Transcriptomic clustering of critically ill COVID-19 patients.

BACKGROUND: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit. METHODS: In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings. RESULTS: We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results. CONCLUSIONS: These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies.

Electrocatalytic Reduction of CO2 in Water by a Palladium-Containing Metallopolymer.

The palladium-salen complex was immobilized by electropolymerization onto a Pt disc electrode and applied as an electrocatalyst for the reduction of CO2 in an aqueous solution. Linear sweep voltammetry measurements and rotating disk experiments were carried out to study the electrochemical reduction of carbon dioxide. The onset overpotential for carbon dioxide reduction was approximately -0.22 V vs. NHE on the poly-Pd(salen) modified electrode. In addition, by combining the electrochemical study with a kinetic study, the rate-determining step of the electrochemical CO2 reduction reaction (CO2RR) was found to be the radial reduction of carbon dioxide to the CO adsorbed on the metal.

Biotrauma during ultra-low tidal volume ventilation and venoarterial extracorporeal membrane oxygenation in cardiogenic shock: a randomized crossover clinical trial.

BACKGROUND: Cardiogenic pulmonary oedema (CPE) may contribute to ventilator-associated lung injury (VALI) in patients with cardiogenic shock. The appropriate ventilatory strategy remains unclear. We aimed to evaluate the impact of ultra-low tidal volume ventilation with tidal volume of 3 ml/kg predicted body weight (PBW) in patients with CPE and veno-arterial extracorporeal membrane oxygenation (V-A ECMO) on lung inflammation compared to conventional ventilation. METHODS: A single-centre randomized crossover trial was performed in the Cardiac Intensive Care Unit (ICU) at a tertiary university hospital. Seventeen adults requiring V-A ECMO and mechanical ventilation due to cardiogenic shock were included from February 2017 to December 2018. Patients were ventilated for two consecutive periods of 24 h with tidal volumes of 6 and 3 ml/kg of PBW, respectively, applied in random order. Primary outcome was the change in proinflammatory mediators in bronchoalveolar lavage fluid (BALF) between both ventilatory strategies. RESULTS: Ventilation with 3 ml/kg PBW yielded lower driving pressures and end-expiratory lung volumes. Overall, there were no differences in BALF cytokines. Post hoc analyses revealed that patients with high baseline levels of IL-6 showed statistically significant lower levels of IL-6 and IL-8 during ultra-low tidal volume ventilation. This reduction was significantly proportional to the decrease in driving pressure. In contrast, those with lower IL-6 baseline levels showed a significant increase in these biomarkers. CONCLUSIONS: Ultra-low tidal volume ventilation in patients with CPE and V-A ECMO may attenuate inflammation in selected cases. VALI may be driven by an interaction between the individual proinflammatory profile and the mechanical load overimposed by the ventilator. Trial registration The trial was registered in ClinicalTrials.gov (identifier NCT03041428, Registration date: 2nd February 2017).

Clinical efficacy of fosfomycin combinations against a variety of gram-positive cocci / Eficacia clínica de las combinaciones de fosfomicina contra una variedad de cocos grampositivos

Introduction: Over recent years we have witnessed an increase in the resistance of microorganisms to the available antimicrobials and a decrease in the number of new antimicrobials. Fosfomycin is a safe and cheap broad-spectrum antibiotic which has shown very promising results in combination therapy, mainly against gram-negative microorganisms. Little is known, however, about its clinical efficacy against gram-positive microorganisms. Methods: We performed a retrospective review of all patients with severe gram-positive infections who received fosfomycin as part of their treatment from 2011 to 2017. We also performed in vitro time-kill assays to study the behaviour of fosfomycin with different antimicrobials against two strains of methicillin-resistant Staphylococcus aureus (MRSA) and two strains of methicillin-susceptible S. aureus (MSSA). Results: Seventy-five patients were treated with different fosfomycin combinations. Among them, 61 (81%) were successfully treated. Daptomycin plus fosfomycin was the most effective combination. Overall, the treatment with fosfomycin was safe, and side effects were minor. There was only one major side effect that resolved after discontinuation of therapy. Time-kill studies demonstrated increased activity of fosfomycin combinations, with daptomycin-fosfomycin being the most active combination against both MRSA and MSSA strains. Conclusions: Our results suggest that antimicrobial combinations including fosfomycin are an alternative and effective approach for gram-positive infections

Introducción: En los últimos años se ha ido produciendo un aumento de la resistencia de los microorganismos a los antimicrobianos disponibles, y una disminución en el número de nuevos antimicrobianos. La fosfomicina es un antibiótico seguro y barato con un amplio espectro de actividad, que ha mostrado resultados muy prometedores en terapia de combinación, principalmente contra microorganismos gramnegativos. Sin embargo, poco se conoce sobre su eficacia clínica frente a microorganismos grampositivos. Métodos: Revisión retrospectiva de todos los pacientes con infecciones graves por microorganismos grampositivos que recibieron fosfomicina como parte de su tratamiento, entre los años 2011 y 2017. También se realizaron curvas de letalidad in vitro para estudiar el comportamiento de la fosfomicina con diferentes antimicrobianos, frente a 2 cepas de Staphylococcus aureus resistentes a meticilina (SARM) y 2 cepas de S. aureus sensible a la meticilina (SASM). Resultados: Setenta y cinco pacientes recibieron tratamiento con diferentes combinaciones de fosfomicina. De ellos, 61 (81%) fueron tratados con éxito. Daptomicina más fosfomicina fue la combinación más efectiva. En general, el tratamiento con fosfomicina fue seguro, con efectos secundarios menores. Hubo solo un efecto secundario importante que se resolvió tras la suspensión del tratamiento. Las curvas de letalidad demostraron buena actividad de las combinaciones de fosfomicina, siendo la combinación daptomicina-fosfomicina la más activa, tanto frente a las cepas de SARM como de SASM. Conclusiones: Nuestros resultados sugieren que combinaciones con fosfomicina, pueden ser un tratamiento alternativo y efectivo en infecciones por grampositivos

Clinical efficacy of fosfomycin combinations against a variety of gram-positive cocci.

INTRODUCTION: Over recent years we have witnessed an increase in the resistance of microorganisms to the available antimicrobials and a decrease in the number of new antimicrobials. Fosfomycin is a safe and cheap broad-spectrum antibiotic which has shown very promising results in combination therapy, mainly against gram-negative microorganisms. Little is known, however, about its clinical efficacy against gram-positive microorganisms. METHODS: We performed a retrospective review of all patients with severe gram-positive infections who received fosfomycin as part of their treatment from 2011 to 2017. We also performed in vitro time-kill assays to study the behaviour of fosfomycin with different antimicrobials against two strains of methicillin-resistant Staphylococcus aureus (MRSA) and two strains of methicillin-susceptible S. aureus (MSSA). RESULTS: Seventy-five patients were treated with different fosfomycin combinations. Among them, 61 (81%) were successfully treated. Daptomycin plus fosfomycin was the most effective combination. Overall, the treatment with fosfomycin was safe, and side effects were minor. There was only one major side effect that resolved after discontinuation of therapy. Time-kill studies demonstrated increased activity of fosfomycin combinations, with daptomycin-fosfomycin being the most active combination against both MRSA and MSSA strains. CONCLUSIONS: Our results suggest that antimicrobial combinations including fosfomycin are an alternative and effective approach for gram-positive infections.

Docencia universitaria y estudiantes con discapacidad: cuestiones sobre accesibilidad y adaptación en el estudio / University teaching and students with disabilities: questions about accessibility and adaptation in the study

Este trabajo aborda la discapacidad en el contexto universitario, desde la adecuación a las necesidades y características de la persona. Esta mirada busca que quienes presenten necesidades especiales asociadas a la discapacidad, dispongan de los medios, apoyos y recursos suficientes para asegurar la igualdad real y efectiva de oportunidades dentro de la comunidad universitaria. De acuerdo con ese objetivo, con este artículo se pretende generar una reflexión en el docente universitario, sobre las cuestiones de accesibilidad y adaptación -como aspectos básicos- en la atención a su alumnado con discapacidad. Estos aspectos se relacionan con la búsqueda de desarrollo tecnológico, formativo y personal-social, propio de una Universidad abierta a la sociedad, apuntando hacia valores de normalización, integración e inclusión. En una primera parte, se tratan generalidades sobre el desarrollo tecnológico y usuarios con discapacidad, para pasar a una segunda en la que se abordan cuestiones de la accesibilidad y la discapacidad, continuando con su concreción en el currículum universitario del alumnado con discapacidad.

This work addresses disability in the higher education context, in terms of reasonable and achievable adjustments related to the individual's needs and features. This approach aims to ensure assistive technology, support, and resources as means to guarantee real and effective access to equal opportunities for those members that may present special needs, due to their disability situation, within the university community. Therefore, this paper attempts to generate a reflection for university lecturers about accessibility and adaptation, as basic aspects in their duty of supporting disabled students. These aspects are directly related to technological, educational and socio-personal development, present in those higher education institutions open to society and oriented to values such as integration and inclusion. In the first place, some general information is provided about technological development and users with disabilities. In the second place, certain aspects related to accessibility and disability are addressed, and their materialization in the university curriculum of disabled students.

A chemiresistor sensor based on a cobalt(salen) metallopolymer for dissolved molecular oxygen.

A resistance detection device for dissolved molecular oxygen in aqueous solutions is prepared using a chemiresistor material as sensor platform. The chemiresistive circuit element is fashioned from a thin film of a cobalt-salen metallopolymer electrodeposited on a platinum electrode. Electrochemical impedance spectroscopy shows that the resistive and capacitive properties of the sensor platform depend on the presence of dissolved oxygen. The electrical circuit models are R(Q/R)(Q/R) and R(Q/R)(Q/RW) in the absence and presence of oxygen, respectively. The chemiresistor sensor exhibits good sensitivity (0.483 kΩ L mg-1), excellent reversibility and excellent linearity over a range of dissolved oxygen concentrations typically found under environmental conditions (2.72-40.9 mg L-1). The sensor fabricated in this work can potentially serve as an alternative sensor for the detection of dissolved oxygen in environmental samples.

Chemical Characterization of an Encapsulated Red Wine Powder and Its Effects on Neuronal Cells.

Red wine polyphenols are known for their implications for human health protection, although they suffer from high instability. For this reason, a red wine powder was prepared by freeze-drying encapsulation in maltodextrin/arabic gum matrix, and its composition was determined by means of high-performance liquid chromatography coupled quadrupole time-of-flight mass spectrometry (HPLC-MS-QTOF). More than thirty polyphenols, including anthocyanins, flavanols, flavonols, phenolic acids and stilbenoids, were identified. Some of the main quantified polyphenols were: malvidin-3-O-glucoside, malvidin 3-O-(6″-acetyl-glucose), petunidin-3-O-glucoside, quercetin-3-O-glucuronide, syringenin-3-O-glucoside, epicatechin, gallic acid and syringic acid. The biological activity of this de-alcoholized and encapsulated red wine on human neuroblastoma SH-SY5Y cells was studied. The results showed that the encapsulated red wine powder has active redox properties, as verified by performing reactive oxygen species (ROS) analysis utilizing a neuronal model. This could help explain its action against the neurotoxicity induced by 6-hydroxydopamine (6-OHDA).

The Influence of Different Air-Drying Conditions on Bioactive Compounds and Antioxidant Activity of Berries.

The aim of the present research was to study the effect of convective drying on color, bioactive compounds, and antioxidant activity of berry fruits and to chemically characterize the polyphenolic composition of raspberry, boysenberry, redcurrants, and blackcurrants fruit. Drying berries at 65 °C provoked the best conservations of color, particularly for boysenberry and blackcurrant. Drying at 65 °C was also the condition that showed higher level of polyphenols, while drying at 50 or 130 °C showed above % degradation of them due to the long time or high temperature drying. Radical scavenging activity was the predominant antioxidant mechanism in all samples, with 65 °C dried berries being the most active ones possibly because of polyphenol depolymerization. The anthocyanin profile showed that delphinidin and cyanidin derivatives were the most abundant anthocyanidins with different predominance between berry genera. Degradation of anthocyanins was increased with drying temperature been Cy 3-glucoside and Cy 3-rutinoside the most abundant.

Necesidades específicas de apoyo educativo en el alumnado con capacidad intelectual límite: aspectos para su intervención psicopedagógica / Specific needs in educational support for students with borderline intellectual capacity: factors for psychoeducational intervention

Los niños y niñas con capacidad intelectual límite presentan unas necesidades específicas de apoyo educativo. Estas están centradas en el desarrollo de la memoria de trabajo con sus asociaciones a lo perceptivo-atencional y al lenguaje, así como en la mejora de los aprendizajes lectoescritor y de razonamiento matemático, debiendo ser reforzado su pensamiento estratégico. En este artículo, se hace un primer acercamiento conceptual y definitorio de la capacidad intelectual límite, situándolo en un ámbito psicopedagógico, estableciendo de forma general sus posibles dificultades de aprendizaje. En una segunda parte, se determinan las necesidades específicas que este alumnado plantea, haciéndose algunas consideraciones sobre la evaluación psicopedagógica las cuales se encuentran fundamentadas en el conocimiento del caso (alumno y contextos), mediante una propuesta de adecuación a ese alumno y con objetivos de compensación y favorecimiento del desarrollo de sus capacidades. Por último, de acuerdo al análisis de la revisión teórica, se concluye que la intervención psicopedagógica en el alumnado con capacidad intelectual límite debe realizarse desde un análisis profundo y riguroso de sus características personales y de contexto. De este modo, los resultados de la evaluación psicopedagógica se convierten en necesidades específicas de apoyo educativo. Todo ello en un ámbito de inclusión social y educativa y desde criterios de normalización.

Children with borderline intellectual functioning present specific needs of educational support. These are focused on the development of work memory associated with perception, attention and language, as well as the improvement of reading and writing skills and mathematic reasoning, enhancing strategic thinking. This paper attempts to provide a general conceptual framework about borderline intellectual functioning, from an educational psychology approach, establishing thus possible learning difficulties from a general perspective. Moreover, the specific needs experienced by these students are determined, taking into account some considerations about psychoeducational assessment that are based on case study (student and contexts), through an educational proposal for this student, which includes compensation objectives and strengthening of their capacities. Finally, according to the literature review, it is concluded that psychoeducational intervention on students with borderline intellectual functioning, must be carried out from a thorough analysis of their personal and contextual characteristics. In this way, the results of psychoeducational assessment become specific needs of educational support, in a framework of socio-educational inclusion and standardization criteria.

Aspectos psicoeducativos en la evaluación del alumnado con altas capacidades intelectuales: análisis de un caso / Psychoeducational aspects in the assessment of students with High intellectual abilities: a single-case study

El presente trabajo trata de favorecer la reflexión, desde la psicología educacional, sobre la respuesta a las necesidades específicas de apoyo educativo de los alumnos y alumnas con Altas Capacidades Intelectuales. Tras una breve exposición sobre las características de este tipo de alumnado, se realiza un análisis de caso con el que establecer la relación entre la evaluación psicoeducativa y la intervención psicopedagógica. Desde la labor de los psicólogos de la educación (interviniendo en todos los procesos psicológicos que afectan al aprendizaje o que se derivan de este) y otros colegas que actúan en el ámbito educativo, se buscaría, en última instancia, relacionar los objetivos de cualquier intervención psicoeducativa: la valoración diagnóstica y la planificación de la intervención pedagógica dentro de la atención a la diversidad desarrollada en el sistema educativo español.

The following paper aims to promote an educational psychology-based reflection on the response to those specific educational needs required by students with high intellectual abilities. After a brief discussion on the characterization of this kind of student, a single-case study is developed in order to establish a relationship between psycho-educational assessments and educational psychology interventions. The work of educational psychologists (intervening in all the psychological processes affecting learning or resulted therefrom) and other acting colleagues in the educational field would ultimately seek to relate the objectives of any psychoeducational intervention: diagnostic assessment and educational intervention planning within the diversity emphasis developed on the Spanish educational system.

In vitro efficacy of daptomycin and teicoplanin combined with ethanol, clarithromycin or gentamicin as catheter lock solutions.

BACKGROUND: Despite widespread use, optimum choice of antimicrobial agents, concentrations, combinations and exposure times have not been determined for antibiotic lock technique (ALT). Our objective was to evaluate the efficacy of different antibiotic combinations using an in vitro model of catheter-related infection. Daptomycin (DAP) 5 mg/mL, teicoplanin (TEC) 5 mg/mL, both alone and combined with gentamicin (GM) 2.5 mg/mL, clarythromycin (CLA) 5 mg/mL or ethanol 35 % were evaluated against four clinical strains of methicillin resistant coagulase negative staphylococci. Lock solutions were renewed every 24 h. RESULTS: After 72 h catheters were reincubated with culture media to investigate bacterial regrowth. All antibiotic combinations resulted in significant reductions (p < 0.05) of Log(10) cfu/mL at 72 h for both organisms compared with controls. DAP resulted in significant reductions of Log(10) for all organism versus TEC (p = 0.001). Only DAP reached the limit of detection at 72 h, however did not prevent regrowth after 24 h of ALT removal. DAP + Ethanol and TEC + ethanol eradicated biofilm at 72 h, but only DAP + ethanol (against all strains) and DAP + CLA (against two strains) prevented regrowth at 24 h after ALT removal. CONCLUSIONS: Based on these data, ALT with DAP + ethanol and DAP + CLA should be explored in clinical trials.

Electrochemical investigation of the voltammetric determination of hydrochlorothiazide using a nickel hydroxide modified nickel electrode.

The preparation and electrochemical characterization of a nickel hydroxide modified nickel electrode as well as its behavior as electrocatalyst toward the oxidation of hydrochlorothiazide (HCTZ) were investigated. The electrochemical behavior of the modified electrode and the electrooxidation of HCTZ were explored using cyclic voltammetry. The voltammetric response of the modified electrode in the detection of HCTZ is based on the electrochemical oxidation of the Ni(II)/Ni(III) and a chemical redox process. The analytical parameters for the electrooxidation of HCTZ by the nickel hydroxide modified nickel electrode were obtained in NaOH solution, in which the linear voltammetric response was in the concentration range from 1.39×10(-5) to 1.67×10(-4)mol L(-1) with a limit of detection of 7.92×10(-6)mol L(-1) and a sensitivity of 0.138 µA Lmmol(-1). Tafel analysis was used to elucidate the kinetics and mechanism of HCTZ oxidation by the modified electrode.

Necesidades específicas de apoyo educativo del alumnado con discapacidades sensorial y motora / Specific needs of learning support pupils with sensory and motor disabilities

En el presente trabajo se pretende hacer una aproximación al estudio de las necesidades específicas de apoyo educativo que tienen los niños y niñas con discapacidad. Tras unos aspectos introductorios de tipo conceptual y definitorio, se pasa al análisis de las necesidades que pueden presentar los niños y niñas con discapacidades, sensorial (visual y auditiva) y motora, a las que se sugieren unos elementos generales de respuesta educativa. Finalmente, con una integración de ese análisis, se trataría de llegar a una conclusión y reflexión para la intervención psicopedagógica y la acción tutorial en base a una perspectiva que atienda la diversidad de los niños y niñas con necesidades específicas de apoyo educativo.

This paper aims to make an approach to the study of specific educational needs in children with disabilities. After an introduction to some conceptual and defining aspects, a needs analysis focus on children with sensorial and motor disabilities has taken place. Based on this one, general elements for educational response have been suggested. Finally, a conclusion and reflection that has been provided through the integration of the mentioned analysis, on both psychological intervention and guidance action, based on a perspective that addressed diversity from specific educational support needy children.

Absence or inhibition of matrix metalloproteinase-8 decreases ventilator-induced lung injury.

Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators. To clarify the role of MMP-8 in a model of VILI and their relevance as a therapeutic target, we ventilated wild-type and MMP-8-deficient mice with low or high pressures for 2 hours. There were no significant differences after low-pressure ventilation between wild-type and knockout animals. However, lack of MMP-8 results in better gas exchange, decreased lung edema and permeability, and diminished histological injury after high-pressure ventilation. Mmp8(-/-) mice had a different immune response to injurious ventilation, with decreased neutrophilic infiltration, lower levels of IFN-γ and chemokines (LPS-induced CXC chemokine, macrophage inflammatory protein-2), and significant increases in anti-inflammatory cytokines (IL-4, IL-10) in lung tissue and bronchoalveolar lavage fluid. There were no differences in MMP-2, MMP-9, or tissue inhibitor of metalloproteinase-1 between wild-type and knockout mice. These results were confirmed by showing a similar protective effect in wild-type mice treated with a selective MMP-8 inhibitor. We conclude that MMP-8 promotes acute inflammation after ventilation with high pressures, and its short-term inhibition could be a therapeutic goal to limit VILI.

Diagnosing brain death by CT perfusion and multislice CT angiography.

INTRODUCTION: Although the diagnosis of brain death (BD) is usually based on clinical criteria, in sedated patients, ancillary techniques are needed. This study was designed to assess the accuracy of cerebral multislice computed tomographic angiography (CTA) and CT perfusion (CTP) in diagnosing BD. METHODS: Prospective observational study in 27 BD patients. RESULTS: All patients were diagnosed as BD based on clinical and electroencephalogram findings. After BD diagnosis, CTP was performed followed by 64-detector multislice CTA from the aortic arch to the vertex. Images were reconstructed from 0.5 mm sections. In 24 patients, a lack of cerebral blood flow (CBF) was detected by CTP, and CTA revealed luminal narrowing of the internal carotid artery in the neck and absence of anterior and posterior intracranial circulation (sensitivity 89%). CTA detected CBF exclusively in extracranial portions of the internal carotid and vertebral arteries. Two patients with anoxic brain injury and decompressive craniectomy showed CBF in the CTA such that the CTP results were considered false negatives, given BD had been confirmed by clinical and EEG findings, along with evoked potentials. In one clinically BD patient, in whom an alpha rhythm was detected in the electroencephalogram, CBF was only observed in the intracranial internal carotid with no posterior circulation noted. This patient was therefore considered exclusively brain stem dead. CONCLUSIONS: The radiological protocol used shows a high sensitivity and excellent specificity for detecting the cerebral circulatory arrest that accompanies BD. As a rapid, non-invasive, and widely available technique it is a promising alternative to conventional 4-vessel angiography.

Effects of melatonin in an experimental model of ventilator-induced lung injury.

Melatonin is a free radical scavenger and a broad-spectrum antioxidant and has well-documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Swiss mice (n = 48). Animals were randomized into three experimental groups: control (not ventilated); low-pressure ventilation [peak inspiratory pressure 15 cmH(2)O, positive end-expiratory pressure (PEEP) 2 cmH(2)O], and high-pressure ventilation (peak inspiratory pressure 25 cmH(2)O, PEEP 0 cmH(2)O). Each group was divided into two subgroups: eight animals were treated with melatonin (10 mg/kg ip, 30 min before the onset of ventilation) and the remaining eight with vehicle. After 2 h of ventilation, lung injury was evaluated by gas exchange, wet-to-dry weight ratio, and histological analysis. Levels of malondialdehyde, glutathione peroxidase, interleukins IL-1beta, IL-6, TNF-alpha, and IL-10, and matrix metalloproteinases 2 and 9 in lung tissue were measured as indicators of oxidation status, pro-/anti-inflammatory cytokines, and matrix turnover, respectively. Ventilation with high pressures induced severe lung damage and release of TNF-alpha, IL-6, and matrix metalloproteinase-9. Treatment with melatonin improved oxygenation and decreased histological lung injury but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF-alpha, IL-1beta, IL-6, or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases VILI by increasing the anti-inflammatory response despite an unexpected increase in oxidative stress.

Mechanical ventilation causes monocyte deactivation in intact and endotoxin-treated mice.

BACKGROUND: Monocyte deactivation, defined as the decrease of surface expression of class II molecules of the main histocompatibility complex (MHC) on circulating monocytes, can occur after severe injuries, like trauma, sepsis, or major surgery. We hypothesized that mechanical ventilation could also be a cause. METHODS: Prospective experimental study. Intact and endotoxin-treated (20 mg/kg of intraperitoneal lipopolysaccharide, 4 hours before the experiment) Swiss mice were tracheotomized and ventilated with one of four possible ventilatory settings: control (no ventilation), low pressure (peak pressure 20 cm H2O, positive end-expiratory pressure [PEEP] 4 cm H2O), high pressure (peak pressure 30 cm H2O, PEEP 0 cm H2O), or high pressure plus an intraperitoneal dose of interferon (IFN)-gamma (40,000 units). After 1 hour, an arterial blood sample was obtained, and the right lung removed to measure gas exchange and the lung wet-to-dry weight ratio. Expression of class II MHC molecules was assessed in peripheral monocytes using flow cytometry. RESULTS: High-pressure ventilation was related to a decrease in oxygenation and to an increase in lung wet-to-dry weight ratio. The expression of class II MHC molecules in blood monocytes decreased in the high-pressure group, but not in IFN-gamma-treated mice. The results were similar in both intact and endotoxin-treated mice. CONCLUSIONS: Mechanical ventilation with high pressure and zero PEEP can cause monocyte deactivation. This phenomenon can be avoided by treatment with IFN-gamma.

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury.

Matrix metalloproteinase-9 (MMP-9) is released by neutrophils at the sites of acute inflammation. This enzyme modulates matrix turnover and inflammatory response, and its activity has been found to be increased after ventilator-induced lung injury. To clarify the role of MMP-9, mice lacking this enzyme and their wild-type counterparts were ventilated for 2 h with high- or low-peak inspiratory pressures (25 and 15 cmH2O, respectively). Lung injury was evaluated by gas exchange, respiratory mechanics, wet-to-dry weight ratio, and histological analysis. The activity of MMP-9 and levels of IL-1beta, IL-4, and macrophage inflammatory protein (MIP-2) were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Cell count and myeloperoxidase activity were measured in BALF. There were no differences between wild-type and Mmp9-/- animals after low-pressure ventilation. After high-pressure ventilation, wild-type mice exhibited an increase in MMP-9 in tissue and BALF. Mice lacking MMP-9 developed more severe lung injury than wild-type mice, in terms of impaired oxygenation and lung mechanics, and higher damage in the histological study. These effects correlated with an increase in both cell count and myeloperoxidase activity in the BALF, suggesting an increased neutrophilic influx in response to ventilation. An increase in IL-1beta and IL-4 in the BALF only in knockout mice could be responsible for the differences. There were no differences between genotypes in MMP-2, MMP-8, or tissue inhibitors of metalloproteinases. These results show that MMP-9 protects against ventilator-induced lung injury by decreasing alveolar neutrophilic infiltration, probably by modulation of the cytokine response in the air spaces.