Neuronal development requires a complex choreography of transcriptional decisions to obtain specific cellular identities. Realizing the ultimate goal of identifying genome-wide signatures that define ...and drive specific neuronal fates has been hampered by enormous complexity in both time and space during development. Here, we have paired high-throughput purification of pyramidal neuron subclasses with deep profiling of spatiotemporal transcriptional dynamics during corticogenesis to resolve lineage choice decisions. We identified numerous features ranging from spatial and temporal usage of alternative mRNA isoforms and promoters to a host of mRNA genes modulated during fate specification. Notably, we uncovered numerous long noncoding RNAs with restricted temporal and cell-type-specific expression. To facilitate future exploration, we provide an interactive online database to enable multidimensional data mining and dissemination. This multifaceted study generates a powerful resource and informs understanding of the transcriptional regulation underlying pyramidal neuron diversity in the neocortex.
Summary Background Preclinical models of stroke have shown that intravenous glyburide reduces brain swelling and improves survival. We assessed whether intravenous glyburide (RP-1127; glibenclamide) ...would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction. Methods For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18–80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82–300 cm3 on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous glyburide group. Intravenous glyburide was given as a 0·13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0·16 mg/h for the first 6 h and then 0·11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov , number NCT01794182. Findings Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous glyburide group and 14 (39%) in the placebo group had an mRS score of 0–4 at 90 days without decompressive craniectomy (adjusted odds ratio 0·87, 95% CI 0·32–2·32; p=0·77). Ten (23%) of 44 participants in the intravenous glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0·76), and four of 20 had serious adverse events (two in the intravenous glyburide group and two in the placebo group, p=1·00). One cardiac death occurred in each group (p=1·00). Interpretation Intravenous glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous glyburide. Funding Remedy Pharmaceuticals.
Objective
We tested the hypothesis that there are readily classifiable electroencephalographic (EEG) phenotypes of early postanoxic multifocal myoclonus (PAMM) that develop after cardiac arrest.
...Methods
We studied a cohort of consecutive comatose patients treated after cardiac arrest from January 2012 to February 2015. For patients with clinically evident myoclonus before awakening, 2 expert physicians reviewed and classified all EEG recordings. Major categories included: Pattern 1, suppression‐burst background with high‐amplitude polyspikes in lockstep with myoclonic jerks; and Pattern 2, continuous background with narrow, vertex spike‐wave discharges in lockstep with myoclonic jerks. Other patterns were subcortical myoclonus and unclassifiable. We compared population characteristics and outcomes across these EEG subtypes.
Results
Overall, 401 patients were included, of whom 69 (16%) had early myoclonus. Among these patients, Pattern 1 was the most common, occurring in 48 patients (74%), whereas Pattern 2 occurred in 8 patients (12%). The remaining patients had subcortical myoclonus (n = 2, 3%) or other patterns (n = 7, 11%). No patients with Pattern 1, subcortical myoclonus, or other patterns survived with favorable outcome. By contrast, 4 of 8 patients (50%) with Pattern 2 on EEG survived, and 4 of 4 (100%) survivors had favorable outcomes despite remaining comatose for 1 to 2 weeks postarrest.
Interpretation
Early PAMM is common after cardiac arrest. We describe 2 distinct patterns with distinct prognostic significances. For patients with Pattern 1 EEGs, it may be appropriate to abandon our current clinical standard of aggressive therapy with conventional antiepileptic therapy in favor of early limitation of care or novel neuroprotective strategies. Ann Neurol 2016;80:175–184
BACKGROUND AND PURPOSE—In patients identified at referring facilities with acute ischemic stroke caused by a large vessel occlusion, bypassing the emergency department (ED) with direct transport to ...the neuroangiography suite may safely shorten reperfusion times.
METHODS—We conducted a single-center retrospective review of consecutive patients transferred to our facility for consideration of endovascular therapy. Patients were identified as admitted directly to the neuroangiography suite (DAN), transferred to the ED before intra-arterial therapy (ED-IA), and transferred to the ED but did not receive IA therapy (ED-IV).
RESULTS—A retrospective review of a prospectively maintained database of transfer patients between January 2013 and October 2016 with large vessel occlusions identified 108 ED-IV patients and 261 patients who underwent mechanical thrombectomy (DAN=111 patients and ED-IA=150 patients). There were no differences in baseline characteristics among the 3 groups. The median computed tomography ASPECTS (Alberta Stroke Program Early CT Score) was lower in the ED-IV group versus the ED-IA and DAN groups (8 versus 9; P=0.001). In the DAN versus ED-IA cohort, there were comparable rates of TICI2b/3 recanalization and access to recanalization time. There was significantly faster hospital arrival to groin access time in the DAN cohort (81 minutes versus 22 minutes; P=0.001). Functional independence at 90 days was comparable in the DAN versus ED-IA cohorts but worse in the ED-IV group (43% versus 44% versus 22%; P=0.001).
CONCLUSIONS—DAN is safe, feasible, and associated with faster times of hospital arrival to recanalization. The clinical benefit of this approach should be assessed in a prospective randomized trial.
OBJECTIVEIn this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints.
...METHODSBlinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined.
RESULTSIn the per-protocol sample, 41 patients received glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 58.5% in IV glyburide vs n = 23 63.9% in placebo, p = 0.91) or the incidence of malignant edema (n = 19 46% in IV glyburide vs n = 17 47% in placebo, p = 0.94). However, treatment with IV glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 2.4% with IV glyburide vs n = 8 22.2% with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV glyburide had less midline shift (p < 0.01) and reduced MMP-9 (matrix metalloproteinase 9) levels (p < 0.01). The glyburide treatment group had lower rate of NIH Stroke Scale (NIHSS) increase of ≥4 during the infusion period (n = 7 37% in IV glyburide vs n = 12 71% in placebo, p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 58% vs n = 15 94%, p = 0.016).
CONCLUSIONIV glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV glyburide in large hemispheric infarction are warranted to corroborate these findings.
CLINICALTRIALS.GOV IDENTIFIERNCT01794182.
LEVEL OF EVIDENCEThis study provides Class II evidence that for patients with large hemispheric infarction, IV glyburide improves some edema-related endpoints.
BACKGROUND AND PURPOSE—The results of the DAWN trial (Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting ...Strokes Undergoing Neurointervention With Trevo) support the benefit of endovascular therapy in patients presenting beyond the 6-hour time window with anterior circulation large vessel occlusions. The impact of these results with respect to additional number of eligible patients in clinical practice remains unknown.
METHODS—A retrospective review of ischemic stroke admissions to a single DAWN trial-participating comprehensive stroke center was performed during the DAWN enrollment period (November 2014 to February 2017) to identify patients meeting criteria for DAWN and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke-3) eligibility. Patients presenting beyond 6 hours were further investigated to clarify reasons for trial exclusion.
RESULTS—Of the 2667 patients with acute ischemic stroke admitted within the study period, 30% (n=792) presented within the 6- to 24-hour time window, and 47% (n=1242) had a National Institutes of Health Stroke Scale ≥6. Further clinical trial-specific selection criteria were applied based on the presence of large vessel occlusion, baseline modified Rankin Scale score, core infarct, and perfusion imaging (when available). There were 45 patients who met all DAWN trial criteria and 47 to 58 patients who would meet DEFUSE-3 trial criteria. Thirty-three percent of DAWN-eligible patients are DEFUSE-3 ineligible.
CONCLUSIONS—Of all patients with acute ischemic stroke presenting to a single comprehensive stroke center, 1.7% of patients qualified for DAWN clinical trial enrollment with an additional 0.6% to 1% qualifying for the DEFUSE-3 trial. These data predict an increase in thrombectomy utilization with important implications for comprehensive stroke center resource optimization and stroke systems of care.
Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in ...cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation.
In a trial of minimally invasive cerebral hematoma removal within 24 hours after onset of hemorrhage, functional outcomes were better with surgery than with medical treatment, particularly among ...patients with lobar hemorrhages.
The molecular mechanisms controlling the differentiation of neural progenitors into distinct subtypes of neurons during neocortical development are unknown. Here, we report that
Fezl is required for ...the specification of corticospinal motor neurons and other subcerebral projection neurons, which are absent from
Fezl null mutant neocortex. There is neither an increase in cell death in
Fezl
−/−
cortex nor abnormalities in migration, indicating that the absence of subcerebral projection neurons is due to a failure in fate specification. In striking contrast, other neuronal populations in the same and other cortical layers are born normally. Overexpression of
Fezl results in excess production of subcerebral projection neurons and arrested migration of these neurons in the germinal zone. These data indicate that
Fezl plays a central role in the specification of corticospinal motor neurons and other subcerebral projection neurons, controlling early decisions regarding lineage-specific differentiation from neural progenitors.
Care of the Post-Thrombectomy Patient Jadhav, Ashutosh P; Molyneaux, Bradley J; Hill, Michael D ...
Stroke,
2018-November, Letnik:
49, Številka:
11
Journal Article
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