Missed Ischemic Stroke Diagnosis in the Emergency Department by Emergency Medicine and Neurology Services.

BACKGROUND AND PURPOSE: The failure to recognize an ischemic stroke in the emergency department is a missed opportunity for acute interventions and for prompt treatment with secondary prevention therapy. Our study examined the diagnosis of acute ischemic stroke in the emergency department of an academic teaching hospital and a large community hospital. METHODS: A retrospective chart review was performed from February 2013 to February 2014. RESULTS: A total of 465 patients with ischemic stroke were included in the analysis; 280 patients from the academic hospital and 185 patients from the community hospital. One hundred three strokes were initially misdiagnosed that is 22% of the included strokes at the combined centers. Fifty-five of these were missed at the academic hospital (22%) [corrected] and 48 were at the community hospital (26%, P=0.11). Thirty-three percent of missed cases presented within a 3-hour time window for recombinant tissue-type plasminogen activator eligibility. An additional 11% presented between 3 and 6 hours of symptom onset for endovascular consideration. Symptoms independently associated with greater odds of a missed stroke diagnosis were nausea/vomiting (odds ratio, 4.02; 95% confidence interval, 1.60-10.1), dizziness (odds ratio, 1.99; 95% confidence interval, 1.03-3.84), and a positive stroke history (odds ratio, 2.40; 95% confidence interval, 1.30-4.42). Thirty-seven percent of posterior strokes were initially misdiagnosed compared with 16% of anterior strokes (P<0.001). CONCLUSIONS: Atypical symptoms associated with posterior circulation strokes lead to misdiagnoses. This was true at both an academic center and a large community hospital. Future studies need to focus on the evaluation of identification systems and tools in the emergency department to improve the accuracy of stroke diagnosis.

Malignant cerebral edema after large anterior circulation infarction: a review.

OPINION STATEMENT: Malignant infarction implies a large middle cerebral artery (MCA) stroke that leads to rapid clinical deterioration and edema formation, and can be associated with hemorrhagic transformation, herniation, and poor functional outcomes, including death. Malignant edema is brain edema formation that occurs in the setting of large territory infarction. This review discusses the most recent efforts in diagnosis, prevention, and management of malignant edema in acute ischemic strokes.

Intracellular domain of the IFNaR2 interferon receptor subunit mediates transcription via Stat2.

We recently demonstrated that IFNaR2, a subunit of the interferon receptor, can be proteolytically cleaved in response to interferon-alpha and other activators of protein kinase C. Cleavage occurs at multiple sites, via a mechanism similar to that employed by Notch and the Alzheimer's precursor protein, and releases the intracellular domain (ICD). In this study, we demonstrate that the IFNaR2 ICD, when fused to the yeast Gal4 DNA binding domain (Gal4DBD) selectively modulates transcription of four different promoters under the control of Gal4 upstream activating sequences. We previously showed that Stat2 binds constitutively to the ICD of IFNaR2, in a manner that is independent of tyrosine phosphorylation. Here, we show that ICD transcriptional modulation is dependent upon the carboxyl-terminal transactivation domain of Stat2. Specifically, complementing Stat2 deficient cells with wild-type Stat2 restored the ICD-mediated transcriptional effects while complementation with a mutant form of Stat2 lacking the transcriptional activation domain (TAD) did not. In addition, mutation of the Stat2 binding site on the ICD reduced the transcriptional activity of the Gal4DBD-ICD. Finally, we demonstrate that the activity of Jak1, a tyrosine kinase also known to bind to IFNaR2, is required for ICD-mediated transcriptional effects.

Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor.

The type I interferons (IFNs) bind surface receptors, induce JAK kinases and activate STAT transcription factors to stimulate the transcription of genes downstream of IFN-stimulated response elements (ISREs). In this study, we demonstrate that IFNaR2, a subunit of the type I IFN receptor, is proteolytically cleaved in a regulated manner. Immunoblotting shows that multi-step cleavage occurs in response to phorbol ester (PMA) and IFN-alpha, generating both a transmembrane 'stub' and the intracellular domain (ICD), similar to Notch proteolysis. Isolated membrane fractions process IFNaR2 to release the ICD. A chimeric receptor construct is utilized to show that cleavage requires the presenilins and occurs in response to epidermal growth factor and protein kinase C-delta overexpression, as well as PMA and type I IFNs. Fluorescence microscopy demonstrates that a green fluorescent protein-ICD fusion localizes predominantly to the nucleus. A fusion between the ICD and the Gal4 DNA-binding domain represses transcription, in a histone deacetylase-dependent manner, of a Gal4 upstream activating sequence-regulated reporter, while overexpression of the ICD alone represses transcription of a reporter linked to an ISRE. Proteolytic cleavage events may facilitate receptor turnover or, more likely, function as a mechanism for signaling similar to that employed by Notch and the Alzheimer's precursor protein.

Stat2 binding to the interferon-alpha receptor 2 subunit is not required for interferon-alpha signaling.

The interferon-alpha (IFNalpha) receptor consists of two subunits, the IFNalpha receptor 1 (IFNaR1) and 2 (IFNaR2) chains. Following ligand binding, IFNaR1 is phosphorylated on tyrosine 466, and this site recruits Stat2 via its SH2 domain. In contrast, IFNaR2 binds Stat2 constitutively. In this study we have characterized the Stat2-IFNaR2 interaction and examined its role in IFNalpha signaling. Stat2 binds the major IFNaR2 protein but not a variant containing a shorter cytoplasmic domain. The interaction does not require a STAT SH2 domain. Both tyrosine-phosphorylated and non-phosphorylated Stat2 bind IFNaR2 in vitro; however, relatively little phosphorylated Stat2 associates with IFNaR2 in vivo. In vitro binding assays defined IFNaR2 residues 418-444 as the minimal interaction domain and site-specific mutation of conserved acidic residues within this domain disrupted in vitro and in vivo binding. An IFNaR2 construct carrying these mutations was either (i) overexpressed in 293T cells or (ii) used to complement IFNaR2-deficient U5A cells. Unexpectedly, the activity of an IFNalpha-dependent reporter gene was not reduced but, instead, was enhanced up to 2-fold. This suggests that this particular IFNaR2-Stat2 interaction is not required for IFNalpha signaling, but might act to negatively inhibit signaling. Finally, a doubly truncated recombinant fragment of Stat2, spanning residues 136-702, associated with IFNaR2 in vitro, indicating that the interaction with IFNaR2 is direct and occurs in a central region of Stat2 marked by a hydrophobic core.