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1.
BMC Infect Dis ; 21(1): 531, 2021 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-34090359

RESUMEN

BACKGROUND: Group B Streptococcus (GBS) is an important cause of invasive infection in neonates and infants. Cerebrospinal fluid (CSF) findings and culture may not show evidence of infection early in GBS meningitis. Next-generation sequencing (NGS) has the potential to detect microbial genetic material in patients with infectious diseases. We report two cases of infantile sepsis of GBS meningitis with negative results for CSF culture tests, but positive results for NGS analysis. CASE PRESENTATION: Patient 1 was a 22-day-old male infant diagnosed with sepsis and meningitis. His CSF findings showed pleocytosis, decreased glucose, and increased protein levels. However, CSF and blood culture results at admission were negative. He received a total of 3 weeks of treatment with ampicillin and cefotaxime, and showed clinical improvement. GBS was detected through NGS analysis of CSF collected at admission. Patient 2 was a 51-day-old male infant with sepsis. CSF findings on admission were normal, and blood and CSF cultures were also negative. Intravenous ampicillin and cefotaxime treatment were initiated. Treatment was de-escalated to ampicillin alone because Enterococcus faecalis was cultured from urine. He was discharged after a total of 1 week of antibiotic treatment. Six days after discharge, he was re-hospitalized for sepsis. Blood and CSF cultures were negative, and E. faecalis was again cultured from urine. He received a total of 3 weeks of ampicillin treatment for enterococcal-induced nephritis and did not relapse thereafter. NGS pathogen searches were retrospectively performed on both blood and CSF collected at the first and second admission. GBS was detected in the CSF collected at the first admission, but no significant pathogen was detected in the other samples. Inadequate treatment for GBS meningitis at the first admission may have caused the recurrence of the disease. CONCLUSION: Infantile sepsis may present bacterial meningitis that is not diagnosed by either culture testing or CSF findings. NGS analysis for CSF may be useful for confirming the diagnosis of bacterial meningitis.


Asunto(s)
Antibacterianos/uso terapéutico , Meningitis Bacterianas/diagnóstico , Meningitis Bacterianas/tratamiento farmacológico , Infecciones Estreptocócicas/diagnóstico , Infecciones Estreptocócicas/tratamiento farmacológico , Ampicilina/uso terapéutico , Cefotaxima/uso terapéutico , Líquido Cefalorraquídeo/microbiología , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Meningitis Bacterianas/microbiología , Estudios Retrospectivos , Sepsis/diagnóstico , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Streptococcus agalactiae/efectos de los fármacos , Streptococcus agalactiae/genética , Streptococcus agalactiae/aislamiento & purificación , Orina/microbiología
2.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(5): 541-545, 2021 May.
Artículo en Chino | MEDLINE | ID: mdl-34112289

RESUMEN

OBJECTIVE: To investigate the protective effect and mechanism of celastrol in acute lung injury (ALI) of septic rats. METHODS: According to random number table, 24 male Sprague-Dawley (SD) rats were divided into control group (Con group), Sham operation group (Sham group), sepsis-induced ALI group by cecal ligation and perforation (CLP group) and celastrol intervention group (CLP+celastrol group, 2 mg/kg intraperitoneal administration 1 hour before surgery), 6 rats in each group. The abdominal aortic blood of the rats was collected for blood gas analysis 24 hours after the surgery, and then the rats were sacrificed and the lung tissues were taken to calculate the lung wet to dry weight ratio (W/D). The pathological characteristics of lung tissues were observed under light microscope and calculated the lung injury score. The protein levels of Toll-like receptor 4 (TLR4), interleukins (IL-6, IL-10), and nuclear factor-κB (NF-κB) of cytoplasm and nucleus in lung tissues were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: The partial arterial oxygen pressure (PaO2), lung W/D ratio, lung injury score and the protein levels of inflammatory factor in lung tissues had no differences between Con group and Sham group. Compared with the Con group, PaO2 in the CLP group was significantly decreased [mmHg (1 mmHg = 0.133 kPa): 60.33±2.01 vs. 109.20±2.99], the lung W/D ratio and lung injury score were significantly increased (lung W/D ratio: 4.44±0.05 vs. 3.27±0.04, lung injury score: 10.67±0.42 vs. 0.50±0.22), and the protein levels of TLR4, IL-6, IL-10 and the nucleus NF-κB in the lung tissues were significantly increased [TLR4 (pg/L): 21.87±0.66 vs. 3.27±0.09, IL-6 (ng/L): 861.10±8.28 vs. 120.30±3.91, IL-10 (ng/L): 212.40±2.57 vs. 41.73±1.02, nuclear NF-κB (ng/L): 707.70±16.82 vs. 403.30±7.46], but the protein level of cytoplasm NF-κB was significantly decreased (ng/L: 213.70±8.67 vs. 408.30±8.71), with statistically significant differences (all P < 0.05). Compared with the CLP group, PaO2 in CLP+celastrol group was significantly increased (mmHg: 76.83±3.21 vs. 60.33±2.01), the lung W/D ratio and lung injury score were significantly decreased (lung W/D ratio: 3.82±0.03 vs. 4.44±0.05, lung injury score: 5.00±0.37 vs. 10.67±0.42), and the protein levels of TLR4, IL-6, IL-10 and nucleus NF-κB in the lung tissue were significantly decreased [TLR4 (pg/L): 7.57±0.21 vs. 21.87±0.66, IL-6 (ng/L): 380.90±6.55 vs. 861.10±8.28, nuclear NF-κB (ng/L): 533.80±9.42 vs. 707.70±16.82], and the protein level of cytoplasm NF-κB was significantly increased (ng/L: 342.70±14.96 vs. 213.70±8.67), with statistically significant differences (all P < 0.05), while the protein level of IL-10 in lung tissues had no significant difference (ng/L: 210.50±3.16 vs. 212.40±2.57, P > 0.05). CONCLUSIONS: Celastrol may regulate the expression and release of inflammatory factors by inhibiting the TLR4/NF-κB pathway, thereby alleviating the ALI induced by sepsis in rats.


Asunto(s)
Lesión Pulmonar Aguda , Sepsis , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Animales , Pulmón , Masculino , FN-kappa B , Triterpenos Pentacíclicos , Ratas , Ratas Sprague-Dawley , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Receptor Toll-Like 4 , Factor de Necrosis Tumoral alfa
3.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(5): 621-625, 2021 May.
Artículo en Chino | MEDLINE | ID: mdl-34112306

RESUMEN

Sepsis is caused by the imbalance of the host body's response to infection, which causes life-threatening organ dysfunction. Disorders of blood coagulation play a very important role in the development of sepsis. In sepsis, the body's coagulation system is activated, leading to hypercoagulability, while the anticoagulation mechanism is significantly inhibited, causing a large number of microthrombi to form, and disseminated intravascular coagulation (DIC) may occur. Although there are obvious controversies about the anticoagulation treatment of sepsis at home and abroad, we cannot deny the significance of anticoagulation treatment in sepsis. Only appropriate anticoagulation can effectively reduce the mortality in septic DIC, septic shock and high-risk population, and ultimately effectively reduce the occurrence of multiple organ dysfunction syndrome. The sepsis-induced coagulation dysfunction (SIC) score is currently used internationally to guide anticoagulation. SIC score is optimized based on the International Society on Thrombosis and Haemostasis (ISTH) overt DIC score and Sepsis-3, including platelet, international normalized ratio (INR) and sequential organ failure assessment (SOFA). The SIC score can sensitively monitor sepsis-induced coagulation dysfunction. When the SIC score is ≥ 4, it is the best timing to initiate anticoagulation therapy. At present, the internationally recommended anticoagulant drugs include antithrombin (AT), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), heparin, etc., while the domestically recommended anticoagulant drugs are only unfractionated heparin and low molecular weight heparin. Before using anticoagulant drugs, it is necessary to evaluate the possibility of bleeding and thrombosis in the patients. At the same time, it is necessary to pay attention to the patient's primary disease. Try to adopt the treatment strategy of transitioning from unfractionated heparin to low molecular weight heparin without obvious anticoagulation contraindications.


Asunto(s)
Coagulación Intravascular Diseminada , Sepsis , Anticoagulantes/uso terapéutico , Coagulación Intravascular Diseminada/tratamiento farmacológico , Heparina/uso terapéutico , Humanos , Insuficiencia Multiorgánica , Sepsis/tratamiento farmacológico
4.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(5): 626-629, 2021 May.
Artículo en Chino | MEDLINE | ID: mdl-34112307

RESUMEN

Sepsis is a life-threatening organ dysfunction due to the dysregulation of host responses during infection. Severe systemic inflammatory response syndrome (SIRS) is the primary pathophysiological feature. Despite the classical antibiotic therapies play an important role in sepsis, the emergence of multi-resistant bacteria makes a greater challenge in clinical. Antimicrobial peptides (AMP) which consist of small cationic peptides, can be found in most organisms. As a result of their board-spectrum antibacterial activities and immunoregulatory functions, AMPs may have an excellent effect on the treatment of sepsis. In this review, we will discuss the basic role of AMPs in sepsis treatment and their application prospect and the challenges which need to be resolved in order to provide ideas for clinical application of AMPs.


Asunto(s)
Antiinfecciosos , Sepsis , Antibacterianos/uso terapéutico , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Humanos , Proteínas Citotóxicas Formadoras de Poros , Sepsis/tratamiento farmacológico
5.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(5): 535-540, 2021 May.
Artículo en Chino | MEDLINE | ID: mdl-34112288

RESUMEN

OBJECTIVE: To explore whether resveratrol (RSV) could activate silent information regulator 1 (SIRT1) to regulate the activation of NOD-like receptor protein 3 (NLRP3) inflammasome in sepsis induced intestinal injury model, and then reduce intestinal inflammation and cell apoptosis, so as to play a protective role in intestinal barrier function. METHODS: (1) In vitro experiment: human Colorectal adenocarcinoma cells (Caco-2) were cultured, which were divided into normal group (normal culture on complete medium for 48 hours), lipopolysaccharide (LPS) group (normal culture on complete medium for 24 hours, then LPS containing 2 mg/L complete medium intervention for 6 hours), RSV low, medium and high concentration groups and SIRT1 inhibitor (EX-527) group (complete medium normal culture for 24 hours, LPS containing 2 mg/L complete medium intervention for 6 hours, followed by RSV 10, 20, 40 µmol/L or EX-527 10 µmol/L intervention for 6 hours, respectively). The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL-6, IL-18, IL-1ß) in the cell supernatant were determined by enzyme linked immunosorbent assay (ELISA). The apoptosis level of the cells was detected by flow cytometry. Western blotting was used to detect the protein levels of NLRP3, SIRT1, caspase-1 and apoptosis-related point-like protein (ASC). (2) In vivo experiment: according to random number table method, 24 male Wistar rats were divided into sham operation group (Sham group), cecal ligation and perforation (CLP) 6 hours group (CLP 6 h group), CLP 24 h group and RSV intervention group [RSV (20 mg/kg) was intraperitoneally injected 6 hours and 12 hours after CLP], with 6 rats in each group. The levels of NLRP3, caspase-1 and ASC in the intestine of rats were detected by immunohistochemistry. RESULTS: (1) Compared with the normal group, the levels of inflammatory factors in the cell supernatant of the LPS group were increased and the expression of SIRT1 protein was decreased, while the protein expressions of NLRP3, caspase-1 and ASC were increased. Compared with LPS group, different concentrations of RSV reduced the level of inflammatory factors, increased the activity of SIRT1, inhibited the expression of NLRP3 inflammasome and its downstream products caspase-1 and ASC, and the effect of high concentration of RSV (40 µmol/L) was the most significant [TNF-α (ng/L): 8.77±0.43 vs. 12.66±0.81, IL-6 (ng/L): 1.35±0.20 vs. 1.93±0.09, IL-1ß (ng/L): 1.05±0.04 vs. 1.31±0.07, IL-18 (ng/L): 519.50±11.16 vs. 622.70±30.69, SIRT1/ß-actin: 0.80±0.05 vs. 0.58±0.02, caspase-1/ß-actin: 0.55±0.06 vs. 0.78±0.06, ASC/ß-actin: 0.78±0.08 vs. 1.04±0.15, all P < 0.05], while SIRT1 inhibitor EX-527 had the opposite effects. There was no significant difference in the apoptosis rate among normal group, LPS group, and low, medium and high concentration RSV groups, as well as EX-527 group [(7.03±0.57)%, (9.67±0.55)%, (9.57±0.70)%, (9.30±2.15)%, (9.87±0.97)%, (9.07±0.93)%, F = 2.590, P = 0.082]. (2) Immunohistochemical results showed that compared with the Sham group, the expressions of NLRP3 inflammasomes and downstream products caspase-1 and ASC in the intestinal epithelial cells in CLP 6 h group, CLP 24 h group and RSV intervention group were significantly increased. The percentage of ASC-positive area in intestinal epithelium of RSV intervention group was significantly lower than that of CLP 6 h group [(15.22±2.73)% vs. (19.88±2.67)%, P < 0.05], and the expressions of NLRP3 and caspase-1 were significantly lower than those of CLP 24 h group [(9.31±1.37)% vs. (13.19±1.92)%, (19.57±3.92)% vs. (27.28±6.33)%, both P < 0.05]. CONCLUSIONS: After sepsis, high concentration of RSV could inhibit the activation of NLRP3 inflammasome by activating SIRT1, thereby reduce the expression of caspase-1 and ASC, and inhibit the secretion of inflammatory factors to reduce the inflammatory response.


Asunto(s)
Proteínas NLR , Sepsis , Sirtuina 1 , Animales , Células CACO-2 , Humanos , Interleucinas , Mucosa Intestinal , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas , Ratas Wistar , Resveratrol/farmacología , Sepsis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa
6.
Cochrane Database Syst Rev ; 5: CD013235, 2021 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-34097767

RESUMEN

BACKGROUND: Rapid antimicrobial susceptibility tests are expected to reduce the time to clinically important results of a blood culture. This might enable clinicians to better target therapy to a person's needs, and thereby, improve health outcomes (mortality, length of hospital stay), and reduce unnecessary prescribing of broad-spectrum antibiotics; thereby reducing antimicrobial resistance rates. OBJECTIVES: To assess the effects of rapid susceptibility testing versus standard susceptibility testing for bloodstream infections (BSIs). SEARCH METHODS: To identify studies with selected outcomes, we searched the Cochrane Infectious Diseases Group Specialised Register, CENTRAL, MEDLINE, LILACS, and two trials registries, between 1987 and October 2020. We used 'bloodstream infection' and 'antimicrobial susceptibility tests' as search terms. We had no language or publication status limitations. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing rapid antimicrobial susceptibility testing (with a time-to-result of ≤ 8 hours) versus conventional antimicrobial susceptibility testing in people with a BSI caused by any bacteria, as identified by a positive blood culture. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed risk of bias. Any disagreement was discussed and resolved with a third review author. For mortality, a dichotomous outcome, we extracted the number of events in each arm, and presented a risk ratio (RR) with 95% confidence interval (CI) to compare rapid susceptibility testing to conventional methods. We used Review Manager 5.4 to meta-analyse the data. For other outcomes, which are time-to-event outcomes (time-to-discharge from hospital, time-to-first appropriate antibiotic change), we conducted qualitative narrative synthesis, due to heterogeneity of outcome measures.  MAIN RESULTS: We included six trials, with 1638 participants. For rapid antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.10, 95% CI 0.82 to 1.46; 6 RCTs, 1638 participants; low-certainty evidence). In subgroup analysis, for rapid genotypic or molecular antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.02, 95% CI 0.69 to 1.49; 4 RCTs, 1074 participants; low-certainty evidence). For phenotypic rapid susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups  (RR 1.37, 95% CI 0.80 to 2.35; 2 RCTs, 564 participants; low-certainty evidence). In qualitative analysis, rapid susceptibility testing may make little or no difference in time-to-discharge (4 RCTs, 1165 participants; low-certainty evidence). In qualitative analysis, rapid genotypic susceptibility testing compared to conventional testing may make little or no difference in time-to-appropriate antibiotic (3 RCTs, 929 participants; low-certainty evidence). In subgroup analysis, rapid phenotypic susceptibility testing compared to conventional testing may improve time-to-appropriate antibiotic (RR -17.29, CI -45.05 to 10.47; 2 RCTs, 564 participants; low-certainty evidence).  AUTHORS' CONCLUSIONS: The theoretical benefits of rapid susceptibility testing have not been demonstrated to directly improve mortality, time-to-discharge, or time-to-appropriate antibiotic in these randomized studies. Future large prospective studies should be designed to focus on the most clinically meaningful outcomes, and aim to optimize blood culture pathways.


Asunto(s)
Antibacterianos/uso terapéutico , Pruebas de Sensibilidad Microbiana/métodos , Sepsis/tratamiento farmacológico , Sesgo , Humanos , Oportunidad Relativa , Ensayos Clínicos Controlados Aleatorios como Asunto , Sepsis/microbiología , Sepsis/mortalidad , Tiempo de Tratamiento
7.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(6): 582-587, 2021 Jun.
Artículo en Chino | MEDLINE | ID: mdl-34130779

RESUMEN

OBJECTIVE: To evaluate the efficacy of sepsis risk calculator (SRC) in guiding antibiotic use in neonates with suspected early-onset sepsis (EOS). METHODS: A total of 284 neonates with a gestational age of ≥ 35 weeks were enrolled as the control group, who were hospitalized in the Children's Hospital of Chongqing Medical University from March to July, 2019 and were suspected of EOS. Their clinical data were retrospectively collected and the use of antibiotics was analyzed based on SRC. A total of 170 neonates with a gestational age of ≥ 35 weeks were enrolled as the study group, who were admitted to the hospital from July to November, 2020 and were suspected of EOS. SRC was used prospectively for risk scoring to assist the decision making of clinical antibiotic management. The two groups were compared in terms of the rate of use of antibiotics, blood culture test rate, clinical outcome, and adherence to the use of SRC. RESULTS: Compared with the control group, the study group had a significantly higher SRC score at birth and on admission (P < 0.05). The rate of use of antibiotics in the study group was significantly lower than that in the control group[84.7% (144/170) vs 91.5% (260/284), 6.8% decrease; P < 0.05]. The blood culture test rate in the study group was also significantly lower than that in the control group (85.3% vs 91.9%, P < 0.05). There was no significant difference between the two groups in the incidence rate of adverse outcomes and the final diagnosis of EOS (P > 0.05). CONCLUSIONS: The use of SRC reduces the rate of empirical use of antibiotics in neonates with suspected EOS and does not increase the risk of adverse outcomes, and therefore, it holds promise for clinical application.


Asunto(s)
Sepsis Neonatal , Sepsis , Antibacterianos/uso terapéutico , Niño , Humanos , Lactante , Recién Nacido , Sepsis Neonatal/diagnóstico , Sepsis Neonatal/tratamiento farmacológico , Estudios Retrospectivos , Medición de Riesgo , Sepsis/diagnóstico , Sepsis/tratamiento farmacológico
8.
Artículo en Alemán | MEDLINE | ID: mdl-34038976

RESUMEN

Vitamin C deficiency often occurs in critical illness and especially in patients with sepsis. Low plasma levels correlate with organ dysfunction and outcome parameters. Vitamin C offers pleiotropic effects possibly attenuating pathophysiology in sepsis. This includes antioxidative effects like scavenging reactive oxygen species or restoring other antioxidants. Vitamin C is a cofactor for norepinephrine biosynthesis and it protects endothelial function. In addition, it modulates immune response. A combined therapy with vitamin C, hydrocortisone and thiamine could be beneficial because of synergistic effects. Some clinical studies have shown reduced mortality due to vitamin C alone or in combination with hydrocortisone and thiamine, others do not. Adverse events are rare. So data supporting a therapy with vitamin C is still unclear. Further randomised controlled trials are necessary.


Asunto(s)
Ácido Ascórbico , Sepsis , Ácido Ascórbico/uso terapéutico , Humanos , Hidrocortisona , Sepsis/tratamiento farmacológico , Tiamina , Vitaminas
9.
Eur J Pharm Sci ; 163: 105868, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-33951483

RESUMEN

Ceftazidime is a third-generation cephalosporin with high activity against many pathogens. But the ambiguity and diversity of the dosing regimens in neonates and young infants impair access to effective treatment. Thus, we conducted a population pharmacokinetic study of ceftazidime in this vulnerable population and recommended a model-based dosage regimen to optimize sepsis therapy. Totally 146 neonates and young infants (gestational age (GA): 36-43.4 weeks, postnatal age (PNA): 1-81 days, current weight (CW): 900-4500 g) were enrolled based on inclusion and exclusion criteria. Ceftazidime bloods samples (203) were obtained using the opportunistic sampling strategy and determined by the high-performance liquid chromatography. The population pharmacokinetic-pharmacodynamic analysis was conducted by nonlinear mixed effects model (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic data. Covariate analysis showed the significance of GA, PNA, and CW on developmental pharmacokinetics. Monte Carlo simulation was performed based on above covariates and minimum inhibitory concentration (MIC). In the newborns with PNA ≤ 3 days (MIC=8 mg/L), the dose regimen was 25 mg/kg twice daily (BID). For the newborns with PNA > 3 days (MIC=16 mg/L), the optimal dose was 30 mg/kg three times daily (TID) for those with GA ≤ 37 weeks and 40 mg/kg TID for those with GA > 37 weeks. Overall, on the basis of the developmental population pharmacokinetic-pharmacodynamic analysis covering the whole range of neonates and young infants, the evidence-based ceftazidime dosage regimens were proposed to optimize neonatal early-onset and late-onset sepsis therapy.


Asunto(s)
Sepsis Neonatal , Sepsis , Antibacterianos/uso terapéutico , Ceftazidima , Humanos , Lactante , Recién Nacido , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Sepsis Neonatal/tratamiento farmacológico , Sepsis/tratamiento farmacológico
10.
Nat Commun ; 12(1): 3185, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-34045461

RESUMEN

Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury. It is also a thrombo-inflammatory condition associated with vascular leakage/hemorrhage and thrombosis that is not effectively treated by current anti-inflammatory or anti-thrombotic drugs. Here, we show that MB2mP6 peptide nanoparticles, targeting the Gα13-mediated integrin "outside-in" signaling in leukocytes and platelets, inhibited both inflammation and thrombosis without causing hemorrhage/vascular leakage. MB2mP6 improved mouse survival when infused immediately or hours after onset of severe sepsis. Furthermore, platelet Gα13 knockout inhibited septic thrombosis whereas leukocyte Gα13 knockout diminished septic inflammation, each moderately improving survival. Dual platelet/leukocyte Gα13 knockout inhibited septic thrombosis and inflammation, further improving survival similar to MB2mP6. These results demonstrate that inflammation and thrombosis independently contribute to poor outcomes and exacerbate each other in systemic inflammation, and reveal a concept of dual anti-inflammatory/anti-thrombotic therapy without exacerbating vascular leakage.


Asunto(s)
Antígenos CD18/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP G12-G13/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Sepsis/tratamiento farmacológico , Trombosis/tratamiento farmacológico , Animales , Antiinflamatorios , Plaquetas/efectos de los fármacos , Plaquetas/inmunología , Plaquetas/metabolismo , Antígenos CD18/metabolismo , Cloruros/administración & dosificación , Cloruros/toxicidad , Modelos Animales de Enfermedad , Compuestos Férricos/administración & dosificación , Compuestos Férricos/toxicidad , Fibrinolíticos , Subunidades alfa de la Proteína de Unión al GTP G12-G13/metabolismo , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Leucocitos/metabolismo , Macrófagos , Ratones , Ratones Noqueados , Nanopartículas/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Adhesividad Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Cultivo Primario de Células , Unión Proteica/efectos de los fármacos , Sepsis/sangre , Sepsis/complicaciones , Sepsis/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Células THP-1 , Trombosis/sangre , Trombosis/inducido químicamente
11.
Medicine (Baltimore) ; 100(18): e25610, 2021 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-33950938

RESUMEN

BACKGROUND: Sepsis is a worldwide health problem that is a leading cause of mortality due to infection. Sepsis is prevalent in infections that are complicated with organ failure. Generally, sepsis is intricate and impaired corticosteroid metabolism leads to complex outcomes. Therefore, the provision of corticosteroids could lead to improved clinical outcomes. The effect of corticosteroids therapy in adult patients with sepsis is not well studied. Therefore, this study is an attempt to evaluate the efficacy of corticosteroids for treating adult cases of sepsis. METHODS: We will systematically search the randomized controlled trials for potential eligible studies from online databases, which includes 5 English databases (PubMed, EMBASE, Web of Science, PsycINFO, and Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure, WanFang Database, VIP information database, and China Biomedical Database) from their origin to March 2021. Languages were restricted to English and Chinese. Two independent authors will be screening the literature, collect, and perform data extraction and quality assessment. Data will be synthesized using appropriate statistical methods. RESULTS: This study will summarize present evidence to evaluate the efficacy of corticosteroids for the treatment of adult cases of sepsis. CONCLUSION: The results of the present study will provide the latest, reliable, superior quality evidence for the clinical application of corticosteroids for treating sepsis patients. ETHICS AND DISSEMINATION: The present study will use published data and does not require ethics approval. PROTOCOL REGISTRATION NUMBER: March 28, 2021.osf.io/tm6sw. (https://osf.io/tm6sw/).


Asunto(s)
Glucocorticoides/uso terapéutico , Sepsis/tratamiento farmacológico , Adulto , Humanos , Metaanálisis como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Revisiones Sistemáticas como Asunto , Resultado del Tratamiento
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(4): 514-520, 2021 Apr 20.
Artículo en Chino | MEDLINE | ID: mdl-33963709

RESUMEN

OBJECTIVE: To investigate the effect of protein C activator (PCA) from Agkistrodon acutus venom (AAV) in modulating early adaptive immune response of septic rats. OBJECTIVE: Rat models of sepsis were established by intraperitoneal injection of lipopolysaccharide (LPS; 10 mg/kg) in 36 SD rats, which were divided into 6 groups (n=6) for sample collection at 4, 6, 8, 12, 16 and 24 h after LPS injection, with 6 rats injected with saline as the control group. Another 36 rats were divided into two groups, and 30 min after LPS injection, the rats were treated with SEW2871 (a sphingosine-1-phosphate receptor 1 agonist; 0.5 mg/kg) or PCA group (0.1 mg/kg), and each group was divided into 3 groups (n=6) for sample collection at 6, 12 and 24 h after LPS injection. Plasma IL-4, S1P, IL-12 and IFN-γ levels of the rats were detected using ELISA, and the expressions of S1PR1 and CD103 in the mesenteric lymph nodes were detected with immunofluorescence assay. OBJECTIVE: The plasma levels of S1P, IL-12, IL-4 and IFN-γ (P < 0.05) and the expressions of S1PR1 and CD103 in the mesenteric lymph nodes (P < 0.05) all increased significantly in the rats 24 h after LPS injection; IFN-γ/IL-4 ratio increased progressively within 6 h after LPS injection and then subsided gradually. Compared with those in the corresponding sepsis model subgroups, the levels of S1P, IL-12 and IFN-γ increased while IL- 4 level decreased significantly (P < 0.05), and the expression of S1PR1 and CD103 were reduced significantly (P < 0.05) in SEW2871-treated rats; both the plasma level of IL-4 and the expression of S1PR1 in the mesenteric lymph nodes increased significantly in PCA-treated rats (P < 0.05). OBJECTIVE: PCA can regulate the balance of inflammation and immune response in the early stage of sepsis in rats possibly through the S1P-S1PR1 pathway.


Asunto(s)
Agkistrodon , Sepsis , Inmunidad Adaptativa , Animales , Proteína C , Ratas , Ratas Sprague-Dawley , Sepsis/tratamiento farmacológico , Ponzoñas
13.
Phytomedicine ; 86: 153567, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33940332

RESUMEN

BACKGROUND: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Several studies have indicated that flavonoids exhibit a wide variety of biological actions including free radical scavenging and antioxidant activities. Quercetin, one of the most extensively distributed flavonoids in the vegetables and fruits, presents various biological activities including modulation of oxidative stress, anti-infectious, anti-inflammatory, and neuroprotective activities. METHODS: The present systematic review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements. We searched Web of Sciences, Google Scholar, PubMed, Scopus, and Embase databases up to February 2021 by using the relevant keywords. RESULTS: Out of 672 records screened, 35 articles met the study criteria. The evidence reviewed here indicates that quercetin supplementation may exert beneficial effects on sepsis by attenuating inflammation and oxidative stress, downregulating the mRNA expression of toll-like receptors (TLRs), modulating the immune response, and alleviating sepsis-related organ dysfunctions. CONCLUSION: Due to the promising therapeutic effects of quercetin on sepsis complications and the lack of clinical trials in this regard, future human randomized clinical trials are warranted.


Asunto(s)
Quercetina/farmacología , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/farmacología , Suplementos Dietéticos , Humanos , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Quercetina/uso terapéutico , Sepsis/inmunología , Sepsis/fisiopatología
14.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806560

RESUMEN

BACKGROUND: Acute lung injury (ALI) or its most advanced form, acute respiratory distress syndrome (ARDS) is a severe inflammatory pulmonary process triggered by a variety of insults including sepsis, viral or bacterial pneumonia, and mechanical ventilator-induced trauma. Currently, there are no effective therapies available for ARDS. We have recently reported that a novel small molecule AVR-25 derived from chitin molecule (a long-chain polymer of N-acetylglucosamine) showed anti-inflammatory effects in the lungs. The goal of this study was to determine the efficacy of two chitin-derived compounds, AVR-25 and AVR-48, in multiple mouse models of ALI/ARDS. We further determined the safety and pharmacokinetic (PK) profile of the lead compound AVR-48 in rats. METHODS: ALI in mice was induced by intratracheal instillation of a single dose of lipopolysaccharide (LPS; 100 µg) for 24 h or exposed to hyperoxia (100% oxygen) for 48 h or undergoing cecal ligation and puncture (CLP) procedure and observation for 10 days. RESULTS: Both chitin derivatives, AVR-25 and AVR-48, showed decreased neutrophil recruitment and reduced inflammation in the lungs of ALI mice. Further, AVR-25 and AVR-48 mediated diminished lung inflammation was associated with reduced expression of lung adhesion molecules with improvement in pulmonary endothelial barrier function, pulmonary edema, and lung injury. Consistent with these results, CLP-induced sepsis mice treated with AVR-48 showed a significant increase in survival of the mice (80%) and improved lung histopathology in the treated CLP group. AVR-48, the lead chitin derivative compound, demonstrated a good safety profile. CONCLUSION: Both AVR-25 and AVR-48 demonstrate the potential to be developed as therapeutic agents to treat ALI/ARDS.


Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Factores Inmunológicos/farmacología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Quitina/farmacología , Modelos Animales de Enfermedad , Femenino , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Neumonía/tratamiento farmacológico , Edema Pulmonar/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Sepsis/tratamiento farmacológico
15.
Eur Rev Med Pharmacol Sci ; 25(7): 3136-3144, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33877683

RESUMEN

OBJECTIVE: Disruption of intracellular Ca2+ homeostasis via excessive and pathological Ca2+ release from the endoplasmic reticulum (ER) and/or sarcoplasmic reticulum (SR) through ryanodine receptor (RyRs) Ca2+ channels play a critical role in the pathology of systemic inflammatory response syndrome (SIRS) and associated multiple organ dysfunction syndrome (MODS) in sepsis or septic shock. Dantrolene, a potent inhibitor of RyRs, is expected to ameliorate SIRS and MODS and decrease mortality in sepsis or septic shock patients. This review summarized the potential mechanisms of therapeutic effects of dantrolene in sepsis or septic shock at molecular, cell, and organ levels and provided suggestions and strategies for future clinical studies.


Asunto(s)
COVID-19/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/uso terapéutico , Dantroleno/uso terapéutico , Sepsis/tratamiento farmacológico , COVID-19/metabolismo , Calcio/metabolismo , Reposicionamiento de Medicamentos , Retículo Endoplásmico/metabolismo , Humanos , Mortalidad , Insuficiencia Multiorgánica , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , SARS-CoV-2 , Retículo Sarcoplasmático/metabolismo , Sepsis/metabolismo , Choque Séptico/tratamiento farmacológico , Choque Séptico/metabolismo
16.
Respir Res ; 22(1): 99, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33823870

RESUMEN

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Asunto(s)
Antiinflamatorios/farmacología , COVID-19/tratamiento farmacológico , Reposicionamiento de Medicamentos , Hipoxia/tratamiento farmacológico , Justicia, Planta , Pulmón/efectos de los fármacos , Extractos Vegetales/farmacología , Neumonía/prevención & control , Fibrosis Pulmonar/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Bleomicina , COVID-19/metabolismo , COVID-19/virología , Ciego/microbiología , Ciego/cirugía , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mediadores de Inflamación/metabolismo , Justicia, Planta/química , Ligadura , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Extractos Vegetales/aislamiento & purificación , Neumonía/genética , Neumonía/metabolismo , Neumonía/microbiología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Sepsis/genética , Sepsis/metabolismo , Sepsis/microbiología , Transcriptoma
17.
Medicina (Kaunas) ; 57(5)2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-33924769

RESUMEN

Carbapenem-resistant Enterobacteriaceae (CRE) are a serious public health threat. Infections due to these organisms are associated with significant morbidity and mortality. Among them, metallo-ß-lactamases (MBLs)-producing Klebsiella pneumoniae are of global concern today. The ceftazidime/avibactam combination and the ceftazidime/avibactam + aztreonam combination currently represent the most promising antibiotic strategies to stave off these kinds of infections. We describe the case of a patient affected by thrombotic thrombocytopenic purpura (TTP) admitted in our ICU after developing a hospital-acquired SarsCoV2 interstitial pneumonia during his stay in the hematology department. His medical conditions during his ICU stay were further complicated by a K. Pneumoniae NDM sepsis. To our knowledge, the patient had no risk factors for multidrug-resistant bacteria exposure or contamination during his stay in the hematology department. During his stay in the ICU, we treated the sepsis with a combination therapy of ceftazidime/avibactam + aztreonam. The therapy solved his septic state, allowing for a progressive improvement in his general condition. Moreover, we noticed that the negativization of the hemocultures was also associated to a decontamination of his known rectal colonization. The ceftazidime/avibactam + aztreonam treatment could not only be a valid therapeutic option for these kinds of infections, but it could also be considered as a useful tool in selected patients' intestinal decolonizations.


Asunto(s)
COVID-19 , Infección Hospitalaria , Púrpura Trombocitopénica Trombótica , Sepsis , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Aztreonam/uso terapéutico , Ceftazidima/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , Combinación de Medicamentos , Humanos , Klebsiella pneumoniae/genética , Pruebas de Sensibilidad Microbiana , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , ARN Viral , SARS-CoV-2 , Sepsis/tratamiento farmacológico , beta-Lactamasas
19.
Oxid Med Cell Longev ; 2021: 6667074, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33927797

RESUMEN

Sepsis-induced myocardial dysfunction considerably increases mortality risk in patients with sepsis. Previous studies from our group have shown that sepsis alters the expression of structural proteins in cardiac cells, resulting in cardiomyocyte degeneration and impaired communication between cardiac cells. Caveolin-3 (CAV3) is a structural protein present in caveolae, located in the membrane of cardiac muscle cells, which regulates physiological processes such as calcium homeostasis. In sepsis, there is a disruption of calcium homeostasis, which increases the concentration of intracellular calcium, which can lead to the activation of potent cellular enzymes/proteases which cause severe cellular injury and death. The purpose of the present study was to test the hypotheses that sepsis induces CAV3 overexpression in the heart, and the regulation of L-type calcium channels directly relates to the regulation of CAV3 expression. Severe sepsis increases the expression of CAV3 in the heart, as immunostaining in our study showed CAV3 presence in the cardiomyocyte membrane and cytoplasm, in comparison with our control groups (without sepsis) that showed CAV3 presence predominantly in the plasma membrane. The administration of verapamil, an L-type calcium channel inhibitor, resulted in a decrease in mortality rates of septic mice. This effect was accompanied by a reduction in the expression of CAV3 and attenuation of cardiac lesions in septic mice treated with verapamil. Our results indicate that CAV3 has a vital role in cardiac dysfunction development in sepsis and that the regulation of L-type calcium channels may be related to its expression.


Asunto(s)
Caveolina 3/metabolismo , Corazón/efectos de los fármacos , Sepsis/tratamiento farmacológico , Verapamilo/uso terapéutico , Animales , Canales de Calcio Tipo L , Humanos , Masculino , Ratones , Sepsis/mortalidad , Sepsis/patología , Análisis de Supervivencia , Verapamilo/farmacología
20.
Phytomedicine ; 85: 153543, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33799226

RESUMEN

BACKGROUND: Xuebijing (XBJ) is a traditional Chinese patent medicine for sepsis. However, the mechanism of action (MoA) of XBJ on sepsis remain unclear. PURPOSE: Elucidate the MoA of XBJ for treating sepsis based on network pharmacology. STUDY DESIGN: Integrate computational prediction, experimental validation and literature reported clinical results analysis based on network pharmacology. METHODS: Computationally, representative compounds of XBJ were characterized by LC-MS/MS and the target profiles of each compound were identified using network-based method. Compounds from XBJ were compared with FDA approved drugs or experimental agents for sepsis by hierarchical clustering of target profile. Key biological functional modules of XBJ for treating sepsis were identified by enrichment analysis. Differential expressed analysis for each biological functional module was conducted from sepsis related public omics datasets. Herb-biological functional module network was constructed to reveal part of the traditional combinatorial rules of herbs for modules. Experimentally, the action of XBJ compounds on genes in biological functional module was validated by detecting quantitative transcriptional profiling and sepsis animal model. Clinically, combined with the clinical results recorded in literature, computational and experimental results were used to interpret the anti-inflammatory effect of XBJ for treating sepsis. RESULTS: The target profiles of compound cover most of the compound's related biomolecules reported in literature, which can characterize the comprehensive function of compound. XBJ has similar pharmacological effect as FDA approved drugs or experimental agents. Four key biological functional modules including inflammation, immune, cell apoptosis and coagulation of XBJ for treating sepsis were identified. Cell line experimental results show that part of ingredients in XBJ regulate the expression of genes in inflammation modules as predicted. Animal experiments show that compounds from XBJ could reduce the expression level of IL-1ß. Combined with literature reported clinical results, XBJ was found to exert anti-inflammatory effect through regulating the NF-kappa B signaling pathway. CONCLUSION: The network pharmacology framework integrating computational prediction, experimental validation and literature reported clinical results analysis provides a novel approach for analyzing MoA of XBJ for treating sepsis.


Asunto(s)
Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Sepsis/tratamiento farmacológico , Animales , Cromatografía Liquida , Células HCT116 , Humanos , Inflamación/tratamiento farmacológico , Medicina China Tradicional , FN-kappa B , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Espectrometría de Masas en Tándem
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