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1.
Arterioscler Thromb Vasc Biol ; 41(1): 401-414, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33196292

RESUMO

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with derangement in biomarkers of coagulation and endothelial function and has been likened to the coagulopathy of sepsis. However, clinical laboratory metrics suggest key differences in these pathologies. We sought to determine whether plasma coagulation and fibrinolytic potential in patients with COVID-19 differ compared with healthy donors and critically ill patients with sepsis. Approach and Results: We performed comparative studies on plasmas from a single-center, cross-sectional observational study of 99 hospitalized patients (46 with COVID-19 and 53 with sepsis) and 18 healthy donors. We measured biomarkers of endogenous coagulation and fibrinolytic activity by immunoassays, thrombin, and plasmin generation potential by fluorescence and fibrin formation and lysis by turbidity. Compared with healthy donors, patients with COVID-19 or sepsis both had elevated fibrinogen, d-dimer, soluble TM (thrombomodulin), and plasmin-antiplasmin complexes. Patients with COVID-19 had increased thrombin generation potential despite prophylactic anticoagulation, whereas patients with sepsis did not. Plasma from patients with COVID-19 also had increased endogenous plasmin potential, whereas patients with sepsis showed delayed plasmin generation. The collective perturbations in plasma thrombin and plasmin generation permitted enhanced fibrin formation in both COVID-19 and sepsis. Unexpectedly, the lag times to thrombin, plasmin, and fibrin formation were prolonged with increased disease severity in COVID-19, suggesting a loss of coagulation-initiating mechanisms accompanies severe COVID-19. CONCLUSIONS: Both COVID-19 and sepsis are associated with endogenous activation of coagulation and fibrinolysis, but these diseases differently impact plasma procoagulant and fibrinolytic potential. Dysregulation of procoagulant and fibrinolytic pathways may uniquely contribute to the pathophysiology of COVID-19 and sepsis.


Assuntos
Transtornos da Coagulação Sanguínea/sangue , Coagulação Sanguínea/fisiologia , Sepse/sangue , Biomarcadores/sangue , Transtornos da Coagulação Sanguínea/etiologia , /epidemiologia , Estudos Transversais , Feminino , Fibrinolisina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Sepse/complicações
2.
Support Care Cancer ; 29(1): 323-330, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32361829

RESUMO

INTRODUCTION: Patients with hematological malignancies (HM) require intensive chemotherapy with curative intent, especially in case of AML that results in more frequent admissions to Intensive Care Units (ICU). Due to our knowledge, this study is the first multicenter retrospective analysis in Polish population. METHODS: A total of 200 patients with HM hospitalized in 4 Polish hematological centers. Data concerning clinical indices and outcomes during admission and ICU stay were collected retrospectively. RESULTS: The most common hematological malignancy was acute leukemia (55%). The main cause of ICU admission was respiratory failure (88.5%), often accompanied by sepsis (58.5%) and acute renal failure (51.5%). In patients with hematological malignancies, the following factors were associated with ICU mortality: prolonged ICU stay (odd ratio [OR] = 6.98, 95% confidence interval [CI]: 1.38-35.33, χ2 = 5.61, p = 0.02), the presence of acute respiratory failure (odd ratio [OR] = 5.35, 95% confidence interval [CI]: 1.01-28.46, χ2 = 3.93, p = 0.04), and the need for renal replacement therapy (odd ratio [OR] = 8.75, 95% confidence interval [CI]: 1.23-62.11, χ2 = 4.78, p = 0.03). There were following associations with in-hospital mortality in patients with hematological malignancies: prolonged ICU stay (odd ratio [OR] = 10.12, 95% confidence interval [CI]: 1.85-55.37, χ2 = 7.21, p = 0.008), the presence of acute respiratory failure (odd ratio [OR] =5.24, 95% confidence interval [CI]: 1.36-20.16, χ2 = 5.87, p = 0.02), the need for catecholamine support (odd ratio [OR] =3.43, 95% confidence interval [CI]: 1.06-11.05, χ2 = 4.32, p = 0.04), and renal replacement therapy (odd ratio [OR] =5.55, 95% confidence interval [CI]: 1.14-26.92, χ2 = 4.59, p = 0.03). CONCLUSIONS: We have demonstrated that ICU and in-hospital mortalities among patients with hematological malignancies are still poor, but easier access to the intensive care unit and close cooperation between hematologists and intensivists may improve outcomes. We have found that acute failure of key organs (acute respiratory failure, end-stage renal failure requires renal replacement therapy) and length of ICU stay (but probably no comorbidities and illness severity) may have impact on mortality (both ICU and in-hospital).


Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/mortalidade , Mortalidade Hospitalar , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Lesão Renal Aguda/complicações , Lesão Renal Aguda/mortalidade , Adulto , Idoso , Antineoplásicos/uso terapêutico , Catecolaminas/uso terapêutico , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Polônia , Terapia de Substituição Renal/estatística & dados numéricos , Insuficiência Respiratória/complicações , Estudos Retrospectivos , Sepse/complicações , Resultado do Tratamento
3.
J Ayub Med Coll Abbottabad ; 32(4): 465-469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33225645

RESUMO

BACKGROUND: Early detection of sepsis in the emergency department is of prime importance and requires tools that are time and cost-effective. The Systemic Inflammatory Response Syndrome (SIRS) has been poorly associated with sepsis. Timothy et al in a retrospective analysis of Emergency Department (ED) visit stated estimate of SIRS at 17.8% accounting to an annual yield of 16.6 million adult visits with SIRS per year, among these only 26% accounted as an infectious aetiology of SIRS, trauma being 10% and other causes being rare. Shock index is found to be independently associated with 30-day mortality in a broad population of ED patients including sepsis. With limited health resources in a low to middle income country, focused utilization is important and so is the need for markers that are non-invasive, readily available, cost effective, and easy to interpret. Shock index can serve this purpose as a surrogate marker of disease severity in patients with severe sepsis and thus resulting in early detection of such patients. METHODS: This cross-sectional study was conducted from December 2014 to May 2015 at a tertiary care setup (Aga Khan University Hospital) in Karachi consisting of all septic patients received at the emergency department. Non-probability sampling technique was used. p-value <0.05 was taken as significant. RESULTS: Out of 180 study participants 94 (52.22%) were males while 86 (47.78%) were females. The mean age was 57.48±18.8 years. Cohen's κ was used to determine an agreement between the Shock index and Lactate levels. Shock index with cut off value of > 0.7 was used and moderate to the strong agreement between the two was found with kappa κ = 0.786 which was statistically significant (p=<0.001). Sensitivity was found to be 0.99, specificity 0.75, NPV 0.98, PPV 0.87. CONCLUSIONS: To conclude the shock index has some very favourable features, including availability, low cost, and direct relevance to sepsis in terms of its high validity. A high SI predicts elevated lactate levels in patients with sepsis.


Assuntos
Hiperlactatemia , Sepse , Adulto , Idoso , Estudos Transversais , Diagnóstico Precoce , Serviço Hospitalar de Emergência , Feminino , Humanos , Hiperlactatemia/diagnóstico , Hiperlactatemia/epidemiologia , Hiperlactatemia/etiologia , Masculino , Pessoa de Meia-Idade , Paquistão , Sepse/complicações , Sepse/diagnóstico , Sepse/epidemiologia , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica
4.
J Vis Exp ; (165)2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33226026

RESUMO

In rodent models, tail vein injections are important methods for intravenous administration of experimental agents. Tail vein injections typically involve warming of the animal to promote vasodilation, which aids in both the identification of the blood vessels and positioning of the needle into the vessel lumen while securely restraining the animal. Although tail vein injections are common procedures in many protocols and are not considered highly technical if performed correctly, accurate and consistent injections are crucial to obtain reproducible results and minimize variability. Conventional methods for inducing vasodilation prior to tail vein injections generally depend on the use of a heat source such as a heat lamp, electrical/rechargeable heat pads, or pre-heated water at 37 °C. Despite being readily accessible in a standard laboratory setting, these tools evidently suffer from poor/limited thermo-regulatory capacity. Similarly, although various forms of restraining devices are commercially available, they must be used carefully to avoid trauma to the animals. These limitations of the current methods create unnecessary variables in experiments or result in varying outcomes between experiments and/or laboratories. In this article, we demonstrate an improved protocol using an innovative device that combines an independent, thermally regulated, warming device with an adjustable restraining unit into one system for efficient streamlined tail vein injection. The example we use is an intravenous model of fungal bloodstream infection that results in sepsis. The warming apparatus consists of a heat-reflective acrylic box installed with an adjustable automatic thermostat to maintain the internal temperature at a pre-set threshold. Likewise, the width and height of the cone restraining apparatus can be adjusted to safely accommodate various rodent sizes. With the advanced and versatile features of the device, the technique shown here could become a useful tool across a range of research areas involving rodent models that employ tail vein injections.


Assuntos
Temperatura Alta , Injeções/instrumentação , Sepse/microbiologia , Cauda/irrigação sanguínea , Veias/patologia , Animais , Candida/imunologia , Modelos Animais de Doenças , Vacinas Fúngicas/imunologia , Injeções Intravenosas , Camundongos Endogâmicos C57BL , Agulhas , Ratos , Sepse/complicações , Vacinação
6.
Zhonghua Nei Ke Za Zhi ; 59(11): 854-859, 2020 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-33120488

RESUMO

Objective: To explore the predictive value of complement and coagulation indicators in sepsis related acute kidney injury (AKI). Methods: Clinical data of 217 patients with sepsis admitted to the Department of Internal Medicine and Intensive Care Unit of Affiliated Hospital of Jiangnan University from January 2018 to June 2019 were retrospectively analyzed. All patients were divided into sepsis with AKI group and without AKI group. Laboratory indicators of all patients were collected, including complement C3, complement C4, activated partial thrombin time (APTT), prothrombin time (PT), international normalized ratio (INR), D-dimer, procalcitonin(PCT), etc. logistic regression analysis was used to explore the risk factors of sepsis related AKI. Receiver operating characteristic curve (ROC) was used to evaluate the predictive value of independent risk factors. Results: Among 217 patients, 120 patients developed sepsis related AKI and 97 patients didn't. PCT, lactic acid, PT, APTT, INR and D-dimer in AKI patients were significantly higher than those without AKI (P<0.01). Complement C3 and complement C4 were significantly lower in AKI group (P<0.01). Multivariate logistic regression analysis suggested that blood pressure<90/60 mmHg (1 mmHg=0.133 kPa)(OR=3.705, 95%CI 1.536-8.934,P=0.004), increased lactic acid (OR=1.479, 95%CI 1.089-2.008, P=0.012), decreased complement C3 (OR=0.027, 95%CI 0.005-0.152, P<0.001) and prolonged APTT (OR=1.090, 95%CI 1.047-1.137,P<0.001)were independent risk factors predicting AKI. The area under the ROC curve (AUC) of these multivariates were 0.741 (95%CI 0.675-0.807), 0.798 (95%CI 0.732-0.864), 0.712 (95%CI 0.643-0.781) and 0.716 (95%CI 0.648-0.783) respectively. The relevant sensitivity was 57.5%, 80.8%, 87.5%, 59.2%, and the specificity was 90.7%, 75.3%, 51.5%, 77.3%, respectively. The AUC of the combined four indicators was 0.880 (95%CI 0.835-0.926) with the sensitivity 75.0% and the specificity 90.7%. Conclusion: The low level of complement C3 and prolonged APTT predict sepsis related AKI, and the predictive value can be enhanced if hypotension and hyperlactacidemia are added.


Assuntos
Lesão Renal Aguda , Coagulação Sanguínea , Complemento C3/análise , Sepse , Lesão Renal Aguda/etiologia , Testes de Coagulação Sanguínea , China , Humanos , Unidades de Terapia Intensiva , Pró-Calcitonina , Prognóstico , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Sepse/complicações
7.
PLoS One ; 15(10): e0239659, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33002070

RESUMO

Sepsis was characterized by systemic inflammatory response and multisystem organ dysfunction, refering to the activation of inflammatory and oxidative stress pathways. Estrogen has been shown to have anti-inflammatory and antioxidant effects as well as extensive organ protective role. However, whether estrogen alleviates sepsis-induced liver injury and the mechanisms involved remain unknown. Septic mice were constructed by intraperitoneal injection lipopolysaccharide, and the effect of estrogen on liver injury was investigated. Furthermore, the roles of NLRP3 inhibitor MCC950 and mitochondrial ROS specific scavenger Mito-tempo, on the liver injury were explored in septic mice. Female septic mice exhibited liver damage with increased serum AST and ALT level as well as the existence of extensive necrosis, and which was more serious in male septic mice. Moreover, Ovariectomy (OVX) aggravated sepsis-induced liver damage and activation of pyroptosis signaling pathway, which was alleviated by estrogen as evidenced by decreased serum AST, ALT level and number of infiltrating inflammatory cell, as well as protein expression related to pyroptosis. OVX aggravated mitochondrial dysfunction and liver injury in septic mice was also partly reversed by Mito-tempo and MCC950. These results demonstrated that estrogen protected against sepsis-induced liver damage through alteration of mitochondrial function and activation of inflammatory-mediated pyroptosis signaling pathway.


Assuntos
Estrogênios/farmacologia , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Fígado/metabolismo , Fígado/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Ovariectomia , Sepse/tratamento farmacológico , Sepse/metabolismo , Superóxidos/metabolismo
8.
Chem Biol Interact ; 331: 109278, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038329

RESUMO

Only in the last decade the long-term consequences of sepsis started to be studied and even less attention has been given to the treatment of psychological symptoms of sepsis survivors. It is estimated that 60% of sepsis survivors have psychological disturbances, including depression, anxiety, and cognitive impairment. Although the causative factors remain largely poorly understood, blood-brain barrier (BBB) disturbances, neuroinflammation, and oxidative stress have been investigated. Therefore, we sought to explore if the immunomodulatory and antioxidant selenocompound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) would be able to ameliorate long-term behavioral and biochemical alterations in sepsis survivors male Swiss mice. CMI treatment (1 mg/kg, given orally for seven consecutive days) attenuated depression- and anxiogenic-like behaviors and cognitive impairment present one month after the induction of sepsis (lipopolysaccharide, 5 mg/kg intraperitoneally). Meantime, CMI treatment modulated the number of neutrophils and levels of reactive species in neutrophils, lymphocytes, and monocytes. In addition, peripheral markers of liver and kidneys dysfunction (AST, ALT, urea, and creatinine) were reduced after CMI treatment in post-septic mice. Notably, CMI treatment to non-septic mice did not alter AST, ALT, urea, and creatinine levels, indicating the absence of acute hepatotoxicity and nephrotoxicity following CMI treatment. Noteworthy, CMI ameliorated BBB dysfunction induced by sepsis, modulating the expression of inflammation-associated genes (NFκB, IL-1ß, TNF-α, IDO, COX-2, iNOS, and BDNF) and markers of oxidative stress (reactive species, nitric oxide, and lipid peroxidation levels) in the prefrontal cortices and hippocampi of mice. In conclusion, we unraveled crucial molecular pathways that are impaired in post-septic mice and we present CMI as a promising therapeutic candidate aimed to manage the long-lasting behavioral alterations of sepsis survivors to improve their quality of life.


Assuntos
Comportamento Animal , Indóis/química , Estresse Oxidativo , Sepse/patologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Indóis/farmacologia , Indóis/uso terapêutico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Neutrófilos/citologia , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações
9.
Am J Physiol Renal Physiol ; 319(6): F979-F987, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33044866

RESUMO

Sepsis-associated acute kidney injury (AKI) is a complex clinical disorder associated with inflammation, endothelial dysfunction, and dysregulated coagulation. With standard regression methods, collinearity among biomarkers may lead to the exclusion of important biological pathways in a single final model. Best subset regression is an analytic technique that identifies statistically equivalent models, allowing for more robust evaluation of correlated variables. Our objective was to identify common clinical characteristics and biomarkers associated with sepsis-associated AKI. We enrolled 453 septic adults within 24 h of intensive care unit admission. Using best subset regression, we evaluated for associations using a range of models consisting of 1-38 predictors (composed of clinical risk factors and plasma and urine biomarkers) with AKI as the outcome [defined as a serum creatinine (SCr) increase of ≥0.3 mg/dL within 48 h or ≥1.5× baseline SCr within 7 days]. Two hundred ninety-seven patients had AKI. Five-variable models were found to be of optimal complexity, as the best subset of five- and six-variable models were statistically equivalent. Within the subset of five-variable models, 46 permutations of predictors were noted to be statistically equivalent. The most common predictors in this subset included diabetes, baseline SCr, angiopoetin-2, IL-8, soluble tumor necrosis factor receptor-1, and urine neutrophil gelatinase-associated lipocalin. The models had a c-statistic of ∼0.70 (95% confidence interval: 0.65-0.75). In conclusion, using best subset regression, we identified common clinical characteristics and biomarkers associated with sepsis-associated AKI. These variables may be especially relevant in the pathogenesis of sepsis-associated AKI.


Assuntos
Lesão Renal Aguda/complicações , Lesão Renal Aguda/diagnóstico , Sepse/complicações , Lesão Renal Aguda/sangue , Lesão Renal Aguda/urina , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/urina , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos
10.
Discov Med ; 29(157): 129-137, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33002409

RESUMO

Sepsis is a life-threatening clinical condition demanding accurate and rapid diagnosis of the culprit pathogen, thereby to improve prognosis. Pathogen determination through blood culture is the gold standard for diagnosis but has limitations due to low sensitivity. Recently, circulating DNAs derived from pathogenic organisms were found in the plasma of patients with sepsis and were further proved to be more sensitive biomarkers for the diagnosis of the pathogen origin in sepsis. However, the fundamental molecular characteristics of circulating DNA in patients with sepsis remain unclear. Here, we used specific PCR and Sanger sequencing to verify the microbiology culture results via the corresponding plasma circulating DNA. We analyzed the composition and molecular characteristics of circulating DNA in septic patients using next-generation sequencing technology. We showed the presence of pathogen-derived circulating DNA in the plasma of patients with sepsis. The sizes of circulating DNA fragments derived from pathogenic bacteria showed a skewed unimodal distribution, while those derived from host cells showed a normal unimodal distribution. Lengths of fragments at peak concentration for both origins ranged from 150 bp to 200 bp, and reads mapping to pathogenic bacteria genome distributed uniformly on the reference. Our findings have improved our understanding of microbial circulating DNA in patients with sepsis as a potential methodology for the accurate diagnosis of sepsis, especially in light of an urgent need for such a diagnosis associated with the COVID-19 infection.


Assuntos
Infecções Bacterianas/microbiologia , Ácidos Nucleicos Livres/sangue , DNA Bacteriano/sangue , Sepse/microbiologia , Adulto , Idoso , Infecções Bacterianas/complicações , Infecções Bacterianas/diagnóstico , Betacoronavirus , Ácidos Nucleicos Livres/análise , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Técnicas de Cultura , DNA Bacteriano/análise , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Pandemias , Pneumonia Viral , Reação em Cadeia da Polimerase , Sepse/complicações , Sepse/diagnóstico , Análise de Sequência de DNA
11.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32978294

RESUMO

BACKGROUND AND OBJECTIVES: The identification of life-threatening infection in febrile children presenting to the emergency department (ED) remains difficult. The quick Sequential Organ Failure Assessment (qSOFA) was only derived for adult populations, implying an urgent need for pediatric scores. We developed and validated a novel, adapted qSOFA score (Liverpool quick Sequential Organ Failure Assessment [LqSOFA]) and compared its performance with qSOFA, Pediatric Early Warning Score (PEWS), and National Institute for Health and Care Excellence (NICE) high-risk criteria in predicting critical care (CC) admission in febrile children presenting to the ED. METHODS: The LqSOFA (range, 0-4) incorporates age-adjusted heart rate, respiratory rate, capillary refill, and consciousness level on the Alert, Voice, Pain, Unresponsive scale. The primary outcome was CC admission within 48 hours of ED presentation, and the secondary outcome was sepsis-related mortality. LqSOFA, qSOFA, PEWS, and NICE high-risk criteria scores were calculated, and performance characteristics, including area under the receiver operating characteristic curve, were calculated for each score. RESULTS: In the initial (n = 1121) cohort, 47 CC admissions (4.2%) occurred, and in the validation (n = 12 241) cohort, 135 CC admissions (1.1%) occurred, and there were 5 sepsis-related deaths. In the validation cohort, LqSOFA predicted CC admission with an area under the receiver operating characteristic curve of 0.81 (95% confidence interval [CI], 0.76 to 0.86), versus qSOFA (0.66; 95% CI, 0.60 to 0.71), PEWS (0.93; 95% CI, 0.90 to 0.95), and NICE high-risk criteria (0.81; 95% CI, 0.78 to 0.85). For predicting CC admission, the LqSOFA outperformed the qSOFA, with a net reclassification index of 10.4% (95% CI, 1.0% to 19.9%). CONCLUSIONS: In this large study, we demonstrate improved performance of the LqSOFA over qSOFA in identifying febrile children at risk for CC admission and sepsis-related mortality. Further validation is required in other settings.


Assuntos
Cuidados Críticos/estatística & dados numéricos , Febre/etiologia , Escores de Disfunção Orgânica , Admissão do Paciente/estatística & dados numéricos , Sepse/diagnóstico , Adolescente , Proteína C-Reativa/análise , Criança , Intervalos de Confiança , Feminino , Humanos , Ácido Láctico/análise , Masculino , Curva ROC , Sepse/complicações , Sepse/mortalidade
12.
Cell Mol Immunol ; 17(10): 1092-1094, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32917983
13.
Life Sci ; 262: 118505, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32998017

RESUMO

AIMS: To investigate the effects of paclitaxel on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and its related mechanisms. MAIN METHODS: The sepsis-associated AKI was induced by LPS using HK-2 cells. Then the mRNA and protein expression levels of relevant genes in the serum of sepsis patients and HK-2 cells with LPS-induced AKI were detected by qRT-PCR and western blot analyses before and after paclitaxel treatment, respectively. Subsequently, the cell counting kit-8 (CCK-8) and flow cytometry assays were performed to estimate the effects of paclitaxel, lnc-MALAT1, miR-370-3p and HMGB1 on the proliferation and apoptosis of HK-2 cells injured by LPS. KEY FINDINGS: Lnc-MALAT1 was increased both in the serum of sepsis patients and cells injured by LPS, which could inhibit the cell proliferation, promote the cell apoptosis and increase the expression of TNF-α, IL-6 and IL-1ß caused by paclitaxel. Moreover, lnc-MALAT1 was sponged with miR-370-3p which had the inverse effects with lnc-MALAT1 in LPS induced HK-2 cells. What's more, miR-370-3p targeted HMGB1 which was induced in serum and cells of sepsis. Knockdown of miR-370-3p inhibited the expression of HMGB1 and suppressed the proliferation but promoted the apoptosis of HK-2 cells injured by LPS as well as the expression of TNF-α, IL-6 and IL-1ß. Besides, paclitaxel restrained the expression of HMGB1 via regulating lnc-MALAT1/miR-370-3p axis. SIGNIFICANCE: Paclitaxel could protect against LPS-induced AKI via the regulation of lnc-MALAT1/miR-370-3p/HMGB1 axis and the expression of TNF-α, IL-6 and IL-1ß, revealing that paclitaxel might act as a therapy drug in reducing sepsis-associated AKI.


Assuntos
Lesão Renal Aguda/prevenção & controle , Antineoplásicos Fitogênicos/farmacologia , Paclitaxel/farmacologia , Sepse/complicações , Lesão Renal Aguda/etiologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/patologia , Proteína HMGB1/genética , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Túbulos Renais/citologia , Túbulos Renais/patologia , Lipopolissacarídeos , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator de Necrose Tumoral alfa/genética
14.
Life Sci ; 261: 118366, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32871182

RESUMO

AIMS: Intensive care unit-acquired weakness (ICU-AW) is a complex spectrum of disability that delays recovery of critically ill-immobilized patients with sepsis. Much discrepancy remain on the use of corticosteroids and their impact on muscle regeneration in critical illness management. Therefore, the aim of this study is to investigate whether hydrocortisone (HCT) modulates muscle mass turnover in ICU-AW induced by sepsis with limb immobilization (SI). MAIN METHODS: Sepsis by cecal ligation puncture (CLP) with forelimb-immobilization were performed in rats. The study consisted of four groups: Sham (left forelimb-immobilization), Sham HCT (left forelimb-immobilization + HCT), SI (CLP + left forelimb-immobilization) and SI HCT (CLP + left forelimb-immobilization + HCT). Motor force, blood and muscle sampling were assessed. KEY FINDINGS: HCT prevented body weight loss associated with SI and attenuated systemic and muscular inflammation. Besides, myosin was restituted in SI HCT group in conjunction to muscle mass and strength restoration. Pro-hypertrophic calcineurin (PP2B-Aß) and nuclear factor of activated T-cells C3 (NFATc3) but not protein kinase B (Akt) were re-activated by HCT. Finally, pro-atrophic extracellular signal-regulated kinases (ERK1/2) and p38 mitogen-activated protein kinases (p38) but not nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) were inhibited in SI HCT group. SIGNIFICANCE: This study unravels new molecular events thought to control muscle protein synthesis in ICU-AW induced by sepsis and limb immobilization. HCT has a potential to fine-tune muscle-signaling pathways and to reduce the negative outcomes of ICU-AW.


Assuntos
Extremidades/patologia , Hidrocortisona/uso terapêutico , Imobilização , Unidades de Terapia Intensiva , Debilidade Muscular/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Sepse/complicações , Transdução de Sinais , Animais , Peso Corporal , Modelos Animais de Doenças , Hidrocortisona/farmacologia , Hipertrofia , Mediadores da Inflamação/sangue , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Debilidade Muscular/sangue , Debilidade Muscular/complicações , Atrofia Muscular/sangue , Atrofia Muscular/complicações , Miosinas/metabolismo , Fatores de Transcrição NFATC/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos Wistar , Sepse/sangue
15.
Eur Rev Med Pharmacol Sci ; 24(16): 8606-8620, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32894568

RESUMO

OBJECTIVE: COVID-19 immune syndrome is a multi-systemic disorder induced by the COVID-19 infection. Pathobiological transitions and clinical stages of the COVID-19 syndrome following the attack of SARS-CoV-2 on the human body have not been fully explored. The aim of this review is to outline the three critical prominent phase regarding the clinicogenomics course of the COVID-19 immune syndrome. MATERIALS AND METHODS: In the clinical setting, the COVID-19 process presents as "asymptomatic/pre-symptomatic phase", "respiratory phase with mild/moderate/severe symptoms" and "multi-systemic clinical syndrome with impaired/disproportionate and/or defective immunity". The corresponding three genomic phases include the "ACE2, ANPEP transcripts in the initial phase", "EGFR and IGF2R transcripts in the propagating phase" and the "immune system related critical gene involvements of the complicating phase". RESULTS: The separation of the phases is important since the genomic features of each phase are different from each other and these different mechanisms lead to distinct clinical multi-systemic features. Comprehensive genomic profiling with next generation sequencing may play an important role in defining and clarifying these three unique separate phases for COVID-19. From our point of view, it is important to understand these unique phases of the syndrome in order to approach a COVID-19 patient bedside. CONCLUSIONS: This three-phase approach may be useful for future studies which will focus on the clinical management and development of the vaccines and/or specific drugs targeting the COVID-19 processes. ANPEP gene pathway may have a potential for the vaccine development. Regarding the specific disease treatments, MAS agonists, TXA127, Angiotensin (1-7) and soluble ACE2 could have therapeutic potential for the COVID-19 course. Moreover, future CRISPR technology can be utilized for the genomic editing and future management of the clinical course of the syndrome.


Assuntos
Doenças Assintomáticas , Infecções por Coronavirus/patologia , Sistema Imunitário/metabolismo , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação da Expressão Gênica , Humanos , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/patologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Prognóstico , Receptor IGF Tipo 2/genética , Receptor IGF Tipo 2/metabolismo , Sepse/complicações , Sepse/patologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
16.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(4): 361-366, 2020 Aug 24.
Artigo em Chinês | MEDLINE | ID: mdl-32935509

RESUMO

OBJECTIVE: To investigate the protective effect of recombinant adult serine protease inhibitor from Trichinella spiralis (TsadSPI) on sepsis-associated acute kidney injury in mice. METHODS: A total of 18 male BALB/c mice were randomly divided into the sham-operation group, the model group, and the TsadSPI treatment group, of 6 mice in each group. Sepsis-associated acute kidney injury was modeled in the model group and TsadSPI treatment group by cecal ligation puncture (CLP), while mice in the sham-operation group were only given exploratory laparotomy without ligation or perforation of the cecum. After 30 min of CLP, mice in the sham-operation group and the model group were intraperitoneally injected with PBS (100 µL), and mice in the TsadSPI treatment group were intraperitoneally injected with PBS (100 µL) containing TsadSPI (2 µg). At 12 h following modeling, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr) and urea nitrogen (BUN) were measured to assess the liver and kidney functions, and the changes of the mouse kidney structure were observed using HE staining. In addition, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-ß were measured using an enzyme-linked immunosorbent assay (ELISA), and the myeloid differentiation factor 88 (MyD88) and nuclear factor kappa-B (NF-κB) p65 expression was determined in kidney tissues using immunohistochemical staining. RESULTS: At 12 h following CLP, there were significant differences in the serum levels of ALT (F = 41.031, P < 0.001), AST (F = 54.757, P < 0.001), Cr (F = 24.142, P < 0.001) and BUN (F = 214.849, P < 0.001) among the three groups, and higher levels of ALT, AST, Cr and BUN were measured in model group than in the sham-operation group (P < 0.001), while lower ALT, AST, Cr and BUN levels were found in the TsadSPI treatment group than in the model group (P < 0.001). HE staining showed severe mouse kidney injuries following CLP, and TsadSPI treatment resulted in remarkable alleviation of the injury. ELISA measured significant differences in the TNF-α (F = 47.502, P < 0.001) and IL-6 levels (F = 222.061, P < 0.001) among the three groups, and showed a remarkable reduction in the TNF-α and IL-6 levels in the TsadSPI treatment group as compared to those in the model group (P < 0.001). In addition, there were significant differences in serum IL-10 (F = 16.227, P < 0.001) and TGF-ß levels (F = 52.092, P < 0.001) among the three groups, and higher IL-10 and TGF-ß levels were seen in the TsadSPI treatment group than in the model group (P < 0.001). Immunohistochemical staining showed greater MyD88 expression and a higher nuclear positive rate of NF-κB p65 in kidney tissues in the model group than in the TsadSPI treatment group. CONCLUSIONS: TsadSPI may reduce the MyD88 expression and nuclear positive rate of NF-κB p65 in mouse kidney tissues to up-regulate the expression of immunomodulatory factors and down-regulate the expression of pro-inflammatory cytokines, thereby protecting sepsis-associated acute kidney injury.


Assuntos
Lesão Renal Aguda , Sepse , Trichinella spiralis , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Animais , Citocinas/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Sepse/complicações , Inibidores de Serino Proteinase/genética , Inibidores de Serino Proteinase/farmacologia , Inibidores de Serino Proteinase/uso terapêutico , Trichinella spiralis/química , Trichinella spiralis/genética
17.
Emerg Med Clin North Am ; 38(4): 857-869, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32981622

RESUMO

The obesity pandemic now affects hundreds of millions of people worldwide. As obesity rates continue to increase, emergency physicians are called on with increasing frequency to resuscitate obese patients. This article discusses important anatomic, physiologic, and practical challenges imposed by obesity on resuscitative care. Impacts on hemodynamic monitoring, airway and ventilator management, and pharmacologic therapy are discussed. Finally, several important clinical scenarios (trauma, cardiac arrest, and sepsis), in which alterations to standard treatments may benefit obese patients, are highlighted.


Assuntos
Obesidade/complicações , Ressuscitação/métodos , Manuseio das Vias Aéreas/métodos , Analgésicos/administração & dosagem , Antibacterianos/administração & dosagem , Composição Corporal , Fármacos Cardiovasculares/administração & dosagem , Doenças Cardiovasculares/complicações , Relação Dose-Resposta a Droga , Serviço Hospitalar de Emergência , Parada Cardíaca/terapia , Humanos , Hipnóticos e Sedativos/administração & dosagem , Medidas de Volume Pulmonar , Consumo de Oxigênio , Farmacocinética , Respiração com Pressão Positiva , Sepse/complicações , Sepse/terapia , Ferimentos e Lesões/complicações , Ferimentos e Lesões/terapia
18.
JAMA Netw Open ; 3(8): e2012974, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32785635

RESUMO

Importance: People who inject drugs (PWID) who are being treated for infective endocarditis remain at risk of new bloodstream infections (BSIs) due to ongoing intravenous drug use (IVDU). Objectives: To characterize new BSIs in PWID receiving treatment for infective endocarditis, to determine the clinical factors associated with their development, and to determine whether new BSIs and treatment setting are associated with mortality. Design, Setting, and Participants: This retrospective cohort study was performed at 3 tertiary care hospitals in London, Ontario, Canada, from April 1, 2007, to March 31, 2018. Participants included a consecutive sample of all PWID 18 years or older admitted with infective endocarditis. Data were analyzed from April 1, 2007, to June 29, 2018. Main Outcomes and Measures: New BSIs and factors associated with their development, treatment setting of infective endocarditis episodes (ie, inpatient vs outpatient), and 90-day mortality. Results: The analysis identified 420 unique episodes of infective endocarditis in 309 PWID (mean [SD] patient age, 35.7 [9.7] years; 213 episodes [50.7%] involving male patients), with 82 (19.5%) complicated by new BSIs. There were 138 independent new BSIs, of which 68 (49.3%) were polymicrobial and 266 were unique isolates. Aerobic gram-negative bacilli (143 of 266 [53.8%]) and Candida species (75 of 266 [28.2%]) were the most common microorganisms. Ongoing inpatient IVDU was documented by a physician in 194 infective endocarditis episodes (46.2%), and 127 of these (65.5%) were confirmed by urine toxicology results. Multivariable time-dependent Cox regression demonstrated that previous infective endocarditis (hazard ratio [HR], 1.89; 95% CI, 1.20-2.98), inpatient treatment (HR, 4.49; 95% CI, 2.30-8.76), and physician-documented inpatient IVDU (HR, 5.07; 95% CI, 2.68-9.60) were associated with a significantly higher rate of new BSIs, whereas inpatient addiction treatment was associated with a significantly lower rate (HR, 0.53; 95% CI, 0.32-0.88). New BSIs were not significantly associated with 90-day mortality (HR, 1.76; 95% CI, 0.78-4.02); significant factors associated with mortality included inpatient infective endocarditis treatment (HR, 3.39; 95% CI, 1.53-7.53), intensive care unit admission (HR, 9.51; 95% CI, 4.91-18.42), and methicillin-resistant Staphylococcus aureus infective endocarditis (HR, 1.77; 95% CI, 1.03-3.03), whereas right-sided infective endocarditis was associated with a significantly lower mortality rate (HR, 0.41; 95% CI, 0.25-0.67). Conclusions and Relevance: In this study, new BSIs were common in PWID receiving parenteral treatment for infective endocarditis. Discharging patients to outpatient treatment was not associated with an increase in new BSI incidence or mortality; carefully selected PWID may therefore be considered for such treatment.


Assuntos
Endocardite , Sepse , Abuso de Substâncias por Via Intravenosa , Adulto , Endocardite/complicações , Endocardite/epidemiologia , Endocardite/mortalidade , Endocardite/terapia , Feminino , Hospitalização , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina , Pessoa de Meia-Idade , Alta do Paciente , Estudos Retrospectivos , Sepse/complicações , Sepse/epidemiologia , Sepse/mortalidade , Infecções Estafilocócicas , Abuso de Substâncias por Via Intravenosa/complicações , Abuso de Substâncias por Via Intravenosa/epidemiologia , Abuso de Substâncias por Via Intravenosa/mortalidade , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-32806705

RESUMO

Sepsis-associated brain dysfunction (SABD) may be the most common type of encephalopathy in critically ill patients. SABD develops in up to 70% of septic patients and represents the most frequent organ insufficiency associated with sepsis. It presents with a plethora of acute neurological features and may have several serious long-term psychiatric consequences. SABD might cause various pathological changes in the brain through numerous mechanisms. Clinical neurological examination is the basic screening method for SABD, although it may be challenging in subjects receiving with opioids and sedative agents. As electrographic seizures and periodic discharges might be present in 20% of septic patients, screening with electroencephalography (EEG) might be useful. Several imaging techniques have been suggested for non-invasive assessment of structure and function of the brain in SABD patients; however, their usefulness is rather limited. Although several experimental therapies have been postulated, at the moment, no specific treatment exists. Clinicians should focus on preventive measures and optimal management of sepsis. This review discusses epidemiology, clinical presentation, pathology, pathophysiology, diagnosis, management, and prevention of SABD.


Assuntos
Encefalopatias , Sepse , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico , Encefalopatias/epidemiologia , Encefalopatias/etiologia , Eletroencefalografia , Humanos , Qualidade de Vida , Sepse/complicações
20.
Sci Rep ; 10(1): 13110, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753644

RESUMO

Sepsis-associated liver dysfunction manifesting as cholestasis is common during multiple organ failure. Three hepatocytic dysfunctions are considered as major hallmarks of cholestasis in sepsis: impairments of microvilli covering canalicular membranes, disruptions of tight junctions sealing bile-collecting canaliculae and disruptions of Mrp2-mediated hepatobiliary transport. PI3Kγ loss-of-function was suggested as beneficial in early sepsis. Yet, the PI3Kγ-regulated cellular processes in hepatocytes remained largely unclear. We analysed all three sepsis hallmarks for responsiveness to massive PI3K/Akt signalling and PI3Kγ loss-of-function, respectively. Surprisingly, neither microvilli nor tight junctions were strongly modulated, as shown by electron microscopical studies of mouse liver samples. Instead, quantitative electron microscopy proved that solely Mrp2 surface availability, i.e. the third hallmark, responded strongly to PI3K/Akt signalling. Mrp2 plasma membrane levels were massively reduced upon PI3K/Akt signalling. Importantly, Mrp2 levels at the plasma membrane of PI3Kγ KO hepatocytes remained unaffected upon PI3K/Akt signalling stimulation. The effect explicitly relied on PI3Kγ's enzymatic ability, as shown by PI3Kγ kinase-dead mice. Keeping the surface availability of the biliary transporter Mrp2 therefore is a cell biological process that may underlie the observation that PI3Kγ loss-of-function protects from hepatic excretory dysfunction during early sepsis and Mrp2 should thus take center stage in pharmacological interventions.


Assuntos
Quimiocinas CC/metabolismo , Colestase/complicações , Colestase/patologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Sepse/complicações , Animais , Linhagem Celular , Membrana Celular/metabolismo , Colestase/metabolismo , Técnicas de Inativação de Genes , Camundongos , Fosfatidilinositol 3-Quinases/deficiência , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
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