Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.214
Filtrar
1.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575946

RESUMO

It has become widely accepted that insulin resistance and glucose hypermetabolism can be linked to acute pathologies, such as burn injury, severe trauma, or sepsis. Severe burns can determine a significant increase in catabolism, having an important effect on glucose metabolism and on muscle protein metabolism. It is imperative to acknowledge that these alterations can lead to increased mortality through organ failure, even when the patients survive the initial trauma caused by the burn. By limiting the peripheral use of glucose with consequent hyperglycemia, insulin resistance determines compensatory increased levels of insulin in plasma. However, the significant alterations in cellular metabolism lead to a lack of response to insulin's anabolic functions, as well as to a decrease in its cytoprotective role. In the end, via pathological insulin signaling associated with increased liver gluconeogenesis, elevated levels of glucose are detected in the blood. Several cellular mechanisms have been incriminated in the development of insulin resistance in burns. In this context, the main aim of this review article is to summarize some of the drugs that might interfere with insulin resistance in burns, taking into consideration that such an approach can significantly improve the prognosis of the burned patient.


Assuntos
Queimaduras/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Resistência à Insulina/genética , Sepse/tratamento farmacológico , Queimaduras/sangue , Queimaduras/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/sangue , Hiperglicemia/patologia , Insulina/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Sepse/sangue , Sepse/patologia , Índice de Gravidade de Doença
2.
Cell Rep ; 37(1): 109793, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34587478

RESUMO

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Infecções por HIV/sangue , Leucócitos Mononucleares/metabolismo , SARS-CoV-2/imunologia , Sepse/sangue , Transcriptoma , COVID-19/virologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Análise de Dados , Conjuntos de Dados como Assunto , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Imunossupressão , Inflamação/sangue , Leucócitos Mononucleares/imunologia , Sepse/imunologia , Análise de Célula Única
3.
PLoS One ; 16(9): e0257177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34499695

RESUMO

Electrical stimulation is proposed to exert an antimicrobial effect according to studies performed using bacterial and cell cultures. Therefore, we investigated the effects of electrification on inflammation in septic rats. Twenty-eight male Wistar albino rats were divided into 4 groups: healthy control (C), electrified healthy (E), sepsis (S), and electrified sepsis (SE) groups. Staphylococcus aureus (1 x 109 colonies) in 1 ml of medium was intraperitoneally injected into rats to produce a sepsis model. The rats in the E and SE groups were exposed to a low direct electrical signal (300 Hz and 2.5 volts) for 40 min and 1 and 6 h after bacterial infection. Immediately after the second electrical signal application, blood and tissue samples of the heart, lung, and liver were collected. An antibacterial effect of a low direct electrical signal was observed in the blood of rats. The effects of electrical signals on ameliorating changes in the histological structure of tissues, blood pH, gases, viscosity and cell count, activities of some important enzymes, oxidative stress parameters, inflammation and tissue apoptosis were observed in the SE group compared to the S group. Low direct electrical signal application exerts antibacterial, antioxidant, anti-inflammatory and antiapoptotic effects on septic rats due to the induction of electrolysis in body fluids without producing any tissue damage.


Assuntos
Eletricidade , Inflamação/complicações , Inflamação/patologia , Estresse Oxidativo , Sepse/complicações , Sepse/patologia , Alanina Transaminase/sangue , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Colesterol/sangue , Citocinas/sangue , Glutationa/sangue , Contagem de Leucócitos , Malondialdeído/sangue , Ratos Wistar , Reologia , Sepse/sangue , Sepse/microbiologia , Staphylococcus aureus/fisiologia , Proteína X Associada a bcl-2/metabolismo
4.
PLoS One ; 16(9): e0257034, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34555053

RESUMO

INTRODUCTION: Sepsis impairs gastrointestinal microcirculation and it is hypothesized that this might increase patient's mortality. Sub-therapeutic vasopressin improves gastric microcirculation under physiologic conditions whereas a therapeutic dosing regimen seems to be rather detrimental. However, the effects of sub-therapeutic vasopressin on gastrointestinal microcirculation in sepsis are largely unknown. Therefore, we conducted this trial to investigate the effect of sub-therapeutic as well as therapeutic vasopressin on gastrointestinal microcirculation in sepsis. METHODS: 40 male Wistar rats were randomized into 4 groups. Colon ascendens stent peritonitis (CASP)-surgery was performed to establish mild or moderate sepsis. 24 hours after surgery, animals received either vasopressin with increasing dosages every 30 min (6.75, 13.5 (sub-therapeutic), 27 mU · kg-1 · h-1 (therapeutic)) or vehicle. Microcirculatory oxygenation (µHBO2) of the colon was recorded for 90 min using tissue reflectance spectrophotometry. Intestinal microcirculatory perfusion (total vessel density (TVD; mm/mm2) and perfused vessel density (PVD; mm/mm2)) were measured using incident dark field-Imaging at baseline and after 60 min. RESULTS: In mild as well as in moderate septic animals with vehicle-infusion intestinal µHbO2, TVD and PVD remained constant. In contrast, in moderate sepsis, sub-therapeutic vasopressin with 13.5 mU · kg-1 · h-1 elevated intestinal µHBO2 (+ 6.1 ± 5.3%; p < 0.05 vs. baseline) and TVD (+ 5.2 ± 3.0 mm/mm2; p < 0.05 vs. baseline). µHBO2, TVD and PVD were significantly increased compared to moderate sepsis alone. However, therapeutic vasopressin did not change intestinal microcirculation. In mild septic animals sub-therapeutic as well as therapeutic vasopressin had no relevant effect on gastrointestinal microcirculation. Systemic blood pressure remained constant in all groups. CONCLUSION: Sub-therapeutic vasopressin improves gastrointestinal microcirculatory oxygenation in moderate sepsis without altering systemic blood pressure. This protective effect seems to be mediated by an enhanced microcirculatory perfusion and thereby increased oxygen supply. In contrast, therapeutic vasopressin did not show this beneficial effect.


Assuntos
Trato Gastrointestinal/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Sepse/sangue , Sepse/tratamento farmacológico , Vasopressinas/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Oxigênio/metabolismo , Perfusão , Placebos , Ratos Wistar , Vasopressinas/farmacologia
5.
Nutrients ; 13(9)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34578983

RESUMO

Sepsis biomarkers and potential therapeutic targets are urgently needed. With proton nuclear magnetic resonance (1H NMR) spectroscopy, several metabolites can be assessed simultaneously. Fifty-three adult medical ICU sepsis patients and 25 ICU controls without sepsis were prospectively enrolled. 1H NMR differences between groups and associations with 28-day and ICU mortality were investigated. In multivariate metabolomic analyses, we found separate clustering of ICU controls and sepsis patients, as well as septic shock survivors and non-survivors. Lipoproteins were significantly different between sepsis and control patients. Levels of the branched-chain amino acids (BCAA) valine (median 43.3 [29.0-53.7] vs. 64.3 [47.7-72.3] normalized signal intensity units; p = 0.005), leucine (57.0 [38.4-71.0] vs. 73.0 [54.3-86.3]; p = 0.034) and isoleucine (15.2 [10.9-21.6] vs. 17.9 [16.1-24.4]; p = 0.048) were lower in patients with septic shock compared to those without. Similarly, BCAA were lower in ICU non-survivors compared to survivors, and BCAA were good discriminators for ICU and 28-day mortality. In uni- and multivariable logistic regression analyses, higher BCAA levels were associated with decreased ICU- and 28-day mortality. In conclusion, metabolomics using 1H NMR spectroscopy showed encouraging potential for personalized medicine in sepsis. BCAA was significantly lower in sepsis non-survivors and may be used as early biomarkers for outcome prediction.


Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Sepse/mortalidade , Idoso , Bacteriemia/sangue , Bacteriemia/mortalidade , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Isoleucina/sangue , Leucina/sangue , Lipoproteínas/sangue , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sepse/sangue , Choque Séptico/sangue , Choque Séptico/mortalidade
6.
Life Sci ; 284: 119882, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34384829

RESUMO

AIMS: Sepsis is a life-threatening organ dysfunction syndrome arising from infection-induced uncontrolled systemic inflammatory responses. Patients surviving severe sepsis also exhibit increased mortality due to enhanced vulnerability to infections. In this study, we examined whether (R)-ketamine could prevent against lethal sepsis-induced systemic inflammation and inflammatory organ injury. MAIN METHODS: Septic model was induced by cecal ligation and puncture (CLP) surgery on adult mice. (R)-ketamine (10 or 15 mg/kg) was administrated intraperitoneally (i.p.) 24 h before and/or immediately after CLP. KEY FINDINGS: Combined prophylactic and therapeutic use of (R)-ketamine (10 mg/kg), as well as either prophylactic or therapeutic use of (R)-ketamine at a single dose of 15 mg/kg did not reduce 14-day mortality after CLP. However, combined prophylactic and therapeutic use of (R)-ketamine (15 mg/kg) significantly increased 14-day survival rate, attenuated sepsis-induced marked drop in the rectal temperature and increase in the plasma levels of inflammatory cytokines [i.e., interleukin (IL)-6, IL-17A, tumor necrosis factor (TNF)-α, IL-1ß, and IL-10] 12 h after CLP. Furthermore, (R)-ketamine alleviated sepsis-induced increase in the organ injury markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), myocardial kinase (CK-MB), and creatinine 24 h after CLP. Moreover, the increased lung wet/dry weight ratio, pulmonary morphological injury and the pulmonary levels of inflammatory cytokines were also attenuated by (R)-ketamine. SIGNIFICANCE: Combined prophylactic and therapeutic use of (R)-ketamine could attenuate systemic inflammation and inflammatory multi-organ injury in mice after CLP-induced lethal sepsis. Therefore, (R)-ketamine would be a potential prophylactic and therapeutic drug for patients prone to sepsis.


Assuntos
Ceco/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Ketamina/uso terapêutico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/patologia , Animais , Biomarcadores/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Inflamação/sangue , Mediadores da Inflamação/sangue , Ketamina/farmacologia , Ligadura , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/sangue , Tamanho do Órgão/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Punções , Sepse/sangue , Sepse/tratamento farmacológico
7.
Eur J Med Res ; 26(1): 90, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376255

RESUMO

BACKGROUND: The goal of this study was to investigate the diagnostic value of miR-29c-3p in sepsis and its role in sepsis-induced inflammatory response and cardiac dysfunction. METHODS: Serum level of miR-29c-3p was detected by qRT-PCR. The ROC curve was used to evaluate the diagnostic value of miR-29c-3p for Sepsis. The cecal ligation and puncture method (CLP) was used to establish a rat sepsis model. To assess cardiac function, left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP) and maximum rate of rise/fall of left ventricle pressure (± dp/dtmax) in different experimental groups were detected, and the serum cardiac troponin I (cTnI), creative kinase isoenzyme MB (CK-MB) were measured by ELISA. Meanwhile, TNF-α, IL-1ß, and IL-6 were detected by ELISA to assess the level of inflammatory response in animals. RESULTS: miR-29c-3p level was upregulated in sepsis patients. ROC curve revealed that miR-29c-3p had the ability to distinguish sepsis patients from healthy controls. Cardiac dysfunction and inflammation were observed in sepsis rat, which were characterized by the decrease of LVSP and + dp/dtmax, the increase of LVEDP, - dp/dtmax, cTnI, CK-MB, TNF-α, IL-1ß, IL-6. All effects were reversed by the injection of miR-29c-3p antagomir. Logistics regression analysis manifested miR-29c-3p is an independent factor in the occurrence of cardiac dysfunction in sepsis patients. CONCLUSIONS: miR-29c-3p has potential as a biomarker for the diagnosis of sepsis, and inhibition of miR-29c-3p expression in animal models reduced sepsis-induced cardiac dysfunction and inflammatory response.


Assuntos
Cardiopatias/sangue , MicroRNAs/sangue , Sepse/sangue , Idoso , Animais , Biomarcadores/sangue , Pressão Sanguínea , Citocinas/sangue , Feminino , Cardiopatias/etiologia , Cardiopatias/patologia , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/patologia , Troponina I/sangue
8.
Biomed Res Int ; 2021: 9969344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327242

RESUMO

Objective: We want to explore the changing law of circulating histones in the acute stage of urosepsis and to find more sensitive and specific biomarkers for diagnosing urosepsis as early as possible. Methods: Twenty healthy male New Zealand rabbits were randomly divided into 4 groups (N = 5): the control group, sham group, model group of LPS 600 µg/kg, and model group of LPS 1000 µg/kg. Heart rate (HR), respiration rate (RR), rectal temperature (T), and mean arterial pressure (MAP) were examined at 1, 3, 6, 12, and 24 hours after operation. Besides, peripheral blood cell counts (RBC, WBC, PLT, and Hb) and C reaction protein (CRP) were tested at 1, 3, and 6 hours after operation, while the levels of histone H3, MMP-9, TIMP-1, and procalcitonin (PCT) in the serum were tested at 1, 3, and 6 hours after operation by ELISA. The heart, left lung, liver, and left kidney were harvested for HE stain and observed to research the pathological change of these tissues. Results: (1) The general status of rabbits: rabbits in the control and sham groups came out in 2 h after operation and regain to drink and eat in 12-24 h after operation. State of the rabbits in the control group was better than that in the sham group. Rabbits in the model groups were languid after operation and stopped to drink and eat. (2) Vital signs of rabbits: there was no statistic difference in HR (P = 0.238) and RR (P = 0.813) among all groups. MAP of the model groups decreased at 3 h postoperative, but transient (P < 0.001). The T of the LPS 1000 group decreased at 6 h postoperative (P = 0.003). (3) The change of biomarkers: H3 level of the LPS groups in the serum increased at 1 h postoperative (P < 0.01); MMP-9 of the LPS 1000 group increased at 1 h postoperative (P < 0.01); WBC of the model groups decreased at 3 h postoperative (P < 0.05); PLT of the LPS 1000 group is significantly increased at 1 h postoperative (P < 0.05); no statistic difference was found in CRP, PCT, and TIMP-1 among all groups. (4) Pathological sections: no abnormal performance was found in the control and sham groups. Glomerulus of the model groups was out of shape and necrosis with obvious renal tubule expansion. Pulmonary pathology showed alveolar septum diffuse increased and inflammatory infiltrate. Change of the LPS 1000 group was more serious than that of the LPS 600 group. Conclusions: Ligating the ureter after an injection of 1000 µg/kg LPS into the ureter of the rabbit can establish the animal model of urosepsis. Histone H3 increase immediately at 1 h postoperative and are promised to be biomarkers of urosepsis, which are more effective than WBC, CRP, and PCT.


Assuntos
Diagnóstico Precoce , Histonas/sangue , Sepse/sangue , Sepse/diagnóstico , Animais , Pressão Arterial , Temperatura Corporal , Proteína C-Reativa/metabolismo , Modelos Animais de Doenças , Contagem de Leucócitos , Lipopolissacarídeos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Especificidade de Órgãos , Contagem de Plaquetas , Pró-Calcitonina/sangue , Curva ROC , Coelhos , Sensibilidade e Especificidade , Sepse/patologia , Sepse/fisiopatologia , Inibidor Tecidual de Metaloproteinase-1/sangue , Sinais Vitais
9.
Medicine (Baltimore) ; 100(27): e26555, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232197

RESUMO

BACKGROUND: The patient suffering from urinary sepsis is often accompanied by elevated serum procalcitonin (PCT) levels and a decline in the average platelet count (PLT), which could result in a poor prognosis. This study aimed to evaluate the value of PCT and PLT in determining the severity of urinary sepsis. METHODS: A total of 120 urosepsis patients enrolled were divided into a survival group and a death group, respectively, according to their status within 14 days after admission. Changes in PCT and PLT levels between the 2 groups were compared at different time points. A receiver operating characteristic (ROC) curve was eventually obtained to predict the prognostic value of PCT and PLT. RESULTS: The PCT levels in the survival group declined gradually after admission, and the PLT decreased at first but increased rapidly in subsequence. The PCT level in the death group, however, declined in a flat-slope trend or was hardly noticeable together with the number of PLT reduced significantly. In particular, it is on the 3rd day that PCT tended to positively correlate with acute physiological and chronic health score II (APACHE II) score (r = 0.730, P < .05), but negatively with PLT (r = 0.472, P < .05). The APACHE II score and PLT (r = 0.612, P < .05) were also negatively correlated with each other. As indicated by the ROC curve, the PCT level on the 3rd day after admission was of great value for the clinical mortality prognosis, and the area under the curve was 0.858. Moreover, PLT also has a high predictive value for prognosis. Area under the curve is 0.951. When the PLT was more than 51 × 109 /L, the sensitivity was up to 90%, and the specificity was 90%. CONCLUSION: PLT and PCT levels are closely related to the APACHE II score, which could indicate the severity of urosepsis in patients. The contribution of this study was to confirm that dynamic monitoring of the changes in PCT and PLT helps determine the prognosis of urosepsis patients.


Assuntos
Plaquetas/patologia , Pró-Calcitonina/sangue , Sepse/sangue , Infecções Urinárias/sangue , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Retrospectivos , Sepse/etiologia , Infecções Urinárias/etiologia
10.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199069

RESUMO

Acute kidney injury (AKI) is a common yet complicated clinical entity with high morbidity and mortality. An essential strategy to improve AKI patients' prognoses is finding optimal biomarkers to identify AKI in a timely manner. Procalcitonin (PCT), a well-recognized biomarker for diagnosing infection and guiding antibiotics therapy, has been proposed to predict AKI development and recovery in many clinical settings. The current review provides comprehensive and updated information from relevant studies to evaluate PCT's AKI-predictive ability and the influence of infection on this predictive ability. PCT has demonstrated optimal predictive ability for AKI in various populations irrespective of infection. However, the predictive ability seems to be blunted by infection since infection and inflammation have a more potent influence than AKI on PCT elevation. We furthermore explain the complicated association between elevated PCT levels and AKI in infection and inflammation situations and recommend directions for further investigations to clarify the essential issue. In conclusion, although conflicting data exist, serum PCT level is a potential biomarker for predicting AKI in many clinical settings regardless of infection. Nevertheless, further studies are warranted to clarify the association between PCT, infection, and AKI and to confirm the utilization of PCT for AKI prediction.


Assuntos
Injúria Renal Aguda/sangue , Injúria Renal Aguda/diagnóstico , Biomarcadores , Pró-Calcitonina/sangue , Injúria Renal Aguda/etiologia , Suscetibilidade a Doenças , Humanos , Testes de Função Renal , Prognóstico , Sepse/sangue
11.
Sci Rep ; 11(1): 14141, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238972

RESUMO

In order to explore the role of exosomal circRNAs in the occurrence and development of sepsis, we looked for potential diagnostic markers to accurately identify sepsis and to lay a molecular basis for precise treatment. Ultracentrifugation was used to extract exosomes from the serum of patients with sepsis and healthy individuals. Then, changes in circRNA expression in exosomes were studied by circRNA microarray analysis. Gene ontology (GO) analysis and Kyoto City Encyclopaedia of Genes and Genomes (KEGG) pathway analysis were used to annotate the biological functions and pathways of genes, and a circRNA-miRNA-mRNA regulatory network was constructed. In the microarray analysis, 132 circRNAs were significantly differentially expressed, including 80 and 52 that were upregulated and downregulated, respectively. RT-qPCR verified the results of microarray analysis: hsa_circRNA_104484 and hsa_circRNA_104670 were upregulated in sepsis serum exosomes. ROC analysis showed that hsa_circRNA_104484 and hsa_circRNA_104670 in serum exosomes have the potential to be used as diagnostic markers for sepsis. The circRNA-miRNA-mRNA network predicted the potential regulatory pathways of differentially expressed circRNAs. There are differences in the expression of circRNA in serum exosomes between patients with sepsis and healthy individuals, which may be involved in the occurrence and development of the disease. Among them, elevations in hsa_circRNA_104484 and hsa_circRNA_104670 could be used as novel diagnostic biomarkers and molecular therapeutic targets.


Assuntos
Biomarcadores/sangue , Exossomos/genética , RNA Circular/genética , Sepse/genética , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , MicroRNAs/genética , RNA Circular/sangue , RNA Mensageiro/genética , Sepse/sangue , Sepse/tratamento farmacológico , Sepse/patologia
12.
Infect Immun ; 89(10): e0016221, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34310884

RESUMO

Extremely drug-resistant (XDR) Acinetobacter baumannii is a notorious and frequently encountered pathogen demanding novel therapeutic interventions. An initial monoclonal antibody (MAb), C8, raised against A. baumannii capsule, proved a highly effective treatment against a minority of clinical isolates. To overcome this limitation, we broadened coverage by developing a second antibody for use in a combination regimen. We sought to develop an additional anti-A. baumannii MAb through hybridoma technology by immunizing mice with sublethal inocula of virulent, XDR clinical isolates not bound by MAb C8. We identified a new antibacterial MAb, 65, which bound to strains in a pattern distinct from and complementary to that of MAb C8. MAb 65 enhanced macrophage opsonophagocytosis of targeted strains and markedly improved survival in lethal bacteremic sepsis and aspiration pneumonia murine models of A. baumannii infection. MAb 65 was also synergistic with colistin, substantially enhancing protection compared to monotherapy. Treatment with MAb 65 significantly reduced blood bacterial density, ameliorated cytokine production (interleukin-1ß [IL-1ß], IL-6, IL-10, and tumor necrosis factor), and sepsis biomarkers. We describe a novel MAb targeting A. baumannii that broadens immunotherapeutic strain coverage, is highly potent and effective, and synergistically improves outcomes in combination with antibiotics.


Assuntos
Infecções por Acinetobacter/imunologia , Acinetobacter baumannii/imunologia , Anticorpos Monoclonais/imunologia , Infecções por Acinetobacter/sangue , Infecções por Acinetobacter/microbiologia , Animais , Antibacterianos/imunologia , Anticorpos Antibacterianos/imunologia , Biomarcadores/sangue , Colistina/imunologia , Citocinas/sangue , Citocinas/imunologia , Farmacorresistência Bacteriana Múltipla/imunologia , Camundongos , Testes de Sensibilidade Microbiana/métodos , Sepse/sangue , Sepse/imunologia , Sepse/microbiologia
13.
Anaesthesiol Intensive Ther ; 53(2): 108-114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34284551

RESUMO

INTRODUCTION: Infection with SARS-CoV-2 in its most severe form leads to acute respiratory distress syndrome requiring mechanical ventilation under the conditions of the Intensive Care Unit (ICU). The state of hypercoagulation described in COVID-19 may deepen respiratory failure, leading to increased mortality. The aim of the presented study is to characterise the haemostatic profile based on the results of clotting system parameters and risk assessment of thromboembolic complications of patients hospitalised in the ICU. MATERIAL AND METHODS: This retrospective study covered the first 10 adult patients hospitalised in the ICU of the Hospital for Infectious Diseases in Warsaw in the second quarter of 2020. Demographic, clinical and laboratory parameters of the coagulation system and the risk of thromboembolic complications were assessed. Well known criteria of haemostatic disorders were used to classify the observed derangements. RESULTS: The most frequently observed deviations in the coagulation system were high concentrations of D-dimer and fibrinogen. In select cases the clotting time was prolonged. No severe thrombocytopenia was observed. All patients presented a high risk of thromboembolic complications as assesed by the Padua score. The observed clotting abnormalities did not meet the criteria for DIC (disseminated intravascular coagulation) and SIC (sepsis-induced coagulopathy) diagnosis. CONCLUSIONS: The main elements of coagulopathy that were observed in our cases differ from those usually seen in patients with recognised sepsis. The unique haemostatic profile of COVID-19 patients treated in the ICU has been described as CAC (COVID-19-associated coagulopathy).


Assuntos
COVID-19/complicações , COVID-19/terapia , Coagulação Intravascular Disseminada/diagnóstico , Sepse/diagnóstico , Adulto , Testes de Coagulação Sanguínea/métodos , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/etiologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Mediadores da Inflamação/sangue , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Polônia , Estudos Retrospectivos , Sepse/sangue , Sepse/etiologia
14.
Biomed Res Int ; 2021: 5595042, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095304

RESUMO

Background: Research has previously been done into the risk factors for mortality in septic shock patients. However, there has been no epidemiological study investigating the effect of the blood urea nitrogen/creatinine ratio (BCR) on the prognosis of critically ill septic shock patients. This study is aimed at determining the relationship between BCR and all-cause mortality in adult septic shock patients. Methods: Data were extracted from the MIMIC-III database. The clinical endpoints were 28-, 90-, and 365-day all-cause mortality rates in critically ill septic shock patients. Cox proportional hazards models and subgroup analyses were used to analyze the relationship between BCR quartiles and all-cause mortality in septic shock patients. Receiver operator characteristic (ROC) curves and areas under the ROC curves (AUCs) were calculated to evaluate how accurately BCR predicts the mortality of septic shock patients. Results: Among the 2484 septic shock patients extracted from the database, 619, 563, 677, and 625 fell into the first (<14.4 mg/dL), second (≥14.4 mg/dL and <20.0 mg/dL), third (≥20.0 mg/dL and <27.3 mg/dL), and fourth (≥27.3 mg/dL) quartiles of BCR, respectively. Male and white patients accounted for 53.8% (1336 patients) and 74.8% (1857 patients) of the population, respectively. The mean age of the population was 67.7 ± 15.8 years. An inverse M-shaped relationship between BCR and mortality in septic shock patients was identified, with a value of ≥27.3 mg/dL providing the highest risk (HR = 1.596, 95% CI: 1.396-1.824, P < 0.001). In the Cox regression model adjusted for different confounding variables, BCR values in the fourth quartiles were significantly associated with increased mortality, using the first quartiles as a reference. The areas under the ROC curves (AUCs) for BCR plus the Sequential Organ Failure Assessment (SOFA) score and BCR plus Acute Physiology Score III (APSIII) were 0.694 (95% CI: 0.673-0.716) and 0.724 (95% CI: 0.703-0.744), respectively. Conclusion: An inverse M-shaped curve was determined between BCR and the mortality of septic shock patients. BCR was identified as a readily available and independent prognostic biomarker for septic shock patients, and higher BCRs were associated with increased mortality in these patients.


Assuntos
Nitrogênio da Ureia Sanguínea , Creatinina/análise , Choque Séptico/mortalidade , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , China , Creatinina/sangue , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Sepse/sangue , Sepse/metabolismo , Sepse/mortalidade , Choque Séptico/sangue , Choque Séptico/metabolismo
15.
Biochem Med (Zagreb) ; 31(2): 020709, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34140832

RESUMO

Introduction: The prognostic value of D-dimer (DD) in sepsis remains controversial. This study aimed to investigate the performance of DD for predicting sepsis mortality in the hospital and for identifying its potential correlates. Materials and methods: The clinical and laboratory data of adult sepsis patients were extracted from the Medical Information Mart for Intensive Care III (MIMIC III, v1.4) database using the structured query language (SQL). The database contains critical illness admitted to the intensive care unit at Beth Israel Deaconess Medical Center between June 2001 and October 2012. The association between DD and mortality was investigated with receiver operating characteristic (ROC) curve, restricted cubic spline and logistic regression analysis. Subgroup analysis was also used for identifying DD correlates. Results: The study population consisted of 358 sepsis patients. Those who died during hospital stay (N = 160) had significantly higher DD values than those who survived (N = 198). The area under the ROC curve (AUC) of DD was 0.59 (P < 0.010). In subgroup analysis, white blood cell (WBC) count > 18 x109/L and vasopressor therapy significantly decreased DD diagnostic performance. Categorical DD value was independently associated with hospital mortality after sequential organ failure score (SOFA) and blood lactate adjustment. Restricted cubic spline analysis revealed a U-shape relationship between DD and in-hospital mortality. Discussion: We conclude that the accuracy of DD for predicting in-hospital sepsis mortality depends on WBC count and vasopressor therapy. Both low and extremely elevated DD values are associated with higher risk of death.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Mortalidade Hospitalar , Unidades de Terapia Intensiva , Sepse/sangue , Sepse/mortalidade , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos
16.
Biochem Med (Zagreb) ; 31(2): 021003, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34140837

RESUMO

This case report describes false shortening of activated partial thromboplastin time (aPTT) due to erroneous optical reading of the clotting point in the presence of unfractionated heparin (UFH), and a biphasic waveform. Activated partial thromboplastin time performed on a coagulometer with photo-optical detection yielded an ambiguous clotting curve characterized by an early and steady decrease in light transmittance throughout the whole measuring range, with the clotting point read at 65 seconds. Further investigations included measurement of aPTT by means of a mechanical clot detection method as well as determination of another heparin-sensitive coagulation assay, that is thrombin time (TT), both being unmeasurably prolonged (> 150 seconds). Communication with clinicians revealed that the patient was on continuous UFH therapy and had an underlying sepsis, with highly elevated C-reactive protein (289 mg/L). The aPTT measurements requested at three timepoints later during the same day revealed gradual aPTT shortening and unveiled a peculiar biphasic waveform pattern. In this case, unmeasurably prolonged aPTT due to UFH therapy was masked by a biphasic aPTT curve pattern making only the first slope of the biphasic waveform visible within the measuring range. The early decrease in plasma light transmittance mimicked optical changes related to clot formation, thus causing erroneous optical reading and yielding a falsely shortened aPTT. This case emphasizes that such a pattern should be carefully inspected, especially when a combination of a critically ill condition and UFH therapy is present, in order to prevent erroneous reporting of aPTT and potential adverse effects on patient care.


Assuntos
Anticoagulantes/administração & dosagem , Proteína C-Reativa/metabolismo , Heparina/administração & dosagem , Sepse/sangue , Sepse/tratamento farmacológico , Anticoagulantes/farmacocinética , Heparina/farmacocinética , Humanos , Masculino , Tempo de Tromboplastina Parcial
17.
Am J Respir Crit Care Med ; 204(5): 557-565, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34038701

RESUMO

Rationale: Sepsis commonly results in elevated serum troponin levels and increased risk for postsepsis cardiovascular complications; however, the association between troponin levels during sepsis and cardiovascular complications after sepsis is unclear.Objectives: To evaluate the association between serum troponin levels during sepsis and 1 year after sepsis cardiovascular events.Methods: We analyzed adults aged ⩾40 years without preexisting cardiovascular disease within 5 years, admitted with sepsis across 21 hospitals from 2011 to 2017. Peak serum troponin I levels during sepsis were grouped as normal (⩽0.04 ng/ml) or tertiles of abnormal (>0.04 to ⩽0.09 ng/ml, >0.09 to ⩽0.42 ng/ml, or >0.42 ng/ml). Multivariable adjusted cause-specific Cox proportional hazards models with death as a competing risk were used to assess associations between peak troponin I levels and a composite cardiovascular outcome (atherosclerotic cardiovascular disease, atrial fibrillation, and heart failure) in the year following sepsis. Models were adjusted for presepsis and intrasepsis factors considered potential confounders.Measurements and Main Results: Among 14,046 eligible adults with troponin I measured, 2,012 (14.3%) experienced the composite cardiovascular outcome, including 832 (10.9%) patients with normal troponin levels, as compared with 370 (17.3%), 376 (17.6%), and 434 (20.3%) patients within each sequential abnormal troponin tertile, respectively (P < 0.001). Patients within the elevated troponin tertiles had increased risks of adverse cardiovascular events (adjusted hazard ratio [aHR]troponin0.04-0.09 = 1.37; 95% confidence interval [CI], 1.20-1.55; aHRtroponin0.09-0.42 = 1.44; 95% CI, 1.27-1.63; and aHRtroponin>0.42 = 1.77; 95% CI, 1.56-2.00).Conclusions: Among patients without preexisting cardiovascular disease, troponin elevation during sepsis identified patients at increased risk for postsepsis cardiovascular complications. Strategies to mitigate cardiovascular complications among this high-risk subset of patients are warranted.


Assuntos
Biomarcadores/sangue , Cardiopatias/etiologia , Sepse/sangue , Sepse/complicações , Sobreviventes/estatística & dados numéricos , Troponina I/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos
18.
PLoS One ; 16(5): e0251317, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33989306

RESUMO

Fibroblast growth factor-23 (FGF23), a bone-produced hormone, plays a critical role in mineral homeostasis. Human diseases associated with excessive intact circulating FGF23 (iFGF23) result in hypophosphatemia and low vitamin D hormone in patients with normal kidney function. In addition, there is accumulating evidence linking FGF23 with inflammation. Based on these studies and the frequent observation of hypophosphatemia among septic patients, we sought to elucidate further the relationship between FGF23 and mineral homeostasis in a clinically relevant murine polymicrobial sepsis model. Medium-severity sepsis was induced by cecum ligation puncture (CLP) in adult CD-1 mice of both sexes. Healthy CD-1 mice (without CLP) were used as controls. Forty-eight hours post-CLP, spontaneous urine was collected, and serum, organs and bones were sampled at necropsy. Serum iFGF23 increased ~20-fold in CLP compared to control mice. FGF23 protein concentration was increased in the bones, but not in spleen or liver of CLP mice. Despite the ~20-fold iFGF23 increase, we did not observe any significant changes in mineral homeostasis or parathyroid hormone levels in the blood of CLP animals. Urinary excretion of phosphate, calcium, and sodium remained unchanged in male CLP mice, whereas female CLP mice exhibited lower urinary calcium excretion, relative to healthy controls. In line with renal FGF23 resistance, expression of phosphate-, calcium- and sodium-transporting proteins did not show consistent changes in the kidneys of male and female CLP mice. Renal expression of the co-receptor αKlotho was downregulated in female, but not in male CLP mice. In conclusion, our data demonstrate that the dramatic, sex-independent rise in serum iFGF23 post-CLP was mainly caused by an upregulation of FGF23 secretion in the bone. Surprisingly, the upsurge in circulating iFGF23 did not alter humoral mineral homeostasis in the acutely septic mice. Hence, the biological function of elevated FGF23 in sepsis remains unclear and warrants further studies.


Assuntos
Osso e Ossos/metabolismo , Fatores de Crescimento de Fibroblastos/sangue , Minerais/sangue , Sepse/sangue , Animais , Cálcio/urina , Ceco/cirurgia , Citocinas/sangue , Feminino , Hipofosfatemia/patologia , Rim/metabolismo , Masculino , Camundongos , Fosfatos/urina , Sepse/microbiologia , Sepse/patologia , Sódio/urina
19.
Sci Rep ; 11(1): 9512, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947887

RESUMO

The role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.


Assuntos
Proteína HMGB1/sangue , Necroptose/fisiologia , Necrose/sangue , Necrose/patologia , Sepse/sangue , Sepse/patologia , Idoso , Apoptose/fisiologia , Estado Terminal/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Necrose/mortalidade , Prognóstico , Estudos Prospectivos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Sepse/mortalidade , Choque Séptico/sangue , Choque Séptico/mortalidade , Choque Séptico/patologia
20.
Biomed Res Int ; 2021: 5516940, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33954170

RESUMO

Background: The present study was aimed to investigate the value of blood interleukin-27 (IL-27) as a diagnostic biomarker of sepsis. Methods: We searched PubMed, EMBASE, the Cochrane Library, and the reference lists of relevant articles. All studies published up to October 21, 2020, which evaluated the accuracy of IL-27 levels for the diagnosis of sepsis were included. All the selected papers were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). We used a bivariate random effects model to estimate sensitivity, specificity, diagnostic odds ratios (DOR), and a summary receiver operating characteristic curve (SROC). Deeks' funnel plot was used to illustrate the potential presence of publication bias. Results: This meta-analysis included seven articles. The pooled sensitivity, specificity, and DOR were 0.85 (95% CI, 0.72-0.93), 0.72 (95% CI, 0.42-0.90), and 15 (95% CI, 3-72), respectively. The area under the summary receiver operating characteristic curve was 0.88 (95% CI, 0.84-0.90). The pooled I 2 statistic was 96.05 for the sensitivity and 96.65 for the specificity in the heterogeneity analysis. Deeks' funnel plot indicated no publication bias in this meta-analysis (P = 0.07). Conclusions: The present results showed that IL-27 is a reliable diagnostic biomarker of sepsis, but it should be investigated in combination with other clinical tests and results.


Assuntos
Interleucinas/sangue , Sepse/diagnóstico , Biomarcadores/sangue , Humanos , Sensibilidade e Especificidade , Sepse/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...