Polymer-supported l-prolinol-based catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines

l-Prolinol-based ligands anchored to Merrifield or Wang-type resins have been shown to form efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines. The enantioselectivity achieved with the polymeric catalyst (ee up to 88%) is slightly lower than the one obtained with the homogeneous ligand N-benzyl-l-prolinol, but the polymer-supported ligand presents the advantage of its recyclability: it can be recovered and used in up to six consecutive catalytic cycles with only a slight decrease in the enantiomeric excess. The phosphinamides obtained as addition products can be transformed into the corresponding enantiomerically enriched α-branched primary amines under mild acidic conditions.This work was generously supported by the Spanish Ministerio de Ciencia e Innovación (MICINN; grant no. CONSOLIDER INGENIO 2010, CSD2007-00006, CTQ2007-65218 and CTQ11-24151) and the Generalitat Valenciana (PROMETEO/2009/039, FEDER and GV/2007/036). R.A. thanks the Spanish Ministerio de Educación y Ciencia for a predoctoral fellowship. J.F.C. thanks the Instituto de Síntesis Orgánica for a fellowship

Association of CD14 rs2569190 polymorphism with mortality in shock septic patients who underwent major cardiac or abdominal surgery: A retrospective study

The aim of this study was to investigate the relationship between the CD14 rs2569190 polymorphism and death related to septic shock in white European patients who underwent major cardiac or abdominal surgery. We carried out a retrospective study in 205 septic shock patients. The septic shock diagnosis was established by international consensus definitions. The outcome variable was the death within 28, 60 and 90 days after septic shock diagnosis. The CD14 rs2569190 polymorphism was analyzed by Agena Bioscience's MassARRAY platform. For the genetic association analysis with survival was selected a recessive inheritance model (GG vs. AA/AG). One hundred thirteen out of 205 patients (55.1%) died with a survival median of 39 days (95%CI = 30.6; 47.4). Patients with rs2569190 GG genotype had shorter survival probability than rs2569190 AA/AG genotype at 60 days (62.3% vs 50%; p = 0.035), and 90 days (62.3% vs 52.6%; p = 0.046). The rs2569190 GG genotype was associated with increased risk of septic shock-related death in the first 60 days (adjusted hazard ratio (aHR) = 1.67; p = 0.016) and 90 days (aHR = 1.64; p = 0.020) compared to rs2569190 AA/AG genotype. In conclusion, the presence of CD14 rs2569190 GG genotype was associated with death in shock septic patients who underwent major surgery. Further studies with bigger sample size are required to verify this relationship.The authors thank the Spanish National Genotyping Center (CEGEN-PRB2-ISCIII) for providing SNP genotyping services (http://www.cegen.org). It is supported by grant PT13/0001, ISCIII-SGEFI/FEDER. We also acknowledge the patients in this study for their participation. This work has been supported by grants given by Instituto de Salud Carlos III (grant numbers PI15/01451 to ET), “Gerencia de Salud, Consejería de Sanidad, Junta de Castilla y Leon” [grant number GRS 463/A/10 and 773/A/13 to ET], and PFIZER [grant number CT25-ESP01-01 to SR]. MAJS, LMM, and AFR are supported by “Instituto de Salud Carlos III” [grant numbers CD13/00013, CD14/00002, and CP14CIII/00010; respectively].S

Early natural killer cell counts in blood predict mortality in severe sepsis

Producción CientíficaIn an attempt to evaluate the quantitative changes in the status of immunocompetence in severe sepsis over time and its potential influence on clinical outcome, we monitored the evolution of immunoglobulins (Igs) (IgG, IgA and IgM), complement factors (C3 and C4) and lymphocyte subsets (CD4+ T cells, CD8+ T cells, B cells (CD19+) and natural killer (NK) cells (CD3-CD16+CD56+)) in the blood of 50 patients with severe sepsis or septic shock at day 1, day 3 and day 10 following admission to the ICU. Twenty-one patients died, ten of whom died within the 72 hours following admission to the ICU. The most frequent cause of death (n = 12) was multiorgan dysfunction syndrome. At day 1, survivors showed significantly higher levels of IgG and C4 than those who ultimately died. On the contrary, NK cell levels were significantly higher in the patients who died. Survivors exhibited a progressive increase from day 1 to day 10 on most of the immunological parameters evaluated (IgG, IgA, IgM, C3, CD4+, CD8+ T cells and NK cells). Multivariate Cox regression analysis, including age, sex, APACHE II score, severe sepsis or septic shock status and each one of the immunological parameters showed that NK cell counts at day 1 were independently associated with increased risk of death at 28 days (hazard ratio = 3.34, 95% CI = 1.29 to 8.64; P = 0.013). Analysis of survival curves provided evidence that levels of NK cells at day 1 (> 83 cells/mm3) were associated with early mortality. Our results demonstrate the prognostic role of NK cells in severe sepsis and provide evidence for a direct association of early counts of these cells in blood with mortality

Pulmonary transcriptomic responses indicate a dual role of inflammation in pneumonia development and viral clearance during 2009 pandemic influenza infection

Background: The interaction between influenza virus and the host response to infection clearly plays an important role in determining the outcome of infection. While much is known on the participation of inflammation on the pathogenesis of severe A (H1N1) pandemic 09-influenza virus, its role in the course of non-fatal pneumonia has not been fully addressed. Methods: A systems biology approach was used to define gene expression profiles, histology and viral dynamics in the lungs of healthy immune-competent mice with pneumonia caused by a human influenza A (H1N1) pdm09 virus, which successfully resolved the infection. Results: Viral infection activated a marked pro-inflammatory response at the lung level paralleling the emergence of histological changes. Cellular immune response and cytokine signaling were the two signaling pathway categories more representative of our analysis. This transcriptome response was associated to viral clearance, and its resolution was accompanied by resolution of histopathology. Discussion: These findings suggest a dual role of pulmonary inflammation in viral clearance and development of pneumonia during non-fatal infection caused by the 2009 pandemic influenza virus. Understanding the dynamics of the host's transcriptomic and virological changes over the course of the infection caused by A (H1N1) pdm09 virus may help identifying the immune response profiles associated with an effective response against influenza virus

Critical COPD respiratory illness is linked to increased transcriptomic activity of neutrophil proteases genes

BACKGROUND: Gene expression profiling (GEP) in cells obtained from peripheral blood has shown that this is a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature available on gene expression markers associated with Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated with critical respiratory illness in this disease is not known at the present moment. FINDINGS: By using Agilent microarray chips, we have profiled gene expression signatures in the whole blood of 28 COPD patients hospitalized with different degrees of respiratory compromise.12 of them needed of admission to the ICU, whilst 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparisons of transcript levels between ICU and non-ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to select, annotate and visualize genes by function and pathway (gene ontology). T-test showed evidence of 1501 genes differentially expressed between ICU and non-ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients had increased levels of neutrophil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], and [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This “neutrophil signature” was paralleled by the necessity of advanced respiratory and vital support, and the presence of bacterial infection. CONCLUSION: Study of transcriptomic signatures in blood suggests an essential role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement and modulation of the expression of these genes could present an option for clinical monitoring and treatment of severe COPD exacerbations

Lymphocytopenia as a Predictor of Mortality in Patients with ICU-Acquired Pneumonia

Background: Intensive care unit-acquired pneumonia (ICU-AP) is a severe complication in patients admitted to the ICU. Lymphocytopenia is a marker of poor prognosis in patients with community-acquired pneumonia, but its impact on ICU-AP prognosis is unknown. We aimed to evaluate whether lymphocytopenia is an independent risk factor for mortality in non-immunocompromised patients with ICU-AP. Methods: Prospective observational cohort study of patients from six ICUs of an 800-bed tertiary teaching hospital (2005 to 2016). Results: Of the 473 patients included, 277 (59%) had ventilator-associated pneumonia (VAP). Receiver operating characteristic (ROC) analysis of the lymphocyte counts at diagnosis showed that 595 cells/mm3 was the best cut-off for discriminating two groups of patients at risk: lymphocytopenic group (lymphocyte count <595 cells/mm3 , 141 patients (30%)) and non-lymphocytopenic group (lymphocyte count ≥595 cells/mm3 , 332 patients (70%)). Patients with lymphocytopenia presented more comorbidities and a higher sequential organ failure assessment (SOFA) score at the moment of pneumonia diagnosis. Also, 28-day mortality and 90-day mortality were higher in patients with lymphocytopenia (28-day: 38 (27%) versus 59 (18%), 90-day: 74 (53%) versus 111 (34%)). In the multivariable model, <595 cells/mm3 resulted to be an independent predictor for 90-day mortality (Hazard Ratio 1.41; 95% Confidence Interval 1.02 to 1.94). Conclusion: Lymphocytopenia is an independent predictor of 90-day mortality in non-immunocompromised patients with ICU-AP

Modelos de riesgo para la predicción de mortalidad hospitalaria en ancianos con neumonía por COVID-19

Producción CientíficaObjetivo. Los objetivos son comparar la utilidad pronóstica de tres escalas de gravedad (Pneumonia Severity Index: PSI; CURB-65 scale; Severity Community Acquired Pneumonia Score: SCAP) y diseñar un nuevo modelo predictivo de mortalidad hospitalaria en pacientes mayores de 75 años ingresados por neumonía por COVID-19. Método. Estudio retrospectivo de pacientes mayores de 75 años ingresados por neumonía por COVID-19 desde el servicio de urgencias entre el 12 de marzo y el 27 de abril de 2020. Se recogieron variables demográficas (edad, sexo, institucionalización), clínicas (síntomas, comorbilidades, índice de Charlson) y analíticas (bioquímica en suero, gasometría, hematimetría, hemostasia). Se derivó un modelo de riesgo y se compararon las escalas de gravedad PSI, CURB-65 y SCAP para predecir la mortalidad intrahospitalaria por cualquier causa. Resultados. Se incluyeron 186 pacientes, con una mediana de edad de 85 años (RIC 80-89), un 44,1% varones. La mortalidad fue del 47,3%. Las escalas PSI, CURB-65 y SCAP tuvieron un área bajo la curva (ABC) de 0,74 (IC 95% 0,64-0,82), 0,71 (IC 95% 0,62-0,79) y 0,72 (IC 95% 0,63-0,81), respectivamente. El modelo predictivo compuesto por la ausencia o presencia de síntomas (tos y disnea), comorbilidad (índice de Charlson) y datos analíticos (aspartato-aminotransferasa, potasio, urea y lactato-deshidrogenasa) tuvo un ABC de 0,81 (IC 95% 0,73-0,88). Conclusión. Este estudio muestra que la escala PSI tiene una capacidad predictiva de mortalidad moderada, notablemente mejor que las escalas CURB-65 y SCAP. Se propone un nuevo modelo predictivo de mortalidad que mejora significativamente el rendimiento de estas escalas, siendo necesario verificar su validez externa.Junta de Castilla y León (project GRS COVID 09/A/2020)Ministerio de Ciencia e Innovación – Agencia Estatal de Investigación, cofinanciada por el Fondo Social Europeo (grant RYC2019-028566-I)Gerencia Regional de Salud de Castilla y León (grant INT/M/15/20

Current gaps in sepsis immunology: new opportunities for translational research

Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care

Host adaptive immunity deficiency in severe pandemic influenza

INTRODUCTION: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. METHODS: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. RESULTS: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. CONCLUSIONS: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.The study was scientifically sponsored by the Spanish Society for Critical Care Medicine (SEMICYUC). Funding: MICCIN-FIS/JCYL-IECSCYL-SACYL (Spain): Programa de Investigación Comisionada en Gripe, GR09/0021-EMER07/050- PI081236-RD07/0067. CIHR-NIH-Sardinia Recherché-LKSF Canada support DJK.S