Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

Risk of Distal Embolization From tPA (Tissue-Type Plasminogen Activator) Administration Prior to Endovascular Stroke Treatment.

BACKGROUND AND PURPOSE: In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion. METHODS: We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes. RESULTS: Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; P<0.001). Distal embolization was associated with an inability to attempt EST: after distal embolization, 26/63 (41.3%) could not have attempted EST because of the new clot location, while in cases without distal embolization, only 8/249 (3.2%) were unable to have attempted EST (P<0.001). Among patients who received IV tPA, 13/242 (5.4%) had sufficient symptom improvement that a catheter angiogram was not performed; 6/342 (2.5%) had improvement to within 2 points of their baseline NIHSS. At catheter angiogram, 2/229 (0.9%) of patients who had received tPA had complete recanalization without distal embolization. Both IV tPA and EST recanalization were associated with improved long-term outcome. CONCLUSIONS: IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.

TRAIL Receptors Serve as Stress-Associated Molecular Patterns to Promote ER-Stress-Induced Inflammation.

Inflammation triggered by infection or cellular necrosis is initiated by a battery of pattern-recognition receptors, such as Toll-like receptors or IL-1 family receptors. Diverse forms of cell stress, such as ER stress or mitochondrial stress, can also promote inflammatory responses that contribute to the chronic inflammation observed in cancer, obesity, and other conditions. However, the molecular mechanisms of cell-stress-induced inflammation are poorly understood. Here, we show that ER stress initiated NF-κB activation and inflammation through transcriptional upregulation and ligand-independent activation of TRAIL receptors. ER-stress-induced TRAIL receptor activation resulted in caspase-8/FADD/RIPK1-dependent NF-κB activation and inflammatory cytokine production. Silencing or deletion of TRAIL receptors, or their downstream effectors caspase-8, FADD, or RIPK1, suppressed ER-stress-induced inflammation. Furthermore, chemotherapeutic stress-induced inflammatory responses were blunted in DR5/TRAIL-R null animals. We propose that, upon ER stress, TRAIL receptors serve as "stress-associated molecular patterns (SAMPs)" coupling ER stress to NF-κB-dependent inflammation.

RIPK3 Activation Leads to Cytokine Synthesis that Continues after Loss of Cell Membrane Integrity.

Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3 and subsequent cell membrane permeabilization by the effector MLKL. RIPK3 activation can also promote immune responses via production of cytokines and chemokines. How active cytokine production is coordinated with the terminal process of necroptosis is unclear. Here, we report that cytokine production continues within necroptotic cells even after they have lost cell membrane integrity and irreversibly committed to death. This continued cytokine production is dependent on mRNA translation and requires maintenance of endoplasmic reticulum integrity that remains after plasma membrane integrity is lost. The continued translation of cytokines by cellular corpses contributes to necroptotic cell uptake by innate immune cells and priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells.

Detection of Anterior Circulation Large Artery Occlusion in Ischemic Stroke Using Noninvasive Cerebral Oximetry.

BACKGROUND AND PURPOSE: Large artery occlusion (LAO) in ischemic stroke requires recognition and triage to an endovascular stroke treatment center. Noninvasive LAO detection is needed to improve triage. METHODS: Prospective study to test whether noninvasive cerebral oximetry can detect anterior circulation LAO in acute stroke. Interhemispheric ΔBrSO2 in LAO was compared with controls. RESULTS: In LAO stroke, mean interhemispheric ΔBrSO2 was -8.3±5.8% (n=19), compared with 0.4±5.8% in small artery stroke (n=17), 0.4±6.0% in hemorrhagic stroke (n=14), and 0.2±7.5% in subjects without stroke (n=19) (P<0.001). Endovascular stroke treatment reduced the ΔBrSO2 in most LAO subjects (16/19). Discrimination of LAO at a -3% ΔBrSO2 cut had 84% sensitivity and 70% specificity. Addition of the G-FAST clinical score (gaze-face-arm-speech- time) to the BrSO2 measure had 84% sensitivity and 90% specificity. CONCLUSIONS: Noninvasive cerebral oximetry may help detect LAO in ischemic stroke, particularly when combined with a simple clinical scoring system.

Impact of Increased Early Statin Administration on Ischemic Stroke Outcomes: A Multicenter Electronic Medical Record Intervention.

BACKGROUND: Statin administration early in ischemic stroke may influence outcomes. Our aim was to determine the clinical impact of increasing statin administration early in ischemic stroke hospitalization. METHODS AND RESULTS: This is a retrospective analysis of a multicenter electronic medical record (EMR) intervention to increase early statin administration in ischemic stroke across all 20 hospitals of an integrated healthcare delivery system. A stroke EMR order set was modified from an "opt-in" to "opt-out" mode of statin ordering. Outcomes were mortality by 90 days, discharge disposition, and increase in stroke severity. We examined the relationship between intervention and outcome using autoregressive integrated moving average (ARIMA) time-series modeling. The EMR intervention increased both overall in-hospital statin administration (from 87.2% to 90.7%, P<0.001) and early statin administration (from 16.9% to 26.3%, P<0.001). ARIMA models showed a small increase in the rate of survival (difference in probability [Pdiff]=0.02, P=0.016) and discharge to home or rehabilitation facility (Pdiff=0.04, P=0.034) associated with the intervention. The increase in statin administration <8 hours was associated with much larger increases in survival (Pdiff=0.17, P=0.033) and rate of discharge to home or rehabilitation (Pdiff=0.29, P=0.011), as well as a decreased rate of neurological deterioration in-hospital (Pdiff=-0.14, P=0.026). CONCLUSIONS: A simple EMR change increased early statin administration in ischemic stroke and was associated with improved clinical outcomes. This is, to our knowledge, the first EMR intervention study to show that a modification of an electronic order set resulted in improved clinical outcomes.

Diverse Activators of the NLRP3 Inflammasome Promote IL-1ß Secretion by Triggering Necrosis.

The NLRP3 inflammasome is involved in caspase-1-dependent maturation of IL-1ß in many contexts. A two-signal model has emerged for IL-1ß maturation, with LPS providing "signal I" and diverse agents such as ATP, Nigericin, streptolysin O, uric acid crystals, and alum salts capable of acting as "signal II." In the absence of signal II, pro-IL-1ß is upregulated but typically fails to be processed or released. What unites signal II stimuli has been debated, with the ability to promote K+ efflux suggested as a common factor, but the mechanism of IL-1ß release remains unclear. Here, we show that all examined inflammasome signal II agents triggered necrosis, which was highly correlated with their ability to promote IL-1ß release. IL-1ß secretion occurred in tandem with the release of many additional proteins and was confined to necrotic cells. Thus, signal II agents initiate inflammation by promoting necrosis-driven IL-1ß release, suggesting that IL-1ß represents an inducible danger signal.

Improved ischemic stroke outcome prediction using model estimation of outcome probability: the THRIVE-c calculation.

BACKGROUND AND PURPOSE: The Totaled Health Risks in Vascular Events (THRIVE) score is a previously validated ischemic stroke outcome prediction tool. Although simplified scoring systems like the THRIVE score facilitate ease-of-use, when computers or devices are available at the point of care, a more accurate and patient-specific estimation of outcome probability should be possible by computing the logistic equation with patient-specific continuous variables. METHODS: We used data from 12 207 subjects from the Virtual International Stroke Trials Archive and the Safe Implementation of Thrombolysis in Stroke - Monitoring Study to develop and validate the performance of a model-derived estimation of outcome probability, the THRIVE-c calculation. Models were built with logistic regression using the underlying predictors from the THRIVE score: age, National Institutes of Health Stroke Scale score, and the Chronic Disease Scale (presence of hypertension, diabetes mellitus, or atrial fibrillation). Receiver operator characteristics analysis was used to assess model performance and compare the THRIVE-c model to the traditional THRIVE score, using a two-tailed Chi-squared test. RESULTS: The THRIVE-c model performed similarly in the randomly chosen development cohort (n = 6194, area under the curve = 0·786, 95% confidence interval 0·774-0·798) and validation cohort (n = 6013, area under the curve = 0·784, 95% confidence interval 0·772-0·796) (P = 0·79). Similar performance was also seen in two separate external validation cohorts. The THRIVE-c model (area under the curve = 0·785, 95% confidence interval 0·777-0·793) had superior performance when compared with the traditional THRIVE score (area under the curve = 0·746, 95% confidence interval 0·737-0·755) (P < 0·001). CONCLUSION: By computing the logistic equation with patient-specific continuous variables in the THRIVE-c calculation, outcomes at the individual patient level are more accurately estimated. Given the widespread availability of computers and devices at the point of care, such calculations can be easily performed with a simple user interface.

Fas and TRAIL 'death receptors' as initiators of inflammation: Implications for cancer.

Fas (CD95/APO-1) and TRAIL (CD253, TNFSF10, APO2) are members of a subset of the TNF receptor superfamily known as 'death receptors'. To date, the overwhelming majority of studies on Fas and TRAIL (TNF-related apoptosis-inducing ligand) have explored the role of these receptors as initiators of apoptosis. However, sporadic reports also suggest that engagement of the Fas and TRAIL receptors can lead to other outcomes such as cytokine and chemokine production, cell proliferation, cell migration and differentiation. Indeed, although transformed cells frequently express Fas and TRAIL, most do not undergo apoptosis upon engagement of these receptors and significant effort has been devoted toward exploring how to sensitize such cells to the pro-apoptotic effects of 'death receptor' stimulation. Moreover, the expression of Fas and TRAIL receptors is greatly elevated in many cancer types such as hepatocellular carcinoma, renal carcinoma and ovarian cancer, suggesting that such tumors benefit from the expression of these receptors. Furthermore, several studies have shown that tumor proliferation, progression and invasion can be impaired through blocking or downregulation of Fas expression, but the mechanistic basis for these effects is largely unknown. Thus, the characterization of Fas and TRAIL as 'death receptors' is a gross oversimplification, especially in the context of cancer. It is becoming increasingly clear that 'death receptor' engagement can lead to outcomes, other than apoptosis, that become subverted by certain tumors to their benefit. Here we will discuss death-independent outcomes of Fas and TRAIL signaling and their implications for cancer.

RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis.

Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.

The THRIVE score predicts symptomatic intracerebral hemorrhage after intravenous tPA administration in SITS-MOST.

BACKGROUND: The Totaled Health Risks in Vascular Events (THRIVE) score is a clinical prediction score that predicts ischemic stroke outcomes in patients receiving intravenous tissue plasminogen activator, endovascular stroke treatment, or no acute therapy. We have previously found an association between THRIVE and risk of post-tissue plasminogen activator symptomatic intracranial hemorrhage in the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator trial and risk of radiographic hemorrhage in Virtual International Stroke Trials Archive. AIMS: The study aims to validate the relationship between THRIVE and symptomatic intracranial hemorrhage among tissue plasminogen activator-treated patients in the large Safe Implementation of Thrombolysis in Stroke - Monitoring Study (SITS-MOST). METHODS: This is a retrospective analysis of the prospective SITS-MOST to examine the relationship between THRIVE and symptomatic intracranial hemorrhage after tissue plasminogen activator treatment. Symptomatic intracranial hemorrhage after tissue plasminogen activator was defined according to each of three standard definitions: the NINDS, European Cooperative Acute Stroke Study (ECASS), and Safe Implementation of Thrombolysis in Stroke (SITS) criteria. Multivariable logistic regression was used to confirm the relationship of THRIVE and individual THRIVE components with the risk of symptomatic intracranial hemorrhage and to examine the relationship of THRIVE, symptomatic intracranial hemorrhage, and functional outcome. RESULTS: The odds ratio for symptomatic intracranial hemorrhage at each increased level of THRIVE score is 1·34 (95% CI 1·27 to 1·41, P < 0·001) for symptomatic intracranial hemorrhage by NINDS criteria, 1·36 (95% CI 1·27 to 1·46, P < 0·001) for symptomatic intracranial hemorrhage by ECASS criteria, and 1·21 (95% CI 1·09 to 1·36, P < 0·001) for symptomatic intracranial hemorrhage by SITS criteria. In receiver-operator characteristics analysis, the C-statistic for THRIVE prediction of symptomatic intracranial hemorrhage was 0·65 (95% CI 0·62 to 0·67) for symptomatic intracranial hemorrhage by NINDS criteria, 0·66 (95% CI 0·63 to 0·69) for symptomatic intracranial hemorrhage by ECASS criteria, and 0·61 (95% CI 0·56 to 0·66) for symptomatic intracranial hemorrhage by SITS criteria. Each component of the THRIVE score predicts the risk of symptomatic intracranial hemorrhage, with independent impact of each component in multivariable analysis. CONCLUSIONS: The THRIVE score predicts the risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator administration. This external validation of the relationship between THRIVE and symptomatic intracranial hemorrhage in a prospective study further strengthens the role of the THRIVE score in the prediction of poststroke outcomes.

Bcl-2 family proteins participate in mitochondrial quality control by regulating Parkin/PINK1-dependent mitophagy.

Mitophagy facilitates the selective elimination of impaired or depolarized mitochondria through targeting the latter to autophagosomes. Parkin becomes localized to depolarized mitochondria in a PINK1-dependent manner and polyubiquitinates multiple mitochondrial outer membrane proteins. This permits ubiquitin-binding proteins (e.g., p62 and NBR1) to target impaired mitochondria to autophagosomes via Atg8/LC3II. Bcl-2 family proteins regulate mitochondrial outer membrane permeabilization during apoptosis and can also influence macroautophagy via interactions with Beclin-1. Here, we show that Parkin-dependent mitophagy is antagonized by prosurvival members of the Bcl-2 family (e.g., Bcl-xL and Mcl-1) in a Beclin-1-independent manner. Bcl-2 proteins suppressed mitophagy through inhibition of Parkin translocation to depolarized mitochondria. Consistent with this, Parkin translocation to mitochondria was enhanced by BH3-only proteins or a BH3-only mimetic. Taken together with their role as regulators of apoptosis-associated mitochondrial permeabilization, as well as mitochondrial fission/fusion dynamics, this suggests that Bcl-2 family proteins act as global regulators of mitochondrial homeostasis.

The THRIVE score strongly predicts outcomes in patients treated with the Solitaire device in the SWIFT and STAR trials.

BACKGROUND: The Totaled Health Risks in Vascular Events (THRIVE) score strongly predicts clinical outcome, mortality, and risk of thrombolytic haemorrhage in ischemic stroke patients, and performs similarly well in patients receiving intravenous tissue plasminogen activator, endovascular stroke treatment, or no acute treatment. It is not known if the THRIVE score predicts outcomes with the Solitaire endovascular stroke treatment device. AIMS: To validate the relationship between the THRIVE score and outcomes after treatment with the Solitaire endovascular stroke treatment device. METHODS: The study conducted a retrospective analysis of the prospective SWIFT and STAR trials to examine the relationship between THRIVE and outcomes after treatment with the Solitaire device. We examined the relationship between THRIVE and clinical outcomes (good outcome or death at 90 days) among patients in SWIFT and STAR. Receiver-operator characteristics curve analysis was used to compare THRIVE score performance with other stroke prediction scores. Multivariable modeling was used to confirm the independence of the THRIVE score from procedure-specific predictors (successful recanalization or device used) and other predictors of functional outcome. RESULTS: The THRIVE score strongly predicts good outcome and death among patients treated with the Solitaire device in SWIFT and STAR (Mantel-Haenszel chi-square test for trend P < 0·001 for good outcome, P = 0·01 for death). In receiver-operator characteristics (ROC) curve comparisons, totaled health risks in vascular events score is superior to Stroke Prognostication using Age and NIH Stroke Scale score-100 (P < 0·001) and performed similarly to Houston Intra-Arterial Therapy score (HIAT) (P = 0·98) and HIAT-2 (P = 0·54). In multivariable models, THRIVE's prediction of good outcome is not altered after controlling for recanalization or after controlling for device used. The THRIVE score remains a strong independent predictor after controlling for the above predictors together with time to procedure, rate of symptomatic haemorrhage, and use of general anesthesia. Of note, use of general anesthesia was not an independent predictor of outcome in SWIFT + STAR after controlling for totaled health risks in vascular events and other factors. CONCLUSIONS: The THRIVE score strongly predicts clinical outcome and mortality in patients treated with the Solitaire device in the SWIFT and STAR trials. The lack of interaction between THRIVE and procedure-specific elements such as vessel recanalization or device choice makes the THRIVE score a reasonable candidate for use as a patient selection criterion in stroke clinical trials.

Validation of the Totaled Health Risks In Vascular Events (THRIVE) score for outcome prediction in endovascular stroke treatment.

BACKGROUND: We recently developed the Totaled Health Risks In Vascular Events (THRIVE) score to predict outcomes after endovascular stroke treatment. The THRIVE score, which incorporates age, National Institutes of Health Stroke Scale score, and three medical comorbidities (hypertension, diabetes mellitus, and atrial fibrillation), was developed using data from the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials. AIMS: We set out to perform external validation of the THRIVE score using data from the largest registry of endovascular stroke treatment performed to date, the Merci Registry. METHODS: We compared the performance of the THRIVE score in two different data sets: the development cohort (the MERCI and Multi MERCI trials, n = 305) and a validation cohort (the Merci Registry, a prospective multicenter registry of patients undergoing endovascular stroke treatment, n = 1000). We examined the predictive utility of the THRIVE score across the range of clinical outcomes and used receiver-operator characteristics curve analysis to compare score performance in the two data sets. RESULTS: The THRIVE score predicted good outcome, death, and the full range of the modified Rankin Scale in a similar fashion between the MERCI trials and the Merci Registry. Receiver-operator characteristics curve comparisons showed no statistically significant difference in the performance of the THRIVE score between the two data sets: for good outcome, the receiver-operator characteristics area under the curve was 0·293 for the MERCI trials and 0·266 for the Merci Registry (P = 0·47) and for death, the receiver-operator characteristics area under the curve was 0·692 for the MERCI trials and 0·717 for the Merci Registry (P = 0·48). The THRIVE score and vessel recanalization were also found to be independent and unrelated predictors of clinical outcome. CONCLUSIONS: The THRIVE score reliably predicts outcomes after endovascular stroke treatment and may be useful as a clinical prognostic tool and to perform severity adjustments in stroke clinical research.

THRIVE score predicts ischemic stroke outcomes and thrombolytic hemorrhage risk in VISTA.

BACKGROUND AND PURPOSE: In previous studies, the Totaled Health Risks in Vascular Events (THRIVE) score has shown broad utility, allowing prediction of clinical outcome, death, and risk of hemorrhage after tissue-type plasminogen activator (tPA) treatment, irrespective of the type of acute stroke therapy applied to the patient. METHODS: We used data from the Virtual International Stroke Trials Archive to further validate the THRIVE score in a large cohort of patients receiving tPA or no acute treatment, to confirm the relationship between THRIVE and hemorrhage after tPA, and to compare the THRIVE score with several other available outcome prediction scores. RESULTS: The THRIVE score strongly predicts clinical outcome (odds ratio, 0.55 for good outcome [95% CI, 0.53-0.57]; P<0.001), mortality (odds ratio, 1.57 [95% confidence interval, 1.50-1.64]; P<0.001), and risk of intracerebral hemorrhage after tPA (odds ratio, 1.34 [95% confidence interval, 1.22-1.46]; P<0.001). The relationship between THRIVE score and outcome is not influenced by the independent relationship of tPA administration and outcome. In receiver operator characteristic curve analysis, the THRIVE score was superior to several other available outcome prediction scores in the prediction of clinical outcome and mortality. CONCLUSIONS: The THRIVE score is a simple-to-use tool to predict clinical outcome, mortality, and risk of hemorrhage after thrombolysis in patients with ischemic stroke. Despite its simplicity, the THRIVE score performs better than several other outcome prediction tools. A free Web calculator for the THRIVE score is available at http://www.thrivescore.org.

Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells.

Apoptosis is commonly thought to represent an immunologically silent or even anti-inflammatory mode of cell death, resulting in cell clearance in the absence of explicit activation of the immune system. However, here we show that Fas/CD95-induced apoptosis is associated with the production of an array of cytokines and chemokines, including IL-6, IL-8, CXCL1, MCP-1, and GMCSF. Fas-induced production of MCP-1 and IL-8 promoted chemotaxis of phagocytes toward apoptotic cells, suggesting that these factors serve as "find-me" signals in this context. We also show that RIPK1 and IAPs are required for optimal production of cytokines and chemokines in response to Fas receptor stimulation. Consequently, a synthetic IAP antagonist potently suppressed Fas-dependent expression of multiple proinflammatory mediators and inhibited Fas-induced chemotaxis. Thus, in addition to provoking apoptosis, Fas receptor stimulation can trigger the secretion of chemotactic factors and other immunologically active proteins that can influence immune responsiveness toward dying cells.

Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced proinflammatory cytokine and chemokine production.

Inhibitor of apoptosis proteins (IAPs) play a major role in determining whether cells undergo apoptosis in response to TNF as well as other stimuli. However, TNF is also highly proinflammatory through its ability to trigger the secretion of multiple inflammatory cytokines and chemokines, which is arguably the most important role of TNF in vivo. Indeed, deregulated production of TNF-induced cytokines is a major driver of inflammation in several autoimmune conditions such as rheumatoid arthritis. Here, we show that IAPs are required for the production of multiple TNF-induced proinflammatory mediators. Ablation or antagonism of IAPs potently suppressed TNF- or RIPK1-induced proinflammatory cytokine and chemokine production. Surprisingly, IAP antagonism also led to spontaneous production of chemokines, particularly RANTES, in vitro and in vivo. Thus, IAPs play a major role in influencing the production of multiple inflammatory mediators, arguing that these proteins are important regulators of inflammation in addition to apoptosis. Furthermore, small molecule IAP antagonists can modulate spontaneous as well as TNF-induced inflammatory responses, which may have implications for use of these agents in therapeutic settings.

The totaled health risks in vascular events (THRIVE) score predicts ischemic stroke outcomes independent of thrombolytic therapy in the NINDS tPA trial.

BACKGROUND: To date, no ischemic stroke outcome prediction scores have been validated for use in the setting of both endovascular and non-endovascular stroke treatments. The Totaled Health Risks in Vascular Events (THRIVE) score has been previously validated in patients undergoing endovascular stroke treatment, and we hypothesized that it would perform similarly well in patients receiving intravenous tissue plasminogen activator (tPA) or no acute therapy. METHODS: We compared the performance of the THRIVE score between patients in the National Institutes of Neurological Disorders and Stroke (NINDS) tPA trial and patients in the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trials of endovascular stroke treatment. The predictive performance of the THRIVE score was compared using receiver operator characteristic (ROC) curve analysis. In the NINDS cohort, separate analyses were also performed for patients receiving tPA versus those receiving placebo. RESULTS: ROC curve analysis revealed a good prediction of outcomes across the range of THRIVE scores in both the NINDS and MERCI datasets. As we have previously found in the MERCI datasets, the THRIVE score, which encompasses the National Institutes of Health Stroke Scale (NIHSS) score, age, and chronic disease burden, was a better predictor of outcomes than NIHSS and age alone in the NINDS trial dataset. THRIVE score and tPA administration both strongly predicted outcome, but these effects were statistically independent. CONCLUSIONS: The THRIVE score provides accurate prediction of long-term neurologic outcomes in patients with acute ischemic stroke regardless of treatment modality. Both the THRIVE score and tPA administration predict outcome, but the THRIVE score does not influence the impact of tPA on outcome, and tPA administration does not influence the impact of THRIVE score on outcome.

A perspective on mammalian caspases as positive and negative regulators of inflammation.

Members of the caspase family of cysteine proteases coordinate the morphological and biochemical events that typify apoptosis. However, neutralization of caspase activity in mammals fails to block death in response to most proapoptotic stimuli. This is because many cell death triggers provoke mitochondrial dysfunction upstream of caspase activation as a consequence of BAX/BAK channel opening. Although genetic or pharmacological inactivation of caspases fails to block cell death in most instances, it does convert the phenotype from apoptosis to necrosis. This has important implications for how the immune system responds to such cells, as necrotic cells provoke inflammation whereas apoptotic cells typically do not. Here, we propose an alternative perspective on apoptosis-associated caspase function by suggesting that these proteases are activated, not to kill, but to extinguish the proinflammatory properties of dying cells. This perspective unifies the mammalian caspase family as either positive or negative regulators of inflammation.

Cardiovascular predictors of long-term outcomes after non-traumatic subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Cardiac injury is common after subarachnoid hemorrhage (SAH) and is associated with adverse early outcomes, but long-term effects are unknown. The first aim of this study was to compare the long-term rates of death, stroke, and cardiac events in SAH survivors versus a matched population without SAH. The second aim was to quantify the effects of cardiac injury on the outcome rates. METHODS: This was a retrospective cohort study of patients with and without non-traumatic SAH. For aim #1, the predictor variable was SAH and the outcome variables were all-cause and cerebrovascular mortality, stroke, cardiac mortality, acute coronary syndrome (ACS), and heart failure (HF) admission. A multivariable Cox proportional hazards analysis was performed. For aim #2, the predictor variables were cardiac injury (elevated serum cardiac enzymes or a diagnosis code for ACS) and dysfunction (pulmonary edema on X-Ray or a diagnosis code for HF). RESULTS: Compared with 4,695 members without SAH, the 910 SAH patients had higher rates of all-cause mortality (hazard ratio [HR 2.6], 95% confidence intervals [CI] 2.0-3.4), cerebrovascular mortality (HR 30.6, CI 13.5-69.4), and stroke (HR 10.2, CI 7.5-13.8). Compared with the non-SAH group, the SAH patients with cardiac injury had increased rates of all-cause mortality (HR 5.3, CI 3.0-9.3), cardiac mortality (HR 7.3, CI 1.7-31.6), and heart failure (HR 4.3, CI 1.53-11.88). CONCLUSIONS: SAH survivors have increased long-term mortality and stroke rates compared with a matched non-SAH population. SAH-induced cardiac injury is associated with an increased risk of death and heart failure hospitalization.