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1.
BMC Infect Dis ; 19(1): 968, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718563

RESUMO

BACKGROUND: This study investigated the clinical value of interleukin-6 (IL-6), pentraxin 3 (PTX3), and procalcitonin (PCT) in patients with sepsis and septic shock diagnosed according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). METHODS: Serum levels of IL-6, PTX3, and PCT were measured in 142 enrolled subjects (51 with sepsis, 46 with septic shock, and 45 as controls). Follow-up IL-6 and PTX3 levels were measured in patients with initial septic shock within 24 h of hospital discharge. Optimal cut-off values were determined for sepsis and septic shock, and prognostic values were evaluated. RESULTS: Serum IL-6 levels could discriminate sepsis (area under the curve [AUC], 0.83-0.94, P <  0.001; cut-off value, 52.60 pg/mL, 80.4% sensitivity, 88.9% specificity) from controls and could distinguish septic shock (AUC, 0.71-0.89; cut-off value, 348.92 pg/mL, 76.1% sensitivity, 78.4% specificity) from sepsis. Twenty-eight-day mortality was significantly higher in the group with high IL-6 (≥ 348.92 pg/mL) than in the group with low IL-6 (< 348.92 pg/mL) (P = 0.008). IL-6 was an independent risk factor for 28-day mortality among overall patients (hazard ratio, 1.0004; 95% confidence interval, 1.0003-1.0005; p = 0.024). In septic shock patients, both the initial and follow-up PTX3 levels were consistently significantly higher in patients who died than in those who recovered (initial p = 0.004; follow-up P <  0.001). CONCLUSIONS: The diagnostic and prognostic value of IL-6 was superior to those of PTX3 and PCT for sepsis and septic shock.


Assuntos
Proteína C-Reativa/análise , Interleucina-6/sangue , Pró-Calcitonina/sangue , Sepse/diagnóstico , Componente Amiloide P Sérico/análise , Choque Séptico/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Fatores de Risco , Sensibilidade e Especificidade , Sepse/mortalidade , Sepse/patologia , Índice de Gravidade de Doença , Choque Séptico/mortalidade , Choque Séptico/patologia
2.
EMBO J ; 38(20): e101266, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31544965

RESUMO

Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1ß by proteolytic cleavage via caspase-1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome-dependent immune responses remain poorly defined. Here, we show that the thiol-specific peroxidase peroxiredoxin-4 (Prdx4) directly regulates IL-1ß generation by interfering with caspase-1 activity. We demonstrate that caspase-1 and Prdx4 form a redox-sensitive regulatory complex via caspase-1 cysteine 397 that leads to caspase-1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS-induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4-ΔLysMCre). Strikingly, we demonstrate that Prdx4 co-localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome-activated macrophages. Purified EVs are able to transmit a robust IL-1ß-dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro-inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell-to-cell communication function of inflammasomes via macrophage-derived EVs.


Assuntos
Caspase 1/metabolismo , Vesículas Extracelulares/metabolismo , Inflamassomos/imunologia , Macrófagos/imunologia , Peroxirredoxinas/fisiologia , Choque Séptico/prevenção & controle , Animais , Caspase 1/genética , Citocinas/metabolismo , Feminino , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Choque Séptico/induzido quimicamente , Choque Séptico/imunologia , Choque Séptico/patologia , Transdução de Sinais
3.
Int J Mol Sci ; 20(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323783

RESUMO

Myocardial dysfunction is common in septic shock and post-cardiac arrest but manifests differently in pediatric and adult patients. By conventional echocardiographic parameters, biventricular systolic dysfunction is more prevalent in children with septic shock, though strain imaging reveals that myocardial injury may be more common in adults than previously thought. In contrast, diastolic dysfunction in general and post-arrest myocardial systolic dysfunction appear to be more widespread in the adult population. A growing body of evidence suggests that mitochondrial dysfunction mediates myocardial depression in critical illness; alterations in mitochondrial electron transport system function, bioenergetic production, oxidative and nitrosative stress, uncoupling, mitochondrial permeability transition, fusion, fission, biogenesis, and autophagy all may play key pathophysiologic roles. In this review we summarize the epidemiologic and clinical phenotypes of myocardial dysfunction in septic shock and post-cardiac arrest and the multifaceted manifestations of mitochondrial injury in these disease processes. Since neonatal and pediatric-specific data for mitochondrial dysfunction remain sparse, conclusive age-dependent differences are not clear; instead, we highlight what evidence exists and identify gaps in knowledge to guide future research. Finally, since focal ischemic injury (with or without reperfusion) leading to myocardial infarction is predominantly an atherosclerotic disease of the elderly, this review focuses specifically on septic shock and global ischemia-reperfusion injury occurring after resuscitation from cardiac arrest.


Assuntos
Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Estado Terminal , Fatores Etários , Metabolismo Energético/fisiologia , Parada Cardíaca/metabolismo , Parada Cardíaca/patologia , Humanos , Choque Séptico/metabolismo , Choque Séptico/patologia
4.
BMJ Case Rep ; 12(6)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31256050

RESUMO

We herein describe an irregular case of toxic-shock syndrome (TSS). A previously healthy 28-year-old Japanese man developed a sudden-onset high fever. The patient was suffering from conjunctival hyperaemia, gastrointestinal symptoms such as vomiting and diarrhoea, and systemically diffused macular erythroderma. Further physical examination detected pustules on his back, which self-destructed over time. Laboratory revealed multiple organ failures. Subsequently, scalded skin on the face and desquamation in the limb extremities emerged by day 10, leading to the diagnosis of TSS, despite his stable circulatory dynamics through the course. Learning points for clinicians include that they should recall TSS as a possible disease concurrently causing high fever, systemic rash and multiple organ dysfunctions, even without being in a state of shock. The characteristic desquamations emerged in the limb extremities after hospitalisation were of help in diagnosing TSS.


Assuntos
Choque Séptico/complicações , Choque Séptico/patologia , Adulto , Antibacterianos/uso terapêutico , Cefazolina/uso terapêutico , Clindamicina/uso terapêutico , Dermatite Esfoliativa/etiologia , Diagnóstico Diferencial , Humanos , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Choque Séptico/tratamento farmacológico , Supuração/patologia
5.
Jpn J Infect Dis ; 72(5): 347-349, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31155601

RESUMO

An 84-year-old man with chronic renal failure, anemia, and diabetes was admitted for hemodialysis initiation. His vital signs were stable until the eighteenth hospital day, before acquiring an influenza A virus infection. Three days later, he died of septic shock with severe liver impairment. His leukocyte count, prothrombin time (PT-INR), and liver enzyme levels such as aspartate transaminase and alanine aminotransferase, were significantly increased. Hypercytokinemia was also observed. Autopsy revealed bilateral diffuse pneumonia with neutrophil infiltration. The liver showed extensive centrilobular hepatocyte necrosis. Immunohistochemistry for influenza A nucleoprotein revealed positivity in the ciliated columnar epithelium of the bronchi and negativity in the trachea, lungs, and liver. Hypoxic hepatitis is characterized by an abrupt and massive increase in aminotransferase levels (> 20 times upper normal limit) due to anoxic centrilobular hepatocyte necrosis. The occurrence of hypoxic hepatitis requires a pre-existing, chronic condition, such as anemia, causing reduced oxygen supply to the liver, followed by an acute decrease in hepatic oxygen supply, such as septic shock. Therefore, this report suggests that hypoxic hepatitis can be an important causative factor for acute liver failure associated with influenza virus infection.


Assuntos
Influenza Humana/complicações , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/patologia , Choque Séptico/diagnóstico , Choque Séptico/patologia , Idoso de 80 Anos ou mais , Anemia/complicações , Autopsia , Complicações do Diabetes , Evolução Fatal , Humanos , Vírus da Influenza A , Falência Renal Crônica/complicações , Masculino , Choque Séptico/complicações
6.
PLoS Pathog ; 15(6): e1007795, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170267

RESUMO

Infection with the Streptococcus suis (S. suis) epidemic strain can cause Streptococcal toxic shock-like syndrome (STSLS), which is characterized by a cytokine storm, dysfunction of multiple organs and a high incidence of mortality despite adequate treatment. Despite some progress concerning the contribution of the inflammatory response to STSLS, the precise mechanism underlying STSLS development remains elusive. Here, we use a murine model to demonstrate that caspase-1 activity is critical for STSLS development. Furthermore, we show that inflammasome activation by S. suis is mainly dependent on NLRP3 but not on NLRP1, AIM2 or NLRC4. The important role of NLRP3 activation in STSLS is further confirmed in vivo with the NLRP3 inhibitor MCC950 and nlrp3-knockout mice. By comparison of WT strain with isogenic strains with mutation of various virulence genes for inflammasome activation, Suilysin is essential for inflammasome activation, which is dependent on the membrane perforation activity to cause cytosolic K+ efflux. Moreover, the mutant strain msly (P353L) expressing mutagenic SLY without hemolytic activity was unable to activate the inflammasome and does not cause STSLS. In summary, we demonstrate that the high membrane perforation activity of the epidemic strain induces a high level of NLRP3 inflammasome activation, which is essential for the development of the cytokine storm and multi-organ dysfunction in STSLS and suggests NLRP3 inflammasome as an attractive target for the treatment of STSLS.


Assuntos
Citocinas/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Choque Séptico/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus suis/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Citocinas/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Inflamassomos/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Choque Séptico/genética , Choque Séptico/patologia , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/patologia
7.
Leg Med (Tokyo) ; 38: 64-68, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30991227

RESUMO

Although fatal colchicine intoxications are rare and mostly related to suicidal intake or accidental overdose, other hypotheses should be considered when dealing with colchicine poisoning. We present a case of double, acute, and subacute, fatal colchicine intoxication in a married couple. The 70-year-old male victim suddenly died after vomiting and diarrhea. The next day his wife showed aggravating gastrointestinal symptoms and was hospitalized with a diagnosis of septic shock. A complete postmortem examination on the man was performed, together with histopathological analysis. Toxicological examination performed through liquid chromatography coupled to mass spectrometry revealed a colchicine blood peripheral concentration of 33 ng/mL. A few days after hospitalization, the woman showed a colchicine plasma concentration of 32 ng/mL. Despite veno-venous hemofiltration, she ultimately died of septic shock and multi-organ failure. Death scene investigation revealed that, a few days before the death of the male victim, the couple had collected wild saffron and had eaten a presumed saffron risotto. The integrated analysis of circumstantial, clinical, postmortem and toxicological data allowed to establish that the couple had died of a fatal accidental intoxication due to the ingestion of natural colchicine, mistaken for saffron. The death of the male was deemed caused by acute cardiovascular collapse induced by acute intoxication, while the female had suffered a subacute poisoning by antimitotic agent, resulting in immunosuppression and systemic infection. Toxicological analyses, promptly performed on the man for forensic purposes, directed the investigations and suggested the clinical diagnosis on the woman.


Assuntos
Antimitóticos/envenenamento , Colchicina/envenenamento , Crocus , Medicina Legal , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/patologia , Choque Séptico/etiologia , Choque Séptico/patologia , Choque/etiologia , Choque/patologia , Acidentes , Doença Aguda , Idoso , Autopsia , Colchicina/sangue , Evolução Fatal , Feminino , Humanos , Masculino , Cônjuges
8.
Clin Dermatol ; 37(2): 148-158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30981295

RESUMO

We have explored the rash that appears as target lesions, with the central and dominant diseases belonging to the Stevens-Johnson syndrome/toxic epidermal necrolysis group. After presenting the clinical patterns of an individual target lesion and classifying them into different types of lesions, the contribution has been organized with groups characterized by such specific findings according to the type of lesion: flat or raised, typical or atypical, presence or absence of fever, presence or absence of mucosal ulcerations, presence or absence of arthralgias, and/or internal organ involvement. Other specific features, such as histologic appearance, immunofluorescence findings, and laboratory changes, are considered. We provide clinicians with an algorithmic, systematic, and logical approach to diagnose the condition of the patients who present with targetoid lesions, and enable them to differentiate between those with serious systemic and life-threatening diseases from others with ordinary skin ailments.


Assuntos
Eritema Multiforme/complicações , Eritema Multiforme/diagnóstico , Exantema/diagnóstico , Exantema/etiologia , Pele/patologia , Síndrome de Stevens-Johnson/complicações , Síndrome de Stevens-Johnson/diagnóstico , Artralgia , Diagnóstico Diferencial , Eritema Multiforme/patologia , Exantema/patologia , Feminino , Febre , Imunofluorescência , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/patologia , Membrana Mucosa , Penfigoide Bolhoso/complicações , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/patologia , Gravidez , Complicações na Gravidez , Choque Séptico/complicações , Choque Séptico/diagnóstico , Choque Séptico/patologia , Síndrome de Stevens-Johnson/patologia , Sífilis/complicações , Sífilis/diagnóstico , Sífilis/patologia , Úlcera , Urticária/complicações , Urticária/diagnóstico , Urticária/patologia
9.
Biomed Res Int ; 2019: 3080827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881985

RESUMO

Background: Urosepsis and septic shock are a critical situation leading to a mortality rate up to 30% in patients with obstructive diseases of the urinary tract. Aim: To analyze the bacterial distribution and drug resistance of pathogenic bacteria in patients with urosepsis and to provide a basis for the rational application of antibacterial drugs in clinical practice. Methods: A retrospective analysis of 94 hospitalized patients with urosepsis for 6 years was performed. The strain composition, resistance characteristics, and the antibiogram of common bacteria from positive blood and midstream urine culture were analyzed. Results: A total of 87 strains were isolated, including 65 strains (74.71%) of Gram-negative bacilli, 14 strains (16.09%) of Gram-positive cocci, and 8 strains (9.20%) of fungi. The Gram-negative bacilli included 42 strains of Escherichia coli (E. coli) (64.62%), among which 34 strains (80.95%) were producing ESBLs, and 14 strains (21.84%) of Klebsiella pneumoniae (K. pneumoniae), among which nine strains (64.29%) were producing ESBLs. The most common pathogenic bacteria, ESBL+ E. coli and K. pneumoniae strains, showed sensitivity towards imipenem, ertapenem, piperacillin/tazobactam, amikacin, and cefotetan, but were highly resistant to quinolones. The cure rate of urosepsis was 88.30%, and the susceptibility rate of septic shock was 45.47%. Significance: Gram-negative bacterial infections are the main cause of urosepsis. The mild patient group showed more E. coli (ESBL-) infections, and the number of ESBL producing E. coli isolated from the mild group showed higher drug resistance rates for aztreonam and levofloxacin compared with isolates from the severe group.


Assuntos
Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Sepse/tratamento farmacológico , Choque Séptico/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Ertapenem/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/patologia , Humanos , Imipenem/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/patogenicidade , Quinolonas/farmacologia , Sepse/microbiologia , Sepse/patologia , Choque Séptico/microbiologia , Choque Séptico/patologia , Infecções Urinárias/microbiologia , Infecções Urinárias/patologia
10.
Vector Borne Zoonotic Dis ; 19(6): 453-454, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30730266

RESUMO

We report a fatal case of Bartonella henselae bacteremic patient. He had negative serology and PCRs from whole blood and liquid culture; only ftsZ nested PCR was positive from the blood liquid culture. The isolate had positive PCRs. When considered, bartonellosis diagnosis can be still challenging because of technical limitations.


Assuntos
Infecções por Bartonella/diagnóstico , Reações Falso-Negativas , Antibacterianos/uso terapêutico , Infecções por Bartonella/tratamento farmacológico , Infecções por Bartonella/microbiologia , Infecções por Bartonella/patologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Choque Séptico/tratamento farmacológico , Choque Séptico/microbiologia , Choque Séptico/patologia
11.
APMIS ; 127(2): 87-92, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30698306

RESUMO

Streptococcal toxic shock syndrome (STSS) is primarily caused by Streptococcus pyogenes, but it may also be caused by Streptococcus dysgalactiae subsp. equisimilis (SDSE). The analyses of S. pyogenes have revealed the important roles of NAD+ -glycohydrolase (Nga) and CovR/CovS, a two-component regulatory system. We examined these factors in SDSE by analyzing mainly two isogenic SDSE strains (12-10-1 and 12-10-3) from the blood of a patient with STSS. The Nga activities were measured and the nucleotide sequences of covR and covS genes were determined. We detected one nucleotide difference between the covR gene of 12-10-1 and that of 12-10-3, and the Nga activity of 12-10-1 was approximately 6.8-fold more than that of 12-10-3. The introduction of covR of 12-10-3 into 12-10-1 significantly reduced the Nga activity, but the introduction of 12-10-1 covR into itself had only a little effect. In addition, the knockout of covR or covS of 12-10-3 remarkably increased the Nga activity. We are the first to report that strains with wild-type and mutated covR were isolated simultaneously from an SDSE STSS patient and that the CovR/CovS two-component regulatory system is involved in the Nga activity in SDSE as well as in S. pyogenes.


Assuntos
Proteínas de Bactérias/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , NAD+ Nucleosidase/metabolismo , Proteínas Repressoras/genética , Infecções Estreptocócicas/patologia , Streptococcus pyogenes/metabolismo , Proteínas de Bactérias/metabolismo , Histidina Quinase , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Repressoras/metabolismo , Choque Séptico/microbiologia , Choque Séptico/patologia , Streptococcus pyogenes/enzimologia , Streptococcus pyogenes/genética , Streptococcus pyogenes/isolamento & purificação
12.
J Int Med Res ; 47(4): 1573-1579, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30656987

RESUMO

OBJECTIVE: To investigate the prognostic significance of serum procalcitonin (PCT) and C-reactive protein (CRP) in patients with sepsis and those with septic shock. METHODS: Fifty-nine patients were divided into sepsis and septic shock groups, as well as survivor and non-survivor groups, according to the severity of the disease and patient survival. Serum PCT and CRP measurements at the time of hospitalization in the intensive care unit were examined. RESULTS: On the 2nd, 3rd, and 5th days, the CRP level was higher in the non-survivor group than in the survivor group, and the serum CRP level was higher in patients in the septic shock group than in patients in the sepsis group. Regarding changes in serum PCT level in each group, the levels of PCT were significantly different between non-survivor and survivor groups, whereas they did not differ between patients in the sepsis and septic shock groups. Serum PCT kinetics (ΔPCT) were similar between groups. CONCLUSIONS: Serum PCT and CRP have good clinical diagnostic and prognostic value for patients with sepsis and septic shock. Kinetic studies of PCT and CRP can improve sensitivity and accuracy when evaluating the prognosis of patients with sepsis and those with septic shock.


Assuntos
Biomarcadores/sangue , Proteína C-Reativa/análise , Unidades de Terapia Intensiva/estatística & dados numéricos , Pró-Calcitonina/sangue , Sepse/mortalidade , Choque Séptico/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Sepse/sangue , Sepse/patologia , Choque Séptico/sangue , Choque Séptico/patologia , Taxa de Sobrevida
13.
Shock ; 51(1): 33-43, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29923896

RESUMO

As outlined in the "International Guidelines for Management of Sepsis and Septic Shock: 2016," initial fluid resuscitation and administration of antibiotics are key steps in the early management of sepsis and septic shock. However, such clear guidelines do not exist for preclinical sepsis models. To address these shortcomings, the Wiggers-Bernard conference on preclinical sepsis models was held in Vienna in May 2017. The participants reviewed 260 of the most highly cited papers between 2003 and 2012 that used sepsis models. The review demonstrated that over 70% of experiments either did not use or failed to report resuscitation and/or antibiotic treatment. This information served as the basis to create a series of recommendations and considerations for preclinical sepsis models; this Part III report details the recommendations for fluid resuscitation and antibiotic treatment that should be addressed in sepsis models. Similar to human sepsis, fluid resuscitation is recommended in the experimental setting unless part of the study. Iso-osmolar crystalloid solutions are preferred. The administration route and its timing should be adjusted to the specific requirements of the model with preference given to dynamic rather than static hemodynamic monitoring. Predefined endpoints for fluid resuscitation and avoidance of fluid overload should be considered. Preclinical sepsis studies display serious inconsistencies in the use of antimicrobial protocols. To remedy this, antimicrobials are recommended for preclinical studies, with choice and dose adjusted to the specific sepsis model and pathogen (s). Ideally, the administration of antimicrobials should closely mimic clinical practice, taking into account the drug's pharmacokinetic profile, alterations in absorption, distribution and clearance, and host factors such as age, weight, and comorbidities. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.


Assuntos
Antibacterianos/uso terapêutico , Hidratação , Modelos Animais , Ressuscitação , Choque Séptico , Animais , Humanos , Choque Séptico/microbiologia , Choque Séptico/patologia , Choque Séptico/terapia
14.
Ann Endocrinol (Paris) ; 80(2): 117-121, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30243475

RESUMO

BACKGROUND: Endogenous ß-endorphin is delivered exclusively from the pituitary gland in various stressful conditions and plays an essential role in the nervous system. Recently, a few studies demonstrated peripheral endogenous opioid secretion from immune cells at inflammatory sites. Here, we investigated the expression of ß-endorphin, the most powerful endogenous opioid peptide, in peripheral tissues in response to systemic administration of lipopolysaccharide in mice. METHODS: Male C57BL/6N mice received intravenously administered lipopolysaccharide to induce an endotoxic shock-like condition. mRNA for proopiomelanocortin, a precursor of ß-endorphin, was quantified in peripheral blood cells, liver and spleen. ß-endorphin peptide was measured in the liver and spleen. RESULTS: Expression of proopiomelanocortin mRNA was detected in peripheral tissues after systemic administration of lipopolysaccharide. Lipopolysaccharide also induced ß-endorphin expression in the liver and spleen. CONCLUSION: Expression of proopiomelanocortin mRNA and ß-endorphin was detected in peripheral tissues after systemic administration of lipopolysaccharide. These results provide new evidence that peripheral endogenous opioids can be produced not only as a result of local inflammation but also by severe systemic stress such as endotoxic shock. Further study is required to clarify the role of peripheral ß-endorphin during endotoxic shock.


Assuntos
Lipopolissacarídeos/administração & dosagem , Choque Séptico/induzido quimicamente , Choque Séptico/genética , beta-Endorfina/genética , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Choque Séptico/metabolismo , Choque Séptico/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Distribuição Tecidual/efeitos dos fármacos , beta-Endorfina/metabolismo
15.
J Cell Biochem ; 120(1): 56-70, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30246452

RESUMO

Endotoxin tolerance is defined as a reduced capacity of a cell to respond endotoxin (lipopolysaccharide, LPS) challenge after an initial encounter with endotoxin in advance. The body becomes tolerant to subsequent challenge with a lethal dose of endotoxin and cytokines release and cell/tissue damage induced by inflammatory reaction are significantly reduced in the state of endotoxin tolerance. The main characteristics of endotoxin tolerance are downregulation of inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), and C-X-C motif chemokine 10 (CXCL10) and upregulation of anti-inflammatory cytokines such as IL-10 and transforming growth factor ß (TGF-ß). Therefore, endotoxin tolerance is often regarded as the regulatory mechanism of the host against excessive inflammation. Endotoxin tolerance is a complex pathophysiological process and involved in multiple cellular signal pathways, receptor alterations, and biological molecules. However, the exact mechanism remains elusive up to date. To better understand the underlying cellular and molecular mechanisms of endotoxin tolerance, it is crucial to investigate the comprehensive cellular signal pathways, signaling proteins, cell surface molecules, proinflammatory and anti-inflammatory cytokines, and other mediators. Endotoxin tolerance plays an important role in reducing the mortality of sepsis, endotoxin shock, and other endotoxin-related diseases. Recent reports indicated that endotoxin tolerance is also related to other diseases such as cystic fibrosis, acute coronary syndrome, liver ischemia-reperfusion injury, and cancer. The aim of this review is to discuss the recent advances in endotoxin tolerance mainly based on the cellular and molecular mechanisms by outline the current state of the knowledge of the involvement of the toll-like receptor 4 (TLR4) signaling pathways, negative regulate factor, microRNAs, apoptosis, chromatin modification, and gene reprogramming of immune cells in endotoxin tolerance. We hope to provide a new idea and scientific basis for the rational treatment of endotoxin-related diseases such as endotoxemia, sepsis, and endotoxin shock clinically.


Assuntos
Apoptose/imunologia , Lipopolissacarídeos , Choque Séptico , Transdução de Sinais , Animais , Humanos , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/toxicidade , Choque Séptico/imunologia , Choque Séptico/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
16.
Ann N Y Acad Sci ; 1437(1): 43-56, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30499145

RESUMO

Sepsis occurs when a systemic infection induces an uncontrolled inflammatory response that results in generalized organ dysfunction. The exacerbated peripheral inflammation can induce, in turn, neuroinflammation which may result in severe impairment of the central nervous system (CNS). Indeed, the ensuing blood-brain barrier disruption associated with sepsis promotes glial activation and starts a storm of proinflammatory cytokines in the CNS that leads to brain dysfunction in sepsis survivors. Endotoxic shock induced in mice by peripheral injection of lipopolysaccharides closely resembles the peripheral and central inflammation observed in sepsis. In this review, we provide an overview of the neuroinflammatory features in sepsis and of recent progress toward the development of new anti-neuroinflammatory therapies seeking to reduce mortality and morbidity in sepsis survivors.


Assuntos
Lesões Encefálicas/prevenção & controle , Lesões Encefálicas/terapia , Inflamação/prevenção & controle , Sepse/terapia , Choque Séptico/terapia , Animais , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Lesões Encefálicas/patologia , Citocinas/imunologia , Estimulação Elétrica , Glucocorticoides/uso terapêutico , Humanos , Inflamação/terapia , Lipopolissacarídeos/toxicidade , Camundongos , Sepse/microbiologia , Choque Séptico/imunologia , Choque Séptico/patologia
17.
J Int Med Res ; 47(1): 44-58, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30477377

RESUMO

OBJECTIVE: This study was performed to compare the predictive performance of serum procalcitonin (PCT), N-terminal brain natriuretic propeptide (NT-proBNP), interleukin-6 (IL-6), prothrombin time (PT), thrombin time (TT), and Sequential Organ Failure Assessment (SOFA) score in the intensive care unit (ICU). METHODS: This retrospective cohort study enrolled 150 patients with sepsis and septic shock and 30 control patients without sepsis. Each patient was followed until death or 28 days. Correlations between variables were assessed with Spearman's rho test. The Kruskal-Wallis and Mann-Whitney U tests were used for between-group comparisons. RESULTS: Receiver operating characteristic curve analysis of the SOFA score, PCT, NT-proBNP, IL-6, PT, and TT showed an area under the curve of 0.872, 0.732, 0.711, 0.706, 0.806, and 0.691, respectively, for diagnosing sepsis. Binary logistic regression demonstrated that the SOFA score was an independent predictor of 28-day mortality and septic shock. The correlation coefficient (r) between SOFA and PCT, NT-proBNP and SOFA, IL-6 and SOFA, PT and SOFA, and TT and SOFA was 0.79, 0.52, 0.57, 0.56, and 0.58, respectively. CONCLUSION: While the SOFA score is the gold standard, analysis of multiple biomarkers could increase the performance capacity for diagnosis and prognosis in patients with sepsis in the ICU.


Assuntos
Interleucina-6/sangue , Peptídeo Natriurético Encefálico/sangue , Escores de Disfunção Orgânica , Fragmentos de Peptídeos/sangue , Pró-Calcitonina/sangue , Choque Séptico/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Tempo de Protrombina/estatística & dados numéricos , Curva ROC , Estudos Retrospectivos , Choque Séptico/sangue , Choque Séptico/mortalidade , Choque Séptico/patologia , Análise de Sobrevida , Tempo de Trombina/estatística & dados numéricos
18.
Biomarkers ; 24(3): 277-285, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30521401

RESUMO

Purpose: Hypercatecholaminemia-related heart failure has been proposed as the main cause of enterovirus A71-related (EV-A71) early mortality. The purpose of this study was to measure urine catecholamine concentrations in severe EV-A71-infected children. Methods: A total of 35 children, aged 2.5 ± 2.1 years, were divided into three groups. Group I: 15 septic shock patients, group II: 17 EV-A71-stage-2 patients, and group III: 3 EV-A71-stage-4 patients. The laboratory results, cardiac biomarkers and urine catecholamine concentrations were statistically analysed. Results: Group I had the highest C-reactive protein (CRP) levels and group II had the lowest B-type natriuretic peptide (BNP) and its N-terminal prohormone among the groups (p = 0.039, <0.01 and <0.01, respectively). Group III patients had significantly higher urine catecholamine and troponin-I values among the groups. If urine epinephrine (Epi) >134 ug/gCr, norepinephrine (NE) >176 ug/gCr and vanillylmandelic acid (VMA) >11.7 mg/gCr were used as the cutoff points to differentiate groups II and III, the sensitivities and specificity were all 100%. Conclusions: The significantly elevated urine catecholamine concentrations in EV-A71-stage-4 patients support the hypothesis that hypercatecholaminemia-related heart failure is involved in severe EV-A71 infection. Urine catecholamines could be used as reliable biomarkers for differentiation of severe EV-A71 infection with or without heart failure and septic shock.


Assuntos
Catecolaminas/urina , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/urina , Choque Séptico/urina , Criança , Pré-Escolar , Infecções por Enterovirus/patologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Lactente , Masculino , Choque Séptico/patologia , Choque Séptico/virologia
19.
mSphere ; 3(6)2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30567900

RESUMO

Sepsis caused by Gram-negative bacteria is the consequence of an unrestrained infection that continuously releases lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to multiorgan failure and death. After scrutinizing the immune modulation exerted by a recombinant Fasciola hepatica fatty acid binding protein termed Fh15, our group demonstrated that addition of Fh15 to murine macrophages 1 h prior to LPS stimulation significantly suppresses the expression of proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL1-ß). The present study aimed to demonstrate that Fh15 could exert a similar anti-inflammatory effect in vivo using a mouse model of septic shock. Among the novel findings reported in this article, (i) Fh15 suppressed numerous serum proinflammatory cytokines/chemokines when injected intraperitoneally 1 h after exposure of animals to lethal doses of LPS, (ii) concurrently, Fh15 increased the population of large peritoneal macrophages (LPMs) in the peritoneal cavity (PerC) of LPS-injected animals, and (iii) Fh15 downregulated the expression on spleen macrophages of CD38, a cell surface ectoenzyme with a critical role during inflammation. These findings present the first evidence that the recombinant parasitic antigen Fh15 is an excellent modulator of the PerC cell content and in vivo macrophage activation, endorsing Fh15's potential as a drug candidate against sepsis-related inflammatory response.IMPORTANCE Sepsis is a potentially life-threatening complication of an infection. Sepsis is mostly the consequence of systemic bacterial infections leading to exacerbated activation of immune cells by bacterial products, resulting in enhanced release of inflammatory mediators. Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, is a critical factor in the pathogenesis of sepsis, which is sensed by Toll-like receptor 4 (TLR4). The scientific community highly pursues the development of antagonists capable of blocking the cytokine storm by blocking TLR4. We report here that a recombinant molecule of 14.5 kDa belonging to the Fasciola hepatica fatty acid binding protein (Fh15) is capable of significantly suppressing the LPS-induced cytokine storm in a mouse model of septic shock when administered by the intraperitoneal route 1 h after a lethal LPS injection. These results suggest that Fh15 is an excellent candidate for drug development against endotoxemia.


Assuntos
Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Proteínas de Ligação a Ácido Graxo/administração & dosagem , Proteínas de Helminto/administração & dosagem , Lipopolissacarídeos/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/fisiologia , Choque Séptico/patologia , ADP-Ribosil Ciclase 1/análise , Animais , Células Cultivadas , Citosol/química , Modelos Animais de Doenças , Ácidos Graxos/análise , Injeções Intravenosas , Glicoproteínas de Membrana/análise , Camundongos , Proteínas Recombinantes/administração & dosagem , Baço/imunologia
20.
Sci Rep ; 8(1): 17296, 2018 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-30470767

RESUMO

Innovative single cell technologies such as mass cytometry (CyTOF) widen possibilities to deeply improve characterisation of immune alterations mechanisms in human diseases. So far, CyTOF has not been used in sepsis - a condition characterized by complex immune disorders. Here, we evaluated feasibility of CyTOF analysis in patients with septic shock. We designed a mass cytometry panel of 25 extracellular markers to study mononuclear cells from 5 septic shock patients and 5 healthy donors. We explored single-cell data with global and specific unsupervised approaches such as heatmaps, SPADE and viSNE. We first validated relevance of our CyTOF results by highlighting established immune hallmarks of sepsis, such as decreased monocyte HLA-DR expression and increased expressions of PD1 and PD-L1 on CD4 T cells and monocytes. We then showed that CyTOF analysis reveals novel aspects of sepsis-induced immune alterations, e.g. B cell shift towards plasma cell differentiation and uniform response of several monocyte markers defining an immune signature in septic patients. This proof of concept study demonstrates CyTOF suitability to analyse immune features of septic patients. Mass cytometry could thus represent a powerful tool to identify novel pathophysiological mechanisms and therapeutic targets for immunotherapy in septic shock patients.


Assuntos
Biomarcadores/análise , Citometria de Fluxo/métodos , Monócitos/imunologia , Choque Séptico/classificação , Choque Séptico/imunologia , Análise de Célula Única/métodos , Antígeno B7-H1/metabolismo , Estudos de Casos e Controles , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Estudo de Prova de Conceito , Choque Séptico/metabolismo , Choque Séptico/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
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