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Background: Optimal blood pressure (BP) management during endovascular stroke treatment in patients with large-vessel occlusion is not well established. We aimed to investigate associations of BP during different phases of endovascular therapy with reperfusion and functional outcome., Methods: We performed a post hoc analysis of a single-center prospective study that evaluated a new simplified procedural sedation standard during endovascular therapy (Keep Evaluating Protocol Simplification in Managing Periinterventional Light Sedation for Endovascular Stroke Treatment). BP during endovascular therapy in patients was managed according to protocol. Data from four different phases (baseline, pre-recanalization, post recanalization, and post intervention) were obtained, and mean BP values, as well as changes in BP between different phases and reductions in systolic BP (SBP) and mean arterial pressure (MAP) from baseline to pre-recanalization, were used as exposure variables. The main outcome was a modified Rankin Scale score of 0-2 three months after admission. Secondary outcomes were successful reperfusion and change in the National Institutes of Health Stroke Scale score after 24 h. Multivariable linear and logistic regression models were used for statistical analysis., Results: Functional outcomes were analyzed in 139 patients with successful reperfusion (defined as thrombolysis in cerebral infarction grade 2b-3). The mean (standard deviation) age was 76 (10.9) years, the mean (standard deviation) National Institutes of Health Stroke Scale score was 14.3 (7.5), and 70 (43.5%) patients had a left-sided vessel occlusion. Favorable functional outcome (modified Rankin Scale score 0-2) was less likely with every 10-mm Hg increase in baseline (odds ratio [OR] 0.76, P = 0.04) and pre-recanalization (OR 0.65, P = 0.011) SBP. This was also found for baseline (OR 0.76, P = 0.05) and pre-recanalization MAP (OR 0.66, P = 0.03). The maximum Youden index in a receiver operating characteristics analysis revealed an SBP of 163 mm Hg and MAP of 117 mm Hg as discriminatory thresholds during the pre-recanalization phase to predict functional outcome., Conclusions: In our protocol-based setting, intraprocedural pre-recanalization BP reductions during endovascular therapy were not associated with functional outcome. However, higher intraprocedural pre-recanalization SBP and MAP were associated with worse functional outcome. Prospective randomized controlled studies are needed to determine whether BP is a feasible treatment target for the modification of outcomes., (© 2021. The Author(s).)

Background: Emergency intubation is an inherent risk of procedural sedation regimens for endovascular treatment (EVT) of acute ischemic stroke. We aimed to characterize the subgroup of patients, who had to be emergently intubated, to identify predictors of the need for intubation and assess their outcomes., Methods: This is a retrospective analysis of the single-center study KEEP SIMPLEST, which evaluated a new in-house SOP for EVT under primary procedural sedation. We used descriptive statistics and regression models to examine predictors and functional outcome of emergently intubated patients., Results: Twenty of 160 (12.5%) patients were emergently intubated. National Institutes of Health Stroke Scale (NIHSS) on admission, premorbid modified Rankin scale (mRS), Alberta Stroke Program Early CT Score, age and side of occlusion were not associated with need for emergency intubation. Emergency intubation was associated with a lower rate of successful reperfusion (OR, 0.174; 95%-CI, 0.045 to 0.663; p = 0.01). Emergently intubated patients had higher in-house mortality (30% vs 6.4%; p = 0.001) and a lower rate of mRS 0-2 at 3 months was observed in those patients (10.5% vs 37%, p = 0.024)., Conclusions: Emergency intubation during a primary procedural sedation regimen for EVT was associated with lower rate of successful reperfusion. Less favorable outcome was observed in the subgroup of emergently intubated patients. More research is required to find practical predictors of intubation need and to determine, whether emergency intubation is safe under strict primary procedural sedation regimens for EVT.

Background and Purpose: Safety and efficacy of endovascular thrombectomy (EVT) in patients with mild stroke syndromes is unclear, especially in distal vessel occlusions., Methods: We analysed in our stroke database (HeiReKa) between 2002 and April 2019 safety and efficacy of EVT compared to intravenous thrombolysis (IVT) in patients with occlusions distal to the M1 segment of the middle cerebral artery and the top of the basilar artery who presented with a National Institute of Health Stroke Scale (NIHSS) below 6. Excellent (good) outcome was defined as modified rankin scale (mRS) 0-1 (0-2) or return to baseline mRS (good) after 3 months. Safety endpoints were mortality after 3 months and intracranial hemorrhage according to the Heidelberg Bleeding Classification (HBC)., Results: Of 4167 patients 94 met the inclusion criteria. Sixty-four patients were allocated to the IVT group and 30 to the EVT group of which 15 also received IVT; three patients (4.6%) in the IVT group received rescue EVT. Baseline characteristics did not differ but more M2 occlusions were found in the EVT group (93.3% vs. 64.1%, p = 0.02). Intracranial bleeding occurred more often in EVT patients (HBC class 2: 13.3% vs. 1.6%, p = 0.01). Excellent and good outcome were not significantly different (75% vs. 70%, p = 0.65 and 87.5% vs. 73.3%, p = 0.14). Mortality was significantly lower in IVT patients (1.6% vs. 13.3%, p = 0.04)., Conclusion: Rates of excellent and good outcome after IVT or EVT were almost similar, but safety parameters were increased after EVT. EVT may be considered in selected patients after careful risk/benefit analysis., Competing Interests: Declaration Competing of Interest Outside the published work personal fees, travel support, speaker honoraria, or research grants were received from Acandis (MAM), Bayer (PAR, SN), Brainomix (SN, CH), BMS Pfizer (PAR, SN), Boehringer Ingelheim (PAR, SN), Cerenovus (SN), Codman (MB, MAM), Medtronic (MAM, SN), Deutsche Forschungsgesellschaft (PAR), Microvention (MAM), Phenox (MAM), Siemens (JP) and Stryker (CH, JP, MAM). SN is a CO-PI of the ENDOLOW trial., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Several studies have shown that thrombectomy is safe and effective in occlusions of the M2 segment of the middle cerebral artery. This retrospective study compared superior and inferior division occlusions regarding radiological and clinical outcomes., Methods: Between 2009 and 2017, patients treated with thrombectomy due to occlusion of the superior or inferior division were selected. Univariate and multivariate analyses were performed to identify predictors of outcome and compare superior and inferior division occlusions., Results: A total of 140 patients with superior (n = 87) and inferior (n = 53) division occlusion were included. Of patients with inferior division occlusion 66.0% achieved good outcome compared to 48.3% in patients with superior division occlusion (P = 0.041). Time from groin puncture to reperfusion, recanalization success, complication rate, hemorrhage rate and follow-up infarct size were similar in both groups. Independent predictors of good outcome were baseline Alberta Stroke Program Early CT Score (ASPECTS) (odds ratio, OR 1.74, 95% confidence interval, CI 1.21-2.58, P = 0.004), time from groin puncture to reperfusion (OR 0.99, 95% CI 0.98-1.0, P = 0.019) and Thrombolysis In Cerebral Infarction (TICI) score 2b-3 (OR 4.51, 95% CI 1.31-18.74, P = 0.024). Superior division occlusion was an independent predictor of poor outcome (OR 2.41, 95% CI 1.05-5.80, P = 0.042). Dominance of the occluded vessel and side of occlusion were not predictive., Conclusion: Patients with superior division occlusion appear to have a lower chance of achieving good outcome despite similar recanalization rates and complication rates compared to inferior division occlusions.

Background and Purpose: Although the treatment window for mechanical thrombectomy (MT) in patients with acute ischemic stroke (AIS) has been extended in recent years, it has been proven that recanalizing treatment must be administered as soon as possible. We present a new standard operating procedure (SOP) to reduce in-house delay, standardize periinterventional management and improve patient safety during MT., Methods: KEep Evaluating Protocol Simplification In Managing Periinterventional Light Sedation for Endovascular Stroke Treatment (KEEP SIMPLEST) was a prospective, single-center observational study aimed to compare aspects of periinterventional management in AIS patients treated according to our new SOP using a combination of esketamine and propofol with patients having been randomized into conscious sedation (CS) in the Sedation versus Intubation for Endovascular Stroke TreAtment (SIESTA) trial. Primary outcome was early neurological improvement at 24h using the National Institutes of Health Stroke Scale, and secondary outcomes were door-to-recanalization, recanalization grade, conversion rate and modified Rankin Scale (mRS) at 3 months., Results: Door-to-recanalization time (128.6 ± 69.47 min vs. 156.8 ± 75.91 min; p = 0.02), mean duration of MT (92.01 ± 52 min vs. 131.9 ± 64.03 min; p < 0.001), door-to-first angiographic image (51.61 ± 31.7 min vs. 64.23 ± 21.53 min; p = 0.003) and computed tomography-to-first angiographic image time (31.61 ± 20.6 min vs. 44.61 ± 19.3 min; p < 0.001) were significantly shorter in the group treated under the new SOP. There were no differences in early neurological improvement, mRS at 3 months or other secondary outcomes between the groups. Conversion rates of CS to general anesthesia were similar in both groups., Conclusion: An SOP using a novel sedation regimen and optimization of equipment and procedures directed at a leaner, more integrative and compact periinterventional management can reduce in-house treatment delays significantly in stroke patients receiving thrombectomy in light sedation and demonstrated the safety and feasibility of our improved approach.

Objective: To identify simplified selection criteria for mechanical thrombectomy (MT) in longer and unknown time windows., Methods: Patients with large vessel occlusion (LVO) in the anterior circulation who underwent MT between January 2014 and November 2017 were identified from the local registry. Patients were selected for analysis if they met the current guideline recommendation for MT treatment except for time window (HERMES-like) and were divided according to time they were last seen well (LSW): LSW <6 hours or LSW >6 hours before MT. The primary endpoint, good outcome, was modified Rankin scale score 0-2 on day 90. Safety outcomes were mortality on day 90 and symptomatic intracranial hemorrhage (sICH). Univariate and multivariate analysis were performed for good outcome in HERMES-like patients., Results: In total, 752 patients were identified and 390 patients (51.9%) fulfilled the HERMES-like criteria. Despite differences in baseline parameters, more diffusion-weighted imaging (DWI) (43.9% vs 11.3%, p<0.001) and fewer cases of thrombolysis (32.7% vs 77%, p<0.001), patients LSW >6 hours (n=107) did not differ in the primary and secondary endpoints: good outcome (44.9% vs 44.9%, p=1.0), mortality (14% vs 15.2%, p=0.87), and sICH (5.6% vs 6%, p=1.0). After multivariate regression analysis, independent predictors of good outcome remained: age, OR=0.96 (95% CI 0.95 to 0.98); National Institutes of Health Stroke Scale score, OR=0.92 (95% CI 0.89 to 0.96); Alberta Stroke Programme Early CT Score (ASPECTS), OR=1.26 (95% CI 1.06 to 1.49); general anesthesia, OR=0.2 (95% CI 0.04 to 0.99), and successful recanalization, OR=12 (95% CI 4.7 to 30.5); but not treatment time and DWI or CT perfusion at baseline., Conclusion: Patients with proven LVO in unknown and longer time windows may be selected for MT based on ASPECTS and clinical criteria., Competing Interests: Competing interests: Outside the published work, personal fees, travel support, speaker honoraria, or research grants were received from Acandis (MAM), Bayer (MB, PAR, SN), Brainomix (SN, CH), BMS Pfizer (MB, PAR, SN), Boehringer Ingelheim (MB, PAR, SN), Codman (MB, MAM), Medtronic (MAM, SN, MB), Deutsche Forschungsgesellschaft (MB, PAR), Guerbet (MB), Hopp foundation (MB), Microvention (MAM), Phenox (MAM), Roche (MB), Siemens (MB, JARP) and Stryker (CH, JARP, MAM), TEVA (MB), Vascular Dynamics (MB)., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Intracranial hemorrhage (ICH) is a potentially severe complication after mechanical thrombectomy (MT). Here, we investigated risk factors for the occurrence of any and symptomatic ICH after MT due to large-vessel occlusion of the anterior circulation., Methods: Consecutive patients with acute ischemic anterior circulation stroke with large-vessel occlusion undergoing MT were analyzed. ICH was categorized according to the Heidelberg Bleeding Classification. Forty-three procedural and clinical parameters were analyzed using univariate tests and multivariate logistic regressions., Results: Of 612 patients, any ICH was detected in 195 (31.9%), while 27 (4.4%) developed a symptomatic ICH. Infarct size > 1/3 of vascular territory in control imaging (OR 2.18, 95% CI 1.45-3.21), higher serum glucose levels (OR 1.23 for change of 15 units mg/dL, 95% CI 1.10-1.39), and higher thrombectomy maneuver count (OR 1.21, 95% CI 1.11-1.32) were significantly associated with a higher risk of developing any ICH compared to no ICH. Wake-up strokes (OR 3.99, 95% CI 1.38-11.60), transfer from an external clinic (OR 3.04, 95% CI 1.24-7.48), and higher serum glucose levels (OR 1.22 for change of 15 units mg/dL, 95% CI 1.05-1.42) were revealed as independent risk factors for development of symptomatic ICH compared to no symptomatic ICH. Patients with no infarct demarcation (OR 0.10, 95% CI 0.01-0.80) and complete recanalization (OR 0.57, 95% CI 0.37-0.86) showed a lower risk of developing any ICH., Conclusion: Wake-up strokes and patients who are treated within a drip-and-ship concept are especially vulnerable for symptomatic ICH, while complete recanalization, contrary to subtotal recanalization only, was revealed as a protective factor against ICH.

Background and Purpose: The e-ASPECTS software is a tool for the automated use of ASPECTS. Our aim was to analyze whether baseline e-ASPECT scores correlate with outcome after mechanical thrombectomy., Materials and Methods: Patients with ischemic strokes in the anterior circulation who were admitted between 2010 and 2015, diagnosed by CT, and received mechanical thrombectomy were included. The ASPECTS on baseline CT was scored by e-ASPECTS and 3 expert raters, and interclass correlation coefficients were calculated. The e-ASPECTS was correlated with functional outcome (modified Rankin Scale) at 3 months by using the Spearman rank correlation coefficient. Unfavorable outcome was defined as mRS 4-6 at 3 months, and a poor scan was defined as e-ASPECTS 0-5., Results: Two hundred twenty patients were included, and 147 (67%) were treated with bridging protocols. The median e-ASPECTS was 9 (interquartile range, 8-10). Intraclass correlation coefficients between e-ASPECTS and raters were 0.72, 0.74, and 0.76 (all, P < .001). e-ASPECTS (Spearman rank correlation coefficient = -0.15, P = .027) correlated with mRS at 3 months. Patients with unfavorable outcome had lower e-ASPECTS (median, 8; interquartile range, 7-10 versus median, 9; interquartile range, 8-10; P = .014). Sixteen patients (7.4%) had a poor scan, which was associated with unfavorable outcome (OR, 13.6; 95% CI, 1.8-104). Independent predictors of unfavorable outcome were e-ASPECTS (OR, 0.79; 95% CI, 0.63-0.99), blood sugar (OR, 1.01; 95% CI, 1.004-1.02), atrial fibrillation (OR, 2.64; 95% CI, 1.22-5.69), premorbid mRS (OR, 1.77; 95% CI, 1.21-2.58), NIHSS (OR, 1.11; 95% CI, 1.04-1.19), general anesthesia (OR, 0.24; 95% CI, 0.07-0.84), failed recanalization (OR, 8.47; 95% CI, 3.5-20.2), and symptomatic intracerebral hemorrhage (OR, 25.8; 95% CI, 2.5-268)., Conclusions: The e-ASPECTS correlated with mRS at 3 months and was predictive of unfavorable outcome after mechanical thrombectomy, but further studies in patients with poor scan are needed., (© 2017 by American Journal of Neuroradiology.)

Background and Purpose: Embolization of thrombus fragments in a new vascular territory is a potential adverse event in neurothrombectomy. This study was performed to evaluate the safety and feasibility of a novel approach combining proximal balloon occlusion and distal aspiration to prevent distal thrombembolic complications., Methods: Patients with ischemic stroke meeting the following inclusion criteria were eligible: occlusion in the anterior circulation, neurothrombectomy using a balloon catheter for proximal flow arrest, and an intermediate catheter for distal aspiration. Pre- and post-interventional Thrombolysis In Cerebral Infarction (TICI) scores were assessed. Clinical presentation at admission and discharge and after 3 months was also evaluated and complications (particularly new thrombembolic events) were recorded., Results: We retrospectively identified 31 patients from our prospectively collected stroke database who met the inclusion criteria. In all patients the initial TICI was 0. A TICI score of ≥2b was achieved in 96.8%. No new thrombembolic complications occurred. The median NIH Stroke Scale score was 19 at admission and 4.5 at discharge. After 3 months, 51.6% of the patients had a favorable clinical outcome (modified Rankin Scale score 0-2) and 19.3% had died., Conclusions: A combination of proximal internal carotid artery occlusion using a balloon catheter and distal aspiration through an intermediate catheter represents a safe and efficient adjunct to mechanical thrombectomy with stent retrievers. In our patient cohort, no new thrombembolic complications were detected., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Importance: Optimal management of sedation and airway during thrombectomy for acute ischemic stroke is controversial due to lack of evidence from randomized trials., Objective: To assess whether conscious sedation is superior to general anesthesia for early neurological improvement among patients receiving stroke thrombectomy., Design, Setting, and Participants: SIESTA (Sedation vs Intubation for Endovascular Stroke Treatment), a single-center, randomized, parallel-group, open-label treatment trial with blinded outcome evaluation conducted at Heidelberg University Hospital in Germany (April 2014-February 2016) included 150 patients with acute ischemic stroke in the anterior circulation, higher National Institutes of Health Stroke Scale (NIHSS) score (>10), and isolated/combined occlusion at any level of the internal carotid or middle cerebral artery., Intervention: Patients were randomly assigned to an intubated general anesthesia group (n = 73) or a nonintubated conscious sedation group (n = 77) during stroke thrombectomy., Main Outcomes and Measures: Primary outcome was early neurological improvement on the NIHSS after 24 hours (0-42 [none to most severe neurological deficits; a 4-point difference considered clinically relevant]). Secondary outcomes were functional outcome by modified Rankin Scale (mRS) after 3 months (0-6 [symptom free to dead]), mortality, and peri-interventional parameters of feasibility and safety., Results: Among 150 patients (60 women [40%]; mean age, 71.5 years; median NIHSS score, 17), primary outcome was not significantly different between the general anesthesia group (mean NIHSS score, 16.8 at admission vs 13.6 after 24 hours; difference, -3.2 points [95% CI, -5.6 to -0.8]) vs the conscious sedation group (mean NIHSS score, 17.2 at admission vs 13.6 after 24 hour; difference, -3.6 points [95% CI, -5.5 to -1.7]); mean difference between groups, -0.4 (95% CI, -3.4 to 2.7; P = .82). Of 47 prespecified secondary outcomes analyzed, 41 showed no significant differences. In the general anesthesia vs the conscious sedation group, substantial patient movement was less frequent (0% vs 9.1%; difference, 9.1%; P = .008), but postinterventional complications were more frequent for hypothermia (32.9% vs 9.1%; P < .001), delayed extubation (49.3% vs 6.5%; P < .001), and pneumonia (13.7% vs 3.9%; P = .03). More patients were functionally independent (unadjusted mRS score, 0 to 2 after 3 months [37.0% in the general anesthesia group vs 18.2% in the conscious sedation group P = .01]). There were no differences in mortality at 3 months (24.7% in both groups)., Conclusions and Relevance: Among patients with acute ischemic stroke in the anterior circulation undergoing thrombectomy, conscious sedation vs general anesthesia did not result in greater improvement in neurological status at 24 hours. The study findings do not support an advantage for the use of conscious sedation., Trial Registration: clinicaltrials.gov Identifier: NCT02126085.

Background: The Alberta Stroke Program Early CT score (ASPECTS) is an established 10-point quantitative topographic computed tomography scan score to assess early ischemic changes. We compared the performance of the e-ASPECTS software with those of stroke physicians at different professional levels., Methods: The baseline computed tomography scans of acute stroke patients, in whom computed tomography and diffusion-weighted imaging scans were obtained less than two hours apart, were retrospectively scored by e-ASPECTS as well as by three stroke experts and three neurology trainees blinded to any clinical information. The ground truth was defined as the ASPECTS on diffusion-weighted imaging scored by another two non-blinded independent experts on consensus basis. Sensitivity and specificity in an ASPECTS region-based and an ASPECTS score-based analysis as well as receiver-operating characteristic curves, Bland-Altman plots with mean score error, and Matthews correlation coefficients were calculated. Comparisons were made between the human scorers and e-ASPECTS with diffusion-weighted imaging being the ground truth. Two methods for clustered data were used to estimate sensitivity and specificity in the region-based analysis., Results: In total, 34 patients were included and 680 (34 × 20) ASPECTS regions were scored. Mean time from onset to computed tomography was 172 ± 135 min and mean time difference between computed tomographyand magnetic resonance imaging was 41 ± 31 min. The region-based sensitivity (46.46% [CI: 30.8;62.1]) of e-ASPECTS was better than three trainees and one expert (p ≤ 0.01) and not statistically different from another two experts. Specificity (94.15% [CI: 91.7;96.6]) was lower than one expert and one trainee (p < 0.01) and not statistically different to the other four physicians. e-ASPECTS had the best Matthews correlation coefficient of 0.44 (experts: 0.38 ± 0.08 and trainees: 0.19 ± 0.05) and the lowest mean score error of 0.56 (experts: 1.44 ± 1.79 and trainees: 1.97 ± 2.12)., Conclusion: e-ASPECTS showed a similar performance to that of stroke experts in the assessment of brain computed tomographys of acute ischemic stroke patients with the Alberta Stroke Program Early CT score method., (© 2016 World Stroke Organization.)

Background and Purpose: Patients with acute ischemic stroke in the anterior circulation are at risk for either primary or, following mechanical thrombectomy, secondary occlusion of the anterior cerebral artery. Because previous studies had only a limited informative value, we report our data concerning the frequency and location of distal anterior cerebral artery occlusions, recanalization rates, periprocedural complications, and clinical outcome., Materials and Methods: We performed a retrospective analysis of prospectively collected data of patients with acute ischemic stroke undergoing mechanical thrombectomy in the anterior circulation between June 2010 and April 2015., Results: Of 368 patients included in this analysis, we identified 30 (8.1%) with either primary (n = 17, 4.6%) or secondary (n = 13, 3.5%) embolic occlusion of the distal anterior cerebral artery. The recanalization rate after placement of a stent retriever was 88%. Periprocedural complications were rare and included vasospasms (n = 3, 10%) and dissection (n = 1, 3.3%). However, 16 (53.5%) patients sustained an (at least partial) infarction of the anterior cerebral artery territory. Ninety days after the ictus, clinical outcome according to the modified Rankin Scale score was the following: 0-2, n = 11 (36.6%); 3-4, n = 9 (30%); 5-6, n = 10 (33.3%)., Conclusions: Occlusions of the distal anterior cerebral artery affect approximately 8% of patients with acute ischemic stroke in the anterior circulation receiving mechanical thrombectomy. Despite a high recanalization rate and a low complication rate, subsequent (partial) infarction in the anterior cerebral artery territory occurs in approximately half of patients. Fortunately, clinical outcome appears not to be predominately unfavorable., (© 2016 by American Journal of Neuroradiology.)

Background: Despite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM), increased in GBM, could contribute to chemoresistance and TMZ-induced recurrence of glioblastoma., Methods: TMZ inducibility of metalloproteases was determined in GBM cell lines, primary GBM cells, and tissues from GBM and recurrent GBM. TMZ sensitivity and invasiveness of GBM cells were assessed in the presence of the metalloprotease inhibitors batimastat (BB-94) and marimastat (BB-2516). Metalloprotease-dependent effects of TMZ on mitochondria and pAkt/phosphatidylinositol-3 kinase (PI3K) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) pathways were analyzed by fluorescence activated cell sorting, morphometry, and immunoblotting. Invasiveness of GBM cells was determined by Matrigel invasion assays. Potential metalloprotease substrates were identified by proteomics and tested for invasion using blocking antibodies., Results: TMZ induces expression of MMP-1, -9, -14, and ADAM8 in GBM cells and in recurrent GBM tissues. BB-94, but not BB-2516 (ADAM8-sparing) increased TMZ sensitivity of TMZ-resistant and -nonresistant GBM cells with different O(6)-methylguanine-DNA methyltransferase states, suggesting that ADAM8 mediates chemoresistance, which was confirmed by ADAM8 knockdown, ADAM8 overexpression, or pharmacological inhibition of ADAM8. Levels of pAkt and pERK1/2 were increased in GBM cells and correlated with ADAM8 expression, cell survival, and invasiveness. Soluble hepatocyte growth factor (HGF) R/c-met and CD44 were identified as metalloprotease substrates in TMZ-treated GBM cells. Blocking of HGF R/c-met prevented TMZ-induced invasiveness., Conclusions: ADAM8 causes TMZ resistance in GBM cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met. Specific ADAM8 inhibition can optimize TMZ chemotherapy of GBM in order to prevent formation of recurrent GBM in patients., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging-related neurodegenerative diseases, such as Parkinson's disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, we studied LC neurons using electrophysiological and optical approaches in ex vivo mouse brain slices. We found that autonomous activity in LC neurons was accompanied by oscillations in dendritic Ca(2+) concentration that were attributable to the opening of L-type Ca(2+) channels. This oscillation elevated mitochondrial oxidant stress and was attenuated by inhibition of nitric oxide synthase. The relationship between activity and stress was malleable, as arousal and carbon dioxide increased the spike rate but differentially affected mitochondrial oxidant stress. Oxidant stress was also increased in an animal model of PD. Thus, our results point to activity-dependent Ca(2+) entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons.

This article provides a systematic framework for the evaluation of the movement toward hybrid pension plans by examining the reasons given by firms for converting their existing pension plans to hybrid plans, illustrating the impact of plan changes on expected pension benefits, and identifying winners and losers.

In preparing for retirement, employees need to consider not only their pension benefits but also the challenge of financing their retirement health care needs. Various trends evolving in our society indicate that future retirees will be increasingly dependent on their own retirement savings. Evidence suggests that employees are not fully aware of the significance of health costs in retirement and must be educated to the need to save for retiree health care expenses. This article discusses the issues of Medicare reduction and retiree health benefit cutbacks and the relative communication and education challenges such issues pose to employers.

This article addresses a range of questions about participation and nonparticipation in the supplemental security income (SSI) program with data collected by the Survey of Low-Income Aged and Disabled (SLIAD) during 1973 and 1974: (1) Can SSI's relatively modest growth be attributed to initial overestimates of the eligible population or to low rates of participation among eligibles? (2) If the latter, what factors inhibited program participation? (3) What is the relation between program participation in SSI's initial years and at the present time? (4) If the factors that initially inhibited participation have not significantly changed, what are the present implications for program policy? The first section of this article discusses the size and composition of the program's target population. Various estimates of the eligible SSI population are compared with microsimulation estimates based on SLIAD. The second section presents the theoretical and empirical framework used to analyze the factors associated with nonparticipation in SSI. The theory of nonparticipation, developed in the context of the "alternative income hypothesis," is presented in a series of propositions used to empirically verify the theory. The third section discusses the factors related to participation in the SSI program during and after the phase-in period. Subsequent response to SSI is presented in a discussion of outreach efforts and trends in program applications and program enrollments. The final section discusses the implications of the existence of an eligible nonparticipant population and what, if any, changes could be made to increase program involvement.

During 1973, interviews were conducted with more than 11,000 adult assistance recipients in the Survey of the Low-Income Aged and Disabled. The sample members were reinterviewed during the last 3 months of 1974, approximately 1 year after the implementation of SSI. This article analyzes the impact of SSI on the economic status of the 1973 adult assistance populations. The analysis considers the United States sample as well as samples for five individual States. Most of the 1973 adult assistance recipients were automatically transferred to SSI on January 1, 1974. The majority realized an improved economic situation during 1974, at least in part because of their transferral to SSI. There was significant improvement for the residents of each of the separate States considered because of increased assistance payments, but SSI generally proved most beneficial to the poorest persons transferred from the State public assistance programs.