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Certain parameters of complete blood count (CBC) such as red cell distribution width (RDW) and mean platelet volume, as well as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and RDW-to-platelet ratio (RPR) have been associated with inflammatory status and outcome in diverse medical conditions. The aim of this study was to describe the evolution pattern of these parameters in adult burned patients. Adult burned patients admitted to the National Burn Center in Uruguay between May 2017 and February 2018 (discovery cohort) and between March 2018 and August 2019 (validation cohort) were included. Patients’ characteristics and outcomes were recorded, as well as CBC parameters on days 1, 3, 5, and 7 after thermal injury. Eighty-eight patients were included in the discovery cohort. Total body surface area burned was 14 [7–23]% and mortality was 15%. Nonsurvivors presented higher RDW and mean platelet volume (P < .01). NLR decreased after admission in all patients (P < .01), but was higher in nonsurvivors (P < .01). Deceased patients also presented higher RPR on days 3, 5, and 7 (P < .001). On the contrary, PLR was reduced in nonsurvivors (P < .05). There was a significant correlation between NLR on admission and burn extension and severity. Kaplan–Meier analysis revealed that NLR, PLR, and RPR could identify patients with increased mortality. These findings were confirmed in the validation cohort (n = 95). Basic CBC parameters and derived indices could be useful as biomarkers to determine prognosis in adults with thermal injuries.

Carbon dioxide (CO2) is sensed by cells and can trigger signals to modify gene expression in different tissues leading to changes in organismal functions. Despite accumulating evidence that several pathways in various organisms are responsive to CO2 elevation (hypercapnia), it has yet to be elucidated how hypercapnia activates genes and signaling pathways, or whether they interact, are integrated, or are conserved across species. Here, we performed a large-scale transcriptomic study to explore the interaction/integration/conservation of hypercapnia-induced genomic responses in mammals (mice and humans) as well as invertebrates (Caenorhabditis elegans and Drosophila melanogaster). We found that hypercapnia activated genes that regulate Wnt signaling in mouse lungs and skeletal muscles in vivo and in several cell lines of different tissue origin. Hypercapnia-responsive Wnt pathway homologues were similarly observed in secondary analysis of available transcriptomic datasets of hypercapnia in a human bronchial cell line, flies and nematodes. Our data suggest the evolutionarily conserved role of high CO2 in regulating Wnt pathway genes.

Resumen La atrofia y la debilidad de los musculos respiratorios y perifericos son un problema frecuente en las Unidades de Cuidados Intensivos (UCI). Su diagnostico es dificultoso, especialmente en las primeras etapas de la enfermedad critica. Esto determina que en muchos casos no sea detectada hasta etapas avanzadas, por ejemplo, frente a dificultad para la desvinculacion de la asistencia ventilatoria mecanica. El objetivo de esta revision es describir las principales herramientas con las que contamos actualmente para la evaluacion muscular en la UCI, tanto periferica como respiratoria. Se mencionan tecnicas con distinto grado de complejidad y especificidad, haciendo particular hincapie en aquellas con mayor aplicabilidad en la practica clinica diaria, como la ecografia.

Atrophy and weakness of the respiratory and peripheral muscles is a common problem in the intensive care unit (ICU). It is difficult to diagnose, particularly in the early stages of critical disease. Consequently, many cases are detected only in advanced stages, for example, when difficulties in mechanical ventilation weaning are encountered. The aim of this review is to describe the main tools that are currently available for evaluation of peripheral and respiratory muscles in the ICU. Techniques of varying complexity and specificity are discussed, and particular emphasis is placed on those with greater relevance in daily clinical practice, such as ultrasound.

Resumen: Introducción: la mortalidad de los pacientes con injuria térmica ha descendido a nivel mundial. Este hecho se ha relacionado en parte con la creación de centros especializados en el tratamiento de esta patología. En nuestro medio no existen estudios recientes que evalúen la evolución de la mortalidad en este tipo de centros. Objetivo: describir las características de la población asistida y la evolución de la mortalidad en el Centro Nacional de Quemados. Material y método: estudio transversal, observacional, descriptivo. Se incluyeron todos los pacientes ingresados con diagnóstico de quemadura cutánea o de injuria inhalatoria desde la inauguración del centro en 1995 hasta el 31 de diciembre de 2017. Resultados: ingresaron en el período de estudio 3.050 pacientes quemados, 25% presentaron una superficie corporal quemada superior o igual a 20%. Existió un predominio de pacientes jóvenes (más de 60% menores de 50 años) y de sexo masculino (62%). El agente causal más frecuente fue el fuego directo (71%), seguido por líquidos calientes (9%) y electricidad (5%). El 43% de los pacientes requirió asistencia ventilatoria mecánica, y la estadía media en el centro fue de 17 días. La mortalidad global fue de 19,7%, similar a la esperada de acuerdo a scores de severidad específicos. La mortalidad de los pacientes más graves ha descendido desde la apertura del centro. Conclusiones: nuestro centro asiste predominantemente a pacientes jóvenes, con siniestros que involucran al fuego como el principal agente causal. La mortalidad es acorde a la esperada de acuerdo a los scores de severidad, destacándose un descenso continuo de la misma a lo largo de los años. Abstract: Introduction: burned patients mortality has decreased because of a better understanding of initial shock pathophysiology, early surgical interventions, antibiotic therapy optimization and appropriate nutritional support. Mortality reduction has also been related to the creation of specialized burn centers. There are no recent reports of burn injury patients in our country. Objective: to describe characteristics and evolution of patients assisted at the national burned center (Centro Nacional de Quemados, Uruguay). Methods: transversal, observational, descriptive study. All patients admitted in the center with diagnosis of skin burns or inhalation injury, from the center’s opening in 1995 through December 31, 2017. Results: during the study period 3,050-burned patients were admitted, 25% of which had a total body surface area burnt of at least 20%. There was a predominance of male sex (62%) and young patients (more than 60% had less than 50 years old). The most frequent responsible agent was direct fire (71%), followed by hot liquids (9%) and electricity (5%). Mechanical ventilation was needed in 43% of the patients, and mean length of stay in the center was 17 days. Overall mortality rate was 19.7%, accordingly to that predicted by specific severity scores. In the sub-group of more severe patients, mortality has progressively decreased since the center opening. Conclusions: our center assists young patients with burn injuries mostly caused by direct fire. Overall mortality is in line with the expected according to severity scores, having decreased progressively since the center inauguration. Resumo: Introdução: a mortalidade dos pacientes com injúria térmica tem diminuído em todo o mundo devido, em parte, à criação de centros especializados no tratamento desta patologia. No nosso meio não existem estudos recentes que avaliem a evolução da mortalidade neste tipo de centro. Objetivo: descrever as características da população atendida e a evolução da mortalidade no Centro Nacional de Quemados. Métodos: estudo transversal, observacional, descritivo. Foram incluídos todos os pacientes admitidos com diagnóstico de queimadura cutânea ou de injúria inalatória desde a inauguração do Centro em 1995 até o dia 31 de dezembro de 2017. Resultados: no período estudado, foram admitidos 3050 pacientes queimados, 25% apresentaram uma superfície corporal queimada maior ou igual a 20%. Observou-se o predomínio de pacientes jovens (mais de 60% com menos de 50 anos) e de sexo masculino (62%). O agente causal mais frequente foi o fogo direto (71%), seguido por líquidos quentes (9%) e eletricidade (5%). 43% dos pacientes necessitaram assistência ventilatória mecânica, e a permanência média no Centro foi de 17 dias. A mortalidade global foi de 19,7%, similar à esperada de acordo com os graus específicos de gravidade. A mortalidade dos pacientes mais graves vem diminuindo desde a abertura do centro. Conclusões: nosso centro atende predominantemente pacientes jovem sendo o fogo o principal agente causal. A mortalidade é similar à esperada de acordo com os graus específicos de gravidade, destacando-se um descenso continuo da mesma ao longo dos anos.

Delayed lung repair leads to alveolopleural fistulae, which are a major cause of morbidity after lung resections. We have reported that intrapleural hypercapnia is associated with delayed lung repair after lung resection. Here, we provide new evidence that hypercapnia delays wound closure of both large airway and alveolar epithelial cell monolayers because of inhibition of epithelial cell migration. Cell migration and airway epithelial wound closure were dependent on Rac1-GTPase activation, which was suppressed by hypercapnia directly through the upregulation of AMP kinase and indirectly through inhibition of injury-induced NF-κB-mediated CXCL12 (pleural CXC motif chemokine 12) release, respectively. Both these pathways were independently suppressed, because dominant negative AMP kinase rescued the effects of hypercapnia on Rac1-GTPase in uninjured resting cells, whereas proteasomal inhibition reversed the NF-κB-mediated CXCL12 release during injury. Constitutive overexpression of Rac1-GTPase rescued the effects of hypercapnia on both pathways as well as on wound healing. Similarly, exogenous recombinant CXCL12 reversed the effects of hypercapnia through Rac1-GTPase activation by its receptor, CXCR4. Moreover, CXCL12 transgenic murine recipients of orthotopic tracheal transplantation were protected from hypercapnia-induced inhibition of tracheal epithelial cell migration and wound repair. In patients undergoing lobectomy, we found inverse correlation between intrapleural carbon dioxide and pleural CXCL12 levels as well as between CXCL12 levels and alveolopleural leak. Accordingly, we provide first evidence that high carbon dioxide levels impair lung repair by inhibiting epithelial cell migration through two distinct pathways, which can be restored by recombinant CXCL12.

Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration–approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A–induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1+/− and atrogin-1−/− mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome.

Atrophy and weakness of the respiratory and peripheral muscles is a common problem in the intensive care unit (ICU). It is difficult to diagnose, particularly in the early stages of critical disease. Consequently, many cases are detected only in advanced stages, for example, when difficulties in mechanical ventilation weaning are encountered. The aim of this review is to describe the main tools that are currently available for evaluation of peripheral and respiratory muscles in the ICU. Techniques of varying complexity and specificity are discussed, and particular emphasis is placed on those with greater relevance in daily clinical practice, such as ultrasound.

Severe acute respiratory distress syndrome (ARDS) presents typically with an initializing event, followed by the need for mechanical ventilation. Most animal models of ALI are limited by the fact that they focus on a singular cause of acute lung injury (ALI) and therefore fail to mimic the complex, multifactorial pathobiology of ARDS. To better capture this scenario, we provide a comprehensive characterization of models of ALI combining two injuries: intra tracheal (i.t.) instillation of LPS or hypochloric acid (HCl) followed by ventilator‐induced lung injury (VILI). We hypothesized, that mice pretreated with LPS or HCl prior to VILI and thus receiving a (“two‐hit injury”) will sustain a superadditive lung injury when compared to VILI. Mice were allocated to following treatment groups: control with i.t. NaCl, ventilation with low peak inspiratory pressure (PIP), i.t. HCl, i.t. LPS, VILI (high PIP), HCl i.t. followed by VILI and LPS i.t. followed by VILI. Severity of injury was determined by protein content and MPO activity in bronchoalveolar lavage (BAL), the expression of inflammatory cytokines and histopathology. Mice subjected to VILI after HCl or LPS instillation displayed augmented lung injury, compared to singular lung injury. However, mice that received i.t. LPS prior to VILI showed significantly increased inflammatory lung injury compared to animals that underwent i.t. HCl followed by VILI. The two‐hit lung injury models described, resulting in additive but differential acute lung injury recaptures the clinical relevant multifactorial etiology of ALI and could be a valuable tool in translational research.

Objective: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. Methods: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. Results: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. Conclusions: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.

The elevation of carbon dioxide (CO(2)) in tissues and the bloodstream (hypercapnia) occurs in patients with severe lung diseases, including chronic obstructive pulmonary disease (COPD). Whereas hypercapnia has been recognized as a marker of COPD severity, a role for hypercapnia in disease pathogenesis remains unclear. We provide evidence that CO(2) acts as a signaling molecule in mouse and human airway smooth muscle cells. High CO(2) activated calcium-calpain signaling and consequent smooth muscle cell contraction in mouse airway smooth muscle cells. The signaling was mediated by caspase-7-induced down-regulation of the microRNA-133a (miR-133a) and consequent up-regulation of Ras homolog family member A and myosin light-chain phosphorylation. Exposure of wild-type, but not caspase-7-null, mice to hypercapnia increased airway contraction and resistance. Deletion of the Caspase-7 gene prevented hypercapnia-induced airway contractility, which was restored by lentiviral transfection of a miR-133a antagonist. In a cohort of patients with severe COPD, hypercapnic patients had higher airway resistance, which improved after correction of hypercapnia. Our data suggest a specific molecular mechanism by which the development of hypercapnia may drive COPD pathogenesis and progression.

Resumen El cancer de mama es la neoplasia mas frecuente en la mujer, siendo su etiologia desconocida y probablemente relacionada con multiples factores. Suele presentarse como masa, siendo imprescindible realizar una prueba de imagen mamaria y biopsiar las lesiones sospechosas. En los estadios precoces o localmente avanzados, el tratamiento incluye la cirugia (conservadora si es posible) seguida de tratamiento adyuvante: radioterapia (si cirugia conservadora y/o afectacion ganglionar), quimioterapia si se considera indicada (en ocasiones como tratamiento sistemico primario), trastuzumab (tumores HER2 positivos) y hormonoterapia (tumores con sobreexpresion de receptores hormonales). En caso de existir metastasis a distancia los objetivos principales del tratamiento son el mantenimiento de la calidad de vida y el aumento de la supervivencia. En funcion de las caracteristicas del tumor y de la localizacion de las metastasis, pueden utilizarse tratamientos sistemicos (hormonoterapia, quimioterapia y agentes biologicos) combinados o no con tratamientos locales como la cirugia y la radioterapia.

Resumen Los microARN (miRs) son pequenas moleculas de ARN no codificante capaces de regular negativamente la expresion genica. Participan activamente en la modulacion de importantes procesos celulares fisiologicos y estan involucrados en la patogenia de enfermedades pulmonares tales como el cancer de pulmon, la fibrosis pulmonar, el asma y la enfermedad pulmonar obstructiva cronica. Un mayor conocimiento del papel que los miRs desarrollan en estas patologias podria abrir las puertas a nuevas herramientas diagnosticas y terapeuticas. En esta revision, repasamos el rol que algunos miRs desempenan en la patogenia de ciertas enfermedades pulmonares, asi como la posible proyeccion de estos descubrimientos hacia la aplicacion clinica.

Adenosine triphosphate (ATP) is released by alveolar epithelial cells during ventilator-induced lung injury (VILI) and regulates fluid transport across epithelia. High CO(2) levels are observed in patients with "permissive hypercapnia," which inhibits alveolar fluid reabsorption (AFR) in alveolar epithelial cells. The authors set out to determine whether VILI affects AFR and whether the purinergic pathway is modulated in cells exposed to hypercapnia. Control group was compared against VILI (tidal volume [Vt] = 35 mL/kg, zero positive end-expiratory pressure [PEEP]) and protective ventilation (Vt = 6 mL/kg, PEEP = 10 cm H(2)O) groups. Lung mechanics, histology, and AFR were evaluated. Alveolar epithelial cells (AECs) were loaded with Fura 2-AM to measure intracellular calcium in the presence ATP (10 μM) at 5% or 10% CO(2) as compared with baseline. High tidal volume ventilation impairs lung mechanics and AFR. Hypercapnia (HC) increases intracellular calcium levels in response to ATP stimulation. HC + ATP is the most detrimental combination decreasing AFR. Purinergic signaling in AECs is modulated by high CO(2) levels via increased cytosolic calcium. The authors reason that this modulation may play a role in the impairment of alveolar epithelial functions induced by hypercapnia.

Resumen Introduccion Las enfermedades con obstruccion cronica de la via aerea, como la enfermedad pulmonar obstructiva cronica, asocian alteraciones funcionales de los musculos respiratorios. Los agonistas adrenergicos β 2 mejoran la fuerza muscular en condiciones fisiologicas y patologicas. Nuestro objetivo ha sido estudiar los efectos del salbutamol sobre la contractilidad diafragmatica en un modelo animal de obstruccion cronica de la via aerea lograda por obstruccion traqueal (OT) extrinseca. Materiales y metodos Se aleatorizaron 24 ratas Sprague-Dawley en 4 grupos: a) control; b) OT; c) OT+salbutamol agudo, y d) OT+salbutamol cronico. Se estudiaron los gases sanguineos, el equilibrio acido-base y la fuerza diafragmatica in vitro, a traves de las siguientes medidas: tension maxima (T max ), tiempo de contraccion (TC), velocidad de contraccion (dT/dt max ), tiempo de relajacion media (TR 1/2 ), velocidad de relajacion (−dT/dt max ) y curvas fuerza-frecuencia. Resultados Los 3 grupos sometidos a OT presentaron una disminucion significativa del pH y un incremento de la presion arterial de anhidrido carbonico y del bicarbonato en sangre arterial (p max , de dT/dt max y de la curva fuerza-frecuencia en comparacion con los otros grupos (p max fue mayor en el grupo OT+salbutamol cronico comparado con el grupo OT (p max fueron: control, 6,46±0,90 N/cm 2 ; OT, 3,28±0,55 N/cm 2 ; OT+salbutamol agudo, 6,18±0,71 N/cm 2 ; OT+salbutamol cronico, 7,09±0,59 N/cm 2 . Conclusiones La disfuncion diafragmatica asociada a obstruccion cronica de la via aerea mejora con salbutamol administrado tanto en forma aguda como cronica. Los mecanismos involucrados en la disfuncion muscular deben analizarse mas profundamente.

Chronic airflow obstruction in conditions such as chronic obstructive pulmonary disease is associated with respiratory muscle dysfunction. Our aim was to study the effects of salbutamol-a beta-adrenergic agonist known to improve muscle strength in physiologic and pathologic conditions-on diaphragm contractility in an animal model of chronic airway obstruction achieved by tracheal banding.Twenty-four Sprague-Dawley rats were randomized into a control group and 3 tracheal banding groups, 1 that received acute salbutamol treatment, 1 that received chronic salbutamol treatment, and 1 that received nothing. Arterial blood gases, acid-base balance, and in vitro diaphragmatic contractility were evaluated by measuring peak twitch tension, contraction time, contraction velocity, half-relaxation time, relaxation velocity, and force-frequency curves.The 3 study groups had significantly reduced arterial pH and increased PaCO2 and bicarbonate levels compared to the control group (P.05). The untreated tracheal banding group had significantly reduced peak twitch tension and contraction velocity, and a significantly lower force-frequency curve in comparison with the other groups (P.05). The chronic treatment group had a higher relaxation velocity than the untreated study group (P.05). The mean (SE) peak twitch tension values were 6.46 (0.90)N/cm(2) for the control group, 3.28 (0.55)N/cm(2) for the untreated tracheal banding group, 6.18 (0.71)N/cm(2) for the acute treatment group, and 7.09 (0.59)N/cm(2) for the chronic treatment group.Diaphragmatic dysfunction associated with chronic airflow obstruction improves with both the acute and chronic administration of salbutamol. The mechanisms involved in respiratory muscle dysfunction warrant further study.