infection. These findings suggest that infection with the virulent CL Brener strain induces a more robust inflammatory response when compared with the non-virulent CL-14 strain. Importantly, the RNA-Seq data also exposed an unexplored role of fibroblasts as sentinel cells that may act by recruiting neutrophils to the initial site of infection. This role for fibroblasts in the regulation of the inflammatory response during infection by T. cruzi was corroborated by measurements of levels of different chemokines/cytokines during in vitro infection and in plasma from Chagas disease patients as well as by neutrophil activation and migration assays.


Assuntos
Doença de Chagas/metabolismo , Fibroblastos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Ativação de Neutrófilo , Neutrófilos , Trypanosoma cruzi/metabolismo , Doença de Chagas/genética , Doença de Chagas/patologia , Fibroblastos/metabolismo , Fibroblastos/parasitologia , Fibroblastos/patologia , Humanos , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Neutrófilos/patologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/patogenicidade , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
15.
Clin Immunol ; 219: 108555, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32771488

RESUMO

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.


Assuntos
Lesão Renal Aguda/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/patogenicidade , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Lesão Renal Aguda/complicações , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/virologia , Adulto , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Ativação do Complemento/efeitos dos fármacos , Complemento C4b/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Imunidade Humoral/efeitos dos fármacos , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Pandemias , Fragmentos de Peptídeos/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia
16.
Int J Antimicrob Agents ; 56(4): 106142, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32853675

RESUMO

This longitudinal, prospective cohort study aimed to assess risk of QTc interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval >470 ms in men or >480 ms in women. Patients were treated under strict cardiac supervision. A total of 105 adults were included [56% male; median (IQR) age 69 (57-79) years]. All patients received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/r). Concomitant medications classified as having risk of developing torsades de pointes (TdP) were simultaneously used in 81 patients (77%). Moderate-to-severe QTc prolongation was observed in 14 patients (13%), mostly at Days 3-5 from baseline, with 6 (6%) developing severe prolongation (>500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/r to HCQ+AZM did not significantly prolong the QTc interval. Multivariable Cox regression revealed that comedications with known risk of TdP (HR = 11.28, 95% CI 1.08-117.41), higher neutrophil-to-lymphocyte (NLR) ratio (HR = 1.10, 95% CI 1.03-1.18 per unit increase) and higher serum hs-cardiac troponin I (HR = 4.09, 95% CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacological therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically higher NLR, are conditions requiring careful QTc interval monitoring.


Assuntos
Anti-Infecciosos/administração & dosagem , Azitromicina/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Lopinavir/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Ritonavir/administração & dosagem , Idoso , Anti-Infecciosos/efeitos adversos , Azitromicina/efeitos adversos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Progressão da Doença , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Unidades de Terapia Intensiva , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Lopinavir/efeitos adversos , Linfócitos/patologia , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Neutrófilos/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Ritonavir/efeitos adversos , Resultado do Tratamento , Troponina I/sangue
17.
EBioMedicine ; 58: 102925, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32745993

RESUMO

BACKGROUND: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. METHODS: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. PATIENT FINDINGS: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. INTERPRETATION: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. FUNDING: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.


Assuntos
Infecções por Coronavirus/patologia , Armadilhas Extracelulares/metabolismo , Microvasos/patologia , Neutrófilos/metabolismo , Pneumonia Viral/patologia , Trombose/metabolismo , Células Cultivadas , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Microvasos/metabolismo , Neutrófilos/patologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Trombose/etiologia , Trombose/patologia
18.
Circulation ; 142(12): 1176-1189, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32755393

RESUMO

BACKGROUND: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. METHODS: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. RESULTS: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. CONCLUSIONS: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Insuficiência Respiratória/etiologia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Plaquetas/citologia , Plaquetas/metabolismo , Plaquetas/patologia , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/metabolismo , Humanos , Rim/patologia , Pulmão/patologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pandemias , Fenótipo , Ativação Plaquetária , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Insuficiência Respiratória/diagnóstico , Índice de Gravidade de Doença , Trombose/complicações , Trombose/diagnóstico
19.
Artigo em Inglês | MEDLINE | ID: mdl-32781787

RESUMO

Secondhand smoke (SHS) and physical inactivity are thought to be associated with type 2 diabetes mellitus (T2DM), but the synergistic effect of SHS with physical inactivity and their relationships with T2DM-associated inflammation biomarkers have not been estimated. We investigated the roles of SHS exposure and physical inactivity and their synergistic effect on T2DM risk and their relationships with T2DM associated inflammation biomarkers, neutrophil-lymphocyte ratio (NLR) and white blood cells (WBCs). A case-control study was conducted in total 588 participants (294 case T2DM and 294 healthy controls) from five community clinics in Indonesia. Participants completed a standardized questionnaire on demographic information, smoking status, physical activity habits and food consumption. WBCs and NLR levels were determined using an automated hematology analyzer. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were analyzed using multiple logistic regression model. The synergistic effect was analyzed using additive interaction for logistic regression. Physical inactive people exposed to SHS exhibited a synergistically increased 7.78-fold risk of T2DM compared with people who were not exposed to SHS and who were physically active. SHS is significantly correlated with a high NLR, WBCs and has a synergistic effect with physical inactivity on increasing susceptibility to T2DM.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Inflamação/sangue , Neutrófilos/metabolismo , Comportamento Sedentário , Poluição por Fumaça de Tabaco/efeitos adversos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Indonésia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Neutrófilos/patologia , Fatores de Risco , Poluição por Fumaça de Tabaco/análise
20.
Epidemiol Infect ; 148: e139, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641174

RESUMO

In December 2019, cases of severe coronavirus 2019 (COVID-19) infection rapidly progressed to acute respiratory failure. This study aims to assess the association between the neutrophil-to-lymphocyte ratio (NLR) and the incidence of severe COVID-19 infection. A retrospective cohort study was conducted on 210 patients with COVID-19 infection who were admitted to the Central Hospital of Wuhan from 27 January 2020 to 9 March 2020. Peripheral blood samples were collected and examined for lymphocyte subsets by flow cytometry. Associations between tertiles of NLR and the incidence of severe illness were analysed by logistic regression.Of the 210 patients with COVID-19, 87 were diagnosed as severe cases. The mean NLR of the severe group was higher than that of the mild group (6.6 vs. 3.3, P < 0.001). The highest tertile of NLR (5.1-19.7) exhibited a 5.9-fold (95% CI 1.3-28.5) increased incidence of severity relative to that of the lowest tertile (0.6-2.5) after adjustments for age, diabetes, hypertension and other confounders. The number of T cells significantly decreased in the severe group (0.5 vs. 0.9, P < 0.001). COVID-19 might mainly act on lymphocytes, particularly T lymphocytes. NLR was identified as an early risk factor for severe COVID-19 illness. Patients with increased NLR should be admitted to an isolation ward with respiratory monitoring and supportive care.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Linfócitos/patologia , Neutrófilos/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Adulto , Idoso , China/epidemiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Citocinas/sangue , Feminino , Humanos , Inflamação/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
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