Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production.

TNF promotes a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing RIPK3. Because necrosis is generally more pro-inflammatory than apoptosis, it is widely presumed that TNF-induced necroptosis may be detrimental in vivo due to excessive inflammation. However, because TNF is intrinsically highly pro-inflammatory, due to its ability to trigger the production of multiple cytokines and chemokines, rapid cell death via necroptosis may blunt rather than enhance TNF-induced inflammation. Here we show that TNF-induced necroptosis potently suppressed the production of multiple TNF-induced pro-inflammatory factors due to RIPK3-dependent cell death. Similarly, necroptosis also suppressed LPS-induced pro-inflammatory cytokine production. Consistent with these observations, supernatants from TNF-stimulated cells were more pro-inflammatory than those from TNF-induced necroptotic cells in vivo. Thus necroptosis attenuates TNF- and LPS-driven inflammation, which may benefit intracellular pathogens that evoke this mode of cell death by suppressing host immune responses.

Inpatient statin use predicts improved ischemic stroke discharge disposition.

OBJECTIVE: To determine whether statin use is associated with improved discharge disposition after ischemic stroke. METHODS: We used generalized ordinal logistic regression to analyze discharge disposition among 12,689 patients with ischemic stroke over a 7-year period at 17 hospitals in an integrated care delivery system. We also analyzed treatment patterns by hospital to control for the possibility of confounding at the individual patient level. RESULTS: Statin users before and during stroke hospitalization were more likely to have a good discharge outcome (odds ratio [OR] for discharge to home = 1.38, 95% confidence interval [CI] 1.25-1.52, p < 0.001; OR for discharge to home or institution = 2.08, 95% CI 1.72-2.51, p < 0.001). Patients who underwent statin withdrawal were less likely to have a good discharge outcome (OR for discharge to home = 0.77, 95% CI 0.63-0.94, p = 0.012; OR for discharge to home or institution = 0.43, 95% CI 0.33-0.55, p < 0.001). In grouped-treatment analysis, an instrumental variable method using treatment patterns by hospital, higher probability of inpatient statin use predicted a higher likelihood of discharge to home (OR = 2.56, 95% CI 1.71-3.85, p < 0.001). In last prior treatment analysis, a novel instrumental variable method, patients with a higher probability of statin use were more likely to have a good discharge outcome (OR for each better level of ordinal discharge outcome = 1.19, 95% CI 1.09-1.30, p = 0.001). CONCLUSIONS: Statin use is strongly associated with improved discharge disposition after ischemic stroke.

Predicting long-term outcome after endovascular stroke treatment: the totaled health risks in vascular events score.

BACKGROUND AND PURPOSE: Endovascular treatments are being increasingly used in acute ischemic stroke, and better tools are needed to determine which patients may benefit most from these techniques. We hypothesized that specific chronic diseases can be used, along with age and stroke severity, to predict endovascular stroke treatment outcomes. MATERIALS AND METHODS: Data from 2 single-arm trials of a thrombectomy device, MERCI and Multi MERCI, were pooled for analysis. A predictive score was developed by using the independent contribution of variables in multivariable analysis. RESULTS: HTN, DM, and AFib were found to predict outcomes. These 3 conditions contribute equally to a CDS that predicts outcomes independent of other predictor variables, including age, stroke severity, and vessel recanalization. A 10-level predictive score, the THRIVE score, which incorporates age, stroke severity, and the CDS, was developed. The THRIVE score strongly predicts outcome and mortality at 90 days. CONCLUSIONS: Specific chronic diseases influence poststroke outcomes among patients undergoing endovascular stroke treatment, independent of other predictors of outcome. The THRIVE score reflects the contributions of chronic disease, age, and stroke severity and strongly predicts endovascular stroke treatment outcomes.

Granzymes in cancer and immunity.

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are indispensable factors in the body's ongoing defence against viral infection and tumor development. CTL/NK cells recognize and kill infected or aberrant target cells by two major pathways: either through introduction of a battery of proteases - called granzymes - to the target cell cytosol, or through TNF superfamily-dependent killing. During granzyme-dependent killing, target cell death is quick and efficient and is mediated by multiple granzymes, acting via redundant cell death pathways. Although granzyme-mediated cell death has been intensively studied, recent work has also hinted at an alternative, proinflammatory role for these enzymes. Thus, in addition to their well-established role as intracellular effectors of target cell death, recent data suggest that granzymes may have an extracellular role in the propagation of immune signals. In this study, we discuss the role of granzymes as central factors in antitumor immunity, as well possible roles for these proteases as instigators of inflammation.

Mechanisms of granule-dependent killing.

Cytotoxic T lymphocyte and natural killer cell-initiated cell death is one of the primary mechanisms used by higher organisms to eliminate viruses and transformed cells. In this context, target cell death is rapid and efficient and initiated via two main pathways, involving either the ligation of death receptors or through the granule-exocytosis pathway. The granule-exocytosis pathway has attracted much attention over the past 10 years and consequently, a mechanism for granule-dependent killing has become reasonably well established. In the granule-dependent pathway, several proteolytic enzymes called granzymes are delivered to the target cell, promoting the activation of a family of death-inducing proteases called caspases. If caspases are inhibited by viral proteins or are inactivated through mutation, granzyme-mediated proteolysis of other cellular substrates ensures the timely death of infected or transformed cells. Here, we examine the findings that have shaped our current understanding of the mechanics of granule-dependent killing and discuss recent insights that have clarified some long-standing discrepancies in the granzyme literature.

Assessment of vasculature of meningiomas and the effects of embolization with intra-arterial MR perfusion imaging: a feasibility study.

BACKGROUND AND PURPOSE: Embolization of meningiomas has emerged as a preoperative adjuvant therapy that has proved effective in mitigating blood loss during surgical resection. Arterial supply to these tumors is typically identified by diffuse areas of parenchymal staining after selective x-ray angiograms. We investigate the benefits that selective injection of MR contrast may have in identifying vascular territories and determining the effects of embolization therapy. MATERIALS AND METHODS: Selective intra-arterial (IA) injection of dilute MR contrast media was used to assess the vascular distribution territories of meningeal tumors before and after embolization therapy. Regions of the tumor that experienced loss of signal intensity after localized contrast injections into the external and common carotid as well as vertebral arteries were used to quantify the specific vessel's volume of distribution. Assessments were made before and after embolization to reveal changes in the vascular supply of the tumor. MR findings were compared with radiographic evaluation of tumor vascular supply on the basis of conventional x-ray angiography. RESULTS: MR proved to be an excellent means to assess tissue fed by selected arteries and clearly demonstrated the treated and untreated portions of the neoplasm after therapy. In some instances, MR revealed postembolization residual enhancement of the tumor that was difficult to appreciate on x-ray angiograms. Very low contrast dose was necessary, which made repeated assessment during therapy practical. CONCLUSION: MR perfusion imaging with selective IA injection of dilute contrast can reveal the distribution territory of vessels. Changes in tumor vasculature could be detected after embolization, which reveal the volumetric fraction of the tumor affected by the therapy.

Long-term outcome of endovascular stenting for symptomatic basilar artery stenosis.

Eighteen patients underwent stenting for symptomatic basilar artery stenosis. There were three major periprocedural complications (16.7%) without fatality. At a mean 26.7 +/- 12.1-month follow-up, 15 patients (83.3%) had an excellent long-term outcome. Only one patient (5.6%) had moderate disability from recurrent stroke, and two patients died of medical illness at 30 and 36 months after stenting. In this uncontrolled study, stenting appeared to be effective in reducing stroke risk and death and worthy of further scrupulous trial.