Circulating Precursor Levels of Endothelin-1 and Adrenomedullin, Two Endothelium-Derived, Counteracting Substances, in Sepsis

Plasma levels of endothelin-1 (ET-1) and adrenomedullin (ADM), two opposingly acting peptides, correlate with mortality in endotoxemia, but their measurement is cumbersome. New sandwich assays have been introduced that measure more stable precursor fragments. The objective of this study was to investigate the counterplay of their precursor peptides in septic patients and to compare them with disease severity and other biomarkers. Blood samples of an observational study in 95 consecutive critically ill patients admitted to the intensive care unit (ICU) were analyzed. CT-proET-1 and MR-proADM concentrations on admission were measured using new sandwich immunoassays. Depending on the clinical severity of the infection, both CT-proET-1 and MR-proADM levels exhibited a gradual increase from Systemic Inflammatory Response Syndrome (SIRS) to sepsis and septic shock (p < .001). Compared to the group of survivors, the group of non-survivors had higher median values of MR-proADM (5.7 nmol/L [range 0.4 to 21.0] versus 1.9 nmol/L [range 0.3 to 17.1], p < .02) and similar CT-proET-1 levels (56.0pmol/L [range 0.5 to 271.0] versus 54.1pmol/L [range 1.0 to 506.0], p = .86). Receiver operating characteristics (ROC) curve analysis showed a higher prognostic accuracy of the calculated ratio of both counteracting substances as compared to CT-proET-1 (p = 0.001) and C-reactive protein (CRP) (p = .001) and in the range of MR-proADM (p = .51), procalcitonin (p = 0.22), and the APACHE II score (p = .61). Endothelin-1 and adrenomedullin precursor peptides gradually increase with increasing severities of infection in critically ill patients. The ratio of the two counteracting peptides correlates with mortality and shows aprognostic accuracy to predict adverse outcome comparable to the APACHE II score

Endothelin Receptor A Antagonism Attenuates Renal Medullary Blood Flow Impairment in Endotoxemic Pigs

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury

Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure

Background: Current paradigms suggest that nitric oxide (NO) produced by endothelial cells (ECs) through endothelial nitric oxide synthase (eNOS) in the vessel wall is the primary regulator of blood flow and blood pressure. However, red blood cells (RBCs) also carry a catalytically active eNOS, but its role is controversial and remains undefined. This study aimed to elucidate the functional significance of RBC eNOS compared with EC eNOS for vascular hemodynamics and nitric oxide metabolism. Methods: We generated tissue-specific loss- and gain-of-function models for eNOS by using cell-specific Cre-induced gene inactivation or reactivation. We created 2 founder lines carrying a floxed eNOS (eNOSflox/flox) for Cre-inducible knockout (KO), and gene construct with an inactivated floxed/inverted exon (eNOSinv/inv) for a Cre-inducible knock-in (KI), which respectively allow targeted deletion or reactivation of eNOS in erythroid cells (RBC eNOS KO or RBC eNOS KI mice) or in ECs (EC eNOS KO or EC eNOS KI mice). Vascular function, hemodynamics, and nitric oxide metabolism were compared ex vivo and in vivo. Results: The EC eNOS KOs exhibited significantly impaired aortic dilatory responses to acetylcholine, loss of flow-mediated dilation, and increased systolic and diastolic blood pressure. RBC eNOS KO mice showed no alterations in acetylcholine-mediated dilation or flow-mediated dilation but were hypertensive. Treatment with the nitric oxide synthase inhibitor Nγ-nitro-l-arginine methyl ester further increased blood pressure in RBC eNOS KOs, demonstrating that eNOS in both ECs and RBCs contributes to blood pressure regulation. Although both EC eNOS KOs and RBC eNOS KOs had lower plasma nitrite and nitrate concentrations, the levels of bound NO in RBCs were lower in RBC eNOS KOs than in EC eNOS KOs. Reactivation of eNOS in ECs or RBCs rescues the hypertensive phenotype of the eNOSinv/invmice, whereas the levels of bound NO were restored only in RBC eNOS KI mice. Conclusions: These data reveal that eNOS in ECs and RBCs contribute independently to blood pressure homeostasis

Affordable Development and Demonstration of a Small NTR engine and Stage: A Preliminary NASA, DOE, and Industry Assessment

In FY'11, Nuclear Thermal Propulsion (NTP) was identified as a key propulsion option under the Advanced In-Space Propulsion (AISP) component of NASA's Exploration Technology Development and Demonstration (ETDD) program A strategy was outlined by GRC and NASA HQ that included 2 key elements -"Foundational Technology Development" followed by specific "Technology Demonstration" projects. The "Technology Demonstration "element proposed ground technology demonstration (GTD) testing in the early 2020's, followed by a flight technology demonstration (FTD) mission by approx. 2025. In order to reduce development costs, the demonstration projects would focus on developing a small, low thrust (approx. 7.5 -16.5 klb(f)) engine that utilizes a "common" fuel element design scalable to the higher thrust (approx. 25 klb(f)) engines used in NASA's Mars DRA 5.0 study(NASA-SP-2009-566). Besides reducing development costs and allowing utilization of existing, flight proven engine hard-ware (e.g., hydrogen pumps and nozzles), small, lower thrust ground and flight demonstration engines can validate the technology and offer improved capability -increased payloads and decreased transit times -valued for robotic science missions identified in NASA's Decadal Study

Affordable Development and Demonstration of a Small NTR Engine and Stage: How Small is Big Enough?

In FY11, NASA formulated a plan for Nuclear Thermal Propulsion (NTP) development that included Foundational Technology Development followed by system-level Technology Demonstrations The ongoing NTP project, funded by NASAs Advanced Exploration Systems (AES) program, is focused on Foundational Technology Development and includes 5 key task activities:(1) Fuel element fabrication and non-nuclear validation testing of heritage fuel options;(2) Engine conceptual design;(3) Mission analysis and engine requirements definition;(4) Identification of affordable options for ground testing; and(5) Formulation of an affordable and sustainable NTP development program Performance parameters for Point of Departure designs for a small criticality-limited and full size 25 klbf-class engine were developed during FYs 13-14 using heritage fuel element designs for both RoverNERVA Graphite Composite (GC) and Ceramic Metal (Cermet) fuel forms To focus the fuel development effort and maximize use of its resources, the AES program decided, in FY14, that a leader-follower down selection between GC and cermet fuel was required An Independent Review Panel (IRP) was convened by NASA and tasked with reviewing the available fuel data and making a recommendation to NASA. In February 2015, the IRP recommended and the AES program endorsed GC as the leader fuel In FY14, a preliminary development schedule DDTE plan was produced by GRC, DOE industry for the AES program. Assumptions, considerations and key task activities are presented here Two small (7.5 and 16.5 klbf) engine sizes were considered for ground and flight technology demonstration within a 10-year timeframe; their ability to support future human exploration missions was also examined and a recommendation on a preferred size is provided

Gene Expression Analysis in Rats Treated with Experimental Acetyl-Coenzyme A Carboxylase Inhibitors Suggests Interactions with the Peroxisome Proliferator-Activated Receptor ␣ Pathway

ABSTRACT Acetyl CoA carboxylase (ACC) 2, which catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, has been identified as a potential target for type 2 diabetes and obesity. Small-molecule inhibitors of ACC2 would be expected to reduce de novo lipid synthesis and increase lipid oxidation. Treatment of ob/ob mice with compound A-908292 (S) ({(S)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methylprop-2-ynyl}-carbamic acid methyl ester), a small-molecule inhibitor with an IC 50 of 23 nM against ACC2, resulted in a reduction of serum glucose and triglyceride levels. However, compound A-875400 (R) ({(R)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), an inactive enantiomer of A-908292 (S) with approximately 50-fold less activity against ACC2, also caused a similar reduction in glucose and triglycerides, suggesting that the glucose-lowering effects in ob/ob mice may be mediated by other metabolic pathways independent of ACC2 inhibition. To characterize the pharmacological activity of these experimental compounds at a transcriptional level, rats were orally dosed for 3 days with either A-908292 (S) or A-875400 (R), and gene expression analysis was performed. Gene expression analysis of livers showed that treatment with A-908292 (S) or A-875400 (R) resulted in gene expression profiles highly similar to known peroxisome proliferator-activated receptor (PPAR)-␣ activators. The results suggest that, in vivo, both A-908292 (S) and A-875400 (R) stimulated the PPAR-␣-dependent signaling pathway. These results were further supported by both an in vitro genomic evaluation using rat hepatocytes and immunohistochemical evaluation using 70-kDa peroxisomal membrane protein. Overall, the gene expression analysis suggests a plausible mechanism for the similar pharmacological findings with active and inactive enantiomers of an ACC2 inhibitor

Analyses of cerebral microdialysis in patients with traumatic brain injury: relations to intracranial pressure, cerebral perfusion pressure and catheter placement

<p>Abstract</p> <p>Background</p> <p>Cerebral microdialysis (MD) is used to monitor local brain chemistry of patients with traumatic brain injury (TBI). Despite an extensive literature on cerebral MD in the clinical setting, it remains unclear how individual levels of real-time MD data are to be interpreted. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are important continuous brain monitors in neurointensive care. They are used as surrogate monitors of cerebral blood flow and have an established relation to outcome. The purpose of this study was to investigate the relations between MD parameters and ICP and/or CPP in patients with TBI.</p> <p>Methods</p> <p>Cerebral MD, ICP and CPP were monitored in 90 patients with TBI. Data were extensively analyzed, using over 7,350 samples of complete (hourly) MD data sets (glucose, lactate, pyruvate and glycerol) to seek representations of ICP, CPP and MD that were best correlated. MD catheter positions were located on computed tomography scans as pericontusional or nonpericontusional. MD markers were analyzed for correlations to ICP and CPP using time series regression analysis, mixed effects models and nonlinear (artificial neural networks) computer-based pattern recognition methods.</p> <p>Results</p> <p>Despite much data indicating highly perturbed metabolism, MD shows weak correlations to ICP and CPP. In contrast, the autocorrelation of MD is high for all markers, even at up to 30 future hours. Consequently, subject identity alone explains 52% to 75% of MD marker variance. This indicates that the dominant metabolic processes monitored with MD are long-term, spanning days or longer. In comparison, short-term (differenced or Δ) changes of MD vs. CPP are significantly correlated in pericontusional locations, but with less than 1% explained variance. Moreover, CPP and ICP were significantly related to outcome based on Glasgow Outcome Scale scores, while no significant relations were found between outcome and MD.</p> <p>Conclusions</p> <p>The multitude of highly perturbed local chemistry seen with MD in patients with TBI predominately represents long-term metabolic patterns and is weakly correlated to ICP and CPP. This suggests that disturbances other than pressure and/or flow have a dominant influence on MD levels in patients with TBI.</p

Diagnostic tools in Rhinology EAACI position paper

This EAACI Task Force document aims at providing the readers with a comprehensive and complete overview of the currently available tools for diagnosis of nasal and sino-nasal disease. We have tried to logically order the different important issues related to history taking, clinical examination and additional investigative tools for evaluation of the severity of sinonasal disease into a consensus document. A panel of European experts in the field of Rhinology has contributed to this consensus document on Diagnostic Tools in Rhinology