Carbon monoxide formation from trimethylamine-boranecarboxylate: DFT studies of SNi and chelotropic mechanisms.

Trimethylamine-boranecarboxylic acid (CH3)3N-BH2COOH and other amine carboxyboranes have been observed to undergo slow decarbonylation in neutral aqueous solution. This reaction, when it occurs in vivo, may have a therapeutic effect by delivering low concentrations of carbon monoxide over an extended period. In order to identify a possible mechanistic pathway for decarbonylation, the smallest tertiary amine derivative and its corresponding carboxylate ion were studied using CCSD(T)/PCM/6-311++G(2d,p)//M06-2X/PCM/6-311++G(2d,p) model chemistry. The proposed mechanistic pathway begins with a trimethylamine boranecarboxylate ion, which first undergoes an internal substitution reaction (SNi) to give free amine and the carboxyborane anion BH2COO-. The latter cyclic ion then releases CO via a rapid chelotropic fragmentation. The role of water solvent in these reactions was explored by structural and energetic analysis of hydrogen-bonded complexes. It was found that complexation with water inhibits dissociation of trimethylamine by stabilizing the trimethylamine carboxyborane anion, whereas water accelerates CO loss by stabilizing the polar chelotropic transition state.

Crystal structure of memantine-carb-oxy-borane.

The synthesis and crystal structure of the title compound, C13H24BNO2 [systematic name: 3,5-di-methyl-adamantanyl-amine-borane-carb-oxy-lic acid or N-(carb-oxy-boranyl-idene)-3,5-di-methyl-adamantan-1-amine], derived from the anti-Alzheimer's disease drug memantine is reported. The C-N-B-CO2 unit is almost planar (r.m.s. deviation = 0.095 Å). The extended structure shows typical carb-oxy-lic acid inversion dimers linked by pairwise O-H⋯O hydrogen bonds [O⋯O = 2.662 (3) Å]. The amino group forms a weak N-H⋯O hydrogen bond [N⋯O = 3.011 (3) Å], linking the dimers into [001] chains in the crystal. Highly disordered solvent mol-ecules were treated using the SQUEEZE routine of PLATON [Spek (2015 ▸). Acta Cryst. C71, 9-18], which treats the electron density as a diffuse contribution without assignment of specific atom locations. A scattering contribution of 255 electrons was removed. The crystal studied was refined as a two-component twin.

Cell-cycle arrest biomarkers in urine to predict acute kidney injury in septic and non-septic critically ill patients.

PURPOSE: To analyse the usefulness of the composite index of the tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) as urinary biomarkers for the early prediction of AKI in septic and non-septic patients. METHODS: This is a prospective, observational study including patients admitted to ICU from acute care departments and hospital length of stay <48 h. The main exclusion criteria were pre-existing eGFR <30 mL/min/1.73 m2 and hospitalisation 2 months prior to current admission. The [TIMP-2]·[IGFBP7] index was analysed twice, within the first 12 h of ICU admission. RESULTS: The sample included 98 patients. AKI incidence during ICU stay was 50%. Sepsis was diagnosed in 40.8%. Baseline renal variables were comparable between subgroups except for a higher baseline eGFR in non-septic patients. Patients were stratified based on the presence of AKI and their highest level of [TIMP-2]·[IGFBP7] within the first 12 h of stay. [TIMP-2]·[IGFBP7] index values were dependent on the incidence of AKI but not of sepsis. [TIMP-2]·[IGFBP7] values were significantly related to AKI severity according to AKIN criteria (p < 0.0001). The AUROC curve to predict AKI of the worst [TIMP-2]·[IGFBP7] index value was 0.798 (sensitivity 73.5%, specificity 71.4%, p < 0.0001). Index values below 0.8 ruled out any need for renal replacement (NPV 100%), whereas an index >0.8 predicted a rate of AKI of 71% and AKIN ≥ 2 of 62.9%. CONCLUSIONS: In our study, urinary [TIMP-2]·[IGFBP7] was an early predictor of AKI in ICU patients regardless of sepsis. Besides, index values <0.8(ng/mL)2/1000 ruled out the need for renal replacement.

Definición y biomarcadores de daño renal agudo: nuevas perspectivas / Definition and biomarkers of acute renal damage: New perspectives

Los criterios del RIFLE y del AKIN han ayudado definitivamente a llamar la atención sobre la relación entre un deterioro de la función renal que produce un pequeño incremente de la concentración sérica de creatinina y un peor pronóstico. Sin embargo, la utilidad clínica concreta del uso de estos criterios permanece por definir. Se cree que la principal utilidad de estos criterios reside en su uso en estudios epidemiológicos y en ensayos clínicos, para definir criterios de inclusión y objetivos de una intervención. La adopción del término DRA, reemplazando a la antigua terminología de IRA, resulta apropiada para designar la condición clínica caracterizada por daño del órgano, de la misma forma que se utiliza el término daño pulmonar agudo para describir la situación de lesión pulmonar que todavía no ha progresado a una situación de insuficiencia del órgano (disfunción). Los biomarcadores séricos y urinarios (creatinina, urea, diuresis) actualmente en uso no son sensibles ni específicos para la detección de daño renal, limitando las opciones terapéuticas y potencialmente comprometiendo el pronóstico. Nuevos biomarcadores se encuentran en estudio con el objeto de diagnosticar de una forma más precoz y específica el DRA, con el potencial de cambio de los criterios de definición y estadificación del DRA, actualmente basados en la diuresis y la concentración sérica de creatinina

The RIFLE and AKIN criteria have definitely help out to draw attention to the relationship between a deterioration of renal function that produces a small increase in serum creatinine and a worse outcome. However, the specific clinical utility of using these criteria remains to be well-defined. It is believed that the main use of these criteria is for the design of epidemiological studies and clinical trials to define inclusion criteria and objectives of anintervention.AKI adopting term, re-summoning former ARF terminology, it is appropriate to describe the clinical condition characterized by damage to kidney, in the same way as the term is used to describe acute lung damage where the lung injury situation still has not increased to a situation of organ failure (dysfunction).The serum and urine biomarkers (creatinine, urea, and diuresis) currently in use are not sensitive or specific for detecting kidney damage, limiting treatment options and potentially compromising the outcome. New biomarkers are being studied in order to diagnose an earlier and more specific AKI, with the potential to change the definition criteria of AKI with different stages, currently based in diuresis and serum creatinine

[Definition and biomarkers of acute renal damage: new perspectives]. / Definición y biomarcadores de daño renal agudo: nuevas perspectivas.

The RIFLE and AKIN criteria have definitely help out to draw attention to the relationship between a deterioration of renal function that produces a small increase in serum creatinine and a worse outcome. However, the specific clinical utility of using these criteria remains to be well-defined. It is believed that the main use of these criteria is for the design of epidemiological studies and clinical trials to define inclusion criteria and objectives of an intervention. AKI adopting term, re-summoning former ARF terminology, it is appropriate to describe the clinical condition characterized by damage to kidney, in the same way as the term is used to describe acute lung damage where the lung injury situation still has not increased to a situation of organ failure (dysfunction). The serum and urine biomarkers (creatinine, urea, and diuresis) currently in use are not sensitive or specific for detecting kidney damage, limiting treatment options and potentially compromising the outcome. New biomarkers are being studied in order to diagnose an earlier and more specific AKI, with the potential to change the definition criteria of AKI with different stages, currently based in diuresis and serum creatinine.

Introducción a la serie «Puesta al día»: ventilación mecánica / Introduction to the series: ‘‘Update’’: Mechanical ventilation

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[Alveolar recruitment maneuvers in respiratory distress syndrome]. / Maniobras de reclutamiento alveolar en el síndrome de distrés respiratorio agudo.

In patients with acute respiratory distress syndrome, heterogeneity in filling of the lung parenchyma results in collapsed or distended lung areas. Protective ventilation strategies based on the use of low volumes have been shown to increase survival in this context. For opening the lung, and in addition to PEEP, recruitment maneuvers are used-this practice remaining the subject of debate. The present review offers an update on the alveolar recruitment techniques, considering the great variability that exists in the application of these maneuvers, and the different factors that influence the response to maneuvering.

Determinantes genéticos del riesgo y pronóstico del daño renal agudo: una revisión sistemática / Genetic determinants of acute renal damage risk and prognosis: a systematic review

Introducción: El daño renal agudo (DRA) es un síndrome frecuente en el paciente hospitalizado. Los factores de riesgo asociados a su desarrollo y evolución clásicamente aceptados se encuentran en relación con el ambiente o la enfermedad de base del paciente. Sin embargo, en los últimos años se ha reconocido la influencia de los factores genéticos. Objetivo: Analizar la influencia de los polimorfismos genéticos en el riesgo de presentar y en la evolución del DRA. Fuente de datos: búsqueda electrónica en MEDLINE. Selección de estudios: manuscritos redactados en idioma inglés o español, publicados entre el 1/1/1995 y el 31/5/2011 y que analizaron la asociación entre polimorfismos genéticos y: (a) susceptibilidad a DRA entre pacientes versus controles sanos o entre diferentes grupos de pacientes; (b) gravedad del DRA. Criterios de exclusión: estudios publicados solo en forma de resumen, casos clínicos o estudios que incluyeran pacientes menores de 16 años, en diálisis crónica o con trasplante renal. Extracción de datos: al menos uno de los investigadores analizó cada artículo mediante formulario predefinido. Resultados: Se encontraron 12 trabajos que incluyeron 4.835 pacientes. Once genes contienen polimorfismos asociados a la susceptibilidad o gravedad del DRA. Hemos clasificado estos genes de acuerdo con su función en aquellos que participan en la respuesta hemodinámica (ACE, eNOS, FNMT y COMT), respuesta inflamatoria (TNFα, IL10, IL6, HIP-1A, EPO), estrés oxidativo (NAPH oxidasa) y en el metabolismo lipídico (APOE). Solo los genes de APOE, ACE y receptor AT1 han sido analizados en más de un estudio. Conclusión: La susceptibilidad y gravedad del DRA están relacionadas con factores genéticos que están implicados en distintos mecanismos fisiopatológicos (AU)

Introduction: Acute renal damage (ARD) is a frequent syndrome in hospitalized patients. It is well accepted that ARD susceptibility and outcome are related to environmental risk factors and to the patient premorbid status. Recently, host factors have also been recognized as important in ARD predisposition and evolution. Objective: To analyze genetic influences related to the risk and severity of ARD. Data sour MEDLINE search. Selection of studies: articles published in English or Spanish between 1/1/1995 and 31/5/2011, analyzing the association between genic polymorphisms and (a) ARD susceptibility in patients versus healthy controls or within groups of patients; or (b) ARD severity. Exclusion criteria: studies published only in abstract form, case reports or including patients less than 16 years of age, on chronic dialysis or having received a renal transplant. Dataextraction: at least one investigator analyzed each manuscript and collected the information using a predefined form. Results: We identified 12 relevant studies that included 4835 patients. Eleven genes showed polymorphisms related to ARD susceptibility or severity. They were related to cardiovascular regulation (ACE I/D, eNOS, FNMT and COMT), inflammatory response (TNFα, IL10, IL6, HIP-1α, EPO), oxidative stress (NAPH oxidase) and lipid metabolism (APO E). Only APO E, ACE and AT1 receptor have been analyzed in more than one study. Conclusion: ARD susceptibility and severity is influenced by genetic factors, which are multiple and involve different physiopathological mechanisms (AU)

[Genetic determinants of acute renal damage risk and prognosis: a systematic review]. / Determinantes genéticos del riesgo y pronóstico del daño renal agudo: una revisión sistemática.

INTRODUCTION: Acute renal damage (ARD) is a frequent syndrome in hospitalized patients. It is well accepted that ARD susceptibility and outcome are related to environmental risk factors and to the patient premorbid status. Recently, host factors have also been recognized as important in ARD predisposition and evolution. OBJECTIVE: To analyze genetic influences related to the risk and severity of ARD. DATA SOURCE: MEDLINE search. SELECTION OF STUDIES: articles published in English or Spanish between 1/1/1995 and 31/5/2011, analyzing the association between genic polymorphisms and (a) ARD susceptibility in patients versus healthy controls or within groups of patients; or (b) ARD severity. EXCLUSION CRITERIA: studies published only in abstract form, case reports or including patients less than 16 years of age, on chronic dialysis or having received a renal transplant. DATA EXTRACTION: at least one investigator analyzed each manuscript and collected the information using a predefined form. RESULTS: We identified 12 relevant studies that included 4835 patients. Eleven genes showed polymorphisms related to ARD susceptibility or severity. They were related to cardiovascular regulation (ACE I/D, eNOS, FNMT and COMT), inflammatory response (TNFα, IL10, IL6, HIP-1α, EPO), oxidative stress (NAPH oxidase) and lipid metabolism (APO E). Only APO E, ACE and AT1 receptor have been analyzed in more than one study. CONCLUSION: ARD susceptibility and severity is influenced by genetic factors, which are multiple and involve different physiopathological mechanisms.

Lung histopathological findings in fatal pandemic influenza A (H1N1) / Resultados histopatológicos pulmonares en la gripe a (H1N1) pandémica letal

Objective: To describe the lung pathological changes in influenza A (H1N1) viral pneumonia. We studied morphological changes, nitro-oxidative stress and the presence of viral proteins in lung tissue. Methods and patients: Light microscopy was used to examine lung tissue from 6 fatal cases of pandemic influenza A (H1N1) viral pneumonia. Fluorescence for oxidized dihydroethydium, nitrotyrosine, inducible NO synthase (NOS2) and human influenza A nucleoprotein (NP)(for analysis under confocal microscopy) was also studied in lung tissue specimens. Results: Age ranged from 15 to 50 years. Three patients were women, and 5 had preexisting medical conditions. Diffuse alveolar damage (DAD) was present in 5 cases (as evidenced by hyaline membrane formation, alveolo-capillary wall thickening and PMN infiltrates), and interstitial fibrosis in one case. In the fluorescence studies there were signs of oxygen radical generation, increased NOS2 protein and protein nitration in lung tissue samples, regardless of the duration of ICU admission. Viral NP was found in lung tissue samples from three patients. Type I pneumocytes and macrophages harbored viral NP, as evidenced by confocal immunofluorescence microscopy. Conclusions: Lung tissue from patients with pandemic influenza A (H1N1) viral pneumonia shows histological findings consistent with DAD. Prolonged nitro-oxidative stress is present despite antiviral treatment. Viral proteins may remain in lung tissue for prolonged periods of time, lodged in macrophages and type I pneumocytes (AU)

Objetivo: Describir la histopatología pulmonar de pacientes que fallecieron con neumonía por virus de la influenza A (H1N1), el tipo celular infectado por el virus y la presencia de stress oxidativo y nitrosativo. Métodos: Hemos examinado tejido pulmonar de 6 pacientes fallecidos en la UCI con el diagnóstico de infección por el virus influenza A (H1N1) (15-50 años de edad) mediante (i) microscopía óptica, (ii) microscopia confocal con tinciones específicas para diferentes tipos celulares (aquoporina 5, factor Von Willebr and, proteína D del surfactante), (iii) inmunofluorescencia (IF) parasonda de dihidroetidio oxidado, óxido nítrico sin tasa inducible (NOS2), anti-3-nitrotirosina y nucleoproteína (NP) del virus de la influenza A (H1N1).Resultados: (1) En 5 casos se encontró daño alveolar difuso (DAD), evidenciado mediante la observación de membranas hialinas, engrosamiento de la pared alveolo-capilar e infiltración de PMN, asociado con hemorragia intensa en un paciente. Un caso presentó fibrosis intersticial.(2) Se demostró en todos los casos aumento de la inmuno-reactividad para DHE oxidado, NOS2y 3-nitrotirosina independientemente de la duración de la estancia en la UCI. (3) Se encontró NP viral en tres pacientes. (4) El virus se localiza en los neumocitos tipo I y en macrófago salveolares. Conclusiones: El tejido pulmonar de pacientes fallecidos con neumonía por virus de la influenza A (H1N1) evidencia hallazgos histológicos compatibles con DAD. El estrés nitro-oxidativo prolongado está presente a pesar del tratamiento antiviral. Las proteínas virales pueden permanecer en el tejido pulmonar durante períodos prolongados de tiempo, albergándose en los macrófagos y neumocitos tipo I (AU)

Dynamic ventilation 3He MRI for the quantification of disease in the rat lung.

Pulmonary diseases are known to be largely inhomogeneous. To evaluate such inhomogeneities, we are testing an image-based method to measure gas flow in the lung regionally. Dynamic, spin-density-weighted hyperpolarized (3)He MR images performed during slow inhalation of this gas were analyzed to quantify regional inflation rate. This parameter was measured in regions of interest (ROIs) that were defined by a rectangular grid that covered the entire rat lung and grew dynamically with it during its inflation. We used regional inflation rate to quantify elastase-induced emphysema and to differentiate healthy (n = 8) from elastase-treated (n = 9) rat lungs as well as healthy from elastase-treated areas of one rat unilaterally treated with elastase in the left lung. Emphysema was also assessed by gold standard morphological and well-established hyperpolarized (3)He MRI diffusion measurements. Mean values of regional inflation rates were significantly different for healthy and elastase-treated animals and correlated well with the apparent diffusion coefficient of (3)He and morphological measurements. The image-based biomarker inflation rate may be useful for the assessment of regional lung ventilation.

Lung histopathological findings in fatal pandemic influenza A (H1N1).

OBJECTIVE: To describe the lung pathological changes in influenza A (H1N1) viral pneumonia. We studied morphological changes, nitro-oxidative stress and the presence of viral proteins in lung tissue. METHODS AND PATIENTS: Light microscopy was used to examine lung tissue from 6 fatal cases of pandemic influenza A (H1N1) viral pneumonia. Fluorescence for oxidized dihydroethydium, nitrotyrosine, inducible NO synthase (NOS2) and human influenza A nucleoprotein (NP) (for analysis under confocal microscopy) was also studied in lung tissue specimens. RESULTS: Age ranged from 15 to 50 years. Three patients were women, and 5 had preexisting medical conditions. Diffuse alveolar damage (DAD) was present in 5 cases (as evidenced by hyaline membrane formation, alveolo-capillary wall thickening and PMN infiltrates), and interstitial fibrosis in one case. In the fluorescence studies there were signs of oxygen radical generation, increased NOS2 protein and protein nitration in lung tissue samples, regardless of the duration of ICU admission. Viral NP was found in lung tissue samples from three patients. Type I pneumocytes and macrophages harbored viral NP, as evidenced by confocal immunofluorescence microscopy. CONCLUSIONS: Lung tissue from patients with pandemic influenza A (H1N1) viral pneumonia shows histological findings consistent with DAD. Prolonged nitro-oxidative stress is present despite antiviral treatment. Viral proteins may remain in lung tissue for prolonged periods of time, lodged in macrophages and type I pneumocytes.

Lesión pulmonar aguda y síndrome de distrés respiratorio agudo: una perspectiva genómica / Acute lung injury and acute respiratory distress syndrome: a genomic perspective

Recientemente la genómica ha adquirido una enorme relevancia, permitiendo sustanciales avances en el conocimiento de la etiología y patogenia de entidades complejas como la lesión pulmonar aguda (LPA) y el síndrome de distrés respiratorio agudo (SDRA).La medicina genómica procura personalizar y optimizar el diagnóstico, pronóstico y tratamiento mediante el reconocimiento de la influencia que ejercen los polimorfismos genéticos en enfermedades específicas. Uno de los principales desafíos que la comunidad científica debe afrontar es lograr que este conocimiento sea transferido pertinente y rápidamente a la práctica clínica. En caso contrario, es posible que los pacientes sean sometidos a un riesgo innecesario. En el presente artículo se describen los principales aspectos de la medicina genómica en la LPA/SDRA y cuáles son las aplicaciones clínicas actuales (AU)

Genomics have allowed important advances in the knowledge of the etiology and pathogenesis of complex disease entities such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).Genomic medicine aims to personalize and optimize diagnosis, prognosis and treatment by determining the influence of genetic polymorphisms in specific diseases. The scientific community must cope with the important challenge of securing rapid transfer of knowledge to clinical practice, in order to prevent patients from becoming exposed to unnecessary risks(AU)

Acute kidney injury in critically ill patients with 2009 influenza A (H1N1) viral pneumonia: an observational study.

OBJECTIVE: To describe the incidence, risk factors, and impact on mortality of acute kidney injury (AKI) in patients with 2009 influenza A (H1N1) viral pneumonia requiring mechanical ventilation. DESIGN: Observational cohort study. PATIENTS AND METHODS: AKI was defined as risk, injury or failure, according to the RIFLE classification. Early and late AKI were defined as AKI occurring on intensive care unit (ICU) day 2 or before, or after ICU day 2, respectively. Demographic data and information on organ dysfunction were collected daily. RESULTS: Of 84 patients, AKI developed in 43 patients (51%). Twenty (24%) needed renal replacement therapy. Early and late AKI were found in 28 (33%) and 15 (18%) patients, respectively. Patients with AKI, as compared with patients without AKI, had higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and ICU mortality (72% versus 39%, p < 0.01) and presented on admission more marked cardiovascular, respiratory, and hematological dysfunction. Patients with early but not late AKI presented on admission higher APACHE II score and more marked organ dysfunction, as compared with patients without AKI. ICU mortality was higher in late versus early AKI (93% versus 61%, p < 0.001). On multivariate analysis, only APACHE II score and late but not early AKI [odds ratio (OR) 1.1 (95% confidence interval 1.0-1.1) and 15.1 (1.8-130.7), respectively] were associated with mortality. CONCLUSIONS: AKI is a frequent complication of 2009 influenza A (H1N1) viral pneumonia. AKI developing after 2 days in ICU appears to be associated with different risk factors than early AKI, and is related to a higher mortality rate.