Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Glucagon effect on rat liver protein synthesis in vivo

The in vivo effect of glucagon administration on hepatic polyribosomal profiles has been studied. Glucagon did not change significantly total, free or bound polyribosomal fractions 30-45 minutes after its administration. The combined administration of glucagon plus antiinsulin serum failed to show any significant effect of glucagon over the antiinsulin serum treated control. Glucagon increased valine production in the perfused isolated liver. These results suggest that the well known amino acid catabolic action of glucagon may be preferentially mediated through an increased proteolysis. Since it is known that glucagon increases considerably in vivo the liver cyclic AMP levels then its lack of effect on polyribosomal profiles might indicate that the postulated role for the cyclic nucleotide on liver protein synthesis must be taken cautiously.This work has been supported by a Grant-in-aid from Lilly Indiana S.A. and a research grant (612/g) from Fondo Nacional para el Desarrollo de la Investigación.Peer reviewe

Cellular metabolite distribution and the control of gluconeogenesis in the perfused isolated rat liver

Glucose production was measured in isolated rat livers perfused with 100 ml of blood-free recirculating medium. The gluconeogenic rate using l-alanine as substrate was only 55% of that obtained with l-lactate. The steady-state concentration of gluconeogenic and tricarboxylic acid cycle intermediates were measured in freeze clamped biopsies. Livers perfused with l-lactate displayed higher concentrations of malate, α-glycerophosphate and β-hydroxybutyrate probably as a result of a higher state of reduction of the nicotinamide system. Hexose-phosphate intermediates were also increased when l-lactate was the substrate. Phosphoenolpyruvate and 3-phosphoglycerate were considerably elevated when l-alanine was the glucose precursor. Livers perfused with l-lactate displayed higher cytosolic concentration of all the tricarboxylic acid cycle intermediates except oxaloacetate while glutamate was slightly and aspartare considerably higher when alanine was the substrate. In the mitochondrial compartment the pattern of distribution tended to be the opposite; that is, livers perfused with l-lactate showed lower concentrations of all the intermediates except α-ketoglutarate. The mitochondrial: cytosolic metabolite gradients of all the intermediates whose distribution was studied were higher in livers perfused with l-alanine. The relevance of these findings to the observed differences in the gluconeogenic fluxes are discussed.This work has been supported in part by a Grant-in-aid from Lilly Indiana and a research grant (612/9) from the Spanish Advisory Commission for the Development of Research.Peer reviewe

Cellular redistribution of metabolites during glucagon and insulin control of gluconeogenesis in the isolated perfused rat liver

Livers isolated from fasted rats were perfused in a blood-free recirculating system using alanine (10 mm) as the carbon source. Glucagon at a concentration of 2.1 × 10−9m enhanced gluconeogenesis, ureogenesis, and ketogenesis. The proportion of alanine utilized to glucose formed remained rather constant in all the situations studied, suggesting that the contribution of glycogen breakdown to the total glucose output was negligible. The glucagon stimulation of gluconeogenesis was accompanied by a decrease in the [ATP]/[ADP]ratio and a rise in the reduction state of the cytosolic and mitochondrial NAD systems. The calculation of the intracellular distribution of metabolites indicates that glucagon increases the intramitochondrial oxaloacetate concentration. This finding seems to support the hypothesis of pyruvate carboxylation, the first nonequilibrium enzymic step in the gluconeogenic sequence, as one of the main sites of glucagon action. The rise in the mitochondrial:cytosolic concentration gradient of malate suggests that glucagon may also act by facilitating the transfer of three-carbon units from the mitochondria to the cytosol. The fact that insulin reversed virtually all the glucagon-induced changes strongly suggests that both hormones act on common steps. It is remarkable that these insulin effects occur at glucagon/insulin ratios similar to those normally found in the portal vein of the intact animal.This work has been supported by grants from Lilly Indiana S.A., Fundación Rodríguez Pascual and Comisión Asesora para el Desarrollo de la InvestigaciónPeer reviewe

Altered Ca2+ homeostasis in lymphoblasts from patients with late-onset Alzheimer disease

The authors report calcium (Ca2+) homeostasis features of transformed lymphocytes from patients with late-onset Alzheimer disease and healthy age-matched controls. Alzheimer lymphoblasts show higher basal cytosolic-free [Ca2+] than controls. The antibodies anti-immunoglobulin M or the beta-amyloid (β-amyloid) peptide fragment 25-35-induced elevation of cytosolic-free [Ca2+] was higher in Alzheimer disease lymphoblasts than in control cells. However, the kinetics of Ca2+ replenishment of Ca2+-depleted cells shows a higher accumulation of cytosolic Ca2+ in Alzheimer disease than in control lymphoblasts, which is better appreciated when the Ca2+ efflux is inhibited. Thus, the authors concluded that Alzheimer disease lymphoblasts have a lower Ca2+ buffering capacity than normal cells, probably because of changes in availability or intrinsic functional properties of the intracellular Ca2+-binding structures. Aging alters the kinetics of the Ca2+ replenishment in lymphoblasts in a manner that resembles Alzheimer disease. However, unlike Alzheimer disease, aging does not change the maximum cytosolic-free [Ca2+], suggesting that the mechanisms underlying the altered Ca2+ homeostasis in aging and late-onset Alzheimer disease are different.Peer reviewe

Glucagon and Insulin Control of Gluconeogenesis in the Perfused Isolated Rat Liver. Effects on Cellular Metabolite Distribution

The metabolic effects of glucagon and glucagon plus insulin on the isolated rat livers perfused with 10 mM sodium L‐lactate as substrate were studied. Glucagon stimulated gluconeogenesis, ketogenesis and ureogenesis at the concentration used of 2.1 nM. The addition of insulin to give a glucagon‐to‐insulin ratio of 0.2 reversed all the glucagon effects. The glucagon enhancement of gluconeogenesis was accompanied by a rise in the cytosolic and mitochondrial state of reduction of the NAD system and a fall in the [ATP]/[ADP] ratio. The analysis of the intermediary metabolite concentrations suggested, as possible sites of glucagon action, the steps between pyruvate and phosphoenolpyruvate as well as the reactions catalyzed by phosphofructokinase and/or fructose bisphosphatase. All the changes in metabolite contents were abolished when insulin was present. Glucagon increased the intramitochondrial concentration of all the metabolites, whose intracellular distribution was calculated. The finding of a significant rise in the calculated intramitochondrial concentration of oxaloacetate points to pyruvate carboxylation as an important site of glucagon interaction with the gluconeogenic pathway. A primary event in the glucagon action redistributing intracellular metabolites seems to be the mitochondrial entry of malate. The possibility is discussed that the changes in metabolite cellular distribution were brought about by the increased cellular state of reduction caused by the hormone.This work has been supported by grants from Lilly Indiana S. A.. Fundación Rodríguez Pascual and Comisión Asesora para el Desarrollo de la Investigación.Peer reviewe

Role of the state of reduction of the NAD system and cAMP on the mechanism of the glucagon induced inhibition of hepatic protein synthesis

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How Robust is Comparative Advantage?

This paper reviews the theoretical development of the concept of comparative advantage, starting with the two-good model of Ricardo and the two-good extension and reinterpretation by Haberler. In both, the presence of comparative advantage provides the scope for countries to gain from trade by specializing, and the pattern of that trade is explained by the pattern of comparative advantage. These strong results of the two-good model can be extended under certain circumstances to multiple goods and countries, but under more general assumptions such strong results no longer are assured. Instead one can derive much weaker results, usually in the form of correlations between comparative advantage and trade, and these weaker results hold in a much wider variety of circumstances. The paper examines those assumptions that permit such generalizations, but then also examines when those assumptions are most likely to fail, and what happens as a result

Control of cell adhesion and migration by Podocalyxin. Implication of Rac1 and Cdc42

23 p.-4 fig.-1 fig.supl.Podocalyxin (PODXL) is a type I membrane sialomucin, originally described in the epithelial cells (podocytes) of kidney glomeruli. PODXL is also found in extra-renal tissues and in certain aggressive tumors, but its precise pathophysiological role is unknown. Expression of PODXL in CHO cells enhances their adhesive, migratory and cell–cell interactive properties in a selectin and integrin-dependent manner. We aimed at defining the PODXL domains responsible for those cell responses. For this purpose we have analyzed the cell adhesion/migration responses to deletion mutants of human PODXL, and the correlation with the activities of Rac1 and Cdc42 GTPases. The results obtained indicate that integrity of the PODXL ectodomain is essential for enhancing cell adhesion but not migration, while the integrity of the cytoplasmic domain is required for both adhesion and migration. Deletion of the carboxy-terminal DTHL domain (PODXL-ΔDTHL) limited only cell adhesion. The activities of Rac1 and Cdc42 GTPases parallel the PODXL-induced variations in cell adhesion and migration. Moreover, silencing the rac1 gene virtually abolished the effect of PODXL in enhancing cell adhesionThe work was funded with Grants from the Spanish Plan of R&D, SAF2007-61701 and BFU2010-15237Peer reviewe

Control of hepatic gluconeogenesis: Role of fatty acid oxidation

Octanoate has been found to activate the gluconeogenic pathway in perfused isolated rat liver. Whether a net increase in the production of glucose is observed is a function of the relative concentrations of the glucose precursor and the fatty acid. The kinetics of octanoate interaction with the gluconeogenic pathway are influenced by the rate changes induced by decreases in pyruvate concentration as a result of the increased NAD redox potential produced by the oxidation of fatty acid. Taking this into account, two distinct effects of octanoate were identified. The first is an increase in the Vmax even at the lowest (25 μm) concentration of the fatty acid tested. The second is a progressive decrease in [pyruvate]0.5 as a function of octanoate concentration. The latter occurs at low (0.5 mm), supraphysiological, concentrations of pyruvate, when its mitochondrial transport is not limiting, indicating that a distal step, presumably pyruvate carboxylation, is activated. The action of octanoate in increasing gluconeogenesis has been found not to be related to a decreased flux through pyruvate dehydrogenase, neither to changes in the NAD redox potential nor to its ability to increase energy production. Actually, the oxygen uptake induced by octanoate was largely accounted for by the production of ketone body and the latter process was found to be independent of variations in energy demand.This work has been supported in part by grants (174 and 431) from Comisión Asesora de Investigación Científica y Técnica and Fondo de Investigaciones Sanitarias (87/1688 and 8’70689). C. González-Manchón is a recipient of a fellowship from the Ministerio de Educación y Ciencia.Peer reviewe