PZR suppresses innate immune response to RNA viral infection by inhibiting MAVS activation in interferon signaling mediated by RIG-I and MDA5.

RNA viral infections seriously endanger human health. Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) suppresses innate immunity against influenza A virus, and pharmacological inhibition of SHP2 provokes hepatic innate immunity. SHP2 binds and catalyzes tyrosyl dephosphorylation of protein zero-related (PZR), but the regulatory effect of PZR on innate immune response to viral infection is unclear. In this study, the transcription and protein level of PZR in host cells were found to be decreased with RNA viral infection, and high level of PZR was uncovered to inhibit interferon (IFN) signaling mediated by RIG-I and MDA5. Through localizing in mitochondria, PZR targeted and interacted with MAVS (also known as IPS-1/VISA/Cardif), suppressing the aggregation and activation of MAVS. Specifically, Y263 residue in ITIM is critical for PZR to exert immunosuppression under RNA viral infection. Moreover, the recruited SHP2 by PZR that modified with tyrosine phosphorylation under RNA viral infection might inhibit phosphorylation activation of MAVS. In conclusion, PZR and SHP2 suppress innate immune response to RNA viral infection through inhibiting MAVS activation. This study reveals the regulatory mechanism of PZR-SHP2-MAVS signal axis on IFN signaling mediated by RIG-I and MDA5, which may provide new sight for developing antiviral drugs.

The Role of REC8 in the Innate Immune Response to Viral Infection.

REC8 meiotic recombination protein (REC8) is a member of structural maintenance of chromosome (SMC) protein partners, which play an important role in meiosis, antitumor activity, and sperm formation. As the adaptor proteins of RIG-I-like receptor (RLR) signaling and cyclic GMP-AMP synthase (cGAS)-DNA signaling, the activity and stability of MAVS (mitochondrial antiviral signaling protein; also known as VISA, Cardif, and IPS-1) and STING (stimulator of interferon genes; also known as MITA) are critical for innate immunity. Here, we report that REC8 interacts with MAVS and STING and inhibits their ubiquitination and subsequent degradation, thereby promoting innate antiviral signaling. REC8 is upregulated through the JAK-STAT signaling pathway during viral infection. Knockdown of REC8 impairs the innate immune responses against vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and herpes simplex virus (HSV). Mechanistically, during infection with viruses, the SUMOylated REC8 is transferred from the nucleus to the cytoplasm and then interacts with MAVS and STING to inhibit their K48-linked ubiquitination triggered by RNF5. Moreover, REC8 promotes the recruitment of TBK1 to MAVS and STING. Thus, REC8 functions as a positive modulator of innate immunity. Our work highlights a previously undocumented role of meiosis-associated protein REC8 in regulating innate immunity. IMPORTANCE The innate immune response is crucial for the host to resist the invasion of viruses and other pathogens. STING and MAVS play a critical role in the innate immune response to DNA and RNA viral infection, respectively. In this study, REC8 promoted the innate immune response by targeting STING and MAVS. Notably, REC8 interacts with MAVS and STING in the cytoplasm and inhibits K48-linked ubiquitination of MAVS and STING triggered by RNF5, stabilizing MAVS and STING protein to promote innate immunity and gradually inhibiting viral infection. Our study provides a new insight for the study of antiviral innate immunity.

TRIM10 binds to IFN-α/ß receptor 1 to negatively regulate type I IFN signal transduction.

The type I interferon (IFN-I) system is important for antiviral and anticancer immunity. Prolonged activation of IFN/JAK/STAT signaling is closely associated with autoimmune diseases. TRIM10 dysfunction may be associated closely with certain autoimmune disorders. Here, we observed that the serum TRIM10 protein level is lower in patients with systemic lupus erythematosus than in healthy control subjects. We speculated the possible involvement of TRIM10-induced modulation of the IFN/JAK/STAT signaling pathway in systemic lupus erythematosus. In line with our hypothesis, TRIM10 inhibited the activation of JAK/STAT signaling pathway triggered by various stimuli. TRIM10 restricted the IFN-I/JAK/STAT signaling pathway, which was independent of its E3 ligase activity. Mechanistically, TRIM10 interacted with the intracellular domain of IFNAR1 and blocked the association of IFNAR1 with TYK2. These data suggest the possible TRIM10 suppresses IFN/JAK/STAT signaling pathway through blocking the interaction between IFNAR1 and TYK2. Targeting TRIM10 is a potential strategy for treating autoimmune diseases.

Data for estimating the U.S. labor wedge.

The after-tax labor wedge is defined as the log difference between the MRS and the MPL excluding taxes. This article introduces the data and approach that are used to estimate the U.S. after-tax labor wedge to provide empirical support for the research article entitled "Credit Crunch, Heterogeneity and the Labor Wedge" (Zhang, 2018 (Forthcoming)) [4]. I measure the U.S. after-tax labor wedge and then decompose it into the sum of the gap between the MPL and the real wage (the MPL component) and the gap between the real wage and the MRS (the MRS component). The after-tax labor wedge and its decomposition are measured using quarterly data from 1947Q1 to 2017Q3.

Nitric Oxide and Hydrogen Peroxide Mediate Wounding-Induced Freezing Tolerance through Modifications in Photosystem and Antioxidant System in Wheat.

Mechanical wounding is a common stress caused by herbivores or manual and natural manipulations, whereas its roles in acclimation response to a wide spectrum of abiotic stresses remain unclear. The present work showed that local mechanical wounding enhanced freezing tolerance in untreated systemic leaves of wheat plants (Triticum aestivum L.), and meanwhile the signal molecules hydrogen peroxide (H2O2) and nitric oxide (NO) were accumulated systemically. Pharmacological study showed that wounding-induced NO synthesis was substantially arrested by pretreatment with scavengers of reactive oxygen species and an inhibitor of NADPH oxidase (respiratory burst oxidase homolog, RBOH). On the contrary, wounding-induced H2O2 accumulation was not sensitive to NO synthetic inhibitors or scavenger, indicating that H2O2 acts upstream of NO in wounding signal transduction pathways. Cytochemical and vascular tissues localizations approved that RBOH-dependent H2O2 acts as long-distance signal in wounding response. Transcriptome analysis revealed that 279 genes were up-regulated in plants treated with wounding and freezing, but not in plants treated with freezing alone. Importantly, freezing- and wounding-induced genes were significantly enriched in the categories of "photosynthesis" and "signaling." These results strongly supported that primary mechanical wounding can induce freezing tolerance in wheat through the systemic accumulation of NO and H2O2, and further modifications in photosystem and antioxidant system.

Postoperative recovery with bispectral index versus anesthetic concentration-guided protocols.

BACKGROUND: Use of the bispectral index (BIS) monitor has been suggested to decrease excessive anesthetic drug administration, leading to improved recovery from general anesthesia. The purpose of this substudy of the B-Unaware and BAG-RECALL trials was to assess whether a BIS-based anesthetic protocol was superior to an end-tidal anesthetic concentration-based protocol in decreasing recovery time and postoperative complications. METHODS: Patients at high risk for awareness were randomized to either BIS-guided or end-tidal anesthetic concentration-guided general anesthesia in the original trials. Outcomes included time to postanesthesia care unit discharge readiness, time to achieve a postoperative Aldrete score of 9-10, intensive care unit length of stay, postoperative nausea and vomiting, and severe postoperative pain. Univariate Cox regression and chi-square tests were used for statistical analyses. RESULTS: The BIS cohort was not superior in time to postanesthesia care unit discharge readiness (hazard ratio, 1.0; 95% CI, 1.0-1.1; n = 2,949), time to achieve an Aldrete score of 9-10 (hazard ratio, 1.2; 95% CI, 1.0-1.4; n = 706), intensive care unit length of stay (hazard ratio, 1.0; 95% CI, 0.9-1.1; n = 2,074), incidence of postoperative nausea and vomiting (absolute risk reduction, -0.5%; 95% CI, -5.8 to 4.8%; n = 789), or incidence of severe postoperative pain (absolute risk reduction, 4.4%; 95% CI, -2.3 to 11.1%; n = 759). CONCLUSIONS: In patients at high risk for awareness, the BIS-guided protocol is not superior to an anesthetic concentration-guided protocol in time needed for postoperative recovery or in the incidences of common postoperative complications.

Relationship between bispectral index values and volatile anesthetic concentrations during the maintenance phase of anesthesia in the B-Unaware trial.

BACKGROUND: Hypnotic depth during anesthesia affects electroencephalography waveforms and electroencephalogram-derived indices, such as the bispectral index (BIS). Titrating anesthetic administration against the BIS assumes reliable relationships between BIS values, electroencephalogram waveforms, and effect site concentration, beyond loss of responsiveness. Associations among BIS, end-tidal anesthetic concentrations (ETAC), and patient characteristics were examined during anesthetic maintenance, using B-Unaware trial data. METHODS: Pharmacokinetically stable ETAC epochs during intraoperative anesthetic maintenance were analyzed. A generalized estimating equation determined independent relationships among BIS, ETAC (in age-adjusted minimum alveolar concentration equivalents), patient characteristics, and 1-yr mortality. Further individual and population characteristics were explored graphically. RESULTS: A total of 3,347,523 data points from 1,100 patients were analyzed over an ETAC range from 0.42 to 1.51 age-adjusted minimum alveolar concentration. A generalized estimating equation yielded a best predictive equation: BIS = 62.9-1.6 (if age younger than 60 yr) -1.6 (if female) -2.5 (if American Society of Anesthesiologists physical status more than 3) -2.6 (if deceased at 1 yr) -2.5 (if N2O was not used) -1.4 (if midazolam dose more than 2 mg) -1.3 (if opioid dose more than 50 morphine equivalents) -15.4 × age-adjusted minimum alveolar concentration. Although a population relationship between ETAC and BIS was apparent, interindividual variability in the strength and reliability of this relationship was large. Decreases in BIS with increasing ETAC were not reliably observed. Individual-patient linear regression yielded a median slope of -8 BIS/1 age-adjusted minimum alveolar concentration (interquartile range -30, 0) and a median correlation coefficient of -0.16 (interquartile range -0.031, -0.50). CONCLUSIONS: Independent of pharmacokinetic confounding, BIS frequently correlates poorly with ETAC, is often insensitive to clinically significant changes in ETAC, and is vulnerable to interindividual variability. BIS is therefore incapable of finely guiding volatile anesthetic titration during anesthetic maintenance.

Prevention of intraoperative awareness in a high-risk surgical population.

BACKGROUND: Unintended intraoperative awareness, which occurs when general anesthesia is not achieved or maintained, affects up to 1% of patients at high risk for this complication. We tested the hypothesis that a protocol incorporating the electroencephalogram-derived bispectral index (BIS) is superior to a protocol incorporating standard monitoring of end-tidal anesthetic-agent concentration (ETAC) for the prevention of awareness. METHODS: We conducted a prospective, randomized, evaluator-blinded trial at three medical centers. We randomly assigned 6041 patients at high risk for awareness to BIS-guided anesthesia (with an audible alert if the BIS value was <40 or >60, on a scale of 0 to 100, with 0 indicating the suppression of detectable brain electrical activity and 100 indicating the awake state) or ETAC-guided anesthesia (with an audible alert if the ETAC was <0.7 or >1.3 minimum alveolar concentration). In addition to audible alerts, the protocols included structured education and checklists. Superiority of the BIS protocol was assessed with the use of a one-sided Fisher's exact test. RESULTS: A total of 7 of 2861 patients (0.24%) in the BIS group, as compared with 2 of 2852 (0.07%) in the ETAC group, who were interviewed postoperatively had definite intraoperative awareness (a difference of 0.17 percentage points; 95% confidence interval [CI], -0.03 to 0.38; P=0.98). Thus, the superiority of the BIS protocol was not demonstrated. A total of 19 cases of definite or possible intraoperative awareness (0.66%) occurred in the BIS group, as compared with 8 (0.28%) in the ETAC group (a difference of 0.38 percentage points; 95% CI, 0.03 to 0.74; P=0.99), with the superiority of the BIS protocol again not demonstrated. There was no difference between the groups with respect to the amount of anesthesia administered or the rate of major postoperative adverse outcomes. CONCLUSIONS: The superiority of the BIS protocol was not established; contrary to expectations, fewer patients in the ETAC group than in the BIS group experienced awareness. (Funded by the Foundation for Anesthesia Education and Research and others; BAG-RECALL ClinicalTrials.gov number, NCT00682825.).

Bispectral index monitoring, duration of bispectral index below 45, patient risk factors, and intermediate-term mortality after noncardiac surgery in the B-Unaware Trial.

BACKGROUND: Postoperative mortality has been associated with cumulative anesthetic duration below an arbitrary processed electroencephalographic threshold (bispectral index [BIS] <45). This substudy of the B-Unaware Trial tested whether cumulative duration of BIS values lower than 45, cumulative anesthetic dose, comorbidities, or intraoperative events were independently associated with postoperative mortality. METHODS: The authors studied 1,473 patients (mean ± SD age, 57.9 ± 14.4 yr; 749 men) who underwent noncardiac surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Multivariable Cox regression analysis was used to determine whether perioperative factors were independently associated with all-cause mortality. RESULTS: A total of 358 patients (24.3%) died during a follow-up of 3.2 ± 1.1 yr. There were statistically significant associations among various perioperative risk factors, including malignancy and intermediate-term mortality. BIS-monitored patients did not have lower mortality than unmonitored patients (24.9 vs. 23.7%; difference = 1.2%, 95% CI, -3.3 to 5.6%). Cumulative duration of BIS values less than 45 was not associated with mortality (multivariable hazard ratio, 1.03; 95% CI, 0.93-1.14). Increasing mean and cumulative end-tidal anesthetic concentrations were not associated with mortality. The multivariable Cox regression model showed a good discriminative ability (c-index = 0.795). CONCLUSIONS: This study found no evidence that either cumulative BIS values below a threshold of 40 or 45 or cumulative inhalational anesthetic dose is injurious to patients. These results do not support the hypothesis that limiting depth of anesthesia either by titration to a specific BIS threshold or by limiting end-tidal volatile agent concentrations will decrease postoperative mortality.

Association of perioperative risk factors and cumulative duration of low bispectral index with intermediate-term mortality after cardiac surgery in the B-Unaware Trial.

BACKGROUND: Current data suggest that mortality after noncardiac surgery may be associated with persistent hypotension and the cumulative duration of low processed electroencephalogram-based bispectral index (BIS). This study assessed the relationships among cumulative duration of low BIS (BIS < 45), intermediate-term mortality, and anesthetic dose after cardiac surgery. METHODS: The authors studied 460 patients (mean age, 63.0 +/- 13.1 yr; 287 men) who underwent cardiac surgery between September 2005 and October 2006 at Washington University Medical Center, St Louis, Missouri. By using multivariable Cox regression analysis, perioperative factors were evaluated for their potential association with intermediate-term all-cause mortality. RESULTS: A total of 82 patients (17.8%) died during a median follow-up of 3 yr (interquartile range, 2.7-3.3 yr). Comparing patients who died with those who survived, there was no statistically significant difference in the relationship between end-tidal anesthetic gas concentrations during the anesthetic maintenance phase and the BIS. Cumulative duration of low BIS was independently associated with intermediate-term mortality. The 1.29 adjusted hazard ratio (95% CI, 1.12-1.49) for intermediate-term mortality with cumulative duration of low BIS translated into a 29% increased risk of death for every cumulative hour spent with a BIS less than 45. The final multivariable Cox regression model showed a good discriminative ability (c-index of 0.78). CONCLUSIONS: This study found an association between cumulative duration of low BIS and mortality in the setting of cardiac surgery. Notably, this association was independent of both volatile anesthetic concentration and duration of anesthesia, suggesting that intermediate-term mortality after cardiac surgery was not causally related to excessive anesthetic dose.

A randomized study in diabetic patients undergoing cardiac surgery comparing computer-guided glucose management with a standard sliding scale protocol.

OBJECTIVE: The aim of this study was to compare a standard insulin protocol with a computer-guided glucose management system to determine which method achieves tighter glucose control. DESIGN: A prospective, randomized trial. SETTING: A cardiothoracic intensive care unit (ICU) in a large academic medical center. PARTICIPANTS: Forty patients with diabetes mellitus who were scheduled for cardiac surgery. INTERVENTIONS: After induction of anesthesia and for the first 9 hours in the ICU, each subject received a standardized infusion of a 10% glucose solution at a rate of 1.0 mL/kg/h (ideal body weight). The subjects were then randomized to have their glucose controlled by either a paper-based insulin protocol or by a computer-guided glucose management system (CG). The desired range for blood glucose was set between 90 and 150 mg/dL. MEASUREMENTS AND MAIN RESULTS: There were no differences between groups in baseline characteristics. Patients in the CG group spent more time in the desired range during both the intraoperative phase (49% v 27%, p = 0.001) and the ICU phase (84% v 60%, p < 0.0001). There were no statistical differences between groups in the number of hypoglycemia episodes. CONCLUSIONS: The computer-guided glucose management system achieved tighter blood glucose control than a standard paper-based protocol in diabetic patients undergoing cardiac surgery. However, the low proportion of blood glucose recordings within the desired range in both groups during the intraoperative period reflects the challenges associated with achieving normoglycemia during cardiac surgery.

Anesthesia awareness and the bispectral index.

BACKGROUND: Awareness during anesthesia is a serious complication with potential long-term psychological consequences. Use of the bispectral index (BIS), developed from a processed electroencephalogram, has been reported to decrease the incidence of anesthesia awareness when the BIS value is maintained below 60. In this trial, we sought to determine whether a BIS-based protocol is better than a protocol based on a measurement of end-tidal anesthetic gas (ETAG) for decreasing anesthesia awareness in patients at high risk for this complication. METHODS: We randomly assigned 2000 patients to BIS-guided anesthesia (target BIS range, 40 to 60) or ETAG-guided anesthesia (target ETAG range, 0.7 to 1.3 minimum alveolar concentration [MAC]). Postoperatively, patients were assessed for anesthesia awareness at three intervals (0 to 24 hours, 24 to 72 hours, and 30 days after extubation). RESULTS: We assessed 967 and 974 patients from the BIS and ETAG groups, respectively. Two cases of definite anesthesia awareness occurred in each group (absolute difference, 0%; 95% confidence interval [CI], -0.56 to 0.57%). The BIS value was greater than 60 in one case of definite anesthesia awareness, and the ETAG concentrations were less than 0.7 MAC in three cases. For all patients, the mean (+/-SD) time-averaged ETAG concentration was 0.81+/-0.25 MAC in the BIS group and 0.82+/-0.23 MAC in the ETAG group (P=0.10; 95% CI for the difference between the BIS and ETAG groups, -0.04 to 0.01 MAC). CONCLUSIONS: We did not reproduce the results of previous studies that reported a lower incidence of anesthesia awareness with BIS monitoring, and the use of the BIS protocol was not associated with reduced administration of volatile anesthetic gases. Anesthesia awareness occurred even when BIS values and ETAG concentrations were within the target ranges. Our findings do not support routine BIS monitoring as part of standard practice. (ClinicalTrials.gov number, NCT00281489 [ClinicalTrials.gov].).

Use of activated recombinant factor VII for severe coagulopathy post ventricular assist device or orthotopic heart transplant.

BACKGROUND: Ventricular assist devices(VAD) implantation/removal is a complex surgical procedure with perioperative bleeding complications occurring in nearly half of the cases. Recombinant activated factor VII (rFVIIa) has been used off-label to control severe hemorrhage in surgery and trauma. We report here our experience with rFVIIa as a rescue therapy to achieve hemostasis in patients undergoing orthotopic heart transplant (OHT) and/or VAD implantation. METHODS: A retrospective review was conducted from Jan 03 to Aug 05 for patients who received rFVIIa for the management of intractable bleeding unresponsive to standard hemostatic blood component therapy. Blood loss and the quantity of blood products, prior to, and for at least 12 hours after, administration of rFVIIa were recorded. RESULTS: Mean patient age was 53, (38-64 yrs), mean dose of rFVIIa administered was 78.3 microg/kg (24-189 microg/kg) in 1-3 doses. All patients received the drug either intraoperatively or within 6 hours of arrival in ICU. Mean transfusion requirements and blood loss were significantly reduced after rFVIIa administration (PRBC's; 16.9 +/- 13.3 to 7.1 +/- 6.9 units, FFP; 13.1 +/- 8.2 to 4.1 +/- 4.9 units, platelets; 4.0 +/- 2.8 to 2.1 +/- 2.2 units, p < 0.04 for all). 5 patients expired including 3 with thromboembolic cause. One patient developed a lower extremity arterial thrombus, and another deep vein thrombosis. CONCLUSION: In this review, there was a significant decrease in transfusion requirement and blood loss after rFVIIa administration. Although, 5/17 developed thromboembolic complications, these patients may have been at higher risk based on the multiple modality therapy used to manage intractable bleeding. Nevertheless, the exact role of rFVIIa with respect to development of thromboembolic complications cannot be clearly determined. Further investigation is needed to determine rFVIIa's safety and its effectiveness in improving postoperative morbidity and mortality.

Transfusion risks and transfusion-related pro-inflammatory responses.

Despite improvements in blood screening and administration techniques, serious adverse events related to transfusion continue to occur, albeit at a much lower incidence. In addition to the development and implementation of new screening and blood purification/modification techniques and implementation of an optimal blood management program, the incidence and consequences of transfusion reactions can be reduced by a basic understanding of transfusion-related complications. Although acute hemolytic transfusion reactions, transfusion-associated anaphylaxis and sepsis, and transfusion-associated acute lung injury occur infrequently, diligence in administration of blood and monitoring for development of respective signs/symptoms can minimize the severity of these potentially life-threatening complications. In addition, emerging blood-banking techniques such as psoralen-UV inactivation of pathogens and use of patient identification systems may attenuate the incidence of adverse events related to transfusion. With respect to optimizing blood management by means of an effective blood management program involving pharmacologic and nonpharmacologic strategies, the ability to reduce use of blood products and to decrease operative time or re-exploration rates has important implications for disease prevention, blood inventory and costs, and overall health care costs.

Transfusion medicine service policies for recombinant factor VIIa administration.

Recombinant FVIIa (rFVIIa) has been approved for treatment of bleeding in hemophilia patients with inhibitors. It has also been successfully used in nonhemophilia patients with acquired antibodies against FVIII (acquired hemophilia). Pharmacological doses of rFVIIa have been found to enhance the thrombin generation on already activated platelets and, therefore, may also likely be of benefit in providing hemostasis in other situations characterized by profuse bleeding and impaired thrombin generation, such as patients with thrombocytopenia and in those with functional platelet defects. Additionally, it has been used successfully in a variety of less well-characterized bleeding situations, as well as in patients with impaired liver function. To date, case reports, anecdotal experience, and limited clinical trials describe these uses; data from randomized clinical trials are limited. Because of the recent trends in rFVIIa usage in non-approved settings among physicians from various disciplines, significant concerns about its safety, efficacy, and costs have arisen. Additionally, dosing of rFVIIa for these potentially broad clinical applications is not standardized. Currently, the decision on when and where to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutics and transfusion committees.