18 research outputs found
Wars2 is a determinant of angiogenesis.
Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. Here we exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is also associated with cardiac capillary density. Mitochondrial tryptophanyl-tRNA synthetase (Wars2), encoding an L53F protein variant within the ATP-binding motif, is prioritized as the candidate at the locus by integrating genomic data sets. WARS2(L53F) has low enzyme activity and inhibition of WARS2 in endothelial cells reduces angiogenesis. In the zebrafish, inhibition of wars2 results in trunk vessel deficiencies, disordered endocardial-myocardial contact and impaired heart function. Inhibition of Wars2 in the rat causes cardiac angiogenesis defects and diminished cardiac capillary density. Our data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart that may have translational relevance given the association of WARS2 with common human diseases
Perfusion Imaging for Endovascular Thrombectomy in Acute Ischemic Stroke Is Associated With Improved Functional Outcomes in the Early and Late Time Windows
Background: The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. Methods: Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early (<6 hours) and late (6-24 hours) time windows, between October 2015 and March 2020, were compared. The primary outcome was the ordinal shift in the modified Rankin Scale score at hospital discharge. Other outcomes included functional independence (modified Rankin Scale score ≤2) and in-hospital mortality, symptomatic intracerebral hemorrhage, successful reperfusion (Thrombolysis in Cerebral Infarction score 2b-3), early neurological deterioration, futile recanalization (modified Rankin Scale score 4-6 despite successful reperfusion) and procedural time metrics. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, prestroke disability, intravenous thrombolysis, mode of anesthesia (Model 1) and including EVT technique, balloon guide catheter, and center (Model 2). Results: We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16-1.83]; P=0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; P=0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage (P=0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; P=0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28-1.78]; P=0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08-1.59]; P=0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50-0.97]; P=0.034; early: adjusted OR, 0.80 [95% CI, 0.65-0.99]; P=0.047). Conclusions: In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials.</p
Perfusion Imaging for Endovascular Thrombectomy in Acute Ischemic Stroke Is Associated With Improved Functional Outcomes in the Early and Late Time Windows
Background: The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. Methods: Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early (<6 hours) and late (6-24 hours) time windows, between October 2015 and March 2020, were compared. The primary outcome was the ordinal shift in the modified Rankin Scale score at hospital discharge. Other outcomes included functional independence (modified Rankin Scale score ≤2) and in-hospital mortality, symptomatic intracerebral hemorrhage, successful reperfusion (Thrombolysis in Cerebral Infarction score 2b-3), early neurological deterioration, futile recanalization (modified Rankin Scale score 4-6 despite successful reperfusion) and procedural time metrics. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, prestroke disability, intravenous thrombolysis, mode of anesthesia (Model 1) and including EVT technique, balloon guide catheter, and center (Model 2). Results: We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16-1.83]; P=0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; P=0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage (P=0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; P=0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28-1.78]; P=0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08-1.59]; P=0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50-0.97]; P=0.034; early: adjusted OR, 0.80 [95% CI, 0.65-0.99]; P=0.047). Conclusions: In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials.</p
2,3-Diphenyltetrahydrofurans (DPTF) - A new class of stereogenic diarylheterocycles as potential COX-2 inhibitors - Computational evaluation of COX-2-DPTF binding behaviour
1692-1698Based on the reported COX-2
selectivity of α,β-diarylheterocycles based NSAIDs' - a
new class of 2,3-diphenyltetrahydrofurans (DPTF) possessing COOH, CH2OH
or CH2NH2 groups at C-5 and three
chiral centers C-2, C-3 and C-5 have been designed. In total 12 title compounds
have been studied for their binding in the active sites of COX-2 and COX-1 enzymes. <span style="color:black;
mso-bidi-language:HI">For comparison, the binding behavior of known COX-2
selective (rofecoxib, celecoxib, valdecoxib) and nonselective (aspirin,
ibuprofen) drugs has also been studied. The trends of COX-2 selectivity of
known NSAIDs' are parallel with their reported results. <span style="color:black;
mso-bidi-language:HI">In general, DPTF derivatives show binding energies in
COX-2 active site better than rofecoxib and comparable to aspirin and poor
binding energies in COX-1 active sites pointing towards these molecules being
selective COX-2 inhibitors. The stereochemistries at C-2, C-3 and C-5 carbons
of DPTF derivatives considerably affect their bindings in the active sites of
COX-1 and COX-2 and the COX-2 selectivity. The ligands with configuration (2S,
3R, 5S)
show higher selectivity for COX-2 over COX-1 in comparison to other configurational
isomers.
</span
Incidence and Predictors of Poor Functional Outcome Despite Complete Recanalisation Following Endovascular Thrombectomy for Acute Ischaemic Stroke
Background: Numerous ischaemic stroke patients experience poor functional outcome despite successful recanalisation following endovascular thrombectomy (EVT). We aimed to identify the incidence and predictors of futile complete recanalisation (FCR) in a national stroke registry.Methods: Patients who achieved complete recanalisation (mTICI 3) following EVT, between October 2015 and March 2020, were included from a United Kingdom national stroke registry. Modified Rankin Scale of 4-6 at discharge was defined as a ‘poor/futile outcome’. Backward stepwise multivariable logistic regression analysis was performed with FCR as the dependent variable, incorporating all baseline characteristics, procedural time metrics and post-procedural events.Results: We included 2132 of 4383 patients (48.8%) with complete recanalisation post-EVT, of which 948 patients (44.4%) developed FCR. Following multivariable regression analysis adjusted for potential confounders, patients with FCR were associated with multiple baseline patient, imaging and procedural factors: age (p=0.0001), admission NIHSS scores (p=0.0001), pre-stroke disability (p=0.007), onset-to-puncture (p=0.0001) and procedural times (p=0.0001), presence of diabetes (p=0.005), and use of general anaesthesia (p=0.0001). Although not predictive of outcome, post-procedural events including development of any intracranial haemorrhage (ICH) (p=0.0001), symptomatic ICH (sICH) (p=0.0001) and early neurological deterioration (END) (p=0.007) were associated with FCR.Conclusion: Nearly half of patients in this national registry experienced FCR following EVT. Significant predictors of FCR included increasing age, admission NIHSS scores, pre-stroke disability, onset-to-puncture and procedural times, presence of diabetes, atrial fibrillation, and use of general anaesthesia. Post procedural development of any ICH, sICH, and END were associated with FCR
Influence of organic amendments on dissipation and leaching potential of penoxsulam under laboratory conditions
Effect of Proximal Blood Flow Arrest During Endovascular Thrombectomy (ProFATE): Study Protocol for a Multicentre Randomised Controlled Trial
BackgroundObservational studies have demonstrated improved outcomes with the adjunctive use of balloon guide catheters (BGC) during endovascular thrombectomy (EVT) for anterior circulation acute ischaemic stroke (AIS). However, the lack of high-level evidence and global practice heterogeneity justifies a randomised controlled trial (RCT) to investigate the effect of transient proximal blood flow arrest on the procedural and clinical outcomes of patients with AIS following EVT.Hypothesis Proximal blood flow arrest in the cervical internal carotid artery during EVT for proximal large vessel occlusion is superior to no flow arrest in achieving complete vessel recanalisation.MethodsProFATE is an investigator-initiated, pragmatic, multicentre RCT with blinding of participants and outcome assessment. An estimated 124 participants with an anterior circulation AIS due to large vessel occlusion, an NIHSS of ≥2, ASPECTS ≥5, and eligible for EVT using a first-line combined technique (contact aspiration and stent retriever) or contact aspiration only will be randomised (1:1) to receive BGC balloon inflation or no inflation during EVT.OutcomesThe primary outcome is the proportion of patients achieving near-complete/complete vessel recanalisation (eTICI 2c-3) at the end of the EVT procedure. Secondary outcomes include the functional outcome (modified Rankin Scale at 90 days), new or distal vascular territory clot embolisation rate, near-complete/complete recanalisation after the first pass, symptomatic intracranial haemorrhage, procedure-related complications and death at 90 days. DiscussionThis is the first RCT to investigate the effect of proximal blood flow arrest during EVT using a BGC on the procedural and clinical outcomes of patients with AIS due to large vessel occlusion
Association between anesthesia modality and clinical outcomes following endovascular stroke treatment in the extended time window.
BACKGROUND
There is a paucity of data on anesthesia-related outcomes for endovascular treatment (EVT) in the extended window (>6 hours from ischemic stroke onset). We compared functional and safety outcomes between local anesthesia (LA) without sedation, conscious sedation (CS) and general anesthesia (GA).
METHODS
Patients who underwent EVT in the early (<6 hours) and extended time windows using LA, CS, or GA between October 2015 and March 2020 were included from a UK national stroke registry. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, pre-stroke disability, EVT technique, center, procedural time and IV thrombolysis.
RESULTS
A total of 4337 patients were included, 3193 in the early window (1135 LA, 446 CS, 1612 GA) and 1144 in the extended window (357 LA, 134 CS, 653 GA). Compared with GA, patients treated under LA alone had increased odds of an improved modified Rankin Scale (mRS) score at discharge (early: adjusted common (ac) OR=1.50, 95% CI 1.29 to 1.74, p=0.001; extended: acOR=1.29, 95% CI 1.01 to 1.66, p=0.043). Similar mRS scores at discharge were found in the LA and CS cohorts in the early and extended windows (p=0.21). Compared with CS, use of GA was associated with a worse mRS score at discharge in the early window (acOR=0.73, 95% CI 0.45 to 0.96, p=0.017) but not in the extended window (p=0.55). There were no significant differences in the rates of symptomatic intracranial hemorrhage or in-hospital mortality across the anesthesia modalities in the extended window.
CONCLUSION
LA without sedation during EVT was associated with improved functional outcomes compared with GA, but not CS, within and beyond 6 hours from stroke onset. Prospective studies assessing anesthesia-related outcomes in the extended time window are warranted