Emergent use of ticagrelor during endovascular reperfusion in large arterial occlusions.

OBJECTIVE: Given many emerging indications for endovascular interventions in ischemic strokes, a safe and effective adjuvant antiplatelet regimen for acute revascularization has become a subject of interest. Ticagrelor is a direct oral P2Y12 inhibitor that may achieve rapid platelet suppression than standard oral therapies. We report our experience of Ticagrelor use in revascularization of acute large arterial steno-occlusive disease, describing procedural post-procedure thrombotic events, major hemorrhages, and other clinical outcomes. METHODS: This was a single-center retrospective case series of large steno-occlusive disease requiring endovascular reperfusion with emergent adjuvant Ticagrelor, defined as 30 min of the procedure from skin puncture to closure of the arteriotomy. Major outcomes investigated were thromboembolism in the target artery, and symptomatic intracranial or extracranial major hemorrhages. Additional analyses were performed with respect to timing of the administration and use of rescue GPIIb/IIIa inhibitors if any. RESULTS: 73 consecutive patients were identified, presenting with severe ischemic stroke (median NIHSS 16) of large artery origin. 67% required stent placement (45% cervical carotid, 22% intracranial artery), 9.5% angioplasty and 23% mechanical thrombectomy only. Two experienced symptomatic in-stent occlusion, and 7 experienced major hemorrhages (9.5%) including 3 fatal symptomatic intracranial hemorrhages (4.1%). Among 19 subjects (26%) who received pretreatment with Ticagrelor, there were fewer GPIIb/IIIa administration, angioplasty and stenting, without yielding benefit in functional outcome or mortality. GPIIb/IIIa was administered as rescue therapy in 45 subjects (62%), which was found associated with increased bleeding compared to patients receiving Ticagrelor only, in whom no bleeding complications were recorded (16% vs. 0%; p = 0.03). CONCLUSION: We report our findings on Ticagrelor as an adjuvant antiplatelet therapy in ischemic stroke of large arterial origin requiring emergent revascularization. Effectiveness, safety, need for additional rescue treatment, and comparison to other commonly used oral antiplatelets should be investigated in future prospective studies.

Intracranial atherosclerosis: Review of imaging features and advances in diagnostics.

Intracranial atherosclerotic disease is one of the leading causes of ischemic strokes and poses a moderate risk of recurrence. Diagnosis is currently limited to stenosis on luminal imaging, which likely underestimates the true prevalence of the disease. Detection of non-stenosing intracranial atherosclerosis is important in order to optimize secondary stroke prevention strategies. This review collates findings from the early seminal trials and the latest studies in advanced radiological techniques that characterize symptomatic intracranial atherosclerotic disease across various imaging modalities. While computed tomography angiography (CTA) and magnetic resonance angiography (MRA) comprise diagnostic mainstays in identifying stenotic changes secondary to atherosclerosis, emerging techniques such as high-resolution MRA, quantitative MRA, and computational fluid dynamics may reveal a myriad of other underlying pathophysiological mechanisms.

Intracranial atherosclerotic disease mechanistic subtypes drive hypoperfusion patterns.

BACKGROUND AND PURPOSE: In symptomatic intracranial atherosclerotic stenosis (ICAS), borderzone infarct pattern and perfusion mismatch are associated with increased risk of recurrent strokes, which may reflect the shared underlying mechanism of hypoperfusion distal to the intracranial atherosclerosis. Accordingly, we hypothesized a correlation between hypoperfusion volumes and ICAS infarct patterns based on the respective underlying mechanistic subtypes. METHODS: We conducted a retrospective analysis of consecutive symptomatic ICAS cases, acute strokes due to subocclusive (50%-99%) intracranial stenosis. The following mechanistic subtypes were assigned based on the infarct pattern on the diffusion-weighted imaging: Branch occlusive disease (BOD), internal borderzone (IBZ), and thromboembolic (TE). Perfusion parameters, obtained concurrently with the MRI, were studied in each group. RESULTS: A total of 42 patients (57% women, mean age 71 ± 13 years old) with symptomatic ICAS received MRI within 24 h of acute presentation. Fourteen IBZ, 11 BOD, and 17 TE patterns were identified. IBZ pattern yielded higher total Tmax > 4 s and Tmax > 6 s perfusion delay volumes, as well as corresponding Tmax  > 4 s and Tmax  > 6 s mismatch volume, compared to BOD. TE pattern exhibited greater median Tmax  > 6 s hypoperfusion delay in volume compared to BOD. In IBZ versus TE, the volume difference between Tmax > 4 s and Tmax > 6 s (Δ Tmax  > 4 s - Tmax  > 6 s) was substantially greater. CONCLUSION: ICAS infarct patterns, in keeping with their respective underlying mechanisms, may correlate with distinct perfusion profiles.

Carotid Webs in Cryptogenic Ischemic Strokes: A Matched Case-Control Study.

BACKGROUND: Young individuals with symptomatic carotid webs may be predisposed to ischemic strokes. However, evidence remains scarce. This investigation reports the frequency of carotid webs among patients with cryptogenic strokes compared to a control group. METHODS: Consecutive cryptogenic ischemic strokes and trauma patients were identified. Additional inclusion criteria required age 18-60 years and availability of head/neck computed tomography (CT) angiography. CT angiogram (CTA) neck images were evaluated independently by 2 fellowshiptrained specialists. A carotid web was defined by a shelf-like, linear filling defect in the posterior internal carotid artery bulb. RESULTS: Of 1877 patients presenting with ischemic strokes in 2015-2017, 165 were diagnosed with cryptogenic strokes, 51 of whom met the inclusion criteria of age and CTA availability. Fifty one trauma cases were matched for age and sex. After imaging analysis, 13 carotid webs (25%) were identified in the 51 cryptogenic stroke group versus 0 (0%; P < .001) in trauma subjects. Thirty-nine of the 51 cryptogenic ischemic stroke patients were found with carotid anterior distribution infarcts, of which 9 (23%) were found with ipsilateral carotid webs. There were more proximal large vessel occlusions in the cryptogenic patients with carotid webs, compared to those without (P = .04). All carotid webs led to less than 30% degree of stenosis. CONCLUSIONS: Carotid webs were found at a significantly higher frequency in patients with cryptogenic ischemic strokes compared to controls, indicating a potentially thrombogenic nature of these lesions in young patients. Additionally, intracranial large vessel occlusions were more common in patients with symptomatic carotid webs, presenting with ipsilateral strokes.

Current Understanding and Gaps in Research of Carotid Webs in Ischemic Strokes: A Review.

Importance: A succession of research has explored the linkage between carotid webs (CaWs) and ischemic strokes. Imaging and pathologic analysis have defined CaW as an intimal variant of fibromuscular dysplasia, which appears as a shelflike lesion on the posterior aspect of the carotid bulb, more specifically at the origin of internal carotid artery. Reported findings of carotid webs in young patients with recurrent ischemic strokes without an otherwise determined cause have raised questions about the mechanism, natural history, and need for intervention. This review addresses the current understanding of CaW and highlights findings that prompt further investigation into this unique vascular entity as a modifiable stroke risk factor. Observations: Imaging analysis demonstrates hemodynamic disturbance in the presence of CaWs. The protuberant shelflike structure creates a pocket therein that may subsequently lead to local thrombosis and cerebral embolism. Computed tomographic angiography is an accurate and often used noninvasive diagnostic modality. Although treatment paradigms have not been systematically evaluated, antiplatelet monotherapy may not be sufficient to reduce recurrent ischemic events in the small series of patients with stroke and symptomatic CaWs. Conclusions and Relevance: The limited clinical data on CaWs, although complicated by selection bias, suggest an increased prevalence of these vascular entities in cerebral ischemic events among patients younger than 60 years. Imaging suggests CaW to be a possible nidus for cerebral thromboembolism. Physicians should consider CaW as a cause of stroke in younger patients with anterior circulation ischemic strokes of an otherwise undetermined cause. Treatment options in CaWs with ischemic strokes have not been extensively investigated. Multicenter observational studies evaluating the natural history of CaW are warranted.

Endovascular Recanalization of Symptomatic Intracranial Arterial Stenosis Despite Aggressive Medical Management.

BACKGROUND: The optimal management of intracranial arterial stenosis is unclear, particularly in patients who have failed medical management. We report a multicenter real-world experience of endovascular recanalization of intracranial atherosclerotic stenosis refractory to aggressive medical therapy. METHODS: Retrospective multicenter case series of consecutive endovascularly treated patients presenting with symptomatic (transient ischemic attack [TIA] or stroke) intracranial stenosis who had failed medical therapy. Patients were divided into 2 groups: patients with recurrent TIA or stroke despite medical management (group 1) versus patients presenting with a stroke and worsening symptoms (progressive or crescendo stroke) despite medical management (group 2). RESULTS: A total of 101 patients were treated in 8 stroke centers from August 2009 to May 2017. Sixty-nine presented with recurrent TIA or stroke and 32 with stroke and worsening symptoms. Successful recanalization was achieved in 84% of patients. Periprocedural stroke occurred in 3 patients and 2 had a recurrent ischemic stroke at the 90-day follow-up. Symptomatic intraparenchymal hemorrhage secondary to reperfusion injury occurred in 3 patients and 1 had a hemorrhagic stroke after discharge. There were 2 periprocedural perforations that resulted in death. At 90 days, 86% of patients (64/74) did not have a recurrence of stroke and the 90-day cumulative ischemic stroke rate was 6.7% with 90-day mortality of 11.2%. The 90-day favorable outcome (modified Rankin Scale score, ≤2) rate was 77.5%. CONCLUSIONS: Endovascular recanalization of unstable intracranial atherosclerotic stenosis in patients who have failed medical therapy is feasible. Future randomized trials need to determine if recanalization is of any value for this population.

Hyperacute unilateral contrast-induced parotiditis during cerebral angiography.

An uncommon complication of iodinated contrast administration is the development of bilateral sialadenitis. We report a unique case of hyperacute unilateral parotiditis during diagnostic cerebral angiography of the external carotid artery, which mimicked possible iatrogenic vascular event associated with cerebral endovascular procedures. Discussion includes the differential diagnosis, diagnostic studies, and treatments for this unusual condition.

Phase 2 enzyme inducer sulphoraphane blocks prostaglandin and nitric oxide synthesis in human articular chondrocytes and inhibits cartilage matrix degradation.

OBJECTIVE: We explored the inhibitory effect of sulphoraphane (SFN), a potent inducer of Phase 2 enzymes, on cytokine-induced prostaglandin E(2) (PGE2) and nitric oxide (NO) production and cartilage degradation in articular chondrocytes. The regulatory mechanism of SFN on nuclear factor (NF)-κB was investigated. METHODS: Chondrocytes were obtained from patients with knee OA. Chondrocytes were stimulated with IL-1ß or TNF-α with or without pre-incubation with SFN. Production of PGE2 and NO was evaluated by the Griess reaction and an ELISA. The expression of microsomal PGE synthase (mPGES), cyclo-oxygenase (COX)-2 and inducible NO synthase (iNOS) was evaluated by real-time RT-PCR and western blot analysis. The regulation of NF-κB activity was explored using luciferase and chromatin immunoprecipitation assays as well as a western blot for phosphorylated IκB kinase (IKK), IκB and the degradation of IκB. Proteoglycan and type II collagen degradation products released from explant cultures were analysed using the dimethylmethylene blue assay and an ELISA for C-terminal telopeptides of type II collagen. RESULTS: SFN inhibited the production of PGE2 and NO induced by IL-1ß and TNF-α. At a concentration as low as 5 µM, SFN completely inhibited mPGES, COX-2 and iNOS at the mRNA and protein levels, and proteoglycan and type II collagen degradation product release in explant culture. Various signalling pathways required for the NF-κB activation were affected by SFN. CONCLUSION: SFN inhibited a broad range of catabolic mechanisms in articular chondrocytes. SFN may be a safe and effective candidate drug for the inhibition of cartilage degradation in arthritic diseases.

Dissociation (Ds) constructs, mapped Ds launch pads and a transiently-expressed transposase system suitable for localized insertional mutagenesis in rice.

We have developed a transiently-expressed transposase (TET)-mediated Dissociation (Ds) insertional mutagenesis system for generating stable insertion lines in rice which will allow localized mutagenesis of a chromosomal region. In this system, a Ds containing T-DNA construct was used to produce Ds launch pad lines. Callus tissues, from single-copy Ds/T-DNA lines, were then transiently infected with Agrobacterium harbouring an immobile Ac (iAc) construct, also containing a green fluorescent protein gene (sgfpS65T) as the visual marker. We have regenerated stable Ds insertion lines at a frequency of 9-13% using selection for Ds excision and GFP counter selection against iAc and nearly half of them were unique insertion lines. Double transformants (iAc/Ds) were also obtained and their progeny yielded approximately 10% stable insertion lines following excision and visual marker screening with 50% redundancy. In general, more than 50% of the Ds reinsertions were within 1 cM of the launch pad. We have produced a large number of single-copy Ds/T-DNA launch pads distributed over the rice chromosomes and have further refined the Ds/T-DNA construct to enrich for "clean" single-copy T-DNA insertions. The availability of single copy "clean" Ds/T-DNA launch pads will facilitate chromosomal region-directed insertion mutagenesis. This system provides an opportunity for distribution of gene tagging tasks among collaborating laboratories on the basis of chromosomal locations.