MicroRNAs 143 and 150 in whole blood enable detection of T-cell immunoparalysis in sepsis.

BACKGROUND: Currently, no suitable clinical marker for detection of septic immunosuppression is available. We aimed at identifying microRNAs that could serve as biomarkers of T-cell mediated immunoparalysis in sepsis. METHODS: RNA was isolated from purified T-cells or from whole blood cells obtained from septic patients and healthy volunteers. Differentially regulated miRNAs were identified by miRNA Microarray (n = 7). Validation was performed via qPCR (n = 31). RESULTS: T-cells of septic patients revealed characteristics of immunosuppression: Pro-inflammatory miR-150 and miR-342 were downregulated, whereas anti-inflammatory miR-15a, miR-16, miR-93, miR-143, miR-223 and miR-424 were upregulated. Assessment of T-cell effector status showed significantly reduced mRNA-levels of IL2, IL7R and ICOS, and increased levels of IL4, IL10 and TGF-ß. The individual extent of immunosuppression differed markedly. MicroRNA-143, - 150 and - 223 independently indicated T-cell immunoparalysis and significantly correlated with patient's IL7R-/ICOS-expression and SOFA-scores. In whole blood, composed of innate and adaptive immune cells, both traits of immunosuppression and hyperinflammation were detected. Importantly, miR-143 and miR-150 - both predominantly expressed in T-cells - retained strong power of discrimination also in whole blood samples. CONCLUSIONS: These findings suggest miR-143 and miR-150 as promising markers for detection of T-cell immunosuppression in whole blood and may help to develop new approaches for miRNA-based diagnostic in sepsis.

Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas.

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery.

BACKGROUND: The endocannabinoid system (ECS) is an endogenous signalling system which includes the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and specific G-protein-coupled endocannabinoid receptors (CB1 and CB2). Recent studies have described important roles of the peripheral ECS in human atherosclerosis, cardiometabolic disorders, heart failure, and systemic inflammation. We sought to study changes in plasma endocannabinoid concentrations during cardiac surgery (CS) under general anaesthesia with isoflurane/sufentanil, and during cardiopulmonary bypass (CPB). METHODS: We studied 30 patients undergoing CS with CPB. All patients received midazolam and sufentanil for induction and isoflurane and sufentanil for maintenance of general anaesthesia. Blood samples were drawn before and after induction of general anaesthesia, after the beginning of surgery, during and after weaning from CPB, and after admission to intensive care unit (ICU) after surgery. Endocannabinoid measurements were performed by HPLC-tandem mass spectrometry. RESULTS: Induction of general anaesthesia led to a significant decline in plasma AEA concentrations [from mean (sd) 0.39 (0.03) to 0.27 (0.03) ng ml(-1), P<0.01]. CPB induced a pronounced increase in 2-AG concentrations [from 112.5 (163.5) to 321.0 (120.4) ng ml(-1), P<0.01], whereas AEA concentrations remained persistently low until admission to the ICU. 2-AG concentrations returned to preoperative values after surgery. CONCLUSIONS: General anaesthesia with isoflurane significantly reduces plasma AEA concentrations. This could be a consequence of stress reduction after loss of consciousness. The significant increase in 2-AG after initiation of CPB may be part of an inflammatory response. These findings suggest that anaesthesia and surgery have differential effects on the ECS which could have substantial clinical consequences.

Risk and outcome analysis of renal replacement therapies in patients after cardiac surgery with pre-operatively normal renal function.

Peri-operative acute renal failure requiring renal replacement therapy is common (5-30%) after cardiac surgery and associated with a mortality of approximately 50%. Pre-operative renal impairment seems to be the most important risk factor for frank postoperative renal failure. To help evaluate the risk factors, we conducted a prospective observational trial of 1574 consecutive patients with normal pre-operative renal function (creatinine < 110 micromol.l(-1)). Renal failure was defined as the need for renal replacement therapy. After univariate analysis of previously described risk factors, those who differed significantly between patients with or without renal failure were enrolled into a multivariate classification and regression tree (CART) statistical model that identifies the most 'predictive' risk factors and creates a ranked list of these. In patients with pre-operatively normal renal function, a serum level of lactate > 1.1 mmol.l(-1) in the first 24 h after the operation was the strongest predictor for the development of renal failure.