Anthropomorphic Tendon-Based Hands Controlled by Agonist-Antagonist Corticospinal Neural Network.

This article presents a study on the neurobiological control of voluntary movements for anthropomorphic robotic systems. A corticospinal neural network model has been developed to control joint trajectories in multi-fingered robotic hands. The proposed neural network simulates cortical and spinal areas, as well as the connectivity between them, during the execution of voluntary movements similar to those performed by humans or monkeys. Furthermore, this neural connection allows for the interpretation of functional roles in the motor areas of the brain. The proposed neural control system is tested on the fingers of a robotic hand, which is driven by agonist-antagonist tendons and actuators designed to accurately emulate complex muscular functionality. The experimental results show that the corticospinal controller produces key properties of biological movement control, such as bell-shaped asymmetric velocity profiles and the ability to compensate for disturbances. Movements are dynamically compensated for through sensory feedback. Based on the experimental results, it is concluded that the proposed biologically inspired adaptive neural control system is robust, reliable, and adaptable to robotic platforms with diverse biomechanics and degrees of freedom. The corticospinal network successfully integrates biological concepts with engineering control theory for the generation of functional movement. This research significantly contributes to improving our understanding of neuromotor control in both animals and humans, thus paving the way towards a new frontier in the field of neurobiological control of anthropomorphic robotic systems.

Electrophilic Hydrosilylation of Electron-Rich Alkenes Derived from Enamines.

The low-electron count, air-stable, platinum complexes [Pt(ItBu')(ItBu)][BArF] (C1) (ItBu=1,3-di-tert-butylimidazol-2-ylidene), [Pt(SiPh)3(ItBuiPr)2][BArF] (C2) (ItBuiPr=1-tert-butyl-3-iso-propylimidazol-2-ylidene), [Pt(SiPh)3(ItBuMe)2][BArF] (C3), [Pt(GePh3)(ItBuiPr)2][BArF] (C4), [Pt(GePh)3(ItBuMe)2][BArF] (C5) and [Pt(GeEt)3(ItBuMe)2][BArF] (C6) (ItBuMe=1-tert-butyl-3-methylimidazol-2-ylidene) are efficient catalysts (particularly the germyl derivatives) in both the silylative dehydrocoupling and hydrosilylation of electron rich alkenes derived from enamines. The steric hindrance exerted by the NHC ligand plays an important role in the selectivity of the reaction. Thus, bulky ligands are selective towards the silylative dehydrocoupling process whereas less sterically hindered promote the selective hydrosilylation reaction. The latter is, in addition, regioselective towards the ß-carbon atom of both internal and terminal enamines, leading to ß-aminosilanes. Moreover, the syn stereochemistry of the amino and silyl groups implies an anti Si-H bond addition across the double bond. All these facts point to a mechanistic picture that, according to experimental and computational studies, involves a non-classical hydrosilylation process through an outer-sphere mechanism in which a formal nucleophilic addition of the enamine to the silicon atom of a platinum σ-SiH complex is the key step. This is in sharp contrast with the classical Chalk-Harrod mechanism prevalent in platinum chemistry.

Ethylene Dimerization and Oligomerization Using Bis(phosphino)boryl Supported Ni Complexes.

We report the dimerization and oligomerization of ethylene using bis(phosphino)boryl supported Ni(II) complexes as catalyst precursors. By using alkylaluminum(III) compounds or other Lewis acid additives, Ni(II) complexes of the type (RPBP)NiBr (R = tBu or Ph) show activity for the production of butenes and higher olefins. Optimized turnover frequencies of 640 molethylene·molNi-1·s-1 for the formation of butenes with 41(1)% selectivity for 1-butene using (PhPBP)NiBr, and 68 molethylene·molNi-1·s-1 for butenes production with 87.2(3)% selectivity for 1-butene using (tBuPBP)NiBr, have been demonstrated. With methylaluminoxane as a co-catalyst and (tBuPBP)NiBr as the precatalyst, ethylene oligomerization to form C4 through C20 products was achieved, while the use of (PhPBP)NiBr as the pre-catalyst retained selectivity for C4 products. Our studies suggest that the ethylene dimerization is not initiated by Ni hydride or alkyl intermediates. Rather, our studies point to a mechanism that involves a cooperative B/Ni activation of ethylene to form a key 6-membered borametallacycle intermediate. Thus, a cooperative activation of ethylene by the Ni-B unit of the (RPBP)Ni catalysts is proposed as a key element of the Ni catalysis.

Simultaneous Sensing and Actuating Capabilities of a Triple-Layer Biomimetic Muscle for Soft Robotics.

This work presents the fabrication and characterization of a triple-layered biomimetic muscle constituted by polypyrrole (PPy)-dodecylbenzenesulfonate (DBS)/adhesive tape/PPy-DBS demonstrating simultaneous sensing and actuation capabilities. The muscle was controlled by a neurobiologically inspired cortical neural network sending agonist and antagonist signals to the conducting polymeric layers. Experiments consisted of controlled voluntary movements of the free end of the muscle at angles of ±20°, ±30°, and ±40° while monitoring the muscle's potential response. Results show the muscle's potential varies linearly with applied current amplitude during actuation, enabling current sensing. A linear dependence between muscle potential and temperature enabled temperature sensing. Electrolyte concentration changes also induced exponential variations in the muscle's potential, allowing for concentration sensing. Additionally, the influence of the electric current density on the angular velocity, the electric charge density, and the desired angle was studied. Overall, the conducting polymer-based soft biomimetic muscle replicates properties of natural muscles, permitting simultaneous motion control, current, temperature, and concentration sensing. The integrated neural control system exhibits key features of biological motion regulation. This muscle actuator with its integrated sensing and control represents an advance for soft robotics, prosthetics, and biomedical devices requiring biomimetic multifunctionality.

Fruit Juices of Etcho (Pachycereus pecten-aboriginum) and Giant Cardon (Pachycereus pringlei) are Sources of Health-Promoting Ingredients with Potential Anticancer Properties.

Mexico is one of the main diversification centers of cacti in the world, with more than 500 endemic species, most of which remain nutritionally and functionally uncharacterized. The columnar cacti of the genus Pachycereus comprise five underutilized endemic Mexican species, whose nutraceutical properties have only been studied in the P. weberi species. Therefore, this study aimed to evaluate the nutritional quality and bioactive properties of etcho (P. pecten-aboriginum) and giant cardon (P. pringlei) fruit. The physical, chemical, and nutritional composition of etcho and giant cardon fruits were characterized, as well as the profile and content of bioactive compounds, antioxidant activity (ABTS•+ and DPPH•), and antiproliferative capacity in cervical (HeLa) and breast cancer (MDA-MB-231, MCF-7, and T-47D) cell lines. Our results suggest that etcho and giant cardon fruits are rich sources of essential nutrients and bioactive phytochemicals (including K, Mg, P, dietary fiber, polyphenolic compounds, vitamin C, betalains, and myo-inositol) with antioxidant and anticancer potential by inhibiting the proliferation of all evaluated cell lines with IC50 values in the range of 198 to 287 µg of gallic acid equivalents/mL. Therefore, etcho and giant cardon fruits could be used for nutraceutical purposes, and their consumption could promote health benefits.

Cleavage of Carbon Dioxide C=O Bond Promoted by Nickel-Boron Cooperativity in a PBP-Ni Complex.

The synthesis and characterization of (tBu PBP)Ni(OAc) (5) by insertion of carbon dioxide into the Ni-C bond of (tBu PBP)NiMe (1) is presented. An unexpected CO2 cleavage process involving the formation of new B-O and Ni-CO bonds leads to the generation of a butterfly-structured tetra-nickel cluster (tBu PBOP)2 Ni4 (µ-CO)2 (6). Mechanistic investigation of this reaction indicates a reductive scission of CO2 by O-atom transfer to the boron atom via a cooperative nickel-boron mechanism. The CO2 activation reaction produces a three-coordinate (tBu P2 BO)Ni-acyl intermediate (A) that leads to a (tBu P2 BO)-NiI complex (B) via a likely radical pathway. The NiI species is trapped by treatment with the radical trap (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) to give (tBu P2 BO)NiII (η2 -TEMPO) (7). Additionally, 13 C and 1 H NMR spectroscopy analysis using 13 C-enriched CO2 provides information about the species involved in the CO2 activation process.

σ-GeH and Germyl Cationic Pt(II) Complexes.

The low electron count Pt(II) complexes [Pt(NHC')(NHC)][BArF] (where NHC is a N-heterocyclic carbene ligand and NHC' its metalated form) react with tertiary hydrogermanes HGeR3 at room temperature to generate the 14-electron platinum(II) germyl derivatives [Pt(GeR3)(NHC)2][BArF]. Low-temperature NMR studies allowed us to detect and characterize spectroscopically some of the σ-GeH intermediates [Pt(η2-HGeR3)(NHC')(NHC)][BArF] that evolve into the platinum-germyl species. One of these compounds has been characterized by X-ray diffraction studies, and the interaction of the H-Ge bond with the platinum center has been analyzed in detail by computational methods, which suggest that the main contribution is the donation of the H-Ge to a σ*(Pt-C) orbital, but backdonation from the platinum to the σ*(Ge-H) orbital is significant. Primary and secondary hydrogermanes also produce the corresponding platinum-germyl complexes, a result that contrasts with the reactivity observed with primary silanes, in which carbon-silicon bond-forming reactions have been reported. According to density functional theory calculations, the formation of Pt-Ge/C-H bonds is both kinetically and thermodynamically preferred over the competitive reaction pathway leading to Pt-H/C-Ge bonds.

TNF-α-activated eNOS signaling increases leukocyte adhesion through the S-nitrosylation pathway.

Nitric oxide (NO) is a key factor in inflammation. Endothelial nitric oxide synthase (eNOS), whose activity increases after stimulation with proinflammatory cytokines, produces NO in endothelium. NO activates two pathways: 1) soluble guanylate cyclase-protein kinase G and 2) S-nitrosylation (NO-induced modification of free-thiol cysteines in proteins). S-nitrosylation affects phosphorylation, localization, and protein interactions. NO is classically described as a negative regulator of leukocyte adhesion to endothelial cells. However, agonists activating NO production induce a fast leukocyte adhesion, which suggests that NO might positively regulate leukocyte adhesion. We tested the hypothesis that eNOS-induced NO promotes leukocyte adhesion through the S-nitrosylation pathway. We stimulated leukocyte adhesion to endothelium in vitro and in vivo using tumor necrosis factor-α (TNF-α) as proinflammatory agonist. ICAM-1 changes were evaluated by immunofluorescence, subcellular fractionation, immunoprecipitation, and fluorescence recovery after photobleaching (FRAP). Protein kinase Cζ (PKCζ) activity and S-nitrosylation were evaluated by Western blot analysis and biotin switch method, respectively. TNF-α, at short times of stimulation, activated the eNOS S-nitrosylation pathway and caused leukocyte adhesion to endothelial cells in vivo and in vitro. TNF-α-induced NO led to changes in ICAM-1 at the cell surface, which are characteristic of clustering. TNF-α-induced NO also produced S-nitrosylation and phosphorylation of PKCζ, association of PKCζ with ICAM-1, and ICAM-1 phosphorylation. The inhibition of PKCζ blocked leukocyte adhesion induced by TNF-α. Mass spectrometry analysis of purified PKCζ identified cysteine 503 as the only S-nitrosylated residue in the kinase domain of the protein. Our results reveal a new eNOS S-nitrosylation-dependent mechanism that induces leukocyte adhesion and suggests that S-nitrosylation of PKCζ may be an important regulatory step in early leukocyte adhesion in inflammation.NEW & NOTEWORTHY Contrary to the well-established inhibitory role of NO in leukocyte adhesion, we demonstrate a positive role of nitric oxide in this process. We demonstrate that NO induced by eNOS after TNF-α treatment induces early leukocyte adhesion activating the S-nitrosylation pathway. Our data suggest that PKCζ S-nitrosylation may be a key step in this process.

S-nitrosylation and its role in breast cancer angiogenesis and metastasis.

S-nitrosylation, the modification by nitric oxide of free sulfhydryl groups in cysteines, has become an important regulatory mechanism in carcinogenesis and metastasis. S-nitrosylation of targets in tumor cells contributes to metastasis regulating epithelial to mesenchymal transition, migration and invasion. In the tumor environment, the role of S-nitrosylation in endothelium has not been addressed; however, the evidence points out that S-nitrosylation of endothelial proteins may regulate angiogenesis, adhesion of tumor cells to the endothelium, intra and extravasation of tumor cells and contribute to metastasis.

S-nitrosylation of VASP at cysteine 64 mediates the inflammation-stimulated increase in microvascular permeability.

We tested the hypothesis that platelet-activating factor (PAF) induces S-nitrosylation of vasodilator-stimulated phosphoprotein (VASP) as a mechanism to reduce microvascular endothelial barrier integrity and stimulate hyperpermeability. PAF elevated S-nitrosylation of VASP above baseline levels in different endothelial cells and caused hyperpermeability. To ascertain the importance of endothelial nitric oxide synthase (eNOS) subcellular location in this process, we used ECV-304 cells transfected with cytosolic eNOS (GFPeNOSG2A) and plasma membrane eNOS (GFPeNOSCAAX). PAF induced S-nitrosylation of VASP in cells with cytosolic eNOS but not in cells wherein eNOS is anchored to the cell membrane. Reconstitution of VASP knockout myocardial endothelial cells with cysteine mutants of VASP demonstrated that S-nitrosylation of cysteine 64 is associated with PAF-induced hyperpermeability. We propose that regulation of VASP contributes to endothelial cell barrier integrity and to the onset of hyperpermeability. S-nitrosylation of VASP inhibits its function in barrier integrity and leads to endothelial monolayer hyperpermeability in response to PAF, a representative proinflammatory agonist.NEW & NOTEWORTHY Here, we demonstrate that S-nitrosylation of vasodilator-stimulated phosphoprotein (VASP) on C64 is a mechanism for the onset of platelet-activating factor-induced hyperpermeability. Our results reveal a dual role of VASP in endothelial permeability. In addition to its well-documented function in barrier integrity, we show that S-nitrosylation of VASP contributes to the onset of endothelial permeability.

The Urea-to-Creatinine Ratio Is Predictive of Worsening Kidney Function in Ambulatory Heart Failure Patients.

BACKGROUND: Changes in kidney function in heart failure patients convey important prognostic information. We investigated the association of the urea-to-creatinine (BUN/Cr) ratio, the fractional excretion of urea (FeUr), and the fractional excretion of sodium (FeNa) and subsequent declines in kidney function in ambulatory heart failure patients. METHODS AND RESULTS: We prospectively enrolled adult patients with ejection fraction <40% at a multidisciplinary heart failure clinic and measured serial measurements of laboratory values from September 2008 to July 2011. The study outcome was changes in the estimated glomerular filtration rate (eGFR). In 138 patients contributing 10,350 patient-hours of follow-up, we found that participants with a decline of >25% in eGFR had higher mean BUN/Cr ratio (0.110 ± 0.043 vs 0.086 ± 0.026; P = .02) and no difference in the FeNa (1.81 vs 1.43; P = .2) or FeUr (32.3 vs 37.2; P = .9) compared with those with no change. There was an association of BUN/Cr ratio with the rate of change of eGFR (coefficient -25.67, 95% confidence interval [CI] -10.99 to -40.35; P < .0001). The BUN/Cr ratio was an independent predictor of eGFR drop >25% (odds ratio 1.19, 95% CI 1.07-1.32) and improved model discrimination (c-statistic increased from 0.624 to 0.693) and reclassification (net reclassification index 11.38% [P < .0001], integrated discrimination improvement 5.24% [P = .02]). CONCLUSIONS: The BUN/Cr ratio is associated with worsening kidney function and adds incremental risk prediction information relative to traditional predictive measures in outpatients with heart failure at risk for worsening kidney disease.

Bioinspired Control Architecture for Adaptive and Resilient Navigation of Unmanned Underwater Vehicle in Monitoring Missions of Submerged Aquatic Vegetation Meadows.

Submerged aquatic vegetation plays a fundamental role as a habitat for the biodiversity of marine species. To carry out the research and monitoring of submerged aquatic vegetation more efficiently and accurately, it is important to use advanced technologies such as underwater robots. However, when conducting underwater missions to capture photographs and videos near submerged aquatic vegetation meadows, algae can become entangled in the propellers and cause vehicle failure. In this context, a neurobiologically inspired control architecture is proposed for the control of unmanned underwater vehicles with redundant thrusters. The proposed control architecture learns to control the underwater robot in a non-stationary environment and combines the associative learning method and vector associative map learning to generate transformations between the spatial and velocity coordinates in the robot actuator. The experimental results obtained show that the proposed control architecture exhibits notable resilience capabilities while maintaining its operation in the face of thruster failures. In the discussion of the results obtained, the importance of the proposed control architecture is highlighted in the context of the monitoring and conservation of underwater vegetation meadows. Its resilience, robustness, and adaptability capabilities make it an effective tool to face challenges and meet mission objectives in such critical environments.

Dual luminescence and infrared circularly polarized luminescence up to 900 nm with platinum complexes bearing a helical donor-acceptor ligand.

Chiral molecular materials able to emit circularly polarized luminescence (CPL) have attracted considerable interest in the last few decades, due to the potential of CP-light in a wide range of applications. While CP luminescent molecules with blue, green, and yellow emissions are now well-reported, NIR CPL from organic and organometallic compounds lags behind due to the dual challenge of promoting radiative deexcitation of the excited state in this low energy region while assuring a significant magnetic dipole transition moment, a prerequisite for generating CPL. Based on a versatile axially chiral arylisoquinoline ligand, we report the synthesis and chiroptical properties of chiral donor-acceptor platinum(ii) complexes displaying CPL that extends up to almost 900 nm. Interestingly, these emitters show both fluorescence and phosphorescence emissions in solution, with intensities depending on the charge-transfer character of the organic ligand. Experimental and theoretical investigations show that this feature strongly impacts the intersystem crossing event between the singlet and triplet excited states of these complexes and the related phosphorescence lifetime. The effect is less important regarding the CPL, and most complexes show luminescence dissymmetry factors with values up to ca. 2 × 10-3 around 800 nm.

Reduced hospitalizations in severe, refractory congestive heart failure with peritoneal dialysis: a consecutive case series.

BACKGROUND: Peritoneal dialysis (PD) for long-term management of diuretic resistant volume overload in heart failure (HF) may provide potential benefit with few adverse consequences. We examined the impact of PD on clinical status hospitalizations, and complications of therapy in severe end-stage HF. METHODS: A consecutive case series of 10 transplant ineligible patients receiving PD solely for HF volume management between 2007 and 2011 was evaluated with clinical data reviewed pre- and post-PD initiation. RESULTS: The mean ejection fraction (EF) pre-PD was 24.5 ± 6.0% with the majority of patients having NYHA class IIIB symptoms and moderate-severe right ventricular dysfunction. 9/10 patients were Stage 3 chronic kidney disease (CKD) or worse. After PD initiation, average weight loss was almost 7 kg (p = 0.016) with improvement in diuretic response, peripheral edema, and functional class. There was a significant decrease in re-hospitalization from an average of 3.2 ± 2.5 to 0.1 ± 0.3 admissions per patient (p = 0.007) and reduced average length of stay from 37 ± 36.7 to 0.78 ± 2.3 days (p = 0.019). SUMMARY: Objective criteriabased institution of PD for the treatment of diuretic refractory severe-end-stage HF was well tolerated and demonstrated favorable outcomes; these included improved clinical status, reduced hospitalizations and length of stay, with very few and easily treatable PDrelated complications. PD appears to be a viable option in refractory, end-stage congestive heart failure (CHF).

Purification, biochemical characterization, and bioactive properties of a lectin purified from the seeds of white tepary bean (phaseolus acutifolius variety latifolius).

The present work shows the characterization of Phaseolus acutifolius variety latifolius, on which little research has been published, and provides detailed information on the corresponding lectin. This protein was purified from a semi-domesticated line of white tepary beans from Sonora, Mexico, by precipitation of the aqueous extract with ammonium sulfate, followed by affinity chromatography on an immobilized fetuin matrix. MALDI TOF analysis of Phaseolus acutifolius agglutinin (PAA) showed that this lectin is composed of monomers with molecular weights ranging between 28 and 31 kDa. At high salt concentrations, PAA forms a dimer of 63 kDa, but at low salt concentrations, the subunits form a tetramer. Analysis of PAA on 2D-PAGE showed that there are mainly three types of subunits with isoelectric points of 4.2, 4.4, and 4.5. The partial sequence obtained by LC/MS/MS of tryptic fragments from the PAA subunits showed 90-100% identity with subunits from genus Phaseolus lectins in previous reports. The tepary bean lectin showed lower hemagglutination activity than Phaseolus vulgaris hemagglutinin (PHA-E) toward trypsinized human A and O type erythrocytes. The hemagglutination activity was inhibited by N-glycans from glycoproteins. Affinity chromatography with the immobilized PAA showed a high affinity to glycopeptides from thyroglobulin, which also has N-glycans with a high content of N-acetylglucosamine. PAA showed less mitogenic activity toward human lymphocytes than PHA-L and Con A. The cytotoxicity of PAA was determined by employing three clones of the 3T3 cell line, demonstrating variability among the clones as follows: T4 (DI50 51.5 µg/mL); J20 (DI50 275 µg/mL), and N5 (DI50 72.5 µg/mL).

Anomalous right coronary artery origin in a high school athlete.

Coronary anomalies are the cause of 12% of sudden deaths among athletes. Similarly anomalous coronary origin from the opposite sinus is often found at autopsy. The use of echocardiography to screen for these types of defects may provide a potentially life-saving diagnosis. The authors present a case that highlights the utility of echocardiography as part of a comprehensive screening program for athletes.

Ambiphilic boryl groups in a neutral Ni(ii) complex: a new activation mode of H2.

The concept of metal-ligand cooperation opens new avenues for the design of catalytic systems that may offer alternative reactivity patterns to the existing ones. Investigations of this concept with ligands bearing a boron center in their skeleton established mechanistic pathways for the activation of small molecules in which the boron atom usually performs as an electrophile. Here, we show how this electrophilic behavior can be modified by the ligand trans to the boron center, evincing its ambiphilic nature. Treatment of diphosphinoboryl (PBP) nickel-methyl complex 1 with bis(catecholato)diboron (B2Cat2) allows for the synthesis of nickel(ii) bis-boryl complex 3 that promotes the clean and reversible heterolytic cleavage of dihydrogen leading to the formation of dihydroborate nickel complex 4. Density functional theory analysis of this reaction revealed that the heterolytic activation of H2 is facilitated by the cooperation of both boryl moieties and the metal atom in a concerted mechanism that involves a Ni(ii)/Ni(0)/Ni(ii) process. Contrary to 1, the boron atom from the PBP ligand in 3 behaves as a nucleophile, accepting a formally protic hydrogen, whereas the catecholboryl moiety acts as an electrophile, receiving the attack from the hydride-like fragment. This manifests the dramatic change in the electronic properties of a ligand by tuning the substituent trans to it and constitutes an unprecedented cooperative mechanism that involves two boryl ligands in the same molecule operating differently, one as a Lewis acid and the other one as a Lewis base, in cooperation with the metal. In addition, reactivity towards different nucleophiles such as amines or ammonia confirmed the electrophilic nature of the Bcat moiety, allowing the formation of aminoboranes.

Reversible carbon-boron bond formation at platinum centers through σ-BH complexes.

A reversible carbon-boron bond formation has been observed in the reaction of the coordinatively unsaturated, cyclometalated, Pt(ii) complex [Pt(I t BuiPr')(I t BuiPr)][BArF], 1, with tricoordinated boranes HBR2. X-ray diffraction studies provided structural snapshots of the sequence of reactions involved in the process. At low temperature, we observed the initial formation of the unprecedented σ-BH complexes [Pt(HBR2)(I t BuiPr')(I t BuiPr)][BArF], one of which has been isolated. From -15 to +10 °C, the σ-BH species undergo a carbon-boron coupling process leading to the platinum hydride derivative [Pt(H)(I t BuiPr-BR2)(I t BuiPr)][BArF], 4. Surprisingly, these compounds are thermally unstable undergoing carbon-boron bond cleavage at room temperature that results in the 14-electron Pt(ii) boryl species [Pt(BR2)(I t BuiPr)2][BArF], 2. This unusual reaction process has been corroborated by computational methods, which indicate that the carbon-boron coupling products 4 are formed under kinetic control whereas the platinum boryl species 2, arising from competitive C-H bond coupling, are thermodynamically more stable. These findings provide valuable information about the factors governing productive carbon-boron coupling reactions at transition metal centers.

Hospital Mortality and Effect of Adjusting PaO2/FiO2 According to Altitude Above the Sea Level in Acclimatized Patients Undergoing Invasive Mechanical Ventilation. A Multicenter Study.

OBJECTIVE: (i) Analyze the effect of altitude above the sea level on the mortality rate in patients undergoing invasive mechanical ventilation. (ii) Validate the traditional equation for adjusting PaO2/FiO2 according to the altitude. DESIGN: A prospective, observational, multicenter and international study conducted during August 2016. PATIENTS: Inclusion criteria: (i) age between 18 and 90 years old, (ii) admitted to intensive care unit (ICU) situated at the same altitude above the sea level (AASL) in which the patients has stayed, at least, during the previous 40 days and (iii) received invasive MV for at least 12h. MATERIAL AND METHODS: All variables were registered the day of intubation (day 0). Patients were followed until death, ICU discharge or day 28. PaO2/FiO2 ratio was adjusted by the AASL according to: PaO2/FiO2*(barometric pressure/760). Categorical variables were compared with χ2 and Cochran-Mantel-Haenszel test. Continuous variables with Mann-Whitney. Correlation between continuous variables was analyzed graphically and analytically. Logistic regression model was constructed to identify factors associated to mortality. Kapplan-Meier method was used to estimate the probability of survival according to the altitude. A 2-side p value <0.05 was consider significant. RESULTS: 249 patients (<1500m n=55; 1500 to <2500m n=20; 2500 to <3500m n=155 and ≥3500m n=19) were included. Adjusted and non-adjusted PaO2/FiO2 were correlated with several respiratory and non respiratory variables. None discordances between non adjusted and adjusted PaO2/FiO2 were identified. However, several correlations were appreciated only in patients situated <1500m or in >1500m. Seventy-nine patients died during the ICU stayed (32%). The mortality curve was not affected by the altitude above the sea level. Variables independently associated to mortality are: PEEP, age, systolic arterial blood pressure, and platelet count. AUROC: 0.72. CONCLUSION: In acclimatized patients undergoing invasive mechanical ventilation, the traditional equation for adjusting PaO2/FiO2 according the elevation above the sea level seems to be inaccurate and the altitude above the sea level does not affect the mortality risk.

Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells.

Glioblastoma is a highly aggressive brain tumor, characterized by the formation of dysfunctional blood vessels and a permeable endothelial barrier. S-nitrosylation, a post-translational modification, has been identified as a regulator of endothelial function. In this work we explored whether S-nitrosylation induced by glioblastoma tumors regulates the endothelial function. As proof of concept, we observed that S-nitrosylation is present in the tumoral microenvironment of glioblastoma in two different animal models. Subsequently, we measured S nitrosylation and microvascular permeability in EAhy296 endothelial cells and in cremaster muscle. In vitro, conditioned medium from the human glioblastoma cell line U87 activates endothelial nitric oxide synthase, causes VE-cadherin- S-nitrosylation and induces hyperpermeability. Blocking Interleukin-8 (IL-8) in the conditioned medium inhibited S-nitrosylation of VE-cadherin and hyperpermeability. Recombinant IL-8 increased endothelial permeability by activating eNOS, S-nitrosylation of VE-cadherin and p120, internalization of VE-cadherin and disassembly of adherens junctions. In vivo, IL-8 induced S-nitrosylation of VE-cadherin and p120 and conditioned medium from U87 cells caused hyperpermeability in the mouse cremaster muscle. We conclude that eNOS signaling induced by glioma cells-secreted IL-8 regulates endothelial barrier function in the context of glioblastoma involving S-nitrosylation of VE-cadherin and p120. Our results suggest that inhibiting S-nitrosylation may be an effective way to control and/or block damage to the endothelial barrier and prevent cancer progression.