Introduction
The ACCM/PALS guidelines address early correction of paediatric septic shock using conventional measures. In the evolution of these recommendations, indirect measures of the balance ...between systemic oxygen delivery and demands using central venous or superior vena cava oxygen saturation (ScvO
2
≥ 70%) in a goal-directed approach have been added. However, while these additional goal-directed endpoints are based on evidence-based adult studies, the extrapolation to the paediatric patient remains unvalidated.
Objective
The purpose of this study was to compare treatment according to ACCM/PALS guidelines, performed with and without ScvO
2
goal-directed therapy, on the morbidity and mortality rate of children with severe sepsis and septic shock.
Design, participants and interventions
Children and adolescents with severe sepsis or fluid-refractory septic shock were randomly assigned to ACCM/PALS with or without ScvO
2
goal-directed resuscitation.
Measurements
Twenty-eight-day mortality was the primary endpoint.
Results
Of the 102 enrolled patients, 51 received ACCM/PALS with ScvO
2
goal-directed therapy and 51 received ACCM/PALS without ScvO
2
goal-directed therapy. ScvO
2
goal-directed therapy resulted in less mortality (28-day mortality 11.8% vs. 39.2%,
p
= 0.002), and fewer new organ dysfunctions (
p
= 0.03). ScvO
2
goal-directed therapy resulted in more crystalloid (28 (20–40) vs. 5 (0–20) ml/kg,
p
< 0.0001), blood transfusion (45.1% vs. 15.7%,
p
= 0.002) and inotropic (29.4% vs. 7.8%,
p
= 0.01) support in the first 6 h.
Conclusions
This study supports the current ACCM/PALS guidelines. Goal-directed therapy using the endpoint of a ScvO
2
≥ 70% has a significant and additive impact on the outcome of children and adolescents with septic shock.
Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 ...inflammasome activation. The synthesis, activation, and release of IL‐1β are crucial for MSU‐induced inflammation. The current study evaluated the mechanism by which TNF‐α contributed to MSU‐induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF‐α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL‐1β, and decreased hypernociception in mice deficient for TNF‐α or its receptors. Pharmacological blockade of TNF‐α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF‐α blockade resulted in lower amounts of IL‐1β protein and pro‐IL‐1β mRNA transcripts in joints. Gene‐modified mice that express only transmembrane TNF‐α had an inflammatory response similar to that of WT mice and blockade of soluble TNF‐α (XPro™1595) did not decrease MSU‐induced inflammation. In conclusion, TNF‐α drives expression of pro‐IL‐1β mRNA and IL‐1β protein in experimental gout and that its transmembrane form is sufficient to trigger MSU‐induced inflammation in mice.
The presence of bacteria in the midgut of mosquitoes antagonizes infectious agents, such as Dengue and Plasmodium, acting as a negative factor in the vectorial competence of the mosquito. Therefore, ...knowledge of the molecular mechanisms involved in the control of midgut microbiota could help in the development of new tools to reduce transmission. We hypothesized that toxic reactive oxygen species (ROS) generated by epithelial cells control bacterial growth in the midgut of Aedes aegypti, the vector of Yellow fever and Dengue viruses. We show that ROS are continuously present in the midgut of sugar-fed (SF) mosquitoes and a blood-meal immediately decreased ROS through a mechanism involving heme-mediated activation of PKC. This event occurred in parallel with an expansion of gut bacteria. Treatment of sugar-fed mosquitoes with increased concentrations of heme led to a dose dependent decrease in ROS levels and a consequent increase in midgut endogenous bacteria. In addition, gene silencing of dual oxidase (Duox) reduced ROS levels and also increased gut flora. Using a model of bacterial oral infection in the gut, we show that the absence of ROS resulted in decreased mosquito resistance to infection, increased midgut epithelial damage, transcriptional modulation of immune-related genes and mortality. As heme is a pro-oxidant molecule released in large amounts upon hemoglobin degradation, oxidative killing of bacteria in the gut would represent a burden to the insect, thereby creating an extra oxidative challenge to the mosquito. We propose that a controlled decrease in ROS levels in the midgut of Aedes aegypti is an adaptation to compensate for the ingestion of heme.
Alzheimer's disease (AD) is one of the most prevalent types of dementia, affecting millions of older people worldwide. AD is stimulating efforts to develop novel molecules targeting its main features ...associated with a decrease in acetylcholine levels, an increase in oxidative stress and depositions of amyloid-β (Aβ) and tau protein. In this regard, selenium-containing compounds have been demonstrated as potential multi-targeted compounds in the treatment of AD. These compounds are known for their antioxidant and anticholinesterase properties, causing a decrease in Aβ aggregation.
In this review, we approach structure-activity relationships of each compound, associating the decrease of ROS activity, an increase of tau-like activity and inhibition of AChE with a decrease in the self-aggregation of Aβ.
We also verify that the molecular descriptors apol, nHBAcc and MlogP may be related to optimized pharmacokinetic properties for anti-AD drugs.
In our analysis, few selenium-derived compounds presented similar molecular features to FDA-approved drugs.
We suggest that unknown selenium-derived molecules with apol, nHBAcc and MlogP like FDA-approved drugs may be better successes with optimized pharmacokinetic properties in future studies in AD.
Infection, sterile injury, and chronic inflammation trigger the acute phase response in order to re-establish homeostasis. This response includes production of positive acute phase proteins in the ...liver, such as members of the serum amyloid A (SAA) family. In humans the major acute phase SAAs comprise a group of closely related variants of SAA1 and SAA2. SAA1 was proven to be chemotactic for several leukocyte subtypes through activation of the G protein-coupled receptor FPRL1/FPR2. Several other biological activities of SAA1, such as cytokine induction, reported to be mediated via TLRs, have been debated recently. Especially commercial SAA1, recombinantly produced in
, was found to be contaminated with bacterial products confounding biological assays performed with this rSAA1. We purified rSAA1 by RP-HPLC to homogeneity, removing contaminants such as lipopolysaccharides, lipoproteins and formylated peptides, and re-assessed several biological activities attributed to SAA1 (chemotaxis, cytokine induction, MMP-9 release, ROS generation, and macrophage differentiation). The homogeneous rSAA1 (hrSAA1) lacked most cell-activating properties, but its leukocyte-recruiting capacity
and it's
synergy with other leukocyte attractants remained preserved. Furthermore, hrSAA1 maintained the ability to promote monocyte survival. This indicates that pure hrSAA1 retains its potential to activate FPR2, whereas TLR-mediated effects seem to be related to traces of bacterial TLR ligands in the
-produced human rSAA1.
The predilection of Mycobacterium leprae (ML) for Schwann cells (SCs) leads to peripheral neuropathy, a major concern in leprosy. Highly infected SCs in lepromatous leprosy nerves show a foamy, ...lipid-laden appearance; but the origin and nature of these lipids, as well as their role in leprosy, have remained unclear. The data presented show that ML has a pronounced effect on host-cell lipid homeostasis through regulation of lipid droplet (lipid bodies, LD) biogenesis and intracellular distribution. Electron microscopy and immunohistochemical analysis of lepromatous leprosy nerves for adipose differentiation-related protein expression, a classical LD marker, revealed accumulating LDs in close association to ML in infected SCs. The capacity of ML to induce LD formation was confirmed in in vitro studies with human SCs. Moreover, via confocal and live-cell analysis, it was found that LDs are promptly recruited to bacterial phagosomes and that this process depends on cytoskeletal reorganization and PI3K signalling. ML-induced LD biogenesis and recruitment were found to be independent of TLR2 bacterial sensing. Notably, LD recruitment impairment by cytoskeleton drugs decreased intracellular bacterial survival. Altogether, our data revealed SC lipid accumulation in ML-containing phagosomes, which may represent a fundamental aspect of bacterial pathogenesis in the nerve.
The Schistosoma mansoni SmKI-1 protein is composed of two domains: a Kunitz-type serine protease inhibitor motif (KD) and a C-terminus domain with no similarity outside the genera. Our previous work ...has demonstrated that KD plays an essential role in neutrophil elastase (NE) binding blockage, in neutrophil influx and as a potential anti-inflammatory molecule. In order to enhance NE blocking capacity, we analyzed the KD sequence from a structure-function point of view and designed specific point mutations in order to enhance NE affinity. We substituted the P1 site residue at the reactive site for a leucine (termed RL-KD), given its central role for KD's inhibition to NE. We have also substituted a glutamic acid that strongly interacts with the P1 residue for an alanine, to help KD to be buried on NE S1 site (termed EA-KD). KD and the mutant proteins were evaluated in silico by molecular docking to human NE, expressed in Escherichia coli and tested towards its NE inhibitory activity. Both mutated proteins presented enhanced NE inhibitory activity in vitro and RL-KD presented the best performance. We further tested RL-KD in vivo in an experimental model of monosodium urate (MSU)-induced acute arthritis. RL-KD showed reduced numbers of total cells and neutrophils in the mouse knee cavity when compared to KD. Nevertheless, both RL-KD and KD reduced mice hypernociception in a similar fashion. In summary, our results demonstrated that both mutated proteins showed enhanced NE inhibitory activity in vitro. However, RL-KD had a prominent effect in diminishing inflammatory parameters in vivo.
RoundUp
(RUp) is a comercial formulation containing glyphosate (N-(phosphono-methyl) glycine), and is the world's leading wide-spectrum herbicide used in agriculture. Supporters of the broad use of ...glyphosate-based herbicides (GBH) claim they are innocuous to humans, since the active compound acts on the inhibition of enzymes which are absent in human cells. However, the neurotoxic effects of GBH have already been shown in many animal models. Further, these formulations were shown to disrupt the microbiome of different species. Here, we investigated the effects of a lifelong exposure to low doses of the GBH-RUp on the gut environment, including morphological and microbiome changes. We also aimed to determine whether exposure to GBH-RUp could harm the developing brain and lead to behavioral changes in adult mice. To this end, animals were exposed to GBH-RUp in drinking water from pregnancy to adulthood. GBH-RUp-exposed mice had no changes in cognitive function, but developed impaired social behavior and increased repetitive behavior. GBH-Rup-exposed mice also showed an activation of phagocytic cells (Iba-1-positive) in the cortical brain tissue. GBH-RUp exposure caused increased mucus production and the infiltration of plama cells (CD138-positive), with a reduction in phagocytic cells. Long-term exposure to GBH-RUp also induced changes in intestinal integrity, as demonstrated by the altered expression of tight junction effector proteins (
and
) and a change in the distribution of syndecan-1 proteoglycan. The herbicide also led to changes in the gut microbiome composition, which is also crucial for the establishment of the intestinal barrier. Altogether, our findings suggest that long-term GBH-RUp exposure leads to morphological and functional changes in the gut, which correlate with behavioral changes that are similar to those observed in patients with neurodevelopmental disorders.
Using oxygen instead of air in a burning process is at present being widely discussed as an option to reduce CO2 emissions. One of the possibilities is to maintain the combustion reaction at the same ...energy release level as burning with air, which reduces fuel consumption and the emission rates of CO2. A thermal simulation was made for metal reheating furnaces, which operate at a temperature in the range of 1150–1250 °C, using natural gas with a 5% excess of oxygen, maintaining fixed values for pressure and combustion temperature. The theoretical results show that it is possible to reduce the consumption of fuel, and this reduction depends on the amount of heat that can be recovered during the air pre-heating process. The analysis was further conducted by considering the 2012 costs of natural gas and oxygen in Brazil. The use of oxygen showed to be economically viable for large furnaces that operate with conventional heat recovering systems (those that provide pre-heated air at temperatures near 400 °C).
•Simulation was performed for reheating furnaces working in oxy-fuel conditions.•Fuel consumption was compared to conventional combustion with pre-heated air.•Conditions are shown for which the use of oxygen is economically viable.
To analyze mortality rates of children with severe sepsis and septic shock in relation to time-sensitive fluid resuscitation and treatments received and to define barriers to the implementation of ...the American College of Critical Care Medicine/Pediatric Advanced Life Support guidelines in a pediatric intensive care unit in a developing country.
Retrospective chart review and prospective analysis of septic shock treatment in a pediatric intensive care unit of a tertiary care teaching hospital. Ninety patients with severe sepsis or septic shock admitted between July 2002 and June 2003 were included in this study.
Of the 90 patients, 83% had septic shock and 17% had severe sepsis; 80 patients had preexisting severe chronic diseases. Patients with septic shock who received less than a 20-mL/kg dose of resuscitation fluid in the first hour of treatment had a mortality rate of 73%, whereas patients who received more than a 40-mL/kg dose in the first hour of treatment had a mortality rate of 33% (P < 0.05). Patients treated less than 30 minutes after diagnosis of severe sepsis and septic shock had a significantly lower mortality rate (40%) than patients treated more than 60 minutes after diagnosis (P < 0.05). Controlling for the risk of mortality, early fluid resuscitation was associated with a 3-fold reduction in the odds of death (odds ratio, 0.33; 95% confidence interval, 0.13-0.85). The most important barriers to achieve adequate severe sepsis and septic shock treatment were lack of adequate vascular access, lack of recognition of early shock, shortage of health care providers, and nonuse of goals and treatment protocols.
The mortality rate was higher for children older than 2 years, for those who received less than 40 mL/kg in the first hour, and for those whose treatment was not initiated in the first 30 minutes after the diagnosis of septic shock. The acknowledgment of existing barriers to a timely fluid administration and the establishment of objectives to overcome these barriers may lead to a more successful implementation of the American College of Critical Care Medicine guidelines and reduced mortality rates for children with septic shock in the developing world.
PDF
