Proteome-wide tagging with an H2O2 biosensor reveals highly localized and dynamic redox microenvironments.

Hydrogen peroxide (H2O2) sensing and signaling involves the reversible oxidation of particular thiols on particular proteins to modulate protein function in a dynamic manner. H2O2 can be generated from various intracellular sources, but their identities and relative contributions are often unknown. To identify endogenous "hotspots" of H2O2 generation on the scale of individual proteins and protein complexes, we generated a yeast library in which the H2O2 sensor HyPer7 was fused to the C-terminus of all protein-coding open reading frames (ORFs). We also generated a control library in which a redox-insensitive mutant of HyPer7 (SypHer7) was fused to all ORFs. Both libraries were screened side-by-side to identify proteins located within H2O2-generating environments. Screening under a variety of different metabolic conditions revealed dynamic changes in H2O2 availability highly specific to individual proteins and protein complexes. These findings suggest that intracellular H2O2 generation is much more localized and functionally differentiated than previously recognized.

Quality of life after multiple trauma: results from a patient cohort treated in a certified trauma network.

PURPOSE: Besides mortality, the patient-reported outcome (PRO) in survivors of multiple trauma is of increasing interest. So far, no data on patient-reported outcome measures (PROMs) after multiple trauma from an entire trauma network are available. Within this study, the course of the PRO over time and differences between level I and level II trauma centers within an entire trauma network was evaluated. METHODS: Multiple injured patients, treated in a rural trauma network over 2 years, were prospectively included in this study. After 6, 12 and 24 months the results of the European Quality of Life (EuroQoL) EQ-5D outcome instrument were evaluated. To adjust for differences in trauma severity between level I and level II centers, the Revised Injury Severity Classification II (RISC II) and the Functional Capacity Index (FCI) were used to adjust the life-quality results of patients. RESULTS: 501 patients were included, 118 patients with an ISS < 16 points, 383 patients reached 16 points or more. Despite a steady increase of EQ-5D index over time (6 months: 0.71 ± 0.31; 12 months: 0.74 ± 0.28; 24 months: 0.76 ± 0.27; p < 0.001), the values of a reference population could not be reached even 2 years after trauma (EQ-5D reference population: 0.9). After adjustment for trauma severity, no significant differences in PROMs between level I and level II centers could be detected (p = 0.188). CONCLUSION: The consistently low EQ-5D index relative the reference population and the lack of a difference between level I and II centers suggest that improved strategies for polytrauma aftercare are called for.

The evolution of activated protein C plasma levels in septic shock and its association with mortality: A prospective observational study.

PURPOSE: Septic shock is commonly associated with hemostatic abnormalities. The endothelium-activated serine protease activated protein C (APC) plays a pivotal role in limiting coagulation and possesses anti-apoptotic and anti-inflammatory properties. We hypothesized that APC levels correlate with established coagulation parameters and provide prognostic information in patients with septic shock. METHODS: We conducted a prospective, observational cohort study in patients with septic shock. APC was measured on admission (day 0) and on days 1, 3, and 6 by a clinically applicable oligonucleotide (aptamer)-based enzyme-capture assay (OECA). The primary endpoint was defined as sepsis-associated 30-day mortality. Furthermore, we analyzed the correlation of APC levels with established coagulation markers. RESULTS: 48 consecutive patients admitted with septic shock were included (mortality 39.6%). APC levels were elevated upon admission (0.59 ng/ml, IQR 0.26-0.97) and showed a strong correlation with established markers of coagulation and lactate. Multivariable logistic regression identified APC (OR 4.3, 95% CI 1.1-17.8, p = 0.04) and lactate levels (OR 7.0, 95% CI 4.1-18.2, p = 0.04) as independent predictors of 30-day mortality. CONCLUSIONS: APC levels are increased in patients with septic shock and are correlated with established markers of coagulation. Elevated APC levels on admission are an independent predictor of mortality.

Biomarker evaluation as a potential cause of gender differences in obesity paradox among patients with STEMI.

BACKGROUND: Obesity with its worldwide growing prevalence is an established cardiovascular risk factor with increased morbidity and mortality. However, the phenomenon, that mild to moderate obesity seems to represent a protective effect on diseases has been termed the "obesity paradox". METHODS: We retrospectively assessed 529 patients (72.6% male, mean age 59.7±12.7years) admitted with ST-elevation myocardial infarction (STEMI). The female and male study populations were separated into four body mass index (BMI) groups: ≤24.9kg/m(2), 25.0-29.9kg/m(2), 30.0-34.9kg/m(2) and ≥35.0kg/m(2). Blood samples of high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) were analyzed. RESULTS: With increasing BMI group the rate of major adverse cardiac events (MACE) decreased in all patients (test for trend p=0.041). No gender difference between MACE and BMI could be noticed (p=0.16). A higher risk for MACE was indicated in group BMI ≤18.5kg/m(2) in comparison to group BMI 25.0-29.9kg/m(2) (OR: 7.93; 95% CI: 1.75-35.89; p=0.0091), whereas group BMI 30.0-34.9kg/m(2) was significant associated with a lower risk in comparison to group BMI 25.0-29.9kg/m(2) (OR: 0.65; 95% CI: 0.21-1.96; p=0.044). An association between HDL-c (p=0.55) or LDL-c (p=0.10) and MACE could not be detected. CONCLUSION: The study demonstrates that patients with STEMI and a BMI of 30.0-34.9kg/m(2) have a decreased risk for MACE compared to patients with normal BMI. No gender related differences were indicated. An association between MACE and lipoproteins could not be detected.