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1.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(7): 877-879, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32788029

RESUMO

Sepsis is a common clinical critical disease, which is one of the main causes of septic shock and multiple organ dysfunction syndrome (MODS). Since traditional clinical interventions are simple and limited, the mortality of sepsis remains high and is also one of the main causes of death of intensive care unit (ICU) patients. Nicotinamide has a wide range of cytoprotective effects. A large number of studies have shown that nicotinamide can play an important role in infection and sepsis by repairing mitochondrial function to restore adenosine triphosphate (ATP) level, inhibiting poly (ADP-ribose) polymerase (PARP) activation, inhibiting proinflammatory mediators and antioxidant damage. This article reviews the pathogenesis of sepsis and the role of nicotinamide in sepsis treatment, aiming to provide references for exploring new therapeutic directions and effective therapeutic measures for sepsis.


Assuntos
Niacinamida/uso terapêutico , Sepse/prevenção & controle , Complexo Vitamínico B/uso terapêutico , Humanos , Insuficiência de Múltiplos Órgãos , Poli(ADP-Ribose) Polimerases , Choque Séptico
2.
PLoS One ; 15(8): e0237871, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817720

RESUMO

Streptococcus pneumoniae is a common cause of infectious diseases such as pneumonia and sepsis. Its colonization is thought to be the first step in the development of invasive pneumococcal diseases. This study aimed to investigate pneumococcal colonization patterns in early childhood. A longitudinal birth cohort study was conducted for investigating nasopharyngeal colonized pneumococci at 1, 6, 12, 18, 24, and 36 months of age, particularly focusing on the serotype distribution and antimicrobial susceptibilities. Pneumococcal conjugate vaccine (PCV) effect on nasopharyngeal colonization was also assessed. During 2013-2017, 855 infants were enrolled and a total of 107 isolates were recovered from 95 infants during the first three years of life. In this period, the prevalence of pneumococcal colonization increased, with values ranging from 0.2% (2/834) at 1 month of age to 5.9% (19/323) at 36 months of age. The investigation of serotype revealed that 81.1% (73/90) belonged to the non-PCV13 serotypes-23A, 15A, 15C, and 15B. Moreover, PCV13 serotypes significantly decreased during 2014-2015, when routine PCV13 vaccination was initiated in Taiwan. PCV13 introduction may lead to the reduction in the rates of pneumococcal isolates resistant (R) to penicillin. Under conditional PCV13 vaccination, pneumococcal isolates primarily belonged to non-PCV13 serotypes. This non-PCV13 serotype replacement exhibited lower rates of penicillin R isolates, suggesting that PCV13 administration may reduce the antibiotic-nonsusceptible pneumococcal disease burden and antibiotic use.


Assuntos
Doenças Nasofaríngeas/tratamento farmacológico , Nasofaringe/efeitos dos fármacos , Infecções Pneumocócicas/tratamento farmacológico , Streptococcus pneumoniae/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Doenças Nasofaríngeas/imunologia , Doenças Nasofaríngeas/microbiologia , Doenças Nasofaríngeas/patologia , Nasofaringe/microbiologia , Penicilinas/administração & dosagem , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/patologia , Vacinas Pneumocócicas/administração & dosagem , Pneumonia/microbiologia , Pneumonia/prevenção & controle , Sepse/microbiologia , Sepse/prevenção & controle , Sorogrupo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/patogenicidade , Taiwan , Vacinas Conjugadas/administração & dosagem
3.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32629817

RESUMO

By attaching to the angiotensin converting enzyme 2 (ACE2) protein on lung and intestinal cells, Sudden Acute Respiratory Syndrome (SARS-CoV-2) can cause respiratory and homeostatic difficulties leading to sepsis. The progression from acute respiratory failure to sepsis has been correlated with the release of high-mobility group box 1 protein (HMGB1). Lack of effective conventional treatment of this septic state has spiked an interest in alternative medicine. This review of herbal extracts has identified multiple candidates which can target the release of HMGB1 and potentially reduce mortality by preventing progression from respiratory distress to sepsis. Some of the identified mixtures have also been shown to interfere with viral attachment. Due to the wide variability in chemical superstructure of the components of assorted herbal extracts, common motifs have been identified. Looking at the most active compounds in each extract it becomes evident that as a group, phenolic compounds have a broad enzyme inhibiting function. They have been shown to act against the priming of SARS-CoV-2 attachment proteins by host and viral enzymes, and the release of HMGB1 by host immune cells. An argument for the value in a nonspecific inhibitory action has been drawn. Hopefully these findings can drive future drug development and clinical procedures.


Assuntos
Betacoronavirus/fisiologia , Proteína HMGB1/metabolismo , Insuficiência Respiratória/patologia , Sepse/patologia , Proteína HMGB1/antagonistas & inibidores , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Exsudatos de Plantas/química , Exsudatos de Plantas/farmacologia , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Insuficiência Respiratória/metabolismo , Insuficiência Respiratória/prevenção & controle , Sepse/metabolismo , Sepse/prevenção & controle , Internalização do Vírus/efeitos dos fármacos
4.
PLoS One ; 15(7): e0236038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658933

RESUMO

The attenuation of hyper-inflammation in sepsis with the administration of anti-inflammatory macrophages is an interesting adjuvant therapy for sepsis. Because the induction of anti-inflammatory macrophages by microRNA (miR), a regulator of mRNA, has been mentioned, the exploration on miR-induced anti-inflammatory macrophages was performed. The over-expression of miR-223 and miR-146a in RAW264.7 induced M2 macrophage-polarization (anti-inflammatory macrophages) as evaluated by the enhanced expression of Arginase-1 and Fizz. However, miR-223 over-expressed cells demonstrated the more potent anti-inflammatory property against LPS stimulation as lesser iNOS expression, lower supernatant IL-6 and higher supernatant IL-10 compared with miR-146a over-expressed cells. Interestingly, LPS stimulation in miR-223 over-expressed cells, compared with LPS-stimulated control cells, demonstrated lower activity of glycolysis pathway and higher mitochondrial respiration, as evaluated by the extracellular flux analysis, and also down-regulated HIF-1α, an important enzyme of glycolysis pathway. In addition, the administration of miR-223 over-expressed macrophages with IL-4 pre-conditioning, but not IL-4 stimulated control cells, attenuated sepsis severity in LPS injected mice as evaluated by serum creatinine, liver enzymes, lung histology and serum cytokines. In conclusion, miR-223 interfered with the glycolysis pathway through the down-regulation of HIF-1α, resulting in the anti-inflammatory status. The over-expression of miR-223 in macrophages prevented the conversion into M1 macrophage polarization after LPS stimulation. The administration of miR-223 over-expressed macrophages, with IL-4 preconditioning, attenuated sepsis severity in LPS model. Hence, a proof of concept in the induction of anti-inflammatory macrophages through the cell-energy interference for sepsis treatment was proposed as a basis of cell-based therapy in sepsis.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Glicólise , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Macrófagos/transplante , MicroRNAs/genética , Sepse/prevenção & controle , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Ativação de Macrófagos , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/induzido quimicamente , Sepse/metabolismo , Sepse/patologia
5.
Toxicol Appl Pharmacol ; 400: 115070, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464219

RESUMO

Vascular dysfunction plays a critical role in the pathogenesis of sepsis. We elucidated the mechanisms underlying the amelioration of lipopolysaccharide (LPS)-induced vascular inflammation by oroxylin A (OroA) post-treatment in rats. The animals were intraperitoneally injected with LPS (10 mg/kg) to induce systemic inflammation and intravenously (iv) administered OroA (15 mg/kg) 6 h after the LPS treatment. The assessments included biochemical changes in peripheral blood, vascular reactivity which was evaluated by blood-vessel myography, morphological/histological assessment of inflammation, toll-like receptor (TLR)-4-mediated interleukin-1-receptor-associated-kinase (IRAK)-4 activation, changes in adhesion molecule expression, and endothelial junctional stability in the aorta. LPS significantly enhanced the proinflammatory cytokine release, increased vascular cell adhesion molecule (VCAM)-1 expression, disrupted endothelial tight junction, reduced vascular endothelial barrier stability, and increased macrophage infiltration and accumulation in the aorta. All observed pathological changes and vascular inflammation were significantly reversed by the OroA post-treatment. Importantly, OroA suppressed the increased adhesion molecule expression and the endothelial barrier disruption by inhibiting LPS-activated IRAK-4-targeted inhibitory nuclear factor kappa B kinase (IKK) α/ß complex phosphorylation, without directly affecting the interaction between LPS and TLR-4. Moreover, the iNOS activity induced by the LPS challenge was inhibited by the OroA pretreatment of the isolated aortic rings. These results suggest that OroA regulates the vascular tone by inhibiting vascular hyporeactivity caused by NO overproduction and reverses the endothelial barrier dysfunction and inflammation by inhibiting the IRAK-4-mediated IKKα/ß phosphorylation. Overall, these findings suggest OroA administration as a potentially useful therapeutic approach for clinical interventions in septic shock.


Assuntos
Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Flavonoides/farmacologia , Sepse/prevenção & controle , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Aorta/imunologia , Aorta/patologia , Células Cultivadas , Quimiocina CCL2/sangue , Citocinas/sangue , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Endotoxinas/farmacologia , Flavonoides/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Ratos Sprague-Dawley , Sepse/sangue , Sepse/patologia
6.
Int J Infect Dis ; 96: 254-259, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32407901

RESUMO

OBJECTIVES: Prophylactic antibiotic use in preterm pre-labor rupture of membranes (PPROM) is associated with a significant reduction in intra-amniotic infection and improved neonatal outcome. However, data is insufficient to determine the optimal antibiotic regimen. Considering the rise in Escherichia coli and Klebsiella pneumonia early-onset sepsis rate and the emergence of ampicillin resistance, our aim is to compare the efficiency of two antibiotic regimens in prolonging pregnancy and reducing infectious morbidity. DESIGN: This multicenter randomized unblinded controlled prospective trial compared two antibiotic prophylactic protocols in PPROM: ampicillin + roxithromycin vs. cefuroxime + roxithromycin in 84 women with PPROM, from 12/2015-12/2019. RESULTS: The median latency period was significantly longer (p = 0.039) in the cefuroxime + roxithromycin group (4.63 [0.59-50.18] days) than in the ampicillin + roxithromycin group (2.3 [0.15-58.3] days). Neonatal admission to neonatal intensive care unit rate, hospitalization length, neonatal respiratory distress syndrome, neonatal fever, and need for respiratory support or mechanical ventilation, were similar between the groups. K. pneumonia cultures were significantly more frequent in the ampicillin + roxithromycin group. None of the cultures were group B Streptococcus positive. CONCLUSIONS: To prolong latency period and reduce gram-negative early-onset sepsis, cefuroxime + roxithromycin is recommended as the first-line protocol in PPROM. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02819570.


Assuntos
Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Ruptura Prematura de Membranas Fetais/tratamento farmacológico , Doenças do Recém-Nascido/prevenção & controle , Sepse/prevenção & controle , Adulto , Ampicilina/uso terapêutico , Feminino , Humanos , Recém-Nascido , Infecções por Klebsiella/tratamento farmacológico , Gravidez , Estudos Prospectivos
8.
Cochrane Database Syst Rev ; 3: CD007137, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32232984

RESUMO

BACKGROUND: Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES: To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Meta-analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95% CI 0.74 to 0.91; typical RD -0.04, 95% CI, -0.06, -0.02; NNTB 25, 95% CI 17 to 50; 12 studies, 5425 participants, low-certainty evidence) and decreased length of hospital stay (MD -2.38, 95% CI, -4.67, -0.09; 3 studies, 1079 participants, low-certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95% CI, 0.78, 0.97; typical RD -0.03, 95% CI, -0.05, -0.0; 9 studies, 4702 participants, low-certainty evidence). There were no differences in NEC stage II or III (typical RR 1.10, 95% CI, 0.86, 1.41; typical RD -0.00, 95% CI, -0.02, 0.01; 7 studies, 4874 participants; low-certainty evidence) or 'all-cause mortality' (typical RR 0.90, 95% CI 0.69, 1.17; typical RD -0.00, 95% CI, -0.01, 0.01; 11 studies, 5510 participants; moderate-certainty evidence). One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (one study, 292 participants, low-certainty evidence). Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.25, 95% CI 0.14 to 0.46; RD -0.13, 95% CI -0.18 to -0.08; NNTB 8, 95% CI 6 to 13; 3 studies, 564 participants; low-certainty evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; 1 study, 496 participants; very low-certainty evidence), but not 'all-cause mortality' (very low-certainty evidence). Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low-certainty evidence). Investigators reported no adverse effects in the included studies. AUTHORS' CONCLUSIONS: We found low-certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreases late-onset sepsis but not NEC ≥ stage II or 'all cause mortality' or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects. Low- to very low-certainty evidence suggests that lactoferrin supplementation of enteral feeds in combination with probiotics decreases late-onset sepsis and NEC ≥ stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality. The presence of publication bias and small studies of poor methodology that may inflate the effect size make recommendations for clinical practice difficult.


Assuntos
Nutrição Enteral , Enterocolite Necrosante/prevenção & controle , Doenças do Prematuro/prevenção & controle , Lactoferrina/administração & dosagem , Probióticos/administração & dosagem , Sepse/prevenção & controle , Administração Oral , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/prevenção & controle , Causas de Morte , Doença Crônica , Enterocolite Necrosante/epidemiologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Lactobacillus rhamnosus , Pneumopatias/epidemiologia , Micoses/epidemiologia , Micoses/prevenção & controle , Números Necessários para Tratar , Ensaios Clínicos Controlados Aleatórios como Assunto , Retinopatia da Prematuridade/epidemiologia
10.
Int J Infect Dis ; 96: 54-60, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32304821

RESUMO

INTRODUCTION: Sepsis is the leading cause of infectious morbidity and mortality among hospitalized neonates. In high-resource pediatric and adult intensive care units, use of aqueous chlorhexidine (CHG) solution has been associated with reduced risk of bloodstream infections (BSI). OBJECTIVES: To assess the impact of bathing of neonates with 2% CHG on BSI, suspected sepsis, and mortality in a low-income country neonatal care unit. METHODS: We conducted a secondary analysis of data from the Sepsis Prevention in Neonates in Zambia (SPINZ) study, a prospective observational cohort study performed at a large public referral hospital in Lusaka, Zambia. The SPINZ study assessed the impact of an infection control bundle (consisting of alcohol hand rub, SMS hygiene reminders, enhanced environmental cleaning, and CHG baths for babies ≥1.5 kg) on sepsis, BSI, and all-cause mortality. Episodic shortages in study staffing resulted in some enrolled babies not receiving a CHG bath. Using Longitudinal Targeted Maximum Likelihood Estimation and Cox proportional hazards regression to adjust for observed confounding, we estimated the causal effect of receiving a CHG bath within the first 3 days of life on suspected sepsis, BSI, and death among inborn babies enrolled during the study implementation and intervention phases. RESULTS: The majority of inborn, enrolled babies ≥1.5 kg received a CHG bath within 3 days of NICU admission (864 of 1233, 70%). We found that CHG bathing reduced the hazard rate of BSI among inborn babies ≥1.5 kg by a factor of 0.58 (p = 0.10, 95% CI: 0.31, 1.11), corresponding to an absolute risk reduction of 9.6 percentage points within a week of admission (p = 0.002, 95% CI: 3.4-15.7 percentage points). We did not find a statistically significant effect of CHG bathing on culture-negative sepsis (p = 0.54) or death (p = 0.85). CONCLUSION: In our single center study, CHG bathing at admission was associated with a reduced risk of BSI due to a pathogenic organism after adjusting for potential confounding. Our results suggest that CHG may be an effective intervention for preventing neonatal sepsis in high-risk, low-income country settings.


Assuntos
Clorexidina , Controle de Infecções , Sepse/prevenção & controle , Banhos , Estudos de Coortes , Feminino , Mortalidade Hospitalar , Humanos , Higiene , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos Prospectivos , Zâmbia
11.
PLoS One ; 15(3): e0229017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130239

RESUMO

We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component. Female C57 BL/6 mice, 6-8 weeks old, were administered a single i.p. injection of LPS at a dose of 10 mg/Kg or 20 mg/Kg with or without concurrent treatment with the above cfCh inactivating agents. Administration of cfCh inactivating agents concurrently with LPS resulted in prevention of following pathological parameters: 1) release of cfCh in extra-cellular spaces of brain, lung and heart and in circulation; 2) release of inflammatory cytokines in circulation; 3) activation of DNA damage, apoptosis and inflammation in cells of thymus, spleen and in PBMCs; 4) DNA damage, apoptosis and inflammation in cells of lung, liver, heart, brain, kidney and small intestine; 5) liver and kidney dysfunction and elevation of serum lactate; 6) coagulopathy, fibrinolysis and thrombocytopenia; 7) lethality. We conclude that cfCh that are released from dying host cells in response to bacterial endotoxin represents a global instigator of sepsis. cfCh inactivation may provide a novel approach to management of sepsis in humans.


Assuntos
Morte Celular , Ácidos Nucleicos Livres/metabolismo , Cromatina/metabolismo , Endotoxinas , Sepse/metabolismo , Sepse/patologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Cromatina/patologia , Cromatina/fisiologia , Cobre/administração & dosagem , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Desoxirribonuclease I/metabolismo , Desoxirribonuclease I/uso terapêutico , Feminino , Histonas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/uso terapêutico , Resveratrol/administração & dosagem , Sepse/induzido quimicamente , Sepse/prevenção & controle
12.
Anesthesiology ; 132(4): 795-807, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32101978

RESUMO

BACKGROUND: Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis. METHODS: The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing L-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13). RESULTS: In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 ± 0.89 vs. 3.29 ± 2.34, mean ± SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 ± 1.17 vs. 7.31 ± 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury. CONCLUSIONS: Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia.


Assuntos
Aptâmeros de Nucleotídeos/administração & dosagem , Complemento C5a/antagonistas & inibidores , Pneumonia Pneumocócica/sangue , Pneumonia Pneumocócica/prevenção & controle , Sepse/sangue , Sepse/prevenção & controle , Animais , Anticorpos Neutralizantes/administração & dosagem , Biomarcadores/sangue , Estudos de Coortes , Complemento C5a/metabolismo , Feminino , Fatores Imunológicos/antagonistas & inibidores , Fatores Imunológicos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Estudos Prospectivos
13.
J Pediatr ; 219: 118-125.e5, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32037149

RESUMO

OBJECTIVES: To determine the effect of bovine lactoferrin on prevention of late-onset sepsis (LOS) and neurodevelopment delay. STUDY DESIGN: Randomized, double-blind, controlled trial in neonates with a birth weight of 500-2000 g in 3 neonatal units in Lima, Peru, comparing bovine lactoferrin 200 mg/kg/day with placebo administered for 8 weeks. The primary outcome was the first episode of culture-proven LOS or sepsis-associated death. Neurodevelopment delay was assessed by the Mullen Scales at 24 months corrected age. RESULTS: Of the 414 infants enrolled, 209 received bovine lactoferrin and 205 received placebo. LOS or sepsis-associated death occurred in 22 infants (10.5%) in the bovine lactoferrin group vs 30 (14.6%) in the placebo group; there was no difference after adjusting for hospital and birth weight; hazard ratio 0.73 (95% CI, 0.42-1.26). For infants with birth weights of <1500 g the hazard ratio was 0.69 (95% CI, 0.39-1.25). The mean age-adjusted normalized Mullen composite score at 24 months was 83.3 ± 13.6 in the bovine lactoferrin group vs 82.6 ± 13.1 in the placebo group. Growth outcomes and rehospitalization rates during the 2-year follow-up were similar in both groups, except for significantly less bronchiolitis in the bovine lactoferrin group (rate ratio, 0.34; 95% CI, 0.14-0.86). CONCLUSIONS: Supplementation with bovine lactoferrin did not decrease the incidence of sepsis in infants with birth weights of <2000 g. Growth and neurodevelopment outcomes at 24 months of age were similar. Neonatal bovine lactoferrin supplementation had no adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01525316.


Assuntos
Lactoferrina/uso terapêutico , Transtornos do Neurodesenvolvimento/prevenção & controle , Sepse/prevenção & controle , Animais , Bovinos , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino
14.
BMC Infect Dis ; 20(1): 41, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937251

RESUMO

BACKGROUND: Patients with asplenia have a significantly increased lifelong risk of severe invasive infections, particular post-splenectomy sepsis (PSS). Clear preventive measures have been described in the literature, but previous studies found poor implementation of prevention recommendations. Aim of the study is to improve the adherence to guideline-based preventive measures and thereby reduce the incidence of PSS by a novel telephone-delivered intervention that involves both patients and their physicians. METHODS: A prospective controlled, two-armed historical control group design is used to evaluate the new intervention compared to usual care. The intervention for patients includes both educational aspects and, building on the Health Action Process Approach (HAPA), intervention components that promote motivation and planning of preventive measures. For physicians the intervention is primarily information-based. The primary outcome, the adherence to preventative measures, is indicated by a study-specific 'Preventing PSS-score' (PrePSS-score), which is assessed at baseline and at 6-months follow-up. Secondary outcomes include, amongst others, patient self-efficacy and action-planning, asplenia-specific health literacy, general self-management and asplenia-specific self-management. In a process-evaluating part of the study interview-data on patients' and physicians' evaluation of the intervention will be gathered. DISCUSSION: This trial will provide evidence about the effectiveness of the novel prevention intervention for asplenic patients. If demonstrated beneficial, the intervention manual will be made publicly available to enable implementation in practice. The experience gained within this trial may also be valuable for prevention strategies in patients with other diseases. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00015238; Trial registration date 07. December 2018.


Assuntos
Síndrome de Heterotaxia/complicações , Complicações Pós-Operatórias/prevenção & controle , Sepse/epidemiologia , Sepse/etiologia , Esplenectomia/efeitos adversos , Seguimentos , Alemanha/epidemiologia , Fidelidade a Diretrizes , Comunicação em Saúde/métodos , Humanos , Incidência , Motivação , Cooperação do Paciente , Educação de Pacientes como Assunto , Médicos , Estudos Prospectivos , Autoeficácia , Sepse/prevenção & controle , Telemedicina/métodos , Telefone , Vacinação/métodos
15.
BMC Pediatr ; 20(1): 40, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996186

RESUMO

BACKGROUND: In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity, late-onset sepsis, or significant necrotizing enterocolitis. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions. Lactoferrin aids in creating an environment for growth of beneficial bacteria in the gut, thus reducing colonization with pathogenic bacteria. It is hypothesized that oral bovine lactoferrin (bLF), through its antimicrobial, antioxidant and anti-inflammatory properties, will reduce the rate of mortality or major morbidity in very low birth weight preterm infants. METHOD: Lactoferrin Infant Feeding Trial_Canada (LIFT_Canada) is a multi-centre, double-masked, randomized controlled trial with the aim to enroll 500 infants whose data will be combined with the data of the 1542 infants enrolled from Lactoferrin Infant Feeding Trial_Australia/New Zealand (LIFT_ANZ) in a pooled intention-to-treat analysis. Eligible infants will be randomized and allocated to one of two treatment groups: 1) a daily dose of 200 mg/kg bLF in breast/donor human milk or formula milk until 34 weeks corrected gestation or for a minimum of 2 weeks, whichever is longer, or until discharge home or transfer, if earlier; 2) no bLF with daily feeds. The primary outcome will be determined at 36 weeks corrected gestation for the presence of neonatal morbidity and at discharge for survival and treated retinopathy of prematurity. The duration of the trial is expected to be 36 months. DISCUSSION: Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. LIFT_Canada is designed with the hope that the pooled results from Australia, New Zealand, and Canada may help to clarify the situation. TRIAL REGISTRATION: Clinical Trials.Gov, Identifier: NCT03367013, Registered December 8, 2017.


Assuntos
Anti-Infecciosos/administração & dosagem , Doenças do Prematuro/prevenção & controle , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Lactoferrina/administração & dosagem , Sepse/prevenção & controle , Lesões Encefálicas/epidemiologia , Lesões Encefálicas/prevenção & controle , Canadá , Paralisia Cerebral/epidemiologia , Método Duplo-Cego , Nutrição Enteral , Enterocolite Necrosante/prevenção & controle , Feminino , Mortalidade Hospitalar , Humanos , Fórmulas Infantis , Recém-Nascido , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/mortalidade , Análise de Intenção de Tratamento , Masculino , Leite Humano
16.
Int J Mol Sci ; 21(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936277

RESUMO

Burn wounds are highly debilitating injuries, with significant morbidity and mortality rates worldwide. In association with the damage of the skin integrity, the risk of infection is increased, posing an obstacle to healing and potentially leading to sepsis. Another limitation against healing is associated with antibiotic resistance mainly due to the use of systemic antibiotics for the treatment of localized infections. Nanotechnology has been successful in finding strategies to incorporate antibiotics in nanoparticles for the treatment of local wounds, thereby avoiding the systemic exposure to the drug. This review focuses on the most recent advances on the use of nanoparticles in wound dressing formulations and in tissue engineering for the treatment of burn wound infections.


Assuntos
Queimaduras/tratamento farmacológico , Nanopartículas/uso terapêutico , Cicatrização , Infecção dos Ferimentos/tratamento farmacológico , Antibacterianos/uso terapêutico , Bandagens , Queimaduras/microbiologia , Queimaduras/patologia , Humanos , Nanopartículas/química , Sepse/microbiologia , Sepse/prevenção & controle , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Engenharia Tecidual/métodos , Infecção dos Ferimentos/patologia
17.
BJOG ; 127(6): 680-691, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31913562

RESUMO

BACKGROUND: Early-onset group B streptococcal (EOGBS) disease (including sepsis, meningitis, and pneumonia) causes significant morbidity and mortality in newborn infants worldwide. Antibiotic prophylaxis can prevent vertical streptococcal transmission, yet no uniform criteria exist to identify eligible women for prophylaxis. Some guidelines recommend universal GBS screening to pregnant women in their third trimester (screening-based protocol), whereas others employ risk-based protocols. OBJECTIVES: To compare the effectiveness of screening-based versus risk-based protocols in preventing EOGBS disease. SEARCH STRATEGY: Key words for the database searches included GBS, Streptococcus agalactiae, pregnancy, screening, culture-based, risk-based. SELECTION CRITERIA: Studies were included if they investigated EOGBS disease incidence in newborn infants and compared screening or risk-based protocols with each other or with controls. DATA COLLECTION AND ANALYSIS: Risk ratios (RR) and 95% confidence intervals (CI) were determined using Mantel-Haenszel analyses with random effects. MAIN RESULTS: Seventeen eligible studies were included. In this meta-analysis, screening was associated with a reduced risk for EOGBS disease compared either with risk-based protocols (ten studies, RR 0.43, 95% CI 0.32-0.56) or with no policy (four studies, RR 0.31, 95% CI 0.11-0.84). Meta-analysis could not demonstrate a significant effect of risk-based protocols versus no policy (seven studies, RR 0.86, 95% CI 0.61-1.20). In studies reporting on the use of antibiotics, screening was not associated with higher antibiotic administration rates (31 versus 29%). CONCLUSIONS: Screening-based protocols were associated with lower incidences of EOGBS disease compared with risk-based protocols, while not clearly overexposing women to antibiotics. This information is of relevance for future policymaking. TWEETABLE ABSTRACT: Meta-analysis: general screening is associated with lower rates of early-onset group B strep. neonatal sepsis compared with risk-based protocols.


Assuntos
Antibioticoprofilaxia , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/diagnóstico , Sepse/prevenção & controle , Infecções Estreptocócicas/prevenção & controle , Streptococcus agalactiae/isolamento & purificação , Feminino , Humanos , Recém-Nascido , Unidade Hospitalar de Ginecologia e Obstetrícia , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/microbiologia , Medição de Risco , Fatores de Risco , Sepse/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico
18.
J Immunol ; 204(5): 1255-1262, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31941655

RESUMO

Gut bacteria-associated sepsis is a serious concern in patients with gastrointestinal acute radiation syndrome (GIARS). In our previous studies, gut bacteria-associated sepsis caused high mortality rates in mice exposed to 6-9 Gy of γ-rays. IL-12+CD38+ iNOS+ Mϕ (M1Mϕ) located in the bacterial translocation site (mesenteric lymph nodes [MLNs]) of unirradiated mice were characterized as host defense antibacterial effector cells. However, cells isolated from the MLNs of GIARS mice were mostly CCL1+IL-10+LIGHT+miR-27a+ Mϕ (M2bMϕ, inhibitor cells for the M1Mϕ polarization). Reduced long noncoding RNA Gas5 and increased miR-222 expression in MLN-Mϕ influenced by the irradiation were shown to be associated with M2bMϕ polarization. In this study, the mortality of mice exposed to 7 Gy of γ-rays (7 Gy GIARS mice) was completely controlled after the administration of glycyrrhizin (GL), a major active ingredient in licorice root (Glycyrrhiza glabra). Bacterial translocation and subsequent sepsis were minimal in 7 Gy GIARS mice treated with GL. Increased Gas5 RNA level and decreased miR-222 expression were shown in MLN-Mϕ isolated from 7 Gy GIARS mice treated with GL, and these macrophages did not display any properties of M2bMϕ. These results indicate that gut bacteria-associated sepsis in 7 Gy GIARS mice was controlled by the GL through the inhibition of M2bMϕ polarization at the bacteria translocation site. Expression of Ccl1, a gene required for M2bMϕ survival, is silenced in the MLNs of 7 Gy GIARS mice because of Gas5 RNA, which is increased in these cells after the suppression of miR-222 (a Gas5 RNA expression inhibitor) by the GL.


Assuntos
Bactérias/imunologia , Infecções Bacterianas , Fenômenos Fisiológicos Bacterianos , Translocação Bacteriana , Raios gama/efeitos adversos , Ácido Glicirrízico/farmacologia , Intestinos , Macrófagos , MicroRNAs/imunologia , RNA Longo não Codificante/imunologia , Lesões Experimentais por Radiação , Animais , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Infecções Bacterianas/prevenção & controle , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Fenômenos Fisiológicos Bacterianos/imunologia , Fenômenos Fisiológicos Bacterianos/efeitos da radiação , Translocação Bacteriana/efeitos dos fármacos , Translocação Bacteriana/imunologia , Translocação Bacteriana/efeitos da radiação , Intestinos/imunologia , Intestinos/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Lesões Experimentais por Radiação/imunologia , Lesões Experimentais por Radiação/microbiologia , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controle , Sepse/imunologia , Sepse/microbiologia , Sepse/patologia , Sepse/prevenção & controle
19.
Life Sci ; 241: 117051, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31733315

RESUMO

AIMS: Sepsis is a severe public health problem affecting millions of individuals, with global mortality rates caused by lower respiratory tract infections are approximately 2.38 million people a year die from respiratory failure caused by infection. Although ACE is known to contribute to damage in septicemia, the pathophysiological mechanisms of sepsis remain unclear. While mortality can be significantly reduced through effective and sensitive antibiotic therapy, antibiotic resistance restricts the use of these drugs, and the investigation of novel agents and targets is therefore essential. Our aim was to determine whether Perindopril (PER) has anti-inflammatory and antioxidant capable of preventing these adverse conditions resulting in injury in previous studies. MAIN METHODS: Sprague Dawley rats were randomly assigned into the control group, received oral saline solution alone for four days. the cecal ligation and puncture (CLP) group, underwent only cecal ligation and puncture induced sepsis, while the CLP + PER (2 mg/kg) underwent cecal ligation and puncture-induced sepsis together with oral administration of 2 mg/kg PER for four days before induction of sepsis. KEY FINDINGS: Malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), Caspase-3 and nuclear factor kappa B (NF-kß/p65) levels increased in the CLP group. On the other hand, PER (2 mg/kg) oral administration to septic rats decreased MDA, TNF-α and increase glutathione (GSH) in the lung tissue. In addition, PER administration also decreased the lung tissue NF-κB and Caspase-3 immunopositivity against sepsis. SIGNIFICANCE: PER treatment may represent a promising means of preventing sepsis-induced lung injury via antioxidant and anti-inflammation effects.


Assuntos
Estresse Oxidativo/efeitos dos fármacos , Perindopril/farmacologia , Substâncias Protetoras/farmacologia , Sepse/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ceco/cirurgia , Vesículas Extracelulares/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Inflamação/tratamento farmacológico , Inflamação/etiologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Punções/efeitos adversos , Ratos Sprague-Dawley , Sepse/etiologia , Sepse/mortalidade , Sepse/patologia , Fator de Necrose Tumoral alfa/metabolismo
20.
Acta Obstet Gynecol Scand ; 99(2): 231-239, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31539171

RESUMO

INTRODUCTION: Cesarean sections are the most common major operation worldwide. One in 10 women develops a surgical-site infection after cesarean section. The PREPS pilot trial was developed to assess the feasibility of a randomized controlled trial of vaginal cleansing with chlorhexidine before cesarean section, to reduce infectious morbidity. MATERIAL AND METHODS: A multi-center, open-label, parallel-group pilot randomized controlled trial across 4 UK maternity units. Women aged ≥16 years, undergoing elective or emergency cesarean section, ≥34 weeks of gestation, and able to give informed consent were eligible. Women were randomized 1:1 to chlorhexidine 0.05% or no cleansing and were followed up until 6 weeks after cesarean section. The feasibility of a larger randomized controlled trial was assessed by the pilot trial's recruitment, ability to use verbal consent in an emergency, adherence, follow-up and withdrawal rates. The main clinical outcome collected was Center for Disease Control and Prevention (CDC) classification of endometritis at 30 days. Trial registration number is ISRCTN33435996. RESULTS: A total of 320 women (128% of target) were randomized. Of these, 93% (95% CI 89%-95%) received their allocated intervention. Of the 88 women who had an emergency cesarean section, verbal consent was initially given by 32 (36%) women, with the remainder having sufficient time to give written consent. Endometritis (CDC definition) was collected from medical notes of 96% of women, 68% (95% CI 63%-73%) were followed up at both 14 and 30 days by telephone, and we were able to collect patient-reported outcomes. In the vaginal cleansing arm 2/152 (1.3%) women had endometritis compared with 1/155 (0.7%) in the no cleansing arm (RR 2.08, 95% CI 0.19-22.31). CONCLUSIONS: It is possible to perform a randomized controlled trial in women undergoing an elective or emergency cesarean section, using a verbal-followed-by-written consent process, while maintaining high adherence and retaining women in the trial.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Cesárea , Clorexidina/administração & dosagem , Endometriose/prevenção & controle , Sepse/prevenção & controle , Infecção da Ferida Cirúrgica/prevenção & controle , Administração Intravaginal , Adulto , Feminino , Humanos , Medidas de Resultados Relatados pelo Paciente , Projetos Piloto
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