Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR₁, PAR₂, PAR₃and PAR₄, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects.In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease.

Introduction: We investigated the incidence of, outcome from and possible risk factors for readmission to the surgical intensive care unit (ICU) at Friedrich Schiller University Hospital, Jena, Germany. Methods: We conducted an analysis of prospectively collected data from all patients admitted to the postoperative ICU between September 2004 and July 2006. Results: Of 3169 patients admitted to the ICU during the study period, 2852 were discharged to the hospital floor and these patients made up the study group (1828 male (64.1%), mean patient age 62 years). The readmission rate was 13.4% (n = 381): 314 (82.4%) were readmitted once, 39 (10.2%) were readmitted twice and 28 (7.3%) were readmitted more than twice. The first readmission to the ICU occurred within a median of seven days (range 5 to 14 days). Patients who were readmitted to the ICU had a higher simplified acute physiology II score (37 +/- 16 versus 33 +/- 16; p < 0.001) and sequential organ failure score (6 +/- 3 versus 5 +/- 3; p = 0.001) on initial admission to the ICU than those who were not readmitted. In-hospital mortality was significantly higher in patients readmitted to the ICU (17.1% versus 2.9%; p < 0.001) than in other patients. In a multivariate analysis, age (odds ratio (OR) = 1.13 per 10 years; 95% confidence interval (CI) = 1.03 to 1.24; p = 0.04), maximum sequential organ failure score (OR = 1.04 per point; 95% CI = 1.01 to 1.08; p = 0.04) and C-reactive protein levels on the day of discharge to the hospital floor (OR = 1.02; 95% CI = 1.01 to 1.04; p = 0.035) were independently associated with a higher risk of readmission to the ICU. Conclusions: In this group of surgical ICU patients, readmission to the ICU was associated with a more than five-fold increase in hospital mortality. Older age, higher maximum sequential organ failure score and higher C-reactive protein levels on the day of discharge to the hospital floor were independently associated with a higher risk of readmission to the ICU.

Introduction: Studies in intensive care unit (ICU) patients have suggested that anemia and blood transfusions can influence outcomes, but these effects have not been widely investigated specifically in surgical ICU patients. Methods: We retrospectively analyzed the prospectively collected data from all adult patients (>18 years old) admitted to a 50-bed surgical ICU between 1^st March 2004 and 30^th July 2006. Results: Of the 5925 patients admitted during the study period, 1833 (30.9%) received a blood transfusion in the ICU. Hemoglobin concentrations were < 9 g/dl on at least one occasion in 57.6% of patients. Lower hemoglobin concentrations were associated with a higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score, greater mortality rates, and longer ICU and hospital lengths of stay. Transfused patients had higher ICU (12.5 vs. 3.2%) and hospital (18.3 vs. 6.5%) mortality rates (both p < 0.001) than non-transfused patients. However, ICU and in-hospital mortality rates were similar among transfused and non-transfused matched pairs according to a propensity score (n = 1184 pairs), and after adjustment for possible confounders in a multivariable analysis, higher hemoglobin concentrations (RR 0.97[0.95-0.98], per 1 g/dl, p < 0.001) and blood transfusions (RR 0.96[0.92-0.99], p = 0.031) were independently associated with a lower risk of in-hospital death, especially in patients aged from 66 to 80 years, in patients admitted to the ICU after non-cardiovascular surgery, in patients with higher severity scores, and in patients with severe sepsis. Conclusions: In this group of surgical ICU patients, anemia was common and was associated with higher morbidity and mortality. Higher hemoglobin concentrations and receipt of a blood transfusion were independently associated with a lower risk of in-hospital death. Randomized control studies are warranted to confirm the potential benefit of blood transfusions in these subpopulations.

Background: The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure.Methods: Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4 % albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model.Results: Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median −68 μmol/L, interquartile range [IQR] −107.5 to −33.5,p = 0.001; SPAD: −59 μmol/L, −84.5 to +36.5,p = 0.001). However, bile acids (MARS: −39 μmol/L, −105.6 to −8.3,p < 0.001; SPAD: −9 μmol/L, −36.9 to +11.4,p = 0.131), creatinine (MARS: −24 μmol/L, −46.5 to −8.0,p < 0.001; SPAD: −2 μmol/L, −9.0 to +7.0/L,p = 0.314) and urea (MARS: −0.9 mmol/L, −1.93 to −0.10,p = 0.024; SPAD: −0.1 mmol/L, −1.0 to +0.68,p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10 %, −0.8 to +20.9 %,p < 0.001; SPAD: +7 %, −7.5 to +15.5 %,p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD.Conclusions: Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation.Trial registration: German Clinical Trials Register (www.drks.de)DRKS00000371. Registered 8 April 2010.

Liver graft dysfunction can deteriorate to complete organ failure and increases perioperative morbidity and mortality after liver transplantation. Therapeutic strategies reducing the rate of graft dysfunction are of current clinical relevance. One approach is the systemic application of prostaglandins, which were demonstrated to be beneficial in reducing ischemia-reperfusion injury. Preliminary data indicate a positive effect of prostacyclin analogue iloprost on allograft viability after liver transplantation. The objective of the study is to evaluate the impact of iloprost in a multi-center trial.

Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described. In the second part, we highlight the types of signaling crosstalk between TGF-β on the one hand and PAR2/PAR1 on the other hand. Both ligand–receptor systems interact at various levels and by several mechanisms including mutual regulation of ligand–ligand, ligand–receptor, and receptor–receptor at the transcriptional, post-transcriptional, and receptor transactivation levels. These mutual interactions between PAR2/PAR1 and TGF-β signaling components eventually result in feed-forward loops/vicious cycles of matrix deposition and malignant traits that exacerbate fibrosis and oncogenesis, respectively. Given the crucial role of PAR2 and PAR1 in controlling TGF-β receptor activation, signaling, TGF-β synthesis and bioactivation, combining PAR inhibitors with TGF-β blocking agents may turn out to be more efficient than targeting TGF-β alone in alleviating unwanted TGF-β-dependent responses but retaining the beneficial ones.