Low Serum Levels of Soluble Receptor Activator of Nuclear Factor κ B Ligand (sRANKL) Are Associated with Metabolic Dysregulation and Predict Long-Term Mortality in Critically Ill Patients

Soluble receptor activator of nuclear factor κ B ligand (sRANKL) is a member of the tumor necrosis factor receptor superfamily, and therefore, involved in various inflammatory processes. The role of sRANKL in the course of bone remodeling via activation of osteoclasts as well as chronic disease progression has been described extensively. However, the potential functional importance of sRANKL in critically ill or septic patients remained unknown. Therefore, we measured sRANKL serum concentrations in 303 critically ill patients, including 203 patients with sepsis and 100 with non-sepsis critical illness. Results were compared to 99 healthy controls. Strikingly, in critically ill patients sRANKL serum levels were significantly decreased at intensive care unit (ICU) admission (p = 0.011) without differences between sepsis and non-sepsis patients. Inline, sRANKL was correlated with markers of metabolic dysregulation, such as pre-existing diabetes and various adipokines (e.g., adiponectin, leptin receptor). Importantly, overall mortality of critically ill patients in a three-year follow-up was significantly associated with decreased sRANKL serum concentrations at ICU admission (p = 0.038). Therefore, our study suggests sRANKL as a biomarker in critically ill patients which is associated with poor prognosis and overall survival beyond ICU stay

Optimisation of antioxidants extraction from soybeans fermented by Aspergillus oryzae

4 figuras, 7 tablasThe extraction of antioxidant compounds from soybeansfermented with Aspergillusoryzae was optimised using a factorial design. A kinetic study of the total phenolic production and DPPH radical scavenging activity was first performed at the points selected in the factorial design. In both cases, the experimental profiles were fitted to a modified first-order kinetic model. To investigate the combined effects of temperature and solvent concentration on the extraction, the parameters obtained from the fitted kinetic models were used as response variables in a rotatable second-order design with quintuple replications in the centre of the experimental domain. The results obtained indicate that temperature had the most significant effect. The response surfaces show a maximum in the experimental domain studied. The optimum conditions for the extraction of total phenolic content were 65.3 °C and 73.1% ethanol, in which 56.2 mg of GAE/g were predicted. A scavenging activity of 81.6% DPPH radical was predicted at the optimum conditions of 61.6 °C and 60% ethanolDrs. Pablo Fuciños and José Antonio Vázquez has been awarded a postdoctoral grant (Programa de bolsas para estadías fóra de Galicia, 2007 and 2008 respectively) by the Dirección Xeral de Investigación, Desenvolvemento e Innovación, Xunta de Galicia, Spain.Peer reviewe

Growth Differentiation Factor-15 Is a Predictor of Mortality in Critically Ill Patients with Sepsis

Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β superfamily related to inflammation and macrophage activation. Serum concentrations of GDF-15 can predict poor survival in chronic diseases, but its role in sepsis is obscure. Therefore, we investigated GDF-15 as a prognostic biomarker in critically ill patients. We measured GDF-15 levels in 219 critically ill patients (146 with sepsis, 73 without sepsis) upon admission to the intensive care unit (ICU), in comparison to 66 healthy controls. GDF-15 levels were significantly increased in ICU patients compared to controls. GDF-15 was further increased in sepsis and showed a strong association with organ dysfunction (kidney, liver and lactate) and disease severity (APACHE II and SOFA score). High GDF-15 concentrations at admission independently predicted ICU (HR 3.42; 95% CI 1.33–8.78) and overall mortality (HR 2.02, 95% CI 1.02–3.88) in all ICU critically ill patients as well as in a large subgroup of sepsis patients (ICU mortality: HR 3.16; 95% CI 1.10–9.07; overall mortality: HR 2.62; 95% CI 1.14–6.02). Collectively, serum GDF-15 levels are significantly increased in critically ill patients, associated with sepsis, organ failure, and disease severity. High GDF-15 levels at ICU admission predict short- and long-term mortality risk

Neutrophils are a main source of circulating suPAR predicting outcome in critical illness

Abstract Background Circulating levels of soluble urokinase plasminogen activation receptor (suPAR) have been proposed as a prognostic biomarker in patients with critical illness and sepsis. However, the origin of suPAR in sepsis has remained obscure. We investigated the potential cellular sources of suPAR by analyzing membrane-bound urokinase plasminogen activator receptor (uPAR, CD87) and evaluated its clinical relevance in critically ill patients. Methods We studied 87 critically ill patients (44 with sepsis, 43 without sepsis) from the medical intensive care unit (ICU) in comparison to 48 standard care patients with infections and 27 healthy controls in a prospective single-center non-interventional cohort study. Cellular uPAR expression of different immune cell subsets (by flow cytometry from peripheral blood) and corresponding serum suPAR concentrations were determined upon ICU admission and at day 3. Furthermore, we analyzed the effects of serum from sepsis patients on the activation and uPAR cleavage of primary human neutrophils and macrophages in vitro. Results In healthy controls, uPAR (CD87) expression was detected on nearly all blood neutrophils and monocytes, but only scarcely on lymphocytes. While uPAR expression on monocytes was maintained in ICU patients, only 58% of neutrophils from critically ill patients expressed uPAR, which was significantly lower than in healthy controls or standard care patients. Concomitantly, serum suPAR levels were significantly increased in ICU patients. We noted a clear inverse correlation between low neutrophilic uPAR and high serum suPAR in standard care and ICU patients, indicating that shedding of uPAR from activated neutrophils represents a main source of suPAR in systemic inflammation. Both low uPAR and high suPAR were closely associated with mortality in critically ill patients. Furthermore, serum from sepsis patients induced uPAR protein expression and subsequent receptor shedding on isolated primary neutrophils, but not on macrophages, in vitro. Conclusions The inverse correlation between low uPAR surface expression on neutrophils and high serum suPAR in critically ill patients supports that neutrophils are a main source of shed suPAR proteins in systemic inflammation. Furthermore, high suPAR levels and low neutrophilic uPAR expression predict mortality in ICU patients

Prognostic Relevance of Altered Lymphocyte Subpopulations in Critical Illness and Sepsis

Lymphopenia and functional defects in lymphocytes may impact the prognosis in patients with critical illness or sepsis. Therefore, we prospectively analyzed peripheral blood leukocytes from 63 healthy volunteers, 50 non-critically ill standard care (SC) patients with infections, and 105 intensive care unit (ICU) patients (52 with sepsis, 53 without sepsis) using flow cytometry. Compared to healthy volunteers, SC and ICU patients showed significant leukocytosis, especially in sepsis, while lymphocyte numbers were significantly decreased. All major lymphocyte populations (B, T, and natural killer (NK) cells) decreased in ICU patients. However, we observed a relative reduction of T cells, alongside decreased CD8+ T cells, in critically ill patients, independent of sepsis. High absolute T cell counts (>0.36/nL) at ICU admission were associated with a significantly reduced mortality, independent of patient’s age. Moreover, patients that survived ICU treatment showed dynamic changes within 48 h towards restoration of lymphopenia and T cell depletion, while non-surviving patients failed to restore lymphocyte counts. In conclusion, the flow-cytometric analysis of peripheral blood revealed striking changes in circulating lymphocyte subsets in critically ill patients, independent of sepsis. Lymphopenia and T cell depletion at ICU admission were associated with increased mortality, supporting their relevance as predictive biomarkers and potential therapeutic targets in intensive care medicine

Diagnostik und Therapie von Clostridium-difficile-Infektionen auf deutschen Intensivstationen: eine Umfrage unter Intensivmedizinern

Zusammenfassung Einleitung Die Clostridium-difficile-assoziierte Kolitis ist eine häufige nosokomiale Durchfallerkrankung auf Intensivstationen mit relevantem Einfluss auf die Prognose kritisch kranker Patienten. In der Intensivmedizin gibt es derzeit kaum kontrollierte Studien zum rationalen Einsatz der verfügbaren Therapieoptionen oder zur Adhärenz gegenüber Leitlinienempfehlungen. Methode Im Auftrag der AG Gastroenterologische Intensivmedizin der DGVS haben wir eine Online-basierte Befragung von Führungskräften deutscher Intensivstationen durchgeführt, um das aktuelle Management der Clostridium-difficile-Infektion auf Intensivstationen zu erfassen. Ergebnis Die Erhebung erzielte einen Rücklauf von 24,2 % (85/351), überwiegend von (leitenden) Oberärzten/innen aus Krankenhäusern verschiedener Versorgungsstufen. Während für die Diagnostik größtenteils (79,3 %) Standards entsprechend der Leitlinien existierten (Toxinnachweis im Stuhl, ggfs. GDH-Screening und Endoskopie), gab es unterschiedliche therapeutische Strategien. Als Erstlinienbehandlung der Clostridium-difficile-Infektion auf der Intensivstation nannten 48,3 % orales Vancomycin, 34,5 % orales Metronidazol; der Therapieerfolg der Erstlinientherapie wurde mit 67 % für primäres Ansprechen, 15 % für persistierende Kolitis, 5 % für Sepsis oder Megakolon, 10 % für Rezidiv und 3 % für Tod abgeschätzt. Krankenhäuser der Grund-/Spezial- und Maximalversorgung setzten häufiger Metronidazol ein als Universitätskliniken. Die Standardbehandlung des Rezidivs bestand überwiegend aus Vancomycin oral (40 % allein, 29,1 % plus Metronidazol), seltener aus Fidaxomicin (25,5 %). Fidaxomicin wurde von 79 % der Befragten bereits mindestens einmal auf der Intensivstation eingesetzt, meist bei schwerem Krankheitsverlauf oder Rezidiv(risiko). Der fäkale Mikrobiomtransfer („Stuhltransplantation“) wurde von 11 % der Befragten bereits auf der Intensivstation in Einzelfällen eingesetzt. Diskussion Die Umfrage unter Führungskräften deutscher Intensivstationen zeigt damit insgesamt eine hohe Sensibilisierung für die Clostridium-difficile-assoziierte Kolitis, allerdings auch deutliche Unterschiede in den lokalen Behandlungsstandards, insbesondere in der Erstlinientherapie.</jats:p