Assessing the effects of Ang-(1-7) therapy following transient middle cerebral artery occlusion

The counter-regulatory axis, Angiotensin Converting Enzyme 2, Angiotensin-(1-7), Mas receptor (ACE2/Ang-1-7/MasR), of the renin angiotensin system (RAS) is a potential therapeutic target in stroke, with Ang-(1-7) reported to have neuroprotective effects in pre-clinical stroke models. Here, an extensive investigation of the functional and mechanistic effects of Ang-(1-7) was performed in a rodent model of stroke. Using longitudinal magnetic resonance imaging (MRI) it was observed that central administration of Ang-(1-7) following transient middle cerebral artery occlusion (MCAO) increased the amount of tissue salvage compared to reperfusion alone. This protective effect was not due to early changes in blood brain barrier (BBB) permeability, microglia activation or inflammatory gene expression. However, increases in NADPH oxidase 1 (Nox1) mRNA expression were observed in the treatment group compared to control. In order to determine whether Ang-(1-7) has direct cerebrovascular effects, laser speckle contrast imaging (LSCI) was performed to measure dynamic changes in cortical perfusion following reperfusion. Delivery of Ang-(1-7) did not have any effect on cortical perfusion following reperfusion however; it showed an indication to prevent the ‘steal phenomenon’ within the contralateral hemisphere. The comprehensive series of studies have demonstrated a moderate protective effect of Ang-(1-7) when given alongside reperfusion to increase tissue salvage

Incidence and predictors of Woven EndoBridge (WEB) shape modification following treatment of intracranial aneurysms in a large multicenter study.

The Woven EndoBridge (WEB) device is FDA-approved for the treatment of bifurcation aneurysms. Despite its wide popularity, it has been under scrutiny for its association with potential aneurysm recanalization and retreatment due to device shape modification. This study aims to analyze the shape modification rate of WEB devices and identify factors associated with this phenomenon, as well as its correlation with aneurysm retreatment. We conducted a retrospective review of the WorldWide WEB Consortium database, including adult patients treated for intracranial aneurysms with the WEB device. We assessed aneurysm occlusion using the WEB Occlusion Scale and defined WEB shape modification as a percentage reduction in the distance between two WEB markers. Logistic regression and Cox proportional hazards models were utilized to evaluate predictors of shape modification and retreatment. Kaplan-Meier curves were used to estimate the time-dependent probability of no or minor shape modification. A total of 405 patients were analyzed, with minor and major shape modification occurring in 31.4% and 10.1% of cases, respectively. Major shape modification was associated with lower rates of adequate occlusion (70.7%) compared to no or minor shape modification (86.6%) and a higher rate of retreatment (26.8% vs. 8.1%). Predictors of major shape modification included the presence of daughter sac, bifurcation aneurysms, absence of immediate flow stagnation, and a WEB width minus aneurysm width ratio ≤ 0.5. The probability of no or minor shape modification declined within the first 25 months and stabilized thereafter. WEB device shape modification is a significant predictor of aneurysm occlusion efficacy and retreatment. Recognizing the factors influencing shape modification can guide treatment decisions and follow-up protocols to improve patient outcomes

Prediction of Persistent Incomplete Occlusion of Intracranial Aneurysms Treated With Woven Endobridge Device

While the Woven EndoBridge (WEB) device has transformed the treatment of wide-neck intracranial aneurysms, incomplete occlusion remains a significant challenge requiring better understanding of contributing factors. A retrospective analysis was conducted on multicenter data from patients who underwent WEB device treatment for intracranial aneurysms between January 2011 and December 2022. Using machine learning models, Cox regression, and time-stratified analyses, we evaluated factors associated with persistent incomplete occlusion, defined as non-improving Raymond-Roy Occlusion Classification grade 2 or 3 at final follow-up. Among 813 patients (607 with \u3c 24 months follow-up, 206 with ≥ 24 months), machine learning analysis identified aneurysm height, Acom location, neck diameter, and pretreatment mRS as predictors of persistent incomplete occlusion. On Cox regression. larger aneurysm neck diameter (HR 1.13, 95% CI 1.01-1.27, p = 0.027) and height (HR 1.14, 95% CI 1.02-1.26, p = 0.017), and radial access (HR 2.68, 95% CI 1.76-4.07, p \u3c 0.001) increased, while posterior circulation location (HR 0.56, 95% CI 0.37-0.84, p = 0.005) decreased the risk of persistent incomplete occlusion. Time-stratified analysis revealed that in short-term follow-up (\u3c 24 months), larger aneurysm neck diameter (OR 1.28, 95% CI 1.08-1.52, p = 0.004) increased the risk of incomplete occlusion. In long-term follow-up (≥ 24 months), smoking (OR 2.69, 95% CI 1.04-7.00, p = 0.04), higher pre-treatment mRS (OR 1.78, 95% CI 1.15-2.76, p = 0.009), and immediate flow stagnation (OR 0.33, 95% CI 0.11-0.96, p = 0.04) increased, while older age (OR 0.94, 95% CI 0.90-0.98, p = 0.002) and WEB-DL (OR 0.06, p \u3c 0.001) and SLS devices (OR 0.02, p = 0.003) decreased the risk of persistent incomplete occlusion. Aneurysm characteristics and device type significantly influence long-term WEB treatment outcomes

Pseudomonas putida AlkA and AlkB Proteins Comprise Different Defense Systems for the Repair of Alkylation Damage to DNA – In Vivo, In Vitro, and In Silico Studies

Alkylating agents introduce cytotoxic and/or mutagenic lesions to DNA bases leading to induction of adaptive (Ada) response, a mechanism protecting cells against deleterious effects of environmental chemicals. In Escherichia coli, the Ada response involves expression of four genes: ada, alkA, alkB, and aidB. In Pseudomonas putida, the organization of Ada regulon is different, raising questions regarding regulation of Ada gene expression. The aim of the presented studies was to analyze the role of AlkA glycosylase and AlkB dioxygenase in protecting P. putida cells against damage to DNA caused by alkylating agents. The results of bioinformatic analysis, of survival and mutagenesis of methyl methanesulfonate (MMS) or N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) treated P. putida mutants in ada, alkA and alkB genes as well as assay of promoter activity revealed diverse roles of Ada, AlkA and AlkB proteins in protecting cellular DNA against alkylating agents. We found AlkA protein crucial to abolish the cytotoxic but not the mutagenic effects of alkylans since: (i) the mutation in the alkA gene was the most deleterious for MMS/MNNG treated P. putida cells, (ii) the activity of the alkA promoter was Ada-dependent and the highest among the tested genes. P. putida AlkB (PpAlkB), characterized by optimal conditions for in vitro repair of specific substrates, complementation assay, and M13/MS2 survival test, allowed to establish conservation of enzymatic function of P. putida and E. coli AlkB protein. We found that the organization of P. putida Ada regulon differs from that of E. coli. AlkA protein induced within the Ada response is crucial for protecting P. putida against cytotoxicity, whereas Ada prevents the mutagenic action of alkylating agents. In contrast to E. coli AlkB (EcAlkB), PpAlkB remains beyond the Ada regulon and is expressed constitutively. It probably creates a backup system that protects P. putida strains defective in other DNA repair systems against alkylating agents of exo- and endogenous origin

Abstract TP6: Factors Influencing Infarct Progression During Ischemic Stroke Patients Transfer: Collaterals Lost is Brain Lost

Introduction: When transferred from a referring hospital (RH) to a thrombectomy capable stroke center (TCSC), patients with initially favorable imaging profile (ASPECT score ≥6) often demonstrate infarct progression significant enough to make them ineligible at arrival. We sought to determine the clinical and imaging factors associated with this phenomenon in transferred ischemic stroke patients. Methods: We identified adult stroke patients transferred from one of 30 RH between 2010 and 2016 for which (1) a RH computed tomography (CT) and (2) a CT Angiography (CTA) at arrival were available for review. ASPECT scores were evaluated by 2 raters. The adequacy of leptomeningeal collateral flow was rated as none/poor, decreased, adequate or augmented per the Maas et al (Stroke 2009), modified scale. ASPECTS decay was defined as an ASPECT initial score ≥6 worsening between RH and TCSC CTs to a score &lt;6. Results: A total of 330 patients were included in the analysis (mean age 70.2 ± 14.2, 43.3% females). Univariable subgroup analyses showed that patients with ASPECTs decay were more likely to be females (55% vs 40%, p=0.02), not on anticoagulants (4% vs 15%, p=0.01), and with higher initial NIHSS (Median [IQR] 19 [15.3-22] vs 11 [6-17], p&lt;0.001), hyperdense vessel sign on initial CT (71% vs 26%, p&lt;0.001) and poor collaterals on CTA (72% vs 19%, p&lt;0.001). In multivariable models, higher NIHSS, lower baseline ASPECTs, CTA evidence of a proximal occlusion, and none/poor collaterals were strong predictors of ASPECTs decay, with collateral status demonstrating the highest odds ratio (aOR 10.3, 95%CI: [4.1-29], p&lt;0.001). Similar results were found after stratification by vessel occlusion level. Conclusion: In ischemic stroke patients transferred for thrombectomy, poor collateral flow, stroke severity and proximal vascular occlusion, but not time interval, are the main determinants of ASPECTs decay. </jats:p